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Neurology News

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

Thursday, May 16, 2019

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Former athletes with a history of multiple concussions had higher levels of total tau (t-tau) in their cerebrospinal fluid (CSF), compared with healthy controls, and lower than patients with Alzheimer's disease (AD), according to a cross-sectional cohort study.

Brain scans showed those with the highest levels of t-tau also experienced a reduction in white matter integrity and scored lower than athletes with normal levels of tau on the Trail Making Test (TMT) Part B test that measures thinking skills.

The results were published May 8 in the online issue of Neurology.

Tau has been associated with chronic traumatic encephalopathy (CTE), which is a rare, neurodegenerative brain disease most often seen in professional football or hockey players who sustain concussive or subconcussive head trauma. People with CTE may experience a series of cognitive, psychiatric, and motor symptoms. However, CTE remains a post-mortem diagnosis, because there is a strong overlap of symptoms with other neurodegenerative diseases, like AD, frontotemporal dementia, and Parkinson's disease.

Yet, "the potential for treating postconcussion degeneration such as CTE depends on being able to detect the in vivo pathology at an early stage to intervene before the disease progresses to an irreversible stage," the researchers, led by Foad Taghdiri, MD, MSc, of the University of Toronto in Ontario, Canada, wrote.

To identify CSF biomarkers related to decreased white matter integrity and poor cognitive performance in former athletes with multiple concussions, the researchers measured concentrations of phosphorylated tau181, t-tau, and amyloid-beta in the CSF of three groups: 22 former professional athletes (mean age 55.9 years) who had multiple concussions, five healthy controls (mean age 57.4 years), and 12 individuals (mean age 60 years) diagnosed with AD. All athletes were male and sports included snowboarding, hockey, and football.

Former athletes underwent diffusion tensor imaging to determine white matter integrity and completed neuropsychological testing. The researchers then divided the former athletes group into those with normal (<300 pg/mL) and high (>300 pg/mL) CSF t-tau.

The average t-tau level in the CSF of athletes was significantly higher than that of controls (349.3 pg/mL vs. 188.8 pg/mL; p= .003) and significantly lower than that of AD patients (349.3 vs 857.0 pg/mL; p= .007).

Twelve of 22 former athletes had high t-tau levels, with an average of 499.3 pg/mL. In this group, the average score on the TMT Part B was significantly lower than the average score among the 10 former athletes with normal CSF t-tau levels (t scores 45.6 vs. 62.3; p= .017).

Results from MRI scans showed that fractional anisotropy values across all the tracts were significantly lower for those with high CSF t-tau levels, compared with those who had normal CSF t-tau levels (p= .036).

The researchers said the study findings offer insight  into the pathophysiology of chronic brain trauma and "suggest that CSF t-tau may be a biomarker of possible neurodegeneration."

But they said the study had several limitations, including its small sample size, a lack of female athletes, and the limited ability to compare white matter integrity between high and normal CSF t-tau groups.

The Toronto General and Western Hospital Foundation, PSI Foundation, and the Canadian Institute of Health Research funded the study.

The researchers had no relevant financial conflicts to disclose.

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Taghdiri F, Multani N, Tarazi A, et al. Elevated cerebrospinal fluid total tau in former professional athletes with multiple concussions. Neurology 2019; Epub 2019 May 8.

Wednesday, May 15, 2019

Short-term administration of the oral agents cilostazol and isosorbide mononitrate (ISMN), alone or in combination, in patients with lacunar ischemic stroke, was well-tolerated as an add-on to conventional secondary stroke prevention, according to the results of a phase 2a randomized clinical trial.

In the study, LACunar Intervention-1 (LACI-1), both cilostazol and isosorbide, which work similarly to prevent small vessel disease, affected systemic hemodynamic function and "may improve vasoreactivity in white matter, reduce white matter lesions, and improve cognitive performance" the researchers wrote.

The study was published online on April 23 in EClinical Medicine, a journal of The Lancet.

Lacunar stroke is a frequent clinical manifestation of small vessel disease (SVD), a common cause of stroke, cognitive decline and dementia. Patients face a high risk of cognitive decline after a lacunar stroke. Yet, there is no specific secondary prevention for lacunar stroke, or SVD-associated cognitive decline.

In Asia-Pacific countries, previous studies have shown cilostazol reduced recurrent stroke and incident dementia. ISMN, commonly used in angina, is suspected to have multiple potential effects that may benefit SVD, but data on ISMN in lacunar stroke are limited.

To test the short-term administration of cilostazol and ISMN, alone and combined, for tolerability, safety, and efficacy after lacunar ischemic stroke, the researchers enrolled 57 participants, 39 men and 18 women (mean age, 66 years) with clinically confirmed lacunar ischemic stroke and without cognitive impairment, between March 2016 and August 2017, at two large stroke centers in the UK.

The researchers randomized participants 1:1:1:1 into four groups: cilostazol alone at 50 mg twice daily, increasing to 100 mg twice daily; ISMN alone  at 25 mg once daily increasing to 25 mg twice daily; cilostazol and ISMN combined, started immediately with ISMN given first; and cilostazol and ISMN combined, with the start delayed for three weeks and  cilostazol given first.

The doses were escalated to target over two weeks and were sustained for eight weeks.

The primary outcome was having participants achieve the target dose by the end of the eight-week trial period.

At the end of the treatment period, 64 percent of patients achieved the full target dose and 87 percent achieved more than half of the target dose. The researchers found no differences between cilostazol versus ISMN and single versus dual drugs.

The researchers found no in-group differences in secondary outcomes, such as blood pressure, pulse-wave velocity, hemoglobin or platelet function. However, pulse rate was higher (p= 0.02) as was platelet count (p= 0.03). They also observed that white matter hyperintensities were reduced more (p= 0.007) with cilostazol compared with those who did not take it. 

Although all participants took prescribed antiplatelet drugs, no drug-related adverse events or bleeding complications were reported.

"LACI-1 demonstrates drug tolerability and supports testing of ISMN and cilostazol in larger trials with clinical endpoints," the researchers concluded.

Study limitations included a small sample size, short-term drug administration, and limited clinical endpoints.

The researchers added LACI-2, which will aim to enroll 400 patients with lacunar stroke and is funded by the British Heart Foundation, is underway. Patients will be treated with cilostazol and ISMN, alone or in combination, for a year to test the effects on recurrent stroke, cognition, tolerability, and safety.

The Alzheimer's Society with support from the UK Stroke Association, the British Heart Foundation, the European Union, the National Institutes of Health Research, and National Health Service Research Scotland primarily funded the study.

The authors reported no relevant disclosures.

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Blair GW, Appleton JP, Flaherty K, et al. Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischemic stroke: The LACunar Intervention-1 (LACI-1) trial, a randomized clinical trial. EClinicalMedicine 2019; Epub 2019 Apr 23.

Friday, May 3, 2019

Out-of-pocket costs for patients with neurologic conditions has risen significantly over the past 12 years, particularly for those enrolled in high-deductible health plans, according to a study published in the May 1 online issue of Neurology.

Among the five common neurologic conditions covered in the analysis—multiple sclerosis (MS), peripheral neuropathy, epilepsy, dementia or Parkinson's disease (PD)—MS patients faced the sharpest rise in costs. Average out-of-pocket costs for MS medications were 20 times higher in 2016 than they were in 2004. Moreover, MS patients with high-deductible health plans had approximately twice the monthly out-of-pocket expense compared with those not enrolled in these plans.

The cost of treating neurologic disorders exceeds $500 billion annually, the authors of the new report said. And the total cost burden on patients is likely to continue to increase, predicted the researchers of the Neurology study, led by Brian C. Callaghan, MD, MS, FAAN, an assistant professor of neurology at the University of Michigan in Ann Arbor.

"Given new high-priced neurologic medications coming to the market and the rise in high-deductible health plans, it is likely that out-of-pocket costs will continue to increase and become even more important to neurologists and patients," Dr. Callaghan and his colleagues, wrote.

For the analysis, the team used a large health care claims database of more than 912,000 people with MS, peripheral neuropathy, epilepsy, dementia or PD, to examine out-of-pocket costs from 2004 to 2016. Participants were privately insured and took at least one neurologic medication.

The researchers investigated the top five most commonly prescribed medications for each condition based on Medicare data and included all Food and Drug Administration-approved MS treatments, lacosamide as a brand name epilepsy medication, and venlafaxine as a peripheral neuropathy medication that went from brand name to generic.

They calculated the average out-of-pocket costs for a 30-day supply of a neurologic prescription, including copay and deductible payments associated with the medication.

In their analysis, the researchers identified 105,355 patients with MS, 314,530 with peripheral neuropathy, 281,073 with epilepsy, 120,720 with dementia, and 90,801 with PD.

From 2004 to 2016, out-of-pocket costs increased for each disorder, with the sharpest rise for MS.

For MS medications, out-of-pocket costs went from $15 a month in 2004 to $309 a month in 2016. MS patients with high-deductible plans saw a higher rise with $661 a month, compared with $246 a month for those not enrolled in high-deductible health plans. The findings also revealed that cumulative out-of-pocket costs averaged $2,238 in the two years after diagnosis, accounting for 77.4 percent of their cumulative medication out-of-pocket costs.

In MS patients, cumulative out-of-pocket costs were associated with total costs and high-deductible health plan status, but not insurance plan type, the researchers reported.

The findings warrant further investigation as to whether higher out-of-pocket costs for patients with MS in high-deductible health plans leads to lower treatment adherence and whether this impacts clinical trial outcomes in this population, the study authors said.

Overall, out-of-pocket costs vary substantially both within and across neurologic conditions, even within the same medication.

"Neurologists should use out-of-pocket cost information to influence their prescribing practices, but first they must have this information available to them at the point of care," the researchers wrote.

They believe that this will encourage patients to ask their doctors for cheaper alternatives to medications being prescribed.

Study limitations included only examining medications costs for five neurologic conditions and also not observing all medications used to treat these conditions.

The AAN supported the study.

Dr. Callaghan receives research support from Impeto Medical Inc and performs medical consultations for Advance Medical, consults for a PCORI grant, consults for the immune tolerance network, and performs medical legal consultations.

Go to Neurology.org/N for full disclosures.

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Callaghan B, Reynolds E, Banerjee M, et al. Out-of-pocket costs are on the rise for commonly prescribed neurologic medications. Neurology 2019; Epub 2019 May 1.

Wednesday, May 1, 2019

Increasing physical activity, even at a light intensity, each day was associated with a higher total cerebral brain volume and less brain aging as measured by brain MRI, according to an observational study published online in JAMA Network Open on April 19.

The effect was observed even among individuals who did not meet the national physical activity guidelines.

Each additional hour of light-intensity physical activity  per day was associated with the equivalent of 1.1 years less brain aging. Individuals who achieved 10,000 or more steps a day had higher brain volume compared with those who achieved fewer than 5,000 steps a day.

"These data are consistent with the notion that the potential benefits of PA [physical activity] on brain aging may accrue at a lower, more achievable level of intensity or duration," the researchers, led by Nicole Spartano, PhD, research assistant professor of medicine of the Boston University School of Medicine, wrote.

Currently, the U.S. Department of Health and Human Services 2018 Physical Activity Guidelines for Americans suggest that some physical activity is better than none, but achieving 150 or more minutes of moderate to vigorous physical activity per week is recommended for optimal health benefits. For the first time, the physical activity guidelines included brain health in the list of benefits.

Previous studies have provided evidence that engaging in regular physical activity may ward off cognitive decline and dementia. But the number of adults who meet the recommended guidelines decreases sharply from middle age to older age.

To assess the association between physical activity levels and brain volumes, the researchers compared the number of total steps walked per day and the dose of exercise (intensity times duration) with MRI total cerebral brain volume in 2,354 third-generation Framingham Heart Study participants from 2016 to February 2019.

Participants' were predominantly white; with a mean age of 53 years; and 54.2 percent were women. A total of 46.7 percent met the nationally recommended physical activity guidelines, averaging 21.4 minutes or more of moderate to vigorous physical activity per day, equivalent to 150 minutes or more per week.

Participants with prevalent dementia or stroke or other disorders that may affect brain MRI measures were excluded.

The researchers measured steps per day, moderate to vigorous physical activity, light-intensity physical activity, and sedentary time with an accelerometer. Participants wore a hip-belt accelerometer for eight days. Activity measures of 200-1,486 counts/minute were classified as light activity and moderate to vigorous activity was classified as more than 1,486 counts/min.

The findings revealed that for every additional hour of light-intensity physical activity per day, participants experienced less brain aging (p= 0.003).

An hour of light-intensity exercise (p= 0.01) and achieving 7,500 steps or more per day (p= 0.02) were associated with higher total brain volume equal to approximately 1.4 to 2.2 years of less brain aging in participants who didn't meet the physical activity guidelines.

Meanwhile, those who achieved 10,000 or more steps a day had a higher brain volume than participants who took fewer than 5,000 steps per day.

After the researchers adjusted for light-intensity physical activity, neither increasing moderate to vigorous physical activity levels nor meeting the moderate to vigorous activity levels recommended by the guidelines were significantly associated with total cerebral brain volume. Based on this study, it's unclear whether individuals can reap more benefit with higher-intensity activity.

The researchers advised caution in interpreting the findings. They suggested longitudinal studies with longer follow-up times are needed to test whether light-intensity physical activity interventions in older adults can influence healthy brain aging.

Other study limitations included the lack of diversity in the cohort sample; participants were predominantly white and of European descent. Effective preventative measures for developing dementia also need to be studied in an ethnically diverse population.

Dr. Spartano reported no conflicts of interest. Co-authors reported relevant disclosures, including grants from National Institutes of Health during the conduct of the study and grants from Boston University during the conduct of the study.

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Spartano NL, Davis-Plourde K, Himali JJ, et al. Association of accelerometer-measured light-intensity physical activity with brain volume: The Framingham Heart Study. JAMA Netw Open 2019; Epub 2019 Apr 19.

Tuesday, April 30, 2019

Patients with multiple sclerosis (MS) who were pregnant and exposed to teriflunomide, an MS drug contraindicated in pregnancy, experienced similar risks of birth defects and spontaneous abortions as that of the general population, according to a study published online on April 10 in the journal, Multiple Sclerosis.

The frequency of reported major birth defects was 3.6 percent in clinical trials and zero percent in the post-marketing setting, consistent with the general population's frequency of 2 percent to 4 percent. Overall, spontaneous abortions occurred in 21.2 percent of women who took teriflunomide. In comparison, the rate of spontaneous abortions in the general population falls between 15 percent and 20 percent.

Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of MS in 80 countries. Previous preclinical studies have found teriflunomide doses that fell in the human therapeutic range were associated with embryotoxicity and teratogenicity in rats and rabbits. The drug is contraindicated in pregnant women and women of childbearing age who do not use effective contraception.

"Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies," the researchers, led by Sandra Vukusic, MD, PhD, professor of neurology, Lyon University Hospital in Lyon, France, wrote in the new study.

In an effort to report outcomes of pregnancies occurring with teriflunomide use, Dr. Vukusic and her team analyzed data from teriflunomide monotherapy clinical trials and their extensions, and more than five years of post-marketing surveillance data extracted from the Sanofi Global Pharmacovigilance Database and related case files.

The researchers calculated estimates of pregnancy duration and teriflunomide exposure. The timing of teriflunomide use in relation to pregnancy outcome was based on the reported dates of teriflunomide use and the administration of cholestyramine or other agents prior to or during pregnancy intended to reduce teriflunomide concentrations in the blood to levels associated with minimal fetal risk, if available.

In addition, maternal characteristics, pregnancy outcomes, and fetal outcomes were included. Pregnancy outcomes included live birth, spontaneous abortion, elective termination, ectopic pregnancy, and fetal death. Fetal outcomes included gestational age and birth weight/length.

The researchers noted 437 pregnancies were confirmed in MS patients, including 70 from clinical trials and 367 from post-marketing data. A total of 222 pregnancies had known outcomes, including 70 from clinical trials cases and 152 post-marketing cases.

Among the findings, they reported that 48.2 percent were live births, 28.4 percent were elective abortions, 21.2 percent were spontaneous abortions, 1.4 percent were ectopic, and 0.5 percent were stillbirths and maternal death leading to fetal death. More than 90 percent of the patients reported no previous pregnancies.

Spontaneous abortions occurred more frequently in post-marketing cases than in clinical trial cases (37 versus 10). The researchers noted this may be related to the older age, on average, of women in post-marketing cases compared to clinical trials (32.5 years vs 30.4 years).

The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was one out of 28 in clinical trials and 0 out of 51 in post-marketing reports. In the clinical trial group, one infant had a major congenital anomaly. In the post-marketing group, three of 84 infants had a birth defect, which none were considered as major.

The findings warrant further research to determine the risks associated with teriflunomide use during pregnancy.

The team advised caution when interpreting the findings since they are based in part on post-marketing data, with a limited number of cases, and lack extensive detail in some case reports.

Study limitations included limited data on post-marketing cases. Outcomes data was only available for approximately 50 percent of the included pregnancies, compared with 100 percent of the pregnancies in clinical trial cases. The researchers noted that this study cannot exclude the chance that defects occurred in the remaining births of unknown outcome.

In addition, age differences between clinical trial and post-marketing cases could mean patient adherence to treatment in post-marketing may be less thorough compared to women who participated in clinical trials.

Dr. Vukusic reported conflict of interests, including consultancy fees, speaker fees (nonpersonal), or honoraria from Biogen, Celgene, GeNeuro, MedDay, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva and research grants from Biogen, GeNeuro, MedDay, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva. Co-authors list conflicts of interest in the full study.

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Vukusic S, Coyle PK, Jurgensen S, et al. Pregnancy outcomes in patients with multiple sclerosis treated with teriflunomide: Clinical study data and 5 years of post-marketing experience. Mult Scler 2019; Epub 2019 Apr 10.