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International Issues: Teleneurology in humanitarian crises: Lessons from the Medecins Sans Frontieres experience

2017-07-17T12:48:33-07:00

Humanitarian emergencies defined by armed conflict, political strife, famine, or natural disaster can devastate populations rapidly. Neurologic disorders accompany these complex humanitarian emergencies but often go unheeded, exacerbated by a scarcity of neurologists. Teleneurology offers the promise of neurologic care remotely in the face of this inadequate local clinician supply. We describe our experiences as voluntary neurology teleconsultants with Médecins Sans Frontières in order to highlight both the promises and challenges of teleneurology in humanitarian contexts. We identified the major advantages of this service as (1) minimal resources and incurred costs while (2) changing a patient's clinical course favorably, and (3) creating a community for the field referrer and neurology specialist. Current challenges include (1) limited diagnostic resources and difficult diagnostic and therapeutic decision-making, (2) need for greater continuity and familiarity between the field site and neurologist, (3) gaps in the US neurology curriculum to provide expertise for all sites, (4) lack of follow-up and feedback from the field to advise future cases, and (5) low frequency of consultations. Growth opportunities include eventual expansion to the development of a community of neurologists who can provide context-specific care and maximize use of multimedia at low Internet bandwidth. Lessons from our experience may help optimize teleneurology's effect and reduce disparities in neurologic care, particularly in humanitarian crises.




Teaching NeuroImages: Amlodipine-responsive trigeminal neuralgia: An alibi for vascular compression theory

2017-07-17T12:48:33-07:00

A 55-year-old woman developed recurrent short-lasting shock-like pain involving her left lower face. Initiation of amlodipine for concurrently detected hypertension relieved her of pain besides normalizing her blood pressure. Interestingly, occasions of noncompliance with amlodipine brought her pain back. Her cranial MRI revealed tortuous blood vessels compressing the left rostro-antero-lateral medulla and left trigeminal nerve root (figure 1). Vascular compression of medulla is known to produce neurogenic hypertension1 (figure e-1 at Neurology.org). Possibly, a decrease in vessel tortuosity2 mediated by voltage-gated L-type calcium channels (antihypertensive effect) and an action on N-type channels (sympathetic modulation/antinociceptive effect) played a role in amlodipine's inadvertent efficacy (figure e-2).




Teaching Video NeuroImages: Bent spine syndrome as an early presentation of late-onset Pompe disease

2017-07-17T12:48:33-07:00

Bent spine syndrome (BSS), an abnormal trunk anteroflexion of at least 45° that increases during walking and abates in supine position, is described in parkinsonism and myopathies.1 We report a 56-year-old man with genetically proven late-onset Pompe disease (LOPD) showing BSS (figure 1 and video at Neurology.org). He complained of axial weakness that progressively forced him to walk stretching his arms backward since his 20s. Whole-body muscle MRI revealed severe fatty replacement of lumbar paraspinal (figure 2) and iliopsoas muscles, and spirometry showed restrictive ventilatory defect. Periodic acid-Schiff–positive vacuoles and reduced acid α-glucosidase activity were demonstrated in muscle biopsy. While lumbar hyperlordosis is a typical feature of LOPD, other trunk abnormalities may appear early in the disease. LOPD must be included in the differential diagnosis of BSS.2




Spotlight on the July 18 issue

2017-07-17T12:48:33-07:00




Chance juxtapositions and (un)biased methods in science: More efficient at inefficiency

2017-07-17T12:48:33-07:00

A recent article in Neurology® hammered home several points made all the more cogent by proposals relative to the Federal budget and allegations made during the 2016 Presidential campaign. Shepheard et al.1 demonstrated that the extracellular domain (ECD) of the low-affinity neurotrophin receptor, p75NTR, is found in higher-than-normal concentration in the urine of patients with amyotrophic lateral sclerosis (ALS). This urinary excess of p75ECD varies in magnitude in proportion to other more cumbersome and more expensive measures of nerve loss and muscle dysfunction. This may make measurement of urinary p75ECD a practical and reliable method for monitoring progression of ALS and response of patients with ALS to experimental therapeutics.




Is all ALS genetic?

2017-07-17T12:48:33-07:00

In this issue of Neurology®, Gibson et al.1 address an important issue in amyotrophic lateral sclerosis (ALS) genetics; namely, what percentage of isolated or sporadic forms of ALS that have an identifiable genetic factor are likely responsible for disease pathogenesis. To address this, the authors used a 3-step approach: first, they selected 87 patients they diagnosed with sporadic ALS (SALS) and who were of European ancestry (to get as a homogenous a study cohort as possible). They then screened the exons of all 23,000 genes, focusing on variants in the 31 genes earlier linked to ALS, as well as 2 repeat intron sequences in the C9orf72 and ATXN2 genes also known to cause ALS. As with the general population, the patients harbored several genetic variants. The critical question is as follows: which of them are pathogenic?




Epilepsy and mortality after aneurysmal subarachnoid hemorrhage

2017-07-17T12:48:33-07:00

Aneurysm rupture causes 85% of spontaneous subarachnoid hemorrhage (SAH), and saccular intracranial aneurysms (SIA) account for the majority of ruptured aneurysms. SAH represents approximately 5% of all strokes. Despite this relatively low proportion, the disease has a disproportionately high burden, accounting for a quarter of life years lost due to cerebrovascular disease in one study,1 largely explained by the relatively young age of affected patients and high fatality.




Chronic headache: What's in a name?

2017-07-17T12:48:33-07:00

"What's in a name? That which we call a rose—By any other name would smell as sweet," Shakespeare wrote in his famous play Romeo and Juliet (II, ii, 1–2). This may be true from a poetic point of view for roses, but we also know how it ended for Romeo and Juliet. When it comes to classification of headache disorders nomenclature, it is crucial for research and clinical practice. In this issue of Neurology®, Probyn et al.1 describe prognostic factors for chronic headache, by means of an extensive systematic review. The enormous amount of work that went into producing this article, as well as its methodologic quality, are to be appreciated. Twenty-seven of 16,556 identified titles were included in the review (17 prospective cohorts and 10 randomized controlled trials with subgroup analyses reported).




The evolving genetic risk for sporadic ALS

2017-07-17T12:48:33-07:00

Objective:

To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)–associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity.

Methods:

Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls.

Results:

Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls.

Conclusions:

Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.




Disease progression in C9orf72 mutation carriers

2017-07-17T12:48:33-07:00

Objective:

To assess changes in 3 clinical measures, the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI), over time in C9orf72 mutation carriers (C9+) with varied clinical phenotypes.

Methods:

Thirty-four unrelated participants with mutations in C9orf72 were enrolled in a prospective natural history study. Participants were classified as asymptomatic, amyotrophic lateral sclerosis (ALS), ALS–familial frontotemporal dementia (FTD), or behavioral-variant FTD by clinical diagnostic criteria. Diagnostic cognitive and motor tests were repeated at 6 and 18 months. The ALSFRS-R, letter fluency, and FBI were administered at baseline and follow-up visits at 6, 12, and 18 months.

Results:

The clinical diagnosis of most patients did not change over the follow-up. ALSFRS-R scores correlated with measures of motor function. Letter fluency correlated with FBI and cognitive tests. ALSFRS-R, letter fluency, and FBI differed among the C9+ diagnostic subgroups at enrollment and worsened over follow-up in symptomatic patients, with different slopes among the subgroups. Most patients survived to the 6-month time point after enrollment. Survival of C9+ patients with ALS and C9+ patients with ALS-FTD declined over the 12- and 18-month follow-up.

Conclusions:

The pattern of scores of the ALSFRS-R, letter fluency, and FBI distinguished between ALS, ALS-FTD, and FTD presentations of C9orf72 mutation carriers and asymptomatic carriers. Longitudinal changes in these measures occurred with disease progression in a manner consistent with presenting phenotype.




Characterization of patients with longstanding idiopathic REM sleep behavior disorder

2017-07-17T12:48:33-07:00

Objective:

To evaluate the presence of prodromal markers of Parkinson disease (PD) in patients with longstanding idiopathic REM sleep behavior disorder (IRBD), a small subgroup of individuals with IRBD with long-term follow-up thought not to be at risk of developing PD.

Methods:

Demographic, clinical, and neuroimaging markers of PD were evaluated in 20 patients with polysomnographic-confirmed longstanding IRBD and in 32 matched controls.

Results:

Patients were 16 men and 4 women with mean age of 72.9 ± 8.6 years and mean follow-up from IRBD diagnosis of 12.1 ± 2.6 years. Patients more often had objective smell loss (35% vs 3.4%, p = 0.003), constipation (50% vs 15.6%, p = 0.008), and mild parkinsonian signs (45% vs 18.8%, p = 0.042) than controls. Unified Parkinson's Disease Rating Scale motor score was higher in patients than in controls (5.6 ± 3.5 vs 2.0 ± 2.1, p < 0.0001). Dopamine transporter imaging showed decreased striatal uptake in 82.4% of the patients and transcranial sonography found substantia nigra hyperechogenicity in 35.3%. α-Synuclein aggregates were found in 3 of 6 patients who underwent colon or submandibular gland biopsies. All 20 patients showed clinical, neuroimaging, or histologic markers of PD. Probability of prodromal PD (according to recent Movement Disorders Society research criteria) was higher in patients than in controls (<0.0001), and 45% of patients surpassed 80% probability.

Conclusions:

Prodromal PD markers are common in individuals with longstanding IRBD, suggesting that they are affected by an underlying neurodegenerative process. This observation may be useful for the design of disease-modifying trials to prevent PD onset in IRBD.




Insulin resistance among obese middle-aged is associated with decreased cerebrovascular reactivity

2017-07-17T12:48:33-07:00

Objective:

To evaluate differences in cerebrovascular reactivity (CVR) to mild hypercapnia in obese/overweight individuals with and without insulin resistance (IR) compared to comparable lean controls.

Methods:

A total of 60 cognitively normal participants (20 lean controls and 24 obese/overweight individuals with and 16 without IR) were evaluated using a high spatial resolution arterial spin labeling MRI technique at rest and during mild hypercapnia. We analyzed group differences in CVR in cerebral cortex and ascertained the relationships between CVR, IR, and body mass index (BMI).

Results:

Obese/overweight participants with and without IR had significantly lower CVR to hypercapnia than lean controls after controlling for age, sex, and the presence of hypertension (F2,53 = 5.578, p = 0.006 = 0.174). In the obese/overweight participants with IR, there was a significant correlation between higher CVR and a measure of insulin sensitivity, even after accounting for BMI (rp = 0.575, p = 0.004). In contrast, there was no relationship between CVR and BMI when controlling for IR. No such relationships existed for the other 2 groups.

Conclusions:

IR is associated with impaired CVR; the relationship appears to be driven by the degree of IR and not by obesity. These rarely reported results suggest that early forms of cerebrovascular dysfunction exist among obese middle-aged individuals with significant IR but without type 2 diabetes mellitus. These functional vascular abnormalities may help explain the associations among IR, diabetes, and dementia, and suggest that interventions aiming to improve IR or CVR may help prevent cognitive decline later in life.




Diagnosis of DWI-negative acute ischemic stroke: A meta-analysis

2017-07-17T12:48:33-07:00

Objective:

To determine the prevalence of diffusion-weighted imaging (DWI)–negative acute ischemic stroke (AIS) and to identify clinical characteristics of patients with DWI-negative AIS.

Methods:

We systematically searched PubMed and Ovid/MEDLINE for relevant studies between 1992, the year that the DWI sequence entered clinical practice, and 2016. Studies were included based upon enrollment of consecutive patients presenting with a clinical diagnosis of AIS prior to imaging. Meta-analysis was performed to synthesize study-level data, estimate DWI-negative stroke prevalence, and estimate the odds ratios (ORs) for clinical characteristics associated with DWI-negative stroke.

Results:

Twelve articles including 3,236 AIS patients were included. The meta-analytic synthesis yielded a pooled prevalence of DWI-negative AIS of 6.8%, 95% confidence interval (CI) 4.9–9.3. In the 5 studies that reported proportion data for DWI-negative and DWI-positive AIS based on the ischemic vascular territory (n = 1,023 AIS patients), DWI-negative stroke was strongly associated with posterior circulation ischemia, as determined by clinical diagnosis at hospital discharge or repeat imaging (OR 5.1, 95% CI 2.3–11.6, p < 0.001).

Conclusions:

A small but significant percentage of patients with AIS have a negative DWI scan. Patients with neurologic deficits consistent with posterior circulation ischemia have 5 times the odds of having a negative DWI scan compared to patients with anterior circulation ischemia. AIS remains a clinical diagnosis and urgent reperfusion therapy should be considered even when an initial DWI scan is negative.




Epilepsy-associated long-term mortality after aneurysmal subarachnoid hemorrhage

2017-07-17T12:48:33-07:00

Objective:

To elucidate the epilepsy-associated causes of death and subsequent excess long-term mortality among 12-month survivors of subarachnoid hemorrhage from saccular intracranial aneurysm (SIA-SAH).

Methods:

The Kuopio SIA Database (kuopioneurosurgery.fi) includes all SIA-SAH patients admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland. The study cohort consists of 779 patients, admitted from 1995 to 2007, who were alive at 12 months after SIA-SAH. Their use of reimbursable antiepileptic drugs and the causes of death (ICD-10) were fused from the Finnish national registries from 1994 to 2014.

Results:

The 779 12-month survivors were followed up until death (n = 197) or December 31, 2014, a median of 12.0 years after SIA-SAH. Epilepsy had been diagnosed in 121 (15%) patients after SIA-SAH, and 34/121 (28%) had died at the end of follow-up, with epilepsy as the immediate cause of death in 7/34 (21%). In the 779 patients alive at 12 months after SIA-SAH, epilepsy was an independent risk factor for mortality (hazard ratio 1.8, 95% confidence interval 1.1–3.0).

Conclusions:

Comorbid epilepsy in 12-month survivors of SIA-SAH is associated with increased risk of death in long-term follow-up. Survivors of SIA-SAH require long-term dedicated follow-up, including identification and effective treatment of comorbid epilepsy to prevent avoidable deaths.




Diagnostic algorithm for relapsing acquired demyelinating syndromes in children

2017-07-17T12:48:33-07:00

Objective:

To establish whether children with relapsing acquired demyelinating syndromes (RDS) and myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) show distinctive clinical and radiologic features and to generate a diagnostic algorithm for the main RDS for clinical use.

Methods:

A panel reviewed the clinical characteristics, MOG-Ab and aquaporin-4 (AQP4) Ab, intrathecal oligoclonal bands, and Epstein-Barr virus serology results of 110 children with RDS. A neuroradiologist blinded to the diagnosis scored the MRI scans. Clinical, radiologic, and serologic tests results were compared.

Results:

The findings showed that 56.4% of children were diagnosed with multiple sclerosis (MS), 25.4% with neuromyelitis optica spectrum disorder (NMOSD), 12.7% with multiphasic disseminated encephalomyelitis (MDEM), and 5.5% with relapsing optic neuritis (RON). Blinded analysis defined baseline MRI as typical of MS in 93.5% of children with MS. Acute disseminated encephalomyelitis presentation was seen only in the non-MS group. Of NMOSD cases, 30.7% were AQP4-Ab positive. MOG-Ab were found in 83.3% of AQP4-Ab–negative NMOSD, 100% of MDEM, and 33.3% of RON. Children with MOG-Ab were younger, were less likely to present with area postrema syndrome, and had lower disability, longer time to relapse, and more cerebellar peduncle lesions than children with AQP4-Ab NMOSD. A diagnostic algorithm applicable to any episode of CNS demyelination leads to 4 main phenotypes: MS, AQP4-Ab NMOSD, MOG-Ab–associated disease, and antibody-negative RDS.

Conclusions:

Children with MS and AQP4-Ab NMOSD showed features typical of adult cases. Because MOG-Ab–positive children showed notable and distinctive clinical and MRI features, they were grouped into a unified phenotype (MOG-Ab–associated disease), included in a new diagnostic algorithm.




Increased rate of venous thrombosis may be associated with inpatient dihydroergotamine treatment

2017-07-17T12:48:33-07:00

Objective:

To review whether the incidence of catheter-associated venous thromboses was higher in patients receiving IV dihydroergotamine compared to lidocaine.

Methods:

We retrospectively reviewed all admissions at the University of California, San Francisco Headache Center from February 25, 2008, through October 31, 2014, for age, sex, diagnosis, aura, treatment dose, type of IV line used, days with line, superficial (SVT) or deep venous thrombosis (DVT), and pulmonary embolism (PE).

Results:

A peripherally inserted central catheter (PICC) or midline catheter was placed in 315 of 589 (53%) admissions. Mean age was 38 years with a range of 6 to 79 years; 121 patients (21%) were ≤18 years old. Seventy-four percent (433 of 589) of patients were female. Of 263 dihydroergotamine admissions using a PICC or midline catheter, 19 (7.2%) had either an SVT or DVT or a PE; 2 patients were diagnosed with both DVT and PE. Of 52 lidocaine admissions using a PICC or midline catheter, none had a thrombotic event (p = 0.05, Fisher exact test). Age, sex, aura, total dihydroergotamine dose, and number of days with line were not significant predictors of venous thrombosis.

Conclusions:

IV dihydroergotamine treatment may be associated with an increased risk of catheter-associated venous thrombosis. A low threshold for diagnostic ultrasound investigation is appropriate because anticoagulation therapy was frequently required.




Hospital safety among neurologic patients: A population-based cohort study of adverse events

2017-07-17T12:48:33-07:00

Objective:

To examine the frequency and type of adverse events (AEs) experienced by neurologic patients in hospital.

Methods:

This population-based, retrospective cohort study used hospital discharge abstract data for children and adults admitted to hospital from 2009 to 2015 with 1 of 9 neurologic conditions (Alzheimer disease and related dementia, brain tumor, epilepsy, motor neuron disease, multiple sclerosis, parkinsonism/Parkinson disease, spinal cord injury, traumatic brain injury, and stroke). Neurologic conditions were identified with ICD-10-CA codes. Eighteen AEs were examined with ICD-10-CA codes. The proportion of AEs was calculated, and regression analysis was used to examine factors and outcomes associated with AEs (age, sex, comorbidity, length of stay, and mortality).

Results:

The overall proportion of admissions associated with an AE among those with a neurologic condition was 11 per 100 admissions. Those with a spinal cord injury had the highest proportion of AEs (39.4 per 100 admissions). The most common AEs were infections and respiratory complications (32.0% and 16.7%, respectively). Age and the presence of comorbidities were associated with higher odds of an AE, while readmission was associated with lower odds of an AE. Having an AE was associated with increased length of stay and higher odds of mortality.

Conclusions:

This study demonstrates that neurologic patients have a high proportion of AEs in hospital. The findings provide information on the quality and safety of care for people with neurologic conditions in hospital, which can help inform future quality improvement initiatives.




Prognostic factors for chronic headache: A systematic review

2017-07-17T12:48:33-07:00

Objective:

To identify predictors of prognosis and trial outcomes in prospective studies of people with chronic headache.

Methods:

This was a systematic review of published literature in peer-reviewed journals. We included (1) randomized controlled trials (RCTs) of interventions for chronic headache that reported subgroup analyses and (2) prospective cohort studies, published in English, since 1980. Participants included adults with chronic headache (including chronic headache, chronic migraine, and chronic tension-type headache with or without medication overuse headache). We searched key databases using free text and MeSH terms. Two reviewers independently extracted data and assessed the methodologic quality of studies and overall quality of evidence identified using appropriate published checklists.

Results:

We identified 16,556 titles, removed 663 duplicates, and reviewed 199 articles, of which 27 were included in the review—17 prospective cohorts and 10 RCTs with subgroup analyses reported. There was moderate-quality evidence indicating that depression, anxiety, poor sleep and stress, medication overuse, and poor self-efficacy for managing headaches are potential prognostic factors for poor prognosis and unfavorable outcomes from preventive treatment in chronic headache. There was inconclusive evidence about treatment expectations, age, age at onset, body mass index, employment, and several headache features.

Conclusions:

This review identified several potential predictors of poor prognosis and worse outcome postinterventions in people with chronic headache. The majority of these are modifiable. The findings also highlight the need for more longitudinal high-quality research of prognostic factors in chronic headache.




Dento-corneal aberrant regeneration as evidence of V2 innervation of the inferior human cornea

2017-07-17T12:48:33-07:00

Aberrant regeneration (AR) of axons may occur following nerve trauma or compression and causes axonal signals to be misdirected to structures other than their original targets. Ocular–oral synkinesis and gustatory hyperlacrimation (crocodile tears), which can each follow facial nerve palsy, are examples of motor and autonomic AR, respectively. Somatosensory AR is rarely reported, and causes the referral of a sensory stimulus at one location to a distant site; the referred sensation is usually perceived as more noxious than the initiating stimulus.1




Multinodular vacuolating and neuronal tumor of the cerebrum

2017-07-17T12:48:33-07:00

A 31-year-old woman presented with chronic headache. MRI revealed an atypical right parietal lesion involving the deep cortical ribbon and adjacent superficial subcortical white matter (figures 1 and 2).




Editors' Note

2017-07-17T12:48:33-07:00

Editors' Note: Commenting on "Transient smartphone blindness: Relevance to misdiagnosis in neurologic practice," Drs. Tripathy and Sengupta discuss additional observations such as monocular viewing in people with binocular vision, the nonspecificity of transient smartphone blindness (TSB) that can occur when viewing any bright object under the right circumstance, and potential conditions that can predispose certain individuals to TSB.




Letter re: Transient smartphone blindness: Relevance to misdiagnosis in neurologic practice

2017-07-17T12:48:33-07:00

A few observations regarding transient smartphone blindness (TSB) being misdiagnosed as multiple sclerosis (MS), as noted by Drs. Sathiamoorthi and Wingerchuk,1 require further discussion:

  • While optic neuritis cases may exhibit amaurosis fugax, diagnosis requires visual decline, relative afferent papillary defect, color vision or visual field changes, and pain during ocular movements with or without changes in the optic disc on funduscopy. Therefore, the ocular features of the presented case did not support the diagnosis of optic neuritis.1 We agree that MS diagnosis requires careful consideration of clinical features and clinical examination in addition to MRI features.

  • Binocular vision has the advantage of increased visual field, stereopsis, compensation for blind spot, and improved visuomotor functions.2 Monocular viewing is uncommon in humans with binocular vision, thus the clinical relevance of TSB needs further evaluation.3

  • Differential visual perception may occur with monocular exposure to any bright object, not only a smartphone.

  • Slow dark adaptation is a feature of diseases affecting the retinoid cycle and signal transduction or transmission of rod photoreceptors.4,5 Vitamin A deficiency and some forms of congenital stationary blindness, which may have an apparently normal fundus, may need to be ruled out in cases with exaggerated TSB.




  • Author response: Transient smartphone blindness: Relevance to misdiagnosis in neurologic practice

    2017-07-17T12:48:33-07:00

    We thank Drs. Tripathy and Sengupta for the interest in our Clinical/Scientific Note.1 We agree that our patient's clinical presentation was not consistent with demyelinating optic neuritis. This was one of several factors that led to misdiagnosis.




    Letter re: Munchausen syndrome by genetics: Next-generation challenges for clinicians

    2017-07-17T12:48:33-07:00

    Zittel et al.1 reported a very interesting patient who presented with a faked genetics test, along with faking clinical symptoms and signs, supporting diagnosis of Munchausen syndrome presenting as pseudo-dopa-responsive dystonia. The Clinical/Scientific Note provided an instructive example of how to pay attention to details that we usually take for granted during the busy clinician routine. It would be crucial to check if the patient had a specific motivation, such as pension application or welfare. Based on ICD-10, this differentiates Munchausen (F68.1) from person feigning illness (with obvious motivation) (Z76.5).




    Author response: Munchausen syndrome by genetics: Next-generation challenges for clinicians

    2017-07-17T12:48:33-07:00

    We thank Dr. Oliveira for the thoughtful commentary on our Clinical/Scientific Note.1 Dr. Oliveira raises the issue of the differential diagnosis of F68.1 (factitious disorder, Munchausen syndrome) vs Z76.5 (feigning illness with obvious motivation). Such a differentiation would indeed be relevant for further patient management.




    Clinical Reasoning: A 54-year-old woman with dementia, myoclonus, and ataxia

    2017-07-10T12:48:26-07:00

    A 54-year-old woman was referred for a second opinion regarding a 3-month history of subacute onset progressive cognitive decline. She complained of memory difficulties particularly with short term recall. Decision-making and organizational skills were increasingly difficult. She also developed sudden brief jerking movements of her body and progressive gait imbalance and incoordination leading to falls. Three months after onset, she could not work, drive, cook, or perform activities of daily living. She had not had episodes suggestive of seizures. Her medical history was remarkable for celiac disease diagnosed 9 years previously, which resolved with a gluten-free diet, collagenous colitis, Raynaud syndrome, osteopenia, anxiety, and prior episodes of hyponatremia related to polydipsia. Current medications included amitriptyline, venlafaxine, and Pepto-Bismol. She worked as a financial analyst, had never consumed tobacco products, and drank 3–4 alcoholic beverages per week. Her father had myasthenia gravis but there was no family history of dementia. General examination revealed a restless woman with pseudobulbar affect who was unable to provide a meaningful history. Neurologic examination revealed multiple abnormalities. Mental status testing revealed a mild to moderate degree of encephalopathy including abnormalities in attention, frontal lobe function, and comprehension. Kokmen short test of mental status score was 23 out of 38 (29/38 or less consistent with dementia). There was multifocal myoclonus and postural tremor. Cerebellar examination revealed appendicular and gait ataxia. Muscle strength and reflexes were normal. Sensory examination was unreliable due to dementia.




    Teaching NeuroImages: Osteochondroma arising from the clavicle causing ipsilateral Horner syndrome

    2017-07-10T12:48:26-07:00

    A 17-year-old female smoker noticed right eyelid droop for 6 months, with a constant right-sided pressure-like headache with photophobia, phonophobia, and nausea, right-sided lacrimation, and right-sided rhinorrhea. Examination revealed right Horner syndrome. A mass was palpable on the anterior aspect of her neck. Ultrasound of the neck, MRI head, and CT thorax showed a bony mass arising from the right medial clavicular head (figure 1). Histopathology from the excision confirmed an osteochondroma (figure 2). This was removed surgically with partial resolution of symptoms. This case demonstrates a rare cause of Horner syndrome1,2 and the importance of thorough imaging of the sympathetic chain.




    Teaching Video NeuroImages: Apraxia of eyelid closure following right hemispheric infarction

    2017-07-10T12:48:26-07:00

    A 56-year-old man presented following a right middle cerebral artery territory infarction (figure). In addition to left hemiparesis and neglect, he was unable to close his left eye on command (video at Neurology.org), though he was able to blink spontaneously and keep his eyes closed during sleep. He could maintain closure of both eyes once manually closed. Apraxia of eyelid closure is distinguished clinically from eyelid closure weakness by ability to blink reflexively and maintain eyelid closure. Activation of the oculomotor cortex has been associated with voluntary eyelid closure and lesions in right frontal and parietal lobes with eyelid closure apraxia.1,2




    Spotlight on the July 11 issue

    2017-07-10T12:48:25-07:00




    Cerebrovascular disease affects brain structural integrity long before clinically overt strokes

    2017-07-10T12:48:25-07:00

    In the current issue of Neurology®, Werden et al.1 examined a group of patients experiencing first-ever or recurrent stroke to understand the relationships between stroke and cortical structural integrity. They performed 3T magnetic resonance scanning within 6 weeks of the most recent stroke and found that stroke patients had smaller hippocampal volumes and greater white matter hyperintensity (WMH) volume compared to controls. Because of the short time lag from stroke to scan, the authors do not believe that the index stroke itself caused the shrinkage in the hippocampus; rather, they believe that the stroke and the structural change in the white matter and hippocampus resulted from a common underlying process.




    Acute flaccid myelitis and enterovirus D68: Deja vu all over again

    2017-07-10T12:48:25-07:00

    In 2012, illnesses presenting with acute flaccid paralysis were reported in the United States—over 150 cases between 2012 and 2015—with a clinical picture of a prodromal illness followed by rapid onset of weakness and cranial nerve dysfunction in association with CSF pleocytosis and elevated protein level. MRI showed abnormal spinal cord gray matter signal. Treatment with IV immunoglobulin, plasmapheresis, steroids, and antiviral agents had no effect on the natural history of what was named acute flaccid myelitis (AFM). Epidemiologic analysis later showed an association with an enterovirus D68, which was grouped into a recently emerged Clade B1 strain. This virus caused a respiratory illness and was identified in respiratory and gastrointestinal samples.1–3




    SUDEP: An important cause of premature mortality in epilepsy across the life spectrum

    2017-07-10T12:48:25-07:00

    Sudden unexpected death in epilepsy (SUDEP) was originally defined as a sudden, unexpected death in an individual with epilepsy, witnessed or not, and not associated with drowning or status epilepticus, for which a cause cannot be identified upon autopsy examination.1 Cases can be divided into definite, probable, and possible based upon the level of diagnostic certainty, especially after postmortem examination.2 As research criteria have evolved, a more comprehensive set of diagnostic criteria has been derived, including the term plus to indicate that another cause could have resulted in death, e.g., SUDEP probable/plus.3 During the last 20 years, SUDEP has become recognized as an important cause of premature mortality in the epilepsy population and is second only to stroke as the most common neurologic disorder responsible for the most potential years of life lost due its occurrence prior to late adulthood.4




    Structural MRI markers of brain aging early after ischemic stroke

    2017-07-10T12:48:25-07:00

    Objective:

    To examine associations between ischemic stroke, vascular risk factors, and MRI markers of brain aging.

    Methods:

    Eighty-one patients (mean age 67.5 ± 13.1 years, 31 left-sided, 61 men) with confirmed first-ever (n = 66) or recurrent (n = 15) ischemic stroke underwent 3T MRI scanning within 6 weeks of symptom onset (mean 26 ± 9 days). Age-matched controls (n = 40) completed identical testing. Multivariate regression analyses examined associations between group membership and MRI markers of brain aging (cortical thickness, total brain volume, white matter hyperintensity [WMH] volume, hippocampal volume), normalized against intracranial volume, and the effects of vascular risk factors on these relationships.

    Results:

    First-ever stroke was associated with smaller hippocampal volume (p = 0.025) and greater WMH volume (p = 0.004) relative to controls. Recurrent stroke was in turn associated with smaller hippocampal volume relative to both first-ever stroke (p = 0.017) and controls (p = 0.001). These associations remained significant after adjustment for age, sex, education, and, in stroke patients, infarct volume. Total brain volume was not significantly smaller in first-ever stroke patients than in controls (p = 0.056), but the association became significant after further adjustment for atrial fibrillation (p = 0.036). Cortical thickness and brain volumes did not differ as a function of stroke type, infarct volume, or etiology.

    Conclusions:

    Brain structure is likely to be compromised before ischemic stroke by vascular risk factors. Smaller hippocampal and total brain volumes and increased WMH load represent proxies for underlying vascular brain injury.




    Coated-platelets predict stroke at 30 days following TIA

    2017-07-10T12:48:25-07:00

    Objective:

    To examine the potential for coated-platelets, a subset of highly procoagulant platelets observed on dual agonist stimulation with collagen and thrombin, for predicting stroke at 30 days in patients with TIA.

    Methods:

    Consecutive patients with TIA were enrolled and followed up prospectively. ABCD2 scores were obtained for each patient. Coated-platelet levels, reported as percent of cells converted to coated-platelets, were determined at baseline. The primary endpoint was the occurrence of stroke at 30 days. Receiver operator characteristic (ROC) analysis was used to calculate area under the curve (AUC) values for a model including coated-platelets to predict incident stroke at 30 days.

    Results:

    A total of 171 patients with TIA were enrolled, and 10 strokes were observed at 30 days. A cutoff of 51.1% for coated-platelet levels yielded a sensitivity of 0.80 (95% confidence interval [CI] 0.55–1.0), specificity of 0.73 (95% CI 0.66–0.80), positive predictive value of 0.16 (95% CI 0.06–0.26), and negative predictive value of 0.98 (95% CI 0.96–1.0). The adjusted hazard ratio of incident stroke in patients with coated-platelet levels ≥51.1% was 10.72 compared to those with levels <51.1%. ROC analysis showed significant improvement in the predictive ability of the coated-platelet model compared to ABCD2 score (AUC 0.78 ± 0.07 vs 0.54 ± 0.07, p = 0.01).

    Conclusions:

    These findings suggest a role for coated-platelets in risk stratification for stroke at 30 days after TIA.




    Outcomes of Colorado children with acute flaccid myelitis at 1 year

    2017-07-10T12:48:25-07:00

    Objective:

    We describe long-term functional, neurodiagnostic, and psychosocial outcomes of a cohort of 12 children from Colorado diagnosed with acute flaccid myelitis (AFM) in 2014.

    Methods:

    Children were assessed every 3 months for 1 year or until clinical resolution. Assessments included neurologic examination, MRI, EMG/nerve conduction studies (NCS), functional measures (Assisting Hand Assessment, Hammersmith Functional Motor Scale), and Patient-Reported Outcomes Measurement Information System questionnaires.

    Results:

    Eight of 12 children completed the study. Six of 8 had persistent motor deficits at 1 year; 2 demonstrated full recovery. Four were not enrolled, 2 of whom reported full recovery. The 6 affected were weakest in proximal muscles, showing minimal to no improvement and significant atrophy at 1 year. All patients improved in distal muscle groups. Cranial nerve dysfunction resolved in 2 of 5 and improved in all. Four of 5 showed progressive functional improvement at 6 and 12 months. Two of 8 reported pain at 1 year. Three of 8 reported depressive symptoms. Repeat MRI was performed in 7 of 8 children a median of 7 months after onset and showed significant improvement or normalization in all but one child. Repeat EMG/NCS was performed on 4 children a median of 8 months after onset and showed ongoing denervation and chronic reinnervation in 3 children with persistent deficits.

    Conclusions:

    At 1 year, children with AFM demonstrated functional gains but weakness persisted. EMG changes correlated with persistent deficits better than imaging. Despite improvements, AFM had substantial long-term functional effects on affected children.




    Baseline motor findings and Parkinson disease prognostic subtypes

    2017-07-10T12:48:25-07:00

    Objective:

    To identify the significance of baseline motor features to the lifelong prognostic motor subtypes in a Parkinson disease (PD) cohort.

    Methods:

    In a previous study of 166 PD cases, we observed different prognosis in tremor-dominant, akinetic-rigid, and mixed subtypes. This study includes the same cases, but we excluded 10 cases with symptoms of ≥15 years duration at baseline. Relative severity of tremor, bradykinesia/akinesia, and rigidity at baseline were evaluated as predictors of the motor subtypes, which are known to have different prognosis.

    Results:

    The most common motor subtype was mixed, followed by akinetic-rigid and then the tremor-dominant. Seventy cases were not receiving antiparkinsonian drugs at baseline. The prognostic subtypes could be predicted at baseline in 85% of all and in 91% of the treatment-naive cases. Sensitivity, specificity, and positive predictive values were strong for the mixed and the akinetic-rigid but weak for the tremor-dominant subtype.

    Conclusions:

    Our data show that motor profile at baseline can predict prognosis in most PD cases. These findings can be incorporated into clinical practice.




    Standard operating procedures improve acute neurologic care in a sub-Saharan African setting

    2017-07-10T12:48:25-07:00

    Objective:

    Quality of neurologic emergency management in an under-resourced country may be improved by standard operating procedures (SOPs).

    Methods:

    Neurologic SOPs were implemented in a large urban (Banjul) and a small rural (Brikama) hospital in the Gambia. As quality indicators of neurologic emergency management, performance of key procedures was assessed at baseline and in the first and second implementation years.

    Results:

    At Banjul, 100 patients of the first-year intervention group exhibited higher rates of general procedures of emergency management than 105 control patients, such as neurologic examination (99.0% vs 91.4%; p < 0.05) and assessments of respiratory rate (98.0% vs 81.9%, p < 0.001), temperature (60.0% vs 36.2%; p < 0.001), and glucose levels (73.0% vs 58.1%; p < 0.05), in addition to written directives by physicians (96.0% vs 88.6%, p < 0.05), whereas assessments of other vital signs remained unchanged. In stroke patients, rates of stroke-related procedures increased: early CT scanning (24.3% vs 9.9%; p < 0.05), blood count (73.0% vs 49.3%; p < 0.01), renal and liver function tests (50.0% vs 5.6%, p < 0.001), aspirin prophylaxis (47.3% vs 9.9%; p < 0.001), and physiotherapy (41.9% vs 4.2%; p < 0.001). Most effects persisted until the second-year evaluation. SOP implementation was similarly feasible and beneficial at the Brikama hospital. However, outcomes did not significantly differ in the hospitals.

    Conclusions:

    Implementing SOPs is a realistic, low-cost option for improving process quality of neurologic emergency management in under-resourced settings.

    Classification of evidence:

    This study provides Class IV evidence that, for patients with suspected neurologic emergencies in sub-Saharan Africa, neurologic SOPs increase the rate of performance of guideline-recommended procedures.




    A randomized trial of telemedicine efficacy and safety for nonacute headaches

    2017-07-10T12:48:25-07:00

    Objective:

    To evaluate long-term treatment efficacy and safety of one-time telemedicine consultations for nonacute headaches.

    Methods:

    We randomized, allocated, and consulted nonacute headache patients via telemedicine (n = 200) or in a traditional manner (n = 202) in a noninferiority trial. Efficacy endpoints, assessed by questionnaires at 3 and 12 months, included change from baseline in Headache Impact Test–6 (HIT-6) (primary endpoint) and pain intensity (visual analogue scale [VAS]) (secondary endpoint). The primary safety endpoint, assessed via patient records, was presence of secondary headache within 12 months after consultation.

    Results:

    We found no differences between telemedicine and traditional consultations in HIT-6 (p = 0.84) or VAS (p = 0.64) over 3 periods. The absolute difference in HIT-6 from baseline was 0.3 (95% confidence interval [CI] –1.26 to 1.82, p = 0.72) at 3 months and 0.2 (95% CI –1.98 to 1.58, p = 0.83) at 12 months. The absolute change in VAS was 0.4 (95% CI –0.93 to 0.22, p = 0.23) after 3 months and 0.3 (95% CI –0.94 to 0.29, p = 0.30) at 12 months. We found one secondary headache in each group at 12 months. The estimated number of consultations needed to miss one secondary headache with the use of telemedicine was 20,200.

    Conclusion:

    Telemedicine consultation for nonacute headache is as efficient and safe as a traditional consultation.

    ClinicalTrials.gov identifier:

    NCT02270177.

    Classification of evidence:

    This study provides Class III evidence that a one-time telemedicine consultation for nonacute headache is noninferior to a one-time traditional consultation regarding long-term treatment outcome and safety.




    Comment: The virtual neurologist

    2017-07-10T12:48:25-07:00

    In 1999, Levine and Gorman1 introduced telestroke as the first major application of telemedicine to neurology. Today telestroke is standard care globally. Now, Müller et al.2 have conducted one of the largest teleneurology clinical trials for nonacute headaches.




    Modulation of intrinsic resting-state fMRI networks in women with chronic migraine

    2017-07-10T12:48:25-07:00

    Objective:

    To evaluate the intrinsic resting functional connectivity of the default mode network (DMN), salience network (SN), and central executive network (CEN) network in women with chronic migraine (CM), and whether clinical features are associated with such abnormalities.

    Methods:

    We analyzed resting-state connectivity in 29 women with CM as compared to age- and sex-matched controls. Relationships between clinical characteristics and changes in targeted networks connectivity were evaluated using a multivariate linear regression model.

    Results:

    All 3 major intrinsic brain networks were less coherent in CM (DMN: p = 0.030, SN: p = 0.007, CEN: p = 0.002) as compared to controls. When stratified based on medication overuse headache (MOH) status, CM without MOH (DMN: p = 0.029, SN: p = 0.023, CEN: p = 0.003) and CM with MOH (DMN: p = 0.016, SN: p = 0.016, CEN: p = 0.015) were also less coherent as compared to controls. There was no difference in CM with MOH as compared to CM without MOH (DMN: p = 0.382, SN: p = 0.408, CEN: p = 0.419). The frequency of moderate and severe headache days was associated with decreased connectivity in SN (p = 0.003) and CEN (p = 0.015), while cutaneous allodynia was associated with increased connectivity in SN (p = 0.011).

    Conclusions:

    Our results demonstrated decreased overall resting-state functional connectivity of the 3 major intrinsic brain networks in women with CM, and these patterns were associated with frequency of moderate to severe headache and cutaneous allodynia.




    The incidence of SUDEP: A nationwide population-based cohort study

    2017-07-10T12:48:25-07:00

    Objective:

    To identify all cases of sudden unexpected death in epilepsy (SUDEP) among people in Sweden during 1 year and to determine the SUDEP incidence in relation to age, sex, and psychiatric comorbidity.

    Methods:

    We included all individuals with a hospital-based ambulatory care or hospital discharge diagnosis of epilepsy in the Swedish National Patient Registry during 1998–2005 who were alive on January 1, 2008. Deaths during 2008 were identified by linkage to the National Cause of Death Registry. Death certificates, medical charts, and police and autopsy reports were extensively reviewed to identify SUDEP cases.

    Results:

    Of 57,775 epilepsy patients alive on January 1, 2008, 1,890 died (3.3%) during 2008. Of these, 99 met the Annegers SUDEP criteria (49 definite, 19 probable, and 31 possible). SUDEP accounted for 5.2% of all deaths and 36% of deaths in the 0–15 years age group. The incidence of definite/probable SUDEP was 1.20/1,000 person-years, and higher in men (1.41) than in women (0.96). All SUDEP cases <16 years were in boys. SUDEP incidence at ages <16, 16–50, and >50 years was 1.11, 1.13, and 1.29, respectively, per 1,000 person-years. The incidence was 5-fold increased among female patients with psychiatric comorbidities compared to those without. Epilepsy was mentioned on the death certificate in only 62 of the 99 (63%) SUDEP cases.

    Conclusions:

    Methods relying on death certificates underestimate SUDEP incidence. SUDEP risk has been underestimated especially in boys and in older people regardless of sex. Patients with psychiatric comorbidities, women in particular, are at increased SUDEP risk.




    CSF sAPP{beta}, YKL-40, and neurofilament light in frontotemporal lobar degeneration

    2017-07-10T12:48:25-07:00

    Objective:

    To analyze the clinical utility of 3 CSF biomarkers and their structural imaging correlates in a large cohort of patients with different dementia and parkinsonian syndromes within the spectrum of frontotemporal lobar degeneration (FTLD).

    Methods:

    We analyzed 3 CSF biomarkers (YKL-40, soluble β fragment of amyloid precursor protein [sAPPβ], neurofilament light [NfL]) and core Alzheimer disease (AD) biomarkers (β-amyloid1-42, total tau, phosphorylated tau) in patients with FTLD-related clinical syndromes (n = 159): behavioral variant of frontotemporal dementia (n = 68), nonfluent (n = 23) and semantic (n = 19) variants of primary progressive aphasia, progressive supranuclear palsy (n = 28), and corticobasal syndrome (n = 21). We also included patients with AD (n = 72) and cognitively normal controls (CN; n = 76). We compared cross-sectional biomarker levels between groups, studied their correlation with cortical thickness, and evaluated their potential diagnostic utility.

    Results:

    Patients with FTLD-related syndromes had lower levels of sAPPβ than CN and patients with AD. The levels of sAPPβ showed a strong correlation with cortical structural changes in frontal and cingulate areas. NfL and YKL-40 levels were high in both the FTLD and AD groups compared to controls. In the receiver operating characteristic analysis, the sAPPβ/YKL-40 and NfL/sAPPβ ratios had areas under the curve of 0.91 and 0.96, respectively, distinguishing patients with FTLD from CN, and of 0.84 and 0.85, distinguishing patients with FTLD from patients with AD.

    Conclusions:

    The combination of sAPPβ with YKL-40 and with NfL in CSF could be useful to increase the certainty of the diagnosis of FTLD-related syndromes in clinical practice.

    Classification of evidence:

    This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes.




    A propensity score analysis for comparison of T-3b and VATET in myasthenia gravis

    2017-07-10T12:48:25-07:00

    Objective:

    We performed propensity score (PS) models to compare the outcome of patients with myasthenia gravis (MG) submitted to 2 different surgical approaches: extended transsternal (T-3b) or thoracoscopic extended thymectomy (VATET).

    Methods:

    Patients' clinical data were retrieved from the MG database of the C. Besta Neurologic Institute Foundation. In the PS analysis, a matching ratio of 1:1 of the main clinical variables was obtained for the 2 groups of patients and treatment effect was estimated by comparing their outcome.

    Results:

    A total of 210 patients met the inclusion criteria, by having a complete set of clinical data, and were included in the PS model; a matched dataset of 122 participants (61 per group) showed an adequate balance of all the covariates. Our analysis demonstrated that 68.9% of patients who had thymectomy by the VATET technique reached the pharmacologic remission/remission status at 2 years from thymectomy compared to 34.4% of those operated on by the T-3b technique (p < 0.001), had a lower INCB-MG score (p < 0.001), and had less muscle fatigability (p = 0.004). Similar results were found considering only nonthymomatous patients with MG. Results were also confirmed by paired statistical tests.

    Conclusions:

    Our PS matching analysis showed that VATET is a reliable and effective surgical approach alternative to T-3b in patients with MG who are candidates for thymectomy.

    Classification of evidence:

    This study provides Class IV evidence that for patients with MG, VATET is more effective than T-3b thymectomy.




    Patients with ALS show highly correlated progression rates in left and right limb muscles

    2017-07-10T12:48:25-07:00

    Objective:

    Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.

    Methods:

    A large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.

    Results:

    This report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent.

    Conclusions:

    First, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials.




    Failure of alemtuzumab therapy to control MOG encephalomyelitis

    2017-07-10T12:48:25-07:00

    Myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG)–associated encephalomyelitis (EM) is a rare autoimmune disorder that displays substantial clinicoradiologic overlap with aquaporin-4 (AQP4)-IgG-seropositive neuromyelitis optica spectrum disorders (NMOSD) and classic multiple sclerosis (MS).1–3,e1 The long-term outcome is often poor.2,3,e1 Recent evidence suggests that many disease-modifying agents approved for the treatment of MS may be ineffective or even harmful in AQP4-IgG-positive and MOG-IgG-positive patients.2–4




    The entire world

    2017-07-10T12:48:25-07:00




    Dramatic improvement of tardive dyskinesia movements by inline skating

    2017-07-10T12:48:25-07:00

    A 25-year-old woman with severe tardive dyskinesia (TD) due to neuroleptics had substantial improvement of movements while inline skating (video at Neurology.org). She received pallidal deep brain stimulation (DBS), and gait and inline skating were assessed before and after DBS; her twin sister served as a control (figures 1 and 2). Possible explanations for her improvement include (1) balance stability required by inline skating provides external cues that are less prominent during gait1; and (2) dystonia consistently responds to geste antagoniste.2 Since TD has variable response to treatments, we propose research into alleviating factors in TD that may advance treatment and rehabilitation in this incapacitating disorder.




    Editors' Note

    2017-07-10T12:48:25-07:00

    Editors' Note: In response to the article "Hand postures in primary and secondary generalized tonic-clonic seizures," Dr. Mintzer explains why the statistical methodology employed by the authors, Fisher exact test with Bonferroni correction for multiple comparisons, was not ideal and that the version for multiple groups would have been preferable.




    Letter re: Hand postures in primary and secondary generalized tonic-clonic seizures

    2017-07-10T12:48:25-07:00

    I congratulate Drs. Siegel and Tatum1 for the novel examination of hand postures in different seizure types. However, I have concerns that the statistical analysis was not done properly.




    Author response: Hand postures in primary and secondary generalized tonic-clonic seizures

    2017-07-10T12:48:25-07:00

    We thank Dr. Mintzer for the interest in our article1 and for the comments on the statistical significance of our findings in response to our prior comment to Dr. Lanska.2,3




    Author update: Sarcoplasmic MxA expression: A valuable marker of dermatomyositis

    2017-07-10T12:48:25-07:00

    Soon after our article published,1 we learned the sale of the myxovirus resistance A (MxA) polyclonal antibodies used in the study (Mx1/2/3 [H-285], sc-50509, Santa Cruz Biotechnology, Dallas, TX) had been discontinued. Furthermore, we received inquiries from several physicians concerning alternate MxA antibodies. We tested the company's monoclonal antibody alternate (Mx1/2/3 [C-1], sc-166412) on frozen muscle sections at various dilutions in 2% bovine serum albumin in PBS using the Ventana immunohistochemistry detection system (Ventana Medical Systems, Tucson, AZ) with or without the enhancement mode. Muscle samples tested included MxA-positive dermatomyositis (n = 3, including 1 juvenile participant), MxA-negative dermatomyositis (n = 3), anti-Jo-1 myopathy (n = 3, MxA-negative), and immune-mediated necrotizing myopathy (n = 3, comprising 1 with anti-signal recognition particle antibodies [MxA-negative], 1 with anti-3-hydroxy-3-methylglutaryl-CoA reductase antibodies [MxA-negative], and 1 without those antibodies [MxA-positive]). We observed essentially the same staining pattern at comparable signal intensity as the original polyclonal antibodies at 1:10 dilution with the enhancement mode although the signal was barely detected at the manufacturer's recommended dilution (starting dilution: 1:50), indicating that the monoclonal antibody alternate can be similarly used to detect sarcoplasmic MxA expression on frozen muscle sections for the diagnosis of dermatomyositis (although higher concentration is necessary).










    Spotlight on the July 4 issue

    2017-07-03T12:48:16-07:00




    Clinical Reasoning: A 58-year-old man with progressive ptosis and walking difficulty

    2017-07-03T12:48:16-07:00

    A 58-year-old man developed progressive walking difficulty over 10 years. He had normal development and an unremarkable birth history. At age 30, he developed bilateral drooping eyelids with double vision. At age 48, he developed progressive gait unsteadiness, slurred speech, and swallowing difficulty. At age 55, he needed to walk with a cane. He did not have seizures, hearing loss, or memory impairment. He did not have any history of alcohol abuse or exposures to anticonvulsants. His mother has congenital cardiac disease and diabetes mellitus, and his sister has had epilepsy since childhood. His daughter is healthy.




    Message from the Editors to our Reviewers

    2017-07-03T12:48:16-07:00

    We cannot adequately convey our gratitude for the dedication of Neurology's peer reviewers. Peer review is an essential mechanism for assessing quality of research and conferring credibility to the content we publish, and authors benefit greatly by receiving your feedback on their work. Listing your names in this message cannot fully reflect our appreciation for your efforts in reviewing papers.




    Teaching NeuroImages: Abnormal cervical and cerebral vasculature in 22q11 deletion syndrome

    2017-07-03T12:48:16-07:00

    A 12-day-old girl with a postnatal microarray diagnosis of 22q11.2 deletion syndrome was transferred for surgical repair of truncus arteriosus. Neurologic examination at the time of transfer was unremarkable. Brain MRI on day of life 9 demonstrated an absent left internal carotid flow void. Magnetic resonance angiography of the head (figure, A) and neck (figure, B) was subsequently obtained prior to cardiac repair. Patients with 22q11 deletion syndromes may have abnormal cervical vessel development.1 Children with congenital heart disease have an elevated stroke risk, particularly for periprocedural stroke.2 Understanding variant cerebrovascular anatomy in these cases may aid in surgical planning to mitigate stroke risk.




    Correcting honest pervasive errors in the scientific literature: Retractions without stigma

    2017-07-03T12:48:16-07:00

    In the June 6 issue of Neurology®, we published a retraction of an article,1 a replacement article,2 and a copy of the original published version of the article with the changes highlighted. We had been alerted by a reader's submission to our WriteClick® Rapid Online Correspondence section that the authors had misdiagnosed a medical condition.3,4 Conversations with the authors revealed that the use of an erroneous term for the diagnosis was an honest mistake caused by an error in translation from another language. Issuing a retraction and a replacement version were vitally important to prevent misinforming readers and to correct the literature.




    Advancing the phenome alongside the genome in epilepsy studies

    2017-07-03T12:48:16-07:00

    The development of high-throughput sequencing technologies has led to remarkable progress in understanding the genetic basis of human epilepsies. Over the last 5 years, more than 20 genes have been identified through genome-first approaches, identifying novel genes first and then working backwards to understand the associated phenotypes. This approach has been useful in epileptic encephalopathies, where family-based exome studies have identified a growing list of genes with causative de novo mutations.1




    White matter changes and social cognitive function in MS: When all is no longer in the eyes

    2017-07-03T12:48:16-07:00

    The mechanisms and consequences of cognitive impairment in people with multiple sclerosis (MS) are slowly being uncovered. Interest in this area has in part increased due to the lack of clear evidence for effective therapies.1 A separate, major motivator is that cognitive impairment is not just a predictor of unemployment but is the leading predictor of occupational disability.2 This increasing interest in cognitive function has been mirrored by a parallel increase in studies of social cognition: a collection of psychological processes that facilitate interpersonal communication and interaction by helping individuals understand how others think and feel. These abilities may influence employment, but also relationships with spouses, caregivers, friends, and family members. Social cognition is therefore potentially of particular relevance to people with MS, for whom peer support is one of the main determinants of quality of life.3 Yet there is a relative lack of research in this area, despite recent evidence that deficits in these social cognitive processes may be similar in magnitude to many of the other neurocognitive deficits that are observed in MS.4




    Dementia with Lewy bodies advances: A new consensus report

    2017-07-03T12:48:16-07:00

    Beginning in the 1980s, a number of studies defined a subset of patients with dementia with brainstem and cortical Lewy bodies and associated clinical characteristics. Based on the accumulated evidence, an international consortium proposed clinical and pathologic criteria for this distinct syndrome, dementia with Lewy bodies (DLB).1 Two subsequent consensus reports refined the diagnostic and pathologic criteria as additional evidence emerged. In this issue of Neurology®, the DLB Consortium publishes the fourth consensus report, further refining the clinical criteria for DLB by incorporating new evidence.2




    Outcome measures in the idiopathic inflammatory myopathies: On the search for the holy grail

    2017-07-03T12:48:16-07:00

    The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune disorders that share some similarities, such as proximal predominant symmetric muscle weakness, also known as myopathy pattern 1,1 except for myopathy pattern 4 (distal arm and proximal leg weakness), in inclusion body myositis (IBM).1,2 Common features in IBM, dermatomyositis, polymyositis, and necrotizing autoimmune myopathy, frequently include serum creatine kinase (CK) elevation and myopathy with muscle membrane irritability on EMG. Muscle histopathology findings vary depending on the underlying disease, and may include inflammatory exudates of variable distribution, intact myofiber lymphocytic invasion, widespread necrosis and phagocytosis, or, in the case of IBM, rimmed vacuoles and protein aggregation.2,3




    Familial aggregation of focal seizure semiology in the Epilepsy Phenome/Genome Project

    2017-07-03T12:48:16-07:00

    Objective:

    To improve phenotype definition in genetic studies of epilepsy, we assessed the familial aggregation of focal seizure types and of specific seizure symptoms within the focal epilepsies in families from the Epilepsy Phenome/Genome Project.

    Methods:

    We studied 302 individuals with nonacquired focal epilepsy from 149 families. Familial aggregation was assessed by logistic regression analysis of relatives’ traits (dependent variable) by probands’ traits (independent variable), estimating the odds ratio for each symptom in a relative given presence vs absence of the symptom in the proband.

    Results:

    In families containing multiple individuals with nonacquired focal epilepsy, we found significant evidence for familial aggregation of ictal motor, autonomic, psychic, and aphasic symptoms. Within these categories, ictal whole body posturing, diaphoresis, dyspnea, fear/anxiety, and déjà vu/jamais vu showed significant familial aggregation. Focal seizure type aggregated as well, including complex partial, simple partial, and secondarily generalized tonic-clonic seizures.

    Conclusion:

    Our results provide insight into genotype–phenotype correlation in the nonacquired focal epilepsies and a framework for identifying subgroups of patients likely to share susceptibility genes.




    Functional network integrity presages cognitive decline in preclinical Alzheimer disease

    2017-07-03T12:48:16-07:00

    Objective:

    To examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD).

    Methods:

    A total of 237 clinically normal older adults (aged 63–90 years, Clinical Dementia Rating 0) underwent baseline β-amyloid (Aβ) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with Aβ burden. Median neuropsychological follow-up was 3 years.

    Results:

    Baseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with Aβ burden in predicting decline, with combined higher Aβ and lower connectivity predicting the steepest curvilinear decline in PACC performance.

    Conclusions:

    In clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Aβ burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings.




    Disconnection as a mechanism for social cognition impairment in multiple sclerosis

    2017-07-03T12:48:16-07:00

    Objective:

    To assess the contribution of microstructural normal-appearing white matter (NAWM) damage to social cognition impairment, specifically in the theory of mind (ToM), in multiple sclerosis (MS).

    Methods:

    We enrolled consecutively 60 patients with MS and 60 healthy controls (HC) matched on age, sex, and education level. All participants underwent ToM testing (Eyes Test, Videos Test) and 3T brain MRI including conventional and diffusion tensor imaging sequences. Tract-based spatial statistics (TBSS) were applied for whole-brain voxel-wise analysis of fractional anisotropy (FA) and mean diffusivity (MD) on NAWM.

    Results:

    Patients with MS performed worse on both tasks of ToM compared to HC (Eyes Test 58.7 ± 13.8 vs 81.9 ± 10.4, p < 0.001, Hedges g –1.886; Videos Test 75.3 ± 9.3 vs 88.1 ± 7.1, p < 0.001, Hedges g –1.537). Performance on ToM tests was correlated with higher values of FA and lower values of MD across widespread white matter tracts. The largest effects (≥90% of voxels with statistical significance) for the Eyes Test were body and genu of corpus callosum, fornix, tapetum, uncinate fasciculus, and left inferior cerebellar peduncle, and for the Videos Test genu and splenium of corpus callosum, fornix, uncinate fasciculus, left tapetum, and right superior fronto-occipital fasciculus.

    Conclusions:

    These results indicate that a diffuse pattern of NAWM damage in MS contributes to social cognition impairment in the ToM domain, probably due to a mechanism of disconnection within the social brain network. Gray matter pathology is also expected to have an important role; thus further research is required to clarify the neural basis of social cognition impairment in MS.




    Intake of dairy foods and risk of Parkinson disease

    2017-07-03T12:48:16-07:00

    Objective:

    To prospectively examine the association between commonly consumed dairy products and the risk of Parkinson disease (PD) in women and men.

    Methods:

    Analyses were based on data from 2 large prospective cohort studies, the Nurses' Health Study (n = 80,736) and the Health Professionals Follow-up Study (n = 48,610), with a total of 26 and 24 years of follow-up, respectively. Both US-based studies were conducted via mailed biennial questionnaires. Dietary intake was assessed with food frequency questionnaires administered repeatedly over the follow-up period. Incident cases of PD (n = 1,036) were identified via questionnaires and subsequently confirmed by reviewing medical records. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on total milk intake and PD risk and 1 study on total dairy intake and PD risk.

    Results:

    While total dairy intake was not significantly associated with PD risk in our cohorts, intake of low-fat dairy foods was associated with PD risk. The pooled, multivariable-adjusted hazard ratio (HR) comparing people who consumed at least 3 servings of low-fat dairy per day to those who consumed none was 1.34 (95% confidence interval [CI] 1.01–1.79, p trend = 0.04). This association appeared to be driven by an increased risk of PD associated with skim and low-fat milk (HR 1.39, 95% CI 1.12–1.73, p trend <0.01). Results were similar in women and men (p for heterogeneity >0.05). In the meta-analysis, the pooled relative risk comparing extreme categories of total milk intake was 1.56 (95% CI 1.30–1.88), and the association between total dairy and PD became significant (HR 1.27, 95% CI 1.04–1.55).

    Conclusions:

    Frequent consumption of dairy products appears to be associated with a modest increased risk of PD in women and men.




    Rapid transitions in the epidemiology of stroke and its risk factors in China from 2002 to 2013

    2017-07-03T12:48:16-07:00

    Objective:

    To estimate the current prevalence, temporal incidence trends, and contribution of risk factors for stroke in China.

    Methods:

    The China National Stroke Screening Survey (CNSSS) is an ongoing nationwide population-based program. A representative sample of 1,292,010 adults over 40 years old with 31,188 identified stroke cases from the 2013 and 2014 CNSSS database was analyzed to provide descriptive statistics of the prevalence and risk factors for stroke in 2014. In addition, a retrospective evaluation of 12,526 first-ever stroke cases in 2002–2013 and stroke mortality data from the 2002–2013 China Public Health Statistical Yearbook was conducted to estimate the incidence rates.

    Results:

    In 2014, the adjusted stroke prevalence was 2.06% in adults aged 40 years and older. After full adjustments, all risk factors assessed showed significant associations with stroke (p < 0.01); the largest contributor was hypertension (population-attributable risk 53.2%), followed by family history, dyslipidemia, atrial fibrillation, diabetes, physical inactivity, smoking, and overweight/obesity. The incidence of first-ever stroke in adults aged 40–74 years increased from 189/100,000 individuals in 2002 to 379/100,000 in 2013—an overall annual increase of 8.3%. Stroke-specific mortality in adults aged 40–74 years has remained stable, at approximately 124 deaths/100,000 individuals in both 2002 and 2013.

    Conclusions:

    In 2002–2013, the incidence of stroke in China increased rapidly. Combined with a high prevalence, a trend toward a younger age, and stable mortality, this finding suggests that additional clinical and behavioral interventions for metabolic and lifestyle risk factors are necessary to prevent stroke, particularly in certain populations.




    Tenecteplase in ischemic stroke offers improved recanalization: Analysis of 2 trials

    2017-07-03T12:48:16-07:00

    Objective:

    To test whether patients with complete vessel occlusion show greater recanalization at 24 hours and have improved clinical outcomes at 24 hours and 90 days when treated with tenecteplase compared to alteplase.

    Methods:

    Pooled clinical and imaging data from 2 phase 2 randomized trials comparing tenecteplase with alteplase allowed CT angiography (CTA) scans to be assessed centrally for occlusion status at baseline and at 24 hours post thrombolysis using the modified thrombolysis in cerebral infarction (TICI) scale. Twenty-four-hour poststroke NIH Stroke Scale (NIHSS) and 90-day modified Rankin Scale (mRS) scores were also compared between treatment groups using linear regression to generate odds ratios (ORs).

    Results:

    From 146 pooled patients, 69 had a TICI 0/1 occlusion overall at baseline. Tenecteplase-treated patients with a complete vessel occlusion had greater complete recanalization rates at 24 hours (71% for tenecteplase vs 43% for alteplase, p < 0.001). Patients with a TICI 0/1 occlusion who were treated with tenecteplase also showed greater early clinical improvement (median NIHSS change with tenecteplase was 9, interquartile range [IQR] 6, alteplase 1, IQR 1, p = 0.001) and higher rates of favorable 90-day outcomes (mRS 0–1 of tenecteplase compared with alteplase, OR 4.82, 95% confidence interval 1.02–7.84, p = 0.05).

    Conclusions:

    Tenecteplase may offer greater recanalization efficacy compared to alteplase, possibly exaggerated in patients with complete vessel occlusions on baseline CTA.




    Long-term unmet needs and associated factors in stroke or TIA survivors: An observational study

    2017-07-03T12:48:16-07:00

    Objective:

    To extensively investigate long-term unmet needs in survivors of stroke or TIA and to identify factors associated with these unmet needs.

    Methods:

    Community-dwelling adults were invited to participate in a survey ≥2 years after discharge for stroke/TIA. Unmet needs were assessed across 5 domains: activities and participation, environmental factors, body functions, post–acute care, and secondary prevention. Factors associated with unmet needs were determined with multivariable negative binomial regression.

    Results:

    Of 485 participants invited to complete the survey, 391 (81%) responded (median age 73 years, 67% male). Most responders (87%) reported unmet needs in ≥1 of the measured domains, particularly in secondary prevention (71%). Factors associated with fewer unmet needs included older age (incident rate ratio [IRR] 0.62, 95% confidence interval [CI] 0.50–0.77), greater functional ability (IRR 0.33, 95% CI 0.17–0.67), and reporting that the general practitioner was the most important in care (IRR 0.69, 95% CI 0.57–0.84). Being depressed (IRR 1.61, 95% CI 1.23–2.10) and receiving community services after stroke (IRR 1.45, 95% CI 1.16–1.82) were associated with more unmet needs.

    Conclusions:

    Survivors of stroke/TIA reported considerable unmet needs ≥2 years after discharge, particularly in secondary prevention. The factors associated with unmet needs could help guide policy decisions, particularly for tailoring care and support services provided after discharge.




    Polyneuropathy relates to impairment in daily activities, worse gait, and fall-related injuries

    2017-07-03T12:48:16-07:00

    Objective:

    To extensively investigate the association of chronic polyneuropathy with basic and instrumental activities of daily living (BADL and IADL), falls, and gait.

    Methods:

    A total of 1,445 participants of the population-based Rotterdam Study (mean age 71 years, 54% women) underwent a polyneuropathy screening involving a symptom questionnaire, neurologic examination, and nerve conduction studies. Screening yielded 4 groups: no, possible, probable, and definite polyneuropathy. Participants were interviewed about BADL (Stanford Health Assessment questionnaire), IADL (Instrumental Activities of Daily Living scale), and frequency of falling in the previous year. In a random subset of 977 participants, gait was assessed with an electronic walkway. Associations of polyneuropathy with BADL and IADL were analyzed continuously with linear regression and dichotomously with logistic regression. History of falling was evaluated with logistic regression, and gait changes were evaluated with linear regression.

    Results:

    Participants with definite polyneuropathy had more difficulty in performing BADL and IADL than participants without polyneuropathy. Polyneuropathy related to worse scores of all BADL components (especially walking) and 3 IADL components (housekeeping, traveling, and shopping). Participants with definite polyneuropathy were more likely to fall, and these falls more often resulted in injury. Participants with polyneuropathy had worse gait parameters on the walkway, including lower walking speed and cadence, and more errors in tandem walking.

    Conclusions:

    Chronic polyneuropathy strongly associates with impairment in the ability to perform daily activities and relates to worse gait and an increased history of falling.




    The botulinum toxin legend of Reinhard Heydrich's death: The end of "Himmler's brain"

    2017-07-03T12:48:16-07:00

    The high-ranking German Nazi Reinhard Heydrich (1904–1942) was one of the main organizers of the mass murder of Jews during the Second World War. He died on June 4, 1942, in Prague after having been wounded in Operation Anthropoid planned by the British intelligence services. Since the 1970s and 1980s, Heydrich's death has been frequently presented in British, American, and French literature as the consequence of a bacteriologic attack. Botulinum toxin would have been used in the grenades or ammunition. We discuss the botulinum toxin hypothesis using the now declassified British archives of Operation Anthropoid and of the chemical and bacteriologic warfare centers to assess this hypothesis.




    Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium

    2017-07-03T12:48:16-07:00

    The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.




    Physical activity monitoring: A promising outcome measure in idiopathic inflammatory myopathies

    2017-07-03T12:48:16-07:00

    Availability of reliable outcomes for idiopathic inflammatory myopathies (IIM) is critical to optimize treatment strategies.1 The current consensus for the assessment of IIM severity and treatment efficacy relies on the evaluation of core set measures comprising manual muscle testing, muscle enzymes, extramuscular disease activity assessment, physician and patient global disease activity assessment, and patient's physical function questionnaires.2 Muscle enzymes such as serum creatine kinase (CK) level are highly sensitive markers for detecting changes in disease activity though this does not correlate well with disease severity. Manual muscle testing is an operator-dependent and semiquantitative evaluation resulting in poor interrater reliability and poor sensitivity to changes. Disease burden may be imprecisely assessed when using self-reported questionnaires. Floor and ceiling effects associated with these metrics are also of major concern.1,2




    Proatlantal intersegmental artery with internal carotid artery stenosis

    2017-07-03T12:48:16-07:00

    A 56-year-old man presented with vertigo of 4 days duration. Neurologic examination was unremarkable. CT angiograms revealed a right internal carotid artery (ICA) stenosis and an ipsilateral proatlantal intersegmental artery (PIA, type 1). The PIA arose from the ICA, ran upward, then took a dorsal course, and continued as the vertebral artery, serving as the major contributor of the posterior circulation (figure, A–C). Catheter-based angiogram showed ICA stenosis of 60% (figure, D). He chose drug therapy and remained asymptomatic on follow-up. Such combination can lead to TIA of the vertebrobasilar system; treatment options include endarterectomy, stenting, balloon angioplasty, or medication.1,2




    Editors' Note

    2017-07-03T12:48:16-07:00

    Editors' Note: Commenting on "Long-term cortisol measures predict Alzheimer disease risk," Drs. Lattanzi and Silvestrini point out the interrelationships among cortisol dysregulation, insulin resistance, and blood pressure variability in Alzheimer disease (AD) and suggest that the authors study the association between cortisol exposure and the risk of non-AD dementias. Dr. Onofrj critiques "Mediodorsal nucleus and its multiple cognitive functions" because it omitted discussion of confabulations.




    Letter re: Long-term cortisol measures predict Alzheimer disease risk

    2017-07-03T12:48:16-07:00

    We read with interest the article by Ennis et al.,1 which found cortisol dysregulation to be related to an increased risk for Alzheimer disease (AD), and built on the unresolved question of whether systemic homeostasis primarily contributes to AD expression or represents an epiphenomenon of the underlying brain pathology. Additional considerations might provide useful insights toward a better and more comprehensive understanding of this issue. Within their pleiotropic effects, corticosteroids can greatly influence metabolic functions as well as blood pressure levels and fluctuations, all of which play key roles in dementia onset and course.2 In the CNS, corticosteroid receptors are not uniformly localized and abnormal glucocorticoid signaling can result in cell type and site-specific differences.3 Accordingly, it would be of great interest to address the interrelationships among cortisol dysregulation, insulin resistance, and blood pressure variability,4 and to investigate the associations between cortisol exposure and the risk of non-AD dementias.5




    Author response: Long-term cortisol measures predict Alzheimer disease risk

    2017-07-03T12:48:16-07:00

    I thank Drs. Lattanzi and Silvestrini for the thoughtful response to our article.1 I fully agree with their suggested mechanisms of action by which cortisol may increase risk for AD. In our sample, we had very few non-AD dementias, which precluded a more comprehensive assessment of how cortisol dysregulation may affect risk for other dementias, though it is a fascinating question.




    Letter re: Mediodorsal nucleus and its multiple cognitive functions

    2017-07-03T12:48:16-07:00

    The review on mediodorsal (thalamic) nucleus by Golden et al.1 omitted referencing relevant information. Mediodorsal nucleus was the focus of a historic debate on the origin of confabulations in Korsakoff syndrome,2–4 which is characterized by confabulations (beyond amnesia) only if mediodorsal nuclei are involved.2–4 Clinical findings observed in isolated lacunes of mediodorsal nuclei could elucidate the point, yet isolated lacunes, like the one described in the representative case,1 are extraordinarily rare.




    Author response: Mediodorsal nucleus and its multiple cognitive functions

    2017-07-03T12:48:16-07:00

    We thank Dr. Onofrj for the comments on our review,1 and for highlighting past literature that suggested the mediodorsal nucleus of the thalamus may also be involved in the development of confabulations in addition to the clinical features described in our case of an isolated left-sided lesion. Indeed, Dr. Onofrj's group's recent clinical case of bilateral lesions of the mediodorsal thalamic nuclei and the associated imaging data lend further support to this concept. Their study and case series would interestingly suggest a possible laterality to the role of the thalamus in the phenomenon of confabulations and provide valuable groundwork for future study in this area.










    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[...]



    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[...]



    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 dysfu[...]



    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[...]



    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 ev[...]



    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[...]



    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