Devic's Neuromyelitis Optica Research Articles

Clinical and Genetic Analysis in Pediatric Patients with Multiple Sclerosis and Related Conditions: Focus on DR Genes of the Major Histocompatibility Complex

Introduction: There are several diseases recognized as variants of MS: post-infectious acute disseminated encephalitis, multiple sclerosis (MS), Rasmussen leukoencephalitis and Schilder's leukoencephalitis and related, but separate neuroimmune condition – Neuromyelitis Devic’s. In Kazakhstan diagnosis of such diseases was rare and immune modified treatment was only admitted after the age of 18. Clinical and immunogenetic study of MS spectrum diseases in Kazakhstan would allow to justify early targeted treatment. Objective: The aim of the study was to investigate genes of the main complex of human histocompatibility (MHC) associated with diseases of MS spectrum in Kazakhstani population. Methods: Complex clinical, neuroimaging and immunogenetic studies were performed in 34 children (24 girls, 10 boys) aged 4 to 18 years. 21 children were diagnosed with MS (11 Kazakh origin and 10 – Russian; 4 boys, 17 girls), 7 with leucoencephalitis (all Kazakh, 5 boys, 2 girls) and 6 with Devic neuromyelitis optica (all Kazakh, 1 boy, 5 girls). Genotyping of HLA DRB1, DQA1, DQB1 genes was performed for all patients. Results: MS group was characterized by classical relapsing-remitting MS. Predominant haplotype as a linkage complex was DRB1*15:01~DQA1*01:02~DQB1*06:02 in 20 (47.6%) of 42 DR-alleles, in 16 (76.2%) patients. MS relative risk (RR) was 13,36 for ethnic Kazakhs and RR=5,55 in Russians. Leukoencephalitis had 7 children, with 28.6% mortality rate. The haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02 as a linkage complex was detected 3 patients (4 alleles), RR=5,88. Devic’s neuromyelitis optica (NMO) clinical course was characterized by fast and prolonged progression. There was predominance of DRB1*14 allele with RR=3,38. Conclusion: Summarizing, in the Kazakh population the haplotype DRB1*15:01∼DQA1*01:02∼DQB1*06:02 as a linkage complex was associated with prediction to MS and leukoencephalitis, but not to Devic’s NMO. Our study highlights the importance of awareness of MS and related disorders diagnosis which allows to implement early admission of disease-modified treatment in pediatric MS in Kazakhstan.

Diagnostic procedures in suspected attacks in patients with neuromyelitis optica spectrum disorders: Results of an international survey

BackgroundCurrently, there is no evidence-based definition of attacks in neuromyelitis optica spectrum disorders (NMOSD). However, to allow their stringent use as valid endpoints, recent phase III trials in NMOSD defined criteria and adjudication of these events in context of these trials. The objective of this study was to investigate diagnostic procedures currently used in routine adjudication of suspected attacks in NMOSD, and to assess whether the standardized attack-criteria from two pivotal trials may be feasible in routine clinical care. MethodsFour global clinical networks were surveyed using an online questionnaire: NEMOS (Neuromyelitis Optica Study Group), IMSVISUAL (International Multiple Sclerosis Visual System Consortium), GJCF-ICC (Guthy Jackson Charitable Foundation-International Clinical Consortium) and NOMADMUS (Devic's neuromyelitis optica and related neurological disorders study group). ResultsSeventy-eight responses were received from September 2018 to February 2019. Median annual number of patients seen with suspected attacks was 10 (range 2–130). Immediate access to MRI was reported by 59.0% of all participants and the majority performs an MRI for new patients with a myelitis, optic neuritis or other symptoms. In patients with established NMOSD diagnosis presenting during routine clinical visits only 10.5% or 9.2% always perform a brain or spinal cord MRI, respectively. Digital records of patients' visits are kept by 98.7% of all participants and 88.5% have direct access to case history. An expert neurological examination is performed for 94.9% of participants reported to perform an expert neurological examination in patients with acute attacs, while only 30.8% seem to perform the assessments according to the Neurostatus-Expanded Disability Status Scale (EDSS) definitions.. The Sakura Star study criteria which are based solely on clinical assessment could be feasible in routine care, provided that more centers use the Neurostatus-EDSS, while only 9% of participants fulfill all requirements for adjudication of the N-Momentum study criteria. ConclusionsThe high percentage of centers using digital records is encouraging. However, routine adjudication of clinical events in NMOSD seems highly heterogeneous. MRI is the mainstay in the majority of queried centers, but its immediate availability is limited. Only a minority of centers are equipped for trial-grade classification of attacks, if this is not solely clinically based. Thus, standard and feasible guidelines for attack adjudication are urgently needed to standardize routine care, optimize future clinical trials and allow studying long-term safety and efficacy of newly approved drugs in phase IV trials.

In vivo CNS chronic infusion of AQP4-IgG induces NMO-like lesions and motor behavioral changes in rat via astrocytopathy and glutamate homeostasis disturbance

Devic's Neuromyelitis Optica (NMO) is now considered an autoimmune primary astrocyte disease associated to central nervous system inflammation, demyelination and neuronal injury. The pathogenicity of anti-aquaporin 4 autoantibody (AQP4-Ab), through complement-dependent astrocyte toxicity was demonstrated. However, autoantibodies can also act as receptor agonists/antagonists or modulate antigen density on their target cells, thus trigger cell dysfunction, prior or in addition to complement activation or secondary inflammatory cell-mediated response.

No evidence for genetic association between glutamate transporter EAAT2 and Devic's neuromyelitis optica in caucasians and afro-caribbeans

Devic's neuromyelitis optica (NMO) is a severe inflammatory and autoimmune disease producing demyelinating lesions. Recent data suggest that a complex genetic component could be involved. While impairment of glutamate homeostasis has emerged as a contributing etiological factor in NMO, a genetic alteration of Excitatory Amino Acid Transporter 2 (EAAT2/SLC1A2), the major glutamate transporter in the Central Nervous System (CNS), could contribute to glutamate excitotoxicity and then must be considered.We evaluated whether mutations and/or single nucleotide polymorphisms (SNPs) in EAAT2 gene, are associated with susceptibility to NMO. We studied a cohort of NMO sporadic cases including afro-caribbean patients (n=81; French cohort of Devic's neuromyelitis optica—NOMADMUS cohort) and compared to control subjects (n=56). We sequenced the whole coding region of EAAT2 gene and splicing consensus sequences flanking each exon. The results obtained from all NMO samples did not show any novel mutations and/or SNPs both in the coding region and splicing sites of EAAT2 gene compared to controls subjects. We reported three synonymous SNPs (rs752949, rs1042113 and rs7102949) but only rs7102949 was found in afro-caribbean. Genotype frequencies did not differ between patients and controls for the three SNPs in caucasians and afro-caribbeans (rs752949: p=0.71 and p=0.37, respectively; rs1042113: p=0.73 and p=0.35, respectively; rs7102949: p=0.08 in afro-caribbeans). Our data showed no evidence for a genetic association between EAAT2 gene and Devic's neuromyelitis optica.

Devic's neuromyelitis optica mimicking multiple sclerosis in pregnancy

Devic's neuromyelitis optica (NMO) is a serious neurological disorder, which is often misdiagnosed as multiple sclerosis (MS). This autoimmune, inflammatory disease typically presents with optic neuritis and transverse myelitis. NMO...

Anti-aquaporin-4 antibodies in Devic's neuromyelitis optica: therapeutic implications.

Devic's neuromyelitis optica (DNMO) is a demyelinating and inflammatory disease of the central nervous system (CNS) essentially restricted to the spinal cord and the optic nerves. It is a rare disorder with a prevalence estimated at less than 1/100,000 in Western countries. Since the first description by Eugène Devic in 1894, the relationship between DNMO and multiple sclerosis (MS) has been controversial. Recent clinical, epidemiological, pathological and immunological data demonstrate that MS and DNMO are distinct entities. This distinction between DNMO and MS is crucial, as prognosis and treatment are indeed different. DNMO is now considered to be an autoimmune, antibody-mediated disease especially since the identification of a specific serum autoantibody, named NMO-IgG and directed against the main water channel of the CNS, aquaporin-4 (AQP4). The assessment of AQP4 antibodies (Abs) has initially been proposed to differentiate DNMO and MS. It has also enlarged the clinical spectrum of DNMO and proved to be helpful in predicting relapses and conversion to DNMO after a first episode of longitudinally extensive transverse myelitis or isolated optic neuritis. Lastly, the discovery of the pathogenic role of AQP4 Abs in DNMO leads to a better understanding of detailed DNMO immunopathology and the elaboration of relevant novel treatment strategies specific to DNMO. In this review, we summarize the present and future therapeutic implications generated by the discovery of the various pathogenic mechanisms of AQP4 Abs in DNMO pathophysiology.

Oligodendrocytes are damaged by neuromyelitis optica immunoglobulin G via astrocyte injury

Devic's neuromyelitis optica is an inflammatory demyelinating disorder normally restricted to the optic nerves and spinal cord. Since the identification of a specific autoantibody directed against aquaporin 4, neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody, neuromyelitis optica has been considered an entity distinct from multiple sclerosis. Recent findings indicate that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody has a pathogenic role through complement-dependent astrocyte toxicity. However, the link with demyelination remains elusive. Autoantibodies can act as receptor agonists/antagonists or alter antigen density in their target cells. We hypothesized that the neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody impairs astrocytic function and secondarily leads to demyelination. Rat astrocytes and oligodendrocytes from primary cultures and rat optic nerves were exposed long-term (24 h) to immunoglobulin G in the absence of complement. Immunoglobulin G was purified from the serum of patients with neuromyelitis optica who were either neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive or negative, as well as from healthy controls. Flow cytometry analysis showed a reduction of membrane aquaporin 4 and glutamate transporter type 1 on astrocytes following contact with immunoglobulin G purified from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody positive serum only. The activity of glutamine synthetase, an astrocyte enzyme converting glutamate into glutamine, decreased in parallel, indicating astrocyte dysfunction. Treatment also reduced oligodendrocytic cell processes and approximately 30% oligodendrocytes died. This deleterious effect was confirmed ex vivo; exposed optic nerves showed reduction of myelin basic protein. Immunoglobulin G from neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody seronegative patients and from healthy controls had no similar effect. Neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody did not directly injure oligodendrocytes cultured without astrocytes. A toxic bystander effect of astrocytes damaged by neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on oligodendrocytes was identified. Progressive accumulation of glutamate in the culture medium of neuromyelitis optica-immunoglobulin G/aquaporin 4-antibody-treated glial cells supported the hypothesis of a glutamate-mediated excitotoxic death of oligodendrocytes in our models. Moreover, co-treatment of glial cultures with neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody and d+2-amino-5-phosphonopentanoic acid, a competitive antagonist at the N-methyl-d-aspartate/glutamate receptor, partially protected oligodendrocytes. Co-immunolabelling of oligodendrocyte markers and neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody showed that astrocytic positive processes were in close contact with oligodendrocytes and myelin in rat optic nerves and spinal cord, but far less so in other parts of the central nervous system. This suggests a bystander effect of neuromyelitis optica-immunoglobulin G-damaged astrocytes on oligodendrocytes in the nervous tissues affected by neuromyelitis optica. In conclusion, in these cell culture models we found a direct, complement-independent effect of neuromyelitis optica-immunoglobulin G/aquaporin 4 antibody on astrocytes, with secondary damage to oligodendrocytes possibly resulting from glutamate-mediated excitotoxicity. These mechanisms could add to the complement-induced damage, particularly the demyelination, seen in vivo.

Neuro-optico-myélite aiguë de Devic et les syndromes neurologiques apparentés

Devic's neuromyelitis optica (DNMO) is a demyelinating and inflammatory disease of the central nervous system (CNS) essentially restricted to the spinal cord and the optic nerves. It is a rare disorder. Since the first description by Eugène Devic in 1894, the relationship between DNMO and multiple sclerosis (MS) has been controversial. Recent clinical, epidemiological, pathological and immunological data suggest that MS and DNMO are distinct entities. This distinction between DNMO and MS is however crucial, as prognosis and treatment are indeed different. The clinical course of NMO deteriorates rapidly without appropriate treatment. Severe disability develop during attacks but is not driven by a progressive phase. Only early immunosuppressive treatment seems effective in NMO, and the standard immunomodulator treatments for MS (e.g., interferon-beta and glatiramer acetate) appear ineffective, and even positively harmful. DNMO is now considered to be an auto-immune, antibody-mediated disease especially since the identification of a specific serum autoantibody, NMO-IgG directed against Aquaporin-4. This antibody was initially proposed to differentiate DNMO and MS. Furthermore, NMO-IgG have enlarged the clinical spectrum of DNMO and could also be helpful to predict relapses or conversion to DNMO after a first episode of longitudinally extensive transverse myelitis or isolated optic neuritis. Finally, NMO-IgG, which seems to be directly pathogenic, might be a clue for a better understanding of intimate DNMO immunopathology.

Devic’s neuromyelitis optica and pregnancy: distinction from multiple sclerosis is essential

Devic's neuromyelitis optica (NMO) is a severe neurological disease characterized by optic neuritis and transverse myelitis, which is commonly misdiagnosed as multiple sclerosis (MS). This rare syndrome has a poor prognosis, and there are very few cases described during pregnancy. We report the occurrence of NMO in a primigravida at 20 weeks, in which gestation had an adverse effect on the disease course, and emphasize the main parameters to distinguish NMO from MS. It is essential that a proper diagnosis is established before pregnancy is planned, since the prognosis for NMO and MS might differ. Although the association of gestation and NMO is extremely rare, the few available data demonstrate a significant risk of disease exacerbation. NMO patients require long term immunossupression and need to carefully evaluate the risk of getting pregnant.

New onset neuromyelitis optica in a young Nigerian woman with possible antiphospholipid syndrome: a case report

IntroductionDevic's neuromyelitis optica is an inflammatory demyelinating disease that targets the optic nerves and spinal cord. It has a worldwide distribution and distinctive features that distinguish it from multiple sclerosis. There has been no previous report of neuromyelitis optica from our practice environment, and we are not aware of any case associated with antiphospholipid syndrome in an African person.Case presentationWe report the case of a 28-year-old Nigerian woman who presented with neck pain, paroxysmal tonic spasms, a positive Lhermitte's sign and spastic quadriplegia. She later developed bilateral optic neuritis and had clinical and biochemical features of antiphospholipid syndrome. Her initial magnetic resonance imaging showed a central linear hyperintense focus in the intramedullary portion of C2 to C4. Repeat magnetic resonance imaging after treatment revealed resolution of the signal intensity noticed earlier.ConclusionNeuromyelitis optica should be considered in the differential diagnoses of acute myelopathy in Africans. We also highlight the unusual association with antiphospholipid syndrome. Physicians should screen such patients for autoimmune disorders.

Devic’s neuromyelitis optica: a critical review

Devic's neuromyelitis optica (NMO) is an idiopathic inflammatory demyelinating and necrotizing disease characterized by predominant involvement of the optic nerves and spinal cord. In Asian countries relapsing NMO has been known as opticospinal multiple sclerosis. It has long been debated if NMO is a variant of multiple sclerosis (MS) or a distinct disease. Recent studies have shown that NMO has more frequently a relapsing course, and results from attack to aquaporin-4 which is the dominant water channel in the central nervous system, located in foot processes of the astrocytes. Distinctive pathological features of NMO include perivascular deposition of IgG and complement in the perivascular space, granulocyte and eosinophil infiltrates and hyalinization of the vascular walls. These features distinguish NMO from other demyelinating diseases such as MS and acute demyelinating encephalomyelopathy. An IgG-antibody that binds to aquaporin-4, named NMO-IgG has high sensitivity and specificity. Magnetic resonance imaging (MRI) studies have revealed that more frequently there is a long spinal cord lesion that extends through three or more vertebral segments in length. Brain MRI lesions atypical for MS are found in the majority of cases. Treatment in the acute phase includes intravenous steroids and plasma exchange therapy. Immunosupressive agents are recommended for prophylaxis of relapses.

Neuromyélite optique de Devic chez l'enfant : à propos de 1 cas, avec revue de la littérature

Devic neuromyelitis optica (NMO) or Devic's syndrome is an uncommon clinical syndrome associating unilateral or bilateral optic neuritis and transverse myelitis. Usually reported in adults, childhood cases constitute a distinctive clinical entity. Case report We report a case of NMO occurring in a 9-year-old girl, admitted for paraplegia, sphincter troubles as acute installation bladder retention and of a sudden decline of the visual acuity. Magnetic resonance imaging (MRI) revealed abnormalities of spinal cord signal with hypo intensity in T1-weighted images and hyper intensity in T2-weighted images along the spinal cord. However, the cerebral region was normal. Visual evoked potentials were consistent with retrobulbar optic neuropathy. Our patient received corticosteroids (methyl prednisolone) during 5 days followed by oral prednisone. At week three, an immunosuppressant (azathioprine) was added. Clinical outcome was favourable with disappearance of sphincter troubles, a correction of the visual acuity and a progressive disappearance of motor troubles. Conclusion Pediatric Devic's NMO is rare. It is a different clinical entity with an excellent visual and neurological prognosis. Review of the literature shows that recurrence is rare in children and seems to be without long-term sequelae with corticosteroids and immunosuppressant therapy.

Devic's Neuromyelitis Optica in an Infant Case

Devic's neuromyelitis optica was orginally described as an acute severe monophasic syndrome characterised by myelitis and optic neuritis. The mean age at onset was reported to be around 40 years, with a wide range. However, Devic's neuromyelitis optica has also been seen in children. Prognosis of the syndrome was poor, and no satisfactory treatment was known. This article reports a 23-month-old boy with acute myelitis and optic neuritis who was diagnosed with Devic's neuromyelitis optica. The response of the patient to therapy was poor, and he developed severe sequelae.

Neuromyélite optique de Devic survenue au cours d’une grossesse

Devic's neuromyelitis optica associates optical neuritis that is either unilateral or bilateral and acute transversal myelopathy. This disease seldom occurs and is rarely associated with pregnancy.We report the case of a young 20-year-old woman who was 8 weeks pregnant. She was admitted to our ophthalmological department for a profound and bilateral drop in visual acuity. The ophthalmological examination showed bilateral optic disc swelling. Three days later, the patient presented a spastic paraplegia with sphincter disorders. Devic's neuromyelitis optica was suspected and then confirmed by examination of cerebrospinal fluid and cerebrospinal MRI. Corticoid treatment in bolus of prednisolone methyl relayed by prednisolone per bone was established. The neurological and visual defects were clearly improved and the case was stabilized at 1 year.Devic's neuromyelitis optica is related to nosologic problems with multiple sclerosis. Clinical, immunological, and pathological elements provide arguments in favor of a separate entity.

Building Different Mouse Models for Human MS

Multiple sclerosis (MS) is a clinically and pathologically heterogeneous inflammatory/demyelinating disease of the central nervous system (CNS). Many patients first present with isolated optic neuritis. In some variants of MS, like Devic's disease or neuromyelitis optica (NMO), lesions are predominantly found in the optic nerves and spinal cord but not in the brain. The immunological bases of the different forms of MS are unknown. Here, we summarize our published findings on two mouse models: 2D2 myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic mice, which develop spontaneous isolated optic neuritis, and 2D2 mice crossed with MOG-specific IgH knockin (TH) mice, which spontaneously develop a severe form of experimental autoimmune encephalomyelitis (EAE) with a selective distribution of meningeal and parenchymal inflammatory lesions in the spinal cord and optic nerves similar to that found in human Devic's disease.

Idiopathic inflammatory-demyelinating diseases of the central nervous system

Idiopathic inflammatory-demyelinating diseases (IIDDs) include a broad spectrum of central nervous system disorders that can usually be differentiated on the basis of clinical, imaging, laboratory and pathological findings. However, there can be a considerable overlap between at least some of these disorders, leading to misdiagnoses or diagnostic uncertainty. The relapsing-remitting and secondary progressive forms of multiple sclerosis (MS) are the most common IIDDs. Other MS phenotypes include those with a progressive course from onset (primary progressive and progressive relapsing) or with a benign course continuing for years after onset (benign MS). Uncommon forms of IIDDs can be classified clinically into: (1) fulminant or acute IIDDs, such as the Marburg variant of MS, Baló's concentric sclerosis, Schilder's disease, and acute disseminated encephalomyelitis; (2) monosymptomatic IIDDs, such as those involving the spinal cord (transverse myelitis), optic nerve (optic neuritis) or brainstem and cerebellum; and (3) IIDDs with a restricted topographical distribution, including Devic's neuromyelitis optica, recurrent optic neuritis and relapsing transverse myelitis. Other forms of IIDD, which are classified clinically and radiologically as pseudotumoral, can have different forms of presentation and clinical courses. Although some of these uncommon IIDDs are variants of MS, others probably correspond to different entities. MR imaging of the brain and spine is the imaging technique of choice for diagnosing these disorders, and together with the clinical and laboratory findings can accurately classify them. Precise classification of these disorders may have relevant prognostic and treatment implications, and might be helpful in distinguishing them from tumoral or infectious lesions, avoiding unnecessary aggressive diagnostic or therapeutic procedures.

1642 Devic's neuromyelitis optica occurring as a paraneoplastic phenomenon

1642 Devic's neuromyelitis optica occurring as a paraneoplastic phenomenon

Cerebrospinal fluid findings in Devic?s neuromyelitis optica

Relapsing Devic's neuromyelitis optica (DNO) may be clinically undistinguishable from multiple sclerosis (MS), thus the differential diagnosis relies mainly on neuroimaging and cerebrospinal fluid (CSF) findings. We studied CSF samples from 44 patients with DNO submitted to at least one lumbar puncture. Pleocytosis, IgG synthesis and blood brain barrier damage were the most frequent abnormalities, pleocytosis being very suggestive of DNO in patients fulfilling clinical and MRI diagnostic criteria. Pleocytosis > or =50 cells/mm3 is more frequent in the active phases of the disease. Oligoclonal bands (OBs) should be re-considered within the diagnostic criteria of DNO for possible variations in time: at variance with MS they may also disappear. Thus, more than one CSF examination should be done in the presence of suspected DNO, preferably in different disease phases. Although uncommon, OBs do not exclude DNO if optic nerve and spinal cord are the only sites of white matter damage, provided that cerebral MRI is normal at onset and during follow up.

Lessons from the neuropathology of atypical forms of multiple sclerosis

Multiple sclerosis (MS) is characterized by multiple demyelinated inflammatory lesions disseminated in the central nervous system (CNS). Additional features of MS pathology include axonal loss and gliosis. Remyelination may take place predominantly in the early stages of lesion formation. Pathologically, important inter-individual differences have been observed with respect to oligodendrocyte preservation. Furthermore, different mechanisms of demyelination, such as T-cell/macrophage-mediated demyelination, antibody/complement-mediated demyelination, and primary damage of the oligodendrocyte have been observed in individual MS patients. Atypical MS forms, such as Marburg's acute MS, Devic's neuromyelits optica, Balò's concentric sclerosis, and Schilder's diffuse sclerosis share key aspects of MS pathology, however, each of them harbors characteristic discriminative features. Devic's neuromyelitis optica may represent the prototypical disease with antibody/complement-mediated demyelination, whereas cases with Balò's concentric sclerosis show oligodendrocyte dystrophy. Acute disseminated encephalomyelitis (ADEM) may be regarded as a related condition lacking extensive demyelination. Thus, atypical MS forms may help to elucidate pathogenic mechanisms in MS.

MR imaging of Devic?s neuromyelitis optica

Devic's neuromyelitis optica (NMO) is a neurological condition characterized by a severe involvement of the optic nerves and spinal cord in a mono- or multi-phasic manner. Recent pathologic, cerebrospinal fluid and conventional magnetic resonance imaging (MRI) studies have shown abnormalities which might help in differentiating patients with NMO from those with multiple sclerosis. This review article summarizes the main results obtained using conventional MRI in NMO, which has contributed to the definition of internationally-accepted diagnostic criteria, and those obtained from the application of modem quantitative MR techniques which are significantly changing our views on NMO pathobiology.