Familial neuromyelitis optica

Background: Detection of aquaporin-4-specific immunoglobulin G (IgG) has expanded the spectrum of neuromyelitis optica (NMO). Rare reports of familial aggregation have suggested a component of genetic susceptibility but these reports mostly antedated the discovery of the NMO-IgG biomarker and recently updated diagnostic criteria. Methods: We report a case series describing the demographic, clinical, neuroimaging, and NMO-IgG serologic status of 12 multiplex NMO pedigrees with a total of 25 affected individuals. Results: Twenty-one patients (84%) were women. Families were Asian (n = 5), Latino (n = 4), white (n = 1), or African (n = 2). Apparent transmission was either maternal (n = 5) or paternal (n = 2). In 1 family, 3 individuals had NMO; in the others, 2 individuals were affected. Sibling pairs (n = 6), parent-child (n = 4), and aunt-niece (n = 3) pairs were observed. Nineteen patients (76%) were NMO-IgG positive. Twelve (48%) had clinical or serologic evidence of another autoimmune disease. Familial occurrence of NMO occurs in approximately 3% of patients with well-established diagnosis of NMO. Conclusions: A small proportion of patients with NMO have relatives with this condition, but familial occurrence is more common than would be expected from its frequency in the general population. Familial NMO is indistinguishable from sporadic NMO based on clinical symptoms, age at onset, sex distribution, and frequency of NMO-IgG detection. One or 2 generations were affected and affected individuals represented a small fraction of family members. Taken together, these data suggest complex genetic susceptibility in NMO. Neurology (R) 2010;75:310-315

Recurrent neuromyelitis optica in Brazilian patients: clinical, immunological, and neuroimaging characteristics

Neuromyelitis optica has not been thoroughly studied in Brazilian patients following the discovery of NMO-IgG and its specific antigen aquaporin-4. In this study we aimed to describe the clinical NMO-IgG immunological status and neuroimaging characteristics of recurrent neuromyelitis optica in a series Brazilian patients. We undertook a retrospective study of 28 patients with recurrent neuromyelitis optica, according to 1999 Wingerchuk`s diagnostic criteria. Data on NMO-IgG status, clinical features, and MRI findings were analyzed. Three men and 25 women were evaluated. Median age at onset of disease was 26 years (range 7-55); median time of follow-up was 7 years (range 2-14). The mean time elapsed between the first and the second attack was 17 months (median 8.5; range 2-88). NMO-IgG was detected in 18 patients (64.3%). Four patients died due to respiratory failure. Most patients presented with cervical (36%) and cervical-thoracic myelitis (46.4%). Holocord lesion was the most common pattern of involvement (50%) on the axial plane. We did not find a statistical association between myelitis extension and NMO-IgG result. Our series of Brazilian patients showed a younger age of onset than previously reported. In our series, in contrast to previous reports, there was no correlation between the extension of myelitis and NMO-IgG positivity.

HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis

Until recently, neuromyelitis optica (NMO) was considered to be a sub-type of multiple sclerosis (MS), which has a strong predilection for Caucasian populations, whereas NMO is more frequent in non-Caucasian individuals. The objective of this study was to compare the HLA-DRB profile in Brazilian Mulatto patients with NMO spectrum disorders (NMOSDs) with that observed for Mulatto MS patients and healthy Mulatto controls. Twenty seven NMOSD patients (20 women), all seropositive for NMO-IgG, 29 MS patients and 28 Mulatto healthy blood donors were evaluated for HLA-DRB allele groups. HLA-DRB1*03 allele group was overrepresented in NMO patients compared with healthy controls (p = 0.0401; OR = 3.23, 95% CI: 1.07-9.82). In contrast, the HLA-DRB1*15 allele group was overrepresented in Brazilian MS patients (OR = 15.89, 95% CI: 3.51-71.85; p<0.0001). DRB3 was overrepresented in NMO (p = 0.0064), and DRB5 overrepresented in MS patients (p = 0.0001). The low frequency of HLA-DRB1*15 alleles was associated with the presence of long and central cord lesions at magnetic resonance. In addition, DRB1*15 alleles were associated with the fulfillment of the Barkhof criteria. In conclusion, these results indicate that the DRB profile of NMO patients is different from that observed for MS patients, further corroborating the distinction between NMO and MS.

HLA-DRB1*1501 tagging rs3135388 polymorphism is not associated with neuromyelitis optica

Background: Association of the HLA-DRB1*1501 allele with multiple sclerosis is well established, but its association with neuromyelitis optica has only been evaluated in small populations. Methods: We performed a case-control genetic association study to evaluate the association of HLA-DRB1*1501 with neuromyelitis optica. The single nucleotide polymorphism rs3135388, which tags HLA-DRB1*1501, was genotyped in 164 patients with neuromyelitis optica, 220 patients with multiple sclerosis and 959 controls matched for age, gender and ethnicity. Genotyping for rs3135388 was performed by Taqman-based 5` nuclease assay. Results: Rs3135388*A was positively associated with multiple sclerosis (OR = 3.93; 95% CI = 2.58-5.97, p = 1.18 x 10(-09)) but negatively associated with NMO (OR = 0.57; 95% CI = 0.36-0.91, p = 0.01). Conclusions: Multiple sclerosis and neuromyelitis optica differ in their associations with DRB1*1501.

Neuromyelitis Optica in Portugal (NEMIPORT) - A Multicentre Study

BACKGROUND: Neuromyelitis Optica (NMO) is an inflammatory demyelinating disease of the CNS. There have been few epidemiologic studies on NMO, none in Portugal. OBJECTIVE: To analyze the clinical, biological and MRI characteristics from a cohort of Portuguese patients who fulfilled the Wingerchuk 2006 NMO/NMOSD criteria. To identify and characterize those who had concomitant autoimmune disease or circulating autoantibodies. METHODS: We performed an observational, retrospective, multicenter study in 5 Hospital Centers in Portugal. RESULTS: Sixty-seven patients fulfilled the inclusion criteria. They were mainly Caucasian, 55 female. Median age at onset was 32.0 years and mean follow-up 7.4±6.0 years. Twenty-one patients were definite NMO and optic neuritis (ON) the most frequent initial presentation. Forty-six were classified as NMO spectrum disorders. The main subtypes were recurrent ON and single longitudinally extensive transverse myelitis. Twenty-four patients had positive AQP4-IgG. Twenty-three had other circulating autoantibodies. Fifteen out of 67 patients had concomitant autoimmune disease. There was a significant correlation between the presence of autoimmune disease and the positivity for AQP4-IgG. Five patients died, all definite NMO. CONCLUSION: This is the first study about this rare disease in Portugal. Demographic features were similar to other studies. The existence of concomitant autoimmune disease was significantly associated with seropositivity for AQP4-IgG.

EFNS guidelines on diagnosis and management of neuromyelitis optica.

BACKGROUND AND PURPOSE: Neuromyelitis optica (NMO) or Devic's disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis (MS). The guidelines are designed to provide guidance for best clinical practice based on the current state of clinical and scientific knowledge. SEARCH STRATEGY: Evidence for this guideline was collected by searches for original articles, case reports and meta-analyses in the MEDLINE and Cochrane databases. In addition, clinical practice guidelines of professional neurological and rheumatological organizations were studied. RESULTS: Different diagnostic criteria for NMO diagnosis [Wingerchuk et al. Revised NMO criteria, 2006 and Miller et al. National Multiple Sclerosis Society (NMSS) task force criteria, 2008] and features potentially indicative of NMO facilitate the diagnosis. In addition, guidance for the work-up and diagnosis of spatially limited NMO spectrum disorders is provided by the task force. Due to lack of studies fulfilling requirement for the highest levels of evidence, the task force suggests concepts for treatment of acute exacerbations and attack prevention based on expert opinion. CONCLUSIONS: Studies on diagnosis and management of NMO fulfilling requirements for the highest levels of evidence (class I-III rating) are limited, and diagnostic and therapeutic concepts based on expert opinion and consensus of the task force members were assembled for this guideline.

European Ancestry Predominates in Neuromyelitis Optica and Multiple Sclerosis Patients from Brazil

Background: Neuromyelitis optica (NMO) is considered relatively more common in non-Whites, whereas multiple sclerosis (MS) presents a high prevalence rate, particularly in Whites from Western countries populations. However, no study has used ancestry informative markers (AIMs) to estimate the genetic ancestry contribution to NMO patients. Methods: Twelve AIMs were selected based on the large allele frequency differences among European, African, and Amerindian populations, in order to investigate the genetic contribution of each ancestral group in 236 patients with MS and NMO, diagnosed using the McDonald and Wingerchuck criteria, respectively. All 128 MS patients were recruited at the Faculty of Medicine of Ribeirão Preto (MS-RP), Southeastern Brazil, as well as 108 healthy bone marrow donors considered as healthy controls. A total of 108 NMO patients were recruited from five Neurology centers from different Brazilian regions, including Ribeirão Preto (NMO-RP). Principal Findings: European ancestry contribution was higher in MS-RP than in NMO-RP (78.5% vs. 68.7%) patients. In contrast, African ancestry estimates were higher in NMO-RP than in MS-RP (20.5% vs. 12.5%) patients. Moreover, principal component analyses showed that groups of NMO patients from different Brazilian regions were clustered close to the European ancestral population. Conclusions: Our findings demonstrate that European genetic contribution predominates in NMO and MS patients from Brazil. © 2013 Brum et al.

Quantification of Retinal Neural Loss in Patients with Neuromyelitis Optica and Multiple Sclerosis with or without Optic Neuritis Using Fourier-Domain Optical Coherence Tomography

PURPOSE. We compared retinal nerve fiber layer (RNFL) and macular thickness measurements in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO) with or without a history of optic neuritis, and in controls using Fourier-domain (FD) optical coherence tomography (OCT). METHODS. Patients with MS (n = 60), NMO (n = 33), longitudinal extensive transverse myelitis (LETM, n = 28) and healthy controls (n = 41) underwent ophthalmic examination, including automated perimetry, and FD-OCT RNFL and macular thickness measurements. Five groups of eyes were compared: MS with or without previous optic neuritis, NMO, LETM, and controls. Correlation between OCT and visual field (VF) findings was investigated. RESULTS. With regard to most parameters, RNFL and macular thickness measurements were significantly smaller in eyes of each group of patients compared to controls. MS eyes with optic neuritis did not differ significantly from MS eyes without optic neuritis, but measurements were smaller in NMO eyes than in all other groups. RNFL (but not macular thickness) measurements were significantly smaller in LETM eyes than in controls. While OCT abnormalities were correlated significantly with VF loss in NMO/LETM and MS, the correlation was much stronger in the former. CONCLUSIONS. Although FD-OCT RNFL and macular thickness measurements can reveal subclinical or optic neuritis-related abnormalities in NMO-spectrum and MS patients, abnormalities are predominant in the macula of MS patients and in RFNL measurements in NMO patients. The correlation between OCT and VF abnormalities was stronger in NMO than in MS, suggesting the two conditions differ regarding structural and functional damage. (ClinicalTrials.gov number, NCT01024985.) Invest Ophthalmol Vis Sci. 2012;53:3959-3966) DOI:10.1167/iovs.11-9324

The expanded spectrum of neuromyelitis optica - evidences for a new definition

Neuromyelitis optica (NMO) has been traditionally described as the association of recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM). Identification of aquaporin-4 antibody (AQP4-IgG) has deeply changed the concept of NMO. A spectrum of NMO disorders (NMOSD) has been formulated comprising conditions which include both AQP4-IgG seropositivity and one of the index events of the disease (recurrent or bilateral optic neuritis and LETM). Most NMO patients harbor asymptomatic brain MRI lesions, some of them considered as typical of NMO. Some patients with aquaporin-4 autoimmunity present brainstem, hypothalamic or encephalopathy symptoms either preceding an index event or occurring isolatedly with no evidence of optic nerve or spinal involvement. On the opposite way, other patients have optic neuritis or LETM in association with typical lesions of NMO on brain MRI and yet are AQP4-IgG seronegative. An expanded spectrum of NMO disorders is proposed to include these cases.

Comparison of Visual Acuity and Automated Perimetry Findings in Patients With Neuromyelitis Optica or Multiple Sclerosis After Single or Multiple Attacks of Optic Neuritis

Objective: To review the clinical characteristics of patients with neuromyelitis optica (NMO) and to compare their visual outcome with those of patients with optic neuritis (ON) and multiple sclerosis (MS). Methods: Thirty-three patients with NMO underwent neuro-ophthalmic evaluation, including automated perimetry along with 30 patients with MS. Visual function in both groups was compared overall and specifically for eyes after a single episode of ON. Results: Visual function and average visual field (VF) mean deviation were significantly worse in eyes of patients with NMO. After a single episode of ON, the VF was normal in only 2 of 36 eyes of patients with NMO compared to 17 of 35 eyes with MS (P < 0.001). The statistical analysis indicated that after a single episode of ON, the odds ratio for having NMO was 6.0 (confidence interval [CI]: 1.6-21.9) when VF mean deviation was worse than -20.0 dB while the odds ratio for having MS was 16.0 (CI: 3.6-68.7) when better than -3.0 dB. Conclusion: Visual outcome was significantly worse in NMO than in MS. After a single episode of ON, suspicion of NMO should be raised in the presence of severe residual VF deficit with automated perimetry and lowered in the case of complete VF recovery.

Myasthenia gravis and neuromyelitis optica spectrum disorder A multicenter study of 16 patients

Objective: To describe 16 patients with a coincidence of 2 rare diseases: aquaporin-4 antibody (AQP4-Ab)-mediated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and acetylcholine receptor antibody (AChR-Ab)-mediated myasthenia gravis (AChR-MG). Methods: The clinical details and antibody results of 16 patients with AChR-MG and AQP4-NMOSD were analyzed retrospectively. Results: All had early-onset AChR-MG, the majority with mild generalized disease, and a high proportion achieved remission. Fifteen were female; 11 were Caucasian. In 14/16, the MG preceded NMOSD (median interval: 16 years) and 11 of these had had a thymectomy although 1 only after NMOSD onset. In 4/5 patients tested, AQP4-Abs were detectable between 4 and 16 years prior to disease onset, including 2 patients with detectable AQP4-Abs prior to thymectomy. AChR-Abs decreased and the AQP4-Ab levels increased over time in concordance with the relevant disease. AChR-Abs were detectable at NMOSD onset in the one sample available from 1 of the 2 patients with NMOSD before MG. Conclusions: Although both conditions are rare, the association of MG and NMOSD occurs much more frequently than by chance and the MG appears to follow a benign course. AChR-Abs or AQP4-Abs may be present years before onset of the relevant disease and the antibody titers against AQP4 and AChR tend to change in opposite directions. Although most cases had MG prior to NMOSD onset, and had undergone thymectomy, NMOSD can occur first and in patients who have not had their thymus removed. Neurology (R) 2012;78:1601-1607

Treatment of neuromyelitis optica: an evidence based review

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterized by severe optic neuritis and transverse myelitis, usually with a relapsing course. Aquaporin-4 antibody is positive in a high percentage of NMO patients and it is directed against this water channel richly expressed on foot processes of astrocytes. Due to the severity of NMO attacks and the high risk for disability, treatment should be instituted as soon as the diagnosis is confirmed. There is increasing evidence that NMO patients respond differently from patients with multiple sclerosis (MS), and, therefore, treatments for MS may not be suitable for NMO. Acute NMO attacks usually are treated with high dose intravenous corticosteroid pulse and plasmapheresis. Maintenance therapy is also required to avoid further attacks and it is based on low-dose oral corticosteroids and non-specific immunosuppressant drugs, like azathioprine and mycophenolate mofetil. New therapy strategies using monoclonal antibodies like rituximab have been tested in NMO, with positive results in open label studies. However, there is no controlled randomized trial to confirm the safety and efficacy for the drugs currently used in NMO.