Optic neuritis in Asian type opticospinal multiple sclerosis (OSMS-ON) in a non-Asian population: A functional-structural paradox.

BACKGROUND: Biomarkers have improved the classification of autoimmune inflammatory disorders, including optic neuritis (ON) as a frequent presentation of multiple sclerosis, neuromyelitis spectrum disorders, MOG antibody-related disease (MOGAD), and opticospinal multiple sclerosis (OSMS). The phenotype of OSMS in non-Asian populations is less well known. OBJECTIVE: We investigated the clinical features and prognosis of OSMS-ON in a Brazilian cohort. METHODS: This was a single-center cohort study of patients from Rio de Janeiro (Brazil) with OSMS. All individuals were MOG- and AQP4-seronegative, clinically diagnosed with ON, and had magnetic resonance imaging-confirmed transverse myelitis (TM). Subjects and healthy controls (HCs) were assessed for visual acuity (logMAR VA), automated perimetry mean deviation (MD), intraocular pressure, and spectral-domain optical coherence tomography (OCT), followed by automated retinal layer segmentation of the peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (mGCIPL). Receiver operator characteristic curves were plotted and the area under the curve (AUC) was calculated for group comparisons of retinal asymmetry of the pRNFL and mGCIPL. RESULTS: The 30 patients with OSMS were predominantly female and white. The mean age was 48 years (range 20-70 years). Unilateral ON was the index event in 83.3% of patients. Over the average 18-year follow-up period, there were 89 relapses of ON. In individuals with OSMS, the average VA was 0.07±0.14 in the right eye (RE) and 0.13±0.30 in the left eye (LE). The MD was -5.37±5.88 dB and -5.23±3.34 dB for the RE and LE, respectively. There was a significant cumulative loss of VA (p = 0.0003) and MD (p = 0.0001) with a higher number of recurrent episodes. Atrophy of the pRNFL thickness was significant in OSMS (RE, 78.62 ± 16.01 µm; LE, 79.86 ± 13.79 µm) relative to the HC group (RE, 98.87 ± 10.68 µm; LE, 97.87 ± 10.85 µm, p = 0.0001). Likewise, there was significant mGCIPL atrophy in patients with OSMS (RE, 74.96 ± 14.46 µm; LE, 73.88 ± 13.79 µm) relative to the HC group (RE, 90.50 ± 6.74 µm; LE, 90.41± 6.89 µm; p = 0.0001). Retinal asymmetry, inter-eye percentage, and absolute differences accurately separated patients with unilateral ON from HCs (AUC=0.89 and AUC=0.85, respectively). CONCLUSION: A structural-functional paradox was found in OSMS with a high diagnostic value for a novel metric based on retinal asymmetry. The functional visual outcome are excellent despite significant structural damage to the inner retinal layers in patients with a high ON relapse rate and long-term bilateral sequential involvement.

Neuromyelitis optica is an HLA associated disease different from Multiple Sclerosis: a systematic review with meta-analysis.

Neuromyelitis Optica and Multiple Sclerosis are idiopathic inflammatory demyelinating diseases of the central nervous system that currently are considered distinct autoimmune diseases, so differences in genetic susceptibility would be expected. This study aimed to investigate the HLA association with Neuromyelitis Optica by a systematic review with meta-analysis. The STROBE instrument guided research paper assessments. Thirteen papers published between 2009 and 2020 were eligible. 568 Neuromyelitis Optica patients, 41.4% Asians, 32.4% Latin Americans and 26.2% Europeans were analyzed. Only alleles of the DRB1 locus were genotyped in all studies. Neuromyelitis Optica patients have 2.46 more chances of having the DRB1*03 allelic group than controls. Ethnicity can influence genetic susceptibility. The main HLA association with Neuromyelitis Optica was the DRB1*03:01 allele in Western populations and with the DPB1*05:01 allele in Asia. Differences in the Multiple Sclerosis and Neuromyelitis Optica genetic susceptibility was confirmed in Afro descendants. The DRB1*03 allelic group associated with Neuromyelitis Optica has also been described in other systemic autoimmune diseases.

Is Asian type MS an MS phenotype, an NMO spectrum disorder, or a MOG-IgG related disease?

BACKGROUND: A specific particularity of neurological diseases in Asia is the relative commonality of neuromyelitis optica (NMO) and Asian type MS (OSMS). Both conditions also occur in South American patients. The Brazilian population differs from the European and the Asian populations due to the mixture of ancestralities between European colonizers and African slaves. To better know the clinical characteristics of Brazilian patients with Asian type MS this study aimed to analyze the clinical, radiological and serological data that would help to distinguish between OSMS and NMO and clarify, in a Non-Asian population, if OSMS is an MS phenotype, an NMO spectrum disorder by 2015 classification, or a complement activating antibody to myelin oligodendrocyte glycoprotein (MOG-IgG) antibody-related disease. METHODS: We selected cases retrospectively with NMO and OSMS in the medical registry of patients with idiopathic inflammatory demyelinating diseases under follow-up since 1997 in Federal Hospital da Lagoa, the principal reference center for MS treatment in Rio de Janeiro, Brazil. OSMS has selective involvement of the optic nerve and spinal cord with no cerebral or cerebellar symptoms associated with small spinal cord lesions and negativity for the aquaporin-4 antibody (AQP4-IgG). NMO full-filled the revised criteria (2006) associated with longitudinally extensive transverse myelitis (LETM). We recorded the following data: ethnicity/skin color, neurologic impairment "at nadir" and "at recovery" of the index events (optic neuritis and transverse myelitis), long term disability, mortality, health quality of life scores by the SF-36 questionnaire, CSF IgG oligoclonal bands and serological AQP4-IgG and MOG-IgG antibodies tested by Cell-based assay. The last brain MRIs were classified as either satisfying or not satisfying MAGNIMS radiologic criteria for MS or typical or not typical for NMOSD. The new classification of NMO spectrum disorders (2015) was applied. RESULTS: Forty-one OSMS and 122 NMO cases were analyzed. OSMS affected mainly young white women, causing unilateral optic neuritis and partial myelitis with excellent recovery. After a mean disease duration of 20 years, 90% of the patients had free ambulation, and 70% had a mild disability or no disability. Only 7.2% presented a secondary progressive course, and no deaths occurred. All cases had negativity to AQP4-IgG and MOG-IgG biomarkers. 95% had resonance criteria for MS. OSMS differed from NMO by ethnicity, morbidity, and mortality: most were African descendants, with severe motor and visual dysfunction, and one third died. Only NMO cases full-filled the new NMOSD classification (52 AQP4-IgG positive, 29 AQP4-IgG negative, and 41 AQP4-IgG unknown). CONCLUSION: In Brazilian patients, OSMS and NMO are different immune-mediated diseases. OSMS is a milder MS phenotype.

Neuromyelitis optica and pregnancy-puerperal cycle.

INTRODUCTION: Since neuromyelitis optic is a disease associated with humoral immunity (Th2), it is speculated that the pregnancy period is associated with increased relapses of the disease, as well as the presence of aquaporin 4 in the placental tissue, could lead to gestational loss. The aim of this study is to evaluate the influence of the puerperal pregnancy cycle on the course of NMO. METHODS: Interviewed women with gestation after diagnosis of optic neuromyelitis and submitted to questionnaires with data on the disease, such as annualized rate of relapses and EDSS score before, during and after gestation. Gestational complications were also investigated. RESULTS AND DISCUSSION: 19 women with 30 pregnancies. In only 8 pregnancies, there were no relapses up to 1 year postpartum, some associated with the use of immunosuppressants and/or human immunoglobulin in immediate delivery. Annualized relapses rates stood out in the puerperal period, especially in the first 3 months postpartum, in relation to before- pregnancy ARR. It was observed that pregnancy also increased functional disability in these women. Gestational complications such as miscarriage have not been shown to be more frequent in pregnant women with NMO than in the general population.

Pediatric Multiple Sclerosis in Rio de Janeiro: Secondary Progression and Disability.

BACKGROUND: The onset of multiple sclerosis (MS) in 2% to 10% of cases occurs prior to 18 years of age. Early age onset appears to affect some aspects of multiple sclerosis. The objective of our study was to evaluate the prevalence, the clinical and demographic characteristics, and the disease progression in a sample of pediatric multiple sclerosis patients from a mixed population. METHODS: In a cross-sectional design, the prevalence, demographic characteristics, and initial clinical forms were compared between 75 cases of pediatric multiple sclerosis (PMS) and 689 adults with MS. Sixty-five PMS patients with complete data and 260 randomly selected adults with relapsing-remitting multiple sclerosis were compared. A Kaplan-Meier analysis was conducted to compare the age at and time to Expanded Disability Status Scale (EDSS) 3, EDSS 6, and secondary progressive multiple sclerosis (SPMS). RESULTS: A total of 9.8% of all MS cases with available data were PMS. All cases of PMS consisted of relapsing-remitting multiple sclerosis. Brazilians of African descent comprised 34.6% of the sample, and the female-to-male ratio was 2.4:1. At the first attack, motor alterations were more common. Benign forms were more common in PMS (84.6% versus 62.2%). Fewer PMS patients reached EDSS 6 (11.6% versus 25.4%) (P = 0.0017) and SPMS (11.1% versus 28.1%) (P = 0.005). PMS patients took longer to reach EDSS 3 (P = 0.017), EDSS 6 (P = 0.001), and SPMS (P < 0.001); however, they reached EDSS 3 earlier (P < 0.001). CONCLUSIONS: In this mixed cohort, the prevalence of PMS was similar to that reported in other studies, and the pediatric patients had a more benign course than adults with MS.

Lower frequency of antibodies to MOG in Brazilian patients with demyelinating diseases: An ethnicity influence?

OBJECTIVE: Antibodies against Myelin Oligodendrocyte glycoprotein (MOG-Ab) have been investigated as potential biological marker for neuromyelitis optica (NMO) and high-risk syndromes (HR) negative for AQP4-Ab in populations with different ethnic background. We tested AQP4 and MOG antibodies in a Brazilian population with high African ethnic background. METHOD: The study population was composed of adult patients from Rio de Janeiro with inflammatory demyelinating diseases (new and old cases). Blood samples were sent blindly to test the AQP4 and MOG antibodies by CBA. The frequency of positive MOG-Ab was estimated in the NMOHR and the NMO spectrum disorders (NMOSD). A systematic review with meta-analysis assessed the frequency of MOG-Ab in Caucasians and non-Caucasians. RESULTS: 200 adult patients (52% Afro-Brazilian) 115 of them with NMOHR were tested. MOG antibodies were found in 5/68 negative cases of AQP4-Ab negative (7%). The criteria for NMOSD were fulfilled by 70 patients with NMOHR and none of them was positive for MOG-Ab. A low prevalence of MOG antibodies and a predominant phenotype of bilateral Optic Neuritis were found in most non-Caucasian patients. CONCLUSION: The low frequency of MOG Ab in patients from Rio de Janeiro and in other non-Caucasian populations suggests a racial/ancestral influence.

Prognostic factors associated with long-term disability and secondary progression in patients with Multiple Sclerosis.

BACKGROUND: Predicting the long-term prognosis of patients with multiple sclerosis (MS) remains an uncertain and difficult task, with most data having been obtained exclusively from Caucasian cohorts. OBJECTIVE: To investigate clinical prognostic factors in a Brazilian mixed-race cohort. METHODS: Demographic, clinical and therapeutic factors were investigated in 303 patients with relapsing-remitting MS in relation to the following outcomes: time until reaching Expanded Disability Status Scale (EDSS) 3 and EDSS 6, and until secondary progression. RESULTS: Benign course was significantly more frequent among Caucasians when compared to Afrodescendants. Patients with a malignant course had more than one relapse in the first year of the disease and reached EDSS 3 faster if treatment was not started. In the multivariate analysis, the following factors were associated with a significantly shorter time until the established outcomes: male gender, being of African descent, non-recovery after the first relapse, two or more relapses during the first year, a short interval between initial relapses, initial polysymptomatic presentation of pyramidal and cerebellar dysfunction and no treatment prior to reaching EDSS 3. CONCLUSIONS: Being of African descent was found to be an unfavorable factor for all outcomes, reinforcing the need to take ethnicity into consideration when defining treatment, particularly in mixed MS populations.

Central Nervous System Idiopathic Inflammatory Demyelinating Disorders in South Americans: A Descriptive, Multicenter, Cross-Sectional Study.

The idiopathic inflammatory demyelinating disease (IIDD) spectrum has been investigated among different populations, and the results have indicated a low relative frequency of neuromyelitis optica (NMO) among multiple sclerosis (MS) cases in whites (1.2%-1.5%), increasing in Mestizos (8%) and Africans (15.4%-27.5%) living in areas of low MS prevalence. South America (SA) was colonized by Europeans from the Iberian Peninsula, and their miscegenation with natives and Africans slaves resulted in significant racial mixing. The current study analyzed the IIDD spectrum in SA after accounting for the ethnic heterogeneity of its population. A cross-sectional multicenter study was performed. Only individuals followed in 2011 with a confirmed diagnosis of IIDD using new diagnostic criteria were considered eligible. Patients' demographic, clinical and laboratory data were collected. In all, 1,917 individuals from 22 MS centers were included (73.7% female, 63.0% white, 28.0% African, 7.0% Mestizo, and 0.2% Asian). The main disease categories and their associated frequencies were MS (76.9%), NMO (11.8%), other NMO syndromes (6.5%), CIS (3.5%), ADEM (1.0%), and acute encephalopathy (0.4%). Females predominated in all main categories. The white ethnicity also predominated, except in NMO. Except in ADEM, the disease onset occurred between 20 and 39 years old, early onset in 8.2% of all cases, and late onset occurred in 8.9%. The long-term morbidity after a mean disease time of 9.28±7.7 years was characterized by mild disability in all categories except in NMO, which was scored as moderate. Disease time among those with MS was positively correlated with the expanded disability status scale (EDSS) score (r=0.374; p=<0.001). This correlation was not observed in people with NMO or those with other NMO spectrum disorders (NMOSDs). Among patients with NMO, 83.2% showed a relapsing-remitting course, and 16.8% showed a monophasic course. The NMO-IgG antibody tested using indirect immunofluorescence (IIF) with a composite substrate of mouse tissues in 200 NMOSD cases was positive in people with NMO (95/162; 58.6%), longitudinally extensive transverse myelitis (10/30; 33.3%) and bilateral or recurrent optic neuritis (8/8; 100%). No association of NMO-IgG antibody positivity was found with gender, age at onset, ethnicity, early or late onset forms, disease course, or long-term severe disability. The relative frequency of NMO among relapsing-remitting MS (RRMS) + NMO cases in SA was 14.0%. Despite the high degree of miscegenation found in SA, MS affects three quarters of all patients with IIDD, mainly white young women who share similar clinical characteristics to those in Western populations in the northern hemisphere, with the exception of ethnicity; approximately one-third of all cases occur among non-white individuals. At the last assessment, the majority of RRMS patients showed mild disability, and the risk for secondary progression was significantly superior among those of African ethnicity. NMO comprises 11.8% of all IIDD cases in SA, affecting mostly young African-Brazilian women, evolving with a recurrent course and causing moderate or severe disability in both ethnic groups. The South-North gradient with increasing NMO and non-white individuals from Argentina, Paraguay, Brazil and Venezuela confirmed previous studies showing a higher frequency of NMO among non-white populations.

The effects of long-term exposure to disease-modifying drugs during pregnancy in multiple sclerosis.

BACKGROUND AND OBJECTIVE: Women with multiple sclerosis (MS) who intend to get pregnant are often advised to discontinue disease modifying therapy (DMT) prior to conception. This recommendation is not based on medical evidence and may interfere with disease control by immunomodulatory drugs. The present study was designed to help discuss the effect of DMT for MS on pregnancy and on disease course. PATIENTS AND METHODS: Retrospective data from 152 pregnancies of 132 women with MS were collected by the physician in charge of the case. All data were entered into a specific file for qualitative and quantitative statistical analysis. RESULTS: From the total group of patients, 89 pregnancies occurred without any exposure to MS drugs, while 61 pregnancies occurred with at least eight weeks of exposure to MS immunomodulatory drugs. The rate of obstetric and neonatal complications was similar in both groups, except for the newborn weight and height which was smaller for mothers receiving medications. Mothers' post-delivery relapse rate and EDSS scores in the follow-up period were significantly higher in the absence of treatment. CONCLUSION: It is possible that, with further such supportive data, international guidelines on MS treatment in young women who intend to get pregnant may need to be revised.

Anti-AQP(4) antibody in idiopathic acute transverse myelitis with recurrent clinical course: frequency of positivity and influence in prognosis.

BACKGROUND: The anti-aquaporin4 (anti-AQP4) antibody is specific for neuromyelitis optica (NMO), but is also found in limited forms. The presence of this antibody in acute transverse myelitis (ATM) has been associated with recurrence and conversion to NMO, but the influence on disability has not yet been described. OBJECTIVE: To describe the frequency of anti-AQP4 in ATM and analyze the influence in long-term prognosis. DESIGN: Cross-sectional and retrospective study. METHODS: Consecutive ATM cases in a multiple sclerosis center in Rio de Janeiro, Brazil, from 2000 through 2009 were reviewed. Recurrent cases tested for anti-AQP4 were selected. ATM with magnetic resonance imaging spinal cord lesions extending over three or more vertebral segments was classified as longitudinally extensive transverse myelitis (LETM); Kurtzke scale was applied at last evaluation. OUTCOME MEASURES: Frequency of anti-AQP4; severity of spinal cord dysfunction at last follow-up. RESULTS: Twenty six patients (21 female:5 male; 17 white:9 African descent) were studied. The first ATM occurred at 38.04 ± 12.7 years. The interval between the first and the second ATM was eight months (1-150) and the number of ATM varied from two to seven. After 40.5 months (12-192) of disease, the median Expanded Disability Status Scale (EDSS) score was three (0-9). Anti-AQP4 antibody was positive in 26.9%. LETM was found in 65.4%. LETM presented later onset, higher disability and higher positivity to anti-AQP4 (LETM 41.2% versus no-LETM 0%, P = 0.024). Dysfunction at long-term follow-up was similar in anti-AQP4 positive and negative cases. CONCLUSION: The frequency of anti-AQP4 in recurrent ATM was 26.9%, increasing to 41.2% among LETM. Presence of the antibody had no influence on morbidity.

The efficacy of natalizumab in patients with multiple sclerosis according to level of disability: results of an observational study.

BACKGROUND: Little is known about how the level of disability at the start of treatment with natalizumab affects its efficacy. OBJECTIVES: The aim of this study was to investigate the effect of natalizumab on relapses in patients with different levels of baseline disability associated with MS. METHODS: This single-centre observational study collected demographic data for patients followed prospectively and who were scheduled to start natalizumab therapy due to the presence of disease activity. The annualized relapse rate (ARR) and Kurtzke Expanded Disability Status Scale scores were analysed for the previous year, on starting treatment (baseline) and 1 year after starting therapy. RESULTS: Seventy-seven patients (mean age: 39.0 years, mean disease duration: 12.4 years) were included. The difference between ARR before and after starting treatment was 0.92 for baseline Expanded Disability Status Scale ≤ 3.5 (p < 0.0005), 0.70 for Expanded Disability Status Scale 4.0-6.0 (p < 0.007) and 0.57 for Expanded Disability Status Scale ≥ 6 (p = 0.386). Expanded Disability Status Scale did not vary during the study. One patient discontinued treatment due to an adverse event and nine patients discontinued due to positive anti-natalizumab antibodies. CONCLUSIONS: The findings support the efficacy of natalizumab in reducing ARR in the year after starting treatment in patients with baseline Expanded Disability Status Scale ≤ 6.

Kinetics and incidence of anti-natalizumab antibodies in multiple sclerosis patients on treatment for 18 months.

Natalizumab is a monoclonal antibody shown to be highly effective in the treatment of relapsing-remitting multiple sclerosis (RRMS). Patients treated with natalizumab can develop antibodies directed against this agent that may affect the efficacy and safety of the drug. In this observational study, the kinetics of the appearance and the incidence of anti-natalizumab antibodies were followed prospectively for 18 months in a cohort of 64 consecutive patients treated with natalizumab for relapsing MS. Blood samples were drawn immediately before starting natalizumab therapy and each month afterwards. The presence of antibodies against natalizumab was assessed by enzyme-linked immunosorbent assay (ELISA) in all patients. Anti-natalizumab antibodies were detected in nine (14.1%) natalizumab-treated patients, three (4.68%) of whom were transiently positive while six (9.37%) were persistently positive (these patients discontinued natalizumab). All positive titres were observed during the first 4 months of treatment. One patient with a hypersensitivity reaction also had persistent antibodies. We conclude that antibodies against natalizumab develop early, within the first 6 months of therapy with natalizumab. Although no antibodies were detected after 4 months of therapy in this particular study, this does not rule out their development later on in exceptional cases.

The clinical course of idiopathic acute transverse myelitis in patients from Rio de Janeiro.

The aim of this study was to describe the demographic, clinical and laboratory features of idiopathic acute transverse myelitis (IATM). Patients with non-compressive ATM receiving care at Hospital da Lagoa, Rio de Janeiro (Brazil) between 2000 and 2008 were selected. Of the 70 cases of acute myelopathies, the idiopathic form was identified in 41 following exclusion of the cases associated with systemic lupus erythematosus (n = 1), Sjogren's syndrome (n = 1), herpes zoster (n = 1), cytomegalovirus in an HIV-positive patient (n = 1), Schistosoma mansoni (n = 1), actinic myelitis (n = 1), infectious myelitis of unknown etiology (n = 2) and those that, following the first attack of myelitis, converted to NMO (n = 19) or to clinically defined MS (n = 2). Of the 41 cases of IATM, the majority of patients were female (68.3%) and white (65.9%). Median age at first myelitis was 37.0 +/- 11.8 years. Over a median observation time of 36 months, 39.0% of patients remained monophasic, while recurrences occurred in 61.0% of cases. The number of ATM/patient ranged from one to seven. Among the recurrent cases the median time between the first and the second ATM was 12 months (range 1-150 months).The first myelitis was characterized mainly by partial myelitis with motor and sensorial dysfunction (63.4%). Complete and severe myelitis occurred more frequently among monophasic patients and partial myelitis with moderate dysfunction at onset in recurrent cases; however, over the long-term, dysfunction and disability were mild in both groups. Serial spine MRI confirmed spinal cord inflammation in 92.0% of cases and extensive spinal cord lesion was identified in 61.0%. Brain MRI was normal or not suggestive of MS in 94.4% of cases. CSF showed pleocytosis in 41.2%, increased IgG index in 24.0% and oligoclonal bands in 38.0% of 34 patients tested. Abnormal visual evoked potentials occurred in 11.5% of 26 patients. Positivity for anti-AQP4 was found in 23.5% of the 17 cases tested, suggesting limited forms of NMO. This study suggests some new aspects of the clinical course of IATM such as the high conversion rate to NMO, the predominance of women and a higher frequency of recurrent forms.

Clinical course of optic neuritis in patients with relapsing neuromyelitis optica.

OBJECTIVE: To describe the clinical characteristics, course, and prognosis of optic neuritis in recurrent neuromyelitis optica. METHODS: We analyzed 60 patients diagnosed using 1999 Mayo Clinic criteria who were seen between 1985 and 2004 at Hospital da Lagoa (Rio de Janeiro, Brazil). RESULTS: Optic neuritis was the initial feature in 53.3% of patients, most with unilateral disease. Recurrent optic neuritis before myelitis occurred in 18.3%. The visual impairment was severe at nadir of the visual index event in 78.3%, with a high remission rate. In the median disease duration of 8 years (range, 0.5-30 years), 380 relapses (118 optic neuritis, 223 myelitis, 39 optic neuritis and myelitis) occurred. At the last follow-up, 53.3% of patients had bilateral visual impairment and 63.3% were blind in at least 1 eye. A high mortality rate (23.3%) was due to cervical myelitis. Mortality rates were significantly higher among Afro Brazilian patients (58.3%). CONCLUSIONS: Optic neuritis in patients with recurrent neuromyelitis optica has a severe and acute onset, with predominantly unilateral lesions followed by improvement of clinical symptoms. In the long-term, the disease leads to severe bilateral visual impairment. Mortality rates are higher among patients of Afro Brazilian descent.