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

2017-06-12T12:48:05-07:00

Objective:

To evaluate the effect of scheduled bedside skills modeling for third-year medical students on their neurology clerkship.

Methods:

During the 2012–2014 academic years, 56 third-year medical students participated in a curricular pilot program involving a scheduled bedside skills modeling experience during the first week of their neurology clerkship, whereas 131 students underwent the typical rotation. The experience consisted of observing a faculty member conduct a comprehensive encounter on a new outpatient. To promote active learning, students were provided an observation guide to document questions and observations. An anonymous survey was conducted at the end of each clerkship block assessing student exposure to bedside skills modeling. Using qualitative thematic analysis, observation guide statements were transcribed and coded into emergent learning themes.

Results:

A total of 57.4% (95% confidence interval [CI] 43.3%–71.5%) of students in the modeling group reported observing both a comprehensive history and neurologic examination vs 37.5% (95% CI 28.2%–46.8%) in the nonmodeling groups (p = 0.023). A total of 253 observation statements were transcribed and coded from the observation guides. The most common learning themes included (1) strategies for performing a neurologic examination, (2) techniques for eliciting a neurologic history, and (3) importance of detail and thoroughness of the history and examination.

Conclusions:

Our study demonstrated that there was a significant increase in structured observation by students of neurologic bedside skills with the inclusion of a scheduled modeling experience, and we provide a qualitative description of the most common learning themes associated with this experience.




Clinical Reasoning: Acute onset facial droop in a 36-year-old pregnant woman

2017-06-12T12:48:05-07:00

A 36-year-old woman, G1P0, 22 weeks pregnant, presented to the emergency department for evaluation of acute onset facial droop. Her medical history included ulcerative colitis, primary sclerosing cholangitis, and heterozygosity for the prothrombin G20210A mutation. She was on 10,000 units of subcutaneous heparin twice daily for a previous deep vein thrombosis secondary to her prothrombin mutation; she was noncompliant with prescribed aspirin.




Pearls & Oy-sters: Retrievable and awake: A case report of solitaire stent employment for venous pulsatile tinnitus

2017-06-12T12:48:05-07:00

A 50-year-old woman presented with a 2-year history of right-sided pulsatile tinnitus. Her medical history was unremarkable. Over the preceding 2 years, with the diagnosis of idiopathic pulsatile tinnitus, a bruit gradually developed and severely disturbed her sleep (Tinnitus Handicap Inventory score of 58).




Spotlight on the June 13 issue

2017-06-12T12:48:05-07:00




Imaging-based selection of patients for acute stroke treatment: Is it ready for prime time?

2017-06-12T12:48:05-07:00

Historically, brain imaging in acute stroke has sought to exclude brain hemorrhage in order to allow therapy aiming at recanalization of the occluded intracranial artery. The National Institute of Neurological Disorders and Stroke study, published in 1995, found a clinical benefit of IV thrombolysis in acute stroke after exclusion of brain hemorrhage based on noncontrast CT (NCCT).1 More than 20 years later, the decision at most centers whether to give thrombolysis within the first 4.5 hours remains based on NCCT; often, the bolus of recombinant tissue plasminogen activator (rt-PA) is administered in the CT scanner suite even before vascular and perfusion imaging is performed to avoid any delay. While acknowledging that time is brain, the experienced stroke neurologist often feels that a more precise selection of patients, at the time of the decision for acute revascularization therapy, would be clinically beneficial. The publication of trials demonstrating higher rates of functional independence at 3 months in 2 studies (SWIFT PRIME2 and EXTEND-IA3) that required the demonstration of substantial ischemic penumbra for inclusion (60% and 71%, respectively) compared to those that did not (MR CLEAN, 33%4; REVASCAT, 44%5; and ESCAPE, 53%6) underscores the dilemma. Better selection can improve patient outcome and avoid futile and costly endovascular treatments.




Beyond clinical syndromes in primary progressive aphasia: Seeking etiologic diagnoses

2017-06-12T12:48:05-07:00

Primary progressive aphasia (PPA) is an acquired disorder in which speech and language problems are the dominant (salient) manifestations during the initial symptomatic illness.1 Because of substantial syndromic–etiologic heterogeneity in some subtypes of PPA, it is a case study in the challenges of linking clinical syndromes to etiology. In a disorder like PPA, there is a pressing need to develop methodologies to diagnose underlying etiology. While definitive treatment for the neurodegenerative cognitive disorders is still in the future, basic and translational neuroscience is at the threshold of testing promising new therapies. Precise diagnosis of underlying brain pathophysiology is integral to success in clinical trials. Development of PET imaging biomarkers has great potential for offering direct confirmation of etiology, but PET imaging is expensive. The article by Giannini et al.2 in this issue of Neurology® applies the low-technology clinical observation approach for seeking indicators of PPA etiologic subtypes.




Thalamus as a "hub" to predict outcome after epilepsy surgery

2017-06-12T12:48:05-07:00

The role of the thalamus in mediating seizure activity has been investigated for decades.1 In 1952, Penfield2 proposed "centrencephalic" interactions as an integral part not only of generalized but also of focal automatisms. The dynamic integration between the centrencephalic system and cerebral cortex was hypothesized as pivotal for normal brain function, as well as a mechanism for seizure propagation. The concept was later hotly debated, and generalized seizures with 3-Hz spike wave discharges were considered mainly centrencephalic.1




Evaluation of hyperacute infarct volume using ASPECTS and brain CT perfusion core volume

2017-06-12T12:48:05-07:00

Objective:

To compare the accuracy of Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and CT perfusion to detect established infarction in acute anterior circulation stroke.

Methods:

We performed an observational study in 59 acute anterior circulation ischemic stroke patients who underwent brain noncontrast CT, CT perfusion, and MRI within 100 minutes from CT imaging. ASPECTS scores were calculated by 4 blinded vascular neurologists. The accuracy of ASPECTS and CT perfusion core volume to detect an acute MRI diffusion lesion of ≥70 mL was evaluated using receiver operating characteristics analysis and optimum cutoff values were calculated using Youden J.

Results:

Median ASPECTS score was 8 (interquartile range [IQR] 5–9). Median CT perfusion core volume was 22 mL (IQR 10.4–71.9). Median MRI diffusion lesion volume was 24.5 mL (IQR 10–63.9). No significant difference was found between the accuracy of CT perfusion and ASPECTS (c statistic 0.95 vs 0.87, p value for difference = 0.17). The optimum ASPECTS cutoff score to detect a diffusion-weighted imaging lesion ≥70 mL was <7 (sensitivity 0.74, specificity 0.86, Youden J = 0.60) and the optimum CT perfusion core volume cutoff was ≥50 mL (sensitivity 0.86, specificity 0.97, Youden J = 0.84). The CT perfusion core lesion covered a median of 100% (IQR 86%–100%) of the acute MRI lesion volume (Pearson R = 0.88; R2 = 0.77).

Conclusions:

We found no significant difference between the accuracy of CT perfusion and ASPECTS to predict hyperacute MRI lesion volume in ischemic stroke.




MR perfusion lesions after TIA or minor stroke are associated with new infarction at 7 days

2017-06-12T12:48:05-07:00

Objective:

To investigate the relationship between acute perfusion-weighted imaging (PWI) lesions occurring within the first hours after a TIA or a minor brain infarction (BI) and the incidence of new BI detected on a systematic MRI at 1 week.

Methods:

Consecutive patients who experienced a TIA or BI with a neurologic deficit that lasted <24 hours, did not receive any revascularization therapy (thrombolysis/thrombectomy), and underwent DWI/PWI at baseline and fluid-attenuated inversion recovery (FLAIR)/DWI 1 week after symptom onset were enrolled. Investigators blinded to clinical information independently assessed the presence of acute ischemic lesions on baseline DWI/PWI and follow-up DWI and FLAIR. Baseline and follow-up MRIs were then compared to determine the occurrence and location of new infarctions.

Results:

Sixty-four patients met the inclusion criteria. Median (IQR) ABCD2 score was 4 (3–5). Median delay from onset to baseline and follow-up MRI was 5 (2–10) hours and 6 (5–7) days, respectively. MRI revealed an acute ischemic lesion on DWI and/or PWI in 38 patients. Nine patients (14%) had a new infarction on follow-up MRI. Each had a PWI and 4 had a DWI lesion on baseline MRI. All new BIs except one were asymptomatic and in the same location as the acute PWI lesion.

Conclusions:

Our results showed that 30% of the acute focal PWI lesions detected after a TIA are associated with a new BI at 1 week. Those new BIs may result from the progression of the initial ischemic injury.




Total small vessel disease score and risk of recurrent stroke: Validation in 2 large cohorts

2017-06-12T12:48:05-07:00

Objective:

In patients with TIA and ischemic stroke, we validated the total small vessel disease (SVD) score by determining its prognostic value for recurrent stroke.

Methods:

Two independent prospective studies were conducted, one comprising predominantly Caucasian patients with TIA/ischemic stroke (Oxford Vascular Study [OXVASC]) and one predominantly Chinese patients with ischemic stroke (University of Hong Kong [HKU]). Cerebral MRI was performed and assessed for lacunes, microbleeds, white matter hyperintensities (WMH), and perivascular spaces (PVS). Predictive value of total SVD score for risk of recurrent stroke was determined and potential refinements considered.

Results:

In 2,002 patients with TIA/ischemic stroke (OXVASC n = 1,028, HKU n = 974, 6,924 patient-years follow-up), a higher score was associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio [HR] per unit increase: 1.32, 1.16–1.51, p < 0.0001; c statistic 0.61, 0.56–0.65, p < 0.0001) and intracerebral hemorrhage (ICH) (HR 1.54, 1.11–2.13, p = 0.009; c statistic 0.65, 0.54–0.76, p = 0.006). A higher score predicted recurrent stroke in SVD and non-SVD TIA/ischemic stroke subtypes (c statistic 0.67, 0.59–0.74, p < 0.0001 and 0.60, 0.55–0.65, p < 0.0001). Including burden of microbleeds and WMH and adjusting the cutoff of basal ganglia PVS potentially improved predictive power for ICH (c statistic 0.71, 0.60–0.81, phet = 0.45), but not for recurrent ischemic stroke (c statistic 0.60, 0.56–0.65, phet = 0.76) on internal validation.

Conclusions:

The total SVD score has predictive value for recurrent stroke after TIA/ischemic stroke. Prediction of recurrence in patients with nonlacunar events highlights the potential role of SVD in wider stroke etiology.




Racial disparities in neurologic health care access and utilization in the United States

2017-06-12T12:48:05-07:00

Objective:

To evaluate racial and ethnic differences in the utilization of neurologic care across a wide range of neurologic conditions in the United States.

Methods:

We analyzed nationally representative data from the 2006–2013 Medical Expenditure Panel Survey (MEPS), including information on demographics, patient-reported health conditions, neurology visit rates, and costs. Using diagnostic codes, we identified persons with any self-identified neurologic disorder except back pain, as well as 5 subgroups (Parkinson disease, multiple sclerosis, headache, cerebrovascular disease, and epilepsy). To assess disparities in neurologic care utilization, we performed logistic regression analyses of outpatient department neurologic care visit rates and expenditures for each racial ethnic group controlling for age, sex, health status, socioeconomic characteristics, and geographic region of care.

Results:

Of the 279,103 MEPS respondents, 16,936 (6%) self-reported a neurologic condition; 5,890 (2%) received a total of 13,685 outpatient neurology visits. Black participants were nearly 30% less likely to see an outpatient neurologist (odds ratio [OR] 0.72, confidence interval [CI] 0.64–0.81) relative to their white counterparts, even after adjustment for demographic, insurance, and health status differences. Hispanic participants were 40% less likely to see an outpatient neurologist (OR 0.61, CI 0.54–0.69). Among participants with known neurologic conditions, blacks were more likely to be cared for in the emergency department, to have more hospital stays, and to have higher per capita inpatient expenditures than their white counterparts.

Conclusions:

Our findings highlight racial and ethnic inequalities in the utilization of neurologic care in the United States.




Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia

2017-06-12T12:48:05-07:00

Objective:

To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA).

Methods:

We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data.

Results:

A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA–). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03).

Conclusions:

Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.




Presurgical thalamic "hubness" predicts surgical outcome in temporal lobe epilepsy

2017-06-12T12:48:05-07:00

Objective:

To characterize the presurgical brain functional architecture presented in patients with temporal lobe epilepsy (TLE) using graph theoretical measures of resting-state fMRI data and to test its association with surgical outcome.

Methods:

Fifty-six unilateral patients with TLE, who subsequently underwent anterior temporal lobectomy and were classified as obtaining a seizure-free (Engel class I, n = 35) vs not seizure-free (Engel classes II–IV, n = 21) outcome at 1 year after surgery, and 28 matched healthy controls were enrolled. On the basis of their presurgical resting-state functional connectivity, network properties, including nodal hubness (importance of a node to the network; degree, betweenness, and eigenvector centralities) and integration (global efficiency), were estimated and compared across our experimental groups. Cross-validations with support vector machine (SVM) were used to examine whether selective nodal hubness exceeded standard clinical characteristics in outcome prediction.

Results:

Compared to the seizure-free patients and healthy controls, the not seizure-free patients displayed a specific increase in nodal hubness (degree and eigenvector centralities) involving both the ipsilateral and contralateral thalami, contributed by an increase in the number of connections to regions distributed mostly in the contralateral hemisphere. Simulating removal of thalamus reduced network integration more dramatically in not seizure-free patients. Lastly, SVM models built on these thalamic hubness measures produced 76% prediction accuracy, while models built with standard clinical variables yielded only 58% accuracy (both were cross-validated).

Conclusions:

A thalamic network associated with seizure recurrence may already be established presurgically. Thalamic hubness can serve as a potential biomarker of surgical outcome, outperforming the clinical characteristics commonly used in epilepsy surgery centers.




Effect of omega-3 supplementation on neuropathy in type 1 diabetes: A 12-month pilot trial

2017-06-12T12:48:05-07:00

Objective:

To test the hypothesis that 12 months of seal oil omega-3 polyunsaturated fatty acids (-3 PUFA) supplementation will stop the known progression of diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes mellitus (T1DM).

Methods:

Individuals with T1DM and evidence of DSP as determined by a Toronto Clinical Neuropathy Score ≥1 were recruited to participate in a single-arm, open-label trial of seal oil -3 PUFA supplementation (10 mL·d–1; 750 mg eicosapentaenoic acid, 560 mg docosapentaenoic acid, and 1,020 mg docosahexaenoic acid) for 1 year. The primary outcome was the 1-year change in corneal nerve fiber length (CNFL) measured by in vivo corneal confocal microscopy, with sensory and nerve conduction measures as secondary outcomes.

Results:

Forty participants (53% female), aged 48 ± 14 years, body mass index 28.1 ± 5.8 with diabetes duration of 27 ± 18 years, were enrolled. At baseline, 23 participants had clinical DSP and 17 did not. Baseline CNFL was 8.3 ± 2.9 mm/mm2 and increased 29% to 10.1 ± 3.7 mm/mm2 (p = 0.002) after 12 months of supplementation. There was no change in nerve conduction or sensory function.

Conclusions:

Twelve months of -3 supplementation was associated with increase in CNFL in T1DM.

ClinicalTrials.govidentifier:

NCT02034266.

Classification of evidence:

This study provides Class IV evidence that for patients with T1DM and evidence of DSP, 12 months of seal oil omega-3 supplementation increases CNFL.




Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease

2017-06-12T12:48:05-07:00

Objective:

To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase.

Methods:

We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters.

Results:

pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%–92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%–94.8%), a specificity of 88.0% (CI 75.7%–95.5%) and a likelihood ratio of 7.6 (CI 3.6–16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement.

Conclusions:

In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration.

Classification of evidence:

This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.




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

2017-06-12T12:48:05-07:00

Objective:

To examine the association between interferon-β (IFN-β) and potential adverse events using population-based health administrative data in British Columbia, Canada.

Methods:

Patients with relapsing-remitting multiple sclerosis (RRMS) who were registered at a British Columbia Multiple Sclerosis Clinic (1995–2004) were eligible for inclusion and were followed up until death, absence from British Columbia, exposure to a non–IFN-β disease-modifying drug, or December 31, 2008. Incidence rates were estimated for each potential adverse event (selected a priori and defined with ICD-9/10 diagnosis codes from physician and hospital claims). A nested case-control study was conducted to assess the odds of previous IFN-β exposure for each potential adverse event with at least 30 cases. Cases were matched by age (±5 years), sex, and year of cohort entry, with up to 20 randomly selected (by incidence density sampling) controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated with conditional logistic regression adjusted for age at cohort entry.

Results:

Of the 2,485 eligible patients, 77.9% were women, and 1,031 were treated with IFN-β during follow-up. From the incidence analyses, 27 of the 47 potential adverse events had at least 30 cases. Patients with incident stroke (ORadj 1.83, 95% CI 1.16–2.89), migraine (ORadj 1.55, 95% CI 1.18–2.04), depression (ORadj 1.33, 95% CI 1.13–1.56), and hematologic abnormalities (ORadj 1.32, 95% CI 1.01–1.72) were more likely to have previous exposure to IFN-β than controls.

Conclusions:

Among patients with RRMS, IFN-β was associated with a 1.8- and 1.6-fold increase in the risk of stroke and migraine and 1.3-fold increases in depression and hematologic abnormalities.




Benefits, pitfalls, and future design of population-based registers in neurodegenerative disease

2017-06-12T12:48:05-07:00

Population-based disease registers identify and characterize all cases of disease, including those that might otherwise be neglected. Prospective population-based registers in neurodegeneration are necessary to provide comprehensive data on the whole phenotypic spectrum and can guide planning of health services. With the exception of the rare disease amyotrophic lateral sclerosis, few complete population-based registers exist for neurodegenerative conditions. Incomplete ascertainment, limitations and uncertainty in diagnostic categorization, and failure to recognize sources of bias reduce the accuracy and usefulness of many registers. Common biases include population stratification, the use of prevalent rather than incident cases in earlier years, changes in disease understanding and diagnostic criteria, and changing demographics over time. Future registers are at risk of funding shortfalls and changes to privacy legislation. Notwithstanding, as heterogeneities of clinical phenotype and disease pathogenesis are increasingly recognized in the neurodegenerations, well-designed longitudinal population-based disease registers will be an essential requirement to complete clinical understanding of neurodegenerative diseases.




Zika virus infection-associated acute transient polyneuritis

2017-06-12T12:48:05-07:00

Zika virus (ZIKV) has been associated with various neurologic complications in adults, including Guillain-Barré syndrome (GBS), transverse myelitis, meningoencephalitis, and ophthalmologic manifestations. Though some of these syndromes may be due to a postinfectious (molecular mimicry) mechanism, a direct viral pathogenic mechanism may be responsible in others. We present 3 cases of a newly described syndrome of ZIKV-associated acute transient polyneuritis.




Square patches of light remember you

2017-06-12T12:48:05-07:00




A prepontine subarachnoid abscess by Escherichia coli

2017-06-12T12:48:05-07:00

A 53-year-old man had 6 months of intermittent fever and worsening headache, with 4/5 left hemiparesis and new unsteady gait, without other deficits. His immune status was normal, and he had self-treated with paracetamol-caffeine-aspirin powder. Two years prior he had purulent meningitis diagnosed by lumbar puncture with negative CSF culture, treated with ceftriaxone/vancomycin for 2 weeks.




Editors' Note

2017-06-12T12:48:05-07:00

Editors' Note: In WriteClick this week, Dr. Sethi asks for additional clarification about ferritin levels and iron supplementation beyond that found in "Practice guideline summary: Treatment of restless legs syndrome in adults." Authors Allen et al. review the pertinent evidence.




Letter re: Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

2017-06-12T12:48:05-07:00

I read with interest the practice guideline summary report for treatment of restless leg syndrome (RLS) in adults by the Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.1 Studies have shown a strong correlation between body iron stores, as determined by serum ferritin level, and the severity of RLS symptoms.2,3 Typically, in patients with RLS with ferritin level <50 mg/L, oral iron supplementation along with vitamin C, to help enhance iron absorption, is advised. How did the subcommittee arrive at a cutoff ferritin value of 75 mg/L? Can the subcommittee recommend how much iron supplementation is needed? What is the recommended ferritin level after supplementation? While studies looking at the efficacy of clonazepam for RLS symptoms may be lacking, giving it a Level U rating, there is ample anecdotal evidence attesting to its efficacy in RLS symptomatology.4




Author response: Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

2017-06-12T12:48:05-07:00

We appreciate Dr. Sethi's emphasis on the often overlooked iron treatment of restless legs syndrome (RLS) in the comment on our article.1 The recommendation to treat patients with serum ferritin less than or equal to 75 μg/L was based on the reviewed placebo-controlled study showing significant RLS benefit and ferritin increase with ferrous sulfate 325 mg (65 mg iron) with vitamin C 100 mg dosed twice daily.2 As described in the full-length guideline,1 only oral iron studies where patients had evidence of iron deficiency were considered for the guideline, and oral iron is absorbed only in the context of low iron levels. An additional placebo-controlled study with no serum ferritin limit (average 135 μg/L) showed no benefit on RLS symptoms or ferritin increase,3 likely reflecting limited absorption of iron for ferritin over 75 μg/L and also limitations in precision secondary to sample size. Optimal iron supplementation strategies are still under investigation.4 Clonazepam data are described in the full guideline report supplement,1,5,6 with insufficient evidence to support an evidence-based recommendation. Anecdotal evidence is subject to multiple types of bias and is insufficient to drive recommendations under the 2004 American Academy of Neurology process.




Letter re: Gram-negative bacterial molecules associate with Alzheimer disease pathology

2017-06-12T12:48:05-07:00

The findings of Zhan et al.1 are intriguing and further the understanding of Alzheimer disease pathogenesis. Although the investigators meticulously described the brain tissue handling procedures, there are concerns about contamination. In forensic pathology, postmortem microbial translocation from the gastrointestinal tract to other organs, especially with longer postmortem intervals, may interfere with the interpretation of microbiology cultures.2 A general autopsy performed before brain procurement could be another source of contamination from the gastrointestinal tract.3 Nevertheless, contamination can be detected by 16S rRNA gene sequencing for microbe identification4; presence of multiple bacterial species would indicate contamination. Another explanation for the presence of Escherichia coli in the brain would be the possibility of E coli bacteremia in the brain donors.




Author response: Gram-negative bacterial molecules associate with Alzheimer disease pathology

2017-06-12T12:48:05-07:00

The comment by Dr. Mente raises critical issues for any postmortem microbial study. We agree that short postmortem intervals (PMI) and precautions against contamination before dissection procedures, coupled with negative blood and organ cultures, would help exclude possible contamination. In our study,1 PMIs were similar in Alzheimer disease (AD) compared to controls, brain procurement was performed before general autopsy, and identical procedures were used for removing and processing samples from AD and control brains. Therefore, contamination is unlikely to explain the markedly increased levels and differing cellular localization of Gram-negative molecules in AD compared to control brains in our study. Our study did not show bacteria in brain, but rather showed that molecules from bacteria are found in AD brain. This supports a growing literature of similar findings and may help explain how gut, and perhaps systemic microbiota, affect brain structure and function.2–4




Clinical Reasoning: A 10-year-old boy with bilateral vision loss

2017-06-05T12:48:01-07:00

A 10-year-old previously healthy Caucasian boy was referred for evaluation of bilateral loss of vision with abnormal appearing optic nerves. Two months before the referral, the patient started to exhibit a decrease in vision both at near and at distance with difficulty reading books and difficulty viewing the chalkboard at school. One month prior to the referral, the patient was seen by his primary care physician with a complaint of intermittent headaches, which varied in severity, occurring as frequently as daily. The patient had been taking ibuprofen regularly to alleviate the pain. Vital signs were within normal limits. The patient weighed 53.5 kg and stood 145 cm tall (body mass index 25.4). The patient's family reported that the patient had gained substantial weight over the previous months. MRI and venography of the brain and orbit were unremarkable with no evidence of inflammation, demyelinating disease, or compressive or infiltrative lesions. A lumbar puncture was performed with an opening pressure of 20 cm H2O with normal cell count, protein, and glucose levels. The patient was started on acetazolamide 250 mg twice a day for a possible diagnosis of idiopathic intracranial hypertension (pseudotumor cerebri) and referred to neuro-ophthalmology for further evaluation.




Clinical Reasoning: A 16-year-old girl with subacute weakness and sensory loss

2017-06-05T12:48:01-07:00

A previously healthy 16-year-old girl developed numbness and tingling in the lower extremities that progressed over a 10-week period to the upper limbs. Two weeks prior to admission, she also developed weakness in her arms and legs, to the point of needing help getting dressed and support for walking. She denied sphincter or systemic symptoms. During the previous year, she had complained of intermittent shooting pains and tingling down her arms. Her psychiatric history was relevant for obsessive-compulsive traits and depression, and family history included autoimmune diseases in 2 sisters, an uncle, and 2 grandparents.




Pearls & Oy-sters: Symptomatic cerebral vasospasm on conventional angiography following temporal lobe epilepsy surgery

2017-06-05T12:48:01-07:00

Cerebral vasospasm is a complication of temporal lobe epilepsy (TLE) surgery.




Teaching NeuroImages: Fahr syndrome caused by hypoparathyroidism

2017-06-05T12:48:01-07:00

A 57-year-old woman with a remote history of thyroidectomy but no prior neurologic symptoms developed seizures, fever, and coma. Limited evaluation at her local hospital in rural Haiti demonstrated serum hypocalcemia (4 mg/dL) and extensive bilateral subcortical calcification in the cerebral and cerebellar hemispheres on CT (figure). This pattern of calcification can occur in inherited conditions such as familial idiopathic basal ganglia calcification (Fahr disease) and acquired conditions (referred to as Fahr syndrome) including parathyroid dysfunction and intrauterine infection.1,2 Given our patient's severe hypocalcemia, Fahr syndrome was attributed to presumed hypoparathyroidism related to prior thyroidectomy in her case.




Teaching NeuroImages: Giant cystic echinococcosis with unusual imaging manifestations

2017-06-05T12:48:01-07:00

A 6-year-old girl presented with a 3-month history of progressive left-eye strabismus and vision loss. MRI scan of the brain showed a single hypointense lesion in the left cerebral hemisphere with no perilesional edema or contrast enhancement (figure 1, A–C). At surgery, the lesion was shown to be a single large parasitic cyst measuring approximately 7.0 x 6.5 x 6.0 cm (figure 2, A–C). The patient underwent a complete resection and then was given antihelminthic therapy. This resulted in an uneventful recovery. Pathology confirmed a diagnosis of brain cyst with scolex. This imaging feature of giant cystic echinococcosis is very unusual.1 In the event of neurologic dysfunction or elevated intracranial pressure, emergent operative intervention should precede the administration of antihelminthic medications as the latter may weaken the cyst membrane and complicate resection. Gross total resection has advantages compared with nonsurgical treatment with antihelminthics.2




Spotlight on the June 6 issue

2017-06-05T12:48:00-07:00




Lacunes: Black holes in our understanding of cerebral amyloid angiopathy

2017-06-05T12:48:00-07:00

The origin of lacunes, small cavities in the brain, remained a matter of great controversy until Fisher1 used serial neuropathologic sections to identify thrombotic occlusion of small cerebral arteries in association with most, but not all, lacunes. Lacunes appear on MRI as black holes on sequences that are T1-weighted or T2-weighted with CSF suppression.




Restless legs syndrome: Losing sleep over the placebo response

2017-06-05T12:48:00-07:00

The placebo response is a vexing problem for clinical trial design and drug development. Defined as a clinical improvement that occurs in participants treated with a physiologically inert substance, the placebo response has been largely ascribed to "expectation of clinical improvement and Pavlovian conditioning."1 Other factors certainly play a role, however, including strict application of inclusion and exclusion criteria at study entry with subsequent reversion to the mean; that is, participants and investigators, knowing entry criteria for a trial, may subconsciously (or intentionally) overrate signs and symptoms to get into a trial, and then present at subsequent visits in their more typical state. Though this is not traditionally considered part of the true placebo response, it is likely that this phenomenon contributes to what is measured as the magnitude of the placebo response. Clinical trial design strategies such as central blinded ratings and avoiding the use of primary outcome measure criteria for screening can mitigate this phenomenon, but these are not routinely utilized.




Distribution of lacunes in cerebral amyloid angiopathy and hypertensive small vessel disease

2017-06-05T12:48:00-07:00

Objective:

To evaluate whether the burden of deep and lobar lacunes differs between patients with intracerebral hemorrhage (ICH) with definite/probable cerebral amyloid angiopathy (CAA) per the Boston criteria and hypertensive small vessel disease (HTN-SVD; ICH in basal ganglia, thalami, brainstem).

Methods:

We defined lobar and deep lacunes similar to the topographic distribution used for ICH and cerebral microbleeds (CMBs). We then compared their distribution between patients with CAA-ICH and those with strictly deep CMB and ICH (HTN-ICH). The independent associations of lacune location with the diagnosis of CAA-ICH and HTN-ICH were evaluated with multivariable models. The relationship between lobar lacunes and white matter hyperintensity (WMH) volume was evaluated by means of partial correlation analyses adjusted for age and a validated visual scale.

Results:

In our final cohort of 316 patients with ICH, lacunes were frequent (24.7%), with similar rates in 191 patients with CAA and 125 with HTN-ICH (23% vs 27.2%, p = 0.4). Lobar lacunes were more commonly present in CAA (20.4% vs 5.7%, p < 0.001), while deep lacunes were more frequent in HTN-ICH (15.2% vs 2.1%, p < 0.001). After correction for demographics and clinical and neuroimaging markers of SVD, lobar lacunes were associated with CAA (p = 0.003) and deep lacunes with HTN-ICH (p < 0.001). Lobar lacunes in 80% of the cases were at least in contact with WMH, and after adjustment for age, they were highly correlated to WMH volume (r = 0.42, p < 0.001).

Conclusions:

Lobar lacunes are associated with CAA, whereas deep lacunes are more frequent in HTN-SVD. Lobar lacunes seem to have a close relationship with WMH, suggesting a possible common origin.




Poststroke epilepsy in long-term survivors of primary intracerebral hemorrhage

2017-06-05T12:48:00-07:00

Objective:

To identify the incidence and predisposing factors for development of poststroke epilepsy (PSE) after primary intracerebral hemorrhage (PICH) during a long-term follow-up.

Methods:

We performed a retrospective study of patients who had had their first-ever PICH between January 1993 and January 2008 in Northern Ostrobothnia, Finland, and who survived for at least 3 months. These patients were followed up for PSE. The associations between PSE occurrence and sex, age, Glasgow Coma Scale (GCS) score on admission, hematoma location and volume, early seizures, and other possible risk factors for PSE were assessed using the Cox proportional hazards regression model.

Results:

Of the 615 PICH patients who survived for longer than 3 months, 83 (13.5%) developed PSE. The risk of new-onset PSE was highest during the first year after PICH with cumulative incidence of 6.8%. In univariable analysis, the risk factors for PSE were early seizures, subcortical hematoma location, larger hematoma volume, hematoma evacuation, and a lower GCS score on admission, whereas patients with infratentorial hematoma location or hypertension were less likely to develop PSE (all variables p < 0.05). In multivariable analysis, we found subcortical location (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.35–3.81, p < 0.01) and early seizures (HR 3.63, 95% CI 1.99–6.64, p < 0.01) to be independent risk factors, but patients with hypertension had a lower risk of PSE (HR 0.54, 0.35–0.84, p < 0.01).

Conclusions:

Subcortical hematoma location and early seizures increased the risk of PSE after PICH in long-term survivors, while hypertension seemed to reduce the risk.




Prospective association between {beta}2-microglobulin levels and ischemic stroke risk among women

2017-06-05T12:48:00-07:00

Objective:

To determine whether elevated β2-microglobulin (B2M) levels were associated with an increased risk of incident ischemic stroke events among women.

Methods:

We performed a nested case-control study among women enrolled in the Nurses' Health Study who provided blood samples between 1989 and 1990 and were free of prior stroke and cancer. We measured B2M levels in 473 ischemic strokes cases confirmed by medical record review and in 473 controls matched 1:1 to the cases on age, race, date of blood collection, menopausal status, postmenopausal hormone use, and smoking status. We analyzed the association between B2M and ischemic stroke using multivariable conditional logistic regression to adjust for traditional stroke risk factors.

Results:

Median levels of B2M were higher among cases (1.86 mg/L) than controls (1.80 mg/L, p = 0.009, Wilcoxon rank-sum test). Women in the highest B2M quartile had a multivariable-adjusted increased risk of ischemic stroke compared to those in the lowest quartile (odds ratio [OR] 1.56, 95% confidence interval [CI] 1.02–2.39). Results were similar when restricted to those without evidence of chronic kidney disease (estimated glomerular filtration rate ≥60 mL·min–1·1.73 m–2) (OR 1.49, 95% CI 1.08–2.06). In an exploratory analysis, the association between B2M and thrombotic stroke was similar to the overall ischemic stroke results, but no association was observed for embolic stroke risk.

Conclusion:

High levels of B2M were associated with an increased risk of ischemic stroke among women.




HLA-A*24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions

2017-06-05T12:48:00-07:00

Objective:

To investigate the involvement of human leukocyte antigen (HLA) loci in aromatic antiepileptic drug–induced cutaneous adverse reactions.

Methods:

A case-control study was performed to detect HLA loci involved in aromatic antiepileptic drug–induced Stevens-Johnson syndrome in a southern Han Chinese population. Between January 1, 2006, and December 31, 2015, 91 cases of Stevens-Johnson syndrome induced by aromatic antiepileptic drugs and 322 matched drug-tolerant controls were enrolled from 8 centers. Important genotypes were replicated in cases with maculopapular eruption and in the meta-analyses of data from other populations. Sequence-based typing determined the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genotypes.

Results:

HLA-B*15:02 was confirmed as strongly associated with carbamazepine-induced Stevens-Johnson syndrome (p = 5.63 x 10–15). In addition, HLA-A*24:02 was associated significantly with Stevens-Johnson syndrome induced by the aromatic antiepileptic drugs as a group (p = 1.02 x 10–5) and by individual drugs (carbamazepine p = 0.015, lamotrigine p = 0.005, phenytoin p = 0.027). Logistic regression analysis revealed a multiplicative interaction between HLA-B*15:02 and HLA-A*24:02. Positivity for HLA-A*24:02 and/or HLA-B*15:02 showed a sensitivity of 72.5% and a specificity of 69.0%. The presence of HLA-A*24:02 in cases with maculopapular exanthema was also significantly higher than in controls (p = 0.023). Meta-analysis of data from Japan, Korea, Malaysia, Mexico, Norway, and China revealed a similar association.

Conclusions:

HLA-A*24:02 is a common genetic risk factor for cutaneous adverse reactions induced by aromatic antiepileptic drugs in the southern Han Chinese and possibly other ethnic populations. Pretreatment screening is recommended for people in southern China.




Early skin denervation in hereditary and iatrogenic transthyretin amyloid neuropathy

2017-06-05T12:48:00-07:00

Objective:

To elucidate early skin denervation in hereditary transthyretin (TTR) amyloidosis and iatrogenic TTR amyloidosis.

Methods:

We investigated intraepidermal nerve fiber density (IENFD) and clinical findings in 32 patients with hereditary TTR amyloidosis, 11 asymptomatic mutation carriers, 6 patients with iatrogenic TTR amyloidosis, and 23 healthy volunteers.

Results:

IENFD values were reduced in patients with the V30M mutation (1.9 ± 2.1 per 1 mm), patients with non-V30M mutations (5.8 ± 3.2 per 1 mm), and patients with iatrogenic TTR amyloidosis (3.5 ± 1.8 per 1 mm) compared with healthy volunteers (11.8 ± 3.2 per 1 mm) (p < 0.01). Skin denervation also occurred, even in presymptomatic V30M mutation carriers (5.0 ± 2.2 per 1 mm). The IENFD was correlated with disease duration ( = –0.533, p = 0.002) and various peripheral neuropathy parameters such as sensory impairment in the Kumamoto clinical score ( = –0.575, p = 0.001), heat-pain detection threshold ( = –0.704, p < 0.001), and sural sensory nerve action potential ( = 0.481, p = 0.005). TTR amyloid deposits frequently occurred in connective tissues and vessels of the dermal reticular layer in patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis.

Conclusions:

Patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis may show early skin denervation even in the presymptomatic stage. IENFD may thus be useful for early diagnosis and may serve as a biomarker in clinical trials for hereditary and iatrogenic TTR amyloidosis.




Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease

2017-06-05T12:48:00-07:00

Objective:

To evaluate the adenosine 2a receptor antagonist preladenant as a nondopaminergic drug for the treatment of Parkinson disease (PD) when given as monotherapy.

Methods:

This was a randomized, 26-week, placebo- and active-controlled, parallel-group, multicenter, double-blind trial conducted in adults diagnosed with PD for <5 years who were not yet receiving l-dopa or dopamine agonists. Patients with a Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 (motor function) score ≥10 and Hoehn & Yahr score ≤3 were randomized 1:1:1:1:1 to preladenant 2, 5, or 10 mg twice daily, rasagiline 1 mg (active-control) once daily, or placebo. The primary endpoint was the change from baseline at week 26 in the sum of UPDRS parts 2 (activities of daily living) and 3 scores (UPDRS2+3).

Results:

The number of patients treated was 1,007. Neither preladenant nor rasagiline was superior to placebo after 26 weeks. The differences vs placebo (95% confidence interval) in UPDRS2+3 scores (with a negative difference indicating improvement vs placebo) were preladenant 2 mg = 2.60 (0.86, 4.30), preladenant 5 mg = 1.30 (–0.41, 2.94), preladenant 10 mg = 0.40 (–1.29, 2.11), and rasagiline 1 mg = 0.30 (–1.35, 2.03). Post hoc analyses did not identify a single causal factor that could explain the finding of a failed trial. Preladenant was generally well-tolerated with few patients discontinuing due to adverse events (preladenant 7%, rasagiline 3%, placebo 4%).

Conclusions:

No evidence supporting the efficacy of preladenant as monotherapy was observed in this phase 3 trial. The lack of efficacy of the active control rasagiline makes it difficult to interpret the results.

Clinical trial registration:

Clinicaltrials.gov: NCT01155479.

Classification of evidence:

This study provides Class I evidence that for patients with early PD, preladenant is not effective as monotherapy at the doses studied (2, 5, 10 mg).




Role of habenula and amygdala dysfunction in Parkinson disease patients with punding

2017-06-05T12:48:00-07:00

Objective:

To assess whether a functional dysregulation of the habenula and amygdala, as modulators of the reward brain circuit, contributes to Parkinson disease (PD) punding.

Methods:

Structural and resting-state functional MRI were obtained from 22 patients with PD punding, 30 patients with PD without any impulsive-compulsive behavior (ICB) matched for disease stage and duration, motor impairment, and cognitive status, and 30 healthy controls. Resting-state functional connectivity of the habenula and amygdala bilaterally was assessed using a seed-based approach. Habenula and amygdala volumes and cortical thickness measures were obtained.

Results:

Compared to both healthy controls and PD cases without any ICB (PD–no ICB), PD-punding patients showed higher functional connectivity of habenula and amygdala with thalamus and striatum bilaterally, and lower connectivity between bilateral habenula and left frontal and precentral cortices. In PD-punding relative to PD–no ICB patients, a lower functional connectivity between right amygdala and hippocampus was also observed. Habenula and amygdala volumes were not different among groups. PD-punding patients showed a cortical thinning of the left superior frontal and precentral gyri and right middle temporal gyrus and isthmus cingulate compared to healthy controls, and of the right inferior frontal gyrus compared to both controls and PD–no ICB patients.

Conclusions:

A breakdown of the connectivity among the crucial nodes of the reward circuit (i.e., habenula, amygdala, basal ganglia, frontal cortex) might be a contributory factor to punding in PD. This study provides potential instruments to detect and monitor punding in patients with PD.




Placebo and nocebo responses in restless legs syndrome: A systematic review and meta-analysis

2017-06-05T12:48:00-07:00

Objective:

To estimate the placebo and nocebo responses in restless legs syndrome (RLS) and explore their determinants.

Methods:

Databases were searched up to October 2015. Randomized, double-blind, placebo-controlled trials of patients with RLS were included if quantitative data were extractable in the placebo arm. Placebo response was defined as the within-group change from baseline, using any scale measuring RLS severity or disability. Nocebo response was defined as the proportion of patients experiencing adverse events in the placebo arm. Random-effects meta-analysis was used to pool data. Statistical heterogeneity was assessed with I2 statistic. Several predetermined subgroup and sensitivity analysis were performed. PROSPERO registration number is CRD42015027992.

Results:

We included 85 randomized controlled trials (5,046 participants). Pooled placebo response effect size was –1.41 (95% confidence interval [CI] –1.56 to –1.25, 64 trials, I2 = 88.1%), corresponding to –6.58 points in the International RLS Study Group Scale (IRLS). Pooled nocebo response was 45.36% (95% CI 40.47%–50.29%, 72 trials; I2 = 89.8%). The placebo and nocebo responses were greater in trials with longer duration, evaluating pharmacologic interventions and idiopathic RLS, and in industry-funded and unpublished studies. The placebo response was considerably smaller in objective as compared to subjective outcomes. In addition, the nocebo response increases proportionally with the placebo response, and has the same predictors.

Conclusions:

The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable. These results are relevant to inform the design and interpretation of future clinical trials.




Effects of MCI subtype and reversion on progression to dementia in a community sample

2017-06-05T12:48:00-07:00

Objective:

We sought to understand the trajectory of mild cognitive impairment (MCI) better by examining longitudinally different MCI subtypes and progression to dementia and reversion to normal cognition in a community sample.

Methods:

We evaluated the stability of MCI subtypes and risk of dementia over 4 biennial assessments as part of an ongoing prospective cohort study, the Sydney Memory and Ageing Study.

Results:

While prevalence of MCI and different MCI subtypes remains relatively stable across all assessments, reversion from MCI and transitions between different MCI subtypes were common. Up to 46.5% of participants classified with MCI at baseline reverted at some point during follow-up. The majority (83.8%) of participants with incident dementia were diagnosed with MCI 2 years prior to their dementia diagnosis. Both reverters and participants with stable MCI were at an increased risk of progression to dementia compared to those without MCI at baseline (HR 6.4, p = 0.02, and HR 24.7, p < 0.001, respectively); however, the risk of dementia in participants with MCI who did not revert was higher than in reverters (HR 2.5, p = 0.01). This effect was specific to amnestic subtypes (MCI reverters vs nonreverters: amnestic MCI HR 3.3, p = 0.006; nonamnestic MCI: HR 1.3, p = 0.67).

Conclusion:

Our findings indicate that the relevance of reversion for progression risk depends on the MCI subtype. Subtype specificity and longitudinal characterization are required for the reliable identification of individuals at high risk of developing dementia.




Pathologic confirmation of retinal ganglion cell loss in multiple system atrophy

2017-06-05T12:48:00-07:00

Multiple system atrophy (MSA) is a rare adult-onset rapidly progressive fatal neurodegenerative disorder characterized by the abnormal aggregation of misfolded α-synuclein primarily in oligodendrocytes.1




Correlating microscopic findings with B-mode ultrasound in cervical artery dissection

2017-06-05T12:48:00-07:00

In a previous study, microscopic findings in superficial temporal artery specimens in patients with cervical artery dissections suggest that the pathophysiologic mechanism is an expanding hematoma in the medial–adventitial border arising from the vasa vasorum.1 The hematoma is half-moon-shaped and can be visualized by T1-weighted fat-saturated MRI.2




Editors' Note

2017-06-05T12:48:00-07:00

Editors' Note: Dr. Del Brutto points out that the "Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations" is actually a cystic hydatid disease, caused by infection with Echinococcus spp. Guo et al., authors of the NeuroImage, agree and blame a translation error for their mistake.




Letter re: Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations

2017-06-05T12:48:00-07:00

The Teaching NeuroImage by Nie et al.1 is not of a cysticercus as mentioned by the authors; instead, it is a clear example of cystic hydatid disease, caused by infection with Echinococcus spp. A single, large, unilocular nonenhancing parenchymal brain cyst with well-defined borders and not surrounded by edema is fairly characteristic of this parasitic disease.2 In addition, scolices are clearly shown in surgical and histopathologic photographs. Proper interpretation of currently available sets of diagnostic criteria for neurocysticercosis is advised to avoid these diagnostic pitfalls.3,4




Author response: Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations

2017-06-05T12:48:01-07:00

We thank Dr. Del Brutto for the interest in and comments on our NeuroImage.1 We made a translation error, as identified by Dr. Del Brutto. A typical example of parasitic disease is a single, large, low lesion without peripheral edema or enhancement. The postoperative pathologic examination showed parasite scolices in left temporal and occipital lobes; the final diagnosis was hydatid disease in Chinese. Accurate translation of hydatid disease is cystic echinococcosis, not cysticercus, in the English–Chinese dictionary; specifically, cystic echinococcosis caused by infection with Echinococcus spp.




Letter re: Teaching NeuroImages: Idiopathic hypertrophic pachymeningitis

2017-06-05T12:48:01-07:00

As alluded to by Drs. Wasilewski and Samkoff,1 immunoglobulin G4 (IgG4)–related disease (RD) is an increasingly recognized cause of hypertrophic pachymeningitis (HP) and likely accounts for a substantial subset of cases previously thought to be idiopathic.2 Although normal IgG4 levels in serum and CSF argue against IgG4-related HP in this case, meningeal biopsy remains the diagnostic gold standard.3,4 Since IgG4-RD is a major consideration, it is of critical importance to immunostain biopsied tissue for the number of IgG4+ cells/high-powered field (HPF) prior to labeling the disease entity idiopathic; more than 10 IgG4+ cells/HPF suggests IgG4-related HP.4 Although both IgG4-related and idiopathic HP are inflammatory steroid-responsive illnesses, differentiation permits better understanding of individual disease mechanisms and may greatly help guide decision-making when selecting second-line therapies in treatment-resistant cases, such as the use of rituximab in refractory IgG4-related HP.5




Author response: Teaching NeuroImages: Idiopathic hypertrophic pachymeningitis

2017-06-05T12:48:01-07:00

As discussed by Dr. Budhram, immunoglobulin G4 (IgG4)–related disease (RD) must be considered in patients with hypertrophic pachymeningitis (HP) as it accounts for a high proportion of cases originally thought to be idiopathic.1 IgG4-related HP is pathologically characterized by a lymphoplasmacytic infiltration of IgG4-positive plasma cells.2 The patient we presented had normal IgG4 levels in both serum and CSF.1 Dural biopsy was consistent with a chronic lymphohistiocytic pachymeningitis without substantial plasma cell infiltrate to suggest IgG4-RD. In addition, immunohistochemistry performed on the dural biopsy specimen was IgG4-negative. Our case highlights the steroid responsiveness of idiopathic HP and the excellent response to immunotherapy with methotrexate.1 We agree with Dr. Budhram that immunostaining of dural specimens should be done in patients with HP, as this may help guide treatment for steroid-refractory HP when IgG4 disease can be identified.




Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations

2017-06-05T12:48:01-07:00

The Neurology® editors and the authors of the article "Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations,"1 published online in conjunction with the November 22, 2016, issue of Neurology, agree to the retraction of the article. Retraction follows publication of a WriteClick® Editor's Choice correspondence exchange in which a pervasive translation error was identified.2,3 The diagnosis should have been "cystic echinococcosis," not "cysticercus." The article has been corrected and republished.4




Mystery Case: Don't fall for pseudo-INO!

2017-05-29T12:47:51-07:00

A 31-year-old woman with a 4-day history of diplopia showed slow adducting saccades in the left eye (pseudo–internuclear ophthalmoplegia [P-INO]1,2; see video 1 at Neurology.org), left inferior rectus muscle weakness, and upper limb fatigability. Edrophonium testing with transient resolution of P-INO led to a diagnosis of myasthenia gravis (MG) (see video 2), which was later confirmed by positive acetylcholine receptor antibodies.




Clinical Reasoning: A 27-year-old man with acute-onset ataxia

2017-05-29T12:47:51-07:00

A 27-year-old man with a history of diabetes mellitus (DM) and asthma presented to the emergency department 1 month after the onset of dysarthria and ataxia. The symptoms were noted abruptly upon waking. He swayed on standing, fell easily, and noted tremor when manipulating objects. His speech was nearly unintelligible. He also had 1 month of mild distal paresthesias and a 30-pound unintentional weight loss. He denied diplopia, dysphagia, preceding illness, or other systemic symptoms. Over the course of the month, his dysarthria improved but his imbalance remained unchanged. His delay in seeking medical attention was due to lack of health insurance.




Clinical Reasoning: A 45-year-old woman with immobility and incontinence

2017-05-29T12:47:51-07:00

A 45-year-old woman presented with immobility and incontinence in July 2016. Her symptoms started 6 months prior to presentation, when she had multiple falls (without major injuries) at home because of weakness in the lower extremities. She experienced urinary incontinence 1 month later. An indwelling catheter was placed and clamped every 2–3 hours in the daytime and kept open during the night. Later, she preferred not to walk for fear of falling. The patient started to feel stiffness and tightness in her lower extremities 3 months later. The condition worsened gradually to the extent that she could barely move her lower extremities in bed and reported it affected her sleep recently. Along with motor dysfunctions, she also experienced numbness in her lower extremities, but denied pain. She was able to sit in a wheelchair for 7 hours per day. A pressure ulcer was noticed in the sacral region 4 months later. She denied other discomfort. Her appetite has been good. She had no significant weight changes during the last half year.




MS and bone marrow transplant: Not for most patients

2017-05-29T12:47:51-07:00

In the article "Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis," Sormani et al.1 found studies that had already been published about autologous hematopoietic stem cell transplantation (aHSCT) for treatment of multiple sclerosis (MS) (see the next page for an introduction to aHSCT in the treatment of MS).




Spotlight on the May 30 issue

2017-05-29T12:47:51-07:00




Genetics, white matter, and cognition: The effects of methylation on FMR1

2017-05-29T12:47:51-07:00

The fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked genetic disorder in which the premutation (55–200 CGG repeats) in fragile X mental retardation 1 (FMR1) causes elevated levels of FMR1 mRNA, which in turn causes RNA toxicity through sequestration of critical proteins, dysregulated DNA repair processes, and production of FMRpolyG, a toxic protein produced from repeat-associated non-AUG (RAN) translation.1,2 FXTAS is associated with tremor and ataxia, and it presents in aging carriers of the premutation. However, there is evidence that the premutation causes changes in the brain far earlier than the onset of tremor and ataxia.3,4 The premutation is unmethylated, whereas those with fragile X syndrome have a full mutation (>200 CGG repeats), and the full mutation is methylated, leading to a lack of mRNA and a lack of fragile X mental retardation protein (FMRP).




Autologous hematopoietic stem cell transplantation for MS: Safer than previously thought

2017-05-29T12:47:51-07:00

Multiple sclerosis (MS) is likely initiated by an autoimmune response that targets the CNS. A common conceptualization of the early stages of MS is that immunocompetent cells of the adaptive immune system, recognizing hitherto unknown autoantigens, invade the CNS. These invasions happen in discrete attacks in focal areas of the CNS, giving rise to the well-known features of blood–brain barrier breakdown and lesion formation visible on MRI. This immune process is critically dependent on immunologic memory, and with time a pool of autoreactive lymphocytes is maintained. What if these immunologic memories could be erased?




Endovascular thrombectomy: Time is still brain

2017-05-29T12:47:51-07:00

The "Time is brain" concept should be familiar to anyone who cares for patients with acute ischemic stroke. IV tissue plasminogen activator (tPA) reduces disability after stroke when administered within 4.5 hours of symptom onset, but the benefit of IV tPA is time-dependent.1 Earlier treatment improves functional outcomes. Quantified many ways, studies provide estimates in terms of functional outcome at 90 days, neurons saved, and days of disability-free life gained.1–3 As a result, door-to-needle time, defined as the time from hospital arrival to the initiation of IV tPA, has become an important quality metric for stroke hospitals around the world.




The American Academy of Neurology affirms the revival of cooling for the revived

2017-05-29T12:47:51-07:00

It is estimated that a cardiac arrest occurs approximately every minute in the United States.1 Beyond the mere return of spontaneous circulation (ROSC) and gross survival at discharge, good neurologic function with minimal disability is the goal for revived cardiac arrest patients. Partnering with the cardiology and emergency and critical care communities, neurologists helped implement therapeutic hypothermia (TH) and targeted temperature management (TTM), major breakthroughs in post–cardiac arrest care.2 Mitigating secondary brain injury after cardiac arrest (BICA) with TH is supported by 2 landmark randomized controlled trials (RCTs); supporting evidence came from nonrandomized studies, large registries, indirect evidence from pediatric trials, and animal studies.3 TH to 33°C became standard for out-of-hospital cardiac arrest with a shockable rhythm, later endorsed in the 2015 guidelines of the American Heart Association (AHA).2 Many experts were more liberal, cooling patients with all arrest rhythms and in-hospital cardiac arrests.3




Personal reflections about Lewis P. (Bud) Rowland (1925-2017)

2017-05-29T12:47:51-07:00

Editor's Note: In the previous issue of Neurology® (May 23, 2017), we lamented the passing of Dr. Rowland with a featured In Memoriam. Bud touched the lives of many, some of whom wrote comments to the AAN and the Neurology Editorial Office upon notification of his death. These comments were included at the end of the In Memoriam, but the remembrances by Dr. Fahn were received too late to include in the last issue. Here we again remember our friend through the memories of Dr. Fahn. —Robert A. Gross, MD, PhD, FAAN




White matter microstructure, cognition, and molecular markers in fragile X premutation females

2017-05-29T12:47:51-07:00

Objective:

To examine the interrelationships between fragile X mental retardation 1 (FMR1) mRNA and the FMR1 exon 1/intron 1 boundary methylation, white matter microstructure, and executive function, in women with a FMR1 premutation expansion (PM; 55–199 CGG repeats) and controls (CGG < 44).

Methods:

Twenty women with PM without fragile X-associated tremor/ataxia syndrome (FXTAS) and 20 control women between 22 and 54 years of age completed this study. FMR1 mRNA and methylation levels for 9 CpG sites within the FMR1 exon 1/intron 1 boundary from peripheral blood samples were analyzed. To measure white matter microstructure, diffusion-weighted imaging was used, from which fractional anisotropy (FA) and mean diffusivity (MD) values from anatomic regions within the corpus callosum and cerebellar peduncles were extracted. Executive function was assessed across a range of tasks.

Results:

No differences were revealed in white matter microstructure between women with PM and controls. However, we reveal that for women with PM (but not controls), higher FMR1 mRNA correlated with lower MD values within the middle cerebellar peduncle and Paced Auditory Serial Addition Test scores, higher methylation of the FMR1 exon 1/intron 1 boundary correlated with lower MD within the inferior and middle cerebellar peduncles and longer prosaccade latencies, and higher FA values within the corpus callosum and cerebellar peduncle regions corresponded to superior executive function.

Conclusions:

We provide evidence linking white matter microstructure to executive dysfunction and elevated FMR1 mRNA and FMR1 exon 1/intron 1 boundary methylation in women with PM without FXTAS. This suggests that the FXTAS phenotype may not be distinct but may form part of a spectrum of PM involvement.




Space and location of cerebral microbleeds, cognitive decline, and dementia in the community

2017-05-29T12:47:51-07:00

Objective:

To assess the association of the number and anatomic location of cerebral microbleeds (CMBs), visible indicators of microvascular damage on MRI, with incident cognitive disease in the general population of older people.

Methods:

In the longitudinal population-based Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study, 2,602 participants 66 to 93 years of age and free of prevalent dementia underwent brain MRI and cognitive testing of verbal memory, processing speed, and executive function at baseline and a mean of 5.2 years later. Adjudicated incident dementia cases were diagnosed according to international guidelines.

Results:

In the multiple linear regression models adjusted for demographic, genetic, cardiovascular risk, and other cerebrovascular MRI markers, the presence of CMBs located in deep or mixed (deep and lobar) areas was associated with a greater decline in all 3 cognitive domains. Mixed CMBs were the strongest correlate for decline in memory and speed. Compared to those with no CMBs, participants with ≥3 CMBs had a steeper decline in a composite measure of global cognitive function, memory, and speed. Among those with ≥3 deep or mixed CMBs, associations were strongest for memory; the association with speed was strongest in those having ≥3 strictly lobar CMBs. People with ≥3 CMBs, regardless of their locations, had a higher incidence of all-cause dementia and vascular dementia.

Conclusions:

Mixed or a higher load of CMBs, with some specificity for location, is associated with accelerated cognitive decline in older people. These findings suggest a role for hypertensive vasculopathy and the combined effect of hypertensive and cerebral amyloid angiopathy in the pathogenesis of cognitive deterioration.




BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

2017-05-29T12:47:51-07:00

Objective:

To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship.

Methods:

One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories.

Results:

Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033).

Conclusions:

In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.




Increased connectivity of hub networks and cognitive impairment in multiple sclerosis

2017-05-29T12:47:51-07:00

Objective:

To investigate default-mode network (DMN) and frontoparietal network (FPN) dysfunction in cognitively impaired (CI) patients with multiple sclerosis (MS) because these networks strongly relate to cognition and contain most of the hubs of the brain.

Methods:

Resting-state fMRI and neuropsychological assessments were performed in 322 patients with MS and 96 healthy controls (HCs). Patients with MS were classified as CI (z score < –2.0 on at least 2 tests; n = 87), mildly cognitively impaired (z score < –1.5 on at least 2 tests and not CI; n = 65), and cognitively preserved (CP; n = 180). Within-network connectivity, connectivity with the rest of the brain, and between-network connectivity were calculated and compared between groups. Connectivity values were normalized for individual means and SDs.

Results:

Only in CI, both the DMN and FPN showed increased connectivity with the rest of the brain compared to HCs and CP, with no change in within- or between-network connectivity. Regionally, this increased connectivity was driven by the inferior parietal, posterior cingulate, and angular gyri. Increased connectivity with the rest of the brain correlated with worse cognitive performance, namely attention for the FPN as well as information processing speed and working memory for both networks.

Conclusions:

In CI patients with MS, the DMN and FPN showed increased connectivity with the rest of the brain, while normal within- and between-network connectivity levels were maintained. These findings indicate that cognitive impairment in MS features disturbed communication of hub-rich networks, but only with the more peripheral (i.e., nonhub) regions of the brain.




Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis

2017-05-29T12:47:51-07:00

Objective:

To summarize the evidence on immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) to manage severe and treatment-refractory multiple sclerosis (MS).

Methods:

We collected all the published studies of aHSCT in any form of MS from 1995 to 2016, carefully excluding reports that were updated in subsequent studies. Endpoints were transplant-related mortality (TRM), rate of disease progression, and no evidence of disease activity (NEDA) status. A weighted metaregression based on a Poisson model was run, assessing whether there were study-specific characteristics with an effect on TRM and progression.

Results:

Fifteen studies including 764 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 2.1% (95% confidence interval [CI] 1.3%–3.4%). TRM was higher in older studies (p = 0.014) and in studies with a lower proportion of patients with relapsing-remitting MS (RRMS) (p = 0.028). A higher baseline Expanded Disability Status Scale (p = 0.013) was also significantly associated with a higher TRM. Pooled rate of progression was 17.1% at 2 years (95% CI 9.7%–24.5%) and 23.3% (95% CI 16.3%–31.8%) at 5 years. Lower 2-year progression rate was significantly associated with higher proportions of patients with RRMS (p = 0.004). The pooled proportion of NEDA patients at 2 years was 83% (range 70%–92%) and at 5 years was 67% (range 59%–70%).

Conclusions:

The emerging evidence on this therapeutic approach in MS indicates that the largest benefit/risk profile form this therapeutic approach can be obtained in patients with aggressive MS with a relapsing-remitting course and who have not yet accumulated a high level of disability.




Endovascular therapy for ischemic stroke: Save a minute--save a week

2017-05-29T12:47:51-07:00

Objective:

To quantify the patient lifetime benefits gained from reduced delays in endovascular therapy for acute ischemic stroke.

Methods:

We used observational prospective data of consecutive stroke patients treated with IV thrombolysis in Helsinki (1998–2014; n = 2,474) to describe distributions of age, sex, stroke severity, onset-to-treatment times, and 3-month modified Rankin Scale (mRS) in routine clinical practice. We used treatment effects by time of endovascular therapy in large vessel occlusion over and above thrombolysis as reported by the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) study to model the shift in 3-month mRS distributions with reducing treatment delays. From the 3-month outcomes we derived patient-expected lifetimes and cumulative long-term disability with incremental treatment delay reductions.

Results:

Each minute saved in onset-to-treatment time granted on average 4.2 days of extra healthy life, with a 95% prediction interval 2.3–5.4. Women gained slightly more than men due to their longer life expectancies. Patients younger than 55 years with severe strokes of NIH Stroke Scale score above 10 gained more than a week per each minute saved. In the whole cohort, every 20 minutes decrease in treatment delays led to a gain of average equivalent of 3 months of disability-free life.

Conclusions:

Small reductions in endovascular delays lead to marked health benefits over patients' lifetimes. Services need to be optimized to reduce delays to endovascular therapy.




Skin nerve phosphorylated {alpha}-synuclein deposits in idiopathic REM sleep behavior disorder

2017-05-29T12:47:51-07:00

Objective:

To test if phosphorylated α-synuclein (p-α-syn) deposits can be detected by means of skin biopsy in patients with idiopathic REM sleep behavior disorder (iRBD) as a potential early histopathologic marker of impending synucleinopathy.

Methods:

Proximal (cervical) and distal (legs) samples of skin biopsy were obtained from 12 patients with polysomnographically confirmed iRBD and 55 sex- and age-matched healthy controls (HC). P-α-syn deposits were assessed with a monoclonal antibody against p-α-syn at serine 129, disclosed by an immunofluorescence method. In addition, patients underwent an extensive workup in order to search for nonmotor symptoms and neuroimaging findings usually associated with impending neurodegeneration and to exclude subtle motor or cognitive signs.

Results:

P-α-syn deposits were detected in 9 (75%) out of 12 patients with iRBD and none of the HC. In iRBD, the sensitivity of the test was higher at the cervical site (67%) when compared to the leg site (58%).

Conclusions:

Our preliminary findings suggest that skin biopsy in patients with iRBD might be a safe and sensitive procedure to be further tested in order to detect p-α-syn deposits in the premotor stage of synucleinopathies.

Classification of evidence:

This study provides Class III evidence that p-α-syn skin deposits identify patients with iRBD.




Novel mutations in dystonin provide clues to the pathomechanisms of HSAN-VI

2017-05-29T12:47:51-07:00

Objective:

To describe a second hereditary sensory autonomic neuropathy type VI (HSAN-VI) family harboring 2 novel heterozygous mutations in the dystonin (DST) gene and to evaluate their effect on neurons derived from induced pluripotent stem cells (iPSC).

Methods:

The family consisted of 3 affected siblings from nonconsanguineous healthy parents. All members underwent clinical and electrophysiologic evaluation and genetic analysis. Two patients underwent quantitative sensory testing (QST), cardiovascular reflexes, dynamic sweat test, and skin biopsy to evaluate somatic and autonomic cutaneous innervation and to get fibroblast cultures for developing iPSC-derived neurons.

Results:

Onset occurred in the first decade, with painless and progressive mutilating distal ulcerations leading to amputation and joint deformity. Sensation to pain, touch, and vibration was reduced. Autonomic disturbances included hypohidrosis, pupillary abnormalities, and gastrointestinal and sexual dysfunction. Nerve conduction studies showed a severe axonal sensory neuropathy. QST and autonomic functional studies were abnormal. Skin biopsy revealed a lack of sensory and autonomic nerve fibers. Genetic analysis revealed 2 pathogenic mutations in the DST gene affecting exclusively the DST neuronal isoform-a2. Neurons derived from iPSC showed absence or very low levels of DST protein and short and dystrophic neuritis or no projections at all.

Conclusions:

Unlike the previous HSAN-VI family, our description indicates that DST mutations may be associated with a nonlethal and nonsyndromic phenotype. Neuronal loss affects large and small sensory nerve fibers as well as autonomic ones. Induced-PSC findings suggest that dystonin defect might alter proper development of the peripheral nerves. Dystonin-a2 plays a major role in the HSAN-VI phenotype.




Practice guideline summary: Reducing brain injury following cardiopulmonary resuscitation: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

2017-05-29T12:47:51-07:00

Objective:

To assess the evidence and make evidence-based recommendations for acute interventions to reduce brain injury in adult patients who are comatose after successful cardiopulmonary resuscitation.

Methods:

Published literature from 1966 to August 29, 2016, was reviewed with evidence-based classification of relevant articles.

Results and recommendations:

For patients who are comatose in whom the initial cardiac rhythm is either pulseless ventricular tachycardia (VT) or ventricular fibrillation (VF) after out-of-hospital cardiac arrest (OHCA), therapeutic hypothermia (TH; 32–34°C for 24 hours) is highly likely to be effective in improving functional neurologic outcome and survival compared with non-TH and should be offered (Level A). For patients who are comatose in whom the initial cardiac rhythm is either VT/VF or asystole/pulseless electrical activity (PEA) after OHCA, targeted temperature management (36°C for 24 hours, followed by 8 hours of rewarming to 37°C, and temperature maintenance below 37.5°C until 72 hours) is likely as effective as TH and is an acceptable alternative (Level B). For patients who are comatose with an initial rhythm of PEA/asystole, TH possibly improves survival and functional neurologic outcome at discharge vs standard care and may be offered (Level C). Prehospital cooling as an adjunct to TH is highly likely to be ineffective in further improving neurologic outcome and survival and should not be offered (Level A). Other pharmacologic and nonpharmacologic strategies (applied with or without concomitant TH) are also reviewed.




Balo concentric sclerosis evolving from apparent tumefactive demyelination

2017-05-29T12:47:51-07:00

Tumefactive demyelination (TD) and Baló concentric sclerosis (BCS) are subtypes of atypical demyelination that may overlap with each other and with prototypic multiple sclerosis (MS). TD and BCS can be distinguished by their different MRI appearance. BCS is associated with alternating rings of T2/fluid-attenuated inversion recovery hypointensity and hyperintensity that correlate pathologically with rings of tissue of varying degrees of demyelination. We present a patient whose initial MRI was consistent with TD but who later developed MRI characteristics in keeping with BCS, emphasizing the difficulty in distinguishing accurately between different subtypes of demyelination early in their course.




Alveolar echinococcosis presenting with simultaneous cerebral and spinal involvement

2017-05-29T12:47:51-07:00

A 37-year-old Tibetan shepherdess presented with headache and weakness of the lower limbs for 10 months. Examination disclosed a positive straight-leg-raising test. Neuroimaging showed a heterogeneous mass in the left temporal lobe (figure 1) and an intradural mass in the lumbosacral canal with L4 vertebral body destruction (figure 2). Chest and abdominal CT scans were negative. Two operations yielded a tissue diagnosis of alveolar echinococcosis and postoperative albendazole therapy was started. Simultaneous involvement of brain and the spinal cord in primary extrahepatic alveolar echinococcosis is rare. Early diagnosis and radical surgery followed by continuous benzimidazole treatment are crucial.1




Editors' Note

2017-05-29T12:47:51-07:00

Editors' Note: In reference to "Formal faculty observation and assessment of bedside skills for 3rd-year neurology clerks," Dr. Sethi and author Dr. Thompson Stone agree that evaluating medical students' neurologic history-taking and examination skills using real patients and then giving feedback is a critical step in combating neurophobia. In reference to "Safety of domperidone in treating nausea associated with dihydroergotamine infusion and headache," Dr. Braillon expands on the safety data available for dihydroergotamine and questions several methodologic points of the study.




Letter re: Formal faculty observation and assessment of bedside skills for 3rd-year neurology clerks

2017-05-29T12:47:51-07:00

I read with interest the study by Thompson Stone et al.,1 in which a formalized bedside skills evaluation (BSE) was instituted for 3rd-year medical students on the neurology clerkship.




Author response: Formal faculty observation and assessment of bedside skills for 3rd-year neurology clerks

2017-05-29T12:47:51-07:00

I appreciate Dr. Sethi's comments on our article,1 and his acknowledgement of the importance of bedside teaching. Measures to combat neurophobia are critical to improve neurologic diagnosis and care across health care providers. I agree that improved formal assessment and feedback of neurologic skills is an important step at the medical student level. When not accomplished formally during medical school, the future non-neurologist is less likely to have an adequate level of confidence in his or her own history and examination skills. Consequently, he or she may feel less confidant making diagnostic and therapeutic decisions. In addition, the use of real over standardized patients is critical in the creation of a realistic and optimally useful opportunity for this assessment.




Letter re: Safety of domperidone in treating nausea associated with dihydroergotamine infusion and headache

2017-05-29T12:47:51-07:00

The retrospective study by Robbins et al.1 warrants comment.




Author response: Safety of domperidone in treating nausea associated with dihydroergotamine infusion and headache

2017-05-29T12:47:51-07:00

We appreciate Dr. Braillon's comments on our recent article.1




Godless State

2017-05-22T12:47:49-07:00

"Jonesy," I say. "It's Dr. Braunstein. He's here to see you."




Child Neurology: LAMA2 muscular dystrophy without contractures

2017-05-22T12:47:49-07:00

The limb-girdle muscular dystrophies (LGMD) comprise a large group of genetic disorders that lead to shoulder and pelvic girdle muscle weakness. Although these disorders are grouped together based on phenotypic presentation, there is extensive genetic variability among them. The dysfunctional protein within each disorder may be found at any level of the muscle fiber structure. Mutations to proteins within the extracellular matrix, including collagen VI and laminin α2 proteins, can disrupt the normal basal lamina architecture and lead to muscle weakness in a limb-girdle distribution.1 We present an interesting case with a novel mutation in the laminin α2 (LAMA2) gene, which has not been reported previously; the patient has a mixed clinical phenotype without contractures.




Teaching NeuroImages: Intraspinal synovial cyst causing Brown-Sequard syndrome: Uncommon cause of a classic syndrome

2017-05-22T12:47:49-07:00

A 65-year-old woman with osteoarthritis presented with 6 weeks of insidiously worsening numbness in the left hemibody and weakness in the right arm and leg. Examination revealed pyramidal weakness in the right arm and leg with hyperreflexia, right Babinski sign, left-sided C4 sensory level to pinprick and temperature, and reduced proprioception in the right extremities. Cervical spine MRI revealed a facet joint synovial cyst at C2-C3 compressing the right hemicord (figure). This was excised, with only mild numbness at 6 months postoperatively. Symptomatic intraspinal cervical synovial cysts are rare and an uncommon cause of myelopathy, typically occurring at C7-T1.1,2




Spotlight on the May 23 issue

2017-05-22T12:47:48-07:00




Preventing Parkinson disease by vagotomy: Fact or fiction?

2017-05-22T12:47:48-07:00

Aggregation of the neuronal protein α-synuclein into insoluble filamentous inclusions may be a determining factor in the development of Parkinson disease (PD). Converging evidence has demonstrated that α-synuclein inclusions have prion-like properties, including cell-to-cell transmission and the ability to induce native α-synuclein to misfold, thus setting the stage for domino-like spreading of cellular pathology.1




Intensive intervention and cognitive impairment: Are lifestyle changes enough for a good brain?

2017-05-22T12:47:48-07:00

The Look AHEAD (Action for Health in Diabetes) study examined how a lifestyle intervention (diet and exercise), compared to diabetes support and education, may help to improve function in a population at high risk for cognitive decline—people with excess weight or obesity and type 2 diabetes.1 Lifestyle is a complex construct that includes behaviors such as cognitive and social engagement as well as diet choices and exercise. There is no clear consensus regarding the nature of the ideal choices and who gets to benefit by adhering. Much data regarding lifestyle come from observational studies, which by design cannot absolutely prove causation and might not motivate behavioral change. There are no proven pharmacologic interventions that prevent or treat cognitive decline, though modifiable risk factors might account for a substantial proportion of the risk for cognitive decline.2




Nothing like a spirited debate!

2017-05-22T12:47:48-07:00

In this issue of Neurology®, 3 opinion pieces provide differing views on the landscape around the management of asymptomatic carotid disease and raise a number of thorny issues.1–3 Heck et al.1 offer an overview; Spence2 and Starke3 offer editorial perspectives. This note introduces the topic as context for those articles.




Optimal management of patients with asymptomatic carotid stenosis

2017-05-22T12:47:48-07:00

Prior trials have shown that carotid endarterectomy (CEA) is superior to nonoperative management of asymptomatic carotid stenosis.1,2 More recent trials have shown surprisingly better outcomes for stroke patients managed with maximal medical therapy.3,4 As such, a number of experts have called for revisiting clinical trials of both CEA and carotid stenting for patients with symptomatic and asymptomatic carotid stenosis using modern medical therapy. Given the current substantial equipoise within the field, modern studies seem reasonable. A number of ongoing trials aim to address current areas of equipoise, but enrollment in these studies has been slow.




Asymptomatic carotid stenosis: Why a moratorium is needed on intervention outside clinical trials

2017-05-22T12:47:48-07:00

In this issue of Neurology®, Heck et al.1 discuss the need for evidence regarding intervention for asymptomatic carotid stenosis (ACS). They say it is not proven that the risk of stroke in asymptomatic carotid stenosis is well below that of intervention. They inveigh against the suggestion that a moratorium on intervention in low-risk ACS outside of randomized trials be accepted in order to foster the development of the evidence we need to settle how to manage ACS. They assert further that only randomized trials can provide valid evidence. However, results in carefully vetted randomized trials do not reflect real-world risks. Recent results in registries2 are much worse than in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST),3 which is being used widely to justify routine intervention in ACS (particularly in the United States). In this editorial, I review the reasons why a moratorium is needed.




Lewis P. Rowland, MD (1925-2017)

2017-05-22T12:47:48-07:00

Lewis P. Rowland, one of the most influential neurologists of our time, died on March 16 following a stroke. It was somehow fitting that his last days were in the neurologic intensive care unit at New York Presbyterian Hospital, one of the first in the country. Critical care neurology was a development that Bud had foreseen and strongly supported as essential for modern neurology and neurosurgery.




Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study

2017-05-22T12:47:48-07:00

Objective: To examine whether vagotomy decreases the risk of Parkinson disease (PD). Methods: Using data from nationwide Swedish registers, we conducted a matched-cohort study of 9,430 vagotomized patients (3,445 truncal and 5,978 selective) identified between 1970 and 2010 and 377,200 reference individuals from the general population individually matched to vagotomized patients by sex and year of birth with a 40:1 ratio. Participants were followed up from the date of vagotomy until PD diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first. Vagotomy and PD were identified from the Swedish Patient Register. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox models stratified by matching variables, adjusting for country of birth, chronic obstructive pulmonary disease, diabetes mellitus, vascular diseases, rheumatologic disease, osteoarthritis, and comorbidity index. Results: A total of 4,930 cases of incident PD were identified during 7.3 million person-years of follow-up. PD incidence (per 100,000 person-years) was 61.8 among vagotomized patients (80.4 for truncal and 55.1 for selective) and 67.5 among reference individuals. Overall, vagotomy was not associated with PD risk (HR 0.96, 95% CI 0.78–1.17). However, there was a suggestion of lower risk among patients with truncal vagotomy (HR 0.78, 95% CI 0.55–1.09), which may be driven by truncal vagotomy at least 5 years before PD diagnosis (HR 0.59, 95% CI 0.37–0.93). Selective vagotomy was not related to PD risk in any analyses. Conclusions: Although overall vagotomy was not associated the risk of PD, we found suggestive evidence for a potential protective effect of truncal, but not se[...]



Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study

2017-05-22T12:47:48-07:00

Objective: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD). Methods: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change. Results: For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] –3.0 [0.45] vs –1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group. Conclusions: In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements. Classification of evidence: This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores. [...]



Hypothalamus as a mediator of chronic migraine: Evidence from high-resolution fMRI

2017-05-22T12:47:48-07:00

Objective:

To identify pathophysiologic mechanisms of migraine chronification using a recently standardized protocol for high-resolution brainstem imaging of trigeminal nociceptive stimulation.

Methods:

Eighteen episodic migraineurs (EMs), 17 chronic migraineurs (CMs), and 19 healthy controls (HCs) underwent painful ammonia stimulation of the left nostril in a 3T MRI scanner. Functional images were acquired with a brainstem-optimized protocol for high-resolution echo-planar imaging.

Results:

We detected a significantly stronger activation of the anterior right hypothalamus in CMs compared to HCs. To exclude the headache as a prime mediator of the hypothalamic activations, we compared all migraineurs with headaches (EMs and CMs) with all migraineurs without headaches (EMs and CMs) and HCs in a second analysis and found a more posterior region of the hypothalamus to be more activated bilaterally during headaches.

Conclusions:

Our data corroborate the fact that the hypothalamus plays a crucial role in the pathophysiology of migraine chronification and acute pain stage of migraineurs. While the more posterior part of the hypothalamus seems to be important for the acute pain stage, the more anterior part seems to play an important role in attack generation and migraine chronification.




How small can the epileptogenic region be?: A case in point

2017-05-22T12:47:48-07:00

Objective:

To present a case that demonstrates that seizures and interictal disturbances can be driven by a small area of functionally abnormal cortex.

Methods:

Two novel functional MRI network analysis methods were used to supplement conventional seizure and lesion localization methods: (1) regional homogeneity to quantify local connectivity, or synchrony, with a resolution of less than 1 cm3 of cortex; and (2) small-worldness to combine information about whole brain network segregation and integration.

Results:

After a small corticectomy in the dominant supramarginal gyrus (13 x 7 x 6 mm) limited to the area of abnormal local connectivity, and smaller than the PET and SPECT abnormalities, the patient has been seizure-free for 3 years with no language deficit. Whole brain network characteristics normalized (small-worldness) to that of healthy controls.

Conclusions:

This case demonstrates that small areas of cortex may be highly epileptogenic, drive intractable epilepsy, and disrupt large-scale networks likely to be involved in core cognitive functions.




Pregabalin use early in pregnancy and the risk of major congenital malformations

2017-05-22T12:47:48-07:00

Objective: To assess whether first-trimester exposure to pregabalin is associated with an increased risk of major congenital malformations, as recently suggested in a pregnancy registry study. Methods: We performed a cohort study nested in the US Medicaid Analytic eXtract (MAX). The study population included 1,323,432 pregnancies resulting in a live-born infant between 2000 and 2010. We examined the risk of major congenital malformations among infants born to women exposed to pregabalin during the first trimester compared with women unexposed to anticonvulsants. We used propensity score fine stratification to control for >50 potential confounders, and we estimated relative risks (RRs) and 95% confidence intervals (CIs) in generalized linear models. The analyses were replicated in the Truven Health MarketScan Commercial Database (MarketScan). Pooled estimates based on the adjusted RR produced in MAX, MarketScan, and the previous registry study were calculated. Results: Of 477 infants exposed to pregabalin during the first trimester in MAX, 28 (5.9%) had malformations compared to 3.3% in nonexposed infants. The crude RR of major congenital malformations for pregabalin was 1.80 (95% CI 1.26–2.58). After propensity score adjustment, the RR moved to 1.16 (95% CI 0.81–1.67). Restriction to pregabalin monotherapy and sensitivity analyses produced similar results. The adjusted RR for major congenital malformations for the 174 infants exposed in MarketScan was 1.03 (95% CI 0.56–1.90). The pooled RR was 1.33 (95% CI 0.83–2.15) for pregabalin any use and 1.02 (95% CI 0.69–1.51) for preg[...]



Effect of a long-term intensive lifestyle intervention on prevalence of cognitive impairment

2017-05-22T12:47:48-07:00

Objective: To assess whether an average of 10 years of lifestyle intervention designed to reduce weight and increase physical activity lowers the prevalence of cognitive impairment among adults at increased risk due to type 2 diabetes and obesity or overweight. Methods: Central adjudication of mild cognitive impairment and probable dementia was based on standardized cognitive test battery scores administered to 3,802 individuals who had been randomly assigned, with equal probability, to either the lifestyle intervention or the diabetes support and education control. When scores fell below a prespecified threshold, functional information was obtained through proxy interview. Results: Compared with control, the intensive lifestyle intervention induced and maintained marked differences in weight loss and self-reported physical activity throughout follow-up. At an average (range) of 11.4 (9.5–13.5) years after enrollment, when participants' mean age was 69.6 (54.9–87.2) years, the prevalence of mild cognitive impairment and probable dementia was 6.4% and 1.8%, respectively, in the intervention group, compared with 6.6% and 1.8%, respectively, in the control group (p = 0.93). The lack of an intervention effect on the prevalence of cognitive impairment was consistent among individuals grouped by cardiovascular disease history, diabetes duration, sex, and APOE 4 allele status (all p ≥ 0.50). However, there was evidence (p = 0.03) that the intervention effect ranged from benefit to harm across participants ordered from lowest to highest baseline BMI. Conclusions: Ten years [...]



Relationship between carotid arterial properties and cerebral white matter hyperintensities

2017-05-22T12:47:48-07:00

Objective: Since arterial stiffness is a functional measure of arterial compliance and may be an important marker of cerebrovascular disease, we examined the association of carotid artery stiffness with white matter hyperintensity volume (WMHV) in a cross-sectional study of 1,166 stroke-free participants. Methods: Carotid beta stiffness index (STIFF) was assessed by M-mode ultrasound of the common carotid artery and calculated as the ratio of natural log of the difference between systolic and diastolic blood pressure over STRAIN, a ratio of the difference between carotid systolic and diastolic diameter (DD) divided by DD. WMHV was measured by fluid-attenuated inversion recovery MRI. The associations of STIFF, DD, and STRAIN with WMHV were examined using linear regression after adjusting for sociodemographic, lifestyle, and vascular risk factors. Results: In a fully adjusted model, larger carotid DD was significantly associated with greater log-WMHV (β = 0.09, p = 0.001). STIFF and STRAIN were not significantly associated with WMHV. In adjusted analyses stratified by race–ethnicity, STRAIN (β = –1.78, p = 0.002) and DD (β = 0.11, p = 0.001) were both associated with greater log-WMHV among Hispanic participants, but not among black or white participants. Conclusions: Large carotid artery diameters are associated with greater burden of white matter hyperintensity (WMH) in this multiethnic population. The association between increased diameters, decreased STRAIN, and greater WMH burden is more pronounced among Hispanics. These ass[...]



Alcohol use and risk of intracerebral hemorrhage

2017-05-22T12:47:48-07:00

Objective: To analyze the dose–risk relationship for alcohol consumption and intracerebral hemorrhage (ICH) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study. Methods: ERICH is a multicenter, prospective, case-control study, designed to recruit 1,000 non-Hispanic white patients, 1,000 non-Hispanic black patients, and 1,000 Hispanic patients with ICH. Cases were matched 1:1 to ICH-free controls by age, sex, race/ethnicity, and geographic area. Comprehensive interviews included questions regarding alcohol consumption. Patterns of alcohol consumption were categorized as none, rare (<1 drink per month), moderate (≥1 drink per month and ≤2 drinks per day), intermediate (>2 drinks per day and <5 drinks per day), and heavy (≥5 drinks per day). ICH risk was calculated using the no-alcohol use category as the reference group. Results: Multivariable analyses demonstrated an ordinal trend for alcohol consumption: rare (odds ratio [OR] 0.57, p < 0.0001), moderate (OR 0.65, p < 0.0001), intermediate (OR 0.82, p = 0.2666), and heavy alcohol consumption (OR 1.77, p = 0.0003). Subgroup analyses demonstrated an association of rare and moderate alcohol consumption with decreased risk of both lobar and nonlobar ICH. Heavy alcohol consumption demonstrated a strong association with increased nonlobar ICH risk (OR 2.04, p = 0.0003). Heavy alcohol consumption was associated with significant increase in nonlobar ICH risk in black (OR 2.34, p = 0.0140) and Hispanic participants (OR 12.32, p < 0.0[...]



Body mass index and outcome after revascularization for symptomatic carotid artery stenosis

2017-05-22T12:47:49-07:00

Objective: To determine whether the obesity paradox exists in patients who undergo carotid artery stenting (CAS) or carotid endarterectomy (CEA) for symptomatic carotid artery stenosis. Methods: We combined individual patient data from 2 randomized trials (Endarterectomy vs Angioplasty in Patients with Symptomatic Severe Carotid Stenosis and Stent-Protected Angioplasty vs Carotid Endarterectomy) and 3 centers in a third trial (International Carotid Stenting Study). Baseline body mass index (BMI) was available for 1,969 patients and classified into 4 groups: <20, 20–<25, 25–<30, and ≥30 kg/m2. Primary outcome was stroke or death, investigated separately for the periprocedural and postprocedural period (≤120 days/>120 days after randomization). This outcome was compared between different BMI strata in CAS and CEA patients separately, and in the total group. We performed intention-to-treat multivariable Cox regression analyses. Results: Median follow-up was 2.0 years. Stroke or death occurred in 159 patients in the periprocedural (cumulative risk 8.1%) and in 270 patients in the postprocedural period (rate 4.8/100 person-years). BMI did not affect periprocedural risk of stroke or death for patients assigned to CAS (ptrend = 0.39) or CEA (ptrend = 0.77) or for the total group (ptrend = 0.48). Within the total group, patients with BMI 25–<30 had lower postprocedural risk of stroke or death than patients with BMI 20–<25 (BMI 25–<30 vs BMI 20–<[...]



Asymptomatic carotid stenosis: Medicine alone or combined with carotid revascularization

2017-05-22T12:47:49-07:00

Two positive randomized trials established carotid endarterectomy (CEA) as a superior treatment to medical management alone for the treatment of asymptomatic carotid artery stenosis. However, advances in medical therapy have led to an active and spirited debate about the best treatment for asymptomatic carotid stenosis. The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST 2) trial aims to better define the best treatment for the average patient with severe asymptomatic carotid stenosis. Enrollment in the trial may be hampered by strong opinions on either side of the debate. It is important to realize that equipoise exists and that neither the old data on CEA nor the new data on optimal medical therapy provide a rigorous answer. The assumption that medical therapy has already been proven superior to revascularization procedures may hinder both enrollment in the trial and technical advancements in revascularization procedures.




Recurrent belly dancer dyskinesia in pregnancy

2017-05-22T12:47:49-07:00

A 37-year-old woman in her 34th week of pregnancy developed continual abdominal movements, which had complicated both her previous pregnancies (video at Neurology.org). Examination, routine bloodwork, and brain MRI were normal. Circumstances precluded prepartum thoracolumbar MRI; postpartum MRI was unrevealing. Clonazepam and levetiracetam suppressed the movements, which remitted postpartum. All babies were healthy.




Editors' Note

2017-05-22T12:47:49-07:00

Editors' Note: Regarding "The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study," Dalla Costa et al. express concerns about the interpretation of results because of the number of patients screened, the clinical and paraclinical characteristics of the misdiagnosed patients, and the lack of specification of fulfilled multiple sclerosis (MS) criteria through which the diagnosis was made. Solomon et al., authors of the study, explain that the study was not designed to assess the frequency of MS misdiagnosis or its specific causes.




Letter re: The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study

2017-05-22T12:47:49-07:00

We read with interest the multicenter observational study by Solomon et al.,1 which assessed the prevalence and possible causes of multiple sclerosis (MS) misdiagnosis. We are concerned about the interpretation of the results and the assertion of the conclusion that misinterpretation and misapplication of MS criteria are substantial contemporary contributors to misdiagnosis.




Author response: The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study

2017-05-22T12:47:49-07:00

We appreciate the comments of Dalla Costa et al. on our Contemporary Issues article.1 As discussed, this study was not designed to assess the frequency of multiple sclerosis (MS) misdiagnosis or its specific causes.1 We catalogued the diagnoses ultimately assigned to patients mistaken as having MS and reported the evaluation of the MS specialists who determined that a misdiagnosis had occurred according to their analysis of what led to misdiagnosis. Accepting this limitation, application of MS diagnostic criteria to a neurologic syndrome not typical for MS contributed to misdiagnosis in 65% of cases.1 MS diagnostic criteria fail in this situation, but are often applied in clinical practice. In 60% of cases, declaring MRI criteria for dissemination in space satisfied in a patient with nonspecific symptoms contributed to misdiagnosis.1 Ultimately, these 2 errors perpetuate one another. Nonspecific symptoms acquire additional and unwarranted attention when nonspecific MRI lesions are present, and nonspecific MRI lesions are accorded undue attention in the presence of symptoms of common conditions such as migraine. Further studies should establish the frequency of misdiagnosis, but the combination of nonspecific symptoms and nonspecific MRI abnormalities is likely a common contemporary source of MS misdiagnosis.