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Response to pain

2017-08-21T12:49:05-07:00

She is lying there behind a glass wall

too covered in white: air too white,

people too white crowded around her

funeral chorus of ridiculous moves:

her arm is raised and left to fall

her eyes are opened and left to close

her blood is food to a machine

that turns it white, its sins forgiven.

White coats, birds of prey!

where have you taken her?

my faith in you has vanished like a hunted animal

you seek to give your prisoner the gift of pain

so she would rise in screams above

the whiteness of that stiffening bed. In vain!

you absurd creatures!

what can you hope to save in violence?

A soul? not possible. The body alone? not possible.

What is the body alone but the cadaver

of both body and soul? The stench of violence

defeats the victor. You stand before life and death helpless

just as before me now, behind that glass wall,

mere animals at the zoo, locked away in unspeakable questions

transparent shadows walled up between us

and no one hears your screams...




Clinical Reasoning: A 57-year-old man with unilateral anosmia, papilledema, and meningismus

2017-08-21T12:49:05-07:00

A 57-year-old previously healthy man was referred to our clinic for bilateral vision loss.




Teaching NeuroImages: Extensive cortical involvement in Creutzfeldt-Jakob disease

2017-08-21T12:49:05-07:00

A 53-year-old alcoholic man presented with a 2-day history of worsening confusion. Initial examination showed appendicular hypertonia with multifocal arrhythmic asynchronous myoclonic jerks suggestive of cortical myoclonus occurring spontaneously intermittently and stimulus sensitive, with exaggerated deep tendon reflexes and extensor plantars. MRI brain demonstrated low-grade restricted diffusion affecting the entire cerebral cortex (figure 1), sparing the subcortical gray matter and cerebellum.1 T1-weighted imaging and fluid-attenuated inversion recovery sequences showed mild cerebral atrophy. 14-3-3 protein testing was positive and generalized slowing was demonstrated on EEG.2 Changes consistent with Creutzfeldt-Jakob disease (CJD) were found on histopathology (figure 2). The patient had no risk factors for familial, new variant, or iatrogenic CJD. Sporadic CJD was the final diagnosis.




Teaching NeuroImages: Huge carotid artery aneurysm in TSC2/PKD1 contiguous gene syndrome

2017-08-21T12:49:05-07:00

A 1-day-old infant developed heart murmur with tachypnea. Echocardiography showed multiple biventricular cardiac rhabdomyomas (figure, A). Brain sonography showed multiple cerebral cortical tubers (figure, B) and subependymal nodules (figure, D and E), confirming tuberous sclerosis. Bilateral renal cysts were present (figure, C).




Teaching Video NeuroImages: Nine syndrome in inferior paramedian pontine infarction: More than meets the eye

2017-08-21T12:49:05-07:00

A 54-year-old man with a medical history notable for diabetes mellitus and coronary artery bypass surgery presented to the emergency department with acute-onset vertigo, diplopia, hemiparesis, and hemihypesthesia of his left arm and leg. On cranial nerve examination, he displayed a conjugate right horizontal gaze palsy, diminished right eye adduction, horizontal left-beating nystagmus on leftward gaze, paralytic pontine exotropia of the left eye, gaze-evoked vertical nystagmus, and peripheral right facial palsy (figure 1; video at Neurology.org). These features were consistent with an ischemic pontine lesion affecting the right (1) paramedian pontine reticular formation and medial longitudinal fasciculus (one-and-a-half syndrome), (2) facial nerve fascicle (seventh cranial nerve palsy), (3) corticospinal tract, and (4) medial lemniscus pathway (the latter 2 comprising the final "half syndrome") (figure 2), thereby constituting the so-called nine syndrome.1




Teaching Video NeuroImages: Missing toe: The relevance of the Brissaud reflex

2017-08-21T12:49:05-07:00

A 70-year-old man who was admitted to neurointensive care with spastic tetraparesis and altered level of consciousness due to acute subdural hematoma and who had a history of left forefoot amputation presented right Babinski sign and left Brissaud reflex (video at Neurology.org). The Brissaud reflex is characterized by a contraction of the tensor fasciae latae due to stimulus over the plantar aspect of the foot, which is better visualized on the lateral aspect of the thigh.1,2 This is a useful neurologic sign in patients with suspected upper motor neuron disease and absent hallux. It was named after Édouard Brissaud, a pupil of Charcot, who described the reflex in 1896 a few days after Babinski’s famous lecture.




2017 Emerging Science Abstracts

2017-08-21T12:49:05-07:00

The Science Committee is committed to presenting the best neuroscientific research at the Annual Meeting and is pleased to share the following Emerging Science abstracts, which qualified by having key aspects of research conducted after the October 24, 2016, abstract submission deadline. They are new and of sufficient scientific importance to warrant expedited presentation and publication.




Spotlight on the August 22 issue

2017-08-21T12:49:04-07:00




Epileptic encephalopathy, movement disorder, and the yin and yang of GNAO1 function

2017-08-21T12:49:04-07:00

GNAO1 encephalopathy comprises a spectrum of neurologic phenotypes that result from de novo heterozygous mutations in GNAO1, a gene coding for the subunit of a G protein that is highly expressed in the CNS and is involved in second messenger signaling. De novo heterozygous mutations in the gene were first described in patients with a severe, infantile-onset epileptic encephalopathy known as Ohtahara syndrome.1 However, patients with a predominant motor disorder, characterized by infantile hypotonia developing into severe chorea and dystonia, have also been identified.2,3 While it is not unusual for novel neurogenetic disorders to have some degree of phenotypic range, the discrepancy between these 2 phenotypes in patients with GNAO1 encephalopathy is striking. What may account for this phenotypic variability?




Recurrent ictal asystole: Are we doing enough to prevent and treat it?

2017-08-21T12:49:04-07:00

Mortality rates are considerably higher in people with epilepsy.1,2 Sudden unexpected death in epilepsy (SUDEP) is the most frightening consequence of uncontrolled epileptic seizures.3 The underlying pathophysiology of SUDEP is unclear; however, the best-documented mechanism is the effect of seizures on the heart, either directly or secondary to apnea.3 Since increased frequency of generalized tonic-clonic seizures is the most important risk factor for SUDEP, the current strategy to prevent SUDEP is to achieve seizure control.4 Although cardiac rhythm abnormalities occur in people with epilepsy, they are underrecognized and often missed,1 because a small proportion of patients have video-EEG monitoring, and even then, the simultaneous ECG recording is not being evaluated with enough detail. Studies with long-term implantable heart rhythm monitors (implantable loop recorder) in epilepsy patients suggest that the frequency of cardiac rhythm abnormalities might be higher than usually reported.5 Implantable ECG loop recorder in a group of 16 patients showed that 4 of them (21%) had bradycardia or periods of asystole; 3 of these had potentially fatal ictal asystole (IA), lasting up to 14 seconds, and underwent permanent pacemaker placement.5




DNA methylation predicts stroke outcome better: The epigenetic clock is ticking

2017-08-21T12:49:04-07:00

As a leading cause of disability worldwide, stroke renders people disabled through several mechanisms. Over half of patients have sensorimotor and cognitive deficits, one-third experience depression and social disability, and half never return to work. Our ability to predict recurrent stroke and disability poststroke remains poor despite modern medical advances.1 The uncertainty surrounding the recovery process creates critical knowledge gaps for clinicians deciding on the most appropriate care plan, and leads to substantial anxiety for patients and their families. Identification of factors that affect prognosis after stroke will not only help clinicians make more comprehensive care plans but also help engage the patient and family early in the recovery process. Recanalization rate and time to recanalization have recently joined age and stroke severity as major predictors of outcome after ischemic strokes.1 Although other factors such as ischemic stroke mechanism and comorbidities also play a role, their value in predicting recovery is not as clear.




Caroline M. Klein, MD, PhD (1960-2017)

2017-08-21T12:49:04-07:00

Caroline Marie Klein, MD, PhD, of Chapel Hill, North Carolina, died on April 27, 2017, at age 56, following a courageous 6-year battle with cancer. Dr. Klein was a noted expert in disorders of the autonomic nervous system and of the peripheral nervous system.




Movement disorder in GNAO1 encephalopathy associated with gain-of-function mutations

2017-08-21T12:49:04-07:00

Objective:

To define molecular mechanisms underlying the clinical spectrum of epilepsy and movement disorder in individuals with de novo mutations in the GNAO1 gene.

Methods:

We identified all GNAO1 mutations reported in individuals with epilepsy (early infantile epileptiform encephalopathy 17) or movement disorders through April 2016; 15 de novo mutant alleles from 25 individuals were introduced into the Gαo subunit by site-directed mutagenesis in a mammalian expression plasmid. We assessed protein expression and function in vitro in HEK-293T cells by Western blot and determined functional Gαo-dependent cyclic adenosine monophosphate (cAMP) inhibition with a coexpressed α2A adrenergic receptor.

Results:

Of the 15 clinical GNAO1 mutations studied, 9 show reduced expression and loss of function (LOF; <90% maximal inhibition). Six other mutations show variable levels of expression but exhibit normal or even gain-of-function (GOF) behavior, as demonstrated by significantly lower EC50 values for α2A adrenergic receptor–mediated inhibition of cAMP. The GNAO1 LOF mutations are associated with epileptic encephalopathy while GOF mutants (such as G42R, G203R, and E246K) or normally functioning mutants (R209) were found in patients with movement disorders with or without seizures.

Conclusions:

Both LOF and GOF mutations in Gαo (encoded by GNAO1) are associated with neurologic pathophysiology. There appears to be a strong predictive correlation between the in vitro biochemical phenotype and the clinical pattern of epilepsy vs movement disorder.




MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes

2017-08-21T12:49:04-07:00

Objective:

To report the 6-month single-blinded results of unilateral thalamotomy with MRI-guided focused ultrasound (MRgFUS) in patients with tremors other than essential tremor.

Methods:

Three patients with tremor due to Parkinson disease, 2 with dystonic tremor in the context of cervicobrachial dystonia and writer's cramp, and 1 with dystonia gene–associated tremor underwent MRgFUS targeting the ventro-intermedius nucleus (Vim) of the dominant hemisphere. The primary endpoint was the reduction of lateralized items of the Tremor Rating Scale of contralateral hemibody assessed by a blinded rater.

Results:

All patients achieved a statistically significant, immediate, and sustained improvement of the contralateral tremor score by 42.2%, 52.0%, 55.9%, and 52.9% at 1 week and 1, 3, and 6 months after the procedure, respectively. All patients experienced transient side effects and 2 patients experienced persistent side effects at the time of last evaluation: hemitongue numbness and hemiparesis with hemihypoesthesia.

Conclusions:

Vim MRgFUS is a promising, incision-free, but nevertheless invasive technique to effectively treat tremors other than essential tremor. Future studies on larger samples and longer follow-up will further define its effectiveness and safety.

Clinicaltrials.gov identifier:

NCT02252380.

Classification of evidence:

This study provides Class IV evidence that for patients with tremor not caused by essential tremor, MRgFUS of the Vim improves the tremor of the contralateral hemibody at 6 months.




Loss of cutaneous large and small fibers in naive and L-dopa-treated PD patients

2017-08-21T12:49:04-07:00

Objective:

To study small and large fiber pathology in drug-naive and l-dopa–treated patients affected by Parkinson disease (PD) in early phases, before the occurrence of neuropathic electrophysiologic abnormalities.

Methods:

We enrolled 85 patients with idiopathic PD (male/female 49/36, age 61.3 ± 9.7 years) without electrophysiologic signs of neuropathy, including 48 participants naive to l-dopa treatment. All patients underwent clinical, functional, and morphologic assessment of sensory and autonomic nerves through dedicated questionnaires, quantitative sensory testing, sympathetic skin response, dynamic sweat test, and punch biopsies from glabrous and hairy skin. Sensory and autonomic innervation was visualized with specific antibodies and analyzed by confocal microscopy. Data were compared with those obtained from sex- and age-comparable healthy controls. In 35 patients, skin biopsies were performed bilaterally to evaluate side-to-side differences.

Results:

Intraepidermal nerve fiber density was lower in patients compared to controls in all the examined sites (p < 0.001). The loss was higher in the more affected side (p < 0.01). A loss of autonomic nerves to vessels, sweat glands, and arrector pili muscles and of Meissner corpuscles and their myelinated endings in glabrous skin was found (p < 0.001). Patients showed increased tactile and thermal thresholds, impairment of mechanical pain perception, and reduced sweat output (p < 0.001). The naive and l-dopa–treated groups differed only for Meissner corpuscle density (p < 0.001).

Conclusions:

Both large and small fiber pathology occurs in the early stages of PD and may account for the sensory and autonomic impairment. l-Dopa affects the 2 populations of fibers differently.




Recurrence risk of ictal asystole in epilepsy

2017-08-21T12:49:04-07:00

Objective:

To determine the recurrence risk of ictal asystole (IA) and its determining factors in people with epilepsy.

Methods:

We performed a systematic review of published cases with IA in 3 databases and additionally searched our local database for patients with multiple seizures simultaneously recorded with ECG and EEG and at least one IA. IA recurrence risk was estimated by including all seizures without knowledge of the chronological order. Various clinical features were assessed by an individual patient data meta-analysis. A random mixed effect logistic regression model was applied to estimate the average recurrence risk of IA. Plausibility of the calculated IA recurrence risk was checked by analyzing the local dataset with available information in chronological order.

Results:

Eighty patients with 182 IA in 537 seizures were included. Recurrence risk of IA amounted to 40% (95% confidence interval [CI] 32%–50%). None of the clinical factors (age, sex, type and duration of epilepsy, hemispheric lateralization, duration of IA per patient) appeared to have a significant effect on the short-term recurrence risk of IA. When considering the local dataset only, IA recurrence risk was estimated to 30% (95% CI 14%–53%). Information whether IA coincided with symptoms (i.e., syncope) or not was given in 60 patients: 100 out of 142 IAs were symptomatic.

Conclusion:

Our data suggest that in case of clinically suspected IA, the recording of 1 or 2 seizures is not sufficient to rule out IA. Furthermore, the high short-term recurrence risk favors aggressive treatment, including pacemaker implantation if seizure freedom cannot be achieved.




Oral fluoroquinolones and risk of secondary pseudotumor cerebri syndrome: Nested case-control study

2017-08-21T12:49:04-07:00

Objective:

To quantify the risk of secondary pseudotumor cerebri syndrome (PTCS) with fluoroquinolones.

Methods:

A case-control study of people 15–60 years of age from the LifeLink Database (QuintilesIMS, Parsippany, NJ) was conducted. Cases had the first ICD-9-CM code for benign intracranial hypertension (BIH) as well as having received a procedure code for an MRI or CT scan and a lumbar puncture within 15 days or 30 days of the BIH code. For each case, 10 controls were selected using density-based sampling. Current users of fluoroquinolones received a prescription within 15 days or 30 days of the date of the diagnosis. For the sensitivity analysis, risk periods for 30 and 60 days were also examined. Adjusted rate ratios (RRs) were computed from a conditional logistic regression model.

Results:

From a cohort of 6,110,723 people, there were 339 cases of PTCS and 3,390 corresponding controls. In the primary analysis, the adjusted RR for current users of fluoroquinolones for both the 15-day and 30-day definitions were 5.67 (95% confidence interval [CI] 2.72–11.83) and 4.15 (95% CI 2.29–7.50), respectively. The risk with tetracycline antibiotics was also increased, with RRs for 15 and 30 days of current use of 2.68 (0.89–8.11) and 3.64 (1.67–7.91), respectively.

Conclusion:

Our study suggests an increase in the risk of PTCS with current users of fluoroquinolones. Although this adverse event is rare, patients who experience symptoms of raised intracranial pressure including headaches, tinnitus, and double vision while taking fluoroquinolones should seek medical attention.




Long-term AIDS-related PCNSL outcomes with HD-MTX and combined antiretroviral therapy

2017-08-21T12:49:04-07:00

Objective:

To assess the characteristics and outcomes of patients with AIDS-related primary CNS lymphoma (AR-PCNSL) in the combined antiretroviral therapy (cART) era systematically treated with high-dose methotrexate (HD-MTX).

Methods:

We retrospectively analyzed (intention-to-treat analysis) 51 consecutive patients with AR-PCNSL (median age 39 years) who were diagnosed from 1996 to 2014 and treated with a median of 6 (range 1–15) infusions of HD-MTX (3 g/m2) combined with cART.

Results:

Median all-patients' and survivors' follow-up lasted 23 (range 0–186) and 76 (range 23–186) months, respectively. At PCNSL diagnosis, 83% of the patients were on cART, median plasma HIV load was 175,600 copies/mL, and median CD4+ T-cell count was 24/μL. Median Eastern Cooperative Oncology Group performance status was 2 (range 1–4). Median overall survival (OS) was 5.7 years, with 5- and 10-year rates of 48% and 41%. Median time to progression was not reached (69% at 10 months). PCNSL was the direct cause of 14 deaths, all observed within the 10 months after its diagnosis: 6 patients died before HD-MTX could be administered, 4 had refractory disease, and 4 relapsed. Multivariate analyses retained time interval between AIDS diagnosis and PCNSL diagnosis, age at AR-PCNSL diagnosis, and deep brain structure involvement as independent OS-predictive factors. To restore effective immune function, cART tailored to HIV genotypes was started and combined with HD-MTX; no interactions and no immune reconstitution inflammatory syndrome occurred. No patient died of acute treatment-related toxicity, and 21 of 51 (41%) patients experienced grade 3/4 toxicity.

Conclusions:

Combined short-term HD-MTX monochemotherapy and optimal cART simply and effectively treat AR-PCNSL, achieving long-term survival with few relapses.

Classification of evidence:

This study provides Class IV evidence that short-term HD-MTX monochemotherapy improves long-term survival of patients with AIDS with primary CNS lymphoma receiving cARTs.




Serum matrix metalloproteinase-9 levels and prognosis of acute ischemic stroke

2017-08-21T12:49:04-07:00

Objective:

To examine the association between serum matrix metalloproteinases-9 (MMP-9) levels and prognosis of acute ischemic stroke.

Methods:

We measured serum MMP-9 levels in 3,186 participants (2,008 men and 1,178 women) from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). Study outcome data on death, major disability (modified Rankin Scale score ≥3), and vascular disease were collected at 3 months after stroke onset.

Results:

During 3 months of follow-up, 767 participants (24.6%) experienced major disability or died. Serum MMP-9 was significantly associated with an increased risk of death and major disability after adjustment for age, sex, time from onset to randomization, current smoking, alcohol drinking, admission NIH Stroke Scale score, diastolic blood pressure, plasma glucose, white blood cell counts, use of antihypertensive medications, and history of hypertension, coronary heart disease, and diabetes mellitus. For example, 1-SD (0.32 ng/mL) higher log–MMP-9 was associated with an odds ratio (95% confidence interval) of 1.16 (1.06–1.28) for the combined outcome of death and major disability, 1.12 (1.01–1.23) for major disability, and 1.29 (1.01–1.66) for death. The addition of serum MMP-9 to conventional risk factors improved risk prediction of the combined outcome of death or major disability (net reclassification index 9.1%, p = 0.033; integrated discrimination improvement 0.4%, p = 0.004).

Conclusions:

Higher serum MMP-9 levels in the acute phase of ischemic stroke were associated with increased risk of mortality and major disability, suggesting that serum MMP-9 could be an important prognostic factor for ischemic stroke.




Magnesium, hemostasis, and outcomes in patients with intracerebral hemorrhage

2017-08-21T12:49:04-07:00

Objective:

We tested the hypothesis that admission serum magnesium levels are associated with hematoma volume, hematoma growth, and functional outcomes in patients with intracerebral hemorrhage (ICH).

Methods:

Patients presenting with spontaneous ICH were enrolled in an observational cohort study that prospectively collected demographic, clinical, laboratory, radiographic, and outcome data. We performed univariate and adjusted multivariate analyses to assess for associations between serum magnesium levels and initial hematoma volume, final hematoma volume, and in-hospital hematoma growth as radiographic measures of hemostasis, and functional outcome measured by the modified Rankin Scale (mRS) at 3 months.

Results:

We included 290 patients for analysis. Admission serum magnesium was 2.0 ± 0.3 mg/dL. Lower admission magnesium levels were associated with larger initial hematoma volumes on univariate (p = 0.02), parsimoniously adjusted (p = 0.002), and fully adjusted models (p = 0.006), as well as greater hematoma growth (p = 0.004, p = 0.005, and p = 0.008, respectively) and larger final hematoma volumes (p = 0.02, p = 0.001, and p = 0.002, respectively). Lower admission magnesium level was associated with worse functional outcomes at 3 months (i.e., higher mRS; odds ratio 0.14, 95% confidence interval 0.03–0.64, p = 0.011) after adjustment for age, admission Glasgow Coma Scale score, initial hematoma volume, time from symptom onset to initial CT, and hematoma growth, with evidence that the effect of magnesium is mediated through hematoma growth.

Conclusions:

These data support the hypothesis that magnesium exerts a clinically meaningful influence on hemostasis in patients with ICH.




Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis

2017-08-21T12:49:04-07:00

Objective:

We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity).

Methods:

This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2–4, 5–10, and >10 CMBs), using random effects models.

Results:

We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2–12.6 vs 1.1%, 95% CI 0.5–1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1–3 years): OR 3.1 (95% CI 1.4–6.8; p = 0.006), 4.3 (95% CI 1.8–10.3; p = 0.001), and 3.4 (95% CI 1.4–8.3; p = 0.007) for 2–4, 5–10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1–15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts.

Conclusions:

CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.




Biological age is better than chronological as predictor of 3-month outcome in ischemic stroke

2017-08-21T12:49:05-07:00

Objective:

To analyze the effect of age-related DNA methylation changes in multiple cytosine-phosphate-guanine (CpG) sites (biological age [b-age]) on patient outcomes at 3 months after an ischemic stroke.

Methods:

We included 511 patients with first-ever acute ischemic stroke assessed at Hospital del Mar (Barcelona, Spain) as the discovery cohort. Demographic and clinical data, including chronological age (c-age), vascular risk factors, initial stroke severity, recanalization treatment, and previous and 3-month modified Rankin Scale (p-mRS and 3-mRS, respectively) were registered. B-age was estimated with an algorithm, based on DNA methylation in 71 CpGs. Bivariate analysis determined variables associated with 3-mRS for inclusion in ordinal multivariate analysis.

Results:

After ordinal regressions for 3-month ischemic stroke outcome (3-mRS), b-age was associated with outcome (odds ratio 1.04 [95% confidence interval 1.01–1.07]), nullifying c-age. Stepwise regression kept b-age, basal NIH Stroke Scale, sex, p-mRS, and recanalization treatment as better explanatory variables, instead of c-age. These results were successfully replicated in an independent cohort.

Conclusions:

B-age, estimated by DNA methylation, is an independent predictor of ischemic stroke outcome regardless of chronological years.




Motor speech signature of behavioral variant frontotemporal dementia: Refining the phenotype

2017-08-21T12:49:05-07:00

Objective:

To provide a comprehensive description of motor speech function in behavioral variant frontotemporal dementia (bvFTD).

Methods:

Forty-eight individuals (24 bvFTD and 24 age- and sex-matched healthy controls) provided speech samples. These varied in complexity and thus cognitive demand. Their language was assessed using the Progressive Aphasia Language Scale and verbal fluency tasks. Speech was analyzed perceptually to describe the nature of deficits and acoustically to quantify differences between patients with bvFTD and healthy controls. Cortical thickness and subcortical volume derived from MRI scans were correlated with speech outcomes in patients with bvFTD.

Results:

Speech of affected individuals was significantly different from that of healthy controls. The speech signature of patients with bvFTD is characterized by a reduced rate (75%) and accuracy (65%) on alternating syllable production tasks, and prosodic deficits including reduced speech rate (45%), prolonged intervals (54%), and use of short phrases (41%). Groups differed on acoustic measures derived from the reading, unprepared monologue, and diadochokinetic tasks but not the days of the week or sustained vowel tasks. Variability of silence length was associated with cortical thickness of the inferior frontal gyrus and insula and speech rate with the precentral gyrus.

Conclusions:

One in 8 patients presented with moderate speech timing deficits with a further two-thirds rated as mild or subclinical. Subtle but measurable deficits in prosody are common in bvFTD and should be considered during disease management. Language function correlated with speech timing measures derived from the unprepared monologue only.




In vivo retention of 18F-AV-1451 in corticobasal syndrome

2017-08-21T12:49:05-07:00

Objective:

To study the usefulness of 18F-AV-1451 PET in patients with corticobasal syndrome (CBS).

Methods:

We recruited 8 patients with CBS, 17 controls, 31 patients with Alzheimer disease (AD), and 11 patients with progressive supranuclear palsy (PSP) from the Swedish BioFINDER study. All patients underwent clinical assessment, 18F-AV-1451 PET, MRI, and quantification of β-amyloid pathology. A subset of participants also underwent 18F-FDG-PET.

Results:

In the 8 patients with CBS, 6 had imaging findings compatible with the corticobasal degeneration pathology and 2 with typical AD pathology. In the 6 patients with CBS without typical AD pathology, there were substantial retentions of 18F-AV-1451 in the motor cortex, corticospinal tract, and basal ganglia contralateral to the most affected body side. These patients could be clearly distinguished from patients with AD dementia or PSP using 18F-AV-1451. However, cortical atrophy was more widespread than the cortical retention of 18F-AV1451 in these CBS cases, and cortical AV-1451 uptake did not correlate with cortical thickness or glucose hypometabolism. These results are in sharp contrast to AD dementia, where 18F-AV-1451 retention was more widespread than cortical atrophy, and correlated well with cortical thickness and hypometabolism.

Conclusions:

Patients with CBS without typical AD pathology exhibited AV-1451 retention in the motor cortex, corticospinal tract, and basal ganglia contralateral to the affected body side, clearly different from controls and patients with AD dementia or PSP. However, cortical atrophy measured with MRI and decreased 18F-fluorodeoxyglucose uptake were more widespread than 18F-AV-1451 uptake and probably represent earlier, yet less specific, markers of CBS.

Classification of evidence:

This study provides Class III evidence that 18F-AV-1451 PET distinguishes between CBS and AD or PSP.




Penfield's ceiling: Seeing brain injury through Galen's eyes

2017-08-21T12:49:05-07:00

The cathedral ceiling located in the entrance hall of the Montreal Neurological Institute, planned by its founder Wilder Penfield, has intrigued visitors since it was erected in 1934. Central to its charm is a cryptic comment by the ancient physician Galen of Pergamum, which refutes a dire Hippocratic aphorism about prognosis in brain injury. Galen's optimism, shared by Penfield, is curious from a fellow ancient. In this article, we use primary sources in Ancient Greek as well as secondary sources to not only examine the origins of Galen's epistemology but also, using a methodology in classics scholarship known as reception studies, illustrate how an awareness of this ancient debate can illuminate contemporary clinical contexts. While Galen based his prognostications on direct clinical observations like the Hippocratics, he also engaged in experimental and anatomic work in both animals and humans, which informed his views on neurologic states and outcomes. Penfield's memorialization of Galen is representative of the evolution of the neurosciences and the ongoing importance of evidence-based prognostication in severe brain injury.




Chemotherapy-induced peripheral neuropathy clinical trials: Review and recommendations

2017-08-21T12:49:05-07:00

Objective:

To assess the design characteristics and reporting quality of published randomized controlled trials (RCTs) for treatments of chemotherapy-induced peripheral neuropathy (CIPN) initiated before or during chemotherapy.

Methods:

In this systematic review of RCTs of preventive or symptomatic pharmacologic treatments for CIPN initiated before or during chemotherapy treatment, articles were identified by updating the PubMed search utilized in the CIPN treatment guidelines published in the Journal of Clinical Oncology in 2014.

Results:

Thirty-eight articles were identified. The majority included only patients receiving platinum therapies (61%) and used a placebo control (79%). Common exclusion criteria were preexisting neuropathy (84%), diabetes (55%), and receiving treatments that could potentially improve neuropathy symptoms (45%). Ninety-five percent of studies initiated the experimental treatment before CIPN symptoms occurred. Although 58% of articles identified a primary outcome measure (POM), only 32% specified a primary analysis. Approximately half (54%) of the POMs were patient-reported outcome measures of symptoms and functional impairment. Other POMs included composite measures of symptoms and clinician-rated signs (23%) and vibration tests (14%). Only 32% of articles indicated how data from participants who prematurely discontinued chemotherapy were analyzed, and 21% and 29% reported the number of participants who discontinued chemotherapy due to neuropathy or other/unspecified reasons, respectively.

Conclusions:

These data identify reporting practices that could be improved in order to enhance readers' ability to critically evaluate RCTs of CIPN treatments and use the findings to inform the design of future studies and clinical practice. Reporting recommendations are provided.




Thiamine-responsive disease due to mutation of tpk1: Importance of avoiding misdiagnosis

2017-08-21T12:49:05-07:00

A first child of unrelated healthy parents was the product of an uneventful pregnancy and delivery. Initial psychomotor development proceeded regularly. At 21 months of age, during an episode of otitis media, she started presenting recurrent vomiting, global hyporeactivity, ataxia, dysmetria, pyramidal signs, and loss of postural control. Cerebral MRI showed bilateral signal abnormalities of putamina (figure).




Listeria rhomboencephalomyelitis complicated by hemorrhagic transformation

2017-08-21T12:49:05-07:00

A 53-year-old woman presented with a 2-week history of diplopia, ataxia, and fevers. Blood cultures and CSF PCR were positive for Listeria monocytogenes. MRI demonstrated hyperintensity in the cerebellum, brainstem, and cervical cord (figure 1) with interval hemorrhagic transformation (figure 2). While a recognized cause of rhomboencephalitis, Listeria rarely involves the spinal cord concurrently.1 Hemorrhagic transformation is a novel finding, possibly secondary to bacterial invasion with localized inflammation and necrosis of brain parenchyma and surrounding blood vessels leading to exudation of blood products. Correlating with clinical improvement after treatment with IV ampicillin, progress MRI demonstrated resolution of the hyperintensities.




Editors' Note

2017-08-21T12:49:05-07:00

Editors' Note: In the February 21, 2017, issue of Neurology®, the American Academy of Neurology Burnout Task Force reported that 60% of American neurologists surveyed experienced at least one symptom of burnout. In the accompanying editorial, Dr. Bernat hypothesizes as to why neurologists are more prone to burnout than other similar specialties and suggests several actions to reverse the trend, including increasing patient care time and decreasing clerical work.




Letter re: How can neurologists avoid burnout?

2017-08-21T12:49:05-07:00

I read Dr. Bernat's editorial with interest.1 It is an excellent summary of the current health of our profession. An additional mitigation strategy, proven successful for me, is engagement with organized medicine. My professional journey took me from a county medical society to a state medical society and on to the American Academy of Neurology (AAN). In each venue, I find thoughtful, engaged physicians and dedicated, intelligent support staff. Clinical practice neurologists often spend their career in a rather isolated setting. When physicians do get together, the current practice environment fosters criticism. My dialogue has shifted from eloquent discontent in the hospital lunchroom to problem-solving in society meetings. I find engagement is often rewarded with positive feedback and the opportunity to contribute more meaningfully. Rather than reacting to changes forced upon me with a sense of helplessness, I feel empowered. I feel that I am shifting the landscape (albeit ever so slightly). I encourage Dr. Bernat and the AAN Burnout Task Force to actively promote engagement with organized medicine as an option for neurologists to avoid burnout.




Letter re: How can neurologists avoid burnout?

2017-08-21T12:49:05-07:00

We read with interest the article by Dr. Bernat,1 which gave an overview on how to avoid or reduce burnout for neurologists. It is a good approach to recreate workflows and give space to meet the most demanding individual requirements. A great way to expand the interventions to promote mental well-being would be by adding mindfulness-based interventions. Goodman and Schorling2 published a pre–post observational study on mindfulness-based stress reduction for health care providers, with impressive results. The intervention was for a period of 8 weeks,2 which is a good index that rapid improvement of individual well-being is possible. Significant improvement was achieved on the emotional exhaustion, depersonalization, and personal accomplishment scales.2 This proposed approach is progressing toward a high-grade solution, including different ways to improve the health of neurologists. It remains to be seen if this approach can be implemented rapidly.




Author response: How can neurologists avoid burnout?

2017-08-21T12:49:05-07:00

I thank Dr. Goldenberg for the comment on my editorial.1 He explains how he, as a busy clinical neurologist, found meaning by representing colleagues in a series of professional medical societies. It is a wonderful testimony of the point made in the article by Busis et al.2 that achieving personal engagement is a powerful preventive to burnout.







Child Neurology: Childhood basilar artery occlusion and stroke

2017-08-14T12:49:02-07:00

Stroke is one of the major causes of childhood mortality. Pediatric arterial ischemic stroke (PAIS) has an annual estimated rate as high as 3.3 cases per 100,000 children (with the vertebrobasilar territory involved in up to 36% of cases); however, the incidence of isolated childhood basilar artery occlusion (BAO) and stroke (BAS) is unknown.1 Adult BAO carries up to a 90% mortality rate, while death or severe neurologic deficits may be seen in 50% of children with BAO/BAS.1,2 The following case report describes a 12-year-old boy with BAO leading to BAS. Clinical symptoms, differential diagnoses, associated comorbidities, and current trends in acute treatment of pediatric BAO/BAS are also discussed.




Clinical Reasoning: A demure teenager and her dystonic foot

2017-08-14T12:49:02-07:00

A 13-year-old girl presented with a 4-year history of abnormal gait. At age 9, her parents noticed that she would run awkwardly "on the balls of her feet" and subsequently, that the rhythm of her running would break down with sustained exercise. There was no diurnal variation in her symptoms. There was no history of perinatal insults and early development was normal. There was no significant medical or psychiatric comorbidity and her family history was unremarkable. Examination of the patient's gait is demonstrated in video 1 at Neurology.org.




Journal Club: Long-term functional outcome in patients with acquired infections after acute spinal cord injury

2017-08-14T12:49:02-07:00

Infections, particularly pneumonia, are the primary cause of mortality in individuals with spinal cord injury (SCI).1 Several factors may contribute to the high rate of infections in the SCI population, including motor paralysis and reduced reflexes resulting in aspiration, invasive procedures, and so-called SCI-induced immune depression syndrome (SCI-IDS).2,3 SCI-IDS is thought to occur when the connection between the CNS and the immune system are disrupted by a lesion in the spinal cord, resulting in a decrease in immune function.3 In addition to increased morbidity and mortality, infections after SCI may affect neurologic recovery.2,3 A recent study found that infections impaired the return of muscle strength up to 1 year postinjury; however, the long-term consequences remain uncertain.2




Teaching NeuroImages: Classic Ramsay Hunt syndrome and associated MRI findings

2017-08-14T12:49:02-07:00

An 85-year-old woman with dementia presented with left ear pain, vertigo, and mild left peripheral facial weakness of unclear chronicity. MRI demonstrated contrast enhancement of cranial nerves (CNs) VII and VIII consistent with Ramsay Hunt syndrome (RHS)1 (figure 1). She was treated with steroids and acyclovir. On evaluation 4 days later, she had developed the classic RHS triad of ear pain, ipsilateral facial paralysis, and vesicular rash, plus hyperacusis and persistent vertigo (figure 2).2




Teaching Video NeuroImages: Trapezius muscle hypertrophy in multifocal motor neuropathy

2017-08-14T12:49:03-07:00

Neurogenic muscle hypertrophy has been reported in spinal muscular atrophy, radiculopathy, postpolio syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, and multifocal motor neuropathy (MMN).




Teaching Video NeuroImages: The underrecognized diphasic dyskinesia of Parkinson disease

2017-08-14T12:49:03-07:00

Dyskinesia is a common motor complication in levodopa-treated Parkinson disease (PD), associated with higher doses, greater disease severity, and longer disease duration.1 Often assumed to be a peak-dose phenomenon, the diphasic (beginning-of-dose or end-of-dose) variant may be ignored, as exemplified by a patient with PD whose dyskinesia was initially interpreted as peak-dose (video at Neurology.org). Rapid improvement with apomorphine, a short-acting levodopa-equipotent dopamine agonist, confirmed its diphasic nature.2 Recognition of dyskinesia subtype based on the relationship with levodopa dose cycles (figure) facilitates their differing management in PD: while dopaminergic stimulation needs reduction in peak-dose dyskinesia, it should be increased in diphasic.




Spotlight on the August 15 issue

2017-08-14T12:49:02-07:00




Affective prosody in frontotemporal dementia: The importance of "pitching it right"

2017-08-14T12:49:02-07:00

"It's not what you said; it's how you said it!" How many times have you said or heard that while interacting with a family member or colleague? It is clear that tone of voice (modulations in pitch, loudness, and rhythm of speech, together called prosody) conveys a great deal of intent and emotion in nearly every exchange. Imagine that your spouse's response to a very special birthday gift is "I've never seen anything like it," spoken in a completely monotone voice. You would not be able to tell if he or she loves it or hates it. On the flip side, suppose you say to your spouse, lovingly, "I can hardly believe we have been married for 20 years." But she thinks you sound angry when you say that, so she retorts that she is happy to divorce you to put you out of your misery. As reported by Nevler et al.1 in this issue of Neurology®, people with the behavioral variant of frontotemporal dementia (bvFTD) often have severe impairments in expression of emotion through affective prosody. They also often have trouble understanding affective prosody in others.2 These deficits can lead to frequent misinterpretation and failures of communication. Deficits in prosody expression and comprehension are not specific to bvFTD. Survivors of right middle cerebral artery stroke3,4 and people with autism,5 schizophrenia,6 and Parkinson disease7 also can have marked impairment in affective prosody recognition or production.




Inpatient quality metrics in neurology: A grand challenge

2017-08-14T12:49:02-07:00

The need to ensure quality in medicine has become paramount in the current environment of health care accountability, affordability, and access. There are many tools that are used to ensure quality, including peer review, continuing medical education, maintenance of certification, formal disease-specific guidelines,1 and quality measures.2 The lines between these various tools can sometimes be blurred and lead to confusion for the clinical neurologist.




Automatic measurement of prosody in behavioral variant FTD

2017-08-14T12:49:02-07:00

Objective:

To help understand speech changes in behavioral variant frontotemporal dementia (bvFTD), we developed and implemented automatic methods of speech analysis for quantification of prosody, and evaluated clinical and anatomical correlations.

Methods:

We analyzed semi-structured, digitized speech samples from 32 patients with bvFTD (21 male, mean age 63 ± 8.5, mean disease duration 4 ± 3.1 years) and 17 matched healthy controls (HC). We automatically extracted fundamental frequency (f0, the physical property of sound most closely correlating with perceived pitch) and computed pitch range on a logarithmic scale (semitone) that controls for individual and sex differences. We correlated f0 range with neuropsychiatric tests, and related f0 range to gray matter (GM) atrophy using 3T T1 MRI.

Results:

We found significantly reduced f0 range in patients with bvFTD (mean 4.3 ± 1.8 ST) compared to HC (5.8 ± 2.1 ST; p = 0.03). Regression related reduced f0 range in bvFTD to GM atrophy in bilateral inferior and dorsomedial frontal as well as left anterior cingulate and anterior insular regions.

Conclusions:

Reduced f0 range reflects impaired prosody in bvFTD. This is associated with neuroanatomic networks implicated in language production and social disorders centered in the frontal lobe. These findings support the feasibility of automated speech analysis in frontotemporal dementia and other disorders.




Early and lethal neurodegeneration with myasthenic and myopathic features: A new ALG14-CDG

2017-08-14T12:49:02-07:00

Objective:

To describe the presentation and identify the cause of a new clinical phenotype, characterized by early severe neurodegeneration with myopathic and myasthenic features.

Methods:

This case study of 5 patients from 3 families includes clinical phenotype, serial MRI, electrophysiologic testing, muscle biopsy, and full autopsy. Genetic workup included whole exome sequencing and segregation analysis of the likely causal mutation.

Results:

All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy. Three patients had congenital contractures. All patients died during their first year of life. In 2 of our patients, electrophysiologic testing showed abnormal decrement, but treatment with pyridostigmine led only to temporary improvement. Causative mutations in ALG14 were identified in all patients. The mutation c.220 G>A (p.Asp74Asn) was homozygous in 2 patients and heterozygous in the other 3 patients. Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A (p.Arg109Gln). In all cases, parents were found to be heterozygous carriers. None of the identified variants has been described previously.

Conclusions:

We report a genetic syndrome combining myasthenic features and severe neurodegeneration with therapy-refractory epilepsy. The underlying cause is a glycosylation defect due to mutations in ALG14. These cases broaden the phenotypic spectrum associated with ALG14 congenital disorders of glycosylation as previously only isolated myasthenia has been described.




Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia

2017-08-14T12:49:02-07:00

Objective:

To determine whether a transcranial magnetic stimulation (TMS) multiparadigm approach can be used to distinguish Alzheimer disease (AD) from frontotemporal dementia (FTD).

Methods:

Paired-pulse TMS was used to investigate short-interval intracortical inhibition (SICI) and facilitation (ICF), long-interval intracortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intracortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis.

Results:

A total of 175 participants met the inclusion criteria. We diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. We found that while patients with AD are characterized by a specific impairment of SAI, FTD shows a remarkable dysfunction of SICI-ICF intracortical circuits. With the use of the best indexes, TMS differentiated FTD from AD with a sensitivity of 91.8% and specificity of 88.6%, AD from HC with a sensitivity of 84.8% and specificity of 90.6%, and FTD from HC with a sensitivity of 90.2% and specificity of 78.1%. These results were confirmed in patients with mild disease.

Conclusions:

TMS is a noninvasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice.

Classification of evidence:

This study provides Class III evidence that TMS measures can distinguish patients with AD from those with FTD.




Pretreatment seizure semiology in childhood absence epilepsy

2017-08-14T12:49:02-07:00

Objective:

To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes.

Methods:

For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit.

Results:

Video of 1,932 electrographic absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%–84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern.

Conclusions:

Almost all absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome.




Cardiovascular health in young adulthood and structural brain MRI in midlife: The CARDIA study

2017-08-14T12:49:02-07:00

Objective:

To examine the association between the American Heart Association (AHA) Life's Simple 7 (LS7) metric and brain structure.

Methods:

We determined cardiovascular health (CVH) according to the AHA LS7, assigning 0, 1, or 2 points for meeting poor, intermediate, or ideal criteria for the 7 components (range 0–14) at baseline (aged 18–30 years in 1985–1986) and year 25 follow-up examination for 518 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) brain MRI substudy. Visit-based CVH score and average score was assessed in relation to percent of intracranial volume of normal tissue of the whole brain, gray matter, and white matter, and abnormal tissue volume of white matter at year 25 using multivariable linear, logistic, and quantile regression, after adjustment for age, sex, race, field center, educational attainment, and alcohol consumption.

Results:

Mean percentage of whole brain volume, normal gray matter, and normal white matter was 81.3% (±2.5), 42.9% (±2.0), and 38.4% (±2.0). Greater CVH score at baseline (per each additional point at year 0: 0.1%, 95% confidence limits 0.01–0.3; p < 0.05) and average CVH score were associated with greater percentage of whole brain volume (per each additional point in average score: 0.2%, 95% confidence limits 0.04–0.3; p < 0.05). Visit-based or average CVH score was not significantly associated with normal gray or white matter volume or abnormal white matter volume.

Conclusions:

Maintaining ideal levels of cardiovascular health, determined by the LS7, in young adulthood is associated with greater whole brain volume in middle age but not regional differences in structure.




Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation

2017-08-14T12:49:02-07:00

Objective:

To perform a systematic review and meta-analysis of studies reporting recurrent intracranial hemorrhage (ICH) and ischemic stroke (IS) in ICH survivors with atrial fibrillation (AF) during long-term follow-up.

Methods:

A comprehensive literature search including MEDLINE, EMBASE, Cochrane library, clinical trials registry was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We considered studies capturing outcome events (ICH recurrence and IS) for ≥3 months and treatment exposure to vitamin K antagonists (VKAs), antiplatelet agents (APAs), or no antithrombotic medication (no-ATM). Corresponding authors provided aggregate data for IS and ICH recurrence rate between 6 weeks after the event and 1 year of follow-up for each treatment exposure. Meta-analyses of pooled rate ratios (RRs) were conducted with the inverse variance method.

Results:

Seventeen articles met inclusion criteria. Seven observational studies enrolling 2,452 patients were included in the meta-analysis. Pooled RR estimates for IS were lower for VKAs compared to APAs (RR = 0.45, 95% confidence interval [CI] 0.27–0.74, p = 0.002) and no-ATM (RR = 0.47, 95% CI 0.29–0.77, p = 0.002). Pooled RR estimates for ICH recurrence were not significantly increased across treatment groups (VKA vs APA: RR = 1.34, 95% CI 0.79–2.30, p = 0.28; VKA vs no-ATM: RR = 0.93, 95% CI 0.45–1.90, p = 0.84).

Conclusions:

In observational studies, anticoagulation with VKA is associated with a lower rate of IS than APA or no-ATM without increasing ICH recurrence significantly. A randomized controlled trial is needed to determine the net clinical benefit of anticoagulation in ICH survivors with AF.




Florbetapir imaging in cerebral amyloid angiopathy-related hemorrhages

2017-08-14T12:49:02-07:00

Objective:

To assess whether 18F-florbetapir, a PET amyloid tracer, could bind vascular amyloid in cerebral amyloid angiopathy (CAA) by comparing cortical florbetapir retention during the acute phase between patients with CAA-related lobar intracerebral hemorrhage (ICH) and patients with hypertension-related deep ICH.

Methods:

Patients with acute CAA-related lobar ICH were prospectively enrolled and compared with patients with deep ICH. 18F-florbetapir PET, brain MRI, and APOE genotype were obtained for all participants. Cortical florbetapir standard uptake value ratio (SUVr) was calculated with the whole cerebellum used as a reference. Patients with CAA and those with deep ICH were compared for mean cortical florbetapir SUVr values.

Results:

Fifteen patients with acute lobar ICH fulfilling the modified Boston criteria for probable CAA (mean age = 67 ± 12 years) and 18 patients with acute deep ICH (mean age = 63 ± 11 years) were enrolled. Mean global cortical florbetapir SUVr was significantly higher among patients with CAA-related ICH than among patients with deep ICH (1.27 ± 0.12 vs 1.12 ± 0.12, p = 0.001). Cortical florbetapir SUVr differentiated patients with CAA-ICH from those with deep ICH (area under the curve = 0.811; 95% confidence interval [CI] 0.642–0.980) with a sensitivity of 0.733 (95% CI 0.475–0.893) and a specificity of 0.833 (95% CI 0.598–0.948).

Conclusions:

Cortical florbetapir uptake is increased in patients with CAA-related ICH relative to those with deep ICH. Although 18F-florbetapir PET can label vascular β-amyloid and might serve as an outcome marker in future clinical trials, its diagnostic value in acute CAA-related ICH seems limited in clinical practice.




Effect of gluten-free diet on cerebellar MR spectroscopy in gluten ataxia

2017-08-14T12:49:02-07:00

Objective:

To evaluate the effect of gluten free diet (GFD) on magnetic resonance spectroscopy (MRS) of the cerebellum in patients with gluten ataxia (GA).

Methods:

Patients with GA, defined as sporadic ataxia with positive antigliadin antibodies in the absence of an alternative cause, routinely undergo MRS at baseline and after the introduction of GFD as part of their clinical care. We present our experience of the effect of GFD on MRS of the cerebellum.

Results:

A total of 117 consecutive patients with GA were included in this report. Sixty-three were on strict GFD with elimination of antigliadin antibodies, 35 were on GFD but were still positive for antigliadin antibodies, and 19 patients opted not to go on GFD. The N-acetylaspartate (NAA)/creatine (Cr) area ratio from the cerebellar vermis increased in 62 out of 63 (98%) patients on strict GFD, in 9 of 35 (26%) patients on GFD but positive antibodies, and in only 1 of 19 (5%) patients not on GFD. The NAA/Cr ratio decreased in all 14 ataxia control patients (cerebellar variant of multisystem atrophy). There were no differences in the MRS results between those patients who had and those who did not have enteropathy (celiac disease) within each group.

Conclusions:

The demonstration of increased NAA/Cr ratio on repeat scanning following strict GFD strengthens previous findings of clinical improvement of the ataxia in patients with GA. The presence of enteropathy is not a prerequisite for such improvement; therefore patients with positive serology and negative duodenal biopsy should still be treated with strict GFD.




Open-label trial of ranolazine for the treatment of myotonia congenita

2017-08-14T12:49:02-07:00

Objective:

To determine open-label, pilot study whether ranolazine could improve signs and symptoms of myotonia and muscle stiffness in patients with myotonia congenita (MC).

Methods:

Thirteen participants were assessed at baseline and 2, 4, and 5 weeks. Ranolazine was started after baseline assessment (500 mg twice daily), increased as tolerated after week 2 (1,000 mg twice daily), and maintained until week 4. Outcomes included change from baseline to week 4 in self-reported severity of symptoms (stiffness, weakness, and pain), Timed Up and Go (TUG), hand grip and eyelid myotonia, and myotonia on EMG.

Results:

Self-reported severity of stiffness (p < 0.0001) and weakness (p < 0.01) was significantly improved compared with baseline. TUG and grip myotonia times were reduced (p = 0.03, p = 0.01). EMG of the abductor digiti minimi and tibialis anterior showed significantly reduced myotonia duration (p < 0.001, p < 0.01) at week 4. No participant discontinued ranolazine because of side effects.

Conclusions:

Ranolazine appeared to be well tolerated over a period of 4 weeks in individuals with MC, and ranolazine resulted in improvement of signs and symptoms of muscle stiffness. The findings of this study suggest that ranolazine should be investigated in a larger controlled study.

Classification of evidence:

This study provides Class IV evidence that ranolazine improves myotonia in myotonia congenita.




MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis

2017-08-14T12:49:02-07:00

Objective:

To identify gadolinium-enhancing lesions affecting the cortex of patients with early multiple sclerosis (MS) and to describe the frequency and evolution of these lesions.

Methods:

We performed a retrospective, observational, longitudinal analysis of MRI scans collected as part of the Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3T MRI Endpoints (BECOME) study. Seventy-five patients with early-stage MS were scanned monthly, over a period of 12–24 months, using 3T MRI after administration of triple-dose gadolinium. A total of 1,188 scans were included in the analysis. A total of 139 were selected using an image pipeline algorithm that integrated the image information from cortical gray matter masks and gadolinium-enhancing lesion masks. These scans were evaluated to identify gadolinium-enhancing lesions affecting the cortex.

Results:

The total number of gadolinium-enhancing lesions was 2,044. The number of gadolinium-enhancing lesions affecting the cortex was 120 (6%), 95% of which were leukocortical. The number of patients who showed gadolinium-enhancing lesions affecting the cortex was 27 (36%). The number of gadolinium-enhancing lesions affecting the cortex at baseline was 25 (21%) and the number of new lesions that developed in follow-up scans was 49 (41%). The number of persistent lesions was 46 (38%).

Conclusions:

The presence of enhancing lesions affecting the cortex and adjacent white matter, although transient and not frequent, suggests that at least some cortical lesions are related to blood–brain barrier disruption. Our data support the concept that there may be an acute inflammatory phase in the development of leukocortical MS lesions.

Clinicaltrials.gov identifier:

NCT00176592.




Anoctamins (TMEM16 proteins): Functions and involvement in neurologic disease

2017-08-14T12:49:02-07:00

Anoctamins (anion channels with 8 transmembrane domains [ANO]), also known as transmembrane proteins with 16 domains (TMEM16), are highly conserved intracellular calcium (Ca2+)–activated proteins with multiple cellular functions. The ANO/TMEM16 family includes 10 members (ANO1/TMEM16A to ANO10/TMEM16K), with distinct distributions in tissues. Some of these proteins, such as ANO1 and ANO2, are prototypical Ca2+-activated chloride (Cl) channels. Others, including ANO6, mediate Ca2+-dependent exposure of phospholipids that are normally expressed in the inner leaflet of the membrane to the extracellular surface; this process is called phospholipid scrambling or scramblase activity. Anoctamins are involved in regulation of neuronal cell excitability, epithelial secretion, smooth muscle contraction, repair of skeletal muscle membrane, and tumorigenesis. The structure, mechanism of activation, and functions of anoctamins have been reviewed recently.1–6 Anoctamins contribute to heat-induced pain7,8 and modulate excitability in neurons in the dorsal root ganglia (DRG),9 hippocampus,10 and cerebellum.11 Mutations affecting different anoctamins have been linked to several neurologic disorders, including muscle disease,12–15 cerebellar ataxia,16–18 and dystonia.19,20 Thus, anoctamins constitute a potential therapeutic target in a wide range of neurologic disorders.




Quality improvement in neurology: Inpatient and emergency care quality measure set: Executive summary

2017-08-14T12:49:02-07:00

The emergence of inpatient neurologic specialists including neurohospitalists and neurointensivists has led to an increased focus on the quality of neurologic care delivered in the hospital. Each year, there are over 1.5 million nonsurgical neurologic hospital discharges in the United States, making neurology a large inpatient specialty even without accounting for nonadmitted emergency patients.1 National quality metrics in other non-neurologic specialties have focused primarily on inpatient care since hospitals, insurers, professional organizations, and the general public have turned their attention to outcomes achieved during and following hospitalization. Many of these metrics have been applied to neurology patients, despite their not being developed with neurology-specific patient populations or disorders in mind. This gap highlights the need for measures for neurology patients in both inpatient and emergency settings.




Effects of exercise on fitness and health of adults with spinal cord injury: A systematic review

2017-08-14T12:49:02-07:00

Objective:

To synthesize and appraise research testing the effects of exercise interventions on fitness, cardiometabolic health, and bone health among adults with spinal cord injury (SCI).

Methods:

Electronic databases were searched (1980–2016). Included studies employed exercise interventions for a period ≥2 weeks, involved adults with acute or chronic SCI, and measured fitness (cardiorespiratory fitness, power output, or muscle strength), cardiometabolic health (body composition or cardiovascular risk factors), or bone health outcomes. Evidence was synthesized and appraised using Grading of Recommendations Assessment, Development, and Evaluation (GRADE).

Results:

A total of 211 studies met the inclusion criteria (22 acute, 189 chronic). For chronic SCI, GRADE confidence ratings were moderate to high for evidence showing exercise can improve all of the reviewed outcomes except bone health. For acute SCI, GRADE ratings were very low for all outcomes. For chronic SCI, there was low to moderate confidence in the evidence showing that 2–3 sessions/week of upper body aerobic exercise at a moderate to vigorous intensity for 20–40 minutes, plus upper body strength exercise (3 sets of 10 repetitions at 50%–80% 1-repetition maximum for all large muscle groups), can improve cardiorespiratory fitness, power output, and muscle strength. For chronic SCI, there was low to moderate confidence in the evidence showing that 3–5 sessions per week of upper body aerobic exercise at a moderate to vigorous intensity for 20–44 minutes can improve cardiorespiratory fitness, muscle strength, body composition, and cardiovascular risk.

Conclusions:

Exercise improves fitness and cardiometabolic health of adults with chronic SCI. The evidence on effective exercise types, frequencies, intensities, and durations should be used to formulate exercise guidelines for adults with SCI.




VCP-related multisystem proteinopathy presenting as early-onset Parkinson disease

2017-08-14T12:49:02-07:00

The valosin-containing protein (VCP) is involved in a plethora of cellular processes including membrane dynamics, DNA damage response, and protein quality control.1 Its essential role in humans is highlighted by diverse clinical phenotypes linked to VCP mutations: (1) inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD); (2) amyotrophic lateral sclerosis; (3) Charcot-Marie-Tooth disease type 2; and (4) hereditary spastic paraplegia (reviewed by Evangelista et al.2). Moreover, mutant VCP has been implicated in the pathogenesis of Parkinson disease (PD).3




Supranuclear gaze palsy and horizontal ocular oscillations in Creutzfeldt-Jakob disease

2017-08-14T12:49:02-07:00

A 59-year-old patient presented with marked cognitive impairment. Examination revealed supranuclear gaze palsy and ocular oscillations (video at Neurology.org). Extremity and axial muscle tone was increased, accompanied by full body tremulousness suggestive of polymyoclonus. Motor abnormalities had progressed over 3 months but cognitive problems developed in 1–2 weeks. MRI (figure) and CSF (positive real-time quaking-induced conversion) were diagnostic of Creutzfeldt-Jacob disease (CJD).




Editors' Note

2017-08-14T12:49:02-07:00

Editors' Note: In "Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials," Drs. Figueroa and Wright reviewed published clinical trials on the effect of hyperbaric oxygen therapy (HBOT) on mild to moderate traumatic brain injury/persistent postconcussion syndrome (mTBI/PPCS) and concluded that HBOT has therapeutic effects on mTBI/PPCS symptoms and can alleviate posttraumatic stress disorder symptoms secondary to a brain injury.




Letter re: Hyperbaric oxygen: B-Level evidence in mild traumatic brain injury clinical trials

2017-08-14T12:49:02-07:00

In their article, Drs. Figueroa and Wright1 reported a reanalysis of hyperbaric oxygen's effect on mild traumatic brain injury and claimed that oxygen content of arterial blood plasma (oxygen dissolved in plasma) during hyperbaric exposure correlates with treatment response.




Author response: Hyperbaric oxygen: B-Level evidence in mild traumatic brain injury clinical trials

2017-08-14T12:49:02-07:00

We thank Drs. Hampson and Holm for commenting on our Views & Reviews article.1 It is true that PaO2 was not measured in the published studies and assumptions were made regarding normal metabolism and pulmonary function of the study participants. This was a valid assumption, as all participants were cleared to be placed inside a pressure vessel and not excluded due to pulmonary or metabolic dysfunctions.




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

2017-08-14T12:49:02-07:00

The article by Thomas et al.1 validated 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of autopsy-proven dementia with Lewy bodies (DLB). The authors depicted 3 patients with DLB who met pathologic criteria for Lewy body disease but had normal 123I-FP-CIT imaging.1 Although further description concerning severity of parkinsonism remains unclear, these patients may not have severe parkinsonism. Thus, the patients' dopaminergic neuroimaging may not be included in scans without evidence of dopaminergic deficit.




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

2017-08-14T12:49:02-07:00

Professor Abe raises the important issue of the involvement of Lewy body disease in the substantia nigra (SN) when making the diagnosis of dementia with Lewy bodies (DLB). It has long been known that, even later on in their illness, about 25% of patients with DLB do not show features of parkinsonism. This is recognized in the consensus criteria for DLB, which do not require parkinsonism for diagnosis. Patients with DLB can have normal dopaminergic imaging because, as with our 3 patients who also had no parkinsonism,1 there is no significant involvement of the SN by Lewy body disease.










Clinical Reasoning: Two see or not two see--Is it really double vision?

2017-08-07T12:49:01-07:00

A 57-year-old right-handed woman presented to the emergency department with complaints of double vision and intractable nausea that began abruptly 2 days earlier. Her visual symptoms were characterized as seeing overlapping or separate horizontally or diagonally displaced objects. She had no history of headaches or stroke. Her cerebrovascular risk factors included hypertension, type II diabetes, coronary artery disease, and cigarette smoking. Her medications included clopidogrel, lisinopril, paroxetine, and oxycodone. Her family history was notable for late-onset ischemic heart disease in her parents with no first-degree relatives with early vascular disease. On examination, her blood pressure was 158/101 mm Hg, pulse rate was 87 bpm, and she was afebrile. She was alert and fully oriented. Her attention, recall of recent events, and general fund of knowledge were normal. Her speech was fluent and nondysarthric. Cranial nerve examination was notable for no dysconjugacy or nystagmus, but double vision predominately in the horizontal plane, in all directions of gaze. The diplopia persisted with monocular vision in each eye, and did not improve with a pinhole test. The degree of diplopia waxed and waned during the examination, with visual field extinction tests being difficult to perform reliably. Her pupils were equal with bilateral hippus. Visual fields were full to confrontation. Direct funduscopy revealed normal optic discs. She had a mild right hemiparesis with mild right arm and leg drift, but no facial asymmetry. There was mild hypesthesia over her right arm and leg and appendicular ataxia in her right arm that was worse with eyes open. She did not have extinction to double simultaneous sensory stimuli. Gait evaluation was deferred during her initial examination.




Pearls & Oy-sters: An uncommon initial presentation of thyrotoxicosis

2017-08-07T12:49:01-07:00

Venous thrombosis is common in patients with thyrotoxicosis, with the cerebral venous system being frequently involved.




Teaching NeuroImages: Artery of Percheron aneurysm masquerading as ICH spot sign

2017-08-07T12:49:01-07:00

A 50-year-old Japanese woman presented with left thalamic intracerebral hemorrhage (ICH). CT angiography demonstrated an ICH spot sign and intracranial vasculopathy consistent with Moyamoya disease (figure 1). Conventional angiography demonstrated that the spot sign was actually a pseudoaneurysm arising from the artery of Percheron (figure 2). Intracranial aneurysms may complicate Moyamoya disease and occur at the circle of Willis, distal peripheral arteries, or Moyamoya vessels at a ratio of 3:1:1.1 Aneurysms in thalamo-perforating arteries are rare2 and an artery of Percheron aneurysm in Moyamoya disease has not been reported. In Moyamoya disease, presence of a spot sign should prompt consideration for angiography.




Teaching NeuroImages: Cerebral amyloid angiopathy-related inflammation presenting with isolated leptomeningitis

2017-08-07T12:49:01-07:00

A 69-year-old woman presented with 1 month of rapid cognitive decline preceded by 1 year of very mild memory changes. Examination showed impaired attention, logopenic aphasia, anosognosia, simultagnosia, graphesthesia, and apraxia. Neuroimaging demonstrated leptomeningeal enhancement without significant parenchymal lesions or cerebral microbleeds (figure 1). A lymphocytic pleocytosis (15 nucleated cells/μL) was noted on CSF analysis. Extensive diagnostic testing was inconclusive, including flow cytometry and cytology, conventional angiography, body CT, and PET. Cerebral amyloid angiopathy–related inflammation (CAA-RI) was confirmed on brain biopsy (figure 2). CAA-RI rarely presents with isolated leptomeningeal enhancement and can be a challenging diagnosis.1,2




Spotlight on the August 8 issue

2017-08-07T12:49:00-07:00




The state of academic neurology departments in the United States, 2016: A national survey

2017-08-07T12:49:00-07:00

Over the last decade, the United States has entered an era of national health care system reform, unprecedented in its scope and velocity. The seismic changes wrought by this process continue unabated and may have widespread effects on the academic medical enterprise throughout the country. To better understand the contemporary structure and features of academic neurology departments in this environment and to create a baseline for tracking future changes, we designed and executed a survey of department chairs in neurology nationwide in the fall of 2016, with the endorsement and support of the Association of University Professors of Neurology. The online survey was distributed to 126 chairs and 97 chairs responded, for a 77% overall response rate, though not all respondents answered every question.




Age and the fuzzy edges of embolic stroke of undetermined source: Implications for trials

2017-08-07T12:49:00-07:00

After an acute ischemic stroke, clinicians pursue further diagnostic assessment to identify the most plausible causes and tailor secondary prevention strategies. Available treatments with a high level of evidence for reducing recurrence stroke risk might include long-term oral anticoagulation in patients with a major-risk cardioembolic source (atrial fibrillation, prosthetic valves, etc), carotid endarterectomy in minor ischemic stroke related to moderate to severe internal carotid artery atherosclerotic stenosis, and best-practice medical management in those with lacunar stroke due to cerebral small vessel disease.1 However, 25% of patients who have had ischemic stroke (an estimated 300,000 new strokes per year in North America and Europe) have no cause identified.2 These strokes, usually called cryptogenic (i.e., of unknown cause), typically include nonlacunar infarcts without an identified cardioembolic source or occlusive atherosclerotic disease. Compared to all other major stroke subtypes, little progress has been achieved in the secondary prevention of this common but obscure entity, and the optimum antithrombotic prophylaxis regimen remains undefined.




Determining the optimal target blood pressure after thrombectomy: High or low?

2017-08-07T12:49:00-07:00

The management of patients with acute ischemic stroke has changed dramatically with modern mechanical thrombectomy (MT) techniques and improved patient selection using CT angiography.1 Although the benefit of early recanalization in large vessel occlusion (LVO) seems clear, the optimal periprocedural management remains uncertain. Unresolved issues include the method of analgesia and sedation, reversal and application of adjunctive periprocedural anticoagulation, glycemic control, ventilatory management, and perhaps most important, blood pressure (BP) control.




Phosphodiesterase 4: Rethinking cognition in Parkinson disease

2017-08-07T12:49:00-07:00

The nosology and treatment options for cognitive impairment in Parkinson disease (PD) remains perhaps the greatest unmet clinical need.1 The reported frequency of mild cognitive impairment (MCI) in newly diagnosed PD has ranged from 22% to 43%.2,3 A proportion of those with PD-MCI progress to PD dementia (PDD), the prevalence of which is variously estimated between 24% and 31%, but is as high as 75% in longitudinal studies.4 Dementia is associated with increased disability, nursing home placement, mortality, and caregiver stress. Global cognition and executive/working memory deficits also occur in individuals at risk for PD.5 Which features of MCI are predictive of development of dementia remain a matter of debate.




Age- and sex-specific analysis of patients with embolic stroke of undetermined source

2017-08-07T12:49:00-07:00

Objective:

To investigate whether the correlation of age and sex with the risk of recurrence and death seen in patients with previous ischemic stroke is also evident in patients with embolic stroke of undetermined source (ESUS).

Methods:

We pooled datasets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. We performed Cox regression and Kaplan-Meier product limit analyses to investigate whether age (<60, 60–80, >80 years) and sex were independently associated with the risk for ischemic stroke/TIA recurrence or death.

Results:

Ischemic stroke/TIA recurrences and deaths per 100 patient-years were 2.46 and 1.01 in patients <60 years old, 5.76 and 5.23 in patients 60 to 80 years old, 7.88 and 11.58 in those >80 years old, 3.53 and 3.48 in women, and 4.49 and 3.98 in men, respectively. Female sex was not associated with increased risk for recurrent ischemic stroke/TIA (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.84–1.58) or death (HR 1.35, 95% CI 0.97–1.86). Compared with the group <60 years old, the 60- to 80- and >80-year groups had higher 10-year cumulative probability of recurrent ischemic stroke/TIA (14.0%, 47.9%, and 37.0%, respectively, p < 0.001) and death (6.4%, 40.6%, and 100%, respectively, p < 0.001) and higher risk for recurrent ischemic stroke/TIA (HR 1.90, 95% CI 1.21–2.98 and HR 2.71, 95% CI 1.57–4.70, respectively) and death (HR 4.43, 95% CI 2.32–8.44 and HR 8.01, 95% CI 3.98–16.10, respectively).

Conclusions:

Age, but not sex, is a strong predictor of stroke recurrence and death in ESUS. The risk is 3- and 8-fold higher in patients >80 years compared with those <60 years of age, respectively. The age distribution in the ongoing ESUS trials may potentially influence their power to detect a significant treatment association.




Blood pressure levels post mechanical thrombectomy and outcomes in large vessel occlusion strokes

2017-08-07T12:49:00-07:00

Objective:

There are limited data evaluating the effect of post mechanical thrombectomy (MT) blood pressure (BP) levels on early outcomes of patients with large vessel occlusions (LVO). We sought to investigate the association of BP course following MT with early outcomes in LVO.

Methods:

Consecutive patients with LVO treated with MT during a 3-year period were evaluated. Hourly systolic BP (SBP) and diastolic BP (DBP) values were recorded for 24 hours following MT and maximum SBP and DBP levels were identified. LVO patients with complete reperfusion following MT were stratified in 3 groups based on post-MT achieved BP goals: <140/90 mm Hg (intensive), <160/90 mm Hg (moderate), and <220/110 mm Hg or <180/105 mm Hg when pretreated with IV thrombolysis (permissive hypertension). Three-month functional independence was defined as modified Rankin Scale score of 0–2.

Results:

A total of 217 acute ischemic stroke patients with LVO were prospectively evaluated. A 10 mm Hg increment in maximum SBP documented during the first 24 hours post MT was independently (p = 0.001) associated with a lower likelihood of 3-month functional independence (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.56–0.87) and a higher odds of 3-month mortality (OR 1.49; 95% CI 1.18–1.88) after adjusting for potential confounders. In addition, achieving a BP goal of <160/90 mm Hg during the first 24 hours following MT was independently associated with a lower likelihood of 3-month mortality (OR 0.08; 95% CI 0.01–0.54; p = 0.010) in comparison to permissive hypertension.

Conclusions:

High maximum SBP levels following MT are independently associated with increased likelihood of 3-month mortality and functional dependence in LVO patients. Moderate BP control is also related to lower odds of 3-month mortality in comparison to permissive hypertension.




Blood pressure reduction and noncontrast CT markers of intracerebral hemorrhage expansion

2017-08-07T12:49:00-07:00

Objective:

To validate various noncontrast CT (NCCT) predictors of hematoma expansion in a large international cohort of ICH patients and investigate whether intensive blood pressure (BP) treatment reduces ICH growth and improves outcome in patients with these markers.

Methods:

We analyzed patients enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) randomized controlled trial. Participants were assigned to intensive (systolic BP <140 mm Hg) vs standard (systolic BP <180 mm Hg) treatment within 4.5 hours from onset. The following NCCT markers were identified: intrahematoma hypodensities, black hole sign, swirl sign, blend sign, heterogeneous hematoma density, and irregular shape. ICH expansion was defined as hematoma growth >33% and unfavorable outcome was defined as modified Rankin Scale score >3 at 90 days. Logistic regression was used to identify predictors of ICH expansion and explore the association between NCCT signs and clinical benefit from intensive BP treatment.

Results:

A total of 989 patients were included (mean age 62 years, 61.9% male), of whom 186/869 experienced hematoma expansion (21.4%) and 361/952 (37.9%) had unfavorable outcome. NCCT markers independently predicted ICH expansion (all p < 0.01) with overall accuracy ranging from 61% to 78% and good interrater reliability (k > 0.6 for all markers). There was no evidence of an interaction between NCCT markers and benefit from intensive BP reduction (all p for interaction >0.10).

Conclusions:

NCCT signs reliably identify ICH patients at high risk of hematoma growth. However, we found no evidence that patients with these markers specifically benefit from intensive BP reduction.

Clinicaltrials.gov identifier:

NCT01176565.




Mortality trends for multiple sclerosis patients in Sweden from 1968 to 2012

2017-08-07T12:49:00-07:00

Objective:

To assess trends in mortality and causes of death for patients with multiple sclerosis (MS) relative to those without MS in Sweden.

Methods:

Patients with an MS diagnosis in Sweden between 1964 and 2012 were identified with the Patient Register and the Multiple Sclerosis Register. For this cohort study, each patient with MS (n = 29,617) was matched with 10 individuals without MS (n = 296,164) on sex, year of birth, vital status, and region of residence at the time of MS diagnosis with the Total Population Register. The Causes of Death Register was used to identify causes of death. Cox proportional hazard models were constructed to assess whether risk of mortality was increased for patients with MS.

Results:

The hazard ratio (HR) for patients with MS was 2.92 (95% confidence interval [CI] 2.86–2.99) for all-cause mortality over the entire study period. The largest differences between the cohorts were death resulting from respiratory (HR 5.07, 95% CI 4.87–5.26) and infectious (HR 4.07, 95% CI 3.70–4.47) diseases. Overall and for each specific cause, there have been improvements for the MS group and a subsequent reduction in the HR. The HR decreased from 6.52 (95% CI 5.79–7.34) for the period of 1968 to 1980 to 2.08 (95% CI 1.95–2.22) for the time period of 2001 to 2012. An interaction between time period and MS exposure showed that the decrease in mortality over time was statistically significant, with a larger decrease for patients with MS than their matched comparators.

Conclusions:

There has been a substantial improvement in mortality overall and for each specified cause of death for patients with MS compared with individuals without MS; however, large differences still remain.




Breastfeeding, ovulatory years, and risk of multiple sclerosis

2017-08-07T12:49:00-07:00

Objective:

To determine whether women who breastfeed their infants longer or have fewer ovulatory years are at lower risk of developing multiple sclerosis (MS).

Methods:

We recruited women with newly diagnosed MS or its precursor, clinically isolated syndrome (CIS) (n = 397), and matched controls (n = 433) into the MS Sunshine Study from the membership of Kaiser Permanente Southern California. A structured in-person questionnaire was administered to collect the behavioral (pregnancies, breastfeeding, hormonal contraceptive use) and biological (age at menarche and menopause, amenorrhea) factors to make up ovulatory years.

Results:

Among women who had live births, a cumulative duration of breastfeeding for ≥15 months was associated with a reduced risk of MS/CIS (adjusted odds ratio [OR] 0.47, 95% confidence interval [CI] 0.28–0.77; p = 0.003 compared to 0–4 months of breastfeeding). Being ≥15 years of age at menarche was also associated with a lower risk of MS/CIS (adjusted OR 0.56, 95% CI 0.33–0.96; p = 0.035). Total ovulatory years and the remaining factors that determine it, including gravidity, parity, episodes of amenorrhea, and hormonal contraceptive use, as well as age at first birth, showed no significant association with the risk of MS/CIS.

Conclusions:

Mothers who breastfeed longer may be at lower subsequent risk of developing multiple sclerosis. This is consistent with the other known maternal health benefits of breastfeeding and with our previous observation that women with MS who breastfeed exclusively are at lower risk of postpartum relapses.




Behavioral-variant frontotemporal dementia: Distinct phenotypes with unique functional profiles

2017-08-07T12:49:00-07:00

Objective: To identify distinct behavioral phenotypes of behavioral-variant frontotemporal dementia (bvFTD) and to elucidate differences in functional, neuroimaging, and progression to residential care placement. Methods: Eighty-eight patients with bvFTD were included in a cluster analysis applying levels of disinhibition and apathy (Cambridge Behavioural Inventory-Revised) to identify phenotypic subgroups. Between-group (Kruskal-Wallis, Mann-Whitney U) functional differences (Disability Assessment for Dementia) and time to residential care placement (survival analyses) were examined. Cortical thickness differences (whole-brain MRI) were analyzed in patients with bvFTD vs healthy controls (n = 30) and between phenotypic subgroups. Results: Four phenotypic subgroups were identified: primary severe apathy (n = 26), severe apathy and disinhibition (n = 26), mild apathy and disinhibition (n = 27), and primary severe disinhibition (n = 9). Patients with severely apathetic phenotypes were more functionally impaired and had more extensive brain atrophy than those with mild apathy or severe disinhibition alone. Further imaging analyses indicated that the right middle temporal region is critical for the development of disinhibition, an association that remains with disease progression and in the context of severe apathy. Finally, no difference in time to residential care admission was found between phenotypes. Conclusions: This study reveals that different clinical behavioral phenotypes of bvFTD have differing profiles of functional decline and distinct patterns of associated cortical changes. These findings emphasize the importance of apathy in functional impairment, highlight the role of the right temporal region in disinhibition, and suggest that disability may be a sensitive outcome measure for treatments targeting reduction of apathy. These phenotypes could also support understanding of prognosis and clinical management. [...]



Neurodegenerative and psychiatric diseases among families with amyotrophic lateral sclerosis

2017-08-07T12:49:01-07:00

Objective: To estimate risks of neurodegenerative and psychiatric diseases among patients with amyotrophic lateral sclerosis (ALS) and their families. Methods: We conducted a register-based nested case-control study during 1990–2013 in Sweden to assess whether patients with ALS had higher risks of other neurodegenerative and psychiatric diseases before diagnosis. We included 3,648 patients with ALS and 36,480 age-, sex-, and county of birth–matched population controls. We further conducted a follow-up study of the cases and controls to assess the risks of other neurodegenerative and psychiatric diseases after ALS diagnosis. To assess the potential contribution of familial factors, we conducted similar studies for the relatives of patients with ALS and their controls. Results: Individuals with previous neurodegenerative or psychiatric diseases had a 49% increased risk of ALS (odds ratio 1.49, 95% confidence interval 1.35–1.66) compared to individuals without these diseases. After diagnosis, patients with ALS had increased risks of other neurodegenerative or psychiatric diseases (hazard ratio 2.90, 95% confidence interval 2.46–3.43) compared to individuals without ALS. The strongest associations were noted for frontotemporal dementia, Parkinson disease, other dementia, Alzheimer disease, neurotic disorders, depression, stress-related disorders, and drug abuse/dependence. First-degree relatives of patients with ALS had higher risk of neurodegenerative diseases, whereas only children of patients with ALS had higher risk of psychiatric disorders, compared to relatives of the controls. Conclusions: Familial aggregation of ALS and other neurodegenerative diseases implies a shared etiopathogenesis among all neurodegenerative diseases. The increased risk of psychiatric disorders among patients with ALS and their children might be attributable to nonmotor symptoms of ALS and severe stres[...]



Loss of phosphodiesterase 4 in Parkinson disease: Relevance to cognitive deficits

2017-08-07T12:49:01-07:00

Objective: To assess in vivo the expression of phosphodiesterase 4 (PDE4) and its relevance to cognitive symptoms in patients with Parkinson disease (PD) using [11C]rolipram PET. Methods: We studied 12 levodopa-treated patients with PD with no concurrent diagnosis of mild cognitive impairment or dementia. Their data were compared with those from 12 healthy controls. All participants underwent neuropsychiatric and cognitive assessment using the Cambridge Neuropsychological Test Automated Battery. Parametric images of [11C]rolipram volume of distribution (VT) values were determined with the Logan plot. Results: Patients with PD performed worse than healthy controls in cognitive examinations assessing psychomotor speed, episodic memory, and spatial working memory and executive function. Patients with PD showed reductions in [11C]rolipram VT compared to healthy controls, in the caudate (28%), thalamus (23%), hypothalamus (32%), and cortex (16%). Within thalamic subregions, [11C]rolipram VT values in patients with PD were decreased by 12%–32%, with most marked decreases observed in prefrontal and temporal thalamic nuclei, whereas motor nuclei were less affected. Within the cortex, [11C]rolipram VT values in patients with PD were decreased by 11%–20%, with most marked decreases observed in posterior dorsolateral frontal cortex, medial frontal cortex, and supplementary motor area, whereas orbitofrontal cortex was less affected. Worse performance in spatial working memory correlated with lower [11C]rolipram VT values in posterior dorsolateral frontal cortex, medial frontal cortex, supplementary motor area, precentral gyrus, caudate, and prefrontal thalamic nuclei. Conclusions: Our findings demonstrate loss of PDE4 expression in the striato-thalamo-cortical circuit, which is associated with deficits of spatial working memory in patients with PD. [...]



The CREST-E study of creatine for Huntington disease: A randomized controlled trial

2017-08-07T12:49:01-07:00

Objective: To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease. Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies. Results: At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits –0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment. Conclusions: Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD. Clinicaltrials.gov identifier: NCT00712426. Classification of evidence: This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline. [...]



Assessing structure and function of myelin in cervical spondylotic myelopathy: Evidence of demyelination

2017-08-07T12:49:01-07:00

Purpose:

To assess the extent of demyelination in cervical spondylotic myelopathy (CSM) using myelin water imaging (MWI) and electrophysiologic techniques.

Methods:

Somatosensory evoked potentials (SSEPs) and MWI were acquired in 14 patients with CSM and 18 age-matched healthy controls. MWI was performed on a 3.0T whole body magnetic resonance scanner. Myelin water fraction (MWF) was extracted for the dorsal columns and whole cord. SSEPs and MWF were also compared with conventional MRI outcomes, including T2 signal intensity, compression ratio, maximum spinal cord compression (MSCC), and maximum canal compromise (MCC).

Results:

Group analysis showed marked differences in T2 signal intensity, compression ratio, MSCC, and MCC between healthy controls and patients with CSM. There were no group differences in MWF and SSEP latencies. However, patients with CSM with pathologic SSEPs exhibited reduction in MWF (p < 0.05). MWF was also correlated with SSEP latencies.

Conclusion:

Our findings provide evidence of decreased myelin content in the spinal cord associated with impaired spinal cord conduction in patients with CSM. While conventional MRI are of great value to define the extent of cord compression, they show a limited correlation with functional deficits (i.e., delayed SSEPs). MWI provides independent and complementary readouts to spinal cord compression, with a high specificity to detect impaired conduction.




Jules Dejerine and the peripheral nervous system

2017-08-07T12:49:01-07:00

Jules Dejerine (1849–1917) was a French neurologist who contributed to the description of numerous neurologic conditions ranging from neurovascular pathology to neuromuscular disorders. A considerable body of his research was devoted to the peripheral nervous system. In this area, the eponymous Dejerine-Sottas syndrome refers to a form of infantile hereditary neuropathy. Dejerine also contributed to the description of many other disorders of the peripheral nervous system and was even a precursor in the study of acquired neuropathies (as well as acute inflammatory neuropathies, before the first description of the Guillain-Barré syndrome) and in the field of radicular pathology. In this centennial year of his death, we emphasize the variety and originality of Dejerine’s opus on diseases of the peripheral nervous system.




Teaching neurology to medical students with a simplified version of team-based learning

2017-08-07T12:49:01-07:00

Objective:

To compare the effect of a simplified version of team-based learning (sTBL), an active learning/small group instructional strategy, with that of the traditionally used small group interactive seminars on the acquisition of knowledge and clinical reasoning (CR) skills.

Methods:

Third- and fourth-year medical students (n = 122) were randomly distributed into 2 groups. A crossover design was used in which 2 neurologic topics were taught by sTBL and 2 by small group interactive seminars. Knowledge was assessed with a multiple-choice question examination (MCQE), CR skills with a key feature problem examination (KFPE). Questionnaires were used for further methodologic evaluation.

Results:

No group differences were found in the MCQE results. sTBL instruction of the topic "acute altered mental status" was associated with a significantly better student performance in the KFPE (p = 0.008), with no differences in the other 3 topics covered. Although both teaching methods were highly rated by the students, a clear majority voted for sTBL as their preferred future teaching method.

Conclusions:

sTBL served as an equivalent alternative to small group interactive seminars for imparting knowledge and teaching CR skills, and was particularly advantageous for teaching CR in the setting of a complex neurologic topic. Furthermore, students reported a strong preference for the sTBL approach, making it a promising tool for effectively teaching neurology.




The spectrum of mild traumatic brain injury: A review

2017-08-07T12:49:01-07:00

Objective:

This review provides an in-depth overview of diagnostic schema and risk factors influencing recovery during the acute, subacute (operationally defined as up to 3 months postinjury), and chronic injury phases across the full spectrum of individuals (e.g., athletes to neurosurgery patients) with mild traumatic brain injury (mTBI). Particular emphasis is placed on the complex differential diagnoses for patients with prolonged postconcussive symptoms.

Methods:

Select literature review and synthesis.

Results:

In spite of an increase in public awareness surrounding the acute and potential long-term effects of mTBI, the medical field remains fragmented both in terms of the diagnostic (different criteria proffered by multiple medical organizations) and prognostic factors that influence patient care.

Conclusions:

Given the lack of objective biomarkers and the spectrum of different disorders that likely encompass mTBI, clinicians are encouraged to adopt a probabilistic, rather than definitive, diagnostic and prognostic framework. The relevance of accurately diagnosing and managing the different manifestations of mTBI becomes clear when one considers the overall incidence of the disorder (42 million people each year worldwide), and the different treatment implications for patients with a true neurodegenerative disorder (e.g., chronic traumatic encephalopathy; rare) vs potentially treatable conditions (e.g., depression or posttraumatic headache; frequent).




Wrist sensor reveals sympathetic hyperactivity and hypoventilation before probable SUDEP

2017-08-07T12:49:01-07:00

We report a probable sudden unexpected death in epilepsy (SUDEP) in a 20-year-old man wearing a smartwatch that recorded wrist motion via 3-axis accelerometer (ACC) and electrodermal activity (EDA). EDA reflects sympathetic activity without parasympathetic antagonism.1 The smartwatch (Empatica [Milan, Italy] Embrace, with CE Medical clearance from the European Union for seizure detection) issued an alert, received by the caregiver at 8:50 am, indicating a probable convulsive seizure. An adult trained in cardiopulmonary resuscitation (CPR) arrived at 9:05 am, found the patient pulseless, prone, face in pillow with mucus in his mouth, and commenced CPR for 15 minutes without recovery. The family declined autopsy.




All noble things

2017-08-07T12:49:01-07:00

Connecticut knows from whales.




Bilateral ape hand deformity

2017-08-07T12:49:01-07:00

A 54-year-old man with a history of alcohol abuse (>2 bottles of wine per day for 40 years) presented with 2 years of progressive weakness in all 4 limbs. Alcoholic polyneuropathy was diagnosed on clinical grounds and gabapentin was used for alcohol withdrawal.1




Editors' Note

2017-08-07T12:49:01-07:00

Editors' Note: In reference to "Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy," Dr. Papanicolaou et al. discuss whether functional MRI (fMRI) evaluation for language dominance in epilepsy surgery can be considered reliable given the high rate of false-positives inherent in fMRI data processing. In support, guideline editors Gloss et al. cite the high concordance between fMRI and amobarbital testing and explain how the method of analysis used in hemispheric language assessment has been shown to be less prone to statistical error.




Letter re: Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

2017-08-07T12:49:01-07:00

The American Academy of Neurology (AAN) endorsement for the use of fMRI evaluation of hemispheric dominance for language in epilepsy surgery candidates1 appears as an odd and disconcerting sequel to the article by Eckland et al.,2 which reported that the clustering approach in functional MRI (fMRI) data processing may be responsible for an excessively high rate of false-positive findings. The latter report implied that up to 70% of the significant fMRI effects reported in approximately 40,000 peer-reviewed publications could represent no brain physiology facts, but type I statistical errors to the degree that they employed clustering of activated voxels.2 Consequently, it is fitting to suggest users of these popular fMRI software packages (SPM, FSL, AFNI) reconsider conclusions based on differences in activation levels of voxel clusters between task conditions. This raises the question of whether those who use the clustering procedure for the purpose of assessing hemisphere dominance for language should be alarmed for having made incorrect assessments in the past and refrain from using them for the same purpose in the future. Our answer is no, since language laterality judgments are typically made on the basis of laterality indices (i.e., the relative degree of activation defined as the ratio of left- and right-hemisphere activated voxels that are equally likely or unlikely to be activated). However, depending on how users of these automated software packages derive estimates of localization of the language network hubs (a practice not endorsed by the AAN),1 they may need to exercise more caution now that the [...]



Author response: Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

2017-08-07T12:49:01-07:00

We thank Papanicolaou et al. for the comment on our article,1 and agree that important issues were raised regarding thresholding methods in functional MRI (fMRI).2 However, the original estimate of the number of studies potentially affected was substantially lowered.3,4 Imprecision is part of every diagnostic test; its presence in thresholded fMRI activation maps is unlikely to lead to spurious lateralized correlations between cognitive tasks and blood oxygenation level–dependent signal, or to agreement between fMRI and other investigations. As Papanicolaou et al. note, laterality measures are likely robust to the occurrence of false-positive clusters, since they are derived from side-to-side ratios.




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

2017-08-07T12:49:01-07:00

Noting variability around epilepsy burden estimates, Fiest et al.1 aimed to provide "a comprehensive synthesis of the prevalence and incidence of epilepsy from published international studies."1 This article, which may be widely cited, is problematic.




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

2017-08-07T12:49:01-07:00

We thank Zack and Kobau for their interest in our article.1 We agree there is marked heterogeneity among studies and acknowledged this throughout the article. We attempted to mitigate heterogeneity by using a random effects model and reported medians with 25th and 75th percentiles alongside pooled estimates to provide readers with a more complete picture of data distribution and heterogeneity. In the article, we also identified geographic outliers.1 Despite marked heterogeneity, pooled estimates and medians were similar. Together, they provide a valid overview of this literature and were accompanied in the article by appropriately cautionary statements about their interpretation.1 Further, we attempted formal analyses of sources of heterogeneity, which proved difficult and did not yield definitive conclusions, and provided these results in supplementary e-tables.1










Clinical Reasoning: A 22-year-old man with diplopia

2017-07-31T12:48:35-07:00

A 22-year-old previously healthy man presented to an ophthalmology clinic with binocular horizontal diplopia. He had recently traveled to the main island of Hawaii. About 2 weeks after returning home, he developed a severe headache with associated fever, emesis, photophobia, phonophobia, and neck stiffness. He also reported a sensation of pressure in his left eye and both ears but denied any pulsatile tinnitus or transient vision loss. Over the next 2 weeks, his headaches worsened, causing him to wake up frequently in the night. He then developed horizontal diplopia that was worse at a distance and was referred to the neuro-ophthalmology clinic.




Pearls & Oy-sters: Transient neurologic events in a patient with leptomeningeal metastases

2017-07-31T12:48:35-07:00

Patients with leptomeningeal metastases (LM) may develop transient neurologic events in the setting of temporary elevations of intracranial pressure (ICP).




Teaching NeuroImages: Bilateral intracerebral hemorrhage in expanded dengue syndrome

2017-07-31T12:48:35-07:00

A 66-year-old Brazilian woman presented with fever, malaise, and myalgia, followed 10 days later by left hemiparesis and altered mental status. Brain MRI revealed bilateral intracerebral hemorrhages (figure, A and B) and CSF showed mild lymphocytic pleocytosis. Serologic testing for dengue fever was positive. Brain biopsy demonstrated nonspecific inflammatory changes and areas of recent hemorrhage and necrosis (figure, C). After 1 month, partial clinical and radiologic improvement occurred (figure, D). Expanded dengue syndrome1 refers to atypical manifestations of dengue such as intracerebral hemorrhage, which is a rare presentation usually reported a week after fever onset, possibly related to release of cytokines with vasogenic activity.2




Teaching Video NeuroImages: Running into a "useless" hand

2017-07-31T12:48:35-07:00

A 68-year-old woman presented with an insidious onset of strictly asymmetric left arm clumsiness (video at Neurology.org) in absence of any brain lesion but mild right hemisphere hypotrophy (figure). The presence of limb apraxia and bradykinesia fostered the clinical diagnosis of possible corticobasal syndrome, in the context of suspected corticobasal degeneration.1 Bradykinesia and apraxia are 2 possible different faces of hypokinesia; their correct discrimination is not a diagnostic problem if a higher-level disturbance of praxis is present. An isolated limb apraxia is a confounder, and its early recognition allows clinicians to suspect parkinsonism with apraxia as a prominent feature.2