Showing papers in "Neurology in 2018"

Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Abstract: Objective To update the 2001 American Academy of Neurology (AAN) guideline on mild cognitive impairment (MCI). Methods The guideline panel systematically reviewed MCI prevalence, prognosis, and treatment articles according to AAN evidence classification criteria, and based recommendations on evidence and modified Delphi consensus. Results MCI prevalence was 6.7% for ages 60–64, 8.4% for 65–69, 10.1% for 70–74, 14.8% for 75–79, and 25.2% for 80–84. Cumulative dementia incidence was 14.9% in individuals with MCI older than age 65 years followed for 2 years. No high-quality evidence exists to support pharmacologic treatments for MCI. In patients with MCI, exercise training (6 months) is likely to improve cognitive measures and cognitive training may improve cognitive measures. Major recommendations Clinicians should assess for MCI with validated tools in appropriate scenarios (Level B). Clinicians should evaluate patients with MCI for modifiable risk factors, assess for functional impairment, and assess for and treat behavioral/neuropsychiatric symptoms (Level B). Clinicians should monitor cognitive status of patients with MCI over time (Level B). Cognitively impairing medications should be discontinued where possible and behavioral symptoms treated (Level B). Clinicians may choose not to offer cholinesterase inhibitors (Level B); if offering, they must first discuss lack of evidence (Level A). Clinicians should recommend regular exercise (Level B). Clinicians may recommend cognitive training (Level C). Clinicians should discuss diagnosis, prognosis, long-term planning, and the lack of effective medicine options (Level B), and may discuss biomarker research with patients with MCI and families (Level C).

Cognition in multiple sclerosis: State of the field and priorities for the future

Abstract: 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 instance, we provide recommendations for improving the scientific basis and methodologic rigor for cognitive rehabilitation research. Toward this end, we call for multidisciplinary collaborations toward development of biologically based theoretical models of cognition capable of empirical validation and evidence-based refinement, providing the scientific context for effective treatment discovery.

Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study.

Abstract: 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 leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab-positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26–0.79) compared to AQP4-Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22–0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07–0.72). Finally, MOG-Ab titers were higher at relapse than in remission (p = 0.009). Conclusion In adults, MOG-Ab-associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients.

Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Abstract: 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 treatment, including adherence monitoring and disease comorbidity assessment. The panel also discussed DMT risks, including counseling about progressive multifocal leukoencephalopathy risk in people with MS using natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate; and made suggestions for future research to evaluate relative merits of early treatment with higher potency DMTs vs standard stepped-care protocols, DMT comparative effectiveness, optimal switching strategies, long-term effects of DMT use, definitions of highly active MS, and effects of treatment on patient-specified priority outcomes. This guideline reflects the complexity of decision-making for starting, switching, or stopping MS DMTs. The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates.

Galcanezumab in chronic migraine: The randomized, double-blind, placebo-controlled REGAIN study

Abstract: 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 compared to placebo (placebo −2.7, galcanezumab 120 mg −4.8, galcanezumab 240 mg −4.6) (p Conclusions Both doses of galcanezumab were superior to placebo in reducing the number of monthly MHDs. Galcanezumab appears efficacious, safe, and well tolerated for the preventive treatment of chronic migraine. ClinicalTrials.gov identifier NCT02614261. Classification of evidence This interventional study provides Class I evidence that galcanezumab is superior to placebo in the reduction of the number of monthly MHDs.

Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.

Abstract: 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 its metabolites was dose-proportional (AUC 0–t ). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed. Conclusions Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated. Classification of evidence This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

Reader response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium.

Abstract: McKeith et al1 revised dementia with Lewy bodies (DLB) criteria with new developments and statistics gathered through updated studies The series of recommendations are in perfect accordance with clinical settings (eg, the exclusion of antipsychotics for acute management of DLB symptoms) However, more explanations on the following 2 issues are needed

Reader response: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB consortium.

Abstract: The Dementia with Lewy Bodies (DLB) Consortium introduced 3 indicative biomarkers (IBs) into the framework for the diagnosis of DLB1 Because DLB is essentially multifocal,2 a combined approach with 4 core clinical features (CCFs) may greatly enhance the diagnostic efficacy by capturing the chameleon-like variability of DLB3

Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer

Abstract: 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 patients) and limb-girdle (7), axial (7), and oculomotor (7) weakness. Four patients had evidence of myocarditis. In all patients, creatine kinase levels were elevated (median 2,668, range 1,059–16,620 U/L), while anti-acetylcholine receptor and myositis-associated antibodies were negative. Electrodiagnostic studies showed myopathic process without decrement in all patients. Muscle biopsy constantly showed multifocal necrotic myofibers, sarcolemmal MHC-I, and endomysial inflammation, consisting mainly of CD68+ cells expressing PD-L1 and CD8+ cells expressing PD-1. ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement. Conclusions irMyositis presents with remarkably homogeneous and unique clinicopathologic features, expanding the nosologic spectrum of inflammatory myopathies in patients with cancer. ICI withdrawal and treatment with corticosteroids improve outcome.

Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research

Abstract: 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 Recovery Scale–Revised can assist prognostication in adults (Level B); no tests are shown to improve prognostic accuracy in children. Pain always should be assessed and treated (Level B) and evidence supporting treatment approaches discussed (Level B). Clinicians should prescribe amantadine (100–200 mg bid) for adults with traumatic VS/UWS or MCS (4–16 weeks post injury) to hasten functional recovery and reduce disability early in recovery (Level B). Family counseling concerning children should acknowledge that natural history of recovery, prognosis, and treatment are not established (Level B). Recent evidence indicates that the term chronic VS/UWS should replace permanent VS, with duration specified (Level B). Additional recommendations are included.

Resistance vs resilience to Alzheimer disease: Clarifying terminology for preclinical studies.

Abstract: 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 studies, we (1) define these concepts and provide recommendations (and common scenarios) for their use; (2) discuss how to employ this terminology in the context of investigating mechanisms and factors; (3) highlight the complementarity and clarity they provide to existing concepts; and (4) discuss different study designs and methodologies. The application of the proposed framework for framing hypotheses, study design, and interpretation of results and mechanisms can provide a consistent framework and nomenclature for researchers to reach consensus on identifying factors that may prevent ADP or delay the onset of cognitive impairment.

Lasmiditan is an effective acute treatment for migraine: A phase 3 randomized study.

Abstract: 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 p p p Conclusions Lasmiditan dosed at 200 and 100 mg was efficacious and well tolerated in the treatment of acute migraine among patients with a high level of cardiovascular risk factors. ClinicalTrials.gov identifier NCT02439320. Classification of evidence This study provides Class I evidence that for adult patients with migraine, lasmiditan increases the proportion of subjects who are headache pain free at 2 hours after treating a migraine attack.

CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease.

Abstract: 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 preclinical, prodromal, and dementia stages of AD High levels of these biomarkers were associated with increased CSF levels of total tau, with the associations, especially for YKL-40, being stronger in Aβ-positive individuals The results were similar for associations between phosphorylated tau and YKL-40, ICAM-1, and VCAM-1 High levels of the biomarkers were also associated with cortical thinning (primarily in the precuneus and superior parietal regions) and with subsequent cognitive deterioration in patients without dementia as measured with Mini-Mental State Examination (YKL-40) and Clinical Dementia Rating Sum of Boxes (YKL-40, ICAM-1, VCAM-1 and IL-15) Finally, higher levels of CSF YKL-40, ICAM-1, and Flt-1 increased risk of development of AD dementia in patients without dementia Conclusions Neuroinflammation and cerebrovascular dysfunction are early events occurring already at presymptomatic stages of AD and contribute to disease progression

Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease

Abstract: 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 in CSF p-tau181 near symptom onset as opposed to continued elevations. Conclusion These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.

Mild TBI and risk of Parkinson disease: A Chronic Effects of Neurotrauma Consortium Study

Abstract: 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 no TBI, those with TBI had higher incidence of PD (no TBI 0.31%, all-severity TBI 0.58%, mTBI 0.47%, moderate-severe TBI 0.75%). In adjusted models, all-severity TBI, mTBI, and moderate-severe TBI were associated with increased risk of PD (hazard ratio [95% confidence interval]: all-severity TBI 1.71 [1.53–1.92]; mTBI 1.56 [1.35–1.80]; moderate-severe TBI 1.83 [1.61–2.07]). Conclusions Among military veterans, mTBI is associated with 56% increased risk of PD, even after adjusting for demographics and medical/psychiatric comorbidities. This study highlights the importance of TBI prevention, long-term follow-up of TBI-exposed veterans, and the need to determine mechanisms and modifiable risk factors for post-TBI PD.

Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease.

Abstract: Objective To examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline. Methods A total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir ( 18 F-AV-1451) tau PET scan, a florbetapir ( 18 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 largest negative influence on tests of episodic memory and executive functioning. Conclusions Together, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression.

Advantages of virtual reality in the rehabilitation of balance and gait: Systematic review.

Abstract: 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 studies presented poor methodologic quality, lacked a clear rationale for intervention programs, and did not utilize motor learning principles meticulously. RCTs with more robust methodologic designs were widely recommended. Conclusion Our results suggest that VR-based rehabilitation is developing rapidly, has the potential to improve balance and gait in neurologic patients, and brings additional benefits when combined with conventional rehabilitation. This systematic review provides detailed information for developing theory-driven protocols that may assist overcoming the observed lack of argued choices for intervention programs and motor learning implementation and serves as a reference for the design and planning of personalized VR-based treatments. Registration PROSPERO CRD42016042051.

Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults.

Abstract: 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 11 C-Pittsburgh compound B [PiB] PET and neurodegeneration via 18 F-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 p interaction Conclusion Lower MeDi adherence was associated with progressive AD biomarker abnormalities in middle-aged adults. These data support further investigation of dietary interventions for protection against brain aging and AD.

Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study

Abstract: 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 randomized sham-controlled trial supports the abortive efficacy of nVNS as early as 30 minutes and up to 60 minutes after an attack. Findings also suggest effective pain relief, tolerability, and practicality of nVNS for the acute treatment of episodic migraine. ClinicalTrials.gov identifier NCT02686034. Classification of evidence This study provides Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 hours poststimulation (absolute difference 13.2%).

Eight-hours adaptive deep brain stimulation in patients with Parkinson disease.

Abstract: 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 = 0506, p r = 0477, p p = 0036; 305 ± 34 vs 222 ± 33, p = 0003]), 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” states compared to “off” states (paired t test p = 0046), and this automatic adjustment of STN-DBS prevented dyskinesias Conclusions The main findings of our study are that aDBS is technically feasible in everyday life and provides a safe, well-tolerated, and effective treatment method for the management of clinical fluctuations Classification of evidence This study provides Class IV evidence that for patients with advanced PD, aDBS is safe, well tolerated, and effective in controlling PD motor symptoms

Longitudinal analysis of impulse control disorders in Parkinson disease

Abstract: 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 years9 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 users 12.4% [95% CI 4.8–30.0]). ICD prevalence increased from 19.7% at baseline to 32.8% after 5 years. ICDs were associated with ever DA use (prevalence ratio 4.23, 95% CI 1.78–10.09). Lifetime average daily dose and duration of treatment were independently associated with ICDs with significant dose-effect relationships. Similar analyses for levodopa were not in favor of a strong association. ICDs progressively resolved after DA discontinuation. Conclusion In this longitudinal study of patients with PD characterized by a high prevalence of DA treatment, the 5-year cumulative incidence of ICDs was ≈46%. ICDs were strongly associated with DA use with a dose-effect relationship; both increasing duration and dose were associated with ICDs. ICDs progressively resolved after DA discontinuation. ClinicalTrials.gov identifier: NCT01564992.

Subjective cognitive decline and risk of MCI: The Mayo Clinic Study of Aging.

Abstract: 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 e4 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 baseline endorsement of any consistent SCD on the ECog (any item scored ≥3; 12-item ECog hazard ratio [HR] 2.17 [95% confidence interval 1.51–3.13]) and worry (HR 1.79 [1.24–2.58]) in an adjusted model combining these dimensions. In continuous models, all ECog domains and the multidomain scores were associated with risk of MCI with a small advantage for multidomain SCD (12-item ECog HR 2.13 [1.36–3.35] per point increase in average score). Information provided by the informant performed comparable to self-perceived SCD. Conclusion Prognostic value of SCD for incident MCI improves when both consistency of SCD and associated worry are evaluated.

Plasma neurofilament light chain concentration in the inherited peripheral neuropathies.

Abstract: 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 r = 0.43, p 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 neuropathy. The significantly raised plasma NfL concentration in patients with CMT and its correlation with disease severity suggest that plasma NfL holds promise as a biomarker of disease activity, not only for inherited neuropathies but for peripheral neuropathy in general.

ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease.

Abstract: 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 Alzheimer9s 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 with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because

Association between diabetes and subsequent Parkinson disease: A record-linkage cohort study.

Abstract: 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 Conclusions We report an increased rate of subsequent PD following T2DM in this large cohort study. These findings may reflect shared genetic predisposition and/or disrupted shared pathogenic pathways with potential clinical and therapeutic implications.

Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production.

Abstract: 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 junction confirmed that 100% of treated patients displayed the expected skipped exon 51 sequence. In treated patients vs untreated controls, Western blot analysis of dystrophin content demonstrated an 11.6-fold increase (p = 0.007), and PDPF analysis demonstrated a 7.4-fold increase (p Conclusion Taken together, the 4 assays, each based on unique evaluation mechanisms, provided evidence of eteplirsen muscle cell penetration, exon skipping, and induction of novel dystrophin expression. Classification of evidence This study provides Class II evidence of the muscle cell penetration, exon skipping, and induction of novel dystrophin expression by eteplirsen, as confirmed by 4 assays.

DNA damage response: Selected review and neurologic implications

Abstract: An estimated 105 DNA lesions occur daily in the mammalian genome as a consequence of spontaneous decay, replication errors, and cell metabolism, including reactive oxygen species produced by the mitochondria. Oxidative stress is a major mechanism of DNA damage in the nervous system. Damaged DNA must be repaired to allow the proper reading of the genetic code. The response to DNA damage involves DNA damage recognition first, followed by resection of the affected site, DNA processing, filling the gap by action of DNA polymerases, and sealing of the nick by DNA ligases. Severe DNA damage also triggers chromatin remodeling, transient interruption of the cell cycle, and, if left unrepaired, programmed cell death. Whereas disturbances in DNA repair have been primarily linked to carcinogenesis or immunodeficiency, they can also affect development or survival of cells in the nervous system. A prototype neurologic disorder of DNA repair is ataxia telangiectasia (A-T) due to mutation of the A-T mutated ( ATM ) gene encoding A-T mutated (ATM), a kinase that coordinates responses to double-strand DNA breaks. Ataxia with oculomotor apraxia (AOA) results from mutations of key proteins involved in DNA end-processing and transcription regulation. Many neurodegenerative disorders are associated with inability to repair oxidative base modifications in both nuclear and mitochondrial DNA. Mismatch and base excision–repair are important modifiers in trinucleotide repeat expansion disorders. There are several reviews on the complex mechanisms involved in DNA repair1–7 and the neurologic disorders associated with defective DNA repair pathways.8–16 A comprehensive discussion of these is beyond the scope of this review and only selected topics are discussed here.

Removing high-frequency oscillations: A prospective multicenter study on seizure outcome

Abstract: 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 seizure-free without removal of the majority of HFO-generating tissue. The investigation of influencing factors, including comparisons of visual and automatic analysis, using a threshold analysis for areas with high HFO activity, and excluding contacts bordering the resection, did not result in improved prognostication. Conclusions On an individual patient level, a prediction of outcome was not possible in all patients. This may be due to the analysis techniques used. Alternatively, HFOs may be less specific for epileptic tissue than earlier studies have indicated.

ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS

Abstract: Objective To elucidate the relationship between disease stage in amyotrophic lateral sclerosis (ALS), as measured with the King9s 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 King9s 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 function and disease stage may be due to letter fluency impairment, whereas higher rates of all behavioral domains were seen in later King9s stage The presence of bulbar signs, but not site of onset, was significantly related to ALS-specific, ECAS total, and behavioral scores Conclusion ALS-specific cognitive deficits and behavioral impairment are more frequent with more severe disease stage By end-stage disease, only a small percentage of patients are free of neuropsychological impairment The presence of bulbar symptoms exaggerates the differences observed between disease stages These findings suggest that cognitive and behavioral change should be incorporated into ALS diagnostic criteria and should be included in future staging systems