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Godless State

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

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




Child Neurology: LAMA2 muscular dystrophy without contractures

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

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




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

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

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




Spotlight on the May 23 issue

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




Preventing Parkinson disease by vagotomy: Fact or fiction?

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

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




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

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

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




Nothing like a spirited debate!

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

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




Optimal management of patients with asymptomatic carotid stenosis

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

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




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

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

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




Lewis P. Rowland, MD (1925-2017)

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

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




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

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

Objective:

To examine whether vagotomy decreases the risk of Parkinson disease (PD).

Methods:

Using data from nationwide Swedish registers, we conducted a matched-cohort study of 9,430 vagotomized patients (3,445 truncal and 5,978 selective) identified between 1970 and 2010 and 377,200 reference individuals from the general population individually matched to vagotomized patients by sex and year of birth with a 40:1 ratio. Participants were followed up from the date of vagotomy until PD diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first. Vagotomy and PD were identified from the Swedish Patient Register. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox models stratified by matching variables, adjusting for country of birth, chronic obstructive pulmonary disease, diabetes mellitus, vascular diseases, rheumatologic disease, osteoarthritis, and comorbidity index.

Results:

A total of 4,930 cases of incident PD were identified during 7.3 million person-years of follow-up. PD incidence (per 100,000 person-years) was 61.8 among vagotomized patients (80.4 for truncal and 55.1 for selective) and 67.5 among reference individuals. Overall, vagotomy was not associated with PD risk (HR 0.96, 95% CI 0.78–1.17). However, there was a suggestion of lower risk among patients with truncal vagotomy (HR 0.78, 95% CI 0.55–1.09), which may be driven by truncal vagotomy at least 5 years before PD diagnosis (HR 0.59, 95% CI 0.37–0.93). Selective vagotomy was not related to PD risk in any analyses.

Conclusions:

Although overall vagotomy was not associated the risk of PD, we found suggestive evidence for a potential protective effect of truncal, but not selective, vagotomy against PD development.




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

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

Objective:

To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD).

Methods:

One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change.

Results:

For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] –3.0 [0.45] vs –1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group.

Conclusions:

In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements.

Classification of evidence:

This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores.




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

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

Objective:

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

Methods:

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

Results:

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

Conclusions:

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




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

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

Objective:

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

Methods:

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

Results:

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

Conclusions:

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




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

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

Objective:

To assess whether first-trimester exposure to pregabalin is associated with an increased risk of major congenital malformations, as recently suggested in a pregnancy registry study.

Methods:

We performed a cohort study nested in the US Medicaid Analytic eXtract (MAX). The study population included 1,323,432 pregnancies resulting in a live-born infant between 2000 and 2010. We examined the risk of major congenital malformations among infants born to women exposed to pregabalin during the first trimester compared with women unexposed to anticonvulsants. We used propensity score fine stratification to control for >50 potential confounders, and we estimated relative risks (RRs) and 95% confidence intervals (CIs) in generalized linear models. The analyses were replicated in the Truven Health MarketScan Commercial Database (MarketScan). Pooled estimates based on the adjusted RR produced in MAX, MarketScan, and the previous registry study were calculated.

Results:

Of 477 infants exposed to pregabalin during the first trimester in MAX, 28 (5.9%) had malformations compared to 3.3% in nonexposed infants. The crude RR of major congenital malformations for pregabalin was 1.80 (95% CI 1.26–2.58). After propensity score adjustment, the RR moved to 1.16 (95% CI 0.81–1.67). Restriction to pregabalin monotherapy and sensitivity analyses produced similar results. The adjusted RR for major congenital malformations for the 174 infants exposed in MarketScan was 1.03 (95% CI 0.56–1.90). The pooled RR was 1.33 (95% CI 0.83–2.15) for pregabalin any use and 1.02 (95% CI 0.69–1.51) for pregabalin monotherapy.

Conclusions:

Findings did not confirm the suggested teratogenic effects of pregabalin, although they cannot rule out the possibility of a small effect.




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

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

Objective:

To assess whether an average of 10 years of lifestyle intervention designed to reduce weight and increase physical activity lowers the prevalence of cognitive impairment among adults at increased risk due to type 2 diabetes and obesity or overweight.

Methods:

Central adjudication of mild cognitive impairment and probable dementia was based on standardized cognitive test battery scores administered to 3,802 individuals who had been randomly assigned, with equal probability, to either the lifestyle intervention or the diabetes support and education control. When scores fell below a prespecified threshold, functional information was obtained through proxy interview.

Results:

Compared with control, the intensive lifestyle intervention induced and maintained marked differences in weight loss and self-reported physical activity throughout follow-up. At an average (range) of 11.4 (9.5–13.5) years after enrollment, when participants' mean age was 69.6 (54.9–87.2) years, the prevalence of mild cognitive impairment and probable dementia was 6.4% and 1.8%, respectively, in the intervention group, compared with 6.6% and 1.8%, respectively, in the control group (p = 0.93). The lack of an intervention effect on the prevalence of cognitive impairment was consistent among individuals grouped by cardiovascular disease history, diabetes duration, sex, and APOE 4 allele status (all p ≥ 0.50). However, there was evidence (p = 0.03) that the intervention effect ranged from benefit to harm across participants ordered from lowest to highest baseline BMI.

Conclusions:

Ten years of behavioral weight loss intervention did not result in an overall difference in the prevalence of cognitive impairment among overweight or obese adults with type 2 diabetes.

Clinicaltrials.gov identifier:

NCT00017953 (Action for Health in Diabetes).

Level of evidence:

This study provides Class II evidence that for overweight adults with type 2 diabetes, a lifestyle intervention designed to reduce weight and increase physical activity does not lower the risk of cognitive impairment.




Relationship between carotid arterial properties and cerebral white matter hyperintensities

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

Objective:

Since arterial stiffness is a functional measure of arterial compliance and may be an important marker of cerebrovascular disease, we examined the association of carotid artery stiffness with white matter hyperintensity volume (WMHV) in a cross-sectional study of 1,166 stroke-free participants.

Methods:

Carotid beta stiffness index (STIFF) was assessed by M-mode ultrasound of the common carotid artery and calculated as the ratio of natural log of the difference between systolic and diastolic blood pressure over STRAIN, a ratio of the difference between carotid systolic and diastolic diameter (DD) divided by DD. WMHV was measured by fluid-attenuated inversion recovery MRI. The associations of STIFF, DD, and STRAIN with WMHV were examined using linear regression after adjusting for sociodemographic, lifestyle, and vascular risk factors.

Results:

In a fully adjusted model, larger carotid DD was significantly associated with greater log-WMHV (β = 0.09, p = 0.001). STIFF and STRAIN were not significantly associated with WMHV. In adjusted analyses stratified by race–ethnicity, STRAIN (β = –1.78, p = 0.002) and DD (β = 0.11, p = 0.001) were both associated with greater log-WMHV among Hispanic participants, but not among black or white participants.

Conclusions:

Large carotid artery diameters are associated with greater burden of white matter hyperintensity (WMH) in this multiethnic population. The association between increased diameters, decreased STRAIN, and greater WMH burden is more pronounced among Hispanics. These associations suggest a potential important pathophysiologic role of extracranial large artery remodeling in the burden of WMH.




Alcohol use and risk of intracerebral hemorrhage

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

Objective:

To analyze the dose–risk relationship for alcohol consumption and intracerebral hemorrhage (ICH) in the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study.

Methods:

ERICH is a multicenter, prospective, case-control study, designed to recruit 1,000 non-Hispanic white patients, 1,000 non-Hispanic black patients, and 1,000 Hispanic patients with ICH. Cases were matched 1:1 to ICH-free controls by age, sex, race/ethnicity, and geographic area. Comprehensive interviews included questions regarding alcohol consumption. Patterns of alcohol consumption were categorized as none, rare (<1 drink per month), moderate (≥1 drink per month and ≤2 drinks per day), intermediate (>2 drinks per day and <5 drinks per day), and heavy (≥5 drinks per day). ICH risk was calculated using the no-alcohol use category as the reference group.

Results:

Multivariable analyses demonstrated an ordinal trend for alcohol consumption: rare (odds ratio [OR] 0.57, p < 0.0001), moderate (OR 0.65, p < 0.0001), intermediate (OR 0.82, p = 0.2666), and heavy alcohol consumption (OR 1.77, p = 0.0003). Subgroup analyses demonstrated an association of rare and moderate alcohol consumption with decreased risk of both lobar and nonlobar ICH. Heavy alcohol consumption demonstrated a strong association with increased nonlobar ICH risk (OR 2.04, p = 0.0003). Heavy alcohol consumption was associated with significant increase in nonlobar ICH risk in black (OR 2.34, p = 0.0140) and Hispanic participants (OR 12.32, p < 0.0001). A similar association was not found in white participants.

Conclusions:

This study demonstrated potential protective effects of rare and moderate alcohol consumption on ICH risk. Heavy alcohol consumption was associated with increased ICH risk. Race/ethnicity was a significant factor in alcohol-associated ICH risk; heavy alcohol consumption in black and Hispanic participants poses significant nonlobar ICH risk.




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

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

Objective:

To determine whether the obesity paradox exists in patients who undergo carotid artery stenting (CAS) or carotid endarterectomy (CEA) for symptomatic carotid artery stenosis.

Methods:

We combined individual patient data from 2 randomized trials (Endarterectomy vs Angioplasty in Patients with Symptomatic Severe Carotid Stenosis and Stent-Protected Angioplasty vs Carotid Endarterectomy) and 3 centers in a third trial (International Carotid Stenting Study). Baseline body mass index (BMI) was available for 1,969 patients and classified into 4 groups: <20, 20–<25, 25–<30, and ≥30 kg/m2. Primary outcome was stroke or death, investigated separately for the periprocedural and postprocedural period (≤120 days/>120 days after randomization). This outcome was compared between different BMI strata in CAS and CEA patients separately, and in the total group. We performed intention-to-treat multivariable Cox regression analyses.

Results:

Median follow-up was 2.0 years. Stroke or death occurred in 159 patients in the periprocedural (cumulative risk 8.1%) and in 270 patients in the postprocedural period (rate 4.8/100 person-years). BMI did not affect periprocedural risk of stroke or death for patients assigned to CAS (ptrend = 0.39) or CEA (ptrend = 0.77) or for the total group (ptrend = 0.48). Within the total group, patients with BMI 25–<30 had lower postprocedural risk of stroke or death than patients with BMI 20–<25 (BMI 25–<30 vs BMI 20–<25; hazard ratio 0.72; 95% confidence interval 0.55–0.94).

Conclusions:

BMI is not associated with periprocedural risk of stroke or death; however, BMI 25–<30 is associated with lower postprocedural risk than BMI 20–<25. These observations were similar for CAS and CEA.




Asymptomatic carotid stenosis: Medicine alone or combined with carotid revascularization

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

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




Recurrent belly dancer dyskinesia in pregnancy

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

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




Editors' Note

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

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




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

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

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




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

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

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




Letter re: Early start of DOAC after ischemic stroke: Risk of intracranial hemorrhage and recurrent events

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

Seiffge et al.1 evaluated the effect of direct, non–vitamin K antagonist oral anticoagulants (DOACs) or vitamin K antagonists on intracranial hemorrhage (ICH) and recurrent ischemic events in patients with acute ischemic stroke or TIA and nonvalvular atrial fibrillation (NVAF). I have a concern about the study.




Author response: Early start of DOAC after ischemic stroke: Risk of intracranial hemorrhage and recurrent events

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

We thank Prof. Kawada for his interest in our article.1 We agree that larger patient cohorts more accurately estimate the risk of intracranial hemorrhage (ICH) from direct, non–vitamin K antagonist oral anticoagulants (DOACs). However, the definition of ICH is crucial. In our study we looked at symptomatic ICH (sICH) only, and observed only 1 patient with sICH.1 In contrast, the cited study of Cappellari et al.2 looked at both sICH and asymptomatic ICH: Of the 7 patients with any ICH after DOAC start, only 1 had sICH. Therefore, the rates of sICH were comparable between the 2 studies.




Teaching NeuroImages: Takayasu arteritis: Neuroimaging progression after immunosuppressant treatment

2017-05-15T12:47:45-07:00

A 29-year-old woman presented with a 2-year history of heel pain, constitutional symptoms, and increased acute phase reactants. CT and magnetic resonance (MR) angiography revealed a thickening of aortic walls and a thread-like appearance of bilateral subclavian and common carotid arteries. The findings were consistent with Takayasu arteritis (TA)1 and the patient was prescribed methylprednisolone, followed by azathioprine. Follow-up MR angiography, 6 years later, showed an important improvement with only a mild luminal narrowing of both common carotid arteries (figures 1 and 2, A and B). TA is a large-artery inflammatory disease of unknown etiology. MRI findings parallel clinical and serologic improvement during follow-up.




Teaching NeuroImages: Prominent spinal cord atrophy and white matter changes in adult polyglucosan body disease

2017-05-15T12:47:45-07:00

A 48-year-old man of Ashkenazi Jewish descent developed neurogenic bladder and mild cognitive dysfunction. Neurologic examination and CSF analysis were unremarkable. Brain MRI demonstrated white matter changes in the internal capsule, optic radiations, mesencephalon, superior cerebellar peduncles, pons, and medulla (figure 1) and prominent medullary and spinal cord atrophy (figure 2). These findings are classically found in adult polyglucosan body disease (APBD).1 Glycogen branching enzyme GBE1 gene sequencing revealed that the patient was compound heterozygous (c.691+2T>C and c.986 A>C). APBD should be considered in patients with adult-onset leukodystrophy and spinal atrophy; genetic testing is crucial to prevent misdiagnosis with multiple sclerosis and other leukodystrophies.2




Spotlight on the May 16 issue

2017-05-15T12:47:44-07:00




Favorable outcome in patients with intracranial hemorrhage due to ruptured brain AVM

2017-05-15T12:47:44-07:00

Despite all efforts, intracranial hemorrhage still has a dismal prognosis, with up to 61% mortality after 2 years.1 Several authors have concluded that intracranial hemorrhage due to a brain arteriovenous malformation (AVM) has a better clinical outcome.1–3 Only one study specifically addressed this issue and used a relatively small sample, comparing the outcome of 90 patients with a ruptured AVM from the Scottish Intracranial Vascular Malformation Study to the outcome of 60 patients with a spontaneous intracranial bleeding included in the Oxford Vascular Study.1 Those investigators found better outcomes after AVM-related hemorrhages independently of patient age and other known predictors of intracranial hemorrhage outcome. This difference in outcome warrants a thorough radiologic investigation in every patient presenting with an intracranial hemorrhage.




Thromboembolism prevention after chronic subdural hematoma in the elderly: A leap in the dark

2017-05-15T12:47:44-07:00

The incidence of chronic subdural hematomas (cSDH) increases with age.1,2 Risk factors that contribute to the occurrence of cSDH, apart from advancing age, include a history of falls, minor head injury, use of anticoagulant or antiplatelet medications, bleeding disorders, heavy alcohol use, epilepsy, low intracranial pressure conditions, and hemodialysis.1 The aged population also endures the highest risk of atrial fibrillation and other conditions that predispose them to devastating ischemic cardiac and cerebral ischemic events.3 Antithrombotic therapy constitutes evidence-based therapy to prevent these ischemic events, but consensus holds that use of antithrombotic medications is also the most important risk factor that accounts for the increasing incidence of cSDH in the elderly.1




Outcomes after intracerebral hemorrhage from arteriovenous malformations

2017-05-15T12:47:44-07:00

Objective:

To compare outcomes after intracerebral hemorrhage (ICH) from cerebral arteriovenous malformation (AVM) rupture and other causes of ICH.

Methods:

We performed a retrospective population-based study using data from the Nationwide Inpatient Sample. We used standard diagnosis codes to identify ICH cases from 2002 to 2011. Our predictor variable was cerebral AVM. Our primary outcomes were inpatient mortality and home discharge. We used logistic regression to compare outcomes between patients with ICH with and without AVM while adjusting for demographics, comorbidities, and hospital characteristics. In a confirmatory analysis using a prospective cohort of patients hospitalized with ICH at our institution, we additionally adjusted for hematoma characteristics and the Glasgow Coma Scale score.

Results:

Among 619,167 ICH hospitalizations, the 4,485 patients (0.7%, 95% confidence interval [CI] 0.6–0.8) with an AVM were younger and had fewer medical comorbidities than patients without AVM. After adjustment for confounders, patients with AVM had lower odds of death (odds ratio [OR] 0.5, 95% CI 0.4–0.7) and higher odds of home discharge (OR 2.0, 95% CI 1.4–3.0) than patients without AVM. In a confirmatory analysis of 342 patients with ICH at our institution, the 34 patients (9.9%, 95% CI 7.2–13.6) with a ruptured AVM had higher odds of ambulatory independence at discharge (OR 4.4, 95% CI 1.4–13.1) compared to patients without AVM.

Conclusions:

Patients with ICH due to ruptured AVM have more favorable outcomes than patients with ICH from other causes.




Anticoagulant and antiplatelet use in seniors with chronic subdural hematoma: Systematic review

2017-05-15T12:47:44-07:00

Objective:

To address whether to restart older patients on anticoagulants or antiplatelet agents in the setting of a chronic subdural hematoma (cSDH).

Methods:

This is an update of a previous review (searched until July 2012). Medline, EMBASE, ISI Web of Knowledge, Google Scholar, PLOS, and the Cochrane Register for Systematic Reviews databases were searched from January 2012 to December 2016. Studies included older adults (those over 65 years) experiencing traumatic subdural hematoma or cSDH who were on anticoagulation or antiplatelet agents.

Results:

Seven studies were included (mean age 72 years). Four out of 7 studies provided combined data on anticoagulants or antiplatelet use. Only one study found anticoagulant or antiplatelet agent use to be a significant factor for cSDH rebleeding. Two studies considered anticoagulant use only and both reported similar increased odds of rebleeding (odds ratio [OR] 1.75, 95% confidence interval [CI] 0.18–16.86; OR 2.7 95% CI 1.42–6.96). Antiplatelets were not found to be associated with rebleeding. Ideal timing to resume anticoagulants or antiplatelets was unclear.

Conclusions:

Anticoagulant medication was associated with increased rebleeding risk in older adults with cSDH. However, antiplatelet medication was not associated with increased risk of rebleeding.




Diagnostic value of prehospital ECG in acute stroke patients

2017-05-15T12:47:44-07:00

Objective:

To investigate the diagnostic yield of prehospital ECG monitoring provided by emergency medical services in the case of suspected stroke.

Methods:

Consecutive patients with acute stroke admitted to our tertiary stroke center via emergency medical services and with available prehospital ECG were prospectively included during a 12-month study period. We assessed prehospital ECG recordings and compared the results to regular 12-lead ECG on admission and after continuous ECG monitoring at the stroke unit.

Results:

Overall, 259 patients with prehospital ECG recording were included in the study (90.3% ischemic stroke, 9.7% intracerebral hemorrhage). Atrial fibrillation (AF) was detected in 25.1% of patients, second-degree or greater atrioventricular block in 5.4%, significant ST-segment elevation in 5.0%, and ventricular ectopy in 9.7%. In 18 patients, a diagnosis of new-onset AF with direct clinical consequences for the evaluation and secondary prevention of stroke was established by the prehospital recordings. In 2 patients, the AF episodes were limited to the prehospital period and were not detected by ECG on admission or during subsequent monitoring at the stroke unit. Of 126 patients (48.6%) with relevant abnormalities in the prehospital ECG, 16.7% received medical antiarrhythmic therapy during transport to the hospital, and 6.4% were transferred to a cardiology unit within the first 24 hours in the hospital.

Conclusions:

In a selected cohort of patients with stroke, the in-field recordings of the ECG detected a relevant rate of cardiac arrhythmia. The results can add to the in-hospital evaluation and should be considered in prehospital care of acute stroke.




Copeptin and NT-proBNP for prediction of all-cause and cardiovascular death in ischemic stroke

2017-05-15T12:47:44-07:00

Objective:

To evaluate long-term mortality in patients with acute ischemic stroke (AIS) by exploring the correlation between death and plasma concentrations of copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in a cohort study.

Methods:

In a prospective, multicenter observational study of 4,215 patients with AIS, copeptin and NT-proBNP levels were measured with a standardized method when patients were admitted to hospital. The primary endpoint was all-cause mortality or cardiovascular disease (CVD) mortality within 1 year.

Results:

During a follow-up period, 906 patients (20.1%, 95% confidence interval [CI] 18.9–21.2) died, including 589 cases of CVD mortality (13.1%, 95% CI 12.1–14.0). With the use of a multivariate analysis, both markers were found to have prognostic value in the same model (CVD mortality: odds ratio [OR] for fourth quartile of copeptin and NT-proBNP 1.68 and 2.58, 95% CI 1.22–2.49 and 1.76–4.05, respectively; all-cause mortality: OR for fourth quartile of copeptin and NT-proBNP 1.48 and 2.47, 95% CI 1.22–2.03 and 1.68–3.95, respectively). In a receiver operating characteristics analysis of CVD mortality, the area under the curve varied from 0.80 to 0.83 (95% CI 0.79–0.87) when the index of NT-proBNP was added and increased to 0.86 (95% CI 0.83–0.90) when both markers were added.

Conclusions:

Copeptin and NT-proBNP may be useful independent prognostic markers of all-cause or CVD mortality in Chinese patients with AIS.




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

2017-05-15T12:47:44-07:00

Objective:

To investigate the short-term time course risks and benefits of clopidogrel with aspirin in minor ischemic stroke or TIA.

Methods:

Data were derived from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. The primary outcome was a new ischemic stroke. Safety outcomes included any bleeding and moderate to severe bleeding. Time course analyses were performed for the outcomes of both stroke and bleeding.

Results:

A total of 145 (71.1%), 13 (6.4%), and 12 (5.9%) of 204 new ischemic strokes in the clopidogrel–aspirin group vs 223 (75.6%), 19 (6.4%), and 8 (2.7%) of 295 in the aspirin alone group occurred at the first, second, and third week, respectively. A total of 23 (38.3%), 15 (25.0%), and 9 (15.0%) of 60 bleeding cases in the clopidogrel–aspirin group vs 15 (36.6%), 8 (19.5%), and 3 (7.3%) of 41 in the aspirin alone group occurred at the first, second, and third week, respectively. Clopidogrel–aspirin treatment numerically reduced the risk of ischemic stroke within the first 2 weeks. From the 10th day, the number of any bleeding cases caused by dual antiplatelets outweighed that of new stroke reduced by dual antiplatelets.

Conclusions:

Clopidogrel–aspirin treatment may have a benefit of reducing stroke risk outweighing the potential risk of increased bleeding especially within the first 2 weeks compared with aspirin alone in patients with minor stroke or TIA.

Clinicaltrials.gov identifier:

NCT00979589.

Classification of evidence:

This study provides Class II evidence that for patients with minor stroke or TIA, the reduction of stroke risk from clopidogrel plus aspirin within the first 2 weeks outweighs the risk of bleeding compared with aspirin alone.




Certainty of genuine treatment increases drug responses among intellectually disabled patients

2017-05-15T12:47:44-07:00

Objective:

To determine the placebo component of treatment responses in patients with intellectual disability (ID).

Methods:

A statistical meta-analysis comparing bias-corrected effect sizes (Hedges g) of drug responses in open-label vs placebo-controlled clinical trials was performed, as these trial types represent different certainty of receiving genuine treatment (100% vs 50%). Studies in fragile X, Down, Prader-Willi, and Williams syndrome published before June 2015 were considered.

Results:

Seventeen open-label trials (n = 261, 65% male; mean age 23.6 years; mean trial duration 38 weeks) and 22 placebo-controlled trials (n = 721, 62% male; mean age 17.1 years; mean trial duration 35 weeks) were included. The overall effect size from pre to post treatment in open-label studies was g = 0.602 (p = 0.001). The effect of trial type was statistically significant (p = 0.001), and revealed higher effect sizes in studies with 100% likelihood of getting active drug, compared to both the drug and placebo arm of placebo-controlled trials. We thus provide evidence for genuine placebo effects, not explainable by natural history or regression toward the mean, among patients with ID.

Conclusions:

Our data suggest that clinical trials in patients with severe cognitive deficits are influenced by the certainty of receiving genuine medication, and open-label design should thus not be used to evaluate the effect of pharmacologic treatments in ID, as the results will be biased by an enhanced placebo component.




Phenotype of GABA-transaminase deficiency

2017-05-15T12:47:44-07:00

Objective:

We report a case series of 10 patients with -aminobutyric acid (GABA)–transaminase deficiency including a novel therapeutic trial and an expanded phenotype.

Methods:

Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil.

Results:

All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued.

Conclusions:

GABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.




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

2017-05-15T12:47:44-07:00

Objective:

To investigate secular trends in the prevalence, incidence, and survival rate of dementia in a Japanese elderly population in a comprehensive manner.

Methods:

Five cross-sectional surveys of dementia were conducted among residents of a Japanese community, aged ≥65 years, in 1985, 1992, 1998, 2005, and 2012. We also established 2 cohorts consisting of the residents of this age group without dementia in 1988 (n = 803) and 2002 (n = 1,231), and each was followed for 10 years.

Results:

The age-standardized prevalence of all-cause dementia and Alzheimer disease (AD) increased with time (for all-cause dementia: 6.8% in 1985, 4.6% in 1992, 5.3% in 1998, 8.4% in 2005, and 11.3% in 2012, p for trend <0.01; for AD: 1.5%, 1.4%, 2.4%, 3.9%, and 7.2%, respectively, p for trend <0.01), while no secular change was observed for vascular dementia (VaD) (2.4%, 1.6%, 1.5%, 2.4%, and 2.4%, respectively, p for trend = 0.59). The age- and sex-adjusted incidence of all-cause dementia and AD, but not VaD, increased from the 1988 cohort to the 2002 cohort (for all-cause dementia: adjusted hazard ratio [aHR] 1.68, 95% confidence interval [CI] 1.38–2.06; for AD: aHR 2.07, 95% CI 1.59–2.70; for VaD: aHR 1.18, 95% CI 0.83–1.69). The 5-year survival rate of all-cause dementia and AD improved from the 1988 cohort to the 2002 cohort (for all-cause dementia: 47.3% to 65.2%; for AD: 50.7% to 75.1%; all p < 0.01).

Conclusions:

The increased incidence and improved survival rate of AD could have resulted in the steep increase in AD prevalence in the Japanese elderly.




Significance of circadian rhythms in severely brain-injured patients: A clue to consciousness?

2017-05-15T12:47:44-07:00

Objective:

To investigate the relationship between the presence of a circadian body temperature rhythm and behaviorally assessed consciousness levels in patients with disorders of consciousness (DOC; i.e., vegetative state/unresponsive wakefulness syndrome or minimally conscious state).

Methods:

In a cross-sectional study, we investigated the presence of circadian temperature rhythms across 6 to 7 days using external skin temperature sensors in 18 patients with DOC. Beyond this, we examined the relationship between behaviorally assessed consciousness levels and circadian rhythmicity.

Results:

Analyses with Lomb-Scargle periodograms revealed significant circadian rhythmicity in all patients (range 23.5–26.3 hours). We found that especially scores on the arousal subscale of the Coma Recovery Scale–Revised were closely linked to the integrity of circadian variations in body temperature. Finally, we piloted whether bright light stimulation could boost circadian rhythmicity and found positive evidence in 2 out of 8 patients.

Conclusion:

The study provides evidence for an association between circadian body temperature rhythms and arousal as a necessary precondition for consciousness. Our findings also make a case for circadian rhythms as a target for treatment as well as the application of diagnostic and therapeutic means at times when cognitive performance is expected to peak.




Nrf2, cellular redox regulation, and neurologic implications

2017-05-15T12:47:44-07:00

Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently.1–5 Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia.6–10 Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection.10–12 This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.




Quality improvement in neurology: Dementia management quality measurement set update

2017-05-15T12:47:44-07:00

Dementia is a neurologic condition manifested by a substantial decline in multiple cognitive abilities that collectively render a person unable to function at expected levels and progressively impede independent ability to perform everyday activities. For decades, public health officials have warned of the coming tsunami of Alzheimer disease (AD), and dementia has even been characterized as the dominant scourge of modern times, replacing cancer.1 Recently, hopeful signs have appeared, including reports from some longitudinal research studies that incidence of dementia is declining,2 and from the federal government that research funding for AD and other dementias will approach $1 billion USD in 2017.3




Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: A systematic review

2017-05-15T12:47:44-07:00

Objective:

To systematically assess the effect of pharmacologic treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life.

Methods:

We searched PubMed and Cochrane Database of Systematic Reviews for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013, to May 24, 2016. We searched Clinicaltrials.gov on March 9, 2016. Two reviewers independently evaluated studies for eligibility, serially abstracted data, and independently evaluated risk of bias and graded strength of evidence (SOE).

Results:

We updated a recently completed systematic review of 57 eligible studies with 24 additional published studies and 25 unpublished studies. For reducing neuropathy-related pain, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine (moderate SOE), the anticonvulsants pregabalin and oxcarbazepine (low SOE), the drug classes tricyclic antidepressants (low SOE) and atypical opioids (low SOE), and botulinum toxin (low SOE) were more effective than placebo. We could not draw conclusions about quality of life due to incomplete reporting. All studies were short-term (less than 6 months), and all effective drugs had more than 9% dropouts from adverse effects.

Conclusions:

For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo. However, quality of life was poorly reported, studies were short-term, drugs had substantial dropout rates, and opioids have significant risks. Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients' quality of life.




Reprogramming cells from Gulf War veterans into neurons to study Gulf War illness

2017-05-15T12:47:44-07:00

Gulf War illness (GWI), which afflicts at least 25% of veterans who served in the 1990–1991 war in the Persian Gulf, is thought to be caused by deployment exposures to various neurotoxicants, including pesticides, anti–nerve gas pills, and low-level nerve agents including sarin/cyclosarin. GWI is a multisymptom disorder characterized by fatigue, joint pain, cognitive problems, and gastrointestinal complaints. The most prominent symptoms of GWI (memory problems, poor attention/concentration, chronic headaches, mood alterations, and impaired sleep) suggest that the disease primarily affects the CNS. Development of urgently needed treatments depends on experimental models appropriate for testing mechanistic hypotheses and for screening therapeutic compounds. Rodent models have been useful thus far, but are limited by their inability to assess the contribution of genetic or epigenetic background to the disease, and because disease-vulnerable proteins and pathways may be different in humans relative to rodents. As of yet, no postmortem tissue from the veterans has become available for research. We are moving forward with a paradigm shift in the study of GWI, which utilizes contemporary stem cell technology to convert somatic cells from Gulf War veterans into pluripotent cell lines that can be differentiated into various cell types, including neurons, glia, muscle, or other relevant cell types. Such cell lines are immortal and will be a resource for GWI researchers to pursue mechanistic hypotheses and therapeutics.




Pure sensory ganglionopathy as the first sign of relapse in non-Hodgkin lymphoma

2017-05-15T12:47:44-07:00

A 34-year-old man with diffuse large B-cell lymphoma in complete remission presented with painful paresthesias of the thorax and proximal legs with loss of patellar reflexes bilaterally. Laboratory studies showed no evidence of autoimmune or infectious processes. CSF cytology was unremarkable. MRI showed enlarged, enhancing dorsal root ganglia (DRG) at L3-L4 bilaterally (figure, A). Whole-body PET showed avidity in these nerve roots and in T2 and T8 (figure, C). Abnormalities on nerve conduction studies were isolated to sensory nerves affecting the same roots. Sensory ganglionopathies can occur with lymphomatous infiltration of the DRG, known as neurolymphomatosis, and can be the initial manifestation of lymphoma relapse.1,2




Editors' Note

2017-05-15T12:47:44-07:00

Editors' Note: In WriteClick this week, Drs. Lynch and Houlden point out an error in the Mystery Case Responses section of "Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy," in which CSF-1R-related leukoencephalopathy is mistaken to be the same as Labrune syndrome.




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

2017-05-15T12:47:44-07:00

Ayrignac et al.1 presented an interesting case that highlighted the importance of CSF-1R in adult-onset leukoencephalopathies. However, we are concerned that the discussion by Dr. Ganesh in the Mystery Case Responses section confused 2 different diseases as the same.1 This case clearly described a typical presentation of CSF-1R-related disease with apparent autosomal dominant inheritance. However, Dr. Ganesh described this as a case of Labrune syndrome (leukoencephalopathy with calcifications and cysts), an autosomal recessive disorder caused by mutations in SNORD118.2 While calcifications occur in both syndromes, they are far more widespread and severe in Labrune syndrome and the imaging appearance of both conditions is distinctive. Dr. Ganesh incorrectly attributed 11% of adult-onset leukoencephalopathy to Labrune syndrome by referencing Guerreiro et al.,3 who clearly referred to CSF-1R-related disease.




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

2017-05-15T12:47:45-07:00

I thank Dr. Lynch and Prof. Houlden for the important comment on our Mystery Case.1 Indeed, calcifications and cysts found in patients with SNORD118 mutations, formerly described in Labrune syndrome, are larger than those seen in patients harboring CSF-1R mutations. Nevertheless, the importance of calcifications in this disorder was recently emphasized.2 Notably, calcifications are small and may have a particular stepping-stone appearance in the frontal pericallosal regions.2




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

2017-05-15T12:47:45-07:00

I thank Dr. Lynch and Prof. Houlden for the response to my editorial summary accompaniment to the Mystery Case,1 and for highlighting the distinction between CSF-1R-related disease and Labrune syndrome for both myself and our readers. This is a helpful learning point I hope to carry forward.







Clinical Reasoning: A 45-year-old man with weakness and myalgia after orthopedic surgery

2017-05-08T12:45:33-07:00

A 45-year-old man underwent rotator cuff surgery and developed fatigue and generalized myalgia postoperatively. After 4 weeks of mild symptoms, he experienced severe muscle aches and bilateral leg weakness after walking 1.5 miles, prompting him to seek medical attention.




Teaching NeuroImages: Traumatic blown pupil without herniation

2017-05-08T12:45:33-07:00

A 29-year-old man was struck by a car and presented with coma and a fixed, dilated left pupil without oculomotor palsy (figure 1). A head CT revealed central midbrain hemorrhage in the absence of uncal herniation (figure 2). Intracranial pressure was normal. At 6 months, he had regained consciousness and reactivity of the left pupil, and was independent in activities of daily living. The syndrome of acute traumatic midbrain hemorrhage is a rare form of coma and abnormal pupils.1 The unreactive pupil and lack of oculomotor palsy in our patient reflect the somatotopic map within the midbrain, namely, that pupillomotor axons from the Edinger-Westphal nucleus run rostral and medial to the oculomotor fibers that eventually comprise the oculomotor nerve.2




Spotlight on the May 9 issue

2017-05-08T12:45:32-07:00




A blood test for concussion?

2017-05-08T12:45:32-07:00

Concussion, pervasive in most sports, epidemic in contact contests, affects millions of individuals ranging from youth sports through professional athletes.1 Those who routinely see patients with sports concussion rely predominately on patient-reported symptoms and a thorough neurologic examination to ascertain the extent of injury and prognosis. Although neuropsychological assessments are helpful, no other routine testing, including conventional neuroimaging, is useful in answering many basic questions regarding the clinical evaluation and management of concussion, let alone determining the severity of CNS damage.2




Isocitrate dehydrogenase mutations: A biomarker for glioma-related excitability and seizures

2017-05-08T12:45:33-07:00

Tumor-related epilepsy (TRE) is common in patients with gliomas (40%–70%) and carries a substantial degree of morbidity and mortality.1,2 The impetus to understand the pathophysiology of TRE has led to the identification of several tumor markers that are associated with increased risk of seizures. Tumor-mediated glutamate release is one proposed mechanism that has more recently gained traction.3,4 Another tumor marker that has attracted the attention of researchers is expression of mutated isocitrate dehydrogenase 1 (IDH1mut), an enzyme whose normal function is key to the Kreb cycle; the nonmutated enzyme catalyzes the conversion of isocitrate to α-ketoglutarate. IDH1mut is an accepted diagnostic biomarker for secondary glioblastomas that is associated with improved survival.5 In its mutated form, IDH1mut reduces α-ketoglutarate to d-2-hydroxyglutarate (D2HG). Structural similarities between D2HG and glutamate have promoted the theory that overproduction of D2HG could mechanistically play a role in neuronal excitation in the glial tumor model. Thus far, the association between mutant IDH expression and epilepsy has been disputed in the work of previous groups.6,7




Use of RS-fMRI in Fabry disease: Do we need it?

2017-05-08T12:45:33-07:00

Clinical studies have shown involvement of motor circuits independently of cerebrovascular symptoms in Fabry disease.1 In this issue of Neurology®, Cocozza et al.2 report alteration of the cortico-striatal pathway in Fabry disease and confirm the involvement of motor circuits in this pathology without cerebrovascular events. Strengths of this case-control study include the use of resting-state (RS) fMRI analysis for functional connectivity of the motor cortex in Fabry disease. They reported a deregulation of the basal ganglia and cortical and right cerebellar hemispheric motor circuits in these patients.




Clinical pearls and scientific advancement: Reconciling tradition with new knowledge

2017-05-08T12:45:33-07:00

"Every child exhibiting dystonia merits an l-dopa trial, lest the potentially treatable condition of dopa-responsive dystonia is missed."1 This is but one of many clinical pearls we as neurologists learn in training. Clinical pearls are rarely evidence-based, yet we remember them well, searching for them as trainees, then passing on these same pearls to new generations. Why are clinical pearls part of our education and practice traditions? These statements distill complex pieces of information, key concepts, and clinical wisdom into short, memorable phrases. Neurology® has a section dedicated to clinical pearls as part of the Resident & Fellow Section: e-Pearls.2




Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports

2017-05-08T12:45:33-07:00

Objective:

To evaluate whether the axonal protein neurofilament light (NFL) in serum is a sensitive biomarker to detect subtle brain injury or concussion in contact sports athletes.

Methods:

Two prospective cohort studies involving (1) 14 Swedish amateur boxers who underwent fluid biomarker assessments at 7–10 days after bout and after 3 months of rest from boxing and (2) 35 Swedish professional hockey players who underwent blood biomarker assessment at 1, 12, 36, and 144 hours after concussion and when the players returned to play were performed. Fourteen healthy nonathletic controls and 12 athletic controls were also enrolled. Serum NFL was measured using ultrasensitive single molecule array technology.

Results:

Serum NFL concentrations were increased in boxers 7–10 days after bout as compared to the levels after 3 months rest as well as compared with controls (p = 0.0007 and p < 0.0001, respectively). NFL decreased following 3 months of rest, but was still higher than in controls (p < 0.0001). Boxers who received many (>15) hits to the head or were groggy after bout had higher concentrations of serum NFL as compared to those who received fewer hits to the head (p = 0.0023). Serum NFL increased over time in hockey players, and the levels returned to normal at return to play. Importantly, serum NFL could separate players with rapidly resolving postconcussion symptoms (PCS) from those with prolonged PCS.

Conclusions:

The results from these 2 independent cohort studies suggest that serum NFL is a highly sensitive biomarker for concussion.




Body composition status and the risk of migraine: A meta-analysis

2017-05-08T12:45:33-07:00

Objective:

To evaluate the association between migraine and body composition status as estimated based on body mass index and WHO physical status categories.

Methods:

Systematic electronic database searches were conducted for relevant studies. Two independent reviewers performed data extraction and quality appraisal. Odds ratios (OR) and confidence intervals (CI) were pooled using a random effects model. Significant values, weighted effect sizes, and tests of homogeneity of variance were calculated.

Results:

A total of 12 studies, encompassing data from 288,981 unique participants, were included. The age- and sex-adjusted pooled risk of migraine in those with obesity was increased by 27% compared with those of normal weight (odds ratio [OR] 1.27; 95% confidence interval [CI] 1.16–1.37, p < 0.001) and remained increased after multivariate adjustments. Although the age- and sex-adjusted pooled migraine risk was increased in overweight individuals (OR 1.08; 95% CI 1.04, 1.12, p < 0.001), significance was lost after multivariate adjustments. The age- and sex-adjusted pooled risk of migraine in underweight individuals was marginally increased by 13% compared with those of normal weight (OR 1.13; 95% CI 1.02, 1.24, p < 0.001) and remained increased after multivariate adjustments.

Conclusions:

The current body of evidence shows that the risk of migraine is increased in obese and underweight individuals. Studies are needed to confirm whether interventions that modify obesity status decrease the risk of migraine.




Mutant IDH1 and seizures in patients with glioma

2017-05-08T12:45:33-07:00

Objective:

Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons.

Methods:

Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5.

Results:

Preoperative seizures were observed in 18%–34% of IDH1 wild-type (IDH1wt) patients and in 59%–74% of IDH1mut patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6–3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5.

Conclusions:

The D2HG product of IDH1mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1mut inhibitors may improve antiepileptic therapy in patients with IDH1mut gliomas.




Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

2017-05-08T12:45:33-07:00

Objective:

To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD).

Methods:

We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET.

Results:

Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction.

Conclusions:

The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.




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

2017-05-08T12:45:33-07:00

Objective:

To evaluate the presence of functional connectivity (FC) alterations of the motor circuits in patients with Fabry disease (FD) and their possible correlation with clinical variables with a resting-state (RS) fMRI analysis.

Methods:

In our cross-sectional study, 32 patients with FD with genetically confirmed classic diagnosis of FD (12 men, mean age 43.3 ± 12.2 years) were enrolled along with 35 healthy controls (HCs) of comparable age and sex (14 men, mean age 42.1 ± 14.5 years). RS-fMRI data were analyzed with a seed-based approach, with 2 different seeds for right and left motor cortex. Patients with FD underwent a clinical examination for the assessment of different motor functions. Correlations with clinical variables were probed with the Spearman correlation coefficient.

Results:

A reduction of FC was found in patients with FD compared to HCs between both motor cortices and 2 clusters encompassing, for each side, the caudate and lenticular nucleus (p < 5 x 10–4 and p < 10–8 for right and left motor cortex, respectively) and between the left motor cortex and dentate nuclei (p = 0.01) and Crus 1 in the right cerebellar hemisphere (p = 0.001). No significant results emerged in tests for possible correlations of FC with clinical scores.

Conclusions:

An alteration of the corticostriatal pathway is present in FD, in line with the recently suggested subclinical involvement of motor circuits in this disease. These results shed new light on the pattern of cerebral involvement in FD.




Meta-analysis of folic acid efficacy trials in stroke prevention: Insight into effect modifiers

2017-05-08T12:45:33-07:00

Objective:

To examine the efficacy and effect modifiers of folic acid supplementation in the prevention of stroke in regions without folic acid fortification based on relevant, up-to-date published randomized trials.

Methods:

Relative risk (RR) was used to measure the effect of folic acid supplementation on risk of stroke using a fixed effects model.

Findings:

Overall, folic acid supplementation significantly reduced the stroke risk by 11% (22 trials, n = 82,723; RR 0.89, 95% confidence interval [CI] 0.84–0.96). The effect was greater in low folate regions (2 trials, n = 24,020; Asia, 0.78, 0.67–0.90) compared to high folate regions (7 trials, n = 14,655; America, 1.05, 0.90–1.23), and among patients without folic acid fortification (11 trials, n = 49,957; 0.85; 0.77–0.94) compared with those with folic acid fortification (7 trials, n = 14,655; 1.05, 0.90–1.23). In further stratified analyses among trials without folic acid fortification, a larger beneficial effect was found in those trials that used a low dosage of folic acid (≤0.8 mg: 0.78, 0.69–0.88) or low baseline vitamin B12 levels (<384 pg/mL: 0.78, 0.68–0.89). In the corresponding comparison groups, the effect sizes were attenuated and insignificant (p for interaction <0.05 for both). Although the interaction tests were not significant, there might be a higher benefit in trials with a low dosage of vitamin B12, a low prevalence of statin use, but a high prevalence of hypertension.

Conclusions:

Folic acid supplementation could reduce the stroke risk in regions without folic acid fortification, particularly in trials using a relatively low dosage of folic acid and with low vitamin B12 levels.




Racial differences in statin adherence following hospital discharge for ischemic stroke

2017-05-08T12:45:33-07:00

Objective:

To compare nonadherence to statins in older black and white adults following an ischemic stroke.

Methods:

We studied black and white adults ≥66 years of age with Medicare fee-for-service insurance coverage hospitalized for ischemic stroke from 2007 to 2012 who filled a statin prescription within 30 days following discharge. Nonadherence was defined as a proportion of days covered <80% in the 365 days following hospital discharge. In addition, we evaluated factors associated with nonadherence for white and black participants separately.

Results:

Overall 2,763 beneficiaries met the inclusion criteria (13.5% black). Black adults were more likely than white adults to be nonadherent (49.7% vs 41.5%) even after adjustment for demographics, receipt of a low-income subsidy, and baseline comorbidities (adjusted relative risk [RR] 1.14, 95% confidence interval [CI] 1.01–1.29). Among white adults, receipt of a low-income subsidy (adjusted RR 1.13, 95% CI 1.02–1.26), history of coronary heart disease (adjusted RR 1.15, 95% CI 1.01–1.30), and discharge directly home following stroke hospitalization (adjusted RR 1.26, 95% CI 1.10–1.44) were associated with a higher risk of nonadherence. Among black adults, a 1-unit increase in the Charlson comorbidity index (adjusted RR 1.04, 95% CI 1.01–1.09), history of carotid artery disease (adjusted RR 2.38, 95% CI 1.08–5.25), and hospitalization during the 365 days prior to the index stroke (adjusted RR 1.34, 95% CI 1.01–1.78) were associated with nonadherence.

Conclusions:

Compared with white adults, black adults were more likely to be nonadherent to statins following hospitalization for ischemic stroke.




Probable REM sleep behavior disorder and risk of stroke: A prospective study

2017-05-08T12:45:33-07:00

Objective:

To examine whether probable REM sleep behavior disorder (pRBD) was associated with increased risk of developing stroke in a community-based cohort.

Methods:

The study included 12,003 participants (mean age 54.0 years) of the Kailuan Study, free of stroke, cancer, Parkinson disease, dementia, and head injury at baseline (2012). We determined pRBD using a validated REM sleep behavior disorder (RBD) questionnaire in 2012. Incident stroke cases were confirmed by review of medical records. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of stroke according to pRBD status, adjusting for several sleep measures (i.e., insomnia, daytime sleepiness, sleep duration, snoring, and use of hypnotics) and other potential confounders.

Results:

During 3 years of follow-up, we documented 159 incident stroke cases. Relative to participants without pRBD at the baseline, those with pRBD had a 157% higher risk (95% CI 59%–313%) of developing stroke. Presence of pRBD was associated with increased risk of both stroke types—the adjusted HR was 1.93 (95% CI 1.07–3.46) for ischemic stroke and 6.61 (95% CI 2.27–19.27) for hemorrhagic stroke.

Conclusions:

Presence of pRBD was associated with a higher risk of developing stroke, including both ischemic and hemorrhagic types. Future studies with clinically confirmed RBD and a longer follow-up would be appropriate to further investigate this association.




Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness

2017-05-08T12:45:33-07:00

Objective:

To assess if visual discrimination training improves performance on visual perimetry tests in chronic stroke patients with visual cortex involvement.

Methods:

24-2 and 10-2 Humphrey visual fields were analyzed for 17 chronic cortically blind stroke patients prior to and following visual discrimination training, as well as in 5 untrained, cortically blind controls. Trained patients practiced direction discrimination, orientation discrimination, or both, at nonoverlapping, blind field locations. All pretraining and posttraining discrimination performance and Humphrey fields were collected with online eye tracking, ensuring gaze-contingent stimulus presentation.

Results:

Trained patients recovered ~108 degrees2 of vision on average, while untrained patients spontaneously improved over an area of ~16 degrees2. Improvement was not affected by patient age, time since lesion, size of initial deficit, or training type, but was proportional to the amount of training performed. Untrained patients counterbalanced their improvements with worsening of sensitivity over ~9 degrees2 of their visual field. Worsening was minimal in trained patients. Finally, although discrimination performance improved at all trained locations, changes in Humphrey sensitivity occurred both within trained regions and beyond, extending over a larger area along the blind field border.

Conclusions:

In adults with chronic cortical visual impairment, the blind field border appears to have enhanced plastic potential, which can be recruited by gaze-controlled visual discrimination training to expand the visible field. Our findings underscore a critical need for future studies to measure the effects of vision restoration approaches on perimetry in larger cohorts of patients.




L-Dopa in dystonia: A modern perspective

2017-05-08T12:45:33-07:00

"Every child exhibiting dystonia merits an l-dopa trial, lest the potentially treatable condition of dopa-responsive dystonia (DRD) is missed" has been a commonly cited and highly conserved adage in movement disorders literature stemming from the 1980s. We here provide a historical perspective on this statement, discuss the current diagnostic and therapeutic applications of l-dopa in everyday neurologic practice, contrast these with its approved indications, and finish with our view on both a diagnostic and therapeutic trial in children and adults with dystonia. In light of the relatively low prevalence of DRDs, the large interindividual variation in the required l-dopa dose, the uncertainty about an adequate trial duration, the substantial advances in knowledge on etiology and pathophysiology of these disorders, and the availability of various state-of-the-art diagnostic tests, we think that a diagnostic l-dopa trial as a first step in the approach of early-onset dystonia (≤25 years) is outdated. Rather, in high-resource countries, we suggest to use l-dopa after biochemical corroboration of a defect in dopamine biosynthesis, in genetically confirmed DRD, or if nigrostriatal degeneration has been demonstrated by nuclear imaging in adult patients presenting with lower limb dystonia. Furthermore, our literature study on the effect of a therapeutic trial to gain symptomatic relief revealed that l-dopa has occasionally proven beneficial in several established "non-DRDs" and may therefore be considered in selected cases of dystonia due to other causes. In summary, we argue against the application of l-dopa in every patient with early-onset dystonia and support a more rational therapeutic use.




If brains could talk

2017-05-08T12:45:33-07:00

Rows of shelved brains

Shuddered in blind horror as

One was taken down for dissection.




Editors' Note

2017-05-08T12:45:33-07:00

Editors' Note: In response to "Acute Zika infection with concurrent onset of Guillain-Barré syndrome," Dr. Gérardin et al. suggest that Zika-related Guillain-Barré syndrome (GBS) may have a different mechanism than postviral GBS.




Letter re: Acute Zika infection with concurrent onset of Guillain-BarrE syndrome

2017-05-08T12:45:33-07:00

Siu et al.1 reported the concurrent onset of polyradiculoneuritis and acute Zika virus (ZIKV) infection, while the virus was not cleared from the serum. Guillain-Barré syndrome (GBS) is usually described as a postinfectious disease during which progressive flaccid paralysis develops after a phase of latency following infection. In the most common pathogenetic framework, this free interval permits the generation of sufficient levels of antibodies that cross-react by molecular mimicry with specific components of peripheral nerves, causing myelin or axonal injury, as previously documented with ZIKV infection.2 However, this case report suggested other mechanisms. Given ZIKV cross-reactivity with dengue virus and increasing reports of ZIKV-associated GBS in dengue-seropositive patients,1,3 a hyperacute immune response is possible.4 Given prolonged ZIKV shedding in bodily fluids, and the overlap between GBS onset and persistent shedding in fomites, a direct viral neuropathic effect may also contribute to ZIKV-associated GBS.4 Indeed, ZIKV is able to infect cranial neural crest cells that stem Schwann cell formation.5 ZIKV-associated GBS could reflect a direct viral neuropathic effect on the blood–nerve barrier, allowing cross-reactive antibodies formed during previous infections to have a deleterious effect on nerve function.




Author response: Acute Zika infection with concurrent onset of Guillain-BarrE syndrome

2017-05-08T12:45:33-07:00

We thank Gérardin et al. for the comments on our Clinical/Scientific Note on Zika virus (ZIKV).1 Our patient was of particular interest because he had an illness clinically and electrophysiologically indistinguishable from Guillain-Barré syndrome (GBS) that developed within a few days of acute ZIKV infection, in the context of contemporaneous Zika viremia.1 Concurrently obtained CSF was negative for ZIKV. Brain and spine MRI were also normal. Importantly, there was no serologic evidence of priming by previous dengue or other flaviviruses.




Letter re: Gray matter MRI differentiates neuromyelitis optica from multiple sclerosis using random forest

2017-05-08T12:45:33-07:00

The article by Eshaghi et al.1 gave a glimpse of where neuroradiology is headed. Pertinent questions include the following:




Author response: Gray matter MRI differentiates neuromyelitis optica from multiple sclerosis using random forest

2017-05-08T12:45:33-07:00

We thank Dr. Avasarala for the comment on our article.1 Since the majority of patients with neuromyelitis optica (NMO) were positive for anti-aquaporin-4 autoantibody, the classification results (table 2)1 are expected to remain similar after excluding seronegative patients (negative predictive value 76%). This is expected as patients with multiple sclerosis (MS) and NMO are heterogeneous in clinical and MRI assessments, and volumes in different brain regions may overlap (figure 1).1 Including other features, such as spinal cord atrophy, may increase the accuracy.2




Media and Book Reviews: Clinical Neurology and Neuroanatomy: A Localization-Based Approach

2017-05-01T12:45:32-07:00

Dr. Berkowitz, a clinical neurologist and gifted teacher, sought to write a clinical neurology textbook that could condense clinical neuroanatomy and clinical neurology into a concise, easily digestible format, a feat in which he has succeeded. Dr Berkowitz's approach to summarizing clinical neurology in just over 300 pages is unique compared to other similar-sized texts in that it is both pragmatic and of sufficient detail to serve as a primary reference text for the neurology resident, enthusiastic medical student, neurologist reviewing for the recertification examination, or interested general internist.




Teaching NeuroImages: Balamuthia mandrillaris amebic encephalitis: Clinical-radiologic-pathologic correlation

2017-05-01T12:45:32-07:00

A 32-year-old immunocompetent man presented with new-onset generalized tonic-clonic seizures. On examination, he had mild right hand weakness, with right-sided Hoffman sign, ankle clonus, and Babinski reflex present. MRI of the brain demonstrated vasogenic edema surrounding a ring-enhancing lesion in the left parietal lobe (figure, A). Repeat brain MRIs showed rapid progression of the lesion, with new lesions appearing in the contralateral hemisphere (figure, B and C). Pathology showed necrotizing meningoencephalitis with organisms consistent with ameba (figure, D). Indirect immunofluorescence and PCR was positive for Balamuthia mandrillaris. About 200 cases of Balamuthia infection have been reported worldwide, and it has a very high mortality rate of 95%.1




Teaching Video NeuroImages: Lithium-induced reversible Pisa syndrome

2017-05-01T12:45:32-07:00

A 49-year-old man on chronic lithium therapy (1,500 mg/d) for bipolar disorder presented with a 2-year history of progressive left-lateral truncal flexion dystonia disappearing on lying supine (video 1 at Neurology.org), known as Pisa syndrome (PS), along with anterocollis and parkinsonism. Lithium serum level was normal (1.1 mmol/L). PS improved substantially 3 months after stopping lithium (video 2), supporting the diagnosis of lithium-induced PS (figure). PS has been reported with chronic use of a single or a combination of antipsychotics, but never with lithium monotherapy.1,2 Parkinsonism and PS may result from lithium-induced dopamine reuptake facilitation or dopamine receptor sensitivity reduction.2




Spotlight on the May 2 issue

2017-05-01T12:45:32-07:00




The changing landscape of anticoagulant-related intracerebral hemorrhage

2017-05-01T12:45:32-07:00

Hailed as a milestone in the management of patients with nonvalvular atrial fibrillation, new oral anticoagulants (NOACs) demonstrated comparable efficacy and similar or improved safety to vitamin K antagonists (VKAs) in randomized clinical trials.1 Their ensuing approvals by central regulatory agencies provoked reservations and caution by many in the medical community. Despite the consistent observation of a lower incidence of intracerebral hemorrhage (ICH) among users of various NOACs,1 the unexplored questions regarding the natural course and prognosis of NOAC-associated ICH, combined with an absence of specific treatment and management options during the initial phases of marketing, heightened the concern related to the safety of these agents. However, a closer look into the trial data was suggestive of similar mortality rates among patients experiencing ICH while using VKAs or NOACs.2–4 Real-world data originating from small single-center studies5,6 and administrative databases7 also showed no sign of excess mortality in NOAC-related ICH. Moreover, hematoma volume, the imaging marker most closely associated with clinical outcome, was smaller in those treated with NOACs, and hence suggested a more favorable profile compared to VKA users.7,8




Cell surface antibody-associated neurodegeneration: The case of anti-IgLON5 antibodies

2017-05-01T12:45:32-07:00

Cell surface autoantibodies have become important biomarkers of acquired autoimmune CNS disorders, and typically define potentially severe but treatable acquired autoimmune encephalitis syndromes. However, the discovery of anti-IgLON5 antibodies has forced a reappraisal of the accepted paradigms regarding cell surface antibodies and their associated clinical manifestations.1 Although anti-IgLON5 antibody is a cell surface antibody, the clinical syndrome is not an encephalitis (there is no lymphocytic inflammatory infiltration), disease onset is more chronic rather than acute, and the neurologic sequelae are not reversible with immunotherapy in most patients, with progressive neurodegeneration and high mortality. This is therefore a novel autoimmune CNS syndrome, inhabiting the borderland between autoimmunity and neurodegeneration: cell surface antibody–associated neurodegeneration. The article by Gaig et al.2 in this issue of Neurology® extends our knowledge of the clinical features of this rare but important form of autoimmune neurodegeneration. The study describes 22 patients who were positive for anti-IgLON5 autoantibodies, as tested by the Neuroimmunology Laboratory in Barcelona, comprising the largest cohort with this condition. The main findings were that the clinical syndrome can present with sleep, brainstem, gait, cognitive, or movement disorders, but during the disease course all patients develop manifestations of disordered sleep and ventilation. The course was chronic and progressive in most patients, and 59% died during follow-up. It should be noted that it is possible that the initial description of this condition has resulted in recruitment bias, and the spectrum of symptoms and signs is different from what is described by Gaig et al.




A single demyelinating attack is enough to limit brain growth in children

2017-05-01T12:45:32-07:00

Acquired demyelinating syndromes (ADS) represent acute neurologic illnesses characterized by deficits persisting for at least 24 hours and involving the optic nerve, brain, or spinal cord, associated with regional areas of increased T2 signal on conventional MRI. In contrast to the 75% of adult patients presenting with clinically isolated syndrome (CIS) who are eventually diagnosed with clinically defined multiple sclerosis (MS),1 the majority of children presenting with ADS have a monophasic illness with a good overall prognosis: more than 90% of children achieve a full neurologic recovery.2 Over the last decade, neuroimaging studies have focused on differentiating between MS and its mimics, and correlating radiologic measures with clinical outcome and neuropsychological testing in pediatric MS.3




Outcome of intracerebral hemorrhage associated with different oral anticoagulants

2017-05-01T12:45:32-07:00

Objective: In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non–vitamin K antagonist oral anticoagulation–related ICH (NOAC-ICH) and vitamin K antagonist–associated ICH (VKA-ICH). Methods: We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score ≤2 and investigated in multivariable logistic regression. ICH volume was measured by ABC/2 or a semiautomated planimetric method. HE was defined as an ICH volume increase >33% or >6 mL from baseline within 72 hours. Results: We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6–38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0–27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52–1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18–1.19 [p = 0.11]). Conclusions: In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH. [...]



Integrity of normal-appearing white matter and functional outcomes after acute ischemic stroke

2017-05-01T12:45:32-07:00

Objective: To characterize the effect of white matter microstructural integrity on cerebral tissue and long-term functional outcomes after acute ischemic stroke (AIS). Methods: Consecutive AIS patients with brain MRI acquired within 48 hours of symptom onset and 90-day modified Rankin Scale (mRS) score were included. Acute infarct volume on diffusion-weighted imaging (DWIv) and white matter hyperintensity volume (WMHv) on T2 fluid-attenuated inversion recovery MRI were measured. Median fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity values were calculated within normal-appearing white matter (NAWM) in the hemisphere contralateral to the acute lesion. Regression models were used to assess the association between diffusivity metrics and acute cerebral tissue and long-term functional outcomes in AIS. Level of significance was set at p < 0.05 for all analyses. Results: Among 305 AIS patients with DWIv and mRS score, mean age was 64.4 ± 15.9 years, and 183 participants (60%) were male. Median NIH Stroke Scale (NIHSS) score was 3 (interquartile range [IQR] 1–8), and median normalized WMHv was 6.19 cm3 (IQR 3.0–12.6 cm3). Admission stroke severity (β = 0.16, p < 0.0001) and small vessel stroke subtype (β = –1.53, p < 0.0001), but not diffusivity metrics, were independently associated with DWIv. However, median FA in contralesional NAWM was independently associated with mRS score (β = –9.74, p = 0.02), along with age, female sex, NIHSS score, and DWIv. Conclusions: FA decrease in NAWM contralateral to the acute infarct is associated with worse mRS category at 90 days after stroke. These data suggest that white matter integrity may contribute to functional recovery after stroke. [...]



Fine particulate matter exposure and incidence of stroke: A cohort study in Hong Kong

2017-05-01T12:45:32-07:00

Objective: We aimed to assess the association of long-term residential exposure to fine particulate matter (PM) with aerodynamic diameter less than 2.5 μm (PM2.5) with the incidence of stroke and its major subtypes. Methods: We ascertained the first occurrence of emergency hospital admission for stroke in a Hong Kong Chinese cohort of 66,820 older people (65+ years) who enrolled during 1998–2001 (baseline) and were followed up to December 31, 2010. High-resolution (1 x 1 km) yearly mean concentrations of PM2.5 were predicted from local monitoring data and US National Aeronautics and Space Administration satellite data using linear regression. Baseline residential PM2.5 exposure was used as a proxy for long-term exposure. We used Cox proportional hazards to evaluate the risk of incident stroke associated with PM2.5 exposure adjusted for potential confounders, including individual and neighborhood factors. Results: Over a mean follow-up of 9.4 years, we ascertained 6,733 cases of incident stroke, of which 3,526 (52.4%) were ischemic and 1,175 (17.5%) were hemorrhagic. The hazard ratio for every 10 μg/m3 higher PM2.5 concentration was statistically significant at 1.21 (95% confidence interval [CI] 1.04–1.41) for ischemic and non-statistically significant at 0.90 (95% CI 0.70–1.17) for hemorrhagic stroke in fully adjusted model 3. The estimates for ischemic stroke were higher in older participants (>70 years), less educated participants, and in men for current smokers. Conclusion: Long-term PM2.5 exposure was associated with higher risk of incident ischemic stroke, but the association with incident hemorrhagic stroke was less clear. [...]



Physical activity, but not body mass index, predicts less disability before and after stroke

2017-05-01T12:45:32-07:00

Objective:

To determine whether physical activity and body mass index (BMI) predict instrumental or basic activities of daily living (I/ADL) trajectories before or after stroke compared to individuals who remained stroke-free.

Methods:

Using a prospective cohort, the Health and Retirement Study, we followed adults without a history of stroke in 1998 (n = 18,117) for up to 14 years. We estimated linear regression models of I/ADL trajectories comparing individuals who remained stroke-free throughout follow-up (n = 16,264), those who survived stroke (n = 1,374), and those who died after stroke and before the next interview wave (n = 479). We evaluated whether I/ADL trajectories differed by physical activity or BMI at baseline (before stroke), adjusting for demographic and socioeconomic covariates.

Results:

Compared to those who were physically active, stroke survivors who were physically inactive at baseline had a lower probability of independence in ADLs and IADLs 3 years after stroke (risk difference = –0.18 and –0.16 for ADLs and IADLs, respectively). However, a similar difference in the probability of independence was also present 3 years before stroke, and we observed no evidence that physical activity slowed the rate of decline in independence before or after stroke. Unlike the results for physical activity, we did not observe a consistent pattern for the probability of independence in ADLs or IADLs comparing obese stroke survivors to normal-weight or to overweight stroke survivors 3 years before stroke or 3 years after stroke.

Conclusions:

Physical inactivity predicts a higher risk of being dependent both before and after stroke.




Burnout, psychological morbidity, job stress, and job satisfaction in Chinese neurologists

2017-05-01T12:45:32-07:00

Objective: To investigate the prevalence of and personal and professional characteristics associated with burnout, psychological morbidity, job stress, and job satisfaction in Chinese neurologists. Methods: The China Neurologist Association conducted a national cross-sectional study from September 2014 to March 2015. A questionnaire including the Maslach Burnout Inventory, the 12-item General Health Questionnaire, the Consultants' Mental Health Questionnaire, and questions assessing personal and professional characteristics, career satisfaction, and current doctor-patient relationships was administered. Results: A total of 693 directors of neurology departments and 6,111 neurologists in 30 Chinese provinces returned surveys. Overall, 53.2% of responding neurologists experienced burnout, 37.8% had psychological morbidity, 50.7% had high levels of job stress, 25.7% had low levels of job satisfaction, 76.9% had poor doctor-patient relationships, and 58.1% regretted becoming a doctor. Factors independently associated with burnout were lower income, more hours worked per week, more nights on call per month, working in public hospitals, psychological morbidity, high levels of job stress, low levels of job satisfaction, and poor doctor-patient relationships. Factors independently associated with psychological morbidity included lower income, more nights on call per month, working in enterprise-owned hospitals, burnout, high levels of job stress, and low levels of job satisfaction. Conclusions: Burnout and psychological morbidity are common in Chinese neurologists. Burnout is the single greatest predictor of neurologists' psychological morbidity, high job stress, and low job satisfaction. [...]



Clinical manifestations of the anti-IgLON5 disease

2017-05-01T12:45:32-07:00

Objective: To report the presentation, main syndromes, human leukocyte antigen (HLA) association, and immunoglobulin G (IgG) subclass in the anti-IgLON5 disease: a disorder with parasomnias, sleep apnea, and IgLON5 antibodies. Methods: This was a retrospective clinical analysis of 22 patients. The IgG subclass was determined using reported techniques. Results: Patients' median age was 64 years (range 46–83). Symptoms that led to initial consultation included sleep problems (8 patients; 36%), gait abnormalities (8; 36%), bulbar dysfunction (3; 14%), chorea (2; 9%), and cognitive decline (1; 5%). By the time of diagnosis of the disorder, 4 syndromes were identified: (1) a sleep disorder with parasomnia and sleep breathing difficulty in 8 (36%) patients; (2) a bulbar syndrome including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency in 6 (27%); (3) a syndrome resembling progressive supranuclear palsy (PSP-like) in 5 (23%); and (4) cognitive decline with or without chorea in 3 (14%). All patients eventually developed parasomnia, sleep apnea, insomnia, or excessive daytime sleepiness. HLA-DRB1*10:01 and HLA-DQB1*05:01 were positive in 13/15 (87%) patients; the DRB1*10:01 allele was 36 times more prevalent than in the general population. Among 16 patients with paired serum and CSF samples, 14 had IgLON5 antibodies in both, and 2 only in serum (both had a PSP-like syndrome). Twenty of 21 patients had IgG1 and IgG4 antibodies; the latter predominated in 16. Conclusions: Patients with IgLON5 antibodies develop a characteristic sleep disorder preceded or accompanied by bulbar symptoms, gait abnormalities, oculomotor problems, and, less frequently, cognitive decline. IgG4 subclass antibodies predominate over IgG1; we confirm a[...]



Monophasic demyelination reduces brain growth in children

2017-05-01T12:45:32-07:00

Objective:

To investigate how monophasic acquired demyelinating syndromes (ADS) affect age-expected brain growth over time.

Methods:

We analyzed 83 pediatric patients imaged serially from initial demyelinating attack: 18 with acute disseminated encephalomyelitis (ADEM) and 65 with other monophasic ADS presentations (monoADS). We further subdivided the monoADS group by the presence (n = 33; monoADSlesion) or absence (n = 32; monoADSnolesion) of T2 lesions involving the brain at onset. We used normative data to compare brain volumes and calculate age- and sex-specific z scores, and used mixed-effect models to investigate their relationship with time from demyelinating illness.

Results:

Children with monophasic demyelination (ADEM, non-ADEM with brain lesions, and those without brain involvement) demonstrated reduced age-expected brain growth on serial images, driven by reduced age-expected white matter growth. Cortical gray matter volumes were not reduced at onset but demonstrated reduced age-expected growth afterwards in all groups. Brain volumes differed from age- and sex-expected values to the greatest extent in children with ADEM. All patient groups failed to recover age-expected brain growth trajectories.

Conclusions:

Brain volume, and more importantly age-expected brain growth, is negatively affected by acquired demyelination, even in the absence of chronicity, implicating factors other than active inflammation as operative in this process.




Randomized controlled trials in mild cognitive impairment: Sources of variability

2017-05-01T12:45:32-07:00

Objective: To examine the variability in performance among placebo groups in randomized controlled trials for mild cognitive impairment (MCI). Methods: Placebo group data were obtained from 2 National Institute on Aging (NIA) MCI randomized controlled trials, the Alzheimer's Disease Cooperative Study (ADCS) MCI trial and the Alzheimer's Disease Neuroimaging Initiative (ADNI), which is a simulated clinical trial, in addition to industry-sponsored clinical trials involving rivastigmine, galantamine, rofecoxib, and donepezil. The data were collated for common measurement instruments. The performance of the placebo participants from these studies was tracked on the Alzheimer's Disease Assessment Scale–cognitive subscale, Mini-Mental State Examination, and Clinical Dementia Rating–sum of boxes, and for progression on these measures to prespecified clinical study endpoints. APOE status, where available, was also analyzed for its effects. Results: The progression to clinical endpoints varied a great deal among the trials. The expected performances were seen for the participants in the 2 NIA trials, ADCS and ADNI, with generally worsening of performance over time; however, the industry-sponsored trials largely showed stable or improved performance in their placebo participants. APOE4 carrier status influenced results in an expected fashion on the study outcomes, including rates of progression and cognitive subscales. Conclusions: In spite of apparently similar criteria for MCI being adopted by the 7 studies, the implementation of the criteria varied a great deal. Several explanations including instruments used to characterize participants and variability among study populations contr[...]






Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden

2017-05-01T12:45:32-07:00

Objective: To identify the functional and pathologic correlates underlying subjective memory complaints (SMCs) in cognitively normal older adults. Methods: Two hundred fifty-one older adults underwent resting-state fluorodeoxyglucose (FDG)-PET and Pittsburg compound B-PET β-amyloid (Aβ) imaging and filled out a questionnaire regarding SMCs. Participants were classified into 2 groups based on their Aβ burden. Age-adjusted voxel-wise correlations were used to examine SMCs, amyloid status (Aβ+ vs Aβ–), and the interaction between SMCs and Aβ status as predictors of metabolism. Region-of-interest (ROI) analyses were performed to confirm the whole-brain analyses and to test for additional covariates. Results: Greater SMCs correlated with decreased FDG metabolism in the bilateral precuneus, bilateral inferior parietal lobes, right inferior temporal lobe, right medial frontal gyrus, and right orbitofrontal gyrus. A significant interaction effect between SMCs and amyloid burden was found such that Aβ+ individuals with increased complaints had decreased FDG metabolism in the bilateral medial temporal lobes. ROI analyses confirmed the voxel-wise analyses result in that decreased precuneus metabolism was associated with greater SMCs regardless of Aβ status, age, or thickness, whereas the relationship between hippocampal metabolism and SMCs was a function of Aβ, even after adjustment for age, hippocampal volume, or depressive symptoms. Conclusions: These data show the relevant role of posterior and anterior midline regions in SMCs in older individuals. Decreased hippocampal metabolism may be a s[...]



A phase 3 trial of IV immunoglobulin for Alzheimer disease

2017-05-01T12:45:32-07:00

Objective: We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia. Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants. Results: No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo. Conclusions: Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who receive[...]



Editors' Note

2017-05-01T12:45:32-07:00

Editors' Note: In WriteClick this week, in reference to "Cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL)," Drs. Fussiger et al. argue for a more logical method of naming autosomal dominant small vessel disease disorders; for example, by utilizing a combination of main phenotype, inheritance pattern, and implicated genes. Authors van der Knaap et al. agree that a consensus on nomenclature would be helpful in avoiding confusion.




Letter re: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)

2017-05-01T12:45:32-07:00

A novel autosomal dominant cerebral small vessel disease (SVD) due to mutations in CTSA was described by Bugiani et al.1 The authors named this condition cathepsin A–related arteriopathy with strokes and leukoencephalopathy (CARASAL).




Author response: Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL)

2017-05-01T12:45:32-07:00

We thank Fussiger et al. for the interest in our article and for the comments. We agree that the nomenclature of genetically determined cerebral small vessel disease is confusing and that using similar acronyms for genetically different variants may increase the confusion. The focus of our article was on adding a gene that is associated with cerebral small vessel disease,1 not on a new classification system. An expert in the field of cerebral small vessel disease or a consortium should consider an overall classification.




Letter re: Comorbidity between central disorders of hypersomnolence and immune-based disorders

2017-05-01T12:45:32-07:00

I read with interest the article by Barateau et al.1 The authors' research is similar to the research of our group in Madrid, but our article was not cited.2 However, the authors do mention, compare, and criticize an article published 2 years ago by our group.3 The fact that "Our results contrast with the retrospective Spanish study showing a high frequency of immunopathologic diseases and allergic comorbidities (16.6%) in NT1" was stressed by the authors,1 but why? Did the authors' relevant data not match our findings or were inconsistencies because of an incorrect comparison? We demonstrated a higher frequency of autoimmune diseases in our series of 158 patients with narcolepsy with cataplexy (narcolepsy type 1) compared with a sample of the Spanish general population (p = 0.04). The association with other allergic diseases was also high, although the difference was not significant.2 In addition, the authors concluded that, compared with controls, autoimmune disease frequency was higher in patients with narcolepsy without cataplexy (narcolepsy type 2), whereas allergies were more common in idiopathic hypersomnia.1 The authors did not give a consistent explanation for these findings.




Author response: Comorbidity between central disorders of hypersomnolence and immune-based disorders

2017-05-01T12:45:32-07:00

We thank Dr. Peraita-Adrados for the comment on our article.1 Our finding that narcolepsy type 1 (NT1) was not associated with increased risk of comorbid immune disorders was previously stated,2 which gave us additional confidence in our results and can be explained by a unique NT1 pathophysiology. We agree that the background in Dr. Peraita-Adrados's research was the same3; however, the methodology was different: our cohort was much larger, with patients included prospectively; the study was multicentric; adult and children populations were analyzed separately; and results were controlled for potential confounders.1 Importantly, we classified immune-based disorders in 3 groups (autoimmune, inflammatory, and allergic diseases).4 A recent article from the same group, not published at time of our submission, retrospectively added a poorly defined control group to the already reported NT1 population.3,5 Limited evidence was found for an association between heterogeneous autoimmune diseases and NT1, including psoriasis as an autoimmune, but not inflammatory, disease. We also found higher frequency of autoimmune diseases in narcolepsy type 2 and allergies in idiopathic hypersomnia, being both central disorders of hypersomnolence with unclear pathophysiology, and hypothesized on immune dysregulation mechanisms that require further study.1