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Clinical Reasoning: A 15-month-old boy with progressive lethargy and spasticity

2017-09-18T12:49:32-07:00

A previously healthy and developmentally normal 15-month-old boy presented to the emergency department with 5 days of worsening altered mental status in the setting of an upper respiratory infection. He initially developed cough, rhinorrhea, and irritability without fever, vomiting, or diarrhea. His mental status at home had slowly declined, with increased sleepiness and progressively decreased activity. At the time of presentation, he had stopped playing, walking, sitting, or drinking. On his initial examination, he was breathing comfortably on room air and was afebrile with normal vital signs. He did not respond to stimuli and had developed intermittent rhythmic shaking of his arms, concerning for seizures. He had no visual tracking and minimal pupil reactivity. He had diffuse hypertonia with bilateral flexion of the upper extremities and extension of the lower extremities without spontaneous movement, minimal withdrawal to noxious stimuli, diffuse hyperreflexia, and several beats of left Achilles tendon clonus.




Clinical Reasoning: A 50-year-old woman with SLE and a tumefactive lesion

2017-09-18T12:49:32-07:00

A 50-year-old woman with a history of systemic lupus erythematosus (SLE) treated with methotrexate and hydroxychloroquine presented to the emergency department for evaluation of numbness and weakness of the left hand that began 12 hours earlier.




Opinion and Special Articles: Creation of a diversity and inclusion certificate program for neurology residents

2017-09-18T12:49:32-07:00

Neurologists must provide excellent care to an increasingly diverse patient population. According to census projections, the United States will become a majority–minority nation by 2060, with no single ethnic or racial group making up a majority of the population.1 Diversity of gender, sex, sexual orientation, race, ethnicity, socioeconomic status, age, ability, and religion must be acknowledged and understood in order to provide equitable patient care.




Teaching NeuroImages: RCVS causing simultaneous convexity subarachnoid hemorrhage and hemimedullary infarction

2017-09-18T12:49:32-07:00

A 34-year-old previously healthy man presented with thunderclap headache, dysphagia, dysarthria, and oscillopsia. Neurologic examination revealed right-beating nystagmus, dysphagia, hypophonia, right hemianesthesia, and left hemiparesis. Brain imaging showed convexity subarachnoid hemorrhage (figure 1A) and left hemimedullary infarct (figure 1B). Catheter angiography showed tapering of left vertebral artery and diffuse segmental vasoconstriction (figure 2). Routine serum and CSF results were unremarkable. Thorough infectious, immunologic, and coagulopathy workup was negative. Reversible cerebral vasoconstriction syndrome (RCVS) is associated with severe headache, stroke, brain edema, and hemorrhage characterized by transient, multifocal intracranial vessel vasoconstriction.1 RCVS can cause simultaneous ischemic and hemorrhagic stroke.2




Spotlight on the September 19 issue

2017-09-18T12:49:32-07:00




The "plus" side of epilepsy phenotyping

2017-09-18T12:49:32-07:00

The first clinical description of generalized epilepsy with febrile seizures plus (GEFS+) by Scheffer and Berkovic1 in their landmark Brain article of 1997 represented a major step forward in the understanding of the genetic basis of the epilepsies. Coming 2 years after their identification, with collaborators, of the genetic basis for a relatively homogenous syndrome, autosomal dominant nocturnal frontal lobe epilepsy, the detailed phenotypic description of a single large Australian family with heterogeneous febrile seizure plus epilepsy phenotypes and a clear dominant pattern of inheritance put a novel perspective on genotype–phenotype relationships in the epilepsies.2 Shortly after, the SCN1A and SCN1B genes were linked to the syndrome, and subsequently the last 2 decades has confirmed that the majority of epilepsy genes show phenotypic heterogeneity and the majority of syndromes reveal genetic heterogeneity.3 Why one individual in a GEFS+ family has a severe developmental and epileptic encephalopathy such as Dravet syndrome and another has simple self-limited febrile seizures is unknown, but is likely to be determined by other genetic factors influencing the SCN1A, or other major genes identified in a family.




Vertebral artery stenosis: The hurdles of stenting are too high

2017-09-18T12:49:32-07:00

Up to a quarter of patients with vertebrobasilar ischemic stroke or TIA have a symptomatic stenosis of the vertebrobasilar arteries.1,2 Patients with vertebral artery (VA) stenosis >50% have a high risk of recurrent stroke, comparable to patients with symptomatic carotid artery stenosis, with the highest risk during the first weeks after the initial TIA or ischemic stroke.3 Endovascular treatment of symptomatic VA stenosis has appeal as a treatment option that is widely performed, despite the scarcity of evidence for its safety or benefit.




Medication overuse headache: An ongoing debate

2017-09-18T12:49:32-07:00

Medication overuse headache (MOH) has incited passionate debate among headache clinicians and researchers in recent years. The existence of MOH as a diagnostic category1 and as a potentially modifiable risk factor for headache chronification is well-recognized by most headache specialists.2 However, the greatest controversies seem to exist over whether medication overuse should be regarded as cause or consequence; and over the treatment strategies, including advice about withdrawal of frequently used symptomatic (acute pain relieving) medication and whether prophylactic treatment should be initiated during withdrawal or after detoxification.3,4 This ongoing debate is undoubtedly a symptom of a lack of high-quality evidence, as Scher et al.5 state in this issue of Neurology®. Other contributing factors include the difficulty of disentangling retrospectively the underlying primary headache type predating medication overuse and cultural differences regarding types of overused symptomatic medication. Most notably, the advice to patients to stop symptomatic medication that may provide transient benefits seems to counter the mission of headache practitioners to minimize pain.




Jean Holowach Thurston, MD (1917-2017)

2017-09-18T12:49:32-07:00

Jean Holowach Thurston, MD, Emeritus Professor of Neurology and Pediatrics at Washington University in St. Louis, died on April 29, 2017, two months short of her 100th birthday. Her career encompassed a spectrum of disciplines that is unfathomable in our current era of subspecialization.




Genetic epilepsy with febrile seizures plus: Refining the spectrum

2017-09-18T12:49:32-07:00

Objective:

Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum.

Methods:

We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years.

Results:

We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene.

Conclusion:

As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.




Incidence and management of seizures after ischemic stroke: Systematic review and meta-analysis

2017-09-18T12:49:32-07:00

Objective:

We conducted a meta-analysis of the incidence of early and late seizures following ischemic stroke as well as a systematic review of their pharmacologic treatment.

Methods:

Observational studies that reported incidence of seizures following ischemic stroke and those that reported treatment response to any particular antiepileptic drugs (AEDs) were included. Risk of bias was assessed by predefined study characteristics. Random effects meta-analysis was conducted for all studies where data were available for the incidence of early and late stroke-related seizures. Heterogeneity was measured with I2 statistic and sensitivity analyses were performed using prespecified variables. A qualitative synthesis of studies reporting use of AEDs for stroke-related seizures was performed.

Results:

Forty-one studies from 10,554 articles were identified; 35 studies reported incidence of stroke-related seizures and 6 studies reported effects of specific AEDs. Most studies were of low to moderate quality. Rate of early seizures was 3.3% (95% confidence interval 2.8%–3.9%, I2 = 92.8%), while the incidence of late seizures or epilepsy was 18 per 1,000 person-years (95% confidence interval 1.5–2.2, I2 = 94.1%). The high degree of heterogeneity could not be explained from the sensitivity analyses. For management of stroke-related seizures, no single AED was found to be more effective over others, though newer AEDs were associated with fewer side effects.

Conclusions:

The burden of stroke-related seizures and epilepsy due to ischemic stroke is substantial. Further studies are required to determine risk factors for epilepsy following ischemic stroke and optimal secondary prevention.




Stenting for symptomatic vertebral artery stenosis: The Vertebral Artery Ischaemia Stenting Trial

2017-09-18T12:49:32-07:00

Objective:

To compare in the Vertebral Artery Ischaemia Stenting Trial (VIST) the risks and benefits of vertebral angioplasty and stenting with best medical treatment (BMT) alone for symptomatic vertebral artery stenosis.

Methods:

VIST was a prospective, randomized, open-blinded endpoint clinical trial performed in 14 hospitals in the United Kingdom. Participants with symptomatic vertebral stenosis ≥50% were randomly assigned (1:1) to vertebral angioplasty/stenting plus BMT or to BMT alone with randomization stratified by site of stenosis (extracranial vs intracranial). Because of slow recruitment and cessation of funding, recruitment was stopped after 182 participants. Follow-up was a minimum of ≥1 year for each participant.

Results:

Three patients did not contribute any follow-up data and were excluded, leaving 91 patients in the stent group and 88 in the medical group. Mean follow-up was 3.5 (interquartile range 2.1–4.7) years. Of 61 patients who were stented, stenosis was extracranial in 48 (78.7%) and intracranial in 13 (21.3%). No periprocedural complications occurred with extracranial stenting; 2 strokes occurred during intracranial stenting. The primary endpoint of fatal or nonfatal stroke occurred in 5 patients in the stent group vs 12 in the medical group (hazard ratio 0.40, 95% confidence interval 0.14–1.13, p = 0.08), with an absolute risk reduction of 25 strokes per 1,000 person-years. The hazard ratio for stroke or TIA was 0.50 (p = 0.05).

Conclusions:

Stenting in extracranial stenosis appears safe with low complication rates. Large phase 3 trials are required to determine whether stenting reduces stroke risk.

ISRCTN.com identifier:

ISRCTN95212240.

Classification of evidence:

This study provides Class I evidence that for patients with symptomatic vertebral stenosis, angioplasty with stenting does not reduce the risk of stroke. However, the study lacked the precision to exclude a benefit from stenting.




Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open-label study

2017-09-18T12:49:32-07:00

Objective:

To assess long-term safety and efficacy of anti–calcitonin gene-related peptide receptor erenumab in patients with episodic migraine (EM).

Methods:

Patients enrolled in a 12-week, double-blind, placebo-controlled clinical trial (NCT01952574) who continued in an open-label extension (OLE) study will receive erenumab 70 mg every 4 weeks for up to 5 years. This preplanned interim analysis, conducted after all participants had completed the 1-year open-label follow-up, evaluated changes in monthly migraine days (MMD), achievement of ≥50%, ≥75%, and 100% reductions, Headache Impact Test (HIT-6) score, Migraine-Specific Quality of Life (MSQ), Migraine Disability Assessment (MIDAS), and safety. Data reported as observed without imputation for missing data.

Results:

Of 472 patients enrolled in the parent study, 383 continued in the OLE with a median exposure to erenumab of 575 days (range 28–822 days). Mean (SD) MMD were 8.8 (2.6) at parent study baseline, 6.3 (4.2) at week 12 (beginning of OLE), and 3.7 (4.0) at week 64 (mean change from baseline [reduction] of 5.0 days). At week 64, 65%, 42%, and 26% achieved ≥50%, ≥75%, and 100% reduction in MMD, respectively. Mean HIT-6 scores were 60.2 (6.3) at baseline and 51.7 (9.2) at week 64. MSQ and MIDAS improvements from baseline were maintained through week 64. Safety profiles during the OLE were similar to those in the double-blind phase, which overall were similar to placebo.

Conclusions:

One-year efficacy, supported by functional improvements and favorable safety and tolerability profiles, supports further investigation of erenumab as a preventive treatment in patients with EM.

Clinicaltrials.gov identifier:

NCT01952574.

Classification of evidence:

This study provides Class IV evidence that for patients with episodic migraine, erenumab reduces long-term MMD and improves headache-related disability and migraine-specific quality of life.




Sleep architecture and the risk of incident dementia in the community

2017-09-18T12:49:32-07:00

Objective:

Sleep disturbance is common in dementia, although it is unclear whether differences in sleep architecture precede dementia onset. We examined the associations between sleep architecture and the prospective risk of incident dementia in the community-based Framingham Heart Study (FHS).

Methods:

Our sample comprised a subset of 321 FHS Offspring participants who participated in the Sleep Heart Health Study between 1995 and 1998 and who were aged over 60 years at the time of sleep assessment (mean age 67 ± 5 years, 50% male). Stages of sleep were quantified using home-based polysomnography. Participants were followed for a maximum of 19 years for incident dementia (mean follow-up 12 ± 5 years).

Results:

We observed 32 cases of incident dementia; 24 were consistent with Alzheimer disease dementia. After adjustments for age and sex, lower REM sleep percentage and longer REM sleep latency were both associated with a higher risk of incident dementia. Each percentage reduction in REM sleep was associated with approximately a 9% increase in the risk of incident dementia (hazard ratio 0.91; 95% confidence interval 0.86, 0.97). The magnitude of association between REM sleep percentage and dementia was similar following adjustments for multiple covariates including vascular risk factors, depressive symptoms, and medication use, following exclusions for persons with mild cognitive impairment at baseline and following exclusions for early converters to dementia. Stages of non-REM sleep were not associated with dementia risk.

Conclusions:

Despite contemporary interest in slow-wave sleep and dementia pathology, our findings implicate REM sleep mechanisms as predictors of clinical dementia.




Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults

2017-09-18T12:49:32-07:00

Objective:

To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure.

Methods:

Participants were 45–64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aβ42, total tau, and p-tau181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE 4 status.

Results:

Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aβ42, total tau, and p-tau181, respectively. There was no significant modifying effect of sex, APOE 4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau181 (p = 0.003), where greater decreases from baseline in CSF p-tau181 concentrations were associated with higher baseline LDL level for the simvastatin group.

Conclusions:

Simvastatin-related reductions in CSF p-tau181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia.




Cognition and gray and white matter characteristics of presymptomatic C9orf72 repeat expansion

2017-09-18T12:49:32-07:00

Objective:

To investigate cognitive function, gray matter volume, and white matter integrity in the presymptomatic stage of chromosome 9 open reading frame 72 repeat expansion (C9orf72RE).

Methods:

Presymptomatic C9orf72RE carriers (n = 18) and first-degree family members without a pathogenic expansion (healthy controls [HC], n = 15) underwent a standardized protocol of neuropsychological tests, T1-weighted MRI, and diffusion tensor imaging within our cohort study of autosomal dominant frontotemporal dementia (FTD). We investigated group differences in cognitive function, gray matter volume through voxel-based morphometry, and white matter integrity by means of tract-based spatial statistics. We correlated cognitive change with underlying gray or white matter.

Results:

Our data demonstrate lower scores on letter fluency, Stroop card I, and Stroop card III, accompanied by white matter integrity loss in tracts connecting the frontal lobe, the thalamic radiation, and tracts associated with motor functioning in presymptomatic C9orf72RE compared with HC. In a subgroup of C9orf72RE carriers above 40 years of age, we found gray matter volume loss in the thalamus, cerebellum, and parietal and temporal cortex. We found no significant relationship between subtle cognitive decline and underlying gray or white matter.

Conclusions:

This study demonstrates that a decline in cognitive functioning, white matter integrity, and gray matter volumes are present in presymptomatic C9orf72RE carriers. These findings suggest that neuropsychological assessment, T1-weighted MRI, and diffusion tensor imaging might be useful to identify early biomarkers in the presymptomatic stage of FTD or amyotrophic lateral sclerosis.




MRI substrates of sustained attention system and cognitive impairment in pediatric MS patients

2017-09-18T12:49:32-07:00

Objective:

To explore the structural and functional integrity of the sustained attention system in patients with pediatric multiple sclerosis (MS) and its effect on cognitive impairment.

Methods:

We enrolled 57 patients with pediatric MS and 14 age- and sex-matched healthy controls (HCs). Patients with >3 abnormal tests at neuropsychological evaluation were classified as cognitively impaired (CI). Sustained attention system activity was studied with fMRI during the Conners Continuous Performance Test (CCPT). Structural integrity of attention network connections was quantified with diffusion tensor (DT) MRI.

Results:

Within-group analysis showed similar patterns of recruitment of the attention network in HCs and patients with pediatric MS. Diffuse network DT MRI structural abnormalities were found in patients with MS. During CCPT, with increasing task demand, patients with pediatric MS showed increased activation of the left thalamus, anterior insula, and anterior cingulate cortex (ACC) and decreased recruitment of the right precuneus compared to HCs. Thirteen patients (23%) were classified as CI. Compared to cognitively preserved patients, CI patients with pediatric MS had decreased recruitment of several areas located mainly in parietal and occipital lobes and cerebellum and increased deactivation of the ACC, combined with more severe structural damage of white matter tracts connecting these regions.

Conclusions:

Our results suggest that the age-expected level of sustained attention system functional competence is achieved in patients with pediatric MS. Inefficient regulation of the functional interaction between different areas of this system, due to abnormal white matter integrity, may result in global cognitive impairment in these patients.




Human dorsal root ganglion in vivo morphometry and perfusion in Fabry painful neuropathy

2017-09-18T12:49:32-07:00

Objective:

To evaluate functional and morphometric magnetic resonance neurography of the dorsal root ganglion and peripheral nerve segments in patients with Fabry painful neuropathy.

Methods:

In this prospective study, the lumbosacral dorsal root ganglia and proximal peripheral nerve segments of the lower extremity were examined in 11 male patients with Fabry disease by a standardized 3T magnetic resonance neurography protocol. Volumes of L3 to S2 dorsal root ganglia, perfusion parameters of L5-S1 dorsal root ganglia and the spinal nerve L5, and the cross-sectional area of the proximal sciatic nerve were compared to healthy controls.

Results:

Dorsal root ganglia of patients with Fabry disease were symmetrically enlarged by 78% (L3), 94% (L4), 122% (L5), 115% (S1), and 119% (S2) (p < 0.001). In addition, permeability of the blood-tissue interface was decreased by 53% (p < 0.001). This finding was most pronounced in the peripheral zone of the dorsal root ganglion containing the cell bodies of the primary sensory neurons (p < 0.001). Spinal nerve permeability showed no difference between patients with Fabry disease and controls (p = 0.7). The sciatic nerve of patients with Fabry disease at the thigh level showed an increase in cross-sectional area by 48% (p < 0.001).

Conclusions:

Patients with Fabry disease have severely enlarged dorsal root ganglia with dysfunctional perfusion. This may be due to glycolipid accumulation in the dorsal root ganglia mediating direct neurotoxic effects and decreased neuronal blood supply. These alterations were less pronounced in peripheral nerve segments. Thus, the dorsal root ganglion might play a key pathophysiologic role in the development of neuropathy and pain in Fabry disease.




A case-control study of hormonal exposures as etiologic factors for ALS in women: Euro-MOTOR

2017-09-18T12:49:32-07:00

Objective:

To investigate the role of hormonal risk factors for amyotrophic lateral sclerosis (ALS) among women from 3 European countries.

Methods:

ALS cases and matched controls were recruited over 4 years in Ireland, Italy, and the Netherlands. Hormonal exposures, including reproductive history, breastfeeding, contraceptive use, hormonal replacement therapy, and gynecologic surgical history, were recorded with a validated questionnaire. Logistic regression models adjusted for age, education, study site, smoking, alcohol, and physical activity were used to determine the association between female hormones and ALS risk.

Results:

We included 653 patients and 1,217 controls. Oral contraceptive use was higher among controls (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.51–0.84), and a dose-response effect was apparent. Hormone replacement therapy (HRT) was associated with a reduced risk of ALS only in the Netherlands (OR = 0.57, 95% CI 0.37–0.85). These findings were robust to sensitivity analysis, but there was some heterogeneity across study sites.

Conclusions:

This large case-control study across 3 different countries has demonstrated an association between exogenous estrogens and progestogens and reduced odds of ALS in women. These results are at variance with previous findings, which may be partly explained by differential regulatory, social, and cultural attitudes toward pregnancy, birth control, and HRT across the countries included. Our results indicate that hormonal factors may be important etiologic factors in ALS; however, a full understanding requires further investigation.




Quality improvement in neurology: Essential Tremor Quality Measurement Set

2017-09-18T12:49:32-07:00

Essential tremor (ET) is one of the most common movement disorders in the world, with prevalence rates in the general population ranging from 0.4% to 4.6%.1,2 The incidence of ET increases with age,1 with the average age at onset in mid-to-late 40s.3 ET is estimated to affect as many as 7 to 10 million Americans.3,4 Clinically, ET is characterized by bilateral, symmetric, postural tremor in hands and forearms, with or without kinetic tremor, in the absence of abnormal posturing or task specificity.5 ET can also affect lower extremities, head, and voice.6,7 Symptoms may be barely noticeable, or severe and disabling.




Medication overuse headache: An entrenched idea in need of scrutiny

2017-09-18T12:49:32-07:00

It is a widely accepted idea that medications taken to relieve acute headache pain can paradoxically worsen headache if used too often. This type of secondary headache is referred to as medication overuse headache (MOH); previously used terms include rebound headache and drug-induced headache. In the absence of consensus about the duration of use, amount, and type of medication needed to cause MOH, the default position is conservative. A common recommendation is to limit treatment to no more than 10 or 15 days per month (depending on medication type) to prevent headache frequency progression. Medication withdrawal is often recommended as a first step in treatment of patients with very frequent headaches. Existing evidence, however, does not provide a strong basis for such causal claims about the relationship between medication use and frequent headache. Observational studies linking treatment patterns with headache frequency are by their nature confounded by indication. Medication withdrawal studies have mostly been uncontrolled and often have high dropout rates. Evaluation of this evidence suggests that only a minority of patients required to limit the use of symptomatic medication may benefit from treatment limitation. Similarly, only a minority of patients deemed to be overusing medications may benefit from withdrawal. These findings raise serious questions about the value of withholding or withdrawing symptom-relieving medications from people with frequent headaches solely to prevent or treat MOH. The benefits of doing so are smaller, and the harms larger, than currently recognized. The concept of MOH should be viewed with more skepticism. Until the evidence is better, we should avoid dogmatism about the use of symptomatic medication. Frequent use of symptom-relieving headache medications should be viewed more neutrally, as an indicator of poorly controlled headaches, and not invariably a cause.




Tetrabenazine and subthalamic stimulation in graft-induced dyskinesias

2017-09-18T12:49:32-07:00

Putaminal fetal ventral mesencephalic stem cell transplantation has been advocated as a sustainable treatment for Parkinson disease (PD). Double-blind randomized clinical trials have inconclusively proven their benefit in the motor symptoms of PD despite evidence of graft viability, as shown by [18F]-fluorodopa PET.1 At variable intervals after grafting, 15%–57% of patients develop graft-induced dyskinesias (GID), which are characterized by violent, choreo-ballistic dyskinesias occurring regardless of the patient's medication state.2 GID are particularly difficult to manage: they do not respond to withdrawal of antiparkinsonian medication and deep brain stimulation (DBS) of the pars interna of the globus pallidus produces variable results.3 The etiopathogenesis of GIDs is debated and implicates both excessive dopaminergic neural transmission and nondopaminergic mechanisms. As for the latter, animal models and imaging studies on grafted patients have hypothesized that grafted tissues comprise a heterogeneous population of neurons, including serotoninergic ones, which in turn may contribute to GID.4 This notion led to the 5HT1A agonist buspirone to be trialed, successfully, to acutely reduce GID.2,4 Chronic treatment with buspirone has not improved all patients experiencing GID.5




Optical coherence tomography angiography in pituitary tumor

2017-09-18T12:49:32-07:00

A 32-year-old man with a pituitary tumor had bitemporal hemianopia (figure 1). Peripapillary retinal nerve fiber layer (RNFL) in optical coherence tomography (OCT) was reduced, which corresponded to visual field defects. OCT angiography showed a dropout of capillaries and correlated well with RNFL loss in the OCT (figure 2). Compressive optic neuropathy may be associated with loss of the retinal ganglion cell layer and impaired peripapillary retinal perfusion. OCT angiography may be helpful to detect various optic neuropathies and in analyzing the vascular status of the optic nerve head and RNFL.1




Editors' Note

2017-09-18T12:49:32-07:00

Editors' Note: In "Long-term cerebral white and gray matter changes after preeclampsia," the authors found that preeclampsia was associated with chronic temporal lobe white matter changes and reduced cortical volume in young women; the changes were consistent with persistent inflammation.




Letter re: Long-term cerebral white and gray matter changes after preeclampsia

2017-09-18T12:49:32-07:00

The article by Siepmann et al.1 identified long-term cerebral white matter changes and reduced cortical volume, presumably of vascular origin, in young women after pregnancy complicated by preeclampsia. The authors invoked persistent inflammation as the putative agent. Sleep apnea may be a link among pregnancy, preeclampsia, and cerebrovascular disease.




Author response: Long-term cerebral white and gray matter changes after preeclampsia

2017-09-18T12:49:32-07:00

We thank Dr. Culebras for the comment on our article.1 Sleep apnea might be among the pathophysiologic pathways linking preeclampsia with increased risk of cerebrovascular disease in previously preeclamptic women. In fact, research recently focused on the role of sleep apnea in the etiopathogenesis of cerebrovascular and cardiovascular disease and demonstrated an increased stroke risk in patients with obstructive sleep apnea (OSA).2,3 Intermittent hypoxia with consecutive vascular dysregulation has been identified as a possible mechanism whereby OSA increases risk of stroke. This might be relevant to previously preeclamptic mothers in whom autonomic neurovascular dysfunction, inter alia mediated by functional changes to the sympathetic nervous system, was also demonstrated.4 It remains to be answered whether this similarity among pathologies indeed points to a causative link between preeclampsia and cerebrovascular disease.




Letter re: The autism "epidemic": Ethical, legal, and social issues in a developmental spectrum disorder

2017-09-18T12:49:32-07:00

Graf et al.1 wrote an interesting review on autism spectrum disorder (ASD), emphasizing the term "autism epidemic," supported by an editorial.2 Among other factors, increasing ASD diagnoses can be attributed to broader diagnostic criteria and the recognition of ASD existence differentiated from other neurodevelopmental diseases.2–4 One important issue, defended by the authors, is early screening and diagnosis with emphasis on the evolving practice of genetic testing for ASD.1




Author response: The autism "epidemic": Ethical, legal, and social issues in a developmental spectrum disorder

2017-09-18T12:49:32-07:00

We thank Machado et al. for the comments on our review,1 and for the observations of abnormal anatomic and functional connectivity using diffusion-weighted MRI (DW-MRI). Innumerable studies have compared patients with autism spectrum disorders (ASD) and nonaffected controls at rest or while performing particular tasks, most often in small selected subject samples. For example, studies linked autism with the retino-collicular magnocellular visual pathways that project via the pulvinar to the amygdala, occipital V1, and multiple other areas, including the dorsal occipito-parietal/midtemporal streams, which participate with the frontal eye fields in processing spatial attention, moving targets, and dynamic facial expression (with inputs from the amygdala and other limbic pathways).2 However, no results consistently demonstrated specific neural networks that are uniquely pathognomonic of autism in the brain despite the fact that broad networks were linked with deficient social cognition in autism.3 Complex behaviors, like ASD, do not have a single endophenotype linked to one discrete neocortical location.4 The critical need for more research in autism should be balanced by caution about generalizing interpretations of neuroimaging findings that suggest the dysregulation of specific neural pathways. At present, DW-MRI and similar techniques, such as diffusion compartment imaging, are considered beneficial for research but not for routine clinical diagnostics.




Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy

2017-09-18T12:49:32-07:00

The authors retract the article "Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy" by X. Ayrignac et al., which appeared in the Resident & Fellow Section in volume 86, page e262, because 4 of the figures were previously published in another journal (European Neurology 2012;67:151–153).2 The earlier article was not cited and there were 3 common authors (Magnin, Berger, and Labauge) on the papers. In addition to the duplicate publication, 1 image attributed to the index case in this article was attributed to his mother in the earlier article and 3 images attributed to his mother in this article were attributed to the index case in the earlier article.




Does compensatory hyperparathyroidism predispose to ischemic stroke? Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy; An alternative to vitamin D supplementation to prevent fractures in patients with MS; High prevalence of vitamin D deficiency and reduced bone mass in Parkinson's disease

2017-09-18T12:49:32-07:00

Because of known issues leading to several retractions of papers by Y. Sato et al., the editors of Neurology® have, as a matter of due diligence, researched other papers that this group published in Neurology. To ensure that the scientific literature is correct, the Editor chooses to publish an Expression of Concern regarding 3 observational studies and a Letter to the Editor published in Neurology prior to the retracted clinical trials.1–4




Emerging Subspecialties in Neurology: Autoimmune neurology

2017-09-11T12:49:32-07:00

Autoimmune neurology is one of the most rapidly evolving fields in modern neurology. Autoantibodies that recognize nervous system self-antigens, including ion channels, receptors for neurotransmitters, and neuronal intrinsic and extrinsic proteins involved in synaptic transmission, are all recognized as targets of pathogenic autoantibodies. The accelerating rate of new antigen discovery in recent decades is impressive (figure). The diversity of neurologic presentations, the unique pathophysiology, and the complexity of treating these disorders justifies dedicated fellowship training to acquire the expertise needed to diagnose and optimally manage these patients. The requisite training is distinct from the classical exposure provided by traditional neuroimmunology fellowships that focus on multiple sclerosis. As a new subspecialty, autoimmune neurology intersects all neurologic subspecialties and other medical specialties, including but not limited to clinical immunology, infectious disease, rheumatology, gastroenterology, oncology, and psychiatry. While this article focuses on autoimmune neurology fellowships currently available in the United States, historically many current leaders in the field trained nationally and internationally under Dr. Jerome Posner, Dr. John Newsom-Davis, and Dr. John Trotter, to name a few of the pioneers.




Teaching NeuroImages: Early-onset dementia and demyelinating neuropathy disclosing cerebrotendinous xanthomatosis

2017-09-11T12:49:32-07:00

A 40-year-old woman presented with a 5-year history of numbness in hands and feet, apathy, compulsive behavior, and aggression towards others. Medical history disclosed juvenile-onset cataracts. Examination disclosed tendinous xanthoma. Electroneuromyography disclosed sensorimotor demyelinating polyneuropathy. Neuroimaging studies showed global cortical atrophy. Tc-99m brain SPECT scan showed marked hypoperfusion involving the frontal and temporal lobes (figure). Plasma cholestanol levels and bile alcohol glycoconjugates were elevated, enabling a diagnosis of cerebrotendinous xanthomatosis (CTX).




Spotlight on the September 12 issue

2017-09-11T12:49:31-07:00




Can immune reprogramming with alemtuzumab induce permanent remission in multiple sclerosis?

2017-09-11T12:49:31-07:00

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) have developed tremendously over the last 2 decades. Currently, more than 16 different products targeting various immunologic components have been approved for MS treatment in several countries.




Immune checkpoint inhibitor therapy: A double-edged sword?

2017-09-11T12:49:31-07:00

Cancer and autoimmunity can be viewed as differing consequences of deranged immune responses. The overexpression of certain molecules could result in development of cancer (failure of the immune system to control tumor cell growth), whereas oversuppression of the same molecules could lead to autoimmunity (failure of the immune system to regulate autoreactive responses). Hence, finely balanced immune surveillance against cancer and autoimmunity is critical.




The virtual house call: A 21st-century innovation in the care of patients with Parkinson disease

2017-09-11T12:49:31-07:00

As the debate on health care reform rages in the United States, one thing is exceedingly clear: chronic disease accounts for a growing majority of American health care costs.1 Many chronic diseases, particularly Parkinson disease (PD), can benefit from specialty care. Patients with PD show more improvements in motor symptoms and less frequently receive inappropriate medications when treated by a specialist.2,3 However, reduced mobility due to PD, combined with the physical distance to the specialist's office, poses substantial travel burdens and may limit access to care. Telemedicine, utilizing video and audio conferencing technology to connect patients and clinicians, can mitigate this problem. However, Centers for Medicare Services (CMS) currently only covers telemedicine encounters under specific criteria: the patient lives in a rural area seen in a covered entity by a consulting physician licensed in the state in which the patient resides.4 Even if the rural designation were removed, requiring travel to a center that offers telemedicine consultation may preclude many patients from using this approach. Modern Internet-based technologies, utilizing Health Information Portability and Accountability Act–compliant software, allow physicians to perform virtual house calls, thus minimizing travel. This has the potential to increase access to care for patients with a debilitating disease dramatically. While remote examiners cannot perform rigidity and balance testing, they can perform a modified motor examination of similar clinical utility without these components.5




As the world turns, why do some people adapt to vestibular failure and others do not?

2017-09-11T12:49:31-07:00

Chronic vertigo and oscillopsia are 2 of the most vexing problems that neurologists encounter. Even when the etiology is known, there is often a limit to the therapy that can be offered to the patient beyond vestibular rehabilitation. Oscillopsia diminishes over time in many individuals, but the mechanism for this adaptive change is unclear. In this issue of Neurology®, Ahmad et al.1 examine the central mechanisms that may be responsible for adaptation after bilateral vestibular failure. Most of the cases in this cohort had vestibular failure from either idiopathic or autoimmune causes. Ahmad et al. found that the patients with bilateral vestibular failure had reduced visual cortical excitability compared to controls under both static and motion conditions.




Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy

2017-09-11T12:49:31-07:00

Objective:

To evaluate 5-year efficacy and safety of alemtuzumab in treatment-naive patients with active relapsing-remitting MS (RRMS) (CARE-MS I; NCT00530348).

Methods:

Alemtuzumab-treated patients received treatment courses at baseline and 12 months later; after the core study, they could enter an extension (NCT00930553) with as-needed alemtuzumab retreatment for relapse or MRI activity. Assessments included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs).

Results:

Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15). Over years 0–5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5. Median yearly BVL improved over years 2–4, remaining low in year 5 (years 1–5: –0.59%, –0.25%, –0.19%, –0.15%, and –0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at year 3 and subsequently declined.

Conclusions:

Based on these data, alemtuzumab provides durable efficacy through 5 years in the absence of continuous treatment, with most patients not receiving additional courses.

ClinicalTrials.gov identifier:

NCT00530348; NCT00930553.

Classification of evidence:

This study provides Class III evidence that alemtuzumab durably improves efficacy outcomes and slows BVL in patients with RRMS.




Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings

2017-09-11T12:49:31-07:00

Objective:

To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy.

Methods:

In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed.

Results:

Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3–5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1–5: –0.48%, –0.22%, –0.10%, –0.19%, –0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter.

Conclusions:

Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment.

Classification of evidence:

This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years.




Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan

2017-09-11T12:49:31-07:00

Objective:

To report the clinical features of myasthenia gravis (MG) induced by treatment with immune checkpoint inhibitors using 2-year safety databases based on postmarketing surveys in Japan.

Methods:

We studied 10,277 patients with cancer who had received monotherapy with either nivolumab or ipilimumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used.

Results:

There were 12 MG cases (0.12%) among 9,869 patients with cancer who had been treated with nivolumab, but none among 408 patients treated with ipilimumab. These 12 patients included 6 men and 6 women with a mean age of 73.5 ± 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG) included 4 patients with mild involvement and 8 patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG. Ten patients were positive for anti–acetylcholine receptor antibodies. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had myocarditis, with 1 of these patients having both. Immunosuppressive therapy was effective. Postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; however, 2 patients died. Immune-related adverse events triggered by nivolumab impaired the patients' daily living activity.

Conclusions:

The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.




Subcutaneous immunoglobulin in myasthenia gravis exacerbation: A prospective, open-label trial

2017-09-11T12:49:31-07:00

Objective:

To investigate the efficacy, tolerability, and safety of subcutaneous immunoglobulin (SCIg) in patients with mild to moderate myasthenia gravis (MG) exacerbation.

Methods:

We performed a prospective, open-label, phase 3 trial in patients with MG aged 18 years or older and mild to moderate worsening (transition from Myasthenia Gravis Foundation of America class I to II/III or class II to III), treated with SCIg (2 g/kg), self-administered over 4 weeks. The primary endpoint was change in quantitative MG (QMG) score from baseline to study end at 6 weeks. Secondary endpoints included change in manual muscle testing (MMT), MG activities of daily living (MG-ADL), and MG composite (MGC) scores, as well as occurrence of adverse events, and tolerability as assessed via Treatment Satisfaction Questionnaire for Medication (TSQM).

Results:

Twenty-two of 23 patients completed the study. QMG score decreased from 14.9 ± 4.1 to 9.8 ± 5.6 (p < 0.0001), MMT score decreased from 16.8 ± 9.5 to 5.2 ± 4.5 (p < 0.0001), MG-ADL score decreased from 9.5 ± 3.0 to 4.6 ± 3.0 (p < 0.0001), and MGC score decreased from 17.4 ± 5.0 to 5.6 ± 4.5 (p < 0.0001). Satisfaction by TSQM was high (79.6 ± 15.6%). Common adverse events included headache and injection site reactions. No serious adverse events occurred.

Conclusions:

SCIg is well-tolerated, safe, and effective in mild to moderate MG exacerbation. Comparative safety and efficacy must be established with randomized controlled trials.

Classification of evidence:

This study provides Class IV evidence that in patients with mild to moderate MG exacerbation, SCIg is safe and effective in reducing MG disability measures.




Direct oral anticoagulant- vs vitamin K antagonist-related nontraumatic intracerebral hemorrhage

2017-09-11T12:49:31-07:00

Objective:

To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF).

Methods:

We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH.

Results:

We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke Scale [NIHSSadm] score 13 points, interquartile range 6–21). DOAC-related (n = 47) and VKA-related (n = 114) ICH did not differ in demographics, vascular risk factors, HAS-BLED and CHA2DS2-VASc scores, and antiplatelet pretreatment except for a higher prevalence of chronic kidney disease in VKA-related ICH. Patients with DOAC-related ICH had lower median NIHSSadm scores (8 [3–14] vs 15 [7–25] points, p = 0.003), median baseline hematoma volume (12.8 [4–40] vs 24.3 [11–58.8] cm3, p = 0.007), and median ICH score (1 [0–2] vs 2 [1–3] points, p = 0.049). Severe ICH (>2 points) was less prevalent in DOAC-related ICH (17.0% vs 36.8%, p = 0.013). In multivariable analyses, DOAC-related ICH was independently associated with lower baseline hematoma volume (p = 0.006), lower NIHSSadm scores (p = 0.022), and lower likelihood of severe ICH (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.13–0.87, p = 0.025). In meta-analysis of eligible studies, DOAC-related ICH was associated with lower baseline hematoma volumes on admission CT (standardized mean difference = –0.57, 95% CI –1.02 to –0.12, p = 0.010) and lower in-hospital mortality rates (OR = 0.44, 95% CI 0.21–0.91, p = 0.030).

Conclusions:

DOAC-related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH.




National randomized controlled trial of virtual house calls for Parkinson disease

2017-09-11T12:49:31-07:00

Objective:

To determine whether providing remote neurologic care into the homes of people with Parkinson disease (PD) is feasible, beneficial, and valuable.

Methods:

In a 1-year randomized controlled trial, we compared usual care to usual care supplemented by 4 virtual visits via video conferencing from a remote specialist into patients' homes. Primary outcome measures were feasibility, as measured by the proportion who completed at least one virtual visit and the proportion of virtual visits completed on time; and efficacy, as measured by the change in the Parkinson's Disease Questionnaire–39, a quality of life scale. Secondary outcomes included quality of care, caregiver burden, and time and travel savings.

Results:

A total of 927 individuals indicated interest, 210 were enrolled, and 195 were randomized. Participants had recently seen a specialist (73%) and were largely college-educated (73%) and white (96%). Ninety-five (98% of the intervention group) completed at least one virtual visit, and 91% of 388 virtual visits were completed. Quality of life did not improve in those receiving virtual house calls (0.3 points worse on a 100-point scale; 95% confidence interval [CI] –2.0 to 2.7 points; p = 0.78) nor did quality of care or caregiver burden. Each virtual house call saved patients a median of 88 minutes (95% CI 70–120; p < 0.0001) and 38 miles per visit (95% CI 36–56; p < 0.0001).

Conclusions:

Providing remote neurologic care directly into the homes of people with PD was feasible and was neither more nor less efficacious than usual in-person care. Virtual house calls generated great interest and provided substantial convenience.

ClinicalTrials.gov identifier:

NCT02038959.

Classification of evidence:

This study provides Class III evidence that for patients with PD, virtual house calls from a neurologist are feasible and do not significantly change quality of life compared to in-person visits. The study is rated Class III because it was not possible to mask patients to visit type.




Utilization of rehabilitation therapy services in Parkinson disease in the United States

2017-09-11T12:49:31-07:00

Objective:

To examine rehabilitation therapy utilization for Parkinson disease (PD).

Methods:

We identified 174,643 Medicare beneficiaries with a diagnosis of PD in 2007 and followed them through 2009. The main outcome measures were annual receipt of physical therapy (PT), occupational therapy (OT), or speech therapy (ST).

Results:

Outpatient rehabilitation fee-for-service use was low. In 2007, only 14.2% of individuals with PD had claims for PT or OT, and 14.6% for ST. Asian Americans were the highest users of PT/OT (18.4%) and ST (18.4%), followed by Caucasians (PT/OT 14.4%, ST 14.8%). African Americans had the lowest utilization (PT/OT 7.8%, ST 8.2%). Using logistic regression models that accounted for repeated measures, we found that African American patients (adjusted odds ratio [AOR] 0.63 for PT/OT, AOR 0.63 for ST) and Hispanic patients (AOR 0.97 for PT/OT, AOR 0.91 for ST) were less likely to have received therapies compared to Caucasian patients. Patients with PD with at least one neurologist visit per year were 43% more likely to have a claim for PT evaluation as compared to patients without neurologist care (AOR 1.43, 1.30–1.48), and this relationship was similar for OT evaluation, PT/OT treatment, and ST. Geographically, Western states had the greatest use of rehabilitation therapies, but provider supply did not correlate with utilization.

Conclusions:

This claims-based analysis suggests that rehabilitation therapy utilization among older patients with PD in the United States is lower than reported for countries with comparable health care infrastructure. Neurologist care is associated with rehabilitation therapy use; provider supply is not.




18F-AV-1451 binds to motor-related subcortical gray and white matter in corticobasal syndrome

2017-09-11T12:49:31-07:00

Objective:

To investigate tau distribution in patients with corticobasal syndrome (CBS) using 18F-AV-1451 PET.

Methods:

Six consecutively recruited patients with CBS and 20 age-matched healthy controls underwent 2 PET scans with 18F-AV-1451 (for tau) and 18F-florbetaben (for β-amyloid). We compared standardized uptake value ratio maps of the 18F-AV-1451 PET images between the patients with CBS and controls.

Results:

Compared to controls, patients with CBS exhibited asymmetrically increased 18F-AV-1451 binding in the putamen, globus pallidus, and thalamus contralateral to the clinically more affected side and in the ipsilateral globus pallidus and dentate nucleus. Voxel-based comparison additionally showed asymmetrically increased 18F-AV-1451 binding in the focal regions of the precentral gray and white matter and in the midbrain, predominantly in the contralateral side. 18F-AV-1451 binding in the precentral white matter correlated with motor severity.

Conclusions:

18F-AV-1451 asymmetrically binds to motor-related subcortical gray and white matter structures in patients with CBS. This pattern corresponds to tau pathology distribution in postmortem studies, and motor deficit in patients with CBS may be associated with tau accumulation predominantly in the subcortical white matter underlying the motor cortex, leading to disruptions in motor-related networks.




Downregulation of early visual cortex excitability mediates oscillopsia suppression

2017-09-11T12:49:31-07:00

Objective:

To identify in an observational study the neurophysiologic mechanisms that mediate adaptation to oscillopsia in patients with bilateral vestibular failure (BVF).

Methods:

We directly probe the hypothesis that adaptive changes that mediate oscillopsia suppression implicate the early visual-cortex (V1/V2). Accordingly, we investigated V1/V2 excitability using transcranial magnetic stimulation (TMS) in 12 avestibular patients and 12 healthy controls. Specifically, we assessed TMS-induced phosphene thresholds at baseline and cortical excitability changes while performing a visual motion adaptation paradigm during the following conditions: baseline measures (i.e., static), during visual motion (i.e., motion before adaptation), and during visual motion after 5 minutes of unidirectional visual motion adaptation (i.e., motion adapted).

Results:

Patients had significantly higher baseline phosphene thresholds, reflecting an underlying adaptive mechanism. Individual thresholds were correlated with oscillopsia symptom load. During the visual motion adaptation condition, no differences in excitability at baseline were observed, but during both the motion before adaptation and motion adapted conditions, we observed significantly attenuated cortical excitability in patients. Again, this attenuation in excitability was stronger in less symptomatic patients.

Conclusions:

Our findings provide neurophysiologic evidence that cortically mediated adaptive mechanisms in V1/V2 play a critical role in suppressing oscillopsia in patients with BVF.




Staying in service with posttraumatic headache: A retrospective cohort study of patient outcome

2017-09-11T12:49:31-07:00

Objective:

To predict the probability of a military outcome (medical discharge/retirement) in patients with mild traumatic brain injury from a clinical analysis of predetermined patient and headache characteristics.

Methods:

This retrospective cohort study sampled all new patients referred for headache evaluation at the Brain Injury Clinic of the Womack Army Medical Center, Ft. Bragg, NC (August 2008–January 2010). Headache characteristics were extracted and analyzed. Multivariable binary logistic regressions were conducted to predict probability of medical discharge/retirement.

Results:

Ninety-five soldiers (age 31.3 ± 7.4 years, male 93.7%) reported 166 headaches. The most common injury cited was a blast (53.7%). Patients with a continuous headache have almost 4 times the odds of a medically related discharge/retirement compared to patients without such a headache (continuous headache regression coefficient estimate: p < 0.042, odds ratio 3.98, 95% Wald confidence interval 1.05–15.07). Results suggest that, compared to service members who did not have a continuous headache, patients with headache histories with severe holocephalic pain who medicate to keep functioning had the highest probability of medical discharge/retirement.

Conclusions:

Certain headache characteristics may be predictive of military outcomes after mild traumatic brain injury, and we propose a profile that may be useful in that prediction. These data could be useful in future attempts to assess and treat patients with posttraumatic headache and to advise longer-term planning for return to duty or discharge.




Rare case of ribose 5 phosphate isomerase deficiency with slowly progressive leukoencephalopathy

2017-09-11T12:49:31-07:00

Ribose 5 phosphate isomerase deficiency (RPID) is a rare inborn error of metabolism in the pentose phosphate pathway (PPP)1 with a single case reported to date.2,3 The previously reported patient had leukoencephalopathy with a mild peripheral neuropathy. The diagnosis was established by demonstration of highly elevated levels of polyols by magnetic resonance spectroscopy (MRS) and body fluid analysis.3 Demonstration of reduced enzyme activity in fibroblasts and detection of mutation in the RPIA gene confirmed the diagnosis.1 We report the second case of RPID with a novel homozygous missense mutation.




Ancillary staff A difficult kind of listening

2017-09-11T12:49:31-07:00

Teflon coated nickel wire

fed through a tungsten guide

spot welded from one gold plate pin to the next

by the numbers.




Proptosis: A forgotten observation by Miller Fisher on his syndrome

2017-09-11T12:49:31-07:00

A 61-year-old man presented with rapidly progressive vision change and facial droop. There was proptosis (figure) and profound facial diplegia in addition to the more classic triad of ophthalmoplegia, ataxia, and areflexia (video at Neurology.org). The clinical diagnosis of Miller Fisher syndrome was confirmed by electrophysiologic studies. He made a complete recovery after IV immunoglobulin infusion.




Editors' Note

2017-09-11T12:49:32-07:00

Editors' Note: In "Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis," authors Filli et al. showed that prolonged-release fampridine improved walking speed, endurance, and self-perceived ambulatory function in patients with multiple sclerosis (MS). Furthermore, patients showed additional drug responsiveness with long-term treatment.




Letter re: Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis

2017-09-11T12:49:32-07:00

I read the article by Filli et al.1 with great interest. The authors reported that the responsiveness (efficacy) of prolonged-release fampridine for improving walking in multiple sclerosis (MS) increases over time.1 While the underlying mechanism is not known, its understanding might provide important insight for enhancing the efficacy of fampridine.




Author response: Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis

2017-09-11T12:49:32-07:00

Encouraged by Dr. Davis' insightful comment on our article,1 we retrospectively quantified the long-term responsiveness to fampridine of the patients with multiple sclerosis in our sample cotreated with natalizumab over a period of 2 years. Of 17 patients (32%) treated with natalizumab at the screening visit, only 6 were still receiving treatment with natalizumab 2 years later; natalizumab was stopped in 5 patients and a further 6 discontinued the study. Monitoring the efficacy of fampridine over 2 years in the 6 patients concomitantly treated with natalizumab did not reveal an increased benefit with respect to walking function compared to the other study participants. Patients cotreated with natalizumab improved by 5.4% in maximal walking speed (vs 3.0% in the rest of the population) and by 0.4% in walking endurance (vs 4.6%) and demonstrated no difference in self-perceived walking ability (vs 6.5 points improvement in the rest of the population). This post hoc analysis is obviously limited by the small number of subjects. Dr. Davis' hypothesis and other potential mechanisms, discussed in our article,1 underlying the observed increased responsiveness to fampridine over time should be investigated in future studies with larger cohorts and of sufficient statistical power.




Letter re: A model for predicting the growth of unruptured intracranial aneurysms: Beyond fortune telling

2017-09-11T12:49:32-07:00

I read with interest the article by Backes et al.,1 which considered risk factors for rupture of intracranial aneurysms. This article could change the treatment of unruptured aneurysms. In addition to the variables studied in this article, there is recent work evaluating the role of computational flow dynamics when assessing aneurysm-specific rupture risk.2 Future studies that include this entity might improve the ability to assess rupture risk.




Editorialist response: A model for predicting the growth of unruptured intracranial aneurysms: Beyond fortune telling

2017-09-11T12:49:32-07:00

I thank Dr. Munakomi for the comments on the prediction of unruptured intracranial aneurysms. I agree that computational fluid dynamics (CFD) may provide valuable insight into the rupture risk of unruptured aneurysms, in addition to currently known patient- and aneurysm-specific predictive factors. However, CFD models require rigorous and prospective validation before they can be applied to clinical decision-making for patients with unruptured aneurysm. Until such time, we must rely on the wisdom of experienced cerebrovascular physicians and published data from high-volume aneurysm treatment centers to extrapolate the risk to benefit ratio of intervention vs conservative management for unruptured aneurysms.







Clinical Reasoning: A 27-year-old man with unsteady gait

2017-09-04T12:49:19-07:00

A 27-year-old man presented to our hospital's emergency department (ED) with an abnormal gait, paresthesias of the lower extremities, and lower back pain that had progressed over 2 weeks. He reported no medical history and a family history notable only for poor folic acid absorption in his father (etiology unknown).




Pearls & Oy-sters: Frontal lobe epilepsy presenting as complex stereotyped movements

2017-09-04T12:49:19-07:00

A 14-year-old boy presented to the University of Rochester Pediatric Movement Disorder clinic for abnormal movements of 1 year’s duration. He was referred to the Movement Disorder clinic for evaluation of complex tics. His movements were stereotyped and often preceded by a blank stare, sometimes associated with a "guttural sound." He also reported having a "numb" sensation prior to the movements. He denied volitional control of the movements or ability to suppress them. He reported movements only occurring during the day although parents recalled a period of nightly episodes witnessed while sharing a hotel room with him. They occurred both at home and at school. His abnormal movement episodes were about 10–15 seconds in duration and followed by immediate return to normal activities (see video at Neurology.org). At the time of our evaluation, he was having over 10 episodes a day.




Teaching NeuroImages: Central neurocytoma

2017-09-04T12:49:19-07:00

A woman in her mid-20s presented with a 6-month history of worsening headaches, amenorrhea, and nausea. Neurologic examination demonstrated word-finding difficulties, mild right-sided weakness of the upper and lower extremities, and mild right-sided neglect. Imaging revealed a complex, cystic, heterogeneously enhancing mass in the left lateral ventricle extending to the foramen of Monro (figure). Pathology after surgical resection was consistent with a central neurocytoma. This benign tumor, comprising 0.25%–0.5% of all brain tumors, typically affects young adults and arises from subependymal neural progenitor cells. Treatment consists of surgery and radiation therapy, and generally carries a favorable prognosis.1,2




Teaching Video NeuroImages: Bilateral abducens ocular neuromyotonia

2017-09-04T12:49:19-07:00

A 44-year-old woman with a history of resolved nasopharyngeal carcinoma presented with an 8-month history of transient binocular horizontal diplopia. She received complete concurrent chemoradiotherapy 7 years ago. Following prolonged eccentric gaze to the right, she developed involuntary contraction of right lateral rectus, which resulted in 60 seconds of right exotropia. These events also occurred following prolonged eccentric gaze to the left, which resulted in left exotropia (video 1 at Neurology.org). Treatment with carbamazepine improved her symptoms (video 2). Ocular neuromyotonia should be included as a differential diagnosis of transient diplopia, especially in those who have undergone prior radiotherapy to the parasellar region.1




Spotlight on the September 5 issue

2017-09-04T12:49:19-07:00




Trends in stroke incidence in the United States: Will women overtake men?

2017-09-04T12:49:19-07:00

Stroke poses a heavy burden on health systems, with serious implications for societies and economies. At the global level, stroke is the second leading cause of death and the third most common cause of disability.1 In the United States, about 795,000 strokes occur every year: on average, someone has a stroke every 40 seconds and someone dies as a result of a stroke every 4 minutes.2 Stroke incidence and mortality rates have decreased in the last decades3; however, the aging of populations and improvements in stroke management have resulted in higher numbers of people experiencing a stroke, and more stroke survivors requiring long-term treatment.1 Assessing changes in morbidity and mortality associated with stroke and potential differences among populations and subpopulations is essential as a basis for health policy planning, proper allocation of resources, and development of strategies aimed at primary and secondary prevention of stroke.




Waxing and waning of white matter hyperintensities

2017-09-04T12:49:19-07:00

Small vessel disease (SVD) manifests in myriad ways, most prominently as white matter hyperintensities (WMH).1,2 By the age of 60 years, virtually every healthy individual has evidence of WMH,3 and those with ischemic stroke have even more extensive changes.4 Cerebral ischemic injury from occlusion or stenosis of deep penetrating arteries due to (uncontrolled) hypertension ranks highest among the potential causes of WMH.5 These WMH are among the most important vascular contributors to cognitive decline, dementia, and parkinsonism.6




Dynamic measurements of {beta}-amyloid accumulation: The early effect of APOE

2017-09-04T12:49:19-07:00

Despite many disappointments, the strongest current in Alzheimer disease (AD) research remains the pursuit of anti-amyloid therapies. There is increasing recognition that if these compounds are to be effective, early initiation of treatment, before there is irreversible neuronal and synaptic loss, is more likely to be successful. Due to the complexity of AD, to assess individual risk we might need algorithms including multiple variables like age, APOE plus other genetic variants, clinical and neuropsychological information, vascular, metabolic, and lifestyle risk factors, comorbidities, and disease biomarkers. The earliest relatively specific AD biomarker that we currently know of is brain accumulation of β-amyloid (Aβ), which we can observe with amyloid PET scans or by detecting a decrease in CSF Aβ levels.1 PET amyloid tracers have been a major step forward in the field of AD biomarkers, allowing for the first time in vivo visualization of brain fibrillary amyloid.2 Imaging markers of brain amyloidosis have been strongly associated with brain atrophy, cognitive impairment, and subsequent clinical dementia.3




Rare disease levels of evidence: Time for a new bar?

2017-09-04T12:49:19-07:00

A report of the Canadian Task Force on the Periodic Health Examination was the first to propose clinical practice recommendations based on evidence in the medical literature, and proposed a rating scheme.1 From that original publication, the categorization of evidence has evolved, with this journal requiring clinical therapeutic studies to provide the level of evidence provided by a report.2 The most rigorous Class I evidence derives from a well-performed randomized controlled clinical trial (RCT). Such trials limit the probability of bias and systematic errors by randomization and masking of treatment assignment. In contrast, Class IV evidence is characterized by retrospective analyses, which have numerous sources of potential bias. However, randomized trials are often not possible because of resource limitations, whether they are financial or organizational. In this issue of Neurology®, Hehir et al.3 identified benefit for rituximab in muscle-specific kinase antibody myasthenia gravis (anti-MuSK MG). Although strictly the report provides Class IV evidence, their unique trial design suggests much greater confidence in rituximab as an effective therapy.




Sex-specific stroke incidence over time in the Greater Cincinnati/Northern Kentucky Stroke Study

2017-09-04T12:49:19-07:00

Objective:

Recent data suggest stroke incidence is decreasing over time, but it is unknown whether incidence is decreasing in women and men to the same extent.

Methods:

Within our population of 1.3 million, all incident strokes among residents ≥20 years old were ascertained at all hospitals during July 1993–June 1994 and calendar years 1999, 2005, and 2010. A sampling scheme was used to ascertain out-of-hospital cases. Sex-specific incidence rates per 100,000 among black and white participants, age- and race-adjusted, were standardized to the 2000 US Census population. Trends over time by sex were compared; a Bonferroni correction was applied for multiple comparisons.

Results:

Over the 4 study periods, there were 7,710 incident strokes; 57.2% (n = 4,412) were women. Women were older than men (mean ± SE 72.4 ± 0.34 vs 68.2 ± 0.32, p < 0.001). Incidence of all strokes decreased over time in men (263 [confidence interval 246–281] to 192 [179–205], p < 0.001) but not in women (217 [205–230] to 198 [187–210], p = 0.15). Similar sex differences were seen for ischemic stroke (men, 238 [223–257] to 165 [153–177], p < 0.01; women, 193 [181–205] to 173 [162–184], p = 0.09). Incidence of all strokes and of ischemic strokes was similar between women and men in 2010. Incidence of intracerebral hemorrhage and subarachnoid hemorrhage were stable over time in both sexes.

Conclusions:

Decreases in stroke incidence over time are driven by a decrease in ischemic stroke in men. Contrary to previous study periods, stroke incidence rates were similar by sex in 2010. Future research is needed to understand why the decrease in ischemic stroke incidence is more pronounced in men.




Validating and comparing stroke prognosis scales

2017-09-04T12:49:19-07:00

Objective:

To compare the prognostic accuracy of various acute stroke prognostic scales using a large, independent, clinical trials dataset.

Methods:

We directly compared 8 stroke prognostic scales, chosen based on focused literature review (Acute Stroke Registry and Analysis of Lausanne [ASTRAL]; iSCORE; iSCORE-revised; preadmission comorbidities, level of consciousness, age, and neurologic deficit [PLAN]; stroke subtype, Oxfordshire Community Stroke Project, age, and prestroke modified Rankin Scale [mRS] [SOAR]; modified SOAR; Stroke Prognosis Instrument 2 [SPI2]; and Totaled Health Risks in Vascular Events [THRIVE]) using individual patient-level data from a clinical trials archive (Virtual International Stroke Trials Archive [VISTA]). We calculated area under receiver operating characteristic curves (AUROC) for each scale against 90-day outcomes of mRS (dichotomized at mRS >2), Barthel Index (>85), and mortality. We performed 2 complementary analyses: the first limited to patients with complete data for all components of all scales (simultaneous) and the second using as many patients as possible for each individual scale (separate). We compared AUROCs and performed sensitivity analyses substituting extreme outcome values for missing data.

Results:

In total, 10,777 patients contributed to the analyses. Our simultaneous analyses suggested that ASTRAL had greatest prognostic accuracy for mRS, AUROC 0.78 (95% confidence interval [CI] 0.75–0.82), and SPI2 had poorest AUROC, 0.61 (95% CI 0.57–0.66). Our separate analyses confirmed these results: ASTRAL AUROC 0.79 (95% CI 0.78–0.80 and SPI2 AUROC 0.60 (95% CI 0.59–0.61). On formal comparative testing, there was a significant difference in modified Rankin Scale AUROC between ASTRAL and all other scales. Sensitivity analysis identified no evidence of systematic bias from missing data.

Conclusions:

Our comparative analyses confirm differences in the prognostic accuracy of stroke scales. However, even the best performing scale had prognostic accuracy that may not be sufficient as a basis for clinical decision-making.




White matter hyperintensity reduction and outcomes after minor stroke

2017-09-04T12:49:19-07:00

Objective:

To assess factors associated with white matter hyperintensity (WMH) change in a large cohort after observing obvious WMH shrinkage 1 year after minor stroke in several participants in a longitudinal study.

Methods:

We recruited participants with minor ischemic stroke and performed clinical assessments and brain MRI. At 1 year, we assessed recurrent cerebrovascular events and dependency and repeated the MRI. We assessed change in WMH volume from baseline to 1 year (normalized to percent intracranial volume [ICV]) and associations with baseline variables, clinical outcomes, and imaging parameters using multivariable analysis of covariance, model of changes, and multinomial logistic regression.

Results:

Among 190 participants (mean age 65.3 years, range 34.3–96.9 years, 112 [59%] male), WMH decreased in 71 participants by 1 year. At baseline, participants whose WMH decreased had similar WMH volumes but higher blood pressure (p = 0.0064) compared with participants whose WMH increased. At 1 year, participants with WMH decrease (expressed as percent ICV) had larger reductions in blood pressure (β = 0.0053, 95% confidence interval [CI] 0.00099–0.0097 fewer WMH per 1–mm Hg decrease, p = 0.017) and in mean diffusivity in normal-appearing white matter (β = 0.075, 95% CI 0.0025–0.15 fewer WMH per 1-unit mean diffusivity decrease, p = 0.043) than participants with WMH increase; those with WMH increase experienced more recurrent cerebrovascular events (32%, vs 16% with WMH decrease, β = 0.27, 95% CI 0.047–0.50 more WMH per event, p = 0.018).

Conclusions:

Some WMH may regress after minor stroke, with potentially better clinical and brain tissue outcomes. The role of risk factor control requires verification. Interstitial fluid alterations may account for some WMH reversibility, offering potential intervention targets.




Assessment of the interaction of age and sex on 90-day outcome after intracerebral hemorrhage

2017-09-04T12:49:19-07:00

Objective:

Because age affects hormonal production differently in women compared with men, we sought to define sex and age interactions across a multiracial/ethnic population after intracerebral hemorrhage (ICH) to uncover evidence that loss of gonadal hormone production would result in loss of the known neuroprotective effects of gonadal hormones.

Methods:

Clinical and radiographic data from participants in the Ethnic/Racial Variations of Intracerebral Hemorrhage study and the Genetic and Environmental Risk Factors for Hemorrhagic Stroke study prior to December 2013 were used. Relationships among sex, age, and outcome after ICH in 616 non-Hispanic black, 590 Hispanic, and 868 non-Hispanic white participants were evaluated using multivariable logistic regression analysis. Poor outcome was defined as modified Rankin Scale score ≥3 at 90 days after ICH.

Results:

Sex differences were found in multiple variables among the racial/ethnic groups, including age at onset, premorbid neurologic status, and neurologic outcome after ICH. Overall, no sex–age interaction effect was found for mortality (p = 0.183) or modified Rankin Scale score (p = 0.378) at 90 days after ICH. In racial/ethnic subgroups, only the non-Hispanic black cohort provided possible evidence of a sex–age interaction on 90-day modified Rankin Scale score (p = 0.003).

Conclusion:

Unlike in ischemic stroke, there was no evidence that patient sex modified the effect of age on 90-day outcomes after ICH in a large multiracial/ethnic population. Future studies should evaluate biological reasons for these differences between stroke subtypes.

Clinicaltrials.gov identifier:

NCT01202864.




Longitudinal diffusion changes following postoperative delirium in older people without dementia

2017-09-04T12:49:19-07:00

Objective:

To investigate the effect of postoperative delirium on longitudinal brain microstructural changes, as measured by diffusion tensor imaging.

Methods:

We studied a subset of the larger Successful Aging after Elective Surgery (SAGES) study cohort of older adults (≥70 years) without dementia undergoing elective surgery: 113 participants who had diffusion tensor imaging before and 1 year after surgery. Postoperative delirium severity and occurrence were assessed during the hospital stay using the Confusion Assessment Method and a validated chart review method. We investigated the association of delirium severity and occurrence with longitudinal diffusion changes across 1 year, adjusting for age, sex, vascular comorbidity, and baseline cognitive performance. We also assessed the association between changes in diffusion and cognitive performance across the 1-year follow-up period, adjusting for age, sex, education, and baseline cognitive performance.

Results:

Postoperative delirium occurred in 25 participants (22%). Delirium severity and occurrence were associated with longitudinal diffusion changes in the periventricular, frontal, and temporal white matter. Diffusion changes were also associated with changes in cognitive performance across 1 year, although the cognitive changes did not show significant association with delirium severity or occurrence.

Conclusions:

Our study raises the possibility that delirium has an effect on the development of brain microstructural abnormalities, which may reflect brain changes underlying cognitive trajectories. Future studies are warranted to clarify whether delirium is the driving factor of the observed changes or rather a correlate of a vulnerable brain that is at high risk for neurodegenerative processes.




APOE genotype and early {beta}-amyloid accumulation in older adults without dementia

2017-09-04T12:49:19-07:00

Objective:

To clarify associations between APOE 4 allele and age on longitudinal rates of β-amyloid (Aβ) accumulation within Aβ+ and Aβ– older individuals without dementia.

Methods:

We analyzed 595 older adults without dementia classified cross-sectionally as Aβ– (n = 325) and Aβ+ (n = 270) using longitudinal florbetapir PET. The influence of age and APOE genotype on longitudinal accumulation of Aβ was examined with linear mixed models.

Results:

APOE 4 and older age were associated with higher risk of being classified as Aβ+ at baseline. The annual rate of Aβ accumulation was significantly greater than zero for Aβ– 3 (0.0021 ± 0.0007 standardized uptake value ratio [SUVR] units) and Aβ– 4 (0.0044 ± 0.0010 SUVR units), as well as Aβ+ 3 (0.0141 ± 0.0019 SUVR units) and Aβ+ 4 (0.0126 ± 0.0018 SUVR units). Aβ accumulation was significantly faster in Aβ– 4 compared to Aβ– 3 and Aβ– 2. Rates of Aβ accumulation did not differ significantly between Aβ+ APOE groups. Older age was associated with higher rates of Aβ accumulation in the Aβ– group.

Conclusions:

APOE 4 carriage and older age were predictors of longitudinal Aβ accumulation within the Aβ– group but not the Aβ+ group. APOE 2 carriage was protective against longitudinal Aβ accumulation within the Aβ– group. APOE genotype in conjunction with chronologic age may aid in participant selection for primary prevention trials aimed at halting Aβ accumulation before abnormal levels are reached.




Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype

2017-09-04T12:49:19-07:00

Objective:

To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.

Methods:

A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation.

Results:

We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable.

Conclusions:

Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.




Clinical and genetic characteristics of sporadic adult-onset degenerative ataxia

2017-09-04T12:49:19-07:00

Objective:

To define the clinical phenotype and natural history of sporadic adult-onset degenerative ataxia and to identify putative disease-causing mutations.

Methods:

The primary measure of disease severity was the Scale for the Assessment and Rating of Ataxia (SARA). DNA samples were screened for mutations using a high-coverage ataxia-specific gene panel in combination with next-generation sequencing.

Results:

The analysis was performed on 249 participants. Among them, 83 met diagnostic criteria of clinically probable multiple system atrophy cerebellar type (MSA-C) at baseline and another 12 during follow-up. Positive MSA-C criteria (4.94 ± 0.74, p < 0.0001) and disease duration (0.22 ± 0.06 per additional year, p = 0.0007) were associated with a higher SARA score. Forty-eight participants who did not fulfill MSA-C criteria and had a disease duration of >10 years were designated sporadic adult-onset ataxia of unknown etiology/non-MSA (SAOA/non-MSA). Compared with MSA-C, SAOA/non-MSA patients had lower SARA scores (13.6 ± 6.0 vs 16.0 ± 5.8, p = 0.0200) and a slower annual SARA increase (1.1 ± 2.3 vs 3.3 ± 3.2, p = 0.0013). In 11 of 194 tested participants (6%), a definitive or probable genetic diagnosis was made.

Conclusions:

Our study provides quantitative data on the clinical phenotype and progression of sporadic ataxia with adult onset. Screening for causative mutations with a gene panel approach yielded a genetic diagnosis in 6% of the cohort.

ClinicalTrials.gov registration:

NCT02701036.




Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS

2017-09-04T12:49:19-07:00

Objective:

To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).

Methods:

Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.

Results:

Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2–3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7–1.1, p = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4–1.1, p = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8–1.3, p = 0.79), or change in disability burden (area under the EDSS-time curve, β = –0.05, p = 0.09). Secondary and sensitivity analyses confirmed the results.

Conclusions:

Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.

Classification of evidence:

This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression.




Clinicopathologic features of myositis patients with CD8-MHC-1 complex pathology

2017-09-04T12:49:19-07:00

Objective:

To determine the clinical features of myositis patients with the histopathologic finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class 1 (CD8-MHC-1 complex), which is shared by polymyositis (PM) and inclusion body myositis (IBM), in relation to the p62 immunostaining pattern of muscle fibers.

Methods:

All 93 myositis patients with CD8-MHC-1 complex who were referred to our hospital from 1993 to 2015 were classified on the basis of the European Neuromuscular Center (ENMC) diagnostic criteria for IBM (Rose, 2013) or PM (Hoogendijk, 2004) and analyzed.

Results:

The 93 patients included were 17 patients with PM, 70 patients with IBM, and 6 patients who neither met the criteria for PM nor IBM in terms of muscle weakness distribution (unclassifiable group). For these PM, IBM, and unclassifiable patients, their mean ages at diagnosis were 63, 70, and 64 years; autoimmune disease was present in 7 (41%), 13 (19%), and 4 (67%); hepatitis C virus infection was detected in 0%, 13 (20%), and 2 (33%); and p62 was immunopositive in 0%, 66 (94%), and 2 (33%), respectively. Of the treated patients, 11 of 16 PM patients and 4 of 6 p62-immunonegative patients in the unclassifiable group showed responses to immunotherapy, whereas all 44 patients with IBM and 2 p62-immunopositive patients in the unclassifiable group were unresponsive to immunotherapy.

Conclusions:

CD8-MHC-1 complex is present in patients with PM, IBM, or unclassifiable group. The data may serve as an argument for a trial of immunosuppressive treatment in p62-immunonegative patients with unclassifiable myositis.




Rituximab as treatment for anti-MuSK myasthenia gravis: Multicenter blinded prospective review

2017-09-04T12:49:19-07:00

Objective:

To evaluate the efficacy of rituximab in treatment of anti-muscle-specific kinase (MuSK) myasthenia gravis (MG).

Methods:

This was a multicenter, blinded, prospective review, comparing anti-MuSK-positive patients with MG treated with rituximab to those not treated with rituximab. The primary clinical endpoint was the Myasthenia Gravis Status and Treatment Intensity (MGSTI), a novel outcome that combines the Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) and the number and dosages of other immunosuppressant therapies used. A priori, an MGSTI of level ≤2 was used to define a favorable outcome. Secondary outcomes included modified MGFA PIS of minimal manifestations or better, mean/median prednisone dose, and mean/median doses of other immunosuppressant drugs.

Results:

Seventy-seven of 119 patients with anti-MuSK MG evaluated between January 1, 2005, and January 1, 2015, at 10 neuromuscular centers were selected for analysis after review of limited clinical data by a blinded expert panel. An additional 22 patients were excluded due to insufficient follow-up. Baseline characteristics were similar between the rituximab-treated patients (n = 24) and the controls (n = 31). Median follow-up duration was >3.5 years. At last visit, 58% (14/24) of rituximab-treated patients reached the primary outcome compared to 16% (5/31) of controls (p = 0.002). Number needed to treat for the primary outcome is 2.4. At last visit, 29% of rituximab-treated patients were taking prednisone (mean dose 4.5 mg/day) compared to 74% of controls (mean dose 13 mg/day) (p = 0.001 and p = 0.005).

Classification of evidence:

This study provides Class IV evidence that for patients with anti-MuSK MG, rituximab increased the probability of a favorable outcome.




Efficacy of single or combined midodrine and pyridostigmine in orthostatic hypotension

2017-09-04T12:49:19-07:00

Objective:

To evaluate the long-term (for up to 3 months) efficacy and safety of single or combined therapy with midodrine and pyridostigmine for neurogenic orthostatic hypotension (OH).

Methods:

This was a randomized, open-label clinical trial. In total, 87 patients with symptomatic neurogenic OH were enrolled and randomized to receive 1 of 3 treatments: midodrine only, pyridostigmine only, or midodrine + pyridostigmine. The patients were followed up at 1 and 3 months after treatment. The primary outcome measures were improvement in orthostatic blood pressure (BP) drop at 3 months. Secondary endpoints were improvement of the orthostatic BP drop at 1 month and amelioration of the questionnaire score evaluating OH-associated symptoms.

Results:

Orthostatic systolic and diastolic BP drops improved significantly at 3 months after treatment in all treatment groups. Orthostatic symptoms were significantly ameliorated during the 3-month treatment, and the symptom severity was as follows: midodrine only < midodrine + pyridostigmine < pyridostigmine only group. Mild to moderate adverse events were reported by 11.5% of the patients.

Conclusions:

Single or combination treatment with midodrine and pyridostigmine was effective and safe in patients with OH for up to 3 months. Midodrine was better than pyridostigmine at improving OH-related symptoms.

Clinicaltrials.gov identifier:

NCT02308124.

Classification of evidence:

This study provides Class IV evidence that for patients with neurogenic OH, long-term treatment with midodrine alone, pyridostigmine alone, or both midodrine and pyridostigmine is safe and has similar effects in improving orthostatic BP drop up to 3 months.




A critique of phrenology in Moby-Dick

2017-09-04T12:49:19-07:00

Phrenology has a fascinating, although controversial, place in the history of localizationism of brain and mental functions. The 2 main proponents of phrenology were 2 German-speaking doctors, Joseph Gall (1758–1828) and Johann Spurzheim (1776–1832). According to their theory, a careful examination of skull morphology could disclose personality characters. Phrenology was initially restricted to medical circles and then diffused outside scientific societies, reaching nonscientific audiences in Europe and North America. Phrenology deeply penetrated popular culture in the 19th century and its tenets can be observed in British and American literature. Here we analyze the presence of phrenologic concepts in Moby-Dick; or, The Whale, by Herman Melville (1819–1891), one of the most prominent American writers. In his masterpiece, he demonstrates that he was familiarized with Gall and Spurzheim's writings, but referred to their theory as "semi-science" and "a passing fable." Of note, Melville's fine irony against phrenology is present in his attempt to perform a phrenologic and physiognomic examination of The Whale. Thus, Moby-Dick illustrates the diffusion of phrenology in Western culture, but may also reflect Melville's skepticism and criticism toward its main precepts.




{beta}-N-methylamino-L-alanine analysis in the brains of patients with Kii ALS/PDC

2017-09-04T12:49:19-07:00

The Kii Peninsula of Japan and the island of Guam are known as high-incidence areas of amyotrophic lateral sclerosis and parkinsonism–dementia complex (ALS/PDC). The disorder is clinically characterized by a variable presentation of parkinsonism, dementia, and motor neuron symptoms and pathologically by tau protein deposits in the CNS.1 Both genetic and environmental factors are implicated in ALS/PDC pathogenesis. Exposure to β-N-methylamino-l-alanine (BMAA), a neurotoxin produced by cyanobacteria, has been proposed as a risk factor for ALS/PDC in Guam.2 It is not known whether Kii ALS/PDC shares the same etiology as Guam ALS/PDC. To address these issues, we conducted BMAA analyses of brain samples from 5 patients with Kii ALS/PDC using high-performance liquid chromatography (HPLC) and liquid chromatography–tandem mass spectrometry (LC/MS/MS).




Intra-arterial milrinone may differentiate fulminant RCVS from vasculitis

2017-09-04T12:49:19-07:00

A 39-year-old woman taking a monoamine oxidase inhibitor presented with a 1-week history of severe non-thunderclap headache and visual field deficits. Brain CT showed infarcts in both parietal lobes, with narrowing of intracranial vessels on CT angiogram (figure 1), suggesting either vasculitis or reversible cerebral vasoconstriction syndrome (RCVS). Despite treatment with both methylprednisolone and nimodipine, she experienced progressive aphasia and right leg weakness. She underwent an urgent cerebral angiogram (figure 2), during which intra-arterial milrinone reversed both the vasoconstriction and its symptoms, thereby confirming RCVS. Intra-arterial milrinone may be useful to differentiate vasculitis from RCVS1 and may serve as a treatment for RCVS, but requires prospective evaluation.




Editors' Note

2017-09-04T12:49:19-07:00

Editors' Note: In the April 4, 2017, issue of Neurology®, Drs. Robbins et al. described the implementation and assessment of a formal scholarly activity program within their residency curriculum. They documented a significant increase in scholarly output associated with the program, including an increase in publications, clinical and laboratory research, and presentations at scientific meetings, as well as an increase in the number of faculty willing to be mentors.




Letter re: A dedicated scholarly research program in an adult and pediatric neurology residency program

2017-09-04T12:49:19-07:00

I applaud Robbins et al.1 for successfully improving scholarly research in their residency program. In general, education on clinical research is inadequate in medical schools and postgraduate clinical programs.2 Flexner3 stressed that original research, and the critical method of research, should play an important role in medical schools. However, clinical research at academic medical centers is under stress.2 The amount of time spent by academic physicians on clinical research has declined over the last several decades due to increasing demands to provide clinical care.2 Another recent publication provided data to this regard from a 2016 survey of US neurologists.4 The survey revealed that academic neurologists spent an average of 16% of their time on research (median 10%).4 These levels fell drastically from reports done in 1984, which found that academic physicians overall spent 41% of their time on research activities.5 I previously offered recommendations to improve clinical research in academic medical centers,2 including training in clinical research methodology and required research by medical students, residents, and clinical fellows. Efforts like those reported by Robbins et al. can improve the situation and affect the overall clinical research environment of a neurology department.




Author response: A dedicated scholarly research program in an adult and pediatric neurology residency program

2017-09-04T12:49:19-07:00

We thank Dr. Meador for the comment on our study examining the effect of the scholarly research program implemented in our neurology residency program.1 We agree that the shifting demands on neurologists relate to the crucial issue of burnout, though academic practice neurologists had lower burnout rates and higher rates of career satisfaction than neurologists in clinical practice.2 However, Dr. Meador previously noted that, in the current climate, younger academic faculty members are uniquely vulnerable to fail in their pursuit of successful research careers based on a variety of factors, including lack of protected time and financial constraints.3 Indeed, the burnout study found that younger neurologists in general experienced more burnout, and academic neurologists experienced more burnout with a higher percentage of time spent in clinical practice and less job autonomy.2




Letter re: Hans Jacob and brain research on Hamburg "euthanasia" victims: "Awaiting further brains!"

2017-09-04T12:49:19-07:00

Can we learn from history? To answer this, it is helpful to take a deeper look at the actions and motivations of Dr. Bayer and Dr. Knigge, 2 doctors from Hamburg who killed children for brains. First, they needed a bureaucratic organization (Reichsausschussverfahren) on which to place the deadly and inhumane decision. Second, they dehumanized the children, labeling them as worthless and a load to parents and society, and identified their cruel decision as a religious type of salvation or grace of charity. Third, and possibly the strongest motivation, their careers greatly benefited.




Author response: Hans Jacob and brain research on Hamburg "euthanasia" victims: "Awaiting further brains!"

2017-09-04T12:49:19-07:00

I appreciate Dr. Burlon's response to my article,1 highlighting not only the tragic actions of 2 doctors, but also a strategy to employ when deciding how to best care for patients. By questioning whether they would have implemented "euthanasia" on neuropsychiatric patients if they were close relatives and not institutionalized "useless eaters," perhaps Drs. Knigge and Bayer would not have murdered. In addition, part of Knigge's motivation, to scientifically evaluate the murdered patients' brains, was fulfilled by Hans Jacob, who performed the neuropathologic examinations. Jacob's work lent legitimacy to Knigge's killing, as did the work of other neuropathologists at the time.2 If Jacob had refused to do the examinations, would Knigge have had that additional motivation?




Clinical Reasoning: A 61-year-old man with conjugate gaze deviation, hemiparesis, and asymmetric reflexes

2017-08-28T12:49:14-07:00

A 61-year-old man with a history of alcoholic cirrhosis was transferred from an outside hospital for spontaneous bacterial peritonitis, septic shock, and respiratory failure after intubation. The patient was initially on sedation; however, more than 48 hours after the sedative was discontinued, his mental status remained depressed and he also developed new onset of conjugate rightward gaze deviation. On neurologic examination, the patient was unresponsive to verbal stimuli and sternal rub. He could not follow any command, including closing or opening eyes and squeezing hands. He had remarkable conjugate, forced eye deviation that could not be corrected to cross the midline using the vestibulo-ocular reflex. Corneal and gag reflexes were preserved. He blinked to visual threat less on the left side, had no clear facial asymmetry, and withdrew on his right arm and knees but had a flaccid left arm. His reflexes were brisker on the left biceps and brachioradialis, and the other deep tendon reflexes were absent. His plantar reflex was upgoing on the left side and downgoing on the right side. CT of the head had no significant findings.




Mystery Case: A case of fulminant encephalopathy in a 69-year-old woman

2017-08-28T12:49:14-07:00

A 69-year-old right-handed woman was admitted to the medical intensive care unit for acute encephalopathy. Her medical history included sickle cell disease (hemoglobin sickle cell [HbSC]) with bone involvement (bilateral femoral head osteonecrosis) and rare sickle cell crises with joint pain and hemolytic anemia requiring red blood cell transfusions, sarcoidosis, diabetes, hypertension, and hypothyroidism. She never smoked cigarettes and never used recreational drugs or alcohol, and there was no history of recent travel. The patient's daughter reported that the patient was found unresponsive lying on the floor in the morning. She was last seen normal the day prior, but had complained of diffuse muscle pain and body aches for 1 day.




Teaching NeuroImages: Reversible brain MRI lesions in adult-onset type II citrullinemia

2017-08-28T12:49:14-07:00

An 18-year-old man presented with recurrent lethargy without triggers for 6 months. Neurologic examinations showed bilateral pyramidal signs. Brain MRI showed bilateral symmetric lesions in the cingulate cortex (figure, A and B). Adult-onset type II citrullinemia was confirmed by hyperammonemia, citrullinemia, and the mutation of the SLC25A13 gene.1 He was treated with low-carbohydrate diets, arginine, and sodium pyruvate but the treatment failed. Finally, the patient underwent liver transplantation, and the symptoms and signs recovered dramatically 2 weeks later. A repeat brain MRI showed the previous lesions nearly resolved (figure, C and D).




Teaching Video NeuroImages: Macrosaccadic oscillations induced by horizontal head impulses

2017-08-28T12:49:14-07:00

A 33-year-old woman experienced chronic dizziness for 2 years. Examination disclosed gaze-evoked nystagmus and hypermetric saccades. Macrosaccadic oscillations (MSOs) were induced by a gaze shift and horizontal head impulses (video at Neurology.org). Brain MRI demonstrated a large (3.8 x 3.9 x 5.3 cm3) epidermoid cyst at the fourth ventricle that compresses the brainstem and cerebellum (figure).




Sudden unexpected death in epilepsy: Taking another look

2017-08-28T12:49:14-07:00

The researchers set out to understand more about the condition of sudden death that can happen in people who have epilepsy (sudden unexpected death in epilepsy [SUDEP]).1 Epilepsy is a disorder of the brain. People who have had 2 seizures without a clear trigger or one seizure and a high risk of more seizures in the future have epilepsy.2 See the "About epilepsy" page for more information about epilepsy.




Spotlight on the August 29 issue

2017-08-28T12:49:13-07:00




Sudden unexpected death in epilepsy patients is often misdiagnosed as sudden cardiac death

2017-08-28T12:49:13-07:00

Sudden unexpected death in epilepsy patients (SUDEP) represents the second main neurologic cause of years of potential life lost, following stroke, with a cumulative lifetime risk reaching 8% for childhood-onset epilepsy.1 In light of these worrying figures, the American Academy of Neurology (AAN) has recently published practice guidelines on the risk of SUDEP. These guidelines emphasize the "considerable uncertainty"of SUDEP incidence in adults with epilepsy, currently estimated at 1.2/1,000 patient-years (95% CI 0.64–2.32).2 Difficulties in assessing the epidemiology of SUDEP are several, including large variation in SUDEP risk across epilepsy populations (up to 100-fold difference between newly diagnosed and refractory epilepsy)3 and a lack of a SUDEP code in the current International Classification of Diseases (ICD). As a result, SUDEP is underreported and underrecognized by medical examiners, coroners, and clinicians who complete death certificates.4 In fact, many physicians view SUDEP as a sudden cardiac death (SCD), for which the relation to seizures is often uncertain. This view is at odds with evidence gathered during the last decade, suggesting that most SUDEP occurs in the immediate aftermath of a generalized tonic-clonic seizure through centrally mediated autonomic failure, distinct from mechanisms at stake in SCD.5 Progress in distinguishing SUDEP from the general framework of SCD is thus needed.




Early genetic testing for neonatal epilepsy: When, why, and how?

2017-08-28T12:49:13-07:00

The incidence of seizures is greatest during the neonatal period, with an estimated rate of 2–4 per 1,000 live births. Although the majority of seizures in the newborn are due to acquired brain disorders, a substantial proportion are due to metabolic and genetic disorders causing neonatal- and infantile-onset epilepsies. For decades, genetics has played a critical role in identification and treatment of seizures in the newborn and infantile period.1,2 With newborn screening, disorders such as phenylketonuria and biotinidase deficiency can be identified before patients develop seizures. Early identification and treatment prevents the development of often severe epilepsy syndromes and associated comorbidities. Detection and early treatment will continue to improve as newborn screening methods advance, whether based in genetics or clinical observation: the first channelopathy that causes epilepsy was identified in families with benign familial neonatal convulsions in the 1990s, before completion of the human genome project and modern genomics.3




Individualized risk prediction of major bleeding in secondary stroke prevention: Are we there yet?

2017-08-28T12:49:13-07:00

In most patients diagnosed with a TIA or ischemic stroke, secondary stroke prevention relies on antiplatelet therapy unless anticoagulation is indicated. Aspirin has the largest evidence base and reduces the risk of early recurrent ischemic stroke without a major risk of early hemorrhagic complications.1 Because antiplatelet therapy typically continues for many years, clinicians and patients need an estimation of the annual bleeding risk to accurately assess future risk. In a meta-analysis of 25 randomized trials of antiplatelet therapy in primary or secondary prevention of cardiovascular disease, aspirin increased the absolute annual risk of major bleeding by 0.13% (number needed to harm 769).2 The reduction in vaso-occlusive events after ischemic stroke seems to outweigh the increased risk of bleeding with antiplatelet therapy. However, might we identify patients more likely harmed than benefited by antiplatelet therapy? Risk models for bleeding risk could direct physicians in deciding to withhold antiplatelet therapy for some patients, but the poor accuracy of available models has hampered implementation in daily clinical practice.3




Isabelle Rapin, MD (1927-2017)

2017-08-28T12:49:13-07:00

On May 24, 2017, academic neurology lost one of its legendary pioneers who shattered our preconceptions of developmental disorders and created entirely new paradigms of thought, realms of nosology, pathogenic mechanisms, and interdisciplinary studies. Isabelle Rapin, MD, professor emerita in the Saul R. Korey Department of Neurology and the Department of Pediatrics, died after a bout with pneumonia. She was 89. A lifelong faculty member at Einstein and founding member of both the Child Neurology Society and the International Child Neurology Association, Rapin's many accomplishments in the scientific realm reflected her lifelong passion for science and singular dedication to alleviating the suffering of patients and families often stigmatized by disorders of unknown provenance and unusual behaviors. An inspirational leader who shunned the limelight, she was often referred to as "a luminary in her field" and "always the guiding light." Rapin was performing "translational research" before the term was introduced, authoring more than 250 unique scholarly contributions in numerous areas, including genetic metabolic diseases/lysosomal storage disorders and DNA repair disorders. However, her passion was language and hearing and other communication disorders, particularly autism spectrum disorders, which she viewed as "syndrome complexes." To accomplish her goals, she enlisted the aid of talented and visionary otolaryngologists, neuropsychologists, and developmental psycholinguists among many nontraditional col[...]



Underestimation of sudden deaths among patients with seizures and epilepsy

2017-08-28T12:49:13-07:00

Objective: To determine the definite and potential frequency of seizures and epilepsy as a cause of death (COD) and how often this goes unrecognized. Methods: Prospective determination of seizures or epilepsy and final COD for individuals aged 18–90 years with out-of-hospital sudden cardiac deaths (SCDs) from the population-based San Francisco POST SCD Study. We compared prospective seizure or epilepsy diagnosis and final COD as adjudicated by a multidisciplinary committee (pathologists, electrophysiologists, and a vascular neurologist) vs retrospective adjudication by 2 epileptologists with expertise in seizure-related mortality. Results: Of 541 SCDs identified during the 37-month study period (mean age 62.8 years, 69% men), 525 (97%) were autopsied; 39/525 (7.4%) had seizures or epilepsy (mean age: 58 years, range: 27–92; 67% men), comprising 17% of 231 nonarrhythmic sudden deaths. The multidisciplinary team identified 15 cases of epilepsy, 6 sudden unexpected deaths in epilepsy (SUDEPs), and no deaths related to acute symptomatic seizures. The epileptologists identified 25 cases of epilepsy and 8 definite SUDEPs, 10 possible SUDEPs, and 5 potential cases of acute symptomatic seizures as a COD. Conclusions: Among the 25 patients identified with epilepsy by the epileptologists, they found definite or possible SUDEP in 72% (18/25) vs 24% (6/25) by the multidisciplinary group (6/15 cases they identified with epilepsy). The epileptologists identified acute sympto[...]



Profile of neonatal epilepsies: Characteristics of a prospective US cohort

2017-08-28T12:49:13-07:00

Objective: Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures. Methods: Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis. Results: Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations (p = 0.03[...]



Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome

2017-08-28T12:49:13-07:00

Objective: To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS). Methods: Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study. Results: Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p < 0.0001) and OCB (p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and [...]



Clinical phenotype and outcome of hepatitis E virus-associated neuralgic amyotrophy

2017-08-28T12:49:13-07:00

Objective: To determine the clinical phenotype and outcome in hepatitis E virus–associated neuralgic amyotrophy (HEV-NA). Methods: Cases of NA were identified in 11 centers from 7 European countries, with retrospective analysis of demographics, clinical/laboratory findings, and treatment and outcome. Cases of HEV-NA were compared with NA cases without evidence of HEV infection. Results: Fifty-seven cases of HEV-NA and 61 NA cases without HEV were studied. Fifty-six of 57 HEV-NA cases were anti-HEV IgM positive; 53/57 were IgG positive. In 38 cases, HEV RNA was recovered from the serum and in 1 from the CSF (all genotype 3). Fifty-one of 57 HEV-NA cases were anicteric; median alanine aminotransferase 259 IU/L (range 12–2,961 IU/L); in 6 cases, liver function tests were normal. HEV-NA cases were more likely to have bilateral involvement (80.0% vs 8.6%, p < 0.001), damage outside the brachial plexus (58.5% vs 10.5%, p < 0.01), including phrenic nerve and lumbosacral plexus injury (25.0% vs 3.5%, p = 0.01, and 26.4% vs 7.0%, p = 0.001), reduced reflexes (p = 0.03), sensory symptoms (p = 0.04) with more extensive damage to the brachial plexus. There was no difference in outcome between the 2 groups at 12 months. Conclusions: Patients with HEV-NA are usually anicteric and have a distinct clinical phenotype, with predominately bilateral asymmetrical involvement of, and more extensi[...]



Association of parathyroid hormone with 20-year cognitive decline: The ARIC study

2017-08-28T12:49:13-07:00

Objective: We hypothesized that elevated parathyroid hormone (PTH) levels will be independently associated with 20-year cognitive decline in a large population-based cohort. Methods: We studied 12,964 middle-aged white and black ARIC participants without a history of prior stroke who, in 1990–1992 (baseline), had serum PTH levels measured and cognitive function testing, with repeat cognitive testing performed at up to 2 follow-up visits. Cognitive testing included the Delayed Word Recall, the Digit Symbol Substitution, and the Word Fluency tests, which were summed as a global Z score. Using mixed-effects models, we compared the relative decline in individual and global cognitive scores between each of the top 3 quartiles of PTH levels to the reference bottom quartile. We adjusted for demographic variables, education, vascular risk factors, and levels of calcium, phosphate, and vitamin D. We imputed missing covariate and follow-up cognitive data to account for attrition. Results: The mean (SD) age of our cohort was 57 (6) years, 57% were women, and 24% were black. There was no cross-sectional association of elevated PTH with cognitive global Z score at baseline (p > 0.05). Over a median of 20.7 years, participants in each PTH quartile showed a decline in cognitive function. However, there was no significant difference in cognitive decline between each of the [...]