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Clinical Reasoning: A 73-year-old man with sarcoidosis and multifocal ischemic strokes

2016-09-19T12:45:32-07:00

A 73-year-old man was admitted for evaluation of acute ischemic strokes. His medical history was notable for pulmonary sarcoidosis treated with oral prednisone 40 mg daily, type 2 diabetes mellitus, hypertension, and hyperlipidemia. Approximately 1 month prior to admission, he underwent elective right total knee arthroplasty at an outside institution and 1 week postoperatively developed acute delirium and fluctuating fevers. No infectious cause was identified. His mental status continued to decline and head MRI was obtained (figure, A), showing small acute infarcts in multiple vascular territories.




Clinical Reasoning: A case of subacute cognitive decline in a 76-year-old man

2016-09-19T12:45:32-07:00

A 76-year-old, right-handed man presented to our emergency department with a 3-day history of cognitive decline following a motor vehicle collision. Medical history included hypertension, atrial fibrillation, and renal dysfunction. He was a high-functioning retired advertising executive who formerly smoked cigarettes, and used neither recreational drugs nor alcohol.




Teaching NeuroImages: Skull and dural lesions in neurosyphilis

2016-09-19T12:45:32-07:00

A 42-year-old man who was HIV negative presented with supraclavicular lymphadenopathy, headache, and soft tissue enlargement in the right temporal region. MRI showed a periosteum enlargement associated with dural thickening (figure, A and B). A venereal disease research laboratory test was 1/1,024, with an increased CSF protein level and cell count. The patient received benzylpenicillin and exhibited complete remission of the lesions (figure, C and D). Although atypical, bone disease in secondary syphilis may occur, especially in the skull. It is usually described as subcutaneous lesions, edema in the adjacent bone medullary, and dural thickening. For patients with this imaging pattern, syphilis should be included in the differential diagnosis.1,2




Teaching Video NeuroImages: Primary writing tremor: Lessons from a patient with multiple sclerosis

2016-09-19T12:45:32-07:00

A 30-year-old woman with recurring optic neuritis presented with tremor affecting her right hand when writing only (video at Neurology.org). An MRI brain (figure) revealed lesions in the left midbrain, right middle cerebellar peduncle, and left cerebellar hemisphere.




Spotlight on the September 20 Issue

2016-09-19T12:45:31-07:00




Hypertension prevention: In need of a grain of salt knowledge

2016-09-19T12:45:31-07:00

Noncommunicable diseases (NCDs) are further deteriorating the health of populations in low-income settings, while those populations are still struggling with a substantial burden of infectious diseases.1,2 Therefore, research aimed at elucidating factors driving NCDs and identifying potential approaches to addressing the NCD burden in these regions is desperately needed. In a collaborative effort between Ugandan investigators and US researchers from Case Western and the University of Kentucky, Kaddumukasa et al.3 report important findings that may offer critical insights into the development of effective interventions for preventing hypertension and its associated adverse outcomes in Africa.




Seeking the "holy grail" of biomarkers to improve stroke risk prediction of clinical scores

2016-09-19T12:45:32-07:00

Biomarkers are defined as "objective indications of medical state observed from outside the patient—which can be measured accurately and reproducibly."1 Biomarkers have 3 major potential roles in clinical practice: (1) to help the patient understand their risk of disease, which could lead to direct improvement of quality of life; (2) to direct the patient to make lifestyle changes that could improve health, such as restricting or improving dietary choices, becoming more active, and adhering to a plan laid out in collaboration with their physician; and (3) to direct a medical professional to make a (better) clinical decision based on known risk factors or disease(s) associated with a specific biomarker(s).2 Given the complex pathophysiology of ischemic stroke, biomarkers that can stratify risk and identify those individuals most likely to have a cerebrovascular event are considered the "holy grail" of prognostic tools.




Lord Walton of Detchant, MD (1922-2016)

2016-09-19T12:45:32-07:00

With the passing of Lord Walton of Detchant—Dr. John Walton—on April 21, 2016, neurology lost one of the most distinguished figures of our specialty and the man who was arguably the founding father of clinical myology. John Walton was born in the United Kingdom in Co. Durham on September 16, 1922. He began his medical career at Newcastle Medical School in 1941, graduating after a course shortened by World War II in 1945. After serving in the Royal Army Medical Corps, he returned to Newcastle as a medical registrar. Inspired by Dr. Henry Miller to become a neurologist, he joined Prof. F.J. Nattras, who directed him to study all of the patients in the region with neuromuscular disorders. He often cited an incident from that time as being a defining moment in his career: meeting a family with 3 sons with Duchenne dystrophy, with the inevitable awful prognosis. The outcome of that work was the seminal publication "On the classification, natural history and treatment of the myopathies."1 In the monograph "Polymyositis," written jointly with Raymond Adams,2 he showed how careful clinical and pathologic assessment could help prevent misdiagnosis, previously common, as muscular dystrophy.




Influence of sodium consumption and associated knowledge on poststroke hypertension in Uganda

2016-09-19T12:45:32-07:00

Objective:

We assessed 24-hour urine sodium levels as an index of dietary salt consumption and its association with dietary salt knowledge and hypertension among poststroke patients with and without a history of hypertension in Uganda.

Methods:

A case-control study in which poststroke patients with a history of hypertension (cases, n = 123) were compared to poststroke patients without known hypertension (controls, n = 112). Dietary salt intake was assessed by 24-hour urine sodium, a valid measure of dietary salt consumption. Dietary salt knowledge was determined by questionnaire. The independent relationships among salt knowledge, 24-hour urine sodium, and blood pressure control were assessed using multiple regression analysis.

Results:

High 24-hour urine sodium (≥8.5 g/d) was 2 times more prevalent among hypertensive poststroke patients than controls (p = 0.002). Patients with minimal poststroke disability who had a choice in determining their diets had higher urine sodium than their more disabled counterparts. Only 43% of the study population had basic dietary salt knowledge, 39% had adequate diet-disease–related knowledge, and 37% had procedural knowledge (report of specific steps being taken to reduce salt consumption). Dietary salt knowledge was similarly poor among cases and controls (p = 0.488) and was not related to education level (p = 0.205).

Conclusions:

High urine sodium and high salt-diet preferences were more frequent among poststroke hypertensive patients in Uganda than in their nonhypertensive counterparts. There was, however, no difference in dietary salt knowledge between these groups. The development of educational strategies that include salt-diet preferences may lead to better blood pressure control in this high-risk population.




Circulating biomarkers and incident ischemic stroke in the Framingham Offspring Study

2016-09-19T12:45:32-07:00

Objective:

We related a panel of inflammatory biomarkers to risk of incident ischemic stroke (IIS) in a community-dwelling sample.

Methods:

Stroke-free Framingham offspring attending examination cycle 7 (1998–2001) had 15 circulating inflammatory biomarkers measured. Cox proportional hazard models were used to calculate the hazard ratios (HRs) of IIS per SD increment of each biomarker. Model 1 included age and sex. Model 2 additionally adjusted for systolic blood pressure, hypertension treatment, current smoking, diabetes, cardiovascular disease, and atrial fibrillation. The continuous net reclassification improvement was used to assess the improvement in IIS risk prediction of statistically significant biomarkers from our main analysis over traditional stroke risk factors.

Results:

In 3,224 participants (mean age 61 ± 9 years, 54% women), 98 experienced IIS (mean follow-up of 9.8 [±2.2] years). In model 1, ln–C-reactive protein (ln-CRP) (HR 1.28, 95% confidence interval [CI] 1.04–1.56), ln–tumor necrosis factor receptor 2 (ln-TNFR2) (HR 1.33, 95% CI 1.09–1.63), ln–total homocysteine (ln-tHcy) (HR 1.32, 95% CI 1.11–1.58), and vascular endothelial growth factor (VEGF) (HR 1.25, 95% CI 1.07–1.46) were associated with risk of IIS. All associations, except for ln-CRP, remained significant in model 2 (ln-TNFR2: HR 1.24, 95% CI 1.02–1.51; ln-tHcy: HR 1.20, 95% CI 1.01–1.43; and VEGF: HR 1.21, 95% CI 1.04–1.42). The addition of these 4 biomarkers to the clinical Framingham Stroke Risk Profile score improved stroke risk prediction (net reclassification improvement: 0.34, 0.12–0.57; p < 0.05).

Conclusions:

Higher levels of 4 biomarkers—CRP, tHcy, TNFR2, and VEGF—increased risk of IIS and improved the predictive ability of the Framingham Stroke Risk Profile score. Further research is warranted to explore their role as potential therapeutic targets.




Accelerated development of cerebral small vessel disease in young stroke patients

2016-09-19T12:45:32-07:00

Objective:

To study the long-term prevalence of small vessel disease after young stroke and to compare this to healthy controls.

Methods:

This prospective cohort study comprises 337 patients with an ischemic stroke or TIA, aged 18–50 years, without a history of TIA or stroke. In addition, 90 age- and sex-matched controls were included. At follow-up, lacunes, microbleeds, and white matter hyperintensity (WMH) volume were assessed using MRI. To investigate the relation between risk factors and small vessel disease, logistic and linear regression were used.

Results:

After mean follow-up of 9.9 (SD 8.1) years, 337 patients were included (227 with an ischemic stroke and 110 with a TIA). Mean age of patients was 49.8 years (SD 10.3) and 45.4% were men; for controls, mean age was 49.4 years (SD 11.9) and 45.6% were men. Compared with controls, patients more often had at least 1 lacune (24.0% vs 4.5%, p < 0.0001). In addition, they had a higher WMH volume (median 1.5 mL [interquartile range (IQR) 0.5–3.7] vs 0.4 mL [IQR 0.0–1.0], p < 0.001). Compared with controls, patients had the same volume WMHs on average 10–20 years earlier. In the patient group, age at stroke (β = 0.03, 95% confidence interval [CI] 0.02–0.04) hypertension (β = 0.22, 95% CI 0.04–0.39), and smoking (β = 0.18, 95% CI 0.01–0.34) at baseline were associated with WMH volume.

Conclusions:

Patients with a young stroke have a higher burden of small vessel disease than controls adjusted for confounders. Cerebral aging seems accelerated by 10–20 years in these patients, which may suggest an increased vulnerability to vascular risk factors.




Diskogenic microspurs as a major cause of intractable spontaneous intracranial hypotension

2016-09-19T12:45:32-07:00

Objective:

To visualize and treat spinal dural CSF leaks in all patients with intractable spontaneous intracranial hypotension (SIH) who underwent spinal microsurgical exploration.

Methods:

Patients presenting between February 2013 and July 2015 were included in this consecutive case series. The workup included spinal MRI without and with intrathecal contrast, dynamic myelography, postmyelography CT, and microsurgical exploration.

Results:

Of 69 consecutive patients, 15 had intractable symptoms. Systematic imaging revealed a suspicious single location of the leak in these 15 patients. Fourteen patients underwent microsurgical exploration; 1 patient refused surgery. Intraoperatively, including intradural exploration, we identified the cause of the CSF leaks as a longitudinal dural slit (6.1 ± 1.7 mm) on the ventral (10), lateral (3), or dorsal (1) aspect of the dura. In 10 patients (71%), a ventral, calcified microspur originating from the intervertebral disk perforated the dura like a knife. Three patients (22%) had a lateral dural tear with an associated spinal meningeal diverticulum, and in 1 patient (7%), a dorsal osteophyte was causal. The microspurs were removed and the dural slits sutured with immediate cessation of CSF leakage.

Conclusion:

The nature of the CSF leak is a circumscribed longitudinal slit at the ventral, lateral, or dorsal dura mater. An extradural pathology, diskogenic microspurs, was the single cause for all ventral CSF leaks. These findings challenge the notion that CSF leaks in SIH are idiopathic or due to a weak dura. Microsurgery is the treatment of choice in cases with intractable SIH.




Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome

2016-09-19T12:45:32-07:00

Objective:

To use multimodal neuroimaging to evaluate the influence of heterogeneous underlying pathology in corticobasal syndrome (CBS) on the neuroanatomical distribution of disease.

Methods:

We performed a retrospective evaluation of 35 patients with CBS with T1-weighted MRI, diffusion tensor imaging, and neuropathologic, genetic, or CSF evidence of underlying pathology. Patients were assigned to 2 groups: those with evidence of Alzheimer pathology (CBS-AD) and those without Alzheimer pathology (CBS–non-AD). Group comparisons of CBS-AD and CBS–non-AD assessed clinical features, gray matter (GM) cortical thickness, and white matter (WM) fractional anisotropy.

Results:

CBS-AD was found in 34% (n = 12) and CBS–non-AD in 66% (n = 23) of CBS patients. Clinical evaluations revealed that CBS–non-AD had a higher frequency of asymmetric rigidity compared to CBS-AD, but groups otherwise did not differ in dementia severity, impairments in cognition, or rates of extrapyramidal symptoms. We found frontoparietal GM and WM disease in each group compared to healthy, demographically comparable controls, as well as multimodal neuroimaging evidence of a double dissociation: CBS–non-AD had WM disease in the corpus callosum, corticospinal tract, and superior longitudinal fasciculus relative to CBS-AD, and CBS-AD had reduced temporoparietal GM relative to CBS–non-AD, including the precuneus and posterior cingulate.

Conclusions:

Patients with CBS have a pathology-mediated dissociation of GM and WM disease. Multimodality neuroimaging may be useful for improving in vivo pathologic diagnosis of CBS.




Enrichment of clinical trials in MCI due to AD using markers of amyloid and neurodegeneration

2016-09-19T12:45:32-07:00

Objective:

To investigate the effect of enriching mild cognitive impairment (MCI) clinical trials using combined markers of amyloid pathology and neurodegeneration.

Methods:

We evaluate an implementation of the recent National Institute for Aging–Alzheimer's Association (NIA-AA) diagnostic criteria for MCI due to Alzheimer disease (AD) as inclusion criteria in clinical trials and assess the effect of enrichment with amyloid (A+), neurodegeneration (N+), and their combination (A+N+) on the rate of clinical progression, required sample sizes, and estimates of trial time and cost.

Results:

Enrichment based on an individual marker (A+ or N+) substantially improves all assessed trial characteristics. Combined enrichment (A+N+) further improves these results with a reduction in required sample sizes by 45% to 60%, depending on the endpoint.

Conclusions:

Operationalizing the NIA-AA diagnostic criteria for clinical trial screening has the potential to substantially improve the statistical power of trials in MCI due to AD by identifying a more rapidly progressing patient population.




Adjunctive pregabalin vs gabapentin for focal seizures: Interpretation of comparative outcomes

2016-09-19T12:45:32-07:00

Objective:

To evaluate the comparative safety and adjunctive efficacy of pregabalin and gabapentin in reducing seizure frequency in patients with partial-onset seizures based on prestudy modeling showing superior efficacy for pregabalin.

Methods:

The design of this comparative efficacy and safety study of pregabalin and gabapentin as adjunctive treatment in adults with refractory partial-onset seizures was randomized, flexible dose, double blind, and parallel group. The study included a 6-week baseline and a 21-week treatment phase. The primary endpoint was the percentage change from baseline in 28-day seizure rate to the treatment phase.

Results:

A total of 484 patients were randomized to pregabalin (n = 242) or gabapentin (n = 242). Of these, 359 patients (187 pregabalin, 172 gabapentin) completed the treatment phase. The observed median and mean in percentage change from baseline was –58.65 and –47.7 (SD 48.3) for pregabalin and –57.43 and –45.28 (SD 60.6) for gabapentin. For the primary endpoint, there was no significant difference between treatments. The Hodges-Lehman estimated median difference was 0.0 (95% confidence interval –6.0 to 7.0). Safety profiles were comparable and consistent with prior trials.

Conclusions:

The absence of the anticipated efficacy difference based on modeling of prior, nearly identical trials and the larger-than-expected response rates of the 2 antiepileptic drugs were unexpected. These findings raise questions that are potentially important to consider in future comparative efficacy trials.

ClinicalTrials.gov identifier:

NCT00537940.

Classification of evidence:

This study provides Class II evidence that for patients with partial seizures enrolled in this study, pregabalin is not superior to gabapentin in reducing seizure frequency. Because of the atypical response rates, the results of this study are poorly generalizable to other epilepsy populations.




Cancer risk in DM1 is sex-related and linked to miRNA-200/141 downregulation

2016-09-19T12:45:32-07:00

Objective:

Describe the incidence of cancer in a large cohort of patients with myotonic dystrophy type 1 (DM1) and to unravel the underlying molecular mechanisms.

Methods:

Standardized incidence ratios (SIRs) were calculated in the Gipuzkoa DM1 cohort (1985–2013), dividing observed numbers by expected numbers for all cancers combined and stratified by sex. An estimation of the expected incidence was achieved by multiplying the age- and sex-specific incidence rates from the Basque population cancer registry by the person-years observed in the study cohort. Large-scale gene expression of peripheral blood mononuclear cell samples derived from 10 individuals with DM1 (5 men, 5 women) and 10 healthy matched controls was analyzed by the Human Gene 1.0 ST Affymetrix microarray.

Results:

During 18,796 person-years of follow-up, corresponding to 424 patients with DM1, we observed 70 cancers in 62 patients giving a 1.81-fold risk (95% confidence interval [CI] 1.37–2.36), which was stronger in women than in men. Ovary (SIR 8.33, 95% CI 1.72–24.31) and endometrium (SIR 6.86, 95% CI 2.23–16.02) in women and thyroid (SIR 23.33, 95% CI 9.38–48.08) and brain (SIR 9.80, 95% CI 3.18–22.88) in both sexes were tumor sites with significantly higher risks in DM1. There were differences in gene expression between healthy controls and patients with DM1 and between men and women with DM1; all patients with DM1 combined and female patients with DM1 displayed significant downregulation of the microRNA (miRNA)-200c/141 tumor suppressor family.

Conclusions:

Oncologic risk is increased in DM1, especially in women and for gynecologic, brain, and thyroid cancer. Expression of the miRNA-200/miRNA-141 tumor suppressor family is decreased in women with DM1.




Acute intermittent porphyria-related leukoencephalopathy

2016-09-19T12:45:32-07:00

Objective:

To identify the genetic etiology of a distinct leukoencephalopathy with autosomal recessive inheritance in a single family.

Methods:

We analyzed available MRIs and retrospectively reviewed clinical information and laboratory investigations. We performed whole-exome sequencing to find the causal gene variants.

Results:

We identified 3 family members with a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons. Cerebellar atrophy was noted in advanced disease stages. Clinical features were childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. Whole-exome sequencing revealed compound heterozygous missense variants in the HMBS gene, both associated with the autosomal dominant disorder acute intermittent porphyria. Sanger sequencing of 6 healthy siblings confirmed the bi-allelic location of the variants and segregation with the disease. Patients had a slight and moderate increase in urinary and plasma porphobilinogen and 5'-aminolevulinic acid, respectively, and a 50% to 66% decrease in hydroxymethylbilane synthase enzyme activity compared to normal.

Conclusions:

Bi-allelic HMBS variants have been reported before as cause of severe encephalopathy with early childhood fatality in acute intermittent porphyria. Our cases demonstrate childhood onset, but milder and slower disease progression in middle-aged patients. With this, a novel phenotype can be added to the disease spectrum associated with bi-allelic HMBS variants: a leukoencephalopathy with early onset, slowly progressive neurologic symptomatology, and long life expectancy.




MR parkinsonism index predicts vertical supranuclear gaze palsy in patients with PSP-parkinsonism

2016-09-19T12:45:32-07:00

Objective:

To identify a biomarker for predicting the appearance of vertical supranuclear gaze palsy (VSGP) in patients affected by progressive supranuclear palsy–parkinsonism (PSP-P).

Methods:

Twenty-four patients with PSP-P were enrolled in the current study. Patients were clinically followed up every 6 months until the appearance of VSGP or the end of the follow-up (4 years). Participants underwent MRI at baseline and at the end of follow-up. Magnetic resonance parkinsonism index (MRPI), an imaging measure useful for diagnosing PSP, was calculated.

Results:

Twenty-one patients with PSP-P completed follow-up, and 3 patients dropped out. Eleven of 21 patients with PSP-P developed VSGP after a mean follow-up period of 28.5 months (range 6–48 months), while the remaining 10 patients with PSP-P did not develop VSGP during the 4-year follow-up period. At baseline, patients with PSP-P who later developed VSGP had MRPI values significantly higher than those of patients not developing VSGP without overlapping values between the 2 groups. MRPI showed a higher accuracy (100%) in predicting VSGP than vertical ocular slowness (accuracy 33.3%) or postural instability with or without vertical ocular slowness (accuracy 71.4% and 42.9%, respectively).

Conclusions:

Our study demonstrates that MRPI accurately predicted, on an individual basis, the appearance of VSGP in patients with PSP-P, thus confirming clinical diagnosis in vivo.




Probiotics and prebiotic fiber for constipation associated with Parkinson disease: An RCT

2016-09-19T12:45:32-07:00

Objectives:

Our objective was to evaluate the efficacy of probiotics and prebiotics in patients with Parkinson disease (PD) and constipation.

Methods:

We conducted a tertiary setting, randomized, double-blind, placebo-controlled trial in patients with PD with Rome III–confirmed constipation based on 2-week stool diary data at baseline. Patients (n = 120) were randomly assigned (2:1) to either a fermented milk, containing multiple probiotic strains and prebiotic fiber, or placebo, once daily for 4 weeks. The primary efficacy endpoint was the increase in the number of complete bowel movements (CBMs) per week. The key secondary endpoints were 3 or more CBMs and an increase by one or more CBMs per week during weeks 3 and 4.

Results:

For the primary endpoint, the consumption of a fermented milk containing probiotics and prebiotics resulted in a higher increase in the number of CBMs (mean 1.2, 95% confidence interval [CI] 0.8–1.6) than placebo (0.1, 95% CI –0.4% to 0.6%) (mean difference 1.1, 95% CI 0.4–1.8; p = 0.002). For the key secondary endpoints, a higher number of patients in the probiotics–prebiotics group vs the placebo group reported 3 or more CBMs (p = 0.030; 58.8% vs 37.5%; odds ratio = 2.4, 95% CI 1.1–5.2) and an increase by one or more CBMs (p = 0.004; 53.8% vs 25.0%; odds ratio = 3.5, 95% CI 1.8–8.1) during weeks 3 and 4.

Conclusions:

The consumption of a fermented milk containing multiple probiotic strains and prebiotic fiber was superior to placebo in improving constipation in patients with PD.

ClinicalTrials.gov identifier:

NCT02459717.

Classification of evidence:

This study provides Class I evidence that for patients with PD who have constipation, fermented milk containing probiotics and prebiotics increases the frequency of CBMs.




AMPA receptors: Dynamics and targets of disease

2016-09-19T12:45:32-07:00

In this and forthcoming reviews, a representative clinical case will serve as an introduction to the topic to be discussed. This will provide the basis to address some recent insights from basic neuroscience research on the normal function of the primary target of the disease process involved in the case presented, as well as putative pathophysiologic and therapeutic implications.




Mercy killing in neurology: The beginnings of neurology on screen (II)

2016-09-19T12:45:32-07:00

The history of Neurocinema includes neuroethics, and this theme was first used in 2 films released in the 1940s in both Germany and the United States. Ich Klage An (I Accuse) is about "terminal" multiple sclerosis in a young woman and the decision to determine one's own fate. The protagonist anticipates becoming "deaf, blind, and idiotic" and asks her husband to administer a toxic drug dose, which he does. The film disturbingly suggests that the diagnosis of multiple sclerosis is tantamount to a death sentence. Ich Klage An (1941) played during the medical murders era ("Aktion T-4" program) but has few references to National Socialism, except for judges with Nazi emblems on their robes making a brief Nazi salute and a jury chamber with a bust of Hitler. Party leadership agreed that the film made a deep impression, but the intended effect on the viewing public is largely unknown. An Act of Murder (1948) involves another young woman with an inoperable brain tumor. When her condition worsens during a trip, her husband deliberately crashes the car, killing her but surviving himself. A subsequent trial finds that she died of an overdose rather than the crash. The trial judge dismisses the murder charge, but the film argues the morals of mercy killing. These films came out during the Nazi euthanasia program and founding of the Euthanasia Society of America in 1938. The choice of neurologic disease by these filmmakers and scriptwriters to defend euthanasia is remarkable.




Report of a workshop on research gaps in the treatment of cerebral palsy

2016-09-19T12:45:32-07:00

Cerebral palsy (CP) is heterogeneous in etiology and manifestations, making research into relevant therapies difficult and limiting the generalizability of the results. We report here on the NIH CP symposium, where stakeholders from academic, clinical, regulatory, and advocacy backgrounds discussed the major challenges and needs for moving forward with clinical research in CP, and outlined priorities and action items. New information is constantly generated through research into pathogenesis and etiology. Clinical research and new therapeutic approaches need to keep pace, through large data registry integration and new research designs. Development of standardized data collection, increasing academic focus on CP research, and iterative approaches to treatment throughout the patients' lives, have all been identified as areas of focus. The workshop identified critical gaps and areas of focus to increase the evidence base for therapeutic approaches to determine which treatments work best for which patients in the near future. These include consolidation and optimization of databases and registries, updates to the research methodology, and better integration of resources and stakeholders.




Spontaneous resolution of an extensive posttraumatic syrinx

2016-09-19T12:45:32-07:00

The prevalence of symptomatic syringomyelia in patients with chronic spinal cord injury (SCI) is around 4.5%.1 It is an important cause of treatable neurologic deterioration, although surgical shunting of the syrinx or arachnoid adhesiolysis of tethered elements have unpredictable results.2 Classically, syrinx extension causes progressive neuropathic pain, often with dissociated sensory loss due to compression of the more central, spinothalamic projection neurons with relative preservation of dorsal column function. We report an unusual case of the total spontaneous resolution of an extensive cervicothoracic syrinx cavity in a patient with symptomatic posttraumatic syringomyelia (PTS) and describe the changes in contact heat-evoked potentials (CHEPs) associated with its development and disappearance.




Acute spinal cord syndrome secondary to venous congestion

2016-09-19T12:45:32-07:00

A 13-year-old boy developed lower limb flaccid paralysis 24 hours after accidental ingestion of an odorless and tasteless potassium hydroxide liquid. He had absent abdominal reflexes, brisk deep tendon reflexes, and no sensation distal to the umbilicus. MRI demonstrated T2 hyperintensities throughout the spinal cord and engorgement of basilar vertebral venous plexus (figure). He made a full recovery within 48 hours of empirical IV methylprednisolone.




Late attacks of paroxysmal ocular tilt reaction

2016-09-19T12:45:32-07:00

A 54-year-old patient had a right mesodiencephalic hemorrhage in 1992, with residual double vision until 2000. He was symptom-free until 2010, when he developed fluctuating diplopia. We observed paroxysmal attacks of a right ocular tilt reaction (OTR) (video at Neurology.org), whereas in the interval he had a left OTR. MRI showed a calcification of the preexisting lesion (figure). The attacks are apparently caused by an excitation of the right interstitial nucleus of Cajal (INC),1 as supported by the effectiveness of carbamazepine (100mg b.i.d.). The delayed onset can be explained by a reorganization of the excitatory and inhibitory synapses found in the INC.2













Clinical Reasoning: A 57-year-old man with subacute gait difficulty and hand tremor

2016-09-12T12:45:38-07:00

A 57-year-old man presented with progressive difficulty in walking for 2 weeks, resting hand tremors for 1 week, and low-volume speech for 2 days. Initially, he had difficulty in initiation of walking. Soon, he developed short-stepped gait with history of en bloc falling forward. Within 2 weeks of the onset of illness, he became bed-bound. While in bed, he remained very stiff and could not sit or turn sides by himself. He also had tremors in his upper limbs on action. His speech volume was reduced, but he always remained coherent. There was no bowel or bladder involvement, flexor spasms, or zonesthesia. The patient had been treated for ankylosing spondylitis (AS) with nonsteroidal anti-inflammatory drugs for 4 years because of low back pain, progressively increasing stooped-forward gait, and sclerosis of sacroiliac joints on X-ray. On examination, he had a masklike face. His blink rate was 1 to 4 blinks per minute. His Mini-Mental State Examination score was 29 of 30. He had hypophonic monotonous speech. His eye movements showed slow saccades and broken pursuit movements. Examination of motor system revealed normal muscle bulk, cogwheel rigidity of the upper limbs, and lead-pipe rigidity in the legs. His strength could not be tested because of profound muscle stiffness. Coarse action tremors were noticed in both hands. The patient had fixed-flexion deformity at the hip joint. Deep tendon jerks could not be elicited because of profound muscle rigidity. Plantar responses and abdominal reflexes also could not be elicited.




Teaching NeuroImages: The half-split man

2016-09-12T12:45:38-07:00

A 51-year-old man was admitted with left lateral medullary infarction due to vertebral artery dissection (figure 1). Neurologic examination revealed nystagmus, dissociated sensory disturbance, and no evidence of paralysis. Miosis and ptosis were observed on the ipsilateral side, but hypohidrosis was not apparent. Thermography revealed a bilateral discrepancy in body temperature, as if the patient were split down the middle (figure 2). Asymmetric skin temperature can occur among patients with Wallenberg syndrome associated with Horner syndrome due to a disturbance of the descending sympathetic tract that causes ipsilateral hypohidrosis and increased cutaneous blood flow.1




Teaching NeuroImages: An extremely rare cause of treatable acute encephalopathy

2016-09-12T12:45:38-07:00

A 32-year-old Brazilian man presented with subacute encephalopathy and gait instability. Examination showed generalized dystonia and lethargy. Brain MRI showed diffuse symmetrical leukoencephalopathy without changes in the basal ganglia (figure). Genetic analysis revealed heterozygous mutations c.74dupT and c.980-14ASLC19A3 gene. There was marked neurologic improvement after high doses of thiamine replacement.




Teaching Video NeuroImages: Bilateral complete horizontal gaze palsy with preserved convergence: The 1 + 1 syndrome

2016-09-12T12:45:38-07:00

Bilateral complete horizontal gaze palsy, the 1 + 1 syndrome, is extremely rare. An otherwise healthy 25-year-old woman shows a recently acquired complete horizontal saccadic palsy. Its association with the absence of improvement with oculocephalic maneuvers and the preservation of convergence clinically suggests a bilateral cranial nerve VI nucleus dysfunction1,2 (video at Neurology.org; figures 1 and 2). Main causes include CNS inflammation, metabolic/toxic disorders, and regional expansive lesions. Mimickers such as myasthenia gravis or Fisher syndrome and anti-GQ1b-mediated disorders have to be meticulously excluded.




Spotlight on the September 13 Issue

2016-09-12T12:45:37-07:00




CSF neurofilament light: A universal risk biomarker in multiple sclerosis?

2016-09-12T12:45:37-07:00

Axonal loss from relapses and neurodegeneration is a main element of multiple sclerosis (MS) pathology, so an objective biomarker to detect and quantify it should be of great value. Neurofilaments belong to the intermediate filament family of proteins and are the major components of the cytoskeleton of neurons. They consist of 3 isotypes: a neurofilament light (NfL) chain of 68 kDa, a neurofilament intermediate (NfM) chain of 150 kDa, and a neurofilament heavy (NfH) chain of 190 to 210 kDa.1 During the process of axonal injury, intracellular components, including neurofilaments, are released into the extracellular fluid and subsequently into the CSF. Thus, analysis of neurofilament levels in the CSF may reliably capture the extent of axonal damage and neurodegeneration in the CNS, regardless of the underlying cause.1 Evidence for increased CSF neurofilament levels in MS mainly exists for NfH and NfL, whereas NfM has not been extensively studied so far.1 Several test systems exist to determine NfH and NfL, and a commercially available ELISA to detect NfL is advantageous in discriminating patients with MS from controls.2




Subarachnoid hemorrhage: Another reason not to smoke

2016-09-12T12:45:37-07:00

Subarachnoid hemorrhage (SAH) has high morbidity and mortality1 and represents a serious and substantial personal and public health burden. Therefore, we need studies of incidence, mortality, and risk factors to understand the disease and enable primary preventive measures.




ALS and physician-assisted suicide

2016-09-12T12:45:37-07:00

Patients with a new diagnosis of amyotrophic lateral sclerosis (ALS) may struggle with uncertainty about progression and the realization that they will lose key functions and how they will ultimately cope. Eventually, most lose abilities to talk, walk or transfer, swallow, and feed themselves, and are increasingly dependent on others. Thus, the diagnosis creates a complex psychodynamic and existential struggle based on current disabilities and future fears. It follows that patients with ALS elect physician-assisted death (PAD) with greater frequency than cancer.1,2




Frederick George Flynn, DO, FAAN (1948-2015)

2016-09-12T12:45:37-07:00

The world lost a wonderful neurologist, husband, father, and friend with the passing of Col. (Ret.) Frederick George Flynn. Dr. Flynn was a distinguished behavioral neurologist, educator, and patient advocate. In addition, he spent many years in service to neurology through his diligent work for the American Academy of Neurology (AAN).




Neurofilament light chain level is a weak risk factor for the development of MS

2016-09-12T12:45:37-07:00

Objective:

To determine the prognostic value of selected biomarkers in clinically isolated syndromes (CIS) for conversion to multiple sclerosis (MS) and disability accrual.

Methods:

Data were acquired from 2 CIS cohorts. The screening phase evaluated patients developing clinically definite MS (CIS-CDMS) and patients who remained as CIS during a 2-year minimum follow-up (CIS-CIS). We determined levels of neurofascin, semaphorin 3A, fetuin A, glial fibrillary acidic protein, and neurofilament light (NfL) and heavy chains in CSF (estimated mean [95% confidence interval; CI]). We evaluated associations between biomarker levels, conversion, disability, and magnetic resonance parameters. In the replication phase, we determined NfL levels (n = 155) using a 900 ng/L cutoff. Primary endpoints in uni- and multivariate analyses were CDMS and 2010 McDonald MS.

Results:

The only biomarker showing significant differences in the screening was NfL (CIS-CDMS 1,553.1 [1,208.7–1,897.5] ng/L and CIS-CIS 499.0 [168.8–829.2] ng/L, p < 0.0001). The strongest associations were with brain parenchymal fraction change (rs = –0.892) and percentage brain volume change (rs = –0.842) at 5 years. NfL did not correlate with disability. In the replication phase, more NfL-positive patients, according to the cutoff, evolved to MS. Every 100-ng/L increase in NfL predicted CDMS (hazard ratio [HR] = 1.009, 95% CI 1.005–1.014) and McDonald MS (HR = 1.009, 95% CI 1.005–1.013), remaining significant for CDMS in the multivariate analysis (adjusted HR = 1.005, 95% CI 1.000–1.011). This risk was lower than the presence of oligoclonal bands or T2 lesions.

Conclusions:

NfL is a weak independent risk factor for MS. Its role as an axonal damage biomarker may be more relevant as suggested by its association with medium-term brain volume changes.




Task-dependent deterioration of balance underpinning cognitive-postural interference in MS

2016-09-12T12:45:37-07:00

Objective:

To investigate which concurrent cognitive task (if any) had the most detrimental effect on balance control of patients with multiple sclerosis (MS).

Methods:

In a dual-task experiment, we evaluated the reciprocal effect of simultaneously performing a postural and a cognitive task on balance and cognition in 52 patients and 26 sex- and age-matched controls. Balance was assessed by static posturography, while cognition was scored as number of correct items at 3 different neuropsychological tests, i.e., the Symbol Digit Modalities Test (SDMT), word list generation (WLG), and Stroop Color-Word Test (SCWT).

Results:

In both single and dual-task conditions, the patients had larger postural sway and worse scores at SDMT, WLG, and SCWT than the controls (p < 0.05). Test-retest reliability was excellent for all dual-task metrics (85%–94%). By means of 2-way analyses of the variance, we found significant main effects of dual task on balance, regardless of the concurrent cognitive task (p < 0.001). There was no main effect of dual task on cognitive performance across all the 3 task conditions (p ≥ 0.1). We observed a significant condition-by-group interaction effect on balance only when the SCWT was administered as concurrent task (p = 0.01), indicating a greater dual-task cost of balance for the patients than controls (53% vs 28%, p = 0.04).

Conclusions:

We suggest that tasks exploring executive functions involved in discriminating conflicting stimuli may be the most suitable to unmask the cognitive-postural interference phenomenon in patients with MS. This may support the hypothesis that MS-related damage constrains brain networks to subserve both postural control and executive functions.




Comment: Dual tasks as a sensitive measure of cognitive deficits in MS

2016-09-12T12:45:37-07:00

Dual task paradigms are gaining traction as a means of detecting subtle cognitive deficits. By dividing performance between 2 separate tasks, they can highlight early cognitive changes, possible hallmarks of later deterioration. In the literature on dementia, dual task conditions differentiate between healthy controls and those with mild cognitive impairment, despite equivalent performance in single task conditions.1 In multiple sclerosis (MS), these early markers look increasingly advantageous. Roughly half of all people with MS go on to develop cognitive impairment, and with this comes increased risk of unemployment, social difficulties, and reduced quality of life.




Predicting Alzheimer disease from a blood-based biomarker profile: A 54-month follow-up

2016-09-12T12:45:37-07:00

Objective:

We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying individuals with high or low neocortical β-amyloid burden (NAB), to determine whether it could also identify individuals at risk of progression to Alzheimer disease (AD) within 54 months.

Methods:

We generated the blood-based signature for 585 healthy controls (HCs) and 74 participants with mild cognitive impairment (MCI) from the Australian Imaging, Biomarkers and Lifestyle Study who underwent clinical reclassification (blinded to biomarker findings) at 54-month follow-up. The individuals were split into estimated high and low NAB groups based on a cutoff of 1.5 standardized uptake value ratio. We assessed the predictive accuracy of the high and low NAB groupings based on progression to mild cognitive impairment or AD according to clinical reclassification at 54-month follow-up.

Results:

Twelve percent of HCs with estimated high NAB progressed in comparison to 5% of HCs with estimated low NAB (odds ratio = 2.4). Forty percent of the participants with MCI who had estimated high NAB progressed in comparison to 5% of the participants with MCI who had estimated low NAB (odds ratio = 12.3). These ratios are in line with those reported for Pittsburgh compound B–PET results. Individuals with estimated high NAB had faster rates of memory decline than those with estimated low NAB.

Conclusion:

These findings suggest that a simple blood-based signature not only provides estimates of NAB but also predicts cognitive decline and disease progression, identifying individuals at risk of progressing toward AD at the prodromal and preclinical stages.




Late-onset depressive symptoms increase the risk of dementia in small vessel disease

2016-09-12T12:45:37-07:00

Objective:

We prospectively investigated the role of depressive symptoms (DS) on all-cause dementia in a population with small vessel disease (SVD), considering onset age of DS and cognitive performance.

Methods:

The RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort) is a prospective cohort study among 503 older adults with SVD on MRI without dementia at baseline (2006), with a follow-up of 5 years (2012). Kaplan-Meier curves stratified for DS and dementia risk were compared using log-rank test. We calculated hazard ratios using Cox regression analyses.

Results:

Follow-up was available for 496 participants (mean baseline age 65.6 years [SD 8.8]; mean follow-up time 5.2 years). All-cause dementia developed in 41 participants. The 5.5-year dementia risk was higher in those with DS (hazard ratio 2.7, 95% confidence interval 1.4–5.2), independent of confounders. This was driven by those with late-onset DS. Five-year cumulative risk difference for dementia was higher in participants with depressive symptoms who had high baseline cognitive performance (no DS 0.0% vs DS 6.9%, log-rank p < 0.001) compared with those who had low cognitive performance at baseline.

Conclusions:

Late-onset DS increases dementia risk, independent of SVD. Especially in those with relatively high cognitive performance, DS indicate a higher risk. In contrast to current practice, clinicians should monitor those with DS who also show relatively good cognitive test scores.




Cortical superficial siderosis: Prevalence and biomarker profile in a memory clinic population

2016-09-12T12:45:37-07:00

Objective:

To gain further insight into cortical superficial siderosis (cSS), a new hemorrhagic neuroimaging marker of cerebral amyloid angiopathy (CAA), and to investigate the clinical, neuroimaging, genetic, and CSF biomarker profile of cSS in a large, consecutive memory clinic series.

Methods:

We included 1,504 memory clinic patients undergoing dementia investigation including a brain MRI in our center. Routine CSF biomarker analysis was performed in 1,039 patients and APOE genotyping in 520 patients. MRIs were systematically evaluated for presumed marker of small vessel disease: cSS, cerebral microbleeds, enlarged perivascular spaces, white matter hyperintensities, and lacunes.

Results:

cSS was detected in 40 patients (2.7%; 95% confidence interval [CI] 1.9–3.6); cSS was focal in 33 cases (2.2%; 95% CI 1.5–3.1) and disseminated in 7 (0.5%; 95% CI 0.2–1). Vascular dementia had the highest cSS prevalence (13%; 95% CI 5.4–24.9), followed by Alzheimer disease (5%; 95% CI 3.1–7.5). The most commonly affected area was the occipital lobe (70%; 95% CI 53.5–83.4). cSS was associated with lobar cerebral microbleeds (odds ratio [OR] 7.9; 95% CI 3.4–18.1; p < 0.001), high-degree centrum semiovale perivascular spaces (OR 1.7; 95% CI 1.2–2.6; p = 0.008), and white matter hyperintensities (OR 1.5; 95% CI 1.0–2.2; p = 0.062). APOE 4/4 genotype was more common in cSS cases compared to those without. CSF β-amyloid 42 was lower in patients with cSS (coefficient –0.09; 95% CI –0.15 to –0.03; p = 0.004).

Conclusions:

Our large series of memory clinic patients provides evidence that cSS is related to cerebrovascular disease and may be a manifestation of severe CAA, even in patients without intracerebral hemorrhage.




Incidence of subarachnoid hemorrhage is decreasing together with decreasing smoking rates

2016-09-12T12:45:37-07:00

Objective:

To determine the nationwide incidence of subarachnoid hemorrhage (SAH) and report nationwide changes in smoking rates between 1998 and 2012 in Finland.

Methods:

In this register-based study, we utilized the nationwide Causes of Death Register and Hospital Discharge Register in identifying SAH events between 1998 and 2012. Population statistics in Finland, which were obtained through a database of Statistics Finland, were used to calculate crude annual incidence rates of SAH. For the direct age standardization of crude incidence rates, we used the European Standard Population (ESP) 2013. Data on changes in nationwide smoking rates between 1998 and 2012 were extracted from a database of the National Institute for Health and Welfare.

Results:

For the total of 79,083,579 cumulative person-years, we identified 6,885 people with SAH. Sudden deaths from SAH away from hospitals or in emergency rooms accounted for 1,771 (26%) of the events. Crude nationwide annual incidence rates varied between 6.2 and 10.0 per 100,000 persons, and increased by age particularly in women. Among 70- to 75-year-old women, the incidence of SAH was highest (22.5 per 100,000 persons). The 3-year average of ESP standardized incidence decreased 24% from 11.7 in 1998–2000 to 8.9 per 100,000 persons in 2010–2012. Daily smoking decreased 30% between 1998 and 2012.

Conclusions:

The incidence of SAH seems to be decreasing. This tendency may be coupled with changes in smoking rates. The incidence of SAH in Finland is similar to other Nordic countries.




Role of atherosclerosis, clot extent, and penumbra volume in headache during ischemic stroke

2016-09-12T12:45:37-07:00

Objective:

To investigate the role of large vessel atherosclerosis, blood clot extent, and penumbra volume in relation to headache in ischemic stroke patients.

Methods:

In this cross-sectional study, we performed noncontrast CT, CT angiography (CTA), and CT perfusion (CTP) in 284 participants from the Dutch Acute Stroke Study and Leiden Stroke Cohort within 9 hours after ischemic stroke onset. We collected headache characteristics prospectively using a semi-structured questionnaire. Atherosclerosis was assessed by evaluating presence of plaques in extracranial and intracranial vessels and by quantifying intracranial carotid artery calcifications. Clot extent was estimated by the clot burden score on CTA and penumbra volume by CTP. We calculated risk ratios (RRs) with adjustments (aRR) for possible confounders using multivariable Poisson regression.

Results:

Headache during stroke was reported in 109/284 (38%) participants. Headache was less prevalent in patients with than in patients without atherosclerosis in the extracranial anterior circulation (35% vs 48%; RR 0.72; 95% confidence interval [CI] 0.54–0.97). Atherosclerosis in the intracranial arteries was also associated with less headache, but this association was not statistically significant. Penumbra volume (aRR 1.08; 95% CI 0.63–1.85) and clot extent (aRR 1.02; 95% CI 0.86–1.20) were not related with headache.

Conclusions:

Headache in the early phase of ischemic stroke tends to occur less often in patients with atherosclerosis than in patients without atherosclerosis in the large cerebral arteries. This finding lends support to the hypothesis that vessel wall elasticity is a necessary contributing factor in the occurrence of headache during acute ischemic stroke.




NALCN channelopathies: Distinguishing gain-of-function and loss-of-function mutations

2016-09-12T12:45:37-07:00

Objective:

To perform genotype–phenotype analysis in an infant with congenital arthrogryposis due to a de novo missense mutation in the NALCN ion channel and explore the mechanism of pathogenicity using a Caenorhabditis elegans model.

Methods:

We performed whole-exome sequencing in a preterm neonate with congenital arthrogryposis and a severe life-threatening clinical course. We examined the mechanism of pathogenicity of the associated NALCN mutation by engineering the orthologous mutation into the nematode C elegans using CRISPR-Cas9.

Results:

We identified a de novo missense mutation in NALCN, c.1768C>T, in an infant with a severe neonatal lethal form of the recently characterized CLIFAHDD syndrome (congenital contractures of the limbs and face with hypotonia and developmental delay). We report novel phenotypic features including prolonged episodes of stimulus-sensitive sustained muscular contraction associated with life-threatening episodes of desaturation and autonomic instability, extending the severity of previously described phenotypes associated with mutations in NALCN. When engineered into the C elegans ortholog, this mutation results in a severe gain-of-function phenotype, with hypercontraction and uncoordinated movement. We engineered 6 additional CLIFAHDD syndrome mutations into C elegans and the mechanism of action could be divided into 2 categories: half phenocopied gain-of-function mutants and half phenocopied loss-of-function mutants.

Conclusions:

The clinical phenotype of our patient and electrophysiologic studies show sustained muscular contraction in response to transient sensory stimuli. In C elegans, this mutation causes neuronal hyperactivity via a gain-of-function NALCN ion channel. Testing human variants of NALCN in C elegans demonstrates that CLIFAHDD can be caused by dominant loss- or gain-of-function mutations in ion channel function.




Comment: Genotype-phenotype correlation with CRISPR-Cas9--: Bedside to bench

2016-09-12T12:45:37-07:00

Technological improvements and decreasing costs have led to increased use of next-generation sequencing as an a priori approach to clinical diagnosis. This approach lends itself to important discoveries of novel genotypic etiologies and phenotypic associations.




Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies

2016-09-12T12:45:37-07:00

Objective:

To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations.

Methods:

Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system.

Results:

The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype–phenotype correlation.

Conclusions:

GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes.




Physician-assisted death: A Canada-wide survey of ALS health care providers

2016-09-12T12:45:37-07:00

Objective:

To survey amyotrophic lateral sclerosis (ALS) health care providers to determine attitudes regarding physician-assisted death (PAD) after the Supreme Court of Canada (SCC) invalidated the Criminal Code provisions that prohibit PAD in February 2015.

Methods:

We conducted a Canada-wide survey of physicians and allied health professionals (AHP) involved in the care of patients with ALS on their opinions regarding (1) the SCC ruling, (2) their willingness to participate in PAD, and (3) the PAD implementation process for patients with ALS.

Results:

We received 231 responses from ALS health care providers representing all 15 academic ALS centers in Canada, with an overall response rate for invited participants of 74%. The majority of physicians and AHP agreed with the SCC ruling and believed that patients with moderate and severe stage ALS should have access to PAD; however, most physicians would not provide a lethal prescription or injection to an eligible patient. They preferred the patient obtain a second opinion to confirm eligibility, have a psychiatric assessment, and then be referred to a third party to administer PAD. The majority of respondents felt unprepared for the initiation of this program and favored the development of PAD training modules and guidelines.

Conclusions:

ALS health care providers support the SCC decision and the majority believe PAD should be available to patients with moderate to severe ALS with physical or emotional suffering. However, few clinicians are willing to directly provide PAD and additional training and guidelines are required before implementation in Canada.




Lenalidomide long-term neurotoxicity: Clinical and neurophysiologic prospective study

2016-09-12T12:45:37-07:00

Objective:

To evaluate long-term lenalidomide neurotoxicity and correlation with cumulative dose and hematologic response.

Methods:

Nineteen myeloma patients (7 men, mean age 63.2 years) underwent clinical and neurophysiologic assessment at baseline and at 2 (8 patients, group A) or 5 years (11 patients, group B) after starting lenalidomide therapy for relapsed/refractory multiple myeloma. Neuropathy was scored with Total Neuropathy Score clinical version (TNSc). Lenalidomide cumulative dose was correlated with severity of neuropathy and hematologic response.

Results:

At enrollment, 7/19 patients (3 in group A, 4 in group B) had neurophysiologic signs of neuropathy secondary to previous chemotherapy, in 2 of them subclinical. Neurophysiologic evidence of sensory axonal neuropathy occurred in 4/8 patients at 2 years follow-up (group A) and in 3/11 patients at 5 years follow-up (group B). Dorsal sural nerve sensory action potential amplitude was the earliest neurophysiologic abnormality. No relevant (≥4) clinical changes were found in TNSc score. Hematologic overall response was 62% in group A and 100% in group B. No correlation was found between lenalidomide cumulative dose and neuropathy or between neuropathy and hematologic response.

Conclusions:

In our study, up to 50% of myeloma patients on long-term lenalidomide therapy developed sensory axonal neuropathy. Reduced dorsal sural nerve sensory action potential amplitude was the first neurophysiologic alteration. Neuropathy was usually subclinical or mild, however. Neurotoxicity was independent of lenalidomide cumulative dose and hematologic response.




W. Ritchie Russell, A.B. Baker, and Fred Plum: Pioneers of ventilatory management in poliomyelitis

2016-09-12T12:45:37-07:00

Historically, neurologists were not involved in the day-to-day management of critically ill patients with bulbar poliomyelitis, but some were. The major contributions of 3 neurologists—W. Ritchie Russell, A.B. Baker, and Fred Plum—in the respiratory management of poliomyelitis have not been recognized. Russell's work was instrumental in identifying multiple types of poliomyelitis defined by their respiratory needs, and he advised treatment that varied from simple postural drainage to use of respirators. He participated in the development of the Radcliffe respiratory pump. Baker recognized the essential involvement of the vagal nerve in respiratory distress, but also observed that involvement of vital centers without cranial nerve involvement would lead to irregular and shallow respiration in some patients and in others with marked dysautonomic features. A similar finding of central involvement of respiration was noted by Plum, who also stressed the importance of hypercapnia. Plum emphasized measurements of vital capacity and techniques to minimize trauma with suctioning after tracheostomy. These 3 neurologists understood the importance of airway and ventilator management, which is currently one of the many pillars of neurocritical care.




Zoonotic bacterial meningitis in human adults

2016-09-12T12:45:37-07:00

Objective:

To describe the epidemiology, etiology, clinical characteristics, treatment, outcome, and prevention of zoonotic bacterial meningitis in human adults.

Methods:

We identified 16 zoonotic bacteria causing meningitis in adults.

Results:

Zoonotic bacterial meningitis is uncommon compared to bacterial meningitis caused by human pathogens, and the incidence has a strong regional distribution. Zoonotic bacterial meningitis is mainly associated with animal contact, consumption of animal products, and an immunocompromised state of the patient. In a high proportion of zoonotic bacterial meningitis cases, CSF analysis showed only a mildly elevated leukocyte count. The recommended antibiotic therapy differs per pathogen, and the overall mortality is low.

Conclusions:

Zoonotic bacterial meningitis is uncommon but is associated with specific complications. The suspicion should be raised in patients with bacterial meningitis who have recreational or professional contact with animals and in patients living in regions endemic for specific zoonotic pathogens. An immunocompromised state is associated with a worse prognosis. Identification of risk factors and underlying disease is necessary to improve treatment.




Primary marginal zone lymphoma of the cns presenting as a diffuse leptomeningeal process

2016-09-12T12:45:37-07:00

Primary CNS (PCNS) lymphoma accounts for less than 3% of all primary brain tumors1; primary extranodal marginal zone B cell lymphoma of the CNS, which includes the mucosa-associated lymphoid tissue (MALT) lymphoma subtype, is extremely rare, comprising up to 5.4% of PCNS lymphomas.2 PCNS MALT lymphomas are localized, low-grade lesions that occur more frequently in women, often present with indolent neurologic symptoms and focal seizures, and manifest as meningioma-like dural-based discrete masses on neuroimaging.3,4 This case illustrates a novel presentation of a rare CNS malignancy.




On family meetings

2016-09-12T12:45:37-07:00




Arteriovenous fistula mimicking vestibular schwannoma

2016-09-12T12:45:38-07:00

A 59-year-old woman presented with progressive left-sided sensorineural hearing loss. Workup revealed an enhancing lesion of the internal auditory canal (IAC) consistent with vestibular schwannoma (figure 1).




Cough tremor as presenting symptom of intraventricular tumor

2016-09-12T12:45:38-07:00

A 39-year-old woman presented with right-hand tremor triggered by coughing. Her examination revealed tremor and irregular myoclonus at rest and transient right-hand tremor precipitated by coughing (video at Neurology.org). Brain MRI showed intraventricular tumor and partial foramen of Monro obstruction (figure). Intraventricular tumors in this location can cause sudden intermittent hydrocephalus,1 and focal thalamic lesions may cause hand tremor.2 We hypothesize that compression of the ventral intermediate nucleus of the thalamus caused by cough-induced hydrocephalus, with dysfunction of cerebello-thalamo-cortical circuit, may be the mechanism for cough-associated tremor of the contralateral hand; this disappeared after surgical removal of the subependymoma. Cough tremor may be associated with intraventricular tumors.







Antibiotic-associated encephalopathy

2016-09-12T12:45:38-07:00




Pearls and Oy-sters: The chapeau de gendarme sign and other localizing gems in frontal lobe epilepsy

2016-09-05T12:45:27-07:00

A 28-year-old right-handed woman with a history of medically intractable localization-related epilepsy was admitted to the epilepsy monitoring unit (EMU) for continuous video-EEG, with the aim of characterizing her seizures and evaluating her surgical eligibility. Her seizures began when she was 18 months of age. There were no perinatal complications, and she attained normal cognitive and motor developmental milestones. Her history was negative for febrile seizures, significant head trauma, or CNS infections. No family history of a seizure disorder was present. She had failed several antiepileptic medications that achieved therapeutic dosing levels, including but not limited to carbamazepine, clonazepam, levetiracetam, and eslicarbazepine.




Teaching NeuroImages: Spinal cord gray matter involvement in complex I deficiency mitochondriopathy

2016-09-05T12:45:27-07:00

A 5-year-old boy presented with progressive bilateral ptosis, ophthalmoplegia, spastic paraparesis, and intention tremor/dysmetria. MRI showed symmetric T2-hyperintensities in diencephalon, brainstem, and spinal gray matter (GM) (figure, A–C). Muscle biopsy disclosed increased citrate synthetase (16.32; normal <10.9) and 31% decrease of complex I activity. Mitochondrial DNA and SURF1 gene sequencing were unrevealing. Leigh-like syndrome was diagnosed based upon the association of clinicoradiologic findings and complex I deficiency.1 After 7 months on ubidecarenone, thiamine, riboflavin, and carnitine, ptosis and dysmetria persisted, paraparesis remitted, and T2 hyperintensities decreased (figure, D–F).




Teaching NeuroImages: Radiographic progression in late-onset Rasmussen encephalitis

2016-09-05T12:45:27-07:00

A 20-year-old man presented who had epilepsy onset at age 15 with a single generalized tonic-clonic seizure, and after 2 years of seizure freedom, experienced emergence of dyscognitive and hypermotor seizures, and in the most recent 18 months, a progressive pattern of dyscognitive and focal motor complex- and simple-partial status epilepticus involving the left extremities. EEG showed multifocal ictal and interictal multifocal epileptiform abnormalities before settling into frequent right central-parietal seizures and slowing. Neuroimaging showed progressive right hemispheric atrophy and hypometabolism (figure), common findings in adult-onset Rasmussen encephalitis.1 No autoimmune or paraneoplastic markers were found. The patient began and continues treatment with monthly IV gamma globulin (IV immunoglobulin) for adult-onset Rasmussen encephalitis.2




Teaching Video NeuroImages: P/Q-type voltage-gated calcium channel-associated paraneoplastic elliptical nystagmus

2016-09-05T12:45:27-07:00

A 71-year-old chronic smoker had an 11-month history of monocular followed by binocular elliptical nystagmus and oscillopsia (video at Neurology.org). MRI brain showed extensive periventricular T2 signal changes (figure) and CSF showed elevated protein to 102 mg/dL. CSF and serum paraneoplastic panel revealed elevated serum titers of anti-P/Q-type voltage-gated calcium channel (VGCC) and anti-neuronal-type voltage-gated potassium channel antibodies. An underlying malignancy was not found after an extensive investigation. The patient was treated with carbamazepine for symptomatic control, followed by high-dose IV methylprednisolone, resulting in moderate improvement. Anti-VGCC antibodies have been implicated in paraneoplastic nystagmus and small cell lung cancer is the most common associated malignancy.1,2




Spotlight on the September 6 Issue

2016-09-05T12:45:26-07:00




Designing the reader's journal

2016-09-05T12:45:26-07:00

In this issue, we present one vision of what Neurology® may look like in the future, side by side with our usual format.




Does early (treatment in) BENEFIT lead to late MS benefit?

2016-09-05T12:45:26-07:00

Contemporary trends in treatment of multiple sclerosis (MS) have embraced the concept "time is brain" to emphasize the importance of utilizing disease-modifying treatments for MS to mitigate irreversible and usually silent damage to axons in early phases of the disease that may result in later progressive axonal degeneration with consequent disability. Recommendations that have emerged from this construct are the need for early treatment,1 possibly with potent therapies ("induction treatment"),2 with strict assessment and rigorous requirements for efficacy ("no evidence of disease activity")3 to achieve better outcomes. Similar approaches are now espoused in other autoimmune diseases in which acute flares ultimately lead to chronic destructive disease, such as rheumatoid arthritis.4




Lumpers or splitters: Evaluation and management of embolic stroke of undetermined source

2016-09-05T12:45:26-07:00

For more than 25 years, neurologists and cardiologists have debated the role of transesophageal echocardiography (TEE) in the evaluation of patients with acute ischemic stroke (AIS) of unknown cause. Approximately 1 in 4 stroke patients do not have a specific cause elucidated by routine inpatient evaluations, and mounting data suggest that many of these patients have occult cardiac sources of embolism (CSE). Recently, the new classification of embolic stroke of undetermined source (ESUS) has been proposed to define the subset of patients in whom there is suspicion, but not proof of, a CSE.1 TEE, however, is not required for a diagnosis of ESUS. Proponents of routine use of TEE in patients with cryptogenic stroke or ESUS note its superiority to transthoracic echocardiography in detection of CSE2 and the higher morbidity and mortality associated with strokes of cardiac cause.3 In contrast, detractors point to increased cost and risk with a relatively low yield of management-changing findings.




mTORC1 inhibition for epilepsy in TSC: Feasibility in question

2016-09-05T12:45:26-07:00

Clinical signs and symptoms have been used to diagnose and define tuberous sclerosis complex (TSC), with the first description being that of the Vogt triad (epilepsy, intellectual disability, and facial angiofibromas).1 The clinical criteria to diagnose TSC no longer include epilepsy and intellectual disability, and have been further expanded. Presence of a disease-causing mutation in TSC1 or TSC2 (the genes involved in TSC) is now included as an independent diagnostic criterion.2




Milton Alter, MD, PhD (1929-2016)

2016-09-05T12:45:26-07:00

Milton Alter, MD, PhD, died on February 4, 2016. He will be remembered as an outstanding neuroepidemiologist whose areas of interest included multiple sclerosis, epilepsy, and stroke.




The 11-year long-term follow-up study from the randomized BENEFIT CIS trial

2016-09-05T12:45:26-07:00

Objective:

To assess outcomes for patients treated with interferon beta-1b immediately after clinically isolated syndrome (CIS) or after a short delay.

Methods:

Participants in BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment) were randomly assigned to receive interferon beta-1b (early treatment) or placebo (delayed treatment). After conversion to clinically definite multiple sclerosis (CDMS) or 2 years, patients on placebo could switch to interferon beta-1b or another treatment. Eleven years after randomization, patients were reassessed.

Results:

Two hundred seventy-eight (59.4%) of the original 468 patients (71.3% of those eligible at participating sites) were enrolled (early: 167 [57.2%]; delayed: 111 [63.1%]). After 11 years, risk of CDMS remained lower in the early-treatment arm compared with the delayed-treatment arm (p = 0.0012), with longer time to first relapse (median [Q1, Q3] days: 1,888 [540, not reached] vs 931 [253, 3,296]; p = 0.0005) and lower overall annualized relapse rate (0.21 vs 0.26; p = 0.0018). Only 25 patients (5.9%, overall; early, 4.5%; delayed, 8.3%) converted to secondary progressive multiple sclerosis. Expanded Disability Status Scale scores remained low and stable, with no difference between treatment arms (median [Q1, Q3]: 2.0 [1.0, 3.0]). The early-treatment group had better Paced Auditory Serial Addition Task–3 total scores (p = 0.0070). Employment rates remained high, and health resource utilization tended to be low in both groups. MRI metrics did not differ between groups.

Conclusions:

Although the delay in treatment was relatively short, several clinical outcomes favored earlier treatment. Along with low rates of disability and disease progression in both groups, this supports the value of treatment at CIS.

ClinicalTrials.gov identifier:

NCT01795872.

Classification of evidence:

This study provides Class IV evidence that early compared to delayed treatment prolongs time to CDMS in CIS after 11 years.




The value of transesophageal echocardiography for embolic strokes of undetermined source

2016-09-05T12:45:26-07:00

Objective:

Our aim was to evaluate the diagnostic yield of transesophageal echocardiography (TEE) in consecutive patients with ischemic stroke (IS) fulfilling the diagnostic criteria of embolic strokes of undetermined source (ESUS).

Methods:

We prospectively evaluated consecutive patients with acute IS satisfying ESUS criteria who underwent in-hospital TEE examination in 3 tertiary care stroke centers during a 12-month period. We also performed a systematic review and meta-analysis estimating the cumulative effect of TEE findings on therapeutic management for secondary stroke prevention among different IS subgroups.

Results:

We identified 61 patients with ESUS who underwent investigation with TEE (mean age 44 ± 12 years, 49% men, median NIH Stroke Scale score = 5 points [interquartile range: 3–8]). TEE revealed additional findings in 52% (95% confidence interval [CI]: 40%–65%) of the study population. TEE findings changed management (initiation of anticoagulation therapy, administration of IV antibiotic therapy, and patent foramen ovale closure) in 10 (16% [95% CI: 9%–28%]) patients. The pooled rate of reported anticoagulation therapy attributed to abnormal TEE findings among 3,562 acute IS patients included in the meta-analysis (12 studies) was 8.7% (95% CI: 7.3%–10.4%). In subgroup analysis, the rates of initiation of anticoagulation therapy on the basis of TEE investigation did not differ (p = 0.315) among patients with cryptogenic stroke (6.9% [95% CI: 4.9%–9.6%]), ESUS (8.1% [95% CI: 3.4%–18.1%]), and IS (9.4% [95% CI: 7.5%–11.8%]).

Conclusions:

Abnormal TEE findings may decisively affect the selection of appropriate therapeutic strategy in approximately 1 of 7 patients with ESUS.




Stroke outcomes with use of antithrombotics within 24 hours after recanalization treatment

2016-09-05T12:45:26-07:00

Objective:

To compare clinical outcomes of patients who received early initiation (<24 hours) of antithrombotics with those who received standard management (antithrombotics administered ≥24 hours).

Methods:

A total of 712 patients who had an acute ischemic stroke and underwent IV or endovascular (intra-arterial [IA]) recanalization between July 2007 and March 2015 were selected from a prospective clinical registry. Antithrombotics were initiated by an individual clinical decision. We systemically gathered information regarding the exact timing of antithrombotic initiation from a database of the electronic barcode medication administration system.

Results:

The recanalization treatment cases included in this study comprised 34% (n = 243) IV only, 32% (n = 229) IA only, and 34% (n = 240) combined IV-IA strategies. Antithrombotics were administered within 24 hours in 64% (n = 456) of the patients. Earlier initiation of antithrombotics was associated with decreased odds of having any hemorrhages (adjusted odds ratio 0.56; 95% confidence interval 0.35–0.89), but was not associated with symptomatic hemorrhages (0.85; 0.35–2.10) or modified Rankin Scale scores of 0–1 at 3 months after stroke (1.09; 0.75–1.59). Ultra-early initiation (<12 hours) did not increase the odds of hemorrhagic transformation (0.26; 0.12–0.52). The effects of earlier antithrombotics on the clinical outcomes were not significantly modified by the modality of recanalization treatment.

Conclusions:

In our retrospective analysis of a prospective registry, early antithrombotic (within 24 hours after initiation) administration did not increase hemorrhages after recanalization treatment. Early antithrombotic therapy may be advantageous for a subset of stroke patients despite the current guidelines.




Retinal microvasculature and white matter microstructure: The Rotterdam Study

2016-09-05T12:45:26-07:00

Objective:

To investigate whether retinal microvascular damage is related to normal-appearing white matter microstructure on diffusion tensor MRI.

Methods:

We included 2,436 participants (age ≥45 years) from the population-based Rotterdam Study (2005–2009) who had gradable retinal images and brain MRI scans. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. White matter microstructure was assessed using diffusion tensor MRI. We used linear regression models to investigate the associations of retinal vascular calibers with markers of normal-appearing white matter microstructure, adjusting for age, sex, the fellow vascular caliber, and additionally for structural MRI markers and cardiovascular risk factors.

Results:

Narrower arterioles and wider venules were associated with poor white matter microstructure: adjusted difference in fractional anisotropy per SD decrease in arteriolar caliber –0.061 (95% confidence interval –0.106 to –0.016), increase in venular caliber –0.054 (–0.096 to –0.011), adjusted difference in mean diffusivity per SD decrease in arteriolar caliber 0.048 (0.007–0.088), and increase in venular caliber 0.047 (0.008–0.085). The associations for venules were more prominent in women.

Conclusions:

Retinal vascular calibers are related to normal-appearing white matter microstructure. This suggests that microvascular damage in the white matter is more widespread than visually detectable as white matter lesions.




Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial

2016-09-05T12:45:26-07:00

Objective:

To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC).

Methods:

Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8–10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5–10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment.

Results:

Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] –69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI –86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely.

Conclusions:

We describe a randomized controlled trial for a non–antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation.

Classification of evidence:

This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.




TDP-43 pathology and cognition in ALS: A prospective clinicopathologic correlation study

2016-09-05T12:45:26-07:00

Objective:

Although a systematic spread of pathologic TDP-43 expression throughout the CNS in amyotrophic lateral sclerosis (ALS) has been proposed, the relationship between cognition and the extent and neuroanatomic distribution of TDP-43 pathology has not received considerable attention.

Methods:

We investigated the association between cognitive functioning and the extent of TDP-43 pathology in postmortem CNS tissue from 18 patients with ALS stratified into 3 groups based on detailed prospective neuropsychological testing (cognitively not impaired, n = 6; cognitively impaired, n = 6; ALS– frontotemporal dementia [FTD], n = 6) and analyzed these cases for clinicopathologic correlations.

Results:

Our findings demonstrate a close relationship between cognition and the extent of TDP-43 pathology in non–primary motor areas with a striking difference between ALS-FTD and the 2 other cognitive groups. The specificity of our results was underscored by 2 key findings: first, the absence of an Alzheimer pathology effect, a common confounder in older patients; second, the lack of correlations between the primary motor regions with the highest TDP-43 intensity and cognitive status.

Conclusions:

Our data suggest a distinct dynamic of TDP-43 progression and distribution in ALS-FTD in contrast to ALS without FTD.




Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

2016-09-05T12:45:26-07:00

Objective:

We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features.

Methods:

Between 2001 and 2015, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives.

Results:

The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank 2[1] = 45.323, p < 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD.

Conclusions:

Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.




Cardiac involvement in hereditary myopathy with early respiratory failure: A cohort study

2016-09-05T12:45:27-07:00

Objective:

To assess whether hereditary myopathy with early respiratory failure (HMERF) due to the c.951434T>C; (p.Cys31712Arg) TTN missense mutation also includes a cardiac phenotype.

Method:

Clinical cohort study of our HMERF cohort using ECG, 2D echocardiogram, and cross-sectional cardiac imaging with MRI or CT.

Results:

We studied 22 participants with the c.951434T>C; (p.Cys31712Arg) TTN missense mutation. Three were deceased. Cardiac conduction abnormalities were identified in 7/22 (32%): sustained atrioventricular tachycardia (n = 2), atrial fibrillation (n = 2), nonsustained atrial tachycardia (n = 1), premature supraventricular complexes (n = 1), and unexplained sinus bradycardia (n = 1). In addition, 4/22 (18%) had imaging evidence of otherwise unexplained cardiomyopathy. These findings are supported by histopathologic correlation suggestive of myocardial cytoskeletal remodeling.

Conclusions:

Coexisting cardiac and skeletal muscle involvement is not uncommon in patients with HMERF arising due to the c.951434T>C; (p.Cys31712Arg) TTN mutation. All patients with pathogenic or putative pathogenic TTN mutations should be offered periodic cardiac surveillance.




Incident parkinsonism in older adults without Parkinson disease

2016-09-05T12:45:27-07:00

Objective:

To determine the incidence of parkinsonism in community-dwelling older adults without Parkinson disease.

Methods:

Four parkinsonian signs were assessed with a modified motor portion of the Unified Parkinson's Disease Rating Scale in 2,001 older adults without parkinsonism. We used Cox proportional hazards models to determine the associations of age and sex with incident parkinsonism (2 or more signs). We calculated the number of events per 1,000 person-years of observation in 3 age strata. Next, we investigated several potential risk factors for incident parkinsonism. Then, we examined longitudinal progression of parkinsonism using discrete-time multistate Markov models.

Results:

Average age at baseline was 76.8 years (SD 7.62 years). During an average of 5 years of follow-up, 964/2,001 (48.2%) developed parkinsonism. Age (hazard ratio [HR] 1.09, 95% confidence interval [CI] 1.08–1.10) but not male sex (HR 1.06, 95% CI 0.91–1.23) was associated with incident parkinsonism. The incidence of parkinsonism per 1,000 person-years of follow-up was 36.0 for adults <75 years of age, 94.8 for those 75–84, and 160.5 for those 85 years or older. Depressive symptoms, neuroticism, urinary incontinence, sleep complaints, and chronic health conditions were associated with incident parkinsonism. Secondary analyses suggest that risk factors are linked with incident parkinsonism via early motor signs of parkinsonism and cognitive function. Transition modeling suggests that while parkinsonism may fluctuate, it is progressive in most older adults and its risk factors increase the odds of its progression.

Conclusions:

Parkinsonism is common in older adults and increases with age. Identifying modifiable risk factors may decrease the magnitude of this growing public health problem.




Evolution of clinical features in possible DLB depending on FP-CIT SPECT result

2016-09-05T12:45:27-07:00

Objective:

To test the hypothesis that core and suggestive features in possible dementia with Lewy bodies (DLB) would vary in their ability to predict an abnormal dopamine transporter scan and therefore a follow-up diagnosis of probable DLB. A further objective was to assess the evolution of core and suggestive features in patients with possible DLB over time depending on the 123I-FP-CIT SPECT scan result.

Methods:

A total of 187 patients with possible DLB (dementia plus one core or one suggestive feature) were randomized to have dopamine transporter imaging or to follow-up without scan. DLB features were compared at baseline and at 6-month follow-up according to imaging results and follow-up diagnosis.

Results:

For the whole cohort, the baseline frequency of parkinsonism was 30%, fluctuations 29%, visual hallucinations 24%, and REM sleep behavior disorder 17%. Clinician-rated presence of parkinsonism at baseline was significantly (p = 0.001) more frequent and Unified Parkinson’s Disease Rating Scale (UPDRS) score at baseline was significantly higher (p = 0.02) in patients with abnormal imaging. There was a significant increase in UPDRS score in the abnormal scan group over time (p < 0.01). There was relatively little evolution of the rest of the DLB features regardless of the imaging result.

Conclusions:

In patients with possible DLB, apart from UPDRS score, there was no difference in the evolution of DLB clinical features over 6 months between cases with normal and abnormal imaging. Only parkinsonism and dopamine transporter imaging helped to differentiate DLB from non-DLB dementia.




Twelve-month recovery of medical decision-making capacity following traumatic brain injury

2016-09-05T12:45:27-07:00

Objective:

To investigate recovery of medical decision-making capacity (MDC) over the first year following traumatic brain injury (TBI).

Methods:

A total of 177 participants (111 persons with TBI and 66 healthy controls) were recruited from an inpatient/outpatient TBI rehabilitation unit and outpatient neurology department. Participants with TBI were classified by injury severity into subgroups: mild TBI (mTBI; n = 28), complicated mild TBI (cmTBI; n = 23), and moderate/severe TBI (msevTBI; n = 60). Control and TBI groups were compared at 1 month (t1), 6 months (t2), and 12 months (t3) postinjury using the Capacity to Consent to Treatment Instrument (CCTI), which evaluates MDC using 5 consent standards: expressing choice, reasonable choice, appreciation, reasoning, and understanding.

Results:

Relative to controls, no TBI group displayed impairment on CCTI expressing choice or reasonable choice at any timepoint. Those with mTBI had reduced appreciation and understanding at t1, which resolved by t2. The cmTBI and msevTBI groups were impaired on all 3 complex consent standards at t1. While patients with cmTBI improved to a level similar to controls by t3, those with msevTBI remained impaired on reasoning and understanding. Across all TBI groups, notable MDC improvement only occurred over the first 6 months postinjury.

Conclusions:

Over 1 year, most individuals with mTBI or cmTBI regain MDC, while many individuals with msevTBI have lingering deficits in reasoning and comprehension of treatment information. Clinical recovery of MDC occurs primarily during the first 6 months post-TBI regardless of injury severity. Clinicians can therefore identify MDC outcomes in TBI at 6 months postinjury.




A marked contrast between serotonergic and dopaminergic changes in dopa-responsive dystonia

2016-09-05T12:45:27-07:00

Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa.1 Autosomal dominant DRD is caused by mutations in GCH1, which encodes GTP cyclohydrolase 1 (GTPCH), the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4; the cofactor for phenylalanine and tyrosine and tryptophan hydroxylases [TH and TPH]).1 Recently, the phenotype of this major form of DRD (GTPCH-deficient DRD) was expanded to include nonmotor symptoms, such as depression, anxiety, and obsessive-compulsive disorder, and these psychiatric symptoms were attributed to serotonin deficiency.2,3 However, the actual status of brain serotonergic involvement in GTPCH-deficient DRD is unknown. To evaluate possible serotonin deficiency, we measured levels of serotonin markers in the striatum (one of the serotonin- and dopamine-rich brain regions)4 in a 19-year-old woman with DRD and a GCH1 nonsense mutation.5 Her dystonia (onset at 5 years of age) was well controlled by levodopa (without a decarboxylase inhibitor) 750 mg/d for 11 years (no psychiatric symptoms and residual motor signs) until her automobile accidental death. Neuropathologic studies revealed a normal population of cells with reduced melanin in the substantia nigra and also no evidence of degeneration in other brain areas.1,5 This study was approved by the institutional review board of the Centre for Addiction and Mental Health.




Cerebral microbleeds and iron depletion of dentate nuclei in ataxia-telangiectasia

2016-09-05T12:45:27-07:00

A 27-year-old man had been diagnosed with ataxia-telangiectasia at age 13 years. He had ocular telangiectasia and motor ataxia, with incoordination of head and eyes in lateral gaze. Laboratory data revealed deficiency of immunoglobulin and elevated α-fetoprotein. MRI demonstrated cerebellar atrophy and cerebral microbleeds1 (figure 1); the dentate nuclei had deficient iron signals, which otherwise should be visible as hypointensities in susceptibility-weighted imaging (figure 2). Iron depletion in dentate nuclei is a novel finding and could be explained by the blockage of axonal iron transport in the olivocerebello-olivary loop.2




Traditional treatment of epilepsy: Trepanation revisited

2016-09-05T12:45:27-07:00

A 29-year-old South Asian man, with epilepsy since childhood, presented to the emergency room with a seizure. CT scan (figure) showed multiple metallic needles projecting from the coronal suture into the brain. In order to expel the demon that a traditional healer believed was haunting the patient, the skull and brain were pierced with needles. It is unclear whether the demon was successfully expelled, but the seizures persisted and could have been worsened by this treatment. Measures are warranted to warn the public against dangerous modes of traditional medicine.1,2










Pediatric demyelinating disorders: Global updates, controversies, and future directions

2016-08-29T12:45:23-07:00

The field of pediatric-onset multiple sclerosis (MS) and other demyelinating diseases in childhood has advanced considerably since the publication of the last International Pediatric Multiple Sclerosis Study Group (IPMSSG)–sponsored Neurology® supplement in 2007. Over the last decade, demyelinating diseases of the CNS in children, and MS in particular, have garnered considerable international focus, both in the clinical and research world but also in the lay press and public awareness. This coming of age resulted in an exponential increase in research efforts and publications, with more than 250 peer-reviewed publications on pediatric MS in the past 10 years. It has also crystallized national and international collaborations that are critical to transform the field.




Pediatric multiple sclerosis: Perspectives from adolescents and their families

2016-08-29T12:45:23-07:00

Supporting young people with pediatric multiple sclerosis can be challenging for families and health care providers. Adolescents may be more resilient than adults in reaction to the diagnosis but can have more difficulty planning for their futures. Appropriate, sensitive, and focused health provision should include consideration of the perspective of both the patient and parents. Multidisciplinary management strategies are often effective, as are referrals to programs that enhance individual and family coping and strengthen a sense of community.




Consensus definitions for pediatric MS and other demyelinating disorders in childhood

2016-08-29T12:45:23-07:00

In light of the published 2012 International Pediatric Multiple Sclerosis Group definitions for pediatric multiple sclerosis (MS) and related disorders and given that pediatric-onset MS is now formally included in the 2010 McDonald criteria for MS, we sought to review these criteria and summarize their application in children with acquired CNS demyelination. In addition, proposals are made for definitions of no evidence of disease activity and inadequate treatment response that are important because of new therapeutic options and trials.




Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases

2016-08-29T12:45:23-07:00

Elucidating pathophysiologic mechanisms underlying the spectrum of pediatric-onset CNS demyelinating diseases, particularly those that may distinguish multiple sclerosis (MS) from other entities, promises to both improve diagnostics and guide more-informed therapeutic decisions. Observations that pediatric- and adult-onset MS share the same genetic and environmental risk factors support the view that these conditions represent essentially the same illness manifesting at different ages. Nonetheless, special consideration must be given when CNS inflammation manifests in early life, at a time when multiple organs (including immune and nervous systems) are actively maturing. CSF analysis in pediatric-onset MS points to chronic CNS inflammation, supported by observations from limited pathologic material available for study. Emerging results implicate abnormalities in both effector and regulatory T cell subsets, and potentially immune senescence, in children with MS. Although CNS-directed antibodies (including antibodies recognizing myelin antigens; Kir4.1) can be documented in pediatric-onset MS, their pathophysiologic significance (as in adults) remains unclear. This is in contrast to the presence of serum and/or CSF antibodies recognizing aquaporin-4, which, when measured using validated cell-based assays, supports the diagnosis of a neuromyelitis optica spectrum disorder, distinct from MS. Presence of anti–myelin oligodendrocyte glycoprotein antibodies documented with similar cell-based assays may also be associated with pathophysiologically distinct disease phenotypes in children. The substantial impact of pediatric-onset MS on normal brain development and function underscores the impo[...]



Environmental and genetic factors in pediatric inflammatory demyelinating diseases

2016-08-29T12:45:23-07:00

The onset of multiple sclerosis (MS) occurs in childhood in about 5% of all patients with MS. The disease in adults has a complex genetic and environmental inheritability. One of the main risk factors, also confirmed in pediatric MS, is HLA DRB1*1501. In addition to genetic factors, a large part of disease susceptibility in adults is conferred by environmental risk factors such as low vitamin D status, exposure to cigarette smoking, and remote Epstein-Barr virus (EBV) infection. In children, both exposure to cigarette smoking and prior EBV infection have been reported consistently as risk factors for MS. The role of vitamin D remains to be confirmed in this age category. Finally, although very likely critical in disease processes, few gene–environment interactions and epigenetic changes have been reported for adult and pediatric MS susceptibility. Of interest, some of the risk factors for MS have also been associated with disease course modification, such as low 25(OH) vitamin D serum levels in pediatric and adult MS. Age is also a clear disease modifier of clinical, CSF, and MRI phenotype in children with the disease. Finally, although much has yet to be unraveled regarding molecular processes at play in MS, there is a larger gap in our knowledge of genetic and environmental risk factors for pediatric neuromyelitis optica spectrum disorders and acute disseminated encephalomyelitis and only collaborative studies will answer those questions.




Differential diagnosis and evaluation in pediatric inflammatory demyelinating disorders

2016-08-29T12:45:23-07:00

Major advances have been made in the clinical and radiologic characterization of children presenting with the different forms of an acquired inflammatory demyelinating syndrome (ADS) such as acute disseminating encephalomyelitis, neuromyelitis optica spectrum disorders, and clinically isolated syndromes. Nevertheless, a proportion of cases that present with similar symptoms are due to a broad spectrum of other inflammatory disorders affecting the white matter, primary CNS tumors, or neurometabolic diseases. The clinician therefore has to be aware of the different forms of ADS, the risk factors for a chronic-relapsing course, and features that indicate an alternative diagnosis. The goal of this article is therefore to provide an outline of a pathway for evaluating pediatric patients with a presumed inflammatory demyelinating disorder and discussing the spectrum of the more common differential diagnoses.




Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome

2016-08-29T12:45:23-07:00

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating CNS disorder with predilection to early childhood. ADEM is generally considered a monophasic disease. However, recurrent ADEM has been described and defined as multiphasic disseminated encephalomyelitis. ADEM often occurs postinfectiously, although a causal relationship has never been established. ADEM and multiple sclerosis are currently viewed as distinct entities, generally distinguishable even at disease onset. However, pathologic studies have demonstrated transitional cases of yet unclear significance. ADEM is clinically defined by acute polyfocal neurologic deficits including encephalopathy. MRI typically demonstrates reversible, ill-defined white matter lesions of the brain and often also the spinal cord, along with frequent involvement of thalami and basal ganglia. CSF analysis may reveal a mild pleocytosis and elevated protein, but is generally negative for intrathecal oligoclonal immunoglobulin G synthesis. In the absence of a specific diagnostic test, ADEM is considered a diagnosis of exclusion, and ADEM mimics, especially those requiring a different treatment approach, have to be carefully ruled out. The role of biomarkers, including autoantibodies like anti–myelin oligodendrocyte glycoprotein, in the pathogenesis and diagnosis of ADEM is currently under debate. Based on the presumed autoimmune etiology of ADEM, the current treatment approach consists of early immunotherapy. Outcome of ADEM in pediatric patients is generally favorable, but cognitive deficits have been reported even in the absence of other neurolog[...]



Pediatric transverse myelitis

2016-08-29T12:45:23-07:00

Pediatric acute transverse myelitis (ATM) is an immune-mediated CNS disorder and contributes to 20% of children experiencing a first acquired demyelinating syndrome (ADS). ATM must be differentiated from other presentations of myelopathy and may be the first presentation of relapsing ADS such as neuromyelitis optica (NMO) or multiple sclerosis (MS). The tenets of the diagnostic criteria for ATM established by the Transverse Myelitis Consortium Working Group can generally be applied in children; however, a clear sensory level may not be evident in some. MRI lesions are often centrally located with high T2 signal intensity involving gray and neighboring white matter. Longitudinally extensive ATM occurs in the majority. Asymptomatic lesions on brain MRI are seen in more than one-third and predict MS or NMO. The role of antibodies such as myelin oligodendrocyte glycoprotein in monophasic and relapsing ATM and their significance in therapeutic approaches remain unclear. ATM is a potentially devastating condition with variable outcome and presents significant cumulative demands on health and social care resources. Children generally have a better outcome than adults, with one-half making a complete recovery by 2 years. There is need for standardization of clinical assessment and investigation protocols to enable international collaborative studies to delineate prognostic factors for disability and relapse. There are no robust controlled trials in children or adults to inform optimal treatment of ATM, with one study currently open to recruitment. This review provides an overview of current [...]



Pediatric optic neuritis

2016-08-29T12:45:23-07:00

Optic neuritis (ON) is a common presenting symptom in pediatric CNS demyelinating disorders and may be associated with dramatic visual loss. Knowledge regarding clinical presentation, associated diseases, therapy, and outcomes in ON in children has grown over the past decade. These studies have shown that younger children (<10 years of age) are more likely to present with bilateral ON and older children with unilateral ON. Furthermore, studies focusing on visual recovery have shown excellent recovery of high-contrast visual acuity in the majority of children, but functional and structural studies have shown evidence of irreversible injury and functional decline after ON in children. Although randomized controlled treatment trials have not been performed in children and adolescents with ON, standard of care suggests that the use of high-dose pulse steroids is safe and likely effective. This article reviews current knowledge about the clinical presentation and management of pediatric ON, with attention to associated syndromes and evaluative tools that may inform diagnosis and interventions.




Neuromyelitis optica spectrum disorders in children and adolescents

2016-08-29T12:45:23-07:00

Neuromyelitis optica (NMO) is a severe autoimmune disease of the CNS characterized by recurrent inflammatory events primarily involving the optic nerves and spinal cord. NMO is infrequent in children, but early recognition is important to start adequate treatment. In this article, we review the evolving diagnostic criteria of NMO and provide an update on the clinical and neuroimaging spectrum of the disorder in pediatric patients, including current knowledge on immunopathogenesis and treatment recommendations for children with NMO.




Pediatric acquired CNS demyelinating syndromes: Features associated with multiple sclerosis

2016-08-29T12:45:23-07:00

Approximately one-third of children with an acquired demyelinating syndrome (ADS) will be diagnosed with multiple sclerosis (MS), either at onset according to the 2010 McDonald criteria, or on the basis of clinical or MRI evidence of relapsing disease, in the majority of patients within 2–4 years. ADS in adolescents, female patients, and patients with polyfocal deficits is associated with the highest likelihood of MS, while children with acute disseminated encephalomyelitis, those with documented preceding infection, and ADS presentation in young children more commonly portends a monophasic outcome. While pediatric MS associates with similar genetic risk alleles as have been documented in adult-onset MS, such associations are not diagnostically valuable at the individual level. The presence of antibodies directed against aquaporin-4 strongly supports a diagnosis of neuromyelitis optica, and should be assayed in children manifesting with severe optic neuritis, longitudinally extensive myelitis, or brainstem/hypothalamic syndromes. Further research will determine whether other antibody signatures are indicative of relapsing demyelination distinct from MS.




Pediatric multiple sclerosis: Clinical features and outcome

2016-08-29T12:45:23-07:00

Multiple sclerosis (MS) in children manifests with a relapsing-remitting MS (RRMS) disease course. Acute relapses consist of new neurologic deficits persisting greater than 24 hours, in the absence of intercurrent illness, and occur with a higher frequency early in the disease as compared to adult-onset RRMS. Most pediatric patients with MS recover well from these early relapses, and cumulative physical disability is rare in the first 10 years of disease. Brainstem attacks, poor recovery from a single attack, and a higher frequency of attacks portend a greater likelihood of future disability. Although prospective pediatric-onset MS cohorts have been established in recent years, there remains very limited prospective data detailing the longer-term clinical outcome of pediatric-onset MS into adulthood. Whether the advent of MS therapies, and the largely off-label access to such therapies in pediatric MS, has improved prognosis is unknown. MS onset during the key formative academic years, concurrent with active cognitive maturation, is an important determinant of long-term outcome, and is discussed in detail in another article in this supplement. Finally, increasing recognition of pediatric MS worldwide, recent launch of phase III trials for new agents in the pediatric MS population, and the clear imperative to more fully appreciate health-related quality of life in pediatric MS through adulthood highlight the need for standardized, validated, and robust outcome measures. [...]



Pediatric multiple sclerosis: Cognition and mood

2016-08-29T12:45:23-07:00

In comparison with the large body of evidence on cognitive functioning in adults with multiple sclerosis (MS), there is limited information on cognition in pediatric-onset MS (POMS). Unique vulnerabilities in POMS can derive from having a disease that occurs during key periods of age-expected brain growth, active myelination in the CNS, and maturation of neural networks during the learning curve and key formative years in the academic career of the patient. Therefore, the consequences of MS on developing cognitive faculties can be assessed only in the pediatric population and cannot be simply extrapolated from studies carried on in the adult population. Until the last decade, research in the pediatric population was mainly represented by small clinical series, often limited by the narrow scope of neuropsychological assessment and lack of adequate control groups. Over the last decade, however, cognitive functioning and mood-related difficulties have become an increasing concern as awareness of this population has grown. A few specialized MS centers have begun performing more systematic research in the field in order to assess the prevalence of cognitive impairments and mood-related difficulties in patients with POMS, to better characterize the neuropsychological pattern and determine the functional consequences of these problems. This chapter summarizes our current understanding of cognitive and mood-related difficulties in POMS and highlights percei[...]



MRI in the evaluation of pediatric multiple sclerosis

2016-08-29T12:45:23-07:00

MRI plays a pivotal role in the diagnosis of multiple sclerosis (MS) in children, as it does in adults. The presence of multiple lesions in CNS locations commonly affected by MS, along with the presence of both enhancing and nonenhancing lesions, can facilitate a diagnosis of MS at the time of a first attack, whereas the accrual of serial lesions or new clinical attacks over time confirms the diagnosis in patients not meeting such criteria at onset. T2 and enhancing lesion accrual could serve as a primary outcome metric for pediatric MS clinical trials of selected therapies with anti-inflammatory activity in order to facilitate feasible trial size numbers. More-advanced MRI techniques reveal the impact of MS on tissue integrity within both T2-bright and T1-hypointense lesions and regions of normal-appearing tissue. Volumetric MRI analyses quantify the impact of MS on age-expected brain growth, and fMRI reveals activation and resting-state functional connectivity patterns in patients with pediatric MS that differ from those seen in healthy age-matched youth. Such studies are of critical importance because MS onset during childhood may profoundly influence maturing and actively myelinating neural networks. High-field MRI visualizes MS pathology at a near-microscopic level and has the potential to more fully explain mechanisms for cognitive impairment, fatigue, and disability in patients with pediatric MS.




Pediatric multiple sclerosis: Conventional first-line treatment and general management

2016-08-29T12:45:23-07:00

Many disease-modifying therapies are currently available for adults with relapsing-remitting multiple sclerosis (MS) but none of them has been tested in pediatric MS in randomized placebo-controlled trials. At present, as suggested by observational studies and experts' guidelines, interferon-β and glatiramer acetate continue to be the standard first-line treatments for pediatric MS. Observational studies and some controlled unblinded trials have shown a positive effect of these meditations in reducing relapse rate and delaying disease progression, with an acceptable safety profile. The goal of this article is to provide an overview of current knowledge with regard to safety, tolerability, and efficacy of first-line treatment options for MS in the pediatric age group, with the aim of providing guidance for planning first-line treatment of MS in children and adolescents.




Pediatric multiple sclerosis: Escalation and emerging treatments

2016-08-29T12:45:23-07:00

Over the last 20 years, there have been significant advances in multiple sclerosis (MS) therapeutics, with regulatory approval for 13 therapies in adults by the European Medicines Agency (EMA) and Food and Drug Administration. However, there is only limited approval for interferon-β and glatiramer acetate use in children 12 years and older by the EMA. Availability of disease-modifying therapies to children and adolescents with MS is variable by region, and is extremely limited in some regions of the world. Up to 30% of children experience breakthrough disease requiring therapies beyond traditional first-line agents. Recent legislation in both the United States and Europe has mandated clinical studies for all new therapeutics applicable to children. Several clinical trials in children are underway that will provide important information regarding the efficacy and safety of newer drugs. This review summarizes the current knowledge of breakthrough disease, escalation, and induction treatment approaches in children with MS, especially pertaining to disease course and disability outcomes in this group of patients. In addition, ongoing clinical trials and approaches and challenges in conducting clinical trials in the pediatric population are discussed.