Toe Walking as the Initial Symptom of a Spinocerebellar Ataxia 13 in a Patient Presenting with a Mutation in the KCNC3 Gene

This article at hand described a 4-year-old patient who initially presented with the symptoms of toe walking. As part of the diagnostic process, the patient was genetically tested to find the cause of the gait anomaly. The genetic test found a mutation in the KCNC3 gene. The variant c.1268G > A; p.Arg423His was found in a heterozygotic state. This variant is frequently described as a cause for spinocerebellar ataxia type 13 (SCA13) in the literature. Apart from toe walking as the most pronounced symptom, the patient displayed an instable gait with frequent falls and delayed speech development. The genetic test to determine the cause of the gait anomaly successfully diagnosed the patient with a previously undiscovered SCA13 and subsequently enabled the recommendation of personalized further treatment

Tolerogenic vaccines for Multiple Sclerosis

Tolerogenic vaccines represent a new class of vaccine designed to re-establish immunological tolerance, restore immune homeostasis, and thereby reverse autoimmune disease. Tolerogenic vaccines induce long-term, antigen-specific, inhibitory memory that blocks pathogenic T cell responses via loss of effector T cells and gain of regulatory T cell function. Substantial advances have been realized in the generation of tolerogenic vaccines that inhibit experimental autoimmune encephalomyelitis in a preclinical setting, and these vaccines may be a prequel of the tolerogenic vaccines that may have therapeutic benefit in Multiple Sclerosis. The purpose here is to provide a snapshot of the current concepts and future prospects of tolerogenic vaccination for Multiple Sclerosis, along with the central challenges to clinical application

Myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies are highly specific in children with acquired demyelinating syndromes

AIM: Our objectives were to evaluate the utility of measuring myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies (Ab) in clinical practice and describe their associated neurological phenotypes in children. METHOD: Between 2012 and 2017, 371 children with suspected acquired demyelinating syndromes (ADS) seen in three tertiary centres were tested for MOG-Ab and AQP4-Ab. Medical notes were retrospectively reviewed, and clinical and demographic data compiled. Clinical phenotyping was performed blinded to the antibody results. RESULTS: After review, 237 of the 371 were diagnosed with ADS. Of these, 76 out of 237 (32.1%) were MOG-Ab positive and 14 out of 237 (5.9%) were AQP4-Ab positive. None were positive for both autoantibodies. All 134 patients with non-ADS were negative for MOG-Ab. MOG-Ab were identified in 45 out of 70 (64.3%) patients presenting with acute disseminated encephalomyelitis (ADEM) and in 24 out of 25 patients with relapsing ADEM. Thirty-six out of 75 (48%) MOG-Ab positive patients relapsed. Of the 33 children with neuromyelitis optic spectrum disorder, 14 were AQP4-Ab positive, 13 were MOG-Ab positive, and 6 were seronegative. Of the children with longitudinal samples, 8 out of 13 AQP4-Ab remained positive during the disease course compared to 35 out of 43 MOG-Ab (13/16 monophasic and 22/27 relapsing). INTERPRETATION: Myelin oligodendrocyte glycoprotein antibodies were identified in a third of children with ADS. Almost half of the MOG-Ab positive children relapsed and the majority of them remained antibody positive over 4-years follow-up. WHAT THIS PAPER ADDS: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are highly specific for acquired demyelinating syndromes (ADS). Myelin oligodendrocyte glycoprotein antibodies are not identified in children with peripheral demyelination or genetic leukodystrophies/hypomyelination. Up to 48% of MOG-Ab ADS paediatric patients relapse, higher than previously thought. Seroconversion to MOG-Ab negative status is infrequent; patients may test MOG-Ab positive at follow-up sampling even when asymptomatic. Myelin oligodendrocyte glycoprotein antibodies status should only be used in conjunction with the clinical information to guide maintenance therapy

MR Findings of Fulminent Leukoencephalopathy in EBV-Associated Hemophagocytic Syndrome

Various manifestations of brain involvement for patients with virus-associated hemophagocytic syndrome have been reported. Here, we report on the sequential magnetic resonance (MR) findings of acute demyelination of the entire brain with subsequent brain atrophy in a follow-up study of a 25-month-old boy who was admitted with fever and then diagnosed with infectious mononucleosis and EBV-associated hemophagocytic syndrome. We also review other conditions that should be included in the differential diagnosis of this disease

E.U. paediatric MOG consortium consensus: Part 1 - Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

Over the past few years, increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a new candidate biomarker in demyelinating central nervous system diseases has arisen. MOG-abs have now consistently been identified in a variety of demyelinating syndromes, with a predominance in paediatric patients. The clinical spectrum of these MOG-ab-associated disorders (MOGAD) is still expanding and differs between paediatric and adult patients. This first part of the Paediatric European Collaborative Consensus emphasises the diversity in clinical phenotypes associated with MOG-abs in paediatric patients and discusses these associated clinical phenotypes in detail. Typical MOGAD presentations consist of demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM) in younger, and optic neuritis (ON) and/or transverse myelitis (TM) in older children. A proportion of patients experience a relapsing disease course, presenting as ADEM followed by one or multiple episode(s) of ON (ADEM-ON), multiphasic disseminated encephalomyelitis (MDEM), relapsing ON (RON) or relapsing neuromyelitis optica spectrum disorders (NMOSD)-like syndromes. More recently, the disease spectrum has been expanded with clinical and radiological phenotypes including encephalitis-like, leukodystrophy-like, and other non-classifiable presentations. This review concludes with recommendations following expert consensus on serologic testing for MOG-abs in paediatric patients, the presence of which has consequences for long-term monitoring, relapse risk, treatments, and for counselling of patient and families. Furthermore, we propose a clinical classification of paediatric MOGAD with clinical definitions and key features. These are operational and need to be tested, however essential for future paediatric MOGAD studies

E.U. paediatric MOG consortium consensus: Part 4 - Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

There is increasing knowledge on the role of antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) in acquired demyelinating syndromes and autoimmune encephalitis in children. Better understanding and prediction of outcome is essential to guide treatment protocol decisions. Therefore, this part of the Paediatric European Collaborative Consensus provides an oversight of existing knowledge of clinical outcome assessment in paediatric MOG-ab-associated disorders (MOGAD). The large heterogeneity in disease phenotype, disease course, treatment and follow-up protocols is a major obstacle for reliable prediction of outcome. However, the clinical phenotype of MOGAD appears to be the main determinant of outcome. Patients with a transverse myelitis phenotype in particular are at high risk of accruing neurological disability (motor and autonomic), which is frequently severe. In contrast, having a single episode of optic neuritis any time during disease course is broadly associated with a lower risk of persistent disability. Furthermore, MOG-ab-associated optic neuritis often results in good functional visual recovery, although retinal axonal loss may be severe. The field of cognitive and behavioural outcome and epilepsy following demyelinating episodes has not been extensively explored, but in recent studies acute disseminated encephalomyelitis (-like) phenotype in the young children was associated with cognitive problems and epilepsy in long-term follow-up. In conclusion, main domains of importance in determining clinical outcome in paediatric MOGAD are visual, motor, autonomic and cognitive function. A standardised evaluation of these outcome domains in all children is of importance to allow adequate rehabilitation and follow-up

Distinct serum and cerebrospinal fluid cytokine and chemokine profiles in autoantibody-associated demyelinating diseases

Background: Demyelinating diseases of the central nervous system associated with autoantibodies against aquaporin-4 and myelin-oligodendrocyte-glycoprotein are mediated by different immunopathological mechanisms compared to multiple sclerosis. Objective: The purpose of this study was to evaluate serum and cerebrospinal fluid cytokine/chemokine profiles in patients with autoantibodies against aquaporin-4 or autoantibodies against myelin-oligodendrocyte-glycoprotein-associated demyelination compared to multiple sclerosis and autoimmune encephalitis. Methods: Serum and cerebrospinal fluid cytokine/chemokine levels were analysed using Procartaplex Multiplex Immunoassays. First, we analysed a panel of 32 cytokines/chemokines in a discovery group (nine aquaporin-4-antibody seropositive, nine myelin oligodendrocyte glycoprotein-antibody seropositive, eight encephalitis, 10 multiple sclerosis). Significantly dysregulated cytokines/chemokines were validated in a second cohort (11 aquaporin-4-antibody seropositive, 18 myelin oligodendrocyte glycoprotein-antibody seropositive, 18 encephalitis, 33 multiple sclerosis). Results: We found 11 significantly altered cytokines/chemokines in cerebrospinal fluid and serum samples in the discovery group (a proliferation-inducing ligand, fractalkine=CX3CL1, growth-regulated oncogene-\u3b1, interleukin-1 receptor antagonist, interleukin-6, interleukin-8=CXCL8, interleukin-10, interleukin-21, interferon-&3-induced protein-10=CXCL10, monokine induced by interferon-&3=CXCL9, macrophage inflammatory protein-1 f=CCL4). Most of these cytokines/chemokines were up-regulated in autoantibodies against aquaporin-4 or autoantibodies against myelin-oligodendrocyte-glycoprotein positive patients compared to multiple sclerosis. We confirmed these results for cerebrospinal fluid interleukin-6 and serum interleukin-8, growth-regulated oncogene-\u3b1, a proliferation-inducing ligand and macrophage inflammatory protein-1\u3b2 in the validation set. Receiver-operating characteristic analysis revealed increased levels of cerebrospinal fluid interleukin-6, serum interleukin-8 and growth-regulated oncogene-\u3b1 in most patients with autoantibody-associated neurological diseases. Conclusion: This study suggests that distinctive cerebrospinal fluid and serum cytokine/chemokine profiles are associated with autoantibody-mediated demyelination, but not with multiple sclerosis

Midbrain–hindbrain malformations in patients with malformations of cortical development and epilepsy: A series of 220 patients

SummaryMidbrain–hindbrain malformations (MHM) may coexist with malformations of cortical development (MCD). This study represents a first attempt to investigate the spectrum of MHM in a large series of patients with MCD and epilepsy. We aimed to explore specific associations between MCD and MHM and to compare two groups of patients: MCD with MHM (wMHM) and MCD without MHM (w/oMHM) with regard to clinical and imaging features.Two hundred and twenty patients (116 women/104 men, median age 28 years, interquartile range 20–44 years at the time of assessment) with MCD and epilepsy were identified at the Departments of Neurology and Pediatrics, Innsbruck Medical University, Austria. All underwent high-resolution MRIs (1.5-T) between 01.01.2002 and 31.12.2011. Midbrain–hindbrain structures were visually assessed by three independent raters.MHM were seen in 17% (38/220) of patients. The rate of patients wMHM and w/oMHM differed significantly (p=0.004) in three categories of MCD (category I – to abnormal neuronal proliferation; category II – to abnormal neuronal migration; and category III – due to abnormal neuronal late migration/organization): MCD due to abnormal neuronal migration (31%) and organization (23%) were more commonly associated with MHM compared to those with MCD due to abnormal neuronal proliferation (9%). Extensive bilateral MCD were seen more often in patients wMHM compared to those w/oMHM (63% vs. 36%; p=0.004). In wMHM group compared to w/oMHM group there were higher rates of callosal dysgenesis (26% vs. 4%; p<0.001) and hippocampal abnormalities (52% vs. 27%; p<0.001). Patients wMHM were younger (median 25 years vs. 30 years; p=0.010) at the time of assessment and had seizure onset at an earlier age (median 5 years vs. 12 years; p=0.043) compared to those w/oMHM. Patients wMHM had higher rates of learning disability (71% vs. 38%; p<0.001), delayed developmental milestones (68% vs. 35%; p<0.001) and neurological deficits (66% vs. 47%; p=0.049) compared to those w/oMHM.The groups (wMHM and w/oMHM) did not differ in their response to antiepileptic treatment, seizure outcome, seizure types, EEG abnormalities and rate of status epilepticus. Presence of MHM in patients with MCD and epilepsy is associated with severe morphological and clinical phenotypes

Is there an immunological cross-reactivity of antibodies to the myelin oligodendrocyte glycoprotein and coronaviruses?

Recent reports indicated that myelin oligodendrocyte glycoprotein antibody-associated disease might be a rare complication after severe acute respiratory syndrome coronavirus 2 infection or vaccination. It is unclear whether this is an unspecific sequel of infection or vaccination or caused by possible immunological cross-reactivity of severe acute respiratory syndrome coronavirus 2 proteins and myelin oligodendrocyte glycoprotein. The aim of this study was therefore to elucidate whether there is an immunological cross-reactivity between severe acute respiratory syndrome coronavirus 2 spike or nucleocapsid proteins and myelin oligodendrocyte glycoprotein and to explore the relation of antibody responses against myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 and other coronaviruses. We analysed serum samples from patients with severe acute respiratory syndrome coronavirus 2 infection and neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 12) or without myelin oligodendrocyte glycoprotein-antibodies (n = 10); severe acute respiratory syndrome coronavirus 2 infection without neurological symptoms (n = 32); vaccinated patients with no history of severe acute respiratory syndrome coronavirus 2 infection and neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 10) or without myelin oligodendrocyte glycoprotein-antibodies (n = 9); and severe acute respiratory syndrome coronavirus 2 negative/naïve unvaccinated patients with neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 47) or without myelin oligodendrocyte glycoprotein-antibodies (n = 20). All samples were analysed for serum antibody responses to myelin oligodendrocyte glycoprotein, severe acute respiratory syndrome coronavirus 2, and other common coronaviruses (CoV-229E, CoV-HKU1, CoV-NL63 and CoV-OC43). Based on sample amount and antibody titres, 21 samples were selected for analysis of antibody cross-reactivity between myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 spike and nucleocapsid proteins using affinity purification and pre-absorption. Whereas we found no association of immunoglobulin G and A myelin oligodendrocyte glycoprotein antibodies with coronavirus antibodies, infections with severe acute respiratory syndrome coronavirus 2 correlated with an increased immunoglobulin M myelin oligodendrocyte glycoprotein antibody response. Purified antibodies showed no cross-reactivity between severe acute respiratory syndrome coronavirus 2 spike protein and myelin oligodendrocyte glycoprotein. However, one sample of a patient with myelin oligodendrocyte glycoprotein antibody-associated disease following severe acute respiratory syndrome coronavirus 2 infection showed a clear immunoglobulin G antibody cross-reactivity to severe acute respiratory syndrome coronavirus 2 nucleocapsid protein and myelin oligodendrocyte glycoprotein. This patient was also seropositive for other coronaviruses and showed immunological cross-reactivity of severe acute respiratory syndrome coronavirus 2 and CoV-229E nucleocapsid proteins. Overall, our results indicate that an immunoglobulin G antibody cross-reactivity between myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 proteins is rare. The presence of increased myelin oligodendrocyte glycoprotein-immunoglobulin M antibodies after severe acute respiratory syndrome coronavirus 2 infection may either be a consequence of a previous infection with other coronaviruses or arise as an unspecific sequel after viral infection. Furthermore, our data indicate that myelin oligodendrocyte glycoprotein-immunoglobulin A and particularly myelin oligodendrocyte glycoprotein-immunoglobulin M antibodies are a rather unspecific sequel of viral infections. Finally, our findings do not support a causative role of coronavirus infections for the presence of myelin oligodendrocyte glycoprotein-immunoglobulin G antibodies