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Infectious Diseases in Obstetrics and Gynecology 1:285-289 (1994) (C) 1994 Wiley-Liss, Inc. Neurobrucellosis Complicating Pregnancy: A Case Report D. Jay Gloeb, Carla Lupi, and Mary Jo O'Sullivan Department ofObstetrics and Gynecology, Division ofMaternal Fetal Medicine, University ofMiami School ofMedicine Memorial Medical Center, Miami, FL ABSTRACT Background: Brucellosis in humans is an infectious disease which may occur following contact with infected domestic animals or the ingestion of unpasteurized dairy products. It has rarely been described in pregnancy. The diagnosis, neuropsychiatric manifestations, and management ofbrucel- losis in a 3rd-trimester pregnant woman are discussed. Case: A 24-year-old Mexican female, G3P2002 at 30 weeks gestation presented with fever, shaking chills, night sweats, a non-productive cough, weakness, nausea, vomiting, anorexia, and vague, dull, upper abdominal pain as well as neuropsychiatric findings. Extensive evaluation re- vealed serologic and culture evidence ofBrucella infection. Her worsening neuropsychiatric condi- tion necessitated preterm delivery with satisfactory neonatal and improved maternal outcomes. Conclusion: Bacteriologic infection of pregnant women with neuropsychiatric manifestations should prompt a careful investigation, and brucellosis should be considered ifthere is a travel history possibly compatible with contact with domestic animals or the ingestion of unpasteurized dairy products. (C) 1994 Wiley-Liss, Inc. KEY WORDS Antepartum infection, brucellosis, neurobrucellosis rucella infection is caused by a gram-negative coccobacillus (Brucella abortus, B. melitensis, and B. suis) found primarily in domestic animals such as goats, sheep, cattle, and swine. In humans, it is an acute and chronic infection. Prevalence depends on multiple factors including endemicity and exposure to infected domestic animals and to contaminated dairy products.2 While there is dis- cussion in the medical literature about the causative role ofBrucella in human abortion, 1,3--6 brucellosis is rare in pregnancy.

an acute and chronic infection. Prevalence depends on multiple factors including endemicity and exposure to infected domestic animals and to contaminated dairy products.2 While there is dis- cussion in the medical literature about the causative role ofBrucella in human abortion, 1,3--6 brucellosis is rare in pregnancy. Little is known about the psychiatric manifestations and management of pro- tracted Brucella infection unresponsive to therapies other than tetracycline. We report a case ofa woman in the 3rd trimester whose acute central nervous system (CNS) symp- toms were the first manifestation of brucellosis and whose psychiatric complications were significant enough to warrant preterm delivery to institute definitive tetracycline therapy. CASE REPORT A 24-year-old Mexican female, G3P2002 at 30 weeks gestation presented to the obstetric emer- gency room at Jackson Memorial Hospital, Mi- ami, FL, complaining offever, shaking chills, and night sweats for 2 days. She had a non-productive cough, weakness, nausea, vomiting, anorexia, and vague, dull, upper abdominal pain for 3-5 days. She had had 2 term, uncomplicated spontaneous vaginal deliveries. There was no significant medi- cal or surgical history. The family history was sig- nificant for a sister-in-law who died of hepatitis 5 months prior to the patient's admission. The patient Address correspondence/reprint requests to Dr. D. Jay Gloeb, Perinatal Associates of Northern California, 5301 F Street, Suite 110, Sacramento, CA 95819. Obstetrics Case Report Received September 3, 1993 Accepted April 7, 1994 NEUROBRUCELLOSIS COMPLICATING PREGNANCY GLOEB ET AL. had immigrated from Mexico City via Texas month prior to being hospitalized. Other than a complaint of mental confusion during the month prior to admission, there was no history of any neurologic or psychiatric condition. The only med- ications she had been taking were prenatal vitamins and an iron supplement. On admission, she was alert and oriented. Her blood pressure was 98/62 mm Hg, pulse 88/min and regular, respirations 24/min and regular, and temperature 38.9C. The relevant physical find- ings included diaphoresis, pale conjunctivae, and anicteric sclerae. The abdomen was soft with mild tenderness in the right upper quadrant; no palpable hepatosplenomegaly was noted. The fundal height was 27 cm with a normal fetal heart rate. There was no focal neurological finding or palpable lymphad- enopathy.

l find- ings included diaphoresis, pale conjunctivae, and anicteric sclerae. The abdomen was soft with mild tenderness in the right upper quadrant; no palpable hepatosplenomegaly was noted. The fundal height was 27 cm with a normal fetal heart rate. There was no focal neurological finding or palpable lymphad- enopathy. The initial laboratory studies revealed a hemoglobin of 8.3 gm/dl, hematocrit 24%, and a white blood cell (WBC) count of 23,000/mm3. There were 48% bands, 29% lymphocytes, 20% polymorphonuclear cells, 2% mononuclear cells, and 1% basophils. The platelet count was 145,000/ mm3 and the sickle cell preparation was negative. The serum B12 was 732 pg/ml and the serum folate was 4.2 pg/ml. The serum sodium was 128 meq/1, potassium 2.9 meq/1, chloride 94 meq/1, carbon dioxide 17 meq/1, glucose 91 mg/dl, blood urea nitrogen 3 mg/dl, and creatinine 0.4 mg/dl. The bilirubin and liver enzymes were within normal limits. A urinalysis revealed moderate ketones. A chest X-ray demonstrated mild perihilar and peri- bronchial thickening. She was given intravenous (IV) fluids to bring her electrolyte levels to normal. Following admission, she was noted to have mild hepatosplenomegaly on abdominal ultrasonography, and hyperplasia and megaloblastic changes were noted on a bone marrow biopsy performed because of leukopenia. Special stains and cultures for acid- fast bacilli and fungi were negative. Skin tests for mumps, Candida, and tuberculosis were negative. Rheumatoid factor, antinuclear antibody test, and serum rapid plasma reagin test were all negative; C3 was 102 mg/dl and C4 was 26 mg/dl (normal, 3rd trimester: C3 165 +-- 4, C4 37 +-- 2). Induced sputum was negative on both direct and concen- trated smears for acid-fast bacilli. On the 3rd hospital day, she became delirious, was oriented to person only, and had gross hand tremors. Her blood pressure was 130/70 mm Hg, pulse 128/min, and respirations 28/min. The fetal heart tones were 184/min. Her temperature re- mained elevated with a maximum reading of 40.1C. Arterial blood gases on room air revealed a mild respiratory alkalosis with normal oxygen satu- ration. The delirium persisted. She became com- bative, disoriented, and uncooperative. Her physi- cal examination was unchanged. A computerized tomographic study of the brain with and without contrast was normal. A lumbar puncture revealed no significant ab- normalities with normal protein electrophoretic studies.

tu- ration. The delirium persisted. She became com- bative, disoriented, and uncooperative. Her physi- cal examination was unchanged. A computerized tomographic study of the brain with and without contrast was normal. A lumbar puncture revealed no significant ab- normalities with normal protein electrophoretic studies. Gram's, acid-fast bacilli, and India ink stains, cryptococcal antigen, and cerebrospinal fluid (CSF) culture were all negative. The CSF Venereal Disease Research Laboratory test was non-reactive. Blood studies for acute and chronic hepatitis A and B, mononucleosis, and human immunodeficiency virus as well as thin and thick smears for malaria were all negative. Urine and multiple blood cul- tures as well as stool for ova and parasites were all negative. Since no studies were diagnostic, she was empir- ically started on IV ampicillin and trimethoprim- sulfamethoxazole for possible typhoid fever or list- eriosis. Peripheral hyperalimentation was started because of reduced food intake and intermittent nausea and vomiting. Additional serum was col- lected for herpesvirus, arboviruses, and leptospiro- sis The herpesvirus titer was found to be 1:32, while titers for Eastern, St. Louis, and Denque viruses and leptospirosis were all negative. A sub- sequent herpesvirus titer measured 1:64 and all other convalescent titers were negative. After day of antibiotic therapy, she became afebrile, but continued to experience periods of confusion, lethargy, agitation, combativeness, de- pression with paranoid features, and intermittent auditory hallucinations through hospital day 7. On hospital day 8 (4th day of antibiotic ther- apy), the fever recurred. A febrile agglutinin panel revealed a serum Brucella titer of 1:320. The IV ampicillin was discontinued and the IV tri- methoprim-sulfamethoxazole dose was increased based on the trimethoprim component, i.e., 400- 500 mg/day (10-15 mg/kg/day in divided doses).7 A repeat serum Brucella titer 6 days later (hospi- tal day 14) was 1:640. A blood culture previously obtained on hospital day 4 grew Brucella, species unidentified. 286 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY NEUROBRUCELLOSIS COMPLICATING PREGNANCY GLOEB ET AL. After 12 days of IV trimethoprim-sulfamethox- azole, she remained agitated with persistent gross tremors of the hands, continually paced the room, and was noted to be experiencing auditory halluci- nations and occasional confusion. An electroenceph- alogram performed on hospital day 23 was nega- tive.

ANCY GLOEB ET AL. After 12 days of IV trimethoprim-sulfamethox- azole, she remained agitated with persistent gross tremors of the hands, continually paced the room, and was noted to be experiencing auditory halluci- nations and occasional confusion. An electroenceph- alogram performed on hospital day 23 was nega- tive. Her altered mental status continued, waxing and waning in severity despite multiple antipsy- chotic agents including haloperidol, thioridazine hydrochloride, mesoridazine besylate, and chlor- promazine hydrochloride. A repeat computerized tomographic study of the brain and lumbar punc- ture was normal. It became obvious that the patient's persistent and significant neuropsychiatric manifestations, now felt to be secondary to Brucella infection, were not responding to the IV trimethoprim-sul- famethoxazole. All fetal surveillance studies were normal with good interval growth. Since she was not improving and tetracycline would be more de- finitive therapy, an amniocentesis for lecithin/ sphingomyelin ratio was performed at 34 weeks gestation (hospital day 27). The ratio was 1.9; there- fore, week later, following an induction, she spontaneously delivered a 2,950 g female neonate with Apgar scores of 7, 8, and 9 at 1, 5, and 10 min, respectively. The patient was immediately started on tetracycline, 500 mg q 6 h. NEUROLOGICAL ASSESSMENT A neurological assessment was conducted prior to delivery after the neuroleptic agents and IV tri- methoprim-sulfamethoxazole had been discontin- ued for 3 days. She was alert and oriented. Her speech was fluent, and repetition and naming were intact. Calculations were performed correctly, as were right and left discriminatory tasks. Short- term memory tasks at 5 min revealed a recall of of 3 objects. Long-term memory was poor. A cranial nerve examination was remarkable for bilateral hor- izontal end-gaze and vertical nystagmoid move- ments. Normal optokinetic movements were present. A motor examination was significant for diffuse marked increased tone with cogwheel rigid- ity at the wrists. Bilateral symmetric hyperreflexia with bilateral ankle clonus and a brisk jaw-jerk were present. Strength in all muscle groups was present. Bradykinesia was prominent. Frontal-re- lease signs, snout, grasp, and palmar-mental re- flexes were present. Coordination was intact with normal finger-to-nose, heel-to-shin, and rapid al- ternating movements. The patient's gait was re- markable for a stooped posture and retropulsion.

in all muscle groups was present. Bradykinesia was prominent. Frontal-re- lease signs, snout, grasp, and palmar-mental re- flexes were present. Coordination was intact with normal finger-to-nose, heel-to-shin, and rapid al- ternating movements. The patient's gait was re- markable for a stooped posture and retropulsion. Some of these findings were extrapyramidal signs attributed to the neuroleptic therapy. On postpartum day 4 (day 42 of hospitalization and 4th day of tetracycline therapy), her mental status was remarkable for a muted affect and evi- dence of depression, though her concentration and memory were improved. She denied auditory hal- lucinations or paranoid delusions. A cranial nerve examination was significant for ocular ataxia and a tremulous tongue. Motor testing revealed persis- tent bradykinesia, cogwheel rigidity, and a festinat- ing gait. On hospital day 45, the patient was transferred to the neurology service where all the neuroleptics were discontinued. On hospital day 50, her behav- ior was still bizarre and combative with unexpected outbursts. Chlorpromazine hydrochloride, 10 mg, was restarted and she again partially responded. She was discharged home 2 days later. On that day, assessment on the Mattis Dementia Scale and the Boston Naming Scale (word retrieval) showed mild and moderate impairment, respectively. Her dis- charge medications included chlorpromazine hy- drochloride, 25 mg bid; diphenhydramine hydro- chloride, 25 mg bid; benztropine mesylate, 2 mg q 8 h prn; tetracycline, 500 mg q 6 h; multivitamins; and an iron supplement. A follow-up neurologic examination 2 weeks after discharge revealed only increased deep-tendon reflexes. DISCUSSION Brucellosis can involve the CNS in a variety of forms including meningoencephalitis, subarachnoid hemorrhage, meningomyelitis, and neuritis. 8'9 Initially, our patient demonstrated many of the systemic manifestations of classic acute Brucella in- fection1 including fever, chills, sweating, gener- alized weakness, anorexia, and a non-productive cough. Brucella endotoxin "contributes significantly to the pathogenesis ofillness in brucellosis."11 Leu- kopenia, anemia, thrombocytopenia, mildly ele- vated liver function tests and total and direct bilir- ubin, fever, abdominal tenderness, splenomegaly, and bone marrow granulomas are all found with varying frequency in the acute phase of brucello- sis.

significantly to the pathogenesis ofillness in brucellosis."11 Leu- kopenia, anemia, thrombocytopenia, mildly ele- vated liver function tests and total and direct bilir- ubin, fever, abdominal tenderness, splenomegaly, and bone marrow granulomas are all found with varying frequency in the acute phase of brucello- sis. 10 In our case, in addition to serologic evidence, INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 287 NEUROBRUCELLOSIS COMPLICATING PREGNANCY GLOEB ET AL. acute Brucella was conclusively diagnosed by cul- ture, though it was never full speciated. The his- tory of eating unpasteurized goat's cheese in Mex- ico (previously reported as a cause of brucellosis12) elicited from the patient after she delivered as well as her marked clinical response to the appropriate antibiotic in the absence of any previous mental condition was corroborating evidence of neurobru- cellosis. Effective standard antibiotic therapy for acute or subacute brucellosis in the past has been a combination oftetracycline and streptomycin.7' 10,13 Presently, the preferred chemotherapy in adults is doxycycline and rifampin.7 It was unclear whether the patient's condition represented CNS involvement (primary neurobru- cellosis) or the toxic systemic effects of Brucella endotoxin (secondary neurobrucellosis). Her altered mental status may have been partially worsened by the neuroleptics she received. Her cranial nerve, motor, reflex, and gait dysfunction may have been secondary to the antipsychotic agents causing a par- kinsonian syndrome and akathisia14 and, finally, the CNS reacts to sulfonamides causing headache, depression, and hallucinations, is Neuropsychiatric symptoms occur in approxi- mately two-thirds ofthose with brucellosis, whereas in less than 10% evidence ofCNS Brucella invasion can be found. 1 Spinal fluid findings consistent with brucellosis include pleocytosis, elevated pro- tein, and increased immunoglobulin concentration. The symptoms are attributed to the irritable effects of Brucella toxins on the nervous system.9 Neu- ropsychiatric symptoms include delusions of perse- cution, psychosis, depression, and irritability. 16,17 In the non-pregnant patient, CNS brucellosis has a variable onset relative to the time of infec- tion. 8 There is a wide spectrum of clinical disease from acute to chronic with minimal, local disease, or massive, widespread CNS disease. Brucellosis may be progressive, episodic, or transient.

on, and irritability. 16,17 In the non-pregnant patient, CNS brucellosis has a variable onset relative to the time of infec- tion. 8 There is a wide spectrum of clinical disease from acute to chronic with minimal, local disease, or massive, widespread CNS disease. Brucellosis may be progressive, episodic, or transient. Neuro- logical complications can occur at the beginning of the disease, but often occur after a few febrile epi- sodes, during convalescence, or long after the ill- ness. 8 In pregnancy, effective intervention with tetracycline must be weighed against the risks to the fetus of bone growth retardation, dental enamel staining and hypoplasia, and maternal hepatic and pancreatic dysfunction. 18-20 While rare, neurobru- cellosis should be considered in the differential di- agnoses ofneurological disorders occurring inpreg- nancy. This case is unique because the neuro- psychiatric manifestations ofthe infection prompted preterm delivery for definitive antibiotic therapy and, fortunately, in the 3rd trimester when fetal pulmonary maturity was possible. Under less fa- vorable circumstances, the risks of tetracycline and the failure of alternative therapy would have to be weighed against the risks of severe, prolonged ma- ternal neurologic and psychiatric deterioration. REFERENCES 1. Sarram M, Feiz J, Foruzandeh M, Gazanfarpour P: Intrauterine fetal infection with Brucella melitensis as a possible cause of second-trimester abortion. Am J Obstet Gynecol 119:657-660, 1974. 2. How does Brucella abortus infect human beings? Lancet 2:1180, 1983. 3. Fernihough TJ, Munoz WP, Mahadeyo I: The role of Brucella abortus in spontaneous abortion among the black population. S Afr Med J 68:379-380, 1985. 4. Porreco RP, Haverkamp AD: Brucellosis in pregnancy. Obstet Gynecol 44:597-602, 1974. 5. Veiga G: Brucelose no aparelho genital feminino. Matern Infanc (Sao Paolo) 33:235-270, 1974. 6. Goobar J, Blank B: La brucelosis cronica en los proble- mas gineco-obstetricos. Obstet Ginecol Lat Am 22:283- 294, 1964. 7. Hall WH: Modern chemotherapy for brucellosis in hu- mans. Rev Infect Dis 12:1060-1099, 1990. 8. Fincham RW, Sahs AL, Joynt RJ: Protean manifesta- tions of nervous system brucellosis. Case histories of a wide variety ofclinical forms. JAMA 184:97-103, 1963. 9. Abramsky O: Neurological features as presenting mani- festations ofbrucellosis. Eur Neurol 15:281-284, 1977. 10. Spink WW: The Nature of Brucellosis. Minneapolis: University of Minnesota Press, 1956. 11.

a- tions of nervous system brucellosis. Case histories of a wide variety ofclinical forms. JAMA 184:97-103, 1963. 9. Abramsky O: Neurological features as presenting mani- festations ofbrucellosis. Eur Neurol 15:281-284, 1977. 10. Spink WW: The Nature of Brucellosis. Minneapolis: University of Minnesota Press, 1956. 11. Abernathy RS, Spink WW: Studies with brucella endo- toxin in humans: The significance of susceptibility to en- dotoxin in the pathogenesis of brucellosis. J Clin Invest 37:219-231, 1958. 12. Eckman MR: Brucellosis linked to Mexican cheese. JAMA 232:636-637, 1975. 13. Spink WW: Current status of therapy of brucellosis in human beings. JAMA 172:697-698, 1960. 14. Baldessarini RJ: Drugs and the treatment of psychiatric disorders. In Goodman Gilman A, Goodman LS, Rail TW, Murad F (eds): The Pharmacological Basis ofTher- apeutics. 7th Ed. New York: Macmillan, pp 402-408, 1985. 15. Mandell GL, Sande MA: Animicrobial agents. In Good- man Gilman A, Goodman LS, Rail TW, Murad F (eds): The Pharmacological Basis ofTherapeutics. 7th Ed. New York: Macmillan, p 1106, 1985. 16. Hobbs FB: A case of Brucella abortus infection. Lancet 2:683-685, 1931. 17. Leys DG: Abortus fever. Br MedJ 1:187-189, 1943. 288 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY NEUROBRUCELLOSIS COMPLICATING PREGNANCY GLOEB ET AL. 18. Whalley PJ, Adams RH, Combes B: Tetracycline toxic- ity in pregnancy. Liver and pancreatic dysfunction. JAMA 189:357-362, 1964. 19. Demers P, Fraser D, Goldbloom RB, et al.: Effects of tetracyclines on skeletal growth and dentition: A report by the Nutrition Committee ofthe Canadian Paediatric Soci- ety. Can Med Assoc J 99:849-854, 1968. 20. Brearley LJ, Stragis AA, Storey E: Tetracycline-induced tooth changes. I. Prevalence in pre-school children. Med J Aust 55:653-658, 1968. INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 289