Neurology News

Follow our Neurology News blog for the latest news on neurologic diseases and research.

Thursday, December 14, 2017

​BY SARAH OWENS

A rapid withdrawal of antiepileptic drugs (AEDs) significantly reduced the duration of long-term video-electroencephalography (EEG) monitoring compared to a slow withdrawal without affecting the diagnostic yield or leading to adverse events, according to a study published online on December 7 in Epilepsia.

Long-term video-EEG monitoring is routinely used to record the number of seizures when tapering patients down from AEDs. However, the relative efficacy of a rapid vs. slow withdrawal has not been examined in a randomized, controlled trial.

The findings suggest that a "rapid AED tapering protocol could be followed by epilepsy monitoring units to reduce the number of admission days and hence the waiting period for this investigation," the study authors, led by Shambhu Kumar, MD, of the department of neurology at the All India Institute of Medical Sciences in New Delhi, wrote.

The findings have important implications, the study authors noted, particularly for countries like India that have long waiting lists for video-EEG. They noted many hospitals lack the resources to perform the monitoring,  and shorter hospital stays have the potential to "clear much of [the] backlog and reduce inconvenience to patients and their caregivers."

For the open-label study, researchers at the All India Institute of Medical Sciences enrolled 140 patients between 2 and 80 years in age who had drug-resistant epilepsy. They randomly assigned them 1:1 to rapid and slow AED taper groups. Daily AED dose was reduced by 30 to 50 percent in the rapid group and by 15 to 30 percent in the slow group. The researchers tapered AEDs one after the other, starting with drugs that could be loaded intravenously or orally (such as phenytoin, levetiracetam, and valproic acid), and following with barbiturates and benzodiazepines if required.

The researchers used long-term video-EEG to monitor seizures. Participants were given rescue midazolam in a 0.1-0.2 mg/kg slow intravenous infusion for generalized tonic–clonic seizure (GTCS) lasting at least five minutes; for intermittent GTCS without regaining consciousness for five minutes or more; and complex partial seizure(s) lasting for more than 10 minutes. The video-EEGs were independently analyzed by two epileptologists who were blinded to the allocation arms the following day.

The researchers' primary outcome was the mean difference in the duration of long-term video-EEG between the rapid and slow AED taper groups. Secondary efficacy outcomes included the diagnostic yield of monitoring and the time to first seizure. Safety outcomes included the occurrence of secondary GTCS, four- and 24-hour seizure clusters, status epilepticus, and the requirement of rescue treatment.

The researchers found that the difference in mean long-term video-EEG duration between the rapid and slow taper groups was 1.8 days (95% confidence interval [CI] -2.9 to -0.8, p=0.0006). Among secondary outcome measures, two were statistically significant: the time to first seizure (2.9±1.7 and 4.6±3.0 days in the rapid and slow taper group, respectively; p=0.0002) and the occurrence of four-hour seizure clusters (11.9 percent and 2.9 percent in the rapid and slow taper groups, respectively; p=0.04). The diagnostic yield of long-term video-EEG did not differ significantly between the two groups: it was 95.7 percent and 97.1 percent in the rapid and slow taper groups, respectively (p=0.46).

Finally, the researchers found that none of the safety outcomes were different between the two groups. But they noted the small sample size of the study, and the fact that the study was not powered to examine safety, means a randomized, controlled trial designed specifically to assess safety is warranted.

The study authors disclosed no conflicts of interest.

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Wednesday, December 13, 2017

BY SARAH OWENS

Differences in symptoms and clinical outcomes distinguish collapsin response-mediator protein-5 (CRMP5) autoimmune neuropathy from anti-neuronal nuclear antibody type 1 (ANNA1)–immunoglobulin G (IgG) neuropathy and other paraneoplastic neuropathies, according to a study published online on December 8 in Neurology.

Patients with CRMP5 autoimmune neuropathy have a distinctive phenotype, including painful, typically asymmetric axonal polyradiculoneuropathy. CRMP5 autoantibodies are a known biomarker of paraneoplastic neurologic autoimmunity, but descriptions of neuropathy associated with CRMP5 are limited and the condition's phenotype has not been well characterized.

The current findings were based on assessments of a large cohort identified using comprehensive service serologic evaluation for neural autoantibodies. The results should help clinicians recognize the CRMP5 phenotype and prompt CRMP5-IgG serologic testing, the study authors, led by Divyanshu Dubey, MD, fellow in the department of neurology at Harvard Medical School, wrote.

For the study, researchers performed a comprehensive  assessment for neural autoantibodies among patients who were tested in the Mayo Clinic Neuroimmunology laboratory between January 1, 1996 and December 31, 2016. They wanted to identify those who were seropositive for CRMP5-IgG and/or ANNA1-IgG. The patients had provided serum and cerebrospinal fluid samples, which were used in assays to identify antibodies specific to CRMP5, ANNA1, and other proteins.

Overall, the study population included 105 patients with CRMP5-IgG neuropathy, as well as 51 patients with ANNA1-IgG neuropathy; of these, 27 had coexisting CRMP5-IgG. To determine phenotypes and clinical outcomes, the researchers reviewed medical records, demographic, clinical, pathologic, and electrophysiologic data, including pattern of neuropathy, and neurophysiologic testing data.

They found that CRMP5 was associated with painful axonal polyradiculoneuropathy (in 65 percent of the patients) with a mostly asymmetric onset (84 percent). Most patients with CRMP5 (79 percent) had moderate to severe neuropathic pain, and all of these were taking neuropathic medications, including 39 percent taking opioids.

Additionally, nerve biopsies in two patients with CRMP5 showed microvascular inflammation with axonal degeneration. Compared to patients who only had ANNA1, CRMP5 neuropathy has a higher prevalence of pain (79 percent vs 46 percent, p=0.008), asymmetric polyradiculoneuropathy (54 percent vs 12 percent, p<0.001), and had inflammatory spinal fluids (elevated CSF protein or nucleated cell count, 92 percent vs 60 percent, p=0.022). Common neurologic complications of CRMP5 included cerebellar ataxia (21 percent), myelopathy (19 percent), and optic neuritis and/or retinitis (11 percent).

Finally, the researchers found that immunotherapy significantly reduced pain in patients with CRMP5 (p<0.001). In particular, the administration of high-dose corticosteroids was associated with improvement or stabilization in neuropathy impairment scores (p=0.012). Overall, patients with CRMP5 had better five-year survival than patients with ANNA1 (67 percent vs 32 percent, p=0.012).

The researchers noted several limitations to their study. Among them, they cited its retrospective design, and that the neuropathy phenotype for 52 patients evaluated at the outside hospital was based on electrophysiologic impression rather than the nerve conduction study and electromyography data.

Dr. Dubey and several other authors had no financial disclosures, but others disclosed consulting fees as well as funding and financial interests related to the autoimmune antibody tests used in the study.

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Monday, December 11, 2017

BY SARAH OWENS

High-intensity treadmill training is safe and feasible for patients with new-onset Parkinson's disease (PD), according to a study published online on December 11 in JAMA Neurology.

Exercise has been shown to have neuroprotective effects, and some evidence exists that moderate- to high-intensity exercise can lower the risk of Parkinson's disease. Limited evidence exists, however, that exercise can modify symptoms or benefit disease progression in patients with existing PD.

While the current findings, which tested high-intensity treadmill training within two target heart rate ranges, found that both approaches were safe and feasible, "further investigation with a phase 3 exercise study is warranted to establish efficacy," the study authors, led by Margaret Schenkman, PhD, PT, director of the physical therapy program and associate dean of physical therapy education at the University of Denver, wrote.

For the Study in Parkinson Disease of Exercise (SPARX), researchers enrolled 128 patients with Parkinson's disease from outpatient and community-based clinics in Chicago, Denver, and Pittsburgh between May 1, 2012 and November 30, 2015. All participants were between 40 and 80 years in age, had stage 1 or 2 disease according to Hoehn and Yahr, had been diagnosed with PD in the previous five years, were not exercising at moderate intensity more than three times per week at the time of enrollment, and were not expected to need dopaminergic medication within six months.

The researchers randomly assigned the participants to undergo high-intensity treadmill exercise (at 80 to 85 percent of their maximum heart rate), moderate-intensity treadmill exercise (at 60 to 65 percent of their maximum heart rate), or usual care (maintaining usual exercise habits) for a period of six months. The researchers' feasibility measures were adherence to the prescribed heart rate and exercise frequency of three days per week and safety, while the clinical outcome was the six-month change in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, a measure of PD motor symptoms.

The researchers found that the mean percent maxiumum heart rates were 80.2 percent ( 95%CI, 78.8%-81.7%) for the high-intensity group and 65.9 percent (95%CI, 64.2%-67.7%) for the moderate-intensity group (p<0.001). The mean change in UPDRS motor score in the high-intensity group was 0.3 (95%CI, −1.7 to 2.3) compared with 3.2 (95%CI, 1.4 to 5.1) in the usual care group (p=0.03; that is, the high-intensity exercise had less motor change compared with usual care. The finding, the study authors wrote, suggests that "high-intensity treadmill exercise warrants further investigation."

Adverse musculoskeletal events that occurred during the study were not determined to be severe.

The researchers noted several limitations to their study. Among them, only treadmill training was tested, and other forms of high-endurance exercise were not; and both treadmill speed and incline were manipulated, and it is not known whether one or both may affect motor symptoms of PD.

The researchers disclosed no conflicts of interest.

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  • Schenkman M, Moore CG, Kohrt WM, et al. Effect of high-intensity treadmill exercise on motor symptoms in patients with de novo Parkinson disease: A phase 2 randomized clinical trial. JAMA Neurol 2017; Epub 2017 Dec 11.​

Friday, December 8, 2017

BY SARAH OWENS

A healthy diet high in fruits, vegetables, and whole grains and low in red meat and added sugars, combined with a healthy lifestyle defined by a healthy body mass index (BMI) and routine exercise, was associated with lower disability and reduced symptom burden in patients with multiple sclerosis (MS), according to a study published online on December 6 in Neurology.

While the current findings from a cross-sectional study do not prove causality, the robust associations observed in a large population suggest that patients with MS "who maintain a healthier lifestyle have a lower prevalence of severe depression, pain, fatigue, and cognitive problems," the study authors, led by Kathryn C. Fitzgerald, ScM, of the Harvard School of Public Health in Boston, MA, wrote.

For the study, researchers assessed data on 7,639 participants in the North American Research Committee on MS Registry. The patients also provided demographic information as well as information on their health, including their smoking status, alcohol intake, physical activity, and their height and weight (used to calculate BMI).

Participants reported whether they had experienced an MS relapse or a gradual worsening of symptoms in the previous six months. They reported their level of disability using the Patient-Determined Disease Steps (PDDS), a scale of MS disability that strongly correlates with clinician-assessed measures such as the Extended Disability Status Scale.

In addition,the participants completed a dietary screener questionnaire (DSQ), a 26-item questionnaire that collects information on dietary intake for different food groups, including fruits, vegetables, legumes, dairy/calcium, added sugars (including those from sugar-sweetened beverages and dessert foods), whole grains/fiber, and red/processed meat. The DSQ applies age- and sex-adjusted scoring algorithms to patients' responses into estimates of total dietary intake for each category. The researchers then constructed an overall diet quality score for each participant based on these food groups, with higher scores denoting a healthier diet.

Finally, the researchers developed standards for a composite healthy lifestyle, defined as maintaining a healthy weight (BMI <25), routine physical activity (defined as running, calisthenics, golf, gardening, or walking in the last month), abstaining from smoking, and consuming a better-than-average diet (>median diet quality score).

The researchers adjusted for age, sex, income, BMI, smoking status, and disease duration.

They found that participants with diet quality scores in the highest quintile had lower levels of disability (PDDS; proportional odds ratio [OR] for Q5 vs Q1 0.80; 95% confidence interval [CI] 0.69–0.93) and lower depression scores (proportional OR for Q5 vs Q1 0.82; 95% CI 0.70–0.97) compared to patients in the lower quintiles. In addition, they found that patients who reported a composite healthy lifestyle had lower odds of reporting MS symptoms, including severe fatigue (0.69; 95% CI 0.59–0.81), depression (0.53; 95% CI 0.43–0.66), pain (0.56; 95% CI 0.48–0.67), or cognitive impairment (0.67; 95% CI 0.55–0.79).

Given that diet and lifestyle are modifiable, the study authors concluded, they "offer a promising, safe avenue to ameliorate MS-associated symptoms and influence the disease course."

In an editorial accompanying the study, James F. Sumowski, PhD, associate professor of neurology at the Mount Sinai Health System in New York; Gavin V. McDonnell, MD, FRCP, neurologist at Belfast Health and Social Care Trust; and Dennis Bourdette, MD, FAAN, the chair and Roy and Eulalia Swank Family Research Professor at Oregon Health and Science University wrote that the study "adds substantive and robust empirical data" to support the benefit of a healthy diet for patients with MS. However, they noted that the study's cross-sectional design prevented the researchers from determining causality, and randomized controlled trials testing the benefits of specific dietary interventions are needed.

The study authors acknowledged that the cross-sectional nature of their study prevented them from making causal inferences. They noted a number of other limitations, including that the study population lacked diversity, and the DSQ lacked detailed information on "potentially important dietary factors," including different types of fats and dairy foods.

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Wednesday, December 6, 2017

BY SARAH OWENS

Infectious prions are detectable in the skin samples of patients with sporadic Creutzfeldt-Jakob disease (sCJD), according to a study published online on November 22 in Science Translational Medicine.

Previous studies have shown that sCJD, the most common prion disease in humans, can be transmitted through surgical instruments or transplants contaminated with infectious prions. Some studies have associated surgeries involving the skin with an increased risk of sCJD, but whether prion infectivity is detectable in the skin of patients with sCJD has not been explored.

While levels of prions in skin samples measured in the current study were much lower than levels of prions in brain samples, the skin samples were infectious in a humanized transgenic mouse model. This "raises concerns about the potential for iatrogenic sCJD transmission via skin," the study authors, led by Christina D. Orrú, PhD, a researcher at the National Institutes of Health in Bethesda, MD, wrote.

For the study, researchers at universities in the United States and China obtained skin samples at autopsy or biopsy from different body areas, including the skin and the brain, of 38 patients with CJD, including 21 with sporadic CJD and two with variant CJD. They also obtained samples from 15 non-CJD patients who had other neurologic conditions or other diseases to use for comparison.

They used ultracentrifugation followed by Western blotting to determine the levels of misfolded forms of prion protein (PrP) in all body samples. Then, to measure prion seeding activity, they performed a highly sensitive real-time quaking-induced conversion (RT-QuIC) assay, which uses an amyloid-sensitive fluorescent dye to monitor the PrP-seeded formation of amyloid fibrils, on the samples, which were then assessed by blinded investigators. Lastly, to find out whether the skin samples of the sCJD patients were infectious, they inoculated 12 mice from two lines of humanized transgenic mice with skin samples from patients with sporadic CJD and measured the levels of infection with prion strains.

They detected PrP in the skin samples of one of the five deceased patients with sporadic CJD and in one of two patients with variant CJD after Western blotting. In addition, the RT-QuIC assay revealed that that prion seeding activity was present in all 23 deceased patients with CJD, but not in the skin samples of any of the non-CJD controls.

Finally, they found that the skin samples of patients with sCJD were infectious. All transgenic mice who had been inoculated with sporadic CJD skin homogenates died from prion disease within 564 days of inoculation, even though the skin samples had much lower prion seeding activity – on the magnitude of about 103- to 105-fold –​ compared to brain tissue samples.

While the findings suggest that iatrogenic transmission of prions is possible, the study authors emphasized that "in no way does our study imply that prion transmission can occur via casual contact." Still, they said, "Further scrutiny is necessary to determine whether extra precautions should be taken during non-CNS surgeries of sCJD patients, especially in the case of procedures where surgical instruments are reused."

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