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Clinical Reasoning: Sudden-onset pulsatile headache in a previously healthy young man

2017-01-16T12:45:29-08:00

A previously healthy 41-year-old man presented to the local hospital with a sudden-onset right-sided pulsatile headache, accompanied by vertigo, unstable gait, nausea, and vomiting. On admission, he additionally presented with left central facial paralysis, left-sided hemiparesis, and NIH Stroke Scale score of 2. The patient denied history of hypertension, diabetes, or any other high-risk factors for cerebral vascular diseases (CVD). Diffusion-weighted imaging (DWI) revealed multiple acute focal infarctions in the right frontoparietal lobe consistent with decreased blood supply through the right carotid artery (figure e-1A1 at Neurology.org).




Teaching Video NeuroImages: Functional saccadic oculomotor disturbances

2017-01-16T12:45:30-08:00

A 37-year-old woman presented with persistent spinning vertigo, diplopia, and blurred vision of acute onset 6 months ago. Neuro-ophthalmologic examination revealed oculomotor disturbances (video at Neurology.org). These eye movements were absent when the patient was not being examined, i.e., when reading or sitting in the waiting hall. Based on these findings and confirmed by video-oculography (figure), the diagnosis of functional oculomotor disturbances could be made. The prevalence of functional oculomotor disturbances is largely unknown, with convergence spasm and functional nystagmus being most common.1 Video-oculographic documentation allows objective quantification of these high-amplitude eye movements in the presence of well-preserved intersaccadic intervals and dependence of attention in contrast to central oculomotor disturbances.2 Further, macro square-wave jerks are mostly asymptomatic, paired, small, saccadic intrusions taking the eye off target at an amplitude of 5°–15° and returning after an intersaccadic interval of 70–150 ms.2 In opsoclonus, symptomatic with blurred vision and oscillopsia, saccadic oscillations occur unpredictably in all directions (horizontal, vertical, and diagonal) without an intersaccadic interval.2




Teaching Video NeuroImages: Alternating horizontal single saccadic pulses in progressive supranuclear palsy

2017-01-16T12:45:30-08:00

Saccadic intrusions refer to inappropriate saccades that interrupt fixation.1 A 69-year-old woman with progressive supranuclear palsy showed alternating horizontal saccades that intruded on steady fixation (video at Neurology.org). The immediate drift-back of the eyes indicates a saccadic pulse without a step signal (pulse-step mismatch) or return saccade, consistent with single saccadic pulses (SSP).1




Spotlight on the January 17 Issue

2017-01-16T12:45:29-08:00




Avoidance of steroids in the reversible cerebral vasoconstriction syndrome

2017-01-16T12:45:29-08:00

Reversible cerebral vasoconstriction syndrome (RCVS), characterized by multifocal constrictions of cerebral arteries resolving spontaneously within 3 months, most commonly presents with unusual, severe, mostly thunderclap headaches (severe pain peaking in less than 1 minute).1,2 Seizures and focal neurologic deficits related to cortical subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, or posterior reversible encephalopathy syndrome may occur.3–5 Treatment relies on rest; withdrawal of any vasoactive drugs; avoidance of triggering factors; administration of nimodipine, given by analogy to aneurysmal subarachnoid hemorrhage–related vasospasm; and classical treatment of associated headache, stroke, or seizure.




A good sleep for a fresh mind in patients with acute traumatic brain injury

2017-01-16T12:45:29-08:00

Sleep is essential to restore body and brain functions. Animal and human data demonstrate in addition a fundamental role of sleep in memory consolidation and learning.1–3 Accordingly, sleep loss and sleep disorders are associated with disturbances of memory, learning, and, more generally, cognitive function.4,5




Glucocorticoid-associated worsening in reversible cerebral vasoconstriction syndrome

2017-01-16T12:45:29-08:00

Objective:

Factors predicting poor outcome in patients with the reversible cerebral vasoconstriction syndrome (RCVS) have not been identified.

Methods:

In this single-center retrospective study, we analyzed the clinical, brain imaging, and angiography data in 162 patients with RCVS. Univariable and multivariable regression analysis were performed to identify predictors of persistent (nontransient) clinical worsening, radiologic worsening, early angiographic progression, and poor discharge outcome (modified Rankin Scale score 4–6).

Results:

The mean age was 44 ± 13 years; 78% of patients were women. Persistent clinical worsening occurred in 14% at 6.6 ± 4.1 days after symptom onset, radiologic worsening in 27% (mainly new infarcts), and angiographic progression in 15%. Clinical worsening correlated with angiographic progression and new nonhemorrhagic lesions. Age and sex did not independently predict any type of worsening. Infarction on baseline imaging predicted poor outcome. Prior serotonergic antidepressant use predicted clinical and angiographic worsening but not poor outcome. Intra-arterial vasodilator therapy independently predicted clinical worsening and poor discharge outcome but was offered to more severe cases. Glucocorticoid treatment proved to be an independent predictor of clinical, imaging, and angiographic worsening and poor outcome. Of the 23 patients with clinical worsening, 17 received glucocorticoids (15 within the preceding 2 days). There were no significant differences in baseline brain lesions and angiographic abnormalities between glucocorticoid-treated and untreated patients.

Conclusion:

Patients with RCVS at risk for worsening can be identified on basis of baseline features. Iatrogenic factors such as glucocorticoid exposure may contribute to worsening.




Have clinicians adopted the use of brain MRI for patients with TIA and minor stroke?

2017-01-16T12:45:29-08:00

Background:

Use of MRI with diffusion-weighted imaging (DWI) can identify infarcts in 30%–50% of patients with TIA. Previous guidelines have indicated that MRI-DWI is the preferred imaging modality for patients with TIA. We assessed the frequency of MRI utilization and predictors of MRI performance.

Methods:

A review of TIA and minor stroke patients evaluated at Veterans Affairs hospitals was conducted with regard to medical history, use of diagnostic imaging within 2 days of presentation, and in-hospital care variables. Chart abstraction was performed in a subset of hospitals to assess clinical variables not available in the administrative data.

Results:

A total of 7,889 patients with TIA/minor stroke were included. Overall, 6,694 patients (84.9%) had CT or MRI, with 3,396/6,694 (50.7%) having MRI. Variables that were associated with increased odds of CT performance were age >80 years, prior stroke, history of atrial fibrillation, heart failure, coronary artery disease, anxiety, and low hospital complexity, while blood pressure >140/90 mm Hg and high hospital complexity were associated with increased likelihood of MRI. Diplopia (87% had MRI, p = 0.03), neurologic consultation on the day of presentation (73% had MRI, p < 0.0001), and symptom duration of >6 hours (74% had MRI, p = 0.0009) were associated with MRI performance.

Conclusions:

Within a national health system, about 40% of patients with TIA/minor stroke had MRI performed within 2 days. Performance of MRI appeared to be influenced by several patient and facility-level variables, suggesting that there has been partial acceptance of the previous guideline that endorsed MRI for patients with TIA.




Endovascular treatment improves cognition after stroke: A secondary analysis of REVASCAT trial

2017-01-16T12:45:29-08:00

Objective:

To investigate the effect of endovascular treatment on cognitive function as a prespecified secondary analysis of the REVASCAT (Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours) trial.

Methods:

REVASCAT randomized 206 patients with anterior circulation proximal arterial occlusion stroke to Solitaire thrombectomy or best medical treatment alone. Patients with established dementia were excluded from enrollment. Cognitive function was assessed in person with Trail Making Test (TMT) Parts A and B at 3 months and 1 year after randomization by an investigator masked to treatment allocation. Test completion within 5 minutes, time of completion (seconds), and number of errors were recorded.

Results:

From November 2012 to December 2014, 206 patients were enrolled in REVASCAT. TMT was assessed in 82 of 84 patients undergoing thrombectomy and 86 of 87 control patients alive at 3 months and in 71 of 79 patients undergoing thrombectomy and 72 of 78 control patients alive at 1 year. Rates of timely TMT-A completion were similar in both treatment arms, although patients undergoing thrombectomy required less time for TMT-A completion and had higher rates of error-free TMT-A performance. Thrombectomy was also associated with a higher probability of timely TMT-B completion (adjusted odds ratio 3.17, 95% confidence interval 1.51–6.66 at 3 months; and adjusted ratio 3.66, 95% confidence interval 1.60–8.35 at 1 year) and shorter time for TMT-B completion. Differences in TMT completion times between treatment arms were significant in patients with good functional outcome but not in those who were functionally dependent (modified Rankin Scale score >2). Poorer cognitive outcomes were significantly associated with larger infarct volume, higher modified Rankin Scale scores, and worse quality of life.

Conclusions:

Thrombectomy improves TMT performance after stroke, especially among patients who reach good functional recovery.

ClinicalTrials.gov identifier:

NCT01692379.

Classification of evidence:

This study provides Class I evidence that for patients with stroke from acute anterior circulation proximal arterial occlusion, thrombectomy improves performance on the TMT at 3 months.




Disparities and guideline adherence in drugs of abuse screening in intracerebral hemorrhage

2017-01-16T12:45:29-08:00

Objective:

To characterize the pattern of urine drug screening in a cohort of intracerebral hemorrhage (ICH) patients at our academic centers.

Methods:

We identified cases of primary ICH occurring from 2009 to 2011 in our academic centers. Demographic data, imaging characteristics, processes of care, and short-term outcomes were ascertained. We performed logistic regression to identify predictors for screening and evaluated preguideline and postguideline reiteration screening patterns.

Results:

We identified 610 patients with primary ICH in 2009–2011; 379 (62.1%) were initially evaluated at an outside hospital. Overall, 142/610 (23.3%) patients were screened, with 21 positive for cocaine and 3 for amphetamine. Of patients <55 years of age, only 65/140 (46.4%) were screened. Black patients <55 years of age were screened more than nonblack patients <55 years of age (38/61 [62.3%] vs 27/79 [34.2%]; p = 0.0009). In the best multivariable model, age group (p = 0.0001), black race (p = 0.4529), first Glasgow Coma Scale score (p = 0.0492), current smoking (p < 0.0001), and age group x black race (p = 0.0097) were associated with screening. Guideline reiteration in 2010 did not improve the proportion <55 years of age who were screened: 42/74 (56.8%) were screened before and 23/66 (34.9%) after (p = 0.01).

Conclusions:

We found disparities in drugs of abuse (DOA) screening and suboptimal guideline adherence. Systematic efforts to improve screening for DOA are warranted. Improved identification of sympathomimetic exposure may improve etiologic classification and influence decision-making and prognosis counseling.




Transcranial direct current stimulation for children with perinatal stroke and hemiparesis

2017-01-16T12:45:29-08:00

Objective:

To determine whether the addition of transcranial direct current stimulation (tDCS) to intensive therapy increases motor function in children with perinatal stroke and hemiparetic cerebral palsy.

Methods:

This was a randomized, controlled, double-blind clinical trial. Participants were recruited from a population-based cohort with MRI-classified unilateral perinatal stroke, age of 6 to 18 years, and disabling hemiparesis. All completed a goal-directed, peer-supported, 2-week after-school motor learning camp (32 hours of therapy). Participants were randomized 1:1 to 1 mA cathodal tDCS over the contralesional primary motor cortex (M1) for the initial 20 minutes of daily therapy or sham. Primary subjective (Canadian Occupational Performance Measure [COPM]), objective (Assisting Hand Assessment [AHA]), safety, and secondary outcomes were measured at 1 week and 2 months after intervention. Analysis was by intention to treat.

Results:

Twenty-four participants were randomized (median age 11.8 ± 2.7 years, range 6.7–17.8). COPM performance and satisfaction scores doubled at 1 week with sustained gains at 2 months (p < 0.001). COPM scores increased more with tDCS compared to sham control (p = 0.004). AHA scores demonstrated only mild increases at both time points with no tDCS effects. Procedures were safe and well tolerated with no decrease in either arm function or serious adverse events.

Conclusion:

tDCS trials appear feasible and safe in hemiparetic children. Lack of change in objective motor function may reflect underdosing of therapy. Marked gains in subjective function with tDCS warrant further study.

ClinicalTrials.gov identifier:

NCT02170285.

Classification of evidence:

This study provides Class II evidence that for children with perinatal stroke and hemiparetic cerebral palsy, the addition of tDCS to moderate-dose motor learning therapy does not significantly improve motor function as measured by the AHA.




Parallel recovery of consciousness and sleep in acute traumatic brain injury

2017-01-16T12:45:29-08:00

Objective:

To investigate whether the progressive recuperation of consciousness was associated with the reconsolidation of sleep and wake states in hospitalized patients with acute traumatic brain injury (TBI).

Methods:

This study comprised 30 hospitalized patients (age 29.1 ± 13.5 years) in the acute phase of moderate or severe TBI. Testing started 21.0 ± 13.7 days postinjury. Consciousness level and cognitive functioning were assessed daily with the Rancho Los Amigos scale of cognitive functioning (RLA). Sleep and wake cycle characteristics were estimated with continuous wrist actigraphy. Mixed model analyses were performed on 233 days with the RLA (fixed effect) and sleep-wake variables (random effects). Linear contrast analyses were performed in order to verify if consolidation of the sleep and wake states improved linearly with increasing RLA score.

Results:

Associations were found between scores on the consciousness/cognitive functioning scale and measures of sleep-wake cycle consolidation (p < 0.001), nighttime sleep duration (p = 0.018), and nighttime fragmentation index (p < 0.001). These associations showed strong linear relationships (p < 0.01 for all), revealing that consciousness and cognition improved in parallel with sleep-wake quality. Consolidated 24-hour sleep-wake cycle occurred when patients were able to give context-appropriate, goal-directed responses.

Conclusions:

Our results showed that when the brain has not sufficiently recovered a certain level of consciousness, it is also unable to generate a 24-hour sleep-wake cycle and consolidated nighttime sleep. This study contributes to elucidating the pathophysiology of severe sleep-wake cycle alterations in the acute phase of moderate to severe TBI.




Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB

2017-01-16T12:45:29-08:00

Objective:

To conduct a validation study of 123I-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard.

Methods:

Patients >60 years of age with dementia who had undergone 123I-FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent 123I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria.

Results:

Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, 123I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%) compared with clinical diagnosis, which had an accuracy of 79% (sensitivity 87%, specificity 72%). Among patients with DLB, 10% (3 patients) met pathologic criteria for Lewy body disease but had normal 123I-FP-CIT imaging.

Conclusions:

This large autopsy analysis of 123I-FP-CIT imaging in dementia demonstrates that it is a valid and accurate biomarker for DLB, and the high specificity compared with clinical diagnosis (20% higher) is clinically important. The results need to be replicated with patients recruited from a wider range of settings, including movement disorder clinics and general practice. While an abnormal 123I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement.

Classification of evidence:

This study provides Class I evidence that 123I-FP-CIT dopaminergic neuroimaging accurately identifies patients with DLB.




Distracting attention in phobic postural vertigo normalizes leg muscle activity and balance

2017-01-16T12:45:29-08:00

Objective:

To examine the triggering causes of inadequate neuromuscular regulation of posture and subjective imbalance in patients with phobic postural vertigo (PPV), a subtype of functional dizziness.

Methods:

Postural performance was assessed by center-of-pressure displacements and surface EMG of lower-limb muscles (the tibialis anterior and soleus) in 10 patients with PPV and 10 healthy controls under 4 stance conditions: standing with eyes open or closed and with or without an additional cognitive dual task. The level of muscle cocontraction and the characteristics of open- and closed-loop postural control were analyzed.

Results:

At baseline (i.e., standing with eyes open without dual task), patients exhibited increased muscle cocontractions (p = 0.003), which were further associated with increased open-loop diffusion activity (p = 0.022) and a lowering of the primary feedback threshold for closed-loop control (p = 0.003). However, postural performance of patients improved considerably and normalized to that of healthy controls when performing an additional dual task.

Conclusions:

PPV is characterized by a dissociation of subjective postural instability and objectively maintained balance capabilities. The dual-task effects on balance in patients with PPV indicate that this dissociation might result from an increased attention to postural adjustments at baseline, which is normally required only during demanding balance situations. This internal focus on balance control promotes an inappropriate neuromuscular regulation of posture, with increased muscle cocontractions, higher short-term body sway, and an oversensitivity to external stimuli. However, if patients are distracted, muscle cocontractions and balance control normalize. Such distraction may therefore be an effective coping strategy for preventing PPV attacks in susceptible patients.




Increased total sodium concentration in gray matter better explains cognition than atrophy in MS

2017-01-16T12:45:29-08:00

Objective:

To investigate whether brain total sodium accumulation assessed by 23Na MRI is associated with cognitive deficit in relapsing-remitting multiple sclerosis (RRMS).

Methods:

Eighty-nine participants were enrolled in the study (58 patients with RRMS with a disease duration ≤10 years and 31 matched healthy controls). Patients were classified as cognitively impaired if they failed at least 2 tasks on the Brief Repeatable Battery. MRI was performed at 3T using 23Na MRI to obtain total sodium concentration (TSC) in the different brain compartments (lesions, normal-appearing white matter [NAWM], gray matter [GM]) and 1H- magnetization-prepared rapid gradient echo to assess GM atrophy (GM fraction).

Results:

The mean disease duration was 3.1 years and the median Expanded Disability Status Scale score was 1 (range 0–4.5). Thirty-seven patients were classified as cognitively preserved and 21 as cognitively impaired. TSC was increased in GM and NAWM in cognitively impaired patients compared to cognitively preserved patients and healthy controls. Voxel-wise analysis demonstrated that sodium accumulation was mainly located in the neocortex in cognitively impaired patients. Regression analysis evidenced than the 2 best independent predictors of cognitive impairment were GM TSC and age. Receiver operating characteristic analyses demonstrated that sensitivity and specificity of the GM TSC to classify patients according to their cognitive status were 76% and 71%, respectively.

Conclusions:

This study provides 2 main findings. (1) In RRMS, total sodium accumulation in the GM is better associated with cognitive impairment than GM atrophy; and (2) total sodium accumulation in patients with cognitive impairment is mainly located in the neocortex.




Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies

2017-01-16T12:45:29-08:00

Objective:

To review population-based studies of the prevalence and incidence of epilepsy worldwide and use meta-analytic techniques to explore factors that may explain heterogeneity between estimates.

Methods:

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed. We searched MEDLINE and EMBASE for articles published on the prevalence or incidence of epilepsy since 1985. Abstract, full-text review, and data abstraction were conducted in duplicate. Meta-analyses and meta-regressions were used to explore the association between prevalence or incidence, age group, sex, country level income, and study quality.

Results:

A total of 222 studies were included (197 on prevalence, 48 on incidence). The point prevalence of active epilepsy was 6.38 per 1,000 persons (95% confidence interval [95% CI] 5.57–7.30), while the lifetime prevalence was 7.60 per 1,000 persons (95% CI 6.17–9.38). The annual cumulative incidence of epilepsy was 67.77 per 100,000 persons (95% CI 56.69–81.03) while the incidence rate was 61.44 per 100,000 person-years (95% CI 50.75–74.38). The prevalence of epilepsy did not differ by age group, sex, or study quality. The active annual period prevalence, lifetime prevalence, and incidence rate of epilepsy were higher in low to middle income countries. Epilepsies of unknown etiology and those with generalized seizures had the highest prevalence.

Conclusions:

This study provides a comprehensive synthesis of the prevalence and incidence of epilepsy from published international studies and offers insight into factors that contribute to heterogeneity between estimates. Significant gaps (e.g., lack of incidence studies, stratification by age groups) were identified. Standardized reporting of future epidemiologic studies of epilepsy is needed.




A population-based epidemiologic study of adult neuromuscular disease in the Republic of Ireland

2017-01-16T12:45:29-08:00

Objective:

To estimate the prevalence rates (PRs) of acquired and inherited neuromuscular diseases (NMD) in the adult Irish population, reflecting the burden of these conditions in a single country.

Methods:

This population-based study was performed in the Republic of Ireland (RoI), with a PR estimated for December 2013. Multiple case ascertainment sources were utilized. Demographic and clinical information and relevant diagnostic results were registered.

Results:

A total of 2,641 adults were identified, giving a PR of 62.6/100,000 (95% confidence interval [CI] 59.95–65.24) for all NMD in RoI. Disease-specific PR include chronic inflammatory demyelinating polyradiculoneuropathy 5.87/100,000 (95% CI 5.06–6.68), Charcot-Marie-Tooth 10.52/100,000 (95% CI 9.44–11.61), hereditary neuropathy with liability to pressure palsies 0.84/100,000 (95% CI 0.54–1.15), myotonic dystrophy type I 6.75/100,000 (95% CI 5.88–7.61), Duchenne muscular dystrophy 3.0/100,000 (95% CI 2.33–3.70), Becker muscular dystrophy 2.2/100,000 (95% CI 1.64–2.88), facioscapulohumeral dystrophy 2.59/100,000 (95% CI 2.05–3.13), limb-girdle muscular dystrophy 2.88/100,000 (95% CI 2.31–3.45), periodic paralysis 1.72/100,000 (95% CI 1.28–2.15), myotonia congenita 0.32/100,000 (95% CI 0.18–0.56), paramyotonia congenita 0.15/100,000 (95% CI 0.06–0.34), Kennedy disease 0.83/100,000 (95% CI 0.40–1.27), Lambert-Eaton myasthenic syndrome 0.29/100,000 (95% CI 0.11–0.47), myasthenia gravis 15.12/100,000 (95% CI 13.82–16.42), and sporadic inclusion body myositis 11.7/100,000 (95% CI 9.82–13.58). PR for amyotrophic lateral sclerosis was established from an existing Register as 7.20/100,000 (95% CI 6.34–8.15).

Conclusions:

The PR of all adult NMD in RoI is relatively high when compared with other chronic neurologic disorders, although some figures may be an underestimate of the true prevalence. The data provide a framework for international comparison and service planning.




Sulfonylurea receptor-associated channels: Involvement in disease and therapeutic implications

2017-01-16T12:45:29-08:00

The sulfonylurea receptors (SURs) 1 (SUR1) and 2 (SUR2) are members of the adenosine triphosphate (ATP) binding cassette transporters superfamily. Unlike other members of this superfamily, these receptors are not involved in transport but associate with pore-forming subunits to form cation channels. Both SUR1 and SUR2 associate with inward rectifying potassium (K+) (Kir) channels (Kir6) subunits to form functional ATP-sensitive K+ channels (KATP).1 These channels are molecular sensors that provide a link between cellular energy state and electrical excitability; they are tonically inhibited by ATP, and their activation in the setting of energy failure results in cell hyperpolarization and vasodilation, leading to cell-protective effects. SUR1 also associates with the pore-forming subunit of the calcium (Ca2+) activated transient receptor potential melastatin 4 (TRPM4) channel.2 In contrast to KATP channels, the SUR1-regulated TRMP4 channels are nonselective monovalent cation channels that trigger depolarization and cerebral vasoconstriction. Upregulation of SUR1-TRPM4 channels in conditions such as cerebral ischemia may result in necrotic cell death, affecting the neurovascular unit and promoting cerebral edema. Whereas in normal conditions KATP channels exert neuroprotective effects, in pathologic conditions their excessive activation may also be deleterious. The presence of regulatory SUR subunits renders KATP and TRPM4 channels sensitive to inhibition by sulfonylureas such as glibenclamide (glyburide). Preclinical evidence from experimental models and early clinical trials indicate that this drug may be of therapeutic benefit in conditions such as that described in this representative case.3,4




Ethical clinical translation of stem cell interventions for neurologic disease

2017-01-16T12:45:29-08:00

The application of stem cell transplants in clinical practice has increased in frequency in recent years. Many of the stem cell transplants in neurologic diseases, including stroke, Parkinson disease, spinal cord injury, and demyelinating diseases, are unproven—they have not been tested in prospective, controlled clinical trials and have not become accepted therapies. Stem cell transplant procedures currently being carried out have therapeutic aims, but are frequently experimental and unregulated, and could potentially put patients at risk. In some cases, patients undergoing such operations are not included in a clinical trial, and do not provide genuinely informed consent. For these reasons and others, some current stem cell interventions for neurologic diseases are ethically dubious and could jeopardize progress in the field. We provide discussion points for the evaluation of new stem cell interventions for neurologic disease, based primarily on the new Guidelines for Stem Cell Research and Clinical Translation released by the International Society for Stem Cell Research in May 2016. Important considerations in the ethical translation of stem cells to clinical practice include regulatory oversight, conflicts of interest, data sharing, the nature of investigation (e.g., within vs outside of a clinical trial), informed consent, risk-benefit ratios, the therapeutic misconception, and patient vulnerability. To help guide the translation of stem cells from the laboratory into the neurosurgical clinic in an ethically sound manner, we present an ethical discussion of these major issues at stake in the field of stem cell clinical research for neurologic disease.




Myoclonia continua in primary CNS natural killer/T-cell lymphoma, nasal type

2017-01-16T12:45:29-08:00

A 58-year-old right-handed man presented with 3 months gradual worsening of twitching in his left hand. He had no remarkable medical or family history. Examination demonstrated continuous twitching in his left upper limb and dystonic posture of his left hand (videos 1 and 2 at Neurology.org). Superficial, deep, and cortical sensations were not disturbed in his left upper limb.




De novo formation of a symptomatic arachnoid cyst in an adult

2017-01-16T12:45:29-08:00

A 49-year-old man presented with 7 months of progressive ataxic gait. He had a minor head injury 4 years prior, with unremarkable imaging (figure 1A). There was no further head trauma, but a repeat study at presentation demonstrated a posterior fossa cyst with mass effect and early hydrocephalus (figure 1B). Intraoperative findings confirmed the lesion was an arachnoid cyst (figure 2). Symptoms improved postoperatively.




Editors' Note

2017-01-16T12:45:29-08:00

Editors' Note: Commenting on "The clinical spectrum of Caspr2 antibody–associated disease," Dr. Chen suggests that cognitive symptoms or seizures are not necessary for the diagnosis of Morvan syndrome. He also asks the authors about one of his patients with persistent hyponatremia and Caspr2 antibodies.




Letter re: The clinical spectrum of Caspr2 antibody-associated disease

2017-01-16T12:45:29-08:00

van Sonderen et al.1 described the clinical spectrum of Caspr2 antibody-associated disease. They defined Morvan syndrome (MoS) as a combination of cognitive symptoms or seizures, peripheral nerve hyperexcitability, and dysautonomia or insomnia.




Author response: The clinical spectrum of Caspr2 antibody-associated disease

2017-01-16T12:45:29-08:00

We appreciate the comments of Dr. Chen. Our study was focused on the clinical picture associated with Caspr2 antibodies, showing a spectrum of symptoms that do not conform to specific syndromes but were present in most of the patients, leading to the terminology "Caspr2 core symptoms."1 In some patients, Caspr2 antibodies associate with the syndrome described by Morvan.




Letter re: Huntington disease reduced penetrance alleles occur at high frequency in the general population

2017-01-16T12:45:29-08:00

There is general consensus that the presence of 40 or more CAG repeats in the Huntington gene (HTT) confers Huntington disease (HD). In their study on CAG-HTT in 7,315 people, Kay et al.1 estimated that 0.246% of the general population have low-penetrance expanded (36–39) CAG repeats and 6.2% have intermediate (27–35). The latter is similar to the 5.1% (50/983) frequency of intermediate CAG repeats in the Prospective Huntington at Risk Observational Study (PHAROS) study and 2.5% (50/1985) in the Cooperative Huntington's Observational Research Trial (COHORT) study.2,3




Author response: Huntington disease reduced penetrance alleles occur at high frequency in the general population

2017-01-16T12:45:29-08:00

We agree with the major point raised by Drs. Jankovic and Squitieri in the comment on our article,1 that HD is likely to be underascertained, particularly in the elderly. It is interesting that some patients with intermediate alleles (IAs) (CAG 27–35) who have signs and symptoms may also, in rare instances, have neuropathologic findings compatible with HD.2–4 Without a very detailed investigation, it may be difficult to rule out phenocopies of HD in isolated cases.5 With such a high frequency of IAs in the general population (5%–6%), an alternative explanation for patients with IAs manifesting neurologic signs and symptoms is chance association. However, it remains possible that some patients with IAs can manifest with HD. These patients provide a unique opportunity to investigate what factors, either genetic or environmental, could have contributed to manifestation of HD at a CAG length that would normally not manifest with signs and symptoms of the disease.










Child Neurology: Neuromyelitis optica spectrum disorders

2017-01-09T12:45:32-08:00

A 3-year-old girl presented with 4 days of progressive bilateral vision loss. Medical history included presumed autoimmune hepatitis at 6 months of age, when she had an extensive evaluation including hepatitis A immunoglobulin G (IgG) detected in her serum, thought to represent maternal antibodies. Liver biopsy suggested autoimmune hepatitis and she was treated with oral prednisolone 2 mg daily for 2 weeks and remained on maintenance 1 mg daily. Family and social histories were unremarkable.




Clinical Reasoning: Labyrinthine hemorrhage: An unusual etiology for peripheral vertigo

2017-01-09T12:45:32-08:00

A 65-year-old man presented with a 2-week history of worsening vertigo. The sensation of vertigo was constant and exacerbated by turning in bed, sitting, and standing. Exacerbations lasted 5–10 minutes and were intense enough to cause gait impairment. Two days prior to presentation, the vertigo had worsened in severity and was associated with one episode of nausea and vomiting. Review of systems was positive for a 3-month history of a whistling noise in the patient's left ear, a 2-week history of acute-on-chronic left-sided hearing impairment, and a recent upper respiratory infection.




Clinical Reasoning: Oculobulbar dysfunction: Central or peripheral?

2017-01-09T12:45:32-08:00

A 45-year-old man presented a few days after an upper respiratory tract infection with complaints of diplopia, dizziness, and difficulty walking that progressed within a few hours to complete ophthalmoplegia and facial diplegia. Brain MRI showed nonspecific T2 hyperintensities prior to transfer to our facility. On arrival, he was alert and oriented to person, place, and time. Pupils were dilated nonreactive and corneal reflexes were absent bilaterally. He had complete ophthalmoplegia, facial diplegia, and areflexia. His strength in the extremities per Medical Research Council (MRC) scale on initial presentation was preserved at 5/5. His clinical status declined rapidly, necessitating intubation for respiratory failure. Routine blood laboratory workup for infections, metabolic derangements including vitamin B1, and thyroid function tests were within normal limits. On day 1, CSF testing showed mildly elevated protein of 47 mg/dL with a normal cell count. CSF cultures and herpes simplex virus (HSV) testing were negative. He also had an EMG/nerve conduction study (NCS), repetitive nerve stimulation (RNS), and single fiber EMG on day 1, all of which were within normal limits. Serum acetylcholine receptor antibody testing was obtained on admission, which was negative.




Teaching NeuroImages: Homotopic motor distribution on fMRI in closed-lip schizencephaly

2017-01-09T12:45:32-08:00

A 16-year-old boy with intractable focal epilepsy with preserved awareness and attention-deficit/hyperactivity disorder underwent evaluation for epilepsy surgery. Epilepsy onset occurred at age 5 years; seizures arise from sleep and are characterized by right arm extension with preserved consciousness. Ictal EEG has no clear localization or lateralization. MRI brain demonstrates bifrontal closed-lip schizencephaly. Functional MRI (fMRI) shows homotopic distribution of tongue/finger/foot motor function at the edge of and along the depth of the schizencephalic cleft, supported by intracranial mapping (figures 1 and 2). fMRI is a reliable tool to identify the eloquent cortex in the planning for epilepsy surgery.1,2




Spotlight on the January 10 Issue

2017-01-09T12:45:31-08:00




Hyperkinetic psychogenic movement disorders remain a diagnosis at first sight

2017-01-09T12:45:31-08:00

Functional or psychogenic movement disorders (FMD) represent a common diagnostic problem in routine neurologic practice. Estimates vary, but most published data suggest that 10%–15% of patients presenting with involuntary movements, such as tremor, myoclonus, or tic, have no evidence for an organic brain disorder.1 However, the exact incidence of FMD remains unknown, given the many challenges in diagnosis including the lack of a gold standard confirmatory test. Moreover, the division between organic and nonorganic etiology has been challenged and functional imaging studies in patients with obvious FMD have suggested abnormal metabolic activity in the sensorimotor cortices, cerebellum, and limbic regions, implying an organic origin of these clinical abnormalities.2,3 Likewise, advanced neuroimaging studies revealed analogous abnormalities of the sensory-motor network and its connections in patients with psychogenic nonepileptic seizures, providing a unifying pathomechanism that may underlie both these conditions.4




Is mitochondrial oxidative metabolism the right therapy target in early Huntington disease?

2017-01-09T12:45:31-08:00

Huntington disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disorder characterized by extrapyramidal motor signs often preceded by cognitive and behavioral disturbances, with a prevalence of 5–10 cases per 100,000 people worldwide1; expanded CAG repeats within the coding sequence of the HTT gene on chromosome 4p2 are the cause. The gene encodes huntingtin (HTT), a ubiquitously expressed protein associated with most intracellular organelles. CAG repeats of 40 or more are associated with nearly full penetrance by age 65 years with a mean age at onset of 40 years and death 15–20 years later.3 Although the function of HTT remains incompletely understood, HD likely arises from gain of function caused by the abnormal conformation of the mutant protein.3




Clinical decision-making in functional and hyperkinetic movement disorders

2017-01-09T12:45:31-08:00

Objective:

Functional or psychogenic movement disorders (FMD) present a diagnostic challenge. To diagnose FMD, clinicians must have experience with signs typical of FMD and distinguishing features from other hyperkinetic disorders. The aim of this study was to clarify the decision-making process of expert clinicians while diagnosing FMD, myoclonus, and tics.

Methods:

Thirty-nine movement disorders experts rated 60 patients using a standardized web-based survey resembling clinical practice. It provided 5 steps of incremental information: (1) visual first impression of the patient, (2) medical history, (3) neurologic examination on video, (4) the Bereitschaftspotential (BP), and (5) psychiatric evaluation. After full evaluation of each case, experts were asked which diagnostic step was decisive. In addition, interim switches in diagnosis after each informational step were calculated.

Results:

After full evaluation, the experts annotated the first impression of the patients as decisive in 18.5% of cases. Medical history was considered decisive in 33.3% of cases. Neurologic examination was considered decisive in 39.7%, the BP in 8%, and the psychiatric interview in 0.5% of cases. Most diagnostic switches occurred after addition of the medical history (34.5%). Addition of the neurologic examination led to 13.8% of diagnostic switches. The BP results led to diagnostic switches in 7.2% of cases. Psychiatric evaluation resulted in the lowest number of diagnostic switches (2.7% of cases).

Conclusions:

Experts predominantly rely on clinical assessment to diagnose FMD. Importantly, ancillary tests do not determine the final diagnosis of this expert panel. In general, the experts infrequently changed their differential diagnosis.




Insights gleaned by measuring patients' stated goals for DBS: More than tremor

2017-01-09T12:45:32-08:00

Objective:

To report prospective repeated measures data detailing the perceived benefit of deep brain stimulation (DBS) on the most commonly cited symptom and activity goals identified by patients with Parkinson disease.

Methods:

Fifty-two participants were recruited from a consecutive series. Participants completed a semi-structured interview soliciting their symptom and behavioral goals and corresponding visual analog scales measuring perceived symptom severity and limits to goal attainment. Severity ratings were completed prior to and at 2 times following DBS. Changes in severity over time were assessed using a mixed effects linear model. The pattern of relationships between the severity ratings and standard clinical research (SCR) measures routinely administered were examined using Pearson correlations.

Results:

The most common symptom goals were improvements in tremor, gait, and nonmotor symptoms, whereas the most frequent behavioral goals related to interpersonal relationships, work, and avocational pursuits. Most severity ratings were significantly correlated with each other but not with the SCR measures. Significant improvements were evident on all SCR measures after DBS. Participants' severity ratings for their symptom and behavioral goals improved significantly over time although not all severity ratings changed in the same manner.

Conclusions:

These data illustrate that improvements in participants' individually defined goals were evident over time and that some of these improvements occurred in areas in which the benefits associated with DBS are not as well-documented. The participants' severity ratings were not redundant with SCR measures, suggesting that novel and potentially important information can be gleaned by systematically assessing patients' goals.




Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations

2017-01-09T12:45:32-08:00

Objective:

To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls.

Methods:

Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes.

Results:

Fibroblasts from 3 biallelic OPA1(–/–) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)–depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA–treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts.

Conclusions:

We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion.




Diagnostic value of sonography in treatment-naive chronic inflammatory neuropathies

2017-01-09T12:45:32-08:00

Objective:

To determine the diagnostic value of high-resolution ultrasound (HRUS) for detection of chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner syndrome (LSS), and multifocal motor neuropathy (MMN).

Methods:

Between January 2013 and January 2015, we enrolled 75 consecutive treatment-naive patients with chronic inflammatory neuropathies and 70 disease controls. We performed extensive nerve conduction and standardized HRUS studies bilaterally of large arm and leg nerves and brachial plexus. We determined optimal sonographic cutoff values of nerve size and used receiver operating characteristic analysis and logistic regression models to identify nerve combinations with optimal diagnostic performance.

Results:

Enlargement of median nerve at forearm >10 mm2, upper arm >13 mm2, and any trunk of brachial plexus >8 mm2 was 99% specific for chronic inflammatory neuropathies. A shortened HRUS protocol for detecting this abnormal nerve enlargement showed high sensitivity (83%–95%), positive predictive value (100%), and negative predictive value (98%) in discriminating CIDP, LSS, and MMN from clinical mimics.

Conclusions:

Sonographic enlargement of proximal median nerve segments in the arms and brachial plexus is a key feature of chronic inflammatory neuropathies, which helps to reliably distinguish them from axonal neuropathies and amyotrophic lateral sclerosis.

Classification of evidence:

This study provides Class II evidence that, in absence of clinical features that suggest a hereditary demyelinating neuropathy, sonographic enlargement of proximal median nerve segments and brachial plexus accurately identifies patients with chronic inflammatory neuropathies.




A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease

2017-01-09T12:45:32-08:00

Objective:

To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD.

Methods:

We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach.

Results:

An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study.

Conclusions:

These data do not justify use of CoQ as a treatment to slow functional decline in HD.

ClinicalTrials.gov identifier:

NCT00608881.

Classification of evidence:

This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.




Blink-associated contralateral eccentric saccades as a rare sign of unilateral brain injury

2017-01-09T12:45:32-08:00

Objective:

To describe a rare sign of unilateral brain injury as a form of unwanted blink-associated contralateral eccentric saccades.

Methods:

A 62-year-old patient who underwent an ischemic stroke affecting the entire right middle cerebral artery territory came to our attention 1 year after stroke, manifesting with transient contralateral conjugate gaze deviations associated with spontaneous blinking. We complemented the regular neurologic evaluation with brain MRI, study of evoked potentials, electroneurography of the facial nerve, and infrared video-oculoscopy.

Results:

The patient had left-sided hemiparesis, hypoesthesia, hemianopia, and hemispatial neglect. He also showed the occurrence of a rapid leftward conjugate deviation of the eyes, followed by a corrective movement to the primary ocular position. MRI showed a wide malacic area spanning the right frontal, temporal, and parietal cortical and subcortical regions, with signs of wallerian degeneration of the descending right corticospinal tract. Motor and somatosensory evoked potentials were centrally altered on the right side. Electroneurography of the facial nerves was normal. Infrared video-oculoscopy indicated persistence of the same blink-related saccades even in darkness.

Conclusions:

It is known that unilateral cerebral lesions may manifest with a contralateral conjugate gaze deviation evoked by closure of the lids. This sign, known as spasticity of conjugate gaze, may be due to the suppression of the fixation reflex. In our case, the persistence of this sign in the darkness allowed us to exclude this diagnosis. We hypothesized that the blink-related neural pathways may improperly activate the oculomotor circuitry at both the cortical and subcortical levels.




Large-scale identification of patients with cerebral aneurysms using natural language processing

2017-01-09T12:45:32-08:00

Objective:

To use natural language processing (NLP) in conjunction with the electronic medical record (EMR) to accurately identify patients with cerebral aneurysms and their matched controls.

Methods:

ICD-9 and Current Procedural Terminology codes were used to obtain an initial data mart of potential aneurysm patients from the EMR. NLP was then used to train a classification algorithm with .632 bootstrap cross-validation used for correction of overfitting bias. The classification rule was then applied to the full data mart. Additional validation was performed on 300 patients classified as having aneurysms. Controls were obtained by matching age, sex, race, and healthcare use.

Results:

We identified 55,675 patients of 4.2 million patients with ICD-9 and Current Procedural Terminology codes consistent with cerebral aneurysms. Of those, 16,823 patients had the term aneurysm occur near relevant anatomic terms. After training, a final algorithm consisting of 8 coded and 14 NLP variables was selected, yielding an overall area under the receiver-operating characteristic curve of 0.95. After the final algorithm was applied, 5,589 patients were classified as having aneurysms, and 54,952 controls were matched to those patients. The positive predictive value based on a validation cohort of 300 patients was 0.86.

Conclusions:

We harnessed the power of the EMR by applying NLP to obtain a large cohort of patients with intracranial aneurysms and their matched controls. Such algorithms can be generalized to other diseases for epidemiologic and genetic studies.




{beta}-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy

2017-01-09T12:45:32-08:00

Objective:

To investigate CSF biomarkers in presymptomatic and symptomatic mutation carriers with hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D), a model for sporadic cerebral amyloid angiopathy, and to determine the earliest deposited form of β-amyloid (Aβ).

Methods:

HCHWA-D mutation carriers and controls were enrolled in the cross-sectional EDAN (Early Diagnosis of Amyloid Angiopathy Network) study. The HCHWA-D group was divided into symptomatic carriers with a previous intracerebral hemorrhage and presymptomatic carriers. CSF concentrations of Aβ40, Aβ42, total tau, and phosphorylated tau181 proteins were compared to those of controls of a similar age. Correlations between CSF biomarkers, MRI markers, and age were investigated with multivariate linear regression analyses.

Results:

We included 10 symptomatic patients with HCHWA-D (mean age 55 ± 6 years), 5 presymptomatic HCHWA-D carriers (mean age 36 ± 13 years), 31 controls <50 years old (mean age 31 ± 7 years), and 50 controls ≥50 years old (mean age 61 ± 8 years). After correction for age, CSF Aβ40 and Aβ42 were significantly decreased in symptomatic carriers vs controls (median Aβ40 1,386 vs 3,867 ng/L, p < 0.001; median Aβ42 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Aβ40 3,501 vs 4,684 ng/L, p = 0.011; median Aβ42 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Aβ40 was associated with higher lobar microbleed count (p = 0.010), increasing white matter hyperintensity volume (p = 0.008), and presence of cortical superficial siderosis (p = 0.02).

Conclusions:

Decreased levels of CSF Aβ40 and Aβ42 occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both Aβ species as early steps in cerebral amyloid angiopathy pathogenesis. CSF Aβ40 and Aβ42 may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.




Blood pressure levels and the risk of intracerebral hemorrhage after ischemic stroke

2017-01-09T12:45:32-08:00

Objective:

To investigate the association between blood pressure (BP) levels and risk of intracerebral hemorrhage (ICH) after ischemic stroke.

Methods:

We performed a post hoc analysis of data from the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, a randomized clinical trial including 20,332 patients with recent noncardioembolic ischemic stroke. BP measurements were divided into predefined categories. We calculated incidence rates per BP category and performed multivariable Cox regression analysis with systolic blood pressure (SBP) and diastolic blood pressure (DBP) categories as time-dependent covariables.

Results:

One hundred thirty-three ICHs occurred during 50,778 person-years of follow-up, resulting in an incidence rate of 2.6 per 1,000 person-years. The incidence rate of ICH increased with increasing SBP and DBP categories. Risk of ICH was significantly higher in patients with SBP ≥160 mm Hg (hazard ratio 2.27, 95% confidence interval 1.34–3.86) compared with those with SBP of 130–<140 mm Hg and in patients with DBP ≥100 mm Hg (hazard ratio 3.08, 95% confidence interval 1.78–5.34) compared with those with DBP of 80–<90 mm Hg. The association between SBP or DBP and ICH did not differ by ischemic stroke subtype (p = 0.55 and 0.93).

Conclusions:

Among patients with recent noncardioembolic ischemic stroke, the risk of ICH is high. High SBP and DBP are associated with an increased risk of ICH. The association between BP and ICH is not dependent on ischemic stroke subtype.




Second monotherapy in childhood absence epilepsy

2017-01-09T12:45:32-08:00

Objective:

To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure.

Methods:

Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16–20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits.

Results:

A total of 208 children were enrolled, randomized, and received second therapy. At both week 16–20 visit and month 12 visit, ethosuximide's (63%, 57%) and valproic acid's (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine's (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine (p < 0.0001). At both the week 16–20 and month 12 visits, attentional dysfunction was numerically more common with valproic acid than with ethosuximide or lamotrigine. For each medication, second monotherapy freedom from failure proportions demonstrated noninferiority to initial monotherapy freedom from failure proportions.

Conclusions:

As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications.

ClinicalTrials.gov identifier:

NCT00088452.

Classification of evidence:

This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine.




Brain activation in high-functioning older adults and falls: Prospective cohort study

2017-01-09T12:45:32-08:00

Objective:

To determine whether brain activity over the prefrontal cortex measured in real time during walking predicts falls in high-functioning older adults.

Method:

We examined166 older persons (mean age 75 years, 51% women) enrolled in a prospective aging study. High-functioning status defined as the absence of dementia or disability with normal gait diagnosed by study clinicians. The magnitude of task-related changes in oxygenated hemoglobin levels over the prefrontal cortex was measured with functional near-infrared spectroscopy during motor (walking at normal pace) and cognitive (reciting alternate letters of the alphabet) single tasks and a dual-task condition (walking while reciting alternate letters of the alphabet). Incident falls were prospectively assessed over a 50-month study period.

Results:

Over a mean follow-up of 33.9 ± 11.9 months, 116 falls occurred. Higher levels of prefrontal cortical activation during the dual-task walking condition predicted falls (hazard ratio adjusted for age, sex, education, medical illnesses and general mental status 1.32, 95% confidence interval 1.03–1.70). Neither behavioral outcomes (velocity or letter rate) on the dual task nor brain activation patterns on the single tasks (normal walk or talk alone) predicted falls in this high-functioning sample. The results remained robust after accounting for multiple confounders and for cognitive status, slow gait, previous falls, and frailty.

Conclusions:

Prefrontal brain activity levels while performing a cognitively demanding walking condition predicted falls in high-functioning seniors. These findings implicate neurobiological processes early in the pathogenesis of falls.




Dementia risk in renal dysfunction: A systematic review and meta-analysis of prospective studies

2017-01-09T12:45:32-08:00

Objective:

Renal dysfunction has been linked with increased risk for cognitive impairment and dementia, but studies are conflicting. For that reason, the aim of the present systematic review and meta-analysis is to summarize the best available evidence on the prospective association between potential markers of renal dysfunction and development of cognitive impairment or dementia.

Methods:

Medline, Embase, and Cochrane Database of Systematic Reviews were searched for potential publications until August 1, 2016. Studies were eligible if they fulfilled the following criteria: population-based study, prospective design, ≥100 participants, aged ≥45 years, ≥1 year follow-up, and cognition/dementia outcomes. Where appropriate, random effects meta-analyses were conducted yielding pooled odds ratios (OR) and 95% confidence intervals (CI).

Results:

Twenty-two out of 8,494 abstracts fulfilled the eligibility criteria. Sufficient evidence was found for albuminuria, mixed results for estimated glomerular filtration rate (eGFR), insufficient support for cystatin C, and tentative evidence for serum creatinine and creatinine clearance. Meta-analyses of 5 studies representing 27,805 persons showed a 35% increased risk of cognitive impairment or dementia in those with albuminuria (OR 1.35, 95% CI 1.06–1.73, p = 0.015), whereas eGFR <60 mL/min/1.73 m2 showed no significant association (OR 1.28, 95% CI 0.99–1.65, p = 0.063). No meta-analyses could be done for serum creatinine, creatinine clearance, or cystatin C.

Conclusions:

The overall evidence for an association between renal dysfunction and cognitive impairment or dementia is modest. Evidence suggests that albuminuria is associated with higher odds of developing cognitive impairment or dementia.




Abnormal neurovascular coupling during status epilepticus migrainosus in Sturge-Weber syndrome

2017-01-09T12:45:32-08:00

Sturge-Weber syndrome is a rare, sporadic, neurocutaneous disorder classically characterized by a facial nevus in the trigeminal distribution (port wine stain), leptomeningeal angiomatosis, and glaucoma, although intracranial changes can be present without cutaneous involvement.1 Seizures occur in up to 75% of individuals, are often associated with headache, and stroke-like episodes causing prolonged neurologic deficits are also described.1,2




Ten-year results of pallidal stimulation for cricopharyngeal dystonia with spasmodic dysphonia

2017-01-09T12:45:32-08:00

Sturge-Weber syndrome is a rare, sporadic, neurocutaneous disorder classically characterized by a facial nevus in the trigeminal distribution (port wine stain), leptomeningeal angiomatosis, and glaucoma, although intracranial changes can be present without cutaneous involvement.1 Seizures occur in up to 75% of individuals, are often associated with headache, and stroke-like episodes causing prolonged neurologic deficits are also described.1,2




A woman from Kenosha

2017-01-09T12:45:32-08:00

My new patient was a charming heavyset woman whose eyelids drooped and cheeks sagged like a bed of flowers after a prolonged spring rain. Despite her expression of exhaustion and sadness, her words were full of hope and optimism.




Imaging stent-thrombus interaction in mechanical thrombectomy

2017-01-09T12:45:32-08:00

A 52-year-old man had a right M1 occlusion, treated with mechanical intra-arterial therapy. After 5 minutes of intra-arterial embedding, the stentriever containing thrombus was retrieved, rinsed, and fixed for microscopy. MicroCT scanning electron and light microscopy was performed on the stentriever to assess stent–thrombus interaction (figure). Twenty-three sites of interaction between thrombus and stentriever were analyzed. Interaction was not mechanical at 12 of these sites. We observed fibrin cross-bridges connecting thrombus to stent wires. Fibrin also created smooth covers overlying erythrocyte-rich areas. Light microscopy further showed thrombus interspersed with leukocytes, consisting of fibrin- and platelet-rich areas coalescing around the stent wire.




Drawing analysis in the assessment of patients with neurodegenerative diseases

2017-01-09T12:45:32-08:00

A drawing may elucidate a cognitive profile in neurodegenerative conditions, as illustrated here. A 64-year-old woman with early-onset Alzheimer disease exhibited impaired visual perception (poor copying), which contrasted with good access to acquired constructional representations or motor routines (well-constructed spontaneous drawings) (figure 1).




Editors' Note

2017-01-09T12:45:32-08:00

Editors' Note: In WriteClick this week, Drs. Fuchs and Strasser propose altered tryptophan metabolism as a possible link between sleep disturbances and the increased risk of stroke seen in "Role of sleep-disordered breathing and sleep-wake disturbances for stroke and stroke recovery."




Letter Re: Role Of Sleep-Disordered Breathing And Sleep-Wake Disturbances For Stroke And Stroke Recovery

2017-01-09T12:45:32-08:00

Drs. Hermann and Bassetti discussed an association between increased risk of stroke and sleep disturbances.1 No clue was provided as to how these aspects could be linked. Accelerated tryptophan breakdown induced by an activated immune system and disturbed tryptophan and serotonin (5-hydroxytryptophan) metabolism might serve as reasonable explanation.




Author Response: Role Of Sleep-Disordered Breathing And Sleep-Wake Disturbances For Stroke And Stroke Recovery

2017-01-09T12:45:32-08:00

Drs. Fuchs and Strasser raise the question of how the increased stroke incidence and disturbed stroke recovery that are observed both in patients with sleep-disordered breathing and sleep-wake disturbances are mediated. Increased stroke incidence may be due to excessive sympathetic activation that results in arterial hypertension, inflammation, and atherosclerosis.1 Conversely, disturbed stroke recovery and neuroplasticity might indeed result from disturbed tryptophan metabolism, as proposed by Drs. Fuchs and Strasser. Reduced formation of serotonin from tryptophan is well-known from inflammation-associated depression, where serotonin decreased due to excessive synthesis of the tryptophan metabolite kynurenine.2 Analogies to depression are compelling, since depression is frequent both in disturbed sleep and stroke recovery. Alternative mechanisms of impaired stroke recovery and neuroplasticity are direct effects of inflammatory cytokines, hypothalamo-pituitary abnormalities (i.e., melanin-concentrating hormone, orexin/hypocretin, adrenocorticotropic hormone, or cortisol elevations), and glutamatergic NMDA overactivation induced by quinolinic acid, a kynurenine metabolite.2,3 In rat models, melanin-concentrating hormone and orexin/hypocretin are excessively induced following sleep deprivation that disturbs stroke recovery and brain plasticity.3,4 In mice, stroke recovery and neuroplasticity can be amplified by sodium oxybate, which promotes slow-wave sleep.5 Further in-depth scrutiny of factors mediating disturbed stroke recovery and poor stroke outcome might reveal new targets for therapy.




Letter Re: Retraction: Risedronate Therapy For Prevention Of Hip Fracture After Stroke In Elderly Women; Risedronate Therapy For Prevention Of Hip Fracture After Stroke In Elderly Women: Reply From The Authors

2017-01-09T12:45:32-08:00

I read with interest the retraction of 3 publications by Sato et al. in the July 12, 2016, issue of Neurology®.1–3 I was astonished to read a sentence by the retracting author, "that none of the coauthors participated in any misconduct and appeared as authors on an honorary basis only."1–3 Without an editorial comment about this sentence, an impression is created that appearing "as authors on an honorary basis only" is regarded as acceptable. Maybe the editors thought that this is already clear enough and self-evident for the reader. Unfortunately, honorary authorships are still part of current practice in many academic and nonacademic settings and there are limited options for an editor to avoid that. This situation with Dr. Sato provides a highly didactic example that coauthorship is also coresponsibility for the integrity of the data. Ultimately a lost opportunity to reinforce author guidelines?




Editor Response: Retraction: Risedronate Therapy For Prevention Of Hip Fracture After Stroke In Elderly Women; Risedronate Therapy For Prevention Of Hip Fracture After Stroke In Elderly Women: Reply From The Authors

2017-01-09T12:45:32-08:00

Dr. Kappos raises an important point in his comment on the retraction of 3 publications by Sato et al.1–3 Current Neurology® authorship criteria are outlined in our Information for Authors and were discussed in part in an editorial for BMJ.4 They are designed to prevent guest or ghost authorship and require each author to sign forms describing his or her contributions to the study or the manuscript. At the time the articles by Sato et al. were published, the corresponding author was trusted to provide the author list according to the International Committee of Medical Journal Editors criteria, but coauthor forms were obtained and retained by the corresponding author. Thus, it was difficult for journal staff to identify honorary authors.




Spotlight on the January 3 Issue

2016-12-26T12:45:35-08:00




Child Neurology: Sjögren-Larsson syndrome

2016-12-26T12:45:36-08:00

Sjögren-Larsson syndrome (SLS), an autosomal recessive disorder of lipid metabolism, was first described in Vasterbotten County, Sweden.1 The worldwide prevalence is not known, but in Sweden, the estimated prevalence is only 0.4 per 100,000 population.1 Deficiency of fatty acid aldehyde dehydrogenase (FALDH) causes an accumulation of fatty alcohols and fatty aldehydes, leading to altered cell-membrane integrity and an increase in biologically active lipids, and primarily affects skin, eyes, and the CNS.2 The clinical triad consists of congenital ichthyosis, spastic diplegia, and intellectual disability.2 Focused research has unraveled biochemical pathways and genetic abnormalities underlying the pathogenesis of this disorder, paving the way for novel treatment strategies.2 We describe an infant with genetically established SLS and discuss clinical, radiologic, genetic, and biochemical features of this rare disorder.




Message from the Editors to our Reviewers

2016-12-26T12:45:35-08:00

Between April 1, 2016, and September 30, 2016, Neurology® received 2,565 new and 650 revised manuscripts (compared to 2,366 new and 646 revised manuscripts during this same period in 2015). We received 4,461 peer reviews (compared to 4,645 during the same period in 2015) for these papers. We can accept only a minority of submitted manuscripts and must often make extremely difficult decisions regarding which articles we believe will most benefit readers and improve patient care. Your thoughtful comments regarding uniqueness of study populations, novel methods, studies that are especially educational, or new strategies for diagnosing and treating neurologic disease are highly appreciated. We thank you also for your cooperation in returning reviews in a timely manner.




Journal Club: Pregnancy outcome following maternal exposure to pregabalin may call for concern

2016-12-26T12:45:36-08:00

Owing to its anticonvulsive, analgesic, and anxiolytic properties, pregabalin is used to treat epilepsy, neuropathic pain, and anxiety, respectively. Common side effects include dizziness, lethargy, and drowsiness. Pregabalin is a structural analogue of -aminobutyric acid and modulates calcium influx on presynaptic nerve terminals by binding to a subunit on voltage-gated calcium channels.1




Teaching Video NeuroImages: Minimal anomalies of dorsal midbrain syndrome (Parinaud syndrome)

2016-12-26T12:45:36-08:00

Parinaud syndrome results from posterior commissure dysfunction, and is associated with 4 major signs: limitation of upgaze, pupillary light-near dissociation, convergence abnormalities, and Collier sign.1,2




Teaching Video NeuroImages: Purposeless groaning in progressive supranuclear palsy

2016-12-26T12:45:36-08:00

A patient had recurrent falls and vertical gaze limitation at age 61. Purposeless groaning began 4 years later, when he was still ambulant and conversing appropriately, and increased over time (video at Neurology.org). Groaning has been reported previously in advanced progressive supranuclear palsy, when patients have lost ambulation.1 The behavior is thought to reflect frontal-subcortical dysfunction resulting in disinhibition and perseveration.1,2 Studies of frontal-subcortical dementias suggest that the frontal signs result from a disruption of the extensive connections between the frontal cortex and the basal ganglia and other subcortical structures.2 Proper recognition of this entity is important to avoid unnecessary investigations and treatments.1




Orthostatic hypotension, cognition, and Parkinson disease: Dumbing down by standing up

2016-12-26T12:45:35-08:00

Orthostatic hypotension (OH) is associated with cognitive impairment in otherwise healthy individuals as well as among those with neurodegenerative diseases. There is much current interest in the OH–cognitive impairment connection.1–4 OH and cognitive impairment are both common in Parkinson disease and can lower quality of life. Nonpharmacologic and pharmacologic treatments for OH are readily available, while treatments to modify the course of neurodegenerative cognitive impairment are nil. If the association between OH and cognitive impairment is causal and OH damages the brain, a promising window of therapeutic opportunity suggests itself. Alternately, OH and cognitive impairment are simply markers of a shared pathologic substrate.




A gestational dose of vitamin D per day keeps the MS doctor away

2016-12-26T12:45:35-08:00

Interest in identifying the cause of multiple sclerosis (MS) remains intense. Two nested case-control studies showed that in young, predominantly white adults in whom samples were collected before clinical disease onset, higher serum levels of 25(OH)D were associated with a reduced risk of developing MS.1,2 In the Nurses' Health Study cohorts, higher dietary intake of vitamin D was associated with a lower risk of developing MS among American nurses; supplemental intake of more than 400 IU daily was associated with a 40% reduced risk. A more recent mendelian randomization study, which included 14,498 MS cases and 24,091 healthy controls with European ancestry, showed that alleles related to lower vitamin D levels were associated with increased MS risk.2,3 This study design increases the confidence that the preceding observations reflect a causal association rather than confounding. However, the time period when vitamin D exposure is relevant to reducing MS risk remains uncertain, including whether early-life exposure to vitamin D influences MS risk.2,4




AEDs after ICH: Preventing the prophylaxis

2016-12-26T12:45:35-08:00

Has the routine use of antiepileptic drugs (AEDs) in intracerebral hemorrhage (ICH) become a habit too difficult to break? Adherents to evidence-based medicine must surely have a conniption in light of this continuing practice. The guidelines have remained clear over the years: Do not use antiseizure medications in ICH unless there has been a seizure. Yet prophylactic AED use after acute ICH remains widespread in the United States. This is brought to our attention in the current issue of Neurology®. Naidech et al.1 report on the patterns of AED use in ICH over 5 years across several academic medical centers in Chicago. Placing the study period into its historical context, it was conducted after the publication of the 2010 American Heart Association/American Stroke Association (AHA/ASA) guidelines on the management of ICH, the first to recommend against this practice.2 The authors show a widespread disregard for this expert recommendation. In fact, over the 5-year study period, the use of AEDs almost doubled, and towards the end of the study period, in 2012, 40% of all patients were given AEDs. The study was done in academic centers, commonly believed to uphold the standards of evidence-based management more strictly than others. During this study period, the use of phenytoin fell dramatically, while that of levetiracetam increased. The authors submit, as a possible explanation for the increased use of AEDs, the ease of use of levetiracetam over phenytoin, with fewer drug interactions and adverse events, despite the guideline recommendations.




Effects of orthostatic hypotension on cognition in Parkinson disease

2016-12-26T12:45:35-08:00

Objective:

To investigate the relation between orthostatic hypotension (OH) and posture-mediated cognitive impairment in Parkinson disease (PD) using a cross-sectional and within-group design.

Methods:

Individuals without dementia with idiopathic PD included 18 with OH (PDOH) and 19 without OH; 18 control participants were also included. Neuropsychological tests were conducted in supine and upright-tilted positions. Blood pressure was assessed in each posture.

Results:

The PD groups performed similarly while supine, demonstrating executive dysfunction in sustained attention and response inhibition, and reduced semantic fluency and verbal memory (encoding and retention). Upright posture exacerbated and broadened these deficits in the PDOH group to include phonemic fluency, psychomotor speed, and auditory working memory. When group-specific supine scores were used as baseline anchors, both PD groups showed cognitive changes following tilt, with the PDOH group exhibiting a wider range of deficits in executive function and memory as well as significant changes in visuospatial function.

Conclusions:

Cognitive deficits in PD have been widely reported with assessments performed in the supine position, as seen in both our PD groups. Here we demonstrated that those with PDOH had transient, posture-mediated changes in excess of those found in PD without OH. These observed changes suggest an acute, reversible effect. Understanding the effects of OH due to autonomic failure on cognition is desirable, particularly as neuroimaging and clinical assessments collect data only in the supine or seated positions. Identification of a distinct neuropsychological profile in PD with OH has quality of life implications, and OH presents itself as a possible target for intervention in cognitive disturbance.




Subthalamic nucleus deep brain stimulation in isolated dystonia: A 3-year follow-up study

2016-12-26T12:45:35-08:00

Objective:

To report long-term safety and efficacy outcomes of a large cohort of patients with medically refractory isolated dystonia treated with subthalamic nucleus (STN) deep brain stimulation (DBS).

Methods:

Twenty patients (12 male, 8 female; mean age 49 ± 16.3 years) with medically refractory isolated dystonia were studied (14 were followed for 36 months). The primary endpoints were change in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score at 36 months compared to preoperative baseline. Multiple secondary outcomes were also assessed (ClinicalTrials.gov NCT00773604).

Results:

Eighteen of 20 patients showed improvement 12 months after STN DBS with sustained benefit persisting for 3 years (n = 14). At 36 months, BFMDRS motor scores improved 70.4% from a mean 17.9 ± 8.5 to 5.3 ± 5.6 (p = 0.0002) and total TWSTRS scores improved 66.6% from a mean 41.0 ± 18.9 to 13.7 ± 17.9 (p = 0.0002). Improvement at 36 months was equivalent to that seen at 6 months. Disability and quality of life measures were also improved. Three hardware-related and 24 stimulation-related nonserious adverse events occurred between years 1 and 3 (including 4 patients with dyskinesia).

Conclusions:

This study offers support for long-term tolerability and sustained effectiveness of STN DBS in the treatment of severe forms of isolated dystonia.

Classification of evidence:

This study provides Class IV evidence that STN DBS decreases long-term dystonia severity in patients with medically refractory isolated dystonia.




Normative reference values for strength and flexibility of 1,000 children and adults

2016-12-26T12:45:35-08:00

Objective:

To establish reference values for isometric strength of 12 muscle groups and flexibility of 13 joint movements in 1,000 children and adults and investigate the influence of demographic and anthropometric factors.

Methods:

A standardized reliable protocol of hand-held and fixed dynamometry for isometric strength of ankle, knee, hip, elbow, and shoulder musculature as well as goniometry for flexibility of the ankle, knee, hip, elbow, shoulder, and cervical spine was performed in an observational study investigating 1,000 healthy male and female participants aged 3–101 years. Correlation and multiple regression analyses were performed to identify factors independently associated with strength and flexibility of children, adolescents, adults, and older adults.

Results:

Normative reference values of 25 strength and flexibility measures were generated. Strong linear correlations between age and strength were identified in the first 2 decades of life. Muscle strength significantly decreased with age in older adults. Regression modeling identified increasing height as the most significant predictor of strength in children, higher body mass in adolescents, and male sex in adults and older adults. Joint flexibility gradually decreased with age, with little sex difference. Waist circumference was a significant predictor of variability in joint flexibility in adolescents, adults, and older adults.

Conclusions:

Reference values and associated age- and sex-stratified z scores generated from this study can be used to determine the presence and extent of impairments associated with neuromuscular and other neurologic disorders, monitor disease progression over time in natural history studies, and evaluate the effect of new treatments in clinical trials.




Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study

2016-12-26T12:45:35-08:00

Objective:

As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS.

Methods:

We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1–2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models.

Results:

We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (<20.7 nmol/L) and lowest among those in the top quintile of 25(OH)D (≥48.9 nmol/L), with an OR for top vs bottom of 0.53 (95% confidence interval [CI] 0.36–0.78). In the analysis treating 25(OH)D as a continuous variable, a 25 nmol/L increase in neonatal 25(OH)D resulted in a 30% reduced risk of MS (OR 0.70, 95% CI 0.57–0.84).

Conclusion:

Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health.




Evolving use of seizure medications after intracerebral hemorrhage: A multicenter study

2016-12-26T12:45:35-08:00

Objective:

Prophylactic medications can be a source of preventable harm, potentially affecting large numbers of patients. Few data exist about how clinicians change prescribing practices in response to new data and revisions to guidelines about preventable harm from a prophylactic medication. We sought to determine the changes in prescribing practice of seizure medications for patients with intracerebral hemorrhage (ICH) across a metropolitan area before and after new outcomes data and revised prescribing guidelines were published.

Methods:

We conducted an observational study using electronic medical record data from 4 academic medical centers in a large US metropolitan area.

Results:

A total of 3,422 patients with ICH, diagnosed between 2007 and 2012, were included. In 2009, after a publication found an association of phenytoin with higher odds of dependence or death, the use of phenytoin declined from 9.6% in 2009 to 2.2% in 2012 (p < 0.00001). Conversely, the use of levetiracetam more than doubled, from 15.1% in 2007 to 35% in 2012 (p < 0.00001). Use of levetiracetam varied among the 4 institutions from 6.7% to 29.8% (p < 0.00001).

Conclusions:

New data that led to revised prescribing guidelines for prophylactic seizure medications for patients with ICH were temporally associated with a significant decrease in use of the medication, potentially reducing adverse outcomes. However, a corresponding increase in the use of an alternative medication, levetiracetam, occurred despite limited knowledge about its potential effects on outcomes. Future guideline changes should anticipate and address alternatives.




Risk of fractures after stroke: Results from the Ontario Stroke Registry

2016-12-26T12:45:35-08:00

Objective:

To determine the risk of fractures after stroke.

Methods:

Using the Ontario Stroke Registry, we identified a population-based sample of consecutive patients seen in the emergency department or hospitalized with stroke (n = 23,751) or TIA (n = 11,240) at any of 11 stroke centers in Ontario, Canada, and discharged alive between July 1, 2003, and March 31, 2012. We compared the risk of low-trauma fractures in patients with stroke vs those with TIA using propensity score methods to adjust for differences in baseline factors. Secondary analyses compared fracture risk poststroke with that in age-/sex-matched controls without stroke or TIA (n = 23,751) identified from the Ontario Registered Persons Database.

Results:

The 2-year rate of fracture was 5.7% in those with stroke compared to 4.8% in those with TIA (adjusted cause-specific hazard ratio [aHR] for those with stroke vs TIA 1.32; 95% confidence interval [CI] 1.19–1.46) and 4.1% in age-/sex-matched controls (aHR for those with stroke vs controls 1.47; 95% CI 1.35–1.60). In the cohort with stroke, factors associated with fractures were older age, female sex, moderate stroke severity, prior fractures or falls, and preexisting osteoporosis, rheumatoid arthritis, hyperparathyroidism, and atrial fibrillation.

Conclusions:

Stroke is associated with an increased risk of low-trauma fractures. Individuals with stroke and additional risk factors for fractures may benefit from targeted screening for low bone mineral density and initiation of treatment for fracture prevention.




Carotid artery web and ischemic stroke: A case-control study

2016-12-26T12:45:35-08:00

Objective:

To determine whether there is an association between carotid artery web and ischemic stroke.

Methods:

This was a single-center, age- and sex-matched, case-control study. Cases were consecutive patients with anterior circulation ischemic stroke of undetermined etiology (Trial of Org 10172 in Acute Stroke Treatment [TOAST] classification). Controls were consecutive patients with cerebral aneurysms, arteriovenous malformations, or primary intracerebral hemorrhages. Additional inclusion criteria were age <60 years and CT angiography of the neck. Two neuroradiologists diagnosed webs according to previously published criteria. One neuroradiologist also assessed for nonstenotic atherosclerotic plaque (carotid wall thickness ≥3 mm or intramural calcification). We used conditional logistic regression to estimate the odds ratio between carotid web and ischemic stroke and its 95% confidence interval.

Results:

Fifty-three of 62 cases (85%) were matched by age (within 1 year) and by sex to 102 controls. There was a carotid web in 4 of 53 cases (9.4%) vs 1 of 102 controls (1.0%, odds ratio = 8.0, 95% confidence interval = 1.2–67, p = 0.032). There was no significant difference in the prevalence of nonstenotic carotid atherosclerotic plaque between the case and control groups. There was agreement on diagnosis of web for 163 of 164 patients (99%) and 7 of 8 webs (88%), and the Cohen for interobserver agreement was 0.93.

Conclusions:

There is an association between carotid artery web and ischemic stroke in patients who lack an alternative cause of stroke. Carotid web may be an underappreciated risk factor for stroke.




Sleep-related hypermotor epilepsy: Long-term outcome in a large cohort

2016-12-26T12:45:35-08:00

Objective:

To assess the long-term outcome of sleep-related hypermotor epilepsy (SHE).

Methods:

We retrospectively reconstructed a representative cohort of patients diagnosed with SHE according to international diagnostic criteria, sleep-related seizures ≥75% and follow-up ≥5 years. Terminal remission (TR) was defined as a period of ≥5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimates to calculate the cumulative time-dependent probability of TR and to generate survival curves. Univariate and multivariate Cox regression analyses were performed.

Results:

We included 139 patients with a 16-year median follow-up (2,414 person-years). The mean age at onset was 13 ± 10 years. SHE was sporadic in 86% of cases and familial in 14%; 16% of patients had underlying brain abnormalities. Forty-five percent of patients had at least 1 seizure in wakefulness lifetime and 55% had seizures only in sleep (typical SHE). At the last assessment, 31 patients achieved TR (TR group, 22.3%), while 108 (NTR group, 77.7%) still had seizures or had been in remission for <5 years. The cumulative TR rate was 20.4%, 23.5%, and 28.4% by 10, 20, and 30 years from inclusion. At univariate analysis, any underlying brain disorder (any combination of intellectual disability, perinatal insult, pathologic neurologic examination, and brain structural abnormalities) and seizures in wakefulness were more frequent among the NTR group (p = 0.028; p = 0.043). Absence of any underlying brain disorder (hazard ratio 4.21, 95% confidence interval 1.26–14.05, p = 0.020) and typical SHE (hazard ratio 2.76, 95% confidence interval 1.31–5.85, p = 0.008) were associated with TR.

Conclusions:

Our data show a poor prognosis of SHE after a long-term follow-up. Its outcome is primarily a function of the underlying etiology.




Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians

2016-12-26T12:45:35-08:00

Objective: To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai). Methods: We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)–induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database. Results: We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all less double equals5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 x 10–10; odds ratio 27.90; 95% confidence interval [CI] 7.84–99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077–0.584). Conclusions: Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further. [...]



Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis

2016-12-26T12:45:35-08:00

Objective:

To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors.

Methods:

We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas.

Results:

Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation.

Conclusions:

The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation.




Comorbidity between central disorders of hypersomnolence and immune-based disorders

2016-12-26T12:45:35-08:00

Objective:

To assess and compare the frequencies of personal and family history of autoimmune diseases (AID), autoinflammatory disorders (ID), and allergies in a population of patients, adults and children, with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH), 3 central hypersomnia disorders, and healthy controls.

Methods:

Personal and family history of AID, ID, and allergies were assessed by questionnaire and medical interview in a large cohort of 450 consecutive adult patients (206 NT1, 106 NT2, 138 IH) and 95 pediatric patients (80 NT1) diagnosed according to the third International Classification of Sleep Disorders criteria in national reference centers for narcolepsy in France and 751 controls (700 adults, 51 children) from the general population.

Results:

Ten adults with NT1 (4.9%) had a comorbid AID vs 3.4% of adult controls, without between-group differences in adjusted models. AID frequency did not differ between children with NT1 and controls. Conversely, compared with controls, AID frequency was higher in adults with NT2 (p = 0.002), whereas ID (p = 0.0002) and allergy (p = 0.003) frequencies were higher in adults with IH. A positive family history of AID was found in the NT1 group and of ID in the IH group.

Conclusions:

NT1 is not associated with increased risk of comorbid immune disorders, in favor of a potentially unique pathophysiology. Conversely, compared with controls, the frequency of autoimmune diseases was higher in adults with NT2, whereas allergies and autoinflammatory disorders were more common in adults with IH, suggesting an immune dysregulation mechanism in these conditions.




Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: A retrospective case series

2016-12-26T12:45:36-08:00

Therapeutic improvements are required for primary CNS lymphoma (PCNSL) and secondary CNS lymphoma. PCNSLs are predominantly diffuse large B-cell lymphoma (DLBCL) classified in the non-germinal center (non-GC) subgroup.1 The role of B-cell receptor (BCR) signaling to continuously activate the NF-B pathway is well-established in non-GC DLBCL.2 Mutations of MYD88, CD79B, and TBL1XR1, genes involved in the NF-B pathway, are frequently encountered in PCNSL.3 Ibrutinib, an inhibitor of BCR signaling, led to an objective response rate of 50% in patients with relapsed or refractory systemic non-GC DLBCL.4 As a small molecule (MW = 440), with promising CNS distribution,5 ibrutinib represents a potential treatment for PCNSL. We report a retrospective case series of patients with relapsed and refractory CNS lymphoma treated with ibrutinib.




Enlargement of deep medullary veins during the early clinical course of Sturge-Weber syndrome

2016-12-26T12:45:36-08:00

Therapeutic improvements are required for primary CNS lymphoma (PCNSL) and secondary CNS lymphoma. PCNSLs are predominantly diffuse large B-cell lymphoma (DLBCL) classified in the non-germinal center (non-GC) subgroup.1 The role of B-cell receptor (BCR) signaling to continuously activate the NF-B pathway is well-established in non-GC DLBCL.2 Mutations of MYD88, CD79B, and TBL1XR1, genes involved in the NF-B pathway, are frequently encountered in PCNSL.3 Ibrutinib, an inhibitor of BCR signaling, led to an objective response rate of 50% in patients with relapsed or refractory systemic non-GC DLBCL.4 As a small molecule (MW = 440), with promising CNS distribution,5 ibrutinib represents a potential treatment for PCNSL. We report a retrospective case series of patients with relapsed and refractory CNS lymphoma treated with ibrutinib.




Identification of aberrant white matter bundles entering the inferior cerebellar peduncle

2016-12-26T12:45:36-08:00

During postmortem examination of a 34-year-old man with accidental death and no prior neurologic dysfunction, bilateral aberrant axon bundles were identified in the brainstem (figure 1). These bundles left the pyramidal tract in the medulla, passed caudally around the inferior olive, and entered the inferior cerebellar peduncle. In sections through the pons, these bundles projected towards pontine nuclei. In the medulla, these bundles were distinct from the pyramidal tract (figure 2). This bundle is termed fascicularis circumolivaris pyramidalis1 and appears to be aberrant pontocerebellar axons.2 This extremely rare variation might be mistaken for hypertrophic olivary degeneration or brainstem glioma.




Lingual epilepsia partialis continua in neurocysticercosis

2016-12-26T12:45:36-08:00

A 60-year-old woman presented with focal clonic movements of her face and abnormal movements of her tongue for 5 months. An MRI revealed a ring enhancing lesion, suggestive of a cysticercal granuloma (figure 1). The patient was started on oxcarbazepine, which produced temporary control, with recurrence of jerky movements of her tongue lasting several minutes with frequent recurrence (videos 1 and 2 at Neurology.org). EEG did not show focal abnormalities (figure 2). The episodes were aborted by levetiracetam, 1 g/d, and escalation of oxcarbazepine dose to 900 mg/d. Lingual epilepsia partialis continua occurs in Rasmussen encephalitis and herpes simplex encephalitis, but neurocysticercosis is an unusual cause.1,2




Editors' Note

2016-12-26T12:45:36-08:00

Editors' Note: Commenting on "Autism and epilepsy: A population-based nationwide cohort study," Dr. Sethi expresses the difficulty in determining what comes first, the epilepsy or the autism, in children who have both. Sundelin et al., authors of the study, agree that the association may be due to a shared mechanism.




Letter re: Autism and epilepsy: A population-based nationwide cohort study

2016-12-26T12:45:36-08:00

I read with interest the article by Sundelin et al.,1 which looked at the risk of autism spectrum disorder (ASD) in individuals with epilepsy and in first-degree relatives. Epilepsy is more common in individuals with ASD and ASD is more common in individuals with childhood-onset epilepsy (and in their siblings and offspring), creating a "chicken or egg" situation: a situation in which it is impossible to say which of the 2 existed first and which caused the other one. The 2 conditions likely share common and yet undetermined genetic pathophysiologic mechanisms. It will be interesting to see the relationship between ASD and epilepsy in other patient population groups, such as India, where epilepsy is common, but not ASD.




Author response: Autism and epilepsy: A population-based nationwide cohort study

2016-12-26T12:45:36-08:00

We thank Dr. Sethi for the interest in our article1 and agree that shared mechanisms, rather than pathophysiologic mechanisms, may be important factors behind our positive association findings between epilepsy and autism that was temporally independent.




Letter re: CSF concentrations of 5-methyltetrahydrofolate in a cohort of young children with autism

2016-12-26T12:45:36-08:00

Shoffner et al.1 reported that "a correlation between CSF 5-MTHF (5-methyltetrahydrofolate) and serum folate was not observed." This finding contrasts previous studies of children where a positive correlation was found.2,3 Further, the previous studies estimated the ratio of CSF to serum folate to be about 3,2,3 which is in contrast to the much lower ratio (approximately 1) found by the authors.1




Author response: CSF concentrations of 5-methyltetrahydrofolate in a cohort of young children with autism

2016-12-26T12:45:36-08:00

On behalf of my coauthors, I thank Dr. Barrett for the comment on our article.1 Dr. Barrett correctly recognizes that one of the central aspects of our study was to investigate whether a relationship of CSF 5-MTHF levels to symptoms in young children with autism exists. As addressed in the article, a major difficulty in diagnosing cerebral folate deficiency using CSF 5-MTHF levels was the lack of reference intervals from a normal population that would allow defining clinical decision limits.1 To gain insight into the relationship between CSF 5-MTHF levels and clinical decision limits for young children with autism, we assessed CSF 5-MTHF over time and correlated these levels with detailed clinical assessments. The CSF 5-MTHF levels varied significantly and were not associated with any measures of adaptive behavior, cognitive ability, or autism spectrum disorder symptom severity. As discussed in the article, pediatric CSF normative data that consider natural CSF 5-MTHF variability over time are essential to defining reference intervals as well as critical decision limits.1 In our cohort of young children with autism, a critical decision limit for CSF 5-MTHF levels was not identified. Further research in patients with autism is needed before CSF 5-MTHF levels can be used to justify lumbar puncture to diagnose cerebral folate deficiency or treatment of patients with compounds such as folinic acid or 5-MTHF.




Right Brain: Breaking bad news: Communication education for neurology trainees

2016-12-12T12:45:34-08:00

The stories are frighteningly similar—a normal pregnancy taken to term, a perinatal crisis, followed by an emergent cesarean section and infant transport to a tertiary hospital, where therapeutic hypothermia is initiated. I usually meet the family shortly after arrival, at which point I am charged with helping them understand the next steps. Like so many others, I frequently find myself in complex discussions with families about prognostic uncertainty, advanced care planning, and lifelong disability. Navigating these conversations poorly can have devastating consequences. In many conditions I treat, whether or not a child dies does not rest on my ability to learn, understand, or recommend treatment, but instead on the outcome of conversations in which a family considers whether to withdraw or withhold life-sustaining treatment. As a neonatal neurointensivist, these high-stakes conversations are the most critical interventions I perform.




Right Brain: Home is where the heart is

2016-12-12T12:45:34-08:00

Home. Few 4-letter words can be more haunting, and at times, more impossible, to a physician. "I want to go home." These were the words that were on 3-second repeat 3 days before my 66-year-old patient died in the intensive care unit (ICU). Whispering in a rumbling murmur, barely audible, my patient's voice was still fervent in its desire to connect, to inform those in his company of his wish.




Teaching NeuroImages: Intracranial vertebral dissection in a 15-year-old boy with sickle cell disease

2016-12-12T12:45:34-08:00

A 15-year-old boy with sickle cell disease became unresponsive after sudden-onset headache. There was no antecedent trauma. A head CT scan demonstrated subarachnoid hemorrhage at the medulla (figure). Magnetic resonance angiography of the head and neck identified the patient's known bilateral internal carotid artery stenosis (a moyamoya-like arteriopathy associated with stroke in sickle cell disease) and a new right vertebral artery dissection, which was confirmed on conventional angiography (figure). Prior MRI performed as part of routine cerebral monitoring did not reveal any preexisting abnormality of the vertebral artery.




Spotlight on the December 13 Issue

2016-12-12T12:45:34-08:00




Maternal autoimmunity is a risk factor for common neurologic diseases of childhood

2016-12-12T12:45:34-08:00

When a child presents with epilepsy, particularly infantile epilepsy, genetic etiologies are often considered. The discoveries of copy number variants and monogenic epilepsy disorders have changed diagnostic considerations in pediatric epilepsy. Despite diagnostic advancements, many epilepsy patients do not receive an etiologic answer. Environmental factors clearly play a role in seizure expression in children, as best illustrated by cases of fever-provoked seizures. Recent descriptions of pathogenic autoantibodies associated with autoimmune encephalitis have been fundamental in establishing immune-mediated mechanisms as a cause of acquired epilepsy.1 In the ongoing iterations of epilepsy classifications, the International League Against Epilepsy now includes infection and immunity as etiologic causes of seizures in children.2




Cardioembolism as the unsuspected missing link between migraine and ischemic stroke

2016-12-12T12:45:34-08:00

First identified in 1975, the relationship between migraine and stroke has received considerable attention.1 Forty years later, solid evidence indicates that those with migraine have a 1.5-fold to 2.5-fold increased risk of stroke.2–4 However, the strength of this relationship varies based on the subtypes of migraine (with vs without aura) and stroke (hemorrhagic vs ischemic). While the majority of data support an increased risk of ischemic stroke in those with migraine, the association between migraine without aura and ischemic stroke seems weaker and more controversial, possibly due to methodologic heterogeneity across studies.2,3




Anatomo-functional basis of nonmotor symptoms in Parkinson disease

2016-12-12T12:45:34-08:00

Increasingly sophisticated neuroimaging techniques have provided important insights into the anatomo-functional basis of many of the nonmotor symptoms in Parkinson disease (PD), including pain, dementia, anosmia, and mood and sleep disorders. Autonomic dysfunction contributes to many troublesome symptoms in PD, yet the underlying pathophysiology has been less well-characterized. The article by Pyatigorskaya et al.1 provides important data linking cardiac and respiratory autonomic dysfunction to diffusion tensor MRI abnormalities within the medulla oblongata.




Does neuroinflammation sustain neurodegeneration in ALS?

2016-12-12T12:45:34-08:00

Amyotrophic lateral sclerosis (ALS), the most prevalent type of motor neuron disease in adults, affecting 4–6 per 100,000, is a fatal neurodegenerative disease. ALS is characterized by the degeneration of both upper motor neurons comprising the corticospinal tract and lower motor neurons arising from the brainstem nuclei and ventral roots of the spinal cord. The only drug approved for ALS—riluzole—provides a modest survival benefit. An improved understanding of the pathophysiology of ALS has potential for the development of more effective therapeutic interventions.




Parental rheumatoid arthritis and childhood epilepsy: A nationwide cohort study

2016-12-12T12:45:34-08:00

Objective: To assess the influence of parental rheumatoid arthritis (RA) on risk of epilepsy. Methods: We performed a nationwide cohort study including all singletons born in Denmark from 1977 to 2008 (n = 1,917,723) through individual linkage to nationwide Danish registries. The children were followed for an average of 16 years. Main outcome measures were adjusted hazard ratios (HRs) for epilepsy with onset in early childhood (29 days–4 years), late childhood (5–15 years), adolescence/adulthood (≥15 years), and at any age until the end of follow-up (December 31, 2010). Results: Compared to unexposed children, children exposed to maternal RA had an increased risk of early and late childhood epilepsy (adjusted HRs 1.34 [95% confidence interval (CI) 1.13–1.60] and 1.26 [95% CI 1.13–1.41]), while children exposed to maternal RA had no increased risk of epilepsy in adolescence/adulthood (HR 1.15 [95% CI 0.92–1.45]). Paternal RA was not associated with an overall risk of epilepsy in the offspring (HR 0.96 [95% CI 0.81–1.15]) or at any age. Children exposed to maternal RA in utero had a more pronounced increased risk of early childhood epilepsy than children exposed to mothers who were diagnosed with RA after childbirth (HR 1.90 [95% CI 1.26–2.86] vs HR 1.26 [95% CI 1.03–1.52], respectively [p = 0.16]). Conclusions: Exposure to maternal RA was associated with an increased risk of childhood epilepsy, while exposure to paternal RA was not, which indicates th[...]



Treatment of neurosarcoidosis: A comparative study of methotrexate and mycophenolate mofetil

2016-12-12T12:45:34-08:00

Objective: To compare the efficacy of methotrexate (MTX) and mycophenolate mofetil (MMF) in the prevention of relapses in neurosarcoidosis. Methods: We conducted a retrospective multicenter study including patients who received MTX or MMF for the treatment of histologically proven neurosarcoidosis. The efficacy of the immunosuppressive drug was assessed by determining the time to relapse. Results: Forty patients with a diagnosis of neurosarcoidosis (24 men, 16 women, median age at diagnosis 43.5 years) who received at least 3 months of MTX (n = 32) or MMF (n = 14) were included. The immunosuppressive drug was always associated with steroids. The rate of relapse was 47% in the MTX group (0.2 relapses per year of exposure) and 79% in the MMF group (0.6 relapses per year of exposure) (p = 0.058). The median time to relapse was significantly shorter in the MMF group (11 months) compared with the MTX group (28 months) (p = 0.049). Adverse events occurred in 11 patients during MTX therapy and in 1 patient during MMF therapy (p = 0.12). Conclusions: Relapses of neurosarcoidosis occur frequently, despite the use of an immunosuppressive drug in addition to corticosteroids. MTX significantly increases the survival time without relapse compared to MMF and should be preferred over MMF for the treatment of neurosarcoidosis. This study provides Class IV evidence that for patients with neurosarcoidosis taking steroids, MTX is superior to MMF in reducing the risk of relapse. [...]



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

2016-12-12T12:45:34-08:00

Objective: To determine the safety of domperidone in the treatment of nausea associated with dihydroergotamine (DHE) infusion and headache. Methods: We audited our use of domperidone for the inpatient management of nausea, focusing on known safety concerns, particularly potential cardiac arrhythmias. Results: We reviewed 103 consecutive admissions of 90 patients admitted for IV DHE by infusion. Most admissions were to treat chronic migraine with (n = 53) or without (n = 46) aura. Domperidone was administered in 85 of 103 encounters and was well-tolerated at doses up to 80 mg/d. A significant side effect, akathisia, was observed in one patient. Baseline ECG with corrected QT interval (QTc) was obtained on all patients. Repeat ECG after domperidone was obtained in 21 patients, whose baseline characteristics did not differ from the group as a whole. ECG was interpreted blindly by a cardiac electrophysiologist. QTc did not differ before and after domperidone administration (Wilcoxon signed-rank test, median [interquartile range] 435.0 [410.5–453.0] at admission and 427.0 [399.0–452.5] after domperidone; p = 0.15). In combination with other antiemetics, domperidone was effective in treating nausea such that no patients had refractory nausea severe enough to limit DHE dose. Conclusions: This retrospective audit demonstrates that domperidone is safe in the treatment of nausea associated with inpatient DHE infusion and headache. While larger [...]



Ischemic stroke subtypes and migraine with visual aura in the ARIC study

2016-12-12T12:45:34-08:00

Objective: To investigate the association among migraine, ischemic stroke, and stroke subtypes in the Atherosclerosis Risk in Communities (ARIC) study. Methods: In this ongoing, prospective, longitudinal community-based cohort study, participants were given an interview ascertaining migraine history in 1993–1995, and were followed for all vascular events, including stroke. All stroke events over the subsequent 20 years were adjudicated and classified into stroke subtypes by standard definitions. Cox proportional hazards models adjusted for stroke risk factors were used to study the relationship between migraine and ischemic stroke, overall, as well as stroke subtypes (cardioembolic, lacunar, or thrombotic). Results: We identified 1,622 migraineurs among 12,758 participants. Mean age of the study population at the 3rd clinical visit was 59 years. When compared to nonheadache participants, there was a significant association between migraine with visual aura and ischemic stroke (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2–2.6, p = 0.008). Migraine without visual aura was not significantly associated with ischemic stroke (HR 1.2, CI 1.0–1.8, p = 0.28) when compared to nonheadache participants. Among the 3 subtypes of ischemic stroke evaluated, migraine with visual aura was significantly associated only with cardioembolic stroke (HR 3.7, 95% CI 1.6–8.7, p = 0.003). Conclusion: In particip[...]



N-terminal pro-brain natriuretic peptide and subclinical brain small vessel disease

2016-12-12T12:45:34-08:00

Objective: To study the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with several brain MRI markers of brain vascular disease in a sample of participants free of stroke and dementia. Methods: NT-proBNP plasma level was determined by means of a sandwich immunoassay method in a cohort study comprising 278 hypertensive patients. The presence of silent brain infarcts, brain microbleeds, enlarged perivascular spaces, and white matter hyperintensity volumes was assessed by brain MRI. We performed univariate and multivariate analyses to determine whether NT-proBNP was independently associated with these imaging markers, individually or combined. Results: Median age was 63 years, and 41.4% were women. NT-proBNP remained independently associated with silent brain infarcts (odds ratio [OR] per 1-SD increase in NT-proBNP 2.11, 95% confidence interval [CI] 1.44–3.10), brain microbleeds (OR 1.79, 95% CI 1.15–2.78), basal ganglia enlarged perivascular spaces (OR 1.55, 95% CI 1.12–2.15), and white matter hyperintensity volumes (β 1.60, 95% CI 0.47–2.74), even after controlling for vascular risk factors, cardiovascular risk, atrial fibrillation, previous heart disease, duration of hypertension, and preventive treatments. A score combining several imaging markers was also related to NT-proBNP levels (common OR per 1-SD increase 1.74, 95% CI 1.21–2.50). [...]



Medulla oblongata damage and cardiac autonomic dysfunction in Parkinson disease

2016-12-12T12:45:34-08:00

Objective: To characterize medulla oblongata damage using diffusion tensor imaging (DTI) in Parkinson disease (PD) and correlate it with dysfunction of the cardiac sympathetic/vagal balance. Methods: Fifty-two patients with PD and 24 healthy controls were included in the study. All participants underwent clinical examination and 3T MRI using 3D T1-weighted imaging and DTI. DTI metrics were calculated within manually drawn regions of interest. Heart rate variability was evaluated using spectral analysis of the R–R cardiac interval during REM and slow-wave sleep based on continuous overnight electrocardiographic monitoring. Respiratory frequency was measured in 30-second contiguous epochs of REM and slow-wave sleep. The relationships between imaging and cardiac variables were calculated using partial correlations followed by the multiple comparisons permutation approach. Results: The changes in heart rate and respiratory frequency variability from slow-wave sleep to REM sleep in healthy controls were no longer detectable in patients with PD. There were significant increases in the mean (p = 0.006), axial (p = 0.006), and radial diffusivities (p = 0.005) in the medulla oblongata of patients with PD. In PD, diffusion changes were specifically correlated with a lower heart rate and respiratory frequency variability during REM sleep. Conclusions: This study provides[...]