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The prognosis of CVST is usually favourable, with more than 80% of patients, as in our case, having a good neurological outcome.24 Learning points Cerebral venous sinus thrombosis (CVST) is a rare condition, and its presentation can mimic various benign conditions. Clinicians should have a high level of suspicion, identifying aetiology and predisposing conditions, to facilitate a prompt diagnosis. More research is needed to confirm or exclude a causal link between norethisterone enanthate and CVST. CVST management should be aggressive to ensure the best possible outcome for patients. Prognosis for CVST is usually favourable. We would like to acknowledge the contribution of the radiologist, and other medical and support staff who assisted in the management of this case. Contributors: MB and MS contributed to the management of the case, prepared and edited the manuscript. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description A 58-year-old woman with no history of smoking was admitted to our hospital with exacerbation of cough. CT of the chest revealed a left upper lobe lung tumour. Bronchoscopic biopsy of the tumour revealed stage IV poorly differentiated adenocarcinoma (figure 1) with epidermal growth factor receptor (EGFR) gene mutation (L858R point mutation). After cytotoxic chemotherapy (cisplatin and pemetrexed) as first-line therapy, disease progression was identified. For the next 3 years, she was treated with erlotinib, an EGFR tyrosine kinase inhibitor (TKI). Regimens were changed several times (cisplatin, gemcitabine, docetaxel and afatinib) due to disease progression or adverse effects. After 2 months with afatinib, disease progression was again noted. We once again performed bronchoscopic biopsy of the primary tumour, and small cell lung cancer (SCLC) was confirmed from histopathological examination (figures 2–4). Levels of tumour markers such as progastrin-releasing peptide and non-specific elastase were elevated. Moreover, a second examination again detected the EGFR gene mutation (L858R point mutation without T790M point mutation). Amrubicin was administered, resulting in radiologically stable disease. Most cases of acquired resistance to EGFR-TKI arise from the emergence of T790M mutation, and morphological transformation to SCLC is rare.1 After the failure of EGFR-TKI, rebiopsy of the tumour is warranted to determine the next treatment strategy. Figure 1 H&E staining. Figure 2 H&E staining. Figure 3 Chromogranin A staining. Figure 4 Synaptophysin staining.

Description A 58-year-old woman with no history of smoking was admitted to our hospital with exacerbation of cough. CT of the chest revealed a left upper lobe lung tumour. Bronchoscopic biopsy of the tumour revealed stage IV poorly differentiated adenocarcinoma (figure 1) with epidermal growth factor receptor (EGFR) gene mutation (L858R point mutation). After cytotoxic chemotherapy (cisplatin and pemetrexed) as first-line therapy, disease progression was identified. For the next 3 years, she was treated with erlotinib, an EGFR tyrosine kinase inhibitor (TKI). Regimens were changed several times (cisplatin, gemcitabine, docetaxel and afatinib) due to disease progression or adverse effects. After 2 months with afatinib, disease progression was again noted. We once again performed bronchoscopic biopsy of the primary tumour, and small cell lung cancer (SCLC) was confirmed from histopathological examination (figures 2–4). Levels of tumour markers such as progastrin-releasing peptide and non-specific elastase were elevated. Moreover, a second examination again detected the EGFR gene mutation (L858R point mutation without T790M point mutation). Amrubicin was administered, resulting in radiologically stable disease. Most cases of acquired resistance to EGFR-TKI arise from the emergence of T790M mutation, and morphological transformation to SCLC is rare.1 After the failure of EGFR-TKI, rebiopsy of the tumour is warranted to determine the next treatment strategy. Figure 1 H&E staining. Figure 2 H&E staining. Figure 3 Chromogranin A staining. Figure 4 Synaptophysin staining. Learning points After the failure of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), rebiopsy of the tumour should be performed to determine the next treatment strategy.

Description A 58-year-old woman with no history of smoking was admitted to our hospital with exacerbation of cough. CT of the chest revealed a left upper lobe lung tumour. Bronchoscopic biopsy of the tumour revealed stage IV poorly differentiated adenocarcinoma (figure 1) with epidermal growth factor receptor (EGFR) gene mutation (L858R point mutation). After cytotoxic chemotherapy (cisplatin and pemetrexed) as first-line therapy, disease progression was identified. For the next 3 years, she was treated with erlotinib, an EGFR tyrosine kinase inhibitor (TKI). Regimens were changed several times (cisplatin, gemcitabine, docetaxel and afatinib) due to disease progression or adverse effects. After 2 months with afatinib, disease progression was again noted. We once again performed bronchoscopic biopsy of the primary tumour, and small cell lung cancer (SCLC) was confirmed from histopathological examination (figures 2–4). Levels of tumour markers such as progastrin-releasing peptide and non-specific elastase were elevated. Moreover, a second examination again detected the EGFR gene mutation (L858R point mutation without T790M point mutation). Amrubicin was administered, resulting in radiologically stable disease. Most cases of acquired resistance to EGFR-TKI arise from the emergence of T790M mutation, and morphological transformation to SCLC is rare.1 After the failure of EGFR-TKI, rebiopsy of the tumour is warranted to determine the next treatment strategy. Figure 1 H&E staining. Figure 2 H&E staining. Figure 3 Chromogranin A staining. Figure 4 Synaptophysin staining. Learning points After the failure of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), rebiopsy of the tumour should be performed to determine the next treatment strategy. But it is unclear when to perform rebiopsy after EGFR-TKI failure.

Figure 3 Chromogranin A staining. Figure 4 Synaptophysin staining. Learning points After the failure of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), rebiopsy of the tumour should be performed to determine the next treatment strategy. But it is unclear when to perform rebiopsy after EGFR-TKI failure. Contributors: YH, JN and NN participated in patient care. YH wrote the manuscript and YK revised it. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description A 53-year-old man was referred to our hospital due to malaise with intermittent high fever. Thoracoabdominal CT scan revealed abdominal lymphadenopathy with splenomegaly. Hepatic disorder (aspartate transaminase 47 IU/L; alanine transaminase 53 IU/L), peripheral blood cytopaenia (red blood cell count 370×104/μL; haemoglobin 11.0 g/dL; haematocrit 32.9%; platelet count 7.9×104/μL), hypertriglyceridaemia (184 mg/dL), hyperferritinaemia (4111 ng/mL) and an increased serum soluble interleukin-2 receptor level (4450 U/mL) were observed. Bone marrow (BM) aspiration showed erythrocyte phagocytosis by macrophages (figure 1A). However, no atypical cells were detected. Additional BM trephine biopsy was not performed. Pathological examination of a laparoscopic lymph node biopsy revealed Reed-Sternberg cells (figure 1B), and atypical cells were positive for CD30 but not for CD3, CD20 or CD79a indicating nodular sclerosis Hodgkin lymphoma (HL). A diagnosis of lymphoma-associated haemophagocytic lymphohistiocytosis (LA-HLH) was established. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) performed for the staging showed splenic and multiple abdominal lymph node lesions and diffuse accumulation within the bones such as the vertebrae and pelvis (figure 2A). After four courses of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy, FDG-PET showed the disappearance of all abnormal accumulations (figure 2B). Involved-field radiation therapy for abdominal lesions was sequentially added.

ulation within the bones such as the vertebrae and pelvis (figure 2A). After four courses of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy, FDG-PET showed the disappearance of all abnormal accumulations (figure 2B). Involved-field radiation therapy for abdominal lesions was sequentially added. Figure 1 Pathological findings. (A) Bone marrow aspirate smear showing macrophages laden with erythrocytes (arrow). (B) Abdominal lymph node biopsy showing scattered large atypical multinucleated cells (Reed-Sternberg cells; arrows) in prominent small lymphocytes. Figure 2 18F-fluorodeoxyglucose positron emission tomography before (A) and after (B) the four courses of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy. (A) Splenic (arrow) and multiple abdominal lymph node (arrowheads) lesions and diffuse accumulation within bones such as vertebras and pelvis. (B) Disappearance of all abnormal accumulations.

tomography before (A) and after (B) the four courses of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy. (A) Splenic (arrow) and multiple abdominal lymph node (arrowheads) lesions and diffuse accumulation within bones such as vertebras and pelvis. (B) Disappearance of all abnormal accumulations. Patients with HLH with FDG-PET images indicating multiple lymphadenopathy and/or patchy multiple bone lesions may appear to be LA-HLH with BM involvement (BMI).1 However, in comparison with BM examinations, FDG-PET can frequently show false-positive for the evaluation of BMI in patients with LA-HLH because HLH can induce diffuse hypermetabolism in BM reflecting a systemic cytokine storm.2 Previously, several cases of HLH due to non-HL with diffuse FDG accumulation in BM were reported.2–3 Since we performed BM aspiration only without BM trephine biopsy, skeletal and/or BM HL involvement cannot be fully ruled out. However, there is a possibility that HLH due to HL also can induce diffuse hypermetabolism in BM. Learning points 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has become a standard tool for the initial staging and reassessment of Hodgkin lymphoma, which is generally characterised by contiguous lymph node involvement. Haemophagocytic lymphohistiocytosis, which is the uncontrolled activation of lymphocytes and macrophages caused by various diseases including malignant lymphoma, can induce diffuse hypermetabolism in the bone marrow reflecting a systemic cytokine storm.

Patients with HLH with FDG-PET images indicating multiple lymphadenopathy and/or patchy multiple bone lesions may appear to be LA-HLH with BM involvement (BMI).1 However, in comparison with BM examinations, FDG-PET can frequently show false-positive for the evaluation of BMI in patients with LA-HLH because HLH can induce diffuse hypermetabolism in BM reflecting a systemic cytokine storm.2 Previously, several cases of HLH due to non-HL with diffuse FDG accumulation in BM were reported.2–3 Since we performed BM aspiration only without BM trephine biopsy, skeletal and/or BM HL involvement cannot be fully ruled out. However, there is a possibility that HLH due to HL also can induce diffuse hypermetabolism in BM. Learning points 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has become a standard tool for the initial staging and reassessment of Hodgkin lymphoma, which is generally characterised by contiguous lymph node involvement. Haemophagocytic lymphohistiocytosis, which is the uncontrolled activation of lymphocytes and macrophages caused by various diseases including malignant lymphoma, can induce diffuse hypermetabolism in the bone marrow reflecting a systemic cytokine storm. Recognition of false-positive findings on FDG-PET is necessary for the evaluation of bone marrow involvement in order to accurately determine the stage of Hodgkin lymphoma, which requires bone marrow examination.

Haemophagocytic lymphohistiocytosis, which is the uncontrolled activation of lymphocytes and macrophages caused by various diseases including malignant lymphoma, can induce diffuse hypermetabolism in the bone marrow reflecting a systemic cytokine storm. Recognition of false-positive findings on FDG-PET is necessary for the evaluation of bone marrow involvement in order to accurately determine the stage of Hodgkin lymphoma, which requires bone marrow examination. Contributors: SH drafted the initial manuscript. TS edited and submitted the manuscript. SH, TS and HM were involved in diagnosing and treating the patient. KN performed pathological studies. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Translocation of the anaplastic lymphoma kinase (ALK) gene echinoderm microtubule-associated proteinlike 4 (EML4) was shown in 5% of patients with lung adenocarcinoma.1 Crizotinib treatment has been reported to safely lead to a response rate of 60% and median progression-free survival of 8 months.2 3 Thyroid metastases of non-thyroid malignancies have been reported in 1.4–3% of all thyroid malignancies.4–9 Thyroid metastases are most common in the kidney, colorectal, lung and breast cancer.4 10 Clinically, the distinction between primary and secondary thyroid tumour is very important to determine staging and to treat the tumour. We herein describe a patient diagnosed as having thyroid metastases with fine-needle aspiration biopsy (FNAB) combined with the reverse transcriptase-PCR (RT-PCR) method. Case presentation A woman aged 42 years who had no relevant history and no history of cigarette smoking visited our hospital reporting of left inguinal pain for 1 month. Ultrasound examination revealed a left inguinal tumour of 60 mm in diameter. The pathological findings from the biopsy of the left inguinal lymph node showed poorly differentiated cancer. Metastasis from a gynaecological malignancy was suspected initially, but a gynaecological malignancy was not recognised.

or 1 month. Ultrasound examination revealed a left inguinal tumour of 60 mm in diameter. The pathological findings from the biopsy of the left inguinal lymph node showed poorly differentiated cancer. Metastasis from a gynaecological malignancy was suspected initially, but a gynaecological malignancy was not recognised. Chest X-ray and CT scan of the chest revealed a 70 mm tumour in the lower lobe of the right lung (figure 1A, B). The pathological findings of the transbronchial lung biopsy showed poorly differentiated adenocarcinoma with positive thyroid transcription factor-1 (TTF-1), carcinoembryonic antigen (CEA) and ALK by immunohistochemistry (IHC) (figure 2A, B). In addition, ALK positivity was revealed by the fluorescence in situ hybridisation (FISH) method, which indicated that 28% of the tumour cells showed either split red and green signals or single red signals. Afterwards, the metastasis of the left inguinal lymph node also was found positive for TTF-1 and ALK by IHC. Positron emission tomography (PET) demonstrated fluorodeoxyglucose (FDG) accumulation in the lower lobe of the right lung, the right thyroid lobe, both adrenal glands and other areas (figure 3). The highest standardised uptake value (SUV) in the right lobe of the thyroid gland was 14.0. We suspected thyroid metastasis from lung cancer and performed a thyroid ultrasound examination, which showed a hypervascular tumour of 16 mm in diameter (figure 4). We performed FNAB of the right lobe of the thyroid gland tumour to evaluate whether this was a primary tumour or metastasis (figure 5). The thyroid tumour was determined to be a metastasis from the lung adenocarcinoma because of the positive finding of EML4-ALK (variant 3a/3b was amplified) obtained using the RT-PCR method. We could not evaluate the thyroid tumour by IHC and FISH methods due to the smaller sample volume of FNAB. Multiple brain metastases in the left cerebellum were also observed with brain contrast-enhanced MRI. Therefore, we diagnosed the patient as having EML4-ALK-positive lung adenocarcinoma with a TNM classification of T3N1M1b, Stage IV. Her laboratory data showed normal thyroid function and a high CEA level (16.5 ng/mL).

Multiple brain metastases in the left cerebellum were also observed with brain contrast-enhanced MRI. Therefore, we diagnosed the patient as having EML4-ALK-positive lung adenocarcinoma with a TNM classification of T3N1M1b, Stage IV. Her laboratory data showed normal thyroid function and a high CEA level (16.5 ng/mL). Figure 1 (A) Chest radiograph shows a mass in the right lower lung field. (B) Chest CT shows ∼70 mm mass in the right lower lobe. The border of the mass is irregular, and the interior is heterogeneous. Figure 2 (A) Tumour cells produce a papillary structure. They partly show an irregular glandular cavity structure (HE stain, ×20). (B) Immunostaining for anaplastic lymphoma kinase demonstrates positive staining of the alveolar tissue. Figure 3 Positron emission tomography shows the highest standardised uptake values to be 14, 17 and 19, respectively, in the right lobe of the thyroid gland, the tumour in the right lower lung lobe and in the left adrenal gland. The right shoulder blade, the left ribs, lumbar vertebrae, the left ilium lymph node, the para-aortic lymph nodes, the bilateral total iliac artery lymph nodes, the left groin and the obturator lymph node also show fluorodeoxyglucose (FDG) accumulation. Arrows show FDG accumulation in the right thyroid lobe. Figure 4 The thyroid ultrasound examination shows a tumour mass in the right lobe of the thyroid gland of ∼16 mm in diameter. Vacularisation is abundant within the mass. Figure 5 Malignant cells are present in the right lobe of the thyroid gland.

Figure 3 Positron emission tomography shows the highest standardised uptake values to be 14, 17 and 19, respectively, in the right lobe of the thyroid gland, the tumour in the right lower lung lobe and in the left adrenal gland. The right shoulder blade, the left ribs, lumbar vertebrae, the left ilium lymph node, the para-aortic lymph nodes, the bilateral total iliac artery lymph nodes, the left groin and the obturator lymph node also show fluorodeoxyglucose (FDG) accumulation. Arrows show FDG accumulation in the right thyroid lobe. Figure 4 The thyroid ultrasound examination shows a tumour mass in the right lobe of the thyroid gland of ∼16 mm in diameter. Vacularisation is abundant within the mass. Figure 5 Malignant cells are present in the right lobe of the thyroid gland. The multiple brain metastases in the left cerebellum were treated with stereotactic radiotherapy, because multiple brain metastases were at two places and tumours of 6 mm in maximum diameter. We initiated molecularly targeted drug therapy with crizotinib (500 mg/day). We judged a partial response 3 months after the beginning of treatment with crizotinib (figure 6A, B). The patient has been obtained effect under crizotinib treatment. Figure 6 (A) CT shows the size in the right lobe of the thyroid gland, the right lower lung lobe and the left inguinal lymph node before treatment. (B) Three months after the beginning of crizotinib therapy. The tumour sizes are all reduced.

The multiple brain metastases in the left cerebellum were treated with stereotactic radiotherapy, because multiple brain metastases were at two places and tumours of 6 mm in maximum diameter. We initiated molecularly targeted drug therapy with crizotinib (500 mg/day). We judged a partial response 3 months after the beginning of treatment with crizotinib (figure 6A, B). The patient has been obtained effect under crizotinib treatment. Figure 6 (A) CT shows the size in the right lobe of the thyroid gland, the right lower lung lobe and the left inguinal lymph node before treatment. (B) Three months after the beginning of crizotinib therapy. The tumour sizes are all reduced. Discussion There have been only a few reports of thyroid metastases from lung cancer.11 12 This is the first report, to the best of our knowledge, of thyroid metastases from lung adenocarcinoma with EML4-ALK rearrangement. Generally, ALK is identified as tyrosine kinase target in non-small-cell lung cancer. ALK is aberrantly activated by chromosomal rearrangement or inversion that leads to the expression of an oncogenic fusion kinase, such as EML4-ALK. ALK is mutually exclusive and is a potential target for treatment.1 Patients with EML4-ALK-positive lung cancer are non-smokers and relatively younger13–15 and tend to be diagnosed at an advanced stage.13 15 In 160 autopsied cases, Abrams et al16 reported rates of metastasis from lung cancer to the thyroid and inguinal lymph nodes of 4% and 1.3%, respectively.

Generally, ALK is identified as tyrosine kinase target in non-small-cell lung cancer. ALK is aberrantly activated by chromosomal rearrangement or inversion that leads to the expression of an oncogenic fusion kinase, such as EML4-ALK. ALK is mutually exclusive and is a potential target for treatment.1 Patients with EML4-ALK-positive lung cancer are non-smokers and relatively younger13–15 and tend to be diagnosed at an advanced stage.13 15 In 160 autopsied cases, Abrams et al16 reported rates of metastasis from lung cancer to the thyroid and inguinal lymph nodes of 4% and 1.3%, respectively. Ho et al17 investigated 4281 cases in which PET was used to determine the initial stage in all malignant tumours. PET in 165 (4%) of these cases showed FDG accumulation in the thyroid gland. Only 4 of the 165 cases were proved to be malignant thyroid tumour. Further, they indicated that the average SUV of malignant thyroid lesions was significantly higher than that of benign lesions. However, it was impossible to identify an optimal cut-off for SUV to differentiate benign from malignant lesions. Even if PET shows FDG accumulation in the thyroid, cytological or histological verification is important to evaluate whether the thyroid tumour is benign or malignant.

ly higher than that of benign lesions. However, it was impossible to identify an optimal cut-off for SUV to differentiate benign from malignant lesions. Even if PET shows FDG accumulation in the thyroid, cytological or histological verification is important to evaluate whether the thyroid tumour is benign or malignant. EML4-ALK rearrangement can be identified by IHC, FISH or RT-PCR methods. IHC and FISH methods are generally reinforced by a screening test. The IHC method shows that the protein producing the EML4-ALK gene variation is stained by using various monoclonal antibodies. The advantage is simple comparatively. But the rates of specificity and sensitivity depend on the type of kit used and the staining strength and are lower than the RT-PCR method.18 19 FISH and RT-PCR methods directly identify the genetic variation and detect EML4-ALK gene rearrangement. However, limitations of the FISH method are that it is expensive and requires a good fluorescence scope and technical expertise.18 In contrast, the advantages of the RT-PCR method is that it shows high specificity and sensitivity even when a smaller sample volume is collected.18 20 However, the limitations of the RT-PCR method need attention because it cannot be detect minor variants of the EML4-ALK gene and it is necessary to acquire a fresh-frozen tissue sample for the extraction of RNA.18 20

is that it shows high specificity and sensitivity even when a smaller sample volume is collected.18 20 However, the limitations of the RT-PCR method need attention because it cannot be detect minor variants of the EML4-ALK gene and it is necessary to acquire a fresh-frozen tissue sample for the extraction of RNA.18 20 Most laboratories examine specimens obtained by FNAB to evaluate thyroid pathology. Thyroid FNAB is a less invasive method than biopsy. Good-quality RNA can be successfully isolated in about 98% of patients with thyroid FNAB.21 We believe that thyroid FNAB is effective for demonstrating cytology or histology, and metastatic thyroid tumour from ALK-positive lung cancer can be diagnosed accurately by RT-PCR. In conclusion, metastatic thyroid tumours from EML4-ALK-positive lung adenocarcinoma are relatively rare, so it is important to prove the thyroid tumour to be metastatic. FNAB combined with RT-PCR can be an effective method to diagnose metastatic thyroid tumour. Learning points This is the first report, to the best of our knowledge, of thyroid metastases from non-small-cell lung cancer with EML4-ALK rearrangement. Fine-needle aspiration biopsy (FNAB) combined with reverse transcriptase-PCR can be an effective method to diagnose metastatic thyroid tumour even when FNAB collects a smaller sample volume. Even if positron emission tomography shows fluorodeoxyglucose accumulation in the thyroid, cytological or histological verification may be important to evaluate whether the thyroid tumour is benign or malignant. Twitter: Follow Hironori Kawamoto at @hironori kawamoto

Fine-needle aspiration biopsy (FNAB) combined with reverse transcriptase-PCR can be an effective method to diagnose metastatic thyroid tumour even when FNAB collects a smaller sample volume. Even if positron emission tomography shows fluorodeoxyglucose accumulation in the thyroid, cytological or histological verification may be important to evaluate whether the thyroid tumour is benign or malignant. Twitter: Follow Hironori Kawamoto at @hironori kawamoto Contributors: HK created a large part of the article. YK was in charge of the outpatient clinic, KR and HK took charge of the patient who was hospitalised. KK proofread the article. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Since choroideremia has received much attention as a disease that might be successfully treated by gene therapy, it has become important to evaluate the physiology and morphology of the retina and choroid using the various retinal imaging techniques. Fundus autofluorescence (FAF) is a relatively new method of evaluating the retinal pigment epithelium (RPE) function. It should be possible to obtain useful information on eyes with choroideremia because this disease is associated with the RPE atrophy. Optical coherence tomography angiography (OCTA) is another new technique that can detect the retinal blood vessel patterns in en face images. However, there are few studies on the choroidal blood pattern using OCTA because the vessels are not visible in normal individuals. However, a recent report shows the choroidal vessels in the OCTA images of eyes with RPE atrophy. OCTA might be helpful to evaluate the choroidal circulation associated with the RPE function in choroideremia.

ew studies on the choroidal blood pattern using OCTA because the vessels are not visible in normal individuals. However, a recent report shows the choroidal vessels in the OCTA images of eyes with RPE atrophy. OCTA might be helpful to evaluate the choroidal circulation associated with the RPE function in choroideremia. Case presentation A 65-year-old man complained of a recent reduction in vision of both eyes. He had been diagnosed with retinitis pigmentosa with non-recordable electroretinograms about 15 years earlier but visited the hospital irregularly. His decimal best-corrected visual acuity was 0.4 in the right eye and 0.6 in the left eye. Perimetric examinations showed a concentric constriction of the visual fields of both eyes. Ophthalmoscopy showed that the large choroidal vessels were visible which is characteristic of eyes with choroideremia, and the vessels were visible from the posterior pole to the periphery in both eyes (figure 1). We presumed this as a choroideremia case because the patient refused the genetic test. OCT (DRI-OCT, Topcon, Japan) showed a loss of the ellipsoid zone and tubulations around the fovea (figure 2). Figure 1 Fundus photographs of both eyes of a patient with choroideremia. Medium and large choroidal vessels can be seen throughout the fundus due to atrophy of the RPE and choriocapillaris. The sclera can be seen except in the area of pigment aggregation in the macular area. RPE, retinal pigment epithelium.

Case presentation A 65-year-old man complained of a recent reduction in vision of both eyes. He had been diagnosed with retinitis pigmentosa with non-recordable electroretinograms about 15 years earlier but visited the hospital irregularly. His decimal best-corrected visual acuity was 0.4 in the right eye and 0.6 in the left eye. Perimetric examinations showed a concentric constriction of the visual fields of both eyes. Ophthalmoscopy showed that the large choroidal vessels were visible which is characteristic of eyes with choroideremia, and the vessels were visible from the posterior pole to the periphery in both eyes (figure 1). We presumed this as a choroideremia case because the patient refused the genetic test. OCT (DRI-OCT, Topcon, Japan) showed a loss of the ellipsoid zone and tubulations around the fovea (figure 2). Figure 1 Fundus photographs of both eyes of a patient with choroideremia. Medium and large choroidal vessels can be seen throughout the fundus due to atrophy of the RPE and choriocapillaris. The sclera can be seen except in the area of pigment aggregation in the macular area. RPE, retinal pigment epithelium. Figure 2 Horizontal optical coherence tomographic images of both eyes. The foveal depression is preserved in both eyes; however, the outer retina is thin except in the foveal area. The ellipsoid zone is indistinct even at the fovea especially in the right eye.

Figure 1 Fundus photographs of both eyes of a patient with choroideremia. Medium and large choroidal vessels can be seen throughout the fundus due to atrophy of the RPE and choriocapillaris. The sclera can be seen except in the area of pigment aggregation in the macular area. RPE, retinal pigment epithelium. Figure 2 Horizontal optical coherence tomographic images of both eyes. The foveal depression is preserved in both eyes; however, the outer retina is thin except in the foveal area. The ellipsoid zone is indistinct even at the fovea especially in the right eye. FAF (HRA2, Heidelberg, Germany) showed that the entire posterior pole was hypoautofluorescent except for an isolated area of hyperautofluorescence which included the fovea (figure 3). Some of the larger choroidal vessels were hyperreflective. The choroid capillary slab of the OCTA (RTVue XR Avanti, Optoview, Fremont, CA) images showed the medium and large choroidal vessels clearly in the 8×8 mm size macular images (figure 4). The small vessels were observed in a relatively wider area than the hyperautofluorescent area in the FAF images. These smaller vessels, probably the choriocapillaris, were seen, especially in the 3×3 mm OCTA images (figure 5). Figure 3 Fundus autofluorescence of both eyes. An isolated area of hyperautofluorescence can be seen in the foveal area. Part of the large choroidal vessels and transparent sclera are observed as hyperreflective tissues. FAF, fundus autofluorescence.

FAF (HRA2, Heidelberg, Germany) showed that the entire posterior pole was hypoautofluorescent except for an isolated area of hyperautofluorescence which included the fovea (figure 3). Some of the larger choroidal vessels were hyperreflective. The choroid capillary slab of the OCTA (RTVue XR Avanti, Optoview, Fremont, CA) images showed the medium and large choroidal vessels clearly in the 8×8 mm size macular images (figure 4). The small vessels were observed in a relatively wider area than the hyperautofluorescent area in the FAF images. These smaller vessels, probably the choriocapillaris, were seen, especially in the 3×3 mm OCTA images (figure 5). Figure 3 Fundus autofluorescence of both eyes. An isolated area of hyperautofluorescence can be seen in the foveal area. Part of the large choroidal vessels and transparent sclera are observed as hyperreflective tissues. FAF, fundus autofluorescence. Figure 4 Optical coherence tomography angiography of both eyes. An 8×8 mm choroid capillary slab clearly shows the medium and large choroidal vessels surrounding the macular area. Small choroidal vessels are seen in the area (enclosed by dot lines) of the hyperautofluorescence shown in figure 3.

Figure 3 Fundus autofluorescence of both eyes. An isolated area of hyperautofluorescence can be seen in the foveal area. Part of the large choroidal vessels and transparent sclera are observed as hyperreflective tissues. FAF, fundus autofluorescence. Figure 4 Optical coherence tomography angiography of both eyes. An 8×8 mm choroid capillary slab clearly shows the medium and large choroidal vessels surrounding the macular area. Small choroidal vessels are seen in the area (enclosed by dot lines) of the hyperautofluorescence shown in figure 3. Figure 5 Optical coherence tomography angiography of both eyes. Choroid capillary slab of 3×3 mm shows the medium and large choroidal vessels clearly even at the foveal area. Small choroidal vessels, most likely the choriocapillaris, are densely distributed in the foveal area in the relatively wider area than the hyperautofluorescent isolated area in the FAF images (figure 3). FAF, fundus autofluorescence. Discussion Choroideremia is an X linked inherited disease caused by a deficiency of the Rab escort protein 1 (REP1) encoded by the CHM gene. Although it is generally believed that it is not possible to treat choroideremia by conventional therapy, a clinical trial of gene therapy using a viral vector for REP1 has been reported to be relatively successful.1 Choroideremia is associated with a degeneration of the RPE and choriocapillaris throughout the fundus.2–6 However, it is unclear whether the RPE or choriocapillaris is the first structure to be altered.

erapy, a clinical trial of gene therapy using a viral vector for REP1 has been reported to be relatively successful.1 Choroideremia is associated with a degeneration of the RPE and choriocapillaris throughout the fundus.2–6 However, it is unclear whether the RPE or choriocapillaris is the first structure to be altered. OCT is a useful method because it can non-invasively examine the morphology of the retina and choroid. Higher resolution images can be obtained for cross-sectional images after averaging many images to increase the signal-to-noise ratio. However, it is not the best method to assess the extent of the lesion such as in eyes with choroideremia. FAF, a relatively new method, can evaluate the functionality of the RPE by the changes in the fluorescence and can examine a wide area of the fundus. However, there are at least two weaknesses for assessing choroideremia by FAF. The first is that the fluorescent values from FAF are not absolute but relative values. Although FAF showed hypoautofluorescence at the periphery and hyperautofluorescence at the foveal area in our patient, it might also be iso-fluorecent and comparable to that of a normal RPE. Another disadvantage is that FAF cannot evaluate the normality of the choriocapillaris. As mentioned, choroideremia is characterised by a degeneration of choriocapillaris and RPE, but it is important to know whether the abnormalities of the choriocapillaris or the RPE are the major cause of the choroideremia disease process.

r disadvantage is that FAF cannot evaluate the normality of the choriocapillaris. As mentioned, choroideremia is characterised by a degeneration of choriocapillaris and RPE, but it is important to know whether the abnormalities of the choriocapillaris or the RPE are the major cause of the choroideremia disease process. OCTA cannot image the choroidal vasculature in normal persons because of the RPE, and there are only a few studies on the choroidal blood pattern using OCTA because the vessels are not visible in normal individuals.7 8 However, Spaide et al9 were able to obtain images of the choroidal vessels by OCTA in eyes with RPE atrophy and discussed the potential artefacts in the OCTA images. Jain et al10 reported that the choriocapillaris in eyes with choroideremia was widely damaged in their OCTA study. In our patient, the large choroidal vessels were observed ophthalmoscopically in the area of the RPE atrophy which may indicate an atrophy of the choriocapillaris as Jain et al described. In contrast, the smaller choroidal vessels, probably the choriocapillaris, in the area of the isolated lesion were more visible than the medium and large choroidal vessels in our case. Generally, the choriocapillaris is not clearly seen in the OCTA images even in the capillary slab of the choroid of normal persons because of the light attenuation by the RPE. This suggests that OCTA can evaluate the state of the choriocapillaris mainly in cases with RPE damage.

and large choroidal vessels in our case. Generally, the choriocapillaris is not clearly seen in the OCTA images even in the capillary slab of the choroid of normal persons because of the light attenuation by the RPE. This suggests that OCTA can evaluate the state of the choriocapillaris mainly in cases with RPE damage. Although this finding from a case report cannot be generalised, the OCTA images in our patient showed the choriocapillaris in a relatively wider area than the hyperautofluorescent isolated area in the FAF images. This suggests that the RPE atrophy occurred before the choriocapillaris atrophy in this eye with choroideremia although the choriocapillaris might be damaged to some degree. Xue et al11 reported that RPE loss is the primary cause of choroideremia in their study of the relationship between outer retina/choroid using OCT and RPE atrophy using FAF. Their study also supported our findings. Further studies of more cases are needed to determine the exact course of the morphological changes in the eyes with choroideremia.

RPE loss is the primary cause of choroideremia in their study of the relationship between outer retina/choroid using OCT and RPE atrophy using FAF. Their study also supported our findings. Further studies of more cases are needed to determine the exact course of the morphological changes in the eyes with choroideremia. Our FAF and OCTA results suggest that the RPE disorder developed before the choriocapillaris atrophy in this case of presumed choroideremia. The findings indicate that multimodal imaging, including FAF and OCTA, can provide new information on the morphology and function of the retina and choroid in different diseases. Learning points Although choroideremia is associated with a degeneration of the RPE and choriocapillaris throughout the fundus due to a deficiency of the Rab escort protein 1, it is unclear whether the RPE or choriocapillaris is the first structure to be altered. FAF can evaluate the functionality of the RPE by the changes in the fluorescence. OCTA can detect the retinal and choroidal blood vessel patterns even in the choriocapillaris slab. Since RPE is supplied by the choriocaplillaris generally, the abnormal areas in RPE should be identical between images of FAF and OCTA.

Our FAF and OCTA results suggest that the RPE disorder developed before the choriocapillaris atrophy in this case of presumed choroideremia. The findings indicate that multimodal imaging, including FAF and OCTA, can provide new information on the morphology and function of the retina and choroid in different diseases. Learning points Although choroideremia is associated with a degeneration of the RPE and choriocapillaris throughout the fundus due to a deficiency of the Rab escort protein 1, it is unclear whether the RPE or choriocapillaris is the first structure to be altered. FAF can evaluate the functionality of the RPE by the changes in the fluorescence. OCTA can detect the retinal and choroidal blood vessel patterns even in the choriocapillaris slab. Since RPE is supplied by the choriocaplillaris generally, the abnormal areas in RPE should be identical between images of FAF and OCTA. In the current study, we evaluated RPE and choriocapillaris damage using FAF and OCTA in choroideremia case with preserved central vision. Hypoautofluorescence except for an isolated area of hyperautofluorescence which included the fovea was seen in FAF. Medium and large choroidal vessels were clearly seen throughout the fundus in OCTA. OCTA also showed the choriocapillaris in a relatively wider area than the hyperautofluorescent isolated area on FAF. It was possible to identify RPE atrophy before the choriocapillaris atrophy in choroideremia. The multimodal imaging, including FAF and OCTA, can provide new information on the morphology and function of the retina and choroid in different diseases.

In the current study, we evaluated RPE and choriocapillaris damage using FAF and OCTA in choroideremia case with preserved central vision. Hypoautofluorescence except for an isolated area of hyperautofluorescence which included the fovea was seen in FAF. Medium and large choroidal vessels were clearly seen throughout the fundus in OCTA. OCTA also showed the choriocapillaris in a relatively wider area than the hyperautofluorescent isolated area on FAF. It was possible to identify RPE atrophy before the choriocapillaris atrophy in choroideremia. The multimodal imaging, including FAF and OCTA, can provide new information on the morphology and function of the retina and choroid in different diseases. The authors thank Professor Emeritus Duco Hamasaki of the Bascom Palmer Eye Institute of the University of Miami for providing critical discussions and suggestions for our study and revision of the final manuscript. Contributors: MK and IM involved in designing and conducting of the study. MK, IM and HK are responsible for acquisition of data. MK, IM and HK are responsible for analysis and interpretation of data. MK, IM and TI drafted the manuscript or revised it. All authors approved the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

e for analysis and interpretation of data. MK, IM and TI drafted the manuscript or revised it. All authors approved the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Competing interests: IM received personal fees from Novartis Pharma K.K., Bayer Yakuhin, Santen Pharmaceutical, Alcon Japan, Topcon, Senju Pharmaceutical and NIDEK. HK received personal fees from Novartis Pharma K.K., Bayer Yakuhin, Santen Pharmaceutical, Alcon Japan, Topcon, Senju Pharmaceutical, HOYA Corp., Canon, Wakamoto Pharmaceutical, NIDEK. TI received grants and personal fees from Novartis Pharma K.K., Bayer Yakuhin  and Santen Pharmaceutical. TI also received grants from Nidek and research support from Chuosangyo (Japan). Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Mondor’s disease is a thrombophlebitis of the superficial veins of the body and it was described by Enri Mondor first time in 1939.1 Thrombosis of the superficial dorsal vein of the penis was described by Braun Falco in a patient with a generalised phlebitis in 1958. Isolated thrombosis of the dorsal superficial vein of penis was first reported by Helm and Hodge in 1958.2 Still today, a few cases of isolated thrombophlebitis of the superficial vein of penis are reported in literature.3 No specific aetiology has been found, and patients’ age ranged between 18 and 79 years. Hypothetical causes of disease include trauma, infections, excessive sexual activity or abstinence, thrombophilia, inguinal hernia, body building exercises, pelvic cancer, pelvic venous occlusion and stasis. In the described case, the spinal stabilisation was performed with left subcostal retroperitoneal approach. During surgery, excessive compression of venous structures by self-retractors and coagulation of abdominal veins were avoided. In this patient, a prompt diagnosis allowed to treat the rare disease and prevent serious complications such as vein occlusion with consequent resection of the dorsal vein of the penis.

Background Cerebral venous sinus thrombosis (CVST) is a rare condition with only two to five cases per million people per year.1 In Trinidad and Tobago, with a population of 1.3 million, few cases are expected. Furthermore, the association between depot-norethisterone enanthate, a progestin-only contraceptive injection and CVST has rarely been reported in the literature. Ramya et al and Rajput et al reported that norethisterone and norethindrone acetate pills caused CVST in a patient with hyperhomocysteinaemia.2 3 This case report highlights the importance of having a high degree of suspicion of CVST in individuals with long-term depot progesterones, and aggressive treatment for optimum and satisfactory outcomes of CVST.

d that norethisterone and norethindrone acetate pills caused CVST in a patient with hyperhomocysteinaemia.2 3 This case report highlights the importance of having a high degree of suspicion of CVST in individuals with long-term depot progesterones, and aggressive treatment for optimum and satisfactory outcomes of CVST. Case presentation A 23-year-old married housewife, with two children, presented with a mild headache that gradually worsened over a period of 2 days. Thereafter, she sought emergency medical attention at a District Health Facility where she was treated with analgesia and discharged the same day. However, she had no significant relief in her headache. Five days after the initial onset of her symptoms, the headache worsened, and was associated with multiple episodes of vomiting and one episode of syncope lasting 2–3 min. She experienced no fever, blurred vision, photophobia, gait disturbance, seizure activity or focal sensory and motor deficit. She had no history of head trauma or neck stiffness. She had not taken any over-the-counter medication or prescription medicines such as antipsychotics or herbal medications, except norethisterone enanthate depot injections, which she received every 2 months for 2 years as a contraception following the birth of her last child. Her last dose was 3 weeks prior to the commencement of her symptoms. She was neither diabetic, hypertensive nor had hypercholesterolaemia. Additionally, she had no significant family history, did not smoke and only had alcohol occasionally.

2 months for 2 years as a contraception following the birth of her last child. Her last dose was 3 weeks prior to the commencement of her symptoms. She was neither diabetic, hypertensive nor had hypercholesterolaemia. Additionally, she had no significant family history, did not smoke and only had alcohol occasionally. Examination on admission revealed a listless, exhausted patient with a Glasgow Coma Scale score of 15/15. She was oriented in time, place and person. Her blood pressure was 107/72 mm Hg, and pulse was 80 beats per minute and regular. Central nervous system examination revealed no abnormalities. Rest of the neurological examination, including cranial nerves, sensory and motor systems, deep tendon reflexes and planters were normal. Kernig’s and Brudzinski’s signs were negative.

pressure was 107/72 mm Hg, and pulse was 80 beats per minute and regular. Central nervous system examination revealed no abnormalities. Rest of the neurological examination, including cranial nerves, sensory and motor systems, deep tendon reflexes and planters were normal. Kernig’s and Brudzinski’s signs were negative. Investigations All routine blood investigations, including complete blood count, liver function tests, renal function tests, fasting lipids and electrolytes were all within normal limits. Furthermore, prothrombin time, partial thromboplastin time and international normalised ratio (INR) were 11 s, 26.2 s and 1.03, (normal range: 9.5–13.5, 27.0–35.0 and 0.8–1.2 s), respectively, as well as an estimated sedimentary rate of 23 mm/hour (0–15) and C reactive protein was 0.7 mg/dL (0–0.5). Antiphospholipid and thrombophilia screens were normal: Protein C 95.6% (70–140), Protein S 113% (63–135), Factor V Leiden 34.6 s (28–50), antithrombin III 117% (85–125) and anticardiolipin antibodies IgA 2.2 (<12 APL U/mL), IgG <2 (<12 GPL U/mL) and IgM 3.70 (<12 MPLU/mL). Urinalysis was normal. A brain CT scan (figure 1) showed two areas of hypodensity in the left parietal lobe and in the left internal capsule, as well as a region of abnormal hyperdensity in the left sigmoid and superior sagittal sinus. These findings were suspicious of a left parietal lobe venous infarct, secondary to a venous dural sinus thrombosis, with MRI and MRV (figure 2) confirming a signal void seen in the posterior 2/3 of the superior sagittal sinus, as well as within the right transverse and sigmoid sinuses.

oid and superior sagittal sinus. These findings were suspicious of a left parietal lobe venous infarct, secondary to a venous dural sinus thrombosis, with MRI and MRV (figure 2) confirming a signal void seen in the posterior 2/3 of the superior sagittal sinus, as well as within the right transverse and sigmoid sinuses. Figure 1 Brain CT findings on admission. The first red arrow shows a left parasagittal parietal lobe high convexity gyral hypodensity (1.8×0.9 cm) region is seen. Appearances may be caused by a venous infarct. The second red arrow shows an abnormal superior sagittal and left sigmoid sinus hyperdensity suspicious for venous sinus thrombosis (empty delta sign). Relative hypodensity in the left internal capsule. No other areas of abnormal attenuation. Otherwise normal appearances of the brain parenchyma, ventricles, cisterns and nuclei. No extra-axial collections. No intraparenchymal haemorrhage detected. Impression: left parietal lobe venous infarct. Venous dural sinus thrombosis. Figure 2 Brain MRI and MRV findings on admission. The red arrows show a signal void seen in the posterior 2/3 of the superior sagittal sinus, as well as within the right transverse and sigmoid sinuses. Correlation with CT suggests venous sinus thrombosis. A diagnosis of drug (norethisterone enanthate)-induced CVST was considered.

Figure 2 Brain MRI and MRV findings on admission. The red arrows show a signal void seen in the posterior 2/3 of the superior sagittal sinus, as well as within the right transverse and sigmoid sinuses. Correlation with CT suggests venous sinus thrombosis. A diagnosis of drug (norethisterone enanthate)-induced CVST was considered. Treatment The patient was treated with antioedema measures comprising mannitol 50 mL intravenously two times for 24 hours and dexamethasone 4 mg orally one time for 3 days. Anticoagulation was initiated with warfarin after bridging with low-molecular-weight heparin enoxaparin. Outcome and follow-up The patient recovered completely within 1 week and was discharged. Her condition remained well throughout her follow-up visits. Anticoagulation was continued for 6 months as recommended, though recanalisation is expected after 3 months of anticoagulation therapy.4 She was also advised to avoid prothrombotic drugs and to use barrier contraception. A follow-up MRI brain with a venogram (figure 3A,B), performed 6 months after the initial presentation confirmed recanalisation, as it revealed no thrombosis in the superior sagittal, right transverse and sigmoid sinuses, and no acute intracranial haemorrhages. All anticoagulation medications were stopped, and the patient was advised lifelong avoidance of norethisterone enanthate contraception. Figures 3 (A and B) Follow-up brain MRI and MRV after 6 months. Normal MRI and MRV of the brain with no defects in the superior sagittal, right transverse and sigmoid sinuses, and no acute intracranial haemorrhages.

A follow-up MRI brain with a venogram (figure 3A,B), performed 6 months after the initial presentation confirmed recanalisation, as it revealed no thrombosis in the superior sagittal, right transverse and sigmoid sinuses, and no acute intracranial haemorrhages. All anticoagulation medications were stopped, and the patient was advised lifelong avoidance of norethisterone enanthate contraception. Figures 3 (A and B) Follow-up brain MRI and MRV after 6 months. Normal MRI and MRV of the brain with no defects in the superior sagittal, right transverse and sigmoid sinuses, and no acute intracranial haemorrhages. Discussion CVST is a rare and potentially fatal condition. This patient’s presentation with a severe headache is present in 90% of the cerebral venous thromboses cases; the list of differential diagnoses can be infectious, inflammatory, structural and even psychological disorders.5 Furthermore, its occurrence in isolation, in the absence of focal neurological signs or papilloedema, and with normal antiphospholipid and thrombophilia screen, poses an even greater diagnostic challenge. This feature has been shown to occur in only 15% of CVST cases.6 A retrospective, cross-sectional study conducted by Coutinho et al, analysed adult cerebral thromboses in 19 hospitals located in two Dutch provinces serving 3.1 million, (which is approximately three times the population of Trinidad), between 1 January 2008 and 31 December 2010. The study revealed an overall annual incidence of 1.32 per 100 000, a significantly higher incidence in women than men (1.86 vs 0.75), and a higher incidence among patients aged 31–50 years (1.71) with a median age of 41 years. Additionally, 52% of female patients used oral contraceptives, and 18% were pregnant or had recently given birth.7

overall annual incidence of 1.32 per 100 000, a significantly higher incidence in women than men (1.86 vs 0.75), and a higher incidence among patients aged 31–50 years (1.71) with a median age of 41 years. Additionally, 52% of female patients used oral contraceptives, and 18% were pregnant or had recently given birth.7 Diagnosis of CVST is made using contrast-enhanced CT, MRI or MRV. Contrast-enhanced CT shows the classic empty delta sign, as was seen in this case (figure 1). This is present in 10%–35% of cases, and is produced by an intraluminal filling defect surrounded by contrast in the posterior part of the superior sagittal sinus.8 The combination of an abnormal signal in a sinus and a corresponding absence of flow on MRV confirms the diagnosis of CSVT.8 The American Heart Association/American Stroke Association 2011 Scientific Statement recommends MRI/MRV as the imaging test of choice for evaluation of suspected cerebral venous thrombosis. Angiography (brain) is reserved for situations in which MRV or CT is inconclusive.9 Thrombosis has been reported to occur in the superior sagittal, transverse and sigmoid sinuses in 62%, 41%–45% and 10% of cases, respectively.9

RI/MRV as the imaging test of choice for evaluation of suspected cerebral venous thrombosis. Angiography (brain) is reserved for situations in which MRV or CT is inconclusive.9 Thrombosis has been reported to occur in the superior sagittal, transverse and sigmoid sinuses in 62%, 41%–45% and 10% of cases, respectively.9 Thrombosis of the cerebral veins causes local effects by venous obstruction, which results in oedema of the brain and venous infarction. Thrombosis of the major sinuses causes impaired absorption of cerebrospinal fluid (CSF) and intracranial hypertension.10 These mechanisms are responsible for the four possible clinical syndromes that are seen. These include: isolated intracranial hypertension, which presents as a severe headache (90%); focal neurological deficits (44%) such as hemiparesis, which usually becomes bilateral in a few days; seizures (30%–40%), which occur more frequently with thrombosis of the sagittal sinus and cortical veins; and encephalopathy (22%), which can result from thrombosis of the straight sinus or from extensive cerebral oedema, large venous infarcts or parenchymal haemorrhages.11 At least one risk factor could be identified in more than 85% of patients with CVST.11 Coutinho et al analysed data from the International Study on Cerebral Vein and Dural sinus Thrombosis (ISCVT), a multicentre prospective observational study, and found that 465 of the 624 patients were women (75%), and a gender-specific risk factor (oral contraceptives, 46%; pregnancy or puerperium, 17%; hormonal replacement therapy, 3%) was present in 65% of the women. Women had a better prognosis than men (complete recovery 81% vs 71%). Congenital and acquired thrombophilia carried similar percentages for men and women (25% vs 22% and 15% vs 16%, respectively). Of note, the incidence of infection and malignancy, as causes of CVST, were two times higher in men than in women (21% vs 10% and 11% vs 6%, respectively).12

men (complete recovery 81% vs 71%). Congenital and acquired thrombophilia carried similar percentages for men and women (25% vs 22% and 15% vs 16%, respectively). Of note, the incidence of infection and malignancy, as causes of CVST, were two times higher in men than in women (21% vs 10% and 11% vs 6%, respectively).12 The patient’s blood and urine investigations were within normal limits. Dehydration was excluded in view of her moist mucous membranes, normal skin turgor and renal function tests. She had no predisposing risk factors associated with cerebral vein thrombosis, except for the use of the progestin-only contraceptive injection.

atient’s blood and urine investigations were within normal limits. Dehydration was excluded in view of her moist mucous membranes, normal skin turgor and renal function tests. She had no predisposing risk factors associated with cerebral vein thrombosis, except for the use of the progestin-only contraceptive injection. Many observational studies have shown that combined oral contraceptives are associated with a twofold to sixfold increased risk of venous thrombosis.13–15 The oestrogen compound (ethinyloestradiol) in oral contraceptive formulations is thought to cause the increased risk of thrombosis, as a reduction in the dose of this compound resulted in a reduced risk of venous thrombosis. Oral contraceptives induced a degree of activated protein C resistance comparable with the resistance caused by a factor V Leiden mutation.16 Clinical studies have shown that this effect on coagulation factors was more pronounced in oral contraceptives containing desogestrel (a third-generation progestogen) than in levonorgestrel (a second-generation progestogen), which may be explained by a less effective compensation of the thrombotic effect of ethinyloestradiol by desogestrel.17 Thus, factors associated with an increased risk of venous thrombosis are higher doses of ethinyloestradiol, as well as a third-generation progestogen.18 However, these findings cannot be related with the depot injections of norethisterone enanthate which our patient used.

c effect of ethinyloestradiol by desogestrel.17 Thus, factors associated with an increased risk of venous thrombosis are higher doses of ethinyloestradiol, as well as a third-generation progestogen.18 However, these findings cannot be related with the depot injections of norethisterone enanthate which our patient used. A study performed by McEwan et al monitored 56 women using depot-norethisterone enanthate injections for 2 years and compared them to a control group of 48, and found there were no significant differences between the treatment and control groups with respect to factor VIIc and antithrombin. Factor Xc, however, was reduced in women who had taken the injections for over 2 years, but less than 5 years; while haemoglobin levels, red cell count and packed cell volume were higher in the treatment group as compared with those in the control group. Therefore, this study concluded that long-term use of norethisterone enanthate is not associated with any markedly deleterious effects on factors VIIc and Xc, antithrombin III or haemoglobin levels.19 The drug norethisterone enanthate, a first-generation progestogen, has a lower risk of causing venous thrombosis when compared with third-generation progestogens. It has been shown to be partly metabolised to ethinyloestradiol, which has been associated with an increased risk of venous thrombosis.18 20

globin levels.19 The drug norethisterone enanthate, a first-generation progestogen, has a lower risk of causing venous thrombosis when compared with third-generation progestogens. It has been shown to be partly metabolised to ethinyloestradiol, which has been associated with an increased risk of venous thrombosis.18 20 The main priority in the treatment for CVST is stabilisation, prevention or reversal of cerebral oedema, and herniation with intravenous mannitol, (which was used in our patient) or decompressive hemicraniectomy, and/or removal of haemorrhagic infarct with surgical procedures.21 A prospective study published in the ISCVT showed that 79% of patients recovered from this treatment.21 Although there is a risk of venous infarcts becoming haemorrhagic, anticoagulation therapy still forms the mainstay of treatment.22 Our patient showed full clinical and radiological improvement following administration of low-molecular-weight heparin and mannitol. Anticoagulation (warfarin) with a target INR of 2.5 was continued for 6 months as there were no predisposing conditions.23 No further treatment was advised, except the avoidance of norethisterone enanthate depot injections. The prognosis of CVST is usually favourable, with more than 80% of patients, as in our case, having a good neurological outcome.24 Learning points Cerebral venous sinus thrombosis (CVST) is a rare condition, and its presentation can mimic various benign conditions. Clinicians should have a high level of suspicion, identifying aetiology and predisposing conditions, to facilitate a prompt diagnosis.

proach. During surgery, excessive compression of venous structures by self-retractors and coagulation of abdominal veins were avoided. In this patient, a prompt diagnosis allowed to treat the rare disease and prevent serious complications such as vein occlusion with consequent resection of the dorsal vein of the penis. Case presentation A 31-year-old man, smoker of 30 cigarettes a day, was admitted to our department with a vertebral trauma and a burst fracture of L1 without neurological deficit. His body mass index was 25. The first procedure was a posterior stabilisation D12-L2 with rods and screws. One month later, a second surgical procedure was performed by an anterior-lateral retroperitoneal left side approach. The patient was positioned in lateral right position with flexion of the legs. A subcostal incision was made, and by a retroperitoneal approach, screws T12-L2 were implanted in one plate. Six-hour surgery was conducted, and no vascular injury was reported. Three days later, the patient walked with a stick. In accordance with our standard protocol, mechanical deep venous prophylaxis and chemoprophylaxis (enoxaparine sodium 4000 UI/day) started the day of surgery and went on for 3 days. After 7 days, at discharge, the patient complained of pain and dorsal induration of the penis. The pain was throbbing. No fever, dysuria and no typical signs of inflammation were present in the serum. Patient clinical examination documented palpable thick cord-like lesion on the dorsal side of his penis, the skin was absolutely intact with no redness (figure 1). There were no signs of lymphadenopathy in the groin region. Ultrasound images revealed a segmental thrombosis of the superficial dorsal vein of the penis (figure 2), which appeared as internal echogenicity without flow signal at colour Doppler sonography.4 Haemocoagulative screening was negative for thrombophilia. Abdominal CT scan did not show venous thrombosis in abdominal veins. Therapy started with enoxaparine sodium 4000 UI/day and antibiotics (levofloxacin 500 mg twice a day for a week). The patient was reassured about the benign nature of his disease and was discharged 2 days later.

reening was negative for thrombophilia. Abdominal CT scan did not show venous thrombosis in abdominal veins. Therapy started with enoxaparine sodium 4000 UI/day and antibiotics (levofloxacin 500 mg twice a day for a week). The patient was reassured about the benign nature of his disease and was discharged 2 days later. Figure 1 Ultrasound image showing thrombosis of the superficial dorsal vein of the penis (arrows). Figure 2 Arrows indicated the superficial dorsal vein thrombosis. Outcome and follow-up Presenting clinical symptoms and signs resolved after 2 weeks of therapy and ultrasound images documented the complete reopening of the vein. At 3-month follow-up examination, there were no findings of disease (both clinical and ecographic), the patient referred no sexual dysfunctions and enoxaparine was stopped.

ow-up Presenting clinical symptoms and signs resolved after 2 weeks of therapy and ultrasound images documented the complete reopening of the vein. At 3-month follow-up examination, there were no findings of disease (both clinical and ecographic), the patient referred no sexual dysfunctions and enoxaparine was stopped. Discussion The thrombosis of the dorsal vein of the penis is a rare condition with only 49 articles found in the literature.5 Correct and fast diagnosis grants a prompt recovery. Venous drainage of penis starts at the base of the glans, then the circumflex veins extend around the corpus cavernosum and reach the dorsal vein perpendicularly. This network of veins reaches the pudendal veins flowing into internal iliac vein that join the external iliac vein to form the common iliac vein that reach the vena cava. In polytraumatised patients with plurifragmental vertebral fractures, the posterior approach with screws and rods may be insufficient to grant stability6 7 especially in the short fixation. In these patients or in case of removal of the posterior instrumentation for infection,8 a second anterior-lateral approach and stabilisation with vertebral plate is mandatory. In the present case, the surgical approach was retroperitoneal on the left side with the patient in lateral position on the right side with flexion of the legs. The mean surgical procedure time was 6 hours in most of the cases. To prevent complications and stasis, the correct positioning of the patient on the operating table is imperative. Postsurgical vascular stasis has been suggested as a cause of the thrombosis9–11 due to prolonged immobility.12 13 A potential complication of anterior vertebral surgery is the vascular injury of the left common iliac vein.14 It is important to release the traction of handheld retractors at regular intervals no longer than 15 min to avoid compression and thrombosis.15 In the described case, we assume that the prolonged position on the patient’s right side with flexion of the legs may have caused a pelvic venous stasis with subsequent thrombosis of the dorsal penile vein. Another potential cause may have been the crushing of the penis on the operating table and finally the visceral compression by the self-retaining retractor during the long surgical procedure.

right side with flexion of the legs may have caused a pelvic venous stasis with subsequent thrombosis of the dorsal penile vein. Another potential cause may have been the crushing of the penis on the operating table and finally the visceral compression by the self-retaining retractor during the long surgical procedure. Another potential cause may be the tendency to thrombosis of the patient (no documented by haematological screening) who 6 months before the vertebral surgery presented a deep vein thrombosis in the leg without permanent sequel or recurrence. Anyway it is important to diagnose the disease by means of ultrasound images and make differential diagnosis from the non-venereal sclerosing lymphangitis. Our patient recovered with enoxaparin sodium while other patients got spontaneous resolution without therapy.3 There is some evidence that people affected with Mondor’s disease are more likely to relapse if predisposing factors persist.16 Finally, most cases resolve within 4 to 6 weeks, in persistent cases surgery with a thrombectomy or resection of the superficial dorsal vein may be necessary.17 Thrombosis of the superficial vein of the penis is a rare benign disease. No specific aetiology has been found but the pelvic venous stasis may be a cause in operated patients. It is important to diagnosis the disease as soon as possible to start an adequate therapy. The diagnosis is made by clinical evaluation and ultrasound imaging. Learning points Mondor’s disease is a benign thrombophlebitis of superficial veins.

Another potential cause may be the tendency to thrombosis of the patient (no documented by haematological screening) who 6 months before the vertebral surgery presented a deep vein thrombosis in the leg without permanent sequel or recurrence. Anyway it is important to diagnose the disease by means of ultrasound images and make differential diagnosis from the non-venereal sclerosing lymphangitis. Our patient recovered with enoxaparin sodium while other patients got spontaneous resolution without therapy.3 There is some evidence that people affected with Mondor’s disease are more likely to relapse if predisposing factors persist.16 Finally, most cases resolve within 4 to 6 weeks, in persistent cases surgery with a thrombectomy or resection of the superficial dorsal vein may be necessary.17 Thrombosis of the superficial vein of the penis is a rare benign disease. No specific aetiology has been found but the pelvic venous stasis may be a cause in operated patients. It is important to diagnosis the disease as soon as possible to start an adequate therapy. The diagnosis is made by clinical evaluation and ultrasound imaging. Learning points Mondor’s disease is a benign thrombophlebitis of superficial veins. The thrombosis of the superficial dorsal veins of the penis is a rare benign complication of pelvis stasis. In spinal surgery with anterior-lateral position, it is important to prevent veins compression or the crushing of the penis on the operating table. Ultrasound images are the gold standard for the diagnosis.

Learning points Mondor’s disease is a benign thrombophlebitis of superficial veins. The thrombosis of the superficial dorsal veins of the penis is a rare benign complication of pelvis stasis. In spinal surgery with anterior-lateral position, it is important to prevent veins compression or the crushing of the penis on the operating table. Ultrasound images are the gold standard for the diagnosis. Contributors: MD: conception and design of the study and writing the manuscript. RB: acquisition of data, reporting and writing the manuscript. DN: analysis and interpretation of data and review of literature. DC: critical review of manuscript and review of literature. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Serotonin–norepinephrine reuptake inhibitors (SNRI) are used to treat depressive disorders and certain types of chronic pain.1 The most common adverse effects of SNRIs are nausea, dry mouth, dizziness and headache.2 It remains unknown which drug is likely to cause drug-related concomitant taste and smell dysfunction.3–5 Here we describe distortion of taste (dysosmia) and smell (dysgeusia) as new adverse effects of duloxetine. Case presentation A 68-year-old Japanese woman with medical histories of type 1 diabetes mellitus, hypertension, insomnia and reflux esophagitis presented to a local hospital with bilateral leg pain due to diabetic neuropathy and was treated with duloxetine. After 4 weeks, she vomited blood and was admitted to our hospital for further investigation. Prior to hospitalisation, she reported a 4-day history of a rotten egg smell, vomiting and an inability to eat. She described that she experienced the smell for the first time when she visited a coffee shop. She had no history of smoking, head trauma, allergic rhinitis or upper respiratory tract infection before the onset of symptoms and also showed no symptoms of chronic or acute recurrent rhinosinusitis or rhinitis. Her medication included long-acting insulin analogue (glargine) 14 units at bed time, rapid-acting insulin analogue (aspart) 8 units each before meals, amlodipine (5 mg/day), lansoprazole (15 mg/day), brotizolam (0.25 mg/day) and duloxetine (20 mg/day).

Case presentation A 68-year-old Japanese woman with medical histories of type 1 diabetes mellitus, hypertension, insomnia and reflux esophagitis presented to a local hospital with bilateral leg pain due to diabetic neuropathy and was treated with duloxetine. After 4 weeks, she vomited blood and was admitted to our hospital for further investigation. Prior to hospitalisation, she reported a 4-day history of a rotten egg smell, vomiting and an inability to eat. She described that she experienced the smell for the first time when she visited a coffee shop. She had no history of smoking, head trauma, allergic rhinitis or upper respiratory tract infection before the onset of symptoms and also showed no symptoms of chronic or acute recurrent rhinosinusitis or rhinitis. Her medication included long-acting insulin analogue (glargine) 14 units at bed time, rapid-acting insulin analogue (aspart) 8 units each before meals, amlodipine (5 mg/day), lansoprazole (15 mg/day), brotizolam (0.25 mg/day) and duloxetine (20 mg/day). Physical examination revealed a body mass index of 20.5 kg/m2, temperature of 37.3°C, pulse of 127 beats/min, blood pressure of 184/100 mm Hg, respiratory rate of 20 breaths/min and oxygen saturation of 96% in room air. She was alert and oriented, with no evidence of dementia. Her mouth was dry, but her capillary refill time was <2 s. There was no sinus or abdominal tenderness. Neurological findings were normal, with no evidence of tremor at rest, rigidity and postural instability.

breaths/min and oxygen saturation of 96% in room air. She was alert and oriented, with no evidence of dementia. Her mouth was dry, but her capillary refill time was <2 s. There was no sinus or abdominal tenderness. Neurological findings were normal, with no evidence of tremor at rest, rigidity and postural instability. Investigations The laboratory data were as follows: white cell count, 10.28x109/L; haemoglobin, 15 g/dL; platelets, 25.9×104/μL; haemoglobin A1c, 5.9%; casual plasma glucose level, 244 mg/dL; blood urea nitrogen, 34 mg/dL; creatinine, 0.49 mg/dL; potassium, 2.9 mmol/L; zinc, 49 µg/dL (65–110); and copper, 128 µg/dL (76–141). Upper gastrointestinal endoscopy showed an oesophageal erosive lesion but no bleeding or obstruction. Head MRI showed fluid intensity in the maxillary sinus but no atrophy of the hippocampus or diffuse changes in the temporal and frontal lobes. Olfactory acuity tests were performed using the T&T olfactometer threshold test (figure 1), which showed that olfactory detection thresholds were <2, except those for the rotten egg smell, and all olfactory recognition thresholds were <3. The filter paper disk method was used for taste assessment, which indicated that recognition levels for sweet, salt, sour and bitter tastes were <4 (table 1). Electrogustometry (table 2) of the areas of the chorda tympani and glossopharyngeal and major petrosus nerves showed that taste recognition levels were all bilaterally >10 dB. Table 1 Filter paper disk method for taste assessment on admission day (HD 1) and 7 days after discontinuing duloxetine (HD 7)

Olfactory acuity tests were performed using the T&T olfactometer threshold test (figure 1), which showed that olfactory detection thresholds were <2, except those for the rotten egg smell, and all olfactory recognition thresholds were <3. The filter paper disk method was used for taste assessment, which indicated that recognition levels for sweet, salt, sour and bitter tastes were <4 (table 1). Electrogustometry (table 2) of the areas of the chorda tympani and glossopharyngeal and major petrosus nerves showed that taste recognition levels were all bilaterally >10 dB. Table 1 Filter paper disk method for taste assessment on admission day (HD 1) and 7 days after discontinuing duloxetine (HD 7) Nerve Taste Sweet Salt Sour Bitter HD 1 HD 7 HD 1 HD 7 HD 1 HD 7 HD 1 HD 7 Chorda tympani Right VI II V III VI I V III Left V IV VI III V II VI IV Glossopharyngeal Right VI III VI III V V V II Left V V V II V III VI VI Major petrosus Right VI VI VI VI VI VI VI VI Left VI VI VI VI VI VI VI V Roman numbers indicate taste concentration (ranges I–V); lower number indicates lighter. VI means no recognition of the taste. HD, hospital day. Figure 1 T&T olfactometer threshold test on admission day (left) and 7 days after discontinuing duloxetine (right). Alphabets represent specific odours: A, rose; B, caramel; C, rotten egg; D, sweet; and E, faeces. Range: −2 to 5, lower number indicates better smell threshold. Circle indicates the smell detection threshold. Saltire indicates the smell recognition. Table 2 Electrogustometry on admission day (HD 1) and 7 days after discontinuing duloxetine (HD 7)

Figure 1 T&T olfactometer threshold test on admission day (left) and 7 days after discontinuing duloxetine (right). Alphabets represent specific odours: A, rose; B, caramel; C, rotten egg; D, sweet; and E, faeces. Range: −2 to 5, lower number indicates better smell threshold. Circle indicates the smell detection threshold. Saltire indicates the smell recognition. Table 2 Electrogustometry on admission day (HD 1) and 7 days after discontinuing duloxetine (HD 7) Nerve Decibel HD 1 HD 7 Chorda tympani Right 10 −6 Left 20 −4 Glossopharyngeal Right 20 8 Left 20 6 Major petrosus Right >34 34 Left >34 30 Values indicate taste detection threshold. Lower value indicates better detection threshold. HD, hospital day. Differential diagnosis The patient showed both smell and taste disorders. Using the history of the patient and laboratory, physiological and imaging findings, the differential diagnosis for the taste disorder included adverse drug effects of duloxetine started before the onset of dysgeusia or the other ongoing medication, zinc deficiency, sinusitis and diabetic neuropathy, and that for the smell disorder included adverse drug effects of duloxetine started before the onset of dysosmia or the other ongoing medication, sinusitis and diabetic neuropathy. Treatment Soon after stopping duloxetine, both smell and taste disorders improved (figure 1 and tables 1 and 2), despite continuing the other ongoing medication.

Differential diagnosis The patient showed both smell and taste disorders. Using the history of the patient and laboratory, physiological and imaging findings, the differential diagnosis for the taste disorder included adverse drug effects of duloxetine started before the onset of dysgeusia or the other ongoing medication, zinc deficiency, sinusitis and diabetic neuropathy, and that for the smell disorder included adverse drug effects of duloxetine started before the onset of dysosmia or the other ongoing medication, sinusitis and diabetic neuropathy. Treatment Soon after stopping duloxetine, both smell and taste disorders improved (figure 1 and tables 1 and 2), despite continuing the other ongoing medication. Outcome and follow-up Seven days after discontinuing duloxetine (hospital day 7), olfactory acuity tests showed improved recognition levels of rose, rotten egg and faeces smells of >3. Taste assessment using the filter paper disk method showed that the recognition level was partially improved by >3 and that using electrogustometry showed that the detection level was improved by >10 dB in the areas of the chorda tympani and glossopharyngeal nerve. If the other differential diagnosis was correct, then the symptom would not have improved only by stopping duloxetine. After discharging from our hospital, her olfactory and taste disorders have not recurred so far.

Outcome and follow-up Seven days after discontinuing duloxetine (hospital day 7), olfactory acuity tests showed improved recognition levels of rose, rotten egg and faeces smells of >3. Taste assessment using the filter paper disk method showed that the recognition level was partially improved by >3 and that using electrogustometry showed that the detection level was improved by >10 dB in the areas of the chorda tympani and glossopharyngeal nerve. If the other differential diagnosis was correct, then the symptom would not have improved only by stopping duloxetine. After discharging from our hospital, her olfactory and taste disorders have not recurred so far. Discussion This report indicates that duloxetine caused dysosmia and subsequent dysgeusia because both smell and taste disorders reversibly recovered 7 days after discontinuing duloxetine, despite continuing the other ongoing medication. This clinical course between the discontinuation of duloxetine and improvement of taste and smell sensation provides objective evidence to support duloxetine as the cause of these adverse effects. Two important clinical issues arise from the clinical course of the present study patient. The first is whether these disorders have already been reported as adverse effects of duloxetine, and the second concerns the mechanism by which duloxetine or by which drug interactions with duloxetine cause these disorders.

cts. Two important clinical issues arise from the clinical course of the present study patient. The first is whether these disorders have already been reported as adverse effects of duloxetine, and the second concerns the mechanism by which duloxetine or by which drug interactions with duloxetine cause these disorders. The primary causes of olfactory dysfunction are allergic and viral rhinitis, influenza, head trauma, dementia of the Alzheimer type, Parkinson’s disease, diabetes mellitus and malnutrition.3 Although this patient had several years’ history of type 1 diabetes mellitus, hypertension, insomnia, reflux esophagitis, and chronic bilateral maxillary sinusitis and low serum zinc levels, which were found at this admission, there had been no problem with her sense of smell before taking duloxetine, and her sense of smell recovered soon after discontinuing duloxetine, despite continuing the other ongoing medication. This clinical course proved that duloxetine was the major cause of dysosmia and subsequent dysgeusia in this patient.

ission, there had been no problem with her sense of smell before taking duloxetine, and her sense of smell recovered soon after discontinuing duloxetine, despite continuing the other ongoing medication. This clinical course proved that duloxetine was the major cause of dysosmia and subsequent dysgeusia in this patient. Although the incidence of drug-induced taste and smell disorders is quite high, there are few reports available in the literature regarding their true incidence.3–5 Thus, the true incidence of drug-induced taste and smell disorder may possibly be underestimated. Available evidence from two reviews3 4 and a report of an Italian database5 indicates that calcium channel blockers (amlodipine, nifedipine, diltiazem), doxazosin, ACE inhibitors (enalapril, ramipril), enalapril maleate-felodipine, enalapril maleate-hydrochlorothiazide, tocainide, amiodarone, statins (lovastatin, atorvastatin), fluoroquinolones (moxifloxacin, levofloxacin), macrolides (clarithromycin, azithromycin, roxithromycin), amoxicillin/clavulanate, terbinafine, beclomethasone and methotrexate impair the sense of both smell and taste. We specifically searched the PubMed database for literature published in English and Japanese until July 2017 to identify eligible articles that simultaneously met the Medical Subject Headings terms ‘duloxetine hydrochloride’ and ‘olfaction disorders’ or ‘taste disorders’, but we could not find any article. To the best of our knowledge, this is the first case report of duloxetine causing dysosmia and subsequent dysgeusia.

2017 to identify eligible articles that simultaneously met the Medical Subject Headings terms ‘duloxetine hydrochloride’ and ‘olfaction disorders’ or ‘taste disorders’, but we could not find any article. To the best of our knowledge, this is the first case report of duloxetine causing dysosmia and subsequent dysgeusia. The specific mechanisms of drug-induced taste and smell disorders elicited by duloxetine and by the other drugs remain unknown. Moreover, the possible drug interactions with duloxetine related to concomitant taste and/or smell dysfunction, particularly ongoing amlodipine6 and lansoprazole5 which were prescribed before and after admission for this patient and, which have been associated with the above side effects, could not be excluded. Two possible hypotheses were proposed by Tuccori et al5 as a mechanism of drug-induced taste and/or smell alternations. The primary mechanisms resulted from a direct action of the drug; drug–receptor interaction, disturbance of action potential propagation in cell membranes, alteration of the neurotransmitter function and changes in connections between neural networks in brain regions associated with sensory coding and modulation. The secondary mechanisms include limiting the access of chemicals to sensing receptors, and changing the chemical or ionic milieu in the environment of sensing receptors.

n of the neurotransmitter function and changes in connections between neural networks in brain regions associated with sensory coding and modulation. The secondary mechanisms include limiting the access of chemicals to sensing receptors, and changing the chemical or ionic milieu in the environment of sensing receptors. By comparing olfactory acuity tests before and after discontinuing duloxetine (figure 1), it was observed that duloxetine impaired all olfactory detection thresholds to <2 levels, except for those of the rotten egg smell. This explains why the patient could smell rotten eggs at the coffee shop. In this patient, duloxetine decreased olfactory recognition thresholds, particularly of rose and rotten egg smells. Conclusions This is the first report of duloxetine causing dysosmia and subsequent dysgeusia. Because duloxetine may impair olfactory cognitive function rather than olfactory detection threshold, close attention must be paid to the decreased sense of smell when duloxetine is prescribed. Learning points This is the first report of duloxetine causing dysosmia and subsequent dysgeusia. This adverse effect was reversible because both dysosmia and dysgeusia were improved when duloxetine was discontinued. Close attention must be paid to the decreased sense of smell and/or taste when duloxetine is prescribed. Contributors: All the authors examined the patient clinically. KY drafted the manuscript. HS and TF edited and revised the final version. All authors agreed and authorised the final document for submission. Competing interests: None declared. Patient consent: Obtained.

Close attention must be paid to the decreased sense of smell and/or taste when duloxetine is prescribed. Contributors: All the authors examined the patient clinically. KY drafted the manuscript. HS and TF edited and revised the final version. All authors agreed and authorised the final document for submission. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description A 49-year-old man was referred to our hospital for atypical chest pain, without severe abdominal or back pain. He had a history of smoking and dyslipidaemia. His ECG showed no ST-T elevation. Coronary CT angiography (CTA) suggested moderate left anterior descending artery stenosis. CTA screening for aortic atherosclerosis showed significant calcification (figure 1A) and a crescent-shaped, mural low-density area in the infrarenal abdominal aorta (figure 1B,C). This was thought to be an intramural haematoma or a thrombosed false lumen. Calcified spots were deposited at the boundaries between the lumen and the low-density area (figure 1B,C). An intramural haematoma or a thrombosed type B dissection can be asymptomatic. Invasive coronary angiography showed no significant stenosis. Figure 1 CT angiography images of the aorta. (A) Maximum intensity projection. Calcification deposited in the infrarenal abdominal aorta; however, a few calcifications were found in other sections. (B) Coronal view of the abdominal aorta. Red arrows show the false lumen. (C) Axial image at the T12–L1 level. Red arrows show the false lumen with calcification.

rta. (A) Maximum intensity projection. Calcification deposited in the infrarenal abdominal aorta; however, a few calcifications were found in other sections. (B) Coronal view of the abdominal aorta. Red arrows show the false lumen. (C) Axial image at the T12–L1 level. Red arrows show the false lumen with calcification. Non-obstructive angioscopy (NOA) with a left brachial approach was performed to evaluate the aortic atherosclerosis.1 Aortic plaques were observed from the right common iliac artery to the aortic arch. NOA initially detected the clear boundary of the dissection. The intima of one side was reddish compared with that of the normal side. Bleeding was then detected from an approximately 1 mm entry tear close to the boundary (figure 2A, video 1), and a mobile white thrombus or flap was detected (figure 2B, video2). The salmon pink-coloured intima with its rough surface was consistently observed (figure 2C). With detection of the entry tear, asymptomatic thrombosed type B dissection was diagnosed. Figure 2 Angioscopic images of aortic ruptured plaques on the surface of the type B thrombosed dissection. (A) Clear boundary (white arrows) of the bright yellow area with smooth surface and red area with irregular surface and bleeding from the entry (blue arrows). (B) Mobile white thrombus or flap (black arrow). (C) Salmon pink-coloured intima. Video 1 Angioscopic video of the boundary of the aortic dissection and normal aortic wall and bleeding from the entry.

Figure 2 Angioscopic images of aortic ruptured plaques on the surface of the type B thrombosed dissection. (A) Clear boundary (white arrows) of the bright yellow area with smooth surface and red area with irregular surface and bleeding from the entry (blue arrows). (B) Mobile white thrombus or flap (black arrow). (C) Salmon pink-coloured intima. Video 1 Angioscopic video of the boundary of the aortic dissection and normal aortic wall and bleeding from the entry. 10.1136/bcr-2018-225268.video015769637523001BMJ Journals Video Playerbcr2018225268media1Video 2 Angioscopic video of the mobile white thrombus or flap. 10.1136/bcr-2018-225268.video025769650054001BMJ Journals Video Playerbcr2018225268media2Blood eosinophil levels on the following day and 30 days later were 0/μL and 63/μL, respectively, with a baseline level of 83/μL. Serum creatinine levels on the following day and 30 days later were 0.82 mg/dL and 0.79 mg/dL, respectively, with a baseline level of 0.86 mg/dL. C reactive protein levels on the following day and 30 days later were 0.79 mg/dL and 0.43 mg/dL, respectively, with a baseline level of 0.59 mg/dL. These results suggested that no embolic complication occurred after NOA. No embolic complications were observed in 324 consecutive patients within 24 hours after aortic NOA.2

reactive protein levels on the following day and 30 days later were 0.79 mg/dL and 0.43 mg/dL, respectively, with a baseline level of 0.59 mg/dL. These results suggested that no embolic complication occurred after NOA. No embolic complications were observed in 324 consecutive patients within 24 hours after aortic NOA.2 The patient’s course has been uneventful with conservative management for 2 years. CTA is performed every 6 months, as aortic size was normal. However, there is a limitation to the size-based determination of indications for treatment to prevent unexpected rupture of an aortic aneurysm with dissection,1 because asymptomatic aortic plaque ruptures may be associated with aortic fragility.3 CTA may overlook such injuries because of limited spatial resolution.3 CT and NOA are capable of spatial resolution at 500 µm and 150 µm, respectively. A disadvantage of CTA may be that images are static and tissue characterisation is only based on CT values, and thus may be unable to differentiate non-calcified plaques. The advantage of NOA in the diagnosis of aortic dissection is its ability to detect the entry tear and intimal injury with direct observation and to record these with both images and videos. NOA may be useful in diagnosing aortic dissection and disrupted intima, including the boundaries of the dissection and entry tear, mobile thrombus and flaps. Learning points Asymptomatic thrombosed type B dissection may be safely diagnosed with non-obstructive angioscopy (NOA).

The patient’s course has been uneventful with conservative management for 2 years. CTA is performed every 6 months, as aortic size was normal. However, there is a limitation to the size-based determination of indications for treatment to prevent unexpected rupture of an aortic aneurysm with dissection,1 because asymptomatic aortic plaque ruptures may be associated with aortic fragility.3 CTA may overlook such injuries because of limited spatial resolution.3 CT and NOA are capable of spatial resolution at 500 µm and 150 µm, respectively. A disadvantage of CTA may be that images are static and tissue characterisation is only based on CT values, and thus may be unable to differentiate non-calcified plaques. The advantage of NOA in the diagnosis of aortic dissection is its ability to detect the entry tear and intimal injury with direct observation and to record these with both images and videos. NOA may be useful in diagnosing aortic dissection and disrupted intima, including the boundaries of the dissection and entry tear, mobile thrombus and flaps. Learning points Asymptomatic thrombosed type B dissection may be safely diagnosed with non-obstructive angioscopy (NOA). NOA is superior to CT angiography because of its higher spatial resolution and its capability of direct recording with both still images and videos. The size-based determination of indications for treatment to prevent unexpected rupture of an aortic aneurysm and dissection is a limitation.

Learning points Asymptomatic thrombosed type B dissection may be safely diagnosed with non-obstructive angioscopy (NOA). NOA is superior to CT angiography because of its higher spatial resolution and its capability of direct recording with both still images and videos. The size-based determination of indications for treatment to prevent unexpected rupture of an aortic aneurysm and dissection is a limitation. Contributors: ST wrote the first version of the manuscript. SK and MT supervised the manuscript and gave expert opinion. KK supervised all the processes and gave final approval of this version of the manuscript. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: Yes, Dr. Kodama, who is the president of Inter-tec Medicals, Co., Ltd developed non-obstructive angioscopy. Dr, Komatsu is a technical consultant for Nemoto Kyorin-do Co., Ltd., Other authors has no conflict of interest. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Shoulder dystocia is an unpredictable obstetric complication with possible severe damage to the new-born as well as the mother. Although some risk factors, for example, maternal diabetes, obesity and macrosomia have been identified, shoulder dystocia is still hard to predict. A broad spectrum of manoeuvres has been described over the years, which are all empirically applied. Shoulder dystocia is a state during childbirth in which the shoulders are too wide to pass through the pelvis and the anterior shoulder of the fetus cannot pass below the pubic symphysis. The official definition is as follows: ‘a vaginal cephalic delivery that requires additional obstetric manoeuvres to deliver the fetus after the head has been delivered and gentle traction failed’.1 According to the Managing Obstetric Emergencies and Trauma (MOET) course, manoeuvres need to be applied in according to the acronym HELPERR (table 1). If all these methods fail, there are a few invasive manoeuvres left. These invasive manoeuvres are intentional breaking of the clavicle (cleidotomy), the Zavanelli manoeuvre followed by an immediate caesarean section or a symphysiotomy. All of these manoeuvres are associated with severe neonatal and maternal morbidity and are often not as easily performed as described in literature. Table 1 The acronym HELPERR

According to the Managing Obstetric Emergencies and Trauma (MOET) course, manoeuvres need to be applied in according to the acronym HELPERR (table 1). If all these methods fail, there are a few invasive manoeuvres left. These invasive manoeuvres are intentional breaking of the clavicle (cleidotomy), the Zavanelli manoeuvre followed by an immediate caesarean section or a symphysiotomy. All of these manoeuvres are associated with severe neonatal and maternal morbidity and are often not as easily performed as described in literature. Table 1 The acronym HELPERR H Help E Episiotomy L Legs (‘McRoberts manoeuvre’) P Pressure suprapubic E Enter manoeuvres (‘Robin and Wood manoeuvre’) R Remove posterior arm R Roll the patient In 2009, a new technique was described by Cluver and Hofmeyr.2 With this technique, a neonatal suction tube is placed under the posterior axilla as a sling, to which traction is applied. They originally tested it on cases where the fetus already died in utero after known methods for shoulder dystocia were unsuccessful. Because of the rapid success they started to practice the technique on several cases with severe shoulder dystocia before intrauterine death occurred.3 In response to this, a case in Switzerland had been described where applying traction to the sling alone was not successful.4 However, rotation of the posterior shoulder using the sling resulted in a quick delivery. We think it is important for all gynaecologists and midwives to know about this minimal invasive, but effective, method.

H Help E Episiotomy L Legs (‘McRoberts manoeuvre’) P Pressure suprapubic E Enter manoeuvres (‘Robin and Wood manoeuvre’) R Remove posterior arm R Roll the patient In 2009, a new technique was described by Cluver and Hofmeyr.2 With this technique, a neonatal suction tube is placed under the posterior axilla as a sling, to which traction is applied. They originally tested it on cases where the fetus already died in utero after known methods for shoulder dystocia were unsuccessful. Because of the rapid success they started to practice the technique on several cases with severe shoulder dystocia before intrauterine death occurred.3 In response to this, a case in Switzerland had been described where applying traction to the sling alone was not successful.4 However, rotation of the posterior shoulder using the sling resulted in a quick delivery. We think it is important for all gynaecologists and midwives to know about this minimal invasive, but effective, method. Case presentation A 35-year-old woman, gravida 2 para 1, was admitted to our inpatient clinic for a vaginal birth during her second pregnancy.

H Help E Episiotomy L Legs (‘McRoberts manoeuvre’) P Pressure suprapubic E Enter manoeuvres (‘Robin and Wood manoeuvre’) R Remove posterior arm R Roll the patient In 2009, a new technique was described by Cluver and Hofmeyr.2 With this technique, a neonatal suction tube is placed under the posterior axilla as a sling, to which traction is applied. They originally tested it on cases where the fetus already died in utero after known methods for shoulder dystocia were unsuccessful. Because of the rapid success they started to practice the technique on several cases with severe shoulder dystocia before intrauterine death occurred.3 In response to this, a case in Switzerland had been described where applying traction to the sling alone was not successful.4 However, rotation of the posterior shoulder using the sling resulted in a quick delivery. We think it is important for all gynaecologists and midwives to know about this minimal invasive, but effective, method. Case presentation A 35-year-old woman, gravida 2 para 1, was admitted to our inpatient clinic for a vaginal birth during her second pregnancy. In her obstetric history, she had undergone a secondary caesarean section due to a prolonged second stage of labour due to high birth weight (GA: 41 weeks and 3 days, 4130 g, p80–84) and a cephalic presentation in the occiput posterior position. In her current pregnancy, there was elaborate counselling regarding the delivery mode, she opted for a vaginal birth after caesarean section. Her pregnancy course and clinical examination were completely normal, except a fetal abdominal circumference above p99. We therefore decided to induce labour at 39+2 weeks of gestation.

current pregnancy, there was elaborate counselling regarding the delivery mode, she opted for a vaginal birth after caesarean section. Her pregnancy course and clinical examination were completely normal, except a fetal abdominal circumference above p99. We therefore decided to induce labour at 39+2 weeks of gestation. At the day of delivery, she had a cervical dilatation of 4 cm and we artificially ruptured the membranes at 08:00. At 08:45, oxytocin was started to stimulate uterine contractions. It was difficult to stimulate the uterus, but on high dose oxytocin the patient eventually reached active phase of labour. At 17:10, she had a pain relief request due to severe labour pains. At that time, her cervix was 8 cm dilated and we decided to start with patient-controlled remifentanil. At 21:10, she reached full cervical dilation and she started second stage of labour while the caput of the fetus was just above the Hodge plane 3. Twenty minutes into the secondary stage of labour, the cardiotocography showed a fetal tachycardia and complicated, but variable, decelerations. At that moment, the fetal caput was at Hodge 4. Because there was rapid progression in the delivery an episiotomy in combination with fundal expression was applied. Directly after these manoeuvres, at 21:48, the fetal head was easily delivered with external rotation. This was immediately followed by a turtle sign. We unsuccessfully applied the McRoberts’ manoeuvre with suprapubic pressure followed by an also unsuccessful Woods corkscrew manoeuvre. Then, the Rubin II on all four was applied, which also failed. As a last step, we tried to manually deliver the posterior shoulder by traction on that posterior axilla; however, this technique also failed. In the moment before we moved on performing a symphysiotomy, we decided to try the posterior axilla sling traction technique. At this time the patient was still in the all fours position.

step, we tried to manually deliver the posterior shoulder by traction on that posterior axilla; however, this technique also failed. In the moment before we moved on performing a symphysiotomy, we decided to try the posterior axilla sling traction technique. At this time the patient was still in the all fours position. At 21:50, a neonatal suction tube was fed around the posterior axilla without any problems, creating a sling around the posterior shoulder. Thereafter, we applied gentle vertical traction on the suction tube and as a result the posterior shoulder was immediately born. Outcome and follow-up At 21:51, the neonate was born with an Apgar-score of 2-8-9 and weighed 4010 g (p90–95). The neonate needed positive pressure ventilation during the first 2 min. Subsequently, the neonate stayed dependent on oxygen and the first days were complicated by an infection. The neonate recovered quickly with antibiotics and was dismissed from the hospital after 8 days. There were no signs of fractures, (central) nerve injuries or soft tissue injuries. The patient had an episiotomy, two vaginal wall lacerations and a second-degree perineal laceration contralateral of the episiotomy. The lacerations and the episiotomy were sutured under local anaesthesia. Furthermore, there was a postpartum haemorrhage with a total blood loss of 1300 cc, mainly coming from the episiotomy. Unfortunately, the puerperium was complicated by endometritis which was adequately treated using antibiotics.

of the episiotomy. The lacerations and the episiotomy were sutured under local anaesthesia. Furthermore, there was a postpartum haemorrhage with a total blood loss of 1300 cc, mainly coming from the episiotomy. Unfortunately, the puerperium was complicated by endometritis which was adequately treated using antibiotics. Discussion As stated before, a case of shoulder dystocia has to be approached according to the MOET guidelines using the HELPERR acronym. All conventional methods according to HELPERR were unsuccessful in this case. Before moving on to invasive manoeuvres, we decided to apply the posterior axilla sling traction technique. With this technique a neonatal suction tube is folded and positioned under the posterior axilla of the neonate using your thumb and index finger (figures 1 and 2). With the fingers of the other hand, the suction tube is caught on the other side of the armpit and pulled underneath (figure 3). Then, a sling is formed to which traction is applied (figures 4 and 5). This will lead to the birth of the posterior arm and the rest of the foetus will follow quickly. Figure 1 A neonatal suction tube is folded and hold together using your thumb and index finger. Figure 2 The suction tube is positioned under the posterior axilla of the neonate. Figure 3 With the fingers of the other hand, the suction tube is caught on the other side of the armpit and pulled underneath. Figure 4 Opposite view of figure 3. Figure 5 A sling is formed to which traction is applied.

Figure 1 A neonatal suction tube is folded and hold together using your thumb and index finger. Figure 2 The suction tube is positioned under the posterior axilla of the neonate. Figure 3 With the fingers of the other hand, the suction tube is caught on the other side of the armpit and pulled underneath. Figure 4 Opposite view of figure 3. Figure 5 A sling is formed to which traction is applied. The technique of the posterior axilla sling traction is based on the digital hitching on the posterior axilla of the neonate, described in 2006 by Menticoglou.2 5 The advantage of the sling compared with the digital hitching of the posterior shoulder is the less needed space in the already narrow birth canal. With this technique, the operator can also apply more power due to a good grip on the sling. One can imagine that the use of a sling will also leave less damage to the birth canal compared with using your own hand. Some case reports show the use of arterial forceps to hold the sling together.3 This ensures an even better grip on the sling. In the case report of Taddei et al, where the traction was not successful, the sling was eventually used to rotate the posterior shoulder.4 This option can be considered if traction alone fails to deliver the posterior shoulder. In most cases, a neonatal suction tube is used as sling material.3 4 In the other cases, a Foley catheter was used, which was believed to be too elastic.3

successful, the sling was eventually used to rotate the posterior shoulder.4 This option can be considered if traction alone fails to deliver the posterior shoulder. In most cases, a neonatal suction tube is used as sling material.3 4 In the other cases, a Foley catheter was used, which was believed to be too elastic.3 Cases of severe shoulder dystocia are rare and always emergency situations. It is impossible to evaluate and investigate this technique in large prospective studies. This and other cases show that the posterior axilla sling traction technique is an effective and relatively non-invasive method to resolve a severe shoulder dystocia. A neonatal suction tube is present in all western world neonatal resuscitation rooms. Furthermore, the technique is easily taught and learnt. Therefore, we believe that the posterior axilla sling traction technique must be included in the MOET-course. Thus, when a shoulder dystocia occurs during labour and the manoeuvres according to HELPERR did not resolve in childbirth, the posterior axilla sling technique must be considered before moving on to an invasive manoeuvre. Learning points The posterior axilla sling traction technique is an effective and non-invasive method to resolve a severe shoulder dystocia. This technique is easily taught and learnt by obstetricians and midwives. This technique should be included in all obstetric emergency courses.

Cases of severe shoulder dystocia are rare and always emergency situations. It is impossible to evaluate and investigate this technique in large prospective studies. This and other cases show that the posterior axilla sling traction technique is an effective and relatively non-invasive method to resolve a severe shoulder dystocia. A neonatal suction tube is present in all western world neonatal resuscitation rooms. Furthermore, the technique is easily taught and learnt. Therefore, we believe that the posterior axilla sling traction technique must be included in the MOET-course. Thus, when a shoulder dystocia occurs during labour and the manoeuvres according to HELPERR did not resolve in childbirth, the posterior axilla sling technique must be considered before moving on to an invasive manoeuvre. Learning points The posterior axilla sling traction technique is an effective and non-invasive method to resolve a severe shoulder dystocia. This technique is easily taught and learnt by obstetricians and midwives. This technique should be included in all obstetric emergency courses. Contributors: JH and BV initiated the writing of the manuscript and wrote the manuscript. JH had contact with the patient and kept in contact with the patient. JH and BV contributed equally to writing of the manuscript. DvH supervised the writing and commented multiple times on the manuscript. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared.

Contributors: JH and BV initiated the writing of the manuscript and wrote the manuscript. JH had contact with the patient and kept in contact with the patient. JH and BV contributed equally to writing of the manuscript. DvH supervised the writing and commented multiple times on the manuscript. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Provenance and peer review: Not commissioned; externally peer reviewed. Patient consent for publication: Obtained.

Background The detection of degenerative cervical myelopathy (DCM), particularly early detection, is challenging1 and currently contributes to long average diagnostic delays of 2.2 years2 and poorer response to treatment.3 Patients with textbook descriptions of DCM present with a range of disabling symptoms1 : limb pain, weakness, stiffness and numbness are prevalent; neck stiffness and neck pain, loss of manual dexterity, imbalance, gait problems and falls are commonly reported. Patients also experience bladder and bowel dysfunction. However, recent studies have described the importance of ‘atypical’ symptoms, such as respiratory dysfunction, chest tightness and headaches. For example, one study found that the OR of chest tightness in myelopathy patients compared with controls was 22.9.4 This case provides an example of an unusual presentation of this common disease. It highlights the frustrations faced by patients in reaching a diagnosis, the numerous consultations required and the progression of symptoms in the interim. It serves to reiterate the importance of taking a full history and performing a comprehensive neurological examination in any patient presenting with possible neurological symptoms before diagnosing a disorder as non-organic.

diagnosis, the numerous consultations required and the progression of symptoms in the interim. It serves to reiterate the importance of taking a full history and performing a comprehensive neurological examination in any patient presenting with possible neurological symptoms before diagnosing a disorder as non-organic. Case presentation A 62-year-old woman was referred to our neurosurgical outpatient service with abnormal sensation in her trunk, arms and legs. The patient had a past medical history of a gastric ulcer, a right ankle plating after fracture 20 years ago and a headlice infection 6 months before first presentation. She was a smoker, social drinker of alcohol and was not taking any regular medication. She lived alone and had been struggling to manage independently. Since her symptoms commenced 3 years previously, the patient had presented to emergency department (ED) on 11 occasions. Her primary complaint was of dysaesthetic sensory symptoms including a feeling of water retention and a gel infiltrating the skin of her face, trunk, arms and legs, feeling there was something stuck on her skin and feeling her hair was stuck down. In the weeks before the onset of her symptoms, the patient started using an olive oil moisturising cream, to which she attributed her symptoms. While dermatological examination was conducted, comprehensive neurological examinations were not documented during the first presentations to the ED, which focused on the patient’s facial dysaesthesia.

Since her symptoms commenced 3 years previously, the patient had presented to emergency department (ED) on 11 occasions. Her primary complaint was of dysaesthetic sensory symptoms including a feeling of water retention and a gel infiltrating the skin of her face, trunk, arms and legs, feeling there was something stuck on her skin and feeling her hair was stuck down. In the weeks before the onset of her symptoms, the patient started using an olive oil moisturising cream, to which she attributed her symptoms. While dermatological examination was conducted, comprehensive neurological examinations were not documented during the first presentations to the ED, which focused on the patient’s facial dysaesthesia. The patient was frustrated that her symptoms were repeatedly dismissed as delusional by the ED staff. She refused assessment by liaison psychiatry and mental health review by her general practitioner. The patient was felt to have capacity throughout all consultations. The patient was not taking any psychiatric medications.

patient was frustrated that her symptoms were repeatedly dismissed as delusional by the ED staff. She refused assessment by liaison psychiatry and mental health review by her general practitioner. The patient was felt to have capacity throughout all consultations. The patient was not taking any psychiatric medications. Over time her symptoms progressed. She started to complain of back pain, multiple falls and episodes of her right leg giving way which had progressed to severely compromised walking and coordination. The patient also complained of episodes of urinary and faecal incontinence. This led to a lumbar MRI which ruled out cauda equina syndrome. In her final presentation before referral, she also complained of stiff legs, difficulty walking, difficulty passing urine, reduced manual dexterity and neck pain. A neurology assessment was finally sought and an MRI for suspected myelopathy was organised. On presentation to our neurosurgical clinic, the patient’s complaint remained sensory dysaesthesia from her neck down, particularly affecting her hands and groins. She complained of her body feeling like a ‘wet gel-like substance’. In addition to the above symptoms, the patient also complained of a 3-year medical history of numbness and tingling in her upper limbs.

e patient’s complaint remained sensory dysaesthesia from her neck down, particularly affecting her hands and groins. She complained of her body feeling like a ‘wet gel-like substance’. In addition to the above symptoms, the patient also complained of a 3-year medical history of numbness and tingling in her upper limbs. On examination in the neurosurgical clinic, the patient had hyperaesthesia from the neck down, most prominent in the hands and groins. The patient had reduced grip strength of 3/5, finger extension and abduction of 3/5, wrist flexion and extension of 3/5, elbow flexion of 4+/5, elbow extension of 4/5 and shoulder abduction of 4+/5 on the Medical Research Council power scale. Hip flexion was 3/5, with all other muscle groups in the lower limb at 4+/5. The patient had very brisk reflexes with pathological spreading in the upper and lower limbs. There was self-limiting clonus in the ankle bilaterally. Hoffmann’s and Babinski reflexes were positive bilaterally. There was a severe loss of coordination and balance. Gait was impaired; the patient required a frame to mobilise. The severity of the patient’s cervical myelopathy was scored as 1 (upper limb motor dysfunction) +3 (lower limb motor dysfunction) +1 (upper limb sensory dysfunction) +1 (sphincter dysfunction) =6 (severe myelopathy) on the modified Japanese Orthopaedic Association scale (mJOA).

he patient required a frame to mobilise. The severity of the patient’s cervical myelopathy was scored as 1 (upper limb motor dysfunction) +3 (lower limb motor dysfunction) +1 (upper limb sensory dysfunction) +1 (sphincter dysfunction) =6 (severe myelopathy) on the modified Japanese Orthopaedic Association scale (mJOA). Investigations The patient underwent MRI imaging and was found to have multilevel degenerative changes of the cervical spine. At C3/4 there was a broad-based disc osteophyte protrusion causing compression of the spinal cord with T2 hyperintense signal changes within the cord. At C5/6, there was a broad-based disc osteophyte protrusion with mild narrowing of the C6 neural foramina (figure 1). Figure 1 Sagittal MRI of cervical spine. Differential diagnosis In addition to DCM, the case highlights a variety of differentials:Delusional disorder. Trichotillomania. Cauda equina syndrome. A possible differential was that the patient’s sensory symptoms were independent of her myelopathy and the result of a sensory delusional disorder. Alternatively, comorbid mild psychiatric illness could have caused the patient to interpret her myelopathic symptoms in an unusual way.

Differential diagnosis In addition to DCM, the case highlights a variety of differentials:Delusional disorder. Trichotillomania. Cauda equina syndrome. A possible differential was that the patient’s sensory symptoms were independent of her myelopathy and the result of a sensory delusional disorder. Alternatively, comorbid mild psychiatric illness could have caused the patient to interpret her myelopathic symptoms in an unusual way. However, there was no history of formally-diagnosed psychiatric illness or evidence of previous complaints of psychiatric aetiology in this 62-year-old patient. In fact, the patient had a strong conviction that the onset of symptoms around the time of her change in moistening cream was not coincidental and was frustrated that her ideas were being dismissed as psychological by some health professionals. Her anger at these suggestions were further interpreted as being evidence of an underlying psychological condition. Treatment The patient was found to be suffering from severe cervical myelopathy which required expedited surgical decompression. She underwent anterior cervical discectomy at C3/4.

However, there was no history of formally-diagnosed psychiatric illness or evidence of previous complaints of psychiatric aetiology in this 62-year-old patient. In fact, the patient had a strong conviction that the onset of symptoms around the time of her change in moistening cream was not coincidental and was frustrated that her ideas were being dismissed as psychological by some health professionals. Her anger at these suggestions were further interpreted as being evidence of an underlying psychological condition. Treatment The patient was found to be suffering from severe cervical myelopathy which required expedited surgical decompression. She underwent anterior cervical discectomy at C3/4. Outcome and follow-up The patient was recovering well on review 3 months post-surgery. Cervical spine radiographs demonstrated appropriate position of her spinal implants. Her wound had healed well. She reported reduced sensory problems and reduced paraesthesia in her fingers. On examination, compared with pre-surgery power, grip strength had improved to 4+/5, wrist flexion and extension had improved to 4/5 and elbow flexion, extension and shoulder abduction had improved to 5/5. Finger extension and abduction remained 3/5. Power had improved to 5/5 in all muscle groups in the patient’s lower limbs. The remainder of the examination was unchanged.

trength had improved to 4+/5, wrist flexion and extension had improved to 4/5 and elbow flexion, extension and shoulder abduction had improved to 5/5. Finger extension and abduction remained 3/5. Power had improved to 5/5 in all muscle groups in the patient’s lower limbs. The remainder of the examination was unchanged. In addition, at 9 months the patient had an improved mJOA of 10 (3+3+2+2) and she reported improved manual dexterity, improved walking, improved bladder function and resolution of incontinence. The dysaesthesia affecting her body was still present, although reduced. Full recovery is unexpected following surgery for DCM, with current evidence suggesting that surgery is highly effective in halting disease progression but has limited benefit in reversing neurological damage already present.3 Thus, the incomplete resolution of her dysaesthetic sensory symptoms is not unexpected. Discussion DCM is defined as symptomatic spinal cord compression secondary to degenerative changes in the cervical spine.5 It is common with a prevalence of up to 5% in the over 40s,1 which is expected to rise as populations age.4 5 However, most patients never get a diagnosis,6 7 and those that do face long diagnostic delays, often with initial misdiagnosis.2 This is significant given that surgery is the only currently-effective treatment but cannot reverse existing damage.3 8 9

% in the over 40s,1 which is expected to rise as populations age.4 5 However, most patients never get a diagnosis,6 7 and those that do face long diagnostic delays, often with initial misdiagnosis.2 This is significant given that surgery is the only currently-effective treatment but cannot reverse existing damage.3 8 9 Misdiagnosis and diagnostic delay are key problems in DCM. As in this case, patients often consult many times and wait years for accurate diagnosis.2 The reasons for this are unclear, but likely include a poor awareness of DCM among non-specialist health professionals,1 subtle non-specific early symptoms10 and poor current understanding of the most common symptoms and natural history.11 Substantial diagnostic delays in the context of the progressive nature of DCM is a likely key factor behind DCM having patient quality of life scores among the worst of any chronic disease.12 Sensory dysaesthesia is defined as abnormal sensation. The involvement of all four limbs in our patient is consistent with a myelopathic aetiology, however we are unaware of previous reports of such widespread sensory dysaesthesia in DCM. Nonetheless, unusual sensory presentations of other common neurological diseases, such as Guillain–Barré syndrome,13 have been reported.

The involvement of all four limbs in our patient is consistent with a myelopathic aetiology, however we are unaware of previous reports of such widespread sensory dysaesthesia in DCM. Nonetheless, unusual sensory presentations of other common neurological diseases, such as Guillain–Barré syndrome,13 have been reported. While facial sensory dysaesthesia would be unexpected secondary to spinal pathology, recent studies report structural and functional changes rostral to the compressive lesion in DCM.14 15 For example, one recent study reported a correlation between depression and activity in the anterior cingulate cortex (ACC) in DCM patients16; spinal decompressive surgery alleviated depression and diminished activity in the ACC. While the precise mechanism remains to be elucidated, cortical reorganisation secondary to reduced efficiency of signal transduction through the compressed segments of spine is plausible. Cortical reorganisation is thus a possible explanation for the facial component of the patient’s dysaesthesia. Unfortunately, eccentric interpretation of aberrant sensation secondary to myelopathy was misinterpreted by health professionals as delusional. At no point in the 11 consultations by doctors ranging from foundation year to consultant level was myelopathy documented as a differential diagnosis. Given that the patient’s myelopathy was severe at time of eventual diagnosis and in the absence of other pathology, it is likely myelopathy was causing the dysaesthetic symptom onset 3 years previously.

ns by doctors ranging from foundation year to consultant level was myelopathy documented as a differential diagnosis. Given that the patient’s myelopathy was severe at time of eventual diagnosis and in the absence of other pathology, it is likely myelopathy was causing the dysaesthetic symptom onset 3 years previously. In conclusion, this case illustrates a novel and unusual example of a common scenario for DCM patients: multiple consultations, diagnostic delay, symptom progression, greater disability and poorer response to surgery after eventual diagnosis. To address these issues, a high index of suspicion, an awareness of the progressive nature of DCM and a comprehensive neurological assessment in any patient with neurological symptoms in the hands and legs are required. Learning points Degenerative cervical myelopathy (DCM) is a common neurological syndrome. DCM is progressive, typically affecting patients over 40 years old, although younger presentations are possible. DCM can present with a range of typical symptoms and should be considered in patients presenting with any neurological symptoms in their limbs or neck. Awareness, a high index of suspicion, comprehensive neurological assessment and a low threshold for obtaining a cervical MRI are required for early diagnosis.

DCM is progressive, typically affecting patients over 40 years old, although younger presentations are possible. DCM can present with a range of typical symptoms and should be considered in patients presenting with any neurological symptoms in their limbs or neck. Awareness, a high index of suspicion, comprehensive neurological assessment and a low threshold for obtaining a cervical MRI are required for early diagnosis. Contributors: ODM, BMD and MRK were involved in conception, planning and design of the manuscript; were involved in redrafting the manuscript, data analysis and interpretation of the data; approved submission of the final version of the manuscript. ODM wrote the first draft and acquired the data presented in the manuscript from electronic hospital records. Funding: Research in the senior author’s laboratory is supported by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. MRNK is supported by a NIHR Clinician Scientist Award. This report is independent research arising from a Clinician Scientist Award (CS-2015-15-023) supported by the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. Competing interests: MRN reports grants from National Institute of Health Research, travel cost grant from AOSpine and is founder and trustee of Myelopathy.org, the first charity dedicated to degenerative cervical myelopathy.

Funding: Research in the senior author’s laboratory is supported by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. MRNK is supported by a NIHR Clinician Scientist Award. This report is independent research arising from a Clinician Scientist Award (CS-2015-15-023) supported by the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. Competing interests: MRN reports grants from National Institute of Health Research, travel cost grant from AOSpine and is founder and trustee of Myelopathy.org, the first charity dedicated to degenerative cervical myelopathy. Provenance and peer review: Not commissioned; externally peer reviewed. Patient consent for publication: Obtained.

Background Myositis ossificans (MO) is a non-neoplastic heterotopic ossification that develops within skeletal muscle or soft tissue. The exact pathophysiological pathway of this rare disease is still not fully understood. It is believed that, in response to tissue injury and subsequent inflammation, stem cells are dysregulated and stimulated to follow osteogenic pathways, resulting in ossification.1 The disorder can be differentiated into four subtypes: (1) MO traumatica; (2) MO progressiva (hereditary form); (3) MO associated with paraplegia and (4) MO associated with burns.2 3 Myositis ossificans traumatica (MOT) is the most common type and accounts for 60%–75% of all cases.4 5 MOT usually occurs in the girdles and limbs of active young men after major or repeated minor trauma. The brachialis, quadriceps and adductor group muscles are more prone to MOT according to the literature.6 7 MOT can be mistaken for malignant lesions such as osteosarcoma or rhabdomyosarcoma. Therefore, appropriate diagnostic tests are of paramount importance. However, the stage of the disease affects its presentation and might lead to difficulties in the interpretation of radiological and histological findings.8 9

Background Myositis ossificans (MO) is a non-neoplastic heterotopic ossification that develops within skeletal muscle or soft tissue. The exact pathophysiological pathway of this rare disease is still not fully understood. It is believed that, in response to tissue injury and subsequent inflammation, stem cells are dysregulated and stimulated to follow osteogenic pathways, resulting in ossification.1 The disorder can be differentiated into four subtypes: (1) MO traumatica; (2) MO progressiva (hereditary form); (3) MO associated with paraplegia and (4) MO associated with burns.2 3 Myositis ossificans traumatica (MOT) is the most common type and accounts for 60%–75% of all cases.4 5 MOT usually occurs in the girdles and limbs of active young men after major or repeated minor trauma. The brachialis, quadriceps and adductor group muscles are more prone to MOT according to the literature.6 7 MOT can be mistaken for malignant lesions such as osteosarcoma or rhabdomyosarcoma. Therefore, appropriate diagnostic tests are of paramount importance. However, the stage of the disease affects its presentation and might lead to difficulties in the interpretation of radiological and histological findings.8 9 As MOT is self-limiting and self-resolving in most cases, conservative treatment with rest, adequate pain relief, and restoring function and range of motion is often effective for returning to sports and activities.8 10 Other non-surgical options include aspirating hematomas, non-steroidal anti-inflammatory drugs (NSAIDs) and extracorporeal shockwave therapy (ESWT). Surgical intervention should be considered when the consolidated mass persists and causes symptoms.11

motion is often effective for returning to sports and activities.8 10 Other non-surgical options include aspirating hematomas, non-steroidal anti-inflammatory drugs (NSAIDs) and extracorporeal shockwave therapy (ESWT). Surgical intervention should be considered when the consolidated mass persists and causes symptoms.11 We present the first reported case of MOT of the adductor longus muscle in a football player, which was treated successfully with surgical excision. Case presentation A 23-year-old male football player, without any relevant medical history, was referred by the general practitioner to our outpatient clinic with complaints of the right groin. One year earlier, during intensive training, the patient felt acute intense pain in the right groin twice when kicking the ball. After training, he felt swelling and pain in the right adductor region. After a period of rest, physiotherapy was started. Low-intensity exercises were gradually performed and he started cycling. He tried to resume his football training sessions. Unfortunately, the pain in his groin recurred. He repeated physical rehabilitation from the beginning three times. However, the intensity of the pain increased over time and began to also limit his activities of daily living.

gradually performed and he started cycling. He tried to resume his football training sessions. Unfortunately, the pain in his groin recurred. He repeated physical rehabilitation from the beginning three times. However, the intensity of the pain increased over time and began to also limit his activities of daily living. On physical examination, palpation of the origin of the adductor muscles at the right pubic bone was painful and revealed a small gap in the tendon located just distal to the insertion. Distal to the gap, a very firm mass of about 7 cm long and 1 cm wide could be palpated. It felt as if a short pencil was lying under the skin. Palpation of the mass was extremely painful. The right adductor muscle was shortened and resisted adductor muscle strength testing was weak and painful. Further examination showed no signs of nerve entrapment with normal sensation of the skin. Clinical examination of the hip joint range of motion was pain free. Investigations Ultrasound imaging showed an old rupture of the right adductor longus muscle with a small fluid collection located proximally. Distally, a calcification of 8 cm was seen, indicating a chronic disease process with signs of active inflammation. An X-ray clearly showed a heterotopic ossification of the right adductor longus muscle (figure 1). Figure 1 Pelvic X-ray showing calcification in the adductor region.

Investigations Ultrasound imaging showed an old rupture of the right adductor longus muscle with a small fluid collection located proximally. Distally, a calcification of 8 cm was seen, indicating a chronic disease process with signs of active inflammation. An X-ray clearly showed a heterotopic ossification of the right adductor longus muscle (figure 1). Figure 1 Pelvic X-ray showing calcification in the adductor region. Differential diagnosis The differential diagnosis of MOT includes benign and malignant diseases. Benign diseases that may be confused with MOT are local abscess formation, a calcified fibrous tumour and periosteal reaction, whereas osteosarcoma and rhabdomyosarcoma are important malignant diseases to consider.9 In the present case, it was possible to distinguish MOT from all these other diagnoses through the combination of the specific history of a sports trauma, the physical examination, combined with both ultrasound and X-ray imaging. Treatment Surgical excision of the MOT was performed. Incision was made in the direction of Langer’s lines at the level of the palpable mass. Subsequently, the great saphenous vein was ligated. After identification of the mass, it was peeled off the adductor longus muscle in one piece (figures 2 and 3). The muscle belly and adductor longus fascia were sutured with Vicryl and the skin was closed intracutaneously with Monocryl. Figure 2 Peroperative photo of resected ossified mass of the right adductor longus muscle. Figure 3 Resected ossification along surgical instruments.

Treatment Surgical excision of the MOT was performed. Incision was made in the direction of Langer’s lines at the level of the palpable mass. Subsequently, the great saphenous vein was ligated. After identification of the mass, it was peeled off the adductor longus muscle in one piece (figures 2 and 3). The muscle belly and adductor longus fascia were sutured with Vicryl and the skin was closed intracutaneously with Monocryl. Figure 2 Peroperative photo of resected ossified mass of the right adductor longus muscle. Figure 3 Resected ossification along surgical instruments. Outcome and follow-up Histopathological analysis showed a round nodulus consisting of bone tissue with bone trabeculae surrounded with osteoblast cells. No typical zones could be recognised and the centre of the nodulus did not contain any cells. At 3 months of follow-up, the patient was free of symptoms and followed the rehabilitation programme at his local football club. Exercises were intensified using weights, as well as with cycling, running and resuming light training sessions. No abnormalities were found on physical examination of the adductors on palpation, stretching and resistance testing. Dynamometry showed adductor strength of 157 N on the right (R) and of 177 N on the left (L), add abductor strength as this is needed to calculate with adductor/abductor ratio of 1.03 R and 1.32 L.

ions. No abnormalities were found on physical examination of the adductors on palpation, stretching and resistance testing. Dynamometry showed adductor strength of 157 N on the right (R) and of 177 N on the left (L), add abductor strength as this is needed to calculate with adductor/abductor ratio of 1.03 R and 1.32 L. At 5 months of follow-up, the patient, although not at full intensity, participated in football training sessions three times a week. Dynamometry showed adductor strength R of 181 N and L of 176 N, with adductor/abductor ratio of 1.16 R and 1.17 L. After 7 months, the patient was fully recovered and participated in football matches without any pain. Dynamometry showed adductor strength R of 213 N and L of 190 N, with adductor/abductor ratio of 1.20 R and 1.10 L. All dynamometry outcomes collected during the follow-up period are presented in table 1 and figure 4. Table 1 Follow-up dynamometry outcomes Dynamotry (in N) Adductor muscles Abductor muscles Adductor/abductor ratio Follow-up postoperative Right Left Right Left Right Left 3 Months 157 177 152 134 1.03 1.32 5 Months 181 176 156 151 1.16 1.17 7 Months 213 190 178 173 1.20 1.10 Figure 4 Follow-up adductor/abductor ratio.

After 7 months, the patient was fully recovered and participated in football matches without any pain. Dynamometry showed adductor strength R of 213 N and L of 190 N, with adductor/abductor ratio of 1.20 R and 1.10 L. All dynamometry outcomes collected during the follow-up period are presented in table 1 and figure 4. Table 1 Follow-up dynamometry outcomes Dynamotry (in N) Adductor muscles Abductor muscles Adductor/abductor ratio Follow-up postoperative Right Left Right Left Right Left 3 Months 157 177 152 134 1.03 1.32 5 Months 181 176 156 151 1.16 1.17 7 Months 213 190 178 173 1.20 1.10 Figure 4 Follow-up adductor/abductor ratio. Discussion MOT of the adductor muscles in athletes has been described previously.11–13 However, to the best of our knowledge, this is the first case reported in the literature of MOT of the adductor longus muscle. In football players, MOT is often the result of direct contusion of the adductor muscles or eccentric muscle overload that leads to an acute muscle/tendon injury.11 The latter was the trauma mechanism in the present case. Muscle tears can cause intermuscular and intramuscular hematoma formation, which is known to be an important event in the cascade of MOT.6 To minimise hematoma formation at the injury site, first aid following the rest, ice, compression and elevation principle is recommended.14 In this case, it is not clear whether the patient has followed this therapy sufficiently to prevent the development of MOT. Local inflammation and macrophage accumulation are also crucial steps in the cascade of heterotopic ossification formation, stimulating osteogenic factors, including bone morphogenetic proteins.1 Hence, NSAID is proposed to prevent MOT in an early phase.15 On the other hand, NSAIDs block the cyclooxygenase-2 pathway which is an essential pathway for skeletal muscle repair and muscle growth.16 17 The effect of the preventive use of NSAIDs in the early phase of MOT is controversial and warrants further investigation. In this case, NSAIDs were prescribed in the late phase as they had not yet been used and we felt it was worth trying both to reduce the pain and to try and prevent further formation. We also considered starting with ESWT. Due to the relatively large size of the calcification, we expected that the ESWT would take many sessions and be very painful. After discussing this with the patient, he decided not to try this.

it was worth trying both to reduce the pain and to try and prevent further formation. We also considered starting with ESWT. Due to the relatively large size of the calcification, we expected that the ESWT would take many sessions and be very painful. After discussing this with the patient, he decided not to try this. Surgical excision of MOT can be considered when pain persists, if muscle weakness is present, or in case of a limited range of motion.10 It is crucial that surgical excision of MOT is planned to take place at least 6 months after the initial trauma, when the ossification is fully matured.11 Excision of immature ossifications often leads to local recurrence.6 Our patient met all the above-mentioned conditions for surgical excision: increased pain, functional impairment and failure to resume sport activities for over 1 year. Imaging can be useful to diagnose MOT correctly. Especially when considering that malignant diseases such as osteosarcoma and rhabdomyosarcoma can have similar clinical presentations.9 Still, the different imaging modalities have to be interpreted with caution, since radiological findings depend on the stage of the disease.8 9 In combination with a thorough patient history and physical examination, MOT can be distinguished adequately from other diseases. Both Devilbiss et al 8 and Li et al 18 provide a clear overview of specific characteristics of MO which could be helpful to differentiate between diagnoses.

d on the stage of the disease.8 9 In combination with a thorough patient history and physical examination, MOT can be distinguished adequately from other diseases. Both Devilbiss et al 8 and Li et al 18 provide a clear overview of specific characteristics of MO which could be helpful to differentiate between diagnoses. Guideline recommendations on return to sports for athletes with MO treated conservatively are lacking, let alone for athletes after surgical excision. Orava et al 11 allowed athletes to return to sports 4–6 weeks after surgical excision of MOT. For athletes with persisting symptoms and those who did not fulfil the return to sport criteria, this period was extended for up to another month. In their series, 30 of the 32 athletes were able to resume preinjury Tegner activity levels.11 In our case, we decided to refer the patient to the well-known physiotherapists of the local football club for postoperative rehabilitation, closely following up the patient with outpatient visits at 4 weeks, 3 months, 5 months and 7 months. Seven months postoperatively, the patient had returned to preinjury activity levels and resumed football matches. To the best of our knowledge, this is the first case of MOT of the adductor longus muscle described in the literature. This case emphasises that surgical excision of MOT of the adductor longus muscle can be an effective option when conservative treatment options have failed.

Guideline recommendations on return to sports for athletes with MO treated conservatively are lacking, let alone for athletes after surgical excision. Orava et al 11 allowed athletes to return to sports 4–6 weeks after surgical excision of MOT. For athletes with persisting symptoms and those who did not fulfil the return to sport criteria, this period was extended for up to another month. In their series, 30 of the 32 athletes were able to resume preinjury Tegner activity levels.11 In our case, we decided to refer the patient to the well-known physiotherapists of the local football club for postoperative rehabilitation, closely following up the patient with outpatient visits at 4 weeks, 3 months, 5 months and 7 months. Seven months postoperatively, the patient had returned to preinjury activity levels and resumed football matches. To the best of our knowledge, this is the first case of MOT of the adductor longus muscle described in the literature. This case emphasises that surgical excision of MOT of the adductor longus muscle can be an effective option when conservative treatment options have failed. Patient’s perspective After the last follow-up moment, we asked the patient to describe the clinical process, including the surgical treatment on his perspective. He described this as follows: at first, I was a bit shocked when I was told that MOT of the adductor longus muscle is a rare disease and that it was never seen by the sports doctor. At the same time, I trusted the sports doctor, thanks to his open and professional approach. I was informed about the potential risk in losing some of the muscle strength of my right leg when choosing to undergo surgery. However, surgery was the obvious choice for me because the MOT affected my activities of daily living. After surgery, the pain was slightly worse than before but this reduced quickly and I could resume my activities of daily living. Furthermore, due to the close follow-up and the rehabilitation programme, I experience no (pain) complaints anymore during football and I am able to fully participate in football matches. I am very satisfied with the treatment and the end result.

ut this reduced quickly and I could resume my activities of daily living. Furthermore, due to the close follow-up and the rehabilitation programme, I experience no (pain) complaints anymore during football and I am able to fully participate in football matches. I am very satisfied with the treatment and the end result. Learning points Myositis ossificans traumatica (MOT) of the adductor muscles is extremely rare. Immediate treatment of a skeletal muscle injury with the rest, ice, compression and elevation principle might help in the prevention of MOT. Surgical excision of MOT of the adductor longus muscle is a good option when conservative treatments fail. Contributors: All authors contributed to the preparation of this manuscript. SEB and AW both were involved in the management of the patient and provided data to GHJdS. GHJdS wrote the main case report manuscript and researched previous literature to include in the case report. SEB and AW revised the manuscript critically. All authors approved the final version of the manuscript. Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Competing interests: None declared. Patient consent for publication: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Introduction A case report is a detailed narrative that describes, for medical, scientific, or educational purposes, a medical problem experienced by one or several patients. Case reports present clinical observations customarily collected in healthcare delivery settings. They have proved helpful in the identification of adverse and beneficial effects, the recognition of new diseases, unusual forms of common diseases and the presentation of rare diseases.1 For example, our understanding of the relationship between thalidomide and congenital abnormalities2 and the use of propranolol for the treatment of infantile haemangiomas began with case reports.3 Case reports may generate hypotheses for future clinical studies, prove useful in the evaluation of global convergences of systems-oriented approaches and guide the individualisation and personalisation of treatments in clinical practice.4 5 Furthermore, case reports offer a structure for case-based learning in healthcare education and may facilitate the comparison of healthcare education and delivery across cultures.

lobal convergences of systems-oriented approaches and guide the individualisation and personalisation of treatments in clinical practice.4 5 Furthermore, case reports offer a structure for case-based learning in healthcare education and may facilitate the comparison of healthcare education and delivery across cultures. Case reports are common and account for a growing number of articles in medical journals6; however, their quality is uneven.7 8 For example, one study evaluated 1316 case reports from four peer-reviewed emergency-medicine journals and found that more than half failed to provide information related to the primary treatment that would have increased transparency and replication.9 Written without the benefit of reporting guidelines, case reports often are insufficiently rigorous to be aggregated for data analysis, inform research design or guide clinical practice.7 9

than half failed to provide information related to the primary treatment that would have increased transparency and replication.9 Written without the benefit of reporting guidelines, case reports often are insufficiently rigorous to be aggregated for data analysis, inform research design or guide clinical practice.7 9 Reporting guidelines exist for a variety of study designs including randomised controlled trials (Consolidated Standards of Reporting Trials, CONSORT),10 observational studies (Strengthening the Reporting of Observational studies in Epidemiology, STROBE)11 and systematic reviews and meta-analyses (Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA).12 Empirical evidence suggests that a journal's adoption of the CONSORT statement as a guide to authors is associated with an increase in the completeness of published randomised trials.13 Guidelines have been developed for adverse-event case reports14; however, general reporting guidelines for case reports do not exist. Our primary objective was to develop reporting guidelines for case reports through a consensus-based process. Methods Research design We followed the Guidance for Developers of Health Research Reporting Guidelines15 and developed a three-phase consensus process.16 This consisted of (1) a premeeting literature review followed by interviews to generate items for a case report checklist, (2) a face-to-face consensus meeting for drafting a reporting guideline and (3) postmeeting feedback and pilot testing followed by finalisation of the case report guidelines.

e consensus process.16 This consisted of (1) a premeeting literature review followed by interviews to generate items for a case report checklist, (2) a face-to-face consensus meeting for drafting a reporting guideline and (3) postmeeting feedback and pilot testing followed by finalisation of the case report guidelines. Participants We contacted 28 individuals who fulfilled at least one of the four criteria17–19 (1) publication of articles related to case reports; (2) publication of a manual, handbook or method guidelines related to case reports; (3) publication of a systematic review of methods or reporting related to case reports and (4) publication of other reporting guidelines for clinical research. Consensus process Phase I: Four of the authors, the steering committee (JG, GK, DM and DR), searched the literature for publications on the role of case reports, recommendations for their publication and surveys on reporting quality. A letter was sent to 28 potential participants explaining the purpose of the meeting, details of the consensus technique, and requesting their participation in generating specific recommendations for case reporting. Twenty-seven people agreed to participate and were scheduled for a telephone interview and sent a selection of key articles on case reports. During the telephone interview, participants were asked (1) what information was required to be included in case-reporting guidelines, (2) the rationale for their suggestions and (3) for references that supported their reasoning.

scheduled for a telephone interview and sent a selection of key articles on case reports. During the telephone interview, participants were asked (1) what information was required to be included in case-reporting guidelines, (2) the rationale for their suggestions and (3) for references that supported their reasoning. Three of the authors (JG, GK and DR) grouped the recommendations from the literature search and interviews by theme together with their rationale, references and operational definitions. No quantitative scoring was performed. Phase II: The face-to-face consensus meeting at the University of Michigan in Ann Arbor (October 2012) included 18 participants from phase I, one research assistant and two student observers. The meeting began with a review of the blinded recommendations elicited during the phase I interviews, in whole group and small group sessions. On the second day, open discussion of each potential item continued, during which clarifications, opinions, justifications, operational definitions and new ideas were expressed. By the end of the second day, the group had agreed upon a set of preliminary reporting recommendations. Phase III: The draft checklist was refined by the steering committee and sent for two rounds of review to the complete group (phases I and II participants). The finalised reporting guidelines incorporated the feedback from the entire CARE group.

Phase II: The face-to-face consensus meeting at the University of Michigan in Ann Arbor (October 2012) included 18 participants from phase I, one research assistant and two student observers. The meeting began with a review of the blinded recommendations elicited during the phase I interviews, in whole group and small group sessions. On the second day, open discussion of each potential item continued, during which clarifications, opinions, justifications, operational definitions and new ideas were expressed. By the end of the second day, the group had agreed upon a set of preliminary reporting recommendations. Phase III: The draft checklist was refined by the steering committee and sent for two rounds of review to the complete group (phases I and II participants). The finalised reporting guidelines incorporated the feedback from the entire CARE group. Results The CAse REport (CARE) guidelines checklist is structured to correspond with key components of a case report and capture useful clinical information (including ‘meaningful use’ information mandated by some insurance plans). The checklist begins with a statement that describes the narrative of a case report. The meeting CARE group felt that a case report should tell a story using prose that has a consistent style across all sections, including the rationale for any conclusions and take-away messages.

Results The CAse REport (CARE) guidelines checklist is structured to correspond with key components of a case report and capture useful clinical information (including ‘meaningful use’ information mandated by some insurance plans). The checklist begins with a statement that describes the narrative of a case report. The meeting CARE group felt that a case report should tell a story using prose that has a consistent style across all sections, including the rationale for any conclusions and take-away messages. We recommend a timeline (item 7) in the form of a table or figure that gives the specific dates and times of important components of the case. This might include family and medical history, genetic information, current symptoms, diagnostic test results, interventions and events that occurred during follow-up. The timeline should show how the key events of the case unfolded. We created separate checklist items for diagnostic assessments (item 8) and therapeutic interventions (item 9) with the recognition that both items will often be relevant in a case report. The group discussed at length whether to include the patient's perspective on his or her experience. In the end, we advocated for patient-reported outcomes and experiences whenever possible (item 12). There was also discussion about the need for guidelines for patient-reported outcomes of their care. In a similar vein, a recent extension of the CONSORT statement was published for patient-reported outcomes in randomised trials; CONSORT-PRO.20

for patient-reported outcomes and experiences whenever possible (item 12). There was also discussion about the need for guidelines for patient-reported outcomes of their care. In a similar vein, a recent extension of the CONSORT statement was published for patient-reported outcomes in randomised trials; CONSORT-PRO.20 Finally, we included an item on informed consent (item 13). We believe that authors have an ethical duty to obtain informed consent from the patient to publish patient information in a case report. Consent becomes informed when the patient or a relative reads the case report and approves its contents. If the patient cannot give consent and attempts to find a relative to give proxy consent have failed, the authors should seek permission to publish from an institutional committee. There may be other circumstances where an ethics committee or Institutional Review Board (IRB) approval may be necessary. The CARE guidelines are shown in the following table 1. Table 1 The CARE guidelines checklist

Finally, we included an item on informed consent (item 13). We believe that authors have an ethical duty to obtain informed consent from the patient to publish patient information in a case report. Consent becomes informed when the patient or a relative reads the case report and approves its contents. If the patient cannot give consent and attempts to find a relative to give proxy consent have failed, the authors should seek permission to publish from an institutional committee. There may be other circumstances where an ethics committee or Institutional Review Board (IRB) approval may be necessary. The CARE guidelines are shown in the following table 1. Table 1 The CARE guidelines checklist The narrative: A case report tells a story in a narrative format that includes the presenting concerns, clinical findings, diagnoses, interventions, outcomes (including adverse events) and follow-up. The narrative should include a discussion of the rationale for any conclusions and any take-away messages. Item name Item no. Brief description Title 1 The words ‘case report’ (or ‘case study’) should appear in the title along with phenomenon of greatest interest (eg, symptom, diagnosis, test, intervention) Keywords 2 The key elements of this case in 2–5 words Abstract 3 a) Introduction—What does this case add? b) Case Presentation: – The main symptoms of the patient – The main clinical findings – The main diagnoses and interventions – The main outcomes c) Conclusion—What were the main ‘take-away’ lessons from this case?

The narrative: A case report tells a story in a narrative format that includes the presenting concerns, clinical findings, diagnoses, interventions, outcomes (including adverse events) and follow-up. The narrative should include a discussion of the rationale for any conclusions and any take-away messages. Item name Item no. Brief description Title 1 The words ‘case report’ (or ‘case study’) should appear in the title along with phenomenon of greatest interest (eg, symptom, diagnosis, test, intervention) Keywords 2 The key elements of this case in 2–5 words Abstract 3 a) Introduction—What does this case add? b) Case Presentation: – The main symptoms of the patient – The main clinical findings – The main diagnoses and interventions – The main outcomes c) Conclusion—What were the main ‘take-away’ lessons from this case? Introduction 4  Brief background summary of this case referencing the relevant medical literature Patient information 5 a) Demographic information (eg, age, gender, ethnicity, occupation) b) Main symptoms of the patient (his or her chief symptoms) c) Medical, family, and psychosocial history—including diet, lifestyle, and genetic information whenever possible, and details about relevant comorbidities including past interventions and their outcomes Clinical findings 6  Describe the relevant physical examination (PE) findings Timeline 7  Depict important dates and times in this case (table or figure). Diagnostic assessment 8 a) Diagnostic methods (eg, PE, laboratory testing, imaging, questionnaires) b) Diagnostic challenges (eg, financial, language/cultural)

c) Medical, family, and psychosocial history—including diet, lifestyle, and genetic information whenever possible, and details about relevant comorbidities including past interventions and their outcomes Clinical findings 6  Describe the relevant physical examination (PE) findings Timeline 7  Depict important dates and times in this case (table or figure). Diagnostic assessment 8 a) Diagnostic methods (eg, PE, laboratory testing, imaging, questionnaires) b) Diagnostic challenges (eg, financial, language/cultural) c) Diagnostic reasoning including other diagnoses considered d) Prognostic characteristics (eg, staging) where applicable Therapeutic intervention 9 a) Types of intervention (eg, pharmacologic, surgical, preventive, self-care) – Administration of intervention (eg, dosage, strength, duration) – Changes in intervention (with rationale) Follow-up and outcomes 10 a) Summarise the clinical course of all follow-up visits including – Clinician and patient-assessed outcomes – Important follow-up test results (positive or negative) – Intervention adherence and tolerability (and how this was assessed) – Adverse and unanticipated events Discussion 11 a) The strengths and limitations of the management of this case b) The relevant medical literature c) The rationale for conclusions (including assessments of cause and effect) d) The main ‘take-away’ lessons of this case report

– Intervention adherence and tolerability (and how this was assessed) – Adverse and unanticipated events Discussion 11 a) The strengths and limitations of the management of this case b) The relevant medical literature c) The rationale for conclusions (including assessments of cause and effect) d) The main ‘take-away’ lessons of this case report Patient perspective 12  The patient should share his or her perspective or experience whenever possible Informed consent 13  Did the patient give informed consent? Please provide if requested Discussion This 13-item checklist provides a framework to satisfy the need for completeness and transparency for published case reports. We attempted to strike a balance between adequate detail and the concise writing that is one of the appealing characteristics of a case report. Our consensus process resulted in a set of essential items for authors to consider when submitting a case report for publication. While case reports have long been an important source of new ideas and information in medicine,21 it appears that case reports are likely to begin to play a role in the discovery of what works and for whom. BioMed Central launched the Journal of Medical Case Reports in 200722 and a Cases Database in 2012 with more than 11 000 published case reports from 50 medical journals. In 6 months, it has grown to more than 26 000 case reports from 212 medical journals.23 The CARE guidelines checklist is part of a growing effort to improve the reporting of case reports.

f Medical Case Reports in 200722 and a Cases Database in 2012 with more than 11 000 published case reports from 50 medical journals. In 6 months, it has grown to more than 26 000 case reports from 212 medical journals.23 The CARE guidelines checklist is part of a growing effort to improve the reporting of case reports. There is substantial empirical evidence that reporting guidelines improve the completeness of published scientific reports.13 24 25 A recent Cochrane review examining the influence of journal endorsement of the CONSORT statement on reporting included 53 publications assessing 16 604 randomised controlled trials and found that CONSORT-endorsing journals consistently have better overall reporting.13 However, the potential impact of the CONSORT statement and related reporting guidelines has not been fully realised. A study examining the instructions to peer reviewers of 116 health research journals found that only 41 (35%) provided online instructions to peer reviewers. Of those, only 19 (46%) mentioned or referred to reporting guidelines as a useful resource.26 In response, the authors provide several recommendations for editors to improve the peer review of submitted manuscripts, suggesting that journals have a responsibility to support peer reviewers.26

tructions to peer reviewers. Of those, only 19 (46%) mentioned or referred to reporting guidelines as a useful resource.26 In response, the authors provide several recommendations for editors to improve the peer review of submitted manuscripts, suggesting that journals have a responsibility to support peer reviewers.26 The developers of reporting guidelines have a responsibility to plan a dissemination and implementation strategy that supports guidelines utilisation.15 Our efforts have several components: The CARE guidelines will be presented at international conferences and workshops including the Peer Review and Biomedical Publication Congress in Chicago on 10 September 2013. This article will be published simultaneously in multiple medical journals and outreach to the 212 journals depositing case reports into the BioMed Central Case Report Database. We will develop a more detailed explanation and elaboration article to outline the rationale for each item and include empirical evidence and examples of good reporting from published case reports. The CARE guidelines are being pilot tested, and preliminary results support the guidelines as currently written (personal communication with Helmut Kiene, Erica Oberg, Bill Manahan). Guidelines extensions for specialties are being developed. The CARE guidelines and related documents will be available on a dedicated website (www.CARE-statement.org), the EQUATOR Network website (www.equator-network.org) and translated into multiple languages.

The CARE guidelines are being pilot tested, and preliminary results support the guidelines as currently written (personal communication with Helmut Kiene, Erica Oberg, Bill Manahan). Guidelines extensions for specialties are being developed. The CARE guidelines and related documents will be available on a dedicated website (www.CARE-statement.org), the EQUATOR Network website (www.equator-network.org) and translated into multiple languages. Authors, journal editors, peer reviewers and the wider medical community are encouraged to use the CARE checklist and provide feedback that can be incorporated into regular updates of the CARE guidelines. We will conduct and support research into the impact of the CARE guidelines on the reporting of case reports.

The CARE guidelines and related documents will be available on a dedicated website (www.CARE-statement.org), the EQUATOR Network website (www.equator-network.org) and translated into multiple languages. Authors, journal editors, peer reviewers and the wider medical community are encouraged to use the CARE checklist and provide feedback that can be incorporated into regular updates of the CARE guidelines. We will conduct and support research into the impact of the CARE guidelines on the reporting of case reports. Limitations The CARE guidelines and their development have several possible limitations. First, these guidelines were developed through a consensus method and thus represent the opinions of the participants. However, consensus was easily reached during our meeting, we referred to the empirical evidence where available, and we received feedback from a wide selection of individuals, beyond those involved in our consensus meeting. Second, we recognise that causality determinations are a challenge for case reports even when following reporting guidelines.27 28 The CARE guidelines emphasise information quality independent of causality assessments. Different specialties, practitioners, and patients are likely to require extensions of the CARE guidelines with specialty specific information. We welcome discussions with groups interested in using the CARE guidelines as the basis for their specific reporting needs.

mation quality independent of causality assessments. Different specialties, practitioners, and patients are likely to require extensions of the CARE guidelines with specialty specific information. We welcome discussions with groups interested in using the CARE guidelines as the basis for their specific reporting needs. Though not mentioned in our guidelines, medical journals often require authors to address three issues: (1) potential competing interests, (2) de-identification of patient-related data and (3) ethics committee or IRB approval if obtained or necessary. Conclusions Anticipating a long future for case reports, we have provided guidance in the form of reporting standards for use by healthcare stakeholders around the world. The growth of case reports in an era in which clinical trials and systematic reviews dominate the tables of content of medical journals indicates that case reports have value, particularly with the increasing importance of individualised care. Unlike randomised controlled trials, case reports are individual reports related to the care of individual patients where the sample size is one. When systematically collected and combined into larger datasets, they can be analysed, enhancing the early discovery of effectiveness and harms.

tance of individualised care. Unlike randomised controlled trials, case reports are individual reports related to the care of individual patients where the sample size is one. When systematically collected and combined into larger datasets, they can be analysed, enhancing the early discovery of effectiveness and harms. We anticipate that the analysis of systematically aggregated information from patient encounters (now mandated by some insurance plans) will provide scalable, data-driven insights into what works for which patients in real time, facilitating comparisons across medical systems and cultures. Practitioners will soon be able to provide—and in some cases they are required to provide—patients with information from their encounters. This will transform how we think about ‘evidence’ and revolutionise its creation, diffusion and use—opening new opportunity landscapes. When it becomes clear how new data contributes to evidence, the stewardship needed to produce high-quality data will be more rewarding and our attitude towards ‘observation’ will shift. The CARE guidelines provide a framework to satisfy the need for precision, completeness and transparency. Authors note: Joel J Gagnier, University of Michigan, and David Riley, Global Advances in Health and Medicine, organised this consensus-based guideline-development project. The volunteer steering committee consisted of Joel J Gagnier, Gunver Kienle, David Moher, and David Riley.

We anticipate that the analysis of systematically aggregated information from patient encounters (now mandated by some insurance plans) will provide scalable, data-driven insights into what works for which patients in real time, facilitating comparisons across medical systems and cultures. Practitioners will soon be able to provide—and in some cases they are required to provide—patients with information from their encounters. This will transform how we think about ‘evidence’ and revolutionise its creation, diffusion and use—opening new opportunity landscapes. When it becomes clear how new data contributes to evidence, the stewardship needed to produce high-quality data will be more rewarding and our attitude towards ‘observation’ will shift. The CARE guidelines provide a framework to satisfy the need for precision, completeness and transparency. Authors note: Joel J Gagnier, University of Michigan, and David Riley, Global Advances in Health and Medicine, organised this consensus-based guideline-development project. The volunteer steering committee consisted of Joel J Gagnier, Gunver Kienle, David Moher, and David Riley. Collaborators: The CARE group: Alyshia Allaire, BS, Portland, OR, USA, Douglas G Altman, DSc, Centre for Statistics in Medicine, University of Oxford, Oxford, UK, Jeffrey Aronson, MB, ChB, MA Dphil, FRCP, FB, PharmacolS, University of Oxford, Oxford, UK*, James Carpenter, MD, Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA, Joel J Gagnier, ND, MSc, PhD, Departments of Orthopaedic Surgery and Epidemiology, University of Michigan, Ann Arbor, MI, USA, Patrick Hanaway, MD, Director of Medical Education, Institute for Functional Medicine, Asheville, NC, USA*, Carolyn Hayes, PhD, RN, NEA-BC, Dana-Farber Brigham and Women's Cancer Center, Boston, MA, USA, David Jones, MD, President, Institute for Functional Medicine, Ashland, OR, USA, Marietta Kaszkin-Bettag, PhD, University of Frankfurt, Pharmalex GmbH, Mannheim, Germany, Michael Kidd, AM, Editor-in-Chief Journal of Medical Case Reports, Faculty of Health Sciences, Flinders University, Adelaide, Australia*, Helmut Kiene, Dr med, Editor, Global Advances in Health and Medicine, Institute for Applied Epistemology and Research Methodology, University of Witten/Herdecke, Freiburg, Germany, Gunver Kienle, Dr med, Editor, Global Advances in Health and Medicine, Institute for Applied Epistemology and Research Methodology, University of Witten/Herdecke, Freiburg, Germany, Ben Kligler, MD, MPH, Co-Editor-in-Chief Explore, Beth Israel Medicine Center, New York, NY, USA*, Lori Knutson, RN, BSN, HN-BC, Integrative Healthcare Solutions, Minneapolis, MN, USA, Christian Koch, Dr med.

Institute for Applied Epistemology and Research Methodology, University of Witten/Herdecke, Freiburg, Germany, Ben Kligler, MD, MPH, Co-Editor-in-Chief Explore, Beth Israel Medicine Center, New York, NY, USA*, Lori Knutson, RN, BSN, HN-BC, Integrative Healthcare Solutions, Minneapolis, MN, USA, Christian Koch, Dr med. Habil., PhD, FACP, FACE, Deputy Editor Journal of Medical Case Reports, University of Mississippi, Jackson, MS, USA*, Karen Milgate, MPP, Independent Health Policy Consultant, Washington, DC, USA*, Michele Mittelman, RN, MPH, Editor, Global Advances in Health and Medicine, Dover, MA, USA, David Moher, PhD, Ottawa Hospital Research Institute; Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON Canada*, Hanna Oltean, MPH, University of Michigan, Ann Arbor, MI, USA, Greg Plotnikoff, MD, MTS, FACP, Editor, Global Advances in Health and Medicine, Allina Center for Healthcare Innovations and the Penny George Institute for Health and Healing, Minneapolis, MN, USA, Richard Alan Rison, MD, FAANEM, Deputy Editor, Journal of Medical Case Reports, Section Editor, BMC Research Notes, PIH Health Hospital, Whittier, University of Southern California, Los Angeles, CA, USA*, David Riley MD, Editor-in-Chief, Global Advances in Health and Medicine, Portland, OR, USA, Anil Sethi, MS, Johns Hopkins School of Medicine—Information architecture and IT, Palo Alto, CA, USA*, Larissa Shamseer, MSc, Ottawa Hospital Research Institute, Ottawa, ON, Canada, Richard Smith, MB, ChB, MSc, United Healthcare Chronic Disease Initiative, London, UK, Harold Sox, MD, The Dartmouth Institute and Geisel School of Medicine at Dartmouth, Hanover, NH, USA, Peter Tugwell, MD, FRCP, University of Ottawa, Ottawa, ON, Canada. *Participated in the guidelines development process, the review and editing of the CARE guidelines and this article, but did not attend the face-to-face consensus meeting.

Dartmouth Institute and Geisel School of Medicine at Dartmouth, Hanover, NH, USA, Peter Tugwell, MD, FRCP, University of Ottawa, Ottawa, ON, Canada. *Participated in the guidelines development process, the review and editing of the CARE guidelines and this article, but did not attend the face-to-face consensus meeting. Contributors: JJG and DR wrote the first draft of the article. DGA, JJG, GK, DM, DR and HS critically reviewed and edited drafts. The entire CARE group participated in parts or all of the guidelines development process and contributed to the editing and revision of the CARE guidelines and this article. Funding: The Department of Orthopaedic Surgery, the Office of the Vice-President of Research at the University of Michigan, and Global Advances in Health and Medicine provided funding for this project. David Moher is funded through a University of Ottawa Research Chair. Funding support was used to reimburse the travel-related expenses of conference attendees. There were no honoraria. Competing interests: None. Provenance and peer review: Not commissioned; internally peer reviewed.

Gout is an ancient disease that has caused pain and suffering over many centuries. The tragedy is that today we have excellent medication for the prevention of chronic gout, yet many people continue to be plagued by gout attacks and develop chronic arthritis. The incidence of gout is increasing worldwide. This is related to ageing and lifestyle changes. Gout is increased in people with the metabolic syndrome, obesity, use of diuretics and intake of beer and sugared drinks. This video and associated Powerpoint presentations should help anyone who manages patients with gout to understand how to elicit a good history, examine them and generate a differential diagnosis; the emphasis is to understand the causes of gout and take a proactive role (see online supplementary video and file). The good news is that gout can improve with lifestyle changes, and medication is relatively inexpensive. I chose not to include pegloticase and rilonacept in the videos. Pegloticase is a recombinant uricase which catalyses the oxidation of uric acid to allantoin. Allantoin is much more soluble than uric acid. Pegloticase must be given intravenously; anaphylactic reactions have been caused by it and it is very expensive. But the reason I did not include pegloticase is its use represents a failure to properly diagnose and treat gout. If patients and medical professionals understand the diagnosis and treatment of gout, we would rarely see tophaceous gout and the need for pegloticase would be limited.

aused by it and it is very expensive. But the reason I did not include pegloticase is its use represents a failure to properly diagnose and treat gout. If patients and medical professionals understand the diagnosis and treatment of gout, we would rarely see tophaceous gout and the need for pegloticase would be limited. Rilonacept is an interleukin 1 inhibitor to be used to prevent flares of gout when initiating therapy with a hypouricaemic agent. The studies to establish efficacy were carried out on patients with a history of gout initiating therapy with allopurinol. The patients were started on allopurinol 300 mg daily and then the dose was titrated upward until target level of serum uric acid was achieved. Patients were divided into two groups; one took rilonacept and the other was not allowed to take medications, such as colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs), which could possibly prevent attacks of gout. The two groups were compared and there were fewer attacks of gout in the group taking rilonacept. The American College of Rheumatology suggested, in 2012, in their guidelines for the treatment of gout that the initial dose of allopurinol should be 100 mg and the dose titrated every 2–5 weeks until target serum uric acid is achieved. The rationale is that by performing the slow titration of allopurinol, there would be fewer attacks of gout. The point is we do not know if this slow titration of allopurinol, with or without NSAIDs or colchicine, is less likely to cause flares of gout as compared with the use of rilonacept. However, rilonacept is a biological agent and is expensive.

ing the slow titration of allopurinol, there would be fewer attacks of gout. The point is we do not know if this slow titration of allopurinol, with or without NSAIDs or colchicine, is less likely to cause flares of gout as compared with the use of rilonacept. However, rilonacept is a biological agent and is expensive. Video 1 10.1136/bcr-2014-203641.video01BMJ Journals Video Playerbcr2014203641media1 Competing interests: None. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Hernias are a common problem in general surgery and about 75% of them occur in the inguinal region.1 An indirect inguinal hernia is the most common type of hernia, irrespective of the gender, and strangulation is its most dreadful complication, occurring in 1–3% of the cases, especially in the extremes of age.1 However, every once in a while, surgeons are surprised by the intraoperatory findings when performing a common procedure such as an inguinal hernia repair. Case presentation An 89-year-old woman presented to the emergency department with lower abdominal pain and a lump in her inguinal left region, since that morning. She had no symptom of bowel movements changes or fever. The patient had recently been discharged from the internal medicine ward after a urinary tract infection and a perianal abscess treated after a 1-week antibiotic course. She also suffered from chronic renal disease, chronic anaemia, high-blood pressure, cerebral vascular disease (with left hemiparesis after an ischaemic vascular accident) and dyslipidaemia. Physical examination revealed a calm, awaked but disoriented patient. She was slightly dehydrated, haemodynamically well and afebrile. Her abdomen was diffusely painful, with rebound tenderness, especially in the lower quadrants. In the left inguinal region, a painful tense mass, of nearly 5 cm was documented. No inflammatory signs were visible and no external genitalia anomalies were found. Laboratory results were within normal ranges. An incarcerated inguinal/femoral hernia was the initial hypothesis and so a pelvic ultrasound (US) was requested.

Physical examination revealed a calm, awaked but disoriented patient. She was slightly dehydrated, haemodynamically well and afebrile. Her abdomen was diffusely painful, with rebound tenderness, especially in the lower quadrants. In the left inguinal region, a painful tense mass, of nearly 5 cm was documented. No inflammatory signs were visible and no external genitalia anomalies were found. Laboratory results were within normal ranges. An incarcerated inguinal/femoral hernia was the initial hypothesis and so a pelvic ultrasound (US) was requested. Investigations The attending radiologist performed an US scan and complemented it with a pelvic CT scan (figures 1–3). On the left femoral duct, a well-defined, fine-walled, non-pure cystic formation was identified; admitting the continuity with the intestinal segment, the possibility of an incarcerated femoral hernia was considered. The same formation also appeared to be in continuity with the round ligament, suggesting the presence of canal of Nuck cyst. Figure 1 Pelvic ultrasound scan. Figure 2 Transverse section of pelvic CT scan. White arrow showing a ‘fine-walled, non-pure cystic formation’, hernial sac. Figure 3 Coronal section of pelvic CT scan. White arrow showing a ‘fine-walled, non-pure cystic formation’, hernial sac. Treatment The patient was proposed for emergency surgery, accepted by the next of kin who signed the informed consent form.

Figure 2 Transverse section of pelvic CT scan. White arrow showing a ‘fine-walled, non-pure cystic formation’, hernial sac. Figure 3 Coronal section of pelvic CT scan. White arrow showing a ‘fine-walled, non-pure cystic formation’, hernial sac. Treatment The patient was proposed for emergency surgery, accepted by the next of kin who signed the informed consent form. Under regional anaesthesia (subarachnoid block), the authors performed an open inguinal hernia approach and found a hernial sac containing the left ovary and fallopian tube. A left oophorosalpingectomy and a Lichtenstein procedure—with a polypropylene mesh—were carried out without complications (figures 4–6). Figure 4 Left inguinal hernia (preoperatory). Figure 5 Opening of the hernial sac. Figure 6 Left ovary inside the inguinal hernial sac. Outcome and follow-up The patient was discharged 5 days after surgery, and referred to the outpatient clinic. The anatomopathological examination revealed an ovarian fibroma (3.2×3.2×1.7 cm) and a fallopian tube (5.5×0.5 cm) without pathological findings. Discussion It is often said that any intra-abdominal viscera can be found inside a hernial sac and in nearly 3% of those cases female adnexa are encountered.2–4 Unlike men, female inguinal canal contains only the round ligament and vessels that run to the labia majora, providing a path to the development of inguinal hernias. The majority of those hernias occur in paediatric ages and are usually associated with congenital anomalies of the genitalia.3

Discussion It is often said that any intra-abdominal viscera can be found inside a hernial sac and in nearly 3% of those cases female adnexa are encountered.2–4 Unlike men, female inguinal canal contains only the round ligament and vessels that run to the labia majora, providing a path to the development of inguinal hernias. The majority of those hernias occur in paediatric ages and are usually associated with congenital anomalies of the genitalia.3 In premenopausal women, a rapid diagnosis and the prompt correction is crucial in order to save the adnexa from torsion and infarction and, therefore, ensure fertility.5 In postmenopausal women it has been hypothesised that the progressive weakness of the ligaments of the adnexa may add to the process of herniation. Furthermore, as these tissues have hormonal receptors, they are under the influence of several hormonal stimuli during a woman's life, from embryogenesis to parity, and even to the effects of systemic disease in intra-abdominal pressure.3 Our patient underwent two types of imaging diagnosis (US and CT), and yet the diagnosis was only confirmed intraoperatively. This case comes as a reminder that attention must be at highest when performing surgical dissection. It is known, that ovarian herniation may also be associated with anomalies of the ovary and fallopian tube; for that reason, we decided to perform an oophorosalpingectomy and requested an anatomopathological examination. Although our patient was a multiparous woman, with several comorbidities, there were no pathological findings in the resected specimen.

It is known, that ovarian herniation may also be associated with anomalies of the ovary and fallopian tube; for that reason, we decided to perform an oophorosalpingectomy and requested an anatomopathological examination. Although our patient was a multiparous woman, with several comorbidities, there were no pathological findings in the resected specimen. As it is our usual practice in elective inguinal hernia repair, a polypropylene mesh was used to close the hernial defect. After discharge, the patient's follow-up was carried out in the outpatient clinic, during several months without evidence of recurrence. She passed a way due to pneumonia, 6 months after surgery. Learning points We describe a rare finding inside an inguinal hernial sac, especially in an adult, multiparous woman. When elaborating the differential diagnosis of an irreducible groin mass, one must consider the possibility of compromised organs in order to avoid severe complications. Even though we are equipped with technological innovations that enable us to achieve imagiological diagnosis before surgery, we also know that some of these examinations are operator dependent. Therefore, a high level of suspicion and adequate patient information must be provided to the attending radiologist in order to improve preoperatory diagnostic accuracy. Nevertheless, some of these cases will only be correctly identified through careful surgical dissection. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description We report the case of a 38-year-old woman who was initially diagnosed with stage II oestrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) negative infiltrating ductal carcinoma of the breast, in 2013. Breast MRI at that time showed multifocal disease in the right breast. The patient underwent a right mastectomy and axillary lymph node dissection, which revealed pT2 N1a breast cancer. Following this, she received four cycles of docetaxel and cyclophosphamide and adjuvant radiation. At that time, she had declined tamoxifen due to her history of lattice degeneration and concerns of retinal detachment. She was also offered letrozole with goserelin but declined due to their side effect profile and risk for retinal complications. The patient did well on routine follow-up until July 2015, when she presented to emergency department with symptoms of dizziness. Workup showed hypercalcaemia. Imaging studies including bone scan and CT scan showed multiple bone metastases, mediastinal and subcarinal lymphadenopathy and hilar masses. MRI was negative for brain lesions. Pathology from one of the lesions showed metastatic breast cancer, ER and PR positive and HER2 negative.

ziness. Workup showed hypercalcaemia. Imaging studies including bone scan and CT scan showed multiple bone metastases, mediastinal and subcarinal lymphadenopathy and hilar masses. MRI was negative for brain lesions. Pathology from one of the lesions showed metastatic breast cancer, ER and PR positive and HER2 negative. The patient underwent bilateral salpingo-oophorectomy and started gemcitabine with denosumab. After 2 months of therapy, she was seen by ophthalmology, for decreasing visual acuity in both eyes. Examination showed bilateral retinal masses suggestive of choroidal lesions consistent with metastatic disease. This was confirmed by MRI of the brain and orbits (figure 1 A, B). Visual fields of both eyes were full. The patient had no history of diabetes mellitus, hypertension or other comorbidities. She was treated with intravitreal injections of bevacizumab 1.25 mg and orbital radiation of 37.5 Gy in 14 fractions. She received the first bevacizumab injection, to the left eye, on 27 October 2015; she then received an injection to the right eye, on 6 November, and finally injections to both eyes 1 month later. Radiation therapy was administered from 16 November to 7 December 2015. The patient reported improvement in vision with the first bevacizumab injection and further recovery with the next dose, with almost complete normalisation of her vision. After completion of bevacizumab and radiation therapy, she was started on palbociclib and letrozole. Currently, she remains on this therapy and after 4 months of follow-up, her visual acuity has improved in the right eye, from 20/30 to 20/20 and in the left eye from 20/40 to 20/30, her visual fields have continued to be full. She underwent a repeat MRI of the brain and orbits in March 2016, which showed marked improvement in both choroidal metastases (figure 2 A, B).

months of follow-up, her visual acuity has improved in the right eye, from 20/30 to 20/20 and in the left eye from 20/40 to 20/30, her visual fields have continued to be full. She underwent a repeat MRI of the brain and orbits in March 2016, which showed marked improvement in both choroidal metastases (figure 2 A, B). Figure 1 Brain MRI showing enhancement along the posterior surface of the bilateral globes consistent with choroidal metastases. Left globe involvement is greater than that of the right globe. (A) axial view. (B) sagittal view. Figure 2 Brain MRI showing response to therapy with interval decrease in size of choroidal metastases. There is mild residual choroidal enhancement along the posterior lateral left globe. (A) axial view. (B) sagittal view. Choroidal metastases can affect vision through different mechanisms, including direct tumour invasion into the retina and other optical structures, and increased fluid secretion caused by the tumour. Given the highly vascular nature of choroidal metastases, these lesions are likely to respond to radiation, but transiently leak more fluid in, which can be treated with antivascular endothelial growth factor intraocular injections. This case highlights the efficacy of intravitreal bevacizumab administration in the management of subretinal fluid along with radiation therapy for choroidal metastases. While these metastases, overall, represent a rare event in breast cancer, it is important to notice the rapid improvement seen with intraocular bevacizumab, which can lead to significant gains in the patient's quality of life.

in the management of subretinal fluid along with radiation therapy for choroidal metastases. While these metastases, overall, represent a rare event in breast cancer, it is important to notice the rapid improvement seen with intraocular bevacizumab, which can lead to significant gains in the patient's quality of life. Learning points Choroidal metastases from breast cancer are rare and it is important to recognise that they can affect the patient's vision and quality of life. Novel treatments for this condition, such as intraocular bevacizumab with radiation therapy, can effectively improve the patient's symptoms by targeting the pathophysiology of subretinal fluid and metastases formation. The authors would like to thank the University of Iowa Libraries for the support received for this publication. Contributors: KN prepared the manuscript. JPL revised the manuscript. Both the authors gathered the data and wrote the manuscript. Both the authors read and approved the final manuscript. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description A woman aged 48 years presented to the accident and emergency department with three episodes of massive haemoptysis of ∼500 mL. On examination, her vitals were stable. She had a history of pulmonary tuberculosis 2 years prior to this episode for which she had taken a complete course of antituberculous drugs for 9 months and was symptom-free and sputum culture-negative at the end of treatment. Her blood routines showed leucocytosis and raised inflammatory markers (ESR). Sputum and bronchoalveolar lavage specimens were smear positive for acid-fast bacilli, thus she was diagnosed to have a relapse with active tuberculosis. Imaging evaluation included a chest radiograph which showed cavitatory lesions with air fluid levels in bilateral lung fields with surrounding air space shadowing (figure 1). A plain multidetector CT (MDCT) was performed, which revealed multiple discrete cavities randomly distributed throughout both lungs (figure 2) and the largest cavity was in the right lower lobe and had hyperdense (blood density) contents within (figure 3). A contrast-enhanced MDCT angiography revealed a well defined, spherical, intracavitary wall-based lesion with homogenous intense enhancement similar to aorta in arterial phase images (figure 4). A branch from the descending right pulmonary artery was noted leading into the lesion (figure 5). The lesion was diagnosed as a Rasmussen's aneurysm within a tubercular cavity. The patient requested a discharge against medical advice and was lost to follow-up.

Background Chordoma is rare, slow growing, locally aggressive tumour that is believed to arise from the remnants of the embryonic notochord, which is a rod-shaped cartilage-like structure that serves as a scaffold for the formation of the spinal column. The most common locations are sacrum and clivus, whereas involvement of the thoracic and lumbar spine comprises only 15% of cases.1 Chordoma occurring in the intramedullary portion of the spinal cord is extremely rare, and only one case had been reported previously in the literature.2 In this case report, we present a rare case of thoracic intramedullary chordoma in a young patient. Case presentation An 8-year-old male patient presented with insidious onset, non-traumatic low back ache of 1-year duration along with paraparesis and urinary incontinence of 3 months duration. There was no history of anorexia, fever or tubercular contact. On clinical examination, there was atrophy of all muscles in the right leg. Power in both lower limbs was 4/5 (Medical Research Council grade) at all levels except at right ankle joint (2/5). Deep tendon reflexes were absent in both lower limbs. Sensory examination was normal.

ement similar to aorta in arterial phase images (figure 4). A branch from the descending right pulmonary artery was noted leading into the lesion (figure 5). The lesion was diagnosed as a Rasmussen's aneurysm within a tubercular cavity. The patient requested a discharge against medical advice and was lost to follow-up. Figure 1 Plain chest radiograph showing cavitary lesions in both lung fields (arrows) with surrounding air space opacities and right costophrenic angle blunting. Figure 2 Axial plain multidetector CT sections of chest in lung window showing well-defined cavitary lesions in both lung fields (arrows). Figure 3 Axial plain multidetector CT section of chest in soft tissue window showing hyperdense intracavitary contents (blood density). Figure 4 Axial plain (A) and contrast-enhanced (B) multidetector CT sections of chest showing a well defined, spherical, intracavitary wall-based lesion with homogenous intense enhancement similar to aorta in arterial phase images (arrow). Figure 5 Coronal MPR reformatted image showing a branch from the right descending pulmonary artery leading into the aneurysm (arrows). Massive haemoptysis in cases with underlying tuberculosis can be due to varied aetiopathologies like bronchiectasis, aspergillomas, broncholiths or vascular abnormalities. Of the vascular complications, bronchial arteries are the most common source of haemorrhage and the pulmonary arteries account for <10% of haemoptysis.1

ive haemoptysis in cases with underlying tuberculosis can be due to varied aetiopathologies like bronchiectasis, aspergillomas, broncholiths or vascular abnormalities. Of the vascular complications, bronchial arteries are the most common source of haemorrhage and the pulmonary arteries account for <10% of haemoptysis.1 Rasmussen's aneurysm is a focal dilation of a branch of the pulmonary artery due to arterial wall erosion secondary to chronic inflammation within a tubercular cavity. Arteries involved are small to medium-sized branch vessels; therefore, the aneurysms are usually peripherally located. The reported incidence is around 5% in cavitatory tuberculosis.2 It is an entity that requires urgent clinical differentiation from bronchial arterial sources of bleeding, due to higher relative intravascular pressures in bronchial circulation which is more challenging to treat, leading to poor outcomes.2 Emergency endovascular techniques like arterial embolisation are the preferred treatment modality for massive haemoptysis due to inflammatory aneurysms.3 Learning points Rasmussen's aneurysm is an inflammatory dilation of a branch of the pulmonary artery adjacent to or within a tubercular cavity. Rasmussen's aneurysm needs to be differentiated from a bronchial or systemic source of bleeding by using multidetector CT angiography. Endovascular techniques like catheter-assisted arterial embolisation are the preferred therapeutic modality for massive haemoptysis due to inflammatory aneurysms. Twitter: Follow Sankar Neelakantan at @drsankar23

Rasmussen's aneurysm needs to be differentiated from a bronchial or systemic source of bleeding by using multidetector CT angiography. Endovascular techniques like catheter-assisted arterial embolisation are the preferred therapeutic modality for massive haemoptysis due to inflammatory aneurysms. Twitter: Follow Sankar Neelakantan at @drsankar23 Contributors: SN is responsible for conceptualisation, write up and editing. RA and AKS are responsible for images. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description We describe a case of a 61-year-old Caucasian man who presented to the emergency department because of severe periumbilical pain associated with nausea and vomiting. On examination, there was gross distension with generalised tenderness, more prominent in the left iliac fossa. The patient was afebrile and parameters were stable. Coronal and axial CT images showed extensive branching radiolucency extending to within 2 cm of the liver capsule, which is characteristic of portal venous gas (PVG) and differentiates it from pneumobilia (figure 1). Gas was also present throughout the superior mesenteric vein and its tributaries (closed arrow, figure 2B). A large portion of the small bowel wall showed band-like intramural gas (open arrow figure 2A), in keeping with pneumatosis intestinalis (PI). Figure 1 (A) Coronal reconstruction showing portal venous gas and dilated small bowel loops with band-like pneumatosis intestinalis; (B and C) showing extensive portal venous gas as well as gas within the stomach wall. Figure 2 (A) Showing dilated bowel loops with fluid levels and extensive pneumatosis intestinalis. The open arrow highlights the band-like distribution of gas within the bowel wall. The closed arrow in (B) showing gas with the tributaries of the superior mesenteric vein.

Figure 1 (A) Coronal reconstruction showing portal venous gas and dilated small bowel loops with band-like pneumatosis intestinalis; (B and C) showing extensive portal venous gas as well as gas within the stomach wall. Figure 2 (A) Showing dilated bowel loops with fluid levels and extensive pneumatosis intestinalis. The open arrow highlights the band-like distribution of gas within the bowel wall. The closed arrow in (B) showing gas with the tributaries of the superior mesenteric vein. A laparotomy was performed and ∼400 cm of infarcted small bowel resected with formation of a jejunostomy and mucous fistula. Intraoperatively, all arteries were found to be patent on palpation. Intestinal integrity was restored 2 months after the first surgery and after 5 months of inpatient care, the patient was discharged with short bowel syndrome. The most common cause of PI and PVG is bowel ischaemia (∼70% of cases); however, with the increased use of CT imaging, both PI and PVG are being encountered more frequently and owing to several other conditions including mechanical causes such as complete or partial bowel obstruction, trauma, radiation and diverticulitis, as well as benign idiopathic causes such as recent surgery, inflammatory bowel disease and kayexalate use.1 Such findings therefore present a dilemma in the differential diagnosis and management of PVG; and/or PI as an exploratory laparotomy performed on all these patients would result in up to 30% of patients being subjected to an unnecessary procedure.2

uch as recent surgery, inflammatory bowel disease and kayexalate use.1 Such findings therefore present a dilemma in the differential diagnosis and management of PVG; and/or PI as an exploratory laparotomy performed on all these patients would result in up to 30% of patients being subjected to an unnecessary procedure.2 Although ischaemic bowel carries a high mortality rate of up to 75–90%, the presence or degree of PVG and PI does not necessarily confer a higher mortality rate. Both PVG and PI may occasionally be found even in patients with only partial mural bowel ischaemia. Therefore, neither PVG nor PI can be used to distinguish between transmural bowel infarction and only partial mural bowel ischaemia, if they are encountered as mild and isolated findings. However, transmural infarction of the affected bowel does become likely if PI is pronounced and band like as opposed to bubble like and, more importantly, if it is combined with PVG, as in the case described.3

owel infarction and only partial mural bowel ischaemia, if they are encountered as mild and isolated findings. However, transmural infarction of the affected bowel does become likely if PI is pronounced and band like as opposed to bubble like and, more importantly, if it is combined with PVG, as in the case described.3 Currently, the basis for determining the mortality or morbidity in cases of PVG or PI is related to the underlying cause and not the presence or extent of these radiological findings. However, there are no data in the literature to suggest whether the presence of PVG or PI on CT is an indicator of an adverse prognosis in patients suffering from transmural infarction. Learning points Although the most common cause of portal venous gas (PVG) or pneumatosis intestinalis (PI) is bowel ischaemia, several other benign causes have been identified and therefore a laparotomy is only indicated when suspecting intestinal ischaemia based on all the radiological and clinical findings. Transmural infarction is more likely in the presence of both PI and PVG, however, they do not necessarily indicate a worse prognosis and prompt surgical intervention is essential to achieving a favourable outcome. Contributors: JV wrote up the manuscript and performed the literature review. JG contributed to the literature review and the editing of the images. KC supplied the images and reviewed the final manuscript. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description Acanthosis nigricans (AN) can be classified into eight variants, including the benign, obesity associated, syndromic, malignant, acral, unilateral, medication induced and mixed type.1 Unilateral nevoid AN (UNAN) is an extremely rare form of AN and may be localised as a solitary lesion or along the Blaschko's lines.2 It is not associated with syndromes, endocrinopathies, drugs or malignancies. Various treatments have been described, including retinoids, calcipotriol, fish oil, ammonium lactate cream, cryotherapy, dermabrasion, excision (if small lesion) and long-pulse alexandrite laser treatment, with variable results.3 We report the case of a 9-year-old girl presenting to our department with asymptomatic, velvety, thickened orange-brown plaques distributed in an arciform pattern along the right scapular region (figure 1A). Her skin lesions appeared at the age of 5 years without any erythematous component, and these slowly increased in size over a 5-year period. Her familial and medical histories were unremarkable. No triggering factor was reported. Histological examination revealed hyperkeratosis, papillomatosis and moderate acanthosis of the epidermis. Based on the clinical and histopathological features, a diagnosis of unilateral nevoid AN was made. Figure 1 (A) Polycyclic velvety thickened orange-brown plaques distributed in an arciform pattern along the right scapular region. (B) Cicatricial plaques 14 months after the last CO2 laser treatment.

We report the case of a 9-year-old girl presenting to our department with asymptomatic, velvety, thickened orange-brown plaques distributed in an arciform pattern along the right scapular region (figure 1A). Her skin lesions appeared at the age of 5 years without any erythematous component, and these slowly increased in size over a 5-year period. Her familial and medical histories were unremarkable. No triggering factor was reported. Histological examination revealed hyperkeratosis, papillomatosis and moderate acanthosis of the epidermis. Based on the clinical and histopathological features, a diagnosis of unilateral nevoid AN was made. Figure 1 (A) Polycyclic velvety thickened orange-brown plaques distributed in an arciform pattern along the right scapular region. (B) Cicatricial plaques 14 months after the last CO2 laser treatment. We performed two cycles of pulsed CO2 laser (2.6 J/cm2), with a 2-month interval between sessions. After 14 months of follow-up, she presents with cicatricial plaques that have gradually disappeared and the final cosmetic result is considered as very satisfactory by the parents (figure 1B). To the best of our knowledge, this is the only case of UNAN successfully treated with CO2 laser. Since no randomised controlled trials exist, we believe this treatment modality should be considered as an option. Learning points Unilateral nevoid acanthosis nigricans is an extremely rare form of acanthosis nigricans that is not associated with syndromes, endocrinopathies, drugs or malignancies. Various treatments have been described with variable results.

To the best of our knowledge, this is the only case of UNAN successfully treated with CO2 laser. Since no randomised controlled trials exist, we believe this treatment modality should be considered as an option. Learning points Unilateral nevoid acanthosis nigricans is an extremely rare form of acanthosis nigricans that is not associated with syndromes, endocrinopathies, drugs or malignancies. Various treatments have been described with variable results. Although not described in the literature, pulsed CO2 laser should be considered as a treatment option. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

of anorexia, fever or tubercular contact. On clinical examination, there was atrophy of all muscles in the right leg. Power in both lower limbs was 4/5 (Medical Research Council grade) at all levels except at right ankle joint (2/5). Deep tendon reflexes were absent in both lower limbs. Sensory examination was normal. Investigations MRI of spine revealed two well-defined heterogenously enhancing lesions, isointense on T1 and hypointense on T2-weighted image along with cystic cap within the intramedullary portion of spinal cord. The extent of the lesion was T11 to L1 vertebral level involving conus medullaris with expansion of the spinal cord (figure 1A–F). Rest of the visualised vertebra was normal in height, alignment, outline and signal intensity. MRI of the brain was normal. Routine blood examination including total leucocyte count and differential leucocyte count were within normal limits. The urodynamic study showed detrusor overactivity with leak along with normal compliance. Figure 1 MRI showing lesion extending from T11 to L1. Differential diagnosis We kept a differential diagnosis of astrocytoma, ependymoma haemangioblastoma and a remote possibility of tuberculoma.

Investigations MRI of spine revealed two well-defined heterogenously enhancing lesions, isointense on T1 and hypointense on T2-weighted image along with cystic cap within the intramedullary portion of spinal cord. The extent of the lesion was T11 to L1 vertebral level involving conus medullaris with expansion of the spinal cord (figure 1A–F). Rest of the visualised vertebra was normal in height, alignment, outline and signal intensity. MRI of the brain was normal. Routine blood examination including total leucocyte count and differential leucocyte count were within normal limits. The urodynamic study showed detrusor overactivity with leak along with normal compliance. Figure 1 MRI showing lesion extending from T11 to L1. Differential diagnosis We kept a differential diagnosis of astrocytoma, ependymoma haemangioblastoma and a remote possibility of tuberculoma. Treatment The patient underwent T11 to L1 laminectomy. Following durotomy, the cord was found to be swollen. After performing dorsal midline myelotomy, a greyish white, firm, moderately vascular tumour with ill-defined plane between tumour and spinal cord was seen. The tumour was decompressed with the help of cavitron ultrasonic aspirator and near total excision was performed. A watertight dural closure was performed.

wollen. After performing dorsal midline myelotomy, a greyish white, firm, moderately vascular tumour with ill-defined plane between tumour and spinal cord was seen. The tumour was decompressed with the help of cavitron ultrasonic aspirator and near total excision was performed. A watertight dural closure was performed. Histopathological examination showed tumour forming cords and whorls around blood vessels in the chondroid background. Individual tumour cells were small round to oval with vacuolated cytoplasm and hyperchromatic nuclei that is, physaliphorous cells. On immunohistochemistry examination (IHC), tumour cells were positive for Vimentin, epithelial membrane antigen (EMA) and S-100, and negative for glial fibrillar acidic protein (GFAP), desmin and leucocyte common antigen (LCA) thereby confirming the diagnosis of chordoma. (figure 2), and (figure 3A–D). Figure 2 Section showing chondroid matrix with tumour cells arranged in cords (H&E×100) along with physaliphorus cells (Inset: H&E×400). Figure 3 Immunohistochemistry: (A) Vimentin was diffusely expressed in cytoplasm of tumour cells; (B) however tumour cells were negative for GFAP, control expression was seen in adjoining glial tissue. There was expression of EMA and S-100 (C and D). EMA, epithelial membrane antigen; GFAP, glial fibrillar acidic protein.

Figure 3 Immunohistochemistry: (A) Vimentin was diffusely expressed in cytoplasm of tumour cells; (B) however tumour cells were negative for GFAP, control expression was seen in adjoining glial tissue. There was expression of EMA and S-100 (C and D). EMA, epithelial membrane antigen; GFAP, glial fibrillar acidic protein. Outcome and follow-up In the immediate postoperative period, there was a significant reduction in pain and power improved to 4+/5 in both lower limbs. However, there was no evidence of any improvement in urinary incontinence. Patient was then referred to radiation oncology department, where he received full course of radiotherapy. At 10 months of follow-up, power remained 4+/5 with power in right ankle improved to 3/5. Discussion In 1857, Virchow first presented a histological description of gelatinous nodules in the prepontine region, projecting from the clivus. He suggested a cartilaginous origin for these nodules and called them as ‘ecchordosis physaliphora’.3 Moritz Ribbert did experimental studies in rabbits 40 years later and tried to analyse the hypothesis and coined the term chordoma for these nodules.4 Chordoma is an uncommon tumour that accounts for 1–4% of all primary malignant bone tumours.1 They affect males more than females in the ratio of 2:1.4 They may occur at any age, but peak incidence is in fifth or sixth decades of life. Most chordomas arise from the clivus (35%) or the sacrococcygeal regions (50%). In the spine, the sacrum is the most common site of disease, followed by the lumbar spine and then the cervical spine.1

e than females in the ratio of 2:1.4 They may occur at any age, but peak incidence is in fifth or sixth decades of life. Most chordomas arise from the clivus (35%) or the sacrococcygeal regions (50%). In the spine, the sacrum is the most common site of disease, followed by the lumbar spine and then the cervical spine.1 They usually involve and destroy the bone, but are found very rarely in an intradural location without bone involvement, with only a few cases reported in the literature.5–8 The intramedullary location of chordoma is even rarer and only one case had been reported until now. It was located in cervicothoracic (C5-T3) and clinically presented with paraparesis along with sphincter involvement.2 Patients with osseous involvement usually present with symptoms related to compression of involved neural structures or other organs. Clinical manifestations are usually gradually progressive increase in pain, spinal instability, radiculopathy or pathological fracture. In contrast, intramedullary chordomas do not present as severe pain or pathological fracture rather they present as the weakness of limbs and sphincter involvement. Our patient also presented with gradually progressive weakness of limbs and sphincter involvement.

nal instability, radiculopathy or pathological fracture. In contrast, intramedullary chordomas do not present as severe pain or pathological fracture rather they present as the weakness of limbs and sphincter involvement. Our patient also presented with gradually progressive weakness of limbs and sphincter involvement. MRI is considered as the radiological study of choice for diagnosis and surgical planning. They are isointense to hypointense on T1-weighted MRI, with variable enhancement on the administration of the contrast. On T2-weighted MRI these tumours are hyperintense, but may have some heterogeneity in signal intensity because of calcification and bony sequestration. In our patient, the lesion was hypointense on T2 with cystic cap and showed strong contrast enhancement without any bony involvement. Macroscopically, chordomas are usually grossly lobulated, soft, greyish in appearance. They are well demarcated in soft tissues but have elusive margins in bone. Microscopically they contain cords or nest of cells with partly vacuolated cytoplasm (physaliphorous cells) embedded in a myxoid matrix and extensive cartilage formation with degenerative calcification.9 On IHC examination, they show strong staining for vimentin, S-100 protein and EMA and pancytokeratin, while negative for GFAP. IHC also helps to differentiate these tumours from chondrosarcoma which stain negative for EMA, GFAP; ependymoma which stains positive for GFAP and negative for EMA; choroid meningioma which stains positive for EMA and negative for GFAP.9

for vimentin, S-100 protein and EMA and pancytokeratin, while negative for GFAP. IHC also helps to differentiate these tumours from chondrosarcoma which stain negative for EMA, GFAP; ependymoma which stains positive for GFAP and negative for EMA; choroid meningioma which stains positive for EMA and negative for GFAP.9 Surgery is the ideal treatment for managing chordomas. The goal of surgery is total decompression but it is rarely possible to fully resect the tumour. Radiation therapy is useful in decreasing recurrence and prolongation of survival though tumour does not respond well to radiotherapy. Gross macroscopic resection during first surgery is the best predictor of survival.10 11 Chemotherapy is ineffective. According to most comprehensive population-based study, median overall survival for chordoma patients in the USA is ∼7 years and the overall 5, 10, 20 years survival rates are 68%, 40%, 13% respectively.12 Patient's perspective It was shocking for me when I came to know that my son had a tumour in the spine. After the operation he is able to do his routine activities, but he is not able to experience fullness in his bladder and has learned to do clean intermittent catheterization. Although, the doctor told me that he may not be able to regain his full bladder control in future, it is my sincere request to explore treatment and do more extensive research so that he may also get rid of this problem. Patient's mother Learning points This is the second report of an intramedullary chordoma in the world literature.

Surgery is the ideal treatment for managing chordomas. The goal of surgery is total decompression but it is rarely possible to fully resect the tumour. Radiation therapy is useful in decreasing recurrence and prolongation of survival though tumour does not respond well to radiotherapy. Gross macroscopic resection during first surgery is the best predictor of survival.10 11 Chemotherapy is ineffective. According to most comprehensive population-based study, median overall survival for chordoma patients in the USA is ∼7 years and the overall 5, 10, 20 years survival rates are 68%, 40%, 13% respectively.12 Patient's perspective It was shocking for me when I came to know that my son had a tumour in the spine. After the operation he is able to do his routine activities, but he is not able to experience fullness in his bladder and has learned to do clean intermittent catheterization. Although, the doctor told me that he may not be able to regain his full bladder control in future, it is my sincere request to explore treatment and do more extensive research so that he may also get rid of this problem. Patient's mother Learning points This is the second report of an intramedullary chordoma in the world literature. Although extremely unusual, chordoma may occur in an intramedullary location within the spinal cord. Generous reporting of such cases is warranted to understand its biological behaviour and long-term outcome. Contributors: MF and QZ collected the material for this report. BO was the main motivating force whereas PA provided the histopathology slides. Competing interests: None declared.

Although extremely unusual, chordoma may occur in an intramedullary location within the spinal cord. Generous reporting of such cases is warranted to understand its biological behaviour and long-term outcome. Contributors: MF and QZ collected the material for this report. BO was the main motivating force whereas PA provided the histopathology slides. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background We report this case because of the diagnostic dilemma we faced during the initial investigations, both radiological and laboratory. The histopathological examination of the specimen resulted in an unexpected diagnosis. Accordingly, further surgical intervention was needed. Case presentation A 74-year-old patient presented to the surgical outpatient department of the hepatopancreaticobiliary unit, referred from a district general hospital, with 3-month history of upper abdominal pain and discomfort, dull aching in nature and radiating to the back and left upper quadrant. It was associated with nausea but no vomiting. There was no change of bowel habit, no loss of weight or appetite. She was also diabetic (type II) on oral hypoglycaemic, hypertensive with ischaemic heart disease. Abdominal examination showed non-tender non-pulsatile epigastric region fullness with ill-defined edges.

nt. It was associated with nausea but no vomiting. There was no change of bowel habit, no loss of weight or appetite. She was also diabetic (type II) on oral hypoglycaemic, hypertensive with ischaemic heart disease. Abdominal examination showed non-tender non-pulsatile epigastric region fullness with ill-defined edges. Investigations An ultrasound scan, performed 2 months prior to the time of presentation, showed a large cystic lesion in the epigastric region with turbid fluid content, suggesting that it might be a pancreatic pseudocyst. However, the patient did not show any history suggestive pancreatitis. Her laboratory investigations showed normal liver and kidney functions with mild anaemia (haemoglobin 11 gm/dL). An abdominal CT scan showed a cyst related to the pancreas measuring 6.6×6×6.3 cm (figure 1A, B). In addition there were other incidental findings such as, bilateral small adrenal adenomata, and a small liver cyst in the right lobe which had no blushing or wall enhancement in the delayed CT images and was deemed a simple liver cyst by the radiologist. Tumour markers including CEA, AFP, CA-19.9 and CA-125 were all within the normal range. Echinococcus granulosus serology was negative. The patient underwent an endoscopic ultrasound assessment with guided fine-needle aspiration cytology. The impression was that of a pancreatic cyst measuring 6×8 cm. The cytology of the cystic fluid was benign and both amylase and lipase levels in the fluid were within the normal range measuring 23 and 24 IU/L, respectively. CEA and CA-19.9 levels in the fluid were within the normal range (1.0 µg/L and 3.84 IU/mL, respectively). The microscopic examination of the fluid revealed no hydatid hooklets. Culture of the cyst fluid showed no growth of any microorganisms.

he fluid were within the normal range measuring 23 and 24 IU/L, respectively. CEA and CA-19.9 levels in the fluid were within the normal range (1.0 µg/L and 3.84 IU/mL, respectively). The microscopic examination of the fluid revealed no hydatid hooklets. Culture of the cyst fluid showed no growth of any microorganisms. Figure 1 (A and B) CT-scan of the liver: (a) showing the site of the cyst (6.6×6×6.3 cm) between the left lobe of the liver and the stomach in the gastrohepatic (lesser) omentum. (B) In the coronal cuts, the proximity of the cyst to the lesser curvature of the stomach is obvious. In addition, one of the two small simple cysts in the right lobe is seen (between segment V and VI) measuring 2.1×1 cm. Differential diagnosis Pancreatic cyst. Simple liver cyst. Hydatid cyst. Duplication of bowel (stomach). Treatment A multidisciplinary meeting including general surgeons, endoscopists and radiologists was held before the first operation. The diagnosis of a pseudopancreatic cyst was highly doubtful according to the surgeons. On reviewing the CT images with the radiologists, there was no evidence of a connection between the cyst and the pancreas which looked healthy. There was a high suspicion of exophytic liver cyst or bowel duplicate.

first operation. The diagnosis of a pseudopancreatic cyst was highly doubtful according to the surgeons. On reviewing the CT images with the radiologists, there was no evidence of a connection between the cyst and the pancreas which looked healthy. There was a high suspicion of exophytic liver cyst or bowel duplicate. The patient underwent diagnostic laparoscopy which showed a thin-walled cystic lesion, freely mobile within the lesser (hepatogastric) omentum with no attachment to the liver or pancreas, but part of its wall (about one-eighth) was attached to the lesser curvature of the stomach. Aspirate from this cyst revealed a brownish thin fluid which was sent for cytology and tumour markers (both were negative) test. The cyst was evacuated and the thin wall was excised leaving the part which is attached to stomach. A drain was inserted and the procedure was terminated awaiting the histopathological examination of the excised part of the wall.

wnish thin fluid which was sent for cytology and tumour markers (both were negative) test. The cyst was evacuated and the thin wall was excised leaving the part which is attached to stomach. A drain was inserted and the procedure was terminated awaiting the histopathological examination of the excised part of the wall. Outcome and follow-up The pathology report revealed an unexpected diagnosis of gastrointestinal stromal tumour (GIST). The case was discussed in our biweekly multidisciplinary oncology meeting in the surgical department in the presence of histopathologists and oncologists. It was agreed in the meeting that the residual tumour should be excised and to start imatinib therapy after the second operation. The patient was recalled and she underwent laparotomy through a bilateral subcostal incision. The remaining part of the tumour together with the adherent parts of lesser omentum and lesser curvature of the stomach were excised within safety margins. In addition, pyloroplasty was carried out for proper drainage of the stomach as the procedure necessitated the sacrifice of the nerve of Laterjet. She had an uneventful recovery and was discharged a week later. The second histopathology report confirmed the diagnosis of GIST (CD 117, DOG 1 and CD 34 were positive) with infiltration of the stomach wall without lymph node involvement (TNM: T3, N0, M0). The tumour was negative for smooth muscle actin (SMA). There was no necrosis seen and the mitosis was 1/50 high power field. The Ki-67 index was 4% and S-100 was negative. Overall, the tumour was labelled of low histological grade (G1) (figure 2A–G).

of the stomach wall without lymph node involvement (TNM: T3, N0, M0). The tumour was negative for smooth muscle actin (SMA). There was no necrosis seen and the mitosis was 1/50 high power field. The Ki-67 index was 4% and S-100 was negative. Overall, the tumour was labelled of low histological grade (G1) (figure 2A–G). Figure 2 (A–G) Histopathology and immunostains: (A and B): low magnification view of sections of the cyst wall removed during the first surgery showing a thin fibrous cyst wall containing islands of cellular spindle cell tumour (black arrows). (C) Partial gastrectomy wall (red arrow) with mural spindle cell tumour (blue arrow). (D) A high magnification view of the tumour showing typical histology of a spindle cell GIST. Immunostains of the tumour show positive staining for Dog1 (E), CD117 (F), with negative staining for SMA (G). GIST, gastrointestinal stromal tumours; SMA, smooth muscle actin. The patient was then referred to the cancer control centre to receive imatinib. She was seen in the surgical outpatient department after 1 month and 6 months and she had no further symptom.

Figure 2 (A–G) Histopathology and immunostains: (A and B): low magnification view of sections of the cyst wall removed during the first surgery showing a thin fibrous cyst wall containing islands of cellular spindle cell tumour (black arrows). (C) Partial gastrectomy wall (red arrow) with mural spindle cell tumour (blue arrow). (D) A high magnification view of the tumour showing typical histology of a spindle cell GIST. Immunostains of the tumour show positive staining for Dog1 (E), CD117 (F), with negative staining for SMA (G). GIST, gastrointestinal stromal tumours; SMA, smooth muscle actin. The patient was then referred to the cancer control centre to receive imatinib. She was seen in the surgical outpatient department after 1 month and 6 months and she had no further symptom. Discussion GISTs became a distinct entity after the discovery of KIT (CD11) in 1998. GISTs originate from the intestinal pace-maker cells of Cajal, therefore are usually confined to the submucosa and muscularis propria.1 It affects both sexes equally and 80% occur in persons over 50 years. They arise as a result of oncogenic mutation in the KIT tyrosine kinase. Most (75–80%) GISTs have KIT mutations, typically affecting the juxtamembrane domain encoded by exon-11. These tumours account for 1% of all intestinal neoplasms, the age-adjusted incidence in Europe and the USA is 7 cases per million.2 Independent adverse prognostic factors are large tumours, high mitotic count, non-gastric location, rupture and male gender.3 4 GISTs can arise anywhere in the GI tract, but most commonly in the stomach and small intestine.2 About 60% of patients are cured by surgery. After complete excision, it may recur within 5 years in approximately 50% of patients. Imatinib is recommended for patients with substantial risk of recurrence.3 4

male gender.3 4 GISTs can arise anywhere in the GI tract, but most commonly in the stomach and small intestine.2 About 60% of patients are cured by surgery. After complete excision, it may recur within 5 years in approximately 50% of patients. Imatinib is recommended for patients with substantial risk of recurrence.3 4 This patient was referred as a case of pseudocyst of the pancreas although the patient never had any previous attack of pancreatitis. On reviewing the images, the pancreas was normal with no radiological evidence of pancreatic abnormality denoting previous pancreatitis and there was no connection with the cyst. To our surprise the first histopathology reported GIST tumour. GISTs are usually solid tumours, however, they may rarely present as cystic lesions. Cystic GIST tumours may be observed as a primary cystic GIST, in which the main structure comprises a cystic tissue with a pseudocapsule, or a rapidly growing malignant GIST with central cystic degeneration due to insufficient blood supply resulting in necrosis and liquefaction. When the tumour metastasises to the liver and pancreas, the metastatic lesion is always cystic in nature, often confused with liver cysts and pancreatic cysts. In addition, with imatinib treatment malignant GISTs may show cystic degeneration.5

ion due to insufficient blood supply resulting in necrosis and liquefaction. When the tumour metastasises to the liver and pancreas, the metastatic lesion is always cystic in nature, often confused with liver cysts and pancreatic cysts. In addition, with imatinib treatment malignant GISTs may show cystic degeneration.5 Cystic GIST lesions are rare and invariably diagnosed late after excision. In 2012 De Vogelaere et al reported a large (12 cm) exophytic cystic tumour with no preoperative diagnosis of its origin. After excision with wedge resection of the greater curvature of the stomach, where the stalk was attached, histopathological examination revealed GIST. The authors suggested that in cases of unusual exophytic pendulated tumour of the stomach, always consider of GIST.6 In 2014 Hansen et al reported a 74-year-old female patient who underwent a Roux-en-Y cyst-jejunostomy for pancreatic pseudocyst. Few weeks postoperatively, she developed several melena episodes with negative upper GI endoscopy. She was surgically reappraised. The main diagnostic concern was a pancreatic cystic neoplasm. A 12×8.0×5.0 cm size retrogastric lesion was resected and pathology report indicated an unsuspected GIST, which was previously misdiagnosed as a pancreatic pseudocyst.7

several melena episodes with negative upper GI endoscopy. She was surgically reappraised. The main diagnostic concern was a pancreatic cystic neoplasm. A 12×8.0×5.0 cm size retrogastric lesion was resected and pathology report indicated an unsuspected GIST, which was previously misdiagnosed as a pancreatic pseudocyst.7 In the same year, Zhu et al reported an exophytic retrogastric large cystic lesion which they reported to have a similar diagnostic dilemma, even after a CT scan and MRI. It was thought to be a pancreas-related cyst. After block excision of the mass with spleen, greater omentum and the attached wall of the stomach the hisopathological examination revealed GIST. They suggested that the use of ultrasound-guided endoscopy might have provided further diagnostic evidence.8 However, we can say from our experience that the use of endoscopic ultrasound did not help that much in a relatively similar case. It helped only in the exclusion of other pathologies. Recently in 2015, Kumar et al reported a 55 year old woman who presented with a painful lump in the epigastrium. A CT scan revealed a large exophytic cystic lesion from the duodenum measuring 15×10×8 cm arising from the lateral wall of the second part. Preoperatively, it was thought to be a duodenal diverticulum. After resection, and pathological examination they were surprised to find that it was a duodenal GIST tumour.9

strium. A CT scan revealed a large exophytic cystic lesion from the duodenum measuring 15×10×8 cm arising from the lateral wall of the second part. Preoperatively, it was thought to be a duodenal diverticulum. After resection, and pathological examination they were surprised to find that it was a duodenal GIST tumour.9 Our case posed a diagnostic difficulty as it was thought to be either a pancreatic pseudocyst or a liver exophytic cyst. Intraoperatively, it had no attachment to any of the two organs. The thick posterior wall however was suspicious. We considered the possibility of organ duplicate, which has been occasionally reported. To our surprise, it turned out to be GIST. The literature search of the last 5 years revealed the aforementioned cases which had the same diagnostic dilemma. We conclude that GIST should be considered one of the differential diagnoses when any bowel-related cystic lesion is encountered. Learning points Gastrointestinal stromal tumours may present as a cyst related to the stomach or in the lesser sac and may give a misleading picture on CT scan. It should be considered as one of the differentials if the sac is attached to the stomach wall. The first-time surgical intervention is technically less demanding, however, with a pathological unexpected diagnosis, a second intervention may be necessary for optimum cure.

Our case posed a diagnostic difficulty as it was thought to be either a pancreatic pseudocyst or a liver exophytic cyst. Intraoperatively, it had no attachment to any of the two organs. The thick posterior wall however was suspicious. We considered the possibility of organ duplicate, which has been occasionally reported. To our surprise, it turned out to be GIST. The literature search of the last 5 years revealed the aforementioned cases which had the same diagnostic dilemma. We conclude that GIST should be considered one of the differential diagnoses when any bowel-related cystic lesion is encountered. Learning points Gastrointestinal stromal tumours may present as a cyst related to the stomach or in the lesser sac and may give a misleading picture on CT scan. It should be considered as one of the differentials if the sac is attached to the stomach wall. The first-time surgical intervention is technically less demanding, however, with a pathological unexpected diagnosis, a second intervention may be necessary for optimum cure. Contributors: RA provided the preoperative workup results at al Jahra Hospital. AMH wrote the manuscript draft. SA and EHA reviewed it. The histopathology and the immunostain microphotographs were provided by IF. The final manuscript was reviewed and approved by all authors. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Post-streptococcal reactive arthritis (PSRA) is well described, but no diagnostic criteria have been agreed on, and there are no guidelines for management or duration of subsequent penicillin prophylaxis. The case presented here illustrates the non-specific nature of the presenting symptoms, with discussion of its management. Case presentation A 35-year-old Asian man, born in the UK, developed polyarthritis for 3 weeks following a holiday in Scotland. His holiday involved mountain climbing on the mainland, and he reported multiple tick bites and a non-specific rash around the right elbow a week prior to the onset of his joint symptoms. The joint pain was associated with night sweats, malaise and fatigue and weight loss of 5 kg in 3 weeks. The rash resolved spontaneously over 2 weeks and was not witnessed by any healthcare professional. He denied a preceding infection and had no symptoms of sore throat, gastrointestinal or genitourinary infection. There was no medical history of joint pain, uveitis, psoriasis or inflammatory back pain. Family history was not significant. A presumptive diagnosis of acute Lyme syndrome was made by his general practitioner, and he was prescribed 3 weeks of twice daily oral doxycycline 100 mg and subsequently 1 week of oral cephalexin pending referral to rheumatology. There was no improvement in joint and constitutional symptoms after completion of 4 weeks of oral antibiotics.

is of acute Lyme syndrome was made by his general practitioner, and he was prescribed 3 weeks of twice daily oral doxycycline 100 mg and subsequently 1 week of oral cephalexin pending referral to rheumatology. There was no improvement in joint and constitutional symptoms after completion of 4 weeks of oral antibiotics. Investigations Examination in rheumatology clinic confirmed widespread active synovitis in the small joints of hands and feet, along with wrist, elbows, knees and ankles synovitis. Shoulder and hip examination confirmed tender joints with globally restricted movement. There was no skin rash, no lymphadenopathy and he was afebrile. Cardiovascular, respiratory, abdominal and neurological examination was normal. Blood investigations revealed C reactive protein (CRP) 67 mg/L (0–10), erythrocyte sedimentation rate (ESR) 42 mm/hour (0–12), rheumatoid factor (RF)-negative, anti-cyclic citrullinated peptide (CCP)-negative, antinuclear antibody-negative and human leucocyte antigen (HLA-B27)-negative, and normal serum electrolytes, liver and renal function. Despite the tick bite history, no supportive serology for Lyme disease was identified. Borrelia burgdorferri serology 6 and 10 weeks after start of symptoms was negative. Serology for hepatitis B and C, HIV, syphilis, Epstein-Barr virus, cytomegalovirus, parvo virus and rubella virus were negative. Throat culture was not undertaken as it was thought that in absence of pharyngitis symptoms and post 4 weeks of oral antibiotics, the diagnostic yield would be low. Serology for other atypical viral and bacterial infections was negative. Antistreptolysin O (A.S.O) titre was 800 IU/mL and anti-DNase B level was 1600 u/mL. Urine was normal. Blood cultures were negative after 48 hours. An ECG and cardiac two-dimensional echo were within normal limits.

e diagnostic yield would be low. Serology for other atypical viral and bacterial infections was negative. Antistreptolysin O (A.S.O) titre was 800 IU/mL and anti-DNase B level was 1600 u/mL. Urine was normal. Blood cultures were negative after 48 hours. An ECG and cardiac two-dimensional echo were within normal limits. Differential diagnosis PSRA; Lyme arthritis; Postinfective (viral/bacterial); Spondyloarthropathy: seronegative arthritis (reactive, psoriatic, enteropathic, spondyloarthritis); Acute rheumatic fever (ARF); Rheumatoid arthritis. Treatment He was prescribed penicillin V 500 mg two times a day for 10 days, with a tapering course of oral prednisolone. Outcome and follow-up He responded well to treatment with resolution of his polyarthritis and constitutional symptoms. Cardiovascular and neurological examination remained normal. He was started on penicillin V 250 mg twice daily for prophylaxis and prednisolone was tapered over the next 4 weeks, with no recurrence of his joint symptoms. Repeat blood samples taken 6 weeks later showed CRP 2 and ESR 2, antistreptococcal titres 400 IU/mL (decreasing) and anti-DNase B levels of 1600 u/mL (stable). He was asymptomatic in the 12-week follow-up, without evidence of polyarthritis or carditis.

ed over the next 4 weeks, with no recurrence of his joint symptoms. Repeat blood samples taken 6 weeks later showed CRP 2 and ESR 2, antistreptococcal titres 400 IU/mL (decreasing) and anti-DNase B levels of 1600 u/mL (stable). He was asymptomatic in the 12-week follow-up, without evidence of polyarthritis or carditis. Discussion The strongly positive streptococcal serology, despite no symptoms of pharyngitis, is indicative of group A streptococcal infection and in this case, PSRA. Lyme arthritis was considered as differential with history of tick bite but negative serologies 6 and 10 weeks after first symptoms make Lyme disease unlikely. Persistent polyarthritis for more than 6 weeks makes postinfection arthritis (viral or bacterial) unlikely. In the presence of strongly positive streptococcal serology and absence of RF and anti-CCP antibodies, rheumatoid arthritis is an unlikely diagnosis. Seronegative arthritis, such as reactive arthritis, enteropathic arthritis, peripheral spondyloarthritis and psoriatic arthritis, were also considered in the differential diagnosis, but the lack of gastrointestinal or genitourinary symptoms, no history and clinical signs of psoriasis, and no history of uveitis and inflammatory back pain went against the possibility of seronegative arthritis. Scarlet fever and invasive Group A streptococcus infections are increasingly being recognised in the UK in the past 5 years. The streptococcal infection presents most commonly in adults with a median age of 62 years (<1–105-year).1 ARF and PSRA are two sequels of streptococcal infection with significant differences (table 1).

fever and invasive Group A streptococcus infections are increasingly being recognised in the UK in the past 5 years. The streptococcal infection presents most commonly in adults with a median age of 62 years (<1–105-year).1 ARF and PSRA are two sequels of streptococcal infection with significant differences (table 1). Table 1 Differences between ARF and PSRA ARF PSRA Age Single peak at 12 years Bimodal peaks 8–14 years and 21–37 years Genetics Increased expression of HLA DRB1*16 alleles Increased expression of HLA DRB1*01 alleles Gender No difference No difference Arthritis 2–3 weeks post-streptococcal infection 7–10 days post-streptococcal infection migratory, flitting, large joints non-migratory, additive, small joints, axial, large joints improves in 2–3 weeks, self-limiting median duration 2 months or more, can be recurrent Treatment Good response to Aspirin or NSAIDs Moderate response to Aspirin/NSAIDs ARF, acute rheumatic fever; HLA, human leucocyte antigen; NSAIDs, non-steroidal anti-inflammatory drugs; PSRA, post-streptococcal reactive arthritis.

s improves in 2–3 weeks, self-limiting median duration 2 months or more, can be recurrent Treatment Good response to Aspirin or NSAIDs Moderate response to Aspirin/NSAIDs ARF, acute rheumatic fever; HLA, human leucocyte antigen; NSAIDs, non-steroidal anti-inflammatory drugs; PSRA, post-streptococcal reactive arthritis. Post-streptococcal arthritis without cardiac involvement was first reported in 1959.2 Since then, the separate entity of PSRA has been further developed to reduce overdiagnosis of patients with ARF without cardiac involvement. The term PSRA was first suggested by Goldsmith and Long in 1982.3 ARF and PSRA differ demographically. ARF shows single peak at 12 years, while PSRA shows a bimodal peak between 8–14 years and 21–37 years. Gender appears not to be of relevance in either ARF or PSRA.4 Ayoub et al5 have proposed diagnostic criteria for PSRA. PSRA is diagnosed in patients with polyarthritis who have a recent evidence of streptococcal infection and no other major Jones criteria. The arthritis in ARF and PSRA have different presentation. PSRA develops within 10 days of streptococcal infection; this arthritis is non-migratoryand non-responsive to aspirin/non-steroidal anti-inflammatory drugs, and is usually of a longer duration (more than 2 months). The arthritis associated with ARF is migratory, responds well to aspirin/NSAIDs and usually improves in 2–3 weeks.6–8 In adults, reactive arthritis secondary to recent streptococcal infection is more likely to be missed as pharyngitis is not a common initial presentation of streptococcal infection.6 7 9 The expressions of HLA DRB1*01 and HLA DRB1*16 alleles are increased in PSRA and ARF, respectively. HLA-B27 expression is not raised in patients with PSRA, suggesting its pathogenesis is more similar to ARF than reactive arthritis.10 Increased expression of alloantigen D8/17 on B lymphocytes has also been demonstrated giving weight to the argument that those individuals susceptible to ARF and PSRA share the same genetic susceptibility.11

not raised in patients with PSRA, suggesting its pathogenesis is more similar to ARF than reactive arthritis.10 Increased expression of alloantigen D8/17 on B lymphocytes has also been demonstrated giving weight to the argument that those individuals susceptible to ARF and PSRA share the same genetic susceptibility.11 The risk of carditis after PSRA in children is ∼8%, but remains unclear in adults. van Bemmel et al12 suggested no increased risk of carditis after median follow-up of 8.9 years, and advised no long-term prophylaxis. This was also reflected in a long-term follow-up case series from Mayo Clinic.13 There are strategies for primary and secondary prevention of carditis in ARF, but the need for chemoprophylaxis after PSRA is still debated. However the American Heart Association recommends 1 year of secondary prophylaxis with clinical monitoring for carditis.8 14

a long-term follow-up case series from Mayo Clinic.13 There are strategies for primary and secondary prevention of carditis in ARF, but the need for chemoprophylaxis after PSRA is still debated. However the American Heart Association recommends 1 year of secondary prophylaxis with clinical monitoring for carditis.8 14 Our case highlights the need of considering PSRA as one of the differentials for acute polyarthritis in adults and raises a number of unanswered questions about the management of PSRA. Most of the data of PSRA has come from paediatric follow-up studies, and adult inception cohort studies are lacking. There is no agreement about the need for and duration of penicillin prophylaxis. Giving 1–2 years of antibiotics prophylaxis to an adult without clear evidence is counterintuitive, particularly in view of increasing antibiotic resistance. As streptococcal infections in the adult population are increasingly reported, it is a timely opportunity to revisit PSRA and develop comprehensive treatment and antibiotic prophylaxis guidelines. Learning points Post-streptococcal reactive arthritis (PSRA) has now emerged as a different clinical entity to acute rheumatic fever. PSRA should be considered as one of the differentials for acute polyarthritis in adults. There is no agreement about the need and duration of penicillin prophylaxis for PSRA in current literature. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Isolated ACTH deficiency (IAD) is a rare disorder, characterised by secondary adrenocortical insufficiency with low or absent cortisol production, normal secretion of pituitary hormones other than adrenocorticotropic hormone (ACTH) and the absence of structural pituitary defects. This diagnosis can result in 20% mortality in the neonatal period if unrecognised. Early and lifelong treatment with glucocorticoid usually reverses the signs and symptoms associated with this condition. We describe a case of a newborn presenting with hypoglycaemia and cholestatic jaundice, who was found to have low cortisol and ACTH levels. A suspected diagnosis of IAD was confirmed with targeted molecular genetic testing of the TBX19 gene, which came back confirming the diagnosis. One of the mutations that the patient had is a new finding.

newborn presenting with hypoglycaemia and cholestatic jaundice, who was found to have low cortisol and ACTH levels. A suspected diagnosis of IAD was confirmed with targeted molecular genetic testing of the TBX19 gene, which came back confirming the diagnosis. One of the mutations that the patient had is a new finding. Case presentation The infant was a term baby boy born to a 28-year-old mother who received regular prenatal care. Maternal prenatal laboratories and ultrasound imaging were within normal limits. The infant's birth weight was 3.8 kg. He was referred to our hospital for further evaluation and management because of signs of jaundice, hypoglycaemia, one episode of apnoea lasting about 20 s and poor feeding at day 11 of life. Initial physical examination revealed a hypoactive neonate with yellowish discolouration of his body, with normal vital signs (axillary temperature of 37.2°C, heart rate 130 bpm, blood pressure 75/40 mm Hg, respiratory rate of 40/min). Weight on admission was 3.9 kg and head circumference was 36 cm. Neither hepatosplenomegaly nor facial dysmorphism was noted. Genital examination was within normal limits.

n of his body, with normal vital signs (axillary temperature of 37.2°C, heart rate 130 bpm, blood pressure 75/40 mm Hg, respiratory rate of 40/min). Weight on admission was 3.9 kg and head circumference was 36 cm. Neither hepatosplenomegaly nor facial dysmorphism was noted. Genital examination was within normal limits. Investigations Laboratory findings including complete blood panel with differential count and electrolytes were within normal limits. Sepsis work up came back negative. Total and direct bilirubin were 18 and 2.4 mg/dL, respectively. Alanine aminotransferase was 32 units/L (normal 12–78 units/L), aspartate aminotransferase was 62 units/L (normal <48 units/L), alkaline phosphatase was 255 units/L (normal 55–176 units/L) and λ-glutamyl transpeptidase was 300 units/L (normal 8–78 units/L). Investigations were started for hypoglycaemia and cholestatic jaundice. The apnoea episode was associated with low blood glucose level of 19 mg/dL; the infant was given 2 mL/kg bolus of dextrose 10% water solution. His blood glucose level improved to 80 mg/dL thereafter.

Investigations Laboratory findings including complete blood panel with differential count and electrolytes were within normal limits. Sepsis work up came back negative. Total and direct bilirubin were 18 and 2.4 mg/dL, respectively. Alanine aminotransferase was 32 units/L (normal 12–78 units/L), aspartate aminotransferase was 62 units/L (normal <48 units/L), alkaline phosphatase was 255 units/L (normal 55–176 units/L) and λ-glutamyl transpeptidase was 300 units/L (normal 8–78 units/L). Investigations were started for hypoglycaemia and cholestatic jaundice. The apnoea episode was associated with low blood glucose level of 19 mg/dL; the infant was given 2 mL/kg bolus of dextrose 10% water solution. His blood glucose level improved to 80 mg/dL thereafter. During work up for hypoglycaemia, the cortisol level was found to be low. Following an ACTH stimulation test the cortisol level increased from <0.2 µg/dL before the ACTH dose to 0.5 µg/dL thereafter. The serum ACTH level was also found to be low. The other hormone levels (luteinising hormone, follicle stimulating hormone, growth hormone, insulin-like growth factor 1, testosterone, thyroid-stimulating hormone, T4, T3) were within normal limits. Urine and serum for amino and organic acids screens were normal. Urine-reducing substances, toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus and herpes viral serology, newborn screen and α 1-antitrypsin were within normal limits. MRI of the brain was obtained to look for pituitary abnormalities, and was normal. Ultrasonography of the abdomen demonstrated a normal gall bladder and normal appearing adrenal glands. Hepatobiliary iminodiacetic acid scan of the liver was normal, ruling out biliary obstructive lesions.

psin were within normal limits. MRI of the brain was obtained to look for pituitary abnormalities, and was normal. Ultrasonography of the abdomen demonstrated a normal gall bladder and normal appearing adrenal glands. Hepatobiliary iminodiacetic acid scan of the liver was normal, ruling out biliary obstructive lesions. Given the high suspicion for IAD, targeted TBX19 mutation analysis by PCR and automated sequencing was obtained and confirmed the diagnosis of IAD, showing two sequence variants in the TBX19 gene, associated with the IAD (table 1). Table 1 TBX19 gene analysis results confirming the diagnosis of IAD TBX19 region Base change Codon change Mutation type Interpretation Exon 1 C.158_159 delGA heterozygous p.Arg53fs Frame-shift deletion Unlisted* Exon 3 C.535C>T heterozygous p.Arg179 Non-sense ACTH deficiency Exon 2, 4–8 No abnormalities No abnormalities Not applicable Negative *Likely to be pathogenic, based on the effects of similar small frame-shift deletions. ACTH, adrenocorticotropic hormone; IAD, isolated adrenocorticotropic hormone deficiency.

TBX19 region Base change Codon change Mutation type Interpretation Exon 1 C.158_159 delGA heterozygous p.Arg53fs Frame-shift deletion Unlisted* Exon 3 C.535C>T heterozygous p.Arg179 Non-sense ACTH deficiency Exon 2, 4–8 No abnormalities No abnormalities Not applicable Negative *Likely to be pathogenic, based on the effects of similar small frame-shift deletions. ACTH, adrenocorticotropic hormone; IAD, isolated adrenocorticotropic hormone deficiency. The first mutation was a heterozygous deletion of two bases in the exon, which causes a reading frame-shift mutation beginning with arginine at codon 53. The second was a heterozygous C to T base change that converts the arginine at codon 179 into a termination signal. The first sequence variant has not been previously identified in the common databases, but is likely to be pathogenic, based on the effects of similar small frame shift deletions. The second sequence variant has been previously identified in at least one other patient with IAD.1 Differential diagnosis Other causes of neonatal cholestasis should be considered in the differential diagnosis (box 1). Box 1 Possible causes for neonatal cholestasis Obstructive/anatomical causes: biliary atresia and choledochal cysts Infections: toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus, and herpes infections, urinary tract infection. Metabolic: tyrosinaemia, α1-antitrypsin, fructosaemia, galactosaemia, hypothyroidism. Genetic: alagille syndrome, progressive familial intrahepatic cholestasis, bile acid defects, cystic fibrosis.

Infections: toxoplasmosis, other (syphilis, varicella-zoster, parvovirus B19), rubella, cytomegalovirus, and herpes infections, urinary tract infection. Metabolic: tyrosinaemia, α1-antitrypsin, fructosaemia, galactosaemia, hypothyroidism. Genetic: alagille syndrome, progressive familial intrahepatic cholestasis, bile acid defects, cystic fibrosis. Toxic or secondary: total parenteral nutrition, medication. Idiopathic. Treatment The patient was started on hydrocortisone supplementation with total daily dose of 15 mg/m2/day given three times a day. He was discharged home with maternal instructions for frequent feeding every 3 hours, and with the plan to continue the lifelong treatment of hydrocortisone replacement therapy.

Toxic or secondary: total parenteral nutrition, medication. Idiopathic. Treatment The patient was started on hydrocortisone supplementation with total daily dose of 15 mg/m2/day given three times a day. He was discharged home with maternal instructions for frequent feeding every 3 hours, and with the plan to continue the lifelong treatment of hydrocortisone replacement therapy. Outcome and follow-up The patient was discharged home on hydrocortisone supplementation. At the follow-up appointment 1 week after discharge, he was doing well clinically. His bilirubin level had decreased to 10 mg/dL and direct bilirubin to 1.3 mg/dL. He was seen at the genetic clinic, where parental testing for TBX19 was recommended given the autosomal recessive inheritance pattern. Also discussed with the parents was that evaluation by endocrinology and neonatology in addition to targeted TBX19 mutation analysis would be essential in the management of future pregnancies. The patient has continued to follow-up with the paediatric endocrinology clinic, and continues to show significant improvement—his bilirubin level had decreased to 0.4 mg/dL with direct bilirubin level of 0.1 mg/dL at around 3 months; 20 months after diagnosis, the patient is thriving well on a weight-adjusted maintenance dose of cortisol. He is under the care of his local paediatric gastroenterologist and endocrinologist.

nificant improvement—his bilirubin level had decreased to 0.4 mg/dL with direct bilirubin level of 0.1 mg/dL at around 3 months; 20 months after diagnosis, the patient is thriving well on a weight-adjusted maintenance dose of cortisol. He is under the care of his local paediatric gastroenterologist and endocrinologist. Discussion Neonatal cholestasis accounts for ∼33% of paediatric hepatobiliary diseases. It is defined as prolonged elevation of conjugated bilirubin beyond 14 days of life and biochemically as a conjugated bilirubin level of ≥2 mg/dL or direct bilirubin level >20% of the total bilirubin. In general, conjugated jaundice that appears within 3 months of life is neonatal cholestasis.2 This diagnosis requires immediate evaluation and management, as some of the causes are fatal in early life, if left untreated, whereas others can result in substantial morbidity by causing chronic liver disease progressing to cirrhosis eventually requiring liver transplantation. There are wide and varied causes of neonatal cholestasis known so far, and the list keeps increasing with descriptions of new causes. Our case is one such uncommon cause of cholestasis. To the best of our knowledge, there have been only 11 of 17 patients with neonatal IAD presenting with neonatal cholestasis and the rest with neonatal hepatitis on biopsy carrying a T-pituitary (TPIT) mutation.3 In that series, symptoms of adrenal insufficiency and cholestatic jaundice disappeared with cortisol replacement therapy in all cases.

ge, there have been only 11 of 17 patients with neonatal IAD presenting with neonatal cholestasis and the rest with neonatal hepatitis on biopsy carrying a T-pituitary (TPIT) mutation.3 In that series, symptoms of adrenal insufficiency and cholestatic jaundice disappeared with cortisol replacement therapy in all cases. Our case describes a neonate who presented with hypoglycaemia and prolonged direct hyperbilirubinaemia, with laboratory results and genetic testing confirming the diagnosis of neonatal IAD. The patient's cholestasis was present since birth until the treatment with hydrocortisone was started; following initiation of the treatment, the patient's condition improved significantly and both, his total and direct bilirubin levels started trending down, with prompt normalisation of blood glucose levels. Our case indicates that the low level of cortisol as a result of low ACTH level was the cause of both hypoglycaemia and neonatal cholestasis, which resolved with supplementation treatment. IAD is rare disorder that can cause life-threatening severe hypoglycaemia and prolonged cholestatic jaundice; the disease can carry a 20% mortality rate if undiagnosed during infancy.4 It is characterised by low or absent production of ACTH hormone, which leads to decreased production of cortisol with otherwise normal secretion of other pituitary hormones and no structural defects of the pituitary gland on imaging studies.

ce; the disease can carry a 20% mortality rate if undiagnosed during infancy.4 It is characterised by low or absent production of ACTH hormone, which leads to decreased production of cortisol with otherwise normal secretion of other pituitary hormones and no structural defects of the pituitary gland on imaging studies. IAD in childhood carries an autosomal recessive inheritance pattern. It has been shown to have a genetic cause in addition to other potential causes, as some patients with IAD do not have a TPIT mutation. TPIT as a T-box gene is a novel T-box transcription factor demonstrated in mice and is present exclusively in the developing corticotroph and melanotroph cells. An exclusive expression, such as this, of TPIT in pituitary proopiomelanocortin (POMC) cells suggests that a loss of TPIT function due to its mutation should produce an isolated deficiency of pituitary POMC and isolated ACTH deficiency. Based on this, it was inferred that the human homologue TBX19 (a T-box gene on chromosome 1q23-24, that encodes TPIT) could also be restricted to the same pituitary cells, and thus loss of TBX19 function might produce an isolated deficiency of pituitary POMC (ACTH).3 Most of the cases with TBX19 mutation have been reported to present in the early neonatal period.5 From a review of the literature, hypoglycaemia, seizures and prolonged jaundice are described as the most common symptoms during the neonatal period. The exact mechanism of cholestasis in IAD is still unclear, but in animal models, cortisol has been shown to play a role in bile formation and flow.6

ly neonatal period.5 From a review of the literature, hypoglycaemia, seizures and prolonged jaundice are described as the most common symptoms during the neonatal period. The exact mechanism of cholestasis in IAD is still unclear, but in animal models, cortisol has been shown to play a role in bile formation and flow.6 The triad of recurrent severe hypoglycaemia, episodes of low cortisol level and cholestasis, is present in almost all reported cases during infancy; which indicates that the age of onset and the severity of cortisol deficiency are important predictors for development of cholestatic jaundice in childhood.5 Learning points The presentation of a young infant with cholestasis and hypoglycaemia should alert paediatricians to the possibility of isolated adrenocorticotropic hormone deficiency (IAD), a potentially life-threatening but treatable condition and prompt investigation of adrenal function should be considered. IAD should be in the differential diagnosis when the rest of the pituitary hormones and brain imaging are within normal limits. The significance of the heterozygous deletion of two bases in the exon, which caused a reading frame-shift mutation beginning with arginine at codon 53, as found in our patient, and which has not so far been reported, needs to be clarified. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Case presentation The Thai-Myanmar border is home to an estimated 104 000 refugees who have fled long-standing ethnic conflict, poverty and unemployment in Myanmar.1 Refugees live in nine established camps along the border and represent a diverse group of Burmese, Karen and Burman Muslim ethnicities, each with their own distinctive cultures, languages and religious beliefs. Many have lived in the camps for decades and the situation is atypical of more acute refugee settings elsewhere. Camp residents have access to bamboo housing, food rations, limited education and basic healthcare. Maela is the largest camp with an estimated population of 40 000.1 Opportunities for further education and paid employment are scarce and freedom of movement is very limited. Some residents take up agricultural work outside of the camp at the risk of incurring fines or arrest by the Thai authorities.

basic healthcare. Maela is the largest camp with an estimated population of 40 000.1 Opportunities for further education and paid employment are scarce and freedom of movement is very limited. Some residents take up agricultural work outside of the camp at the risk of incurring fines or arrest by the Thai authorities. Two medical non-governmental organisations (NGOs) provide maternal, neonatal, paediatric and general adult medical care.1 The majority of health workers are locally trained staff without tertiary education. Mental health services are severely lacking. A small team of psychosocial workers with 3 months' training provides basic counselling and community follow-up. No psychiatrist is available within the camp. Severe cases are referred to the local Thai government hospital where one psychiatrist is currently employed. However, language and cultural differences between Myanmar refugees and Thai healthcare staff often result in suboptimal diagnosis and treatment. NGOs' lack of funding for mental health disorders also acts as a barrier for referral. Patients who are considered at high risk of suicide are admitted for observation at one of the camp's medical facilities. With the permission of the patient, family members and camp leaders are notified. Patients who require longer term support are offered accommodation in a patient house or referred to the safe houses of one of the other NGOs.

d at high risk of suicide are admitted for observation at one of the camp's medical facilities. With the permission of the patient, family members and camp leaders are notified. Patients who require longer term support are offered accommodation in a patient house or referred to the safe houses of one of the other NGOs. M, an 18-year-old woman of Karen ethnicity living in Maela camp, attended her first antenatal clinic (ANC). Ultrasound examination confirmed a healthy pregnancy of 9 weeks' gestation. All routine investigations were normal. As part of an ongoing study of perinatal depression in this population, M completed a Structured Clinical Interview for the Diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Disorders (SCID).2 During the interview, she described episodes of depressed mood, anhedonia, low energy and ‘thinking too much’. These episodes occurred once or twice a month and usually lasted no more than 1 or 2 hours each time. She also described occasional passive suicidal ideation with no previous attempts and no active intent.

).2 During the interview, she described episodes of depressed mood, anhedonia, low energy and ‘thinking too much’. These episodes occurred once or twice a month and usually lasted no more than 1 or 2 hours each time. She also described occasional passive suicidal ideation with no previous attempts and no active intent. M attributed these symptoms to family problems. She experienced conflict with her parents-in-law, who disapproved of her marriage to their son and felt she did not contribute sufficiently to household finances. M's own mother had died 5 years previously and M described ongoing feelings of grief. M's father had remarried and M had a good relationship with her stepmother, whom she described as kind and caring. M also had a strong and loving relationship with her husband and said she felt close to him and able to share her feelings with him. She was happy to be pregnant. Objectively, M appeared healthy, content, well-kempt and had a normal affect. She engaged well during the SCID. Owing to the short-lived and intermittent nature of the symptoms she described, she did not meet DSM-IV criteria for major or minor depressive disorder.3

e her feelings with him. She was happy to be pregnant. Objectively, M appeared healthy, content, well-kempt and had a normal affect. She engaged well during the SCID. Owing to the short-lived and intermittent nature of the symptoms she described, she did not meet DSM-IV criteria for major or minor depressive disorder.3 M's husband, O, was a 22-year-old man of Karen ethnicity who worked in the camp crematorium and was known to use alcohol and recreational drugs. O had spent his entire life in the camp. His mother was known to be heavily alcohol dependent. O had a tense relationship with his mother due to her overt disapproval of M. Until recently, M and O had lived with O's parents. However, during a recent dispute, O's mother had aggressively kicked M and O out of the house, telling them they were a burden on the household. At the time of M's ANC visit, M and O had been living with M's father and stepmother for a few weeks. Since O was not a patient and had never sought medical care, we know little about him or his psychological state.

ther had aggressively kicked M and O out of the house, telling them they were a burden on the household. At the time of M's ANC visit, M and O had been living with M's father and stepmother for a few weeks. Since O was not a patient and had never sought medical care, we know little about him or his psychological state. Two days after M's ANC attendance, O sourced a bottle of herbicide outside the camp premises, remarking to an acquaintance in passing, “today will be the last day you see me”. In the bathroom of their home, M and O each drank a cup of herbicide. They were seen by M's stepmother leaving the bathroom and calmly entering their sleeping area together. They were found shortly after on their bed, struggling to breathe and frothing at the mouth. They were driven to the camp medical clinic but pronounced dead on arrival. The cause of death as reported by the medical team was suicide by pesticide ingestion. No suicide note was left by the couple and, apart from the remark made by O, neither party had discussed their plans with any friends or relatives. The camp committee and camp security force confirmed death by suicide.

ad on arrival. The cause of death as reported by the medical team was suicide by pesticide ingestion. No suicide note was left by the couple and, apart from the remark made by O, neither party had discussed their plans with any friends or relatives. The camp committee and camp security force confirmed death by suicide. While we are unable to determine with certainty the motivation for this paired suicide, a number of factors are likely to have played a role. Parental disapproval of the couple's relationship acted as a chronic, daily stressor, as recounted by M during her interview. Their eviction from the home of O's parents may have been a sign of worsening tensions between the couple and O's parents. Alcohol and substance abuse are common within this refugee setting and are known risk factors for suicide.4 5 The alcohol dependency of O as well as his mother may have compounded aggressions with the family and exacerbated financial difficulties. Chronic poverty and the lack of employment opportunities are additional underlying risk factors.4

se are common within this refugee setting and are known risk factors for suicide.4 5 The alcohol dependency of O as well as his mother may have compounded aggressions with the family and exacerbated financial difficulties. Chronic poverty and the lack of employment opportunities are additional underlying risk factors.4 M and O also faced challenges related more specifically to their refugee status. The limited freedom of movement coupled with the dearth of work opportunities within refugee camps is disheartening for residents. Uncertainty regarding the future can be unsettling and evoke feelings of hopelessness, especially in a setting as protracted as the Thai-Myanmar border, where displacement has occurred continuously over a period of 30 years.6 Many of Maela's residents have spent decades awaiting resettlement to a third country or repatriation to their homeland whenever this becomes a viable and safe option. Both paths involve significant challenges. Those returning to Myanmar may find reintegration difficult following prolonged absence. For residents born in Maela, repatriation may be the first time they enter their native country. Those who are granted resettlement in third countries such as the UK or the USA face the arduous task of adapting to life in new and unfamiliar surroundings, language and cultural differences, loss of extended community networks, social isolation and, often, poor access to health and social services.7 The young couple we describe had spent a significant proportion of their lives in a camp with very little control over their own destinies. In the months preceding the suicide, rumours were spreading that registration for resettlement abroad was closing. Pregnancy may have further exacerbated the perceived futility of the couple's situation. Feelings of hopelessness, despair and uncertainty over the future, exacerbated by family conflict, substance abuse and long-term financial insecurity, may have become unbearable for this newly-wed, recently pregnant couple at a time in their lives which should have been full of hope and opportunity.

couple's situation. Feelings of hopelessness, despair and uncertainty over the future, exacerbated by family conflict, substance abuse and long-term financial insecurity, may have become unbearable for this newly-wed, recently pregnant couple at a time in their lives which should have been full of hope and opportunity. Global health problem list Suicide is one of the leading causes of death in young people globally. Marginalised populations such as refugees are at high risk of mental disorders and suicide. Mental disorders such as depression are common during the perinatal period. In settings with good antenatal attendance, pregnancy offers a valuable time to identify and support women at risk of mental disorders and suicide. Tackling suicide requires multifaceted approaches and collaborative working between health services, social services and policymakers but these tend to be non-existent or weak in refugee settings. Global health problem analysis Suicide is a significant global health problem. It is the second leading cause of death among people aged 15–29 years worldwide, and the burden is inequitably distributed with 75% of all suicides occurring within low and middle income countries (LMIC).4 Risk factors for suicide are multifactorial and complex, spanning health systems, societal, community and individual levels. They include trauma and abuse, discrimination, isolation and poor social support, dislocation, relationship discord, unemployment and mental disorders.8 Refugee communities carry many of these risk factors and are thus a vulnerable group.7

and complex, spanning health systems, societal, community and individual levels. They include trauma and abuse, discrimination, isolation and poor social support, dislocation, relationship discord, unemployment and mental disorders.8 Refugee communities carry many of these risk factors and are thus a vulnerable group.7 Several factors are likely to have contributed to the suicides of this couple. Their refugee status is likely to have been a major factor. Some of the social stressors this couple faced—including alcohol and substance abuse and financial insecurity—are common to many populations living in poverty and not unique to refugees. However, for refugee populations, these social adversities are compounded by psychological stressors. Prior to leaving their homes, refugees are exposed to traumatic experiences which may have long-term effects on their mental health.9 Transit can be arduous and involve further trauma.9 On arrival at a camp, refugee communities face limited freedom of movement, a lack of opportunities to engage in paid employment or higher education and uncertainty over the future. Trapped ‘between the tiger and the crocodile’, refugees often face the difficult choice of awaiting repatriation to their homes or resettlement to a new country, both of which are associated with their own challenges.10 Following resettlement or repatriation, life can remain difficult as a result of ongoing socioeconomic adversity, difficulty integrating into local communities as a result of language and cultural differences and poor access to educational, social and health services.11 These multilayered psychosocial challenges have significant and long-lasting effects on the psychological well-being of refugee communities.

cioeconomic adversity, difficulty integrating into local communities as a result of language and cultural differences and poor access to educational, social and health services.11 These multilayered psychosocial challenges have significant and long-lasting effects on the psychological well-being of refugee communities. To the best of our knowledge, this was the first paired suicide in our setting. Paired suicides—the mutual agreement of two individuals to kill themselves simultaneously—are rare, representing <1% of all suicides.12–14 In Western settings, paired suicides tend to involve older married couples of higher socioeconomic status.14 Case reports suggest that in non-Western settings, younger couples whose relationship lacks parental or societal approval may be more typical, as is likely to have been the case in our couple.14–16 In paired suicides, one party typically acts as the initiator.14 15 Since O sourced the pesticide, he may have taken the lead in this act. We cannot say to what extent coercion played a role. In our setting, an estimated 15% of women experience interpersonal violence during pregnancy.17 Against this backdrop, coerciveness in relationships is also likely to be common. The non-violent method of suicide, the absence of violence during the act and the fact that no calls for help were made by either party following pesticide ingestion perhaps suggest a willingness of both parties to carry out the act successfully.12 However, we cannot rule out psychological coercion. The lack of psychiatric assessment of O is an important limitation of our understanding of this case. M's father described the couple as being very much in love; this perhaps provides reason to believe that the suicides were carried out in mutual agreement. Both M and O were Buddhists. Buddhism regards death not as the end of life, but merely as a transition to the next life.18 M and O may have carried out their suicides together in the belief that this would offer an escape from their suffering and a means of being reborn together in their next lives.

n mutual agreement. Both M and O were Buddhists. Buddhism regards death not as the end of life, but merely as a transition to the next life.18 M and O may have carried out their suicides together in the belief that this would offer an escape from their suffering and a means of being reborn together in their next lives. The couple's pregnancy status and young age may also have played a role in their decision to commit suicide. Mental disorders such as depression are common during the perinatal period and women who are socially marginalised or living in poverty are at greatest risk.19 Suicide is an important cause of maternal death both in high-income and low-income settings.20 21 On the Thai-Myanmar border, the rate of maternal suicide is high at 16.4 per 100 000 live births.22 This contrasts significantly with total female suicide rates of 11.8 per 100 000 in those aged 15–29 years in Myanmar and 3.6 per 100 000 in those aged 15–29 years in Thailand in 2012.4 M described subthreshold symptoms of depression and occasional passive suicidal ideation. Although she was happy to be pregnant, her pregnancy may have brought to the forefront concerns and uncertainties around her and O's future and the life they could provide for their baby. Many suicides occur impulsively during moments of crisis, and young people are more likely to act on an impulse and carry out a suicide more quickly.15 Our young couple's actions may have been carried out in reaction to the recent family dispute in which M and O were evicted from O's parents' house, for example. Impulsive suicide attempts have a higher likelihood of being lethal when fatal means are easily available.4 Pesticides, one of the most common means of suicide globally and the leading method of suicide in rural areas of LMICs, are cheap and accessible in our setting and may have facilitated suicide in this case.

mple. Impulsive suicide attempts have a higher likelihood of being lethal when fatal means are easily available.4 Pesticides, one of the most common means of suicide globally and the leading method of suicide in rural areas of LMICs, are cheap and accessible in our setting and may have facilitated suicide in this case. Addressing suicide requires cross-sector collaboration and must include both population-wide and targeted approaches. Public awareness initiatives can reduce stigma and empower communities to support vulnerable individuals.4 Training health workers, educators, police and community leaders enables better identification and management of those in need of care.4 In resource-poor settings, health workers and community members can be trained to deliver effective and evidence-based care to individuals with mental disorders.23 Restricting access to suicide means—for example, through centralised storage of pesticides away from individuals' homes—can be effective.24 Improved availability and quality of data is essential in order to monitor trends and identify patterns in attempted and completed suicides.

to individuals with mental disorders.23 Restricting access to suicide means—for example, through centralised storage of pesticides away from individuals' homes—can be effective.24 Improved availability and quality of data is essential in order to monitor trends and identify patterns in attempted and completed suicides. Risk factors such as mental disorders and alcohol abuse must be identified early. Previous suicide attempt is the single greatest predictor of completed suicide, and families and communities can be mobilised to support those who have attempted suicide to find positive ways of coping.4 Screening may be feasible for certain groups. In our setting, pregnant women attend ANC frequently, and this period of increased contact offers a good opportunity for routine screening for mental disorders as well as substance misuse and interpersonal violence. In our case, one of the suicides occurred in a woman with subthreshold symptoms of depression. The failure of the SCID to identify this woman as high risk highlights the urgent need for a more in-depth understanding of local experiences of mental disorders and their association with suicide, and for culturally and locally validated tools. The addition of a more detailed assessment of suicidal intent may also be warranted. A number of tools are available to aid the assessment of individual suicide risk, though these first need to be validated locally.25 Greater emphasis on the SCID item relating to future-oriented thinking and feelings of hopelessness could also be incorporated into the suicide assessment. It may also be important to increase the community's understanding of what services are available to those with mental disorders or suicidal ideation. If individuals are aware that despite the scarcity of resources within the camp there are health workers who can provide counselling, treatment, housing support and referral if necessary, they may be more willing to reveal suicidal intent and seek care.

are available to those with mental disorders or suicidal ideation. If individuals are aware that despite the scarcity of resources within the camp there are health workers who can provide counselling, treatment, housing support and referral if necessary, they may be more willing to reveal suicidal intent and seek care. The rarity of paired suicides globally, the fact that this was the first case in our setting and the lack of psychiatric assessment of O limit our understanding of the risk factors specific to this suicide. Alongside the approaches outlined above, initiatives to promote strong personal relationships, develop positive coping strategies and empower women are likely to be helpful in addressing paired suicide. While some of these interventions can be conducted locally, others require collaboration with national and international policymakers. Addressing these core determinants is essential in order to ensure that the mental health needs of vulnerable populations are adequately met. Learning points Suicide is one of the leading causes of death in young people globally. Refugees are at high risk of developing mental disorders, and refugee women are especially vulnerable during the perinatal period. Perinatal depression causes significant distress for families and places strain on the wider society in multiple ways. Paired suicides are rare and in non-Western settings often involve young couples. Mental health resources, social care and policymakers must work together to tackle mental disorders and suicide in vulnerable populations.

Perinatal depression causes significant distress for families and places strain on the wider society in multiple ways. Paired suicides are rare and in non-Western settings often involve young couples. Mental health resources, social care and policymakers must work together to tackle mental disorders and suicide in vulnerable populations. Contributors: GF, MMO and BL provided clinical care to the patient and family members. GF, MMO, BL and RM wrote the report. All the authors have seen and approved the final version. GF accepts responsibility for the overall content as a guarantor. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description A 51-year-old man presented with a history of vague abdominal pain and progressively increasing abdominal distension. Abdominal examination revealed hepatomegaly with a firm nodular liver palpable below the costal margin with mild tenderness in the right hypochondriac region. General examination revealed no pedal oedema, ascites or jaundice. No significant history or drug history was elicited. Imaging work up included a transabdominal ultrasound scan performed elsewhere which showed a multilocular cystic lesion in the right lobe of the liver with coarsened hepatic echotexture and surface nodularity. Serology was positive for hydatid disease.

Description A 51-year-old man presented with a history of vague abdominal pain and progressively increasing abdominal distension. Abdominal examination revealed hepatomegaly with a firm nodular liver palpable below the costal margin with mild tenderness in the right hypochondriac region. General examination revealed no pedal oedema, ascites or jaundice. No significant history or drug history was elicited. Imaging work up included a transabdominal ultrasound scan performed elsewhere which showed a multilocular cystic lesion in the right lobe of the liver with coarsened hepatic echotexture and surface nodularity. Serology was positive for hydatid disease. Contrast-enhanced CT scan (CECT) of the abdomen performed at our centre revealed a large multilocular cystic lesion in the right lobe of the liver with enhancing walls and daughter cysts within (figure 1), with extrahepatic extension into the gastrohepatic ligament and transdiaphragmatic extension into the middle mediastinum through the bare area of the liver (figure 2). The lesion was noted to cause extrinsic compression of the retrohepatic inferior vena cava (IVC) so that the right and middle hepatic veins were not visible (figures 3 and 4). Volume redistribution, surface nodularity and altered parenchymal enhancement of the liver were also noted (figure 5). There was also omental fat stranding with mild ascites (figures 4 and 5). Based on the clinical presentation and imaging findings, a diagnosis of hepatic hydatid cyst causing secondary Budd-Chiari syndrome was made. The patient was advised surgery, but refused further treatment due to financial constraints. The patient was started on long-term albendazole and anticoagulation, and was advised follow-up after 3 months. On 3-month follow-up, he had significant relief of symptoms.

cyst causing secondary Budd-Chiari syndrome was made. The patient was advised surgery, but refused further treatment due to financial constraints. The patient was started on long-term albendazole and anticoagulation, and was advised follow-up after 3 months. On 3-month follow-up, he had significant relief of symptoms. Figure 1 Axial contrast-enhanced section of the liver showing a large multilocular cystic lesion in the right lobe of the liver with enhancing walls and daughter cysts (star) within. Figure 2 Axial contrast-enhanced CT section showing a transdiaphragmatic mediastinal extension of the lesion (arrows) through the bare area of the liver. Figure 3 Sagittal contrast-enhanced CT section of the abdomen showing extrinsic compression of the retrohepatic (arrows) by the hepatic lesion. Figure 4 Sagittal contrast-enhanced section of the abdomen showing the lesion with mediastinal component (*), omental fat stranding (star) and ascites (arrow). Figure 5 Axial contrast-enhanced CT section showing volume redistribution, surface nodularity and altered parenchymal enhancement of the liver. Hydatid disease, endemic to the tropics is caused by multiple species of the parasite Echinococcus, most commonly by E. granulosus.1 Budd-Chiari syndrome is described as extrinsic or intrinsic hepatic venous outflow obstruction at the level of hepatic venules, large hepatic veins, IVC or right atrium.2

Figure 5 Axial contrast-enhanced CT section showing volume redistribution, surface nodularity and altered parenchymal enhancement of the liver. Hydatid disease, endemic to the tropics is caused by multiple species of the parasite Echinococcus, most commonly by E. granulosus.1 Budd-Chiari syndrome is described as extrinsic or intrinsic hepatic venous outflow obstruction at the level of hepatic venules, large hepatic veins, IVC or right atrium.2 The clinical presentation of hydatid disease can vary from incidental findings to severe complications such as cyst rupture, infection, portal hypertension, biliary communication, hollow viscera perforation or haematogenous spread to other organs such as the lungs, kidney and brain.3 However, hydatid cyst causing extrinsic compression of the IVC and presenting as Budd-Chiari syndrome is rare, as obstruction of at least two main suprahepatic veins should be present and the cysts should be considerably large and in appropriate position to cause significant compression. Apart from mechanical compression, inflammatory response to the cyst contents leading to phlebitis and subsequent thrombosis also contributes to the development of Budd-Chiari syndrome in hydatid disease.4

e present and the cysts should be considerably large and in appropriate position to cause significant compression. Apart from mechanical compression, inflammatory response to the cyst contents leading to phlebitis and subsequent thrombosis also contributes to the development of Budd-Chiari syndrome in hydatid disease.4 Ultrasonography (USG) can be used as an initial screening tool in these patients to assess the size and position of the cyst, its relationship to the hepatic veins and IVC and to look for features of Budd-Chiari syndrome such as caudate lobe enlargement, ascites, splenomegaly and non-visualisation, narrowing or thrombosis of hepatic veins and IVC. Colour Doppler imaging shows monophasic or absent flow within the hepatic veins, IVC or both and intrahepatic collaterals.1 2 Cross-sectional imaging modalities such as CECT abdomen and MRI aid in better evaluation of the hepatic parenchyma, hepatic veins and IVC along with better delineation of the relationship of the cyst with these vascular structures, thereby aiding in surgical planning. Surgery is generally required for cases of secondary Budd-Chiari syndrome due to hydatid cyst. However, venoplasty with stenting has also been performed in these patients, with good results. Medical management is usually only supplementary.5 Learning points Hepatic hydatid disease can rarely present with symptoms of chronic parenchymal liver disease secondary to Budd-Chiari syndrome.

yndrome due to hydatid cyst. However, venoplasty with stenting has also been performed in these patients, with good results. Medical management is usually only supplementary.5 Learning points Hepatic hydatid disease can rarely present with symptoms of chronic parenchymal liver disease secondary to Budd-Chiari syndrome. Budd-Chiari syndrome in hydatid disease is caused by extrinsic compression of the hepatic veins and/or inferior vena cava by the cyst, and also due to venous thrombosis secondary to inflammatory response elicited against the cyst contents. Ultrasonography with Colour Doppler can be used as an initial screening tool in these patients; however, cross-sectional imaging modalities such as contrast-enhanced CT abdomen and MRI help in better delineation of anatomy and surgical planning. Twitter: Follow Sankar Neelakantan at @drsankar23 Contributors: SN contributed to the idea/conceptualisation and contributed to the writeup. SN contributed to the writeup. AASB was involved in. editing. RA was responsible for final approval. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description A 36-year-old man presented with a history of painless swelling on his right distal foot progressively increasing in size since 2 years. Physical examination revealed a non-pulsatile, non-tender, firm swelling over the medial aspect of distal right foot. No discharging sinuses were noted. Plain radiograph showed normal underlying bones with soft tissue swelling of the medial aspect of the right distal foot (figure 1). Ultrasound examination showed multiple, conglomerate hypoechoic lesions with a hyperechoic centre with diffusely increased Doppler signal pick up within (figure 2). MRI revealed hypointense intralesional signals on T1-weighted images and hyperintense intralesional signals on T2-weighted and short tau inversion recovery (STIR) images, involving the subcutaneous and muscular planes of the dorsal and plantar aspects of the medial aspect of the right distal foot. Also noted were multiple, conglomerate, spherical T2 and STIR hyperintense intralesional foci, with hypointense rims, few of which also showed a central hypointensity (Dot in circle sign). The underlying bone appeared normal (figures 3 and 4). Figure 1 Plain radiograph of right foot showing soft tissue swelling with no calcifications in the medial aspect of the distal foot. The adjacent bone appears to be normal. Figure 2 Transverse high-resolution USG grey scale image (7–11 MHz) image (A) of medial aspect of distal foot showing hypoechoic lesions with central hyperechoic fungal grains (arrow).

Figure 1 Plain radiograph of right foot showing soft tissue swelling with no calcifications in the medial aspect of the distal foot. The adjacent bone appears to be normal. Figure 2 Transverse high-resolution USG grey scale image (7–11 MHz) image (A) of medial aspect of distal foot showing hypoechoic lesions with central hyperechoic fungal grains (arrow). Figure 3 Sagittal T2-weighted MR image of the foot showing conglomerates of discrete small round hyperintense lesions with peripheral hypointense rim and central hypointensities within (arrows) in the dorsal and plantar aspects of medial aspect of distal right foot, few lesions are noted to infiltrate into the muscles. The underlying bone appears to be normal. Figure 4  STIR image showing conglomerates of well-defined hyperintense lesions with hypointense rims in the medial aspect of distal foot (arrows). The underlying bone appears to be normal. STIR, short tau inversion recovery. On the basis of clinical presentation, examination and imaging features a diagnosis of mycetoma foot was made and confirmed with punch biopsy and histopathological analysis, which revealed filamentous fungal grains with amorphous brown matrix, suggestive of Madurella mycetomatis. The patient was started on itraconazole therapy for 12 months and showed significant resolution of the swelling on follow-up clinical evaluation at 9 months.

irmed with punch biopsy and histopathological analysis, which revealed filamentous fungal grains with amorphous brown matrix, suggestive of Madurella mycetomatis. The patient was started on itraconazole therapy for 12 months and showed significant resolution of the swelling on follow-up clinical evaluation at 9 months. Mycetoma foot is a chronic granulomatous disease of the subcutaneous tissue native to the tropics. It was first reported in Madurai district of South India, hence the name Madura foot.1 A total of 8753 cases have been reported in the past 50 years, according to a meta-analysis based on 50 full articles.2 Mycetoma commonly affects adults in the age group of 20–40 years, with men being more commonly affected than women with a ratio 3.5:1.3 The disease is caused due to direct transcutaneous implantation of the causative organism Actinomycetes (bacteria) or Eumyces (fungus) which are normal soil inhabitants, secondary to a penetrating wound like a thorn prick.1

age group of 20–40 years, with men being more commonly affected than women with a ratio 3.5:1.3 The disease is caused due to direct transcutaneous implantation of the causative organism Actinomycetes (bacteria) or Eumyces (fungus) which are normal soil inhabitants, secondary to a penetrating wound like a thorn prick.1 Histologically, mycetoma is characterised by aggregates of the organism, known as grains within micro abscesses surrounded by abundant granulation tissue. This appearance is postulated to give rise to the ‘Dot in circle’ sign first described by Sarris et al4 This sign described on T2-weighted, STIR recovery, T1-weighted fat-suppressed gadolinium-enhanced images is characterised by a well-defined spherical hyperintense focus (representing inflammatory granulation tissue), surrounded by a hypointense rim (representing the intervening fibrous septa). The central hypointensity seen within the spherical mass is due to the susceptibility effects of the fungal grain.4 This sign is considered to be specific for the diagnosis of soft tissue mycetoma, seen in up to 80% of individuals with the disease.3 Ultrasound appearance of mycetoma was first described by Fahal et al5 as hyperechoic foci within hypoechoic lesions, where the hyperechoic foci were shown to be fungal grains.

al grain.4 This sign is considered to be specific for the diagnosis of soft tissue mycetoma, seen in up to 80% of individuals with the disease.3 Ultrasound appearance of mycetoma was first described by Fahal et al5 as hyperechoic foci within hypoechoic lesions, where the hyperechoic foci were shown to be fungal grains. Demonstration of the causative organism by biopsy and microbial culture is often difficult and necessitates repeat biopsy leading to delayed diagnosis and increased patient morbidity. Characteristic MRI and ultrasound features can lead to early diagnosis and prompt therapy. Depending on the extent of the disease, patients with only soft tissue involvement can be managed with antimicrobial therapy alone. Bone involvement would require surgical intervention with partial resection or amputation. Learning points A diagnosis of mycetoma is to be considered in the list of differential diagnosis for patients with long-standing, painless swelling of the extremities from endemic areas, even in the absence of multiple draining sinuses. ‘Dot in circle’ sign is a characteristic ultrasound and MR imaging finding for the diagnosis of mycetoma. Inclusion of MRI in the workup of patients with suspected mycetoma can aid in early diagnosis, as well as assess the extent of disease thereby aiding in the initiation of appropriate therapy. Twitter: Follow Sankar Neelakantan at @drsankar23 Contributors: AASB and SN conceived the idea and wrote the manuscript. Pictures were taken by RA. SN has approved the final draft of the manuscript. Competing interests: None declared. Patient consent: Obtained.

Inclusion of MRI in the workup of patients with suspected mycetoma can aid in early diagnosis, as well as assess the extent of disease thereby aiding in the initiation of appropriate therapy. Twitter: Follow Sankar Neelakantan at @drsankar23 Contributors: AASB and SN conceived the idea and wrote the manuscript. Pictures were taken by RA. SN has approved the final draft of the manuscript. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Left ventricular (LV) thrombus is usually seen in situations with reduced LV function, and is mostly seen in patients with large anterior ST-elevation myocardial infarction (MI) with anteroapical aneurysm formation.1 Many of these patients will have an LV apical aneurysm with akinesis or dyskinesis. In most cases, thrombus is located within or adjacent to the LV apex1 but can also occur with large inferolateral infarctions/aneurysms. In observational studies and meta-analyses, most embolic events, in patients with LV thrombus formation, occur within the first 3–4 months, thus the recommendations regarding the duration of anticoagulant therapy.2–6 According to guidelines, an oral vitamin K antagonist (VKA), warfarin, is being used as an anticoagulant for this period.7 8 Novel oral anticoagulants (NOACs: dabigatran, rivaroxaban, apixaban, etc) were found to be either non-inferior or superior compared with warfarin in prevention of thromboembolism in patients with non-valvular atrial fibrillation.9 However, the data about the role of NOACs in the management of LV thrombus are scarce and mostly limited to case reports. Here, we report on the dissolution of LV apical thrombus in three patients with anterior ST-elevation MI receiving dual antiplatelet therapy (DAPT) and rivaroxaban on a reduced dose (15 mg) for 3 months. Case presentation Case 1 A Caucasian male aged 52 years was admitted with retrosternal chest pain evolving during the past 5 days. The ECG showed a subacute anterior STEMI with marked ST elevation and Q waves in leads V2–V6.

Here, we report on the dissolution of LV apical thrombus in three patients with anterior ST-elevation MI receiving dual antiplatelet therapy (DAPT) and rivaroxaban on a reduced dose (15 mg) for 3 months. Case presentation Case 1 A Caucasian male aged 52 years was admitted with retrosternal chest pain evolving during the past 5 days. The ECG showed a subacute anterior STEMI with marked ST elevation and Q waves in leads V2–V6. Transthoracic echocardiography revealed an anteroapical severe hypokinesia with an EF of 35% and an apical sessile thrombus which was confirmed using contrast (figure 1). Figure 1 Contrast echocardiography study confirmed the presence of an apical sessile thrombus and a severe anteroapical hypokinesia with an EF of 35%. HAS-BLED score was 1 point. The coronary angiogram revealed a total occlusion of the midpart of the left anterior descending coronary artery (LAD) and collateral circulation from the right coronary artery. The vessel was treated using newer-generation drug-eluting stent (Resolute Onyx stents, 3.5 Å∼ 26 mm) with a good angiographic final result. HAS-BLED score was 1 point. Case 2 A Caucasian male aged 75 years was admitted with a left-sided thoracic chest pain that started 4 hours prior to presentation. The ECG showed an acute anteroseptal ST-elevation MI with subtle ST elevation in leads V2–V4. Coronary angiography revealed a tight proximal LAD disease that was directly stented using an everolimus 4 Å∼ 18 mm drug-eluting stent with great angiographic final result. DAPT was started using acetylsalicylic acid (150 mg/day) and prasugrel (10 mg/day).

Case 2 A Caucasian male aged 75 years was admitted with a left-sided thoracic chest pain that started 4 hours prior to presentation. The ECG showed an acute anteroseptal ST-elevation MI with subtle ST elevation in leads V2–V4. Coronary angiography revealed a tight proximal LAD disease that was directly stented using an everolimus 4 Å∼ 18 mm drug-eluting stent with great angiographic final result. DAPT was started using acetylsalicylic acid (150 mg/day) and prasugrel (10 mg/day). Transthoracic echocardiography was performed 3 days after the percutaneous coronary invention and revealed a penduculated apical thrombus measuring 1.6×1.7 cm (figure 2) in an akinetic distal anteroapical area and hypokinetic anteroseptal segment with an estimated EF of 35–40%. Figure 2 Transthoracic echocardiography revealed a penduculated apical thrombus measuring 1.6×1.7 cm in an akinetic distal anteroapical area and hypokinetic anteroseptal segment with an estimated EF of 35–40%. HAS-BLED score was 2 points. Case 3 A Caucasian female aged 69 years was admitted with an epigastric pain that started 11 hours prior to presentation. The ECG showed an acute anterolateral ST-elevation MI with ST elevation in leads V1–V6, I, aVL. Coronary angiography revealed a tight proximal to mid-long LAD disease that was directly stented using an everolimus 4 Å∼ 32 mm drug-eluting stent with great angiographic final result. DAPT was started using acetylsalicylic acid (75 mg/day) and ticagrelor (180 mg/day).

Case 3 A Caucasian female aged 69 years was admitted with an epigastric pain that started 11 hours prior to presentation. The ECG showed an acute anterolateral ST-elevation MI with ST elevation in leads V1–V6, I, aVL. Coronary angiography revealed a tight proximal to mid-long LAD disease that was directly stented using an everolimus 4 Å∼ 32 mm drug-eluting stent with great angiographic final result. DAPT was started using acetylsalicylic acid (75 mg/day) and ticagrelor (180 mg/day). Transthoracic echocardiography was performed 4 days after the percutaneous coronary invention and revealed a penduculated and elongated apical thrombus measuring 2.5×1.8 cm (figure 3) and a severely anteroapically hypokinetic LV with an EF of 30%. Figure 3 Transthoracic echocardiography revealed a penduculated and elongated apical thrombus measuring 2.5×1.8 cm and a severely anteroapically hypokinetic left ventricle with an EF of 30%. HAS-BLED score was 2 points. Treatment Regarding the patient reported in case 1, DAPT was initiated with acetylsalicylic acid (100 mg/day) and clopidogrel (75 mg/day), while a reduced dose of rivaroxaban (15 mg/day) was given in order to limit the bleeding risk (triple therapy). At 1 month, echocardiography was repeated and revealed complete dissolution of the thrombus, despite persistence of the apical akinesia. The triple therapy was continued for another 2 months.

rel (75 mg/day), while a reduced dose of rivaroxaban (15 mg/day) was given in order to limit the bleeding risk (triple therapy). At 1 month, echocardiography was repeated and revealed complete dissolution of the thrombus, despite persistence of the apical akinesia. The triple therapy was continued for another 2 months. Regarding the patient reported in case 2, low dose of rivaroxaban was initiated (15 mg/day), while prasugrel was switched to clopidogrel (75 mg/day) and aspirin to 75 mg/day in order again to reduce the bleeding risk as possible. At 1 month, echocardiography was repeated and revealed complete dissolution of the thrombus and normal LV systolic function. Again, and in concordance with the guidelines that refer to VKA after acute coronary syndrome and LV thrombus formation, the above triple therapy (DAPT+rivaroxaban 15 mg/day) was continued for a total of 3 months. The patient on case 4 was started on rivaroxaban (15 mg/day), and ticagrelor was replaced by clopidogrel (75 mg/day). At 2 weeks, echocardiography was repeated and revealed complete dissolution of the thrombus and an improved LV systolic function (EF 40–45%). Again, the above triple therapy was continued for a total of 3 months. Outcome and follow-up All three patients received a triple therapy that consisted of low dose of rivaroxaban (15 mg/day), and DAPT (aspirin 75–100 mg/day plus clopidogrel 75 mg/day) for a total of 3 months. In all patients, complete dissolution of the thrombi was evident by repeat echocardiography study in 2 weeks–1 month. Follow-up for a year was uneventful for all three cases.

erapy that consisted of low dose of rivaroxaban (15 mg/day), and DAPT (aspirin 75–100 mg/day plus clopidogrel 75 mg/day) for a total of 3 months. In all patients, complete dissolution of the thrombi was evident by repeat echocardiography study in 2 weeks–1 month. Follow-up for a year was uneventful for all three cases. Discussion Rivaroxaban is an oral inhibitor that binds directly to factor Xa. It is currently approved for the treatment of deep venous thrombosis, non-valvular atrial fibrillation and pulmonary embolism.9–12 Azizi et al13 describe a case of postinfarction LV thrombus dissolution using a combination of DAPT (aspirin 100 mg/day plus clopidogrel 75 mg/day) plus rivaroxaban for 3 months; nevertheless, the daily dose of rivaroxaban they used was 20 mg/day. We, however, used the low dose of rivaroxaban (15 mg/day) for the reasons we will advocate further down. Ventricular thrombi have been successfully treated using novel anticoagulant, either in cases of old myocardial infarction, where dabigatran was used (220 mg/day),14 or in cases of LV thrombus secondary to tachycardia-induced heart failure using rivaroxaban 15 mg/day.15 Rivaroxaban was also used for treating a case of intraventricular thrombus in Chagas disease16 and in a setting of dilated cardiomyopathy where again 15 mg/day was used.17 Similarly, reported cases have shown the effectiveness of apixaban as well, in the resolution of left atrial thrombus.18

Ventricular thrombi have been successfully treated using novel anticoagulant, either in cases of old myocardial infarction, where dabigatran was used (220 mg/day),14 or in cases of LV thrombus secondary to tachycardia-induced heart failure using rivaroxaban 15 mg/day.15 Rivaroxaban was also used for treating a case of intraventricular thrombus in Chagas disease16 and in a setting of dilated cardiomyopathy where again 15 mg/day was used.17 Similarly, reported cases have shown the effectiveness of apixaban as well, in the resolution of left atrial thrombus.18 Another case report described the growth of a left atrial appendage thrombus, despite well-conducted treatment with a VKA, which then disappeared during treatment with rivaroxaban 15 mg/day.19 In this report, repeated TEE showed a markedly increased giant thrombus mass in the LAA under well-controlled VKA therapy for 6 weeks. After that, the authors decided to switch the oral anticoagulation to rivaroxaban based on the increasing evidence that VKAs had a poor capability to resolve large intracardiac thrombi. This novel direct acting factor Xa inhibitor is reported to have the potential not only to prevent a thrombosis but also to resolve established thrombi by direct inhibition of free and thrombus-associated Factor Xa.20 Note that in a congestive heart failure rat model, rivaroxaban reduced platelet activation by attenuating the secondary phase of ADP-induced platelet aggregation.21

ve the potential not only to prevent a thrombosis but also to resolve established thrombi by direct inhibition of free and thrombus-associated Factor Xa.20 Note that in a congestive heart failure rat model, rivaroxaban reduced platelet activation by attenuating the secondary phase of ADP-induced platelet aggregation.21 In the reported cases, we demonstrate LV thrombus dissolution using a rivaroxaban 15 mg/day in the setting of acute coronary syndromes that forced administration of DAPT. In general, in the setting of ACS, triple therapy with DAPT and NOACs is associated with at least a doubling of the risk of major bleeding, as similarly reported for VKAs in the WOEST trial22 and consistent with the nationwide registry data from Denmark.23 Therefore, there is no strong evidence to suggest that NOACs behave differently to VKAs in the setting of ACS or stenting.

and NOACs is associated with at least a doubling of the risk of major bleeding, as similarly reported for VKAs in the WOEST trial22 and consistent with the nationwide registry data from Denmark.23 Therefore, there is no strong evidence to suggest that NOACs behave differently to VKAs in the setting of ACS or stenting. Thus and even though data are limited, the principle of continuing an existing NOAC seems reasonable at present as stated by the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA).24 It is also stated at the same paper that when VKA is given in combination with clopidogrel and/or low-dose aspirin, the dose intensity of VKA should be carefully regulated, with a target INR range of 2.0–2.5 (Class IIa) and where an NOAC is used in combination with clopidogrel and/or low-dose aspirin, the lower tested dose for stroke prevention in AF (ie, dabigatran 110 mg two times per day, rivaroxaban 15 mg o.d. or apixaban 2.5 mg two times per day) may be considered (Class IIb). Thus, our decision to use the low dose of rivaroxaban stated (15 mg/day).

Thus and even though data are limited, the principle of continuing an existing NOAC seems reasonable at present as stated by the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA).24 It is also stated at the same paper that when VKA is given in combination with clopidogrel and/or low-dose aspirin, the dose intensity of VKA should be carefully regulated, with a target INR range of 2.0–2.5 (Class IIa) and where an NOAC is used in combination with clopidogrel and/or low-dose aspirin, the lower tested dose for stroke prevention in AF (ie, dabigatran 110 mg two times per day, rivaroxaban 15 mg o.d. or apixaban 2.5 mg two times per day) may be considered (Class IIb). Thus, our decision to use the low dose of rivaroxaban stated (15 mg/day). In the setting of patients requiring oral anticoagulation after percutaneous coronary intervention, the European Society of Cardiology25 states that triple therapy should be limited in duration, depending on the clinical setting, thromboembolic (CHA2DS2-VASc) score and bleeding risks (HAS-BLED) score (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol). The duration depends on the individual risk for ischaemic and bleeding events.

ration, depending on the clinical setting, thromboembolic (CHA2DS2-VASc) score and bleeding risks (HAS-BLED) score (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol). The duration depends on the individual risk for ischaemic and bleeding events. The use of prasugrel or ticagrelor as part of triple therapy should be avoided, given the lack of established benefit and the greater risk of major bleeding compared with clopidogrel. In a prospective observational study of 377 patients who underwent drug-eluting stent placement and who had an indication for OAC, 5.6% received prasugrel and the rest ckopidogrel.26 All patients were treated with triple therapy for at least 6 months. The primary end point of thrombolysis in MI major and minor bleeding occurred more often in the prasugrel group (28.6% vs 6.7%). In an analysis of the TRANSLATE-ACS study with 11 756 MI patients, 526 (4.5%) were discharged on triple therapy that included aspirin, clopidogrel and warfarin and 91 (0.8%) on triple prasugrel, aspirin and warfarin therapy.27 Triple therapy of the prasugrel arm was associated with a greater risk of any bleeding events compared with the triple-clopidogrel arm. Gastric protection should be implemented with a proton-pump inhibitor. Triple therapy using an NOAC could be hazardous and only a few studies have investigated triple therapy, including an NOAC in patients suffering from coronary artery disease and non-valvular atrial fibrillation.

In an analysis of the TRANSLATE-ACS study with 11 756 MI patients, 526 (4.5%) were discharged on triple therapy that included aspirin, clopidogrel and warfarin and 91 (0.8%) on triple prasugrel, aspirin and warfarin therapy.27 Triple therapy of the prasugrel arm was associated with a greater risk of any bleeding events compared with the triple-clopidogrel arm. Gastric protection should be implemented with a proton-pump inhibitor. Triple therapy using an NOAC could be hazardous and only a few studies have investigated triple therapy, including an NOAC in patients suffering from coronary artery disease and non-valvular atrial fibrillation. In the APPRAISE-2, apixaban was combined with aspirin and clopidogrel in 81% of patients, and led to a significant increase in fatal and intracranial bleeding without clinical benefit.28 In ATLAS ACS 2, low-dose rivaroxaban (2.5–5 mg two times per day) was administered with aspirin and clopidogrel in 92% of patients. This was associated with a 16% reduction in the composite efficacy end point (cardiovascular death, myocardial infarction and stroke) and a small increase in major bleedings.29 The twice daily 2.5 mg dose of rivaroxaban resulted in significantly lower rates of all-cause and cardiovascular mortality, which was not observed with the twice daily 5.0 mg dose.

In ATLAS ACS 2, low-dose rivaroxaban (2.5–5 mg two times per day) was administered with aspirin and clopidogrel in 92% of patients. This was associated with a 16% reduction in the composite efficacy end point (cardiovascular death, myocardial infarction and stroke) and a small increase in major bleedings.29 The twice daily 2.5 mg dose of rivaroxaban resulted in significantly lower rates of all-cause and cardiovascular mortality, which was not observed with the twice daily 5.0 mg dose. The HAS-BLED score was 1–2 for the abovementioned patients, who had normal creatinine clearance and based on the above as well as on observational studies and meta-analyses, that report that most embolic events, in patients with LV thrombus formation, occur within the first 3–4 months, we decided to use rivaroxaban 15 mg/day in addition to DAPT (aspirin 75 mg/day plus clopidogrel 75 mg/day) for a total of 3 months. All patients had complete thrombus resolution and no bleeding complications. Learning points Short-duration rivaroxaban at a low dose (15 mg/day) in combination with a dual antiplatelet therapy (DAPT) was effective for the treatment of left ventricular (LV) thrombus in patients with acute coronary syndromes and drug-eluting stent implantation, and at low to intermediate bleeding risk.

ications. Learning points Short-duration rivaroxaban at a low dose (15 mg/day) in combination with a dual antiplatelet therapy (DAPT) was effective for the treatment of left ventricular (LV) thrombus in patients with acute coronary syndromes and drug-eluting stent implantation, and at low to intermediate bleeding risk. Randomised controlled trials are needed to confirm these encouraging observational data, and to possibly confirm the optimal low dosage of NOACs when associated with DAPT, demonstrating that these molecules can effectively replace VKAs in the treatment of post-STEMI LV thrombi in patients undergoing percutaneous coronary intervention. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Primary aortoduodenal fistulae (ADF) are very uncommon. Data from autopsy series show a prevalence of 0.07%. These cause an estimated 3% of massive gastrointestinal (GI) haemorrhages but comprise 6% of all deaths.1 Secondary ADF (fistulae occurring after abdominal aneurysm repair) occur over 10 times more frequently than primary at a rate of 0.5–1.1%. This accounts for over 80% of all aortoenteric fistulae (AEF), and occur following an estimated 4% of open aortic repairs.2–4 The rarity of primary AEF or ADF make it difficult to ascertain aetiology. While the treatment for massive GI bleeding follows an established algorithm, diagnosis of a primary ADF can be more difficult due to its infrequency as well as its occasionally insidious presentation. Early diagnosis of ADF is critical due to their significant lethality, with an estimated 5% of patients dying prior to surgical intervention. No one study has been able to quantify what the exact mortality is, but based on our literature review, it appears to be anywhere from 30% to 70%.2 5 6 ADF is three times more common in men than women and features an average age at presentation of 64 years. As mentioned above, it is significantly more likely in patients who previously had an aortic intervention (eg, open aortic aneurysm repair). Unfortunately, elderly patients frequently present to emergency departments with upper GI bleeding and even with a high index of suspicion, ADF is rarely thought to be likely in a standard differential diagnosis.

cantly more likely in patients who previously had an aortic intervention (eg, open aortic aneurysm repair). Unfortunately, elderly patients frequently present to emergency departments with upper GI bleeding and even with a high index of suspicion, ADF is rarely thought to be likely in a standard differential diagnosis. Case presentation A man aged 78 years presented to the emergency room at an outside hospital with symptoms of new-onset left lower extremity numbness, tingling and a presyncopal episode. While in the emergency department, he began to have severe intermittent abdominal pain with multiple reported episodes of haematochezia. A nasogastric (NG) tube was placed with interval removal of an unknown quantity of sanguineous output. CT angiogram (CTA) of his chest, abdomen and pelvis was performed along with a lower extremity arterial duplex. These showed a 4.6 cm abdominal aortic aneurysm (AAA) without evidence of rupture and a 1.6 cm left iliac aneurysm (figures 1 and 2). It also revealed non-visualisation of two of three mesenteric vessels with severe atherosclerosis of both external iliac arteries with near occlusion on the left. He was started on a proton-pump inhibitor infusion, transfused 2 units of packed red blood cells (PRBCs) and was transferred to our hospital for further care.

t also revealed non-visualisation of two of three mesenteric vessels with severe atherosclerosis of both external iliac arteries with near occlusion on the left. He was started on a proton-pump inhibitor infusion, transfused 2 units of packed red blood cells (PRBCs) and was transferred to our hospital for further care. Figure 1 Saggital CT angiography demonstrating separation between the patient's known 4.6 cm saccular (red arrow), infrarenal abdominal aortic aneurysm and the eventual site of exsanguinating haemorrhage (blue arrow). Note: there is no extravasation of contrast to suggest the presence of an aortoduodenal fistula. Figure 2 Coronal CT angiography demonstrating separation between the patient's known 4.6 cm saccular (red arrow), infrarenal abdominal aortic aneurysm and the eventual site of exsanguinating haemorrhage (blue arrow). Note: there is no extravasation of contrast to suggest the presence of an aortoduodenal fistula.

Figure 1 Saggital CT angiography demonstrating separation between the patient's known 4.6 cm saccular (red arrow), infrarenal abdominal aortic aneurysm and the eventual site of exsanguinating haemorrhage (blue arrow). Note: there is no extravasation of contrast to suggest the presence of an aortoduodenal fistula. Figure 2 Coronal CT angiography demonstrating separation between the patient's known 4.6 cm saccular (red arrow), infrarenal abdominal aortic aneurysm and the eventual site of exsanguinating haemorrhage (blue arrow). Note: there is no extravasation of contrast to suggest the presence of an aortoduodenal fistula. On arrival, the gastroenterology service was consulted by the intensive care unit (ICU), but endoscopy was initially deferred because the patient had two bowel movements in the ICU without evidence of melena, he had no recurrence of haematochezia and NG tube output was non-bloody. Furthermore, he had a stable haemoglobin, his vital signs were within normal limits and his other symptoms seemed imperative at the time. Review of his medical history was notable for peripheral arterial disease, an AAA previously measuring 4.4 cm in size, a left iliac aneurysm measuring 1.6 cm and a splenectomy for lymphoma (unknown type). Several hours following admission, the patient became increasingly tachycardic, tachypnoeic, febrile, with worsening abdominal pain and a worsening leucocytosis. General surgery was consulted and his abdominal examination demonstrated peritonitis. Further, he was found to have a cold, pulseless left lower extremity with decreased sensation but preserved motor function. A lower extremity arterial duplex showed sluggish, monophasic flow to the left foot with occlusion of the femoral vessels and reconstitution at the popliteal artery. A presumptive diagnosis of mesenteric ischaemia and acute on chronic critical limb ischaemia was made, and the patient was prepared for an emergent exploratory laparotomy. A vascular surgery consult was placed and they recommended initiation of a heparin infusion postoperatively and aspirin for his threatened limb, with possible further interventions after stabilisation of his general surgical issues. The patient was given broad-spectrum antibiotics, full anticoagulation with heparin though a bolus dose was withheld due to his reported prior GI bleeding and he was taken to the operating theatre for exploration.

s threatened limb, with possible further interventions after stabilisation of his general surgical issues. The patient was given broad-spectrum antibiotics, full anticoagulation with heparin though a bolus dose was withheld due to his reported prior GI bleeding and he was taken to the operating theatre for exploration. In the operating theatre, he was found to have a necrotic descending and sigmoid colon. An intraoperative oesophagogastroduodenoscopy (EGD) demonstrated clotted blood in the stomach and in the duodenum to the ampulla, with no evidence of active bleeding. A left colectomy was performed and the patient was left in discontinuity with temporary abdominal closure due to the patient's extremis and expectation of a ‘second-look’ operation. The possibility of an ADF was discussed initially but in the light of the ischaemic left colon and unimpressive EGD, this diagnosis was thought to be unlikely.

performed and the patient was left in discontinuity with temporary abdominal closure due to the patient's extremis and expectation of a ‘second-look’ operation. The possibility of an ADF was discussed initially but in the light of the ischaemic left colon and unimpressive EGD, this diagnosis was thought to be unlikely. The patient was taken back to the ICU for further resuscitation. After receiving 4 units of PRBCs perioperatively, his haemoglobin had increased appropriately to 14.7 g/dL. His vital signs and base deficit normalised. He was kept on antibiotics for ischaemic colitis and low-dose heparin for suspected acute on chronic critical ischaemia of the left lower extremity. The second-look operation was planned for 24–36 hours after his initial surgery in order to further investigate the source of his GI bleeding, reassess the viability of his bowel, mature a stoma and possibly close his abdomen. The patient remained stable for 20 hours until the night of postoperative day 1 when he experienced sudden-onset tachycardia and hypotension requiring vasopressor support, dropping haemoglobin and worsening abdominal distension. Shortly thereafter, he began to have grossly sanguineous output from his NG tube. A massive transfusion protocol was initiated and the patient was emergently taken to the operating theatre for haemorrhagic shock due to an upper GI bleed from an unclear source.

t, dropping haemoglobin and worsening abdominal distension. Shortly thereafter, he began to have grossly sanguineous output from his NG tube. A massive transfusion protocol was initiated and the patient was emergently taken to the operating theatre for haemorrhagic shock due to an upper GI bleed from an unclear source. In the operating theatre, no extraluminal bleeding was appreciated. The small bowel and remaining colon appeared healthy. Given continued sanguineous drainage from the patient's NG tube, an anterior gastrotomy was made. This revealed a large volume of clot that was subsequently evacuated. The mucosal surface was otherwise intact and healthy appearing. During inspection of the stomach, a large volume of arterial blood was appreciated to be coming retrograde via the pylorus. A proximal, longitudinal duodenotomy was made, but there was no bleeding appreciated to be coming from the first or second part of the duodenum. Profuse bleeding continued from the distal small bowel and the patient went into cardiac arrest. His aorta was cross-clamped at the diaphragmatic hiatus and advanced cardiovascular life support was initiated. Despite maximal resuscitative efforts, the patient was pronounced dead 20 min later. Differential diagnosis Gastric or duodenal ulcer, gastric or duodenal perforation, AAA, mesenteric ischaemia, Mallory Weiss tear, gastric or duodenal mass, aortoenteric fistula.

In the operating theatre, no extraluminal bleeding was appreciated. The small bowel and remaining colon appeared healthy. Given continued sanguineous drainage from the patient's NG tube, an anterior gastrotomy was made. This revealed a large volume of clot that was subsequently evacuated. The mucosal surface was otherwise intact and healthy appearing. During inspection of the stomach, a large volume of arterial blood was appreciated to be coming retrograde via the pylorus. A proximal, longitudinal duodenotomy was made, but there was no bleeding appreciated to be coming from the first or second part of the duodenum. Profuse bleeding continued from the distal small bowel and the patient went into cardiac arrest. His aorta was cross-clamped at the diaphragmatic hiatus and advanced cardiovascular life support was initiated. Despite maximal resuscitative efforts, the patient was pronounced dead 20 min later. Differential diagnosis Gastric or duodenal ulcer, gastric or duodenal perforation, AAA, mesenteric ischaemia, Mallory Weiss tear, gastric or duodenal mass, aortoenteric fistula. Treatment Treatment of AEF includes repair of the aorta via either in situ graft placement or extra-anatomic bypass along with possible placement of in situ grafts. Omentum should then be placed over the repair. The repair of the small bowel is generally performed primarily but at times may require resection and anastomosis.

Treatment Treatment of AEF includes repair of the aorta via either in situ graft placement or extra-anatomic bypass along with possible placement of in situ grafts. Omentum should then be placed over the repair. The repair of the small bowel is generally performed primarily but at times may require resection and anastomosis. Outcome and follow-up Postmortem, further exploration and medial visceral rotation of the duodenum revealed a 4 mm ulcer in the third portion. Blood was expressed via this penetrating ulcer with manual compression of the underlying aorta, consistent with a primary ADF.

The repair of the small bowel is generally performed primarily but at times may require resection and anastomosis. Outcome and follow-up Postmortem, further exploration and medial visceral rotation of the duodenum revealed a 4 mm ulcer in the third portion. Blood was expressed via this penetrating ulcer with manual compression of the underlying aorta, consistent with a primary ADF. Discussion Diagnosis of an ADF or AEF can be challenging as a frequent presentation is that of a minor upper GI bleed. In primary and secondary ADF, the most common symptoms of an actively bleeding fistula are haematemesis, melena, the sequelae of hypotension (such as fatigue or syncope) and abdominal pain. Non-bleeding fistulae may simply present as abdominal pain.7–9 The aetiology of secondary ADF or AEF appears to involve either sepsis, mechanical trauma between the graft and adherent intestine or a combination of both.3 Secondary AEF most frequently occur 36 months postoperatively but can vary in time to presentation from a few months to several years. Most AEF involve the duodenum (60%), but fistulae between the aorta and the GI tract can occur from the oesophagus to the colon.5 The declining incidence of oesophageal aortic fistulae is primarily due to the declining prevalence of syphilis, but the remainder of the distribution appears to have stayed the same since its first discovery in the midnineteenth century.10 The aetiology of primary ADF is more controversial and likely more idiosyncratic. In the patient described above, there was a stable AAA, which was significantly more inferior than the level of the fistula. It is possible that this was involved in the aetiology of this particular patient's ADF, but seems highly unlikely to be a direct cause in the light of the physical separation of the AAA from the ADF. It is more likely that the advanced atherosclerotic disease that contributed to the development of an AAA also caused the primary ADF.

that this was involved in the aetiology of this particular patient's ADF, but seems highly unlikely to be a direct cause in the light of the physical separation of the AAA from the ADF. It is more likely that the advanced atherosclerotic disease that contributed to the development of an AAA also caused the primary ADF. CT has an estimated sensitivity of 60%. While this is the most sensitive of available imaging modalities, the false-negative rate is quite high. As no one imaging modality is highly sensitive, CT scan, barium swallow and angiography can all be complementary to elicit the correct diagnosis.6 11 Endoscopy, as was performed in this case, may not visualise the bleed and may disrupt a clot. Conversely, it may also provide essential diagnostic information. We suggest that endoscopy be performed in the operating theatre by a highly experienced endoscopist if there is high clinical suspicion for an ADF due to the potential for sudden, life-threatening bleeding. Had the endoscopist in this scenario reached the third portion of the duodenum, it is possible that the ADF would have been discovered prior to exsanguination. Classically, a ‘herald bleed’ is described as a form of self-limited period of bleeding, providing warning for a subsequent massive haemorrhage. The frequency of this poorly understood phenomenon is unknown, and by definition, it may be subclinical. There can also be a significant variance in the time course between the ‘herald bleed’ and a massive haemorrhage, anywhere from 6 hours to 3 weeks. While resuscitation is the first step in the treatment of ADF, preventing hypertension and even permissive hypotension may just as critical to avoid disruption of a formed thrombus.4 12–14

e a significant variance in the time course between the ‘herald bleed’ and a massive haemorrhage, anywhere from 6 hours to 3 weeks. While resuscitation is the first step in the treatment of ADF, preventing hypertension and even permissive hypotension may just as critical to avoid disruption of a formed thrombus.4 12–14 An estimated 50% of all AEF repairs (to include primary and secondary ADF or AEF) involve an extra-anatomic bypass with in situ grafts placed nearly 40% of the time. The placement of omentum over the repair and in situ (versus extra-anatomic) graft placement are two factors that appear to reduce the overall mortality. The most frequent cause of death in patients who survived the initial repair is recurrent ADF (49%), multiorgan system failure (16%) and sepsis (16%). The repair infrequently involves resection of small bowel with most enteric repairs being performed primarily. In patients requiring resection, resection and anastomosis are performed significantly more frequently than other procedures such as gastrojejunostomy or Roux en Y.6

rgan system failure (16%) and sepsis (16%). The repair infrequently involves resection of small bowel with most enteric repairs being performed primarily. In patients requiring resection, resection and anastomosis are performed significantly more frequently than other procedures such as gastrojejunostomy or Roux en Y.6 This patient's herald bleed likely led to acute on chronic ischaemia in his left lower extremity as well as colonic ischaemia. The CTA was negative and the patient had no history of prior intervention on his known AAA. During the first operation, a plausible explanation for this patient's upper GI bleed was not discovered and would not be discovered until too late. While primary AEF is a rare clinical entity, nearly every other possible source of bleeding had been excluded by the time the patient exsanguinated. This speaks to the need for heightened clinical suspicion that must exist even for such unusual sources of life-threatening GI bleeding. In the immortal words of Sir Arthur Conan Doyle, ‘When you have excluded the impossible, whatever remains, however improbable, must be the truth’.15 Hence with the known poor sensitivity and specificity of all forms of imaging, negative test results rule out little. In the current era with highly sophisticated imaging, it can be easy to forget that direct visualisation is sometimes the only form of direct evidence possible. Additionally, it seems that there is a trend towards limiting the invasiveness of large open surgeries as minimally invasive techniques are now the norm. It is better to have a negative exploratory laparotomy, or even a negative duodenotomy, than a dead patient.

n is sometimes the only form of direct evidence possible. Additionally, it seems that there is a trend towards limiting the invasiveness of large open surgeries as minimally invasive techniques are now the norm. It is better to have a negative exploratory laparotomy, or even a negative duodenotomy, than a dead patient. Learning points Owing to the difficulty in diagnosis of aortoenteric fistulae (AEF), a high index of suspicion is necessary to make a timely diagnosis. While CT angiography is the best studied imaging modality available, its sensitivity is poor for AEF. The standard presentation of this diagnosis may be confounded by patient-specific comorbidities. When exploring the abdomen for massive upper gastrointestinal bleeding, it is imperative to examine the third portion of the duodenum. Contributors: CRNR provided manuscript editing as well as literature review. EC and RM provided manuscript writing and review. SR provided intellectual content and manuscript editing. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background The natural history of a mycotic abdominal aortic aneurysm (MAAA) is that of a rapid progression to rupture and usually death.1 2 Campylobacter fetus is an actual infective agent for MAAA, especially in elderly or debilitated patients.3 4 We report here the first case efficiently treated by endovascular aortic repair (EVAR) and antibiotic therapy. In frail patients, EVAR could be a suitable alternative, allowing immediate less invasive treatment. Even if it is generally considered a bridge therapy, it could also sometimes represent a more durable treatment option with total remission of the infection. Case presentation A 73-year-old male patient presented to our emergency department after 4 days of fever, chills and pain in the lower abdomen irradiating to the back. He also reported having diarrhoea for 3 days. Medical history was relevant for ischaemic and hypertensive heart disease. Seven days previously he had a coronarography. He had a temperature of 37.8°C, normal blood pressure and heart rate and abdominal pain without signs of peritonitis. No pulsatile abdominal mass was palpable.

reported having diarrhoea for 3 days. Medical history was relevant for ischaemic and hypertensive heart disease. Seven days previously he had a coronarography. He had a temperature of 37.8°C, normal blood pressure and heart rate and abdominal pain without signs of peritonitis. No pulsatile abdominal mass was palpable. Investigations Blood tests showed an elevated white cell count of 15.5 G/L (normal value: 4–10 G/L), an elevated C reactive protein of 315 mg/L (normal value<5 mg/L) and a haemoglobin value of 105 g/L (normal value: 120–180 g/L). An abdominal CT scan showed a partially thrombosed infrarenal atherosclerotic aortic aneurysm of 38 mm with periaortitis (figure 1). A CT scan performed the next day because of worsening abdominal pain showed a contained rupture (figure 2A, B). Blood cultures were positive for C. fetus. Figure 1 Abdominal CT scan showing an infrarenal atheroscleroting aortic aneurysm of 38 mm with periaortitis. Figure 2 (A and B) CT scan performed the second day because of acute abdominal pain showing signs of contained rupture. Differential diagnosis Contained rupture of a MAAA following infectious aortitis was the main diagnostic hypothesis. The hypothesis of a postcoronarography aneurysmal infection was invalidated by the blood cultures showing C. fetus, no cutaneous germs and by the absence of previous aneurysmal disease.

Figure 2 (A and B) CT scan performed the second day because of acute abdominal pain showing signs of contained rupture. Differential diagnosis Contained rupture of a MAAA following infectious aortitis was the main diagnostic hypothesis. The hypothesis of a postcoronarography aneurysmal infection was invalidated by the blood cultures showing C. fetus, no cutaneous germs and by the absence of previous aneurysmal disease. Treatment Intravenous empiric antibiotic treatment with amoxicilline–clavulanate was initiated immediately after the first abdominal CT scan, and the patient was admitted to the intensive care unit. He was operated 24 hours later after clinical deterioration and a CT scan showing a contained rupture of the aneurism. He was considered unfit for open surgery because of severe ischaemic heart disease. A ‘bridge therapy’ with EVAR was therefore planned. He underwent a percutaneous endovascular aneurysmal exclusion with endograft (Endurant II ETLW 16×16 C 93 and ETLW 16×16 C 82) under local anaesthesia. After blood cultures were found to be positive for C. fetus, the initial antibiotic therapy was replaced by an intravenous treatment with imipenem–cilastatin for 3 weeks followed by oral ciprofloxacin for 3 weeks.

rysmal exclusion with endograft (Endurant II ETLW 16×16 C 93 and ETLW 16×16 C 82) under local anaesthesia. After blood cultures were found to be positive for C. fetus, the initial antibiotic therapy was replaced by an intravenous treatment with imipenem–cilastatin for 3 weeks followed by oral ciprofloxacin for 3 weeks. Outcome and follow-up Our patient had a favourable postoperative outcome. An abdominal CT scan on postoperative day 3 showed exclusion of the aneurysm by the endoprosthesis. A small type II endoleak required no specific treatment. The patient was discharged 9 days after surgery and followed up regularly. At 12 months, the clinical evolution was favourable. The clinical examination and CT scan showed no endoleak or signs of infection, so it was decided not to convert to open surgery.

hesis. A small type II endoleak required no specific treatment. The patient was discharged 9 days after surgery and followed up regularly. At 12 months, the clinical evolution was favourable. The clinical examination and CT scan showed no endoleak or signs of infection, so it was decided not to convert to open surgery. Discussion The entity of mycotic aneurysm was first described by William Osler in 1885.2 The term is, however, misleading since the majority of mycotic aneurysms are due to bacterial infection and are not fungal in nature. Since the classical triad of fever, abdominal pain and pulsatile abdominal mass is not always present, the diagnosis of a mycotic aneurysm can be very challenging and requires a high degree of suspicion.3 4 The most commonly cultured organisms include Staphylococcus (30%), Streptococcus (10%) and Salmonella (10%).1–4 Other microorganisms such as Brucella can be responsible for aortitis.5 C. fetus is a very rare cause of mycotic aneurysm especially in the elderly with other underlying pathologies.3 In our case, the patient was an elderly ex-smoker with ischaemic heart disease and a recent history of gastroenteritis. He was not known for having an abdominal aortic aneurysm. During hospitalisation, he had no gastrointestinal symptoms and stool cultures that could have shown that he was an asymptomatic germ carrier were unfortunately not performed. The fact that the blood cultures were positive for C. fetus indicates that the patient had in all probability first suffered from bacteraemia with C. fetus, which led to an aortits that itself degenerated into a mycotic aneurysm. Regarding the treatment of MAAA, antibiotic therapy is essential but is inadequate if given alone.3 6–9 The appropriate dose, duration and regimen of antibiotic therapy have not yet been established. Some authors report that a period of 4–8 weeks of antibiotic treatment is sufficient, whereas others insist on lifelong antibiotic therapy.1 3 There is no widely accepted consensus on this point, and the indications must therefore be determined case by case. Surgical intervention for MAAA remains challenging. Extra-anatomic bypass has been replaced9 by in situ graft replacement surgery as the gold standard treatment.4 10 EVAR has been introduced as an alternative allowing minimally invasive intervention with prompt aneurysmal exclusion and immediate control of bleeding. It is particularly useful in the case of severely ill or elderly patients.

s has been replaced9 by in situ graft replacement surgery as the gold standard treatment.4 10 EVAR has been introduced as an alternative allowing minimally invasive intervention with prompt aneurysmal exclusion and immediate control of bleeding. It is particularly useful in the case of severely ill or elderly patients. Until recently, EVAR was considered to be a temporary treatment prior to definitive open repair and was therefore called a ‘bridge to open surgery’.2 However, a recent study comparing the results of EVAR with those of conventional surgery for treatment of MAAA showed that EVAR appears to be equivalent to surgery.4 Additionally, the European multicentre collaboration trial, the largest ever on mycotic aortic aneurysm, studied the durability of EVAR by assessing late infection-related complications and long-term survival. The study concludes that EVAR can be a durable treatment option for most patients. Open repair shows short-term mortality rates of 20–40% and significant short-term and long-term morbidities related to the operation with a 5-year survival of 35%.2 According to the same study, EVAR has a good short-term outcome with 91% survival at 30 days and 55% at 5 years. However, the implantation of prosthetic material in an infected site remains a major problem. The study shows 19% of fatal infection-related complications, mostly occurring during the first postoperative year for EVAR, versus only 7–10% for open surgery. Non-Salmonella-positive blood cultures seem to be the main factor associated with serious late infectious complications.2 Long-term antibiotic treatment and strict follow-up are required in order to minimise late infections that are often fatal. Our patient was successfully treated with EVAR and 6 weeks of antibiotics. At 1 year, he showed no signs of infectious complications. To the best of our knowledge, this is the 29th case of MAAA infected with C. fetus to be reported in the English literature and the first case to be successfully treated with EVAR (table 1).1 6–24

t was successfully treated with EVAR and 6 weeks of antibiotics. At 1 year, he showed no signs of infectious complications. To the best of our knowledge, this is the 29th case of MAAA infected with C. fetus to be reported in the English literature and the first case to be successfully treated with EVAR (table 1).1 6–24 Table 1 A summary of mycotic abdominal aneurysms caused by Campylobacter fetus

t was successfully treated with EVAR and 6 weeks of antibiotics. At 1 year, he showed no signs of infectious complications. To the best of our knowledge, this is the 29th case of MAAA infected with C. fetus to be reported in the English literature and the first case to be successfully treated with EVAR (table 1).1 6–24 Table 1 A summary of mycotic abdominal aneurysms caused by Campylobacter fetus Author Year Antibiotic therapy Operation Outcome Dolev et al6 1971 – Replaced-Dacron graft Died few hours after operation File et al7 1979 – – Died before operation Taylor et al8 1979 – – Died before operation Anolik et al9 1983 Long term Aneurysm excision, AXBF Alive, 45 months Marty et al10 1983 7 months Replaced-Dacron graft Alive, 2 years Blabey et al11 1983 7 weeks Aneurysm excision, AXBF Alive, 18 months Righter Woods12 1985 1 week Replaced-Dacron graft Alive, 3 years Perry13 1985 8 weeks Replaced-Dacron graft Alive, 6 months Rutherford et al14 1989 5 months Dacron graft Alive, 2 years Jacobs et al15 1989 – Aneurysm excision, AXBF Died after 7 days Kato et al16 1990 2 weeks Aneurysm excision, AXBF Alive, 36 months Allerberger et al17 1991 – – Died, before operation Grollier et al18 1993 – Replaced-Dacron graft ND Mii et al19 1998 3 months Replaced-Dacron graft Alive, 1 year Tran et al20 2007 Life long Replaced-Polyester graft Alive, 9 months Cochennec et al21 2008 Long term Replaced-Dacron graft Alive, 6 months Cochennec et al21 2008 Long term Dacron graft Alive, 5 months Cochennec et al21 2008 Long term EVAR Died, after 2 weeks Cochennec et al21 2008 Long term Replaced-Allograft Alive, 18 months Brossier et al22 2010 – Replaced-Dacron graft Alive, 34 months Brossier et al22 2010 – Replaced- Silver graft Alive, 28 months Brossier et al22 – Replaced-Dacron graft Alive, 5 months Brossier et al22 2010 – EVAR Died, after 15 days Brossier et al22 2010 – Replaced-Allograft Alive, 38 months Maeda et al1 2011 – Replaced-Polyester graft Alive Maeda et al1 2011 – Replaced-Polyester graft Alive Noda et al23 2011 More than 4 weeks Replaced-Dacron graft Alive, 1 year Hagiya et al24 2013 Long term Replaced-Polyester J graft Alive, 1 year Present case 2015 6 weeks EVAR (Endurant II stent graft) Alive, 1 year AXBF, axillobifemoral bypass operation; EVAR, endovascular aortic repair.

– Replaced-Polyester graft Alive Noda et al23 2011 More than 4 weeks Replaced-Dacron graft Alive, 1 year Hagiya et al24 2013 Long term Replaced-Polyester J graft Alive, 1 year Present case 2015 6 weeks EVAR (Endurant II stent graft) Alive, 1 year AXBF, axillobifemoral bypass operation; EVAR, endovascular aortic repair. Learning points Mycotic aneurysms are rare, regardless of aetiology, and should be suspected when symptoms and patient characteristics make it an actual differential diagnosis. In such circumstances, a CT scan and blood cultures are mandatory. Ideal duration of antibiotic treatment has not yet been established. In our case, 6 weeks seem to have been sufficient; however, follow-up is probably too short for final conclusions. This case supports the use of EVAR in patients with mycotic aneurysms with Campylobacter fetus, even though earlier attempts of EVAR in similar cases failed. Dr Dominique Hennion is a radiologist in the Department of Radiology of Hôpital Cantonal de Fribourg for the CT reconstructions. Contributors: MD and FC were responsible for database search and writing of the article. SD performed the surgery. SD and EP were responsible for correction of the article and supervision. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Autoimmune lymphoproliferative syndrome (ALPS), also known as the Canale-Smith syndrome, is a rare disorder. The increase in DNT cells, interleukin 10 (IL-10) and polyclonal elevation of gamma globulin (IgG) can be diagnostically relevant in patients under suspicion of this syndrome. The genetic defect found in most patients is a mutation in the FAS gene, which encodes a cell surface receptor, on stimulation, and induces a programmed cell death. This entity typically develops in childhood and, in contrast, there are a few reported adult-onset cases.1–3 Case presentation A 41-year-old man, with a history of pulmonary tuberculosis and with no family history of lymphoproliferative and autoimmune diseases, was taken to the emergency department and exhibited multiple cervical, axillary and inguinal lymph node enlargements, and epistaxis with more than a 6-month history. He had had an intermittent fever lasting for 4 months. There was no loss of weight or appetite, neither night sweats nor any other localising symptoms, namely pulmonary symptoms or signs. On physical examination, he had pallor, petechial and oral haemorrhagic bullae.

nts, and epistaxis with more than a 6-month history. He had had an intermittent fever lasting for 4 months. There was no loss of weight or appetite, neither night sweats nor any other localising symptoms, namely pulmonary symptoms or signs. On physical examination, he had pallor, petechial and oral haemorrhagic bullae. Investigations According to our research on this patient, we found out that he had bicytopaenia with a haemoglobin of 8.7 g/dL and platelet count of 4000/µL, total leucocyte count was 6650/µL with normal differentials. Liver and renal function tests, prothrombin time and vitamin B12 were all within normal range. Biochemical evidence of haemolysis was supported by serum decresead haptoglobin level, increased indirect bilirubin and lactate dehydrogenase levels. Direct anti-globulin test was positive (IgG3+; C3d1+). Abdominal ultrasound revealed a hepatomegaly (17 cm), splenomegaly (14,5 cm), as well as retroperitoneal and external iliac adenomegaly about 3×1 cm. Thoracic CT showed axillary adenomegaly of 2×2.5 cm. The infection diagnostic work-up, including blood and urine culture, screening for tuberculosis, HIV, toxoplasmosis, parvovirus, cytomegalovirus, Brucella and hepatitis, was all negative. The autoimmune work-up was also negative. The patient’s bone marrow biopsy was normal. In addition, ganglion excisional biopsy excluded malignancy and mycobacteriology cultures were negative for Mycobacterium tuberculosis or other non-tuberculous Mycobacterium. Flow cytometry of peripheral blood reported that 8% of the lymphocytes were DNT cells. Plasma concentrations of soluble interleukin-10 (IL-10) were increased, but none FAS and FASL mutations was detected (tables 1 and 2). A probable ALPS diagnosis was made.

bacterium tuberculosis or other non-tuberculous Mycobacterium. Flow cytometry of peripheral blood reported that 8% of the lymphocytes were DNT cells. Plasma concentrations of soluble interleukin-10 (IL-10) were increased, but none FAS and FASL mutations was detected (tables 1 and 2). A probable ALPS diagnosis was made. Table 1 Results of laboratory tests released to patient during the study Patient values Reference values Total bilirubin 2.07 mg/dL 0.1–1.1 Directed bilirubin 0.69 mg/dL 0.1–0.3 Lactate dehydrogenase 618 U/L 135–225 Haptoglobin <10.0 ng/mL 30–200 Direct antiglobulin test IgG 3+; C3d1+ Aspartate aminotransferase 44 U/L 4–33 Alanine aminotransferase 50 U/L 4–50 γ-glutamyl transferase 71 U/L 5–61 C reactive protein 3.79 mg/dL 0–0.5 Polyclonal hypergammaglobulinaemia 2710 mg/dL Activated partial thromboplastin time 42.4 s 28.0–40.0 Peripheral blood assays IL-10: 22.8 pg/mL ≤20 FASL: 143 pg/mL ≤200 Immunophenotyping of peripheral blood lymphocytes 8% TCRab CD3+CD4−CD8− T-cells IL-10, interleukin 10; s, seconds. Table 2 Results of histopathological and genetics analysis released during the study

Patient values Reference values Total bilirubin 2.07 mg/dL 0.1–1.1 Directed bilirubin 0.69 mg/dL 0.1–0.3 Lactate dehydrogenase 618 U/L 135–225 Haptoglobin <10.0 ng/mL 30–200 Direct antiglobulin test IgG 3+; C3d1+ Aspartate aminotransferase 44 U/L 4–33 Alanine aminotransferase 50 U/L 4–50 γ-glutamyl transferase 71 U/L 5–61 C reactive protein 3.79 mg/dL 0–0.5 Polyclonal hypergammaglobulinaemia 2710 mg/dL Activated partial thromboplastin time 42.4 s 28.0–40.0 Peripheral blood assays IL-10: 22.8 pg/mL ≤20 FASL: 143 pg/mL ≤200 Immunophenotyping of peripheral blood lymphocytes 8% TCRab CD3+CD4−CD8− T-cells IL-10, interleukin 10; s, seconds. Table 2 Results of histopathological and genetics analysis released during the study Bone marrow biopsy Anatomopathological examination: 3 haematopoietic lines were observed. The erythroid line was increased with normoblasts and megakaryocytic line with many dysmorphic elements. No changes to granulocytic line. Without malignancy characteristics. Immunophenotyping: without changes. Axillary lymph node excisional biopsy Anatomopathological examination: preservation of lymph node architecture and reactive character changes without malignancy characteristics; Acid-alcohol resistant bacillus: negative; Mycobacteriology cultures: negative; Immunophenotyping: without changes. Fas gene detection Mutations not detected, but the method used does not exclude mutations outside the FAS gene regions analysed or not detectable by sequencing. Unrealised searching for deletions or duplications in the FAS gene and sequencing of FASL or CASP10 genes. Treatment In the acute phase, 1 mg/kg of IgG was first administered and 10 mg/kg methylprednisolone over 3 days, followed by maintenance dose of 1.5 mg/kg per day prednisolone. He began to show a response after 2 weeks and the platelet count was normal in just 1 month. A complete remission of the clinical and laboratory abnormalities was achieved after a prolonged prednisolone tapering over the period of 12 months.

e over 3 days, followed by maintenance dose of 1.5 mg/kg per day prednisolone. He began to show a response after 2 weeks and the platelet count was normal in just 1 month. A complete remission of the clinical and laboratory abnormalities was achieved after a prolonged prednisolone tapering over the period of 12 months. Outcome and follow-up We have been closely following him up every month, and his lymphadenopathy and hepatosplenomegaly have regressed (ultrasound liver 15.7 cm and spleen 10.8 cm). The axillary nodes have disappeared, and the cervical nodes have been just palpable for 2 months. After a 24-month follow-up without any treatment, the patient is asymptomatic and with no evidence of recurrence. It was programmed a lymphocyte apoptosis assay and a positron emission tomography (PET) scans to keep the patient under surveillance.

isappeared, and the cervical nodes have been just palpable for 2 months. After a 24-month follow-up without any treatment, the patient is asymptomatic and with no evidence of recurrence. It was programmed a lymphocyte apoptosis assay and a positron emission tomography (PET) scans to keep the patient under surveillance. Discussion ALPS is a disease characterised by immune dysregulation due to an inability to regulate lymphocyte homoeostasis through abnormalities in lymphocyte apoptosis or programmed cell death. The required clinical criteria are the presence of chronic lymphadenopathy and splenomegaly, present for more than 6 months, which may be asymptomatic and incidentally identified during routine physical examinations. In our case, the patient presented with hepatomegaly, splenomegaly and multiple lymph node enlargements during a period of 6 months. Patients with ALPS may present initially with episodes of fatigue, pallor and icterus due to haemolytic anaemia. They may also be more likely to have easy bruising and mucocutaneous bleeding caused by thrombocytopenia. In our case, the patient was taken to the emergency room with pallor, petechial, oral haemorrhagic bullae and a platelet count of 4000/µL.

lly with episodes of fatigue, pallor and icterus due to haemolytic anaemia. They may also be more likely to have easy bruising and mucocutaneous bleeding caused by thrombocytopenia. In our case, the patient was taken to the emergency room with pallor, petechial, oral haemorrhagic bullae and a platelet count of 4000/µL. Patients with ALPS can also have multilineage cytopenias, more typically in adults,4 5 which are chronic and can be refractory to therapy. The autoimmune haemolytic anaemia is also a common manifestation while immune neutropenia is rare.4 In this case, patient showed a haptoglobin decrease, an indirect bilirubin and a lactate dehydrogenase increased and a positive direct antiglobulin test (IgG 3+; C3d1+), compatible with autoimmune haemolytic anaemia. The incidence of lymphomas is quite significant. Therefore, a bone marrow aspiration was performed which showed no suggestive lymphoproliferative disorders of marrow involvement. In ALPS diagnosis, the peripheral blood immune phenotyping is essential to find the DNT cells elevation.5 6 Moreover, regarding our patient, it was observed a flow cytometry which showed 8% of the lymphocytes total to be DNT cells, one the required criterion (to have more than 1.5% in the setting of normal lymphocyte counts). When this condition is suspected, mutation molecular genetic test of FAS, FASL and CASP10 genes are necessary, because they have diagnostic and prognostic value, as there is an increased risk of lymphoma development.4 The pathogenesis of ALPS in the majority of patients result in defective apoptosis of lymphocytes (table 2) mediated through the FAS/FAS ligand (FASL) pathway or mutations in CASP10. In cases where no mutation was identified, a functional deficiency of FAS-mediated apoptosis was also observed.1 4 5 In our case, we did not search into two separate assays the lymphocyte apoptosis or searched deletions or duplications in the FAS gene and sequencing of FASL or CASP10 genes, as required in the ALPS additional primary criteria (box 1). However, it is no longer considered essential for the diagnosis of ALPS, as patients with somatic or germline FAS mutations, FASL mutations can present with normal in vitro FAS-induced apoptosis assays.5 These findings led the authors in the National Institutes of Health Clinical Center Group to propose a classification scheme based on the several different molecular abnormalities.

of ALPS, as patients with somatic or germline FAS mutations, FASL mutations can present with normal in vitro FAS-induced apoptosis assays.5 These findings led the authors in the National Institutes of Health Clinical Center Group to propose a classification scheme based on the several different molecular abnormalities. Patients who fulfil ALPS diagnostic criteria and have germline homozygous or heterozygous mutations in FAS, should be named as ALPS-FAS; if they have somatic FAS mutations as ALPS-SFAS; if they have FAS ligand mutations as ALPS-FASL or if they have caspase-10 mutations, they should be classified as ALPS-CASP10. However, when patients have an indeterminate genetic defect, like in your patient's case, they are categorised as ALPS-U (undetermined).4 Some biomarkers, which are increased in ALPS, include soluble FASL, circulating IL-10 and vitamin B12, whose biological origin is unknown.5 The combinations of these markers can be highly likely to diagnose ALPS instead of FAS sequencing. The new consensus ALPS classification and the inclusion of these biomarkers in diagnostic criteria will expedite ALPS diagnosis.1 4

ude soluble FASL, circulating IL-10 and vitamin B12, whose biological origin is unknown.5 The combinations of these markers can be highly likely to diagnose ALPS instead of FAS sequencing. The new consensus ALPS classification and the inclusion of these biomarkers in diagnostic criteria will expedite ALPS diagnosis.1 4 According to reviewed ALPS criteria, the lymphocyte apoptosis defects detection and somatic or germline mutation identification (FAS, FASL, or CASP10 genes) are primary additional criteria (box 1). Whereas an elevation of biomarkers, anatomopathological findings, autoimmune cytopenias with an elevated IgG levels and family history disease are considered as secondary additional ALPS diagnostic criteria (box 1). In our patient's case, no autoimmunity or lymphadenopathy has occurred in his family background. Also, we observed haemolytic anaemia with polyclonal hypergammaglobulinaemia and an increased IL-10. Box 1 Autoimmune lymphoproliferative syndrome (ALPS) diagnostic criteria based on the first international workshop of ALPS 20095 Required criteria Chronic (>6 months), non-malignant, non-infectious lymphadenopathy and/or splenomegaly Elevated CD3+ TCRαβ+CD4−CD8− DNT cells (>1.5% of total lymphocytes or >2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts Additional criteria Primary Defective lymphocyte apoptosis in two separate assays Somatic or germline pathogenic mutation in Fas, FASL or Casp10 Secondary

Chronic (>6 months), non-malignant, non-infectious lymphadenopathy and/or splenomegaly Elevated CD3+ TCRαβ+CD4−CD8− DNT cells (>1.5% of total lymphocytes or >2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts Additional criteria Primary Defective lymphocyte apoptosis in two separate assays Somatic or germline pathogenic mutation in Fas, FASL or Casp10 Secondary Elevated plasma sFASL levels (>200 pg/mL), plasma interleukin 10 (IL-10) levels (>20 pg/mL), serum or plasma vitamin B12 levels (>1500 ng/L) or plasma IL-18 levels >500 pg/mL Typical immunohistological findings as reviewed by a haematopathologist Autoimmune cytopenias (haemolytic anaemia, thrombocytopenia or neutropenia) with elevated IgG levels (polyclonal hypergammaglobulinaemia) Family history of a non-malignant/non-infectious lymphoproliferation with or without autoimmunity Definitive diagnosis: Both required criteria plus one primary accessory criterion. Probable diagnosis: Both required criteria plus one secondary accessory criterion.

Autoimmune cytopenias (haemolytic anaemia, thrombocytopenia or neutropenia) with elevated IgG levels (polyclonal hypergammaglobulinaemia) Family history of a non-malignant/non-infectious lymphoproliferation with or without autoimmunity Definitive diagnosis: Both required criteria plus one primary accessory criterion. Probable diagnosis: Both required criteria plus one secondary accessory criterion. Although some patients do not need treatment, most of them require immunosuppressive therapy, mainly those who develop cytopenias.1 4 The treatment is based on high doses of glucocorticoids and G-immunoglobulin intravenous associated4 with a good response.5 The glucocorticoids should be used only in exacerbations, but discouraged as chronic therapeutic due to its association with many side effects and complications.5 6 In exacerbation disease, the methylprednisolone pulses (5–10 mg/kg) must be used for 7–10 days, the prednisolone maintenance therapy (1–2 mg/kg) for 1 week, followed by a decreased dose to discontinuation over 8 to 12 weeks.6 In the case of severe and refractory cytopenias, patients may need intensive care due to hypoxia, and the use of 30 mg/kg methylprednisolone pulses.6 The G immunoglobulin (1–2 g/kg) should be administered concomitantly with methylprednisolone to avoid an increment of erythrocyte destruction in autoimmune haemolytic anaemia.5 In the acute phase, our patient needed 1 mg/kg of G-immunoglobulin and 10 mg/kg methylprednisolone for 3 days and after 1.5 mg/kg per day of prednisolone. The mycophenolate mofetil and sirolimus are becoming an alternative in infancy refractory cytopenias.4 6

f erythrocyte destruction in autoimmune haemolytic anaemia.5 In the acute phase, our patient needed 1 mg/kg of G-immunoglobulin and 10 mg/kg methylprednisolone for 3 days and after 1.5 mg/kg per day of prednisolone. The mycophenolate mofetil and sirolimus are becoming an alternative in infancy refractory cytopenias.4 6 Some patients with thrombocytopenia and ALPS do not have a response to G immunoglobulin; in selected cases of non-controlled hypersplenism and medical treatment failure,4 patients can be treated by splenectomy and rituximab (375 mg/m2 per week for four doses), respectively.4 6 The experience with other immunosuppressants in the ALPS is very limited.4 The haematopoietic stem cell transplantation is the unique potential curative therapy, which is reserved for the highly refractory disease.4 Novel and non-toxic targeted lymphocytic therapies may become available in the future, but it is mandatory to search for new genetic mutations in the subgroup of patients with ALPS with unknown genetic defects.4 6 In this clinical case, we assumed probable ALPS due to the presence of both required and three secondary accessory criteria. Additionally, after the beginning of immunosuppressive therapy with steroids, the patient had a dramatic clinical improvement. The patient remained in remission after a 24-month corticosteroids treatment.

linical case, we assumed probable ALPS due to the presence of both required and three secondary accessory criteria. Additionally, after the beginning of immunosuppressive therapy with steroids, the patient had a dramatic clinical improvement. The patient remained in remission after a 24-month corticosteroids treatment. In fact, the hallmark of this case is the diagnosis made in adulthood. The ALPS is usually diagnosed in childhood, presenting at an average age of 2.5 years, whereas adult cases have rarely been reported.3 On the other hand, follow-up studies in individuals who share genetic apoptosis defects revealed that clinical expression of ALPS might be highly variable.2 The penetrance of the disease seems to be indirectly related to the site of the mutations. Thus, the diagnosis may be delayed, usually until the development of the first signs of the autoimmune disease. The occurrence of immune cytopenias associated with lymphoproliferation in adulthood should also prompt the physician to consider a diagnosis of ALPS. We classified this case as ALPS-U as there was no detection of a genetic defect. However, mutations outside of the regions analysed as FAS gene deletions or duplications neither FASL, nor CASP10 genes were not excluded. At this point, we know that the patients with mutations in the FAS protein are at risk of developing lymphomas, so they require a lifelong follow-up.5

detection of a genetic defect. However, mutations outside of the regions analysed as FAS gene deletions or duplications neither FASL, nor CASP10 genes were not excluded. At this point, we know that the patients with mutations in the FAS protein are at risk of developing lymphomas, so they require a lifelong follow-up.5 Learning points Autoimmune lymphoproliferative syndrome (ALPS) is an uncommon disease in adult patients, and this disorder is associated with abnormalities in lymphocyte apoptosis and a high number of circulating TCRab CD3+CD4−CD8− T-cells (DNT cells). Patients do not need treatment, but when they develop cytopenias, they require immunosuppressive therapy. This is based on high doses of glucocorticoids and IgG intravenous, and the experience with other immunosuppressants in ALPS is very limited. Genotyping of the genes associated with ALPS are no longer considered essential for the diagnosis but it can be helpful in patients with confusing clinical and/or laboratory findings and in prognosis definition. The incidence of lymphomas is quite significant and therefore a permanent follow-up is needed. Contributors: All authors had been involved in this patient's care. FLS and GSC contributed to the drafting of the manuscript. HPC contributed to the interpretation of data. AO revised the content and accepts responsibility for the overall content as a guarantor. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background In this manuscript, we report a clinical case in which a patient with Millar-Gubler syndrome underwent a surgical procedure to correct her VI nerve palsy. We planned a different technique, a partial transposition of vertical rectus with a silicone band, which represents a natural evolution of the vertical rectus muscles transposition techniques. With this approach, there is no need of tenectomy as well as in Hummelsheim’s or Schillinger’s approaches (as Jensen also looked for) and there is also no need to split the lateral rectus, a point already achieved with the technique of Inatomi and Nishida (figure 1). With the silicone band transposition, we believe that it also can support the tension of the transposed muscles, in order to ensure the desired surgical results, unlike the muscles sutures onto sclera of the latter authors. As such, this paper should be of interest to a broad readership, including those interested in strabismus surgery. Figure 1 Schematic representations of vertical rectus transpositions in sixth nerve palsies. The operative eye in the figure is a left eye. (A) Hummelsheim; (B) Foster—augmented transposition; (C) Inatomi and Nishida. LR, lateral rectus, SR, superior rectus, IR, inferior rectus.

Background In this manuscript, we report a clinical case in which a patient with Millar-Gubler syndrome underwent a surgical procedure to correct her VI nerve palsy. We planned a different technique, a partial transposition of vertical rectus with a silicone band, which represents a natural evolution of the vertical rectus muscles transposition techniques. With this approach, there is no need of tenectomy as well as in Hummelsheim’s or Schillinger’s approaches (as Jensen also looked for) and there is also no need to split the lateral rectus, a point already achieved with the technique of Inatomi and Nishida (figure 1). With the silicone band transposition, we believe that it also can support the tension of the transposed muscles, in order to ensure the desired surgical results, unlike the muscles sutures onto sclera of the latter authors. As such, this paper should be of interest to a broad readership, including those interested in strabismus surgery. Figure 1 Schematic representations of vertical rectus transpositions in sixth nerve palsies. The operative eye in the figure is a left eye. (A) Hummelsheim; (B) Foster—augmented transposition; (C) Inatomi and Nishida. LR, lateral rectus, SR, superior rectus, IR, inferior rectus. Case presentation Six years before the presentation at our department, a woman aged 60 years had a VI left palsy following a diagnosis of a meningioma of the lateral wall of cavernous sinus (figure 2). She had the tumour surgically removed and, 1 year later, she underwent a 3 mm recession of medial rectus and a 4 mm resection of lateral rectus of the left eye. After this surgery, her eyes were straight, but afterwards she developed a consecutive exotropia. Four years later, she was diagnosed a cavernous angioma in the median and paramedian areas of the pons and developed a Millard-Gubler syndrome (figure 3). In this context, she presented at our department with a right VI nerve palsy, right conjugate gaze palsy, right facial palsy, right hipoacusia and left hemiparesis and with symptoms of severe horizontal torticollis (figure 4). The best corrected visual acuity was 3/10 in the right eye and light perception in the left eye, with afferent pupillary defect due to tumour-related optic atrophy. She had torsional nystagmus. Her visual field was compromised by the >45°right head turn with total adducing fixing right eye. On the ocular motility examination, we found a complete limitation of abduction and supraduction in the right eye, while adduction could not be correctly evaluated due to fixating in adduction with this only seeing eye; in the left eye, there was a severe limitation in adduction and supraduction, with mild limitation in abduction due to previous medial rectus recession; infraduction was normal in both eyes (figure 5).

he right eye, while adduction could not be correctly evaluated due to fixating in adduction with this only seeing eye; in the left eye, there was a severe limitation in adduction and supraduction, with mild limitation in abduction due to previous medial rectus recession; infraduction was normal in both eyes (figure 5). Figure 2 Sagital and coronal contrast MRI T1-weighting showing the meningioma of the lateral wall of cavernous sinus. Figure 3 MRI images demonstrating the cavernous angioma of the pons (artefacts due to poor collaboration of the patient). Figure 4 Horizontal torticollis. Figure 5 Preoperative photographs in different positions of gaze. Treatment We planned a surgery in the right eye, with transposition of vertical rectus and a weakening procedure (recession) of the medial rectus. To do both procedures in one-time surgery, the authors planned a modified transposition approach, in which procedure we made a partial transposition of vertical rectus with a silicone band (Labtican Ophtalmics, style#240 2.5 mm circling band) that was fixated posteriorly (figure 6), minimising the risk of anterior ischaemia, and a simultaneous medial rectus recession. Figure 6 Vertical muscle transposition with silicone band belting. LR, lateral rectus, SR, superior rectus, IR, inferior rectus, SB, silicone band, S, sleeve.

Treatment We planned a surgery in the right eye, with transposition of vertical rectus and a weakening procedure (recession) of the medial rectus. To do both procedures in one-time surgery, the authors planned a modified transposition approach, in which procedure we made a partial transposition of vertical rectus with a silicone band (Labtican Ophtalmics, style#240 2.5 mm circling band) that was fixated posteriorly (figure 6), minimising the risk of anterior ischaemia, and a simultaneous medial rectus recession. Figure 6 Vertical muscle transposition with silicone band belting. LR, lateral rectus, SR, superior rectus, IR, inferior rectus, SB, silicone band, S, sleeve. The surgical technique was initiated by a 360° limbal conjuntival peritomy. The fascia surrounding the inferior, superior and lateral rectus muscles was dissected free. A silicone band was placed belting the lateral halves of the superior (figure 7B) and the inferior (figure 7F) rectus muscles, passing under the lateral rectus muscle (figure 7D). Then, a single-armed 5-0 polyester non-absorbable braided fixation suture was used to fixate the lateral halves of the vertical rectus muscles to the band and then the band to the sclera 16 mm posterior to the limbus in each temporal quadrant (figure 7G–I). The sleeve (Labtican Ophtalmics, style#270 silicone sleeve 5/Box) was placed in the superior temporal quadrant (figure 7I), where the silicone band was pulled tight and tied in position to shorten the distance between the vertical rectus muscles and the lateral rectus, to change the force vectors of the muscles, increasing their passive elastic forces and creating a tone through the transposed muscles in the primary position. Finally, an 11 mm recession of the medial rectus muscle was then performed (figure 7J). The conjunctiva was closed with 8-0 polyglactin suture.

lateral rectus, to change the force vectors of the muscles, increasing their passive elastic forces and creating a tone through the transposed muscles in the primary position. Finally, an 11 mm recession of the medial rectus muscle was then performed (figure 7J). The conjunctiva was closed with 8-0 polyglactin suture. Figure 7 Intraoperative pictures illustrating the steps of the surgical technique. Outcome and follow-up After the procedure, the patient gained the ability to slightly abduct the right eye. We found no compensatory torticollis in the primary position of gaze. There was also an improvement of elevation and depression movements of the right eye (figure 8). Figure 8 Postoperative pictures showing the improvement of torticollis and ocular motility in the different positions of gaze.

Outcome and follow-up After the procedure, the patient gained the ability to slightly abduct the right eye. We found no compensatory torticollis in the primary position of gaze. There was also an improvement of elevation and depression movements of the right eye (figure 8). Figure 8 Postoperative pictures showing the improvement of torticollis and ocular motility in the different positions of gaze. Discussion Hummelsheim was the first to describe the use of vertical rectus muscles in cases of complete sixth nerve palsy: the lateral halves of the superior and inferior rectus muscles were transposed to the lateral rectus insertion as a method to improve abduction.1 Since then, a variety of transposition procedures have been proposed.2 In 1959, Schillinger3 reported a full tendon transposition that changes the force vectors of the transposed vertical muscles. In 1997, Foster4 described a modification of this technique, with vertical rectus full tendon transposition augmentation using non-absorbable sutures to enhance lateralisation of each transposed rectus muscle, reducing the space between the muscles and increasing the effect of the procedure. In 2003, Inatomi and Nishida introduced another technique where the lateral halves of the vertical muscles were sutured onto the sclera, sparing lateral muscle splitting or transposition.5

lateralisation of each transposed rectus muscle, reducing the space between the muscles and increasing the effect of the procedure. In 2003, Inatomi and Nishida introduced another technique where the lateral halves of the vertical muscles were sutured onto the sclera, sparing lateral muscle splitting or transposition.5 Silicone bands have already been used in strabismus surgery for several years. Its application include surgeries for myopic esotropia and strabismus fixus,6 7 manifest exotropia,7 superior oblique muscle approaches8 9 and may be also used as an alternative to the retroequatorial myopexy.10 Achieving acceptable postoperative alignment is difficult in patients with complete abducens palsy. The main goal is orthotropia in the primary position of gaze. The method of surgical treatment of VI nerve palsy depends on the degree of paresis/palsy of the affected lateral rectus. In incomplete paresis, horizontal rectus muscle surgery is the procedure of choice, whereas cases of complete paresis are best managed with a muscle transposition; a medial rectus recession is usually necessary.

surgical treatment of VI nerve palsy depends on the degree of paresis/palsy of the affected lateral rectus. In incomplete paresis, horizontal rectus muscle surgery is the procedure of choice, whereas cases of complete paresis are best managed with a muscle transposition; a medial rectus recession is usually necessary. We want to show that a transposition procedure can be performed simultaneously with medial rectus surgery. If we use a silicone band, there is no need of tenectomy or muscle detachment and some of the anterior circulation is left intact, minimising anterior segment ischaemia. Moreover, there is no need to split the lateral rectus, avoiding its displacement or surgical trauma. On the other hand, we believe that it also can support the tension of the transposed muscles, in order to ensure the desired surgical results, unlike the muscles sutures onto sclera. As such, it is a theoretically reversible approach that is adjustable intraoperatively as the silicone band can be tightened as needed and also retains all the advantages of the vertical muscles transpositions and the posterior fixation technique. Learning points Achieving acceptable postoperative alignment is difficult in patients with complete abducens palsy. Variety of transposition procedures have been proposed. Using a silicone band, there is no need of tenectomy or muscle detachment and some of the anterior circulation is left intact, minimising anterior segment ischaemia. Can be performed simultaneously with medial rectus surgery.

Learning points Achieving acceptable postoperative alignment is difficult in patients with complete abducens palsy. Variety of transposition procedures have been proposed. Using a silicone band, there is no need of tenectomy or muscle detachment and some of the anterior circulation is left intact, minimising anterior segment ischaemia. Can be performed simultaneously with medial rectus surgery. Contributors: The idea of creating this modification of vertical muscle transposition with Silicone Band Belting in VI nerve palsy came from SG. SG, CF and RDL performed the surgical technique. RDL was in charge of drafting the publication, always with the collaboration of both colleagues. The three coauthors have participated in the preparation of this publication accordingly. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Mixed connective tissue disease (MCTD) is a well-defined entity with a wide spectrum of clinical manifestations. Some patients initially diagnosed with MCTD eventually manifest symptoms more consistent with systemic lupus erythematosus (SLE) and vice versa.1 Neurological manifestations are reported in 10% cases of MCTD.2 Recent studies suggest that prevalence may be greater than reported before,3 4 involving central and peripheral nervous system. The most common disorders are trigeminal neuralgia, vascular-type headache, aseptic meningitis, psychosis and convulsions.4 5 Isolated cases of intracranial haemorrhage, cauda equina syndrome, transverse myelitis, optic neuropathy and retinal vasculitis have been reported as well.6–10 Adhesive arachnoiditis is a relatively uncommon chronic pathological disorder, characterised by an inflammatory insult to the arachnoid layer of the meninges that leads to fibrosis. As a sequel, the arachnoid becomes abnormally thick and adherent to the surrounding layers of pia and dura mater. The subsequent abnormal adhesion of nerve roots to the dural sac or to each other (clumping) can produce neurological impairment. The usual symptoms of arachnoiditis are severe back pain, paraesthesia, lower limb weakness and dissociative sensory loss. Common causes are prior spinal surgery, spinal inflammation or infection such as tuberculosis meningitis, trauma, haemorrhage, injection of anaesthetic agents and oil-based myelographic contrast agents. It is diagnosed on clinical grounds and supportive MRI findings.11 12

er limb weakness and dissociative sensory loss. Common causes are prior spinal surgery, spinal inflammation or infection such as tuberculosis meningitis, trauma, haemorrhage, injection of anaesthetic agents and oil-based myelographic contrast agents. It is diagnosed on clinical grounds and supportive MRI findings.11 12 The pathogenesis of adhesive archnoiditis has not been fully elucidated. We present to the best of our knowledge the first case of adhesive arachnoiditis in an MCTD patient that resulted in myeloradiculopathic symptoms leading to significant neurological comprise. This manuscript also captures the challenges of correct diagnosis and subsequent management of this uncommon debilitating clinical entity. Case presentation A woman aged 33 years presented with 2-year history of low back pain, getting worse within last couple of months. Seven years ago, she was diagnosed as MCTD when she presented to rheumatology service with polyarthritis, photosensitive butterfly rash, fatigue and scarring alopecia. Laboratory investigations showed raised ESR (25 mm/hour, N=5–12), normal C reactive protein, polyclonal hypergammaglobulinemia (IgG=23.74 g/L, N=5.4–16.1: IgA=5.11 g/L, N=0.9–3.4), C4 hypocomplementemia (0.11 g/L, N=0.16–0.38), positive serology for ANA (titre1/400,speckled pattern), anti-U1RNP and anti-Ro antibody and negative for anti-dsDNA antibody and antineutrophil cytoplasmic antibody. Her urine examination was normal.

rgammaglobulinemia (IgG=23.74 g/L, N=5.4–16.1: IgA=5.11 g/L, N=0.9–3.4), C4 hypocomplementemia (0.11 g/L, N=0.16–0.38), positive serology for ANA (titre1/400,speckled pattern), anti-U1RNP and anti-Ro antibody and negative for anti-dsDNA antibody and antineutrophil cytoplasmic antibody. Her urine examination was normal. She was a non-smoker, non-alcoholic, professional beauty therapist who was happily married and had two successful pregnancies with full term normal delivery. There was no history of rheumatological diseases in her family. She was treated with immunosuppressants (hydroxy chloroquine/azathioprine/mycophenolate mofetil), oral steroids and aspirin over the course of her disease. She had a number of acute exacerbations, requiring steroids, typified by fatigue, hair loss and arthralgia. There had been no major systemic aspects of MCTD in conjunction with the neurological symptoms in last few years.

ine/azathioprine/mycophenolate mofetil), oral steroids and aspirin over the course of her disease. She had a number of acute exacerbations, requiring steroids, typified by fatigue, hair loss and arthralgia. There had been no major systemic aspects of MCTD in conjunction with the neurological symptoms in last few years. On her recent presentation, she reported of severe lower back pain radiating to right leg associated with pins and needles from waist down, 2–3 episodes of faecal incontinence, poor balance, perineal and perianal numbness and globally altered sensations in both legs. She acknowledged involuntary jerking of both lower extremities at night. Clinically, she had restricted right straight leg raise test, absent right knee jerk and diminished bilateral ankle jerks. Sensory examination showed diminished pinprick sensation in both extremities, more pronounced on right, extending up into the waist in a symmetrical distribution to the T10 level with no sacral sparing. Her Romberg's test was positive. There was no abnormality in cranial nerves, upper extremities or upper trunk. Rest of deep tendon reflexes were well preserved with good 2-point discrimination, vibration, proprioception, pinprick and temperature sensation. Muscle bulk and tone was also preserved in upper and lower limbs with flexor planter response.

. There was no abnormality in cranial nerves, upper extremities or upper trunk. Rest of deep tendon reflexes were well preserved with good 2-point discrimination, vibration, proprioception, pinprick and temperature sensation. Muscle bulk and tone was also preserved in upper and lower limbs with flexor planter response. Investigations Laboratory investigations showed raised ESR (46 mm/hour, N=5–12 mm/hour), persistent C4 hypocomplementemia, positive ANA (titre1/1600, speckled pattern) and anti-U1RNP. This time her serology was positive for anti-dsDNA antibody (quantitative enzyme immunoassay=268, N=0–100), antiribosomal P-protein and negative for anticardiolipin IgG and anti-β-2 glycoprotein IgG antibody. Full blood count, renal, liver and bone profile was normal. At this stage, she clearly had MTCD with Lupus overlap.

time her serology was positive for anti-dsDNA antibody (quantitative enzyme immunoassay=268, N=0–100), antiribosomal P-protein and negative for anticardiolipin IgG and anti-β-2 glycoprotein IgG antibody. Full blood count, renal, liver and bone profile was normal. At this stage, she clearly had MTCD with Lupus overlap. On her urgent MRI lumbar-spine, conus medullaris and cauda equina were found within normal limits without any spinal cord signal abnormality, oedema or tumour. Her immunosuppressants (azathioprine and prednisolone) were up-titrated and given the huge impact of her symptoms limiting her activities of daily living, she received two fluoroscopic-guided caudal epidural injections 1 month apart with partial improvement in backache. Given the unusual nature of her symptoms, she underwent lumbar puncture and the cerebral spinal fluid (CSF) analysis was normal for white cell count (white cells <5), glucose and proteins. She underwent right lower limb neurophysiological studies (EMG/NCS) which did not report evidence of right L4 through S1 radiculopathy or sensorimotor polyneuropathy. On account of worsening symptoms, she had a non-contrast CT scan of thoracolumbar spine, which documented thoracic spinal cord arachnoid calcification (figure 1) and raised concern for chronic adhesive arachnoiditis. It was further evaluated with MRI thoracolumbar spine which reported abnormally distributed lower lumbar spine and thecal sac nerve roots demonstrating clumping (figures 2 and 3) and augmented the existing concern for chronic arachnoiditis.

calcification (figure 1) and raised concern for chronic adhesive arachnoiditis. It was further evaluated with MRI thoracolumbar spine which reported abnormally distributed lower lumbar spine and thecal sac nerve roots demonstrating clumping (figures 2 and 3) and augmented the existing concern for chronic arachnoiditis. Figure 1 CT scan of thoracic spine: axial soft tissue window image (left) and sagittal reformatted image (right) demonstrating tram-like intrathecal calcifications (arrows) delineating the spinal cord compatible with arachnoiditis ossificans. Stars represent incidental finding of Schmorl's nodes. Figure 2 Sagittal T2-weighted lumbar spine MRI demonstrating T2 hyperintense signal changes (arrow) consistent with thickened, clumped nerve roots. Figure 3 MRI lumbar spine: axial T1 postintravenous contrast image with fat suppression. The arrow points to the peripheral clumping of lumbar spinal nerve roots in the thecal sac. Differential diagnosis Our top differential diagnosis was cauda equina syndrome. Other possible differentials that could mimic symptoms of our patient were spinal cord tumours, syringomyelia, complex regional pain syndrome and multiple sclerosis which were ruled out by appropriate investigations. Failed back surgery syndrome is an important differential of adhesive arachnoiditis in postoperative phase.

r possible differentials that could mimic symptoms of our patient were spinal cord tumours, syringomyelia, complex regional pain syndrome and multiple sclerosis which were ruled out by appropriate investigations. Failed back surgery syndrome is an important differential of adhesive arachnoiditis in postoperative phase. Treatment Our patient's imaging studies were discussed with neuroradiology and in the light of her background history of MCTD, recent unusual neurological presentation and results of investigations, especially neuroimaging findings, it was decided that she likely had adhesive arachnoiditis related to her connective tissue disorder (MCTD Lupus overlap) which possibly started at the time when she initially presented with backache and had progressed since then possibly due to scarring. While she was on azathioprine for immunomodulation, rituximab (anti-CD20 monoclonal antibody) was added aimed at her neurological symptoms which successfully stopped progression of her symptoms. Outcome and follow-up Eighteen-month follow-up showed progressive improvement in her neurological symptoms with no recurrence. Her backache responded to analgesics.

While she was on azathioprine for immunomodulation, rituximab (anti-CD20 monoclonal antibody) was added aimed at her neurological symptoms which successfully stopped progression of her symptoms. Outcome and follow-up Eighteen-month follow-up showed progressive improvement in her neurological symptoms with no recurrence. Her backache responded to analgesics. Discussion In 1972, Sharp et al13 described MCTD, an apparently distinct overlap syndrome sharing many features of SLE, scleroderma and polymyositis. As mentioned earlier, neurological manifestations are reported in 10% cases of MCTD.2 Recent studies suggest that prevalence may be greater than reported before,3 4 involving central and peripheral nervous system. The most common disorders are trigeminal neuralgia, vascular-type headache, aseptic meningitis, psychosis and convulsions.4 5 Isolated cases of intracranial haemorrhage, cauda equina syndrome, transverse myelitis, optic neuropathy and retinal vasculitis have been reported as well.6–10

ral and peripheral nervous system. The most common disorders are trigeminal neuralgia, vascular-type headache, aseptic meningitis, psychosis and convulsions.4 5 Isolated cases of intracranial haemorrhage, cauda equina syndrome, transverse myelitis, optic neuropathy and retinal vasculitis have been reported as well.6–10 Arachnoiditis, first described by Victor Horsley in 1909,14 is a rare inflammatory condition characterised by thickening of the arachnoid membrane and adhesions of dura mater that causes intractable lower back pain and various other devastating neurological complications that include cranial neuropathies, myelopathies and radiculopathies. The most common aetiological factors in the development of spinal arachnoiditis are infection, intrathecal injection of steroids or anaesthetic agents, trauma, subarachnoid haemorrhage, ionic myelographic contrast materials, multiple back surgeries and lumbar puncture.15 16 Adhesive arachnoiditis, the most severe type of chronic arachnoiditis, results in scar tissue formation, which compresses nerve roots and disrupts their blood supply and also normal flow of CSF. It can progress to arachnoiditis ossificans, an end-stage complication of adhesive arachnoiditis characterised by the pathological ossification of the spinal arachnoid.17 Arachnoiditis can also mimic the symptoms of other diseases, such as spinal cord tumours, cauda equina syndrome, arachnoiditis ossificans and syringomyelia.18 MRI is the gold standard in the diagnosis of arachnoiditis; however, unenhanced CT (CT scan) better elucidates the presence and extent of arachnoid ossifications and is thus interrelated to MRI.

symptoms of other diseases, such as spinal cord tumours, cauda equina syndrome, arachnoiditis ossificans and syringomyelia.18 MRI is the gold standard in the diagnosis of arachnoiditis; however, unenhanced CT (CT scan) better elucidates the presence and extent of arachnoid ossifications and is thus interrelated to MRI. The pathogenesis of adhesive arachnoiditis is not clear. Burton19 suggested this to be the end point of an inflammatory process starting with radiculitis and progressing to arachnoiditis and adhesive arachnoiditis. As a result of inappropriate proliferation of arachnoid cells and production to dense collagen deposits surrounding nerve roots causes them to scar the meninges. Idris et al20 hypothesised an autoimmune-related mechanism which implicates nervous, immune and viscera musculoskeletal systems as important adjuncts in its pathophysiology, though its association with MCTD is yet to be evaluated. As mentioned before, a number of inflammatory insults have been associated with adhesive arachnoiditis. With our patient, underlying autoimmune connective tissue disease was possible inciting inflammatory event after ruling out all other possible causes on basis of laboratory data, neurophysiological studies and neuroimaging. True incidence of adhesive arachnoiditis and relationship to MCTD remains to be accurately documented.

ur patient, underlying autoimmune connective tissue disease was possible inciting inflammatory event after ruling out all other possible causes on basis of laboratory data, neurophysiological studies and neuroimaging. True incidence of adhesive arachnoiditis and relationship to MCTD remains to be accurately documented. Being a rare disorder, there is no consensus on standard treatment of adhesive arachnoiditis. To date, conservative approach (medications, physical therapy, psychotherapy, epidural steroid injections) and surgical treatment options are decided on a case-by-case basis with mixed clinical outcomes. In our case, likely autoimmune basis of our patient's presentation guided us towards augmentation of immunosuppressive therapy and addition of rituximab which worked out well in our patient. Learning points Mixed connective tissue disease (MCTD), a distant overlap syndrome, can eventually manifest symptoms more consistent with systemic lupus erythematosus (or scleroderma/polymyositis) and vice versa. Adhesive arachnoiditis could be considered in an MCTD patient presenting with myeloradiculopathic symptoms. Arachnoiditis can also mimic the symptoms of other diseases, such as cauda equine syndrome, spinal cord tumours, arachnoiditis ossificans and syringomyelia, so it is important to differentiate between arachnoiditis and other neurological manifestations of MCTD. MRI and CT scans are important diagnostic investigations in suspected adhesive arachnoiditis.

Arachnoiditis can also mimic the symptoms of other diseases, such as cauda equine syndrome, spinal cord tumours, arachnoiditis ossificans and syringomyelia, so it is important to differentiate between arachnoiditis and other neurological manifestations of MCTD. MRI and CT scans are important diagnostic investigations in suspected adhesive arachnoiditis. Further studies will help to define the complex underlying pathophysiology of adhesive arachnoiditis, involvement of the nervous system and role of immune system as currently only limited publications are available to address this uncommon entity. Contributors: MUK was the chief author of the article and undertook most of the literature review. AF was the primary treating physician of the patient and was actively involved in subsequent revision of the article. JAJD consulted on the management of the patient. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Ocular melanoma is the most common primary cancer of the eye. The incidence of ocular melanoma is six cases per million populations per year with about 70% of cases identified in the fifth through seventh decades.1–4 Patients with ocular primaries have high incidence of distant metastases, and short subsequent survival. Case presentation A 52-year-old Caucasian male was brought to the emergency department after an episode of seizures. It started with involuntary movement in the right hand lasting for 2–3 min, dizziness followed by episode of generalised tonic–clonic seizures witnessed by his wife. He reported of headache while recovering from the postictal phase. He had a history of (1) enucleation of right eye 23 years ago for ocular melanoma and (2) depression. He was a non-smoker and worked in a rubber factory. His vitals were stable on presentation. Investigations Routine laboratory investigations including full blood count, renal profile, liver function tests, coagulation profile and ECG were unremarkable. Chest radiograph revealed left hilar lymphadenopathy and nodules in the left lower lobe. Initial brain CT scan was organised to rule out any possible space occupying lesion; it revealed two nodular ring-shaped lesions (each about 2 cm in diameter) situated in the left frontal and parietal lobe with ring-like uptake of contrast with adjacent significant vasogenic oedema with no midline shift (figure 1). Appearances were suggestive of metastatic disease with primary lesion elsewhere in the body. Brain MRI with contrast confirmed the above findings.

cm in diameter) situated in the left frontal and parietal lobe with ring-like uptake of contrast with adjacent significant vasogenic oedema with no midline shift (figure 1). Appearances were suggestive of metastatic disease with primary lesion elsewhere in the body. Brain MRI with contrast confirmed the above findings. Figure 1 Brain CT scan pre and post contrast study showing ring enhancing lesions left frontal region with extensive perilesional oedema, consistent with metastatic lesions. He subsequently had a thorax-abdomen-pelvis CT scan with contrast which showed large left hilar lymphadenopathy with 3–4 soft tissue density nodules in the left lower lobe, the largest measuring ∼4 cm (figure 2). Liver showed a 2 cm hypodense lesion in segment 8 (figure 3). Initial diagnosis was left lung primary malignancy with satellite lesion in ipsilateral lung and metastatic disease in brain and liver. Figure 2 Thorax CT scan showing multiple nodules in the left lower lobe. Figure 3 Liver CT scan showing 2 cm hypodense metastatic lesion in segment 8. A bronchoscopy with transbronchial biopsy of the mediastinal lymph nodes was organised in a tertiary care centre. Melanoma markers including HMB45, MelA and S100 were positive which confirmed melanocytic lineage. However, BRAF V600 mutation was not detected. Differential diagnosis Lung malignancy Recurrence of ocular melanoma. Treatment The patient was informed of the above diagnosis and referred to medical oncologist and radiation oncologist for further care. He received palliative radiotherapy which was well tolerated by him.

A bronchoscopy with transbronchial biopsy of the mediastinal lymph nodes was organised in a tertiary care centre. Melanoma markers including HMB45, MelA and S100 were positive which confirmed melanocytic lineage. However, BRAF V600 mutation was not detected. Differential diagnosis Lung malignancy Recurrence of ocular melanoma. Treatment The patient was informed of the above diagnosis and referred to medical oncologist and radiation oncologist for further care. He received palliative radiotherapy which was well tolerated by him. Outcome and follow-up However, about 6 months later patient died of metastatic disease. Discussion Ocular melanoma is the second most common type of melanoma after cutaneous and most common primary malignancy of eye with 95% of melanomas occurring in uvea and remainder arising in conjunctiva. The incidence of ocular melanoma is six cases per million population per year with about 70% of cases identified in the fifth through seventh decades.2–4 In Europe uveal melanoma shows a decreasing incidence from north-to-south from over 8 per million in northern countries to <2 per million in southern countries.5 Risk factors like host pigmentation factor including light eye colour, fair skin, ultraviolet rays' exposure and atypical cutaneous or iris naevi have been implicated.6–8 The incidence of uveal melanoma has remained stable for the last three decades; however conjunctival melanoma has shown an increasing trend.9

tries.5 Risk factors like host pigmentation factor including light eye colour, fair skin, ultraviolet rays' exposure and atypical cutaneous or iris naevi have been implicated.6–8 The incidence of uveal melanoma has remained stable for the last three decades; however conjunctival melanoma has shown an increasing trend.9 The most common symptoms of ocular melanoma are blurring of vision, irritation in eyes and photopsia. However, a fair number of patients may be asymptomatic and ocular melanoma may be an incidental finding during eye examination. Enucleation was the standard treatment for ocular melanoma and used in most of the patients at that time. For most small and medium size tumours, radiation is the current recommended treatment, for instance plaque radiotherapy (aka brachytherapy), proton beam radiotherapy and stereotactic radiotherapy. There are no studies showing that one form of radiation is better than the other form. Surgery is often recommended for tumours of larger size and for iris melanomas in particular. Also, surgery may be recommended for recurrent disease, after initial radiation treatment.10

am radiotherapy and stereotactic radiotherapy. There are no studies showing that one form of radiation is better than the other form. Surgery is often recommended for tumours of larger size and for iris melanomas in particular. Also, surgery may be recommended for recurrent disease, after initial radiation treatment.10 It was suggested that manipulation of the globe and the consequent fluctuations in intraocular pressure may actually cause dissemination of tumour cells.11 Late recurrence of melanoma is common; the 5-year and 10-year recurrence rates are 25% and 34%, respectively. In our patient the recurrence occurred more than two decades after the initial presentation. Hepatic metastases developed in 92% and in 55% of these, the liver was the only organ involved initially. Pulmonary parenchymal metastases developed in 31%. Bone involvement accounted for 23%, mostly affecting the spine. Again 17% had skin or subcutaneous metastases.12 The prognosis of metastatic melanoma is poor and currently there are no approved treatments for metastatic disease, though there are several palliative treatments, as well as new clinical trials offered in the USA and Europe. Liver directed treatment may be offered and systemic treatments using agents such as ipilimumab (Yervoy), may be given.10 Learning points Increasing cases of recurrence after prolonged period of quiescence has been reported with dim prognosis in most circumstances. Despite paucity of a proven effective treatment regime and therefore questionable benefit of surveillance, an optimal follow-up plan may still seem favourable.

The prognosis of metastatic melanoma is poor and currently there are no approved treatments for metastatic disease, though there are several palliative treatments, as well as new clinical trials offered in the USA and Europe. Liver directed treatment may be offered and systemic treatments using agents such as ipilimumab (Yervoy), may be given.10 Learning points Increasing cases of recurrence after prolonged period of quiescence has been reported with dim prognosis in most circumstances. Despite paucity of a proven effective treatment regime and therefore questionable benefit of surveillance, an optimal follow-up plan may still seem favourable. Therefore, more efforts towards follow-up care in terms of method of screening and time interval needs to be encouraged, which may seemingly improve patient outcome. Contributors: SRK was involved in patient care and writing and editing of the case report. PRB was involved in patient care, editing of case report, data collection and consent form. NR, consultant radiologist, was involved in all imaging studies for the patient and providing images for the purpose of case report. SA was involved in patient care and data collection. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Patient with GBM has a poor prognosis despite aggressive therapy. This case describes an outlier in the survival curve, doing well currently. A detailed insight into his story offers us plausible explanations for the regression of this tumour. Spontaneous regression of the tumour versus a combined antineoplastic effect of antiepileptic drugs (AEDs) and dexamethasone (DEX) are the leading hypothesis. This case reviews preclinical and retrospective data, which support our hypothesis, and also emphasizes that further clinical studies are a prerequisite for validation and for developing treatment protocols in a tumour with a poor prognosis.

antiepileptic drugs (AEDs) and dexamethasone (DEX) are the leading hypothesis. This case reviews preclinical and retrospective data, which support our hypothesis, and also emphasizes that further clinical studies are a prerequisite for validation and for developing treatment protocols in a tumour with a poor prognosis. Case presentation A 55-year-old man was admitted on March 2014 for acute-onset lethargy and confusion. His medical history includes biopsy-proven right frontal lobe grade II astrocytoma, diagnosed in April 2000. After undergoing definite radiation, he achieved a long-term remission. In May 2009, MRI of the brain demonstrated a new heterogeneous mass in the right frontal and temporal lobe with minimal mass effect over right anterior horn. As the patient declined surgery, he was empirically treated with oral temozolamide (TMZ) at 150 mg/m2 (days 1–5 and repeated every 28 days) from August 2009 to December 2011. As patient stopped taking TMZ secondary to fatigue, he was kept on observation until January 2013. In January 2013, MRI of the brain (figure 1A) revealed new findings concerning for glioblastoma multiforme (GBM). Patient declined surgery again and was lost to follow-up until March 2014, when he presented with this acute clinical presentation.

g TMZ secondary to fatigue, he was kept on observation until January 2013. In January 2013, MRI of the brain (figure 1A) revealed new findings concerning for glioblastoma multiforme (GBM). Patient declined surgery again and was lost to follow-up until March 2014, when he presented with this acute clinical presentation. Figure 1 (A) MRI brain T1 with contrast demonstrating features concerning for GBM. (B) MRI brain T1 with contrast demonstrating a large bi-frontal solid expansive mass with vasogenic oedema. (C) H&E staining of frontal lobe mass from (B) showing WHO grade IV astrocytoma. (D and E) MRI brain T1 with contrast at days 57 and 99 demonstrating a decrease in size of frontal and parasagittal mass. (F) MRI brain T1 day 810 reveals further improvement in the lesions. GBM, glioblastoma multiforme.

vasogenic oedema. (C) H&E staining of frontal lobe mass from (B) showing WHO grade IV astrocytoma. (D and E) MRI brain T1 with contrast at days 57 and 99 demonstrating a decrease in size of frontal and parasagittal mass. (F) MRI brain T1 day 810 reveals further improvement in the lesions. GBM, glioblastoma multiforme. MRI of the brain revealed a large bi-frontal solid expansive mass with vasogenic oedema (figure 1B). Patient was immediately started on intravenous DEX (4 mg intravenously every 6 hours for 7 days followed by oral dosing of 4 mg two times per day) and levetiracetam (LEV) 500 mg orally two times per day for seizure prophylaxis. Brain biopsy revealed anaplastic fibrillar astrocytes with high mitosis and infiltrating into the adjacent brain parenchyma with associated satellitosis and with large areas of necrosis. Patient was diagnosed with WHO grade IV astrocytoma or GBM (figure 1C). Over the next 2-month period, patient's cognition gradually improved with resolution of delirium and speech problems, while he remained on oral DEX and LEV. Brain MRI on day 57 revealed mild improvement (figure 1D). On day 99, brain MRI showed further reduction of frontal, parasagittal mass size (figure 1E). On day 120, he was started on concurrent TMZ and radiation followed by the maintenance of TMZ. At the time of writing this manuscript, patient continues to do well with brain MRI showing no signs of recurrence (figure 1F).

D). On day 99, brain MRI showed further reduction of frontal, parasagittal mass size (figure 1E). On day 120, he was started on concurrent TMZ and radiation followed by the maintenance of TMZ. At the time of writing this manuscript, patient continues to do well with brain MRI showing no signs of recurrence (figure 1F). Discussion GBM is the most aggressive and lethal primary brain tumour and carries a dismal prognosis.1 2 Maximal safe resection followed by adjuvant concurrent chemoradiotherapy with oral TMZ remains the treatment of choice.3 While rare cases of long-term survival with GBM have been described,4 spontaneous regression in GBM setting has never been published. Continuous regression of GBM was noted in our patient while on DEX and LEV, without any cancer-targeted therapy, suggesting that the response may be secondary to DEX and/or LEV. DEX's inherent role in altering the natural course of GBM by itself or in congruence with chemotherapy and radiation is unknown.5 In contrary, high-dose DEX (>4.1 mg/day) was proposed to mitigate the effects of chemotherapy resulting in lower overall survival (OS) in patients with GBM.6

Discussion GBM is the most aggressive and lethal primary brain tumour and carries a dismal prognosis.1 2 Maximal safe resection followed by adjuvant concurrent chemoradiotherapy with oral TMZ remains the treatment of choice.3 While rare cases of long-term survival with GBM have been described,4 spontaneous regression in GBM setting has never been published. Continuous regression of GBM was noted in our patient while on DEX and LEV, without any cancer-targeted therapy, suggesting that the response may be secondary to DEX and/or LEV. DEX's inherent role in altering the natural course of GBM by itself or in congruence with chemotherapy and radiation is unknown.5 In contrary, high-dose DEX (>4.1 mg/day) was proposed to mitigate the effects of chemotherapy resulting in lower overall survival (OS) in patients with GBM.6 Most of the understanding of DEX antineoplastic effects in GBM comes from in vitro studies. Takahashi et al7 demonstrated that DEX inhibits adrenomedullin (AM) induced by inflammatory cytokines inteferon-γ, tumour necrosis factor-α and interleukin-1 in human GBM cell line T98G. Hypoxia and inflammatory cytokines induce AM, which in turn increases vascular endothelial growth factor (VEGF) production.8–11 Increased VEGF worsens the vicious cycle of more hypoxia and more AM, thereby potentiating angiogenesis, tumour proliferation, invasion and metastasis.7 12 Along with above mechanisms, DEX, via the glucocorticoid receptor pathway, is shown to directly inhibit VEGF production in glioblastoma cells.13 There is also growing body of evidence that DEX inhibits glioma cell proliferation in vitro and tumour growth in vivo.4 Its capability to inhibit neural stem cells by decreasing cyclin D1 level has been also demonstrated.14–16

icoid receptor pathway, is shown to directly inhibit VEGF production in glioblastoma cells.13 There is also growing body of evidence that DEX inhibits glioma cell proliferation in vitro and tumour growth in vivo.4 Its capability to inhibit neural stem cells by decreasing cyclin D1 level has been also demonstrated.14–16 Inhibition of migration and invasion in various glioma cell lines (C6, U251, U373 and A172) by DEX has been shown by Bauman et al.17 In U87MG glioma cells, DEX reduces matrix metalloproteinase-2 secretion and thereby tumour invasion.18 DEX direct cytotoxic effect on glioblastoma cell lines (A172, T98G and 86HG39) has been described.11 Recent preclinical and clinical studies elucidating antitumorous efficacy of AEDs in brain tumours demonstrate encouraging results. Valproic acid (VPA) was shown to cause growth arrest and apoptosis in medulloblastoma cell lines by regulating expression of p21Cip1, cyclin-dependent Kinase 4 (CDK4) and c-myc proteins through histone hyperacetylation.19 Van Nifterik et al20 demonstrated increased cytotoxicity in human glioma cells subjected to TMZ and γ-radiation in the presence of VPA. Data from EORTC 26981-22981 and NCIC CE.3 clinical trial database have revealed that the OS of patients who were receiving VPA alone appeared to increase survival benefit from TMZ and radiation compared to those who were on enzyme-inducing AEDs only (HR 0.39, 95% CI 0.24 to 0.63) or those not receiving any AED (HR: 067, 95% CI 0.49 to 0.93).21

81 and NCIC CE.3 clinical trial database have revealed that the OS of patients who were receiving VPA alone appeared to increase survival benefit from TMZ and radiation compared to those who were on enzyme-inducing AEDs only (HR 0.39, 95% CI 0.24 to 0.63) or those not receiving any AED (HR: 067, 95% CI 0.49 to 0.93).21 On the other hand, Bobustuc et al22 demonstrated that LEV increased histone deacetylase 1 (HDAC1) transcription and recruited HDAC1/mSin3A compressor complex to the p53-binding site in the O6 methylguanine-DNA methyltransferase (MGMT) promoter, consequently silencing MGMT and enhancing the anticancer effects of TMZ. In a single institutional retrospective study, Kim et al23 noticed that the median progression-free survival (PFS) and OS for patients who received LEV in combination with TMZ was significantly prolonged compared to those who did not receive LEV (PFS 9.4 vs 6.7 months, p=0.010; OS 25.7 vs 16.7 months, p=0.027).

of TMZ. In a single institutional retrospective study, Kim et al23 noticed that the median progression-free survival (PFS) and OS for patients who received LEV in combination with TMZ was significantly prolonged compared to those who did not receive LEV (PFS 9.4 vs 6.7 months, p=0.010; OS 25.7 vs 16.7 months, p=0.027). Tumour molecular profiling using Caris Life Sciences (Phoenix, Arizona, USA) revealed a deficiency of the DNA repair system at multiple levels (table 1): BRCA1/2 mutation, along with MGMT gene silencing by methylation. isocitrate dehydrogenase 1 (IDH1) mutation and 1p/19q codeletion, known for their correlation with improved sensitivity to chemotherapy and other genotoxic stress, were present. It is possible that the impaired DNA repair system has conferred an improved sensitivity to DEX and LEV. This observation needs to be proven through cell lines model harbouring defect at different levels in their DNA repair system and from large clinical database. Although DEX and LEV's role in GBM regression is supported by few preclinical and retrospective clinical data, randomised clinical trials are still lacking. Further efforts are needed to define the antineoplastic role of DEX and LEV in GBM. Table 1 Pertinent findings of molecular profiling of the recurrent tumour performed by Caris Moleculare Intelligence (CARIS)

Tumour molecular profiling using Caris Life Sciences (Phoenix, Arizona, USA) revealed a deficiency of the DNA repair system at multiple levels (table 1): BRCA1/2 mutation, along with MGMT gene silencing by methylation. isocitrate dehydrogenase 1 (IDH1) mutation and 1p/19q codeletion, known for their correlation with improved sensitivity to chemotherapy and other genotoxic stress, were present. It is possible that the impaired DNA repair system has conferred an improved sensitivity to DEX and LEV. This observation needs to be proven through cell lines model harbouring defect at different levels in their DNA repair system and from large clinical database. Although DEX and LEV's role in GBM regression is supported by few preclinical and retrospective clinical data, randomised clinical trials are still lacking. Further efforts are needed to define the antineoplastic role of DEX and LEV in GBM. Table 1 Pertinent findings of molecular profiling of the recurrent tumour performed by Caris Moleculare Intelligence (CARIS) Test Method Result BRCA 1 NGS Exon 3/E33K; mutated variant of unknown significance BRCA2 NGS Exon 17/A263v; mutated variant of unknown significance ERCC1 IHC Negative IDH1 NGS Mutated Exon 4/R132H MGMT Pyro Seq Methylated 1p19q FISH Positive FGFR1 NGS Mutated, variant of unknown significance; Exon 4 E126K FGFR2 NGS Mutation negative PD-L1 IHC Negative TP53 NGS Mutated; Exon 8/P2785 EGFR NGS Mutation negative EGFR vIII FA Absent NRAS/KRAS/HRAS NGS Mutation negative Her2/Neu (ERBB2) NGS Mutation negative PIK3CA NGS Mutation negative EGFR, epithelial growth factor receptor; EGFR, epithelial growth factor receptor; ERBB, epidermal growth factor receptor; ERCC, excision repair cross-complementing; FGFR, fibroblast growth factor receptor; FA, Fragment Analysis ; FISH, fluorescence in situ hybridization; IDH, isocitrate dehydrogenase; IHC, Immunohistochemistry; MGMT, O6 methylguanine-DNA methyltransferase; NGS, Next-Generation sequencing; NRAS/KRAS/HRAS, N-rat sarcoma gene; K-rat sarcoma gene; H-rat sarcoma gene; PD-L1, programmed death ligand 1; PIK3CA, Phosphoinositide 3-kinase oncogene; TP53, tumor protein 53.

tion; IDH, isocitrate dehydrogenase; IHC, Immunohistochemistry; MGMT, O6 methylguanine-DNA methyltransferase; NGS, Next-Generation sequencing; NRAS/KRAS/HRAS, N-rat sarcoma gene; K-rat sarcoma gene; H-rat sarcoma gene; PD-L1, programmed death ligand 1; PIK3CA, Phosphoinositide 3-kinase oncogene; TP53, tumor protein 53. Learning points Secondary glioblastoma multiforme (GBM) progress from astrocytoma and have a better prognosis than primary GBM. Patients with tumours having O6 methylguanine-DNA methyltransferase promoter methylation respond better to alkylating agents such as temozolamide, translating to longer survival. Dexamethasone and levetiracetam have been shown in in vitro studies and retrospective studies to play a role in directly inhibiting tumour proliferation and increasing sensitivity to chemotherapy. Randomised control trials can validate the role of antiepileptic drugs and dexamethasone in the treatment of GBM Contributors: PP and NEA conceived and designed the manuscript, and also drafted the manuscript. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

up according to our previous protocols.1 ECMO was started 52 min after the estimated arrest. At that time, the patient had at least 8 min of no flow followed by 44 min of manual CPR after arrival of the EMT. Neurological re-evaluation after ECMO initiation gave a GCS score of 4–5 with intubation (eye, E1; motor, M3–4). Based on our prior experience, including 230 adult ECPR cases,7 a prognosis was constructed based on out-of-hospital cardiac arrest, age, GCS score, initial rhythm, and period of no flow and low flow before the start of ECMO. For similar patients, the prognosis for survival is 22–25%, and the prognosis for a good neurological recovery is lower. The patient was expected to have an unfavorable clinical outcome. Investigations Based on the prognosis, the medical team offered the patient's family the option of applying the investigational CSDH protocol as an adjunct to our center's standard ECPR protocol. All of the hospital's standard institutional review board emergency approval procedures were followed for the case reported here.

Background The association of ulcerative colitis (UC) with antineutrophil cytoplasmic antibodies (ANCAs) has been studied. ANCA testing is helpful in distinguishing UC from Crohn's disease.1 2 Although UC-associated ANCAs do not have the potential for development of systemic vasculitis or for neutrophil activation,3 the pathogenic role of ANCAs in inflammatory bowel diseases remains unknown. It is also unknown whether the ANCA level shows simultaneous changes with UC disease activity. We describe a case of unilateral abducens nerve palsy associated with proteinase 3 (PR3)-ANCA-positive UC, where serum PR3-ANCA levels and neurological symptoms improved simultaneously during the course of tapering steroid therapy. Case presentation A 72-year-old man with a 5-year history of UC was referred to our hospital reporting double vision that had started 40 days previously. Since his UC symptoms were unresponsive to steroid therapy, he was treated with vedolizumab and his UC was stable on admission to our hospital. Clinical examination revealed complete left abducens nerve palsy, with no evidence of uveitis and a normal fundus. No other abnormal neurological findings were detected. His temperature was normal.

were unresponsive to steroid therapy, he was treated with vedolizumab and his UC was stable on admission to our hospital. Clinical examination revealed complete left abducens nerve palsy, with no evidence of uveitis and a normal fundus. No other abnormal neurological findings were detected. His temperature was normal. Investigations His C reactive protein (2.2 mg/dL) and PR3-ANCA (31.1 U/mL; ELISA) levels were elevated. Cerebrospinal fluid (CSF) analysis revealed pleocytosis (25/mm3), elevated protein (127 mg/dL) and interleukin (IL)-6 (437 pg/mL) levels, and normal glucose and intracranial pressure levels. Results of extensive microbiological and immunological studies were normal. Antibodies and antigens for HIV were negative. CT of the chest, abdomen and pelvis were unremarkable, except for findings of UC. Brain MRI showed a swollen nasal cavity mucosal membrane and no significant change in the left abducens nerve and around it (figure 1). Magnetic resonance angiography showed no stenotic lesions. Nasal cavity mucosal membrane biopsy showed no specific changes and no evidence of granuloma. There was no evidence of granulomatosis with polyangiitis, and the lungs and kidneys were normal. Figure 1 (A) T2-weighted axial (1.5 T; TR, 3160 ms; TE, 183.3 ms) images show no significant changes in the left abducens nerve or around it. (B) T2-weighted axial (1.5 T; TR, 4025 ms; TE, 88.4 ms) images showed a swollen nasal cavity mucosal membrane (arrow).

Investigations His C reactive protein (2.2 mg/dL) and PR3-ANCA (31.1 U/mL; ELISA) levels were elevated. Cerebrospinal fluid (CSF) analysis revealed pleocytosis (25/mm3), elevated protein (127 mg/dL) and interleukin (IL)-6 (437 pg/mL) levels, and normal glucose and intracranial pressure levels. Results of extensive microbiological and immunological studies were normal. Antibodies and antigens for HIV were negative. CT of the chest, abdomen and pelvis were unremarkable, except for findings of UC. Brain MRI showed a swollen nasal cavity mucosal membrane and no significant change in the left abducens nerve and around it (figure 1). Magnetic resonance angiography showed no stenotic lesions. Nasal cavity mucosal membrane biopsy showed no specific changes and no evidence of granuloma. There was no evidence of granulomatosis with polyangiitis, and the lungs and kidneys were normal. Figure 1 (A) T2-weighted axial (1.5 T; TR, 3160 ms; TE, 183.3 ms) images show no significant changes in the left abducens nerve or around it. (B) T2-weighted axial (1.5 T; TR, 4025 ms; TE, 88.4 ms) images showed a swollen nasal cavity mucosal membrane (arrow). Treatment On the basis of diagnosis of autoimmune cranial mononeuritis of the abducens nerve, high-dose methylprednisolone (1000 mg/day) steroid therapy was initiated intravenously and continued for 3 days (figure 2). The left abducens nerve palsy partially improved; therefore, another course of high-dose methylprednisolone steroid therapy was continued followed by oral prednisolone (20 mg/day) steroid therapy.

high-dose methylprednisolone (1000 mg/day) steroid therapy was initiated intravenously and continued for 3 days (figure 2). The left abducens nerve palsy partially improved; therefore, another course of high-dose methylprednisolone steroid therapy was continued followed by oral prednisolone (20 mg/day) steroid therapy. Figure 2 Two courses of high-dose methylprednisolone (1000 mg/day for 3 days) were initiated intravenously followed by oral prednisolone (20 mg/day). After the steroid therapy was started, the left abducens nerve palsy and CSF findings improved. During the course of tapering steroid therapy, serum PR3-ANCA and CSF IL-6 levels decreased. Four months after symptom onset, the left abducens nerve palsy was completely resolved with treatment of oral prednisolone (10 mg/day). CSF, cerebrospinal fluid; mPSL, methylprednisolone; PSL, prednisolone. Outcome and follow-up Two months from its onset, the left abducens nerve palsy along with CSF findings had improved. During the course of tapering steroid therapy, serum PR3-ANCA and CSF IL-6 (1.2 pg/mL) levels decreased. Four months after the onset, the left abducens nerve palsy had completely resolved with the treatment of oral prednisolone (10 mg/day).

its onset, the left abducens nerve palsy along with CSF findings had improved. During the course of tapering steroid therapy, serum PR3-ANCA and CSF IL-6 (1.2 pg/mL) levels decreased. Four months after the onset, the left abducens nerve palsy had completely resolved with the treatment of oral prednisolone (10 mg/day). Discussion We report a case of unilateral abducens nerve palsy associated with PR3-ANCA-positive UC caused by autoimmune mechanisms. Neurological disorders associated with UC are uncommon, although other extraintestinal manifestations have been described. Neurological disorders have been reported in 3% of cases with inflammatory bowel disease,4 and only a few cases of cranial neuropathy associated with UC have been reported (table 1).5–9 Some cases of olfactory dysfunction, optic neuritis and sensorineural hearing loss have been reported. Table 1 Case reports of cranial nerve disorder associated with UC Author Cranial nerve lesion Suspected mechanism Treatment Clinical course Steinbach et al5 Olfactory nerve Autoimmune NA NA Alexandre et al6 Optic nerve Autoimmune Anti-TNF therapy associated Steroid Steroid Improvement Improvement Present study Abducens nerve Autoimmune Steroid Improvement Gondim Fde et al7 Facial nerve NA NA NA Kumar et al8 Vestibulocochlear nerve Autoimmune Steroid Improvement Kawashima et al9 Hypogrosal nerve Autoimmune Steroid Improvement TNF, tumour necrosis factor; UC, ulcerative colitis.

Anti-TNF therapy associated Steroid Steroid Improvement Improvement Present study Abducens nerve Autoimmune Steroid Improvement Gondim Fde et al7 Facial nerve NA NA NA Kumar et al8 Vestibulocochlear nerve Autoimmune Steroid Improvement Kawashima et al9 Hypogrosal nerve Autoimmune Steroid Improvement TNF, tumour necrosis factor; UC, ulcerative colitis. Biological therapies may cause neurological complications. Central nervous system vasculitis secondary to anti-tumour necrosis factor therapy has been reported, including other diseases.4 The safety of vedolizumab with respect to neurological complications for UC has been evaluated.10 Our patient developed abducens nerve palsy 10 months after initiating vedolizumab therapy. His neurological symptoms improved with steroid therapy without cessation of the vedolizumab, but the possibility of an association with vedolizumab in the present case cannot be excluded. Pathophysiologically, three major mechanisms are reported to cause neurological disorders associated with UC: (i) cerebrovascular disease as a consequence of thrombosis and thromboembolism, (ii) systemic and cerebral vasculitis and (iii) probably immune-mediated neuropathy and cerebral demyelination.11 There are no reports about CSF IL-6 levels in neurological complications associated with UC; however, simultaneous improvement of neurological symptoms along with decreasing CSF IL-6 levels and responsiveness to steroid therapy suggests inflammatory and autoimmune mechanisms in our patient.

nd cerebral demyelination.11 There are no reports about CSF IL-6 levels in neurological complications associated with UC; however, simultaneous improvement of neurological symptoms along with decreasing CSF IL-6 levels and responsiveness to steroid therapy suggests inflammatory and autoimmune mechanisms in our patient. It is interesting that the serum PR3-ANCA level; CSF findings, including the IL-6 level; and neurological symptoms showed simultaneous improvement during the course of tapering steroid therapy in the present case. Clinical implications of PR3-ANCA levels in UC have not been defined. It has been suggested that the serum PR3-ANCA level could be a useful serological diagnostic marker for UC,1 2 but it is not known whether or not the PR3-ANCA level and UC disease activity show simultaneous changes. Neurological disorders associated with UC may occur independent of the UC activity.4 11 12 In our case, neurological symptoms developed independent of the UC disease activity, and the serum PR3-ANCA levels and neurological symptoms showed simultaneous improvement, indicating that the serum PR3-ANCA level may have been a useful parameter of the neurogenic complications accompanying ANCA-positive UC in the present case.

e, neurological symptoms developed independent of the UC disease activity, and the serum PR3-ANCA levels and neurological symptoms showed simultaneous improvement, indicating that the serum PR3-ANCA level may have been a useful parameter of the neurogenic complications accompanying ANCA-positive UC in the present case. We described a case of unilateral abducens nerve palsy associated with PR3-ANCA-positive UC where serum PR3-ANCA levels and neurological symptoms improved simultaneously during the course of tapering steroid therapy. Serum PR3-ANCA and CSF IL-6 levels appeared to be useful parameters of neurogenic complications in this patient. More studies are needed to define the role of PR3-ANCA in UC. Learning points Neurological disorders associated with UC are uncommon. Neurological disorders associated with UC may occur independent of the UC activity. We describe a case of unilateral abducens nerve palsy associated with PR3-ANCA-positive UC, where serum PR3-ANCA levels and neurological symptoms improved simultaneously during the course of tapering steroid therapy. Serum PR3-ANCA level may have been a useful parameter of the neurogenic complications accompanying ANCA-positive UC in the present case, although the pathogenic role of PR3-ANCA in UC remains unknown. Contributors: YK is a major contributor in writing the manuscript. DY and TU also treated the patient and interpreted the patient data. All authors read and approved the final manuscript. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Infantile botulism is a rare neuromuscular disorder resulting from toxins produced by Clostridium botulinum.1 There are seven distinct serotypes named A–G. Only subtypes A, B, E and F cause disease in humans.2 Infant botulism occurs when the clostridial spores of the C. botulinum release botulinum neurotoxin (BoNT) into the bloodstream which irreversibly binds to cholinergic receptors in the presynaptic cell membrane preventing the release of acetylcholine into the synaptic cleft.1 Infantile botulism was first recognised in 1976 in California3 and is most commonly reported in the USA with 128 cases reported to the Center of Disease Control in 2014.4 However, infantile botulism appears to be uncommon in Malaysia. We are not aware of any previous case report. Case presentation The infant was born preterm at 36 weeks gestation via spontaneous vertex delivery with birth weight of 2.52 kg to non-consanguineous parents. He was initially admitted and treated with intravenous penicillin and gentamycin for presumed sepsis as he was born prematurely. His initial blood culture was negative, and he was discharged well. However, at day 10 of life, he was re-admitted for fever and ulcer at the umbilical region. Otherwise, he was active, febrile with a temperature of 38°C and other vital signs were stable with no respiratory distress. He was treated with intravenous penicillin and cloxacillin in addition to local application of medicated honey.

at day 10 of life, he was re-admitted for fever and ulcer at the umbilical region. Otherwise, he was active, febrile with a temperature of 38°C and other vital signs were stable with no respiratory distress. He was treated with intravenous penicillin and cloxacillin in addition to local application of medicated honey. At day 30 of life, his wound condition worsened (figure 1) and he needed wound debridement for necrotising fasciitis of the anterior abdominal wall under general anaesthesia. Postoperatively, he required re-intubation as he was noted to have poor respiratory effort, generalised hypotonia and areflexia. Figure 1 Picture of the abdominal wound postmedicated honey application and diagnosis of necrotising fasciitis of the anterior abdominal wall was made. Blood culture was negative, and swab culture showed mixed growth. Nerve conduction study revealed predominantly axonal neuropathy (figure 2). Ultrasound scan of the cranium and lumbar puncture were normal. Primary immunodeficiency screening was negative. Figure 2 Limited nerve conduction study was performed over left ulnar and tibial nerves. The compound motor action potential was reduced with prolonged distal latency. This nerve conduction study was abnormal suggestive of predominantly axonal neuropathy. The diagnosis of infant botulism was made based on the clinical presentation, nerve conduction study and his clinical progress. He was treated with intravenous immunoglobulin and oral pyridostigmine.

Figure 2 Limited nerve conduction study was performed over left ulnar and tibial nerves. The compound motor action potential was reduced with prolonged distal latency. This nerve conduction study was abnormal suggestive of predominantly axonal neuropathy. The diagnosis of infant botulism was made based on the clinical presentation, nerve conduction study and his clinical progress. He was treated with intravenous immunoglobulin and oral pyridostigmine. Outcome and follow-up His condition improved with our supportive care. Subsequently, he was successfully extubated after 37 days and is currently doing well. Discussion In infants, botulism may present with constipation, drooling, poor feeding and weak sucking and in extreme cases, loss of muscle tone which may progress to bilateral cranial nerve palsies, flaccid paralysis and diaphragmatic weakness.1 Infants are more susceptible due to the immaturity of the gut flora.1 Honey has been used as a biological wound dressing with broad-spectrum antibacterial activity and high osmolality.5 In this case, the infant presented with infected wound treated with the application of medicated honey raised a high index of suspicion of infantile botulism. There have been case reports associating the ingestion of honey in infants with botulism.6 7 9 If C. botulinum can be present in ingested honey, it can certainly be present in honey dressings. However, there is no reported case of infant botulism associated with application of medicated honey.

Honey has been used as a biological wound dressing with broad-spectrum antibacterial activity and high osmolality.5 In this case, the infant presented with infected wound treated with the application of medicated honey raised a high index of suspicion of infantile botulism. There have been case reports associating the ingestion of honey in infants with botulism.6 7 9 If C. botulinum can be present in ingested honey, it can certainly be present in honey dressings. However, there is no reported case of infant botulism associated with application of medicated honey. Botulinum toxin is readily detected in stool sample and would confirm the diagnosis. However, this test is currently unavailable in Malaysia. In 2003, US Food and Drug Administration approved the Orphan Drug Baby BIGR for the treatment of infant botulism which acts by neutralising free botulinum toxin.8 10 Treatment should be ideally given as soon as possible after hospital admission and should not be delayed for confirmatory test. Learning points This case report highlights the unusual presentation of infant botulism. To have a high index of suspicion of botulism in an infant who presents with flaccid paralysis in association with a contaminated wound. Unfamiliarity with the presentation could result in misdiagnosis. The authors would also like to caution the use of medicated honey for infants.

Learning points This case report highlights the unusual presentation of infant botulism. To have a high index of suspicion of botulism in an infant who presents with flaccid paralysis in association with a contaminated wound. Unfamiliarity with the presentation could result in misdiagnosis. The authors would also like to caution the use of medicated honey for infants. We would like to thank the Director General of Ministry of Health of Malaysia for the permission to publish this case, Associate Professor Dr Lim Kean Ghee MBChB, FRCS, FAMM for critically reviewing this paper, and Dr Goh Pik Pin, Head of Clinical Research Center Malaysia for encouragement and support. Contributors: CJJ, TBK and KYL contributed to conception and design, writing of the abstract and case report. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Extracorporeal cardiopulmonary resuscitation (ECPR) has become a useful approach in treating adult refractory cardiac arrest patients. The ECPR protocol implemented at our center1 has shown improved survival and neurological outcomes.2 3 Following refractory arrest, when the patient arrives at the emergency room (ER), the ECPR protocol involves application of extracorporeal membrane oxygenation (ECMO) to end their period of low flow ischemia. The ECMO circuit is then used to support recovery of cardiac output over a period of several days before a controlled weaning process is initiated. Currently, systemic therapeutic hypothermia at 33–35°C is a complementary neuroprotection strategy used at our center, applied to the subset of ECPR patients with a Glasgow Coma Scale (GCS) score of <6, as evaluated following ECMO initiation. This procedure is within the current ILCOR guidelines,4 although the guidelines have no specific recommendation for ECPR refractory arrest patients. Any improved neuroprotection approach would be valuable in refractory cardiac arrest patients and possibly in other patients with ischemic injury. The investigators had two motivations in the design of the cerebral selective deep (<30°C) hypothermia (CSDH) protocol: (1) to enable therapeutic hypothermia to be applied to the cerebral region without negative side effects on the core; (2) to enable application of temperatures below 30°C in ECPR, following two studies of selective hypothermia below 30°C in surgical animal stroke models.5 6

ive deep (<30°C) hypothermia (CSDH) protocol: (1) to enable therapeutic hypothermia to be applied to the cerebral region without negative side effects on the core; (2) to enable application of temperatures below 30°C in ECPR, following two studies of selective hypothermia below 30°C in surgical animal stroke models.5 6 In the present case, implementation of the CSDH protocol demonstrated that it is feasible to establish prolonged (>12 hours) separate temperature controlled zones for the core and cerebral regions. Hence it may be a feasible procedure to allow potential neuroprotective hypothermia to be applied to the brain while not incurring the negative effects of hypothermic temperatures on core organ systems. We do not believe or assert that the case demonstrates efficacy or clinical value, even though the specific outcome was favorable. Evaluation of the efficacy of the CSDH protocol and choice of target temperatures will require larger studies.

urring the negative effects of hypothermic temperatures on core organ systems. We do not believe or assert that the case demonstrates efficacy or clinical value, even though the specific outcome was favorable. Evaluation of the efficacy of the CSDH protocol and choice of target temperatures will require larger studies. Case presentation A bystander found a 38-year-old man unconscious, alone in the driver's seat. No cardiopulmonary resuscitation (CPR) was performed before arrival of the emergency medical team (EMT). The EMT recorded an initial rhythm of pulseless ventricular tachycardia. Several attempts at defibrillation were made but failed. The patient was transferred to the hospital ER under continuous manual CPR. Initial laboratory reports in the ER showed a pH of 7.03 and lactate value of 6.31. The patient was deemed appropriate for ECPR, and ECMO was set up according to our previous protocols.1 ECMO was started 52 min after the estimated arrest. At that time, the patient had at least 8 min of no flow followed by 44 min of manual CPR after arrival of the EMT. Neurological re-evaluation after ECMO initiation gave a GCS score of 4–5 with intubation (eye, E1; motor, M3–4).

tigations Based on the prognosis, the medical team offered the patient's family the option of applying the investigational CSDH protocol as an adjunct to our center's standard ECPR protocol. All of the hospital's standard institutional review board emergency approval procedures were followed for the case reported here. Treatment The CSDH protocol was applied as an adjunct to the standard ECPR protocol by adding a second independent extracorporeal circuit, as shown in figure 1. The first circuit was inserted in the ER for standard ECMO/ECPR, and the second was inserted through the opposite leg, implementing CSDH. Each extracorporeal circuit has an independent heat exchange system, allowing independent temperature control. The time course and strategy of the underlying ECPR protocol is not changed by CSDH, and the CSDH circuit can be established and removed without disruption of the ECPR protocol. The cannula for the CSDH circuit is a 14 F concentric lumen catheter (TwinFlo; ThermopeutiX, San Diego, USA). The TwinFlo catheter is inserted through a single puncture in the left femoral artery and its outer lumen is placed in the aortic arch, while its inner lumen is advanced into the right internal carotid artery (figure 2).

a for the CSDH circuit is a 14 F concentric lumen catheter (TwinFlo; ThermopeutiX, San Diego, USA). The TwinFlo catheter is inserted through a single puncture in the left femoral artery and its outer lumen is placed in the aortic arch, while its inner lumen is advanced into the right internal carotid artery (figure 2). Figure 1 Schematic diagram of the protocol. The extracorporeal membrane oxygenation–cerebral selective deep hypothermia (ECMO–CSDH) protocol uses two independent extracorporeal circuits: the one for standard ECMO is established using a cut-down in the emergency room and continues for 3–5 days; the other is established by a single standard femoral percutaneous puncture for placement of the TwinFlo cannula. CSDH circuit inserts, operates, and may be removed independently of the ECMO circuit. Figure 2 The TwinFlo catheter used in the cerebral selective deep hypothermia protocol. The outer lumen opening (A) is placed into the aortic arch and core temperature blood is removed through the outer lumen. The distal tip of the inner lumen (B) is advanced into the internal carotid and cooled blood is injected there. Systemic hypothermia was started in the intensive care unit using the ECMO circuit heat exchange system. The initial systemic target temperature was 34°C, as measured with a bladder temperature probe.

Figure 2 The TwinFlo catheter used in the cerebral selective deep hypothermia protocol. The outer lumen opening (A) is placed into the aortic arch and core temperature blood is removed through the outer lumen. The distal tip of the inner lumen (B) is advanced into the internal carotid and cooled blood is injected there. Systemic hypothermia was started in the intensive care unit using the ECMO circuit heat exchange system. The initial systemic target temperature was 34°C, as measured with a bladder temperature probe. After the consent process, the patient was sent to the catheterization laboratory to set up the CSDH circuit in the right carotid artery. Angiography was performed to confirm the patency of the coronary artery and absence of carotid stenosis. After insertion of the CSDH circuit, the patient was sent back to the intensive care unit for CSDH cooling initiation and operation. The patient's temperature was monitored using probes at the bladder, right (ipsilateral to the cooling catheter tip) nasal, and left nasal locations. At the start of systemic hypothermia, the ECMO circuit heat exchanger is initially set to maintain bladder temperature at 34°C.

After the consent process, the patient was sent to the catheterization laboratory to set up the CSDH circuit in the right carotid artery. Angiography was performed to confirm the patency of the coronary artery and absence of carotid stenosis. After insertion of the CSDH circuit, the patient was sent back to the intensive care unit for CSDH cooling initiation and operation. The patient's temperature was monitored using probes at the bladder, right (ipsilateral to the cooling catheter tip) nasal, and left nasal locations. At the start of systemic hypothermia, the ECMO circuit heat exchanger is initially set to maintain bladder temperature at 34°C. The CSDH protocol was designed to cool to the target temperature and to hold that temperature for 12 hours, followed by gradual rewarming at 0.5°C/hour. The target temperature was a right nasal temperature of 27±3°C. The flow in the CSDH circuit was kept between 200 and 250 mL/min during the procedure, as needed. Figure 3 shows the observed temperature profiles during the CSDH part of the procedure. While CSDH was operating, the ECMO circuit was used to maintain core (bladder) temperature in a normothermic range. During CSDH, the right and left nasal probes were within 1.5±0.58°C of each other.

during the procedure, as needed. Figure 3 shows the observed temperature profiles during the CSDH part of the procedure. While CSDH was operating, the ECMO circuit was used to maintain core (bladder) temperature in a normothermic range. During CSDH, the right and left nasal probes were within 1.5±0.58°C of each other. Figure 3 Temperature versus time from estimated arrest. The extracorporeal membrane oxygenation (ECMO) circuit flow started 52 min from arrest, systemic hypothermia via the ECMO circuit started at 3.7 hours, and cerebral selective deep hypothermia (CSDH) circuit cooling started at 13.7 hours and reached the target band for ipsilateral nasal temperature (right) (27±2°C) at 17.7 hours. The CSDH temperature was held for 12 hours until hour 29.7 and then gradual rewarming was implemented for ∼24 hours. Following the rewarming period, the CSDH circuit was shut down and removed, although the ECMO operation continued to support flow until ECMO weaning on day 3. The patient received 11 hours of cerebral temperature below 30°C (based on right nasal temperature), and over the period from initial achievement of the target temperature to the start of rewarming, the difference between the right nasal temperature and the core temperature was 5.6±0.9°C. CSDH cooling started at hour 13, target temperature was reached at hour 15, rewarming started at hour 29, and rewarming ended and the CSDH circuit was withdrawn at hour 51.

Figure 3 Temperature versus time from estimated arrest. The extracorporeal membrane oxygenation (ECMO) circuit flow started 52 min from arrest, systemic hypothermia via the ECMO circuit started at 3.7 hours, and cerebral selective deep hypothermia (CSDH) circuit cooling started at 13.7 hours and reached the target band for ipsilateral nasal temperature (right) (27±2°C) at 17.7 hours. The CSDH temperature was held for 12 hours until hour 29.7 and then gradual rewarming was implemented for ∼24 hours. Following the rewarming period, the CSDH circuit was shut down and removed, although the ECMO operation continued to support flow until ECMO weaning on day 3. The patient received 11 hours of cerebral temperature below 30°C (based on right nasal temperature), and over the period from initial achievement of the target temperature to the start of rewarming, the difference between the right nasal temperature and the core temperature was 5.6±0.9°C. CSDH cooling started at hour 13, target temperature was reached at hour 15, rewarming started at hour 29, and rewarming ended and the CSDH circuit was withdrawn at hour 51. Following the center's standard ECPR protocol, activated clotting time was monitored every hour for the first 4 hours until stable, and then every 4–8 hours for the rest of the protocol. Continuous heparin was infused to maintain an activated clotting time of 200–220 s. On day 3, the patient experienced a mild seizure of the face which was controlled with valproic acid. At that time a corticosteroid was administered to block potential swelling.

Following the center's standard ECPR protocol, activated clotting time was monitored every hour for the first 4 hours until stable, and then every 4–8 hours for the rest of the protocol. Continuous heparin was infused to maintain an activated clotting time of 200–220 s. On day 3, the patient experienced a mild seizure of the face which was controlled with valproic acid. At that time a corticosteroid was administered to block potential swelling. Echocardiography demonstrated good ventricular function recovery at hour 54, after which the ECMO weaning process started. The ECMO circuit was removed at hour 81 without complications. Outcome and follow-up The time course of the patient's recovery was faster than expected. The patient's consciousness level improved to E3M5 on day 4 and to E4M6 on day 5. The patient was extubated on day 8 without obvious motor neurological signs except for short term memory loss. Brain CT and MRI studies 1 week after the episode demonstrated several minimal infarcts without significant symptoms. On day 9, the patient was diagnosed with Brugada syndrome, and on day 11 was treated by implantation of a cardioverter defibrillator. The patient was discharged without significant neurological deficits (Cerebral Performance Categories Scale 1) 32 days after the episode. The patient returned to his professional work as a urologist 2 months later.

agnosed with Brugada syndrome, and on day 11 was treated by implantation of a cardioverter defibrillator. The patient was discharged without significant neurological deficits (Cerebral Performance Categories Scale 1) 32 days after the episode. The patient returned to his professional work as a urologist 2 months later. Discussion This is the first case presentation of CSDH for refractory out-of-hospital cardiac arrest in a patient. The long no flow (at least 8 min) and low flow (44 min) period before ECMO initiation was expected to hinder the recovery of the neurological insult, and we thought recovery might take more than 2–3 weeks. The cerebral temperature applied was much lower than that previously obtainable by systemic means. Recovery from the neurological insult was more rapid than expected. Several initial observations about implementation of the CSDH protocol in this case include: (a) a difference of 5–6°C between the core (bladder) and ipsilateral nasal temperatures was achieved and sustained; (b) left and right nasal probes were within ∼1.5°C; (c) within 2 hours from the start of CSDH, cerebral temperature had dropped below 30°C; (d) the protocol demonstrated rapid achievement of the cerebral target and a 12 hour stable hold of core normothermia and the target cerebral temperature; and (e) the same system provided adequate controlled rewarming.

ithin ∼1.5°C; (c) within 2 hours from the start of CSDH, cerebral temperature had dropped below 30°C; (d) the protocol demonstrated rapid achievement of the cerebral target and a 12 hour stable hold of core normothermia and the target cerebral temperature; and (e) the same system provided adequate controlled rewarming. This case demonstrates that implementing a CSDH protocol is feasible. We do not believe or assert that the case demonstrates efficacy or clinical value, even though the specific outcome was favorable. Evaluation of the efficacy of the CSDH protocol and choice of target temperatures will require larger studies. Contributors: C-HW: writing and designing the system. Y-TL and H-WC: patient care. Y-CW and J-JH: catheter intervention. JRG: design. YSC: writing, design of the system, and intervention. Competing interests: Chih-Hsien Wang, Yu-Ting Lin, Mao Ting, Heng-Wen Chou, Yi-Chih Wang, Juey-Jen Hwang, Yih-Sharng Chen: none. John R. Gilbert is both the CTO and a shareholder of APMTD, which is the master distributor for the TwinFlo® Device in Taiwan. Patient consent: Obtained. Ethics approval: The institutional review board approved the study (series No 2016-03049 BIPA). Provenance and peer review: Not commissioned; externally peer reviewed. Data sharing statement: The authors agree to share unpublished data if requested.

sures (PIP) of 23–45 cm H2O, positive end-expiratory pressure (PEEP) of 7 cm H2O, backup respiratory rate (RR) of 34). A chest X-ray of the thorax was performed on admission (figure 1A), and a month after the first surgery (figure 1B), showing improvement of the bilateral posterior atelectasis in the base of the lungs. Figure 1 Chest X-ray. (A) At admission 2015, May: white left lung without mediastinal shift. Multiple vertebral anomalies. Tracheostomy. (B) 2015, June: bilateral pulmonary hyperinflation. Pleural drainage tube distal end to right paramediastinal level. Implantable venous access device (Port-a-cath), tracheostomy and right and left Vertical Expandable Prosthetic Titanium Ribs (VEPTRs). Treatment Owing to the difficulty of progressing in the weaning process from mechanical ventilation after the VEPTRs were implanted to expand the thorax, a bronchoscopy was performed, showing bronchomalacia predominantly in both upper lobar bronchi. As prolonged mechanical ventilation was expected, a tracheostomy was previously performed. After an initial CT scan (figure 2A), a follow-up CT scan (figure 2B) a month after the surgery showed a resolution of the posterior-basal atelectasis, coinciding with a decrease of FiO2 to 0.21.

Background Calcium-channel blockers are the first-line treatment for hypertension in the elderly.1 Macrolides such as clarithromycin are the most widely prescribed antibiotics to outpatients.2 However, it is not widely known that hypotension can be induced by the interaction between these two types of drugs. Here we report a case of hypotension caused by the concomitant use of a calcium-channel blocker and clarithromycin. Case presentation A 78-year-old man visited a hospital for cough and sputum, and he was prescribed with clarithromycin. The following day, he was admitted to our hospital due to loss of consciousness. His medical history included hypertension, atrial fibrillation and chronic kidney disease. His baseline blood pressure was 140/60 mm Hg. He reportedly took two calcium-channel blockers, nifedipine and diltiazem, as well as carvedilol, and a few other drugs (irbesartan, azosemide, warfarin, ranitidine, sitagliptin, sodium ferrous citrate, isosorbide dinitrate and dypiridamole). His Glasgow Coma Scale score was 14/15 (E4V4M6). He had a blood pressure of 96/38 (mean 57) mm Hg, pulse rate of 44 bpm, respiratory rate of 20 breaths/min, oxygen saturation of 97% (room air) and temperature of 36.4°C. Physical examination showed no abnormal findings. The peripheries were warm.

rate and dypiridamole). His Glasgow Coma Scale score was 14/15 (E4V4M6). He had a blood pressure of 96/38 (mean 57) mm Hg, pulse rate of 44 bpm, respiratory rate of 20 breaths/min, oxygen saturation of 97% (room air) and temperature of 36.4°C. Physical examination showed no abnormal findings. The peripheries were warm. A 12-lead ECG at admission revealed atrial fibrillation with ST-segment depression in V6, and T-wave inversions in I and aVL (figure 1). The corrected QT interval was 360–400 ms. Trunk CT scan showed no abnormal findings. Laboratory data showed leukocytosis (11 400/µL) and an elevated creatinine level (1.95 mg/dL). Figure 1 12-Lead electrocardiogram at admission. Differential diagnosis The following differential diagnoses were considered: septic shock, cardiogenic shock and hypovolaemic shock. Septic shock was our initial consideration. However, the patient's respiratory symptoms were mild, and he required no supplemental oxygen. Furthermore, no consolidation was found in his lungs. Second, we suspected cardiogenic shock. Although his ECG showed atrial fibrillation with bradycardia, a transthoracic echocardiogram revealed normal ventricular wall motion with preserved ejection fraction. Even after his heart rate increased to 70 bpm after atropine administration, his blood pressure showed no improvement (mean arterial pressure was 45 mm Hg). Third, we suspected hypovolaemic shock. However, his history of present illness and physical examination showed no signs of fluid loss. Furthermore, the administration of intravenous fluids did not improve his blood pressure.

Second, we suspected cardiogenic shock. Although his ECG showed atrial fibrillation with bradycardia, a transthoracic echocardiogram revealed normal ventricular wall motion with preserved ejection fraction. Even after his heart rate increased to 70 bpm after atropine administration, his blood pressure showed no improvement (mean arterial pressure was 45 mm Hg). Third, we suspected hypovolaemic shock. However, his history of present illness and physical examination showed no signs of fluid loss. Furthermore, the administration of intravenous fluids did not improve his blood pressure. After the other causes of hypotension were ruled out, we attributed his hypotension to a drug interaction between a calcium-channel blocker and clarithromycin. Treatment The patient was transferred to the intensive care unit, and all his medications were discontinued. Norepinephrine (0.1 µg/kg/min) and isoproterenol (0.008 µg/kg/min) were administered to maintain a mean arterial pressure of >60 mm Hg and a heart rate of >60 bpm. On hospital day 2, norepinephrine was gradually reduced and discontinued. Isoproterenol was still required that morning because his heart rate fell below 50 bpm and an ECG revealed a second-degree atrioventricular block after discontinuation of isoproterenol. In the evening, however, isoproterenol was also discontinued (figure 2). His serum creatinine level gradually recovered (1.34 mg/dL on the morning of hospital day 3). He remained stable, and on hospital day 3, he was transferred out of the intensive care unit. Figure 2 Haemodynamics during ICU stay.

Treatment The patient was transferred to the intensive care unit, and all his medications were discontinued. Norepinephrine (0.1 µg/kg/min) and isoproterenol (0.008 µg/kg/min) were administered to maintain a mean arterial pressure of >60 mm Hg and a heart rate of >60 bpm. On hospital day 2, norepinephrine was gradually reduced and discontinued. Isoproterenol was still required that morning because his heart rate fell below 50 bpm and an ECG revealed a second-degree atrioventricular block after discontinuation of isoproterenol. In the evening, however, isoproterenol was also discontinued (figure 2). His serum creatinine level gradually recovered (1.34 mg/dL on the morning of hospital day 3). He remained stable, and on hospital day 3, he was transferred out of the intensive care unit. Figure 2 Haemodynamics during ICU stay. Outcome and follow-up The patient was healthy on review at 2 weeks after discharge. Discussion We realised two important clinical issues through this case. First, the combination of calcium-channel blockers and clarithromycin can cause hypotension because of excessive vasodilation. Second, the addition of another calcium-channel blocker and a β blocker can lower cardiac output due to bradycardia and thus worsen hypotension.

ntly in both upper lobar bronchi. As prolonged mechanical ventilation was expected, a tracheostomy was previously performed. After an initial CT scan (figure 2A), a follow-up CT scan (figure 2B) a month after the surgery showed a resolution of the posterior-basal atelectasis, coinciding with a decrease of FiO2 to 0.21. Figure 2 CT scan of the thorax. (A) At admission 2015, May: posterior-basal bilateral atelectasis. Hyperinflation with air trapping in the anterior lung parenchyma. Fusion anomalies and segmentation of all vertebral bodies. (B) After VEPTR insertion 2015, August. 1 week after starting NAVA mode: partial atelectasis in upper and lower lobes, less than prior CT. Hyperinflation with air trapping in the rest of the lung parenchyma. NAVA, Neurally Adjusted Ventilatory Assist; VEPTRs, Vertical Expandable Prosthetic Titanium Ribs.

two important clinical issues through this case. First, the combination of calcium-channel blockers and clarithromycin can cause hypotension because of excessive vasodilation. Second, the addition of another calcium-channel blocker and a β blocker can lower cardiac output due to bradycardia and thus worsen hypotension. To confirm a diagnosis of drug-induced hypotension in this case, it was necessary to rule out other causes of hypotension. In this case, septic shock was first suspected but was excluded because his respiratory symptoms were too mild. Cardiogenic shock was ruled out because the echocardiogram showed normal ventricular wall motion with preserved ejection fraction, and the patient's blood pressure remained low even after his bradycardia improved. Hypovolaemic shock was also ruled out because the administration of intravenous fluids failed to improve his blood pressure. Calcium-channel blockers are metabolised by the CYP3A4 enzyme, which are inhibited by macrolide antibiotics. Concomitant use of these drugs can result in vasodilatory hypotension.3 It is reported that a combination of these drugs increases hospitalisation with hypotension or acute kidney injury. When calcium-channel blockers were used with clarithromycin, 1 in 464 people were hospitalised. One in 160 people were hospitalised when nifedipine, which our patient had been taking, was given along with clarithromycin. This was more frequent than any other calcium blocker.3

on with hypotension or acute kidney injury. When calcium-channel blockers were used with clarithromycin, 1 in 464 people were hospitalised. One in 160 people were hospitalised when nifedipine, which our patient had been taking, was given along with clarithromycin. This was more frequent than any other calcium blocker.3 Vasodilatory shock can worsen with bradycardia caused by other drugs. In this case, hypotension due to a drug interaction occurred the day after the patient began using a combination of calcium-channel blockers and clarithromycin. Previous reports, however, showed that most patients develop clinical symptoms 2–3 days after using this drug combination.4–6 The inhibitory effect of a 14-membered ring macrolide, such as clarithromycin and erythromycin, on CYP 3A4 does not occur immediately because these antibiotics need to be metabolised before showing their inhibitory effect. The time difference between our case and previous ones may be due to the influence of diltiazem (benzothiazepine calcium-channel blocker) and carvedilol (β blocker), which the patient was taking in addition to nifedipine. Benzothiazepine calcium-channel blockers have negative inotropic and chronotropic effects and, in excess, can disturb the cardiac conduction system. β-Blockers prevent the increase in heart rates.7 Consequently, these additional effects can lower cardiac output and worsen hypotension. Since carvedilol is also metabolised by CYP3A4, its plasma concentration could be increased by the inhibitory effect of clarithromycin on CYP3A4.

Vasodilatory shock can worsen with bradycardia caused by other drugs. In this case, hypotension due to a drug interaction occurred the day after the patient began using a combination of calcium-channel blockers and clarithromycin. Previous reports, however, showed that most patients develop clinical symptoms 2–3 days after using this drug combination.4–6 The inhibitory effect of a 14-membered ring macrolide, such as clarithromycin and erythromycin, on CYP 3A4 does not occur immediately because these antibiotics need to be metabolised before showing their inhibitory effect. The time difference between our case and previous ones may be due to the influence of diltiazem (benzothiazepine calcium-channel blocker) and carvedilol (β blocker), which the patient was taking in addition to nifedipine. Benzothiazepine calcium-channel blockers have negative inotropic and chronotropic effects and, in excess, can disturb the cardiac conduction system. β-Blockers prevent the increase in heart rates.7 Consequently, these additional effects can lower cardiac output and worsen hypotension. Since carvedilol is also metabolised by CYP3A4, its plasma concentration could be increased by the inhibitory effect of clarithromycin on CYP3A4. In conclusion, the combination of calcium-channel blockers and clarithromycin can cause hypotension. Adding another calcium-channel blocker and a β blocker can worsen hypotension by inducing bradycardia and reducing cardiac output. Our society is ageing rapidly and more elderly people will require calcium-channel blockers. We need to consider the possibility of a drug interaction in a hypotensive patient when its cause is unknown.

r calcium-channel blocker and a β blocker can worsen hypotension by inducing bradycardia and reducing cardiac output. Our society is ageing rapidly and more elderly people will require calcium-channel blockers. We need to consider the possibility of a drug interaction in a hypotensive patient when its cause is unknown. Learning points Hypotension can be induced by the interaction between calcium-channel blockers and clarithromycin, which are widely prescribed drugs. Adding another calcium-channel blocker and a β blocker can worsen hypotension. It is important to consider drug interactions when cause of hypotension is unknown. Contributors: ST and YK wrote and edited the case report. TT had the idea for this case report and was involved in the review. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Injection of histoacryl glue is not without risk. In our case, glue migrated to the pelvis with no consequence to the patient. There are well-documented cases of glue causing pulmonary embolism.26 27 We therefore urge caution with the use of histoacryl glue. This should ideally be performed by an experienced endoscopist. Learning points Duodenal varices are a rare manifestation of portal hypertension in patients with cirrhosis and can lead to life-threatening haemorrhage. Duodenal varices should be considered in patients presenting with melaena with no identifiable cause of bleeding on visualisation of the oesophagus and presence of hepatofugal flow on ultrasound. Although treatment of duodenal varices is not well researched, endoscopic variceal sclerotherapy with histoacryl glue is effective in the management of this life-threatening presentation. Injection of histoacryl glue can lead to complications such as migration to the lungs, abdomen and pelvis. Competing interests: None declared. Provenance and peer review: Not commissioned; externally peer reviewed.

Background It is important to question the validity of the test used if results are inconsistent or conflicting with clinical and other laboratory findings. Clinicians should be familiar with the method used to measure serum creatinine at their local laboratory and should be aware of alternative tests to measure kidney function. Jaffé method which is based on reaction of creatinine with picric acid is a commonly used for creatinine measurement but large number of substances can interfere with this method including bilirubin, acetoacetate and various drugs.1 Newer enzymatic tests such as Siemens Advia enzymatic assay are thought to be more specific but they are also subject to interference as we demonstrated in this case, also here, unravelling the cause of test interference helped towards making the right diagnosis. Case presentation A 62-year-old woman presented to her general practitioner with fatigue, headache and itching over a period of 6 weeks. There was no history of fever, jaundice or weight loss. She was treated for otitis externa with erythromycin 2 weeks before her presentation. Routine bloods tests showed elevated serum creatinine at 285 µmol/L (estimated glomerular filtration rate (eGFR) 16 mL/min/1.73 m2). Her serum creatinine was 56 µmol/L (eGFR>60 mL/min/1.73 m2) 5 months prior to her presentation, for summary of her laboratory investigations see table 1. Table 1 Patient laboratory results with corresponding reference interval

Case presentation A 62-year-old woman presented to her general practitioner with fatigue, headache and itching over a period of 6 weeks. There was no history of fever, jaundice or weight loss. She was treated for otitis externa with erythromycin 2 weeks before her presentation. Routine bloods tests showed elevated serum creatinine at 285 µmol/L (estimated glomerular filtration rate (eGFR) 16 mL/min/1.73 m2). Her serum creatinine was 56 µmol/L (eGFR>60 mL/min/1.73 m2) 5 months prior to her presentation, for summary of her laboratory investigations see table 1. Table 1 Patient laboratory results with corresponding reference interval Investigation Result Reference Leukocytes (109/L) 6.4 4–10 Haemoglobin (g/L) 101 13–17 Erythrocyte cell volume (MCV) 92 82–99 Platelets (109/L) 225 140–400 Sodium (mmol/L) 133 133–146 Potassium (mmol/L) 3.5 3.5–4.8 Phosphate (mmol/L) 1.26 0.8–1.5 Urate (υmol/L) <30 140–360 Protein total (g/L) 72 60–80 Albumin (g/L) 36 35–50 IgA (g/L) 1.97 0.8–4.0 IgM (g/L) 8.58 0.5–3.0 IgG (g/L) 5.69 6.0–16 Paraprotein type IgM lambda C3 (mg/dL) 112.0 90–180 C4 (mg/dL) <1.7 10–40 C reactive protein (mg/dL) 40 0–4 ANA Negative ANCA Anti-MPO (IU/mL) <0.1 Normal: 0.0–3.5 Anti-PR3 (IU/mL) 0.2 Normal: 0.0–2.0 Anti-GBM (U/mL) 1.0 Negative <7 ANA, anti-nuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM, anti-glomerular basement membrane antibodies; anti-MPO, myeloperoxidase antibodies; anti-PR3, anti-proteinase 3 antibodies.

ve ANCA Anti-MPO (IU/mL) <0.1 Normal: 0.0–3.5 Anti-PR3 (IU/mL) 0.2 Normal: 0.0–2.0 Anti-GBM (U/mL) 1.0 Negative <7 ANA, anti-nuclear antibody; ANCA, anti-neutrophil cytoplasmic antibody; anti-GBM, anti-glomerular basement membrane antibodies; anti-MPO, myeloperoxidase antibodies; anti-PR3, anti-proteinase 3 antibodies. Medical history included: hypertension, anxiety, depression, hysterectomy, cholecystectomy and herpes zoster infection. Her medications included: hormonal replacement patches, bendroflumethiazide 2.5 mg once daily and venlafaxine 75 mg once daily. She was a non-smoker and her alcohol consumption was <2 units per week. Investigations The patient was admitted to the renal unit for further assessment and consideration of performing a renal biopsy. Abdominal examination revealed splenomegaly. There was no evidence of generalised lymphadenopathy. The urine dipstick was bland on multiple occasions. Chest X-ray was normal. Abdominal ultrasound confirmed splenomegaly (17 cm) with normal-size kidneys. Serum protein electrophoresis and immunofixation showed IgM band at a level of 8.58 g/L (normal range 0.5–3 g/L). A significant degree of fluctuation in serum creatinine was noted following her hospitalisation (figure 1). Figure 1 Plasma levels of Creatinine and urea before and after treatment. This fluctuating pattern along with normal urea concentration raised suspicion about the validity of serum creatinine measurement particularly with the presence of paraproteinaemia.

A significant degree of fluctuation in serum creatinine was noted following her hospitalisation (figure 1). Figure 1 Plasma levels of Creatinine and urea before and after treatment. This fluctuating pattern along with normal urea concentration raised suspicion about the validity of serum creatinine measurement particularly with the presence of paraproteinaemia. To investigate this possibility further, serum creatinine was measured using the picric acid Jaffé method. Renal excretory function was also assessed with Cr51 EDTA isotope GFR measurement. Serum creatinine concentration was found to be 86 µmol/L by the Jaffé method and it was consistent with the Cr51 EDTA GFR result of 71 mL/min (table 2). Table 2 Results obtained by three different methods arranged over 48 hours Method used Serum creatinine (µmol/L) eGFR Siemens Advia enzymatic assay 412 10 Jaffé method 86 >60 Cr51 EDTA GFR 71 mL/min eGFR, estimated glomerular filtration rate. Taken together, these findings indicated that serum creatinine was falsely elevated when measured with enzymatic assay due to the presence of an interfering compound. IgM paraprotein was the culprit substance in this case. A bone marrow biopsy was performed and the histology and immunohistochemistry findings were in keeping with a diagnosis of low-grade B-cell non-Hodgkin's lymphoma.

Taken together, these findings indicated that serum creatinine was falsely elevated when measured with enzymatic assay due to the presence of an interfering compound. IgM paraprotein was the culprit substance in this case. A bone marrow biopsy was performed and the histology and immunohistochemistry findings were in keeping with a diagnosis of low-grade B-cell non-Hodgkin's lymphoma. Treatment, outcome and follow-up Patient was treated initially with combination of rituximab and bendamustine. She developed an allergic reaction to rituximab. She eventually completed five cycles of bendamustine with good response. Postchemotherapy serum creatinine returned to normal range, which also coincides with paraprotein disappearance (figure 1). Discussion It is important that clinicians are aware of limitations of commonly used laboratory tests. Such knowledge aids in avoiding unnecessary and potentially invasive investigation. In the UK, ∼25% of laboratories use an enzymatic method to measure creatinine. In general, the enzymatic method, although more expensive, is preferred over the kinetic Jaffé assay as it is less affected by interferences such as bilirubin, protein, glucose and ketones.1 However, in this case, we demonstrate how an enzymatic creatinine method was subject to interference by IgM paraproteinaemia. Paraproteins have been shown to artificially influence different methodologies of automated assays, including nephelometry, turbidimetry and immunoassays.2 3

Discussion It is important that clinicians are aware of limitations of commonly used laboratory tests. Such knowledge aids in avoiding unnecessary and potentially invasive investigation. In the UK, ∼25% of laboratories use an enzymatic method to measure creatinine. In general, the enzymatic method, although more expensive, is preferred over the kinetic Jaffé assay as it is less affected by interferences such as bilirubin, protein, glucose and ketones.1 However, in this case, we demonstrate how an enzymatic creatinine method was subject to interference by IgM paraproteinaemia. Paraproteins have been shown to artificially influence different methodologies of automated assays, including nephelometry, turbidimetry and immunoassays.2 3 Reports in the literature highlight cases where paraproteins have been shown to interfere with various assays available on the automated analysers, including calcium, bilirubin, chloride, phosphate and glucose.3 In one case report, IgM test interference was observed using Siemens Advia enzymatic assay but not Abbott Architect method.4 Both assays are using similar enzymatic reactions but differ in methods of hydrogen peroxide and chromogen detection. The mechanism behind this IgM paraprotein interference is unclear.

Reports in the literature highlight cases where paraproteins have been shown to interfere with various assays available on the automated analysers, including calcium, bilirubin, chloride, phosphate and glucose.3 In one case report, IgM test interference was observed using Siemens Advia enzymatic assay but not Abbott Architect method.4 Both assays are using similar enzymatic reactions but differ in methods of hydrogen peroxide and chromogen detection. The mechanism behind this IgM paraprotein interference is unclear. Scott et al suggested that interference phenomenon might depend on the variable region of the IgM monoclonal antibody. Using Roche creatinine plus enzymatic method, they reported that only one in five patients with IgM paraproteinaemia showed a falsely elevated serum creatinine.5 An alternative explanation is that the IgM paraprotein may form complexes with the reagents and increase the turbidity of the sample interfering with the absorbance measurement.6

ne plus enzymatic method, they reported that only one in five patients with IgM paraproteinaemia showed a falsely elevated serum creatinine.5 An alternative explanation is that the IgM paraprotein may form complexes with the reagents and increase the turbidity of the sample interfering with the absorbance measurement.6 In our case, the monoclonal IgM band associated with lymphoplasmacytoid lymphoma caused a false elevation in the serum creatinine concentration when measured by Siemens Advia enzymatic assay method. This method is based on the enzymatic reaction where creatinine is converted to creatine by the action of creatininase, to produce creatine and sarcosine. The sarcosine is metabolised by sarcosine oxidase to produce glycine, formaldehyde and hydrogen peroxide. The hydrogen peroxide in the presence of peroxidase yields a blue pigment. The creatinine concentration is calculated by measuring the absorbance of the blue colour at 596/694 nm. This case highlights the significance of paraprotein interference with commonly used laboratory test. We recommend considering this possibility when assessing individual with elevated serum creatinine and detectable IgM paraprotein. Learning points Paraproteinaemia should be considered as a cause of falsely elevated serum creatinine concentration. Validity of any test should be questioned if results are inconsistent or conflicting with the clinical condition of the patient. Good communication between clinicians and laboratories is crucial when investigating challenging cases like this.

Learning points Paraproteinaemia should be considered as a cause of falsely elevated serum creatinine concentration. Validity of any test should be questioned if results are inconsistent or conflicting with the clinical condition of the patient. Good communication between clinicians and laboratories is crucial when investigating challenging cases like this. Contributors: E-HM is primary author and performed writing, editing and literature search. DK is senior author involved in writing, editing and supervising manuscript. HR helped in editing and case discussion. JL helped in editing. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Spondylocostal dysostosis or Jarcho-Levin syndrome is a rare disorder characterised by defects in vertebral and costal segmentation of varying severity. It is inherited in an autosomal-recessive manner in the majority of cases, although several autosomal-dominant variants have been described.1 Respiratory complications are the main cause of death or severe comorbidity in the first years of life. These are mainly due to a restrictive rib cage, chronic respiratory failure and frequent respiratory exacerbations.2 Patients with associated tracheobronchomalacia have been described in the literature.3 The patients affected with malacia of the airway are especially difficult to manage as the episodes of airway collapse frequently imply the need for sedation and even muscular relaxants, consequently requiring prolonged mechanical ventilation in intensive care units (ICU).4 5 The Neurally Adjusted Ventilatory Assist (NAVA) mode has been shown to offer better patient–ventilator synchrony,6 which was the reason for its use in this case. Ventilatory support in this mode is determined by the electrical activity of the diaphragm (Edi) which is converted to a proportional pressure support, varying in function of the diaphragmatic electrical activity and the level of support (NAVA level) set by the clinician.

which was the reason for its use in this case. Ventilatory support in this mode is determined by the electrical activity of the diaphragm (Edi) which is converted to a proportional pressure support, varying in function of the diaphragmatic electrical activity and the level of support (NAVA level) set by the clinician. Our experience with a patient with Spondylocostal dysostosis and associated bronchomalacia is presented here, where the NAVA mode was used to improve adaptation to mechanical ventilation during the weaning process after Vertical Expandable Prosthetic Titanium Ribs (VEPTRs) were implanted. Case presentation A 3-month-old infant from the UAE with a genetically-confirmed diagnosis of Jarcho-Levin syndrome and dependent on mechanical ventilation since birth was admitted to our centre for the implantation of VEPTRs. We received an intubated patient, mechanically ventilated in a volume-controlled mode, with a 0.30–0.45 fraction of inspired oxygen (FiO2) (peak inspiratory pressures (PIP) of 23–45 cm H2O, positive end-expiratory pressure (PEEP) of 7 cm H2O, backup respiratory rate (RR) of 34). A chest X-ray of the thorax was performed on admission (figure 1A), and a month after the first surgery (figure 1B), showing improvement of the bilateral posterior atelectasis in the base of the lungs.

tebral bodies. (B) After VEPTR insertion 2015, August. 1 week after starting NAVA mode: partial atelectasis in upper and lower lobes, less than prior CT. Hyperinflation with air trapping in the rest of the lung parenchyma. NAVA, Neurally Adjusted Ventilatory Assist; VEPTRs, Vertical Expandable Prosthetic Titanium Ribs. Postoperatively, the patient was on the Servo-i ventilator in a volume-controlled mode and needed variable PIPs between 25 and 45 cm H2O and PEEP values of 7–11 cm H2O. During the attempts to wean the patient off the ventilator in the following months, he was unable to activate the inspiratory flow trigger and required significant sedoanalgesia to adapt to the ventilator due to repeated episodes of desaturation, on some occasions with bradycardia, associated to bronchial collapse. He continued to have asynchrony which required boluses of sedation in addition to existing medications. He initially received fentanyl and midazolam through a continuous infusion pump with progressive increase in the doses as well as continuous cisatracurium as a muscular relaxant to adapt to mechanical ventilation (figure 3). As clinical stabilisation was achieved, the muscular relaxant was withdrawn and a progressive decrease of sedation was initiated along with a change in the drug regimen. During this period, the patient developed an ocular flutter which was attributed to a pharmacological cause after neurological alterations were ruled out with normal EEG, ophthalmoscopy, metabolic workup and cranial MRI.

drawn and a progressive decrease of sedation was initiated along with a change in the drug regimen. During this period, the patient developed an ocular flutter which was attributed to a pharmacological cause after neurological alterations were ruled out with normal EEG, ophthalmoscopy, metabolic workup and cranial MRI. Figure 3 Sedoanalgesia administered according to time of admission. The sedoanalgesia dose administered by continuous infusion. On the vertical axis, scale of values from 0 to 1, where 1 is the maximum dose received and 0 is the suspension of the dose (equivalents: 1 Fentanyl=3 µg/kg/hour, 1 midazolam=0.28 mg/kg/hour, 1 cisatracurium=6 µg/kg/min, 1 morphine chloride=48 µg/kg/hour). On the horizontal axis: weeks. At 5 months of age, the NAVA mode started to improve the patient's adaptation to the ventilator through the use of a neural trigger. The NAVA catheter additionally costs around €200 per catheter; according to the manufacturer it should be changed every 5 days. It was required for 7 months; nevertheless the catheters were changed every 15 days without observing a deterioration of the Edi signal. According to the literature, Jarcho-Levin syndrome does not appear with mental retardation and life expectancy is pretty long, so ethically, we considered that this patient should have an opportunity to overcome his thoracic insufficiency if it were technically possible.

out observing a deterioration of the Edi signal. According to the literature, Jarcho-Levin syndrome does not appear with mental retardation and life expectancy is pretty long, so ethically, we considered that this patient should have an opportunity to overcome his thoracic insufficiency if it were technically possible. Tachypnoea was initially observed with a RR of 55 without other signs of increase in his work of breathing and his RR eventually returned to normal for his age (40) over the next few days. The synchrony achieved with the ventilator allowed a progressive decrease of the sedoanalgesia he received until it was completely withdrawn in 10 days; and the need for extra boluses of sedation was reduced to zero. Concurrently to the reduction of sedation, his ocular flutter disappeared and he showed significant progress in his psychomotor development. The settings used were: NAVA level of 1 cm H2O/µV, PEEP 11 cm H2O, Edi trigger 0.5 µV. The patient had tidal volumes (Vt) of 6–7 mL/kg (figure 3). After 10 days on the NAVA mode, he did not require any type of sedation and the sporadic episodes of bronchial collapse were resolved with a quick increase of PEEP to 20 cm H2O or manual ventilation with the self-inflating bag. Once he was stabilised on the NAVA mode, his PIPs oscillated between 15 and 45 cm H2O with a NAVA level of 0.4 and Edi peaks between 15 and 100 µV.

type of sedation and the sporadic episodes of bronchial collapse were resolved with a quick increase of PEEP to 20 cm H2O or manual ventilation with the self-inflating bag. Once he was stabilised on the NAVA mode, his PIPs oscillated between 15 and 45 cm H2O with a NAVA level of 0.4 and Edi peaks between 15 and 100 µV. A posterior pulmonary CT scan performed 2 months after the first surgery, 1 month after starting NAVA and prior to the first thoracic expansion, showed a significant reduction in the posterobasal atelectases previously observed (figure 2B). Outcome and follow-up When he turned 1 year old, after several attempts with different devices Trilogy 100 (Philips), Astral 150 (ResMed), the patient finally tolerated mechanical ventilation with a home ventilator (Monnal T-50, Air Liquide) in a volume assisted/controlled mode with the following settings: Vt 80 mL (9 mL/kg), PEEP 10 cm H2O, flow trigger 0.5 L/min. His PIPs were around 30 cm H2O. He did not tolerate a decrease of PEEP below 9 cm H2O or short disconnections from the ventilator. Currently, the patient is 19 months old, is able to walk and his neurodevelopment seems to be normal. Discussion Although the use of VEPTRs in the treatment of severe scoliosis7 is widely described, their use in Jarcho-Levin syndrome is more recent.8 9 We believe that our patient could be one of the youngest infants with VEPTRs implanted as we did not find any younger cases in the bibliography to date.

Outcome and follow-up When he turned 1 year old, after several attempts with different devices Trilogy 100 (Philips), Astral 150 (ResMed), the patient finally tolerated mechanical ventilation with a home ventilator (Monnal T-50, Air Liquide) in a volume assisted/controlled mode with the following settings: Vt 80 mL (9 mL/kg), PEEP 10 cm H2O, flow trigger 0.5 L/min. His PIPs were around 30 cm H2O. He did not tolerate a decrease of PEEP below 9 cm H2O or short disconnections from the ventilator. Currently, the patient is 19 months old, is able to walk and his neurodevelopment seems to be normal. Discussion Although the use of VEPTRs in the treatment of severe scoliosis7 is widely described, their use in Jarcho-Levin syndrome is more recent.8 9 We believe that our patient could be one of the youngest infants with VEPTRs implanted as we did not find any younger cases in the bibliography to date. The clinical and radiological improvement of the lung parenchyma observed in this patient could be influenced by various factors in combination. On one hand, the implantation of VEPTRs and their use for thoracic expansion which result in an increase of the rib cage volume, less restriction and an improvement of the atelectasis;2 on the other hand, the use of NAVA and the consequent decrease in sedation. In any case, a third CT scan prior to the first thoracic expansion continued to show resolution of the atelectasis, a phenomenon which reinforces the possible beneficial effects of combining the use of thoracic expansion with the use of NAVA. Asynchrony, a problem which is present in 25% of mechanically-ventilated patients10 is associated with increased sedation needs, worse comfort and quality of the patient's sleep, increased morbi-mortality, as well as a longer time on mechanical ventilation and length of stay in the ICU.

expansion with the use of NAVA. Asynchrony, a problem which is present in 25% of mechanically-ventilated patients10 is associated with increased sedation needs, worse comfort and quality of the patient's sleep, increased morbi-mortality, as well as a longer time on mechanical ventilation and length of stay in the ICU. Our patient presented with severe inspiratory asynchrony with episodes of airway collapse which finally led to a need for increased sedation various times a day. The option used to improve this type of asynchrony was ventilation with the NAVA mode together with an elevated PEEP level. The decrease of sedation until it was withdrawn was, we believe, related to the change in ventilation mode. It has been shown that sedation results in atelectasis of the posterior lung. The NAVA accompanied by PEEP in our case allowed us to remove sedation with consequent resolution of the atelectasis.11 Learning points The better patient–ventilator synchrony which allowed weaning of sedation in our case suggests that this mode could be an option to consider in selected patients with difficult weaning from mechanical ventilation due to tracheobronchomalacia in paediatric intensive care units. The evolution of this patient suggests that the combined use of Vertical Expandable Prosthetic Titanium Ribs technology for thoracic expansion and ventilation using Neurally Adjusted Ventilatory Assist can favour the global improvement of a highly-complex patient.

Learning points The better patient–ventilator synchrony which allowed weaning of sedation in our case suggests that this mode could be an option to consider in selected patients with difficult weaning from mechanical ventilation due to tracheobronchomalacia in paediatric intensive care units. The evolution of this patient suggests that the combined use of Vertical Expandable Prosthetic Titanium Ribs technology for thoracic expansion and ventilation using Neurally Adjusted Ventilatory Assist can favour the global improvement of a highly-complex patient. The authors are acknowledged to Port-Aventura and Investforchildren foundations who granted Hospital Sant Joan de Déu to do research in paediatric critical care The authors would like also to thank the clinicians and nurses of the intensive care unit of Hospital Sant Joan de Déu for their daily support to the clinical research in respiratory care. Twitter: Follow Martí Pons-Odena @Martí and Alba Verges @AVergés Contributors: MP-O conceived the case report and contributed to writing the manuscript. AV and NA were involved in acquisition of data and equally contributed to writing the manuscript. FJC contributed to writing the manuscript. All the authors read, reviewed and approved the final version of this case report.

Twitter: Follow Martí Pons-Odena @Martí and Alba Verges @AVergés Contributors: MP-O conceived the case report and contributed to writing the manuscript. AV and NA were involved in acquisition of data and equally contributed to writing the manuscript. FJC contributed to writing the manuscript. All the authors read, reviewed and approved the final version of this case report. Competing interests: Although MP-O has been speaker for MAQUET and our institution received disposable material 6 years ago to start using this technique, we honestly consider that we are not promoting an specific product in order to favour commercial interests of the company. So, we declare this potential conflict of interest, nothing to hide, but we believe there is no a real conflict of the interest of the authors. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Brain abscesses of odontogenic origin are rarely seen and account for only a small fraction of all reported cerebral abscesses. The incidence of cerebral abscesses ranges from 0.4 to 0.9 cases per 100 000 people and is more frequent in immunocompromised patients. Oral pathogens cause 3–10% of abscesses,1 while other causative pathogens are non-oral bacteria, mycobacteria, fungi or parasites. The underlying pathogenic mechanisms are poorly understood. Contiguous spread of a pathogen is the most frequent route of infection. Haematogenous or lymphatic dissemination is seen in a limited number of cases.2 The initial presentation, symptoms and results from clinical and radiological investigations vary widely and are non-specific for the causative pathogen.3–4 Morbidity and mortality have improved in recent years due to better imaging techniques and therapeutic options. Mortality ranges from 0 to 24% for odontogenic brain abscesses.5 Porphyromonas gingivalis, a gram-negative oral pathogen, has rarely been reported in subjects with cerebral abscess formation, but has been widely associated with periodontitis. Its pathogenesis is still being investigated, but includes a wide variety of immunological escape mechanisms.

or odontogenic brain abscesses.5 Porphyromonas gingivalis, a gram-negative oral pathogen, has rarely been reported in subjects with cerebral abscess formation, but has been widely associated with periodontitis. Its pathogenesis is still being investigated, but includes a wide variety of immunological escape mechanisms. We searched databases (Medline, Scopus, Web of Science, EMBASE, Cochrane library) and manually searched reference lists for relevant articles and related cases. Well-accepted reviews served as the foundation for this article. Additional original articles were selected by reading the abstract and obtaining the full text when needed. Search terms included: brain abscess, cerebral abscess, P. gingivalis, odontogenic, periodontitis, parodontitis, tooth infection and oral pathogen. Five articles were selected that discussed intracranial abscess formation by P. gingivalis.

s were selected by reading the abstract and obtaining the full text when needed. Search terms included: brain abscess, cerebral abscess, P. gingivalis, odontogenic, periodontitis, parodontitis, tooth infection and oral pathogen. Five articles were selected that discussed intracranial abscess formation by P. gingivalis. Case presentation We report the case of a 65-year-old man with a medical history of prostate carcinoma, for which he underwent radical prostatectomy with adjuvant radiotherapy. The patient also had type 2 diabetes, hypertension, hypercholesterolaemia and epilepsy of unknown origin during his childhood. Home medications included acetylsalicylic acid, olmesartan medoxomil, rosuvastatin, lixisenatide, metformin and gliclazide. The patient was previously treated with valproate, which was reduced and then stopped 6 months earlier as the patient was seizure free for over 20 years. Previous imaging reports never mentioned intracranial anomalies. Detailed findings and events are illustrated in the patient’s timeline (figure 1). Figure 1 Timeline of patient showing important clinical events, imaging and intervention dates, and antibiotic and antiepileptic treatments. T°, temperature; CRP, C reactive protein.

Case presentation We report the case of a 65-year-old man with a medical history of prostate carcinoma, for which he underwent radical prostatectomy with adjuvant radiotherapy. The patient also had type 2 diabetes, hypertension, hypercholesterolaemia and epilepsy of unknown origin during his childhood. Home medications included acetylsalicylic acid, olmesartan medoxomil, rosuvastatin, lixisenatide, metformin and gliclazide. The patient was previously treated with valproate, which was reduced and then stopped 6 months earlier as the patient was seizure free for over 20 years. Previous imaging reports never mentioned intracranial anomalies. Detailed findings and events are illustrated in the patient’s timeline (figure 1). Figure 1 Timeline of patient showing important clinical events, imaging and intervention dates, and antibiotic and antiepileptic treatments. T°, temperature; CRP, C reactive protein. In August 2016, he was admitted after a generalised epileptic seizure at home. The patient's wife reported that he was increasingly confused in the preceding days. The clinical neurological examination was normal with a Glasgow Coma scale (GCS) of 15/15. Blood tests were unremarkable except for a slightly increased C reactive protein (CRP) of 5.9 mg/L (reference <5.0 mg/L). An EEG was normal. A CT scan of the skull was performed showing a hypodense, contrast-enhanced lesion surrounded by oedema in the right frontal lobe (figure 2, video 1). No midline shift or ventricular anomalies were noted. An initial oncologic screening was advised with imaging of the chest and abdomen due to the medical history, but did not show primary malignancies or recurrence. After neurosurgical counsel, MRI with diffusion-weighted imaging (DWI) was added to the diagnostic workup and a brain abscess with pachymeningitis was diagnosed (figure 3, video 2). In light of these findings, a transthoracic ultrasound was negative for cardiac vegetations or signs of infection. Initial treatment consisted of systemic valproate (1.5 g/day), levetiracetam (1 g/day), vancomycin (2 g/day), ornidazole (1 g/day) and ceftriaxone (2 g/day). Stereotactic drainage was performed and MALDI-TOF spectrometry of the pus (Bruker Daltonik Maldi Biotyper) revealed P. gingivalis as the sole causative bacterium (score 2.231, high-confidence identification). Intraoral inspection showed partial dentition complicated with parodontitis. On previous CT imaging, apical periodontitis was seen around the elements 16, 23 and 34 (figure 4), and the sinus cavities appeared normal. The antibiotic regimen was reduced to intravenous ornidazole (1 g/day) and ceftriaxone (2 g/day).

ion). Intraoral inspection showed partial dentition complicated with parodontitis. On previous CT imaging, apical periodontitis was seen around the elements 16, 23 and 34 (figure 4), and the sinus cavities appeared normal. The antibiotic regimen was reduced to intravenous ornidazole (1 g/day) and ceftriaxone (2 g/day). Figure 2 Initial contrast-enhanced CT imaging at the day of admission showing a hypodense nodular lesion in the right frontal lobe with peripheral ring-like contrast uptake as well as perilesional oedema. The conclusion was possible malignancy, preferably metastasis. Figure 3 MRI with T1 (left) and diffusion-weighted imaging (right) showing central diffusion restriction suggestive of a cerebral abscess. The dural layer is thickened, indicating pachymeningitis. Figure 4 Periodontal apical radiolucent areas of elements 16 (left), 23 (middle) and 34 (right).

Figure 2 Initial contrast-enhanced CT imaging at the day of admission showing a hypodense nodular lesion in the right frontal lobe with peripheral ring-like contrast uptake as well as perilesional oedema. The conclusion was possible malignancy, preferably metastasis. Figure 3 MRI with T1 (left) and diffusion-weighted imaging (right) showing central diffusion restriction suggestive of a cerebral abscess. The dural layer is thickened, indicating pachymeningitis. Figure 4 Periodontal apical radiolucent areas of elements 16 (left), 23 (middle) and 34 (right). Nineteen days after initial drainage, left hemiparesis and left hemineglect developed as well as an increase in epileptic seizures with one tonic–clonic seizure. The patient further deteriorated with need for intubation and intravenous sedation. Imaging showed the intracerebral abscess was extending to the subdural space and subcutis, forming a subdural empyema and spreading to the occipital–parietal regions; therefore, incision and drainage (figure 5) was necessary. Owing to clinical instability, total extraction of the remaining dentition was performed in a separate procedure. Antibiotic treatment included intravenous ceftriaxone (2 g/day) and ornidazole (1 g/day), which were continued for a total of 43 days until clinical, biochemical and radiological improvement. The patient was discharged from the neurosurgical ward after 59 days with almost complete resolution of the neurological deficit. He was referred for inhospital physiotherapy to regain full motor function.

e (1 g/day), which were continued for a total of 43 days until clinical, biochemical and radiological improvement. The patient was discharged from the neurosurgical ward after 59 days with almost complete resolution of the neurological deficit. He was referred for inhospital physiotherapy to regain full motor function. Figure 5 CT imaging 12 days after initial abscess drainage. Subcutaneous collection (arrow) with gas locules (arrowhead), new manifestation of the subdural occipitoparietal empyema (small arrow) and increased cerebral oedema. Video 1 Initial contrast-enhanced CT imaging at the day of admission showing a hypodense nodular lesion in the right frontal lobe with peripheral ring-like contrast uptake as well as perilesional oedema. The conclusion was possible malignancy, preferably metastasis. 10.1136/bcr-2016-218845.video01BMJ Journals Video Playerbcr2016218845media1 Video 2 MRI with diffusion-weighted imaging showing central diffusion restriction, suggestive of a cerebral abscess. The dural layer is thickened, indicating pachymeningitis. 10.1136/bcr-2016-218845.video02BMJ Journals Video Playerbcr2016218845media2

Video 1 Initial contrast-enhanced CT imaging at the day of admission showing a hypodense nodular lesion in the right frontal lobe with peripheral ring-like contrast uptake as well as perilesional oedema. The conclusion was possible malignancy, preferably metastasis. 10.1136/bcr-2016-218845.video01BMJ Journals Video Playerbcr2016218845media1 Video 2 MRI with diffusion-weighted imaging showing central diffusion restriction, suggestive of a cerebral abscess. The dural layer is thickened, indicating pachymeningitis. 10.1136/bcr-2016-218845.video02BMJ Journals Video Playerbcr2016218845media2 Discussion To the best of our knowledge, this is the sixth reported case of intracranial abscess formation by P. gingivalis and the third case of a true intracerebral parenchymal abscess.6–10 An overview of reported cases is given in table 1. It is well known that the oral cavity hosts a wide variety of microbiological organisms. Studies identified up to 350 different bacterial strains in marginal periodontitis and up to 150 strains in endodontic infection.5 Some of these oral commensals cause opportunistic infections, for example, streptococcal endocarditis after dental procedures has been the rationale for endocarditis prophylaxis in high-risk cardiac patients. Iatrogenic or covert bacteremia arising from the oral cavity rarely causes clinical pathology requiring intervention. It is extremely rare for P. gingivalis to cause an intracranial abscess and it has only been reported five times in current literature (table 1). This highly adapted non-motile gram-negative oral anaerobe is strongly associated with periodontitis and can be cultured in 85.7% of patients diagnosed with periodontitis compared with 23.1% of healthy subjects.11 Being an opportunistic pathogen, it has high virulence as indicated by biofilm formation, dipeptidyl peptidase intravenous activity, strong induction of proinflammatory cytokine secretion and the invasion potential of epithelial cells to escape immune response activation.12 Other reported extraoral infections, other than intracranial, caused by P. gingivalis include otitis media, appendicitis, gas gangrene, thoracic empyema and lung abscess formation.13

ng induction of proinflammatory cytokine secretion and the invasion potential of epithelial cells to escape immune response activation.12 Other reported extraoral infections, other than intracranial, caused by P. gingivalis include otitis media, appendicitis, gas gangrene, thoracic empyema and lung abscess formation.13 Table 1 Reported cases of intracranial abscesses caused by Porphyromonas gingivalis

ng induction of proinflammatory cytokine secretion and the invasion potential of epithelial cells to escape immune response activation.12 Other reported extraoral infections, other than intracranial, caused by P. gingivalis include otitis media, appendicitis, gas gangrene, thoracic empyema and lung abscess formation.13 Table 1 Reported cases of intracranial abscesses caused by Porphyromonas gingivalis Reference Sex Age (years) Predisposing factors Pathogen Oral pathology Presenting symptoms Localisation Treatment Outcome 8 F 64 Eisenmenger’s syndrome, ventricular septal defect Lactobacillus catenaformis P. gingivalis Fusobacterium nucleatum Periodontitis 15 Seizures Right temporal lobe Initial AB: Ceftriaxone, metronidazole, vancomycin Switched AB (D2): sulbactam/ampicillin Surgical: drainage (D2), craniotomy (D26) Discharge after 27 days, referred to other hospital 6 F 57 ? P. gingivalis detected in CSF Single tooth infection, not further specified Fever Headache Gait disturbance Site not specified. Additional ventriculitis Initial AB: fosfomycin, panipenem, cephalothin (intraspinal) Switched AB (D10): piperacillin, cefozopran, cephalothin (ventricular injection) Surgical: tooth extraction Discharge after 21 days. Full recovery 10 M 67 None reported P. gingivalis None reported Throbbing right-sided headache Right cavernous sinus Infraorbital cavity Sphenoid sinus Initial AB: carbapenem Switched AB (D15): ampicillin, sulbactam Surgical: drainage, endoscopic sphenoidotomy Full recovery 7 M 54 None reported P. gingivalis Periodontitis Right-sided homonymous hemianopsia Right hemiparesis Left parieto-occipital lobe Initial AB: vancomycin, 3rd generation cephalosporin, metronidazole Switched AB (D10): ampicillin, sulbactam Switched AB (D14): amoxicillin, clavulanate Surgical (D0): craniotomy Full recovery 9 M 34 None reported P. gingivalis Sinusitis (bilateral frontal, ethmoid, and left maxillary) Fever Headache Photophobia Left hemiparesis Repeated vomiting Right frontal subdural empyema Initial AB: ceftriaxone, metronidazole Surgical: frontoparietal craniectomy (D2), ethmoidectomy (D2), bilateral anterior ethmoidectomy (D2), bilateral frontal sinectomy (D2), second drainage (D15) Full recovery AB, antibiotic treatment; CSF, cerebrospinal fluid; D, day; F, female; M, male.

ight frontal subdural empyema Initial AB: ceftriaxone, metronidazole Surgical: frontoparietal craniectomy (D2), ethmoidectomy (D2), bilateral anterior ethmoidectomy (D2), bilateral frontal sinectomy (D2), second drainage (D15) Full recovery AB, antibiotic treatment; CSF, cerebrospinal fluid; D, day; F, female; M, male. An analysis of the cases (table 1) indicated most subjects present over the age of 50; however, one case of subdural empyema was reported in a 34-year-old man. In all previous case reports, no underlying immunodeficiency was reported. Our patient suffered from type 2 diabetes mellitus, an autoimmune inflammatory condition known to disrupt the blood–brain barrier leading to leakage of small arterioles, possibly facilitating haematogenous dissemination.14 Presenting symptoms were non-specific for the causative organism and depended on the location and elevated intracranial pressure. Suspicion should be raised when an oral or dental pathology is present. Comorbidities must be taken into account. A full blood count with inflammatory markers, electrolytes, kidney and liver function tests, blood glucose levels and blood cultures are advised. Cranial contrast-enhanced CT imaging is the preferred initial radiologic investigation followed by MRI with DWI. This case demonstrates the additional benefit of MRI-DWI in differentiating benign abscesses from primary or metastatic malignancies; moreover, MRI-DWI can screen for ventriculitis. If present, hydrocephalus can develop with the need for ventricular drainage. After a diagnosis is made, possible sites of origin should be further clinically or radiologically investigated. Transthoracic ultrasound to visualise possible endocarditis or valvulitis with bacterial vegetations and oral inspection is of paramount importance to treat underlying infective sources.

entricular drainage. After a diagnosis is made, possible sites of origin should be further clinically or radiologically investigated. Transthoracic ultrasound to visualise possible endocarditis or valvulitis with bacterial vegetations and oral inspection is of paramount importance to treat underlying infective sources. Treatment should always include neurosurgical expertise to assess the feasibility of diagnostic and therapeutic stereotactic aspiration. Empiric antibiotic treatment should begin as soon as a brain abscess is suspected. Usually a third-generation broad spectrum antibiotic such as cephalosporin, metronidazole and vancomycin is administered intravenously until positive culture growth or identification through mass spectrometry directs the antibiotic treatment. In most previously reported cases, this approach was followed (4/5). Treatment duration varies but is usually 4–6 weeks. The need for additional interventions should be based on clinical, laboratory and radiological findings. Drainage was performed in all reported cases. Tooth extraction was only reported in one previous case. The mortality and morbidity rates after intracranial P. gingivalis abscess formation are hopeful. All patients (6/6) made a full recovery; however, reported mortality rates vary from 0 to 24% in cerebral abscesses due to odontogenic infection.5 Small sample size does not allow to draw statistically significant conclusions however, we caution not to minimize the possible pathological severity of this organism.

eful. All patients (6/6) made a full recovery; however, reported mortality rates vary from 0 to 24% in cerebral abscesses due to odontogenic infection.5 Small sample size does not allow to draw statistically significant conclusions however, we caution not to minimize the possible pathological severity of this organism. Learning points Porphyromonas gingivalis is a rare but potentially life-threatening anaerobe that can cause intracerebral abscesses. CT imaging cannot always diagnose a cerebral abscess; thus, MRI with diffusion-weighted imaging should be added to the diagnostic workup. Quick initiation of broad-spectrum antibiotics, preferably after taking cultures, is paramount. Neurosurgical intervention and timing depends on clinical, laboratory and radiological findings but can be useful diagnostically to elucidate the causative pathogen. The source of infection should be investigated and treated accordingly. Contributors: FVdC was responsible for the study concept and design. FVdC carried out the literature search. KG and HM were responsible for initial proof reading. KG, HM and CP critically reviewed the manuscript for important intellectual content. CP was the study supervisor. All authors read and approved the final version of the manuscript. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease characterised by eosinophilic hyaline intranuclear inclusions, which are widely observed in neuronal and somatic cells.1–6 NIID has been considered to be a heterogeneous disease with highly variable clinical manifestations such as neuropathy, cerebellar ataxia and dementia, which may occur concomitantly in certain patients. Sporadic and familial patients have been reported, and the onset of disease varies from the infantile stages to late middle age. These factors made the ante mortem diagnosis of NIID difficult, but Sonoe et al5 6 reported possible usefulness of skin or muscle biopsy and suggested a possible antemortem diagnostic biomarker for NIID. However, longitudinal observation of characteristic leucoencephalopathy in NIID has never been reported. In this study, we present a sporadic NIID patient with neuropathy followed by cognitive dysfunction along with brain MRIs findings of leucoencephalopathy.

ggested a possible antemortem diagnostic biomarker for NIID. However, longitudinal observation of characteristic leucoencephalopathy in NIID has never been reported. In this study, we present a sporadic NIID patient with neuropathy followed by cognitive dysfunction along with brain MRIs findings of leucoencephalopathy. Case presentation A 62-year-old woman noticed jingling sensation bilaterally in the feet since she was 52 years old and consulted to our clinic. On the neurological examination, she had sensory disturbances bilaterally in the feet, but her deep tendon reflexes were normal. She had normal findings including her cognitive function. She showed 30 out of 30 in the total scores of mini-mental state examination (MMSE). She showed relatively prolonged sensory nerve conductive velocities (NCVs) (30 m/sec) in the median nerves, ulnar nerves and anterior tibial nerves, but had normal motor NCVs in those nerves. The results of NCVs supported that she had neuropathy. On the MRIs, she showed ischaemic lesions in the white matter in the T2-weighted images (TWIs), high-intensity lesion in the corpus callosum in the fluid attenuated inversion recovery (FLAIR) images (figure 1).

ial nerves, but had normal motor NCVs in those nerves. The results of NCVs supported that she had neuropathy. On the MRIs, she showed ischaemic lesions in the white matter in the T2-weighted images (TWIs), high-intensity lesion in the corpus callosum in the fluid attenuated inversion recovery (FLAIR) images (figure 1). Figure 1 Brain MRI findings. Brain MRI findings showed leucoencephalopathy in T2-weighted and fluid attenuation recovery (FLAIR) images, and showed high-intensity lesions in the corpus callosum. On diffusion-weighted images (DWIs), high intensities were observed from the corticomedullary junction to around the root of gyrus. These abnormal MRI findings were gradually expanded from the frontal to the occipital that were more prominent in DWIs. During 3 years from the first admission, she gradually developed attention deficits and forgetfulness. At that time, she showed 27 out of 30 in the total scores of MMSE. On the MRIs, in addition to findings in the first admission, she showed high-intensity lines along with U-fibres in diffusion-weighted images (DWIs). In the consecutive MRIs, these findings in the MRIs gradually worsened (figure 1). However, at 10 years after the first admission, her neuropathy remained as the level of the first admission. She had attention deficits and forgetfulness and showed 26 out of 30 in the total scores of MMSE. Outcome and follow-up We followed her in this time.

During 3 years from the first admission, she gradually developed attention deficits and forgetfulness. At that time, she showed 27 out of 30 in the total scores of MMSE. On the MRIs, in addition to findings in the first admission, she showed high-intensity lines along with U-fibres in diffusion-weighted images (DWIs). In the consecutive MRIs, these findings in the MRIs gradually worsened (figure 1). However, at 10 years after the first admission, her neuropathy remained as the level of the first admission. She had attention deficits and forgetfulness and showed 26 out of 30 in the total scores of MMSE. Outcome and follow-up We followed her in this time. Discussion We reported a patient of leucoencephalopathy with NIID who presented with cognitive dysfunction. The high intensity of the U-fibres in the DWIs is a characteristic finding in NIID that imply existence of intranuclear inclusions in the cerebral cortex. The parallel MRI changes in the DWIs along with cognitive decline supports those U-fibres changes in the DWIs play a pathogenic role in NIID. Sone et al7 recently reported clinicopathological features of NIID, and in that sporadic patients developed initially dementia followed by sensory disturbances, ataxia. Our patient has no family history and developed sensory disturbances followed by dementia. Her sensory disturbances remain rather unchanged, but cognitive impairment gradually progressed along with abnormal intensity lesions in DWIs. Her initial symptom was forgetfulness and inattention. Her total scores in MMSE deteriorated from 30 to 26 and those of frontal assessment battery from 18 to 16 due to verbal influency. This pathological and clinical deterioration resemble pathological process in prion diseases that implies similar pathological processes affected in NIID. Recently, on the basis of neuropathological studies, Masuda-Suzukake M et al8 indicated that α-synuclein fibrils have prion-like properties9 and inoculation into wild-type brain induces α-synuclein pathology in vivo.

le pathological process in prion diseases that implies similar pathological processes affected in NIID. Recently, on the basis of neuropathological studies, Masuda-Suzukake M et al8 indicated that α-synuclein fibrils have prion-like properties9 and inoculation into wild-type brain induces α-synuclein pathology in vivo. Accumulation of consecutive MRI observation in NIID patients may be useful to elucidate the mechanism of pathological processes affected in NIID. This is the first report to follow MRIs changes for over long period. Learning points Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease characterised by eosinophilic hyaline intranuclear inclusions. MRI observation in NIID patients may be useful. Prion-like properties. Contributors: KA performed project development, data collection and manuscript writing. MF performed manuscript writing. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Portal hypertension is the progressive complication of liver cirrhosis, and gives rise to the development of portosystemic collaterals commonly at the oesophagogastric junction, the abdominal wall and the rectum. Ectopic varices are a term reserved for varices, which exist outside the oesophagogastric region.1 Although a rare cause of gastrointestinal (GI) bleeding, they are reported to have a high mortality, around 40%.1–7 Up to 17% of ectopic varices occur in the duodenum,3 4 but they are not a common cause of variceal bleeding. Case presentation A man aged 57 years presented with a 2-day history of melaena, right-sided chest pain, abdominal pain and shortness of breath. He had a background of antimitochondrial antibody-positive primary biliary cholangitis diagnosed 10 years previously. He reported an alcohol intake of 23 units (∼200 g) per week and was an ex-smoker. His only medication was urseodeoxycholic acid (15 mg/kg). He had previously declined a screening gastroscopy. Ultrasound scan 10 months prior to this admission showed a cirrhotic liver with hepatopetal flow of the portal vein.

previously. He reported an alcohol intake of 23 units (∼200 g) per week and was an ex-smoker. His only medication was urseodeoxycholic acid (15 mg/kg). He had previously declined a screening gastroscopy. Ultrasound scan 10 months prior to this admission showed a cirrhotic liver with hepatopetal flow of the portal vein. At presentation, he was and remained cardiovascularly stable. Examination of his abdomen elicited mild tenderness in the epigastrium, with no evidence of guarding. Digital rectal examination confirmed the presence of melaena. Investigations were as follows: haemoglobin (Hb) 135 g/L (range 135–170 g/L), WCC 12×109/L, platelets 219×109/L, MCV 91 fL, clotting, U&Es and LFTs normal. His vital signs on admission were: blood pressure 153/104 mm Hg, heart rate 140 bpm, temperature 36.5°C and saturations >96%. He underwent an oesophagogastroduodenoscopy (OGD) 21 hours after admission, which confirmed the presence of a small amount of altered blood in the stomach and 4 grade 2 oesophageal varices without any stigmata of recent bleeding (fibrin plugs) but with red spots (figure 1A). Figure 1 (A) Grade 2 oesophageal varices. (B) Banding of oesophageal varices.

At presentation, he was and remained cardiovascularly stable. Examination of his abdomen elicited mild tenderness in the epigastrium, with no evidence of guarding. Digital rectal examination confirmed the presence of melaena. Investigations were as follows: haemoglobin (Hb) 135 g/L (range 135–170 g/L), WCC 12×109/L, platelets 219×109/L, MCV 91 fL, clotting, U&Es and LFTs normal. His vital signs on admission were: blood pressure 153/104 mm Hg, heart rate 140 bpm, temperature 36.5°C and saturations >96%. He underwent an oesophagogastroduodenoscopy (OGD) 21 hours after admission, which confirmed the presence of a small amount of altered blood in the stomach and 4 grade 2 oesophageal varices without any stigmata of recent bleeding (fibrin plugs) but with red spots (figure 1A). Figure 1 (A) Grade 2 oesophageal varices. (B) Banding of oesophageal varices. The duodenum was reported to be normal. Ligation bands were applied to the oesophageal varices (figure 1B). Treatment was started with terlipressin and broad-spectrum antibiotics. Although his haemoglobin began to slowly drop, he remained stable until 3 days after the first gastroscopy, when he experienced further melaena and a number of presyncopal episodes. His Hb dropped to 77 g/L, urea 8.6 mmol/L and all other blood results were normal. The Blatchford score8 was 17. Once stable, he underwent a second OGD under general anaesthesia (4 hours after the episode of melaena). There was no visible blood in the upper GI tract. Banding-induced ulceration was present in the oesophagus and the brisk self-limiting bleeding was presumed to be due to oesophageal ulceration. The endoscopist reported a possible 2 cm polyp/lipoma in the second part of the duodenum. Again, the melaena settled and he remained stable postendoscopy (Hb 70 g/L). Two days later, he had two further episodes of melaena and failed to augment his Hb, despite 2 units of blood. A third OGD was carried out under conscious sedation on day 7 of his admission. Again, the upper GI tract was blood-free and the findings were similar to the second OGD (figure 2A). The endoscopist thought the previously described duodenal polyp could be a prominent ampulla, which prompted the request for an abdominal CT scan (figure 2B) to exclude a potential cause for haemobilia.

his admission. Again, the upper GI tract was blood-free and the findings were similar to the second OGD (figure 2A). The endoscopist thought the previously described duodenal polyp could be a prominent ampulla, which prompted the request for an abdominal CT scan (figure 2B) to exclude a potential cause for haemobilia. Figure 2 (A) Postbanding ulceration of oesophageal varices. (B) Duodenal polyp—suspected prominent ampulla. The next day, his Hb continued to drop to 55g/L, and he reported ongoing melaena. His vital signs at this point were: blood pressure 125/66 mm Hg, heart rate 125 bpm, temperature 38.9°C and saturations >96%. The decision was made to resuscitate with blood and proceed to an urgent fourth OGD. On this examination, there was altered blood in the stomach but again no obvious actively bleeding point. It was noted that the tip of the duodenal lesion was red (figure 3). The endoscopist was pondering over this finding when the lesion briefly spurted blood (figure 4). Figure 3 Duodenal lesion tip. Figure 4 Duodenal lesion actively spurting blood. The possible diagnosis of haemobilia crossed the endoscopist's mind and a side viewing scope (duodenoscope) was used to attempt further therapy. The duodenal lesion was felt to be in the third part of the duodenum and indeed, on closer inspection, the ampulla was located in the second part of the duodenum and found to be normal (figure 5). Figure 5 Ampulla.

The possible diagnosis of haemobilia crossed the endoscopist's mind and a side viewing scope (duodenoscope) was used to attempt further therapy. The duodenal lesion was felt to be in the third part of the duodenum and indeed, on closer inspection, the ampulla was located in the second part of the duodenum and found to be normal (figure 5). Figure 5 Ampulla. It is at this point that the diagnosis of duodenal variceal bleed was made. The varix was treated successfully with 2.4 mL histoacryl glue using a normal gastroscope. The patient subsequently remained stable and free of any further GI bleeding. He was discharged 48 hours later. His Hb remained stable at 92 g/L. Outcome and follow-up A repeat OGD was planned for 2 weeks postdischarge, but the patient declined this. He did proceed to an OGD 4 months after discharge and the duodenal varix had completely resolved (figure 6A, B). The patient remained well and asymptomatic of any GI bleed. A CT scan post-treatment confirmed the presence of retroperitoneal glue around the third part of the duodenum, the retroperitoneal veins and aorto-caval space (figure 7). Of note, there was translocation of glue to the pelvis, but the patient was asymptomatic. Figure 6 (A) Follow-up endoscopy, view from D2. (B) Follow-up endoscopy, view from D3. Figure 7 Abdominal CT showing retroperitoneal glue.

Outcome and follow-up A repeat OGD was planned for 2 weeks postdischarge, but the patient declined this. He did proceed to an OGD 4 months after discharge and the duodenal varix had completely resolved (figure 6A, B). The patient remained well and asymptomatic of any GI bleed. A CT scan post-treatment confirmed the presence of retroperitoneal glue around the third part of the duodenum, the retroperitoneal veins and aorto-caval space (figure 7). Of note, there was translocation of glue to the pelvis, but the patient was asymptomatic. Figure 6 (A) Follow-up endoscopy, view from D2. (B) Follow-up endoscopy, view from D3. Figure 7 Abdominal CT showing retroperitoneal glue. Discussion Liver disease in the UK is an exception to the vast improvements made in health and life expectancy over the past 30 years, with mortality increasing by 400% since 1970, and a fivefold increase in those under 65.9 The prevalence of cirrhosis is estimated to be around 100 cases per 100 000 people, with equal incidence in men and women. The UK saw a steep rise in the rate of cirrhosis in the 1990s due to the surge in alcohol consumption.10 Variceal bleeding is a life-threatening presentation of portal hypertension, a progressive complication of liver cirrhosis,7 with inhospital mortality estimated at 15%.11

ople, with equal incidence in men and women. The UK saw a steep rise in the rate of cirrhosis in the 1990s due to the surge in alcohol consumption.10 Variceal bleeding is a life-threatening presentation of portal hypertension, a progressive complication of liver cirrhosis,7 with inhospital mortality estimated at 15%.11 Portal hypertension is a result of increased resistance to portal flow, commonly due to distortion in liver architecture. Portosystemic collaterals form due to splanchnic hypertension, commonly in the oesophagus, rectum and umbilical regions. Additionally, portosystemic communications can occur between the pancreaticoduodenal veins and systemic veins via the veins of Retizus, bringing rise to venous dilation at the duodenum, resulting in duodenal varices.3 4 12–14 Duodenal varices were first described by Alberti,15 and visualised endoscopically in 1973 by Kunisaki et al.16 Duodenal varices can result in massive GI bleeding, reported at around 40% mortality; diagnosis and treatment is often difficult and controversial as experience is limited.17 They most commonly arise at the duodenal bulb, and less frequently more distally.6 18 19 Two-thirds of duodenal varices are a result of portal vein hypertension due to hepatic cirrhosis, and the remaining third are due to extrahepatic portal hypertension, for example, portal vein thrombosis.

as experience is limited.17 They most commonly arise at the duodenal bulb, and less frequently more distally.6 18 19 Two-thirds of duodenal varices are a result of portal vein hypertension due to hepatic cirrhosis, and the remaining third are due to extrahepatic portal hypertension, for example, portal vein thrombosis. Pharmacological therapy is recommended and can be initiated as soon as variceal bleeding is suspected. Vasopressin analogues, such as terlipressin, are potent splanchnic vasoconstrictors reducing blood flow to all splanchnic organs, thereby decreasing portal pressure. In addition, the use of short-term prophylactic antibiotics has been shown to decrease the rate of bacterial infections and the rate of mortality. The British Society of Gastroenterology guidelines recommends initiation of vasoconstrictors such as terlipressin as soon as variceal bleeding is suspected, and antibiotics within 1 day.11 OGD can be limited as the scope is unable to stretch to the distal end of the duodenum and often the varix is buried in the submucosal or serosal layer making visualisation difficult.3 4 6 The thin nature of the duodenal wall compared with the rest of the GI tract increases the risk of perforation with any intervention.6 12 13 There are no currently randomised controlled trials related to the management of this relatively uncommon presentation and the evidence available is based on small studies and case reports. Table 1 summarises the benefits and risks of the therapeutic interventions used in the treatment of duodenal varices.20–25

6 12 13 There are no currently randomised controlled trials related to the management of this relatively uncommon presentation and the evidence available is based on small studies and case reports. Table 1 summarises the benefits and risks of the therapeutic interventions used in the treatment of duodenal varices.20–25 Table 1 Summary of risks and benefits of the current therapeutic options in management of duodenal varices Therapeutic options Benefits Risks Endoscopic Variceal banding Relatively non-invasive23 Reported success2 14 17 22 24 Risk of recurrence Rebleeding rate high24 Can cause wider defect1 2 6 22 Visualisation difficult1 2 6 22 Variceal sclerotherapy Relatively non-invasive23 Reported success3 13 20 21 24 Tissue damage3 6 17 24 Ulceration3 6 17 24 Perforation3 6 17 24 Risk of pulmonary embolism of sclerosant3 6 17 24 Visualisation difficult3 6 17 24 Interventional radiology Transjugular intrahepatic portosystemic shunt (TIPSS) Very effective Option in poor surgical candidate6 25 Option in refractory cases6 25 Decrease portosystemic pressure gradient6 25 Hepatic encephalopathy6 25 Stenosis of stent common (55–70%)6 25 Balloon occluded retrograde transvenous obliteration (BRTO) Management for life-threatening bleeding14 24 Recanalisation or development of collaterals14 24 Surgical Variceal ligation For cases refractory to endoscopic intervention7 14 Rebleeding rate high7 14 Risk of further management7 14 Invasive7 14 Duodenectomy For cases refractory to endoscopic intervention7 14 Rebleeding rate high7 14 Risk of further management Invasive7 14 Shunt surgery Little risk of rebleeding7 14

Recanalisation or development of collaterals14 24 Surgical Variceal ligation For cases refractory to endoscopic intervention7 14 Rebleeding rate high7 14 Risk of further management7 14 Invasive7 14 Duodenectomy For cases refractory to endoscopic intervention7 14 Rebleeding rate high7 14 Risk of further management Invasive7 14 Shunt surgery Little risk of rebleeding7 14 Decrease portosystemic pressure gradient7 14 30% mortality rate6 Require good hepatic function7 14 Invasive7 14 Our case exemplifies the difficulties of identifying the source of duodenal variceal bleeding. It took four OGDs to locate the source of bleeding and this was possible because of active bleeding at the time of the fourth OGD. Had this not been the case, the next option would have been a CT angiogram or red cell scan at the time of bleeding. Injection of histoacryl glue is not without risk. In our case, glue migrated to the pelvis with no consequence to the patient. There are well-documented cases of glue causing pulmonary embolism.26 27 We therefore urge caution with the use of histoacryl glue. This should ideally be performed by an experienced endoscopist. Learning points Duodenal varices are a rare manifestation of portal hypertension in patients with cirrhosis and can lead to life-threatening haemorrhage. Duodenal varices should be considered in patients presenting with melaena with no identifiable cause of bleeding on visualisation of the oesophagus and presence of hepatofugal flow on ultrasound.

Description A male patient aged 81 years reported with dyspnoea and loss of consciousness, at our emergency department. His respiratory rate was 30 breaths/min, and his level of consciousness determined using the Glasgow Coma Scale was eye (1), verbal (1) and motor (4). Despite oxygen administration via a bag valve mask, his percutaneous oxygen saturation level was measured as only 81%. Physical examination revealed weak vesicular sound on auscultation, suggesting he had severe emphysema. Arterial blood gas analysis after continuous bag valve mask ventilation revealed pH 7.014, undetectably high pCO2 and pO2 of 89 tor. The patient was admitted with the diagnosis with acute exacerbation of chronic obstructive pulmonary disease (COPD). Insufficient spontaneous breathing required installation of mask-type non-invasive positive pressure ventilation (NIPPV: FiO2, 0.35, IPAP, 10 cm H2O, EPAP, 3 cm H2O). After continuous NIPPV support for 8 days, an intraoral ulcer was detected on the patient's lower lip (figure 1). Despite the ulcer penetrating his lip (figure 2), the patient did not complain of any pain. The continuous tight ventilator pressure caused the lesion because the patient had only two teeth on his lower jaw, which were in contact with his lip. Subsequently, the patient required another course of NIPPV owing to re-exacerbation of COPD. Hence, the only alternative was to extract the two teeth to avoid ulcer formation. Although skin ulcer due to NIPPV has been reported,1–3 and caregivers must pay attention to the exclusively internal complication in the oral cavity and the nasal bridge.

required another course of NIPPV owing to re-exacerbation of COPD. Hence, the only alternative was to extract the two teeth to avoid ulcer formation. Although skin ulcer due to NIPPV has been reported,1–3 and caregivers must pay attention to the exclusively internal complication in the oral cavity and the nasal bridge. Figure 1 Lower lip ulcer against patient's teeth caused by non-invasive positive pressure ventilation pressure. Figure 2 Ulcer penetrating the lower lip. Learning points Non-invasive positive pressure ventilation (NIPPV) mask can cause ulcer on the nasal bridge and also in the intraoral region. The oral cavity should be carefully observed routinely in the case of mask NIPPV treatment. Contributors: KM wrote the article. AC edited the article. IN designed this case and wrote the article. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background There are many indications for parenteral iron administration such as chronic kidney disease, heart failure, inflammatory bowel disease and postbariatric surgery. Iron deficiency with or without anaemia is, however, most prevalent in the otherwise healthy menstruating women. The parenteral route is also preferred in these patients since oral iron has low bioavailability and can cause gastrointestinal side effects.1 Ferric carboxymaltose is one of the most commonly used parenteral iron formulations because of the ease of administration of a relatively large dose in a single infusion (up to 1 g of elemental iron) and fewer allergic side effects when compared with older iron preparations. Severe hypophosphataemia has been described as a potential complication of certain parenteral iron formulations (such as ferric carboxymaltose, saccharated ferric oxide).2–11 In 2008, FDA reported that 2.1% of patients treated with ferric carboxymaltose developed hypophosphataemia, but severe hypophosphataemia was rare. Mild hypophosphataemia is mentioned as a common complication in product labelling information of ferric carboxymaltose, but not widely acknowledged.12 Recently, Schaefer et al13 revealed high prevalence of severe hypophosphataemia (32.1%) after treatment of iron deficiency with high-dose intravenous ferric carboxymaltose in a patient population with gastrointestinal disorders.

n in product labelling information of ferric carboxymaltose, but not widely acknowledged.12 Recently, Schaefer et al13 revealed high prevalence of severe hypophosphataemia (32.1%) after treatment of iron deficiency with high-dose intravenous ferric carboxymaltose in a patient population with gastrointestinal disorders. Case presentation A woman of Mexican origin aged 38 years was referred to our clinic for the evaluation of tiredness, diffuse muscle pain and weakness for the past year. She was advised to get her adrenal function checked in a consultation in her own country, which is why she specifically asked for a referral to an endocrinology clinic. She had no family history of bone or mineral metabolism disorders. She grew and developed normally as a child, and denied alcohol consumption and smoking. Her general physician detected iron deficiency anaemia 7 weeks before consultation in our clinic; ferritin was 7.8 μg/L (13–150) and haemoglobin 111 g/L (117–153). At the same time, vitamin B12 was 146 pmol/L (>220). She received an intramuscular injection of 1 mg vitamin 12 injection the next day (2 weeks before the first iron administration). Her folate levels were not measured. She was treated with parenteral ferric carboxymaltose at a dose of 500 mg which was given twice (4, respectively, 3 weeks before presentation to our clinic). The cause of her iron deficiency anaemia was heavy menstrual bleeding, for which her gynaecologist inserted a levonorgestrel-containing IUD before her first presentation in our clinic.

arenteral ferric carboxymaltose at a dose of 500 mg which was given twice (4, respectively, 3 weeks before presentation to our clinic). The cause of her iron deficiency anaemia was heavy menstrual bleeding, for which her gynaecologist inserted a levonorgestrel-containing IUD before her first presentation in our clinic. Her history revealed intravenous iron administration 1 year before. Interestingly, she reported no symptom relief after iron administration recently as well as in the past. She reported an exacerbation of her muscle pain and weakness after her previous iron infusion. Her complaints and symptoms were believed to be manifestation of depression. Physical examination findings were as follows: height 145 cm (within her midparental range), weight 54 kg, BMI 25.8 kg/m2, blood pressure 125/80 mm Hg, pulse 80/min with normal cardiac and pulmonary auscultation findings. The abdominal examination revealed slight tenderness in the right midabdomen with normal bowel sounds. Her overall appearance did not indicate any bone or facial deformity. Investigations Laboratory tests on presentation (table 1, day 0) revealed severe hypophosphataemia, 0.23 mmol/L (0.87–1.45), a slightly low albumin-adjusted calcium, 1.99 mmol/L (2.09–2.54) and a low 25-hydroxy-vitamin D, 12 μg/L (recommended value >20). Table 1 Evolution of laboratory values since presentation in our clinic

Investigations Laboratory tests on presentation (table 1, day 0) revealed severe hypophosphataemia, 0.23 mmol/L (0.87–1.45), a slightly low albumin-adjusted calcium, 1.99 mmol/L (2.09–2.54) and a low 25-hydroxy-vitamin D, 12 μg/L (recommended value >20). Table 1 Evolution of laboratory values since presentation in our clinic Days since presentation 0 2 25 51 101 Calcium, albumin-corrected (2.09–2.54 mmol/L) 1.99 2.05 2.22 2.21 2.15 Phosphate (0.87–1.45 mmol/L) 0.23 0.30 0.93 1.06 1.17 Creatinine (44–80 µmol/L) 42 40 52 43 45 PTH (15–65 ng/L) 52.7 69.5 46.5 46.3 25-hydroxyvitamin D (>20 µg/L) 12 28 1,25-dihydroxy-vitamin D (26.1–95 ng/L) 23.8 74.8 71.8 TmP/GFR (0.8–1.35 mmol/L) 0.21 0.83 0.91 The patient presented with hypophosphataemia on day 0 (which was 3 weeks following the last intravenous administration of ferric carboxymaltose), and hypophosphataemia was confirmed on day 2, along with the finding of increased renal phosphate loss and a low calcitriol. Coeliac screening was negative. Liver enzymes were not elevated. Serum ferritin was 662 μg/L (reflecting the recent iron infusions). Haemoglobin was normalised (124 g/L). Creatinine was in the low normal range, 42 μmol/L (44–80). Morning cortisol was 324 nmol/L, which together with normal serum sodium and potassium values and lack of specific symptoms (no hyperpigmentation and weight loss) made primary adrenal insufficiency an unlikely diagnosis. There was no history of glucocorticoid use in the past.

in the low normal range, 42 μmol/L (44–80). Morning cortisol was 324 nmol/L, which together with normal serum sodium and potassium values and lack of specific symptoms (no hyperpigmentation and weight loss) made primary adrenal insufficiency an unlikely diagnosis. There was no history of glucocorticoid use in the past. Along with confirming hypophosphataemia (day 2), we investigated its cause. We measured the concentration of phosphate and creatinine in a fasting spot urine sample to evaluate renal phosphate transport by calculating TmP/GFR. This value corresponds to the theoretical lower limit of plasma phosphate below which all filtered phosphate would be absorbed (normal range, 0.80–1.35 mmol/L). where PP  , UP  , PCrea and UCrea refer to the plasma and urinary concentration of phosphate and creatinine, respectively.14 A low value indicates renal phosphate wasting. In our patient, it was 0.21 mmol/L. Intact parathyroid hormone (PTH) was slightly increased, 69.5 ng/L (15–65), presumably as an adaptive response to vitamin D deficiency. Her calcium was low due to vitamin D deficiency. Alkaline phosphatase and its bone-specific isoform were not elevated, suggesting that her hypophosphataemia was probably of recent onset and did not result in a serious mineralisation disorder.

9.5 ng/L (15–65), presumably as an adaptive response to vitamin D deficiency. Her calcium was low due to vitamin D deficiency. Alkaline phosphatase and its bone-specific isoform were not elevated, suggesting that her hypophosphataemia was probably of recent onset and did not result in a serious mineralisation disorder. The absence of albuminuria and glucosuria ruled out a generalised proximal tubular disorder (Fanconi syndrome). 1,25-dihydroxyvitamin D was low, 23.8 ng/L (26.1–95), which in the face of hypophosphataemia suggested excessive fibroblast growth factor 23 (FGF23) to be the cause of increased renal phosphate excretion since FGF23 promotes renal phosphate loss and impairs 1-α-hydroxylation of vitamin D. Treatment We started vitamin D replacement with 2000 IU/day for 4 weeks and continued with 1000 IU/day thereafter. She was also treated with calcitriol 0.25 μg two times per day for a total duration of 36 days. Outcome and follow-up Our patient reported relief of her tiredness, muscle pain and weakness on vitamin D replacement and calcitriol within 2 days of starting the treatment. Phosphate values normalised under treatment and remained normal 1 week after stopping calcitriol (table 1). At the same time 1,25-dihydroxyvitamin D was high normal. Vitamin D replacement was continued. 25-hydroxyvitamin D levels normalised in the follow-up 3 months later. Her monthly bleeding reduced after insertion of levonorgestrel-containing IUD. Haemoglobin and ferritin values remained stable in the follow-up 3 months later.

e same time 1,25-dihydroxyvitamin D was high normal. Vitamin D replacement was continued. 25-hydroxyvitamin D levels normalised in the follow-up 3 months later. Her monthly bleeding reduced after insertion of levonorgestrel-containing IUD. Haemoglobin and ferritin values remained stable in the follow-up 3 months later. Discussion In our case, hypophosphataemia was severe, prolonged and symptomatic. Low TmP/GFR confirmed that hypophosphataemia was due to renal phosphate wasting which can occur in proximal tubular disorders, in hyperparathyroidism and in disorders of FGF23 excess. We excluded Fanconi syndrome. Secondary hyperparathyroidism (calcium was low normal) causes only mild renal phosphate loss and is associated with high normal 1,25-dihydroxyvitamin D levels. FGF23 excess appeared to be the most likely cause of renal phosphate wasting. Disorders of FGF23 excess can be either acute or chronic. Chronic FGF23 excess as in tumour-induced osteomalacia is usually associated with mineralisation disorder reflected by increased bone-specific alkaline phosphatase.15 This was not the case in our patient. Our patient received ferric carboxymaltose infusion twice, making increased FGF23 activity the most likely cause of hypophosphataemia as supported by renal phosphate wasting and low 1,25-dihydroxyvitamin D.10 15 Hypovitaminosis D was detected but not treated by her physician before iron administration, making baseline hypophosphataemia (and secondary hyperparathyroidism) as a probable additional risk factor. However, phosphate values were not measured.

Our patient received ferric carboxymaltose infusion twice, making increased FGF23 activity the most likely cause of hypophosphataemia as supported by renal phosphate wasting and low 1,25-dihydroxyvitamin D.10 15 Hypovitaminosis D was detected but not treated by her physician before iron administration, making baseline hypophosphataemia (and secondary hyperparathyroidism) as a probable additional risk factor. However, phosphate values were not measured. Increased erythropoiesis after correction of iron deficiency could also result in mild hypophosphataemia by increased cellular uptake of phosphate, but this would not explain increased renal phosphate loss.11 FGF23 is a phosphatonin secreted by osteocytes leading to phosphate wasting through inhibition of Na+-dependent phosphate cotransporters in the proximal renal tubules. Iron deficiency per se increases FGF23 transcription as well as its degradation. Administration of ferric carboxymaltose inhibits FGF23 degradation and thereby increases the biologically active FGF23, which then can cause hypophosphataemia.2–11 Owing to the complex interplay of different FGF23 forms and their processing in iron deficiency, measuring FGF23 values is not recommended in clinical practice. Furthermore, FGF23 assays are not routinely available and expensive. TmP/GFR and 1,25-dihydroxyvitamin D are simple tests providing useful information about the mechanism of hypophosphataemia in severe cases.

forms and their processing in iron deficiency, measuring FGF23 values is not recommended in clinical practice. Furthermore, FGF23 assays are not routinely available and expensive. TmP/GFR and 1,25-dihydroxyvitamin D are simple tests providing useful information about the mechanism of hypophosphataemia in severe cases. The nadir of serum phosphate is usually reached 2 weeks after administration of intravenous iron. The median time to normalisation of phosphate after a single iron infusion is 84 days, but may be prolonged after repetitive iron infusions.13 Vitamin D deficiency should be screened and corrected in all patients. Calcitriol cannot correct FGF23 excess, but its replacement plays an important role as it helps to increase intestinal phosphate absorption, attenuates secondary hyperparathyroidism and thereby corrects and shortens the duration of hypophosphataemia. 1,25-dihydroxyvitamin D was low at baseline reflecting the suppressive effect of FGF23 on 1-α-hydroxylation of vitamin D. We also chose calcitriol in our patient since phosphate and calcium were low (and PTH elevated presumably due to coexisting vitamin D deficiency). Also in patients with normal vitamin D status and normal calcium values, calcitriol can be considered as 1,25-dihydroxyvitamin D levels are low due to excessive FGF23 activity. As our patient responded well to calcitriol, we did not give phosphate supplementation. Additionally, large amount of phosphate needed to correct hypophosphataemia in renal phosphate wasting often cause gastrointestinal side effects.

considered as 1,25-dihydroxyvitamin D levels are low due to excessive FGF23 activity. As our patient responded well to calcitriol, we did not give phosphate supplementation. Additionally, large amount of phosphate needed to correct hypophosphataemia in renal phosphate wasting often cause gastrointestinal side effects. Considering the expanding use of intravenous iron, we hope our case contributes to the awareness of general physicians as well as specialists for this potential complication. Patients should be informed and instructed to report for follow-up if they experience new musculoskeletal symptoms or worsening of tiredness. Recently, Schaefer et al13 found significantly less hypophosphataemia with ferric isomaltoside (not yet available in our country) compared with ferric carboxymaltose. This iron form might be preferred in patients prone to hypophosphataemia. However, risk of hypersensitivity reactions is higher with ferric isomaltoside. The possibility of different side effects needs to be carefully considered and balanced.16 Patient's perspective I always wanted to know the reason for my tiredness and muscle pain, which actually worsened after getting iron infusion. I never felt any depression, which was initially thought to be the cause of my symptoms. I am happy to know the cause of my symptoms now. The treatment immediately worked as an energy boost. Now I work and do daily activities as a normal person. Learning points Clinicians prescribing ferric carboxymaltose should be aware of the potential complication of hypophosphataemia.

Patient's perspective I always wanted to know the reason for my tiredness and muscle pain, which actually worsened after getting iron infusion. I never felt any depression, which was initially thought to be the cause of my symptoms. I am happy to know the cause of my symptoms now. The treatment immediately worked as an energy boost. Now I work and do daily activities as a normal person. Learning points Clinicians prescribing ferric carboxymaltose should be aware of the potential complication of hypophosphataemia. Serum phosphate levels should be measured at least in symptomatic patients after administration of iron infusion. Cause of severe hypophosphataemia can be determined by estimating TmP/GFR and 1,25-dihydroxyvitamin D. Correction of coexisting vitamin D deficiency could be a simple measure to mitigate hypophosphataemia. Hypophosphataemia, if symptomatic and severe, can be treated with calcitriol and possibly phosphate supplements until its remission. Contributors: GA planned, wrote and edited the case report. She also treated the patient. CS provided guidance in all steps and edited the case report. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Ureteral hernias were first described in 1880 and <140 cases have been reported in the literature,1 with even fewer described with incarceration and ureteric obstruction.2 Majority of these cases are associated with inguinal hernias and incarceration is relatively uncommon due to the large size of the inguinal hernia.3 Ureteral inguinal hernias are more common in men, typically in the fifth and sixth decades of life. Many cases occur in patients with a history of kidney transplantation given the anterior location of the transplanted ureter within the space of Retzius. Ureteral inguinal hernias also occur more commonly on the right side than the left side. This is because on the left, the fascia of Toldt sits at the level of the secondary root of the sigmoid mesocolon which appears to tighten and fix the ureter in the retroperitoneum.4 5 Ureteral inguinal hernias are predominantly indirect rather than direct (80% vs 20%), and can occur in two anatomical variants. A paraperitoneal type, where the ureter slides beside a peritoneal sac and constitutes part of the hernia wall, occurs in 80% of cases. Less commonly an extraperitoneal type occurs (20%), where the ureter is accompanied only by retroperitoneal fat and no peritoneal sac is present.5 Bladder involvement is very rare as it is associated with direct hernia and usually presents with symptoms of bladder outlet obstruction such as urinary retention, frequency and haematuria.

extraperitoneal type occurs (20%), where the ureter is accompanied only by retroperitoneal fat and no peritoneal sac is present.5 Bladder involvement is very rare as it is associated with direct hernia and usually presents with symptoms of bladder outlet obstruction such as urinary retention, frequency and haematuria. A ureteral inguinal hernia often goes undiagnosed until surgical repair is performed, where the ureter is inadvertently injured. This highlights the importance of preoperative assessment. A CT urogram can be used to identify this phenomenon; however, it is difficult to justify these tests in every patient who presents with a groin lump and can be considered as a first line of investigation for a patient with unexplained renal failure or unilateral hydronephrosis on ultrasound scan (USS). Ureteroinguinal hernias are treated surgically due to the risk of obstructive uropathy. An open hernia repair with simple reduction of the ureter may be sufficient, or in more complex cases resection of redundant ureter followed by primary anastomosis or ureteroneocystostomy. In the latter, postoperative imaging with USS or CT should be done to ensure patency and proper replacement of the ureter.6 7 Laparoscopic repair has no role in ureteroinguinal hernias and has only been described in the management of urinary bladder hernias.8

ter followed by primary anastomosis or ureteroneocystostomy. In the latter, postoperative imaging with USS or CT should be done to ensure patency and proper replacement of the ureter.6 7 Laparoscopic repair has no role in ureteroinguinal hernias and has only been described in the management of urinary bladder hernias.8 The present case confirms the importance of preoperative assessment and diagnosis of ureteral inguinal hernias. It also highlights that this phenomenon can be missed in the routine preoperative assessment for an elective routine day case repair of an inguinal hernia. In such case, an awareness of the condition, a high index of suspicion and careful tissue dissection is essential. Case presentation An 81-year-old man from nursing home care presents with multiple facial lacerations after a mechanical fall requiring plastic surgery. He was admitted under a general medical unit due to comorbidities which includes congestive cardiac failure, rheumatoid arthritis, bilateral hip replacements, benign prostatic hypertrophy and chronic alcoholism. He had known bilateral inguinal hernias containing fat of which the right side has been mildly symptomatic.

He was admitted under a general medical unit due to comorbidities which includes congestive cardiac failure, rheumatoid arthritis, bilateral hip replacements, benign prostatic hypertrophy and chronic alcoholism. He had known bilateral inguinal hernias containing fat of which the right side has been mildly symptomatic. Investigations He was found to have an Escherichia coli urinary tract infection which was treated with oral antibiotics. An outpatient genitourinary USS 3 months prior to his admission had shown a non-obstructing renal stone in the right proximal ureter. A CT urogram was performed which showed bilateral small renal and ureteric stones. In particular, within the distal right ureter 5 cm from the vesicoureteric junction there was a 5 mm calculus. The ureter proximal to the calculus was mildly dilated though tapered distally, and was looped within a right-sided indirect inguinal hernia (figures 1 and 2). Figure 1 Computed Tomography (CT) intravenous pyelogram showing a partially dilated right ureter extending down towards a right inguinal hernia (arrow). Figure 2 Sagittal view of CT intravenous pyelogram showing dilated proximal right ureter extending down to inguinal canal (arrow). Note that retroperitoneal structures, including the pancreas (A), are sitting forward and extending down into hernia sac (B). Differential diagnosis Indirect inguinal hernia with bowel, omentum or extraperitoneal fat Femoral hernia Hydrocele or varicocele Ureteric, bladder or prostate malignancy Pelvic or retroperitoneal malignancy

Figure 2 Sagittal view of CT intravenous pyelogram showing dilated proximal right ureter extending down to inguinal canal (arrow). Note that retroperitoneal structures, including the pancreas (A), are sitting forward and extending down into hernia sac (B). Differential diagnosis Indirect inguinal hernia with bowel, omentum or extraperitoneal fat Femoral hernia Hydrocele or varicocele Ureteric, bladder or prostate malignancy Pelvic or retroperitoneal malignancy Treatment They proceeded to having a cystoureteroscopy and stent insertion was performed by a urologist who was unable to retrieve the calculus. This was due to the looping nature of the distal right ureter within a sliding irreducible inguinal hernia. Intraoperative retrograde pyelogram showed a ‘fish hook’ appearance of the distal ureter (figure 3). Figure 3 Intraoperative retrograde pyelogram showing the right ureter (A) before and (B) after inguinal hernia repair. Note the position of the ureter in relation to the prosthesis in (A) as it extends below the right superior pubic rami.

Treatment They proceeded to having a cystoureteroscopy and stent insertion was performed by a urologist who was unable to retrieve the calculus. This was due to the looping nature of the distal right ureter within a sliding irreducible inguinal hernia. Intraoperative retrograde pyelogram showed a ‘fish hook’ appearance of the distal ureter (figure 3). Figure 3 Intraoperative retrograde pyelogram showing the right ureter (A) before and (B) after inguinal hernia repair. Note the position of the ureter in relation to the prosthesis in (A) as it extends below the right superior pubic rami. The patient was referred to the general surgical unit and after a preoperative assessment he proceeded to having an elective open right inguinal hernia repair with mesh (Lichtenstein repair). Intraoperatively, a sliding indirect hernia was identified containing fat which was initially thought to be a large lipoma of the cord. Careful dissection of the fatty tissue eventually revealed a deeper component with a large broad base extending from the internal ring. The surgical team concluded that this was actually retroperitoneal fat which was further dissected, exposed and suture-ligated before excision. The right ureter, with a palpable stent in situ, was easily identified and preserved throughout. The inguinal canal was short with a weak posterior wall and there was no appreciable sac, nor any intraperitoneal structures found.

etroperitoneal fat which was further dissected, exposed and suture-ligated before excision. The right ureter, with a palpable stent in situ, was easily identified and preserved throughout. The inguinal canal was short with a weak posterior wall and there was no appreciable sac, nor any intraperitoneal structures found. Outcome and follow-up The patient recovered from his hernia repair with no complications. He was subsequently recalled for his second cystoureteroscopy where his distal ureteric calculus was successfully extracted and a new stent was inserted as a precaution in view of removal in 6-week time. He recovered from his urinary tract infection and continues to see the urologists as an outpatient. Review of the patient's medical records revealed he had been seen by two general surgeons in the past 3 years for his bilateral inguinal hernias and was deemed not fit for surgery due to his comorbidities. Only his right inguinal hernia was mildly symptomatic at the time and it was agreed that the risks associated with surgery outweighed the benefits. With the ureteric obstruction, his hernia repair was a necessity rather than a luxury operation. One can only speculate what would happen if this patient had proceeded to his hernia repair without identifying radiologically the contents of his inguinal hernia prior to surgery.

ated with surgery outweighed the benefits. With the ureteric obstruction, his hernia repair was a necessity rather than a luxury operation. One can only speculate what would happen if this patient had proceeded to his hernia repair without identifying radiologically the contents of his inguinal hernia prior to surgery. Discussion Inguinal hernias have been described to contain wide range of intraperitoneal structures such as small bowel, large bowel, the appendix (Amyand's hernia), a Meckel's diverticulum (Littre's hernia), omentum and bladder (especially in direct hernia). Protrusion of these retroperitoneal structures (or part of them) through the inguinal canal is defined as a sliding hernia. Herniation of the kidney and ureter, whole or partial, can happen in patients with renal transplant.9 This condition is out of the scope of this paper.

m and bladder (especially in direct hernia). Protrusion of these retroperitoneal structures (or part of them) through the inguinal canal is defined as a sliding hernia. Herniation of the kidney and ureter, whole or partial, can happen in patients with renal transplant.9 This condition is out of the scope of this paper. Ureter-containing inguinal hernias can be of two types: paraperitoneal and extraperitoneal. In the paraperitoneal type, a loop of ureter is extended alongside a peritoneal sac. The herniated ureter is adherent to the posterior peritoneum, both of which are present in the hernia. It is a sliding type of hernia that is thought to be due to traction of underlying structures or adhesions that attach the ureter to the posterior peritoneum. Paraperitoneal type of ureteral hernia is believed to be acquired. Herniated bowel may also be present. It has been noted that the ureteral loop is located medial to the peritoneal sac, and when the ureter is extended into the scrotum it is more likely to be obstructed.9 In contrast to the paraperitoneal type of ureteral hernia, the extraperitoneal type is thought to be due to a congenital embryonic defect that results in fusion between the ureter and the genitoinguinal ligaments. It is theorised to be the result of failure of separation of the ureteric bud from the Wolffian duct, both of which are then drawn down to the scrotum to form the epididymis and vas deferens.9 10 In a case reported by McKay et al,1 the patient needed to squeeze his scrotum to initiate micturition.

toinguinal ligaments. It is theorised to be the result of failure of separation of the ureteric bud from the Wolffian duct, both of which are then drawn down to the scrotum to form the epididymis and vas deferens.9 10 In a case reported by McKay et al,1 the patient needed to squeeze his scrotum to initiate micturition. There have been multiple case reports and case series quoted in the literature.1 Obesity and anterior displacement of the ipsilateral ureter from psoas muscle at L4 level seem to be among risk factors.11 Scarring from previous hernia repair has also been raised as another possible risk factor.12 Diagnosis can be made preoperatively or intraoperatively. Ipsilateral hydronephrosis with inguinal hernia should alert the clinician to the presence of ureter in the hernia. This would warrant a CT urography.9 A ureteral inguinal hernia often does not lead to strangulation and obstructive uropathy due to the large size of majority of these inguinal hernias.3 The condition is often diagnosed incidentally, either during or after herniorrhaphy, when the ureter is inadvertently injured. In the case described, ureteral involvement was successfully identified during investigation for a urinary tract infection during a completely unrelated hospital admission. It is believed that the infection was a result of renal stones, a common and often asymptomatic condition; however, in the presence of abnormal anatomy, calculi had become obstructed in the mid ureter. With a low likelihood of passing the calculus spontaneously, appropriate intervention was initiated by the urology unit.

is believed that the infection was a result of renal stones, a common and often asymptomatic condition; however, in the presence of abnormal anatomy, calculi had become obstructed in the mid ureter. With a low likelihood of passing the calculus spontaneously, appropriate intervention was initiated by the urology unit. Not many patients, nor surgeons for that matter, are fortunate enough to have diagnosed a ureteral inguinal hernia before surgery is performed. If the diagnosis is made preoperatively, we suggest stenting the ureter preoperatively to facilitate identifying, reducing and preserving the ureter. This was the case with our patient. However, the same approach as described above can be adopted in difficult cases where there is some ambiguity. We suggest an algorithm to identify such hernias to avoid the caveat of ureteric injury (figure 4). In an open inguinoscrotal hernia repair, if the hernia contains fat that does not meet the characteristics of a cord lipoma and lacks the presence of the classical peritoneal sac, the possibility of herniating retroperitoneal structures, particularly the ureter, should be raised. In this situation, careful reduction of the fat should be performed. If the fat is completely irreducible, careful dissection at the level of the deep ring should be sought to avoid damaging a ureter. Figure 4 Algorithm for suspected ureteral involvement in the symptomatic inguinal hernia.

However, the same approach as described above can be adopted in difficult cases where there is some ambiguity. We suggest an algorithm to identify such hernias to avoid the caveat of ureteric injury (figure 4). In an open inguinoscrotal hernia repair, if the hernia contains fat that does not meet the characteristics of a cord lipoma and lacks the presence of the classical peritoneal sac, the possibility of herniating retroperitoneal structures, particularly the ureter, should be raised. In this situation, careful reduction of the fat should be performed. If the fat is completely irreducible, careful dissection at the level of the deep ring should be sought to avoid damaging a ureter. Figure 4 Algorithm for suspected ureteral involvement in the symptomatic inguinal hernia. Learning points A ureteral inguinal hernia should be considered when a clinical inguinal hernia is diagnosed concurrently with unexplained unilateral hydronephrosis, renal failure or urinary tract infection. Preoperative assessment should be performed on all patients having inguinal hernia repair, with minimum investigations being a urine full ward test and basic blood tests to assess renal function. Majority of cases occur in the absence of ureteral obstruction, hence it may be near impossible to make the diagnosis preoperatively. In such cases, an awareness of the condition, a high index of suspicion and careful surgical dissection is of utmost importance. These principles and techniques may avoid inadvertent injury to the ureter and avoid significant patient morbidity.

Majority of cases occur in the absence of ureteral obstruction, hence it may be near impossible to make the diagnosis preoperatively. In such cases, an awareness of the condition, a high index of suspicion and careful surgical dissection is of utmost importance. These principles and techniques may avoid inadvertent injury to the ureter and avoid significant patient morbidity. Department of General Surgery, Box Hill Hospital Eastern Health, Victoria, Australia. Contributors: As corresponding author, ZY was responsible for conception and design of the case report as well as collection and interpretation of relevant patient data. Both ZY and YA performed a literature review. ZY and YA drafted and critically revised the article for accuracy and appropriateness of intellectual content. As the Director of General Surgery, SH provided valuable insights, guidance and direction in drafting the article. SH also proof-read the article and along with ZA and YA gave approval for the final manuscript to be submitted. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Haemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome characterised by an uncontrolled hyperinflammatory response with heterogeneous aetiology.1 2 HLH is categorised as primary HLH (or familial HLH) in patients with underlying genetic causes and as secondary HLH (SHLH) when family history or known genetic causes are absent. SHLH is associated with a wide spectrum of underlying conditions: viral infections have been reported as the most common triggers (29%), followed by other infections, malignancies, autoimmune disorders and immune suppression.1 Among viral infections, Epstein–Barr virus (EBV) has been described as the most frequent virus that associates with SHLH, herpes simplex virus 1 as the next most common virus.3–6 In healthy, immunocompetent persons at any age, EBV and herpes simplex virus (HSV) infection are usually self-limiting, rarely lead to complications and are both uncommon causes of acute liver failure (ALF).7–11 The case presented in this report highlights the possibility of a synergistic effect of these two closely succeeding viral primary infections in the development of a severe systemic disease in an immunocompetent person. In addition, it emphasises that SHLH should be suspected routinely when severe systemic illness with multiorgan failure develops following a viral infection and that the diagnosis should be confirmed rapidly by laboratory and histopathological investigations. In addition to suppression of the severe hyperinflammation which is the main therapeutic aim in HLH, early diagnosis and treatment of the potential underlying disease may also influence the clinical outcome.12

fection and that the diagnosis should be confirmed rapidly by laboratory and histopathological investigations. In addition to suppression of the severe hyperinflammation which is the main therapeutic aim in HLH, early diagnosis and treatment of the potential underlying disease may also influence the clinical outcome.12 Case presentation A 21-year-old patient presented at a peripheral hospital with a protracted febrile urinary tract infection. The patient did not have any significant medical history, and on admission physical examination was normal. Mild thrombocytopenia and elevated liver enzymes were explained by the serological diagnosis of primary EBV infection. MRI of the kidneys revealed no abnormalities, however, splenomegaly and multiple, smallest, inconclusive hepatic lesions were detected. Owing to the inconclusive MRI of the liver, the antibiotic therapy was stopped immediately and paracetamol was replaced by metamizole. Neither microbiological urine culture nor blood culture revealed a causative microorganism.

es, however, splenomegaly and multiple, smallest, inconclusive hepatic lesions were detected. Owing to the inconclusive MRI of the liver, the antibiotic therapy was stopped immediately and paracetamol was replaced by metamizole. Neither microbiological urine culture nor blood culture revealed a causative microorganism. By day 4 after admission the liver function had decreased dramatically and ALF followed by acute renal failure developed. Leucopenia, thrombopenia and a significantly elevated ferritin level indicated the beginning of severe immune dysregulation (table 1). The patient was transferred to the University Hospital Vienna where on admission genital lesions suggestive of HSV infection were detected and intravenous acyclovir was started immediately. Within only a few hours, the patient's condition rapidly deteriorated, the patient developed multiorgan failure and died—despite intensive care treatment—only 6 days after the initial admission to hospital. Table 1 Course of laboratory and virological findings during hospital stay

By day 4 after admission the liver function had decreased dramatically and ALF followed by acute renal failure developed. Leucopenia, thrombopenia and a significantly elevated ferritin level indicated the beginning of severe immune dysregulation (table 1). The patient was transferred to the University Hospital Vienna where on admission genital lesions suggestive of HSV infection were detected and intravenous acyclovir was started immediately. Within only a few hours, the patient's condition rapidly deteriorated, the patient developed multiorgan failure and died—despite intensive care treatment—only 6 days after the initial admission to hospital. Table 1 Course of laboratory and virological findings during hospital stay Day of hospitalisation 1 3 4 5 6 ALT (U/L) 375 822 1213 1831 2650 AST (U/L) 475 1929 3387 6319 11 150 γGT (U/L) 198 230 248 336 326 ALP (U/L) 263 352 570 648 Total bilirubin (mg/dL) 1.9 3.1 4.32 Ferritin (ng/mL) 1844 7058 Creatinine (mg/dL) 0.8 0.9 2.5 4.01 WCC (G/L) 11.2 6.32 4.29 1.52 HgB (g/dL) 12 11,5 10.5 6.5 Platelet (G/L) 130 122 113 23 sCD25 (U/mL) 338.6 HSV-1 (cp/mL serum) 1.48E+07 1.88E+08 Anti-HSV IgM Negative Negative Anti-HSV IgG Negative Borderline/positive EBV (cp/mL serum) 1.77E+04 2.14E+04 Anti-EBV VCA IgM Positive Positive Anti-EBV VCA IgG Positive Positive Anti-EBV VCA IgG avidity Low Anti-EBV EBNA1 Negative Borderline/negative ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; EBNA, Epstein–Barr virus nuclear antigen 1; EBV, Epstein–Barr virus; HgB, haemoglobin; HSV, Herpes Simplex virus type 1; IgG, immunoglobulin G; IgM, immunoglobulin M; VCA, viral capsid antigen; WCC, white cell count; γGT, γ-glutamyltransferase.

kaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; EBNA, Epstein–Barr virus nuclear antigen 1; EBV, Epstein–Barr virus; HgB, haemoglobin; HSV, Herpes Simplex virus type 1; IgG, immunoglobulin G; IgM, immunoglobulin M; VCA, viral capsid antigen; WCC, white cell count; γGT, γ-glutamyltransferase. In a serum sample taken on day 5, EBV DNA was detected by PCR and primary EBV infection was again confirmed by serology, as VCA IgM antibodies and VCA IgG antibodies of low avidity were detected. In addition, HSV1 PCR was also highly positive in this serum sample and the detection of HSV IgG antibody seroconversion confirmed additional primary infection with HSV1 (table 1). As expected, postmortem analysis of small tissue samples of liver, spleen, kidney and gallbladder by PCR revealed HSV1 and EBV DNA in all of the samples. Particularly high concentrations of HSV1 DNA were detected in liver and spleen tissues (8.40E+06 and 7.20E+06 copies/mg, respectively). EBV DNA concentration in these tissues was 1.76E+03 copies/mg (liver) and 7.60E+04 copies/mg (spleen).

n, kidney and gallbladder by PCR revealed HSV1 and EBV DNA in all of the samples. Particularly high concentrations of HSV1 DNA were detected in liver and spleen tissues (8.40E+06 and 7.20E+06 copies/mg, respectively). EBV DNA concentration in these tissues was 1.76E+03 copies/mg (liver) and 7.60E+04 copies/mg (spleen). Histopathology of the postmortem liver samples displayed the typical necrosis pattern of HSV hepatitis with confluent necroses in a geographical pattern without zonal binding (figure 1A) and a mixed reactive inflammatory infiltrate including a substantial number of polymorph nuclear leucocytes (figure 1B). Hepatocytes showed typical nuclear inclusions with the virus (figure 1B). Immunoperoxidase staining confirmed the diagnosis of HSV1 hepatitis (figure 1C). In some areas, the characteristic features of EBV-hepatitis could still be found (figure 1D). The diagnosis was confirmed by the detection of EBV LMP1 by alkaline phosphatase staining (figure 1E) and the detection of EBV by PCR after extraction of EBV DNA from the liver tissue (figure 1F). In portal macrophages, a trapping of erythrocytes was found and in the sinusoids the activated Kupffer cells showed a conspicuous erythrophagocytosis, consistent with SHLH (figure 2).

alkaline phosphatase staining (figure 1E) and the detection of EBV by PCR after extraction of EBV DNA from the liver tissue (figure 1F). In portal macrophages, a trapping of erythrocytes was found and in the sinusoids the activated Kupffer cells showed a conspicuous erythrophagocytosis, consistent with SHLH (figure 2). Figure 1 (A) Large confluent areas of necrosis without zonal binding (H&E staining, ×60). (B) In the margin of the necrosis, hepatocytes display nuclei with typical viral inclusions (arrow). The necroinflammatory infiltrate consists of lymphocytes and a lot of polymorph nuclear leucocytes (H&E staining, ×400). (C) HSV1-infected hepatocytes detected with immunoperoxidase staining (×240). (D) In some areas of the liver, typical features of EBV hepatitis with abundant lymphocytic infiltrates in the sinusoids were still present (H&E staining, ×240). (E) EBV LMP1 detected by immunostaining with alkaline phosphatase, ×240 (arrow). (F) After extraction of EBV DNA and subsequent PCR, viral DNA could be demonstrated. (a and f) DNA ladder; (b) empty; (c) patient; (d) negative control; (e) positive control. Figure 2 Acute hepatitis: haemophagocytosis with trapped erythrocytes in activated Kupffer cells (arrows), besides many inflammatory infiltrates and damaged hepatocytes (H&E staining, ×500).

Figure 1 (A) Large confluent areas of necrosis without zonal binding (H&E staining, ×60). (B) In the margin of the necrosis, hepatocytes display nuclei with typical viral inclusions (arrow). The necroinflammatory infiltrate consists of lymphocytes and a lot of polymorph nuclear leucocytes (H&E staining, ×400). (C) HSV1-infected hepatocytes detected with immunoperoxidase staining (×240). (D) In some areas of the liver, typical features of EBV hepatitis with abundant lymphocytic infiltrates in the sinusoids were still present (H&E staining, ×240). (E) EBV LMP1 detected by immunostaining with alkaline phosphatase, ×240 (arrow). (F) After extraction of EBV DNA and subsequent PCR, viral DNA could be demonstrated. (a and f) DNA ladder; (b) empty; (c) patient; (d) negative control; (e) positive control. Figure 2 Acute hepatitis: haemophagocytosis with trapped erythrocytes in activated Kupffer cells (arrows), besides many inflammatory infiltrates and damaged hepatocytes (H&E staining, ×500). These characteristic histopathological changes in liver tissue along with the laboratory and clinical findings indicated the initiation of SHLH by these two closely succeeding viral primary infections. Unfortunately, histopathological investigation of bone marrow and spleen, as suggested in the diagnostic guidelines used in the HLH-2004 trial,13 could not be performed because the relatives denied further postmortem investigations. Nevertheless, regarding the clinical, laboratory and histopathological findings, five out of the eight diagnostic criteria defined by the Histiocyte Society1 were fulfilled. With the considerably elevated level of soluble CD25 (sCD25) retrospectively detected in the serum sample of day 6 (table 1), a sixth diagnostic criterion was fulfilled which further supported the diagnosis of SHLH.

l findings, five out of the eight diagnostic criteria defined by the Histiocyte Society1 were fulfilled. With the considerably elevated level of soluble CD25 (sCD25) retrospectively detected in the serum sample of day 6 (table 1), a sixth diagnostic criterion was fulfilled which further supported the diagnosis of SHLH. Outcome and follow-up In summary, laboratory, virological and pathological findings together with the clinical presentation suggest multiorgan failure due to SHLH initiated by EBV and closely succeeding HSV1 primary infection in a previously healthy young person. Discussion Systemic immune dysregulation triggered by an external agent has been described as a cause of a disease continuum including HLH, sepsis, multiple organ dysfunction syndrome and systemic hyperinflammatory syndrome.13 Here we report a case of foudroyant immune dysregulation following closely succeeding viral primary infections with EBV and HSV1. Clinical findings (fever, splenomegaly), laboratory parameters (cytopenia in two blood cell lines, elevated ferritin and sCD25) and haemophagocytosis in liver tissue suggest the diagnosis of SHLH based on the HLH-2004 criteria.13 In our patient serological findings indicated that primary EBV infection preceded primary HSV infection. The impairment of the immune response caused by primary EBV infection, especially the suppression of the T-cell function, may have enabled the vicious course of primary HSV1 infection in a previously healthy young adult, and both the viruses may have been subsequent triggers for the hyperinflammatory syndrome.3 13

ion. The impairment of the immune response caused by primary EBV infection, especially the suppression of the T-cell function, may have enabled the vicious course of primary HSV1 infection in a previously healthy young adult, and both the viruses may have been subsequent triggers for the hyperinflammatory syndrome.3 13 Viral infections have been reported as common triggers of SHLH,1 2 and the possible synergistic effects of two viral infections in the initiation of SHLH have been described in a previous report of SHLH after the close occurrence of EBV and Hepatitis A infection.14 SHLH after EBV or HSV1 infection has been described previously, and also induction of SHLH by coinfection with EBV and HSV1 has been observed before in two patients. In these cases of SHLH following EBV and HSV1 coinfection, however, EBV viraemia was due to reactivation of latent infection.3 Therefore, initiation of SHLH by primary infections with EBV and HSV1 seems to represent a unique feature of our case.

by coinfection with EBV and HSV1 has been observed before in two patients. In these cases of SHLH following EBV and HSV1 coinfection, however, EBV viraemia was due to reactivation of latent infection.3 Therefore, initiation of SHLH by primary infections with EBV and HSV1 seems to represent a unique feature of our case. Diagnosing HLH or SHLH as defined by the Histiocyte Society1 is challenging because of its rare occurrence, variable presentation and non-specific findings and should be suspected routinely in patients with unexplained multiorgan failure.2 12 13 Early diagnosis and appropriate treatment including supportive intensive care, elimination of the triggers and suppression of the inflammatory response are essential to improve the outcome of this syndrome.13 Our case highlights that in a patient with unexplained fever and elevated liver function tests, HSV in addition to EBV and cytomegalovirus (CMV) should be taken into consideration as causative agent. As reported before, the absence of mucocutaneous lesions—which initially was the case in our patient—does not exclude HSV hepatitis.

hlights that in a patient with unexplained fever and elevated liver function tests, HSV in addition to EBV and cytomegalovirus (CMV) should be taken into consideration as causative agent. As reported before, the absence of mucocutaneous lesions—which initially was the case in our patient—does not exclude HSV hepatitis. Owing to the rapid and malignant course of the disease in our patient, the diagnosis of SHLH could only be established retrospectively. Although the severe immune dysregulation may have been untreatable already on initial admission, we would like to emphasise that a delay in diagnosis and initiation of specific antiviral therapy and immunosuppressive treatment in addition to supportive intensive care may have contributed to the poor outcome.7 13 Learning points Primary infection with two different herpes viruses may occur simultaneously or in close succession, adversely affecting the course of the disease. Herpes simplex virus (HSV) and Epstein–Barr virus (EBV) should be considered in the differential diagnosis of fulminant hepatitis. Early virological diagnosis and immediate initiation of specific antiviral therapy is of high importance. EBV and HSV may cause severe disease in immunocompetent persons and secondary haemophagocytic lymphohistiocytosis should be suspected routinely when severe systemic illness develops.

Herpes simplex virus (HSV) and Epstein–Barr virus (EBV) should be considered in the differential diagnosis of fulminant hepatitis. Early virological diagnosis and immediate initiation of specific antiviral therapy is of high importance. EBV and HSV may cause severe disease in immunocompetent persons and secondary haemophagocytic lymphohistiocytosis should be suspected routinely when severe systemic illness develops. The authors thank Professor Ingrid Simonitsch-Klupp (Institute of Clinical Pathology, Medical University of Vienna) for pathological investigations and Professor Winfried Pickl and Doris Trapin, MSc (Institute for Immunology, Medical University of Vienna) for carrying out the sCD25 assay. Contributors: CH is responsible for acquisition of patient data, study of literature, virological diagnosis, analysis and interpretation of findings and creating the manuscript. SB is responsible for access to medical history, critical discussion and revision. JT is responsible for access to medical history, critical discussion and revision. HPD is responsible for pathological examination of the liver, photographic documentation (Figure 1A–D), discussion of the case and critical review of the manuscript. Competing interests: None declared. Patient consent: Not obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Description A woman aged 65 years had a sudden onset of severe headache after swimming. She had prolonged headache; therefore, she presented at the emergency department. During the examination in the emergency department, her physical and neurological examinations were unremarkable. Haematological findings were normal. The CT scan of the head revealed a cortical subarachnoid haemorrhage (cSAH) in the right frontal and left temporal lesion (figure 1A, B). The cerebrospinal fluid analysis revealed normal protein and cell counts. A brain MRI showed only high-intensity changes for cSAH with no findings of microbleeds (figure 1C, D). The magnetic resonance angiography (MRA) showed mild stenotic changes on the right posterior cerebral artery (PCA) (figure 2A). There was no evidence of any aneurysm. Based on the constriction findings, reversible cerebral vasoconstriction syndrome (RCVS) in conjunction with cSAH was suspected, and intravenous nicardipine was initiated followed by oral lomerizine in the same way as previously reported.1 On day 9, the MRA showed findings of systemic constriction which were particularly emphasised in the right middle cerebral artery and the left PCA (figure 2B). On day 27, the constriction findings had improved (figure 2C). The reversible vasoconstriction findings were consistent with RCVS. RCVS and cerebral amyloid angiopathy (CAA) are common aetiologies of atraumatic cSAH.2 In younger patients, RCVS is the most common cause of cSAH, and CAA should be considered in older patients, especially in those over 60 years of age.2 3 It is unusual that a relatively elderly woman would develop a cSAH with RCVS; however, we should consider the possibility of RCVS, although the patient may not be young. Figure 1 (A and B) CT of the head reveals a mild cortical subarachnoid haemorrhage (cSAH) in the right frontal and left temporal lesion (arrow). (C and D) Brain MRI on admission shows high-intensity changes for cSAH on fluid-attenuated inversion recovery imaging and low-intensity changes on gradient echo T2*-weighted imaging (arrow).

B) CT of the head reveals a mild cortical subarachnoid haemorrhage (cSAH) in the right frontal and left temporal lesion (arrow). (C and D) Brain MRI on admission shows high-intensity changes for cSAH on fluid-attenuated inversion recovery imaging and low-intensity changes on gradient echo T2*-weighted imaging (arrow). Figure 2 (A) The magnetic resonance angiography (MRA) on admission shows mild segmental stenotic changes in the right posterior cerebral artery (PCA) (arrow). (B) The MRA on day 9 shows the findings of systemic constriction, which are particularly prominent in the right middle cerebral artery and left PCA (arrow). (C) The MRA on day 27 shows improvement in the constriction findings. Learning points Reversible cerebral vasoconstriction syndrome (RCVS) is the most common cause of cortical subarachnoid haemorrhage (cSAH) in younger patients. Cerebral amyloid angiopathy is the most common cause in elderly patients, particularly those older than 60 years of age. However, there have been a few reports in which a case of RCVS presented with cSAH in patients over 60 years of age; therefore, we should consider the possibility of RCVS even though the patient is not young. Contributors: YC was a major contributor in writing the manuscript. DY and TU also treated the patient, and interpreted the patient data. All authors read and approved the final manuscript. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Extracorporeal membrane oxygenation (ECMO) has been shown to be effective in treating patients with acute respiratory distress syndrome (ARDS),1 while the use of ECMO for an irreversible cause is considered contraindicated. Extracorporeal life support organisation (ELSO) guidelines suggest that a status predicting poor outcome despite ECMO should be considered a relative contraindication.2 Previously, the prognosis of patients with AIDS was considered poor, but a recent study showed that mortality in patients with recovered CD4(+) cell counts are not inferior compared with the general population.3 Reports from 2014 showed that patients with AIDS complicated with ARDS were successfully treated with ECMO.4–6 Therefore, the indications for ECMO in patients with AIDS should be considered on an individual basis. Acute respiratory failure in patients with AIDS is associated with various conditions including infections by Pneumocystis jirovecii, multidrug-resistant bacteria and fungus, which were successfully treated with ECMO.4–6 However, acute respiratory failure can also result from immune reconstitution inflammatory syndrome (IRIS), a paradoxical clinical worsening after the initiation of antiretroviral therapy (ART). While ECMO seems useful as reported in these case reports,4–6 the indication of ECMO for IRIS-associated respiratory failure was not discussed. Cawcutt et al reported a patient with AIDS, complicated with ARDS due to probable IRIS,4 where the patient required a treatment of ECMO, but was finally deceased from multiorgan failure.

seems useful as reported in these case reports,4–6 the indication of ECMO for IRIS-associated respiratory failure was not discussed. Cawcutt et al reported a patient with AIDS, complicated with ARDS due to probable IRIS,4 where the patient required a treatment of ECMO, but was finally deceased from multiorgan failure. We treated a patient with newly diagnosed AIDS who presented with P. jirovecii pneumonia (PjP) and was subsequently complicated with probable IRIS. The patient experienced two ARDS episodes due to PjP and probable IRIS, both of which were successfully treated with ECMO, resulting in the patient full recovery. Case presentation A 23-year-old man presented with fever (>40°C), dyspnoea and dry cough. He visited a community hospital, where he was found to be hypoxic with arterial oxygen tension (PaO2) of 58 mm Hg on 15 L/min of oxygen via mask with a reservoir, requiring non-invasive positive pressure mode of ventilation (NPPV) to maintain arterial oxygen saturation. Chest X-ray and chest CT scan showed diffuse bilateral ground glass opacities. The patient received empirical antibiotics (ceftriaxone and ciprofloxacin) and methylprednisolone 1 g daily for 3 days with no improvement in respiratory status, and the patient was transferred to our hospital. After admission, the patient’s respiratory status further deteriorated, requiring intensive care unit (ICU) admission and endotracheal intubation with ventilator support.

iprofloxacin) and methylprednisolone 1 g daily for 3 days with no improvement in respiratory status, and the patient was transferred to our hospital. After admission, the patient’s respiratory status further deteriorated, requiring intensive care unit (ICU) admission and endotracheal intubation with ventilator support. The following day, the diagnosis of AIDS was made with a CD4 count of 8.5 cells/µL and an HIV virus load of 550 000 copies/mL. A PCR was positive for P. jirovecii in the bronchoalveolar lavage fluid. Trimethoprim/sulfamethoxazole (TMP/SMX) was initiated for the treatment of PjP. In addition, the antibacterial regimen was changed to meropenem, vancomycin, ciprofloxacin, micafungin and ganciclovir. Methylprednisolone 1 mg/kg per day was continued. Unfortunately, he developed hypoxaemia refractory to mechanical ventilation; arterial blood gas analysis showed persistent hypoxaemia (PaO2 of 48 mm Hg) on 100% fraction of inspired oxygen (FiO2) with positive end expiratory pressure of 12 cm H2O on ICU day 3 (figure 1). Figure 1 Chest X-ray on the day of extracorporeal membrane oxygenation initiation (intensive care unit day 3).

Unfortunately, he developed hypoxaemia refractory to mechanical ventilation; arterial blood gas analysis showed persistent hypoxaemia (PaO2 of 48 mm Hg) on 100% fraction of inspired oxygen (FiO2) with positive end expiratory pressure of 12 cm H2O on ICU day 3 (figure 1). Figure 1 Chest X-ray on the day of extracorporeal membrane oxygenation initiation (intensive care unit day 3). A decision was made to treat the patient with venous-venous ECMO. He was subsequently initiated with circuit flow of 4.0 L/min and sweep gas of 3.0 L/min of oxygen (FiO2 of 100%). Simultaneously, ART (tenofovir, emtricitabine and raltegravir) was initiated for the treatment of AIDS. During ECMO, lung protective ventilation and the treatment of PjP with corticosteroids and TMP/SMX were continued. Blood and sputum cultures suggested no bacterial involvement, and antibiotics (meropenem, vancomycin and ciprofloxacin) were discontinued after 2 weeks. Gradually, chest X-ray and arterial blood gas analysis showed improvement and he was weaned from a 12-day course of ECMO support on ICU day 15 (figure 2). After removal of ECMO, the respiratory status was stable. Two days after stopping ECMO (12 days after initiating ART), however, the patient developed high fever, acute worsening hypoxia and hypercapnia refractory to increased ventilatory support, and therefore ECMO was reinstituted (figure 3). Figure 2 Chest X-ray on the day of termination of the first extracorporeal membrane oxygenation session (intensive care unit day 15).

Gradually, chest X-ray and arterial blood gas analysis showed improvement and he was weaned from a 12-day course of ECMO support on ICU day 15 (figure 2). After removal of ECMO, the respiratory status was stable. Two days after stopping ECMO (12 days after initiating ART), however, the patient developed high fever, acute worsening hypoxia and hypercapnia refractory to increased ventilatory support, and therefore ECMO was reinstituted (figure 3). Figure 2 Chest X-ray on the day of termination of the first extracorporeal membrane oxygenation session (intensive care unit day 15). Figure 3 Chest X-ray when the patient progressed re-worsening of respiratory status and requiring the second session of extracorporeal membrane oxygenation (intensive care unit day 17). Differential diagnosis Due to the continuation of TMP/SMX for PjP and a negative bacterial culture result on reinstitution of ECMO, recurrent worsening of the primary disease or a new bacterial infection was less likely. Therefore, we suspected IRIS, a paradoxical clinical worsening after the initiation of ART, as the cause of his deteriorating respiratory status. Treatment Venous-venous ECMO was reinstituted with circuit flow of 4.0 L/min and sweep gas of 3 L/min of oxygen (FiO2 of 100%). On reinstitution of ECMO, lung protective ventilation, ART (tenofovir, emtricitabine and raltegravir) for the treatment of AIDS and the treatment of PjP with corticosteroids and TMP/SMX were continued.

Venous-venous ECMO was reinstituted with circuit flow of 4.0 L/min and sweep gas of 3 L/min of oxygen (FiO2 of 100%). On reinstitution of ECMO, lung protective ventilation, ART (tenofovir, emtricitabine and raltegravir) for the treatment of AIDS and the treatment of PjP with corticosteroids and TMP/SMX were continued. Outcome and follow-up After reinitiation of ECMO, his respiratory status gradually improved despite the development of a pneumothorax. On ICU day 30, ECMO was discontinued (14 days after reinstitution) (figure 4). Thirty days after stopping ECMO (a total of 62 days after admission), the patient was discharged home. Figure 4 Chest X-ray on the day of termination of the second extracorporeal membrane oxygenation session (intensive care unit day 30). Discussion We treated a patient with newly diagnosed AIDS and PjP, who survived two ARDS episodes due to PjP and probable IRIS, using ECMO.

Outcome and follow-up After reinitiation of ECMO, his respiratory status gradually improved despite the development of a pneumothorax. On ICU day 30, ECMO was discontinued (14 days after reinstitution) (figure 4). Thirty days after stopping ECMO (a total of 62 days after admission), the patient was discharged home. Figure 4 Chest X-ray on the day of termination of the second extracorporeal membrane oxygenation session (intensive care unit day 30). Discussion We treated a patient with newly diagnosed AIDS and PjP, who survived two ARDS episodes due to PjP and probable IRIS, using ECMO. ECMO is effective in treating patients with acute respiratory failure due to potentially reversible processes, but there are no standard contraindications.2 Although ELSO guidelines suggest that there are no absolute contraindications to ECMO, a status predicting poor outcome despite ECMO should be considered a relative contraindication2 (eg, major pharmacological immunosuppression (absolute neutrophil count <0.4x109/L)). Davies et al suggested that ECMO is not indicated in patients with AIDS and excluded these patients from their trial in 2009.1 However, Rodger et al reported that mortality in well-controlled patients with HIV infection, who maintained or had recovery of CD4(+) cell counts to at least 500 cells/µL, are not inferior compared with the general population.3 Thus, the indications for ECMO in patients with AIDS should be considered on an individual basis with respect to the risks and the benefits. In fact, patients with ARDS and AIDS were successfully treated with ECMO.4–6 Similar to these patients, the current patient suggests that ECMO is a reasonable option for the treatment of ARDS, even in patients with AIDS.

s with AIDS should be considered on an individual basis with respect to the risks and the benefits. In fact, patients with ARDS and AIDS were successfully treated with ECMO.4–6 Similar to these patients, the current patient suggests that ECMO is a reasonable option for the treatment of ARDS, even in patients with AIDS. IRIS is a paradoxical clinical worsening after the initiation of ART, in ART-naive patients, and presents with various symptoms depending on the characteristics and sites of the primary opportunistic infection. Low CD4 counts and high HIV-RNA counts are risk factors for the development of IRIS.7 For the diagnosis of IRIS, the following conditions should be excluded: (1) worsening of the primary disease, (2) new bacterial infection as a complication and (3) allergic reaction to drugs. In this patient, the CD4 count was not confirmed when the respiratory status deteriorated although an increasing CD4 count is a clue to establish the diagnosis of IRIS. However, other criteria for the diagnosis of IRIS were sufficiently met by the clinical course.

n as a complication and (3) allergic reaction to drugs. In this patient, the CD4 count was not confirmed when the respiratory status deteriorated although an increasing CD4 count is a clue to establish the diagnosis of IRIS. However, other criteria for the diagnosis of IRIS were sufficiently met by the clinical course. It is uncertain whether ECMO is effective for IRIS-associated ARDS or not. One retrospective study suggested that patients with AIDS who developed IRIS had a higher risk of death than those who did not.8 A case with newly diagnosed AIDS, complicated by both PjP and probable IRIS-associated ARDS did not survive the ICU due to the multiorgan failure despite a successful separation from ECMO.4 However, IRIS is considered a self-limiting condition, depending on pathogens and organs involved.9 In the current patient, full recovery was achieved. For this reason, to use ECMO for the treatment of refractory ARDS in patients with IRIS is a reasonable option. We used ECMO for probable IRIS, and the present patient successfully recovered from respiratory failure and was discharged home. To the best of our knowledge, this is the first report of the successful use of ECMO for IRIS-associated ARDS. Learning points Extracorporeal membrane oxygenation (ECMO) may be indicated for patients with severe acute respiratory failure associated with AIDS. Immune reconstitution inflammatory syndrome (IRIS) is a diagnosis of exclusion in patients with acute respiratory worsening after the initiation of ART. ECMO may be effective in the treatment of patients with IRIS.

Learning points Extracorporeal membrane oxygenation (ECMO) may be indicated for patients with severe acute respiratory failure associated with AIDS. Immune reconstitution inflammatory syndrome (IRIS) is a diagnosis of exclusion in patients with acute respiratory worsening after the initiation of ART. ECMO may be effective in the treatment of patients with IRIS. The authors thank Drs. Hideyuki Mouri, Tetsuya Komuro, Hiroshi Koyama, Tadashi Kamio, Wataru Matsunaga, and Hirofumi Nakahari for their important contributions to the care of the patient. Contributors: SH, MS and YF contributed to the conception of the case report, acquisition of patient information, analysis and interpretation of the data. SH, MS and AKL drafted the article and revised it critically for important intellectual content. MS contributed to the care of the patient. All the authors made final approval of the version published. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Palpitations, presyncope and syncope are potentially debilitating symptoms that can have a significant functional impact on patients. We present an unusual case of these symptoms that were inducible with a simple deep breath, which after extensive investigation was refractory to traditional treatments. These were successfully treated with the centrally acting sympatholytic, clonidine. Case presentation A 26-year-old man presented to our tertiary syncope centre following previous investigation and treatment elsewhere with daily palpitations, shortness of breath, sweating, presyncope and syncope. Onset of his symptoms followed several weeks of a severe cough and viral respiratory illness 4 years previously. His symptoms were induced on deep respiration or on minimal exertion and showed a diurnal variation, being more pronounced in the early morning and evening, and were not reproducibly related to postural changes. He had over 30 attendances in a year to his local emergency department and had been forced to stop work due to his debilitating symptoms. Investigations Transthoracic echocardiography was normal, and an electrophysiological study showed suprahisian block with Mobitz type II block interval. There was no evidence of dual AV node physiology, accessory pathway or inducible supraventricular tachycardia.

Case presentation A 26-year-old man presented to our tertiary syncope centre following previous investigation and treatment elsewhere with daily palpitations, shortness of breath, sweating, presyncope and syncope. Onset of his symptoms followed several weeks of a severe cough and viral respiratory illness 4 years previously. His symptoms were induced on deep respiration or on minimal exertion and showed a diurnal variation, being more pronounced in the early morning and evening, and were not reproducibly related to postural changes. He had over 30 attendances in a year to his local emergency department and had been forced to stop work due to his debilitating symptoms. Investigations Transthoracic echocardiography was normal, and an electrophysiological study showed suprahisian block with Mobitz type II block interval. There was no evidence of dual AV node physiology, accessory pathway or inducible supraventricular tachycardia. A subsequent permanent pacemaker led to no further episodes of frank syncope. However his ongoing debilitating exertional and respiratory-driven palpitations with presyncope remained. Conservative measures including increased fluid intake and compression stockings had no effect. Trials of medication including fludrocortisone, flecainide, β blockers and ivabradine were either not tolerated or had no significant effect on his symptoms.

onal and respiratory-driven palpitations with presyncope remained. Conservative measures including increased fluid intake and compression stockings had no effect. Trials of medication including fludrocortisone, flecainide, β blockers and ivabradine were either not tolerated or had no significant effect on his symptoms. During a simple active stand over 3 min, his heart rate increased from 90 to 112 bpm. His 12 lead ECG at 30° head-up tilt is shown in figure 1 with an initial heart rate of 91 bpm. Following deep inspiration (arrow), his heart rate rapidly increased to 150 bpm within 6 s with no change in P wave or QRS morphology. Maximal heart rate with deep inspiration alone was 167 bpm. Coughing, isometric hand exercise and passive leg raises all led to similar increases in heart rate and reproduction of symptoms despite taking ivabradine 5 mg two times a day. Figure 1 12 lead ECG at 30° head up tilt, initially at 91 bpm. Deep inspiration (arrows, left) is followed by an increase in heart rate to 150 bpm within seconds. Outcome and follow-up He was started on clonidine 0.1 mg two times a day in combination with ivabradine. This led to a rapid resolution of his respiratory-induced palpitations at rest with no further admissions to hospital. Notably, his quality of life improved sufficiently to allow him to return to work and complete his university degree. Although initially troubled by side effects of drowsiness and fatigue leading to temporary discontinuation of treatment, he has since been re-established on therapy and continues to see benefits from clonidine over 2 years later.

e improved sufficiently to allow him to return to work and complete his university degree. Although initially troubled by side effects of drowsiness and fatigue leading to temporary discontinuation of treatment, he has since been re-established on therapy and continues to see benefits from clonidine over 2 years later. Discussion Variation in heart rate with the respiratory cycle is a well described, but not yet a fully understood phenomenon known as respiratory sinus arrhythmia. Through a predominantly vagally mediated response, the normal response to inspiration is an increase in heart rate. Suggested mechanisms for this response include the activation of pulmonary stretch receptors, increased firing of atrial and arterial baroreceptors and modulation by central respiratory drive.1 Treatments acting on the efferent end points of this pathway alone, such as ivabradine and β blockers, failed to show any improvement. However, we were able to achieve an excellent response by combining these therapies with the centrally acting clonidine.

Discussion Variation in heart rate with the respiratory cycle is a well described, but not yet a fully understood phenomenon known as respiratory sinus arrhythmia. Through a predominantly vagally mediated response, the normal response to inspiration is an increase in heart rate. Suggested mechanisms for this response include the activation of pulmonary stretch receptors, increased firing of atrial and arterial baroreceptors and modulation by central respiratory drive.1 Treatments acting on the efferent end points of this pathway alone, such as ivabradine and β blockers, failed to show any improvement. However, we were able to achieve an excellent response by combining these therapies with the centrally acting clonidine. Patient's perspective Email from the patient (31 October 2016): This condition is far from what I would wish on anyone. However, I have managed to cope with it, as much as can be expected. I still am on clonidine and have been titrated down to 50 µg three times a day. This is one of the tablets that I felt helps me as it stops the forceful contractions of my heart. I find that exercise is still a very big no-no for me. However, I am managing to do everyday things like go to university. Since I last came down to London, this condition has flourished and affected my sleep. It seems like I am using medication to compensate for a switch from parasympathetic to sympathetic state and the reverse (especially at night). Clonidine is one of the tablets that has the least effect on my blood pressure but stops the ‘adrenal storms’ I usually get. To be honest, I find that the medication I am on only suppresses symptoms and I normally have to prepare for a couple of days of breakthrough symptoms that last longer than if I was not on medication. However, I would prefer to have it this way as it allows me to gain a bit of control over my life. I thank your team for everything they did as you were 100% right in your diagnosis.

s symptoms and I normally have to prepare for a couple of days of breakthrough symptoms that last longer than if I was not on medication. However, I would prefer to have it this way as it allows me to gain a bit of control over my life. I thank your team for everything they did as you were 100% right in your diagnosis. Learning points Respiratory sinus arrhythmia remains a not yet fully understood mechanism where the respiratory cycle leads to variations in the heart rate in sinus rhythm. While an exaggerated respiratory sinus arrhythmia is commonly seen during tilt testing, such a marked symptomatic sinus tachycardia following a single deep breath proved difficult to manage. When traditional peripherally acting treatments for palpitations such as β blockers and ivabradine have failed, we have shown an excellent response with the addition of the centrally acting agent clonidine. Contributors: MELKW authored the manuscript. PT, SH and PBL were responsible for the clinical management of the patient in this case report and coauthored the manuscript. Funding: This work is supported by the National Institute for Health Research Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Patients with cancer have a substantial risk of ischaemic strokes, increasing their morbidity and mortality by more than twofold. This is a commonly recognised but poorly studied clinical situation, which represents a significant management challenge and brings together several medical fields. Ischaemic stroke is the second most common brain lesion in patients with cancer and, after an initial ischaemic stroke, accounts for 31% of all recurrent thromboembolic incidents in these patients.1 2 The pathophysiology of cancer-associated ischaemic stroke has been described, but the specific mechanisms linked to distinct patient and disease characteristics are not well known.3–6 There are no current diagnostic or therapeutic guidelines for the prevention and treatment of cancer-associated strokes. Initiation of anticoagulation therapy for secondary stroke prevention in such circumstance remains controversial and clinical management of these patients is challenging. We describe a case of multiple recurrent ischaemic strokes in a patient with cholangiocarcinoma. We present this case to emphasise the need for more studies that could shed light on the risk stratification and appropriate management of recurrent strokes in patients with a history of remote or current cancer. We also want to highlight the lack of current guidelines for the initiation of anticoagulation therapy for secondary stroke prevention in cancer-associated strokes.

es that could shed light on the risk stratification and appropriate management of recurrent strokes in patients with a history of remote or current cancer. We also want to highlight the lack of current guidelines for the initiation of anticoagulation therapy for secondary stroke prevention in cancer-associated strokes. Case presentation This is the case of a 52-year-old woman with a recently diagnosed liver mass with multiple bilateral metastatic pulmonary nodules (figure 1A,B). She had a history of cervical and thyroid cancer 10 and 4 years ago, respectively, both currently in remission. The malignancy was initially detected as a new unexpected liver finding on surveillance imaging for her cervical cancer history. MRI with MR cholangiopancreatography and pathology via CT-guided percutaneous core biopsy confirmed the diagnosis of cholangiocarcinoma. The patient also had a medical history of hypertension, uncontrolled diabetes mellitus, dyslipidaemia, asthma, morbid obesity, hypothyroidism, neuropathy and arthritis, as well as a 62 pack-years smoking history. The patient underwent systemic palliative chemotherapy with cisplatin and gemcitabine for 5 months, and 6 days after her eighth cycle of chemotherapy, she presented to the emergency department with altered mental status, sudden onset of left upper and lower extremities’ weakness and slurred speech for 1 day. The patient also described having mild shortness of breath for a few days and diffuse bilateral wheezing was noted during examination. The patient was not in acute respiratory distress; vital signs and oxygen saturation on room air were within normal limits during this admission. The patient had a medical history of asthma and received a combination of beta-adrenergic and anticholinergic bronchodilator (DuoNeb) which improved her symptoms. With regard to the neurological symptoms, the last known normal (LKN) time was determined as 7 hours prior to admission. A non-contrast head CT scan was unremarkable; however, brain MRI findings were consistent with acute multiple non-haemorrhagic strokes. These infarcts involved the right frontal and temporoparietal areas, in the vascular territory of the right middle cerebral artery bilaterally (figure 2A,B). Infarcts also involved the left cerebellum corresponding to the vascular distribution of the posteroinferior cerebellar artery (figure 2C,D). The patient was admitted to the neurology stroke service for stroke workup and poststroke care.

vascular territory of the right middle cerebral artery bilaterally (figure 2A,B). Infarcts also involved the left cerebellum corresponding to the vascular distribution of the posteroinferior cerebellar artery (figure 2C,D). The patient was admitted to the neurology stroke service for stroke workup and poststroke care. On the second day of hospitalisation, she experienced agitation, worsening dysarthria and left-sided weakness. MRI studies showed a new small infarct in the deep white matter of the right hemisphere, specifically in the right parasagittal frontal lobe (figure 3). On hospital day 5, the patient re-experienced worsening dysarthria and increased weakness at the left upper and lower extremities. There was also sensory deficits to light touch and proprioception at the left side. A repeat brain MRI demonstrated a new stroke within the body of the corpus callosum and right cingulate gyrus (figure 4A,B), as well as the superior aspect of the right cerebellar hemisphere (figure 4C,D). When compared with the patient’s prior brain imaging studies, the remaining acute and subacute strokes were essentially stable in appearance. After this clinical event, the patient had a stable hospital stay until discharge to an acute rehabilitation centre. Figure 1 Non-contrast abdominal MRI showing a mass on the left liver lobe (arrow) as a typical hypointense lesion on a T1-weighted image (A). Non-contrast chest CT showing discrete multiple bilateral lung nodules at the time of diagnosis (B; arrowheads).

On the second day of hospitalisation, she experienced agitation, worsening dysarthria and left-sided weakness. MRI studies showed a new small infarct in the deep white matter of the right hemisphere, specifically in the right parasagittal frontal lobe (figure 3). On hospital day 5, the patient re-experienced worsening dysarthria and increased weakness at the left upper and lower extremities. There was also sensory deficits to light touch and proprioception at the left side. A repeat brain MRI demonstrated a new stroke within the body of the corpus callosum and right cingulate gyrus (figure 4A,B), as well as the superior aspect of the right cerebellar hemisphere (figure 4C,D). When compared with the patient’s prior brain imaging studies, the remaining acute and subacute strokes were essentially stable in appearance. After this clinical event, the patient had a stable hospital stay until discharge to an acute rehabilitation centre. Figure 1 Non-contrast abdominal MRI showing a mass on the left liver lobe (arrow) as a typical hypointense lesion on a T1-weighted image (A). Non-contrast chest CT showing discrete multiple bilateral lung nodules at the time of diagnosis (B; arrowheads). Figure 2 Hospital day 1, brain MRI showed bilateral middle cerebral artery strokes (A,B) and left posterior inferior cerebellar artery strokes (C,D: ADC, apparent diffusion coefficient; DWI, diffusion weighted imaging. Figure 3 Hospital day 2, brain MRI showed small newly developed strokes in the right parasagittal frontal lobe. ADC, apparent diffusion coefficients; DWI, diffusion weighted imaging.

Figure 2 Hospital day 1, brain MRI showed bilateral middle cerebral artery strokes (A,B) and left posterior inferior cerebellar artery strokes (C,D: ADC, apparent diffusion coefficient; DWI, diffusion weighted imaging. Figure 3 Hospital day 2, brain MRI showed small newly developed strokes in the right parasagittal frontal lobe. ADC, apparent diffusion coefficients; DWI, diffusion weighted imaging. Figure 4 Hospital day 5, brain MRI showed two foci of new ischaemia within the body of the corpus and right cingulate gyrus, as well as the superior aspect of the right cerebellar hemisphere. DWI= diffusion weighted imaging; ADC= apparent diffusion coefficient. Investigations At the acute presentation and after the two episodes of sudden neurological deterioration, the patient underwent urgent non-contrast head CT and brain MRI studies. Initial tests were performed and showed that haemoglobin A1c was 6.8%, low-density lipoprotein was 100 mg/dL and high-density lipoprotein was 51 mg/dL. They also showed pancytopenia associated with the recent chemotherapy treatments and elevated alkaline phosphatase levels due to the underlying cholangiocarcinoma. Extensive workup to investigate the stroke aetiology was conducted, and the relevant findings are discussed below in relation to each differential diagnosis. Differential diagnosis Several differential diagnoses wereconsidered, as described in the following sections.

Investigations At the acute presentation and after the two episodes of sudden neurological deterioration, the patient underwent urgent non-contrast head CT and brain MRI studies. Initial tests were performed and showed that haemoglobin A1c was 6.8%, low-density lipoprotein was 100 mg/dL and high-density lipoprotein was 51 mg/dL. They also showed pancytopenia associated with the recent chemotherapy treatments and elevated alkaline phosphatase levels due to the underlying cholangiocarcinoma. Extensive workup to investigate the stroke aetiology was conducted, and the relevant findings are discussed below in relation to each differential diagnosis. Differential diagnosis Several differential diagnoses wereconsidered, as described in the following sections. Embolic strokes due to cardiac aetiology The patient had history of several major conventional vascular risk factors such as hypertension, uncontrolled diabetes mellitus, heavy smoking and dyslipidaemia. Imaging studies confirmed recurrent acute ischaemic strokes in multiple vascular territories, suggestive of embolic or—less likely—hypotensive or watershed aetiologies. Workup was done to investigate a cardioembolic aetiology for the acute stroke: head and neck CT angiography with and without contrast was unremarkable. Continuous ECG did not reveal any concomitant acute myocardiac ischaemia or arrhythmias, and cardiac enzymes were unremarkable. A transthoracic echocardiogram (TTE) showed no atrial enlargement and no evidence of intracardiac thrombus or patent foramen ovale. However, there was moderate hypokinesis in the anterior septal wall with a left ventricular ejection fraction of 40%. This mild left ventricular systolic dysfunction was considered to be a result of the recent use of chemotherapeutic agents and less likely to be the predisposing source for thrombus formation. After discussion with cardiology team, no loop recorder was implanted at the moment given the patient’s cancer diagnosis, poor prognosis and immunocompromised state. Instead, an event monitor was to be considered prior to discharge for the purpose of long-term rhythm monitoring.

disposing source for thrombus formation. After discussion with cardiology team, no loop recorder was implanted at the moment given the patient’s cancer diagnosis, poor prognosis and immunocompromised state. Instead, an event monitor was to be considered prior to discharge for the purpose of long-term rhythm monitoring. Embolic strokes due to infective endocarditis Given the immunocompromised state of the patient secondary to recent chemotherapy, blood cultures, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) studies were obtained to address a suspicion of endocarditis. A high ESR of 45 mg/dL (normal range 0–20 mg/dL) and a high CRP of 1.52 mg/dL (normal <0.5 mg/dL) were found. There was one positive blood culture for Gram-positive cocci in clusters, coagulase negative, but subsequent blood cultures were negative which favoured the probability of a contaminated specimen. Throughout the hospital stay, there was no evidence of bacteraemia and no clinical findings sustained suspicion for endovascular infection.

sitive blood culture for Gram-positive cocci in clusters, coagulase negative, but subsequent blood cultures were negative which favoured the probability of a contaminated specimen. Throughout the hospital stay, there was no evidence of bacteraemia and no clinical findings sustained suspicion for endovascular infection. In light of her advanced malignancy, non-bacterial thrombotic endocarditis (NBTE) was also considered as a manifestation of the cancer-associated hypercoagulability. In contrast to infectious endocarditis, in NBTE there is deposition of small, sterile and friable vegetations on valvular surfaces leading to a thrombogenic state and embolic strokes. Notably, no valve vegetations or murmur were reported in this patient on the TTE.4 7 8 But, the lesions on the heart valves in NBTE are commonly missed and transoesophageal echocardiography (TEE) has been shown to be more sensitive in detecting vegetations than TTE.7 The team considered conducting a TEE once the patient was in a more stable clinical condition, but this was not done due to comorbidities and high risk of bleeding. Early in the inpatient management, the patient had severe thrombocytopenia due to recent chemotherapy. Later, after the multiple recurrent episodes of acute ischaemic events, the patient was placed on full dose anticoagulation for secondary stroke prevention. The TEE was going to be pursued as outpatient, but after discharge the patient discontinued any interventions and opted for supportive care only. Since conducting a more sensitive TEE was not possible in this patient, the diagnosis of NBTE cannot be completely rule out.7

anticoagulation for secondary stroke prevention. The TEE was going to be pursued as outpatient, but after discharge the patient discontinued any interventions and opted for supportive care only. Since conducting a more sensitive TEE was not possible in this patient, the diagnosis of NBTE cannot be completely rule out.7 Brain metastasis in the setting of advanced cholangiocarcinoma Notably, multiple, non-specific, left-sided hyperintensities were seen in the initial brain MRI fluid-attenuated inversion recovery (FLAIR)images and, given the patient’s known advanced cancer state, these findings suggested the possibility of metastatic brain disease. For further investigation, a complete non-contrast and contrast brain MRI was conducted. This study confirmed the prior ischaemic findings, and the multiple areas of mild contrast enhancement observed were considered to be due to blood–brain barrier breakdown rather than brain metastases.

y of metastatic brain disease. For further investigation, a complete non-contrast and contrast brain MRI was conducted. This study confirmed the prior ischaemic findings, and the multiple areas of mild contrast enhancement observed were considered to be due to blood–brain barrier breakdown rather than brain metastases. Ischaemic stroke associated with the chemotherapy agents There is a likely relationship between ischaemic stroke and malignancy, and the risk elevates even higher in patients treated with chemotherapy. This has been reported in association with cisplatin-based chemotherapy and in some cases with gemcitabine. Our patient was undergoing a regimen combining these two medications and therefore there was a chance of ischaemic stroke as an adverse effect of the chemotherapy itself. Similar to published reports, the initial stroke developed within 1–2 weeks after the last chemotherapy session; however, it is not common to have multiple recurrent strokes linked to chemotherapy agents and a definitive proof of causality is difficult to establish.9 Although less likely, another possible aetiology was chemotherapy-induced thrombotic microangiopathy such as thrombotic thrombocytopenic purpura related to gemcitabine exposure, but the patient did not have the clinical features indicative of this clinical scenario.10–12

e proof of causality is difficult to establish.9 Although less likely, another possible aetiology was chemotherapy-induced thrombotic microangiopathy such as thrombotic thrombocytopenic purpura related to gemcitabine exposure, but the patient did not have the clinical features indicative of this clinical scenario.10–12 Embolic source due to hypercoagulable state in the setting of remote and active malignancy After the multiple recurrent ischaemic events, and in the setting of malignancy and obesity, hypercoagulable states were investigated. Main coagulation studies (prothrombin time, partial thromboplastin time, and international normalised ratio) were within normal ranges. Duplex ultrasonogram of the lower extremities ruled out deep venous thrombosis (DVT) as the source of the embolic events, and notably the patient was undergoing DVT prophylaxis since admission. Extensive hypercoagulable workup was conducted and results for fibrinogen, antithrombin III, protein C, protein S, factor V Leiden, prothrombin gene mutation analysis, dilute Russell’s venom viper time screen, cardiolipins, antiphospholipid antibodies and heparin-induced antibodies were all found to be normal. The only significant finding was an elevated D-dimer level of 3.19 mg/dL (normal value <0.5 mg/dL). Similarly, a second D-dimer level was measured and found to be elevated at 5.7 mg/dL after the third recurrent stroke. Interestingly, several studies have reported elevated D-dimer levels in recurrent cancer-associated strokes and have suggested it as a biomarker of a hypercoagulable state and a predictor of the short-term risk of ischaemic strokes in cancer patients.13–20

d to be elevated at 5.7 mg/dL after the third recurrent stroke. Interestingly, several studies have reported elevated D-dimer levels in recurrent cancer-associated strokes and have suggested it as a biomarker of a hypercoagulable state and a predictor of the short-term risk of ischaemic strokes in cancer patients.13–20 In cancer-associated thrombosis, the Khorana score is the most validated method that helps to assess venous thromboembolism (VTE) risk in cancer outpatients receiving chemotherapy and to inform recommendation for thromboprophylaxis.21 22 The calculated Khorana score for our patient using baseline data at the time of chemotherapy was 1 point (body mass index >35 kg/m2) for an intermediate VTE risk of 1.8%–2.0% at 2.5 months. Our patient developed three ischaemic strokes and one VTE all within 6 months after initiation of chemotherapy. Of note, to the best of our knowledge, there is no published data on large cohort studies using this score for risk prediction of arterial events such as ischaemic strokes in patients with cancer.

2.5 months. Our patient developed three ischaemic strokes and one VTE all within 6 months after initiation of chemotherapy. Of note, to the best of our knowledge, there is no published data on large cohort studies using this score for risk prediction of arterial events such as ischaemic strokes in patients with cancer. Treatment Following the first diagnosis of acute ischaemic stroke, the patient was stabilised clinically and was promptly initiated on the early key poststroke medical protocol according to national guidelines. The patient had a LKN time of more than 4.5 hours and also had pancytopenia with a low platelet count secondary to the recent chemotherapy treatments. Thrombolytic therapy was not appropriate, and she was admitted to a dedicated stroke unit for medical management. Treatment included blood pressure and glucose control, fluid management and swallowing assessment. Antihypertensives were withheld on day 1 of admission to facilitate permissible hypertension given a mild hypotensive state; they were then resumed to achieve moderate blood pressure control during the rest of the hospital course. She was also initiated antithrombotic therapy with aspirin and statin therapy, as well as inpatient DVT prophylaxis with subcutaneous heparin. After the third stroke, full-dose anticoagulation with therapeutic low molecular weight heparin (LMWH) was initiated (enoxaparin 120 mg twice a day subcutaneously). Although guidelines about anticoagulation for stroke prevention in patients with are unclear, this approach was initiated by consensus between neurology and haematology–oncology in view of the patient’s dramatic high-stroke recurrent risk. The possible hypercoagulable state due to the advanced malignancy and the potential for bleeding on anticoagulation were also discussed with the patient.

ts with are unclear, this approach was initiated by consensus between neurology and haematology–oncology in view of the patient’s dramatic high-stroke recurrent risk. The possible hypercoagulable state due to the advanced malignancy and the potential for bleeding on anticoagulation were also discussed with the patient. With regard to the metastatic cholangiocarcinoma, the patient’s most recent cycle of palliative chemotherapy was 6 days prior to the onset of the first neurological event, and further oncological regimen was put on hold until acute neurological issues were resolved. In general, the prognosis of patients with unresectable stage IV cholangiocarcinoma is poor, and therapies such as systemic chemotherapy have failed to show any significant increase in survival. Thus, the benefit of palliative measures should always be weighted against the potential side effects of the therapy. Prior to discharge, the goals of cancer care were discussed with the oncology team and the patient. It was recommended a multidisciplinary supportive care to achieve clinical stabilisation and a close follow-up with oncology as outpatient to decide about resuming palliative chemotherapy. Also, it was discussed additional palliative measures such as relief of symptoms, placement of a biliary stent to bypass obstructions and management of cholangitis to address future quality-of-life concerns due to possible progression of the malignancy.

gy as outpatient to decide about resuming palliative chemotherapy. Also, it was discussed additional palliative measures such as relief of symptoms, placement of a biliary stent to bypass obstructions and management of cholangitis to address future quality-of-life concerns due to possible progression of the malignancy. Outcome and follow-up After a 7-day hospitalisation, the patient was discharged to acute rehabilitation with instructions to receive continuous anticoagulation with enoxaparin (120 mg subcutaneously, twice a day). The patient followed up with haematology–oncology as an outpatient 2 weeks after discharge, and still had significant residual dysarthria and weakness in the left upper and lower extremities. Given her overall medical status, the patient decided not to resume the palliative chemotherapy treatments and to continue supportive care at the rehabilitation centre. One month later, the patient presented to the ED complaining of abdominal pain, nausea, vomiting and anorexia for 3 days. She was found to have sepsis secondary to acalculous cholecystitis, progression of the cancer and a complicated urinary tract infection related to long-term Foley catheterisation and chronic urinary retention. The patient also had shortness of breath and mild hypoxaemia, and subsequent workup found remarkable progression of her multiple lung metastases and a new onset pulmonary embolism (figure 5A,B); despite being prescribed anticoagulation therapy with enoxaparin as an outpatient. Due to her advanced cholangiocarcinoma, overall disease burden and multiple comorbidities, the patient was not a surgical candidate for cholecystectomy or for additional palliative chemotherapy. She opted for a cholecystostomy tube placement for symptomatic relief, and after achieving clinical stability, the patient and her family decided on her discharge home with hospice assistance and with the appropriate comfort measures. The patient died 2 days after being discharged.

r additional palliative chemotherapy. She opted for a cholecystostomy tube placement for symptomatic relief, and after achieving clinical stability, the patient and her family decided on her discharge home with hospice assistance and with the appropriate comfort measures. The patient died 2 days after being discharged. Figure 5 Contrast chest CT and pulmonary embolism protocol showing disease burden and significant progression of the multiple bilateral lung metastasis (A) and filling defect consistent with pulmonary embolism in the right lower lobe pulmonary artery (B).

r additional palliative chemotherapy. She opted for a cholecystostomy tube placement for symptomatic relief, and after achieving clinical stability, the patient and her family decided on her discharge home with hospice assistance and with the appropriate comfort measures. The patient died 2 days after being discharged. Figure 5 Contrast chest CT and pulmonary embolism protocol showing disease burden and significant progression of the multiple bilateral lung metastasis (A) and filling defect consistent with pulmonary embolism in the right lower lobe pulmonary artery (B). Discussion In this report, we present a patient who developed multiple early recurrent ischaemic strokes while undergoing chemotherapy for metastatic cholangiocarcinoma. As in this case, patients with active cancer may have multiple conventional vascular risk factors which could be the main underlying stroke aetiology.5 6 However, compared with the general population, patients with cancer are in a hypercoagulable state that increases their risk of events such as venous thromboembolism, arterial thrombosis, migratory superficial thrombophlebitis, NBTE and disseminated intravascular coagulation.7 23 24 In addition, besides coagulation disorders, other mechanisms such as direct cancer effect, paraneoplastic syndrome and complications of cancer treatment have been identified as possible causes of stroke in patients with cancer.1 25–27 In our patient, a number of factors pointed towards the probability of an embolic stroke aetiology due to cancer-associated thrombosis. These factors included the patient’s negative workup for the main traditional stroke risk factors, the presence of advanced-stage cancer, the occurrence of multiple early recurrent strokes in distinct vascular territories and the elevated D-dimer levels. In regard to D-dimer levels, several groups have studied D-dimer as a marker of a cancer-associated hypercoagulable state and in some cases high levels of D-dimer have been correlated with an increased risk of early recurrent events in patients with cancer after an initial acute ischaemic stroke.13–18 However, it is important to note that the predictive utility of this biomarker is not always this straightforward.

ed hypercoagulable state and in some cases high levels of D-dimer have been correlated with an increased risk of early recurrent events in patients with cancer after an initial acute ischaemic stroke.13–18 However, it is important to note that the predictive utility of this biomarker is not always this straightforward. This is because D-dimer levels could also be influenced by the advanced malignancy itself (such as large tumour burden, progression and metastasis without thrombosis), increased age, diabetes and other factors.14 15 28–31 Nonetheless, elevated D-dimer levels may be helpful in recognising ischaemic stroke as the initial presentation of an underlying malignancy in patients with cryptogenic stroke and multiterritorial brain lesions.32 33 That being said, in this patient, the suspicion of cancer-associated thrombosis was further strengthened when the patient also developed a new pulmonary embolism, a manifestation of hypercoagulability more frequently identified in patients with active cancer.

cryptogenic stroke and multiterritorial brain lesions.32 33 That being said, in this patient, the suspicion of cancer-associated thrombosis was further strengthened when the patient also developed a new pulmonary embolism, a manifestation of hypercoagulability more frequently identified in patients with active cancer. Further research is needed to better understand cancer-specific prothrombotic effects and how active inflammatory and immune response mechanisms may play a role in the pathogenesis of stroke.26 27 There are only a few large-scale epidemiological reports that systemically study the incidence, mechanism and appropriate treatment of recurrent stroke in patients with cancer. One of the most recent comprehensive studies determined that the majority of patients with cancer with recurrent thromboembolic events after ischaemic stroke had reached a metastatic disease stage. In addition, the most common histological tumour type was adenocarcinoma and the most common type of malignancy was lung cancer.1 Prior studies have determined that other common cancer types linked to recurrent stroke in patients are breast, gastrointestinal and gynaecological cancers.1 27 34 In the literature, we only found one reported case of recurrent ischaemic stroke in the setting of cholangiocarcinoma.35 Some studies found that the median time from diagnosis of underlying cancer to stroke was about 1 year, but in a number of patients with stroke could occur as early as 1 month or as late as several years after the cancer diagnosis. Interestingly, in some patients with stroke can be the initial sign of cancer, and approximately 84% of such patients had a second stroke within the following 4 months.1 2 32–34

about 1 year, but in a number of patients with stroke could occur as early as 1 month or as late as several years after the cancer diagnosis. Interestingly, in some patients with stroke can be the initial sign of cancer, and approximately 84% of such patients had a second stroke within the following 4 months.1 2 32–34 Anticoagulation in high-risk vascular events is an established treatment. However, the use of risk-stratified thromboprophylaxis in patients with active malignancy as a strategy for the prevention of arterial, as well as venous, thromboembolic events is a less common intervention. Most clinical trials of cancer-associated thrombosis and the use of anticoagulation have focused on the treatment and prevention of cancer-associated venous thrombosis and clear guidelines have been established.36 37 Several large studies have focused on the risk assessment, safety and compliance with thromboprophylaxis for VTE in patients with cancer.38–42 However, it is uncertain how much these data can be extrapolated to guide clinical decision making for the use of anticoagulation in regards to arterial thrombotic events such as ischaemic strokes.

s have focused on the risk assessment, safety and compliance with thromboprophylaxis for VTE in patients with cancer.38–42 However, it is uncertain how much these data can be extrapolated to guide clinical decision making for the use of anticoagulation in regards to arterial thrombotic events such as ischaemic strokes. Controversies remain concerning the initiation of anticoagulation therapy and the optimal choice of medication for secondary stroke prevention in the setting of active malignancy. The goal of anticoagulation therapy in these patients would be to decrease their substantial risk of short-term stroke recurrence while also considering their risk of bleeding. However, there is not enough data to support the claim that early anticoagulation would be beneficial. One retrospective study suggested that treatment with LMWH may be more effective than warfarin for lowering the risk of stroke recurrence, but it was limited by a small sample size, confounding factors and a short study period.16 There is also an ongoing randomised phase I/II trial evaluating enoxaparin versus aspirin in patients with active cancer and first-ever acute ischaemic stroke to compare these treatments’ safety and efficacy in preventing recurrent thromboembolic events (ClinicalTrials.gov, NCT01763606). But, currently, the role of thromboprophylaxis for secondary stroke prevention in patients with active cancer is not addressed in current stroke or cancer treatment guidelines. Since this is an important evolving area of research, large-scale randomised prospective studies are needed to establish patient-specific and disease-specific diagnostic and treatment algorithms for acute and recurrent strokes in patients with cancer.

r is not addressed in current stroke or cancer treatment guidelines. Since this is an important evolving area of research, large-scale randomised prospective studies are needed to establish patient-specific and disease-specific diagnostic and treatment algorithms for acute and recurrent strokes in patients with cancer. In closing, the interrelationship between ischaemic stroke and cancer is a complex one. As the life expectancy of the general population increases and the survival rate of patients with cancer improves, the coexistence of stroke and cancer in adult patients will continue to be common. This report seeks to highlight the intricacies of this correlation. It emphasises the relevance of establishing a distinct stroke aetiology on a patient-by-patient basis, especially when active malignancy is present. This, in turn, can have important implications for the prognosis, therapeutic management and prevention of recurrent stroke in patients with cancer. Learning points Clinicians should remain alert for thromboembolic events (both arterial and venous) in patients with cancer as a possible cause of any clinical deterioration. Even though their risk is significantly increased with advanced cancer, delay in diagnosis is not uncommon and may negatively impact patient morbidity and mortality. Identifying stroke aetiology in the setting of malignancy can be complex due to the presence of traditional cerebrovascular risk factors in many adult oncology patients, but this is crucial to defining treatment and prevention strategies.

Learning points Clinicians should remain alert for thromboembolic events (both arterial and venous) in patients with cancer as a possible cause of any clinical deterioration. Even though their risk is significantly increased with advanced cancer, delay in diagnosis is not uncommon and may negatively impact patient morbidity and mortality. Identifying stroke aetiology in the setting of malignancy can be complex due to the presence of traditional cerebrovascular risk factors in many adult oncology patients, but this is crucial to defining treatment and prevention strategies. Some studies have associated elevated D-dimer levels with a high risk of early recurrent ischaemic strokes in patients with cancer. Thus, it can be beneficial to consider D-dimer levels for risk stratification of recurrent events as part of the acute inpatient stroke management of certain patients with active cancer. There are no current recommendations to support any benefit of early anticoagulation for secondary stroke prevention after acute stroke in patients with cancer. However, it should be considered if cancer-associated hypercoagulability is likely to be the main stroke aetiology.

Some studies have associated elevated D-dimer levels with a high risk of early recurrent ischaemic strokes in patients with cancer. Thus, it can be beneficial to consider D-dimer levels for risk stratification of recurrent events as part of the acute inpatient stroke management of certain patients with active cancer. There are no current recommendations to support any benefit of early anticoagulation for secondary stroke prevention after acute stroke in patients with cancer. However, it should be considered if cancer-associated hypercoagulability is likely to be the main stroke aetiology. Contributors: GAS-A: substantial contributions to the conceptualisation of the work, data acquisition and interpretation; drafting and revision of the work, final approval of the final version and analysis or interpretation of data; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. JZC: substantial contributions to the conceptualisation of the work, data acquisition and interpretation; revision of the work, approval of the final version; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. RKT: substantial contributions to the conceptualisation and design of the work and data supervision and interpretation; revision of the work, approval of the final version; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

ceptualisation and design of the work and data supervision and interpretation; revision of the work, approval of the final version; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Competing interests: None declared. Patient consent: Detail has been removed from this case description to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making. Provenance and peer review: Not commissioned; externally peer reviewed.

Background Re-expansion pulmonary oedema (Re-PE) reportedly has an incidence of 0.2% to 14% and, recently has been shown to be <1%.1 2 The mechanism of Re-PE is unclear. A possible causative link is sought in amount of fluid removed, applied negative suction pressure and duration of lung collapse. The cut-off for amount drained is reported in a wide range between 1.0 and 6.5 litres.1 Mentioned also is an increased likelihood of Re-PE in patients with lung collapse lasting more than 7 days and particularly in those who need more than 3 litres of pleural fluid drained.2 There are multiple variables when evaluating the response to evacuation of pleural fluid which may include changes in blood pressure, heart rate, contractility, filling pressures and gas exchange. We present an educational case of a chronic cardiac patient fully dependent on a single-chamber ventricular pacemaker (VVI) pacing set at a constant rate throughout the episode of Re-PE. Case presentation A 75-year-old man was admitted for 4 days of progressive dyspnoea to the pulmonary department. The patient’s medical history consisted of chronic heart insufficiency with a dual chamber (DDD type) pacemaker implanted 8 years ago for intermittent symptomatic atrioventricular blockage, arterial hypertension, type 2 diabetes mellitus with complications of chronic renal insufficiency and polyneuropathy.

department. The patient’s medical history consisted of chronic heart insufficiency with a dual chamber (DDD type) pacemaker implanted 8 years ago for intermittent symptomatic atrioventricular blockage, arterial hypertension, type 2 diabetes mellitus with complications of chronic renal insufficiency and polyneuropathy. He was started on antibiotics due to clinical suspicion of pneumonia along with elevated inflammatory markers (C reactive protein, leucocytes). Furosemide was also given with regards to high admission brain natriuretic peptide. Due to progression of respiratory insufficiency, the patient was transferred to the intensive care department (ICU).

otics due to clinical suspicion of pneumonia along with elevated inflammatory markers (C reactive protein, leucocytes). Furosemide was also given with regards to high admission brain natriuretic peptide. Due to progression of respiratory insufficiency, the patient was transferred to the intensive care department (ICU). Investigations On admission, he was conscious, co-operative, tachypnoeic with peripheral saturation of 85% on 10 L/min O2 given via Hudson mask. Patient was normotensive (130/70 mm Hg) with atrial fibrillation (AF) and fully dependent on VVI pacing to 70 bpm (beats per minute). Cardiac biochemistry (troponin I, CK-MB mass, myoglobin) was negative. Transthoracic echocardiography (TTE) was performed which showed congestive heart failure, hypokinetic anteroseptal left ventricular (LV) wall and apex with an ejection fraction (EF) of 38%, moderate mitral regurgitation (MR), dilated left atrium (LA), mild aortic regurgitation (AR), moderately dilated right ventricle (RV) with a tricuspid annular plane systolic excursion (TAPSE) of 23 mm, moderate tricuspid regurgitation and an estimated right-sided pleural effusion of 300–400 mL.3 TAPSE correlates with RV longitudinal contractility and RVEF in the absence of tricuspid valve surgery, normal value is above 18 mm.4

ed right ventricle (RV) with a tricuspid annular plane systolic excursion (TAPSE) of 23 mm, moderate tricuspid regurgitation and an estimated right-sided pleural effusion of 300–400 mL.3 TAPSE correlates with RV longitudinal contractility and RVEF in the absence of tricuspid valve surgery, normal value is above 18 mm.4 With a cardiac output (CO) of 3.5 L/min, on non-invasive ventilation (pressure support ventilation (PSV) 10 mbar, positive end expiratory pressure (PEEP) 6 mbar, fractional inspired oxygen (FiO2) 0.60) and diuretics (furosemide by continuous infusion 3–5 mg/hour titrated according to his urine output), the patient had his VVI pacing reset to 90 bpm. Despite therapy, 36 hours after admission, there were signs of limited aeration of the right lower lobe with bronchial breathing (figure 1A). The patient had to be intubated for exhaustion, and a bronchoscopy was performed which excluded atelectasis, confirmed tracheobronchitis and enabled a bronchoalveolar lavage from the right lower lobe to be obtained and be sent for microbiological analysis. A norepinephrine infusion (NAD) was then started at 0.15 µg/kg/min. Shortly after bronchoscopy, the patient was placed on PSV of 14 cmH2O, PEEP of 8 cmH2O and FiO2 0.50.

s, confirmed tracheobronchitis and enabled a bronchoalveolar lavage from the right lower lobe to be obtained and be sent for microbiological analysis. A norepinephrine infusion (NAD) was then started at 0.15 µg/kg/min. Shortly after bronchoscopy, the patient was placed on PSV of 14 cmH2O, PEEP of 8 cmH2O and FiO2 0.50. Figure 1 All parameters are taken with a heart rate (HR) of 90 bpm (beats per minute). (A) Chest X-ray after intubation and central venous catheter insertion on pressure support ventilation and vasopressor infusion. (B) Pulmonary artery systolic pressure of 50 mm Hg was equal to the transtricuspid continuous wave Doppler systolic gradient of 42 mm Hg plus central venous pressure of 8 mm Hg. (C) Mean velocity time interval in the left ventricular outflow tract (LVOT) was 17.5 cm. (D) Right pleural fluid separating parietal and visceral pleura in the thoracic transverse plane taken above the right diaphragm in the posterior axillary line. Volume estimate in millilitres is equal to the maximum separation in the transverse plane in millimetres multiplied by 20.3

Hereditary angioedema typically presents in adults with recurrent attacks of cutaneous and gastrointestinal oedema. It is due to deficiency or dysfunction of C1 inhibitor. Unlike the generalised oedema of SCLS, the cutaneous swelling of hereditary angioedema is usually localised. Toxic shock syndrome presents with high fever, hypotension and rash. The presence of skin findings along with infection source and/or blood cultures will help distinguish toxic shock syndrome from SCLS. Gleich syndrome is characterised by recurrent episodes of angioedema, urticaria, pruritus, fever, weight gain, oliguria and eosinophilia. Symptoms occur in cycles of 3–4 weeks and resolve spontaneously. Our patient did not exhibit features of this disease. Treatment Initial evaluation for an infectious aetiology was negative. The patient received several doses of intravenous albumin 25 g along with midodrine. Despite escalating doses of midodrine, the patient continued to have refractory hypotension, requiring intravenous fluid boluses.

r outflow tract (LVOT) was 17.5 cm. (D) Right pleural fluid separating parietal and visceral pleura in the thoracic transverse plane taken above the right diaphragm in the posterior axillary line. Volume estimate in millilitres is equal to the maximum separation in the transverse plane in millimetres multiplied by 20.3 The patient was thus on a vasopressor and mechanical ventilation with persisting loss of aeration of the right lower lobe. Therefore, another TTE was done on VVI 90/min (see video 1) which showed moderate LV dysfunction and regional wall motion abnormalities of the anterior wall and apex. There was a moderate-to-severe MR into a dilated LA (biplanar LA volume indexed to body surface area 80 mL/m2) which was in AF. The RV was severely dilated with moderately decreased contractility, the right atrium was dilated and the estimated pulmonary artery systolic pressure (PAPs) was 50 mm Hg (figure 1B). Mild AR was found, stroke volume (SV) was 72 mL (figure 1C) and CO was 6.4 L/min. Right pleural fluid estimate was 800–1000 mL (figure 1D).3 Video 1 Apical four-chamber view showing a hypokinetic apex and interventricular septum, dilated left atrium and right ventricle and collapsibility of the inferior vena cava in inspirium. 10.1136/bcr-2017-219340.video015500353363001BMJ Journals Video Playerbcr2017219340media1A right pleural tap was performed with a 12F drain and a closed collection system, and 850 mL of transudate was evacuated without an active suction (figure 2A).

Video 1 Apical four-chamber view showing a hypokinetic apex and interventricular septum, dilated left atrium and right ventricle and collapsibility of the inferior vena cava in inspirium. 10.1136/bcr-2017-219340.video015500353363001BMJ Journals Video Playerbcr2017219340media1A right pleural tap was performed with a 12F drain and a closed collection system, and 850 mL of transudate was evacuated without an active suction (figure 2A). Figure 2 All parameters are taken with a heart rate (HR) of 90 bpm (beats per minute). (A) Chest X-ray immediately after drainage of 850 mL from the right pleura. (B) Transmitral pulsed wave Doppler in a patient with atrial fibrillation and a significant mitral regurgitation (MR) (E 1.61 m/s). (C) Lateral velocity time interval (VTI) with measured e′ of 12–13 cm/s. E/e′ was 12–14 indicating an elevated left ventricular end-diastolic pressure. (D) Systolic continuous wave (CW) Doppler of an MR jet showing peak systolic gradient of 109 mm Hg. With a systolic blood pressure (BPs) of 136 mm Hg, the patient had a left atrial pressure of 27 mm Hg (BPs−CWmax). (E) Systolic transtricuspid CW Doppler gradient of 45 mm Hg added to a central venous pressure of 12 mm Hg produced an estimate of 57 mm Hg pulmonary artery systolic pressure. TR, tricuspid regurgitation. (F) After drainage, the mean VTI in the left ventricular outflow tract (LVOT) was 13.4 cm.

of 27 mm Hg (BPs−CWmax). (E) Systolic transtricuspid CW Doppler gradient of 45 mm Hg added to a central venous pressure of 12 mm Hg produced an estimate of 57 mm Hg pulmonary artery systolic pressure. TR, tricuspid regurgitation. (F) After drainage, the mean VTI in the left ventricular outflow tract (LVOT) was 13.4 cm. With the patient being constantly on VVI 90/min and on the same PSV settings, he became tachypnoeic with increasing requirements for oxygen (FiO2 0.80), exhibited no signs of a pneumothorax (video 2) and had decreased blood pressure and urine output. The control TTE revealed an elevated left ventricular end-diastolic pressure (LVEDP) (lateral mitral E/e′ 12–13, figure 2B,C), a moderate-to-severe MR into a dilated LA with a continuous wave (CW) Doppler-based left atrial pressure (LAP) estimate of 27 mm Hg (figure 2D), an increase of PAPs to 57 mm Hg (figure 2E), a non-collapsing inferior vena cava with spontaneously triggered inspirium (video 3) and a decreased SV of 56 mL (figure 2F) with a CO of 5.04 L/min. Video 2 The right lung after drainage of the pleural effusion showing pleural sliding, lung pulse and multiple coalescent B lines. The findings are consistent with alveolar-interstitial syndrome (lung oedema) and excludes a pneumothorax. 10.1136/bcr-2017-219340.video025500332503001BMJ Journals Video Playerbcr2017219340media2Video 3 Apical five-chamber view with moderate-to-severe mitral regurgitation into a dilated left atrium, dilated right ventricle and non-collapsing inferior vena cava during the respiratory cycle.

Video 2 The right lung after drainage of the pleural effusion showing pleural sliding, lung pulse and multiple coalescent B lines. The findings are consistent with alveolar-interstitial syndrome (lung oedema) and excludes a pneumothorax. 10.1136/bcr-2017-219340.video025500332503001BMJ Journals Video Playerbcr2017219340media2Video 3 Apical five-chamber view with moderate-to-severe mitral regurgitation into a dilated left atrium, dilated right ventricle and non-collapsing inferior vena cava during the respiratory cycle. 10.1136/bcr-2017-219340.video035500353364001BMJ Journals Video Playerbcr2017219340media3The worsening lung congestion in parallel with systolic heart dysfunction after drainage of a large pleural effusion in a patient with no changes in ventilation modality, heart rate, fluid therapy and vasopressor dosage was concluded as a Re-PE. Differential diagnosis Congestive heart failure—echocardiography confirmed the diagnosis, enabled to estimate elevated heart filling pressures with further impact on therapy. The ultrasound examination also helped diagnose and quantify a large fluidothorax with an implication for a safe drainage. Acute myocardial infarction—excluded by repeatedly negative cardiac biochemistry (troponin I and CK-MB mass) taken in a patient with a non-diagnostic 12-lead ECG due to VVI pacing and not changing regional wall motion abnormalities seen on echocardiography.

Differential diagnosis Congestive heart failure—echocardiography confirmed the diagnosis, enabled to estimate elevated heart filling pressures with further impact on therapy. The ultrasound examination also helped diagnose and quantify a large fluidothorax with an implication for a safe drainage. Acute myocardial infarction—excluded by repeatedly negative cardiac biochemistry (troponin I and CK-MB mass) taken in a patient with a non-diagnostic 12-lead ECG due to VVI pacing and not changing regional wall motion abnormalities seen on echocardiography. Pulmonary embolism—the patient showed a dilated RV with preserved contractility throughout this episode, without any signs of acute cor pulmonale or changes in the elimination of CO2. After the drainage of pleural fluid which was performed on systemic anticoagulation, the mild increase of pulmonary artery pressure could be ascribed to the parallel increase of LAP, that is, presence of postcapillary pulmonary hypertension in heart failure. This deterioration after drainage was reversed swiftly with improvement of the LV function on dobutamine. All of this renders a possible diagnosis of a significant pulmonary embolism very unlikely as a cause of his transient deterioration. Respiratory insufficiency due to tracheobronchitis or pneumonia—diagnosed with the help of positive inflammatory markers and clinical signs of increased bronchial secretions. Fibreoptic bronchoscopy confirmed the diagnosis of tracheobronchitis and excluded atelectasis.

Pulmonary embolism—the patient showed a dilated RV with preserved contractility throughout this episode, without any signs of acute cor pulmonale or changes in the elimination of CO2. After the drainage of pleural fluid which was performed on systemic anticoagulation, the mild increase of pulmonary artery pressure could be ascribed to the parallel increase of LAP, that is, presence of postcapillary pulmonary hypertension in heart failure. This deterioration after drainage was reversed swiftly with improvement of the LV function on dobutamine. All of this renders a possible diagnosis of a significant pulmonary embolism very unlikely as a cause of his transient deterioration. Respiratory insufficiency due to tracheobronchitis or pneumonia—diagnosed with the help of positive inflammatory markers and clinical signs of increased bronchial secretions. Fibreoptic bronchoscopy confirmed the diagnosis of tracheobronchitis and excluded atelectasis. Pneumothorax—excluded predrainage and postdrainage by the presence of pleural sliding, B lines and a lung pulse. A large pneumothorax was also excluded by the chest X-ray taken after admission to the ICU and again after pleural drainage.

Respiratory insufficiency due to tracheobronchitis or pneumonia—diagnosed with the help of positive inflammatory markers and clinical signs of increased bronchial secretions. Fibreoptic bronchoscopy confirmed the diagnosis of tracheobronchitis and excluded atelectasis. Pneumothorax—excluded predrainage and postdrainage by the presence of pleural sliding, B lines and a lung pulse. A large pneumothorax was also excluded by the chest X-ray taken after admission to the ICU and again after pleural drainage. Treatment The patient was administered dobutamine 5.0 µg/kg/min with a positive effect on CO (figure 3) and oxygenation. The decision for inotropic support as first-line therapy rather than increasing the intermittent positive pressure ventilation (IPPV) requirements was supported by the presence of congestive heart failure with pulmonary hypertension and RV dysfunction. With a positive response to therapy, he was weaned off the mechanical ventilation within 24 hours, extubated and continued on Hudson mask and FiO2 of 0.6. Figure 3 A control transthoracic echocardiography on dobutamine 5 µg/kg/min showing increased mean velocity time interval (VTI) in the left ventricular outflow tract (LVOT) to 17.3 cm. Heart rate (HR) is 90 bpm (beats per minute). ED end-diastolic; PS peak systolic Outcome and follow-up The patient was then discharged to a high dependency unit after another 24 hours with sufficient expectoration, without dobutamine, on antibiotics, NAD 0.08 µg/kg/min and VVI 90 bpm. He was discharged on day 19.

Figure 3 A control transthoracic echocardiography on dobutamine 5 µg/kg/min showing increased mean velocity time interval (VTI) in the left ventricular outflow tract (LVOT) to 17.3 cm. Heart rate (HR) is 90 bpm (beats per minute). ED end-diastolic; PS peak systolic Outcome and follow-up The patient was then discharged to a high dependency unit after another 24 hours with sufficient expectoration, without dobutamine, on antibiotics, NAD 0.08 µg/kg/min and VVI 90 bpm. He was discharged on day 19. Discussion This case shows an episode of Re-PE in a patient after drainage of a large pleural effusion, with a constant heart rate and IPPV settings. His previously stable haemodynamics decompensated after drainage of 850 mL without any application of negative suction pressure. The observation of a Re-PE suggests that it might be rather a cardiac decompensation in a large pleural effusion which had increased the pleural pressure and decreased the LV transmural pressure. During drainage, the LV afterload increased with a parallel decrease of LV systolic performance. All this happened in a septic patient with chronic ischaemic heart disease and moderately decreased LV systolic function regardless of being treated on IPPV. The mechanism of so-called Re-PE could be due to heart–lung interactions during and after drainage rather than in re-expansion of the lung compressed by an effusion. Administration of inotropic therapy improved the Re-PE symptoms.

in 1.6 g/dL. Haematocrit was 41%. Urinalysis revealed trace (30–50 mg/dL) proteinuria. Given the multiple hospitalisations and the patient’s general decline in health, she opted to forego all treatment, including corticosteroids and pursued hospice care. She passed away shortly thereafter. An autopsy was not performed. Discussion SCLS is a rare and potentially fatal disorder characterised by recurrent episodes of generalised oedema, haemoconcentration and severe hypotension. Dr Clarkson first described it in 1960 and since then both case reports and case series have been published in literature.1 7 The exact incidence of the disorder is unknown as most cases go undiagnosed. The incidence seems to have increased in the past 15 years, due to increased awareness and successful identification of the disease with the help of classic laboratory findings.8 Most patients present with a prodrome of fatigue, abdominal pain, nausea, myalgias, polydipsia and sudden increase in body weight. Episodes of hypotension presenting as lightheadedness and dizziness are common. The hypotension usually lasts for several days accompanied by massive extravasation of fluid resulting in oedema and anasarca. During quiescent periods between attacks, patients are usually asymptomatic.

isease and moderately decreased LV systolic function regardless of being treated on IPPV. The mechanism of so-called Re-PE could be due to heart–lung interactions during and after drainage rather than in re-expansion of the lung compressed by an effusion. Administration of inotropic therapy improved the Re-PE symptoms. The haemodynamic observations were facilitated by the routinely performed bedside critical care echocardiography. Keys to understanding the case were the observations of worsening postcapillary pulmonary hypertension and SV decrease after drainage of a significant fluidothorax. The regular Doppler indices of LV filling pressures are fraught with limitations in non-sinus rhythm; however, the transmitral and tissue Doppler parameters demonstrate improved specificity in atrial arrhythmia with a regular ventricular response and with a peripheral pulse deficit (ppd) of up to 10–15 bpm. The high transmitral E of 1.61 m/s may not be useful for confirmation of an elevated LVEDP as a sole parameter due to concomitant significant MR. Deceleration time of early diastolic transmitral flow of 177 ms (figure 2B) was borderline and did not exclude elevated filling pressures with its specificity of about 80%–85%.5 In this case, the heart was constantly paced at 90/min with no ppd and a lateral E/e′ above 12 suggested elevated LVEDP. This was confirmed by the LAP estimate using the CW signal of the MR.5 6

ow of 177 ms (figure 2B) was borderline and did not exclude elevated filling pressures with its specificity of about 80%–85%.5 In this case, the heart was constantly paced at 90/min with no ppd and a lateral E/e′ above 12 suggested elevated LVEDP. This was confirmed by the LAP estimate using the CW signal of the MR.5 6 On Re-PE incidence, Echevarria et al 2 provided an insightful paper where they went through Medline and searched for papers dated from 1950 to January 2008. Of the 233 papers, 13 provided some insight into the existence of Re-PE with a reported incidence of 0%–1%. Mynarek et al 7 found zero occurrence of Re-PE after investigating 711 ultrasound-guided thoracentesis procedures performed on 371 patients. Rozenman et al 8 detailed their experience over an 8-year period where 180 patients who experienced 320 episodes of pneumothorax, and only 3 of 320 cases of Re-PE were diagnosed. All these insightful papers conclude that Re-PE is overall a rare entity. Stawicki et al 9 stated some risk factors of Re-PE as: size of effusion or pneumothorax, duration of collapse, technique used for re-expansion and pulmonary artery pressure changes among others. The British Thoracic Society guidelines advocate for pleural drainage of no more than 1.5 litres.1 Sohara10 has alluded to these being the two major causes of Re-PE: (1) histological pulmonary microvasculature abnormality due to continual lung collapse and (ii) mechanical stress imposed on pulmonary microvasculature by the re-expansion process.

ty guidelines advocate for pleural drainage of no more than 1.5 litres.1 Sohara10 has alluded to these being the two major causes of Re-PE: (1) histological pulmonary microvasculature abnormality due to continual lung collapse and (ii) mechanical stress imposed on pulmonary microvasculature by the re-expansion process. Moving on to evaluate the relationship between cardiac compromise and Re-PE, Chowdhary et al 11 documented a fatal Re-PE in a patient with LV compromise. They postulated that lung re-expansion causes shifts in fluid, and as a result, the oedematous lung impedes ventricular filling in a situation where the LV is compromised. The authors thus suggest that thoracentesis in LV compromise be prudently performed. There is no mention of incorporation of echocardiography to monitor the heart function or preload assessment in light of knowledge of a compromised ventricle when performing a thoracentesis. Thus, a question sneaks into the reported relationship between a ‘non-compliant LV’ and Re-PE which may be reversed with the primary cause known in LV compromise.

ion of echocardiography to monitor the heart function or preload assessment in light of knowledge of a compromised ventricle when performing a thoracentesis. Thus, a question sneaks into the reported relationship between a ‘non-compliant LV’ and Re-PE which may be reversed with the primary cause known in LV compromise. Tan et al 12 studied the haemodynamic traits among patients with pneumothorax and documented an increase in CO after chest tube insertion and alluded to this as a possible indicator to a possible occurrence of Re-PE. Their data, however, do not confer any significant difference. The authors also reported no change in the pulmonary capillary wedge pressure in the patients who developed Re-PE, which is still possible after drainage in obstruction. They thus concluded that the reason for the increase in CO seen here is a topic for further research. To comprehend heart–lung interactions, the effects of modifications in intrathoracic pressure (ITP) and in the volume of the lung on the venous return and on LV ejection are vital.13 Increases in pleural pressure (due to a pleural effusion in this instance) decrease the transmural pressure of the LV, therefore, decreasing LV ejection pressure which will in turn lead to decreased pressures upstream. With thoracocentesis, the pleural pressure decreases, and at constant arterial pressure, the LV ejection pressure increases.14 Also, very negative swings in ITP (eg, negative suction pressure) increase LV afterload which may lead to LV failure and pulmonary oedema particularly if LV systolic function is already compromised.

Gleich syndrome is characterised by recurrent episodes of angioedema, urticaria, pruritus, fever, weight gain, oliguria and eosinophilia. Symptoms occur in cycles of 3–4 weeks and resolve spontaneously. Our patient did not exhibit features of this disease. Treatment Initial evaluation for an infectious aetiology was negative. The patient received several doses of intravenous albumin 25 g along with midodrine. Despite escalating doses of midodrine, the patient continued to have refractory hypotension, requiring intravenous fluid boluses. On further review of the patient’s history and records, the episodes of hypotension appeared to be temporally linked to the infusions of gemcitabine. When the patient did not respond to midodrine, we considered the diagnosis of capillary leak syndrome induced by gemcitabine. The patient was started on methylprednisolone (1 mg/kg), and VEGF levels from peripheral blood were sent. The patient responded quickly to treatment with resolution of hypotensive episodes within 24 hours. The albumin gradually increased to 2.2 g/dL over a period of 2 weeks. VEGF levels were elevated at 707 pg/mL (reference range: 9–86 pg/mL). The patient was treated with high-dose steroids prednisone (1 mg/kg) for a week and then discharged on 10 mg daily. Given the above clinical events gemcitabine was permanently discontinued.

thoracocentesis, the pleural pressure decreases, and at constant arterial pressure, the LV ejection pressure increases.14 Also, very negative swings in ITP (eg, negative suction pressure) increase LV afterload which may lead to LV failure and pulmonary oedema particularly if LV systolic function is already compromised. An important variable to be considered is the difference between spontaneously triggered ventilation modality (in our case PSV) and mandatory mode of mechanical ventilation. In our case, the course of ITPs likely resembled spontaneous ventilation. In a fully mechanically ventilated patient without spontaneous breathing activity, ventilator-generated pressures in inspirium might be theoretically higher, and the impact of pleural fluid removal on the LV transmural pressure might be tapered because of higher mean airway and plateau pressures. In conclusion, Re-PE seems to be a rare finding and might be anticipated in a compromised LV operating at elevated filling pressures, and attention should be paid particularly to large pleural effusions. Regardless of mechanical ventilation, if an elevated LVEDP is found on echocardiography or on invasive monitoring, a decrease of SV and CO might be observed with pleural drainage. This mechanism deserves further attention in the form of a prospective study applying bedside echocardiography in the critically ill with various aetiologies of pleural effusions and modalities of IPPV.

found on echocardiography or on invasive monitoring, a decrease of SV and CO might be observed with pleural drainage. This mechanism deserves further attention in the form of a prospective study applying bedside echocardiography in the critically ill with various aetiologies of pleural effusions and modalities of IPPV. Learning points Re-expansion pulmonary oedema (Re-PE) might be rather a cardiac decompensation in large pleural effusions increasing pleural pressure and decreasing left ventricle (LV) transmural pressure. During drainage, the pleural and intrathoracic pressures decrease and LV afterload increases with a parallel decrease of the LV systolic performance. This happened in a patient with moderately decreased LV systolic function regardless of being treated with intermittent positive pressure ventilation (IPPV). Re-PE could be due to heart–lung interactions during and after pleural drainage. Re-PE seems to be a very rare finding and might be anticipated in a large pleural effusion drained in a patient with compromised LV operating at elevated filling pressures. This mechanism deserves further attention in the form of prospective studies applying bedside echocardiography in patients with various aetiologies of pleural effusions and on different modalities of IPPV.

Re-PE seems to be a very rare finding and might be anticipated in a large pleural effusion drained in a patient with compromised LV operating at elevated filling pressures. This mechanism deserves further attention in the form of prospective studies applying bedside echocardiography in patients with various aetiologies of pleural effusions and on different modalities of IPPV. Contributors: CMM is a postgraduate student in the field of Imaging methods at the 1st Medical Faculty of the Charles University in Prague. MB, CMM’s tutor and Head of the Intensive Care Unit of the Department of Anaesthesia and Intensive Care, General University Hospital in Prague, performed the echocardiographic examination and reviewed the original data. They both contributed to the write up of the manuscript. Funding: The study was supported inpart from projectreg.no. CZ.2.16/3.1.00/21565 from OP Prague Competitiveness. Competing interests: None declared. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.