Gene-Environment Interactions in Progressive Supranuclear Palsy.

Several genetic and environmental factors have been reported in progressive supranuclear palsy (PSP), although none were identified as a definitive cause. We aimed to explore potential gene-environment interactions in PSP. Two hundred and ninety two PSP cases and 292 controls matched for age, sex, and race from the ENGENE-PSP were analyzed to determine the association between PSP and minor alleles of 5 single nucleotide polymorphisms (SNPs) in 4 genes (MAPT, MOBP, EIF2AK3, and STX6), which were previously associated with PSP risk. Interactions between these SNPs and environmental factors, including previously reported occupational and agricultural risk factors for PSP, were assessed for PSP odds and age of symptom onset. Minor alleles of MAPTrs242557 and EIF2AK3rs7571971 were individually associated with increased odds; MAPTrs8070723 minor alleles were associated with lower PSP odds. There were several gene-environment interactions for PSP odds and age of symptom onset, however, they did not remain significant after FDR-correction. Larger scale studies are required to determine potential interactions.

Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To systematically review evidence regarding ataxia treatment. METHODS: A comprehensive systematic review was performed according to American Academy of Neurology methodology. CONCLUSIONS: For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis-associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).

Practice guideline summary: Reducing brain injury following cardiopulmonary resuscitation: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To assess the evidence and make evidence-based recommendations for acute interventions to reduce brain injury in adult patients who are comatose after successful cardiopulmonary resuscitation. METHODS: Published literature from 1966 to August 29, 2016, was reviewed with evidence-based classification of relevant articles. RESULTS AND RECOMMENDATIONS: For patients who are comatose in whom the initial cardiac rhythm is either pulseless ventricular tachycardia (VT) or ventricular fibrillation (VF) after out-of-hospital cardiac arrest (OHCA), therapeutic hypothermia (TH; 32-34°C for 24 hours) is highly likely to be effective in improving functional neurologic outcome and survival compared with non-TH and should be offered (Level A). For patients who are comatose in whom the initial cardiac rhythm is either VT/VF or asystole/pulseless electrical activity (PEA) after OHCA, targeted temperature management (36°C for 24 hours, followed by 8 hours of rewarming to 37°C, and temperature maintenance below 37.5°C until 72 hours) is likely as effective as TH and is an acceptable alternative (Level B). For patients who are comatose with an initial rhythm of PEA/asystole, TH possibly improves survival and functional neurologic outcome at discharge vs standard care and may be offered (Level C). Prehospital cooling as an adjunct to TH is highly likely to be ineffective in further improving neurologic outcome and survival and should not be offered (Level A). Other pharmacologic and nonpharmacologic strategies (applied with or without concomitant TH) are also reviewed.

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

OBJECTIVE: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. METHODS: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. RESULTS: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. CONCLUSIONS: These data do not justify use of CoQ as a treatment to slow functional decline in HD. CLINICALTRIALSGOV IDENTIFIER: NCT00608881. CLASSIFICATION OF EVIDENCE: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

IMPORTANCE: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01795859.

Practical steps for implementing quality measurement in practice.

All neurologists must begin incorporating quality measurement and quality improvement into their practice. Efforts to pay physicians based on the quality of their care and patient outcomes moves quality measurement beyond reporting to satisfy regulatory requirements and pushes physicians to select and use quality measures to improve patient outcomes and patient experience. This article provides practical steps and proposes considerations for neurologic practices advancing quality measurement and improvement.

Quality improvement in neurology: Distal symmetric polyneuropathy quality measures.

Peripheral neuropathy is a common neurologic disorder, affecting 2% to 8% of the population in population-based studies with confirmation by neurologist examination. These prevalence numbers are remarkably stable across developed countries. In 1999, 8.6% of Medicare beneficiaries had neuropathy as a primary or secondary diagnosis, and the cost of treatment was estimated at $3.5 billion (Consumer Price Index adjusted to 2013 $4.9 billion), which did not include outpatient medications. Peripheral neuropathy has many causes and varies in regard to its clinical manifestations and severity. Distal symmetric polyneuropathy (DSP) is the most common pattern of peripheral neuropathy generally and the most common phenotype of neuropathy due to diabetes. Reported prevalence rates of DSP among diabetic patients range from 15% to 37% across large population-based studies, and the prevalence among those with impaired glucose tolerance has been reported to be 11%. DSP can result in weakness, sensory loss, pain, autonomic dysfunction, gait impairment, falls, disability, and impaired quality of life.

Is there an increased risk of hip fracture in multiple sclerosis? Analysis of the Nationwide Inpatient Sample.

BACKGROUND: Impaired ambulation, frequent falls, and prolonged immobilization combined with the high rate of vitamin D deficiency in people with multiple sclerosis (MS) could lead to an increased risk of hip fracture. METHODS: A retrospective cohort analysis of 20 years of the Nationwide Inpatient Sample (AHRQ.gov), a 20% stratified yearly sample of USA hospital admissions from the year 1988-2007, was performed. Based on International Classification of Diseases Ninth Revision (ICD9) codes, admissions with a primary diagnosis of acute hip fracture (ICD9 code 226.xx) and a secondary diagnosis of MS (ICD9 code 340) was identified. Indirect adjustment was used to compare the prevalence of MS in this population with that of the USA. Significance was set a priori at P<0.0001 due to the large number of records and multiple comparisons. RESULTS: A total of 1,066,404 hip fracture admissions were identified and 0.25% had MS. Those with MS were younger, had lower mortality rates (0.25% for people with MS versus 2.97% for those without MS, P<0.0001) and lower rates of discharge to nursing home or rehabilitation (69.25% for people with MS versus 72.17% for those without MS, P<0.0001). When compared with the population prevalence, the predicted prevalence of MS among patients with hip fracture was 2.844 (95% confidence interval [CI] 2.837-2.852) greater than expected when adjusted for age, 2.505 (95% CI 2.499-2.512) when adjusted for sex and age, and 2.175 (95% CI 2.168-2.182) when adjusted for race (white, black). Race was specified for only 65% of the sample. CONCLUSION: In this nationwide sample of 20 years of hospital admissions in the USA, the prevalence of MS in the population with hip fracture was greater than twice that predicted, and MS patients suffered an acute fracture at an earlier age.

Is there an increased risk of hip fracture in Parkinson's disease? A nationwide inpatient sample.

OBJECTIVE: The aim of this study was to determine whether people with Parkinson's disease (PD) are overrepresented in a national cohort of hip-fracture admissions. BACKGROUND: Frequent falls, combined with a higher rate of osteoporosis in people with PD, should lead to an increased risk of hip fracture. METHODS: This work was a retrospective cohort analysis from the Nationwide Inpatient Sample from 1988 to 2007, a stratified sample of 20% of U.S. hospital admissions. Admissions with a primary diagnosis of acute hip fracture were identified, as was a subset with a secondary diagnosis of PD. RESULTS: A total of 3.63% of 1,066,404 hip-fracture admissions had PD. When compared to the population of prevalence among patients with hip fracture, the prevalence of PD was up to 4.48 times (95% confidence interval [CI]: 4.46, 4.49) more than predicted, and when adjusted for gender and age, it was 4.02 (95% CI: 4.00, 4.03). CONCLUSIONS: In this 20-year nationwide sample of hip fractures, patients with PD were overrepresented by a factor of 4.

Driving simulator performance in patients with possible and probable Alzheimer's disease.

Drivers with more advanced stages of Alzheimer's disease (AD) have been previously associated with an increased rate of motor vehicle accidents. Drivers suffering from early AD are also involved in, and may even cause motor vehicle accidents with greater frequency than "normal" drivers. Consequently there is considerable public concern regarding traffic safety issues for those with AD and subsequently for society, but there has been little research in understanding whether deterioration in driving ability is progressive, or has a sudden onset once the disease has reached a certain severity. The purpose of this study was to identify possible degradation in simulated driving performance that may occur at the earliest stages of AD, and compare these decrements to a control group of normal drivers.Using a single blind design, seventeen AD subjects, eight at a Clinical Dementia Rating (CDR) of 0.5 (possible AD) and nine at a CDR of 1 (probable AD), were compared to 63 cognitively normal, elderly controls. All subjects were trained to drive a computerized interactive driving simulator and then tested on a 19.3 km (12 mile) test course.The AD subjects demonstrated impaired driving performance when compared to the controls. The simulated driving performance of the CDR 1 AD subjects was so degraded that it would be regarded as unsafe by standard assessment criteria. The CDR 0.5 subjects made similar errors, suggesting that driving impairment may occur at the earliest stages of the disease. Further work will be necessary to determine the significance of these findings.

Assessment: efficacy of transcutaneous electric nerve stimulation in the treatment of pain in neurologic disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To determine if transcutaneous electric nerve stimulation (TENS) is efficacious in the treatment of pain in neurologic disorders. METHODS: We performed a systematic literature search of Medline and the Cochrane Library from inception to April 2009. RESULTS: There are conflicting reports of TENS compared to sham TENS in the treatment of chronic low back pain, with 2 Class II studies showing benefit, but 2 Class I studies and another Class II study not showing benefit. Because the Class I studies are stronger evidence, TENS is established as ineffective for the treatment of chronic low back pain (2 Class I studies). TENS is probably effective in treating painful diabetic neuropathy (2 Class II studies). RECOMMENDATIONS: Transcutaneous electric nerve stimulation (TENS) is not recommended for the treatment of chronic low back pain (Level A). TENS should be considered in the treatment of painful diabetic neuropathy (Level B). Further research into the mechanism of action of TENS is needed, as well as more rigorous studies for determination of efficacy.

Mortality from combined carotid endarterectomy and coronary artery bypass surgery in the US.

We determined hospital mortality and postoperative stroke rates after combined carotid endarterectomy (CEA) and coronary artery bypass graft surgery (CABG) vs CABG alone, using the US Nationwide Inpatient Sample. CEA-CABG combined was 1.06%. After correcting for comorbidities, the odds ratio for postoperative stroke or death for CEA-CABG was 1.38 (95% CI 1.27 to 1.50) vs CABG. With the increase in postoperative stroke and death, a randomized, controlled clinical trial of combined CEA-CABG is indicated.

No going home for hospitalized Huntington's disease patients.

Little is known as to what happens to people with Huntington's disease (HD) at the end of life. Exploratory analysis was performed for all admissions of people with HD in the Nationwide Inpatient Sample database, a 20% stratified sample of all US hospitalizations, from 1996 to 2002. Using the principal diagnosis and procedure, admission cohorts were determined. The common HD-associated reasons for admission were pneumonia (including aspiration, 22%), psychiatric (21.5%), debilitation (hypovolemia, nutritional deficiencies, and decubitus ulcers, 15.5%), trauma (5.7%), and nonpulmonary infections (urinary tract infections and sepsis, 11.%). Twenty-two percent were admitted for medical problems unrelated to HD. Emergency departments were the most frequent source of admission (60%), most had Medicare or Medicaid as the expected payer (80.6%), 54.4% of all admissions were discharged to long-term care facilities (LTCFs), and 3.7% died. The highest mortality was seen in the pneumonia (7.68%) and sepsis (7.39%) cohorts. Of the elective admissions, between 49.71% and 60.31% were discharged to LTCFs, representing new LTCF admissions. Based on this exploratory analysis, hospitalized HD patients are admitted late in the course of their illness, are severely disabled, and are commonly discharged to LTCFs. With 60.31% of the discharges representing new LTCF admissions, this finding shows that there is no going home from the hospital for people with HD.