Multiple sclerosis and pregnancy in the 'treatment era'

The influence of pregnancy on the course of multiple sclerosis (MS) has long been controversial; until the end of 1990s, women with MS were discouraged from having children owing to a biased belief that pregnancy would worsen the disease course. Since the first large prospective study in 1998, counselling of women with MS has changed radically, and many patients have attained their desire of motherhood. Although many disease-modifying drugs have come to market in the past two decades, when used during pregnancy and lactation, their beneficial effects on the course of MS have to be balanced with fears concerning potential risks to the fetus or child. The wealth of treatment options and the various associated risks have created a growing need for counselling on family planning for women with MS. Most importantly, such counselling should address the concerns that women with MS might have regarding pregnancy. Second, as soon as a woman starts considering pregnancy, a treatment plan should be established. This plan needs to weigh the risk posed to the fetus by potentially harmful drug exposure, and the risk to the mother from a reappearance of disease activity. Finally, breastfeeding and treatment options after delivery should be discussed to outline the options for prevention of postpartum relapses, and the possible resumption of disease-modifying drugs.

Nature Reviews Neurology 2015

Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neurons, which results in weakness and atrophy of voluntary skeletal muscles. Treatments do not modify the disease trajectory effectively, and only modestly improve survival. A complex interaction between genes, environmental exposure and impaired molecular pathways contributes to pathology in patients with ALS. Epigenetic mechanisms control the hereditary and reversible regulation of gene expression without altering the basic genetic code. Aberrant epigenetic patterns—including abnormal microRNA (miRNA) biogenesis and function, DNA modifications, histone remodeling, and RNA editing—are acquired throughout life and are influenced by environmental factors. Thus, understanding the molecular processes that lead to epigenetic dysregulation in patients with ALS might facilitate the discovery of novel therapeutic targets and biomarkers that could reduce diagnostic delay. These achievements could prove crucial for successful disease modification in patients with ALS. We review the latest findings regarding the role of miRNA modifications and other epigenetic mechanisms in ALS, and discuss their potential as therapeutic targets.

Nature Reviews Neurology 2015

Modulating the pain network—neurostimulation for central poststroke pain

Central poststroke pain (CPSP) is one of the most under-recognized consequences of stroke, occurring in up to 10% of patients, and is also one of the most difficult to treat. The condition characteristically develops after selective lesions to the spinothalamic system, most often to the ventral posterior thalamus. Here, we suggest that CPSP is best characterized as a disorder of brain network reorganization, and that this characterization offers insight into the inadequacy of most current pharmacological treatments. Accordingly, we review the progress in identification of nonpharmacological treatments, which could ultimately lead to mechanism-based therapeutics. Of the invasive neurostimulation treatments available, electrical motor cortex stimulation seems to be superior to deep brain stimulation of the thalamus or brainstem, but enthusiasm for clinical use of the procedure is limited by its invasiveness. The current preference is for noninvasive transcranial magnetic stimulation, which, though effective, requires repeated application, causing logistical difficulties. Although CPSP is often severe and remains difficult to treat, future characterization of the precise underlying neurophysiological mechanisms, together with technological innovation, should allow new treatments to evolve.

Nature Reviews Neurology 2015

Defining high, medium and low impact prognostic factors for developing multiple sclerosis

Natural history studies have identified factors that predict evolution to multiple sclerosis or risk of disability accumulation over time. Although these studies are based on large multicentre cohorts with long follow-ups, they have limitations such as lack of standardized protocols, a retrospective data collection or lack of a systematic magnetic resonance imaging acquisition and analysis protocol, often resulting in failure to take magnetic resonance and oligoclonal bands into account as joint covariates in the prediction models. To overcome some of these limitations, the aim of our study was to identify and stratify baseline demographic, clinical, radiological and biological characteristics that might predict multiple sclerosis development and disability accumulation using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndromes. From 1995 to 2013, 1058 patients with clinically isolated syndromes were included. We evaluated the influence of baseline prognostic factors on the risk for developing clinically definite multiple sclerosis, McDonald multiple sclerosis, and disability accumulation (Expanded Disability Status Scale score of 3.0) based on univariate (hazard ratio with 95% confidence intervals) and multivariate (adjusted hazard ratio with 95% confidence intervals) Cox regression models. We ultimately included 1015 patients followed for a mean of 81 (standard deviation = 57) months. Female/male ratio was 2.1. Females exhibited a similar risk of conversion to multiple sclerosis and of disability accumulation compared to males. Each younger decade at onset was associated with a greater risk of conversion to multiple sclerosis and with a protective effect on disability. Patients with optic neuritis had a lower risk of clinically definite multiple sclerosis [hazard ratio 0.6 (0.5–0.8)] and disability progression [hazard ratio 0.5 (0.3–0.8)]; however, this protective effect remained marginal only for disability [adjusted hazard ratio 0.6 (0.4–1.0)] in adjusted models. The presence of oligoclonal bands increased the risk of clinically definite multiple sclerosis [adjusted hazard ratio 1.3 (1.0–1.8)] and of disability [adjusted hazard ratio 2.0 (1.2–3.6)] independently of other factors. The presence of 10 or more brain lesions on magnetic resonance increased the risk of clinically definite multiple sclerosis [adjusted hazard ratio 11.3 (6.7–19.3)] and disability [adjusted hazard ratio 2.9 (1.4–6.0)]. Disease-modifying treatment before the second attack reduced the risk of McDonald multiple sclerosis [adjusted hazard ratio 0.6 (0.4–0.9)] and disability accumulation [adjusted hazard ratio 0.5 (0.3–0.9)]. We conclude that the demographic and topographic characteristics are low-impact prognostic factors, the presence of oligoclonal bands is a medium-impact prognostic factor, and the number of lesions on brain magnetic resonance is a high-impact prognostic factor.

Brain 2015

Brain Stimulation for Torsion Dystonia

Importance  Dystonia is a heterogeneous neurologic disorder characterized by abnormal muscle contractions for which standard medical therapy is often inadequate. For such patients, therapeutic brain stimulation is becoming increasingly used.

Objectives  To review the evidence and effect sizes for treating different types of dystonia with different types of brain stimulation and to discuss recent advances relevant to patient selection, surgical approach, programming, and mechanism of action.

Evidence Review  PubMed was searched for publications on the clinical effect of brain stimulation in dystonia up through December 31, 2014. Recent meta-analyses, consensus statements, and evidence-based guidelines were incorporated. Emphasis was placed on deep brain stimulation (DBS) and randomized clinical trials; however, other stimulation modalities and trial designs were included. For each intervention the mean change in dystonia severity, number of patients studied, and evidence of efficacy based on American Academy of Neurology criteria were determined.

Findings  Strong (level B) evidence supports the use of DBS for the treatment of primary generalized or segmental dystonia, especially when due to mutation in the DYT1 gene, as well as for patients with cervical dystonia. Large effect sizes have also been reported for DBS treatment of tardive dystonia, writer’s cramp, cranial dystonia, myoclonus dystonia, and off-state dystonia associated with Parkinson disease. Lesser benefit is generally seen in dystonia secondary to structural brain damage. Other brain stimulation techniques, including epidural cortical stimulation and noninvasive brain stimulation, have been investigated, but generally report smaller effect sizes in fewer patients.

Conclusions and Relevance  Patients with dystonia that is not adequately controlled with standard medical therapy should be referred for consideration of DBS, especially patients with generalized, segmental, or cervical dystonia. Other less-invasive stimulation modalities require further research before being considered a therapeutic alternative.

JAMA Neurology 2015

Effect of Cognitive Reserve on Age-Related Changes in Cerebrospinal Fluid Biomarkers of Alzheimer Disease

Importance  Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology.

Objective  To investigate whether cognitive reserve (CR) modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD.

Design, Setting, and Participants  A cross-sectional cohort of 268 individuals (211 in a cognitively normal group and 57 in a cognitively impaired group) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center participated in this study. They underwent lumbar puncture for collection of CSF samples, from which Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed. In addition, we computed t-tau/Aβ42 and p-tau/Aβ42 ratios. Cognitive reserve was indexed by years of education, with 16 or more years taken to confer high reserve. Covariate-adjusted regression analyses were used to test whether the effect of age on CSF biomarkers was modified by CR. The study dates were March 5, 2010, to February 13, 2013.

Main Outcomes and Measures  Cerebrospinal fluid levels of Aβ42, t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42.

Results  There were significant age × CR interactions for CSF t-tau (β [SE] = −6.72 [2.84], P = .02), p-tau (β [SE] = −0.71 [0.27], P = .01), t-tau/Aβ42 (β [SE] = −0.02 [0.01], P = .02), and p-tau/Aβ42 (β [SE] = −0.002 [0.001], P = .004). With advancing age, individuals with high CR exhibited attenuated adverse alterations in these CSF biomarkers compared with individuals with low CR. This attenuation of age effects by CR tended to be more pronounced in the cognitively impaired group compared with the cognitively normal group. There was evidence of a dose-response relationship such that the effect of age on the biomarkers was progressively attenuated given additional years of schooling.

Conclusions and Relevance  In a sample composed of a cognitively normal group and a cognitively impaired group, higher CR was associated with a diminution of age-related alterations in CSF biomarkers of AD. This suggests one pathway through which CR might favorably alter lifetime risk for symptomatic AD.

JAMA Neurology 2015

Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine Receptors in the Diagnosis of Seronegative Myasthenia Gravis

Importance  Cell-based assays (CBAs) were shown to improve detection of acetylcholine receptor (AChR) antibodies in patients with myasthenia gravis (MG). Herein, we asked whether these assays were able to help determine the diagnosis in patients studied in routine clinical practice.

Objectives  To determine the diagnostic usefulness of CBAs in the diagnosis of MG and to compare the clinical features of patients with antibodies only to clustered AChRs with those of patients with seronegative MG (SNMG).

Design, Setting, and Participants  All patients with clinical suspicion of MG who were seen within the Division of Clinical Neurology at the John Radcliffe Hospital in Oxford, England, between November 1, 2009, and November 30, 2013. Their serum antibodies and clinical features were studied.

Exposures  Radioimmunoprecipitation assay (RIPA) and CBA were used to test for standard AChR antibodies and antibodies to clustered AChRs in 138 patients. All available samples from patients with SNMG were retrospectively tested for lipoprotein receptor–related protein 4 (LRP4) antibodies.

Main Outcomes and Measures  Demographic, clinical, neurophysiological, and laboratory data.

Results  In total, 138 patients were tested for antibodies to clustered AChRs, and 42 had a final diagnosis of MG. The clustered AChR CBA detected antibodies in 38.1% (16 of 42) of RIPA-negative patients with MG with 100% specificity. All patients with SNMG who were tested for LRP4 antibodies (21 of 26) were negative by CBA. Compared with patients with SNMG, patients with antibodies only to clustered AChRs had frequent prepubertal onset (62.5% [median age, 6 years; age range, 1-52 years] vs 11.5% [median age, 38 years; age range, 2-72 years], P ≤ .05), high prevalence of ocular MG (62.5% vs 42.3%), milder disease severity with less bulbar involvement (25.0% vs 46.2%), and absence of respiratory symptoms (0% vs 23.1%). Response to treatment and prognosis was good, with a reduced need for thymectomy (6.3% vs 19.2%) and a high proportion of patients going into remission (50.0% vs 8.3%, P ≤ .05). These observations also apply to the classic AChR MG phenotype seen in large series.

Conclusions and Relevance  Cell-based assay is a useful procedure in the routine diagnosis of RIPA-negative MG, particularly in children. Patients with antibodies only to clustered AChRs appear to be younger and have milder disease than other patients with MG. These observations will have implications in planning treatment

JAMA Neurology 2015

Stenting versus medical treatment in patients with symptomatic vertebral artery stenosis: a randomised open-label phase 2 trial

Background

Patients with a recent vertebrobasilar transient ischaemic attack or ischaemic stroke and vertebral artery stenosis of at least 50% have a high risk of future vertebrobasilar stroke. Stenting of vertebral artery stenosis is promising, but of uncertain benefit. We investigated the safety and feasibility of stenting of symptomatic vertebral artery stenosis of at least 50%, and assessed the rate of vascular events in the vertebrobasilar supply territory to inform the design of a phase 3 trial.

Methods

Between Jan 22, 2008, and April 8, 2013, patients with a recent transient ischaemic attack or minor stroke associated with an intracranial or extracranial vertebral artery stenosis of at least 50% were enrolled from seven hospitals in the Netherlands in a phase 2 open-label trial with masked assessment of outcome. Patients were randomly allocated in a 1:1 ratio to stenting plus best medical treatment or best medical treatment alone by the local investigators using a web-based randomisation system. The primary outcome was the composite of vascular death, myocardial infarction, or any stroke within 30 days after the start of treatment. The secondary outcomes were stroke in the supply territory of the symptomatic vertebral artery during follow-up, the composite outcome during follow-up, and the degree of stenosis in the symptomatic vertebral artery at 12 months. The trial is registered, number ISRCTN29597900.

Findings

The trial was stopped after inclusion of 115 patients because of new regulatory requirements, including the use of a few prespecified stent types and external monitoring, for which no funding was available. 57 patients were assigned to stenting and 58 to medical treatment alone. Three patients in the stenting group had vascular death, myocardial infarction, or any stroke within 30 days after the start of treatment (5%, 95% CI 0–11) versus one patient in the medical treatment group (2%, 0–5). During a median follow-up of 3 years (IQR 1·3–4·1), seven (12%, 95% CI 6–24) patients in the stenting group and four (7%, 2–17) in the medical treatment group had a stroke in the territory of the symptomatic vertebral artery; 11 (19%) patients in the stenting group and ten (17%) in the medical treatment group had vascular death, myocardial infarction, or any stroke. The small size of the vertebral artery and stent artifacts did not allow exact grading of restenosis on CT angiography. During the complete period of follow-up, there were 60 serious adverse events (eight strokes) in the stenting group and 56 (seven strokes) in the medical treatment alone group.

Interpretation

Stenting of symptomatic vertebral artery stenosis is associated with a major periprocedural vascular complication in about one in 20 patients. In the population we studied, the risk of recurrent vertebrobasilar stroke under best medical treatment alone was low, questioning the need for and feasibility of a phase 3 trial.

Lancet Neurology 2015

Status epilepticus in adults

Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes.

Lancet Neurology 2015

Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability.

Mitochondrial complex I (CI) deficiencies are causing debilitating neurological diseases, among which, the Leber Hereditary Optic Neuropathy and Leigh Syndrome are the most frequent. Here we describe the first germinal pathogenic mutation in the NDUFA13/GRIM19 gene encoding a CI subunit, in two sisters with early onset hypotonia, dyskinesia and sensorial deficiencies, including a severe optic neuropathy. Biochemical analysis revealed a drastic decrease in CI enzymatic activity in patient muscle biopsies, and reduction of CI driven respiration in fibroblasts, while the activities of complex II, III and IV were hardly affected. Western blots disclosed that the abundances of NDUFA13 protein, CI holoenzyme and super complexes were drastically reduced in mitochondrial fractions, a situation that was reproduced by silencing NDUFA13 in control cells. Thus, we established here a correlation between the first mutation yet identified in the NDUFA13 gene, which induces CI instability and a severe but slowly evolving clinical presentation affecting the central nervous system.

Hum Mol Genet 2015

Increased oxidative stress is related to disease severity in the ALS motor cortex A PET study

Objective: To investigate cerebral oxidative stress based on an over-reductive state caused by mitochondrial dysfunction and its relationship to disease severity in patients with amyotrophic lateral sclerosis (ALS) using PET with [⁶²Cu]diacetyl-bis(N⁴-methylthiosemicarbazone) (⁶²Cu-ATSM).

Methods: Twelve patients with ALS and 9 age-matched healthy controls underwent a 20-minute dynamic brain PET scan after ⁶²Cu-ATSM injection. The standardized uptake value (SUV) images obtained from the last 10 minutes of frames were normalized by the global mean (nSUV). Regional ⁶²Cu-ATSM retention in the nSUV images was compared between groups using statistical parametric mapping (SPM) and region of interest (ROI) analysis. Secondary analyses evaluated the correlations between regional nSUVs and the clinical characteristics of the participants.

Results: In SPM mapping, patients with ALS showed a significantly greater accumulation of ⁶²Cu-ATSM compared to controls in the bilateral cortices around the central sulcus, including the motor cortex, and the right superior parietal lobule. ROI analysis also revealed significantly greater nSUVs in patients than controls in these regions. Increases in nSUV for these regions were associated with decreases in the revised ALS Functional Rating Scale score, suggesting a good correlation with the severity of ALS. In controls, age was correlated with nSUV for the bilateral cortices around the central sulcus, although this correlation was not observed in patients with ALS.

Conclusions: ⁶²Cu-ATSM PET imaging demonstrated increased oxidative stress based on an over-reductive state, primarily in the motor cortex, in patients with ALS. The magnitude of oxidative stress correlated well with clinical severity, indicating that it may be associated with neurodegenerative changes in ALS.

Neurology 2015

A novel AARS mutation in a family with dominant myeloneuropathy

Objective: To determine the genetic cause of neurodegeneration in a family with myeloneuropathy.

Methods: We studied 5 siblings in a family with a mild, dominantly inherited neuropathy by clinical examination and electrophysiology. One patient had a sural nerve biopsy. After ruling out common genetic causes of axonal Charcot-Marie-Tooth disease, we sequenced 3 tRNA synthetase genes associated with neuropathy.

Results: All affected family members had a mild axonal neuropathy, and 3 of 4 had lower extremity hyperreflexia, evidence of a superimposed myelopathy. A nerve biopsy showed evidence of chronic axonal loss. All affected family members had a heterozygous missense mutation c.304G>C (p.Gly102Arg) in the alanyl-tRNA synthetase (AARS) gene; this allele was not identified in unaffected individuals or control samples. The equivalent change in the yeast ortholog failed to complement a strain of yeast lacking AARS function, suggesting that the mutation is damaging.

Conclusion: A novel mutation in AARS causes a mild myeloneuropathy, a novel phenotype for patients with mutations in one of the tRNA synthetase genes.

Neurology 2015

Evidence-based guideline: Management of an unprovoked first seizure in adults

Results and recommendations: Adults with an unprovoked first seizure should be informed that their seizure recurrence risk is greatest early within the first 2 years (21%–45%) (Level A), and clinical variables associated with increased risk may include a prior brain insult (Level A), an EEG with epileptiform abnormalities (Level A), a significant brain-imaging abnormality (Level B), and a nocturnal seizure (Level B). Immediate antiepileptic drug (AED) therapy, as compared with delay of treatment pending a second seizure, is likely to reduce recurrence risk within the first 2 years (Level B) but may not improve quality of life (Level C). Over a longer term (.3 years), immediate AED treatment is unlikely to improve prognosis as measured by sustained seizure remission (Level B). Patients should be advised that risk of AED adverse events (AEs) may range from 7% to 31% (Level B) and that these AEs are likely predominantly mild and reversible. Clinicians’ recommendations whether to initiate immediate AED treatment after a first seizure should be based on individualized assessments that weigh the risk of recurrence against the AEs of AED therapy, consider educated patient preferences, and advise that immediate treatment will not improve the long-term prognosis for seizure remission but will reduce seizure risk over the subsequent 2 years. 

Neurology 2015

Early and effective treatment of KCNQ2 encephalopathy

To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of life.

Methods

We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data.

Results

Seizure onset was between 1 and 4 days of age with daily tonic asymmetric, focal and clonic seizures in nine patients and status epilepticus in the remaining six. Electroencephalography (EEG) showed multifocal epileptiform abnormalities in nine patients and a burst-suppression pattern in six. All patients were trialed with adequate daily doses of several AEDs before they reached seizure freedom. Six patients (40%) achieved seizure control within 2 weeks of carbamazepine (CBZ) administration and five (33%) were seizure-free with phenytoin (PHT). The last four patients (27%) were successfully treated with topiramate (TPM) (two patients), levetiracetam (LEV) (one), and a combination of LEV with TPM (one). Most patients reached seizure freedom within the first year of life and remained seizure-free thereafter. Twelve patients had moderate-to-severe developmental delay at follow-up. However, the two patients whose seizures ceased within a few days of onset showed only mild cognitive impairment.

Significance

Our findings suggest that drugs acting on sodium channels including CBZ and PHT should be considered as first-line treatment in patients with KCNQ2 encephalopathy. Voltage-gated sodium and potassium channels co-localize at the neuronal membrane. Therefore, the efficacy of drugs acting as sodium-channel blockers could be linked to their modulating effect on both channels. The type of KCNQ2mutation might influence AED response as well as developmental outcome. Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder.

Epilepsia 2015

Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans

Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51–84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (Pcorrected = 0.020) and primary motor cortex (Pcorrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements.

Brain 2015

The relative phases of basal ganglia activities dynamically shape effective connectivity in Parkinson's disease

Optimal phase alignment between oscillatory neural circuits is hypothesized to optimize information flow and enhance system performance. This theory is known as communication-through-coherence. The basal ganglia motor circuit exhibits exaggerated oscillatory and coherent activity patterns in Parkinson's disease. Such activity patterns are linked to compromised motor system performance as evinced by bradykinesia, rigidity and tremor, suggesting that network function might actually deteriorate once a certain level of net synchrony is exceeded in the motor circuit. Here, we characterize the processes underscoring excessive synchronization and its termination. To this end, we analysed local field potential recordings from the subthalamic nucleus and globus pallidus of five patients with Parkinson's disease (four male and one female, aged 37–64 years). We observed that certain phase alignments between subthalamic nucleus and globus pallidus amplified local neural synchrony in the beta frequency band while others either suppressed it or did not induce any significant change with respect to surrogates. The increase in local beta synchrony directly correlated with how long the two nuclei locked to beta-amplifying phase alignments. Crucially, administration of the dopamine prodrug, levodopa, reduced the frequency and duration of periods during which subthalamic and pallidal populations were phase-locked to beta-amplifying alignments. Conversely ON dopamine, the total duration over which subthalamic and pallidal populations were aligned to phases that left beta-amplitude unchanged with respect to surrogates increased. Thus dopaminergic input shifted circuit dynamics from persistent periods of locking to amplifying phase alignments, associated with compromised motoric function, to more dynamic phase alignment and improved motoric function. This effect of dopamine on local circuit resonance suggests means by which novel electrical interventions might prevent resonance-related pathological circuit interactions.

Brain 2015

Risk Factors Associated With Incident Cerebral Microbleeds According to Location in Older People The Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study

Importance  The spatial distribution of cerebral microbleeds (CMBs), which are asymptomatic precursors of intracerebral hemorrhage, reflects specific underlying microvascular abnormalities of cerebral amyloid angiopathy (lobar structures) and hypertensive vasculopathy (deep brain structures). Relatively little is known about the occurrence of and modifiable risk factors for developing CMBs, especially in a lobar location, in the general population of older people.

Objective  To investigate whether lifestyle and lipid factors predict new CMBs in relation to their anatomic location.

Design, Setting, and Participants  We enrolled 2635 individuals aged 66 to 93 years from the population-based Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study in a brain imaging study. Participants underwent a baseline magnetic resonance imaging (MRI) examination of the brain from September 1, 2002, through February 28, 2006, and returned for a second MRI examination from April 1, 2007, through September 30, 2011.

Exposures  Lifestyle and lipid factors assessed at baseline included smoking, alcohol consumption, body mass index, and serum levels of total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides.

Main Outcomes and Measures  Incident CMBs detected on MRIs, which were further categorized as exclusively lobar or as deep.

Results  During a mean follow-up of 5.2 years, 486 people (18.4%) developed new CMBs, of whom 308 had lobar CMBs only and 178 had deep CMBs. In the multivariate logarithm-binomial regression model adjusted for baseline cardiovascular risk factors, including blood pressure, antihypertensive use, prevalent CMBs, and markers of cerebral ischemic small-vessel disease, heavy alcohol consumption (vs light to moderate consumption; relative risk [RR], 2.94 [95% CI, 1.23-7.01]) was associated with incident CMBs in a deep location. Baseline underweight (vs normal weight; RR, 2.41 [95% CI, 1.21-4.80]), current smoking (RR, 1.47 [95% CI, 1.11-1.94]), an elevated serum level of high-density lipoprotein cholesterol (RR per 1-SD increase, 1.13 [95% CI, 1.02-1.25]), and a decreased triglyceride level (RR per 1-SD decrease in natural logarithm-transformed triglyceride level, 1.17 [95% CI, 1.03-1.33]) were significantly associated with an increased risk for lobar CMBs exclusively but not for deep CMBs.

Conclusions and Relevance  Lifestyle and lipid risk profiles for CMBs were similar to those for symptomatic intracerebral hemorrhage and differed for lobar and deep CMBs. Modification of these risk factors could have the potential to prevent new-onset CMBs, particularly those occurring in a lobar location

JAMA Neurology 2015

Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Disease

Importance  The dream enactment of rapid eye movement sleep behavior disorder (RBD) is often the first indication of an impending α-synuclein disorder, such as Parkinson disease, multiple-system atrophy, or dementia with Lewy bodies.

Objective  To provide an overview of RBD from the onset of dream enactment through the emergence of a parkinsonian disorder.

Evidence Review  Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized trials, and basic science investigations, were identified in a PubMed search of articles on RBD from January 1, 1986, through July 31, 2014.

Findings  Under normal conditions, vivid dream mentation combined with skeletal muscle paralysis characterizes rapid eye movement sleep. In RBD, α-synuclein abnormalities in the brainstem disinhibit rapid eye movement sleep motor activity, leading to dream enactment. The behaviors of RBD are often theatrical, with complexity, aggression, and violence; fighting and fleeing actions can be injurious to patients as well as bed partners. Rapid eye movement sleep behavior disorder is distinguished from other parasomnias by clinical features and the demonstration of rapid eye movement sleep without atonia on polysomnography. Consistent with early neurodegeneration, patients with RBD demonstrate subtle motor, cognitive, and autonomic impairments. Approximately 50% of patients with spontaneous RBD will convert to a parkinsonian disorder within a decade. Ultimately, nearly all (81%-90%) patients with RBD develop a neurodegenerative disorder. Among patients with Parkinson disease, RBD predicts a non–tremor-predominant subtype, gait freezing, and an aggressive clinical course. The most commonly cited RBD treatments include low-dose clonazepam or high-dose melatonin taken orally at bedtime.

Conclusions and Relevance  Treatment of RBD can prevent injury to patients and bed partners. Because RBD is a prodromal syndrome of Parkinson disease (or related disorder), it represents a unique opportunity for developing and testing disease-modifying therapies.

JAMA Neurology 2015