Paediatric neuromyelitis optica: clinical, MRI of the brain and prognostic features.

BACKGROUND: Neuromyelitis Optica (NMO) is a severe and rare inflammatory condition, where relapses are predictive of disability. METHODS: We describe a national paediatric NMO cohort's clinical, MRI, outcome, and prognostic features in relation to Aquaporin-4 antibody (AQP4-Ab) status, and compared to a non NMO control cohort. OBSERVATIONS: Twenty NMO cases (females = 90%; AQP4-Ab positive = 60%; median age = 10.5 yrs) with median follow-up = 6.1 yrs were compared to a national cohort sample of known sequential AQP4-Ab negative first episode CNS acquired demyelination cases (n = 29; females = 55%; all AQP4-Ab negative; median age = 13.6 yrs). At presentation, 40% NMO cases had unilateral optic neuritis (ON); 20% bilateral ON; 15% transverse myelitis (TM); 15% simultaneous TM&ON; 10% Acute disseminated encephalomyelitis. At follow up, 55% had a clinical demyelinating episode involving the brain; 30% of cases had abnormal brain MRI at onset and 75% by follow up. NMO brain scan lesions compared to controls were large (> 2 cm), acute lesions largely resolved on repeat imaging, and often showed T1 hypointense lesions. Mean time to relapse = 0.76 yrs (95% CI 0.43-1.1 yrs) for AQP4-Ab positive vs 2.4 yrs in AQP4-Ab negative cases (95% CI 1.1-3.6 yrs). In AQP4-Ab positive cases, 10/12 had visual acuity < 6/60 Snellen in ≥ 1 eye (0/8 AQP4-Ab negative), and 3 AQP4-Ab negative cases were wheelchair-dependent. CONCLUSIONS: In children, NMO is associated with early recurrence and visual impairment in AQP4-Ab positivity and physical disability in AP4-Ab negative relapsing cases. Distinct MRI changes appear more commonly and earlier compared to adult NMO. Early AQP4-Ab testing may allow prompt immunomodulatory treatment to minimise disability.

Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK.

BACKGROUND: Azathioprine (AZA) is a common immunosuppressive drug used for relapse prevention in neuromyelitis optica (NMO). OBJECTIVES: The objective of this paper is to assess efficacy, tolerability and retention of AZA in a large NMO cohort. METHODS: We conducted a retrospective review of medical records of 103 aquaporin-4 antibody-positive NMO and NMO spectrum disorder (NMOSD) patients treated with AZA. RESULTS: This is the largest reported cohort of AQP4-Ab positive patients treated with AZA. Eighty-nine per cent (n = 92) had reduction in median annualised relapse rates from 1.5 (IQR 0.6-4.0) to 0 (IQR 0-0.27, p < 0.00005) with treatment. Sixty-one per cent (n = 63) remained relapse free at a median follow-up of 18 months. Neurological function improved or stabilised in 78%. At last follow-up, treatment was discontinued in 46% (n = 47). Of these, 62% (n = 29) were because of side effects, 19% (n = 9) because of death, 15% (n = 7) because of ongoing disease activity, and 2% (n = 1) because of pregnancy. Using Kaplan-Meyer curves, we estimate that 73%, 58%, 47% and 33% of patients will remain on AZA for longer than one, three, five and 10 years, respectively, after initiation of treatment. CONCLUSIONS: AZA is a modestly effective treatment for NMO. However, many patients discontinue AZA over time and this seems to reflect poor tolerability more than lack of efficacy.

Methotrexate is an alternative to azathioprine in neuromyelitis optica spectrum disorders with aquaporin-4 antibodies.

BACKGROUND: Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disorder associated with considerable relapse-related disability. Immunosuppression is the mainstay of treatment but many patients do not tolerate first-line immunosuppressive agents, or experience ongoing relapses. OBJECTIVE: To evaluate the effectiveness and tolerability of methotrexate in aquaporin-4 antibody seropositive NMO spectrum disorders. METHODS: Retrospective observational case series of 14 aquaporin-4 antibody positive NMO and NMO spectrum disorder patients treated with methotrexate at two specialist centres within the UK. Annualised relapse rates, Expanded Disability Status Scale scores and tolerability were evaluated. RESULTS: Median duration of treatment with methotrexate was 21.5 months (range 6-28 months) and only three patients were prescribed it first line. Median annualised relapse rate significantly decreased following treatment (0.18 during methotrexate therapy vs 1.39 premethotrexate; p<0.005). On treatment, 43% patients were relapse free, although this increased to 64% when relapses occurring within the first 3 months of treatment or on subtherapeutic doses were excluded. Disability stabilised or improved in 79%. No patients stopped methotrexate due to adverse effects. CONCLUSIONS: Methotrexate is a commonly prescribed drug in general practice and when used in NMO it reduces relapse frequency, stabilises disability and is well tolerated, even in patients who have failed one or more other treatments. We would therefore recommend methotrexate as a treatment option in NMO patients who do not tolerate first-line therapy, experience ongoing relapses or in situations where financial constraints limit the available treatment options.

Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan.

Neuromyelitis optica and neuromyelitis optica spectrum disorders have been recently associated with the disease-specific autoantibody aquaporin-4, thought to be pathogenic. Identifying this antibody has allowed the clinical phenotype to be broadened. It is clear that some patients with similar clinical features do not have this antibody and may have a different condition with different outcomes and prognosis. Previous clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies have included such patients. We investigated clinical outcomes and prognostic characteristics of 106 aquaporin-4 antibody-seropositive patients from the UK and Japan. We looked at predictors of disability outcomes, namely visual disability (permanent bilateral visual loss with visual acuity of <6/36 in the best eye), motor disability (permanent inability to walk further than 100 m unaided), wheelchair dependence and mortality. Data were collected largely retrospectively through review of case records. After median disease duration of 75 months, 18% had developed permanent bilateral visual disability, 34% permanent motor disability, 23% had become wheelchair dependent and 9% had died. Age at disease onset appeared to be an important predictor of disability type. Young-onset patients in the UK, but not the Japanese cohort, commonly presenting with optic neuritis, had a high risk of visual disability while older patients in both cohorts had a high risk of motor disability, regardless of their onset symptom. Genetic factors also appeared important. The UK cohort seemed to have more severe disease than the Japanese cohort, with more severe onset attacks, a higher relapse frequency and greater disability at follow-up, despite earlier immunosuppression. Moreover, within the UK cohort, there were important differences between ethnic groups, with Afro-Caribbean patients having a younger age at disease onset, more brain and multifocal attacks and higher likelihood of visual disability than Caucasian patients. Thus, age at disease onset and genetic factors are both likely to be important in determining clinical outcomes in aquaporin-4 disease. This has important implications for interpreting clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies, since clinical features and outcomes appear not to be generic across populations and may need to be tailored to individual groups. These factors need to be explored further in future prospective neuromyelitis optica and neuromyelitis optica spectrum disorder studies.

Detrimental role of granulocyte-colony stimulating factor in neuromyelitis optica: clinical case and histological evidence.

In a recent study, administration of granulocyte colony stimulating factor (G-CSF) increased neuromyelitis optica (NMO) lesions in mice. Here we report a patient whose first episode of NMO may have been exacerbated by inadvertent administration of G-CSF. Histological examination of brain and spinal cord samples from three other NMO patients revealed markedly increased expression of G-CSF in neurons located in and around the lesions, with little or no expression in multiple sclerosis lesions or normal white matter. Taken together, these cases support a detrimental role for G-CSF in NMO pathogenesis.

Seasonal distribution of attacks in aquaporin-4 antibody disease and myelin-oligodendrocyte antibody disease.

BACKGROUND: Seasonal variation in incidence and exacerbations has been reported for neuroinflammatory conditions such as multiple sclerosis and acute disseminated encephalomyelitis (ADEM). It is unknown whether seasonality also influences aquaporin-4 antibody (AQP4-Ab) disease and myelin-oligodendrocyte antibody (MOG-Ab) disease. OBJECTIVE: We examined the seasonal distribution of attacks in AQP4-Ab disease and MOG-Ab disease. METHODS: Observational study using data prospectively recorded from three cohorts in the United Kingdom. RESULTS: There was no clear seasonal variation in AQP4-Ab or MOG-Ab attacks for either the onset attack nor subsequent relapses. In both groups, the proportion of attacks manifesting with each of the main phenotypes (optic neuritis, transverse myelitis, ADEM/ADEM-like) appeared stable across the year. This study is the first to examine seasonal distribution of MOG-Ab attacks and the largest in AQP4-Ab disease so far. CONCLUSION: Lack of seasonal distribution in AQP4-Ab and MOG-Ab disease may argue against environment factors playing a role in the aetiopathogenesis of these conditions.

Therapeutic options in neuromyelitis optica spectrum disorders.

Neuromyelitis optica is a relapsing inflammatory disorder of the central nervous system that manifests predominantly with attacks of optic neuritis and longitudinally extensive transverse myelitis; attacks are often severe. In contrast to multiple sclerosis, a secondary progressive phase is rare, and disability in neuromyelitis optica spectrum disorders is related to relapses. Thus, prompt and effective treatment of relapses, and early initiation of long-term immunosuppression to prevent subsequent attacks is required in order to prevent morbidity and mortality.

Pregnancy outcomes in aquaporin-4-positive neuromyelitis optica spectrum disorder.

OBJECTIVE: To investigate the association between neuromyelitis optica spectrum disorder (NMOSD) and pregnancy outcome. METHODS: An international cohort of women with aquaporin-4 antibody-positive NMOSD and ≥1 pregnancy was studied retrospectively. Multivariate logistic regression was used to investigate whether pregnancy after NMOSD onset was associated with an increased risk of miscarriage (cohort of 40 women) or preeclampsia (cohort of 57 women). RESULTS: Miscarriage rate was higher in pregnancies after NMOSD onset (42.9% [95% confidence interval 17.7%-71.1%] vs. 7.04% [2.33%-15.7%]). Pregnancies conceived after, or up to 3 years before, NMOSD onset had an increased odds ratio of miscarriage (7.28 [1.03-51.6] and 11.6 [1.05-128], respectively), independent of maternal age or history of miscarriage. Pregnancies after, or up to 1 year before, NMOSD onset ending in miscarriage were associated with increased disease activity from 9 months before conception to the end of pregnancy, compared to viable pregnancies (mean annualized relapse rate 0.707 vs. 0.100). The preeclampsia rate (11.5% [6.27%-18.9%]) was significantly higher than reported in population studies. The odds of preeclampsia were greater in women with multiple other autoimmune disorders or miscarriage in the most recent previous pregnancy, but NMOSD onset was not a risk factor. CONCLUSIONS: Pregnancy after NMOSD onset is an independent risk factor for miscarriage, and pregnancies conceived at times of high disease activity may be at increased risk of miscarriage. Women who develop NMOSD and have multiple other autoimmune disorders have greater odds of preeclampsia, independent of NMOSD onset timing.

Predictive value of MRI parameters in severity and recovery of first-episode myelitis in aquaporin-4 antibody disease.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) associated with aquaporin-4 antibodies (AQP4-Ab) typically causes longitudinally-extensive transverse myelitis (LETM). Few data exist about the association of MRI features with LETM attack severity and recovery. METHODS: AQP4-Ab positive NMOSD patients with a first myelitis attack were retrospectively identified and spinal MRI scans reviewed. Association of MRI features with EDSS scores at attack nadir and recovery was evaluated. RESULTS: 22 patients were included. Median nadir EDSS score was 8 (range 1 to 8.5). Nadir EDSS scores correlated with total MRI lesion length (r=0.48, p=0.025), higher scores were seen in those with gadolinium enhancement (p=0.025) and there was a trend towards higher scores with central cord involvement. The median recovery EDSS was 6 (range 0 to 10). Total lesion length correlated with poor recovery (r=0.48, p=0.027) but this was confounded by correlation between nadir and recovery EDSS scores. CONCLUSION: We confirm that myelitis in AQP4-Ab disease is severe and show that the severity correlates with lesion length and residual disability. Spinal cord lesions in first myelitis attacks are similar to appearances reported later in the disease course, with propensity to involve the central grey matter and high frequency of cord oedema and T1 hypointensity.

Aquaporin-4 antibody isoform binding specificities do not explain clinical variations in NMO.

OBJECTIVE: To assess the clinical relevance of the differential binding of antibodies against the 2 main aquaporin-4 (AQP4) isoforms in neuromyelitis optica (NMO) patient sera using stably transfected human embryonic kidney cells. METHODS: Flow cytometry of human embryonic kidney cells stably transfected with either M23 or M1 AQP4 was used to measure antibody endpoint titers in 52 remission samples and 26 relapse samples from 34 patients with clinically well-characterized AQP4 antibody-positive NMO/NMO spectrum disorder. RESULTS: The AQP4 M23 (40-61,440) and AQP4 M1 (<20-20,480) titers varied widely between patients, as did the M23:M1 antibody ratio (1-192). In 76 of 78 samples, binding to M23 was higher than binding to M1, including during relapses and remissions (p < 0.0001), and the M23:M1 ratio was relatively constant within an individual patient. Titers usually fell after immunosuppression, but the titers at which relapses occurred varied markedly; no threshold level for relapses could be identified, and relapses could occur without a rise in titers. Relapse severity did not correlate with M23 or M1 antibody titers, although there was a correlation between the earliest M23 titers and annualized relapse rates. The M23:M1 ratio and absolute M23 and M1 titers did not relate to age at disease onset, ethnicity, disease severity, phenotype, or relapses at different anatomical sites. CONCLUSION: Relative AQP4 antibody binding to M23 and M1 isoforms differs between patients but there is no consistent association between these differences and clinical characteristics of disease. Nevertheless, the M23 isoform provided a slightly more sensitive substrate for AQP4-antibody assays, particularly for follow-up studies.

Catastrophic brain relapse in seronegative NMO after a single dose of natalizumab.

Natalizumab, an effective treatment for MS, has been shown to exacerbate neuromyelitis optica (NMO) with aquaporin-4 antibodies, but whether this is the case in antibody negative NMO and atypical MS/NMO spectrum disorder overlap syndromes is unknown. We describe a patient with a relapsing optico-spinal demyelinating syndrome, negative for aquaporin-4 antibodies, who experienced a catastrophic brain relapse shortly after a single dose of natalizumab, highlighting that MS immunomodulatory drugs may worsen demyelination in patients with seronegative NMO and atypical MS/NMO overlap syndromes even if they are aquaporin-4 antibody negative. We summarise the treatments considered safe and effective in NMO, and those with potential to exacerbate disease.

Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study.

IMPORTANCE: Most patients with neuromyelitis optica (NMO) and many with NMO spectrum disorder have autoantibodies against aquaporin-4 (AQP4-Abs), but recently, myelin-oligodendrocyte glycoprotein antibodies (MOG-Abs) have been found in some patients. Here, we showed that patients with NMO/NMOSD with MOG-Abs demonstrate differences when compared with patients with AQP4-Abs. OBJECTIVE: To characterize the features of patients with NMO/NMOSD with MOG-Abs and compare them with patients with AQP4-Ab-positive NMO/NMOSD. DESIGN, SETTING, AND PARTICIPANTS: This observational study was conducted at a single UK specialist center for NMO. Patients with a first demyelinating event between January 1, 2010, and April 1, 2013, seen within the Oxford NMO service and who tested positive for MOG-Abs or AQP4-Abs were included in the study. EXPOSURE: Cell-based assays using C-terminal-truncated human MOG and full-length M23-AQP4 were used to test patient serum samples for AQP4-Abs and MOG-Abs. MAIN OUTCOMES AND MEASURES: Demographic, clinical, and disability data, and magnetic resonance imaging findings. RESULTS: Twenty AQP4-Ab-positive patients and 9 MOG-Ab-positive patients were identified. Most patients in both groups were white. Ninety percent of AQP4-Ab-positive patients but only 44% MOG-Ab-positive patients were females (P = .02) with a trend toward older age at disease onset in AQP4-Ab-positive patients (44.9 vs 32.3 years; P = .05). MOG-Ab-positive patients more frequently presented with simultaneous/sequential optic neuritis and myelitis (44% vs 0%; P = .005). Onset episode severity did not differ between the 2 groups, but patients with MOG-Abs had better outcomes from the onset episode, with better recovery Expanded Disability Status Scale scores and a lower risk for visual and motor disability. Myelin-oligodendrocyte glycoprotein antibody-positive patients were more likely to have conus involvement on spinal magnetic resonance imaging (75% vs 17%; P = .02) and involvement of deep gray nuclei on brain magnetic resonance imaging (P = .03). Cerebrospinal fluid characteristics were similar in the 2 groups. A higher proportion of AQP4-Ab-positive patients relapsed (40% vs 0%; P = .03) despite similar follow-up durations. CONCLUSIONS AND RELEVANCE: Despite the fact that patients with MOG-Abs can fulfill the diagnostic criteria for NMO, there are differences when compared with those with AQP4-Abs. These include a higher proportion of males, younger age, and greater likelihood of involvement of the conus and deep gray matter structures on imaging. Additionally, patients with MOG-Abs had more favorable outcomes. Patients with AQP4-Ab-negative NMO/NMOSD should be tested for MOG-Abs.

Opportunistic infections of the retina in patients with aquaporin-4 antibody disease.

IMPORTANCE: Patients with neuromyelitis optica who have aquaporin-4 antibodies are being identified and receiving immunosuppressant treatment earlier and more aggressively as a result of increasing awareness of the importance of preventing relapses responsible for the high morbidity and mortality associated with the disease. To our knowledge, opportunistic retinal infection in patients with aquaporin-4 antibodies who are receiving immunosuppressants has not been reported to date. OBSERVATIONS: We describe 2 patients with aquaporin-4 antibodies who were receiving conventional doses of first-line immunosuppressive therapy. Both patients presented with vision loss that was initially thought to be optic neuritis attacks. The subsequent diagnoses were ocular toxoplasmosis and cytomegalovirus retinitis. CONCLUSIONS AND RELEVANCE: Retinal opportunistic infections can occur in patients with aquaporin-4 antibodies who are receiving relatively low levels of immunosuppression, may mimic optic neuritis, and are a potentially reversible cause of vision loss when treated promptly.

Longitudinally extensive transverse myelitis with and without aquaporin 4 antibodies.

IMPORTANCE: Aquaporin 4 antibody (AQP4-Ab)-negative patients with longitudinally extensive transverse myelitis (LETM) behave differently from those with AQP4-Ab. Aquaporin 4 antibody-negative neuromyelitis optica (NMO) is rare when good assays are used. OBJECTIVE: To assess if AQP4-Ab-negative patients with LETM share similar disease characteristics with AQP4-Ab-positive patients or whether they have distinct features and alternative diagnoses. DESIGN We collated clinical and paraclinical data on patients with LETM identified through the Oxford NMO clinical database. Aquaporin 4 antibodies were tested using 2 sensitive assays. We describe the features of patients with LETM, compare findings between patients with and without AQP4-Ab, and describe alternative diagnoses in AQP4-Ab-negative patients. SETTING: Single specialist UK center for NMO. PARTICIPANTS: Seventy-six adult patients with LETM. MAIN OUTCOMES AND MEASURES: Comparison of clinical and paraclinical data. RESULTS: Fifty-eight percent of patients were AQP4-Ab positive. Alternative diagnoses could usually be identified in AQP4-Ab-negative patients, including those fulfilling NMO diagnostic criteria. Only 6.5% of patients had "true" seronegative NMO and 6.5% had idiopathic LETM. There were some important differences between AQP4-Ab-positive and -negative cases, including older onset age, higher proportion of females, lower incidence of simultaneous optic neuritis, lower frequency of conus involvement, and higher prevalence of coexisting autoimmune disorders in AQP4-Ab-positive cases. Attack severity and degree of recovery were similar in the 2 groups. CONCLUSIONS AND RELEVANCE: Patients with LETM without AQP4-Ab include a number of different diagnostic categories and it is not surprising therefore that they show important differences compared with AQP4-Ab-positive patients, even when considering only those fulfilling current NMO diagnostic criteria. Thus, we suggest that diagnoses such as myelin-oligodendrocyte glycoprotein antibody disease, multiple sclerosis, acute disseminated encephalomyelitis, and postinfectious disorders should be exclusions in the NMO diagnostic criteria and AQP4-Ab-positive and antibody-negative NMO/NMO spectrum disorder cohorts should be analyzed separately.

Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype.

OBJECTIVES: To report an association of myelin-oligodendrocyte glycoprotein (MOG) antibodies with aquaporin-4 (AQP4) antibody-seronegative neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) in adults. METHODS: We describe the clinical and serologic features of 4 adult patients with an NMO/NMOSD phenotype who had antibodies to MOG. RESULTS: Twenty-seven adult AQP4-seronegative NMO/NMOSD patients were tested for MOG antibodies. Four patients (3 male, 1 female) with severe optic neuritis and/or longitudinally extensive transverse myelitis were positive. All 4 made good recoveries with steroids or plasma exchange. Two patients experienced recurrence of symptoms when corticosteroids were withdrawn quickly but none have experienced further relapses over a mean follow-up of 12 months, although 3 patients remain on treatment. Imaging abnormalities resolved fully following clinical recovery and MOG antibody titers fell in all 4 patients. MOG antibodies were not found in 44 AQP4 antibody-positive NMO/NMOSD patients, 75 adult patients with multiple sclerosis, or 47 healthy individuals. CONCLUSIONS: MOG antibody-associated NMO/NMOSD could account for some cases thought previously to be AQP4-seronegative NMO/NMOSD. Our 4 patients appear to have more favorable clinical outcomes than those with typical AQP4 antibody-mediated disease. However, further studies of NMO/NMOSD and other demyelinating conditions are required to help clarify the diagnostic and prognostic relevance of MOG antibodies.

Neurologic manifestations of the cryopyrin-associated periodic syndrome.

BACKGROUND: The cryopyrin-associated periodic syndrome (CAPS) is a rare but treatable hereditary autoinflammatory condition. Without treatment, one third of patients develop amyloidosis with consequent renal failure and death. CAPS encompasses 3 conditions: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile, neurologic, cutaneous, and articular syndrome. Neurologic complications are common in children with the chronic infantile, neurologic, cutaneous, and articular phenotype, but there are no previous published reports of neurologic features in adults with milder phenotypes. METHODS: In this case series, we report in detail an adult case of CAPS and summarize the neurologic features seen in 12 other adults with genetically proven CAPS. These patients participated in a recent randomized study of canakinumab in CAPS and we used pretreatment data collected in this study. RESULTS: Twelve of the 13 patients (92%) had headache, of whom 10 (77%) had features of migraine. Seven patients (54%) had sensorineural deafness. Nine patients (69%) reported myalgia. Six patients (46%) had papilledema and a further 2 (15%) had optic disc pallor. MRI brain scan was normal in all patients. CONCLUSION: CAPS is a rare but treatable condition that may be encountered by neurologists in adult clinical practice since it can present with headache, myalgia, papilledema, sensorineural deafness, and aseptic meningitis. Unrecognized and untreated, it can lead to significant morbidity and mortality from renal failure. Treatment with anti-interleukin-1 therapy leads to complete resolution of symptoms and should also prevent progression to amyloidosis and subsequent renal failure.