Michael Karenfort

Anti–Myelin Oligodendrocyte Glycoprotein Antibodies in Pediatric Patients With Optic Neuritis

OBJECTIVE To study the humoral immune response directed at myelin oligodendrocyte glycoprotein (MOG)in pediatric patients with isolated and recurrent optic neuritis(ON). DESIGN Observational prospective case series. SETTING Six pediatric hospitals in Germany and Austria. PATIENTS Thirty-seven patients 18 years or younger with single or recurrent episodes of ON were recruited from 6 different hospitals. MAIN OUTCOME MEASURES Clinical features, magnetic resonance imaging findings, intrathecal IgG synthesis,and outcome were recorded. A live cell–based immunofluorescence assay was used to measure serum IgG antibodies to MOG and aquaporin 4. RESULTS A single episode of ON was observed in 10 patients,and 15 experienced 2 to 12 episodes. The acute episode of ON was part of a clinically isolated syndrome in 12 patients, of whom 8 were subsequently classified as having multiple sclerosis. High-titer serum MOG-IgG antibodies (1:160) were detected in 17 patients (46%).In addition, high titers of MOG-IgG antibodies were more frequently observed in 12 of the 15 patients with recurrent episodes of ON (80%; median titer, 1:640)compared with 2 of the 10 patients with monophasic ON(20%; median titer, 0) and 3 of the 12 patients with ON as part of a clinically isolated syndrome (25%; median titer, 0). CONCLUSION High-titer MOG-IgG antibodies are predominantly detected in pediatric patients with recurrent ON, indicating that anti-MOG-specific antibodies may exert a direct role in the pathogenesis of ON in this subgroup.

Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein

Background Myelin oligodendrocyte glycoprotein (MOG) antibodies have been recently described in children with acute disseminating encephalomyelitis (ADEM), but the clinical and neuroradiological characterisation of this subgroup is lacking. Objective To compare the clinical and neuroradiological features of paediatric ADEM with and without MOG antibodies. Methods Clinical course, cerebrospinal fluid (CSF)-, MRI studies, outcome and MOG status of 33 paediatric ADEM prospectively studied were reviewed. Results MOG antibodies (median 1:2560; range 1:160–1:20 480) were detected in 19 children with ADEM. The majority of children showed a decline of serum MOG-IgG titres over time. Children with MOG antibodies did not differ in their age at presentation, sex ratio, the presence of oligoclonal bands, clinical symptoms or initial severity, apart from a higher CSF cell count (p=0.038), compared with children without MOG antibodies. In addition, further relapsing demyelinating episodes associated with MOG antibodies were observed only in children with MOG antibodies. All 19 children with MOG antibodies had a uniform MRI pattern, characterised by large, hazy and bilateral lesions and the absence of atypical MRI features (eg, mainly small lesions, well-defined lesions), which was significantly different compared to that of children without MOG antibodies (p=0.003; and p=0.032, respectively). In addition, children with MOG antibodies had involvement of more anatomical areas (p=0.035) including the myelon characterised by a longitudinally extensive transverse myelitis (p=0.003), more often a complete resolution of lesions (p=0.036) and a better outcome (p=0.038). Conclusions Patients with ADEM with MOG antibodies in our cohort had a uniform MRI characterised by large, bilateral and widespread lesions with an increased frequency of longitudinal extensive transverse myelitis and a favourable clinical outcome in contrast to children lacking MOG antibodies.

Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients

Background: Some pediatric patients with inflammatory demyelinating central nervous system disorders cannot be classified under any of the established disease entities, making their treatment and prognosis difficult. Objective: The objective of this study is to characterize a subgroup of pediatric patients with recurrent demyelinating central nervous system disorders. Methods: This study includes a case series of pediatric patients with monophasic or recurrent acute disseminated encephalomyelitis (ADEM) who later presented with either monophasic or recurrent optic neuritis (ON). Results: We describe seven patients with a median follow-up of six years (five females, two males) who presented at a median age of 6 years (range 4–8 years) with monophasic (n = 4) or recurrent ADEM (two to four attacks) followed by monophasic (n = 3) or recurrent ON (two to nine attacks). Cranial magnetic resonance imaging (MRI) was typical for ADEM (n = 6) with complete or almost complete resolution of lesions on follow-up. Cerebrospinal (CSF) studies at the time of ADEM showed a pleocytosis in six patients and were negative for oligoclonal bands (OCBs) in all. In all patients high titers for serum anti-MOG antibodies were detected. Conclusion: ADEM followed by ON is a rare but distinct clinical phenotype among pediatric patients. Further studies are needed to allow recommendations on treatment or prognosis.

Children with multiphasic disseminated encephalomyelitis and antibodies to the myelin oligodendrocyte glycoprotein (MOG): Extending the spectrum of MOG antibody positive diseases

Background: Myelin oligodendrocyte glycoprotein (MOG) antibodies have been described in children with acute disseminated encephalomyelitis (ADEM), recurrent optic neuritis, neuromyelitis optica spectrum disorders and more recently in children with multiphasic disseminated encephalomyelitis (MDEM). Objective: To delineate the clinical, cerebrospinal fluid (CSF) and radiological features of paediatric MDEM with MOG antibodies. Methods: Clinical course, serum antibodies, CSF, magnetic resonance imaging (MRI) studies and outcome of paediatric MDEM patients were reviewed. Results: A total of 8 children with two or more episodes of ADEM were identified from a cohort of 295 children with acute demyelinating events. All children had persisting MOG antibodies (median titre: 1:1280). All ADEM episodes included encephalopathy, polyfocal neurological signs and a typical MRI. Apart from ADEM episodes, three children had further clinical attacks without encephalopathy. Median age at initial presentation was 3 years (range: 1–7 years) and median follow-up 4 years (range: 1–8 years). New ADEM episodes were associated with new neurological signs and new MRI lesions. Clinical outcome did range from normal (four of the eight) to mild or moderate impairment (four of the eight). A total of four children received monthly immunoglobulin treatment during the disease course. Conclusion: Children with MDEM and persisting MOG antibodies constitute a distinct entity of relapsing demyelinating events and extend the spectrum of MOG antibody–associated diseases.

Natalizumab Therapy for Highly Active Pediatric Multiple Sclerosis

IMPORTANCE Given the high frequency of failure of first-line therapies, there is an urgent need for second-line treatment strategies for pediatric patients with multiple sclerosis (MS). OBJECTIVE To report the use of natalizumab in pediatric MS. Natalizumab, a humanized monoclonal antibody targeting α4 integrin, is effective against active relapsing-remitting MS in adults. DESIGN Retrospective study. SETTING Eleven centers for neurology and pediatric neurology in Germany and Austria. PARTICIPANTS A total of 20 pediatric patients with MS who started treatment with natalizumab prior to 18 years of age. These patients underwent magnetic resonance imaging as clinically indicated, despite the fact that 19 of these 20 patients were undergoing first-line disease-modifying therapy. The mean (SD) age at initiation of natalizumab therapy was 16.7 (1.1) years, and the mean (SD) pretreatment period was 18 (10) months. INTERVENTION Natalizumab, 300 mg every 4 weeks. MAIN OUTCOME MEASURES Annualized relapse rates, Expanded Disability Status Scale scores, number of new T2/fluid-attenuated inversion recovery lesions and contrast-enhancing lesions on magnetic resonance imaging, number of adverse events, the prevalence of neutralizing antibodies against natalizumab, and serum JC virus-antibody status. RESULTS Treatment with natalizumab was associated with reductions in mean annualized relapse rates (3.7 without treatment vs 0.4 with treatment; P < .001), median Expanded Disability Status Scale scores (2 without treatment vs 1 with treatment; P < .02), and mean number of new T2/fluid-attenuated inversion recovery lesions per year (7.8 without treatment vs 0.5 with treatment; P < .001). Two patients developed high-titer neutralizing antibodies against natalizumab and had to stop therapy. Adverse events included headaches, asthenia, infections, and hypersensitivity. Abnormal laboratory results were found for 8 patients. JC virus antibodies were found in 5 of 13 patients. After the discontinuation of natalizumab therapy, relapse activity occurred in 6 of 8 patients within 6 months. CONCLUSIONS AND RELEVANCE Our data indicate that natalizumab may be safe and effective against MS in pediatric patients with breakthrough disease.

Evaluation of the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome

Background: Magnetic resonance imaging diagnostic criteria for paediatric multiple sclerosis have been established on the basis of brain imaging findings alone. The 2010 McDonald criteria for the diagnosis of multiple sclerosis, however, include spinal cord imaging for detection of lesion dissemination in space. The new criteria have been recommended in paediatric multiple sclerosis. Objective: (1) To evaluate the 2010 McDonald multiple sclerosis criteria in children with a clinically isolated syndrome and to compare them with recently proposed magnetic resonance criteria for children; (2) to assess whether the inclusion of spinal cord imaging provided additional value to the 2010 McDonald criteria. Methods: We performed a retrospective analysis of brain and spinal cord magnetic resonance imaging scans from 52 children with a clinically isolated syndrome. Sensitivity, specificity and accuracy of the magnetic resonance criteria were assessed. Results and conclusion: The 2010 McDonald dissemination in space criteria were more sensitive (85% versus 74%) but less specific (80% versus 100%) compared to the 2005 McDonald criteria. The Callen criteria were more accurate (89%) compared to the 2010 McDonald (85%), the 2005 McDonald criteria for dissemination in space (81%), the KIDMUS criteria (46%) and the Canadian Pediatric Demyelinating Disease Network criteria (76%). The 2010 McDonald criteria for dissemination in time were more accurate (93%) than the dissemination in space criteria (85%). Inclusion of the spinal cord did not increase the accuracy of the McDonald criteria.

Oligoclonal bands predict multiple sclerosis in children with optic neuritis

We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow‐up of 4.0 years. Multiple Cox proportional‐hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.39–10.39, p < 0.001), presence of cerebrospinal fluid immunoglobulin G oligoclonal bands (OCB; HR = 3.69, 95% CI = 2.32–5.86, p < 0.001), and age (HR = 1.08 per year of age, 95% CI = 1.02–1.13, p = 0.003) as independent predictors of conversion, whereas sex and laterality (unilateral vs bilateral) had no influence. Combined cMRI and OCB positivity indicated a 26.84‐fold higher HR for developing MS compared to double negativity (95% CI = 12.26−58.74, p < 0.001). Accordingly, cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON. Ann Neurol 2015;77:1076–1082

Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.

Objective To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. Methods Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays. Results 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). Conclusions 67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.

Rituximab as a highly effective treatment in a female adolescent with severe multiple sclerosis

Michael Karenfort MD, Bernd C Kieseier MD, Daniel Tibussek MD, Birgit Assmann MD, Joerg Schaper MD, Ertan Mayatepek MD 1 Department of General Pediatrics, Heinrich-Heine-University, D sseldorf, Germany. 2 Department of Neurology, Heinrich-Heine-University, D sseldorf, Germany. 3 Department of Diagnostic Radiology, Heinrich-Heine-University, D sseldorf, Germany. Correspondence to: michael.karenfort@med.uni-duesseldorf.de

Antiepileptic Drugs and Bone Metabolism in Children: Data from 128 Patients

There are conflicting results concerning bone metabolism in children receiving antiepileptic medication, with data concentrating on neurologically impaired patients. We performed a multicenter cross-sectional study in otherwise healthy children who received monotherapy with valproic acid, oxcarbazepine, lamotrigine, sulthiame, levetiracetam, or topiramate for at least 6 months. Data on calcium, phosphorus, alkaline phosphatase, 25-OH vitamin D, and parathormone were collected. Among 128 patients, 24.4% had hypocalcemia, 25.4% hypophosphatemia, and 13.3% (n = 17) 25-OH vitamin D levels <10 ng/mL. All patients were clinically asymptomatic. Mean calcium concentrations were found to be significantly lower among the study population (2.41 mmol/L) compared with healthy controls (2.53 mmol/L). Lowest mean concentration was observed in patients treated with sulthiame followed by oxcarbazepine and valproic acid. No influence of calcium intake or therapy on bone metabolism was noted. Effects on bone metabolism of anticonvulsive monotherapy are not restricted to neurologically impaired children but also affect otherwise healthy children.