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Clinical Reasoning: Prognostication after cardiac arrest: What do we really know?

2017-11-13T12:45:28-08:00

A 43-year-old woman with a history of hypertension had a witnessed collapse while smoking crack cocaine. Immediate bystander cardiopulmonary resuscitation was performed for 15 minutes; total downtime was estimated at 30 minutes with return of spontaneous circulation (ROSC) achieved after defibrillation of ventricular fibrillation and a total of 5 mg IV epinephrine. Cardiac catheterization showed normal coronary vasculature. Initial neurologic examination 2 hours after fentanyl and vecuronium boluses was significant for nonreactive pupils, absent gag reflex, and no motor response to noxious stimulation, but intact corneal and oculocephalic reflexes. Head CT (obtained to rule out intracerebral hemorrhage in the setting of cocaine use) showed no acute abnormalities. Targeted temperature management (TTM) was initiated 3 hours after ROSC, targeting 32–34°C, and maintained for 24 hours. Continuous EEG initially showed a discontinuous pattern with widespread attenuation, followed by left temporal lateralized periodic discharges, and then by generalized spike and wave discharges. These EEG changes occurred during hypothermia and did not have any clinical correlate. The patient was treated with levetiracetam 55 mg/kg/d with improvement in hyperexcitable patterns. Ten hours after achieving normothermia, she developed frequent myoclonic jerking of her lower extremities, time-locked with epileptiform bursts, consistent with myoclonic status epilepticus (MSE) (figure 1A). Neurologic examination 48 hours after rewarming was unchanged, except for the development of 1–3 Hz myoclonic blinking and jerking of the upper and lower extremities.




Teaching Video NeuroImages: The pathologic deep abdominal reflex

2017-11-13T12:45:28-08:00

A 68-year-old man presented with progressive asymmetric limb weakness and muscle wasting over 12 months. There were profuse fasciculations and hyperreflexia in the limbs and abdominal muscles (see video at Neurology.org), consistent with amyotrophic lateral sclerosis.




Spotlight on the November 14 issue

2017-11-13T12:45:28-08:00




The new Neurology: Redesigns, short articles for print, full articles online, and data availability policies

2017-11-13T12:45:28-08:00

Readers will note sweeping changes in Neurology® as of the January 2, 2018, issue, changes that were carefully considered as the Editors reimagined the journal in the context of changes in scientific publishing in general, and supported by extensive research in readers' habits and preferences. The most notable changes occur both in print and online, for which there are new designs, the result of 2 years' work and crafting. For print, we are publishing articles in a short format, allowing a more comprehensive reading experience in a shorter time. For the online, canonical version of the journal, we are now able to accommodate longer full articles. Along with the new design and format of the reimagined journal, the Editors and Editorial Board have put in place new policies on data availability.




Amyloid PET scan: Staging beyond reading?

2017-11-13T12:45:28-08:00

The advent of in vivo β-amyloid (Aβ) PET imaging has revolutionized the field of Alzheimer disease (AD). The opportunity to visualize, during life, one of the main neuropathologic hallmarks of the disease, i.e., Aβ deposition, has yielded considerable hope for diagnosis and treatment efficacy. From a clinical perspective, although the presence of Aβ deposition in the brain is not a sufficient criterion for AD dementia diagnosis, Aβ PET imaging is used to support or rule out the diagnosis, especially in patients with a complicated clinical course.1 Moreover, Aβ PET imaging is a powerful tool for clinical trials to enrich the sample for Aβ-positive participants, and to evaluate treatment effects on Aβ deposition. Finally, Aβ PET imaging has provided a unique opportunity to assess how Aβ deposition relates to cognitive and functional decline, brain atrophy, and hypometabolism, both cross-sectionally and longitudinally.




In vivo staging of regional amyloid deposition

2017-11-13T12:45:28-08:00

Objectives:

To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology.

Methods:

Multiregional analysis of florbetapir (18F-AV45)–PET data was used to determine individual amyloid distribution profiles in a sample of 667 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including cognitively normal older individuals (CN) as well as patients with mild cognitive impairment and Alzheimer disease (AD) dementia. The frequency of regional amyloid positivity across CN individuals was used to construct a 4-stage model of progressing amyloid pathology, and individual distribution profiles were used to evaluate the consistency of this hierarchical stage model across the full cohort.

Results:

According to a 4-stage model, amyloid deposition begins in temporobasal and frontomedial areas, and successively affects the remaining associative neocortex, primary sensory-motor areas and the medial temporal lobe, and finally the striatum. Amyloid deposition in these brain regions showed a highly consistent hierarchical nesting across participants, where only 2% exhibited distribution profiles that deviated from the staging scheme. The earliest in vivo amyloid stages were mostly missed by conventional dichotomous classification approaches based on global florbetapir-PET signal, but were associated with significantly reduced CSF Aβ42 levels. Advanced in vivo amyloid stages were most frequent in patients with AD and correlated with cognitive impairment in individuals without dementia.

Conclusions:

The highly consistent regional hierarchy of PET-evidenced amyloid deposition across participants resembles neuropathologic observations and suggests a predictable regional sequence that may be used to stage an individual's progress of amyloid pathology in vivo.




Weighting and standardization of frequencies to determine prevalence of AD imaging biomarkers

2017-11-13T12:45:28-08:00

Objective:

To estimate the prevalence of elevated brain amyloid and reduced cortical thickness (as a marker for neurodegeneration) in a defined population.

Methods:

Mayo Clinic Study of Aging participants underwent MRI to assess a composite Alzheimer disease (AD) signature cortical thickness measure and PET to assess brain amyloid accumulation. Participants were characterized as having elevated amyloid (A+/A–), reduced cortical thickness (N+/N–), and A+N+, A+N–, A–N+, or A–N–. The prevalence of AD biomarkers was derived by adjusting for nonparticipation and standardizing to the Olmsted County, Minnesota, population.

Results:

Among 1,646 participants without dementia (mean age 70.8 years; 53.2% men), the prevalence (95% confidence interval) of amyloidosis was 21.1% (19.1%–23.2%): women, 24.3%; men, 17.5%. The prevalence of reduced cortical thickness was 28.9% (26.4%–31.5%): women, 27.9%; men, 30.2%. The prevalence estimates of biomarker categories were as follows: A–N–: 61.4%; A+N–: 9.7%; A–N+: 17.4%; and A+N+: 11.5%, and varied by sex and by APOE 4 carrier status. In men, prevalence estimates were as follows: A–N–: 62.6%; A+N–: 7.3%; A–N+: 19.9%; and A+N+: 10.2%. In women, prevalence estimates were as follows: A–N–: 60.4%; A+N–: 11.7%; A–N+: 15.3%; and A+N+: 12.6%. In 4 carriers, prevalence estimates were as follows: A–N–: 54.6%; A+N–: 16.6%; A–N+: 12.4%; and A+N+: 16.4%. In non-4 carriers, prevalence estimates were as follows: A–N–: 63.3%; A+N–: 6.9%; A–N+: 19.9%; and A+N+: 10.0%.

Conclusions:

These prevalence estimates are important for understanding age-related trends in amyloid positivity and AD signature cortical thickness in the population, and for potentially projecting the future burden of biomarkers in elderly persons.




The social and economic burden of frontotemporal degeneration

2017-11-13T12:45:28-08:00

Objective:

To quantify the socioeconomic burden of frontotemporal degeneration (FTD) compared to previously published data for Alzheimer disease (AD).

Methods:

A 250-item internet survey was administered to primary caregivers of patients with behavioral-variant FTD (bvFTD), primary progressive aphasia, FTD with motor neuron disease, corticobasal syndrome, or progressive supranuclear palsy. The survey included validated scales for disease staging, behavior, activities of daily living, caregiver burden, and health economics, as well as investigator-designed questions to capture patient and caregiver experience with FTD.

Results:

The entire survey was completed by 674 of 956 respondents (70.5%). Direct costs (2016 US dollars) equaled $47,916 and indirect costs $71,737, for a total annual per-patient cost of $119,654, nearly 2 times higher than reported costs for AD. Patients ≥65 years of age, with later stages of disease, and with bvFTD correlated with higher direct costs, while patients <65 years of age and men were associated with higher indirect costs. An FTD diagnosis produced a mean decrease in household income from $75,000 to $99,000 12 months before diagnosis to $50,000 to $59,999 12 months after diagnosis, resulting from lost days of work and early departure from the workforce.

Conclusions:

The economic burden of FTD is substantial. Counting productivity-related costs, per-patient costs for FTD appear to be greater than per-patient costs reported for AD. There is a need for biomarkers for accurate and timely diagnosis, effective treatments, and services to reduce this socioeconomic burden.




Adding quantitative muscle MRI to the FSHD clinical trial toolbox

2017-11-13T12:45:28-08:00

Objective:

To add quantitative muscle MRI to the clinical trial toolbox for facioscapulohumeral muscular dystrophy (FSHD) by correlating it to clinical outcome measures in a large cohort of genetically and clinically well-characterized patients with FSHD comprising the entire clinical spectrum.

Methods:

Quantitative MRI scans of leg muscles of 140 patients with FSHD1 and FSHD2 were assessed for fatty infiltration and TIRM hyperintensities and were correlated to multiple clinical outcome measures.

Results:

The mean fat fraction of the total leg musculature correlated highly with the motor function measure, FSHD clinical score, Ricci score, and 6-minute walking test (correlation coefficients –0.845, 0.835, 0.791, –0.701, respectively). Fat fraction per muscle group correlated well with corresponding muscle strength (correlation coefficients up to –0.82). The hamstring muscles, adductor muscles, rectus femoris, and gastrocnemius medialis were affected most frequently, also in early stage disease and in patients without leg muscle weakness. Muscle involvement was asymmetric in 20% of all muscle pairs and fatty infiltration within muscles showed a decrease from distal to proximal of 3.9%. TIRM hyperintense areas, suggesting inflammation, were found in 3.5% of all muscles, with and without fatty infiltration.

Conclusions:

We show a strong correlation between quantitative muscle MRI and clinical outcome measures. Muscle MRI is able to detect muscle pathology before clinical involvement of the leg muscles. This indicates that quantitative leg muscle MRI is a promising biomarker that captures disease severity and motor functioning and can thus be included in the FSHD trial toolbox.




Volumetric brain changes in migraineurs from the general population

2017-11-13T12:45:28-08:00

Objective:

To assess volumetric brain changes in migraineurs from the general population compared with controls.

Methods:

Structural brain changes in migraineurs from the general population-based MRI Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis (CAMERA)-2 observational cohort study were assessed by state-of-the-art voxel-based morphometry. T1-weighted MRIs of 84 migraineurs (52 with aura, 32 without aura) and 35 headache-free controls were evaluated. Regional volumes were compared voxelwise, corrected for age, sex, and total intracranial volume, with region-of-interest and whole-brain analyses.

Results:

In region-of-interest analyses, migraineurs showed decreased gray matter volume in the visual areas V3 and V5 of the right occipital cortex compared to controls (p < 0.05, familywise error correction). Post hoc analyses revealed that similar changes were present regardless of migraine aura status, disease activity (>1 year attack-free [inactive] vs ≥1 attack within the last year [active] and attack frequency [≤1 (low) vs ≥1 attack per month [high]). In exploratory whole-brain analyses (p < 0.001, uncorrected for multiple comparisons), we identified additional structural differences in migraineurs in other cortical and subcortical areas, including white matter tracts, that are particularly involved in visual processing.

Conclusions:

Migraineurs from the general population showed small volumetric brain changes, mainly in cortical areas involved in visual motion processing, compared to controls. The presence of morphologic changes regardless of the presence of migraine aura or disease activity suggests that migraines with and without aura share common pathophysiologic pathways and suggests that these changes are (partially) irreversible or might have been present throughout life.




Randomized study of IV prochlorperazine plus diphenhydramine vs IV hydromorphone for migraine

2017-11-13T12:45:28-08:00

Objective:

To determine outcomes among patients with migraine in the emergency department (ED) who receive IV hydromorphone vs IV prochlorperazine + diphenhydramine.

Methods:

This study was conducted in 2 EDs in New York City. Patients who met international criteria for migraine were eligible for participation if they had not used an opioid within the previous month. Clinicians, participants, investigators, and research personnel were blinded to treatment. Patients were randomized in blocks of 4. Participants received hydromorphone 1 mg or prochlorperazine 10 mg + diphenhydramine 25 mg. Diphenhydramine was administered to prevent akathisia, a common side effect of IV prochlorperazine. The primary outcome was sustained headache relief, defined as achieving a headache level of mild or none within 2 hours of medication administration and maintaining that level for 48 hours without the requirement of rescue medication. A planned interim analysis was conducted once 48-hour data were available for 120 patients.

Results:

The trial was halted by the data monitoring committee after 127 patients had been enrolled. The primary outcome was achieved in the prochlorperazine arm by 37 of 62 (60%) participants and in the hydromorphone arm by 20 of 64 (31%) participants (difference 28%, 95% confidence interval 12–45, number needed to treat 4, 95% confidence interval 2–9).

Conclusions:

IV hydromorphone is substantially less effective than IV prochlorperazine for the treatment of acute migraine in the ED and should not be used as first-line therapy.

ClinicalTrials.gov identifier:

NCT02389829.

Classification of evidence:

This study provides Class I evidence that for patients in the ED with migraine, IV prochlorperazine + diphenhydramine is superior to IV hydromorphone.




Optimal deep brain stimulation site and target connectivity for chronic cluster headache

2017-11-13T12:45:28-08:00

Objective:

To investigate the mechanism of action of deep brain stimulation for refractory chronic cluster headache and the optimal target within the ventral tegmental area.

Methods:

Seven patients with refractory chronic cluster headache underwent high spatial and angular resolution diffusion MRI preoperatively. MRI-guided and MRI-verified electrode implantation was performed unilaterally in 5 patients and bilaterally in 2. Volumes of tissue activation were generated around active lead contacts with a finite-element model. Twelve months after surgery, voxel-based morphometry was used to identify voxels associated with higher reduction in headache load. Probabilistic tractography was used to identify the brain connectivity of the activation volumes in responders, defined as patients with a reduction of ≥30% in headache load.

Results:

There was no surgical morbidity. Average follow-up was 34 ± 14 months. Patients showed reductions of 76 ± 33% in headache load, 46 ± 41% in attack severity, 58 ± 41% in headache frequency, and 51 ± 46% in attack duration at the last follow-up. Six patients responded to treatment. Greatest reduction in headache load was associated with activation in an area cantered at 6 mm lateral, 2 mm posterior, and 1 mm inferior to the midcommissural point of the third ventricle. Average responders' activation volume lay on the trigeminohypothalamic tract, connecting the trigeminal system and other brainstem nuclei associated with nociception and pain modulation with the hypothalamus, and the prefrontal and mesial temporal areas.

Conclusions:

We identify the optimal stimulation site and structural connectivity of the deep brain stimulation target for cluster headache, explicating possible mechanisms of action and disease pathophysiology.




Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series

2017-11-13T12:45:28-08:00

Objective:

To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor–α.

Methods:

Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes.

Results:

Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24–71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4–8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location.

Conclusions:

Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments.

Classification of evidence:

This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.




Association between percent decline in serum total homocysteine and risk of first stroke

2017-11-13T12:45:28-08:00

Objective:

To examine whether a change in serum total homocysteine (tHcy) levels is associated with first stroke risk in a post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT).

Methods:

We analyzed 16,867 participants of the CSPPT with tHcy measurements at both baseline and exit visits. The primary outcome was first stroke. The secondary outcome was a composite of cardiovascular events consisting of cardiovascular death, myocardial infarction, and stroke. The percent decline in tHcy was calculated as [(baseline tHcy – exit tHcy)/baseline tHcy x 100].

Results:

Over the median treatment duration of 4.5 years, participants who developed a first stroke had a significantly lower percent decline in tHcy (β = –5.7; 95% confidence interval [CI] –8.8 to –2.6) compared to their counterparts. A 20% tHcy decline was associated with a reduction in stroke risk of 7% (hazard ratio [HR] 0.93; 95% CI 0.90–0.97). When percent decline in tHcy was assessed as tertiles, a significantly lower stroke risk was found in those in tertiles 2–3 (HR 0.79; 95% CI 0.64–0.97) compared with participants in tertile 1. Similar results were observed for the composite of cardiovascular events. The beneficial effect associated with greater tHcy reduction was observed across strata for age, sex, treatment group (with vs without folic acid), MTHFR C677T genotypes, baseline tHcy and serum folate levels, and blood pressure control.

Conclusions:

Percent lowering in tHcy was significantly associated with a reduction in first stroke risk in Chinese adults with hypertension, and if further confirmed, may serve as a useful indicator for folic acid treatment efficacy on stroke prevention.

Clinicaltrials.gov identifier:

NCT00794885.




Serum neurofilament light is sensitive to active cerebral small vessel disease

2017-11-13T12:45:28-08:00

Objective:

To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner.

Methods:

In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls.

Results:

Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up.

Conclusions:

Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.




Successful motor mapping with transcranial magnetic stimulation in an infant: A case report

2017-11-13T12:45:28-08:00

Accurate assessment of motor function is critical, particularly in the context of presurgical functional mapping. There are a few noninvasive tools available for preoperative motor mapping in older children and adults undergoing surgery for brain tumor or refractory epilepsy including fMRI, magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS).1,2 However, assessing motor function is challenging in very young children. Direct cortical stimulation, a standard procedure in adults, is associated with a high incidence of intraoperative seizures, and is often unsuccessful in young children.3,4 Alternately, noninvasive motor mapping using MEG and fMRI attempted during sleep or under sedation primarily localize the somatosensory cortex from which the location of motor cortex is inferred.5,6 Furthermore, these methods have a low success rate (~25%) and have risks associated with sedation.6 However, TMS has the advantage of mapping the motor cortex directly without requiring sedation. We have previously reported on successful mapping of the motor cortex in young children aged between 17 and 35 months.7 Here we describe a case of an 11-month-old infant who is, to our knowledge, the youngest person to undergo successful presurgical motor mapping with TMS.




Home for the holidays

2017-11-13T12:45:28-08:00

Your hug wasn't your hug. Your

left arm didn't encircle me as tightly, and the

left side of your smile didn't arch upward

as completely.




Systemic vasculitis with dermatomyositis, hearing loss, neuropathy, and multiorgan dysfunction

2017-11-13T12:45:28-08:00

A 39-year-old woman presented with 10 months of steadily progressive weakness, myalgia, weight loss, and intermittent feet tingling. During the course of her illness, she developed refractory atrial fibrillation, left followed by right-sided hearing loss, amenorrhea, and hematuria. She had been on rituximab for years for "polyarthralgias," which was stopped at symptom onset. Examination showed severe proximal weakness and mildly decreased toe proprioception. Deltoid biopsy (figure) was diagnostic of dermatomyositis. Liver and enteric biopsies showed lymphocytosis. Suspicion for vasculitis led to sural nerve biopsy (figure), showing large-arteriole vasculitis. Despite treatment with high-dose prednisone and cyclophosphamide, the patient died. This is a unique case of systemic vasculitis associated with dermatomyositis, hearing loss, neuropathy, and multiorgan dysfunction. The histologic findings and the relentless progression despite stopping rituximab argue against a role for rituximab in the pathogenesis.




Editors' Note

2017-11-13T12:45:28-08:00

Editors' Note: In "Risks and benefits of clopidogrel–aspirin in minor stroke or TIA: Time course analysis of CHANCE," authors Pan et al. compared the use of dual antiplatelet therapy (DAPT) with aspirin alone for secondary stroke prevention in patients after a minor stroke or TIA. Drs. Gutierrez and Lekic point out that DAPT appeared to have a greater benefit than aspirin alone in patients with intracranial arterial stenosis (ICAS) in the first 2 weeks and ask the authors to provide a time-course analysis for the risk of ischemic stroke and hemorrhage by ICAS status.




Letter re: Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: Time course analysis of CHANCE

2017-11-13T12:45:28-08:00

We read with interest the article by Pan et al.,1 which reported that the use of dual antiplatelet therapy (DAPT) showed an early benefit, compared to aspirin alone, for secondary ischemic stroke prevention after a minor stroke or TIA. The absolute risk reduction in the first week after the indexed event was 4.5%.1 The authors previously reported a nonsignificant absolute risk reduction in recurrent ischemic stroke of 2.3% with DAPT compared to aspirin alone in Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) participants with intracranial arterial stenosis (ICAS) over the 90-day follow-up period.2 In figure 1 from the article by Pan et al.,1 the benefit of DAPT compared with aspirin alone appears greater in the first 2 weeks among those with ICAS, with parallel risk curves thereafter. In this context, it would be valuable if the authors reported the time-course analysis for the risk of ischemic stroke and hemorrhage in the first, second, and third week by ICAS status. These data could help formulate possible mechanism-based interventions for acute stroke, which could then be tested in trials.




Author response: Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: Time course analysis of CHANCE

2017-11-13T12:45:28-08:00

We appreciate Drs. Gutierrez and Lekic's emphasis on the time-course analysis of dual antiplatelet therapy (DAPT) by intracranial arterial stenosis (ICAS) in their comments on our article.1 Only 1,089 patients were included in the imaging substudy.2 In patients with ICAS, 19 (8.2%), 3 (1.3%), and 0 ischemic strokes in the DAPT group (n = 231) vs 25 (10.0%), 6 (2.4%), and 0 in the aspirin alone group (n = 250), and 4 (1.7%), 0, and 2 (0.9%) bleeding in the DAPT group vs 1 (0.4%), 0, and 0 in the aspirin alone group, occurred at the first, second, and third week, respectively. In patients without ICAS, 11 (3.7%), 1 (0.3%), and 0 ischemic strokes in the DAPT group (n = 300) vs 9 (2.9%), 1 (0.3%), and 2 (0.6%) in the aspirin alone group (n = 308), and 5 (1.7%), 0, and 0 bleeding in the DAPT group vs 4 (1.3%), 1 (0.3%), and 0 in the aspirin alone group, occurred at the first, second, and third week, respectively. The absolute risk reduction in ischemic stroke in the first 2 weeks was 2.9% with DAPT compared to aspirin alone in patients with ICAS and –0.8% among those without ICAS, compared with 3.2% (not 4.5%, which is the proportion of events occurred at each week among total events) in the total 5,170 patients in our article.1




Letter re: Effects of orthostatic hypotension on cognition in Parkinson disease

2017-11-13T12:45:28-08:00

We read with interest the article by Centi et al.,1 which investigated the relation between orthostatic hypotension (OH) and posture-mediated cognitive impairment in 18 patients with idiopathic Parkinson disease (PD) with OH (PDOH) and 19 patients with PD without OH and 18 controls.1 The authors demonstrated that, during upright posture, PDOH exhibited a transient wider range of deficits in executive function, memory, and visuospatial function in excess of those found in PD without OH.




Author response: Effects of orthostatic hypotension on cognition in Parkinson disease

2017-11-13T12:45:28-08:00

We thank Guaraldi et al. for their comment on our article,1 and for drawing our attention to their work assessing cognitive function in patients with peripheral autonomic disorders, pure autonomic failure (PAF), and autoimmune autonomic neuropathy.2 The results in their study are similar to our results in Parkinson disease (PD),2 and to data we reported earlier on reversible cognitive impairment in individuals with orthostatic hypotension (OH) due to the peripheral disorder autoimmune autonomicganglionopathy.3 Cognitive changes in all of these studies are most significant in the domains of attention and executive functioning; while disease-specific decrements vary across each participant group regardless of posture, the totality of these data strongly suggest an independent effect of OH that may go unnoticed during standard clinical assessment. This is perhaps most relevant for PD, where the management focus tends to be on motor features and OH may be unrecognized whereas dysautonomic signs are prioritized in autoimmune autonomic ganglionopathy, autonomic neuropathies, and PAF. All these studies highlight the need for clinical awareness of cognitive impairment in association with OH, and for additional work to delineate the pathophysiologic mechanisms underlying OH-induced cognitive impairment.1–3




Clinical Reasoning: A patient with a history of encephalomyelitis and recurrent optic neuritis

2017-11-06T12:45:27-08:00

A 4-year-old girl presented to an outside hospital after waking up with inability to stand or walk. She had a viral prodrome with fever for several days. Brain and spine MRIs revealed lesions in the left caudate, bilateral insular cortex, right thalamus, and right temporal cortex as well as longitudinally extensive cervical and thoracic cord lesions. Spinal fluid showed pleocytosis with 200 white blood cells (mixed neutrophils and lymphocytes), elevated CSF protein (103 mg/dL), and negative bacterial and viral cultures and PCR. Oligoclonal bands were negative. During the hospitalization, she developed encephalopathy and was diagnosed with acute disseminated encephalomyelitis (ADEM). She received a course of IV steroids followed by an oral steroid taper, and her neurologic symptoms resolved fully. However, within 2 weeks, she experienced painless bilateral vision loss. A repeat brain and orbit MRI revealed swelling in the bilateral optic nerves and decrease in size or resolution of prior brain lesions. Optic neuritis (ON) was diagnosed based on clinical and radiographic presentation. She was given a course of IV immunoglobulin, followed by IV steroids, and a longer steroid taper.




Teaching NeuroImages: Sucking candy sign in Bell palsy

2017-11-06T12:45:27-08:00

A 20-year-old woman presented with spontaneous onset of facial weakness. Examination revealed House-Brackmann grade IV1 right facial paresis and a contralaterally pigmented tongue (figure) from habitual sucking candy use. Contemporaneous taste loss on the anterior right tongue led her to keep the candy as far away from that area as possible—the posterior left tongue.




Teaching NeuroImages: Craniofacial fibrous dysplasia: Loss of vision after head trauma

2017-11-06T12:45:27-08:00

A 24-year-old woman presented with blurred vision of her left eye 1 hour after a mild head trauma. Examination revealed left-sided exophthalmos and left side 20/40 vision with relative afferent pupillary defect. CT (figure 1) and MRI scan (figure 2) revealed ground-glass bone abnormalities involving the left frontal, orbital, and sphenoidal bones causing compression of the left optic nerve, all pathognomonic of fibrous dysplasia (FD). FD is a rare slowly progressive benign disorder where normal bone is replaced with abnormal fibrous tissue.1 IV methylprednisolone was given to treat supposed posttraumatic edema around the left optic nerve. The patient's vision normalized.




Teaching Video NeuroImages: Upbeat and horizontal gaze-evoked nystagmus in bilateral medial medullary infarction

2017-11-06T12:45:27-08:00

A 41-year-old man with progressive quadriparesis and generalized tingling sensation showed spontaneous upbeating nystagmus and horizontal gaze-evoked nystagmus (video at Neurology.org). The initial diffusion-weighted images showed an equivocal hyperintensity at midline of rostral medulla (upper row). Follow-up MRIs (lower row) showed characteristic heart appearance sign (figure).




Spotlight on the November 7 issue

2017-11-06T12:45:26-08:00




Alzheimer dementia's other victim: The spouse

2017-11-06T12:45:26-08:00

Editor's Note: The initial portion of this essay is an excerpt from the author's book (Before I Forget: Love, Hope, Help, and Acceptance in our Fight Against Alzheimer's. Copyright © 2016 by B. Smith, Dan Gasby, and Michael Shnayerson. Published by Harmony Books, an imprint of Penguin Random House LLC), reprinted with permission. Following this excerpt is an update from the events chronicled in the book.




To sleep or not to sleep during deep brain stimulation surgery for Parkinson disease?

2017-11-06T12:45:26-08:00

In functional stereotactic neurosurgery, precise placement of lesions or deep brain stimulation (DBS) electrodes is paramount. From the beginning of the specialty, electrical stimulation of the brain target prior to lesioning, and confirmation of accuracy of targeting by postoperative imaging, have been critical.1 Two schools subsequently evolved: one using macroelectrode stimulation in the awake patient with careful on-table assessment and one using microelectrode recording (MER) to map out boundaries of the target followed by microstimulation to assess efficacy and avoid side effects. For many, the latter technique was adopted as the gold standard, but the evidence to support the superior efficacy or better safety of this stance was lacking.2




Big data trends in stroke epidemiology in the United States: But are they good data?

2017-11-06T12:45:26-08:00

Based on prior epidemiologic studies in the United States, approximately 80% of first-time strokes can be explained by modifiable risk factors such as hypertension, and therefore optimal control or elimination of known risk factors might prevent these strokes.1 Campaigns such as the American Heart Association (AHA) initiative, Life's Simple 7, have set ambitious goals for optimal cardiovascular and stroke risk factor control; in addition, a wealth of online resources are available for an increasingly health-conscious society.2 There are indeed some glimmers of hope. Efforts to prevent stroke, in large part from emphasis on improved detection and behavioral and pharmacologic treatment of risk factors, have led to substantial declines in stroke incidence and mortality in Western countries over the last several decades.3




Jessica Anne Panzer, MD, PhD (1977-2017)

2017-11-06T12:45:27-08:00

Jessica Anne Panzer, MD, PhD, Assistant Professor of Neurology and Pediatrics at The Children's Hospital of Philadelphia (CHOP) and The Perelman School of Medicine at The University of Pennsylvania, died on May 13, 2017, at age 40 years, after a brief struggle with cancer.




Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease

2017-11-06T12:45:27-08:00

Objective:

To compare motor and nonmotor outcomes at 6 months of asleep deep brain stimulation (DBS) for Parkinson disease (PD) using intraoperative imaging guidance to confirm electrode placement vs awake DBS using microelectrode recording to confirm electrode placement.

Methods:

DBS candidates with PD referred to Oregon Health & Science University underwent asleep DBS with imaging guidance. Six-month outcomes were compared to those of patients who previously underwent awake DBS by the same surgeon and center. Assessments included an "off"-levodopa Unified Parkinson’s Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson's Disease Questionnaire, motor diaries, and speech fluency.

Results:

Thirty participants underwent asleep DBS and 39 underwent awake DBS. No difference was observed in improvement of UPDRS III (+14.8 ± 8.9 vs +17.6 ± 12.3 points, p = 0.19) or UPDRS II (+9.3 ± 2.7 vs +7.4 ± 5.8 points, p = 0.16). Improvement in "on" time without dyskinesia was superior in asleep DBS (+6.4 ± 3.0 h/d vs +1.7 ± 1.2 h/d, p = 0.002). Quality of life scores improved in both groups (+18.8 ± 9.4 in awake, +8.9 ± 11.5 in asleep). Improvement in summary index (p = 0.004) and subscores for cognition (p = 0.011) and communication (p < 0.001) were superior in asleep DBS. Speech outcomes were superior in asleep DBS, both in category (+2.77 ± 4.3 points vs –6.31 ± 9.7 points (p = 0.0012) and phonemic fluency (+1.0 ± 8.2 points vs –5.5 ± 9.6 points, p = 0.038).

Conclusions:

Asleep DBS for PD improved motor outcomes over 6 months on par with or better than awake DBS, was superior with regard to speech fluency and quality of life, and should be an option considered for all patients who are candidates for this treatment.

Clinicaltrials.gov identifier:

NCT01703598.

Classification of evidence:

This study provides Class III evidence that for patients with PD undergoing DBS, asleep intraoperative CT imaging–guided implantation is not significantly different from awake microelectrode recording–guided implantation in improving motor outcomes at 6 months.




Longitudinal decline of driving safety in Parkinson disease

2017-11-06T12:45:27-08:00

Objective:

To longitudinally assess and predict on-road driving safety in Parkinson disease (PD).

Methods:

Drivers with PD (n = 67) and healthy controls (n = 110) drove a standardized route in an instrumented vehicle and were invited to return 2 years later. A professional driving expert reviewed drive data and videos to score safety errors.

Results:

At baseline, drivers with PD performed worse on visual, cognitive, and motor tests, and committed more road safety errors compared to controls (median PD 38.0 vs controls 30.5; p < 0.001). A smaller proportion of drivers with PD returned for repeat testing (42.8% vs 62.7%; p < 0.01). At baseline, returnees with PD made fewer errors than nonreturnees with PD (median 34.5 vs 40.0; p < 0.05) and performed similar to control returnees (median 33). Baseline global cognitive performance of returnees with PD was better than that of nonreturnees with PD, but worse than for control returnees (p < 0.05). After 2 years, returnees with PD showed greater cognitive decline and larger increase in error counts than control returnees (median increase PD 13.5 vs controls 3.0; p < 0.001). Driving error count increase in the returnees with PD was predicted by greater error count and worse visual acuity at baseline, and by greater interval worsening of global cognition, Unified Parkinson's Disease Rating Scale activities of daily living score, executive functions, visual processing speed, and attention.

Conclusions:

Despite drop out of the more impaired drivers within the PD cohort, returning drivers with PD, who drove like controls without PD at baseline, showed many more driving safety errors than controls after 2 years. Driving decline in PD was predicted by baseline driving performance and deterioration of cognitive, visual, and functional abnormalities on follow-up.




Longitudinal CSF biomarkers in patients with early Parkinson disease and healthy controls

2017-11-06T12:45:27-08:00

Objective:

To analyze longitudinal levels of CSF biomarkers in drug-naive patients with Parkinson disease (PD) and healthy controls (HC), examine the extent to which these biomarker changes relate to clinical measures of PD, and identify what may influence them.

Methods:

CSF α-synuclein (α-syn), total and phosphorylated tau (t- and p-tau), and β-amyloid 1–42 (Aβ42) were measured at baseline and 6 and 12 months in 173 patients with PD and 112 matched HC in the international multicenter Parkinson's Progression Marker Initiative. Baseline clinical and demographic variables, PD medications, neuroimaging, and genetic variables were evaluated as potential predictors of CSF biomarker changes.

Results:

CSF biomarkers were stable over 6 and 12 months, and there was a small but significant increase in CSF Aβ42 in both patients with patients with PD and HC from baseline to 12 months. The t-tau remained stable. The p-tau increased marginally more in patients with PD than in HC. α-syn remained relatively stable in patients with PD and HC. Ratios of p-tau/t-tau increased, while t-tau/Aβ42 decreased over 12 months in patients with PD. CSF biomarker changes did not correlate with changes in Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale motor scores or dopamine imaging. CSF α-syn levels at 12 months were lower in patients with PD treated with dopamine replacement therapy, especially dopamine agonists.

Conclusions:

These core CSF biomarkers remained stable over 6 and 12 months in patients with early PD and HC. PD medication use may influence CSF α-syn. Novel biomarkers are needed to better profile progressive neurodegeneration in PD.




Population-based study of home-time by stroke type and correlation with modified Rankin score

2017-11-06T12:45:27-08:00

Objective:

To describe home-time, stratified by stroke type, in a complete population and to determine its correlation with modified Rankin Scale (mRS) scores.

Methods:

We used linked administrative data to derive home-time in all patients admitted for a cerebrovascular event in Alberta, Canada, between 2012 and 2016. Home-time is the number of days spent outside a health institution in the first 90 days after index hospitalization. We used negative binomial regression, adjusted for age, sex, Charlson comorbidity index, and hospital location, to determine the association between home-time and stroke type. In 552 patients enrolled in 4 acute ischemic stroke clinical trials, we used multivariable ordinal logistic regression analysis to determine the association between home-time and mRS score at 90 days.

Results:

Among 15,644 patients (n = 10,428 with ischemic stroke, n = 1,415 with intracerebral hemorrhage, n = 760 with subarachnoid hemorrhage, n = 3,041 with TIA), patients with TIA have the longest home-time, almost triple the number of days at home compared to patients with intracerebral hemorrhage (incidence rate ratio 2.85, 95% confidence interval [CI] 2.58–3.15). Among clinical trial ischemic stroke patients, longer home-time was associated with a lower mRS score at 90 days (adjusted common odds ratio 1.04, 95% CI 1.04–1.05).

Conclusions:

We showed that home-time is an objective and graded indicator that is correlated with disability after stroke. It is obtainable from administrative data, applicable to different stroke types, and a valuable outcome indicator in population-based health services research.




Radiographic and symptomatic brain ischemia in CEA and CAS: A systematic review and meta-analysis

2017-11-06T12:45:27-08:00

Objective:

In a systematic review, we compared ratio of new periprocedural radiographic brain ischemia (RBI) to the number of strokes and TIAs among patients undergoing carotid endarterectomy (CEA) and carotid artery stenting (CAS).

Methods:

We searched 5 databases for entries related to brain ischemia in CEA or CAS from inception through September 2015. We included articles with CEA or CAS and systematic performance of preprocedural and postprocedural brain MRI and reporting of RBI and stroke incidence. We calculated a symptomatic risk ratio of number of strokes and TIAs to RBI. Random effects models were used.

Results:

Fifty-nine studies (5,431 participants) met the inclusion criteria. There were 22 cohorts in CEA, 34 in CAS with distal protection, 8 in CAS with proximal protection, 9 in CAS without protection, and 9 in CAS with unspecified devices. Overall, 30.7% (95% confidence interval [CI] 26.6%–34.7%) had RBI, while 3.2% (95% CI 2.6%–3.8%) had clinical strokes or TIAs, with a stroke and TIA to RBI weighted ratio of 0.18 (95% CI 0.15–0.22). CEA had lower incidence of RBI compared to CAS (13.0% vs 37.4%) and also lower number of strokes and TIAs (1.8% vs 4.1%). The stroke and TIA to RBI ratio did not differ across 5 different types of carotid interventions (p = 0.58).

Conclusions:

One in 5 persons with periprocedural radiographic brain ischemia during CEA and CAS had strokes and TIAs. The stable ratio of stroke and TIA to radiographic ischemia suggests that MRI ischemia could serve as a surrogate measure of periprocedural risk.




Increasing prevalence of vascular risk factors in patients with stroke: A call to action

2017-11-06T12:45:27-08:00

Objective:

To evaluate trends in prevalence of cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking, and drug abuse) and cardiovascular diseases (carotid stenosis, chronic renal failure [CRF], and coronary artery disease [CAD]) in acute ischemic stroke (AIS) in the United States.

Methods:

We used the 2004–2014 National Inpatient Sample to compute weighted prevalence of each risk factor in hospitalized patients with AIS and used joinpoint regression to evaluate change in prevalence over time.

Results:

Across the 2004–2014 period, 92.5% of patients with AIS had ≥1 risk factor. Overall age- and sex-adjusted prevalence of hypertension, diabetes, dyslipidemia, smoking, and drug abuse were 79%, 34%, 47%, 15%, and 2%, respectively, while those of carotid stenosis, CRF, and CAD were 13%, 12%, and 27%, respectively. Risk factor prevalence varied by age (hypertension: 44% in 18–39 years vs 82% in 60–79 years), race (diabetes: Hispanic 49% vs white 30%), and sex (drug abuse: men 3% vs women 1.4%). Using joinpoint regression, prevalence of hypertension increased annually by 1.4%, diabetes by 2%, dyslipidemia by 7%, smoking by 5%, and drug abuse by 7%. Prevalence of CRF, carotid stenosis, and CAD increased annually by 13%, 6%, and 1%, respectively. Proportion of patients with multiple risk factors also increased over time.

Conclusions:

Despite numerous guidelines and prevention initiatives, prevalence of hypertension, diabetes, dyslipidemia, smoking, and drug abuse in AIS increased across the 2004–2014 period. Proportion of patients with carotid stenosis, CRF, and multiple risk factors also increased. Enhanced risk factor modification strategies and implementation of evidence-based recommendations are needed for optimal stroke prevention.




Prevalence and clinical features of neuromyelitis optica spectrum disorders in northern Japan

2017-11-06T12:45:27-08:00

Objective:

To clarify the prevalence and clinical characteristics of neuromyelitis optica spectrum disorders (NMOSD) in Japan and compare them with those in other ethnic populations.

Methods:

Data processing sheets were sent to all related institutions in northern Japan and were collected from April to May 2016. Prevalence was determined on March 31, 2016, using the 2015 International Panel for NMO Diagnosis criteria.

Results:

The crude prevalence was 4.1/100,000 (95% confidence interval 2.2–6.9) for NMOSD in northern Japan, with a significantly higher number of female than male patients (female: male 12:2). The positivity for anti-aquaporin-4 antibody was 78.6%, and the mean age at onset was 45.2 years. All patients were subjected to preventive therapy in the form of treatment with steroids or immunosuppressive agents.

Conclusions:

Our results showed that the prevalence of NMOSD in the Japanese population is similar to that in Caucasians.




Subjective cognitive decline and {beta}-amyloid burden predict cognitive change in healthy elderly

2017-11-06T12:45:27-08:00

Objective:

To assess in a longitudinal study whether subjective cognitive decline (SCD) and brain β-amyloid (Aβ) contribute unique information to cognitive decline.

Methods:

One hundred thirty-six healthy elderly from the Berkeley Aging Cohort Study were followed up for a mean of 4 years. SCD and affective measures were generated from the Geriatric Depression Scale (GDS) with factor analysis on data from a larger set of 347 healthy, nondepressed (GDS <11) elderly individuals. Cognition was summarized with previously validated factor scores. Pittsburgh compound B (PiB)-PET scans were acquired to determine the presence (PiB+) or absence (PiB–) of Aβ pathology. Mixed models were used to assess the independent and interactive effects of SCD, affective features, PiB status, and time on cognition, with adjustment for demographic variables.

Results:

SCD score demonstrated good construct validity compared to an existing measure of subjective memory and was partially explained by several lower-order measurements. Mixed models revealed that SCD interacted with PiB status to predict change in episodic memory and global cognition over time, with adjustment for affective features. PiB+ individuals with more severe SCD demonstrated the steepest cognitive decline. Worse SCD predicted faster decline in working memory independently of PiB status. No such effects were seen for affective scores when adjusted for SCD.

Conclusions:

PiB+ individuals with SCD are at greatest risk of cognitive decline. Evidence for amyloid alone is not sufficient to indicate risk of rapid cognitive decline in healthy elderly. Effects of GDS on cognitive decline in nondepressed cohorts may be driven by SCD rather than subsyndromal depression.




Effect of concussion and blast exposure on symptoms after military deployment

2017-11-06T12:45:27-08:00

Objective:

To examine whether blast exposure alone and blast-associated concussion result in similar neurologic and mental health symptoms.

Methods:

A 14-item questionnaire was administered to male US Marines on their return from deployment in Iraq and/or Afghanistan.

Results:

A total of 2,612 Marines (median age 22 years) completed the survey. Of those, 2,320 (88.9%) reported exposure to ≥1 blast during their current and/or prior deployments. In addition, 1,022 (39.1%) reported ≥1 concussion during the current deployment, and 731 (28.0%) had experienced at least 1 prior lifetime concussion. Marines were more likely to have sustained a concussion during the current deployment if they had a history of 1 (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2–2.0) or ≥1 (OR 2.3, 95% CI 1.7–3.0) prior concussion. The most common symptoms were trouble sleeping (38.4%), irritability (37.9%), tinnitus (33.8%), and headaches (33.3%). Compared to those experiencing blast exposure without injury, Marines either experiencing a concussion during the current deployment or being moved or injured by a blast had an increased risk of postinjury symptoms.

Conclusions:

There appears to be a continuum of increasing total symptoms from no exposure to blast exposure plus both current deployment concussion and past concussion. Concussion had a greater influence than blast exposure alone on the presence of postdeployment symptoms. A high blast injury score can be used to triage those exposed to explosive blasts for evaluation.




Anti-cytosolic 5'-nucleotidase 1A (cN1A) autoantibodies in motor neuron diseases

2017-11-06T12:45:27-08:00

Inclusion body myositis (IBM) is the most common acquired muscle disease in patients older than 50 years. Asymmetric weakness and early involvement of quadriceps and forearm flexors are key clinical features. Muscle biopsy remains the gold standard diagnostic test, which has high specificity, but low sensitivity.1 In addition to the canonical pathologic features of IBM, upregulation of major histocompatibility complex class I and accumulation of various proteins (p62, SMI-31, and TDP-43) have been adopted to the 2011 European Neuromuscular Center diagnostic criteria for IBM.1 The recent identification of anti-cytosolic 5'-nucleotidase 1A (cN1A) autoantibodies by immunoblotting in patients with IBM has raised the question whether we should incorporate these particular antibodies into the diagnostic criteria for IBM.2,3 Anti-cN1A antibodies may be positive several years predating the IBM diagnosis.3 The clinical features of patients with motor neuron disease (MND) with lower motor neuron findings could resemble those of patients with IBM, given their common age group and asymmetry in muscle weakness and atrophy. Here I present 2 patients with MND who had positive anti-cN1A antibodies.




Granulocytic sarcoma of the choroid plexus complicating acute leukemia

2017-11-06T12:45:27-08:00

A 38-year-old patient with type 5 acute myeloid leukemia relapsed after 4 years of treatment including chemotherapy and bone marrow transplant. He underwent imaging for vertigo, with an otherwise normal neurologic examination. Brain MRI showed diffuse choroid plexus enlargement, without hydrocephalus, a rare typical image of granulocytic sarcoma (figure, A).1 The patient also had spine MRI, to explore right L5 radiculopathy, which showed signs of meningitis with radicular and diffuse epidural enhancement (figure, B).




Ping-pong gaze and ocular nodding in bacterial meningitis

2017-11-06T12:45:27-08:00

A 27-year-old man presented with fever, somnolence, seizure, and nuchal rigidity. CSF culture indicated Streptococcus pneumoniae, confirming the diagnosis of bacterial meningitis. Ping-pong gaze was observed initially, and then replaced by what we called ocular nodding after IV administration of diazepam (video at Neurology.org). The eyes went downward and returned to primary position slowly, smoothly, and periodically (with a cycle lasting 12–17 seconds and a pause between 2 cycles), resembling a nodding head. He became alert with free eye movement within 3 days of antibiotic treatment. Ping-pong gaze has been reported,1 but ocular nodding is a novel finding.




Editors' Note

2017-11-06T12:45:27-08:00

Editors' Note: In "Evaluating the safety of β-interferons in MS: A series of nested case-control studies," de Jong et al. found that exposure to β-interferons was associated with a 1.8-fold increased risk of stroke. Commenting on the study, Dr. Jongen shares his own prospective study on adverse events in 284 patients with multiple sclerosis treated with intramuscular interferon-β-1a: one patient died from a stroke sinus thrombosis 22 months after start of treatment.




Letter re: Evaluating the safety of {beta}-interferons in MS: A series of nested case-control studies

2017-11-06T12:45:27-08:00

In a series of case-control studies of patients with multiple sclerosis (MS), de Jong et al.1 found that exposure to β-interferons was associated with a 1.8-fold increased risk of stroke. The authors rightfully state that stroke is not well-recognized as a potential adverse event of β-interferons, referring to cases reported in 2006 and 2008.2,3




Author response: Evaluating the safety of {beta}-interferons in MS: A series of nested case-control studies

2017-11-06T12:45:27-08:00

I thank Dr. Jongen for the interest in our article,1 and agree with the points made. While space precluded us from citing all the relevant literature in the main text of our article, interested readers can access an extensive review, including the article by Jongen et al.,2 as an appendix to our article (appendix e-1).1 The appendix includes over 100 studies and case reports related to potential adverse effects of the β-interferons and outlines the article referred to by Dr. Jongen.2




Letter re: Education Research: Positive effect of scheduled faculty modeling on clerkship student bedside skills exposure and learning

2017-11-06T12:45:27-08:00

I read with interest the Education Research article by Thompson Stone et al.,1 which evaluated the effect of scheduled bedside skills modeling on the neurology clerkship of third-year medical students.




Author response: Education Research: Positive effect of scheduled faculty modeling on clerkship student bedside skills exposure and learning

2017-11-06T12:45:27-08:00

We thank Dr. Sethi for his letter on our article.1 Dr. Sethi advocates for a scheduled assessment of bedside skills by a faculty member during the last week of the clerkship. Indeed, at the University of Rochester, all clerkship students participate in a faculty-observed bedside skills examination of a neurology inpatient during the final week of the clerkship. The examination is scheduled for 1 hour, during which the student is observed taking a complete history, performing a complete neurologic examination, and presenting and discussing the case with the attending physician. Feedback is provided following the examination, which counts for 15% of the clerkship final grade. We published our experience with this faculty-observed bedside skills examination in a previous issue of Neurology®.2




Mystery Case: Widespread plexiform neurofibromas in neurofibromatosis type 1: An uncommon cause of back pain

2017-10-30T12:45:39-07:00

A 23-year-old man with known neurofibromatosis type 1 (NF1) presented with low back pain described as a "wringing" sensation, with radiation to both legs and painful spasms upon awakening. Examination was significant for reduced reflexes bilaterally. The figure is a coronal T2-weighted MRI revealing extensive plexiform neurofibromas arising from all lumbosacral nerve roots. Neurofibromas appear as high signal intensity on T2-weighted images due to increased fluid in myelin associated with dysplastic glial proliferation.1 In patients with NF1 presenting with back pain or polyradiculopathy, imaging should be obtained to evaluate for neurofibroma-mediated spinal cord pathology.




Clinical Reasoning: A case of ataxia, seizure, and choreoathetosis in a 34-year-old woman

2017-10-30T12:45:39-07:00

A 34-year-old woman of Chinese Han descent was admitted to the neurology department after complaining of gait instability for 20 years and seizure attacks for 6 years. At age 14, she began experiencing slurred speech and unsteady gait. Meanwhile, she had learning difficulties and her academic performance was poor. Since then, her intelligence regressed gradually. At age 28, she developed recurrent generalized tonic-clonic seizures and myoclonus refractory to valproic acid and oxcarbazepine. She developed choreoathetosis at age 29. In the following years, the seizures and choreoathetosis progressively worsened. Two years later, she could no longer walk independently due to postural instability caused by ataxic gait. Concurrently, she presented with mild cognitive impairment and memory loss. Medical, birth, and family histories were noncontributory; no other family members were known to be affected.




Teaching NeuroImages: Bilateral hypertrophic olivary degeneration following posterior circulation stroke

2017-10-30T12:45:39-07:00

A 40-year-old comatose man was brought to the hospital with a history of posterior circulation stroke 4 months earlier due to hypertension. On examination, he had spastic quadriplegia, bilateral extensor plantar reflex, and palatal myoclonus. MRI revealed enlarged olives (figure 1) and chronic infarcts involving midbrain and pons (figure 2) suggestive of hypertrophic olivary degeneration seen after 4 months of insult. Hypertrophic olivary degeneration is a transsynaptic degeneration involving interconnecting fibers of inferior olivary nucleus, red nucleus, and contralateral dentate nucleus forming the 3 corners of the Guillain-Mollaret triangle.1,2 Symmetric enlargement and T2 hyperintense olives help differentiate this entity from demyelination, tumors, and inflammatory processes.




Teaching Video NeuroImages: Hemifacial spasm due to cerebellopontine angle mass

2017-10-30T12:45:39-07:00

A 21-year-old woman presented with tremor of the right eyelid that progressed in 1 year to involve the ipsilateral cheek and lip and ipsilateral hearing loss since childhood. Her lack of medical comorbidities prompted imaging that revealed a mass in the right cerebellopontine angle cistern. She underwent debulking of the mass, which resolved the tremors. Her pathology revealed pilocytic astrocytoma (figure; video at Neurology.org). Cranial nerve 7 is predisposed to injury due to its anatomic location. There are many case reports of hemifacial spasms due to mass effect.1 Imaging should be performed in otherwise healthy patients to exclude secondary causes of spasms.2




Virtual reality may relieve pain in patients with spinal cord injury

2017-10-30T12:45:39-07:00

Body ownership is the ongoing feeling that our body and body parts belong to us, and are related to us in a different way than things in the external world. This sense of body ownership may seem trivial to us, yet our brain needs to connect sensory inputs (e.g., touch, pain, and visual information), internal inputs (from our body's internal milieu), and higher cognitive inputs like memories of our body in different events to generate the sense of ownership. For instance, hand ownership is generated by the visual input we get from our eyes that tracks its location, sensory input on its posture (known as proprioception), and the touch of the table that we lean on, as well as our sense of familiarity with our hand and our memories of the hand along our personal history.




Spotlight on the October 31 issue

2017-10-30T12:45:38-07:00




Polycystic kidney disease and intracranial aneurysms: Some answers, but many questions remain

2017-10-30T12:45:38-07:00

Unruptured intracranial aneurysms (UIA) occur in about 2%–3% of the population. Several medical conditions are associated with a UIA presence, including autosomal dominant polycystic kidney disease (ADPKD). Clinicians and patients want to know the risk of aneurysm growth, rupture, or de novo development, predictors of clinical outcomes, and the optimal initial and follow-up screening for individuals with UIA and ADPKD. Such data are unavailable. The recent American Heart Association–American Stroke Association statement on UIAs recommends that patients with familial risk and patients with conditions in which aneurysms are prevalent such as ADPKD be offered screening.1 The evidence for this recommendation comes from cross-sectional studies of screening in patients with clinically diagnosed ADPKD and follow-up for aneurysmal subarachnoid hemorrhage (aSAH) with substantial variation in prevalence estimates. A few studies, with a small sample size, have clinical and radiologic follow-up for aSAH, aneurysmal change, or new aneurysm development.




Oral antidiabetic drugs and dementia risk: Does treatment matter?

2017-10-30T12:45:38-07:00

As the population ages, dementia grows as a public health problem. The rising life expectancy and the aging of the so-called baby boomer cohort translate to a substantial number of people reaching ages of high risk for age-related conditions like dementia. As a major cause of disability and dependency in elderly people, dementia puts social and economic burden on patients and their families and affects health care systems worldwide. In the absence of a cure, primary prevention will have the largest effect on the reduction of dementia occurrence.1 Thus, public health research should focus on the identification of modifiable risk factors for dementia. Diabetes mellitus is an established risk factor for dementia. Patients with diabetes have an increased risk for any dementia, Alzheimer disease, and vascular dementia.2 The exact mechanisms of cognitive impairment in diabetic patients remain unknown. The main contributors to diabetes-associated cognitive decline include hyperglycemia, decreased insulin secretion, obesity, increased oxidative stress, and inflammation.3 Diabetes not only promotes neurodegeneration but also induces cerebrovascular pathologies such as stroke, which in turn are further risk factors for dementia.4 Furthermore, patients with diabetes often have other comorbidities such as high blood pressure and cardiovascular disease that may contribute to the development of dementia. About 12%–14% of US adults have diabetes.5 An effective treatment could prevent harmful effects of diabetes on cognition. Several studies have examined the association of different antidiabetic medications and cognitive function. Results from epidemiologic studies conflict. Some found protective effects of oral antidiabetic medications such as metformin on dementia risk; others detected deleterious effects.6,7




The beginning of precision medicine in ALS?: Treatment to fit the genes

2017-10-30T12:45:38-07:00

Amyotrophic lateral sclerosis (ALS) affects approximately 1 in 400 adults of western European ancestry, making it the most common degenerative disease of the motor neuron network. ALS has a mean age at onset of 65 and 85%–90% of cases occur sporadically. Ten to fifteen percent of cases have a recognized genetic contribution, usually in known ALS gene-carrying families.1 In populations of European extraction, the commonest cause of familial ALS, accounting for up to 40% of familial cases, is the C9orf72 hexanucleotide repeat expansion.2 C9orf72 has a broader associated phenotype including frontotemporal dementia and a more rapid clinical progression. Men with spinal-onset disease have a lower median age at onset and drive the more rapid clinical progression.2 Other gene variants also associate with earlier age at onset and more rapid progression; for example, the A4V variant mutated SOD1 gene.3




Polycystic kidney disease among 4,436 intracranial aneurysm patients from a defined population

2017-10-30T12:45:38-07:00

Objective:

To define the association of autosomal dominant polycystic kidney disease (ADPKD) with the characteristics of aneurysmal subarachnoid hemorrhage (aSAH) and unruptured intracranial aneurysm (IA) disease.

Methods:

We fused data from the Kuopio Intracranial Aneurysm database (n = 4,436 IA patients) and Finnish nationwide registries into a population-based series of 53 IA patients with ADPKD to compare the aneurysm- and patient-specific characteristics of IA disease in ADPKD and in the general IA population, and to identify risks for de novo IA formation.

Results:

In total, there were 33 patients with ADPKD with aSAH and 20 patients with ADPKD with unruptured IAs. The median size of ruptured IAs in ADPKD was significantly smaller than in the general population (6.00 vs 8.00 mm) and the proportion of small ruptured IAs was significantly higher (31% vs 18%). Median age at aSAH was 42.8 years, 10 years younger than in the general IA population. Multiple IAs were present in 45% of patients with ADPKD compared to 28% in the general IA population. Cumulative risk of de novo IA formation was 1.3% per patient-year (vs 0.2% in the general IA population). Hazard for de novo aneurysm formation was significantly elevated in patients with ADPKD (Cox regression hazard ratio 7.7, 95% confidence interval 2.8–20; p < 0.0005).

Conclusions:

Subarachnoid hemorrhage occurs at younger age and from smaller IAs in patients with ADPKD and risk for de novo IAs is higher than in the general Eastern Finnish population. ADPKD should be considered as an indicator for long-term angiographic follow-up in patients with diagnosed IAs.




Thrombolysis in acute ischemic stroke in patients with dementia: A Swedish registry study

2017-10-30T12:45:38-07:00

Objective:

To compare access to intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) and its outcomes in patients with and without dementia.

Methods:

This was a longitudinal cohort study of the Swedish dementia and stroke registries. Patients with preexisting dementia who had AIS from 2010 to 2014 (n = 1,356) were compared with matched patients without dementia (n = 6,755). We examined access to thrombolysis and its outcomes at 3 months (death, residency, and modified Rankin Scale [mRS] score). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with logistic and ordinal logistic regression.

Results:

The median age at stroke onset was 83 years in both groups. IVT was administered to 94 (7.0%) patients with dementia and 639 (9.5%) patients without dementia. The OR of receiving IVT was 0.68 (95% CI 0.54–0.86) for patients with dementia. When the analysis was repeated exclusively among patients independent in everyday activities, dementia status was no longer significant (OR 0.79, 95% CI 0.60–1.06). However, differences persisted in patients ≤80 years of age (OR 0.58, 95% CI 0.36–0.94). In patients who received thrombolysis, the incidence of symptomatic intracerebral hemorrhage (sICH; 7.4% vs 7.3%) and death at 3 months (22.0% vs 18.8%) did not differ significantly between the 2 groups. However, mRS score and accommodation status were worse among patients with dementia after 3 months in adjusted analyses (both p < 0.001). Unfavorable outcomes with an mRS score of 5 to 6 were doubled in patients with dementia (56.1% vs 28.1%).

Conclusions:

Younger patients with dementia and AIS are less likely to receive IVT. Among patients receiving thrombolysis, there are no differences in sICH or death, although patients with dementia have worse accommodation and functional outcomes at 3 months.




Change in multimodal MRI markers predicts dementia risk in cerebral small vessel disease

2017-10-30T12:45:38-07:00

Objective:

To determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD).

Methods:

In the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH). Progression to dementia was determined in all patients. Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined.

Results:

Over 5 years of follow-up, 18 patients (18.2%) progressed to dementia. A significant change in all MRI markers, representing deterioration, was observed. The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning. Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia. A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85.

Conclusions:

This longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia. It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions.




Metformin vs sulfonylurea use and risk of dementia in US veterans aged >=65 years with diabetes

2017-10-30T12:45:38-07:00

Objective:

To determine whether metformin is associated with a lower incidence of dementia than sulfonylureas.

Methods:

This was a retrospective cohort study of US veterans ≥65 years of age with type 2 diabetes who were new users of metformin or a sulfonylurea and had no dementia. Follow-up began after 2 years of therapy. To account for confounding by indication, we developed a propensity score (PS) and used inverse probability of treatment weighting (IPTW) methods. Cox proportional hazards models estimated the hazard ratio (HR) of incident dementia.

Results:

We identified 17,200 new users of metformin and 11,440 new users of sulfonylureas. Mean age was 73.5 years and mean HbA1c was 6.8%. Over an average follow-up of 5 years, 4,906 cases of dementia were diagnosed. Due to effect modification by age, all analyses were conducted using a piecewise model for age. Crude hazard ratio [HR] for any dementia in metformin vs sulfonylurea users was 0.67 (95% confidence interval [CI] 0.61–0.73) and 0.78 (95% CI 0.72–0.83) for those <75 years of age and ≥75 years of age, respectively. After PS IPTW adjustment, results remained significant in veterans <75 years of age (HR 0.89; 95% CI 0.79–0.99), but not for those ≥75 years of age (HR 0.96; 95% CI 0.87–1.05). A lower risk of dementia was also seen in the subset of younger veterans who had HbA1C values ≥7% (HR 0.76; 95% CI 0.63–0.91), had good renal function (HR 0.86; 95% CI 0.76–0.97), and were white (HR 0.87; 95% CI 0.77–0.99).

Conclusions:

After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age. Further work is needed to identify which patients may benefit from metformin for the prevention of dementia.




Female sex, early-onset hypertension, and risk of dementia

2017-10-30T12:45:38-07:00

Objective:

To evaluate the association of early-adulthood and mid-adulthood hypertension with dementia in men and women.

Methods:

We evaluated 5,646 members of a diverse integrated health care delivery system who had clinical examinations and health survey data from 1964 to 1973 (mean age 32.7 years; early adulthood) and 1978–1985 (mean age 44.3 years; mid-adulthood) and were members as of January 1, 1996 (mean age 59.8 years). Hypertension categories based on measurements of blood pressure (BP) and change in hypertension categories between the 2 examinations (e.g., onset hypertension) were used to predict dementia incidence from January 1, 1996, to September 30, 2015. Cox proportional hazard models were adjusted for demographics, vascular comorbidities, and hypertension treatment; inverse probability weighting accounted for differential attrition between first BP measurement and start of follow-up.

Results:

A total of 532 individuals (9.4%) were diagnosed with dementia. Early adulthood hypertension was not associated with dementia, though effect estimates were elevated among women. Mid-adulthood hypertension was associated with 65% (95% confidence interval [CI] 1.25–2.18) increased dementia risk among women but not men. Onset of hypertension in mid-adulthood predicted 73% higher dementia risk in women (95% CI 1.24–2.40) compared to stable normotensive. There was no evidence that hypertension or changes in hypertension increased dementia risk among men.

Conclusions:

Though midlife hypertension was more common in men, it was only associated with dementia risk in women. Sex differences in the timing of dementia risk factors have important implications for brain health and hypertension management.




Virtual reality improves embodiment and neuropathic pain caused by spinal cord injury

2017-10-30T12:45:39-07:00

Objective:

To investigate changes in body ownership and chronic neuropathic pain in patients with spinal cord injury (SCI) using multisensory own body illusions and virtual reality (VR).

Methods:

Twenty patients with SCI with paraplegia and 20 healthy control participants (HC) participated in 2 factorial, randomized, repeated-measures design studies. In the virtual leg illusion (VLI), we applied asynchronous or synchronous visuotactile stimulation to the participant's back (either immediately above the lesion level or at the shoulder) and to the virtual legs as seen on a VR head-mounted display. We tested the effect of the VLI on the sense of leg ownership (questionnaires) and on perceived neuropathic pain (visual analogue scale pain ratings). We compared illusory leg ownership with illusory global body ownership (induced in the full body illusion [FBI]), by applying asynchronous or synchronous visuotactile stimulation to the participant's back and the back of a virtual body as seen on a head-mounted display.

Results:

Our data show that patients with SCI are less sensitive to multisensory stimulations inducing illusory leg ownership (as compared to HC) and that leg ownership decreased with time since SCI. In contrast, we found no differences between groups in global body ownership as tested in the FBI. VLI and FBI were both associated with mild analgesia that was only during the VLI specific for synchronous visuotactile stimulation and the lower back position.

Conclusions:

The present findings show that VR exposure using multisensory stimulation differently affected leg vs body ownership, and is associated with mild analgesia with potential for SCI neurorehabilitation protocols.




Comment: Is virtual reality a useful adjunct to rehabilitation after spinal cord injury?

2017-10-30T12:45:39-07:00

Spinal cord injury (SCI) has devastating effects on the CNS, leading to disruption of various neuromuscular, sensory, and autonomic pathways. However, the changes induced in the nervous system extend well beyond the tracts and neurons directly disrupted starting soon after the injury.1 There is substantial neural plasticity that takes place throughout the CNS, including the cortex.2 Trying to improve function and pain after a peripheral injury by intervening at the cortical level has been explored since the mid-1990s with classic mirror box therapy for phantom limb pain.3




Effects of acute intermittent hypoxia on hand use after spinal cord trauma: A preliminary study

2017-10-30T12:45:39-07:00

Objective:

To test the hypothesis that daily acute intermittent hypoxia (AIH) combined with hand opening practice improves hand dexterity, function, and maximum hand opening in persons with chronic, motor-incomplete, cervical spinal cord injury.

Methods:

Six participants completed the double-blind, crossover study. Participants received daily (5 consecutive days) AIH (15 episodes per day: 1.5 minutes of fraction of inspired oxygen [FIo2] = 0.09, 1-minute normoxic intervals) followed by 20 repetitions of hand opening practice and normoxia (sham, FIo2 = 0.21) + hand opening practice. Hand dexterity and function were quantified with Box and Block and Jebsen-Taylor hand function tests. We also recorded maximum hand opening using motion analyses and coactivity of extensor digitorum and flexor digitorum superficialis muscles using surface EMG.

Results:

Daily AIH + hand opening practice improved hand dexterity, function, and maximum hand opening in all participants. AIH + hand opening practice improved Box and Block Test scores vs baseline in 5 participants (p = 0.057) and vs sham + hand opening practice in all 6 participants (p = 0.016). All participants reduced Jebsen-Taylor Hand Function Test (JTHF) time after daily AIH + hand opening practice (–7.2 ± 1.4 seconds) vs baseline; 4 of 6 reduced JTHF time vs sham + hand opening practice (p = 0.078). AIH + hand opening practice improved maximum hand aperture in 5 of 6 participants (8.1 ± 2.7 mm) vs baseline (p = 0.018) and sham + hand opening practice (p = 0.030). In 5 participants, daily AIH–induced changes in hand opening were accompanied by improved EMG coactivity (p = 0.029).

Conclusions:

This report suggests the need for further study of AIH as a plasticity "primer" for task-specific training in spinal cord injury rehabilitation. Important clinical questions remain concerning optimal AIH dosage, patient screening, safety, and effect persistence.

ClinicalTrials.gov identifier:

NCT01272336.




Prediction of work resumption and sustainability up to 1 year after mild traumatic brain injury

2017-10-30T12:45:39-07:00

Objective:

To study return to work (RTW) after mild traumatic brain injury (mTBI) at several intervals after injury and to predict RTW on the basis of occupational factors in addition to demographic, personality, and injury-related factors at 6 and 12 months after injury.

Methods:

This was a prospective cohort study (UPFRONT study, n = 1,151) of patients with mTBI admitted to the emergency department. Patients received questionnaires at 2 weeks and 3, 6, and 12 months after injury. RTW was divided into 3 levels: complete (cRTW), partial (pRTW), and no RTW.

Results:

Rates of cRTW increased from 34% at 2 weeks to 77% at 12 months after injury, pRTW varied from 8% to 16% throughout the year. Logistic regression (complete vs incomplete RTW) demonstrated that apart from previously identified predictors such as demographics (e.g., age and education) and injury characteristics (e.g., cause and severity of injury) and indicators of psychological distress, occupational factors were of influence on work resumption after 6 months (area under the curve [AUC] = 0.82), At 12 months, however, the model was based solely on the presence of extracranial injuries and indicators of maladaptation after injury (AUC = 0.81).

Conclusions:

RTW after mTBI is a gradual process, with varying levels of RTW throughout the first year after injury. Different predictors were relevant for short- vs long-term work resumption, with occupational factors influencing short-term RTW. However, for both short- and long-term RTW, posttraumatic complaints and signs of psychological distress early after injury were relevant predictors, allowing early identification of patients at risk for problematic work resumption.




Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

2017-10-30T12:45:39-07:00

Objective:

To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.

Methods:

Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.

Results:

Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7–1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3–4.3; p = 0.006 and HR 2.5, 95% CI 1.1–5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2–69.1) to 69.7% (95% CI 50.4–96.3).

Conclusions:

This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.




Traumatic brain injury may not increase the risk of Alzheimer disease

2017-10-30T12:45:39-07:00

Traumatic brain injury (TBI) commonly occurs in civilian and military populations. Some epidemiologic studies previously have associated TBI with an increased risk of Alzheimer disease (AD). Recent clinicopathologic and biomarker studies have failed to confirm the relationship of TBI to the development of AD dementia or pathologic changes, and suggest that other neurodegenerative processes might be linked to TBI. Additional studies are required to determine the long-term consequences of TBI.




Neurolymphomatosis of the thoracic sympathetic chain

2017-10-30T12:45:39-07:00

Neurolymphomatosis (NL) is defined as lymphomatous invasion of cranial or peripheral nerves by non-Hodgkin lymphoma (NHL). While most cases of NL are due to secondary dissemination from systemic or CNS sites, in rare cases it can be the primary manifestation of the malignancy.1–3 Early recognition of the disease and its precise neuroanatomic localization is critical for successful treatment.




Post viral upper and lower motor neuron injuries

2017-10-30T12:45:39-07:00

A 20-year-old man presented with subacute dysarthria, along with bilateral facial and brachial palsy, after a febrile odynophagia. Initially brisk, his upper limb deep tendon reflexes decreased with muscle wasting concerning the C5-T1 myotomes. MRI showed bilateral prefrontal gyri and thalami lesions with anterior cervical spinal cord lesion (figures 1 and 2). Upper limb lower motor neuron involvement was confirmed by EMG. CSF analysis showed lymphocytic pleiocytosis, elevated protein, and normal glucose levels. Epstein-Barr virus (EBV) serology revealed acute infection with the presence of viral capsid antigen (VCA) immunoglobulin M and VCA immunoglobulin G (IgG), in the absence of Epstein-Barr nuclear antigen–1 IgG. EBV DNA load was increased in blood and CSF. Other investigations including HIV screening remained negative. Simultaneous upper and lower motor neuron injury, well-described in HIV, is an unusual finding in EBV infection.1




Editors' Note

2017-10-30T12:45:39-07:00

Editors' Note: In "Trends in dementia prevalence, incidence, and survival rate in a Japanese community," the authors found an increase in Alzheimer disease (AD) prevalence in Japan between 1985 and 2012. Dr. Grant presents findings from other studies, supporting the explanation that the transition from a traditional Japanese diet to a westernized diet, replete with meat and other animal products, correlates to rising rates of AD and of cancers common in Western countries, with a lag time of several decades.




Letter re: Trends in dementia prevalence, incidence, and survival rate in a Japanese community

2017-10-30T12:45:39-07:00

I read with interest the article by Ohara et al.1 regarding trends in dementia prevalence, incidence, and survival rate in a Japanese community. The findings were similar to those reported in 2012 by Dodge et al.,2 in which Alzheimer disease (AD) rates for the elderly increased from 1% in 1985 to 7% in 2008. I explained that findings were due to the nutrition transition from the traditional Japanese diet to the Western diet, heavy in meat and other animal products, with a lag of 15–25 years.3 More recently, in a multicountry study, I found that dietary animal products other than milk were strongly correlated with AD prevalence 5–10 years prior to the prevalence data.4 The nutrition transition in Japan was also associated with the large increases in types of cancer common in Western countries, such as breast cancer, for which it was found that "the estimated time lag values for the influence of fat, animal protein, and TDF [total dietary fiber] were 20–32 years, 19–31 years, and 9–35 years, respectively."5 While increased survival plays an important role, it appears that the transition to the Western diet explains the bulk of increased AD rates in Japan. Owing to these concerns, the p values reported by the authors may provide an inaccurate picture of statistical significance. The data should be reanalyzed.




Author response: Trends in dementia prevalence, incidence, and survival rate in a Japanese community

2017-10-30T12:45:39-07:00

We thank Dr. Grant for the comment on our article.1 According to the data on dietary supply from the Food and Agriculture Organization of the United Nations, the consumption of meat (from 7.6 to 33.7 kg/capita/y), animal fat (from 5 to 35 kg/capita/y), and energy from animal products (from 249 to 580 kcal/capita/d) increased from 1961 to 1985 in Japan.2 As Dr. Grant pointed out, the increasing consumption of animal products was highly correlated with data on the prevalence of Alzheimer disease (AD) in Japan with a lag of 25 years (correlation coefficient = 0.92).3 In addition, a multicountry ecologic study revealed that the dietary intake of animal products other than milk was also strongly associated with AD prevalence 5–15 years later.4 These findings suggest that increasing consumption of animal products due to the westernization of dietary habits may be partly responsible for the rapid increase in AD prevalence from 1985 to 2012 in Japan.1




Letter re: Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

2017-10-30T12:45:39-07:00

Ng et al.1 reported that Neuropsychiatric Inventory (NPI) scores predict hypometabolism in the posterior cingulate cortex (PCC) in preclinical Alzheimer disease (AD) with PCC hypermetabolism at baseline preceding hypometabolism 2 years later. Early and progressive hypometabolism/atrophy of the PCC in AD is a well-established finding,2,3 but early hypermetabolism is more difficult to reconcile with current network-based models of neurodegeneration. Whether it is suitable to classify groups according to average metabolic changes in the same regions that emerge in subsequent analyses (e.g., orbitofrontal, PCC) is unclear.




Author response: Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

2017-10-30T12:45:39-07:00

We thank Landin-Romero and Kumfor for the comments. Our regression techniques showed an association between neuropsychiatric inventory (NPI) scores and [18F]fluorodeoxyglucose (FDG) uptake in preclinical Alzheimer disease (AD).1 We did not find posterior cingulate cortex (PCC) hypermetabolism, but higher PCC-FDG uptake was found in patients with preclinical AD with higher NPI scores at baseline. We did not find hypermetabolism even when we contrasted the mean FDG uptake at the local maxima within the cluster.




Senses

2017-10-23T12:48:24-07:00

Scent of newborn wrapped in a knitted blanket

Watch her grow, first day of school

Track her on the playground, never a moment of rest

Chew on oatmeal raisin cookies baked together

Shut our eyes for hide-and-seek

Hear her cry, she skinned her knees

Cheer as she scores a goal

Carry her when she falls down

Run to catch up, now she's too fast

Clap and celebrate, it's graduation

Point to her suitcase, she is ready to pack

Hug her tight and hope she comes back

She walks to the gate, college here she comes

Reflex to wake her up for school, no longer there

Home feels off-balance, too quiet

Sharp pain from the tough goodbye

Cold sheets of her bed, now vacant

Buzz of the phone, could that be her

Soft touch of her yarn blanket

Person, Place, and Time: Mother, at home, waiting.




Clinical Reasoning: A common cause for Phelan-McDermid syndrome and neurofibromatosis type 2: One ring to bind them

2017-10-23T12:48:24-07:00

An 8-year-old girl with mild dysmorphic features presented for evaluation of developmental delay and staring spells. She had been born late preterm and spent 1 month in the neonatal intensive care unit. She was generally healthy other than her developmental delay, which improved somewhat with physical, occupational, and speech therapy. At the first clinic visit, her mother reported loss of previously mastered vocabulary and struggles with fine motor skills such as buttoning. She also noted repetitive movements, obsessive behaviors, and hand flapping.




Pearls & Oy-sters: CNS lymphoma in a patient with relapsing-remitting multiple sclerosis treated with interferon

2017-10-23T12:48:24-07:00

Early clinical suspicion for CNS lymphoma is important for appropriate diagnosis and treatment in patients with preexisting multiple sclerosis (MS).




Teaching NeuroImages: Hypoglossal nerve palsy due to basilar invagination

2017-10-23T12:48:24-07:00

A woman in her 50s presented to the emergency room with complaints of gait instability. Her examination was notable for tongue deviation to the left. Imaging demonstrated basilar invagination and compression of the preolivary sulci near the cranial nerve 12 nerve root exit zone (figures 1 and 2). Basilar invagination is a rare craniocervical malformation, which can cause neurologic deficits and instability of the craniocervical junction.1,2 Imaging is also notable for platybasia, which is often associated with basilar invagination. The patient underwent a posterior occiput-C3 decompression and fusion without any complications. The patient had a stable neurologic examination on 3-month follow-up.




Teaching NeuroImages: New-onset focal epilepsy: The curious case of the camel and the jawbone

2017-10-23T12:48:24-07:00

A 54-year-old right-handed woman was referred for evaluation of drug-resistant epilepsy. At age 16, while riding in a park in Perth, Western Australia, she had been thrown from her horse, which had been startled by a rogue camel. There was no significant head injury but the patient subsequently noted a "clicky" jaw. At age 37, she developed recurrent episodes involving a sense of disconnection followed by dysphasia.




Spotlight on the October 24 issue

2017-10-23T12:48:24-07:00




Deciphering neurodegeneration: A paradigm shift from focality to connectivity

2017-10-23T12:48:24-07:00

"Wet or dry" is the fundamental dichotomy of biomarker research, referring to biofluid vs imaging-based approaches. Biomarker development in neurodegeneration has gained unprecedented momentum in recent years. Despite the substantial diagnostic advantages of molecular PET and biofluid markers, accurate prognostic indicators and sensitive monitoring markers are urgently required both for clinical trial designs and individualized patient care.




Can lifestyle modification slow progression of Parkinson disease?

2017-10-23T12:48:24-07:00

Parkinson disease (PD), similar to other neurodegenerative conditions, is characterized by relentless clinical progression with gradual worsening of both motor and nonmotor features. Potential neuroprotective therapies focusing on aspects of neurodegeneration in PD such as impaired mitochondrial function with abnormalities of oxidative phosphorylation, increased oxidative stress, and suppressed neuroinflammation, have failed to alter the clinical course of PD.1,2 New insights into PD pathophysiology have identified potential molecular targets, including accumulation and potential prion-like spreading of aggregates containing misfolded α-synuclein protein.3 These therapies are only approaching clinical testing, and their true therapeutic potential remains unknown. Even if successful, they are many years away from clinical availability. Thus, at present, we do not have any proven pharmacologic options to modify the progressive decline of patients with PD.




Virtually reducing fall risk in Parkinson disease

2017-10-23T12:48:24-07:00

Falls are common and often represent devastating events for patients with advanced Parkinson disease (PD). Prospective studies report that 70% of people with PD have at least one fall in a year, and that 39% fall recurrently. Falls have serious consequences (fractures and other injury, hospital admission, fear of falls, and an increase in caregiver burden).1,2 The few available treatment options are not highly effective.




Brain network connectivity differs in early-onset neurodegenerative dementia

2017-10-23T12:48:24-07:00

Objective: To investigate functional brain network architecture in early-onset Alzheimer disease (EOAD) and behavioral variant frontotemporal dementia (bvFTD). Methods: Thirty-eight patients with bvFTD, 37 patients with EOAD, and 32 age-matched healthy controls underwent 3D T1-weighted and resting-state fMRI. Graph analysis and connectomics assessed global and local functional topologic network properties, regional functional connectivity, and intrahemispheric and interhemispheric between-lobe connectivity. Results: Despite similarly extensive cognitive impairment relative to controls, patients with EOAD showed severe global functional network alterations (lower mean nodal strength, local efficiency, clustering coefficient, and longer path length), while patients with bvFTD showed relatively preserved global functional brain architecture. Patients with bvFTD demonstrated reduced nodal strength in the frontoinsular lobe and a relatively focal altered functional connectivity of frontoinsular and temporal regions. Functional connectivity breakdown in the posterior brain nodes, particularly in the parietal lobe, differentiated patients with EOAD from those with bvFTD. While EOAD was associated with widespread loss of both intrahemispheric and interhemispheric functional correlations, bvFTD showed a preferential disruption of the intrahemispheric connectivity. Conclusions: Disease-specific patterns of functional network topology and connectivity alterations were observed in patients with EOAD and bvFTD. Graph analysis and connectomics may aid clinical diagnosis and help elucidate pathophysiologic differences between neurodegenerative dementias. [...]



Mixed neuropathologies and associations with domain-specific cognitive decline

2017-10-23T12:48:24-07:00

Objective: To test whether decline in specific cognitive domains associated with Alzheimer disease neuropathologic change (ADNC) is modified by co-occurrence of other neuropathologies such as Lewy body disease (LBD) or vascular brain injury (VBI). Methods: Data came from 1,603 autopsied participants evaluated at US Alzheimer's Disease Centers. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed-effects models assessed associations between neuropathologies and longitudinal trajectories of domain scores. Results: Compared to other participants, those with ADNC + LBD generally had worse cognitive trajectories, particularly lower initial executive function and faster attention decline. Participants with ADNC + VBI typically had less impairment and slower decline. Interactions were significant between LBD and ADNC for memory (p = 0.046) and between VBI and ADNC for language (p = 0.03); decline was slower than expected if these neuropathologies acted additively on the rate of decline. In secondary models, these interactions were limited to those with high ADNC (but not intermediate ADNC). In a subset of 260 participants with data on microinfarct location, cortical and subcortical microinfarcts were associated with decline in memory, language, and executive function in those without ADNC, but this effect was reduced among those with ADNC. Conclusions: ADNC + LBD (but not ADNC + VBI) was associated with poorer executive function and attention compared to other pathology groupings. However, the effect of co-occurring pathologies on cognitive trajectories may depend on the severity of ADNC. Fut[...]



Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers

2017-10-23T12:48:24-07:00

Objective: To determine the association between synaptic functioning as measured via neurogranin in CSF and cognition relative to established Alzheimer disease (AD) biomarkers in neurologically healthy older adults. Methods: We analyzed CSF concentrations of neurogranin, β-amyloid (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) among 132 neurologically normal older adults (mean 64.5, range 55–85), along with bilateral hippocampal volumes and a measure of episodic memory (Auditory Verbal Learning Test, delayed recall). Univariable analyses examined the relationship between neurogranin and the other AD-related biomarkers. Multivariable regression models examined the relationship between neurogranin and delayed recall, adjusting for age and sex, and interaction terms (neurogranin x AD biomarkers). Results: Higher neurogranin concentrations were associated with older age ( = 0.20, p = 0.02), lower levels of p-tau and t-tau, and smaller hippocampal volumes (p < 0.03), but not with CSF Aβ42 (p = 0.18). In addition, CSF neurogranin demonstrated a significant relationship with memory performance independent of the AD-related biomarkers; individuals with the lowest CSF neurogranin concentrations performed better on delayed recall than those with medium or high CSF neurogranin concentrations (p < 0.01). Notably, CSF p-tau, t-tau, and Aβ42 and hippocampal volumes were not significantly associated with delayed recall scores (p > 0.40), and did not interact with neurogranin to predict memory (p > 0.10). Conclusions: Synaptic dysfunction (assessed via neurogranin) may be an early pathologic process in age-related neurodegeneration, and a sensitive marker[...]



Association of metabolic syndrome and change in Unified Parkinson's Disease Rating Scale scores

2017-10-23T12:48:24-07:00

Objective: To explore the association between metabolic syndrome and the Unified Parkinson’s Disease Rating Scale (UPDRS) scores and, secondarily, the Symbol Digit Modalities Test (SDMT). Methods: This is a secondary analysis of data from 1,022 of 1,741 participants of the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1, a randomized, placebo-controlled trial of creatine. Participants were categorized as having or not having metabolic syndrome on the basis of modified criteria from the National Cholesterol Education Program Adult Treatment Panel III. Those who had the same metabolic syndrome status at consecutive annual visits were included. The change in UPDRS and SDMT scores from randomization to 3 years was compared in participants with and without metabolic syndrome. Results: Participants with metabolic syndrome (n = 396) compared to those without (n = 626) were older (mean [SD] 63.9 [8.1] vs 59.9 [9.4] years; p < 0.0001), were more likely to be male (75.3% vs 57.0%; p < 0.0001), and had a higher mean uric acid level (men 5.7 [1.3] vs 5.3 [1.1] mg/dL, women 4.9 [1.3] vs 3.9 [0.9] mg/dL, p < 0.0001). Participants with metabolic syndrome experienced an additional 0.6- (0.2) unit annual increase in total UPDRS (p = 0.02) and 0.5- (0.2) unit increase in motor UPDRS (p = 0.01) scores compared with participants without metabolic syndrome. There was no difference in the change in SDMT scores. Conclusions: Persons with Parkinson disease meeting modified criteria for metabolic syndrome experienced a greater increase in total UPDRS scores over time, mainly as a result of increas[...]



Caffeine as symptomatic treatment for Parkinson disease (Cafe-PD): A randomized trial

2017-10-23T12:48:24-07:00

Objective: To assess effects of caffeine on Parkinson disease (PD). Methods: In this multicenter parallel-group controlled trial, patients with PD with 1–8 years disease duration, Hoehn & Yahr stages I–III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6–18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society–sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]–III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life. Results: Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups –0.48 [95% confidence interval –3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo). Conclusion: Caffeine did not pro[...]



Comment: Caffeine and PD--Time to consider other interventions

2017-10-23T12:48:24-07:00

Caffeine had shown promise in a small (61 patients), short (6 weeks), randomized study1 for improving motor function in patients with Parkinson disease. Caffeine holds appeal as an inexpensive intervention that is well-tolerated in most individuals. The investigators for that small study now report the results of a multicenter randomized study2 using the same outcome. They designed the study to have approximately 4 times as many participants, an extended follow-up to evaluate the persistence of any effects, and adequate power to detect a similar effect size as observed in the smaller study. The study focused on symptomatic improvement and not disease progression given the lack of any biological model in which caffeine would affect the latter.




Disparate effects of training on brain activation in Parkinson disease

2017-10-23T12:48:24-07:00

Objective: To compare the effects of 2 forms of exercise, i.e., a 6-week trial of treadmill training with virtual reality (TT + VR) that targets motor and cognitive aspects of safe ambulation and a 6-week trial of treadmill training alone (TT), on brain activation in patients with Parkinson disease (PD). Methods: As part of a randomized controlled trial, patients were randomly assigned to 6 weeks of TT (n = 17, mean age 71.5 ± 1.5 years, disease duration 11.6 ± 1.6 years; 70% men) or TT + VR (n = 17, mean age 71.2 ± 1.7 years, disease duration 7.9 ± 1.4 years; 65% men). A previously validated fMRI imagery paradigm assessed changes in neural activation pretraining and post-training. Participants imagined themselves walking in 2 virtual scenes projected in the fMRI: (1) a clear path and (2) a path with virtual obstacles. Whole brain and region of interest analyses were performed. Results: Brain activation patterns were similar between training arms before the interventions. After training, participants in the TT + VR arm had lower activation than the TT arm in Brodmann area 10 and the inferior frontal gyrus (cluster level familywise error–corrected [FWEcorr] p < 0.012), while the TT arm had lower activation than TT + VR in the cerebellum and middle temporal gyrus (cluster level FWEcorr p < 0.001). Changes in fall frequency and brain activation were correlated in the TT + VR arm. Conclusions: Exercise modifies brain activation patterns in patients with PD in a mode-specific manner. Motor-cognitive training decreased the reliance on frontal regi[...]



A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy

2017-10-23T12:48:24-07:00

Objective: To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD). Methods: Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg–1·d–1, tadalafil 0.6 mg·kg–1·d–1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome. Results: Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state. Conclusions: Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age. Clinicaltrials.gov identifier: NCT01865084. Clas[...]



UFM1 founder mutation in the Roma population causes recessive variant of H-ABC

2017-10-23T12:48:24-07:00

Objective: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations. Methods: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression. Results: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all 16 patients. All patients shared a common haplotype, indicative of a founder effect. Screening of 1,000 controls from different European Roma panels demonstrated an overall carrier rate of the mutation of 3%–25%. Transfection assays showed that the deletion significantly reduced expression in specific CNS cell lines. Conclusions: UFM1 encodes ubiquitin-fold modifier 1 (UFM1), a member of the ubiquitin-like family involved in posttranslational modification of proteins. Its exact biological role is unclear. This study associates a UFM1 gene[...]



COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls

2017-10-23T12:48:24-07:00

Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. Results: A locus in COL4A2 was associated (significance threshold p < 3.5 x 10–4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 x 10–8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 x 10–5). A SNP in HTRA1 was associated (significance threshold p < 5.5 x 10–4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 x 10–4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype. Conclusions: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic[...]



Pilocytic astrocytoma with anaplasia arising from the optic chiasm in a very elderly patient

2017-10-23T12:48:24-07:00

An 81-year-old man presented with a 3-week history of impaired visual acuity (100/200 right eye, 2/200 left eye). He had a central scotoma (left eye) and bitemporal hemianopsia, with no abnormality in the optic discs. Cranial MRI suggested a tumor predominantly located at the optic chiasm and extending to the optic nerves, identified pathologically as pilocytic astrocytoma with anaplasia (PAA) (figure). He received temozolomide (for 14 months) and irradiation, but the tumor eventually extended to the hypothalamus. This unusual case of histologically proven PAA demonstrates an origin from the optic chiasm,1 which is extremely rare in the elderly.2




Head flutter

2017-10-23T12:48:24-07:00

A previously healthy 30-year-old man presented with oscillopsia, involuntary head movements, and imbalance. His examination showed intermittent ocular flutter (OF), bursts of back-to-back horizontal head movements time-locked with OF (head flutter) (figure; video at Neurology.org), and generalized ataxia. Head MRI, paraneoplastic antibody testing, CSF analysis, toxicology and serology panel, and CT of chest/abdomen/pelvis were unrevealing. The patient fully recovered after 6 months with monthly IV immunoglobulin.




Editors' Note

2017-10-23T12:48:24-07:00

Editors' Note: Motor involvement is not considered a typical feature of Fabry disease (FD). However, recent studies reported slower gait, reduced hand speed, and poorer fine manual dexterity, independently of cerebrovascular symptoms, in patients with FD. To further study alterations in motor circuits of patients with FD, Cocozza et al. used resting-state (RS)–fMRI.




Letter re: Alterations of functional connectivity of the motor cortex in Fabry disease: An RS-fMRI study

2017-10-23T12:48:24-07:00

Cocozza et al.1 confirmed, by use of resting-state (RS)–fMRI, previous clinical and electrophysiologic studies showing involvement of cerebral motor circuits in Fabry disease (FD), independently of cerebrovascular signs/symptoms and brain MRI lesions.1–3 In particular, they showed alterations of functional connectivity in a polysynaptic motor circuit involving motor cortices, basal ganglia, and right cerebellar hemisphere.1 In metabolic/lysosomal storage diseases, a subclinical CNS impairment is common and may be related, regardless of brain MRI findings, either to a structural irreversible or to a biochemical reversible brain lesion.4,5 A crucial unsettled question in the article is the usefulness of RS-fMRI in detecting subtle and potentially reversible biochemical brain lesions in patients with FD at a rather early appearance. We investigated this question in a previous study by analyzing the effect of 1 year of enzyme replacement therapy (ERT) on cortical excitability in 5 patients with FD without brain MRI lesions, and an increase of excitatory neurotransmission in motor cortex circuits, documented by transcranial magnetic stimulation (TMS).3 We observed a reduction in motor cortex hyperexcitability in all patients after ERT, indicating the possible utility of TMS, and likely of other techniques such as RS-fMRI, in monitoring the disease course and the response to therapy. [...]



Author response: Alterations of functional connectivity of the motor cortex in Fabry disease: An RS-fMRI study

2017-10-23T12:48:24-07:00

We thank Sechi et al. for the comments on our article.1 We agree that investigating the relationship between functional changes and disease course is a core issue for defining the role of functional imaging in both pathophysiology and clinical studies in Fabry disease (FD). The findings of Ortu et al.2 help define the role of the functional connectivity (FC) alterations in patients. Indeed, in their study,2 motor cortex hyperexcitability partly subsided when enzyme replacement therapy was started (although the small number of patients and the incomplete reversal of transcranial magnetic stimulation findings, possibly related to insufficient follow-up, does not allow for firm conclusions due to its complete reversibility). On the contrary, we found that resting-state–fMRI alterations were present in successfully treated patients, mitigating against the hypothesis that these changes may reflect reversible FD features.1 While our view is that "a direct relationship between motor cortex hyperexcitability...and present FC changes remains speculative,"1 longitudinal studies with suitable sample sizes assessing both FC and motor cortex excitability are needed. Only this approach will demonstrate if FC changes are related to a residual, nonreversible hyperexcitability, or if different neural circuit alterations are probed by the 2 techniques. [...]