PracticeUpdate: Neurology - Winter 2018

EDITOR’S PICKS 7

The Diagnostic Dilemma of Traumatic Lumbar

CNS-LCH: Common Hematopoietic Origin For LCH-Associated Neurodegeneration and Mass Lesions Take-home message • Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm associated with BRAFV600E mutation. CNS involvement (CNS-LCH) presents as intraparenchymal brain lesions or a poorly understood neurodegenera- tive disorder (LCH-ND). Here, McClain and colleagues identify osteopontin as a disease-specific CSF biomarker of CNS-LCH. BRAFV6003 detection in peripheral blood mononuclear cells was associated with an increased risk of LCH-ND (sensitivity 0.59; specificity 0.86). Of 4 CNS-LCH patients treated with BRAFV600E inhibitors, 3 had a complete or partial clinical response. • The data suggest a direct role of BRAFV600E-mutated myeloid neoplastic cells in LCH-ND, rather than paraneo- plasia, and suggest that BRAFV600E inhibition may result in clinical improvement in patients with CNS-LCH. Abstract BACKGROUND Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neu- rodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define themechanisms of pathogenesis that drive CNS-LCH. METHODS Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhib- itor was evaluated in 4 patients with progressive disease. RESULTS Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infil- tration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION In LCH-ND patients, BRAFV600E+ cells in PBMCs and infil- trating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoi- etic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK sig- naling may be effective for LCH-ND. CNS Langerhans Cell Histiocytosis: Common Hematopoietic Origin For LCH-Associated Neurodegeneration and Mass Lesions. Cancer 2018 Jun 15;124(12)2607-2620, KL McClain, J Picarsic, R Chakraborty, et al. www.practiceupdate.com/c/70898 Cancer

Puncture Journal of Child Neurology

Take-home message • Meningitis is more common in the first months of life than at any other age, and thus lumbar puncture is an important part of the evaluation of the febrile infant. As many as one-third of infants can have traumatic taps, which limits the diagnostic certainty of CSF interpretation. Studies in adults have sought to use biomarkers such as CSF procalcitonin and lactate to help evaluate for meningitis in complicated scenarios such as post neurosurgery. The authors of this prospective cohort study evaluated these biomarkers in 252 infants aged 3 to 90 days old with meningitis and a traumatic tap seen in their ER over a 4-year period. CSF procalcitonin, lactate, and CSF:serum lactate ratio were more efficient at diagnosing meningitis than uncorrected or corrected CSF WBC count. • These data may be very helpful in a practical way for pedi- atric neurologists. Sarah Matteson Kranick MD Abstract OBJECTIVE To assess the diagnostic efficiency of cerebrospinal fluid mark- ers of procalcitonin, lactate, and cerebrospinal fluid/serum lactate ratio for detecting bacterial meningitis during traumatic lumbar puncture, and to compare these markers with routinely used uncorrected and corrected leukocyte measurements. METHODS Infants aged ≤90 days with traumatic lumbar puncture were pro- spectively studied. The diagnostic characteristics of cerebrospinal fluid assays of uncorrected and corrected leukocyte count, procalcitonin, lac- tate, and lactate ratio were described and compared. RESULTS Considering the area under the curve (95% CI) analysis and stand- ard cutoff values, the lactate-ratio (0.985 [0.964-0.989] at cutoff 1.2) had the best test indexes for identifying meningitis, followed by lactate (0.964 [0.945-0.984] at cutoff 2.2 mmol/L) and procalcitonin (0.939 [0.891-0.986] at cutoff 0.33 ng/mL) measurement, whereas the corrected total leukocyte count assay (0.906 [0.850-0.962] at cutoff 350 cells/mm 3 ) had diagnos- tic properties moderately superior to uncorrected total leukocyte count measurement (0.870 [0.798-0.943] at cutoff 430 cells/mm 3 ). CONCLUSION Cerebrospinal fluid levels of procalcitonin, lactate, and lactate-ratio are reliable markers to diagnose bacterial meningitis in blood-contaminated cerebrospinal fluid. The Diagnostic Dilemma of Traumatic Lumbar Puncture: Current Stand- ing of Cerebrospinal Fluid Leukocyte Corrections and Our Experience With Cerebrospinal Fluid Biomarkers. J Child Neurol 2018 Jun 01;33(7)441- 448, M Nazir, WA Wani, K Kawoosa, et al. www.practiceupdate.com/c/69190 " CSF procalcitonin, lactate, and CSF:serum lactate ratio were more efficient at diagnosing meningitis than uncorrected or corrected CSFWBC count. "

VOL. 3 • NO. 3 • 2018