The 100 most-cited articles in Neurology, 2016

OBJECTIVE: To review population-based studies of the prevalence and incidence of epilepsy worldwide and use meta-analytic techniques to explore factors that may explain heterogeneity between estimates. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed. We searched MEDLINE and EMBASE for articles published on the prevalence or incidence of epilepsy since 1985. Abstract, full-text review, and data abstraction were conducted in duplicate. Meta-analyses and meta-regressions were used to explore the association between prevalence or incidence, age group, sex, country level income, and study quality. RESULTS: A total of 222 studies were included (197 on prevalence, 48 on incidence). The point prevalence of active epilepsy was 6.38 per 1,000 persons (95% confidence interval [95% CI] 5.57-7.30), while the lifetime prevalence was 7.60 per 1,000 persons (95% CI 6.17-9.38). The annual cumulative incidence of epilepsy was 67.77 per 100,000 persons (95% CI 56.69-81.03) while the incidence rate was 61.44 per 100,000 person-years (95% CI…

Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the "A/T/N" system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. "A" refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); "T," the value of a tau biomarker (CSF phospho tau, or tau PET); and "N," biomarkers of neurodegeneration or neuronal injury ([(18)F]-fluorodeoxyglucose-PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N-, or A+/T-/N-, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker…

OBJECTIVE: To develop formal consensus-based guidance for the management of myasthenia gravis (MG). METHODS: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements. Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG. An in-person panel meeting then determined 7 treatment topics to be addressed. Initial guidance statements were developed from literature summaries. Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input. RESULTS: Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy.…

OBJECTIVE: To evaluate the diagnostic accuracy of clinical diagnosis of Parkinson disease (PD) reported in the last 25 years by a systematic review and meta-analysis. METHODS: We searched for articles published between 1988 and August 2014. Studies were included if reporting diagnostic parameters regarding clinical diagnosis of PD or crude data. The selected studies were subclassified based on different study setting, type of test diagnosis, and gold standard. Bayesian meta-analyses of available data were performed. RESULTS: We selected 20 studies, including 11 using pathologic examination as gold standard. Considering only these 11 studies, the pooled diagnostic accuracy was 80.6% (95% credible interval [CrI] 75.2%-85.3%). Accuracy was 73.8% (95% CrI 67.8%-79.6%) for clinical diagnosis performed mainly by nonexperts. Accuracy of clinical diagnosis performed by movement disorders experts rose from 79.6% (95% CrI 46%-95.1%) of initial assessment to 83.9% (95% CrI 69.7%-92.6%) of refined diagnosis after follow-up. Using UK Parkinson's Disease Society Brain Bank Research Center…

OBJECTIVE: This nationwide study gives a detailed description of the clinical features and long-term outcome of anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis. METHODS: We collected patients prospectively from October 2013, and retrospectively from samples sent to our laboratory from January 2007. LGI1 antibodies were confirmed with both cell-based assay and immunohistochemistry. Clinical information was obtained in interviews with patients and their relatives and from medical records. Initial MRI and follow-up MRI were revised blindly. Neuropsychological assessment was performed in those patients with follow-up over 2 years. RESULTS: Annual incidence in the Netherlands was 0.83/million. A total of 34/38 patients had a limbic encephalitis. Subtle focal seizures (66%, autonomic or dyscognitive) and faciobrachial dystonic seizures (FBDS, 47%) mostly occurred before onset of memory disturbance. Later in the disease course, 63% had tonic-clonic seizures. Initial MRI showed hippocampal T2 hyperintensity in 74% of the patients. These lesions evolved regularly into mesial…

OBJECTIVE: To update the 2008 American Academy of Neurology (AAN) guidelines regarding botulinum neurotoxin for blepharospasm, cervical dystonia (CD), headache, and adult spasticity. METHODS: We searched the literature for relevant articles and classified them using 2004 AAN criteria. RESULTS AND RECOMMENDATIONS: Blepharospasm: OnabotulinumtoxinA (onaBoNT-A) and incobotulinumtoxinA (incoBoNT-A) are probably effective and should be considered (Level B). AbobotulinumtoxinA (aboBoNT-A) is possibly effective and may be considered (Level C). CD: AboBoNT-A and rimabotulinumtoxinB (rimaBoNT-B) are established as effective and should be offered (Level A), and onaBoNT-A and incoBoNT-A are probably effective and should be considered (Level B). Adult spasticity: AboBoNT-A, incoBoNT-A, and onaBoNT-A are established as effective and should be offered (Level A), and rimaBoNT-B is probably effective and should be considered (Level B), for upper limb spasticity. AboBoNT-A and onaBoNT-A are established as effective and should be offered (Level A) for lower-limb spasticity. Headache: OnaBoNT-A is…

OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. RESULTS: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical…

Trigeminal neuralgia (TN) is an exemplary condition of neuropathic facial pain. However, formally classifying TN as neuropathic pain based on the grading system of the International Association for the Study of Pain is complicated by the requirement of objective signs confirming an underlying lesion or disease of the somatosensory system. The latest version of the International Classification of Headache Disorders created similar difficulties by abandoning the term symptomatic TN for manifestations caused by major neurologic disease, such as tumors or multiple sclerosis. These diagnostic challenges hinder the triage of TN patients for therapy and clinical trials, and hamper the design of treatment guidelines. In response to these shortcomings, we have developed a classification of TN that aligns with the nosology of other neurologic disorders and neuropathic pain. We propose 3 diagnostic categories. Classical TN requires demonstration of morphologic changes in the trigeminal nerve root from vascular compression. Secondary TN is due to an identifiable underlying neurologic disease.…

OBJECTIVES: To estimate the lifetime risk, prevalence, incidence, and mortality of the principal clinical syndromes associated with frontotemporal lobar degeneration (FTLD) using revised diagnostic criteria and including intermediate clinical phenotypes. METHODS: Multisource referral over 2 years to identify all diagnosed or suspected cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) in 2 UK counties (population 1.69 million). Diagnostic confirmation used current consensus diagnostic criteria after interview and reexamination. Results were adjusted to the 2013 European standard population. RESULTS: The prevalence of FTD, PSP, and CBS was 10.8/100,000. The incidence and mortality were very similar, at 1.61/100,000 and 1.56/100,000 person-years, respectively. The estimated lifetime risk is 1 in 742. Survival following diagnosis varied widely: from PSP 2.9 years to semantic variant FTD 9.1 years. Age-adjusted prevalence peaked between 65 and 69 years at 42.6/100,000: the age-adjusted prevalence for persons older than 65 years…

Objective: We determined whether Gram-negative bacterial molecules are associated with Alzheimer disease (AD) neuropathology given that previous studies demonstrate Gram-negative Escherichia coli bacteria can form extracellular amyloid and Gram-negative bacteria have been reported as the predominant bacteria found in normal human brains. Methods: Brain samples from gray and white matter were studied from patients with AD (n = 24) and age-matched controls (n = 18). Lipopolysaccharide (LPS) and E coli K99 pili protein were evaluated by Western blots and immunocytochemistry. Human brain samples were assessed for E coli DNA followed by DNA sequencing. Results: LPS and E coli K99 were detected immunocytochemically in brain parenchyma and vessels in all AD and control brains. K99 levels measured using Western blots were greater in AD compared to control brains (p < 0.01) and K99 was localized to neuron-like cells in AD but not control brains. LPS levels were also greater in AD compared to control brain. LPS colocalized with Aβ1-40/42 in amyloid plaques and with Aβ1-40/42 around vessels in…

Objective:To test whether plasma tau is altered in Alzheimer disease (AD) and whether it is related to changes in cognition, CSF biomarkers of AD pathology (including β-amyloid [Aβ] and tau), brain atrophy, and brain metabolism. Methods:This was a study of plasma tau in prospectively followed patients with AD (n = 179), patients with mild cognitive impairment (n = 195), and cognitive healthy controls (n = 189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied patients with AD (n = 61), mild cognitive impairment (n = 212), and subjective cognitive decline (n = 174) and controls (n = 274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were studied. Associations were tested between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18fluorodeoxyglucose-PET, and cognition. Results:Higher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ42, but the correlations were weak and differed between ADNI and…

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating CNS disorder with predilection to early childhood. ADEM is generally considered a monophasic disease. However, recurrent ADEM has been described and defined as multiphasic disseminated encephalomyelitis. ADEM often occurs postinfectiously, although a causal relationship has never been established. ADEM and multiple sclerosis are currently viewed as distinct entities, generally distinguishable even at disease onset. However, pathologic studies have demonstrated transitional cases of yet unclear significance. ADEM is clinically defined by acute polyfocal neurologic deficits including encephalopathy. MRI typically demonstrates reversible, ill-defined white matter lesions of the brain and often also the spinal cord, along with frequent involvement of thalami and basal ganglia. CSF analysis may reveal a mild pleocytosis and elevated protein, but is generally negative for intrathecal oligoclonal immunoglobulin G synthesis. In the absence of a specific diagnostic test, ADEM is considered a diagnosis of…

OBJECTIVE: To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder. METHODS: Serum and CSF samples were assessed at 2 neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients' informed consent. RESULTS: Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4…

OBJECTIVE: To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease. METHODS: Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume. RESULTS: Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL [SD 51.3 pg/mL]) than controls (19.6 pg/mL [SD 8.2 pg/mL]; p < 0.001). Concentrations were also significantly higher in bvFTD (57.8 pg/mL [SD 33.1…

OBJECTIVE: To identify reliable predictors of outcome in comatose patients after cardiac arrest using a single routine EEG and standardized interpretation according to the terminology proposed by the American Clinical Neurophysiology Society. METHODS: In this cohort study, 4 EEG specialists, blinded to outcome, evaluated prospectively recorded EEGs in the Target Temperature Management trial (TTM trial) that randomized patients to 33°C vs 36°C. Routine EEG was performed in patients still comatose after rewarming. EEGs were classified into highly malignant (suppression, suppression with periodic discharges, burst-suppression), malignant (periodic or rhythmic patterns, pathological or nonreactive background), and benign EEG (absence of malignant features). Poor outcome was defined as best Cerebral Performance Category score 3-5 until 180 days. RESULTS: Eight TTM sites randomized 202 patients. EEGs were recorded in 103 patients at a median 77 hours after cardiac arrest; 37% had a highly malignant EEG and all had a poor outcome (specificity 100%, sensitivity 50%). Any malignant EEG…

OBJECTIVE: To develop consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results. METHODS: A panel of experienced OCT researchers (including 11 neurologists, 2 ophthalmologists, and 2 neuroscientists) discussed requirements for performing and reporting quantitative analyses of retinal morphology and developed a list of initial recommendations based on experience and previous studies. The list of recommendations was subsequently revised during several meetings of the coordinating group. RESULTS: We provide a 9-point checklist encompassing aspects deemed relevant when reporting quantitative OCT studies. The areas covered are study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition data analysis, recommended nomenclature, and statistical analysis. CONCLUSIONS: The Advised Protocol for OCT Study Terminology and Elements recommendations include core items to standardize and improve quality of reporting in quantitative OCT studies. The recommendations will…

OBJECTIVES: Our objective was to evaluate the efficacy of probiotics and prebiotics in patients with Parkinson disease (PD) and constipation. METHODS: We conducted a tertiary setting, randomized, double-blind, placebo-controlled trial in patients with PD with Rome III-confirmed constipation based on 2-week stool diary data at baseline. Patients (n = 120) were randomly assigned (2:1) to either a fermented milk, containing multiple probiotic strains and prebiotic fiber, or placebo, once daily for 4 weeks. The primary efficacy endpoint was the increase in the number of complete bowel movements (CBMs) per week. The key secondary endpoints were 3 or more CBMs and an increase by one or more CBMs per week during weeks 3 and 4. RESULTS: For the primary endpoint, the consumption of a fermented milk containing probiotics and prebiotics resulted in a higher increase in the number of CBMs (mean 1.2, 95% confidence interval [CI] 0.8-1.6) than placebo (0.1, 95% CI -0.4% to 0.6%) (mean difference 1.1, 95% CI 0.4-1.8; p = 0.002). For the key secondary endpoints, a higher number of patients in the…

OBJECTIVE: Spontaneous spinal CSF leaks cause spontaneous intracranial hypotension but no systematic study of the different types of these CSF leaks has been reported. Based on our experience with spontaneous intracranial hypotension, we propose a classification system of spontaneous spinal CSF leaks. METHODS: We reviewed the medical records, radiographic studies, operative notes, and any intraoperative photographs of a group of consecutive patients with spontaneous intracranial hypotension. RESULTS: The mean age of the 568 patients (373 [65.7%] women) was 45.7 years. Three types of CSF leak could be identified. Type 1 CSF leaks consisted of a dural tear (151 patients [26.6%]) and these were almost exclusively associated with an extradural CSF collection. Type 1a represented ventral CSF leaks (96%) and type 1b posterolateral CSF leaks (4%). Type 2 CSF leaks consisted of meningeal diverticula (240 patients [42.3%]) and were the source of an extradural CSF collection in 53 of these patients (22.1%). Type 2a represented simple diverticula (90.8%) and type 2b complex meningeal…

Recent publications on both the genetics and environmental factors of restless legs syndrome (RLS) defined as a clinical disorder suggest that overlapping genetic risk factors may play a role in primary (idiopathic) and secondary (symptomatic) RLS. Following a systematic literature search of RLS associated with comorbidities, we identified an increased prevalence of RLS only in iron deficiency and kidney disease. In cardiovascular disease, arterial hypertension, diabetes, migraine, and Parkinson disease, the methodology of studies was poor, but an association might be possible. There is insufficient evidence for conditions such as anemia (without iron deficiency), chronic obstructive pulmonary disease, multiple sclerosis, headache, stroke, narcolepsy, and ataxias. Based on possible gene-microenvironmental interaction, the classifications primary and secondary RLS may suggest an inappropriate causal relation. We recognize that in some conditions, treatment of the underlying disease should be achieved as far as possible to reduce or eliminate RLS symptoms. RLS might be seen as a…

OBJECTIVE: To explore clinical phenotype and characteristics of Parkinson disease (PD) at different ages at onset in recently diagnosed patients with untreated PD. METHODS: We have analyzed baseline data from the Parkinson's Progression Markers Initiative database. Four hundred twenty-two patients with a diagnosis of PD confirmed by DaTSCAN imaging were divided into 4 groups according to age at onset (onset younger than 50 years, 50-59 years, 60-69 years, and 70 years or older) and investigated for differences in side, type and localization of symptoms, occurrence/severity of motor and nonmotor features, nigrostriatal function, and CSF biomarkers. RESULTS: Older age at onset was associated with a more severe motor and nonmotor phenotype, a greater dopaminergic dysfunction on DaTSCAN, and reduction of CSF α-synuclein and total tau. The most common presentation was the combination of 2 or 3 motor symptoms (bradykinesia, resting tremor, and rigidity) with rigidity being more common in the young-onset group. In about 80% of the patients with localized onset, the arm was the most…

OBJECTIVE: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). METHODS: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded. RESULTS: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25).…

OBJECTIVE: We investigated a series of patients with LGI1 antibody (Ab)-related cognitive deterioration to determine the clinical presentation, long-term outcome, and LGI1 Ab evolution. METHODS: We retrospectively analyzed the clinical information of 76 patients with LGI1 Ab-related cognitive deterioration. Presenting syndromes were classified as limbic encephalitis (LE), non-LE, or encephalopathy (normal MRI and no CSF pleocytosis). Frequency of relapses and clinical outcome were assessed in 48 patients with prolonged follow-up (median 39 months, range 18-200). RESULTS: Sixty-three patients (83%) developed LE, 3 (4%) non-LE, and 10 (13%) encephalopathy. All patients received steroids, IV immunoglobulins (Ig), or both. At 2 years, 17 (35%; 95% CI 21%-49%) fully recovered, 17 (35%) became functionally independent but not at baseline or were unable to return to work, 11 (23%) required assistance because of moderate or severe cognitive deficits, and 3 (6%) died. Predictors of bad outcome included no response to initial immunotherapy (odds ratio 23.0, 95% CI 2.4-215.6, p = 0.006) and…

OBJECTIVE: To characterize patients misdiagnosed with multiple sclerosis (MS). METHODS: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. RESULTS: Of 110 misdiagnosed patients, 51 (46%) were classified as "definite" and 59 (54%) "probable" misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of…

OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or…

The syndrome known as nocturnal frontal lobe epilepsy is recognized worldwide and has been studied in a wide range of clinical and scientific settings (epilepsy, sleep medicine, neurosurgery, pediatric neurology, epidemiology, genetics). Though uncommon, it is of considerable interest to practicing neurologists because of complexity in differential diagnosis from more common, benign sleep disorders such as parasomnias, or other disorders like psychogenic nonepileptic seizures. Moreover, misdiagnosis can have substantial adverse consequences on patients' lives. At present, there is no consensus definition of this disorder and disagreement persists about its core electroclinical features and the spectrum of etiologies involved. To improve the definition of the disorder and establish diagnostic criteria with levels of certainty, a consensus conference using formal recommended methodology was held in Bologna in September 2014. It was recommended that the name be changed to sleep-related hypermotor epilepsy (SHE), reflecting evidence that the attacks are associated with sleep rather than…

OBJECTIVE: We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies. METHODS: In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested. RESULTS: Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155-negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n = 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes.…

Delirium is a common and costly complication of hospitalization. Although medications are a known cause of delirium, antibiotics are an underrecognized class of medications associated with delirium. In this article, we comprehensively review the clinical, radiologic, and electrophysiologic features of antibiotic-associated encephalopathy (AAE). AAE can be divided into 3 unique clinical phenotypes: encephalopathy commonly accompanied by seizures or myoclonus arising within days after antibiotic administration (caused by cephalosporins and penicillin); encephalopathy characterized by psychosis arising within days of antibiotic administration (caused by quinolones, macrolides, and procaine penicillin); and encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging weeks after initiation of antibiotics (caused by metronidazole). We correlate these 3 clinical phenotypes with underlying pathophysiologic mechanisms of antibiotic neurotoxicity. Familiarity with these types of antibiotic toxicity can improve timely diagnosis of AAE and prompt antibiotic discontinuation,…

OBJECTIVE: To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network. METHODS: We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness. RESULTS: A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of…

OBJECTIVE: To estimate the US commercially insured multiple sclerosis (MS) annual prevalence from 2008 to 2012. METHODS: The study was a retrospective analysis using PharMetrics Plus, a nationwide claims database for over 42 million covered US representative lives. Annual point prevalence required insurance eligibility during an entire year. Our primary annual MS identification algorithm required 2 inpatient claims coded ICD-9 340 or 3 outpatient claims coded ICD-9 340 or 1 MS-indicated disease-modifying therapy claim. Age-adjusted annual prevalence estimates were extrapolated to the US population using US Census data. RESULTS: The 2012 MS prevalence was 149.2 per 100,000 individuals (95% confidence interval 147.6-150.9). Prevalence was consistent over 2008-2012. Female participants were 3.13 times more likely to have MS. The highest prevalence was in participants aged 45-49 years (303.5 per 100,000 individuals [295.6-311.5]). The East Census region recorded the highest prevalence (192.1 [188.2-196.0]); the West Census region recorded the lowest prevalence (110.7 [105.5-116.0]). The…

OBJECTIVE: To investigate the topographical distribution of tau pathology and its effect on functional and structural changes in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) by using (18)F-AV-1451 PET. METHODS: We included 20 patients with AD, 15 patients with MCI, and 20 healthy controls, and performed neuropsychological function tests, MRI, as well as (18)F-florbetaben (for amyloid) and (18)F-AV-1451 (for tau) PET scans. By using the regional volume-of-interest masks extracted from MRIs, regional binding values of standardized uptake value ratios and volumes were measured. We compared regional binding values among 3 diagnostic groups and identified correlations among the regional binding values, performance in each cognitive function test, and regional atrophy. RESULTS: (18)F-AV-1451 binding was increased only in the entorhinal cortex in patients with MCI, while patients with AD exhibited greater binding in most cortical regions. In the 35 patients with MCI and AD, (18)F-AV-1451 binding in most of the neocortex increased with a worsening of global…

OBJECTIVE: To evaluate the feasibility, safety, and tolerability of noninvasive vagus nerve stimulation (nVNS) for the prevention of chronic migraine (CM) attacks. METHODS: In this first prospective, multicenter, double-blind, sham-controlled pilot study of nVNS in CM prophylaxis, adults with CM (≥15 headache d/mo) entered the baseline phase (1 month) and were subsequently randomized to nVNS or sham treatment (2 months) before receiving open-label nVNS treatment (6 months). The primary endpoints were safety and tolerability. Efficacy endpoints in the intent-to-treat population included change in the number of headache days per 28 days and acute medication use. RESULTS: Fifty-nine participants (mean age, 39.2 years; mean headache frequency, 21.5 d/mo) were enrolled. During the randomized phase, tolerability was similar for nVNS (n = 30) and sham treatment (n = 29). Most adverse events were mild/moderate and transient. Mean changes in the number of headache days were -1.4 (nVNS) and -0.2 (sham) (Δ = 1.2; p = 0.56). Twenty-seven participants completed the open-label phase. For the 15…

OBJECTIVE: To establish reference values for isometric strength of 12 muscle groups and flexibility of 13 joint movements in 1,000 children and adults and investigate the influence of demographic and anthropometric factors. METHODS: A standardized reliable protocol of hand-held and fixed dynamometry for isometric strength of ankle, knee, hip, elbow, and shoulder musculature as well as goniometry for flexibility of the ankle, knee, hip, elbow, shoulder, and cervical spine was performed in an observational study investigating 1,000 healthy male and female participants aged 3-101 years. Correlation and multiple regression analyses were performed to identify factors independently associated with strength and flexibility of children, adolescents, adults, and older adults. RESULTS: Normative reference values of 25 strength and flexibility measures were generated. Strong linear correlations between age and strength were identified in the first 2 decades of life. Muscle strength significantly decreased with age in older adults. Regression modeling identified increasing height as the most…

OBJECTIVE: To compare motor symptoms, cognition, mood, and behavior 3 years after deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and subthalamic nucleus (STN) in advanced Parkinson disease (PD). METHODS: Patients with PD eligible for DBS were randomized to bilateral GPi DBS and bilateral STN DBS (1:1). The primary outcome measures were (1) improvement in motor symptoms in off-drug phase measured with the Unified Parkinson Disease Rating Scale (UPDRS) and (2) a composite score for cognitive, mood, and behavioral effects, and inability to complete follow-up at 36 months after surgery. RESULTS: Of the 128 patients enrolled, 90 were able to complete the 3-year follow-up. We found significantly more improvement of motor symptoms after STN DBS (median [interquartile range (IQR)] at 3 years, GPi 33 [23-41], STN 28 [20-36], p = 0.04). No between-group differences were observed on the composite score (GPi 83%, STN 86%). Secondary outcomes showed larger improvement in off-drug functioning in the AMC Linear Disability Scale score after STN DBS (mean ± SD, GPi 65.2 ±…

Patients with the main clinical phenotypes of multiple sclerosis (MS) manifest varying degrees of brain atrophy beyond that of normal aging. Assessment of atrophy helps to distinguish clinically and cognitively deteriorating patients and predicts those who will have a less-favorable clinical outcome over the long term. Atrophy can be measured from brain MRI scans, and many technological improvements have been made over the last few years. Several software tools, with differing requirements on technical ability and levels of operator intervention, are currently available and have already been applied in research or clinical trial settings. Despite this, the measurement of atrophy in routine clinical practice remains an unmet need. After a short summary of the pathologic substrates of brain atrophy in MS, this review attempts to guide the clinician towards a better understanding of the methods currently used for quantifying brain atrophy in this condition. Important physiologic factors that affect brain volume measures are also considered. Finally, the most recent research on brain…

Treatment goals for epilepsy are no seizures, no side effects, as soon as possible, but these goals are too often unmet. Approximately 1 million people in the United States continue to have seizures despite adequate treatment with antiseizure drugs, representing 40% of those with epilepsy, and 80% of the cost of epilepsy. Drug-resistant epilepsy (DRE) can be associated with developmental delay in infants and young children, and severe disability and morbidity in older children and adults, as well as a mortality rate 5-10 times that of the general population. While diagnosis and treatment at a full-service (levels 3 and 4) epilepsy center are demonstrated to improve seizure control, fewer than 1% of people with DRE are referred, and those who are, are referred an average of over 20 years after onset of habitual seizures. A possible reason for this is the misconception that all these epilepsy centers offer is surgery. Specialized multidisciplinary teams, consisting of neurologists, clinical neurophysiologists, neurosurgeons, neuroradiologists, psychologists, psychiatrists, social…

OBJECTIVE: To test the hypothesis that effects of estrogen-containing hormone therapy on cognitive abilities differ between postmenopausal women near to, and further from, menopause. METHODS: In this randomized, double-blind, placebo-controlled trial, healthy women within 6 years of menopause or 10+ years after menopause were randomly assigned to oral 17β-estradiol 1 mg/d or placebo. Women with a uterus received cyclic micronized progesterone vaginal gel or placebo. The primary outcome assessed at 2.5 and 5 years, compared between treatment groups, was change in a standardized composite of neuropsychological test scores assessing verbal episodic memory. Secondary outcomes assessed executive functions and global cognition. RESULTS: A total of 567 women were included in modified intention-to-treat analyses after a mean treatment duration of 57 months. For verbal memory, the mean estradiol minus placebo standardized difference in composite scores (-0.06, 95% confidence interval -0.22 to 0.09) was not significant (2-tailed p = 0.33). Differences were similar in early and late…

OBJECTIVES: We tested whether brain-derived neurotrophic factor (BDNF) gene expression levels are associated with cognitive decline in older adults. METHODS: Five hundred thirty-five older participants underwent annual cognitive assessments and brain autopsy at death. BDNF gene expression was measured in the dorsolateral prefrontal cortex. Linear mixed models were used to examine whether BDNF expression was associated with cognitive decline adjusting for age, sex, and education. An interaction term was added to determine whether this association varied with clinical diagnosis proximate to death (no cognitive impairment, mild cognitive impairment, or dementia). Finally, we examined the extent to which the association of Alzheimer disease (AD) pathology with cognitive decline varied by BDNF expression. RESULTS: Higher brain BDNF expression was associated with slower cognitive decline (p < 0.001); cognitive decline was about 50% slower with the 90th percentile BDNF expression vs 10th. This association was strongest in individuals with dementia. The level of BDNF expression was lower in…

OBJECTIVE: We investigated sex differences in verbal memory across different levels of neural dysfunction, measured by temporal lobe glucose metabolic rates (TLGluMR). METHODS: F]-fluorodeoxyglucose-PET. Cross-sectional analyses were conducted using linear regression to examine the sex by TLGluMR interaction on RAVLT performance in the overall sample and within diagnostic groups adjusting for age, education, and APOE ε4 genotype. RESULTS: Across groups, female sex and higher TLGluMR and their interaction were associated with better verbal memory (p values ≤ 0.005). The female advantage in verbal memory varied by TLGluMR such that the advantage was greatest among individuals with moderate to high TLGluMR and minimal or absent among individuals with lower TLGluMR. Diagnosis-stratified analyses revealed that this interaction was driven by the aMCI group (p values = 0.009). The interaction was not significant in control and AD dementia groups. CONCLUSIONS: Women show better verbal memory than men in aMCI despite similar levels of brain hypometabolism. The lifelong advantage that females…

OBJECTIVE: To evaluate the direct and indirect influences of physical comorbidity, symptoms of depression and anxiety, fatigue, and disability on health-related quality of life (HRQoL) in persons with multiple sclerosis (MS). METHODS: A large (n = 949) sample of adults with MS was recruited from 4 Canadian MS clinics. HRQoL was assessed using the patient-reported Health Utilities Index Mark 3. Expanded Disability Status Scale scores, physical comorbidity, depression, anxiety, and fatigue were evaluated as predictors of HRQoL in a cross-sectional path analysis. RESULTS: All predictors were significantly associated with HRQoL and together accounted for a large proportion of variance (63%). Overall, disability status most strongly affected HRQoL (β = -0.52) but it was closely followed by depressive symptoms (β = -0.50). The direct associations of physical comorbidity and anxiety with HRQoL were small (β = -0.08 and -0.10, respectively), but these associations were stronger when indirect effects through other variables (depression, fatigue) were also considered (physical comorbidity: β…

BACKGROUND: Sleep-disordered breathing (SDB) and sleep-wake disturbances (SWD) are highly prevalent in stroke patients. Recent studies suggest that they represent both a risk factor and a consequence of stroke and affect stroke recovery, outcome, and recurrence. METHODS: Review of literature. RESULTS: Several studies have proven SDB to represent an independent risk factor for stroke. Sleep studies in TIA and stroke patients are recommended in view of the very high prevalence (>50%) of SDB (Class IIb, level of evidence B). Treatment of obstructive SDB with continuous positive airway pressure is recommended given the strength of the increasing evidence in support of a positive effect on outcome (Class IIb, level of evidence B). Oxygen, biphasic positive airway pressure, and adaptive servoventilation may be considered in patients with central SDB. Recently, both reduced and increased sleep duration, as well as hypersomnia, insomnia, and restless legs syndrome (RLS), were also suggested to increase stroke risk. Mainly experimental studies found that SWD may in addition impair…

OBJECTIVE: As blood-brain barrier (BBB) dysfunction may occur in normal aging but may also play a pivotal role in the pathophysiology of cerebral small vessel disease (cSVD), we used dynamic contrast-enhanced (DCE)-MRI to quantify the rate and the spatial extent of BBB leakage in patients with cSVD and age- and sex-matched controls to discern cSVD-related BBB leakage from aging-related leakage. METHODS: We performed structural brain MRI and DCE-MRI in 80 patients with clinically overt cSVD and 40 age- and sex-matched controls. Using the Patlak pharmacokinetic model, we calculated the leakage rate. The mean leakage rate and relative leakage volume were calculated using noise-corrected histogram analysis. Leakage rate and leakage volume were compared between patients with cSVD and controls for the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter. RESULTS: Multivariable linear regression analyses adjusting for age, sex, and cardiovascular risk factors showed that the leakage volume of the NAWM, WMH, and CGM was…

OBJECTIVE: To assess the specificity of the dendritic protein neurogranin (Ng) in CSF from patients with a broad range of neurodegenerative diseases including a variety of dementias, tauopathies, and synucleinopathies. METHOD: An optimized immunoassay was used to analyze CSF Ng in a retrospective cohort of 331 participants with different neurodegenerative diseases, including healthy controls (n = 19), biomarker-proven Alzheimer disease (AD) (n = 100), genetic AD (n = 2), behavioral variant frontotemporal dementia (n = 20), speech variant frontotemporal dementia (n = 21), Lewy body dementia (n = 13), Parkinson disease (n = 31), progressive supranuclear palsy (n = 46), multiple system atrophy (n = 29), as well as a heterogeneous group with non-neurodegenerative cognitive impairment (n = 50). CSF Ng concentrations and correlations of CSF Ng with total tau, phosphorylated tau, and β-amyloid 42 concentrations, Mini-Mental State Examination score, and disease duration in the different groups were investigated. RESULTS: Median CSF Ng concentration was higher in patients with AD compared to…

OBJECTIVE: To identify different white matter hyperintensity (WMH) patterns between 2 hemorrhage-prone cerebral small vessel diseases (SVD): cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). METHODS: Consecutive patients with SVD-related intracerebral hemorrhage (ICH) from a single-center prospective cohort were analyzed. Four predefined subcortical WMH patterns were compared between the CAA and HA groups. These WMH patterns were (1) multiple subcortical spots; (2) peri-basal ganglia (BG); (3) large posterior subcortical patches; and (4) anterior subcortical patches. Their associations with other imaging (cerebral microbleeds [CMBs], enlarged perivascular spaces [EPVS]) and clinical markers of SVD were investigated using multivariable logistic regression. RESULTS: The cohort included 319 patients with CAA and 137 patients with HA. Multiple subcortical spots prevalence was higher in the CAA compared to the HA group (29.8% vs 16.8%; p = 0.004). Peri-BG WMH pattern was more common in the HA- vs the CAA-ICH group (19% vs 7.8%; p = 0.001). In multivariable logistic…

Investigations during the last 10 years have revealed a group of disorders mediated by antibodies against ion channels and synaptic receptors, which cause both neurologic and psychiatric symptoms. In this review, I discuss the process of discovery and immunologic triggers of these disorders, and use anti-NMDA receptor encephalitis to emphasize the importance of understanding the underlying physiopathologic mechanisms in those diseases. A better knowledge of these mechanisms reveals points of convergence with other disorders (e.g., schizophrenia), suggests treatment strategies beyond immunotherapy, and is helping us understand how memories are formed and retrieved.

OBJECTIVE: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. METHODS: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. RESULTS AND RECOMMENDATIONS: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline…

OBJECTIVE: To investigate the neural mechanisms underlying impaired self-agency in patients with functional movement disorders using resting-state functional MRI (fMRI). METHODS: We obtained resting-state fMRI on 35 patients with clinically definite functional movement disorders and 35 age- and sex-matched healthy controls. Between-group differences in functional connectivity from the right temporo-parietal junction (TPJ), a region previously demonstrated to play a critical role in self-agency by comparing internal predictions of movement with actual external events, were assessed using t tests. All participants were screened for psychiatric diagnoses using a structured clinical interview and completed the Beck Depression Inventory and Childhood Trauma Questionnaire. RESULTS: Compared to the healthy controls, patients with functional movement disorders showed decreased functional connectivity between the right TPJ and the right sensorimotor cortex, cerebellar vermis, bilateral supplementary motor area, and right insula. These findings were independent of depression, anxiety, and…

OBJECTIVE: Our prespecified dose-response analyses of A Very Early Rehabilitation Trial (AVERT) aim to provide practical guidance for clinicians on the timing, frequency, and amount of mobilization following acute stroke. METHODS: Eligible patients were aged ≥18 years, had confirmed first (or recurrent) stroke, and were admitted to a stroke unit within 24 hours of stroke onset. Patients were randomized to receive very early and frequent mobilization, commencing within 24 hours, or usual care. We used regression analyses and Classification and Regression Trees (CART) to investigate the effect of timing and dose of mobilization on efficacy and safety outcomes, irrespective of assigned treatment group. RESULTS: A total of 2,104 patients were enrolled, of whom 2,083 (99.0%) were followed up at 3 months. We found a consistent pattern of improved odds of favorable outcome in efficacy and safety outcomes with increased daily frequency of out-of-bed sessions (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.18, p < 0.001), keeping time to first mobilization and mobilization…

OBJECTIVE: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. METHODS: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions. RESULTS: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy…

OBJECTIVE: To determine the nationwide incidence of subarachnoid hemorrhage (SAH) and report nationwide changes in smoking rates between 1998 and 2012 in Finland. METHODS: In this register-based study, we utilized the nationwide Causes of Death Register and Hospital Discharge Register in identifying SAH events between 1998 and 2012. Population statistics in Finland, which were obtained through a database of Statistics Finland, were used to calculate crude annual incidence rates of SAH. For the direct age standardization of crude incidence rates, we used the European Standard Population (ESP) 2013. Data on changes in nationwide smoking rates between 1998 and 2012 were extracted from a database of the National Institute for Health and Welfare. RESULTS: For the total of 79,083,579 cumulative person-years, we identified 6,885 people with SAH. Sudden deaths from SAH away from hospitals or in emergency rooms accounted for 1,771 (26%) of the events. Crude nationwide annual incidence rates varied between 6.2 and 10.0 per 100,000 persons, and increased by age particularly in women. Among 70-…

Editors' Note: The international consensus diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD) article prompted reactions from our readers. Tan is concerned that the new criteria may include patients without true neuromyelitis optica and may affect treatment funding. Recounting their own experience, Mao et al. caution about overinterpretation of MRI results and suggest that aquaporin-4 antibody (AQP4-Ab) testing be considered in late-onset demyelinating disease. In response, Wingerchuk et al., authors of the guidelines, stress that the diagnostic category of NMOSD without AQP4–immunoglobulin G requires exclusion of alternative diagnoses, believe that the new criteria will facilitate—rather than hinder—insurance coverage for appropriate immunosuppressive treatments, and agree with the observations raised by Mao et al. —Chafic Karam, MD, and Robert C. Griggs, MD Wingerchuk et al.1 proposed criteria for neuromyelitis optica (NMO) spectrum disorders (NMOSD) that incorporated unifying the terms NMO and NMOSD, including patients with aquaporin-4 (AQP4)–immunoglobulin G…

OBJECTIVE: To examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/intracranial volume ratio [HpVR]) across AD stages. METHODS: The sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE ε4 status. RESULTS: Across groups, there were significant sex × HpVR interactions for immediate and delayed recall (p < 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR × sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for…

OBJECTIVE: To determine the prevalence of chronic polyneuropathy in an unselected community-dwelling population of middle-aged and elderly people. METHODS: The current study was embedded in the prospective, population-based Rotterdam Study. Between June 2013 and October 2015, 1,310 participants (mean age 70 years, 55% female) were screened for the presence of polyneuropathy. This screening consisted of a questionnaire, neurologic examination, and nerve conduction studies. Polyneuropathy was diagnosed by a consensus panel that categorized participants into no, possible, probable, or definite polyneuropathy, depending on the level of abnormality of the screening. Medical records were scrutinized to evaluate whether the disorder was diagnosed before and laboratory investigations were performed to determine the presence of associated risk factors. RESULTS: Prevalence of definite polyneuropathy was 5.5% (95% confidence interval 4.4-6.9), age-standardized to the population of the Netherlands 4.0% (3.1-5.3). Prevalence was higher in male participants (6.7% compared to 4.5%) and increased…

OBJECTIVE: To determine the degree to which preinjury and acute postinjury psychosocial and injury-related variables predict symptom duration following sport-related concussion. METHODS: A total of 2,055 high school and collegiate athletes completed preseason evaluations. Concussed athletes (n = 127) repeated assessments serially (<24 hours and days 8, 15, and 45) postinjury. Cox proportional hazard modeling was used to predict concussive symptom duration (in days). Predictors considered included demographic and history variables; baseline psychological, neurocognitive, and balance functioning; acute injury characteristics; and postinjury clinical measures. RESULTS: Preinjury somatic symptom score (Brief Symptom Inventory-18 somatization scale) was the strongest premorbid predictor of symptom duration. Acute (24-hour) postconcussive symptom burden (Sport Concussion Assessment Tool-3 symptom severity) was the best injury-related predictor of recovery. These 2 predictors were moderately correlated (r = 0.51). Path analyses indicated that the relationship between preinjury somatization…

Objective: We assessed the therapeutic potential of the plasma-cell-depleting proteasome inhibitor bortezomib in severe and therapy-refractory cases of anti–NMDA receptor (anti-NMDAR) encephalitis. Methods: Five severely affected patients with anti-NMDAR encephalitis with delayed treatment response or resistance to standard immunosuppressive and B-cell-depleting drugs (corticosteroids, IV immunoglobulins, plasma exchange, immunoadsorption, rituximab, cyclophosphamide) who required medical treatment and artificial ventilation on intensive care units were treated with 1–6 cycles of 1.3 mg/m2 bortezomib. Occurrence of adverse events was closely monitored. Results: Bortezomib treatment showed clinical improvement or disease remission, which was accompanied by a partial NMDAR antibody titer decline in 4 of 5 patients. With respect to disease severity, addition of bortezomib to the multimodal immunosuppressive treatment regimen was associated with an acceptable safety profile. Conclusions: Our study identifies bortezomib as a promising escalation therapy for severe and therapy-refractory…

OBJECTIVE: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study is the first stroke prevention trial to include protocol-driven intensive management of multiple risk factors. In this prespecified analysis, we aimed to investigate the relationship between risk factor control during follow-up and outcome of patients in the medical arm of SAMMPRIS. METHODS: Data from SAMMPRIS participants in the medical arm (n = 227) were analyzed. Risk factors were recorded at baseline, 30 days, 4 months, and then every 4 months for a mean follow-up of 32 months. For each patient, values for all risk factor measures were averaged and dichotomized as in or out of target. RESULTS: Participants who were out of target for systolic blood pressure and physical activity, as well as those with higher mean low-density lipoprotein cholesterol and non-high-density lipoprotein, were more likely to have a recurrent vascular event (stroke, myocardial infarction, or vascular death) at 3 years compared to those who had good risk factor control. In…

OBJECTIVE: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. METHODS: We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes. RESULTS: We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.…

OBJECTIVE: To assess whether epilepsy surgery is associated with a reduction in mortality rate and if postoperative seizure frequency and severity affect mortality. METHODS: A total of 1,110 patients were evaluated (1,006 surgically and 104 nonsurgically treated) for a total follow-up of 8,126.62 person-years from 1986 to 2013. Deaths were ascertained through database and Social Security Death Index query. Patients were grouped by surgery type and seizure status; standardized mortality ratio and deaths per 1,000 person-years were calculated. Survival analysis and Cox proportional hazard regression were performed. RESULTS: Eighty-nine deaths were observed. Surgically treated patients had a lower mortality rate (8.6 per 1,000 person-years [95% confidence interval (CI) 6.58-11.15]) than nonsurgically treated patients (25.3 per 1,000 person-years [14.50-41.17]; p < 0.001). Seizure-free patients had a lower mortality rate (5.2 per 1,000 person-years [95% CI 2.67-9.02]) than non-seizure-free patients (10.4 per 1,000 person-years [95% CI 7.67-13.89] p = 0.03). More frequent postoperative…

OBJECTIVE: To determine patient and hospital characteristics associated with not providing IV tissue plasminogen activator (tPA) to eligible patients with acute ischemic stroke (AIS) in clinical practice. METHODS: We performed a retrospective cohort study of patients with AIS arriving within 2 hours of onset to hospitals participating in Get With The Guidelines-Stroke without documented contraindications to IV tPA from April 2003 through December 2011, comparing those who received tPA to those who did not. Multivariable generalized estimating equation logistic regression modeling identified factors associated with not receiving tPA. RESULTS: Of 61,698 eligible patients with AIS presenting within 2 hours of onset (median age 73 years, 51% female, 74% non-Hispanic white, median NIH Stroke Scale score 11, interquartile range 6-18), 15,282 (25%) were not treated with tPA within 3 hours. Failure to give tPA decreased over time from 55% in 2003 to 2005 to 18% in 2010 to 2011 (p < 0.0001). After adjustment for all covariates, including stroke severity, factors associated with failure to…

OBJECTIVE: To determine efficacy and safety of rituximab treatment as a second-line immunotherapy treatment for autoimmune limbic encephalitis (ALE) and to determine factors associated with functional improvement and favorable outcome following rituximab treatment. METHODS: We recruited 80 patients with ALE who were treated with rituximab as a second-line immunotherapy from the Korea Autoimmune Synaptic and Paraneoplastic Encephalitis Registry and reviewed 81 patients without rituximab as a control. We grouped patients according to the detection or type of antibodies; in addition, we evaluated clinical, laboratory, first-line immunotherapy, and rituximab treatment profiles and defined main outcomes as improvements on the modified Rankin Scale (mRS) score and a favorable mRS score (0-2) at the last follow-up. RESULTS: Functional improvement occurred more frequently in the rituximab group compared to the control group. In the rituximab group, 30 (37.5%) patients had synaptic autoantibodies, 15 (18.8%) in the paraneoplastic autoantibodies, and 35 (43.8%) were antibody-negative. The…

OBJECTIVE: We hypothesized that nonalcoholic fatty liver disease (NAFLD) is independently associated with cognitive impairment in a representative sample of the general US population regardless of the presence of cardiovascular disease (CVD) or its risk factors. METHODS: This was a cross-sectional study of 4,472 adults aged 20-59 years who participated in the Third National Health and Nutritional Examination Survey. The participants underwent assessment of liver enzyme activity and hepatic steatosis by ultrasound, and underwent cognitive evaluation using the following computer-administered tests: the Simple Reaction Time Test (SRTT), the Symbol-Digit Substitution Test (SDST), and the Serial Digit Learning Test (SDLT). We defined NAFLD as moderate/severe steatosis as determined by ultrasound in the absence of hepatitis B or C or excessive alcohol consumption. We used multiple linear regression models to examine the association between NAFLD and cognitive function while controlling for potential confounders. RESULTS: Participants with NAFLD showed lower overall performance on the SDLT…

OBJECTIVE: To report migraine postdrome symptoms in patients who report nonheadache symptoms as part of their attacks. METHODS: A prospective daily electronic diary study was conducted over 3 months in 120 patients with migraine. Nonheadache symptoms before, during, and after headache were collected on a daily basis. Visual analogue scales were used to capture the overall level of functioning and the severity of the headache. The postdrome was defined as the time from resolution of troublesome headache to return to normal. RESULTS: Of 120 evaluable patients, 97 (81%) reported at least one nonheadache symptom in the postdrome. Postdrome symptoms, in order of frequency, included feeling tired/weary and having difficulty concentrating and stiff neck. Many patients also reported a mild residual head discomfort. In most attacks (93%), there was return to normal within 24 hours after spontaneous pain resolved. There was no relationship between medication taken for the headache and the duration of the postdrome. The severity of the migraine was not associated with the duration of the…

OBJECTIVE: We pooled the results of studies on natural history of cavernous malformations (CM) to calculate point estimates and investigate main sources of heterogeneity. METHODS: We searched MEDLINE, EMBASE, and ISI Web of Science for relevant studies published before May 2015. We used fixed or random effects models and meta-regression to pool the data. RESULTS: Twenty-five studies were entered into the meta-analysis (90-1,295 patients depending on the analysis). Bleeding was defined as symptomatic hemorrhage plus radiologic evidence of hemorrhage. Sources of heterogeneity were identified as mixture of hemorrhage and rehemorrhage, mixture of rehemorrhage before and after 2 years of first bleeding, brainstem vs other locations, and calculation method. The rehemorrhage rate was higher than the hemorrhage rate (incidence rate ratio 16.5, p < 0.001, 95% confidence interval [CI] 9.7-28.0). Rehemorrhage within 2 years of the first hemorrhage was higher than after that (incidence rate ratio 1.8, p = 0.042, 95% CI 1.5-2.0). In two metaregression models, rough estimate of the annual…

OBJECTIVE: To explore the effects of microglial activation on brain function and structure, and its relationship with peripheral inflammatory markers, in treated, HIV-positive individuals, using in vivo [(11)C]PBR28 PET (to measure the 18 kDa translocator protein [TSPO]). METHODS: Cognitively healthy HIV-positive individuals on suppressive antiretroviral therapy and HIV-negative individuals (controls) underwent brain [(11)C]PBR28 PET and MRI. HIV-positive patients completed neuropsychological testing and CSF testing for chemokines. The concentration of bacterial ribosomal 16sDNA in plasma was measured as a marker of microbial translocation. RESULTS: HIV-positive individuals showed global increases in TSPO expression compared to controls (corrected p < 0.01), with significant regional increases in the parietal (p = 0.001) and occipital (p = 0.046) lobes and in the globus pallidus (p = 0.035). TSPO binding in the hippocampus, amygdala, and thalamus were associated with poorer global cognitive performance in tasks assessing verbal and visual memory (p < 0.05). Increased TSPO binding…

OBJECTIVE: To investigate the local immune status and its prognostic value in glioma. METHODS: A cohort of 297 glioma samples with whole genome microarray expression data from the Chinese Glioma Genome Atlas database were included for discovery. The Cancer Genome Atlas (TCGA) database was used for validation. Principal components analysis and gene set enrichment analysis were used to explore the bioinformatic implication. RESULTS: Distinct local immune status was identified according to histologic grade. Glioblastoma (GBM) exhibited an enhanced immune phenotype compared to lower grade glioma. We profiled the immune-related gene set and identified 8 genes (FOXO3, IL6, IL10, ZBTB16, CCL18, AIMP1, FCGR2B, and MMP9) with the greatest prognostic value in GBM. A local immune-related risk signature was developed from the genes to distinguish cases as high or low risk of unfavorable prognosis, which could be validated in TCGA database. High-risk patients conferred an enhanced intensity of local immune response compared to low-risk ones. Additionally, the signature exhibited different…

OBJECTIVE: To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD). METHODS: This phase III, double-blind, randomized, placebo-controlled, multicenter study evaluated muscle strength among 196 boys aged 5-15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995. RESULTS: All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12…

BACKGROUND: The aim of the current study was to assess the influence of anesthetic management on the effect of treatment in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). METHODS: MR CLEAN was a multicenter, randomized, open-label trial of intra-arterial therapy (IAT) vs no IAT. The intended anesthetic management at the start of the procedure was used for this post hoc analysis. The primary effect parameter was the adjusted common odds ratio (acOR) for a shift in direction of a better outcome on the modified Rankin Scale (mRS) at 90 days, estimated with multivariable ordinal logistic regression analysis, which included a term for general anesthesia (GA). RESULTS: GA was associated with significant (p = 0.011) effect modification, resulting in estimated decrease of 51% (95% confidence interval [CI] 31%-86%) in treatment effect compared to non-GA. We found a shift in the distribution on the mRS in favor of non-GA compared to control group (acOR 2.18 [95% CI 1.49-3.20]). The shift in distribution between GA…

BACKGROUND: Failure to detect depression in patients with Parkinson disease (PD) can lead to worsened outcomes for patients and caregivers. Accurate identification of depression would enable practitioners to provide comprehensive care for their patients with PD. METHODS: Our objective was to examine the diagnostic accuracy of tools for detecting depression in adult outpatients with PD. We searched MEDLINE, PsycINFO, and EMBASE (inception to December 1, 2015), gray literature, and bibliographies of included studies. The pooled prevalence of depression across studies and diagnostic accuracy estimates were calculated using random-effects models. Diagnostic accuracy estimates were calculated across the best-reported cutoffs from each study and across specific cutoffs, when feasible. RESULTS: Out of 8,184 citations, 21 studies were included, evaluating 24 tools, with 4 amenable to meta-analysis. The pooled prevalence of major depression was 22.9% (95% confidence interval [CI] 18.1-27.7). The 15-item Geriatric Depression Scale (GDS-15) had a pooled sensitivity of 0.81 (95% CI 0.64-0.91)…

OBJECTIVE: To assess whether multifocal, high-frequency repetitive transcranial magnetic stimulation (rTMS) of motor and prefrontal cortex benefits motor and mood symptoms in patients with Parkinson disease (PD). METHODS: Patients with PD and depression were enrolled in this multicenter, double-blind, sham-controlled, parallel-group study of real or realistic (electric) sham rTMS. Patients were randomized to 1 of 4 groups: bilateral M1 ( + sham dorsolateral prefrontal cortex [DLPFC]), DLPFC ( + sham M1), M1 + DLPFC, or double sham. The TMS course consisted of 10 daily sessions of 2,000 stimuli for the left DLPFC and 1,000 stimuli for each M1 (50 × 4-second trains of 40 stimuli at 10 Hz). Patients were evaluated at baseline, at 1 week, and at 1, 3, and 6 months after treatment. Primary endpoints were changes in motor function assessed with the Unified Parkinson's Disease Rating Scale-III and in mood with the Hamilton Depression Rating Scale at 1 month. RESULTS: Of the 160 patients planned for recruitment, 85 were screened, 61 were randomized, and 50 completed all study visits. Real…

Although levodopa is widely recognized as the most effective therapy for Parkinson disease (PD), its introduction 5 decades ago was preceded by several years of uncertainty and equivocal clinical results. The translation of basic neuroscience research by Arvid Carlsson and Oleh Hornykiewicz provided a logical pathway for treating PD with levodopa. Yet the pioneering clinicians who transformed PD therapeutics with this drug--among them Walther Birkmayer, Isamu Sano, Patrick McGeer, George Cotzias, Melvin Yahr, and others--faced many challenges in determining whether the concept and the method for replenishing deficient striatal dopamine was correct. This article reviews highlights in the early development of levodopa therapy. In addition, it provides an overview of emerging drug delivery strategies that show promise for improving levodopa's pharmacologic limitations.

OBJECTIVE: To investigate risk factors for postherpetic neuralgia, the neuropathic pain that commonly follows herpes zoster. METHODS: Using primary care data from the Clinical Practice Research Datalink, we fitted multivariable logistic regression models to investigate potential risk factors for postherpetic neuralgia (defined as pain ≥90 days after zoster, based on diagnostic or prescription codes), including demographic characteristics, comorbidities, and characteristics of the acute zoster episode. We also assessed whether the effects were modified by antiviral use. RESULTS: Of 119,413 zoster patients, 6,956 (5.8%) developed postherpetic neuralgia. Postherpetic neuralgia risk rose steeply with age, most sharply between 50 and 79 years (adjusted odds ratio [OR] for a 10-year increase, 1.70, 99% confidence interval 1.63-1.78). Postherpetic neuralgia risk was higher in women (6.3% vs 5.1% in men: OR 1.19, 1.10-1.27) and those with severely immunosuppressive conditions, including leukemia (13.7%: 2.07, 1.08-3.96) and lymphoma (12.7%: 2.45, 1.53-3.92); autoimmune conditions, including…

OBJECTIVE: To determine whether there is an association between carotid artery web and ischemic stroke. METHODS: This was a single-center, age- and sex-matched, case-control study. Cases were consecutive patients with anterior circulation ischemic stroke of undetermined etiology (Trial of Org 10172 in Acute Stroke Treatment [TOAST] classification). Controls were consecutive patients with cerebral aneurysms, arteriovenous malformations, or primary intracerebral hemorrhages. Additional inclusion criteria were age <60 years and CT angiography of the neck. Two neuroradiologists diagnosed webs according to previously published criteria. One neuroradiologist also assessed for nonstenotic atherosclerotic plaque (carotid wall thickness ≥3 mm or intramural calcification). We used conditional logistic regression to estimate the odds ratio between carotid web and ischemic stroke and its 95% confidence interval. RESULTS: Fifty-three of 62 cases (85%) were matched by age (within 1 year) and by sex to 102 controls. There was a carotid web in 4 of 53 cases (9.4%) vs 1 of 102 controls (1.0%, odds…

OBJECTIVE: To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies. METHODS: We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18-35 years). RESULTS: Within participants without dementia, elevated PGRS was associated with worse memory (p = 0.002) and smaller hippocampus (p = 0.002) at baseline, as well as greater longitudinal cognitive decline (memory: p = 0.0005, executive function: p = 0.01) and clinical progression (p < 0.00001). High PGRS was associated with AD-like levels of β-amyloid burden as measured with florbetapir PET (p = 0.03) but did not…

OBJECTIVE: To correlate time to loss of ambulation (LoA) and different truncating DMD gene mutations in a large, prospective natural history study of Duchenne muscular dystrophy (DMD), with particular attention to mutations amenable to emerging molecular treatments. METHODS: We analyzed data from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study for participants with DMD single- or multi-exon deletions or duplications with defined exon boundaries (n = 186), or small mutations identified by sequencing (n = 26, including 16 nonsense point mutations). We performed a time-to-event analysis of LoA, a strong indicator of overall disease severity, adjusting for glucocorticoid treatment and genetic modifiers. RESULTS: Participants with deletions amenable to skipping of exon 44 had later LoA (median 14.8 years, hazard ratio 0.31, 95% confidence interval 0.14-0.69, p = 0.004). Age at LoA did not differ significantly in participants with deletions amenable to exon 45, 51, and 53 skipping, duplications, and small rearrangements. Nonsense mutation DMD also…

OBJECTIVE: To evaluate differences in amyloid deposition in a community-based cohort without dementia by age, sex, race, education, and APOE ε4 allele status. METHODS: Recruited from the longitudinal Atherosclerosis Risk in Communities study, 329 participants without dementia, ages 67-88 years, were imaged using florbetapir PET at 3 US community sites (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi). Standardized uptake value ratios (SUVRs) were calculated; global cortical SUVR >1.2 was evaluated as the primary outcome. Age, race, sex, education level, and number of APOE ε4 alleles were evaluated in multivariable models including vascular risk factors, brain white matter hyperintensity and total intracranial volume, and cognitive status. RESULTS: A total of 141 of the participants (43%) were black. In multivariable models, odds of elevated SUVR was increased in participants with increasing age (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.01-2.65 per 10 years of age) and black race (OR 2.08, 95% CI 1.23-3.51) but did not differ by…

OBJECTIVE: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels. METHODS: The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined. RESULTS: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no…

OBJECTIVE: To quantify the magnitude of deficits in theory of mind (ToM) and facial emotion recognition among patients with multiple sclerosis (MS) relative to healthy controls. METHODS: An electronic database search of Ovid MEDLINE, PsycINFO, and Embase was conducted from inception to April 1, 2016. Eligible studies were original research articles published in peer-reviewed journals that examined ToM or facial emotion recognition among patients with a diagnosis of MS and a healthy control comparison group. Data were independently extracted by 2 authors. Effect sizes were calculated using Hedges g. RESULTS: Twenty-one eligible studies were identified assessing ToM (12 studies) and/or facial emotion recognition (13 studies) among 722 patients with MS and 635 controls. Deficits in both ToM (g = -0.71, 95% confidence interval [CI] -0.88 to -0.55, p < 0.001) and facial emotion recognition (g = -0.64, 95% CI -0.81 to -0.47, p < 0.001) were identified among patients with MS relative to healthy controls. The largest deficits were observed for visual ToM tasks and for the recognition of…

OBJECTIVE: To determine the diagnostic value of high-resolution ultrasound (HRUS) for detection of chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner syndrome (LSS), and multifocal motor neuropathy (MMN). METHODS: Between January 2013 and January 2015, we enrolled 75 consecutive treatment-naive patients with chronic inflammatory neuropathies and 70 disease controls. We performed extensive nerve conduction and standardized HRUS studies bilaterally of large arm and leg nerves and brachial plexus. We determined optimal sonographic cutoff values of nerve size and used receiver operating characteristic analysis and logistic regression models to identify nerve combinations with optimal diagnostic performance. RESULTS: was 99% specific for chronic inflammatory neuropathies. A shortened HRUS protocol for detecting this abnormal nerve enlargement showed high sensitivity (83%-95%), positive predictive value (100%), and negative predictive value (98%) in discriminating CIDP, LSS, and MMN from clinical mimics. CONCLUSIONS: Sonographic enlargement of proximal median nerve…

Objective: To conduct a validation study of 123I-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard. Methods: Patients >60 years of age with dementia who had undergone 123I-FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent 123I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria. Results: Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, 123I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%)…

OBJECTIVE: To evaluate the diagnostic value of myxovirus resistance A (MxA) expression in the cytoplasm of myofibers in the diagnosis of dermatomyositis (DM). METHODS: We assessed the sensitivity and specificity of the sarcoplasmic expression of MxA in muscles with DM by immunohistochemistry in consecutive cases of DM (n = 34) and other idiopathic inflammatory myopathies (n = 120: 8 with polymyositis, 16 with anti-tRNA-synthetase antibody-associated myositis, 46 with immune-mediated necrotizing myopathy, and 50 with inclusion body myositis) and compared them with conventional pathologic hallmarks of DM, including perifascicular atrophy (PFA) and membrane attack complex (MAC) deposition on endomysial capillaries. RESULTS: The sensitivity and specificity of sarcoplasmic MxA expression were 71% and 98%, respectively. While the specificity was almost comparable to that of PFA and capillary MAC deposition, the sensitivity was higher, with PFA showing 47% sensitivity and 98% specificity and capillary MAC deposition showing 35% sensitivity and 93% specificity. Of note, in patients with DM…

OBJECTIVE: To visualize and treat spinal dural CSF leaks in all patients with intractable spontaneous intracranial hypotension (SIH) who underwent spinal microsurgical exploration. METHODS: Patients presenting between February 2013 and July 2015 were included in this consecutive case series. The workup included spinal MRI without and with intrathecal contrast, dynamic myelography, postmyelography CT, and microsurgical exploration. RESULTS: Of 69 consecutive patients, 15 had intractable symptoms. Systematic imaging revealed a suspicious single location of the leak in these 15 patients. Fourteen patients underwent microsurgical exploration; 1 patient refused surgery. Intraoperatively, including intradural exploration, we identified the cause of the CSF leaks as a longitudinal dural slit (6.1 ± 1.7 mm) on the ventral (10), lateral (3), or dorsal (1) aspect of the dura. In 10 patients (71%), a ventral, calcified microspur originating from the intervertebral disk perforated the dura like a knife. Three patients (22%) had a lateral dural tear with an associated spinal meningeal…

OBJECTIVE: To assess the clinical relevance of a positive voltage-gated potassium channel (VGKC) test in patients lacking antibodies to LGI1 and Caspr2. METHODS: VGKC-positive patients were tested for LGI1 and Caspr2 antibodies. Patients lacking both antibodies were matched (1:2) to VGKC-negative patients. Clinical and paraclinical criteria were used to blindly determine evidence for autoimmune inflammation in both groups. Patients with an inconclusive VGKC titer were analyzed in the same way. RESULTS: A total of 1,455 patients were tested by VGKC radioimmunoassay. Fifty-six patients tested positive, 50 of whom were available to be included. Twenty-five patients had antibodies to LGI1 (n = 19) or Caspr2 (n = 6) and 25 patients lacked both antibodies. Evidence for autoimmune inflammation was present in 7 (28%) of the VGKC-positive patients lacking LGI1 and Caspr2, compared to 9 (18%) of the VGKC-negative controls (p = 0.38). Evidence for autoimmune inflammation was mainly found in patients with limbic encephalitis/encephalomyelitis (57%), but not in other clinical phenotypes (5%, p <…

OBJECTIVE: To describe the clinical features, etiology, findings from neuroimaging, and treatment results in a series of 29 patients with Holmes tremor (HT). METHODS: A retrospective study was performed based on review of medical records and videos of patients with HT diagnosis. RESULTS: A total of 16 women and 13 men were included. The mean age at the moment of CNS insult was 33.9 ± 20.1 years (range 8-76 years). The most common causes were vascular (48.3%), ischemic, or hemorrhagic. Traumatic brain injury only represented 17.24%; other causes represented 34.5%. The median latency from lesion to tremor onset was 2 months (range 7 days-228 months). The most common symptoms/signs associated with HT were hemiparesis (62%), ataxia (51.7%), hypoesthesia (27.58%), dystonia (24.1%), cranial nerve involvement (24.1%), and dysarthria (24.1%). Other symptoms/signs were vertical gaze disorders (6.8%), bradykinesia/rigidity (6.8%), myoclonus (3.4%), and seizures (3.4%). Most of the patients had lesions involving more than one area. MRI showed lesions in thalamus or midbrain or cerebellum in…

OBJECTIVE: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). METHODS: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. RESULTS: , including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. CONCLUSIONS: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.

OBJECTIVE: To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers. METHODS: This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale-Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups. RESULTS: Adverse events…

OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. METHODS: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. RESULTS: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel…

OBJECTIVE: To evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC). METHODS: Everolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life. RESULTS: Of the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported ≥50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical…

OBJECTIVE: To examine whether long-term measures of cortisol predict Alzheimer disease (AD) risk. METHOD: We used a prospective longitudinal design to examine whether cortisol dysregulation was related to AD risk. Participants were from the Baltimore Longitudinal Study of Aging (BLSA) and submitted multiple 24-hour urine samples over an average interval of 10.56 years. Urinary free cortisol (UFC) and creatinine (Cr) were measured, and a UFC/Cr ratio was calculated to standardize UFC. To measure cortisol regulation, we used within-person UFC/Cr level (i.e., within-person mean), change in UFC/Cr over time (i.e., within-person slope), and UFC/Cr variability (i.e., within-person coefficient of variation). Cox regression was used to assess whether UFC/Cr measures predicted AD risk. RESULTS: UFC/Cr level and UFC/Cr variability, but not UFC/Cr slope, were significant predictors of AD risk an average of 2.9 years before AD onset. Elevated UFC/Cr level and elevated UFC/Cr variability were related to a 1.31- and 1.38-times increase in AD risk, respectively. In a sensitivity analysis,…

OBJECTIVE: This was a longitudinal single-center cohort study to comprehensively explore multimodal progression markers for Parkinson disease (PD) in patients with recently diagnosed PD (n = 123) and age-matched, neurologically healthy controls (HC; n = 106). METHODS: Thirty tests at baseline and after 24 months covered nonmotor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers. Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95% confidence intervals (CI). RESULTS: A composite panel of 10 informative markers was identified. Significant relative worsening (PD vs HC) was seen with the following markers: the Unified Parkinson's Disease Rating Scale I (d 0.39; CI 0.09-0.70), the Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25; CI 0.06-0.46), the Epworth Sleepiness Scale (d 0.47; CI 0.24-0.71), the RBD Screening Questionnaire (d 0.44; CI 0.25-0.64), and RBD by PSG (d 0.37; CI…

OBJECTIVE: To determine whether neuroanatomically heterogeneous strokes causing hemichorea-hemiballismus localize to a common functional network. METHODS: We identified 29 cases of lesion-induced hemichorea-hemiballismus from the literature and mapped each lesion volume onto a reference brain. Using a recently validated technique termed lesion network mapping, we tested whether these lesions belonged to the same functional network. To accomplish this, the network of brain regions functionally connected to each lesion was identified using a connectome dataset from healthy participants. Network maps were overlapped to identify any region functionally connected to our set of lesions. Specificity was evaluated using a case-control design; control cohorts included a group of similar lesions randomized to different brain locations and a second group of lesions causing a separate movement disorder, asterixis. Reproducibility was evaluated using an independent cohort of 10 additional hemichorea-hemiballismus cases. RESULTS: Lesions showed heterogeneity in anatomical location, consistent…

OBJECTIVE: To image β-amyloid (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer disease (AD). METHODS: Patients 11 months to 17 years after moderate-severe TBI underwent (11)C-Pittsburgh compound B ((11)C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of (11)C-PiB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with (11)C-PiB BPND. RESULTS: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased (11)C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional…

OBJECTIVE: Factors predicting poor outcome in patients with the reversible cerebral vasoconstriction syndrome (RCVS) have not been identified. METHODS: In this single-center retrospective study, we analyzed the clinical, brain imaging, and angiography data in 162 patients with RCVS. Univariable and multivariable regression analysis were performed to identify predictors of persistent (nontransient) clinical worsening, radiologic worsening, early angiographic progression, and poor discharge outcome (modified Rankin Scale score 4-6). RESULTS: The mean age was 44 ± 13 years; 78% of patients were women. Persistent clinical worsening occurred in 14% at 6.6 ± 4.1 days after symptom onset, radiologic worsening in 27% (mainly new infarcts), and angiographic progression in 15%. Clinical worsening correlated with angiographic progression and new nonhemorrhagic lesions. Age and sex did not independently predict any type of worsening. Infarction on baseline imaging predicted poor outcome. Prior serotonergic antidepressant use predicted clinical and angiographic worsening but not poor outcome.…

OBJECTIVE: To assess the efficacy of a progressive aerobic exercise training program on cognitive and everyday function among adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). METHODS: This was a proof-of-concept single-blind randomized controlled trial comparing a 6-month, thrice-weekly, progressive aerobic exercise training program (AT) with usual care plus education on cognitive and everyday function with a follow-up assessment 6 months after the formal cessation of aerobic exercise training. Primary outcomes assessed were general cognitive function (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog]), executive functions (Executive Interview [EXIT-25]), and activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living [ADCS-ADL]). RESULTS: Seventy adults randomized to aerobic exercise training or usual care were included in intention-to-treat analyses (mean age 74 years, 51% female, n = 35 per group). At the end of the intervention, the aerobic exercise training group had significantly improved ADAS-Cog…

OBJECTIVE: To determine associations between cerebral microbleed (CMB) burden with recurrent ischemic stroke (IS) and intracerebral hemorrhage (ICH) risk after IS or TIA. METHODS: We identified prospective studies of patients with IS or TIA that investigated CMBs and stroke (ICH and IS) risk during ≥3 months follow-up. Authors provided aggregate summary-level data on stroke outcomes, with CMBs categorized according to burden (single, 2-4, and ≥5 CMBs) and distribution. We calculated absolute event rates and pooled risk ratios (RR) using random-effects meta-analysis. RESULTS: We included 5,068 patients from 15 studies. There were 115/1,284 (9.6%) recurrent IS events in patients with CMBs vs 212/3,781 (5.6%) in patients without CMBs (pooled RR 1.8 for CMBs vs no CMBs; 95% confidence interval [CI] 1.4-2.5). There were 49/1,142 (4.3%) ICH events in those with CMBs vs 17/2,912 (0.58%) in those without CMBs (pooled RR 6.3 for CMBs vs no CMBs; 95% CI 3.5-11.4). Increasing CMB burden increased the risk of IS (pooled RR [95% CI] 1.8 [1.0-3.1], 2.4 [1.3-4.4], and 2.7 [1.5-4.9] for 1 CMB, 2-4…

OBJECTIVE: While compensatory saccades indicate vestibular loss in the conventional head impulse test paradigm (HIMP), in which the participant fixates an earth-fixed target, we investigated a complementary suppression head impulse paradigm (SHIMP), in which the participant is fixating a head-fixed target to elicit anticompensatory saccades as a sign of vestibular function. METHODS: HIMP and SHIMP eye movement responses were measured with the horizontal video head impulse test in patients with unilateral vestibular loss, patients with bilateral vestibular loss, and in healthy controls. RESULTS: Vestibulo-ocular reflex gains showed close correlation (R(2) = 0.97) with slightly lower SHIMP than HIMP gains (mean gain difference 0.06 ± 0.05 SD, p < 0.001). However, the 2 paradigms produced complementary catch-up saccade patterns: HIMP elicited compensatory saccades in patients but rarely in controls, whereas SHIMP elicited large anticompensatory saccades in controls, but smaller or no saccades in bilateral vestibular loss. Unilateral vestibular loss produced covert saccades in HIMP, but…

OBJECTIVE: To report a novel autoimmune encephalitis in which the antibodies target neurexin-3α, a cell adhesion molecule involved in the development and function of synapses. METHODS: Five patients with encephalitis and antibodies with a similar pattern of brain reactivity were selected. Antigen precipitation and determination of antibody effects on cultured rat embryonic neurons were performed with reported techniques. RESULTS: Immunoprecipitation and cell-based assays identified neurexin-3α as the autoantigen of patients' antibodies. All 5 patients (median age 44 years, range 23-50; 4 female) presented with prodromal fever, headache, or gastrointestinal symptoms, followed by confusion, seizures, and decreased level of consciousness. Two developed mild orofacial dyskinesias, 3 needed respiratory support, and 4 had findings suggesting propensity to autoimmunity. CSF was abnormal in all patients (4 pleocytosis, 1 elevated immunoglobulin G [IgG] index), and brain MRI was abnormal in 1 (increased fluid-attenuated inversion recovery/T2 in temporal lobes). All received steroids, 1 IV…

OBJECTIVE: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations. METHODS: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system. RESULTS: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients…

OBJECTIVE: To compare daily sex hormone levels and rates of change between women with history of migraine and controls. METHODS: History of migraine, daily headache diaries, and daily hormone data were collected in ovulatory cycles of pre- and early perimenopausal women in the Study of Women's Health Across the Nation. Peak hormone levels, average daily levels, and within-woman day-to-day rates of decline over the 5 days following each hormone peak were calculated in ovulatory cycles for conjugated urinary estrogens (E1c), pregnanediol-3-glucuronide, luteinizing hormone, and follicle-stimulating hormone. Comparisons were made between migraineurs and controls using 2-sample t tests on the log scale with results reported as geometric means. RESULTS: The sample included 114 women with history of migraine and 223 controls. Analyses of within-woman rates of decline showed that E1c decline over the 2 days following the luteal peak was greater in migraineurs for both absolute rate of decline (33.8 [95% confidence interval 28.0-40.8] pg/mgCr vs 23.1 [95% confidence interval 20.1-26.6]…

OBJECTIVE: To examine whether higher plasma urate concentrations are associated with a lower risk of developing Parkinson disease (PD) and whether there is a sex difference in the potential urate-PD relationship. METHODS: We conducted a nested case-control study based on 90,214 participants of 3 ongoing US cohorts. We identified 388 new PD cases (202 men and 186 women) since blood collection, which were then matched to 1,267 controls. PD cases were confirmed by medical record review. Conditional logistic regression estimated relative risks (RRs) and 95% confidence intervals (95% CIs), after adjustment for age, smoking, caffeine intake, plasma concentrations of cholesterol and ferritin, and other covariates. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on urate and PD risk. RESULTS: In the present nested case-control study, the multivariate-adjusted RRs of PD comparing extreme quartiles of urate were 0.63 (95% CI 0.35, 1.10; ptrend = 0.049) in men and 1.04 (95% CI 0.61, 1.78; ptrend = 0.44) in women (pheterogeneity = 0.001).…

OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the safety and efficacy of IV thrombolysis (IVT) with tissue plasminogen activator (tPA) delivered through telestroke networks in patients with acute ischemic stroke. METHODS: We conducted a systematic review and meta-analysis according to PRISMA guidelines. Literature searches on MEDLINE, Embase, and CENTRAL databases covered prospective randomized controlled and nonrandomized studies comparing telemedicine-guided IVT to IVT administered at stroke centers and were published from the earliest date available until April 1, 2015. Outcomes of interest were symptomatic intracerebral hemorrhage, mortality, and functional independence (modified Rankin Scale scores 0-1) at 3 months. Random-effects meta-analysis was used to compute pooled effect estimates and the I(2) statistic to assess heterogeneity. RESULTS: Of 529 records identified, 7 studies totaling 1,863 patients fulfilled our eligibility criteria. Among these, thrombolysis was largely restricted to the 3-hour time window. Symptomatic intracerebral…

OBJECTIVE: To systematically review the literature and assess agreement on the Alberta Stroke Program Early CT Score (ASPECTS) among clinicians involved in the management of thrombectomy candidates. METHODS: Studies assessing agreement using ASPECTS published from 2000 to 2015 were reviewed. Fifteen raters reviewed and scored the anonymized CT scans of 30 patients recruited in a local thrombectomy trial during 2 independent sessions, in order to study intrarater and interrater agreement. Agreement was measured using intraclass correlation coefficients (ICCs) and Fleiss kappa statistics for ASPECTS and dichotomized ASPECTS at various cutoff values. RESULTS: The review yielded 30 articles reporting 40 measures of agreement. Populations, methods, analyses, and results were heterogeneous (slight to excellent agreement), precluding a meta-analysis. When analyzed as a categorical variable, intrarater agreement was slight to moderate (κ = 0.042-0.469); it reached a substantial level (κ > 0.6) in 11/15 raters when the score was dichotomized (0-5 vs 6-10). The interrater ICCs varied between…