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Neurology News

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

Wednesday, October 17, 2018


A behavioral intervention program that taught stroke patients of different racial/ethnic groups how to lower their blood pressure and prevent a secondary stroke led to a decrease in systolic blood pressure 12 months post-discharge among certain groups, according to a randomized, clinical trial published online on October 8 in JAMA Neurology.

In DESERVE (Discharge Educational Strategies for Reduction of Vascular Events), Hispanic patients who had a mild or moderate stroke or transient ischemic attack (TIA) experienced a 9.9 mm HG greater decrease in systolic blood pressure.

"The SBP [systolic blood pressure] reduction in Hispanic individuals translates to nearly 40% risk reduction for secondary stroke events," the researchers, led by Bernadette Boden-Albala, DrPH, MPH, of NYU College of Global Public Health in New York City, wrote.

The behavioral intervention did not lead to a significant difference in systolic blood pressure among non-Hispanic white or black populations, however.

The randomized trial aimed to investigate whether a behavioral intervention program could improve long-term vascular risk reduction among different racial/ethnic groups who had mild/moderate stroke/transient ischemic attack. The team followed 151 non-Hispanic white, 83 non-Hispanic black, and 180 Hispanic individuals at four New York City hospitals. The patients were randomized to receive either a culturally tailored, skills-based education intervention, or usual care-discharge instructions and American Heart Association pamphlets, from August 2012 to May 2016.

Prior to hospital discharge, patients in the DESERVE arm received an interactive educational session that included a patient-paced workbook and video emphasizing three skills-based thematic areas: patient-physician communication, medication adherence, and accurate stroke risk perception with risk reduction skills.

The DESERVE intervention was designed with community input from African-American and Hispanic community members. Among Hispanic patients, the educational video framed recovery in the context of faith and spirituality, whereas for African-American patients, recovery was framed as a matter of self-determination.

Participants in the DESERVE arm also received follow-up calls from a coordinator at 72 hours, one month, usually right before a neurology appointment, and three months to enhance strategies for patient-physician communication, clarify medication regimens, and provide social support to motivate behavior change.

Health coordinators helped participants identify areas of confusion about their treatment and create a checklist of questions for their doctors. They also helped to reinforce these skills prior to doctor visits through phone calls. The researchers believed this would be a more effective way for patients to achieve control of risk factors.

Researchers measured participants' blood pressure at one-year follow-up. The findings revealed no significant difference in systolic blood pressure reduction between the intervention and the usual care groups (beta 2.5 mm Hg, 95% CI -1.9 to 6.9). However, systolic blood pressure did increase in Hispanic patients in the usual care group. This effect was not observed in other control populations.

The researchers were not sure why Hispanic patients in the DESERVE arm had the most significant reduction in systolic blood pressure.

"We hypothesize that the intervention was beneficial for Hispanic participants because it was based on the needs of patients and was closely evidence based," they wrote.

Recurrent strokes disproportionately affect African Americans and Hispanic patients compared to non-Hispanic white patients, the researchers pointed out.  Persistent racial/ethnic disparities in secondary prevention, mostly due to cultural and behavioral factors not addressed in standard prevention programs, and a lack of integration into community resources, can contribute to failure to comply with secondary stroke prevention, they wrote.

The researchers stressed that their trial was not powered to identify differences in subgroup intervention effects. But, they did conclude culturally tailored, skills-based interventions may help with secondary stroke prevention and address racial/ethnic disparities in stroke. The findings warrant further research to replicate the results.

Study limitations included the inability to identify subgroup differences and distributing health literate and linguistically appropriate educational materials, which may not occur in real-world settings.

The National Institute of Neurological Disorders and Stroke of the National Institutes of Health supported the research.

The researchers reported no conflicts of interest.


Boden-Albala B, Goldmann E, Parikh NS, et al. Efficacy of a discharge educational strategy vs standard discharge care on reduction of vascular risk in patients with stroke and transient ischemic attack: The DESERVE randomized clinical trial. JAMA Neurol 2018; Epub 2018 Oct 8.

Wednesday, October 10, 2018


On October 5, the US Food and Drug Administration (FDA) approved inotersen (Tegsedi, Akcea Therapeutics and Ionis Pharmaceuticals), an antisense oligonucleotide inhibitor of transthyretin protein production, to treat polyneuropathy in adults with hereditary transthyretin amyloidosis (hATTR).

Inotersen can be self-injected once weekly and patients don't need to go to a hospital or infusion center to receive it.

In hATTR amyloidosis, misfolded TTR proteins accumulate as amyloid deposits in multiple sites, including the peripheral nerves, heart, and gastrointestinal track. It is a rare, progressive life-threatening disease that can lead to multiorgan failure. The life expectancy of hATTR amyloidosis patients is between 2.5 to 15 years from symptom onset.

The FDA approval's of inotersen was based on the results of a randomized, double-blind, placebo-controlled phase 3 trial that evaluated its efficacy in patients hATTR amyloidosis polyneuropathy. The study was presented at the American Academy of Neurology Annual Meeting in April.

As reported by Neurology Today, the 15-month trial, NEURO-TTR, included 172 patients with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hATTR-PN who were randomly assigned to either weekly self-administered subcutaneous injections of inotersen 300 mg or placebo. On average, patients treated with inotersen had a 79 percent decrease from baseline in serum TTR protein. In the inotersen group, common serious side effects included glomerulonephritis and thrombocytopenia; one death was associated with one of the cases of grade 4 thrombocytopenia.

Commenting on the findings from the AAN Annual Meeting, John W. Day, MD, PhD, professor of neurology at Stanford University, said the effects on neuropathy were "tremendous." But he said he would be interested to see the drug's ability to limit cardiac effects.

"The benefits they're seeing are fairly clear in terms of the neuropathy and I'm eager to see the same benefits systemically," Dr. Day said. He added that he had concerns about side effects, particularly thrombocytopenia. Time will tell whether improved monitoring can limit these problems, he said.

Inotersen is the second drug approved by the FDA for treatment of hATTR. Patisiran, which also inhibits production of the TTR protein production and required an IV infusion every three weeks, was approved by the FDA in August.

The FDA's approval of inotersen came with a boxed warning and mandatory monitoring to detect the possibility of life-threatening thrombocytopenia and glomerulonephritis. Due to these risks, the drug will only be available through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS).

Inotersen received marketing authorization in the European Union and Canada for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hATTR.


Benson A, Waddington-Cruz M, Berk JL et al Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med 2018; 379:22-31.

Adams D, Gonzalez-Duarte A, O'Riordan WD et al Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018; 379;11-21.

Monday, October 8, 2018


Greater levels of physical activity were associated with a delay in symptoms of early-onset autosomal dominant Alzheimer's disease (ADAD) among mutation carriers, according to a cross-sectional analysis published online on September 21 in Alzheimer's & Dementia.

Physical activity of at least 150 minutes per week was associated with lower levels of AD biomarkers in cerebrospinal fluid (CSF), better cognition, and a delayed diagnosis of very mild dementia in the study population.

The researchers, led by Stephan Muller, PhD, of University Hospital of Tubingen in Germany, believe this shows "a significant relationship between PA [physical activity], cognition and functional status, and AD pathology even in individuals with genetically driven ADAD."

Previous studies have shown the beneficial effects of physical activity on the rate of cognitive decline among healthy older people with mild cognitive impairment or mild dementia related to AD. In addition, physical activity has been associated with a lower risk of AD. Researchers hypothesized physical activity works by delaying AD-related neuropathological changes in the brain.

Dr. Muller and his research team analyzed data from participants involved in the DIAN Study, a longitudinal observational study that included participants of a parent or a first-degree relative with a known causative mutation in these three genes: APP, PSEN1, or PSEN2 genes.

The researchers assessed a total of 224 mutation carriers, with an average age of 38.4 years and classified them as either high or low exercisers, based on the World Health Organization and American College of Sports Medicine recommendations of a minimum of 150 minutes of physical activity per week. Participants reported exercise intensity; the type of exercise and how often participants' exercise was confirmed by family or friends.

Overall, 70 percent of participants reported high physical activity (≥150 minutes/week), and 30 percent reported low physical activity (<150 minutes/week).

To estimate participants' years to symptom onset, the researchers used the baseline age of carriers minus the age their parents or first-degree relative had symptom onset.

For example, if a participant's age was 37 years and the parent's or first-degree relative's age at onset was 45 years, then the estimated years for expected symptom onset would be 8, according to the researchers.

Using the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating Sum of Boxes (CDR-SOB), the researchers assessed participants' cognition and function.

Mutation carriers who were more physically active scored better on these tests and had lower levels of tau protein and other AD biomarkers in their CSF, the researchers found. Participants with high physical activity scored 3.4 points better on the MMSE at their expected symptom onset than those with low levels of physical activity. Moreover, these participants fulfilled the diagnosis of very mild dementia 15.1 years later than their low exercise counterparts. Moreover, mutation carriers with high physical activity showed less decline in global cognition on the Clinical Dementia Rating Scale and had lower CSF levels of AD pathology.

The researchers concluded a physically active lifestyle can be achieve and play an influential role in delaying the development and progression of ADAD.

"Individuals at genetic risk for dementia should therefore be counseled to pursue a physically active lifestyle," they wrote.

However, they emphasized the findings should be interpreted with caution since they're based on cross-sectional data. They were unable to assess the trajectories of cognitive changes in each of the participants.

Further research is needed to assess how exercise and other lifestyle factors could protect cognitive function in older adults susceptible to cognitive decline.

The study received support by the Dominantly Inherited Alzheimer's Network, US National Institute on Aging, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, AMED, and Korea Health Industry Development Institute.

Dr. Muller revealed no relevant conflicts of interest. Other researchers disclosed relevant relationships with Aesku, Bayer Vital, Willi Gross Foundation, AXON Neuroscience, Ionis Pharmaceuticals, AbbVie, Link Medicine, JAI, Bristol-Myers Squibb, Pfizer, Merck, SPRI, Elan Corporation, Eisai, Medtronic, Astra Zeneca Pharmaceuticals, Alzhyme, KaRa Minds Institute, Takeda Pharmaceuticals, Janssen Immunotherapy, Eli Lilly, Avid Radiopharmaceuticals.


Muller S, Preische O, Sohrabi HR, et al Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer's disease. AlzheimersDement 2018; Epub 2018 Sep 21.

Thursday, October 4, 2018


Ibudilast significantly reduced the progression of brain atrophy in primary and secondary progressive multiple sclerosis (MS), according to the findings of a phase 2 multicenter study published in the August 30 issue of the New England Journal of Medicine.

The drug has been approved for use in Japan as a treatment for asthma and post-stroke dizziness. But the study in MS was too small — 129 people received the drug and 126 people received a placebo — to answer the question of whether the pathological finding led to a functional slowing in progression of disability, the study authors said.

"Our findings showed that cortical atrophy is a robust measure of a treatment effect," said the lead investigator of the study, Robert J. Fox, MD, FAAN, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. "The study was not powered to show a clinical benefit, and we have a lot more data to analyze. We hope that the drug moves forward into phase 3 testing.

"We have very limited treatment options for progressive forms of MS," he added, so there is a big unmet need."

Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood–brain barrier. Other studies have shown that levels of macrophage migration inhibitory factor and toll-like receptor 4 are increased in the cerebrospinal fluid (CSF) of patients with progressive multiple sclerosis.

First approved for asthma two decades ago in Japan, the drug's anti-inflammatory properties led scientists to test it in relapsing-remitting MS. It did not reduce new lesions in a phase 2 study, so it was not going to move forward for relapsing-remitting MS. But scientists noted that the drug appeared to slow down brain atrophy in that study.

The relapsing-remitting MS study results were published in 2010 in Neurology. In an accompanying editorial, Dr. Fox suggested that although the results for the most common form of MS were disappointing, ibudilast could be an attractive therapy for progressive MS. Dr. Fox and his colleagues submitted a grant proposal to the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), a federal program funded by the National Institutes of Neurological Disorders and Stroke that brings academics, private foundations and industry together to carry out phase 2 clinical trials. This collaboration was also funded by the National Multiple Sclerosis Society and MediciNova, which contributed less than 10 percent of the cost of the clinical trial.


There were several firsts for this phase 2 study: The scientists decided to test the drug in patients with primary or secondary progressive MS. (The symptoms and the pathology are thought by many to be the same, but studies have usually separated the two patient groups.) While the primary outcome was magnetic resonance imaging (MRI) findings of brain atrophy, they also included secondary outcome measures of four other imaging modalities: diffusion tensor imaging; magnetization transfer ratio imaging; retinal nerve fiber layer imaging with an optical coherence tomography scan; and cortical atrophy measured by a cortical longitudinal atrophy detection algorithm, CLADA. This was no easy feat over 28 centers across the country, especially since imaging machines varied across the sites.

The investigators enrolled and randomized 255 men and women to receive up to 100 mg daily dose of ibudilast or an equal number of placebo pills. Patients, ranging in age between 21 and 65, could stay on their immune modulating treatments during the 96-week study. (That accounted for a third of study patients.)

In addition to the inflammatory disease activity (T1 and T2 lesion volumes and relapse rate), they also collected measures of disability and quality of life. Finally, they used the Brief Pain Inventory to collect information on neuropathic pain. Clinical disability was assessed every 24 weeks, when MRI and optical coherence tomography scanning took place.

An independent monitor, Stephen Krieger, MD, an MS neurologist at the Icahn School of Medicine at Mount Sinai, collected and reviewed safety data throughout the study period. The data was also reviewed by an NINDS-appointed data and safety monitoring board and the NeuroNEXT central institutional review board.

The primary outcome MRI measure showed a 48 percent difference in the progression of brain atrophy between those who received the drug and those who took the placebo. The rate of change in the brain parenchymal fraction — brain size relative to the volume of the outer surface contour of the brain — was −0.0010 per year with ibudilast and −0.0019 per year with placebo (p=0.04).

Dr. Fox said that this represents approximately 2.5 mL less brain-tissue loss with ibudilast over the study period. The secondary measures were also heading in the same positive direction, although Dr. Fox said that they are still analyzing the data.

The patients on the active drug reported more gastrointestinal symptoms, headache, and depression than those on placebo. (During the study, neurologists were also allowed to lower the active dose to 60 mg or 80 mg per day if they felt that the patient's side effects were compromising their quality of life.) Sixteen percent of patients on the active drug and 11 percent of the patients on placebo stopped taking the pills or withdrew from the study. Many continued with the follow-up assessments. Eight patients (6 percent) receiving ibudilast and three (2 percent) receiving placebo who withdrew from the trial were not included in the final analysis.

The scientists are still analyzing the secondary outcome data. Dr. Fox said that the number of patients may have been too small to assess whether a change in brain volume was associated with a slowed progression of neurologic disability assessed during the study. The study authors reported that there was not a statistically significant difference in the decline in disability progression between study patients on active medication and those on a placebo dose.

Study investigator, Patricia K. Coyle, MD, FAAN, professor of neurology and director of the MS Comprehensive Care Center at Stony Brook University in New York, said that the study "was a proof of principle that we can use standard and non-conventional imaging techniques across dozens of centers for MS trials. It also proved that we can include primary and secondary progressive MS when designing these studies."

Mount Sinai's Dr. Krieger, the independent medical monitor, agreed. "One of the drivers of disability is the acceleration of loss of brain volume. The hope is that reducing this is an indication of the slowing down of the degenerative process in MS. It remains to be seen whether this reduction translates into a benefit in the reduction of disability."    


"This is an important study. I was skeptical that the study would be successful because the odds of hitting the primary endpoint were low. But it clearly showed an effect on overall brain volume, and a trend in slowing disability," said Bruce A. Cree, MD, PhD, FAAN, the George A. Zimmermann endowed professor in multiple sclerosis and professor of clinical neurology and clinical research director at the University of California, San Francisco Weill Institute for Neurosciences.

"Now, they need to increase the sample size," Dr. Cree said. "Also, we need to know the target in the brain. Once we know the target it could usher in the development of new treatments for progressive forms of multiple sclerosis."

"We don't think of progressive MS as an inflammatory problem as much as a neurodegenerative one," said Lauren B. Krupp, MD, FAAN, director of the MS Center at NYU Langone Health. "I think it is important that the drug had a favorable impact on brain volume. It was concerning that there was not even a trend on the clinical measures, but this was a small study with a big signal on the neuroimaging primary outcome of change in brain volume. Will it spill over into clinical measures? It will be interesting to figure out how the drug is working in these patients."

The study raises many questions, she added. "To what extent were the secondary MRI measures correlated with the primary [neuroimaging] measures? We are not even sure what all the short-term changes in these neuroimaging outcomes mean to the disease and to progression. But the fact that investigators can do them reliably over 28 centers with different scanners is very exciting and encouraging for future clinical trials."


Fox RJ, Coffey CS, Conwit R, et al. for the NN102/SPRINT-MS Trial Investigators. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med 2018; 379(9): 846-855.

Tuesday, October 2, 2018


The US Food and Drug Administration (FDA) has approved galcanezumab (Emgality), a calcitonin gene-related inhibitor (CGRP), for the prevention of migraine in adults. Galcanezumab is the third CGRP inhibitor approved by the FDA.

Galcanezumab, a humanized monoclonal antibody, can be self-administered subcutaneously at 240 milligrams as a loading dose — with two consecutive injections of 120 mg each — followed by monthly injections of 120 mg.

The FDA based its approval of galcanezumab on the results of three phase 3 double-blind, randomized, placebo-controlled clinical trials that evaluated its safety and efficacy in a cohort of episodic migraine patients and chronic migraine patients. The studies were presented at the 2017 International Headache Congress last September. 

The first two six-month trials, EVOLVE-1 and EVOLVE-2, included more than 1,700 patients with episodic migraine — defined as four to 14 migraine headache days per month. In EVOLVE-1, the drug significantly reduced monthly migraine days — 4.7 days for 120 mg and 4.6 days for 240 mg — versus 2.8 days for placebo (p<0.001.)

"The reduction among galcanezumab-treated patients during 6 months of treatment translates to the equivalent of approximately 8 weeks of additional migraine-free days over the course of a year," the researchers, led by Virginia L. Stauffer, of Eli Lilly and Company, in Indianapolis, Indiana, wrote in EVOLVE-1, published in JAMA Neurology.

Similarly, in EVOLVE-2, participants had a mean reduction of 4.3 days for 120 mg and 4.2 days for 240 mg versus 2.3 days for placebo (p<0.001).

REGAIN, the third phase 3 study, tested both doses of galcanezumab over three months in patients with chronic migraine — defined as at least 15 headache days per month, with eight migraine days per month. Participants experienced greater reductions in migraine days than with placebo: 4.8 days for 120 mg and 4.6 days for 240 mg versus 2.7 days for placebo (p<0.001).

Adverse events reported in all three trials, included injection site pain, reactions, and erythema.

The FDA added that the drug is contraindicated in patients with serious hypersensitivity to galcanezumab or to any of the excipients.

Hypersensitivity reactions in the clinical studies included rash, urticaria (hives), and dyspnea (shortness of breath).

In the US, Eli Lilly reported the list price for the drug will be $575 once monthly or $6,900 annually. However, patients who have commercial insurance may be eligible to receive it for up to 12 months free as part of Eli Lilly's patient support program.

The FDA added the drug will be available to patients "shortly after approval."

As reported by Neurology Today, the FDA recently approved two other CGRP inhibitors, including erenumab (Aimovig, Amgen and Novaritis) in May, followed by fremanezumab in mid-September.

Eptinezumab (Alder BioPharmaceuticals) remains in various stages of development.


Stauffer VL, Dodick DW, Zhang Q, et al Evaluation of galcanezumab for the prevention of episodic migraine: The EVOLVE-1 Randomized Clinical TrialJAMA Neurology 2018;75(9):1080-1088.

Skljarevski V, Stauffer VL, Zhang Q, et al. Phase 3 studies (EVOLVE-1 & EVOLVE-2) of galcanezumab in episodic migraine: results of 6-month treatment phase. Late-Breaking Abstracts of the 2017 International Headache Society; Abstract PO-01-197.