The 100 most-cited articles in Neurology, 2018

OBJECTIVE: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition on minimally conscious state (MCS) and provide care recommendations for patients with prolonged disorders of consciousness (DoC). METHODS: Recommendations were based on systematic review evidence, related evidence, care principles, and inferences using a modified Delphi consensus process according to the AAN 2011 process manual, as amended. RECOMMENDATIONS: Clinicians should identify and treat confounding conditions, optimize arousal, and perform serial standardized assessments to improve diagnostic accuracy in adults and children with prolonged DoC (Level B). Clinicians should counsel families that for adults, MCS (vs vegetative state [VS]/unresponsive wakefulness syndrome [UWS]) and traumatic (vs nontraumatic) etiology are associated with more favorable outcomes (Level B). When prognosis is poor, long-term care must be discussed (Level A), acknowledging that prognosis is not universally poor (Level B). Structural MRI, SPECT, and the Coma…

OBJECTIVE: To develop recommendations for disease-modifying therapy (DMT) for multiple sclerosis (MS). METHODS: A multidisciplinary panel developed DMT recommendations, integrating findings from a systematic review; followed an Institute of Medicine-compliant process to ensure transparency and patient engagement; and developed modified Delphi consensus-based recommendations concerning starting, switching, and stopping DMTs pertinent to people with relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndromes of demyelination. Recommendations were supported by structured rationales, integrating evidence from one or more sources: systematic review, related evidence (evidence not from the systematic review), principles of care, and inference from evidence. RESULTS: Thirty recommendations were developed: 17 on starting DMTs, including recommendations on who should start them; 10 on switching DMTs if breakthrough disease develops; and 3 on stopping DMTs. Recommendations encompassed patient engagement strategies and individualization of…

Objective To evaluate the efficacy and safety of galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, in the preventive treatment of chronic migraine. Methods A phase 3, randomized, double-blind, placebo-controlled study of LY2951742 in patients with chronic migraine (Evaluation of Galcanezumab in the Prevention of Chronic Migraine [REGAIN]) was a phase 3 study with a 3-month double-blind, placebo-controlled treatment phase and a 9-month open-label extension. Eligible patients 18 to 65 years of age with chronic migraine were randomized 2:1:1 to monthly subcutaneous injections of placebo (n = 558), galcanezumab 120 mg (with a 240-mg loading dose, n = 278), or galcanezumab 240 mg (n = 277). The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days (MHDs) during the 3-month double-blind treatment phase. Results Mean number of monthly MHDs at baseline was 19.4 for the total sample. Both galcanezumab dose groups demonstrated greater overall mean reduction in the number of monthly MHDs…

Objective To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis. Methods Clinical data were obtained from 197 MOG-Ab-positive patients ≥18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included. Results Median age at onset was 36.46 (range 18.0–76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab-positive patients were thalamic and pontine lesions. Cortical and…

Cognitive decline is recognized as a prevalent and debilitating symptom of multiple sclerosis (MS), especially deficits in episodic memory and processing speed. The field aims to (1) incorporate cognitive assessment into standard clinical care and clinical trials, (2) utilize state-of-the-art neuroimaging to more thoroughly understand neural bases of cognitive deficits, and (3) develop effective, evidence-based, clinically feasible interventions to prevent or treat cognitive dysfunction, which are lacking. There are obstacles to these goals. Our group of MS researchers and clinicians with varied expertise took stock of the current state of the field, and we identify several important practical and theoretical challenges, including key knowledge gaps and methodologic limitations related to (1) understanding and measurement of cognitive deficits, (2) neuroimaging of neural bases and correlates of deficits, and (3) development of effective treatments. This is not a comprehensive review of the extensive literature, but instead a statement of guidelines and priorities for the field. For…

Objective To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. Methods Patients aged 4–10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality. Results Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and…

OBJECTIVE: To update the 1995 American Academy of Neurology (AAN) practice parameter on persistent vegetative state and the 2002 case definition for the minimally conscious state (MCS) by reviewing the literature on the diagnosis, natural history, prognosis, and treatment of disorders of consciousness lasting at least 28 days. METHODS: Articles were classified per the AAN evidence-based classification system. Evidence synthesis occurred through a modified Grading of Recommendations Assessment, Development and Evaluation process. Recommendations were based on evidence, related evidence, care principles, and inferences according to the AAN 2011 process manual, as amended. RESULTS: No diagnostic assessment procedure had moderate or strong evidence for use. It is possible that a positive EMG response to command, EEG reactivity to sensory stimuli, laser-evoked potentials, and the Perturbational Complexity Index can distinguish MCS from vegetative state/unresponsive wakefulness syndrome (VS/UWS). The natural history of recovery from prolonged VS/UWS is better in traumatic than…

A minority of headache patients have a secondary headache disorder. The medical literature presents and promotes red flags to increase the likelihood of identifying a secondary etiology. In this review, we aim to discuss the incidence and prevalence of secondary headaches as well as the data on sensitivity, specificity, and predictive value of red flags for secondary headaches. We review the following red flags: (1) systemic symptoms including fever; (2) neoplasm history; (3) neurologic deficit (including decreased consciousness); (4) sudden or abrupt onset; (5) older age (onset after 65 years); (6) pattern change or recent onset of new headache; (7) positional headache; (8) precipitated by sneezing, coughing, or exercise; (9) papilledema; (10) progressive headache and atypical presentations; (11) pregnancy or puerperium; (12) painful eye with autonomic features; (13) posttraumatic onset of headache; (14) pathology of the immune system such as HIV; (15) painkiller overuse or new drug at onset of headache. Using the systematic SNNOOP10 list to screen new headache patients will…

Preventing or delaying Alzheimer disease (AD) through lifestyle interventions will come from a better understanding of the mechanistic underpinnings of (1) why a significant proportion of elderly remain cognitively normal with AD pathologies (ADP), i.e., amyloid or tau; and (2) why some elderly individuals do not have significant ADP. In the last decades, concepts such as brain reserve, cognitive reserve, and more recently brain maintenance have been proposed along with more general notions such as (neuro)protection and compensation. It is currently unclear how to effectively apply these concepts in the new field of preclinical AD specifically separating the 2 distinct mechanisms of coping with pathology vs avoiding pathology. We propose a simplistic conceptual framework that builds on existing concepts using the nomenclature of resistance in the context of avoiding pathology, i.e., remaining cognitively normal without significant ADP, and resilience in the context of coping with pathology, i.e., remaining cognitively normal despite significant ADP. In the context of preclinical AD…

OBJECTIVE: To measure CSF levels of biomarkers reflecting microglia and astrocytes activation, neuroinflammation, and cerebrovascular changes and study their associations with the core biomarkers of Alzheimer disease (AD) pathology (β-amyloid [Aβ] and tau), structural imaging correlates, and clinical disease progression over time. METHODS: The study included cognitively unimpaired elderly (n = 508), patients with mild cognitive impairment (MCI, n = 256), and patients with AD dementia (n = 57) from the longitudinal Swedish BioFINDER cohort. CSF samples were analyzed for YKL-40, interleukin (IL)-6, IL-7, IL-8, IL-15, IP-10, monocyte chemoattractant protein 1, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), placental growth factor, and fms-related tyrosine kinase 1 (Flt-1). MRI data were available from 677 study participants. Longitudinal clinical assessments were conducted in control individuals and patients with MCI (mean follow-up 3 years, range 1-6 years). RESULTS: CSF levels of YKL-40, ICAM-1, VCAM-1, IL-15, and Flt-1 were increased during the…

OBJECTIVE: To report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis). METHODS: We retrospectively analyzed patients diagnosed with irMyositis in tertiary centers in Paris, France, and Berlin, Germany, from January 2015 to July 2017. The main outcomes were clinical manifestations and muscle histology, which included major histocompatibility complex class I (MHC-I), C5b-9, CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L) 1, and programmed cell death 1 ligand 2 (PD-L2). RESULTS: Ten patients with metastatic cancer were included; median age was 73 (range 56-87) years. Median follow-up duration was 48 (range 16-88) weeks. Six patients developed myositis during nivolumab therapy, 1 patient during pembrolizumab, 1 patient during durvalumab, and 2 patients during combined nivolumab and ipilimumab. Median delay between ICI initiation and myositis onset was 25 (range 5-87) days. Clinical manifestations were dominated by acute or subacute myalgia (8…

Objective To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates. Methods We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals9 estimated years to symptom onset and to compare mutation carriers and noncarriers. Results Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7–10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline…

Objective We investigated different dimensions of subjective cognitive decline (SCD) to determine which was the best prognostic risk factor for incident mild cognitive impairment (MCI) among cognitively unimpaired participants. Methods We included 1,167 cognitively unimpaired participants, aged 70 to 95 years, from the Mayo Clinic Study of Aging based on 2 concurrent SCD scales (part of the Blessed memory test and the 39-item Everyday Cognition [ECog] scale, which included a validated 12-item derivative) and a single question assessing worry about cognitive decline. We evaluated multiple ways to dichotomize scores. In continuous models, we compared average scores on 4 ECog domains and multidomain (39- and 12-item) ECog scores. Cox proportional hazards models were used to assess the association between each measure and risk of MCI in models adjusted for objective memory performance, depression, anxiety, sex, APOE ε4 carriership, and medical comorbidities. Results It was possible to select a substantial group of participants (14%) at increased risk of incident MCI based on combined…

Objective To construct a grading score that predicts neurologic function 1 year after diagnosis of anti-NMDA receptor (NMDAR) encephalitis. Methods Three hundred eighty-two patients with detailed information and functional status at 1 year were studied. Factors associated with poor status (defined as modified Rankin Scale score ≥3) were identified and incorporated into a multivariate logistic regression model. This model was used to develop a 5-point prediction score, termed the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. Results Intensive care unit admission (p < 0.001), treatment delay >4 weeks (p = 0.012), lack of clinical improvement within 4 weeks (p < 0.001), movement disorder (p = 0.001), central hypoventilation (p < 0.001), elevated CSF white blood cell count (p < 0.001), elevated CSF protein level (p = 0.027), and abnormal MRI (p = 0.002) were associated with 1-year functional status in univariate analysis. Intensive care unit admission, treatment delay >4 weeks, lack of clinical improvement within 4 weeks, abnormal MRI, and CSF white blood cell count…

BACKGROUND: Virtual reality (VR) has emerged as a therapeutic tool facilitating motor learning for balance and gait rehabilitation. The evidence, however, has not yet resulted in standardized guidelines. The aim of this study was to systematically review the application of VR-based rehabilitation of balance and gait in 6 neurologic cohorts, describing methodologic quality, intervention programs, and reported efficacy. METHODS: This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. VR-based treatments of Parkinson disease, multiple sclerosis, acute and chronic poststroke, traumatic brain injury, and cerebral palsy were researched in PubMed and Scopus, including earliest available records. Therapeutic validity (CONTENT scale) and risk of bias in randomized controlled trials (RCT) (Cochrane Collaboration tool) and non-RCT (Newcastle-Ottawa scale) were assessed. RESULTS: Ninety-seven articles were included, 68 published in 2013 or later. VR improved balance and gait in all cohorts, especially when combined with conventional rehabilitation. Most…

OBJECTIVE: To examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline. METHODS: F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed. RESULTS: Results from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the…

OBJECTIVE: Our aim was to assess risk of Parkinson disease (PD) following traumatic brain injury (TBI), including specifically mild TBI (mTBI), among care recipients in the Veterans Health Administration. METHODS: In this retrospective cohort study, we identified all patients with a TBI diagnosis in Veterans Health Administration databases from October 2002 to September 2014 and age-matched 1:1 to a random sample of patients without TBI. All patients were aged 18 years and older without PD or dementia at baseline. TBI exposure and severity were determined via detailed clinical assessments or ICD-9 codes using Department of Defense and Defense and Veterans Brain Injury Center criteria. Baseline comorbidities and incident PD more than 1 year post-TBI were identified using ICD-9 codes. Risk of PD after TBI was assessed using Cox proportional hazard models adjusted for demographics and medical/psychiatric comorbidities. RESULTS: Among 325,870 patients (half with TBI; average age 47.9 ± 17.4 years; average follow-up 4.6 years), 1,462 were diagnosed with PD during follow-up. Compared to…

Objective To assess the efficacy and safety of lasmiditan in the acute treatment of migraine. Methods Adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo and were asked to treat their next migraine attack within 4 hours of onset. Over 48 hours after dosing, patients used an electronic diary to record headache pain and the presence of nausea, phonophobia, and photophobia, one of which was designated their most bothersome symptom (MBS). Results Of the 1,856 patients who treated an attack, 77.9% had ≥1 cardiovascular risk factors in addition to migraine. Compared with placebo, more patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours after dosing (32.2% vs 15.3%; odds ratio [OR] 2.6, 95% confidence interval [CI] 2.0–3.6, p< 0.001), similar to those dosed with lasmiditan 100 mg (28.2%; OR 2.2, 95% CI 1.6–3.0, p< 0.001). Furthermore, compared with those dosed with placebo, more patients dosed with lasmiditan 200 mg (40.7% vs 29.5%; OR 1.6, 95% CI 1.3–2.1, p< 0.001) and lasmiditan 100…

OBJECTIVE: To elucidate the relationship between disease stage in amyotrophic lateral sclerosis (ALS), as measured with the King's Clinical Staging System, and cognitive and behavioral change, measured with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). METHODS: A large multicenter observational cohort of 161 cross-sectional patients with ALS and 80 healthy matched controls were recruited across 3 research sites (Dublin, Edinburgh, and London). Participants were administered the ECAS and categorized into independent groups based on their King's clinical disease stage at time of testing. RESULTS: Significant differences were observed between patients and controls on all subtests of the ECAS except for visuospatial functioning. A significant cross-sectional effect was observed across disease stages for ALS-specific functions (executive, language, letter fluency) and ECAS total score but not for ALS-nonspecific functions (memory, visuospatial). Rates of ALS-specific impairment and behavioral change were also related to disease stage. The relationship between cognitive…

Objective To evaluate the efficacy, safety, and tolerability of noninvasive vagus nerve stimulation (nVNS; gammaCore; electroCore, LLC, Basking Ridge, NJ) for the acute treatment of migraine in a multicenter, double-blind, randomized, sham-controlled trial. Methods A total of 248 participants with episodic migraine with/without aura were randomized to receive nVNS or sham within 20 minutes from pain onset. Participants were to repeat treatment if pain had not improved in 15 minutes. Results nVNS (n = 120) was superior to sham (n = 123) for pain freedom at 30 minutes (12.7% vs 4.2%; p = 0.012) and 60 minutes (21.0% vs 10.0%; p = 0.023) but not at 120 minutes (30.4% vs 19.7%; p = 0.067; primary endpoint; logistic regression) after the first treated attack. A post hoc repeated-measures test provided further insight into the therapeutic benefit of nVNS through 30, 60, and 120 minutes (odds ratio 2.3; 95% confidence interval 1.2, 4.4; p = 0.012). nVNS demonstrated benefits across other endpoints including pain relief at 120 minutes and was safe and well-tolerated. Conclusion This…

OBJECTIVE: To investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD). METHODS: We used data from a multicenter longitudinal cohort of consecutive patients with PD with ≤5 years' disease duration at baseline followed up annually up to 5 years. ICDs were evaluated during face-to-face semistructured interviews with movement disorder specialists. Generalized estimating equations and Poisson models with robust variance were used to study the association between several time-dependent definitions of dopamine agonist (DA) use, taking dose and duration of treatment into account, and ICDs at each visit. Other antiparkinsonian drugs were also examined. RESULTS: Among 411 patients (40.6% women, mean age 62.3 years, average follow-up 3.3 years, SD 1.7 years), 356 (86.6%) took a DA at least once since disease onset. In 306 patients without ICDs at baseline, the 5-year cumulative incidence of ICDs was 46.1% (95% confidence interval [CI] 37.4-55.7, DA ever users 51.5% [95% CI 41.8-62.1], DA never…

Objective To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). Methods In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73. Results The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF β-amyloid 1-42 levels that correlated…

Objectives To assess the feasibility and clinical efficacy of local field potentials (LFPs)–based adaptive deep brain stimulation (aDBS) in patients with advanced Parkinson disease (PD) during daily activities in an open-label, nonblinded study. Methods We monitored neurophysiologic and clinical fluctuations during 2 perioperative experimental sessions lasting for up to 8 hours. On the first day, the patient took his/her daily medication, while on the second, he/she additionally underwent subthalamic nucleus aDBS driven by LFPs beta band power. Results The beta band power correlated in both experimental sessions with the patient9s clinical state (Pearson correlation coefficient r = 0.506, p < 0.001, and r = 0.477, p < 0.001). aDBS after LFP changes was effective (30% improvement without medication [3-way analysis of variance, interaction day × medication p = 0.036; 30.5 ± 3.4 vs 22.2 ± 3.3, p = 0.003]), safe, and well tolerated in patients performing regular daily activities and taking additional dopaminergic medication. aDBS was able to decrease DBS amplitude during motor “on”…

Objective To examine in a 3-year brain imaging study the effects of higher vs lower adherence to a Mediterranean-style diet (MeDi) on Alzheimer disease (AD) biomarker changes (brain β-amyloid load via 11C-Pittsburgh compound B [PiB] PET and neurodegeneration via 18F-fluorodeoxyglucose [FDG] PET and structural MRI) in midlife. Methods Seventy 30- to 60-year-old cognitively normal participants with clinical, neuropsychological, and dietary examinations and imaging biomarkers at least 2 years apart were examined. These included 34 participants with higher (MeDi+) and 36 with lower (MeDi−) MeDi adherence. Statistical parametric mapping and volumes of interest were used to compare AD biomarkers between groups at cross section and longitudinally. Results MeDi groups were comparable for clinical and neuropsychological measures. At baseline, compared to the MeDi+ group, the MeDi− group showed reduced FDG-PET glucose metabolism (CMRglc) and higher PiB-PET deposition in AD-affected regions (p < 0.001). Longitudinally, the MeDi−-group showed CMRglc declines and PiB increases in these regions,…

Objective To investigate whether diabetes mellitus is associated with Parkinson-like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease. Methods We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline. Results The presence of diabetes mellitus was associated with higher motor scores (p < 0.01), lower striatal dopamine transporter binding (p < 0.05), and higher tau CSF levels (p < 0.05) in patients with…

Objective To investigate the association between type 2 diabetes mellitus (T2DM) and subsequent Parkinson disease (PD). Methods Linked English national Hospital Episode Statistics and mortality data (1999–2011) were used to conduct a retrospective cohort study. A cohort of individuals admitted for hospital care with a coded diagnosis of T2DM was constructed, and compared to a reference cohort. Subsequent PD risk was estimated using Cox regression models. Individuals with a coded diagnosis of cerebrovascular disease, vascular parkinsonism, drug-induced parkinsonism, and normal pressure hydrocephalus were excluded from the analysis. Results A total of 2,017,115 individuals entered the T2DM cohort and 6,173,208 entered the reference cohort. There were significantly elevated rates of PD following T2DM (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.29–1.35; p < 0.001). The relative increase was greater in those with complicated T2DM (HR 1.49, 95% CI 1.42–1.56) and when comparing younger individuals (HR 3.81, 95% CI 2.84–5.11 in age group 25–44 years). Conclusions We report an…

Objective To perform a cross-sectional study to determine whether plasma neurofilament light chain (NfL) concentration is elevated in patients with Charcot-Marie-Tooth disease (CMT) and if it correlates with disease severity. Methods Blood samples were collected from 75 patients with CMT and 67 age-matched healthy controls over a 1-year period. Disease severity was measured using the Rasch modified CMT Examination and neuropathy scores. Plasma NfL concentration was measured using an in-house-developed Simoa assay. Results Plasma NfL concentration was significantly higher in patients with CMT (median 26.0 pg/mL) compared to healthy controls (median 14.6 pg/mL, p < 0.0001) and correlated with disease severity as measured using the Rasch modified CMT examination (r = 0.43, p < 0.0001) and neuropathy (r = 0.37, p = 0.044) scores. Concentrations were also significantly higher when subdividing patients by genetic subtype (CMT1A, SPTLC1, and GJB1) or into demyelinating or axonal forms compared to healthy controls. Conclusion There are currently no validated blood biomarkers for peripheral…

Objective To describe the quantification of novel dystrophin production in patients with Duchenne muscular dystrophy (DMD) after long-term treatment with eteplirsen. Methods Clinical study 202 was an observational, open-label extension of the randomized, controlled study 201 assessing the safety and efficacy of eteplirsen in patients with DMD with a confirmed mutation in the DMD gene amenable to correction by skipping of exon 51. Patients received once-weekly IV doses of eteplirsen 30 or 50 mg/kg. Upper extremity muscle biopsy samples were collected at combined study week 180, blinded, and assessed for dystrophin-related content by Western blot, Bioquant software measurement of dystrophin-associated immunofluorescence intensity, and percent dystrophin-positive fibers (PDPF). Results were contrasted with matched untreated biopsies from patients with DMD. Reverse transcription PCR followed by Sanger sequencing of newly formed slice junctions was used to confirm the mechanism of action of eteplirsen. Results Reverse transcription PCR analysis and sequencing of the newly formed splice…

Objective To explore the utility of serum neurofilament light chain (NfL) as a biomarker for primary and secondary neuroaxonal injury after ischemic stroke (IS) and study its value for the prediction of clinical outcome. Methods We used an ultrasensitive single-molecule array assay to measure serum NfL levels in healthy controls (n = 30) and 2 independent cohorts of patients with IS: (1) with serial serum sampling at hospital arrival (n = 196), at days 2, 3, and 7 (n = 89), and up to 6 months post stroke; and (2) with standardized MRI at baseline and at 6 months post stroke, and with cross-sectional serum sampling at 6 months (n = 95). We determined the temporal profile of serum NfL levels, their association with imaging markers of neuroaxonal injury, and with clinical outcome. Results Patients with IS had higher serum NfL levels compared with healthy controls starting from admission until 6 months post stroke. Serum NfL levels peaked at day 7 (211.2 pg/mL [104.7–442.6], median [IQR]) and correlated with infarct volumes (day 7: partial r = 0.736, p = 1.5 × 10−15). Six months post…

Objective Emerging evidence suggests that comorbidity may influence disability outcomes in multiple sclerosis (MS); we investigated the association between psychiatric comorbidity and MS disability progression in a large multiclinic population. Methods This retrospective cohort study accessed prospectively collected information from linked clinical and population-based health administrative databases in the Canadian provinces of British Columbia and Nova Scotia. Persons with MS who had depression, anxiety, or bipolar disorder were identified using validated algorithms using physician and hospital visits. Multivariable linear regression models fitted using an identity link with generalized estimating equations were used to determine the association between psychiatric comorbidity and disability using all available Expanded Disability Status Scale (EDSS) scores. Results A total of 2,312 incident cases of adult-onset MS were followed for a mean of 10.5 years, during which time 35.8% met criteria for a mood or anxiety disorder. The presence of a mood or anxiety disorder was associated…

OBJECTIVE: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS). METHODS: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion. RESULTS: < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate…

Objective Amyotrophic lateral sclerosis (ALS) incidence rates are consistent with the hypothesis that ALS is a multistep process. We tested the hypothesis that carrying a large effect mutation might account for ≥1 steps through the effect of the mutation, thus leaving fewer remaining steps before ALS begins. Methods We generated incidence data from an ALS population register in Italy (2007–2015) for which genetic analysis for C9orf72, SOD1, TARDBP , and FUS genes was performed in 82% of incident cases. As confirmation, we used data from ALS cases diagnosed in the Republic of Ireland (2006–2014). We regressed the log of age-specific incidence against the log of age with least-squares regression for the subpopulation carrying disease-associated variation in each separate gene. Results Of the 1,077 genetically tested cases, 74 (6.9%) carried C9orf72 mutations, 20 (1.9%) had SOD1 mutations, 15 (1.4%) had TARDBP mutations, and 3 (0.3%) carried FUS mutations. In the whole population, there was a linear relationship between log incidence and log age ( r 2 = 0.98) with a slope estimate of…

The demographic structure of Latin American countries (LAC) is fast approaching that of developing countries, and the predicted prevalence of dementia in the former already exceeds the latter. Dementia has been declared a global challenge, yet regions around the world show differences in both the nature and magnitude of such a challenge. This article provides evidence and insights on barriers which, if overcome, would enable the harmonization of strategies to tackle the dementia challenge in LAC. First, we analyze the lack of available epidemiologic data, the need for standardizing clinical practice and improving physician training, and the existing barriers regarding resources, culture, and stigmas. We discuss how these are preventing timely care and research. Regarding specific health actions, most LAC have minimal mental health facilities and do not have specific mental health policies or budgets specific to dementia. In addition, local regulations may need to consider the regional context when developing treatment and prevention strategies. The support needed nationally and…

Objective To evaluate whether APOE ε4 is associated with severity of Lewy body (LB) pathology, independently of Alzheimer disease (AD) pathology. Methods Six hundred fifty-two autopsy-confirmed LB disease (LBD) cases and 660 clinical controls were genotyped for APOE. In case-control analysis, LBD cases were classified into 9 different groups according to severity of both LB pathology (brainstem, transitional, diffuse) and AD pathology (low, moderate, high) to assess associations between APOE ε4 and risk of different neuropathologically defined LBD subgroups in comparison to controls. In LBD cases only, we also measured LB counts from 5 cortical regions and evaluated associations with ε4 according to severity of AD pathology. Results As expected, APOE ε4 was associated with an increased risk of transitional and diffuse LBD in cases with moderate or high AD pathology (all odds ratios ≥3.42, all p ≤ 0.004). Of note, ε4 was also associated with an increased risk of diffuse LBD with low AD pathology (odds ratio = 3.46, p = 0.001). In the low AD pathology LBD subgroup, ε4 was associated…

Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s–50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic…

Objective To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. Methods Patients were recruited via investigators9 practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients9 phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. Results We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%)…

OBJECTIVE: To update the 2004 American Academy of Neurology guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs). METHODS: 2004 criteria were used to systemically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. RESULTS: Forty-two articles were included. RECOMMENDATIONS: The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment); rufinamide for Lennox-Gastaut syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal…

Misdiagnosis of multiple sclerosis (MS) (the incorrect assignment of a diagnosis of MS) remains a problem in contemporary clinical practice. Studies indicate that misdiagnosed patients are often exposed to prolonged unnecessary health care risks and morbidity. The recently published 2017 revision of the McDonald criteria for the diagnosis of MS provides an opportunity to consider the effect of these revisions on the problem of MS misdiagnosis. The 2017 McDonald criteria include several new recommendations to reduce potential for misdiagnoses. The criteria should be used for the types of patients in which validation studies were performed, specifically those patients who present with typical demyelinating syndromes. MRI lesion characteristics were defined for which McDonald criteria would be expected to perform with accuracy. However, 2017 revisions, which now include assessment for cortical lesions, and the inclusion of symptomatic lesions and positive oligoclonal bands for the fulfillment of diagnostic criteria, may have the potential to lead to misdiagnosis of MS if not applied…

OBJECTIVE: To evaluate the use of interictal high-frequency oscillations (HFOs) in epilepsy surgery for prediction of postsurgical seizure outcome in a prospective multicenter trial. METHODS: We hypothesized that a seizure-free outcome could be expected in patients in whom the surgical planning included the majority of HFO-generating brain tissue while a poor seizure outcome could be expected in patients in whom only a few such areas were planned to be resected. Fifty-two patients were included from 3 tertiary epilepsy centers during a 1-year period. Ripples (80-250 Hz) and fast ripples (250-500 Hz) were automatically detected during slow-wave sleep with chronic intracranial EEG in 2 centers and acute intraoperative electrocorticography in 1 patient. RESULTS: There was a correlation between the removal of HFO-generating regions and seizure-free outcome at the group level for all patients. No correlation was found, however, for the center-specific analysis, and an individual prognostication of seizure outcome was true in only 36 patients (67%). Moreover, some patients became…

Objective To report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody–associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters. Methods Clinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques. Results From January 2005 to May 2017, 11 patients (median age 29 years, range 6–75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm3) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4)…

Objective To characterize muscle fiber necrosis in immune-mediated necrotizing myopathies (IMNM) with anti–signal recognition particle (SRP) or anti–3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) antibodies and to explore its underlying molecular immune mechanisms. Methods Muscle biopsies from patients with IMNM were analyzed and compared to biopsies from control patients with myositis. In addition to immunostaining and reverse transcription PCR on muscle samples, in vitro immunostaining on primary muscle cells was performed. Results Creatine kinase levels and muscle regeneration correlated with the proportion of necrotic fibers (r = 0.6, p < 0.001). CD68+iNOS+ macrophages and a Th-1 immune environment were chiefly involved in ongoing myophagocytosis of necrotic fibers. T-cell densities correlated with necrosis but no signs of cytotoxicity were detected. Activation of the classical pathway of the complement cascade, accompanied by deposition of sarcolemmal immunoglobulins, featured involvement of humoral immunity. Presence of SRP and HMGCR proteins on altered myofibers was…

OBJECTIVE: To define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS). METHODS: An International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG-positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers. RESULTS: Analysis of an international database for AQP4-IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20…

OBJECTIVE: To describe the pattern of development of incidence of multiple sclerosis (MS) over 60 years in Denmark with age-period-cohort analyses and seasonality of birth. METHODS: Data on virtually all patients with onset of MS have since 1950 been prospectively recorded and kept in the Danish Multiple Sclerosis Registry with multiple sources of notification. Annualized incidence rates per 100,000 were directly standardized to the European Standard Population. RESULTS: We have registered 19,536 cases with clinical onset of confirmed MS in Denmark from 1950 to 2009. From the 1950-1959 to the 2000-2009 onset period, incidence more than doubled in women, with an increase from 5.91 (95% confidence interval [CI]: 5.60-6.24) to 12.33 (95% CI: 11.91-12.75) per 100,000 per year compared with a modest 24% increase in men from 4.52 (95% CI: 4.24-4.81) to 6.08 (95% CI: 5.79-6.38). With age at onset of 50 years and older, incidence increased with a factor 4.30 in women and 2.72 in men. The female/male sex ratio increased over time and with year of birth. Age-period-cohort analysis revealed a…

OBJECTIVE: To compare neurofilament light (NfL) and tau as blood-based biomarkers for acute sports-related concussion (SRC) and determine whether their concentrations at different time points after the injury are associated with prolonged time to return to play (RTP). METHODS: A total of 288 professional hockey players were followed longitudinally from September 1, 2012, to April 30, 2015. Data collection and biomarker analyses were conducted between 2015 and 2017. Associations were tested between blood concentrations of NfL and tau, and RTP time. Serum concentrations of S100B and neuron-specific enolase (NSE) were also measured for comparison. RESULTS: Of 288 players, 105 sustained an SRC. Of these, 87 underwent blood sampling 1, 12, 36, and 144 hours after SRC and at the RTP time point. Serum NfL concentrations 1, 12, 36, and 144 hours after SRC were related to prolonged RTP time, and could separate players with RTP >10 days from those with RTP ≤10 days (area under the receiver operating characteristic curve [AUROC] 0.82). Also, serum NfL 144 hours after SRC discriminated players…

OBJECTIVE: To investigate whether greater cardiovascular fitness in midlife is associated with decreased dementia risk in women followed up for 44 years. METHODS: A population-based sample of 1,462 women 38 to 60 years of age was examined in 1968. Of these, a systematic subsample comprising 191 women completed a stepwise-increased maximal ergometer cycling test to evaluate cardiovascular fitness. Subsequent examinations of dementia incidence were done in 1974, 1980, 1992, 2000, 2005, and 2009. Dementia was diagnosed according to DSM-III-R criteria on the basis of information from neuropsychiatric examinations, informant interviews, hospital records, and registry data up to 2012. Cox regressions were performed with adjustment for socioeconomic, lifestyle, and medical confounders. RESULTS: Compared with medium fitness, the adjusted hazard ratio for all-cause dementia during the 44-year follow-up was 0.12 (95% confidence interval [CI] 0.03-0.54) among those with high fitness and 1.41 (95% CI 0.72-2.79) among those with low fitness. High fitness delayed age at dementia onset by 9.5…

OBJECTIVE: To assess the relevance of quantitative EEG (qEEG) measures as outcomes of disease severity and progression in Parkinson disease (PD). METHODS: Main databases were systematically searched (January 2018) for studies of sufficient methodologic quality that examined correlations between clinical symptoms of idiopathic PD and cortical (surface) qEEG metrics. RESULTS: Thirty-six out of 605 identified studied were included. Results were classified into 4 domains: cognition (23 studies), motor function (13 studies), responsiveness to interventions (7 studies), and other (10 studies). In cross-sectional studies, EEG slowing correlated with global cognitive impairment and with diffuse deterioration in other domains. In longitudinal studies, decreased dominant frequency and increased θ power, reflecting EEG slowing, were biomarkers of cognitive deterioration at an individual level. Results on motor dysfunction and treatment yielded contrasting findings. Studies on functional connectivity at an individual level and longitudinal studies on other domains or on connectivity measures…

Objective To characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy. Methods This was a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video-EEG, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and ECG were analyzed. Results We studied 148 GCS in 87 patients. Nineteen patients had generalized epilepsy; 65 had focal epilepsy; 1 had both; and the epileptogenic zone was unknown in 2. Ictal central apnea (ICA) preceded GCS in 49 of 121 (40.4%) seizures in 23 patients, all with focal epilepsy. Postconvulsive central apnea (PCCA) occurred in 31 of 140 (22.1%) seizures in 22 patients, with generalized, focal, or unknown epileptogenic zones. In 2 patients, PCCA occurred concurrently with asystole (near-SUDEP), with an incidence rate of 10.2 per 1,000 patient-years. One patient with PCCA died of probable SUDEP during follow-up, suggesting a SUDEP…

Objective We aimed to evaluate racial differences in the clinical features of neuromyelitis optica spectrum disorder. Methods This retrospective review included 603 patients (304 Asian, 207 Caucasian, and 92 Afro-American/Afro-European), who were seropositive for anti–aquaporin-4 antibody, from 6 centers in Denmark, Germany, South Korea, United Kingdom, United States, and Thailand. Results Median disease duration at last follow-up was 8 years (range 0.3–38.4 years). Asian and Afro-American/Afro-European patients had a younger onset age than Caucasian patients (mean 36, 33, and 44 years, respectively; p < 0.001). During the disease course, Caucasian patients (23%) had a lower incidence of brain/brainstem involvement than Asian (42%) and Afro-American/Afro-European patients (38%) (p < 0.001). Severe attacks (visual acuity ≤0.1 in at least one eye or Expanded Disability Status Scale score ≥6.0 at nadir) at onset occurred more frequently in Afro-American/Afro-European (58%) than in Asian (46%) and Caucasian (38%) patients (p = 0.005). In the multivariable analysis, older age at onset,…

Objective Arterial stiffness has been associated with evidence of cerebral small vessel disease (cSVD) and fibrillar β-amyloid (Aβ) deposition in the brain. These complex relationships have not been examined in racially and cognitively diverse cohorts. Methods The Atherosclerosis Risk in Communities (ARIC)–Neurocognitive Study collected detailed cognitive testing for adjudication of dementia and mild cognitive impairment (MCI), brain MRI, and arterial stiffness by pulse wave velocity (PWV, carotid-femoral [cfPWV] and heart-carotid [hcPWV]). The ARIC-PET ancillary study added Aβ imaging using florbetapir ([18F]-AV-45) to obtain standardized uptake volume ratios and defined global Aβ-positivity as standardized uptake volume ratio >1.2. One-SD increase in PWV was related to brain volume, MRI-defined cSVD (e.g., cerebral microbleeds and white matter hyperintensity), and cortical Aβ deposition adjusted for age, body mass index, sex, race, and APOE ε4 status. We examined the cross-sectional relationships including interactions by race, APOE ε4 status, and cognition. Results Among the 320…

OBJECTIVE: To examine mortality and associated risk factors, including possible effects of mild cognitive impairment, imaging, and CSF abnormalities, in a community-based population with incident parkinsonism and Parkinson disease. METHODS: One hundred eighty-two patients with new-onset, idiopathic parkinsonism were diagnosed from January 2004 through April 2009, in a catchment area of 142,000 inhabitants in Sweden. Patients were comprehensively investigated according to a multimodal research protocol and followed prospectively for up to 13.5 years. A total of 109 patients died. Mortality rates in the general Swedish population were used to calculate standardized mortality ratio and expected survival, and Cox proportional hazard models were used to investigate independent predictors of mortality. RESULTS: < 0.001). Patients with atypical parkinsonism (multiple system atrophy or progressive supranuclear palsy) had the highest mortality. In early Parkinson disease, a mild cognitive impairment diagnosis, freezing of gait, hyposmia, reduced dopamine transporter activity in the caudate,…

OBJECTIVE: To determine the accuracy of automated detection of generalized tonic-clonic seizures (GTCS) using a wearable surface EMG device. METHODS: We prospectively tested the technical performance and diagnostic accuracy of real-time seizure detection using a wearable surface EMG device. The seizure detection algorithm and the cutoff values were prespecified. A total of 71 patients, referred to long-term video-EEG monitoring, on suspicion of GTCS, were recruited in 3 centers. Seizure detection was real-time and fully automated. The reference standard was the evaluation of video-EEG recordings by trained experts, who were blinded to data from the device. Reading the seizure logs from the device was done blinded to all other data. RESULTS: The mean recording time per patient was 53.18 hours. Total recording time was 3735.5 hours, and device deficiency time was 193 hours (4.9% of the total time the device was turned on). No adverse events occurred. The sensitivity of the wearable device was 93.8% (30 out of 32 GTCS were detected). Median seizure detection latency was 9 seconds…

OBJECTIVE: To systematically examine the incidence of cognitive impairment in individuals with spinal cord injury (SCI), as well as identify potential contributing and confounding factors. METHODS: Studies quantitatively reporting cognitive ability after spinal cord injury were searched electronically via Medline, CINAHL, Embase, and PsycINFO. Manual screening for references within articles was also performed. A total of 2,481 studies were screened and a total of 70 were included in this review, 21 reporting cognitive function after SCI compared to an able-bodied control group and 49 with no able-bodied controls. Studies were analyzed for the incidence of impairment and the interactions with concomitant traumatic brain injury, psychological or somatic complaints, decentralized cardiovascular control, sleep apnea, neurologic level of injury, and age. RESULTS: There is a high volume of evidence reporting substantial cognitive impairment in individuals with SCI. Potential co-contributors include concomitant brain injury, psychological or somatic comorbidities, decentralized…

OBJECTIVE: To assess the reliability and usefulness of an EEG-based brain-computer interface (BCI) for patients with advanced amyotrophic lateral sclerosis (ALS) who used it independently at home for up to 18 months. METHODS: Of 42 patients consented, 39 (93%) met the study criteria, and 37 (88%) were assessed for use of the Wadsworth BCI. Nine (21%) could not use the BCI. Of the other 28, 27 (men, age 28-79 years) (64%) had the BCI placed in their homes, and they and their caregivers were trained to use it. Use data were collected by Internet. Periodic visits evaluated BCI benefit and burden and quality of life. RESULTS: Over subsequent months, 12 (29% of the original 42) left the study because of death or rapid disease progression and 6 (14%) left because of decreased interest. Fourteen (33%) completed training and used the BCI independently, mainly for communication. Technical problems were rare. Patient and caregiver ratings indicated that BCI benefit exceeded burden. Quality of life remained stable. Of those not lost to the disease, half completed the study; all but 1 patient…

OBJECTIVE: To evaluate deep brain stimulation (DBS) of the posterior subthalamic area (PSA) in essential tremor (ET) and compare it to the ventral intermediate nucleus of the thalamus (VIM) in terms of stimulation efficacy, efficiency, and side effects. METHODS: DBS leads were implanted such that contacts were placed in the VIM, on the intercommissural line, and in the PSA. Thirteen patients with ET entered a randomized, double-blind crossover phase and completed a 1-year follow-up. RESULTS: PSA-DBS significantly reduced tremor severity and improved quality of life. There were no relevant differences in quality and frequency of stimulation side effects between VIM and PSA, with a tendency toward greater tremor improvement with PSA stimulation. Clinical benefit was achieved at significantly lower stimulation amplitudes in the PSA. The majority of patients remained with PSA-DBS after 1 year. CONCLUSION: In accordance with previous retrospective investigations, our prospective data suggest that PSA-DBS is at least equally effective as but possibly more efficient than VIM-DBS.…

Objective To characterize continuous EEG (cEEG) use patterns in the critically ill and to determine the association with hospitalization outcomes for specific diagnoses. Methods We performed a retrospective cross-sectional study with National Inpatient Sample data from 2004 to 2013. We sampled hospitalized adult patients who received intensive care and then compared patients who underwent cEEG to those who did not. We considered diagnostic subgroups of seizure/status epilepticus, subarachnoid or intracerebral hemorrhage, and altered consciousness. Outcomes were in-hospital mortality, hospitalization cost, and length of stay. Results In total, 7,102,399 critically ill patients were identified, of whom 22,728 received cEEG. From 2004 to 2013, the proportion of patients who received cEEG increased from 0.06% (95% confidence interval [CI] 0.03%–0.09%) to 0.80% (95% CI 0.62%–0.98%). While the cEEG cohort appeared more ill, cEEG use was associated with reduced in-hospital mortality after adjustment for patient and hospital characteristics (odds ratio [OR] 0.83, 95% CI 0.75–0.93, p <…

Objective To investigate whether REM sleep behavior disorder (RBD) is associated with worse motor and cognitive decline in Parkinson disease (PD) Methods Four-hundred twenty-one drug-naive patients with early-stage PD and 196 controls without PD were included in this study. All participants underwent a [123I]FP-CIT SPECT scan, CSF assessment, 3-tesla MRI, and thorough clinical assessments. Results At cross-sectional analyses, patients with PD and probable RBD (PD-RBD) had lower CSF β-amyloid 1–42 (Aβ42) levels and higher total tau to Aβ42 CSF ratio, higher nonmotor symptoms burden, and worse scores on neuropsychological tests of processing speed, visuospatial functioning, and delayed recognition memory compared to patients with PD without RBD. At longitudinal analyses, the presence of RBD was associated with faster motor progression (hazard ratio [HR] = 1.368, 95% confidence Interval [CI] = 1.036–1.806; p = 0.027) and cognitive decline (HR = 1.794, 95% CI = 1.163–2.768; p = 0.008) over 60-month follow-up. The presence of RBD was a predictor for motor progression only in patients…

OBJECTIVE: infantile developmental and epileptic encephalopathy (EIEE13, OMIM #614558). METHODS: Twenty-two patients, aged 19 months to 22 years, underwent electroclinical assessment. RESULTS: Sixteen of 22 patients had mildly delayed development since birth. Drug-resistant epilepsy started at a median age of 4 months, followed by developmental slowing, pyramidal/extrapyramidal signs (22/22), movement disorders (12/22), cortical blindness (17/22), sialorrhea, and severe gastrointestinal symptoms (15/22), worsening during early childhood and plateauing at age 5 to 9 years. Death occurred in 4 children, following extreme neurologic deterioration, at 22 months to 5.5 years. Nonconvulsive status epilepticus recurred in 14 of 22 patients. The most effective antiepileptic drugs were oxcarbazepine, carbamazepine, phenytoin, and benzodiazepines. EEG showed background deterioration, epileptiform abnormalities with a temporo-occipital predominance, and posterior delta/beta activity correlating with visual impairment. Video-EEG documented focal seizures (FS) (22/22), spasm-like episodes…

Neuropalliative care is an emerging subspecialty in neurology and palliative care. On April 26, 2017, we convened a Neuropalliative Care Summit with national and international experts in the field to develop a clinical, educational, and research agenda to move the field forward. Clinical priorities included the need to develop and implement effective models to integrate palliative care into neurology and to develop and implement informative quality measures to evaluate and compare palliative approaches. Educational priorities included the need to improve the messaging of palliative care and to create standards for palliative care education for neurologists and neurology education for palliative specialists. Research priorities included the need to improve the evidence base across the entire research spectrum from early-stage interventional research to implementation science. Highest priority areas include focusing on outcomes important to patients and families, developing serious conversation triggers, and developing novel approaches to patient and family engagement, including…

Objective Resective surgery is effective in treating drug-resistant focal epilepsy, but it remains unclear whether improved diagnostics influence postsurgical outcomes. Here, we compared practice and outcomes over 2 periods 15 years apart. Methods Sixteen European centers retrospectively identified 2 cohorts of children and adults who underwent epilepsy surgery in the period of 1997 to 1998 (n = 562) or 2012 to 2013 (n = 736). Data collected included patient (sex, age) and disease (duration, localization and diagnosis) characteristics, type of surgery, histopathology, Engel postsurgical outcome, and complications, as well as imaging and electrophysiologic tests performed for each case. Postsurgical outcome predictors were included in a multivariate logistic regression to assess the strength of date of surgery as an independent predictor. Results Over time, the number of operated cases per center increased from a median of 31 to 50 per 2-year period (p = 0.02). Mean disease duration at surgery decreased by 5.2 years (p < 0.001). Overall seizure freedom (Engel class 1) increased from…

OBJECTIVE: To examine whether the Montreal Cognitive Assessment (MoCA) administered within 7 days after stroke predicts long-term cognitive impairment, functional impairment, and mortality. METHODS: MoCA was administered to 274 patients from 2 prospective hospital-based cohort studies in Germany (n = 125) and France (n = 149). Cognitive and functional outcomes were assessed at 6, 12, and 36 months after stroke by comprehensive neuropsychological testing, the Clinical Dementia Rating (CDR) scale, the modified Rankin Scale (mRS), and Instrumental Activities of Daily Living (IADL) and analyzed with generalized estimating equations. All-cause mortality was investigated by Cox proportional hazard models. Analyses were adjusted for demographic variables, education, vascular risk factors, premorbid cognitive status, and NIH Stroke Scale scores. The additive predictive value of MoCA was examined with receiver operating characteristic curves. RESULTS: = 0.047). CONCLUSION: Early cognitive testing by MoCA predicts long-term cognitive outcome, functional outcome, and mortality after stroke.…

OBJECTIVES: To determine whether a panel of blood-based biomarkers can discriminate between patients with suspected mild traumatic brain injury (mTBI) with and without neuroimaging findings (CT and MRI). METHODS: Study participants presented to the emergency department with suspected mTBI (n = 277) with a CT and MRI scan and healthy controls (n = 49). Plasma concentrations of tau, glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and neurofilament light chain (NFL) were measured using the single-molecule array technology. RESULTS: 's < 0.01). GFAP yielded an area under the curve (AUC) of 0.93 (95% confidence interval [CI] 0.90-0.96), confirming its discriminatory power for distinguishing mTBI from controls. Levels of GFAP, tau, and NFL were higher in patients with trauma-related intracranial findings on CT compared with those with normal CT, with the only significant predictor being GFAP (AUC 0.77, 95% CI 0.70-0.84). Among patients with mTBI, tau, NFL, and GFAP differentiated subjects with and without MRI abnormalities with an AUC of 0.83, with GFAP…

Objective Extensive cortical β-amyloid (Aβ positivity) has been linked to cognitive decline, but the clinical significance of elevations in Aβ within the negative range is unknown. Methods We examined amyloid and cognitive trajectories (memory, executive function) in 142 cognitively normal older individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative who were Aβ-negative at baseline and who had at least 2 [18F]-florbetapir PET scans over 3.9 ± 1.4 years. We determined whether Aβ accumulation was associated with longitudinal changes in memory or executive function. Results Among baseline-negative individuals, florbetapir slope (mean annual increase 0.002 ± 0.008 standardized uptake value ratio units/y) was not related to age, sex, education, APOE4 status, baseline memory or executive function, temporoparietal glucose metabolism, baseline hippocampal volume, or hippocampal volume change; but it was related to higher baseline cortical florbetapir, indicating that Aβ accumulation was ongoing at baseline in those who accumulated during the study. Over the course of…

Objective To assess the safety and efficacy of elamipretide, an aromatic-cationic tetrapeptide that readily penetrates cell membranes and transiently localizes to the inner mitochondrial membrane where it associates with cardiolipin, in adults with primary mitochondrial myopathy (PMM). Methods A Study Investigating the Safety, Tolerability, and Efficacy of MTP-131 for the Treatment of Mitochondrial Myopathy (MMPOWER) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial of elamipretide in 36 participants with genetically confirmed PMM. Participants were randomized to intravenous elamipretide (0.01, 0.1, and 0.25 mg/kg/h or placebo for 2 hours in a dose-escalating sequence). The primary efficacy measure was the change in distance walked in the 6-minute walk test (6MWT) after 5 days of treatment. Other efficacy measures included changes in cardiopulmonary exercise testing parameters, in participant-reported symptoms, and in serum and urinary biomarkers. Safety, tolerability, and pharmacokinetics were also measured. Results Participants who received the…

OBJECTIVE: To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms. METHODS: Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used. RESULTS: Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For…

OBJECTIVE: To systematically review evidence regarding ataxia treatment. METHODS: A comprehensive systematic review was performed according to American Academy of Neurology methodology. CONCLUSIONS: For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are…

Epilepsy is a common condition in the United States. It is estimated that 1.2% of the population or 3.4 million people have epilepsy. This figure may be underestimated because of potential repercussions and stigma in disclosing epilepsy.1 Studies have shown that people with epilepsy are more likely to be unemployed or unable to work, have lower annual household incomes, be obese and physically inactive, and be less likely to marry.2,3 People with epilepsy can have poor overall health status, impaired intellectual and physical functioning, elevated risk of accidents and injuries, and negative side effects from antiseizure medications.2,3 It is estimated the annual direct medical cost of epilepsy in the United States is $9.6 billion; combined with indirect costs, the total rises to $15.5 billion yearly.2

OBJECTIVE: We describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder. METHODS: The Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod. RESULTS: As of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6…

Objective To provide detailed long-term outcome data of children and adolescents following pediatric anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, to identify neuropsychological impairments, and to evaluate the influence of these factors on quality of life (QoL). Methods All Dutch children diagnosed with anti-NMDAR encephalitis were identified. Patients currently aged 4 years or older were included in the follow-up study, consisting of a visit to our clinic for a detailed interview and a standardized neuropsychological assessment. The following domains were included: attention, memory, language, executive functioning, QoL, and fatigue. Primary outcome measures were z scores on sustained attention, long-term verbal memory, QoL, fatigue, and working memory. Results Twenty-eight patients were included. Median Pediatric Cerebral Performance Category at last visit was 1 (interquartile range 1–2, range 1–4), and 64% (18/28) of patients returned consistently to their previous school level. Twenty-two patients were included in the cross-sectional part of the long-term…

Objective To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry.…

OBJECTIVE: To disentangle the different forms of postural tremors in Parkinson disease (PD). METHODS: In this combined observational and intervention study, we measured resting and postural tremor characteristics in 73 patients with tremulous PD by using EMG of forearm muscles. Patients were measured both "off" medication (overnight withdrawal) and after dispersible levodopa-benserazide 200/50 mg. We performed an automated 2-step cluster analysis on 3 postural tremor characteristics: the frequency difference with resting tremor, the degree of tremor suppression after posturing, and the dopamine response. RESULTS: The cluster analysis revealed 2 distinct postural tremor phenotypes: 81% had re-emergent tremor (amplitude suppression, frequency difference with resting tremor 0.4 Hz, clear dopamine response) and 19% had pure postural tremor (no amplitude suppression, frequency difference with resting tremor 3.5 Hz, no dopamine response). This finding was manually validated (accuracy of 93%). Pure postural tremor was not associated with clinical signs of essential tremor or dystonia, and…

OBJECTIVE: We sought to identify motor features that would allow the delineation of individuals with sleep study-confirmed idiopathic REM sleep behavior disorder (iRBD) from controls and Parkinson disease (PD) using a customized smartphone application. METHODS: A total of 334 PD, 104 iRBD, and 84 control participants performed 7 tasks to evaluate voice, balance, gait, finger tapping, reaction time, rest tremor, and postural tremor. Smartphone recordings were collected both in clinic and at home under noncontrolled conditions over several days. All participants underwent detailed parallel in-clinic assessments. Using only the smartphone sensor recordings, we sought to (1) discriminate whether the participant had iRBD or PD and (2) identify which of the above 7 motor tasks were most salient in distinguishing groups. RESULTS: Statistically significant differences based on these 7 tasks were observed between the 3 groups. For the 3 pairwise discriminatory comparisons, (1) controls vs iRBD, (2) controls vs PD, and (3) iRBD vs PD, the mean sensitivity and specificity values ranged from…

OBJECTIVE: To investigate the prevalence of neutralizing antibodies (NAbs) against botulinum neurotoxin type A (BoNT/A) during long-term BoNT/A treatment in different neurologic indications. METHODS: In this monocentric, observational cross-sectional study, 596 outpatients treated with BoNT/A for different indications were tested for BoNT/A binding antibodies by ELISA. Positive samples were investigated for NAbs with the mouse hemidiaphragm test. The prevalence of NAbs was analyzed for different indications: facial hemispasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. Besides the rate of NAb-positive patients overall and per patient subgroup, a Kaplan-Meier analysis of the probability of remaining NAb negative with duration of treatment is provided, and a stepwise binary logistic regression analysis is performed to identify factors significantly contributing to the induction of NAbs. RESULTS: Overall, 83 of 596 patients (13.9%) had measurable NAbs. The probability of developing NAbs increased with the single and cumulative dose of treatment and was influenced…

OBJECTIVES: To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH). METHODS: MRI scans of 1,836 participants (median age 52.2 ± 13.16 years) encompassing a wide age range (22-84 years) from the cross-sectional Study of Health in Pomerania (Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8 ± 10.2 years, with 747 observations) from the Baltimore Longitudinal Study of Aging (United States) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer disease (AD) genetics, and cognition were then investigated using linear regression. RESULTS: WMH were found to occur nonuniformly, with higher frequency within spatially heterogeneous patterns encoded by 4 components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal, and dorsal…

Objective To assess the association of early morning serum cortisol with cognitive performance and brain structural integrity in community-dwelling young and middle-aged adults without dementia. Methods We evaluated dementia-free Framingham Heart Study (generation 3) participants (mean age 48.5 years, 46.8% men) who underwent cognitive testing for memory, abstract reasoning, visual perception, attention, and executive function (n = 2,231) and brain MRI (n = 2018) to assess total white matter, lobar gray matter, and white matter hyperintensity volumes and fractional anisotropy (FA) measures. We used linear and logistic regression to assess the relations of cortisol (categorized in tertiles, with the middle tertile as referent) to measures of cognition, MRI volumes, presence of covert brain infarcts and cerebral microbleeds, and voxel-based microstructural white matter integrity and gray matter density, adjusting for age, sex, APOE, and vascular risk factors. Results Higher cortisol (highest tertile vs middle tertile) was associated with worse memory and visual perception, as well as…

OBJECTIVE: To validate an amended protocol for clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) including real-time quaking-induced conversion (RT-QuIC) and to observe its use in CJD surveillance. METHODS: In the framework of a prospective epidemiologic study, all neuropathologically confirmed cases with sCJD who received CSF RT-QuIC analysis during diagnostic workup (n = 65) and a control group of individuals without CJD (n = 118) were selected to investigate the accuracy of an amended diagnostic protocol. The patients had been referred to the German National Reference Center for Transmissible Spongiform Encephalopathies. The influence of the amended protocol on incidence figures was evaluated in the context of 3 years of surveillance activity (screened cases using 14-3-3 test n = 18,789, highly suspicious cases of CJD n = 704). Annual incidences were calculated with current criteria and the amended protocol. RESULTS: The amended protocol showed a sensitivity of 97% and a specificity of 99%. When it was applied to all suspected cases who were referred to the…

Impaired synaptic plasticity and dendritic loss in excitatory glutamatergic synapses are early events in Alzheimer disease (AD). These synaptic abnormalities are triggered by accumulation of soluble fibrillary β-amyloid (Aβ) oligomers, which bind to several postsynaptic and presynaptic partners. Many of the synaptic effects of Aβ oligomers involve NMDA receptors (NMDARs) and type 1 metabotropic glutamate receptor 5 (mGluR5). These receptors mediate use-dependent plasticity of glutamatergic synapses in the hippocampus and other brain regions. Synaptic plasticity includes long-term potentiation (LTP) and long-term depression (LTD) of efficacy of synaptic transmission. Studies both in vitro and in animal models indicate that Aβ oligomers disrupt LTP and promote LTD; these effects are associated with decreased density of dendritic spines. The mechanisms by which Aβ oligomers elicit these synaptic changes are similar to those normally utilized in the CNS during development and learning. In addition, interactions of β oligomers with extrasynaptic NMDARs and mGluR5 promote…

OBJECTIVE: -methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis. METHODS: Evaluation of IgG, IgA, and IgM NMDAR antibodies in serum of 300 patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining. Retrospective analysis of the clinical diagnoses of a cohort of 1,147 patients with IgG NMDAR antibodies identified since 2005. RESULTS: Among the 300 patients studied, IgG NMDAR antibodies were only identified in those with anti-NMDAR encephalitis and all reacted with brain and live neurons. By cell-based assay, IgA or IgM antibodies were detected in 22 of 300 patients (7%) with different diseases, but only 10 (3%) reacted with brain and 7 (2%) with live neurons. In cultured neurons, IgG but not IgA or IgM antibodies caused a decrease of synaptic and extrasynaptic NMDAR. Among the cohort of 1,147 patients…

OBJECTIVE: amyotrophic lateral sclerosis (ALS). METHODS: -mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS). RESULTS: Thirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32-1.80). ALSFRS-R…

Objective To investigate the association of enlarged perivascular spaces (ePVS) with cognition in elderly without dementia. Methods We included 5 studies from the Uniform Neuro-Imaging of Virchow-Robin Space Enlargement (UNIVRSE) consortium, namely the Austrian Stroke Prevention Family Study, Study of Health in Pomerania, Rotterdam Study, Epidemiology of Dementia in Singapore study, and Risk Index for Subclinical Brain Lesions in Hong Kong study. ePVS were counted in 4 regions (mesencephalon, hippocampus, basal ganglia, and centrum semiovale) with harmonized rating across studies. Mini-Mental State Examination (MMSE) and general fluid cognitive ability factor (G-factor) were used to assess cognitive function. For each study, a linear regression model was performed to estimate the effect of ePVS on MMSE and G-factor. Estimates were pooled across studies with the use of inverse variance meta-analysis with fixed- or random-effect models when appropriate. Results The final sample size consisted of 3,575 persons (age range 63.4–73.2 years, 50.6% women). Total ePVS counts were not…

Objective To update the 2004 American Academy of Neurology guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs). Methods 2004 criteria were used to systemically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results Forty-two articles were included. Recommendations The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment); rufinamide for Lennox-Gastaut syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal…

OBJECTIVE: To compare neurodevelopmental outcomes of preterm infants with and without intervention for posthemorrhagic ventricular dilatation (PHVD) managed with an "early approach" (EA), based on ventricular measurements exceeding normal (ventricular index [VI] <+2 SD/anterior horn width <6 mm) with initial temporizing procedures, followed, if needed, by permanent shunt placement, and a "late approach" (LA), based on signs of increased intracranial pressure with mostly immediate permanent intervention. METHODS: Observational cohort study of 127 preterm infants (gestation <30 weeks) with PHVD managed with EA (n = 78) or LA (n = 49). Ventricular size was measured on cranial ultrasound. Outcome was assessed at 18-24 months. RESULTS: < 0.003), with scores <-2 SD in 81%. CONCLUSION: In preterm infants with PHVD, those with early intervention, even when eventually requiring a shunt, had outcomes indistinguishable from those without intervention, all being within the normal range. In contrast, in infants managed with LA, need for intervention predicted worse outcomes. Benefits of EA…

Objective To determine the independent and additive effects of aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet on executive functioning in adults with cognitive impairments with no dementia (CIND) and risk factors for cardiovascular disease (CVD). Methods A 2-by-2 factorial (exercise/no exercise and DASH diet/no DASH diet) randomized clinical trial was conducted in 160 sedentary men and women (age >55 years) with CIND and CVD risk factors. Participants were randomly assigned to 6 months of AE, DASH diet nutritional counseling, a combination of both AE and DASH, or health education (HE). The primary endpoint was a prespecified composite measure of executive function; secondary outcomes included measures of language/verbal fluency, memory, and ratings on the modified Clinical Dementia Rating Scale. Results Participants who engaged in AE (d = 0.32, p = 0.046) but not those who consumed the DASH diet (d = 0.30, p = 0.059) demonstrated significant improvements in the executive function domain. The largest improvements were observed for participants…

OBJECTIVE: To evaluate the effect of chenodeoxycholic acid treatment on disease progression in cerebrotendinous xanthomatosis (CTX). METHODS: In this retrospective cohort study, we report the clinical long-term follow-up characteristics of 56 Dutch patients with CTX. Age at diagnosis was correlated with clinical characteristics and with the course of modified Rankin Scale (mRS) and Expanded Disability Status Scale (EDSS) scores at follow-up. RESULTS: Median follow-up time was 8 years (6 months-31.5 years). Patients diagnosed and treated before the age of 24 years had a significantly better outcome at follow-up. When considering only patients with a good treatment adherence (n = 43), neurologic symptoms, if present, disappeared in all patients who were diagnosed before the age of 24 and treated since. Furthermore, treatment prevented the development of new neurologic symptoms during follow-up. In contrast, 61% of the patients diagnosed and treated after the age of 24 showed deterioration of the neurologic symptoms, with parkinsonism as a treatment-resistant feature. There was an…

OBJECTIVE: To investigate the efficacy and safety of belimumab, a fully human immunoglobulin G1λ monoclonal antibody against B-lymphocyte stimulator, in participants with generalized myasthenia gravis (MG) who remained symptomatic despite standard of care (SoC) therapy. METHODS: Eligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo in this phase II, placebo-controlled, multicenter, double-blind study (NCT01480596; BEL115123). Participants received SoC therapies throughout the 24-week treatment phase and 12-week follow-up period. The primary efficacy endpoint was mean change from baseline in the Quantitative Myasthenia Gravis (QMG) scale at week 24; safety assessments included the frequency and severity of adverse events (AEs) and serious AEs. RESULTS: = 0.256). There were no statistically significant differences between treatment groups for secondary endpoints, including the MG Composite and MG-Activity of Daily Living scores. Acetylcholine receptor antibody levels decreased over time in both treatment groups. No unexpected AEs were identified…

OBJECTIVE: To quantify atrophy, demyelination, and iron accumulation over 2 years following acute spinal cord injury and to identify MRI predictors of clinical outcomes and determine their suitability as surrogate markers of therapeutic intervention. METHODS: We assessed 156 quantitative MRI datasets from 15 patients with spinal cord injury and 18 controls at baseline and 2, 6, 12, and 24 months after injury. Clinical recovery (including neuropathic pain) was assessed at each time point. Between-group differences in linear and nonlinear trajectories of volume, myelin, and iron change were estimated. Structural changes by 6 months were used to predict clinical outcomes at 2 years. RESULTS: The majority of patients showed clinical improvement with recovery stabilizing at 2 years. Cord atrophy decelerated, while cortical white and gray matter atrophy progressed over 2 years. Myelin content in the spinal cord and cortex decreased progressively over time, while cerebellar loss decreases decelerated. As atrophy progressed in the thalamus, sustained iron accumulation was evident. Smaller…

OBJECTIVE: In this study, we aimed to determine whether insulin resistance is associated with clinical outcomes after acute ischemic stroke. METHODS: We enrolled 4,655 patients with acute ischemic stroke (aged 70.3 ± 12.5 years, 63.5% men) who had been independent before admission; were hospitalized in 7 stroke centers in Fukuoka, Japan, from April 2009 to March 2015; and received no insulin therapy during hospitalization. The homeostasis model assessment of insulin resistance (HOMA-IR) score was calculated using fasting blood glucose and insulin levels measured 8.3 ± 7.8 days after onset. Study outcomes were neurologic improvement (≥4-point decrease in NIH Stroke Scale score or 0 at discharge), poor functional outcome (modified Rankin Scale score of ≥3 at 3 months), and 3-month prognosis (stroke recurrence and all-cause mortality). Logistic regression analysis was used to evaluate the association of the HOMA-IR score with clinical outcomes. RESULTS: The HOMA-IR score was associated with neurologic improvement (odds ratio, 0.68 [95% confidence interval, 0.56-0.83], top vs bottom…

Objective To determine the incidence of sudden unexpected death in epilepsy (SUDEP) in children in Ontario, Canada. Methods Cases of suspected pediatric SUDEP occurring between January 1, 2014, and December 31, 2015, in Ontario, Canada, were eligible for inclusion. Potential cases were identified through 3 sources: a national pediatrician surveillance program, child neurologist report, and screening of provincial forensic autopsies. Cases were classified as definite, definite plus, probable, possible, and near/near plus according to criteria described by Nashef et al. (Epilepsia 2012). Overall crude pediatric SUDEP incidence and the incidence of definite or probable pediatric SUDEP were calculated using estimates of the prevalence of pediatric epilepsy in Canada drawn from government survey data and the number of children living in Ontario. Capture-recapture analysis was used to estimate the number of missing cases and determine an adjusted definite/probable SUDEP incidence. Results Seventeen cases of pediatric SUDEP resulted in an overall incidence of 1.17 (95% confidence interval…

Over the last few decades, the improved diagnostic criteria, the wide use of MRI, and the growing availability of effective pharmacologic treatments have led to substantial advances in the management of multiple sclerosis (MS). The importance of early diagnosis and treatment is now well-established, but there is still no consensus on how to define and monitor response to MS treatments. In particular, the clinical relevance of the detection of minimal MRI activity is controversial and recommendations on how to define and monitor treatment response are warranted. An expert panel of the Magnetic Resonance Imaging in MS Study Group analyzed and discussed published studies on treatment response in MS. The evolving concept of no evidence of disease activity and its effect on predicting long-term prognosis was examined, including the option of defining a more realistic target for daily clinical practice: minimal evidence of disease activity. Advantages and disadvantages associated with the use of MRI activity alone and quantitative scoring systems combining on-treatment clinical relapses…

Objective To assess whether global or regional changes in amyloid burden over 4 years predict early declines in episodic memory in initially amyloid-negative adults. Methods One hundred twenty-six initially amyloid-negative, cognitively normal participants (age 30–89 years) were included from the Dallas Lifespan Brain Study who completed florbetapir PET and a cognitive battery at baseline and 4-year follow-up. Standardized uptake value ratio (SUVR) change was computed across 8 bilateral regions of interest. Using general linear models, we examined the relationship between change in global and regional SUVR and change in episodic memory, controlling for baseline SUVR, baseline memory, age, sex, education, and APOE status. Results In initially amyloid-negative adults, we detected a regionally specific relationship between declining episodic memory and increasing amyloid accumulation across multiple posterior cortical regions. In addition, these amyloid-related changes in memory persisted when we focused on middle-aged adults only and after controlling for atrophy in global cortical,…

ObjectiveTo compare how 3 common representations (ordinal vs dichotomized as 0–1/2–6 or 0–2/3–6) of the modified Rankin Scale (mRS)—a commonly used trial outcome measure—relate to long-term outcomes, and quantify trial ineligibility rates based on premorbid mRS. MethodsIn consecutive patients with ischemic stroke in a population-based, prospective, cohort study (Oxford Vascular Study; 2002–2014), we related 3-month mRS to 1-year and 5-year disability and death (logistic regressions), and health/social care costs (generalized linear model), adjusted for age/sex, and compared goodness-of-fit values (C statistic, mean absolute error). We also calculated the proportion of patients in whom premorbid mRS score >1 or >2 would result in exclusion from trials using dichotomous analysis. ResultsAmong 1,607 patients, the ordinal mRS was more strongly related to 5-year mortality than both the 0–1/2–6 and 0–2/3–6 dichotomies (all p < 0.0001). Results were similar for 5-year disability, and 5-year care costs were also best captured by the ordinal model (change in mean absolute error vs age/sex:…

OBJECTIVE: To investigate the influence of prestroke physical activity (PA) on acute stroke severity. METHODS: Data from patients with first stroke were retrieved from registries with a cross-sectional design. The variables were PA, age, sex, smoking, diabetes, hypertension and statin treatment, stroke severity, myocardial infarction, new stroke during hospital stay, and duration of inpatient care at stroke unit. PA was assessed with Saltin-Grimby's 4-level Physical Activity Level Scale, and stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Logistic regression was used to predict stroke severity, and negative binomial regression was used to compare the level of PA and stroke severity. RESULTS: The study included 925 patients with a mean age of 73.1 years, and 45.2% were women. Patients who reported light or moderate PA levels were more likely to present a mild stroke (NIHSS score 0 to 5) compared with physically inactive patients in a model that also included younger age as a predictor (odds ratio = 2.02 for PA and odds ratio = 0.97 for age).…

The recent discoveries of the glymphatic and lymphatic systems of the brain have helped advance our understanding of CSF physiology and may allow new insights in the understanding of idiopathic intracranial hypertension (IIH). The clinical and radiologic presentations of IIH appear to be related to congestion of the glymphatic system associated with an overflow of the lymphatic CSF outflow pathway. By revisiting the role of "vascular arachnoid granulations" in the brain, we hypothesize that an initial impairment of the transport of interstitial fluid from the glymphatic system to the venous blood of the dural sinuses may trigger the hydrodynamic cascade of IIH. Furthermore, we speculate that, similar to other water-exchange systems in the brain, a specific subtype of aquaporin is involved in this transport. This theory may eventually help to provide an underlying explanation for IIH and its associated conditions, since in most of them, the expression of several aquaporins is altered.

Objective To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA). Methods Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed. Results A total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9–8.5, p < 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) was associated with lower length and weight of the babies (p < 0.001).…

Objective To develop and prospectively evaluate a method of epileptic seizure detection combining heart rate and movement. Methods In this multicenter, in-home, prospective, video-controlled cohort study, nocturnal seizures were detected by heart rate (photoplethysmography) or movement (3-D accelerometry) in persons with epilepsy and intellectual disability. Participants with >1 monthly major seizure wore a bracelet (Nightwatch) on the upper arm at night for 2 to 3 months. Major seizures were tonic-clonic, generalized tonic >30 seconds, hyperkinetic, or others, including clusters (>30 minutes) of short myoclonic/tonic seizures. The video of all events (alarms, nurse diaries) and 10% completely screened nights were reviewed to classify major (needing an alarm), minor (needing no alarm), or no seizure. Reliability was tested by interobserver agreement. We determined device performance, compared it to a bed sensor (Emfit), and evaluated the caregivers’ user experience. Results Twenty-eight of 34 admitted participants (1,826 nights, 809 major seizures) completed the study. Interobserver…

OBJECTIVE: To present the current terminology and natural history of neurofibromatosis 1 (NF1) cutaneous neurofibromas (cNF). METHODS: NF1 experts from various research and clinical backgrounds reviewed the terms currently in use for cNF as well as the clinical, histologic, and radiographic features of these tumors using published and unpublished data. RESULTS: Neurofibromas develop within nerves, soft tissue, and skin. The primary distinction between cNF and other neurofibromas is that cNF are limited to the skin whereas other neurofibromas may involve the skin, but are not limited to the skin. There are important cellular, molecular, histologic, and clinical features of cNF. Each of these factors is discussed in consideration of a clinicopathologic framework for cNF. CONCLUSION: The development of effective therapies for cNF requires formulation of diagnostic criteria that encompass the clinical and histologic features of these tumors. However, there are several areas of overlap between cNF and other neurofibromas that make distinctions between cutaneous and other neurofibromas…

Objective To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS). Methods In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS. Results Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model,…

Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer disease (AD), a progressive neurodegenerative disease with currently no therapies that prevent, slow, or halt disease progression. Like other chronic diseases of old age, the progressive pathology of AD begins decades before the onset of symptoms. Many decades of research in biological gerontology have revealed common processes that are relevant to understanding why the aging brain is vulnerable to AD. In this review, we frame the development of novel therapeutics for AD in the context of biological gerontology. The many therapies currently in development based on biological gerontology principles provide promise for the development of a new generation of therapeutics to prevent and treat AD.

OBJECTIVE: To examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort. METHODS: CSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS). RESULTS: NfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology,…

Objective To determine the prevalence of preclinical Alzheimer disease (AD) according to current classification systems by examining CSF from a representative general population sample of 70-year-olds from Gothenburg, Sweden. Method The sample was derived from the population-based H70 Gothenburg Birth Cohort Studies in Gothenburg, Sweden. The participants (n = 322, age 70 years) underwent comprehensive neuropsychiatric, cognitive, and somatic examinations. CSF levels of β-amyloid (Aβ) 42 , Aβ 40 , total tau, and phosphorylated tau were measured. Preclinical AD was classified according to criteria of the A/T/N system, Dubois 2016, National Institute on Aging–Alzheimer's Association (NIA-AA) criteria, and International Working Group-2 (IWG-2) criteria. Individuals with Clinical Dementia Rating score >0 were excluded, leaving 259 cognitively unimpaired individuals. Results The prevalence of amyloid pathology was 22.8%, of total tau pathology was 33.2%, and of phosphorylated tau pathology was 6.9%. With the A/T/N system, the prevalence of A+/T−/N− was 13.1%, A+/T−/N+ was 7.3%, A+/T+/N+…

OBJECTIVE: To characterize the functional brain changes involved in δ-9-tetrahydrocannabinol (THC) modulation of chronic neuropathic pain. METHODS: Fifteen patients with chronic radicular neuropathic pain participated in a randomized, double-blind, placebo-controlled trial employing a counterbalanced, within-subjects design. Pain assessments and functional resting state brain scans were performed at baseline and after sublingual THC administration. We examined functional connectivity of the anterior cingulate cortex (ACC) and pain-related network dynamics using graph theory measures. RESULTS: THC significantly reduced patients' pain compared to placebo. THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex. Moreover, the degree of reduction was predictive of the response to THC. Graph theory analyses of local measures demonstrated reduction in network connectivity in areas involved in pain processing, and specifically in the dorsolateral prefrontal cortex (DLPFC), which were correlated…