Citations

ObjectiveTo define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.MethodsOne hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the United States. Seventy‐four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests.ResultsAt enrollment, patients were 68 ± 12 years old (median ± interquartile range) and had had autonomic failure for 5 ± 7 years. Within 4 years of follow‐up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt > 10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell.InterpretationPatients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287–297

Treatment of symptomatic intracranial atherosclerotic stenosis usually involves maximizing medical therapy. In patients with medically refractory symptoms despite maximum pharmacologic therapy, intracranial angioplasty and/or stenting has become an accepted treatment option. The use of percutaneous transluminal angioplasty (PTA) for idiopathic intracranial stenoses has not been reported to date. We describe a case of idiopathic intracranial stenosis which was refractory to medical therapy and was successfully treated with percutaneous transluminal angioplasty. The presenting symptoms included multiple episodes of aphasia and right-sided weakness as well as a left basal ganglia infarct. The patient underwent treatment with two intracranial angioplasty procedures. There was a recurrence of the stenosis and symptoms following the first procedure. However, after a second treatment with a slightly larger balloon, flow in the MCA normalized. Furthermore, the symptoms attributed to her MCA stenosis had essentially resolved. This case suggests that patients with medically refractory idiopathic intracranial stenosis can be successfully treated with percutaneous transluminal angioplasty.

AbstractObjectiveTo identify the molecular basis and elucidate the pathogenesis of a fatal congenital myasthenic syndrome.MethodsWe performed clinical electrophysiology studies, exome and Sanger sequencing, and analyzed functional consequences of the identified mutation.ResultsClinical electrophysiology studies of the patient revealed several‐fold potentiation of the evoked muscle action potential by high frequency nerve stimulation pointing to a presynaptic defect. Exome sequencing identified a homozygous c.340delA frameshift mutation in synaptobrevin 1 (SYB1), one of the three SNARE proteins essential for synaptic vesicle exocytosis. Analysis of both human spinal cord gray matter and normal human muscle revealed expression of the SYB1A and SYB1D isoforms, predicting expression of one or both isoforms in the motor nerve terminal. The identified mutation elongates the intravesicular C‐terminus of the A isoform from 5 to 71, and of the D isoform from 4 to 31 residues. Transfection of either mutant isoform into bovine chromaffin cells markedly reduces depolarization‐evoked exocytosis, and transfection of either mutant isoform into HEK cells significantly decreases expression of either mutant compared to wild type.InterpretationThe mutation is pathogenic because elongation of the intravesicular C‐terminus of the A and D isoforms increases the energy required to move their C‐terminus into the synaptic vesicle membrane, a key step for fusion of the synaptic vesicle with the presynaptic membrane, and because it is predicted to reduce expression of either isoform in the nerve terminal.

Interferon β-1b (Betaseron) has been shown in a randomized, double-blind, placebo-controlled study to reduce relapse rate, relapse severity and MRI progression in patients with relapsing-remitting MS. The recently published Betaseron extension trial and studies from the National Institutes of Health provide additional evidence suggesting an important treatment effect The major new findings from these studies are reviewed in this paper. Other findings from these recent studies merit attention, however. Specifically, neutralizing antibody formation was seen in 38% of patients receiving high-dose Betaseron at 3 years. With the development of these antibodies, there was no longer clinical evidence that the drug remained effective. This observation must be considered carefully when initiating Betaseron therapy. The Betaseron trial suggests that MRI is an imperfect predictor of clinical disease activity. Of particular interest was the finding that patients receiving low-dose Betaseron developed ‘confirmed treatment failure’ sooner than placebo-treated patients, despite a clear treatment benefit on MRI-detected evidence of subclinical disease activity.

Introduction: The increasing use of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology to examine pancreatic neoplasms has led to an increase in the diagnosis of metastases to the pancreas. Renal cell carcinoma (RCC) is the most common metastasis to the pancreas. Our study examines 33 cases of metastatic RCC to the pancreas sampled by EUS-FNA from four large tertiary care hospitals. Materials and Methods: We searched the cytopathology database for RCC metastatic to the pancreas diagnosed by EUS-FNA from January 2005 to January 2015. Patient age, history of RCC, nephrectomy history, follow-up postnephrectomy, radiological impression, and EUS-FNA cytologic diagnosis were reviewed. Results: Thirty-three patients were identified. The average age was 67.5 years (range, 49–84 years). Thirty-two patients had a previous documented history of RCC. One patient had the diagnosis of pancreatic metastasis at the same time of the kidney biopsy. Thirty-one patients had been treated with nephrectomy. Twenty-seven patients were being monitored annually by computed tomography or magnetic resonance imaging. Twenty-five patients had multiple masses by imaging, but 8 patients had a single mass in the pancreas at the time of EUS-FNA. EUS-FNA of 20 cases showed classic morphology of RCC. Thirteen cases had either “atypical” clinical-radiologic features or morphologic overlaps with primary pancreatic neoplasms or other neoplasms. Cell blocks were made on all 13 cases and immunochemical stains confirmed the diagnosis. Conclusions: EUS-FNA cytology is useful for the diagnosis of metastatic RCC to the pancreas. Cytomorphology can be aided with patient history, imaging analyses, cell blocks, and immunochemical stains.

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real‐world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene–drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

Despite major changes in US Graduate Medical Education, from Core Competencies (2002) to the Next Accreditation System (2012), few studies have evaluated the role of the Residency Coordinator in program accreditation. This role may be especially challenging in child neurology, which involves separate, accredited child and adult neurology residencies. The present study of Child Neurology Program Coordinators evaluated workforce factors and first-year implementation of new training requirements. The response rate was 65% (48/74). Concerning workforce features included high turnover, unpaid overtime, inconsistent job titles, limited career paths, inadequate training, and nonacademic supervision. Programs’ average implementation of 14 new accreditation items averaged 7.5 (standard deviation 2.5). This survey demonstrated that greater Next Accreditation System implementation is linked to increased coordinator experience, supervision within Graduate Medical Education, and greater administrative support for the coordinator role. Changes in these areas could improve future compliance of US child neurology programs with Graduate Medical Education accreditation requirements.