Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder

Objective: To investigate the expression of α-synuclein in colonic biopsies of patients with idiopathic REM sleep behavior disorder (iRBD) and address if α-synuclein immunostaining of tissue obtained via colonic biopsies holds promise as a diagnostic biomarker for prodromal Parkinson disease (PD).

Methods: Patients with iRBD, patients with PD, and healthy controls were prospectively recruited to undergo colonic biopsies for comparison of α-synuclein immunoreactivity patterns between the groups by using 2 different antibodies.

Results: There was no difference in colonic mucosal and submucosal immunostaining between groups using the 15G7 α-synuclein antibody, which was found in almost all participants enrolled in this study. By contrast, immunostaining for serine 129-phosphorylated α-synuclein (pSyn) in submucosal nerve fibers or ganglia was found in none of 14 controls but was observed in 4 of 17 participants with iRBD and 1 out of 19 patients with PD.

Conclusions: The present findings of pSyn immunostaining of colonic biopsies in a substantial proportion of iRBD participants raise the possibility that this tissue marker may be a suitable candidate to study further as a prodromal PD marker in at-risk cohorts.

Neurology 2015

Infection, vaccination, and childhood arterial ischemic stroke

Objectives: Minor infection can trigger adult arterial ischemic stroke (AIS) and is common in childhood. We tested the hypotheses that infection transiently increases risk of AIS in children, regardless of stroke subtype, while vaccination against infection is protective.

Methods: The Vascular Effects of Infection in Pediatric Stroke study is an international case-control study that prospectively enrolled 355 centrally confirmed cases of AIS (29 days–18 years old) and 354 stroke-free controls. To determine prior exposure to infections and vaccines, we conducted parental interviews and chart review.

Results: Median (interquartile range) age was 7.6 years for cases and 9.3 for controls (p = 0.44). Infection in the week prior to stroke, or interview date for controls, was reported in 18% of cases, vs 3% of controls, conferring a 6.3-fold increased risk of AIS (p < 0.0001); upper respiratory infections were most common. Prevalence of preceding infection was similar across stroke subtypes: arteriopathic, cardioembolic, and idiopathic. Use of vasoactive cold medications was similarly low in both groups. Children with some/few/no routine vaccinations were at higher stroke risk than those receiving all or most (odds ratio [OR] 7.3, p = 0.0002). In an age-adjusted multivariate logistic regression model, independent risk factors for AIS included infection in the prior week (OR 6.3, p < 0.0001), undervaccination (OR 8.2, p = 0.0004), black race (compared to white; OR 1.9, p = 0.009), and rural residence (compared to urban; OR 3.0, p = 0.0003).

Conclusions: Infection may act as a trigger for childhood AIS, while routine vaccinations appear protective. Hence, efforts to reduce the spread of common infections might help prevent stroke in children.

Neurology 2015

Autoimmune post–herpes simplex encephalitis of adults and teenagers

Objective: To report 14 patients with immune-mediated relapsing symptoms post–herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children.

Methods: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously.

Results: Among the teenage and adult group (8 patients, median age 40 years, range 13–69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6–20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17–296, vs 4 days, range 0–33, p = 0.037).

Conclusion: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.

Neurology 2015

Pisa syndrome in Parkinson disease An observational multicenter Italian study

Objective: To estimate the prevalence of Pisa syndrome (PS) in patients with Parkinson disease (PD) and to assess the association between PS and demographic and clinical variables.

Methods: In this multicenter cross-sectional study, consecutive outpatients with PD attending 21 movement disorders Italian tertiary centers were enrolled and underwent standardized clinical evaluation. PS was defined as trunk lateral deviation ≥10°. Patients with PD were compared according to the presence of PS for several demographic and clinical variables.

Results: Among 1,631 enrolled patients with PD, PS was detected in 143 patients (8.8%, 95% confidence interval 7.4%–10.3%). Patients with PS were older, had lower body mass index, longer disease duration, higher disease stages, and poorer quality of life. Falls were more frequent in the PS group as well as occurrence of “veering gait” (i.e., the progressive deviation toward one side when patient walked forward and backward with eyes closed). Patients with PS received higher daily levodopa equivalent daily dose and were more likely to be treated with combination of levodopa and dopamine agonists. Osteoporosis and arthrosis were significantly the most frequent associated medical conditions in patients with PS. Multiple explanatory variable logistic regression models confirmed the association of PS with the following variables: Hoehn and Yahr stage, ongoing combined treatment with levodopa and dopamine agonist, associated medical conditions, and presence of veering gait.

Conclusions: Our results suggest that PS is a relatively frequent and often disabling complication in PD, especially in the advanced disease stages. The association is dependent on a number of potentially relevant demographic and clinical variables.

Neurology 2015

Brain morphologic changes in asymptomatic C9orf72 repeat expansion carriers

Objective: To investigate possible effects of the C9orf72 repeat expansion before disease onset, we assessed brain morphology in asymptomatic carriers.

Methods: Aiming to diminish the effects of genetic variation between subjects, apart from the C9orf72 repeat expansion, 16 carriers of the repeat expansion were compared with 23 noncarriers from the same large family with a history of amyotrophic lateral sclerosis (ALS). Cortical thickness, subcortical volumes, and white matter connectivity, as assessed from high-resolution T1-weighted and diffusion-weighted MRIs, were evaluated. For comparison, we included 14 C9orf72 carriers with ALS and 28 healthy, unrelated controls.

Results: We found temporal, parietal, and occipital regions to be thinner (p < 0.05) and the left caudate and putamen to be smaller (p < 0.05) in asymptomatic carriers compared with noncarriers. Cortical thinning of the primary motor cortex and decreased connectivity of white matter pathways (global, corticospinal tract, and corpus callosum) were observed in patients with C9orf72-associated ALS, but not in asymptomatic carriers.

Conclusions: Asymptomatic C9orf72 carriers show cortical and subcortical differences compared with noncarriers from the same family, possibly effects of the C9orf72 repeat expansion on the brain. Of note, changes in the primary motor regions and motor-related tracts were found exclusively in patients with ALS, indicating that such motor changes may be a disease phenomenon.

Neurology 2015

Idiopathic phrenic neuropathies: A case series and review of the literature

Introduction: Phrenic neuropathies (PNs) are a major cause of dyspnea, orthopnea, and hypercapnic respiratory failure. The aim of the study was to obtain diagnostic findings, assess therapeutic options, and review outcomes in PN patients. Methods: From 2004 to 2013, patients with PN referred to the author's institution were studied using clinical, pulmonary function, and electrodiagnostic tests. A PubMed search of published PN reports was also done. Unilateral PN (UPN) and bilateral PN (BPN) patients were compared. Results: The analysis consisted of 10 UPN and 9 BPN patients seen by the author, plus previous reports of 18 UPN and 40 BPN patients. BPN patients were older (in the author's series) and were more often hypertensive. They reported pain less often, dyspnea and orthopnea more often, and had worse results on pulmonary function tests than UPN patients. Conclusions: UPN and BPN are probably 2 variants of the same, immune-mediated focal neuropathy. Electrodiagnosis is a valuable confirmatory test for PN

Muscle Nerve 2015

Spinal muscular atrophy functional composite score: A functional measure in spinal muscular atrophy

Introduction: With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA). Methods: Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale—Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores. Results: The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component. Conclusions: This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients.

Muscle Nerve 2015