Oral corticosteroid dosage and taper duration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse.

BACKGROUND: We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure. METHODS: In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy. RESULTS: We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8-38); median follow-up 6.2 years (IQR 2.6-9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect. CONCLUSIONS: The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients. METHODS: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated. RESULTS: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%). CONCLUSIONS: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

The association between disability progression, relapses, and treatment in early relapse onset MS: an observational, multi-centre, longitudinal cohort study.

The indirect contribution of multiple sclerosis (MS) relapses to disability worsening outcomes, and vice-versa, remains unclear. Disease modifying therapies (DMTs) are potential modulators of this association. Understanding how these endo-phenotypes interact may provide insights into disease pathogenesis and treatment practice in relapse-onset MS (ROMS). Utilising a unique, prospectively collected clinical data from a longitudinal cohort of 279 first demyelinating event cases followed for up to 15 years post-onset, we examined indirect associations between relapses and treatment and the risk of disability worsening, and vice-versa. Indirect association parameters were estimated using joint models for longitudinal and survival data. Early relapses within 2.5 years of MS onset predicted early disability worsening outcomes (HR = 3.45, C.I 2.29-3.61) per relapse, but did not contribute to long-term disability worsening thereinafter (HR = 0.21, C.I 0.15-0.28). Conversely, disability worsening outcomes significantly contributed to relapse risk each year (HR = 2.96, C.I 2.91-3.02), and persisted over time (HR = 3.34, C.I 2.90-3.86), regardless of DMT treatments. The duration of DMTs significantly reduced the hazards of relapses (1st-line DMTs: HR = 0.68, C.I 0.58-0.79; 3rd-line DMTs: HR = 0.37, C.I 0.32-0.44) and disability worsening events (1st-line DMTs: HR = 0.74, C.I 0.69-0.79; 3rd-line DMTs: HR = 0.90, C.I 0.85-0.95), respectively. Results from time-dynamic survival probabilities further revealed individuals having higher risk of future relapses and disability worsening outcomes, respectively. The study provided evidence that in ROMS, relapses accrued within 2.5 years of MS onset are strong indicators of disability worsening outcomes, but late relapses accrued 2.5 years post onset are not overt risk factors for further disability worsening. In contrast, disability worsening outcomes are strong positive predictors of current and subsequent relapse risk. Long-term DMT use and older age strongly influence the individual outcomes and their associations.

A pro-inflammatory diet in people with multiple sclerosis is associated with an increased rate of relapse and increased FLAIR lesion volume on MRI in early multiple sclerosis: A prospective cohort study.

BACKGROUND: A pro-inflammatory diet has been posited to induce chronic inflammation within the central nervous system (CNS), and multiple sclerosis (MS) is an inflammatory disease of the CNS. OBJECTIVE: We examined whether Dietary Inflammatory Index (DII®)) scores are associated with measures of MS progression and inflammatory activity. METHODS: A cohort with a first clinical diagnosis of CNS demyelination was followed annually (10 years, n = 223). At baseline, 5- and 10-year reviews, DII and energy-adjusted DII (E-DIITM) scores were calculated (food frequency questionnaire) and assessed as predictors of relapses, annualised change in disability (Expanded Disability Status Scale) and two magnetic resonance imaging measures; fluid-attenuated inversion recovery (FLAIR) lesion volume and black hole lesion volume. RESULTS: A more pro-inflammatory diet was associated with a higher relapse risk (highest vs. lowest E-DII quartile: hazard ratio = 2.24, 95% confidence interval (CI) = -1.16, 4.33, p = 0.02). When we limited analyses to those assessed on the same manufacturer of scanner and those with a first demyelinating event at study entry (to reduce error and disease heterogeneity), an association between E-DII score and FLAIR lesion volume was evident (ß = 0.38, 95% CI = 0.04, 0.72, p = 0.03). CONCLUSION: There is a longitudinal association between a higher DII and a worsening in relapse rate and periventricular FLAIR lesion volume in people with MS.

Genetically determined serum serine level has a novel causal effect on multiple sclerosis risk and predicts disability progression.

BACKGROUND: There are currently no specific biomarkers for multiple sclerosis (MS). Identifying robust biomarkers for MS is crucial to improve disease diagnosis and management. METHODS: This study first used six Mendelian randomisation methods to assess causal relationship of 174 metabolites with MS, incorporating data from European-ancestry metabolomics (n=8569-86 507) and MS (n=14 802 MS cases, 26 703 controls) genomewide association studies. Genetic scores for identified causal metabolite(s) were then computed to predict MS disability progression in an independent longitudinal cohort (AusLong study) of 203 MS cases with up to 15-year follow-up. RESULTS: We found a novel genetic causal effect of serine on MS onset (OR=1.67, 95% CI 1.51 to 1.84, p=1.73×10-20), such that individuals whose serine level is 1 SD above the population mean will have 1.67 times the risk of developing MS. This is robust across all sensitivity methods (OR ranges from 1.49 to 1.67). In an independent longitudinal MS cohort, we then constructed time-dynamic and time-fixed genetic scores based on serine genetic instrument single-nucleotide polymorphisms, where higher scores for raised serum serine level were associated with increased risk of disability worsening, especially in the time-dynamic model (RR=1.25, 95% CI 1.10 to 1.42, p=7.52×10-4). CONCLUSIONS: These findings support investigating serine as an important candidate biomarker for MS onset and disability progression.

Ensemble machine learning identifies genetic loci associated with future worsening of disability in people with multiple sclerosis.

Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR 0.92, P = 2.4 × 10-5; rs12211604: HR 1.16, P = 3.2 × 10-7; rs55858457: HR 0.93, P = 3.7 × 10-7; rs10271373: HR 0.90, P = 1.1 × 10-7; rs11256593: HR 1.13, P = 5.1 × 10-57; rs12588969: HR = 1.10, P = 2.1 × 10-10; rs1465697: HR 1.09, P = 1.7 × 10-128) associated with risk worsening of disability; most of which were located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles produced a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.

Response to treatment in NMOSD: the Australasian experience.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is associated with significant morbidity and mortality. Several therapies have been recommended for NMOSD and more recently clinical trials have demonstrated efficacy for three monoclonal antibody therapies. We present a retrospective observational study of treatment response in NMOSD. METHODS: This was a retrospective, unblinded, observational study of treatment efficacy for rituximab and traditional immunosuppressive therapy in patients with AQP4 antibody positive NMOSD. Treatment efficacy was assessed using annualised relapse rates (ARR), time to first relapse and expanded disability status scale (EDSS) scores. RESULTS: Complete relapse and treatment data were available for 43/68 (63%) of AQP4 antibody positive NMOSD cases covering 74 episodes of treatment. In a time to first relapse analysis rituximab showed a risk ratio of 0.23 (95% CI 0.08 - 0.65) when compared with no treatment and there was a non-significant reduction in ARR of 35% compared to pre-treatment. ß-interferon (p = 0.0002) and cyclophosphamide (p = 0.0034) were associated with an increased ARR compared to pre-treatment. Rituximab (median 4.0 [range 0.0 - 7.0]; p = 0.042) and traditional immunosuppressive therapy (median 4.0 [range 0.0 - 8.0]; p = 0.016) were associated with a lower final EDSS compared to ß-interferon (median 6.0 [range 4.0 - 7.5]). CONCLUSIONS: These data provide additional support for the use of rituximab in preference to traditional immunosuppressive agents and MS disease modifying therapies as first line treatment of NMOSD.

Low vitamin D levels do not predict risk of autoimmune disease following alemtuzumab treatment for multiple sclerosis.

Alemtuzumab is a highly effective treatment for multiple sclerosis (MS) and the treatment strategy of two cycles 12 months apart has a lot of appeal to patients. Widespread use of alemtuzumab has been tempered by treatment emergent autoimmunity which is seen in approximately one-third of patients in the 5 years after treatment. It has been postulated that relative vitamin D deficiency may be a causative factor in this setting. We have conducted a retrospective case-control study looking at the association of vitamin D and other potentially relevant clinical factors on the likelihood of treatment emergent autoimmune disease following alemtuzumab. Occurrence of autoimmunity was monitored for clinically and through the Bloodwatch® monitoring program. Clinical data and vitamin D levels obtained as part of routine clinical practice were recorded. Vitamin D levels were seasonally adjusted. Only cases with complete data were included. Univariable and multivariable Cox proportional hazards analyses were performed. There were 113 patients treated with alemtuzumab for whom there was complete data. Median follow up was 4.4 years. Risk of autoimmune disease was not associated with lower vitamin D levels. Risk of autoimmune disease was associated with female sex (HR 3.5) and with higher EDSS score at treatment. The association with EDSS was lost when analysis was restricted to those with 4 or more years of follow up. These data do not support a role for vitamin D supplementation in the prevention of autoimmune disease following alemtuzumab. Males have a lower risk of autoimmunity following alemtuzumab.

NMOSD and MS prevalence in the Indigenous populations of Australia and New Zealand.

BACKGROUND: We studied the prevalence of neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) in Indigenous populations of Australia and New Zealand with the aim of assessing potential differences. METHODS: Cases of possible NMOSD and MS were collected from Australia and New Zealand. Clinical details, MR imaging, and serologic results were used to apply 2015 IPND diagnostic criteria for NMOSD and 2010 McDonald criteria for MS. Frequencies of self-determined ethnic ancestry were calculated for confirmed NMOSD, suspected NMOSD, and MS. Prevalence rates for NMOSD and MS according to ancestry were compared. RESULTS: There were 75 cases with NMOSD, 89 with suspected NMSOD, and 101 with MS. NMOSD cases were more likely to have Asian, Indigenous, or Other ancestry compared to suspected NMOSD or MS. There were no differences in the clinical phenotype of NMOSD seen in Indigenous compared to European ancestry populations. Per 100,000, the prevalence estimate for NMOSD in people with Maori ancestry was 1.50 (95% CI 0.52-2.49) which was similar to those with Asian ancestry 1.57 (95% CI 1.15-1.98). NMOSD prevalence in Australian Aboriginal and Torres Strait Islander populations was 0.38 (95% CI 0.00-0.80) per 100,000. CONCLUSION: The prevalence of NMOSD in the Maori population is similar to South East Asian countries, reflecting their historical origins. The prevalence of MS in this group is intermediate between those with South East Asian and European ancestry living in New Zealand. Both NMOSD and particularly MS appear to be uncommon in the Indigenous populations of Australia.

Effects of Cannabis in Parkinson's Disease: A Systematic Review and Meta-Analysis.

The legalization of cannabis in many countries has allowed many Parkinson's disease (PD) patients to turn to cannabis as a treatment. As such there is a growing interest from the PD community to be properly guided by evidence regarding potential treatment benefits of cannabis. This systematic review and meta-analysis aims to compile the best available evidence to help guide patients and their family, clinicians and researchers make informed decisions. A systematic search of the literature was conducted in June 2021. Five randomized controlled studies and eighteen non-randomized studies investigated cannabis treatment in PD patients. No compelling evidence was found to recommend the use of cannabis in PD patients. However, a potential benefit was identified with respect to alleviation of PD related tremor, anxiety, pain, improvement of sleep quality and quality of life. Given the relative paucity of well-designed randomized studies, there is an identified need for further investigation, particularly in these areas.

Effects of cannabinoids in Parkinson's disease animal models: a systematic review and meta-analysis.

Objectives: Cannabis has been proposed as a potential treatment for Parkinson's disease (PD) due to its neuroprotective benefits. However, there has been no rigorous review of preclinical studies to evaluate any potential treatment effect. This systematic review was undertaken to provide evidence in support or against a treatment effect of cannabinoids in animal models of PD. Methods: Databases were searched for any controlled comparative studies that assessed the effects of any cannabinoid, cannabinoid-based treatment or endocannabinoid transport blocker on behavioural symptoms in PD animal models. Results: A total of 41 studies were identified to have met the criteria for this review. 14 of these studies were included in meta-analyses of rotarod, pole and open field tests. Meta-analysis of rotarod tests showed a weighted mean difference of 31.63 s for cannabinoid-treated group compared with control. Meta-analysis of pole tests also showed a positive treatment effect, evidenced by a weighted mean difference of -1.51 s for cannabinoid treat group compared with control. However, meta-analysis of open field test demonstrated a standardised mean difference of only 0.36 indicating no benefit. Conclusion: This review demonstrates cannabinoid treatment effects in alleviating motor symptoms of PD animal models and supports the conduct of clinical trials of cannabis in PD population. However, there is no guarantee of successful clinical translation of this outcome because of the many variables that might have affected the results, such as the prevalent unclear and high risk of bias, the different study methods, PD animal models and cannabinoids used.

Magnetic resonance imaging in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) associated with antibodies to aquaporin-4 (AQP4), which has distinct clinical, radiological and pathological features, but also has some overlap with multiple sclerosis and myelin oligodendrocyte glycoprotein (MOG) antibody associated disease. Early recognition of NMOSD is important because of differing responses to both acute and preventive therapy. Magnetic resonance (MR) imaging has proved essential in this process. Key MR imaging clues to the diagnosis of NMOSD are longitudinally extensive lesions of the optic nerve (more than half the length) and spinal cord (three or more vertebral segments), bilateral optic nerve lesions and lesions of the optic chiasm, area postrema, floor of the IV ventricle, periaqueductal grey matter, hypothalamus and walls of the III ventricle. Other NMOSD-specific lesions are denoted by their unique morphology: heterogeneous lesions of the corpus callosum, 'cloud-like' gadolinium (Gd)-enhancing white matter lesions and 'bright spotty' lesions of the spinal cord. Other lesions described in NMOSD, including linear periventricular peri-ependymal lesions and patch subcortical white matter lesions, may be less specific. The use of advanced MR imaging techniques is yielding further useful information regarding focal degeneration of the thalamus and optic radiation in NMOSD and suggests that paramagnetic rim patterns and changes in normal appearing white matter are specific to MS. MR imaging is crucial in the early recognition of NMOSD and in directing testing for AQP4 antibodies and guiding immediate acute treatment decisions. Increasingly, MR imaging is playing a role in diagnosing seronegative cases of NMOSD.

Using eye movements in the dot-probe paradigm to investigate attention bias in illness anxiety disorder.

BACKGROUND: Illness anxiety disorder (IAD) is a common, distressing, and debilitating condition with the key feature being a persistent conviction of the possibility of having one or more serious or progressive physical disorders. Because eye movements are guided by visual-spatial attention, eye-tracking technology is a comparatively direct, continuous measure of attention direction and speed when stimuli are oriented. Researchers have tried to identify selective visual attention biases by tracking eye movements within dot-probe paradigms because dot-probe paradigm can distinguish these attentional biases more clearly. AIM: To examine the association between IAD and biased processing of illness-related information. METHODS: A case-control study design was used to record eye movements of individuals with IAD and healthy controls while participants viewed a set of pictures from four categories (illness-related, socially threatening, positive, and neutral images). Biases in initial orienting were assessed from the location of the initial shift in gaze, and biases in the maintenance of attention were assessed from the duration of gaze that was initially fixated on the picture per image category. RESULTS: The eye movement of the participants in the IAD group was characterized by an avoidance bias in initial orienting to illness-related pictures. There was no evidence of individuals with IAD spending significantly more time viewing illness-related images compared with other images. Patients with IAD had an attention bias at the early stage and overall attentional avoidance. In addition, this study found that patients with significant anxiety symptoms showed attention bias in the late stages of attention processing. CONCLUSION: Illness-related information processing biases appear to be a robust feature of IAD and may have an important role in explaining the etiology and maintenance of the disorder.

Efficacy of Face-to-Face Delivered Cognitive Behavioral Therapy in Improving Health Status of Patients With Insomnia: A Meta-Analysis.

Background: Face-to-face cognitive behavioral therapy (CBT) is one of the most widely used non-pharmacological treatment approaches for insomnia. The aim of this study is to assess the efficacy of face-to-face delivered CBT on health outcomes and to evaluate the effect of CBT components as subgroup variables to explain the efficacy of face-to-face delivered CBT on health outcomes in adults over 18 years old with insomnia. Methods: Relevant randomized controlled trial studies published in the past 22 years were searched through the electronic databases. The Physiotherapy Evidence Database (PEDro) scale was used to assess the quality of the 31 included studies. The mean difference and standard deviation of outcome variables and subgroup variables were analyzed using random effect model, and the heterogeneity among the articles was assessed with the Q-test and I 2. Egger regression analysis was used to assess publication bias. Results: The meta-analysis showed a significant reduction in Insomnia Severity Index [standardized mean difference (SMD) = -2.56, 95% CI -3.81 to -1.30, p < 0.001], Pittsburgh Sleep Quality Index (SMD = -0.96, 95% CI -1.25 to -0.68, p < 0.001), sleep onset latency (SMD = -1.31, 95% CI -2.00 to -0.63, p < 0.001), wakening after sleep onset (SMD = -1.44, 95% CI -2.14 to -0.74, p < 0.001), number of awakenings (SMD = -1.18, 95% CI -2.10 to -0.26, p < 0.05), depression (SMD = -1.14, 95% CI -1.85 to -0.42, p < 0.01), and fatigue (SMD = -2.23, 95% CI -3.87 to -0.58, p < 0.01), and a significant increase in total sleep time (SMD = 0.63, 95% CI 0.28 to 0.98, p < 0.001), sleep efficiency (SMD = 1.61, 95% CI 0.92 to 2.29, p < 0.001), and physical health (SMD = 0.42, 95% CI 0.08 to 0.76, p < 0.05), in the CBT intervention group compared with the control group. There was no significant change in anxiety (SMD = -0.62, 95% CI -1.55 to 0.32, p > 0.05) and mental health (SMD = 1.09, 95% CI -0.59 to 2.77, p > 0.05) in CBT intervention group compared with control group. Group-delivered studies with larger number of intervention sessions and longer duration of single session provided a larger improvement in sleep quality. Conclusion: Face-to-face delivered CBT is effective in increasing total sleep time, sleep efficiency, and physical health, and reducing Insomnia Severity Index scores, Pittsburgh Sleep Quality Index scores, sleep onset latency, wakening after sleep onset, number of awakenings, depression, anxiety, and fatigue in patients with insomnia. Face-to-face delivered CBT is more effective when delivered through a larger number of sessions with longer duration of each session, and when delivered in groups. Face-to-face CBT is recommended to provide treatment to patients with insomnia in clinical settings. Systematic Review Registration: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020200091, identifier: CRD4202020009.

Overlapping central and peripheral nervous system syndromes in MOG antibody-associated disorders.

OBJECTIVE: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody-associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort. METHODS: Using a live cell-based assay, we diagnosed 271 adults with MOGAD (2013-2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement. RESULTS: We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls (p = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model. CONCLUSIONS: Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.

Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review.

OBJECTIVE: Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies. METHODS: PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group-specific incidence or prevalence. RESULTS: We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45-1.01] and 10/100 000 persons [95% CI: 6.8-13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036-0.038] and 0.7/100,000 persons [95% CI: 0.66-0.74]). There was prominent female predominance in adults and the AQP4-Ab-seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time. CONCLUSION: NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors.

Homozygous frameshift mutation of SPG11 as a cause of progressive flaccid paralysis, ataxia and dysphagia.

Hereditary spastic paraplegias (HSP) are phenotypically and genotypically diverse. We describe a unique case of autosomal recessive HSP (ARHSP) diagnosed at age 44 in a patient previously described as having "spinal muscular ataxia" [sic]. Predominant lower motor neuron findings and lack of clinical spasticity reduced suspicion for HSP in early life. The identified SPG11 mutation was novel and the presentation was atypical for HSP in general and SPG11 disease specifically.

Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide.

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon inflammatory disease of the central nervous system, manifesting clinically as optic neuritis, myelitis, and certain brain and brainstem syndromes. Cases clinically diagnosed as NMOSD may include aquaporin 4 (AQP4)-antibody-seropositive autoimmune astrocytopathic disease, myelin oligodendrocyte glycoprotein (MOG)-antibody-seropositive inflammatory demyelinating disease, and double-seronegative disease. AQP4-antibody disease has a high female-to-male ratio (up to 9:1), and its mean age at onset of ~40 years is later than that seen in multiple sclerosis. For MOG-antibody disease, its gender ratio is closer to 1:1, and it is more common in children than in adults. Its clinical phenotypes differ but overlap with those of AQP4-antibody disease and include acute disseminated encephalomyelitis, brainstem and cerebral cortical encephalitis, as well as optic neuritis and myelitis. Double-seronegative disease requires further research and clarification. Population-based studies over the past two decades report the prevalence and incidence of NMOSD in different populations worldwide. One relevant finding is the varying prevalence observed in different racial groups. Consistently, the prevalence of NMOSD among Whites is ~1/100,000 population, with an annual incidence of <1/million population. Among East Asians, the prevalence is higher, at ~3.5/100,000 population, while the prevalence in Blacks may be up to 10/100,000 population. For MOG-antibody disease, hospital-based studies largely do not observe any significant racial preponderance so far. This disorder comprises a significant proportion of NMOSD cases that are AQP4-antibody-seronegative. A recent Dutch nationwide study reported the annual incidence of MOG-antibody disease as 1.6/million population (adult: 1.3/million, children: 3.1/million). Clinical and radiological differences between AQP4-antibody and MOG-antibody associated diseases have led to interest in the revisions of NMOSD definition and expanded stratification based on detection of a specific autoantibody biomarker. More population-based studies in different geographical regions and racial groups will be useful to further inform the prevalence and incidence of NMOSD and their antibody-specific subgroups. Accessibility to AQP4-antibody and MOG-antibody testing, which is limited in many centers, is a challenge to overcome. Environmental and genetic studies will be useful accompaniments to identify other potential pathogenetic factors and specific biomarkers in NMOSD.

PRES-like presentation in MOG antibody-related demyelination (MARD).

A 33-year-old male presented with a progressive four-week history of frontal headache and left visual field impairment. MRI brain confirmed bilateral, asymmetric, occipital vasogenic oedema, suggestive of posterior reversible encephalopathy syndrome (PRES). Serum testing for MOG antibodies was positive, confirming a diagnosis of MOG antibody-related demyelination (MARD). A similar PRES-like pattern of white matter inflammation has been reported previously in neuromyelitis optica spectrum disorder but has not previously been reported in MARD.

AQP4 Antibody Assay Sensitivity Comparison in the Era of the 2015 Diagnostic Criteria for NMOSD.

We have compared five different assays for antibodies to aquaporin-4 in 181 cases of suspected Neuromyelitis optica spectrum disorders (NMOSD) and 253 controls to assess their relative utility. As part of a clinically-based survey of NMOSD in Australia and New Zealand, cases of suspected NMOSD were referred from 23 centers. Clinical details and magnetic imaging were reviewed and used to apply the 2015 IPND diagnostic criteria. In addition, 101 age- and sex-matched patients with multiple sclerosis were referred. Other inflammatory disease (n = 49) and healthy controls (n = 103) were also recruited. Samples from all participants were tested using tissue-based indirect immunofluorescence assays and a subset were tested using four additional ELISA and cell-based assays. Antibodies to myelin oligodendrocyte glycoprotein (MOG) were also assayed. All aquaporin-4 antibody assays proved to be highly specific. Sensitivities ranged from 60 to 94%, with cell-based assays having the highest sensitivity. Antibodies to MOG were detected in 8/79 (10%) of the residual suspected cases of NMOSD. Under the 2015 IPND diagnostic criteria for NMOSD, cell-based assays for aquaporin-4 are sensitive and highly specific, performing better than tissue-based and ELISA assays. A fixed cell-based assay showed near-identical results to a live-cell based assay. Antibodies to MOG account for only a small number of suspected cases.