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The utility of brain biopsy in pediatric cryptogenic neurological disease. OBJECTIVE: The authors' aim was to characterize a single-center experience of brain biopsy in pediatric cryptogenic neurological disease. METHODS: The authors performed a retrospective review of consecutive brain biopsies at a tertiary pediatric neurosciences unit between 1997 and 2017. Children < 18 years undergoing biopsy for neurological pathology were included. Those with presumed neoplasms and biopsy performed in the context of epilepsy surgery were excluded. RESULTS: Forty-nine biopsies in 47 patients (25 females, mean age ± SD 9.0 ± 5.3 years) were performed during the study period. The most common presenting symptoms were focal neurological deficit (28.6%) and focal seizure (26.5%). Histopathological, microbiological, and genetic analyses of biopsy material were contributory to the diagnosis in 34 cases (69.4%). Children presenting with focal seizures or with diffuse (> 3 lesions) brain involvement on MRI were more likely to yield a diagnosis at biopsy (OR 3.07 and 2.4, respectively). Twelve patients were immunocompromised and were more likely to yield a diagnosis at biopsy (OR 6.7). Surgery was accompanied by severe complications in 1 patient. The most common final diagnoses were infective (16/49, 32.7%), followed by chronic inflammatory processes (10/49, 20.4%) and occult neoplastic disease (9/49, 18.4%). In 38 cases (77.6%), biopsy was considered to have altered clinical management. CONCLUSIONS: Brain biopsy for cryptogenic neurological disease in children was contributory to the diagnosis in 69.4% of cases and changed clinical management in 77.6%. Biopsy most commonly revealed underlying infective processes, chronic inflammatory changes, or occult neoplastic disease. Although generally safe, the risk of severe complications may be higher in immunocompromised and myelosuppressed children.