Neuromyelitis optica (Devic's syndrome): no association with the primary mitochondrial DNA mutations found in Leber hereditary optic neuropathy.

Devic's neuromyelitis optica is a rare syndrome characterised by the combination of acute or subacute optic neuritis and transverse myelitis, in some cases considered to be a variant of multiple sclerosis. Mutations of mitochondrial DNA (mtDNA) associated with Leber hereditary optic neuropathy (LHON) have been identified in some patients with multiple sclerosis in whom optic neuritis is a prominent early feature. Using restriction enzyme digestion of mtDNA products amplified by the polymerase chain reaction, the primary LHON mtDNA mutations at positions 3460 bp, 11,778 bp, and 14,484 bp have been excluded in four women with Devic's neuromyelitis optica. A mutation at 4160 bp associated in some LHON families with more widespread neurological disease was also not detected. It is concluded that the primary mtDNA mutations currently associated with LHON are not responsible for the prominence of optic nerve disease in Devic's neuromyelitis optica.     

The clinical course of neuromyelitis optica (Devic's syndrome).

OBJECTIVES: To evaluate the spectrum of neuromyelitis optica (NMO), including characteristics of the index events (optic neuritis [ON]) and myelitis), neuroimaging, CSF, and serologic studies, and to evaluate the long-term course. METHODS: Review of 71 patients with NMO evaluated at the Mayo Clinic between 1950 and 1997. RESULTS: NMO was either monophasic or relapsing. Patients with a monophasic course (n = 23) usually presented with rapidly sequential index events (median 5 days) with moderate recovery. Most with a relapsing course (n = 48) had an extended interval between index events (median 166 days) followed within 3 years by clusters of severe relapses isolated to the optic nerves and spinal cord. Most relapsing patients developed severe disability in a stepwise manner, and one-third died because of respiratory failure. Features of NMO distinct from "typical" MS included >50 cells/mm3 in CSF (often polymorphonuclear), normal initial brain MRI, and lesions extending over three or more vertebral segments on spinal cord MRI. CONCLUSIONS: Clinical, laboratory, and imaging features generally distinguish neuromyelitis optica from MS. Patients with relapsing optic neuritis and myelitis may have neuromyelitis optica rather than MS. Patients with a relapsing course of neuromyelitis optica have a poor prognosis and frequently develop respiratory failure during attacks of cervical myelitis.     

Neuromyelitis optica in a young child with positive serum autoantibody

Relapsing neuromyelitis optica is rare in children. The identification of a highly specific serum autoantibody marker (neuromyelitis optica-immunoglobulin G) differentiates neuromyelitis optica from other demyelinating disorders, particularly in clinically challenging cases. We present a child with multiple episodes of transverse myelitis and optic neuritis with positive neuromyelitis optica-immunoglobulin G titers, consistent with a diagnosis of relapsing neuromyelitis optica. Serial titers of neuromyelitis optica-immunoglobulin G normalized during remission.     

Pediatric familial neuromyelitis optica in two sisters with long term follow-up

Neuromyelitis optica causes bilateral optic neuritis and longitudinal extensive transverse myelitis. Although usually sporadic, 3% of cases of neuromyelitis optica are familial. The interval over which attacks continue and the long term prognosis for pediatric-onset neuromyelitis optica are not well defined. We describe two patients with pediatric familial neuromyelitis optica with the longest clinical follow-up of a pediatric case reported in the literature to our knowledge. One woman developed blindness with bilateral eye involvement within a few weeks at age 3. This was followed by transverse myelitis with paraparesis at age 19 leading to diagnosis of neuromyelitis optica. Her serum anti-aquaporin 4 antibody was later found to be positive. She continued with sporadic myelitis-related relapses but remained ambulant until age 40 when she had a more severe relapse. There was evidence of longitudinal extensive T2 hyperintensity in the thoracic spinal cord. Her sister also developed blindness at age 3.5 followed by myelitis 1 year later with multiple relapses of gait impairment until her death from pneumonia at age 21. These patients represent the rare occurrence of neuromyelitis optica in children within the same family and show that this disease can have prolonged periods of remission but a continued tendency to relapse, supporting the need for lifelong immunosuppression.     

视神经脊髓炎临床与病理

目的：分析视神经脊髓炎（NMO）的特征。方法：对114例NMO患者的临床资料,3例尸检结果,28例随访情况进行研究。结果：该病患者男女之比为1：2．5,发病年龄以12－50岁居多（85％）,急性和亚急性起病占大多数（74．84％）,视神经症状为首发占58．77％,视神经与脊髓症状的间隔时间在1年内者60例,占52．33％。脊髓以横贯性损害为主,有95例（83．33％）,以胸段损害最多（64．33％）,尸体解剖例2、3为NMO;病程中有缓解－复发者65例,其中有14例发展为多发性硬化,包括尸体解剖例1。结论：NMO有两种类型;复发型中有一小部分可发展成为MS,MRI,脑干视觉诱发电位和长期随访有利于NMO和MS的鉴别。     

Neuromyelitis optica (Devic's syndrome) and pulmonary tuberculosis

Neuromyelitis optica and acute necrotic myelopathy occur in association with pulmonary tuberculosis. We studied 8 patients with either neuromyelitis optica (6), acute myelopathy (1), or acute optic neuropathy (1) in close temporal association with pulmonary tuberculosis, but with no evidence for CNS tuberculosis. Neurologic symptoms preceded the use of antituberculosis medication in 5 patients. Different patients showed similar clinical features, suggesting a consistent disease pattern. Autopsy examination (1 patient) revealed extensive spinal cord and optic nerve demyelination. We identified only 5 additional patients seen over the same period with idiopathic neuromyelitis optica, thus suggesting that the close temporal relationship to pulmonary tuberculosis is not coincidental. The syndrome is most likely due to an immune reaction to tuberculosis rather than the use of antituberculosis medication.     

血清抗核抗体在视神经脊髓炎谱系疾病和多发性硬化中的分布

目的 研究血清抗核抗体(ANAs)在视神经脊髓炎谱系疾病(NMOSDs)和多发性硬化(MS)中的分布.方法 收集2009-01-2011-03间在作者医院神经内科门诊和住院诊治并行血清ANAs筛查的NMOSDs患者74例,包括视神经脊髓炎(NMO)53例、复发长节段横贯性脊髓炎(rLETM)20例和复发性视神经炎(RON)1例,以及MS患者49例,统计其血清ANAs阳性率并进行分析.结果 NMOSDs患者血清ANAs阳性率为45.9%(34/74),其中ANA(本文中特指用间接免疫荧光法检测的抗核抗体)、抗dsDNA、抗着丝粒抗体(ACA)、抗SSA抗体、抗SSB抗体阳性率分别为36.5%(27/74)、5.4%(4/74)、1.4%(1/74)、27.0%(20/74)、9.5%(7/74),MS组仅1例ANAs阳性,阳性率为2.0%(1/49),两组间差异有统计学意义(P<0.01).血清ANAs诊断NMOSDs的灵敏度为45.9%,特异度达98.0%;NMO和rLETM患者血清ANAs阳性率分别为47.2%和40.0%,两者无统计学差异(P=0.635).结论 NMO和rLETM患者血清ANAs阳性率高于MS组,支持NMO和rLETM同属于NMOSDs的观点.ANAs有可能是NMOSDs和MS两组疾病的鉴别指标之一.     

Clinical features of Chinese patients with multiple sclerosis with aquaporin-4 antibodies in cerebrospinal fluid but not serum

The objective of this study was to determine the levels of aquaporin-4 (AQP4) antibodies in the cerebrospinal fluid (CSF) of patients meeting the diagnostic criteria for multiple sclerosis (MS) and to describe some of the clinical features of CSF-positive cases. Thirty-five patients fulfilling the diagnostic criteria for MS but not neuromyelitis optica were included in this study. AQP4 antibodies were detected using a cell-based assay. None of the serum samples were positive for AQP4 antibodies. Five CSF samples (14.3%, 5/35) were positive for AQP4 antibodies. All CSF-positive patients had atypical brain lesions in areas known to have high levels of AQP4 expression. CSF AQP4 antibody testing is an important diagnostic aid in patients meeting MS criteria but with atypical brain or spinal lesions and serum negative for AQP4 antibodies.     

Neuromyelitis optica immunoglobulin G in a child

Neuromyelitis optica or Devic's syndrome is an uncommon demyelinating disorder that preferentially attacks the spinal cord and optic nerves. Although it is well described in adults, childhood neuromyelitis optica has rarely been reported in the literature and is frequently misdiagnosed as severe multiple sclerosis. Recently, a serum immunoglobulin G test for neuromyelitis optica has become available which may clarify and accelerate the diagnosis. This report describes a child with recurrent myelitis and an elongated spinal cord lesion who was found to have positive neuromyelitis optica autoantibody. We believe that neuromyelitis optica autoantibody testing should be performed in cases of pediatric transverse myelitis with multiple vertical segments or recurrence.     

Therapeutic efficacy of double filtration plasmapheresis in patients with anti-aquaporin-4 antibody-positive multiple sclerosis

Multiple sclerosis (MS) in Asian countries, including Japan, is classified into two types: conventional MS (C-MS), characterized mainly by cerebral lesions, and opticospinal MS (OS-MS) or neuromyelitis optica (NMO), characterized by selective involvement of the optic nerve and spinal cord. Recently, a serum immunoglobulin-G-antibody was discovered in patients with NMO that targets aquaporin-4 (AQP4). The existence of the anti-AQP4 antibody shows the pathogenetic role of humoral immune factors in OS-MS/NMO. We treated eight patients with anti-AQP4 antibody-positive MS with double filtration plasmapheresis (DFPP) to remove the antibody. Improvement of vision was observed in two patients. Motion improvement was seen in seven patients. Sensory improvement was observed in four patients. In total, six out of eight patients (75%) showed therapeutic improvement after DFPP treatment. We propose that DFPP might be an effective therapeutic option for patients with anti-AQP4 antibody-positive MS.     

Two unusual neuropathologically proven cases of multiple sclerosis from bombay

Two unusual cases of multiple sclerosis (MS), both from Bombay, have been reported with detailed clinical and histopathological findings, which evidenced dissemination in time and in space. They were both women in their twenties, with total duration of the neurological illness of 5–6 months.

The first patient had initial signs related to the optic nerves and then, after remission, to the brain stem and spinal cord. There were chronic plaques in the medulla, in 1 optic nerve and lesions of varying stages throughout the cervical spinal cord, with glial cellular and fibrillar reaction, and some preservation of axons. This appeared to be a case of MS with features simulating neuromyelitis optica.

The second patient had initial signs related to the lumbar cord, like a transverse myelitis and then, after a remission, evidence of a progressive cerebral disorder with clinical and ventriculographic findings suggesting a space-occupying lesion in the corpus callosum and frontal lobes. The more chronic demyelination was in the spinal cord. The brain showed large, recent, symmetrical, periventricular plaques, with total absence of myelin except in some of the U-fibres, throughout the frontal and parietal lobes and anterior corpus callosum. There was moderate lymphocytic reaction in and around the vessels, extensive accumulation of myelin breakdown products in histiocytes (gemistocytes and gitter cells) with some preservation of axons and early gliosis. This appeared to be a case of MS with some features of diffuse cerebral sclerosis, or what is often called transitional type of MS.

A history of smallpox vaccination 5 weeks before the illness in the first case, and the chronic inflammatory reaction in the second, together with the rapid tempo of the disease in both, which determined the characteristic patterns of clinical and pathological changes, has led us to discuss the infectious and allergic hypotheses of aetiology in MS.     

Comparative immunopathogenesis of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis

PURPOSE OF REVIEW: Advanced immunopathological techniques hold promise for more precise diagnosis of idiopathic demyelinating diseases of the central nervous system. We review recent progress in differentiating and understanding the disease mechanisms of acute disseminated encephalomyelitis, neuromyelitis optica, and classical multiple sclerosis. RECENT FINDINGS: Four distinct immunopathological patterns have been described in multiple sclerosis patients, potentially implicating different inflammatory, demyelinating, and apoptotic mechanisms. A specific serum biomarker, neuromyelitis optica immunoglobulin G, is strongly associated with neuromyelitis optica and identifies patients with severe optic nerve and spinal cord lesions with specific pathological features such as eosinophilic and neutrophilic inflammatory infiltrates, necrosis, vascular hyalinization, and extensive vasculocentric immunoglobulin and complement deposition. This biomarker targets the water channel aquaporin-4, which is lost in neuromyelitis optica lesions. Acute disseminated encephalomyelitis still has no validated clinical diagnostic criteria but its perivenous pathological findings distinguish it from multiple sclerosis and neuromyelitis optica. SUMMARY: The clinically heterogeneous group of idiopathic inflammatory demyelinating diseases of the central nervous system is characterized by several immunopathological patterns that suggest the involvement of diverse pathogenic effector mechanisms. Future advances in experimental pathology, immunology, molecular genetics, and neuroimaging, as well as the discovery of specific biomarkers, will more precisely define these disorders and lead to better targeted therapies.     

First-ever optic neuritis: distinguishing subsequent neuromyelitis optica from multiple sclerosis

To identify factors distinguishing subsequent neuromyelitis optica (NMO) from multiple sclerosis (MS) after first-ever optic neuritis (ON), we compared ophthalmic findings and MRI features of 24 NMO and 55 MS patients who initially presented with ON. The female-to-male ratio was higher, and bilateral ON was more common in NMO patients than in MS patients (p = 0.044 and p = 0.020, respectively). The visual acuity (VA) score was higher in NMO patients (p = 0.034), and a greater proportion of NMO patients had a VA score ≥5 (p = 0.003). The frequency of patients without pattern-reversal and flash visual evoked potentials was higher in the NMO group (p = 0.015). Brain MRI abnormalities were more common in the MS group (p = 0.001). The optic chiasm was affected in 25 % of NMO patients and was unaffected in MS patients, although it did not reach statistical significance (p = 0.096). There were no differences with respect to the severity of swelling and enhancement of the optic nerve. In conclusion, severe optic nerve damage at the first ON attack was associated with subsequent development of NMO, whereas presence of brain MRI abnormalities was associated with developing MS.     

Is Devic's neuromyelitis optica a separate disease? A comparative study with multiple sclerosis

Devic's neuromyelitis optica (NMO) associates optic neuritis and myelopathy without other neurological signs. Many patients with NMO may be diagnosed as having multiple sclerosis (MS). However, there have been no previous studies comparing these two pathologies and it is still unclear if NMO is a separate entity or a subtype of MS. In the present study, we compared a series of NMO patients with a series of MS patients for whom optic neuritis or myelopathy was the presenting symptom, in order to determine the place of NMO in the spectrum of MS. We retrospectively studied 30 patients diagnosed with NMO and we compared these patients with 50 consecutive MS cases revealed by optic neuritis or acute myelopathy. MS patients were only included if a relapse occurred demonstrating time and space dissemination. We compared the two groups in terms of clinical presentation, laboratory findings (MRI and CSF) and clinical outcome. NMO patients were older and more frequently women than MS patients but the difference was not significant. CSF and MRI data were clearly different: oligoclonal bands (OCB) were found in 23% of NMO cases and 88% of MS (P < 0.001), abnormal brain MRI data were observed in 10% of NMO cases and 66% of MS (P < 0.001) and a large spinal cord lesion was observed in 67% of NMO cases and 7.4% of MS cases (P < 0.001). Clinical outcome was evaluated as more severe in the NMO group (P < 0.001). On the basis of clinical data, all NMO patients but three had dissemination in time and space. When we included MRI parameters, only two of the NMO patients met criteria for MS and one of the MS patients met criteria for NMO. Our study demonstrates that NMO and MS should be considered as two different entities. The respective criteria for NMO and MS were able to distinguish these two pathologies but only when MRI data were applied. This finding could have implications for future therapeutic trials.     

Neuromyelitis optica in a child with atypical onset and severe outcome

We report on a seven-year-old boy with inflammatory relapsing-remitting CNS disease, involving the optic nerves and spinal cord, with increasingly severe sequelae after each relapse. Clinical course, neuroimaging and laboratory findings were consistent with neuromyelitis optica. Biopsy of leptomeninges and underlying nervous tissue showed increased vascularization and thickened hyalinized vessel walls, reported as suggestive for neuromyelitis optica. Clinical features at onset were atypical, rendering the case highly unusual and the diagnosis tentative.     

Aboriginals with multiple sclerosis: HLA types and predominance of neuromyelitis optica

BACKGROUND: MS is common in people of northern European ethnicity who live in northern geographic areas; however, MS is rarely identified among aboriginal peoples living in the same areas. OBJECTIVES: To determine the prevalence, clinical features, HLA type, and viral infections associated with MS among aboriginals in Manitoba, Canada. METHODS: A retrospective study was performed in which the clinical features of all aboriginal patients with MS together with HLA type and human herpesvirus-6, HIV-1, human T-cell lymphotropic virus-1, and endogenous retrovirus associated with MS (MSRV) infections were analyzed and compared with results from nonaboriginal patients with MS. RESULTS: Seven aboriginals with MS were identified with a period prevalence among aboriginals of 40:100,000. Clinical features included relapsing-remitting (n = 6) or primary progressive (n = 1) phenotypes with aggressive disease courses and frequent involvement of optic nerves and spinal cord (n = 5) compared with nonaboriginal patients. Autopsy of one patient showed necrosis and eosinophil infiltrates in a cervical spinal cord lesion and a demyelinated optic nerve. Analysis of HLA alleles at the DRB1 and DQB1 loci indicated that the HLA types detected were common in aboriginals, but there were no HLA alleles previously associated with the development of MS. Analysis of the copy number of MSRV did not show differences among aboriginals and nonaboriginals with or without MS. CONCLUSIONS: Aboriginals of Algonkian background are at increased risk for an aggressive type of MS, resembling neuromyelitis optica, which is resistant to conventional MS treatments and occurs independently of HLA alleles previously associated with MS.     

The spectrum of neuromyelitis optica

Neuromyelitis optica (also known as Devic's disease) is an idiopathic, severe, demyelinating disease of the central nervous system that preferentially affects the optic nerve and spinal cord. Neuromyelitis optica has a worldwide distribution, poor prognosis, and has long been thought of as a variant of multiple sclerosis; however, clinical, laboratory, immunological, and pathological characteristics that distinguish it from multiple sclerosis are now recognised. The presence of a highly specific serum autoantibody marker (NMO-IgG) further differentiates neuromyelitis optica from multiple sclerosis and has helped to define a neuromyelitis optica spectrum of disorders. NMO-IgG reacts with the water channel aquaporin 4. Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica. The knowledge gained from further assessment of the exact role of NMO-IgG in the pathogenesis of neuromyelitis optica will provide a foundation for rational therapeutic trials for this rapidly disabling disease.     

Acquired inflammatory white matter diseases

Objects: During the last decades there have been various attempts to define the characteristics of white matter inflammatory diseases. Most of the authors concerned agree in considering Schilder’s myelinoclastic diffuse sclerosis (SD), Devic’s neuromyelitis optica (NMO) and Balo’s concentric sclerosis to be variants of typical multiple sclerosis (MS). Moreover, in childhood even typical MS presents more aggressive behaviour, with frequent evidence of giant, tumefactive, necrotic or haemorrhagic plaques. Methods: The authors review the literature and cite atypical cases that appear to be intermediate between MS and SD, NMO and SD. Conclusions: Finally, some critical revisions are proposed concerning cases with clinical presentation, history, laboratory and MR findings intermediate between those of acute disseminated encephalomyelitis and of MS. Received: 22 January 2000