Steffen Leiz

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.

Potassium channel KIR4.1-specific antibodies in children with acquired demyelinating CNS disease

Objective: A serum antibody against the inward rectifying potassium channel KIR4.1 (KIR4.1-IgG) was recently discovered, which is found in almost half of adult patients with multiple sclerosis. We investigated the prevalence of KIR4.1-IgG in children with acquired demyelinating disease (ADD) of the CNS. We also compared antibody responses to KIR4.1 and myelin oligodendrocyte glycoproteins (MOGs), another potential autoantigen in childhood ADDs. Methods: We measured KIR4.1-IgG by ELISA in children with ADD (n = 47), other neurologic disease (n = 22), and autoimmune disease (n = 22), and in healthy controls (HCs) (n = 18). One hundred six samples were also measured by capture ELISA. Binding of KIR4.1-IgG human subcortical white matter was analyzed by immunofluorescence. Anti-MOG antibodies were measured using a cell-based assay. Results: KIR4.1-IgG titers were significantly higher in children with ADD compared with all control groups by ELISA and capture ELISA (p < 0.0001, p < 0.0001). Overall, 27 of 47 patients with ADD (57.45%) but none of the 62 with other neurologic disease or autoimmune disease or the HCs (0%) were KIR4.1-IgG antibody positive by ELISA. Sera containing KIR4.1-IgG stained glial cells in brain tissue sections. No correlation among KIR4.1-IgG, age, or MOG-IgG was observed in the ADD group. Conclusion: Serum antibodies to KIR4.1 are found in the majority of children with ADD but not in children with other diseases or in HCs. These findings suggest that KIR4.1 is an important target of autoantibodies in childhood ADD.

Pediatric Herpes Simplex Virus Encephalitis A Retrospective Multicenter Experience

Knowledge on pediatric herpes simplex virus encephalitis is limited. Here we summarize 6 neonates and 32 children diagnosed by polymerase chain reaction (n = 37) or serological studies (n = 1), respectively. Diagnosis was difficult, as only 15 patients presented neurologic symptoms. Moreover, cerebrospinal fluid glucose, protein, and leukocytes were normal in 6 patients. Subsequently, all but 2 showed neurologic symptoms. Diffusion-weighted neuroimaging was the most sensitive early imaging method. Despite acyclovir treatment, 8 patients experienced early relapses, showing movement abnormalities, impaired vigilance, and seizures. Diffuse white matter changes, found in 3 of 5 relapse patients on neuroimaging, and a negative cerebrospinal fluid herpes simplex virus polymerase chain reaction suggested inflammatory processes. All relapse patients were again treated with acyclovir, and 3 responded to additional corticosteroid treatment. Whereas outcome after relapses was poor, overall outcome was good. No child died; 14 were asymptomatic at discharge, and neuroimaging remained normal in 7 of 30 patients studied.

Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome

Objective: To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS). Methods: Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study. Results: Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p < 0.0001) and OCB (p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%. Conclusions: Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course.

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.

Impact of Hippotherapy on Gross Motor Function and Quality of Life in Children with Bilateral Cerebral Palsy: A Randomized Open-Label Crossover Study

Abstract This study investigated the effect of hippotherapy on gross motor function (Gross Motor Function Measure [GMFM]‐66, GMFM dimension E and D) and quality of life (Child Health Questionnaire [CHQ 28], KIDSCREEN‐27 parental versions) in children with bilateral spastic cerebral palsy. Seventy‐three children (age: 9.1 ± 3.3 years; male = 44; GMFCS levels II = 27; III = 17; IV = 29) were randomized to an early (n = 35) or late (n = 38) treatment group. Data from 66 probands were available for further analysis. Probands received hippotherapy once to twice weekly during a period of 16 to 20 weeks (mean: 17 treatments) in a crossover approach. Whereas no significant changes were found for total GMFM scores and quality of life parameters, a significant increase in GMFM dimension E was found. Children terminating the study early showed lower mean psychosocial quality of life scores than children who completed the whole study (CHQ‐28 “psychosocial dimension”; KIDSCREEN‐27 “mood and emotional dimension”). Our data are in line with previous reports and suggest that hippotherapy shows distinct therapeutic strengths with regard to promoting upright stand and gait in children with cerebral palsy. Children with higher psychosocial burden of disease may need special support to get access to and benefit from intensified physiotherapy programs.