Predicting time to serologic diagnosis of AQP4+ NMOSD based on clinical factors and social determinants of health.

BACKGROUND: Early serologic diagnosis and initiation of targeted therapy are associated with better outcomes in aquaporin-4 IgG positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: To determine predictors of time to serologic diagnosis of AQP4+ NMOSD. METHODS: In CANOPTICS, a multi-centre, Canadian cohort study of NMOSD, we retrospectively evaluated time from the first clinical attack to first positive AQP4-IgG serology. We used a multivariable negative binomial regression model to evaluate possible predictors of time to diagnosis. RESULTS: We identified 129 participants with AQP4+ NMOSD from 7 centres. Diagnostic delay of >1 month was observed in 82 (63.6 %). Asian compared to European (White) ethnicity (IRR:0.40, 95 % CI:0.21-0.78), female sex (IRR:0.56, 95 % CI:0.32-0.99), later calendar year (IRR:0.84, 95 % CI:0.81-0.86), and hospitalization for the first attack (IRR:0.35, 95 % CI:0.20-0.62) were associated with shorter times to serologic diagnosis. We did not observe any overall effect of Afro-Caribbean ethnicity, but in exploratory analyses, Afro-Caribbean individuals with low income had longer times to diagnosis. CONCLUSION: More than 60 % of patients with NMOSD experienced delays to AQP4-IgG serologic diagnosis in this cohort. Given evidence of more adverse long-term outcomes in Afro-Caribbean individuals with NMOSD, intersectional effects of ethnicity and social determinants of health merit further study.

Comorbidity and persistence of disease-modifying therapy use in relapsing remitting multiple sclerosis.

BACKGROUND: Comorbidity decreases the likelihood of initiating disease-modifying therapy (DMT) for multiple sclerosis (MS). Our objective was to characterize the relationship between comorbidity and initial DMT persistence along with reasons for DMT discontinuation. METHODS: We identified individuals with relapsing remitting MS or clinically isolated syndrome starting a platform DMT (interferon-ß, glatiramer acetate, dimethyl fumarate, teriflunomide) as initial therapy in the Canadian province of Nova Scotia from 2001 to 2016. Cases were identified using a clinic database for the only clinic providing specialty MS care in a province with universal publicly-funded health care. Comorbidity was determined by linkage of MS cases to provincial health administrative data using validated case definitions for mental health disorder, hypertension, hyperlipidemia, diabetes, chronic lung disease, ischemic heart disease, epilepsy, and inflammatory bowel disease. Cox proportional hazards models explored the relationship between comorbidity, as a count or individual comorbidities, and time to discontinuation of initial DMT. Logistic regression models explored reasons for DMT discontinuation. RESULTS: Among 1464 individuals starting platform therapy as initial DMT, the median duration on first DMT was 4 years (95% CI 4 - 4). Comorbidity count (0, 1, ≥2) was not associated with time to discontinuation of initial DMT. However, the presence of a mental health disorder was associated with an increased hazard of discontinuing DMT (hazard ratio 1.22, 95% CI 1.03-1.44). Comorbidity count was not associated with discontinuation for lack of efficacy or lack of tolerability after adjusting for covariates. CONCLUSION: Individuals with mental health comorbidity may have unique challenges that affect persistence on DMT after treatment initiation.

Dietary interventions for multiple sclerosis-related outcomes.

BACKGROUND: Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system. Although the exact pathogenesis remains unknown, the leading theory is that it results from immune system dysregulation. Approved disease-modifying therapy appears to modulate the immune system to improve MS-related outcomes. There is substantial interest in the ability of dietary interventions to influence MS-related outcomes. This is an update of the Cochrane Review 'Dietary interventions for multiple sclerosis' (Farinotti 2003; Farinotti 2007; Farinotti 2012). OBJECTIVES: To assess the effects of dietary interventions (including dietary plans with recommendations for specific whole foods, macronutrients, and natural health products) compared to placebo or another intervention on health outcomes (including MS-related outcomes and serious adverse events) in people with MS. SEARCH METHODS: On 30 May 2019, we searched CENTRAL, MEDLINE, Embase, and Web of Science. We also searched ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (ICTRP), and Networked Digital Library of Theses and Dissertations (NDLTD). We checked reference lists in identified trials and requested information from trial authors to identify any additional published or unpublished data. SELECTION CRITERIA: We included any randomized controlled trial (RCT) or controlled clinical trial (CCT) examining the effect of a dietary intervention versus placebo or another intervention among participants with MS on MS-related outcomes, including relapses, disability progression, and magnetic resonance imaging (MRI) measures. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Planned primary outcomes were number of participants experiencing relapse and change in disability progression, according to a validated disability scale at the last reported follow-up. Secondary outcomes included MRI activity, safety, and patient-reported outcomes. We entered and analysed data in Review Manager 5. MAIN RESULTS: We found 41 full-text articles examining 30 trials following full-text review. Participants were adults with MS, defined by established criteria, presenting to MS clinics in Europe, North America, and the Middle East. Study design varied considerably, although all trials had at least one methodological issue leading to unknown or high risk of bias. Trials examined: supplementation to increase polyunsaturated fatty acids (PUFAs) (11 trials); a variety of antioxidant supplements (10 trials); dietary programmes (3 trials); and other dietary supplements (e.g. acetyl L-carnitine, biotin, creatine, palmitoylethanolamide, probiotic, riboflavin) (6 trials). In three trials comparing PUFAs with monounsaturated fatty acids (MUFAs), the evidence was very uncertain concerning difference in relapses (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.88 to 1.20; 3 studies, 217 participants; 75% in the PUFA group versus 74% in the MUFA group; very low-certainty evidence). Among four trials comparing PUFAs with MUFAs, there may be little to no difference in global impression of deterioration (RR 0.85, 95% CI 0.71 to 1.03; 4 studies, 542 participants; 40% in the PUFA group versus 47% in the MUFA group; low-certainty evidence). In two trials comparing PUFAs with MUFAs (102 participants), there was very low-certainty evidence for change in disability progression. None of the PUFA versus MUFA trials examined MRI outcomes. In one trial comparing PUFAs with MUFAs (40 participants), there were no serious adverse events; based on low-certainty evidence. In two trials comparing different PUFAs (omega-3 versus omega-6), there may be little to no difference in relapses (RR 1.02, 95% CI 0.62 to 1.66; 2 studies, 129 participants; 30% in the omega-3 versus 29% in the omega-6 group; low-certainty evidence). Among three trials comparing omega-3 with omega-6, there may be little to no difference in change in disability progression, measured as mean change in Expanded Disability Status Scale (EDSS) (mean difference (MD) 0.00, 95% CI -0.30 to 0.30; 3 studies, 166 participants; low-certainty evidence). In one trial comparing omega-3 with omega-6, there was likely no difference in global impression of deterioration (RR 0.99, 95% CI 0.51 to 1.91; 1 study, 86 participants; 29% in omega-3 versus 29% in omega-6 group; moderate-certainty evidence). In one trial comparing omega-3 with omega-6 (86 participants), there was likely no difference in number of new T1- weighted gadolinium-enhancing lesions, based on moderate-certainty evidence. In four trials comparing omega-3 with omega-6, there may be little to no difference in serious adverse events (RR 1.12, 95% CI 0.38 to 3.31; 4 studies, 230 participants; 6% in omega-3 versus 5% in omega-6 group; low-certainty evidence). In four trials examining antioxidant supplementation with placebo, there may be little to no difference in relapses (RR 0.98, 95% CI 0.59 to 1.64; 4 studies, 345 participants; 17% in the antioxidant group versus 17% in the placebo group; low-certainty evidence). In six trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning change in disability progression, measured as mean change of EDSS (MD -0.19, 95% CI -0.49 to 0.11; 6 studies, 490 participants; very low-certainty evidence). In two trials examining antioxidant supplementation with placebo, there may be little to no difference in global impression of deterioration (RR 0.99, 95% 0.50 to 1.93; 2 studies, 190 participants; 15% in the antioxidant group versus 15% in the placebo group; low-certainty evidence). In two trials examining antioxidant supplementation with placebo, the evidence was very uncertain concerning difference in gadolinium-enhancing lesions (RR 0.67, 95% CI 0.09 to 4.88; 2 studies, 131 participants; 11% in the antioxidant group versus 16% in the placebo group; very low-certainty evidence). In three trials examining antioxidant supplementation versus placebo, there may be little to no difference in serious adverse events (RR. 0.72, 95% CI 0.17 to 3.08; 3 studies, 222 participants; 3% in the antioxidant group versus 4% in the placebo group; low-certainty evidence). AUTHORS' CONCLUSIONS: There are a variety of controlled trials addressing the effects of dietary interventions for MS with substantial variation in active treatment, comparator, and outcomes of interest. PUFA administration may not differ when compared to alternatives with regards to relapse rate, disability worsening, or overall clinical status in people with MS, but evidence is uncertain. Similarly, at present, there is insufficient evidence to determine whether supplementation with antioxidants or other dietary interventions have any impact on MS-related outcomes.

Clinical Course of Relapsing Remitting Multiple Sclerosis Post-Natalizumab.

Natalizumab is an efficacious disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS), often limited by risk of progressive multifocal leukoencephalopathy. We describe the clinical course of RRMS patients switched from natalizumab to another DMT. We identified all RRMS patients treated with natalizumab ≥3 months with JC virus antibody positivity who switched to another DMT. Overall, 84 individuals switched DMT with 57 (68%) beginning fingolimod. On fingolimod, survival without a relapse was 74% (55.8-85.6%) at 36 months and survival without disease progression was 78% (62.6-87.6%) at 36 months. In conclusion, fingolimod is an effective therapy post-natalizumab.

L'évolution clinique de patients atteints de la forme cyclique de la sclérose en plaques ayant opté pour un traitement autre que celui au natalizumab. Le natalizumab est un médicament modificateur de l'évolution de la sclérose en plaques (MMSP) efficace pour le traitement de la sclérose en plaques récurrente-rémittente (SEP-RR), souvent limité par le risque de la leucoencéphalopathie multifocale progressive. Nous décrivons l'évolution clinique des patients atteints de SEP-RR qui sont passés du natalizumab à un autre MMSP. Nous avons identifié tous les patients atteints de SEP-RR ayant été traités avec le natalizumab ≥3 mois avec la positivité des anticorps anti-virus JC et ayant opté pour un autre MMSP. Globalement, 84 personnes ont changé de MMSP avec 57 (68%) ayant changé au fingolimod. Parmi les patients sous le fingolimod, la survie sans rechute était de 74% (55,8 à 85,6%) à 36 mois et la survie sans progression était de 78% (62,6 à 87,6%) à 36 mois. En conclusion, le fingolimod est une thérapie post-natalizumab efficace.

Population-based study of "no evident disease activity" in MS.

OBJECTIVE: To determine the persistence of no evident disease activity (NEDA) in a population-based relapsing-remitting MS (RRMS) cohort. METHODS: All incident cases of RRMS in Olmsted County between 2000 and 2011 were identified using a medical records linkage system. Persistence of NEDA after RRMS diagnosis was determined by retrospective chart review. MRI activity, relapse, or Expanded Disability Status Scale (EDSS) worsening resulted in failure of NEDA. RESULTS: We identified 93 incident cases of RRMS including 82 individuals with sufficient follow-up to determine the persistence of NEDA. There were 44 individuals not on disease-modifying therapy (DMT), whereas 37 individuals were prescribed an injectable DMT and 1 received mitoxantrone during the interval over which NEDA was maintained. NEDA was maintained by 63% at 1 year, 38% at 2 years, 19% at 5 years, and 12% at 10 years according to routine care assessment. At 10 years, there was no difference in EDSS disability among patients who maintained NEDA vs those who failed NEDA at 1 year (p = 0.3). CONCLUSIONS: NEDA infrequently persists beyond 2 years in a population-based cohort of newly diagnosed patients with RRMS.

Neuroradiologic manifestations of Erdheim-Chester disease.

BACKGROUND: We describe the neuroradiologic features of a cohort of patients with Erdheim-Chester disease. METHODS: We assessed patients at Mayo Clinic Rochester between January 1, 1990, and July 31, 2016, with pathologically confirmed Erdheim-Chester disease (n = 53). RESULTS: Neuroimaging, including head CT (n = 17), brain MRI (n = 39), orbital MRI (n = 15), and spine MRI (n = 16), was available for 42 participants. Median age at diagnosis was 55 years (interquartile range 46-66) with higher male prevalence (33:20). Neurologic symptoms were identified in 47% (25/53); BRAFV600E mutation in 58% (15/26). Median follow-up was 2 years (range 0-20) with 18 patients deceased. Radiologic disease evidence was seen in dura (6/41), brainstem (9/39), cerebellum (8/39), spinal cord (2/16), spinal epidura (2/16), hypothalamic-pituitary axis (17/39), and orbits (13/42). T2 white matter abnormalities (Fazekas score ≥1) were present in 21/34 patients. Diabetes insipidus was present in 30% (16/53); 8 had abnormal hypothalamic-pituitary axis imaging. Radiographic evidence of CNS involvement (i.e., dural, brain, including Fazekas score >1, or spinal cord) occurred in 55% (22/40) and was unassociated with significantly increased mortality. CONCLUSIONS: Erdheim-Chester disease commonly and variably involves the neuraxis. Patients with suspected Erdheim-Chester disease should undergo MRI brain and spine and screening investigations (serum sodium, serum and urine osmolality) for diabetes insipidus to clarify extent of neurologic disease.

NEDA treatment target? No evident disease activity as an actionable outcome in practice.

"No evident disease activity" (NEDA) is a proposed measure of disease activity-free status in multiple sclerosis (MS) that is typically defined as absence of relapses, disability progression, and MRI activity over a defined time period. NEDA is increasingly reported in randomized controlled trials of MS disease modifying therapies where it has some perceived advantages over outcomes such as annualized relapse rate. NEDA has also been proposed as a treatment goal in clinical care. At this point, the long-term implications of early NEDA remain largely unknown. We review current NEDA definitions, use in clinical trials, and its prospects for routine use as an actionable treatment target in clinical practice.

Pathogenic implications of cerebrospinal fluid barrier pathology in neuromyelitis optica.

Pathogenic autoantibodies associated with neuromyelitis optica (NMO) induce disease by targeting aquaporin-4 (AQP4) water channels enriched on astrocytic endfeet at blood-brain interfaces. AQP4 is also expressed at cerebrospinal fluid (CSF)-brain interfaces, such as the pial glia limitans and the ependyma and at the choroid plexus blood-CSF barrier. However, little is known regarding pathology at these sites in NMO. Therefore, we evaluated AQP4 expression, microglial reactivity, and complement deposition at pial and ependymal surfaces and in the fourth ventricle choroid plexus in 23 autopsy cases with clinically and/or pathologically confirmed NMO or NMO spectrum disorder. These findings were compared to five cases with multiple sclerosis, five cases of choroid plexus papilloma, and five control cases without central nervous system disease. In the NMO cases, AQP4 immunoreactivity was reduced relative to control levels in the pia (91%; 21/23), ependyma (56%; 9/16), and choroid plexus epithelium (100%; 12/12). AQP4 immunoreactivity was normal in MS cases in these regions. Compared to MS, NMO cases also showed a focal pattern of pial and ependymal complement deposition and more pronounced microglial reactivity. In addition, AQP4 loss, microglial reactivity, and complement deposition colocalized along the pia and ependyma only in NMO cases. Within the choroid plexus, AQP4 loss was coincident with C9neo immunoreactivity on epithelial cell membranes only in NMO cases. These observations demonstrate that NMO immunopathology extends beyond perivascular astrocytic foot processes to include the pia, ependyma, and choroid plexus, suggesting that NMO IgG-induced pathological alterations at CSF-brain and blood-CSF interfaces may contribute to the occurrence of ventriculitis, leptomeningitis, and hydrocephalus observed among NMO patients. Moreover, disruption of the blood-CSF barrier induced by binding of NMO IgG to AQP4 on the basolateral surface of choroid plexus epithelial cells may provide a unique portal for entry of the pathogenic antibody into the central nervous system.

Treatment for cryoglobulinemic and non-cryoglobulinemic peripheral neuropathy associated with hepatitis C virus infection.

BACKGROUND: Peripheral neuropathy is the most common neurologic complication of hepatitis C virus (HCV) infection. The pathophysiology of the neuropathy associated with HCV is not definitively known; however, proposed mechanisms include cryoglobulin deposition in the vasa nervorum and HCV-mediated vasculitis. The optimal treatment for HCV-related peripheral neuropathy has not been established. OBJECTIVES: To assess the effects of interventions (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) for cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection. SEARCH METHODS: On 26 August 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We also searched two trials registers, the Networked Digital Library of Theses and Dissertations (NDLTD) (October 2014), and three other databases. We checked references in identified trials and requested information from trial authors to identify any additional published or unpublished data. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and quasi-RCTs involving participants with cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection. We considered any intervention (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) alone or in combination versus placebo or another intervention ('head-to-head' comparison study design) evaluated after a minimum interval to follow-up of at least six months. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. The planned primary outcome was change in sensory impairment (using any validated sensory neuropathy scale or quantitative sensory testing) at the end of the follow-up period.  Other planned outcomes were: change in impairment (any validated combined sensory and motor neuropathy scale), change in disability (any validated disability scale), electrodiagnostic measures, number of participants with improved symptoms of neuropathy (global impression of change), and severe adverse events. MAIN RESULTS: Four trials of HCV-related cryoglobulinemia fulfiled selection criteria and the review authors included three in quantitative synthesis. All studies were at high risk of bias. No trial addressed the primary outcome of change in sensory impairment. No trial addressed secondary outcomes of change in combined sensory and motor impairment, disability, or electrodiagnostic measures. A single trial of HCV-related mixed cryoglobulinemia treated with pegylated interferon alfa (peginterferon alfa), ribavirin, and rituximab versus peginterferon alfa and ribavirin did not show a significant difference in the number of participants with improvement in neuropathy at 36 months post treatment (risk ratio (RR) 4.00, 95% confidence interval (CI) 0.27 to 59.31, n = 9). One study of interferon alfa (n = 22) and two studies of rituximab (n = 61) provided adverse event data. Severe adverse events were no more common with interferon alfa (RR 7.00, 95% CI 0.38 to 128.02) or rituximab (RR 3.00, 95% CI 0.13 to 67.06) compared to the control group. AUTHORS' CONCLUSIONS: There is a lack of RCTs and quasi-RCTs addressing the effects of interventions for peripheral neuropathy associated with HCV infection. At present, there is insufficient evidence from RCTs and quasi-RCTs to make evidence-based decisions about treatment.

Dysmetropsia and Cotard's syndrome due to migrainous infarction - or not?

INTRODUCTION: Migrainous infarction accounts for 12.8% of ischemic strokes of unusual etiology. CASE REPORT: A 59-year-old woman with longstanding migraine with aura experienced what appeared to be migrainous infarction characterized by dysmetropsia and transient Cotard's syndrome. Imaging demonstrated right temporal-parietal-occipital changes with apparent cortical laminar necrosis. CONCLUSION: The spectrum of the pathophysiology of migrainous infarction has not been established; however, cortical spreading depression may explain the appearance of imaging findings that do not obey a vascular territory.

Teaching NeuroImages: neurodegeneration with brain iron accumulation in aceruloplasminemia.

A 55-year-old African Canadian man with insulin-dependent diabetes mellitus and alcohol abuse presented with diabetic ketoacidosis. Progressive cognitive decline over the previous 5 years resulted in long-term care placement. Aside from pigmentary retinopathy, general examination was unremarkable. MRI demonstrated iron accumulation in the brain (figure 1) and liver (figure 2A). Ceruloplasmin, a ferroxidase enzyme important in iron homeostasis, was undetectable and associated with low serum iron, low serum copper, and 10-fold increase in serum ferritin. Liver biopsy confirmed increased hepatocyte iron storage (figure 2B). Aceruloplasminemia was diagnosed.(1,2) Iron chelation was not administered given advanced dementia at presentation.

Management of goitre and small nodule disease by Canadian otolaryngologists.

OBJECTIVE: To describe current management practices among Canadian otolaryngologists for small thyroid nodule disease and nodules in the context of goitre. METHODS: An online survey was e-mailed to all active members of the Canadian Society of Otolaryngology-Head and Neck Surgery (CSOHNS). The responses were anonymous. Information was gathered on practice demographics and individual practices pertaining to diagnostic workup, surgical management, and follow-up of patients with goitre and small nodule disease. RESULTS: A total of 113 surveys were returned from 431 active CSOHNS members (26% response). The majority of respondents were less than 40 years (54%), resided in Ontario or Quebec (63%), and described their practice as academic (65%). Management of a small thyroid nodule following fine-needle aspiration cytology results reported as benign, nondiagnostic, abnormal, or papillary thyroid cancer was inconsistent. Papillary thyroid cancer was managed by total thyroidectomy (59%), total thyroidectomy plus level VI neck dissection (38%), hemithyroidectomy plus level VI neck dissection (2%), and hemithyroidectomy (1%). Management of goitre was not uniform. Symptomatic goitre management included discharge from practice (6%), follow-up with serial ultrasonography (12%), hemithyroidectomy (15%), and total thyroidectomy (66%). Practice demographics had a significant effect on intraoperative techniques, such as the use of an electromyographic nerve monitor. CONCLUSION: There was a lack of consensus among Canadian otolaryngologists regarding treatment of small thyroid nodules and nodules in the context of goitre. Canadian guidelines for management of small nodule disease may standardize care.

Fatigue impact scale demonstrates greater fatigue in younger stroke survivors.

BACKGROUND: Fatigue affects 33-77% of stroke survivors. There is no consensus concerning risk factors for fatigue post-stroke, perhaps reflecting the multifaceted nature of fatigue. We characterized post-stroke fatigue using the Fatigue Impact Scale (FIS), a validated questionnaire capturing physical, cognitive, and psychosocial aspects of fatigue. METHODS: The Stroke Outcomes Study (SOS) prospectively enrolled ischemic stroke patients from 2001-2002. Measures collected included basic demographics, pre-morbid function (Oxford Handicap Scale, OHS), stroke severity (Stroke Severity Scale, SSS), stroke subtype (Oxfordshire Community Stroke Project Classification, OCSP), and discharge function (OHS; Barthel Index, BI). An interview was performed at 12 months evaluating function (BI; Modified Rankin Score, mRS), quality of life (Reintegration into Normal living Scale, RNL), depression (Geriatric Depression Scale, GDS), and fatigue (FIS). RESULTS: We enrolled 522 ischemic stroke patients and 228 (57.6%) survivors completed one-year follow-up. In total, 36.8% endorsed fatigue (59.5% rated one of worst post-stroke symptoms). Linear regression demonstrated younger age was associated with increased fatigue frequency (ß=-0.20;p=0.01), duration (ß=-0.22;p<0.01), and disability (ß=-0.24;p<0.01). Younger patients were more likely to describe fatigue as one of the worst symptoms post-stroke (ß=-0.24;p=0.001). Younger patients experienced greater impact on cognitive (ß=-0.27;p<0.05) and psychosocial (ß=-0.27;p<0.05) function due to fatigue. Fatigue was correlated with depressive symptoms and diminished quality of life. Fatigue occurred without depression as 49.0% of respondents with fatigue as one of their worst symptoms did not have an elevated GDS. CONCLUSIONS: Age was the only consistent predictor of fatigue severity at one year. Younger participants experienced increased cognitive and psychosocial fatigue.