Neurology News

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

Wednesday, July 18, 2018

BY LIZETTE BORRELI

People exposed to occupational organic solvents faced a 50 percent higher risk of developing multiple sclerosis (MS), and the risk was even greater among carriers of the MS risk human leukocyte antigen (HLA) genes, according to a population-based case-control study published online on July 3 in Neurology.

Participants exposed to smoking and organic solvents who carried MS genetic risk factors had a 30-fold increased MS risk compared with non-exposed participants without the genetic risk factors.

"We demonstrate a significant interaction between the MS risk HLA [human leukocyte antigen] genes and exposure to organic solvents regarding MS risk," wrote the researchers. led by Anna Hedstrom, MD, PhD, of the Institute of Environmental Medicine and the department of clinical neuroscience, at the Karolinska Institute in Sweden.

The association between lung irritation and MS is still under investigation. But, the researchers believe the mechanism associated with both smoking and exposure to organic solvents may involve lung inflammation with a proinflammatory profile.

"We hypothesize that different sources of lung irritation may contribute to induce an immune reaction against modified self proteins induced by lung irritation or against potentially auto aggressive cells resident in the lungs, and promote MS development in people with a genetic susceptibility to the disease," the researchers said.

MS is believed to be influenced by both genetic and environmental factors, the study authors pointed out. The strongest genetic factors in MS include the human leukocyte antigen (HLA) gene complex: the HLA-DRB1*15 allele is linked a higher MS risk; the HLA-A*02 allele may have a protective effect. Epstein-Barr virus infection, vitamin D status, sun exposure habits, adolescent obesity, and smoking are environmental exposures linked to MS risk, they said.

A 2011 study in the journal Brain previously reported a gene-environment interaction in MS. Smoking status, a source of lung irritation, strongly influenced the risk of MS in carriers of HLA genes. The researchers hypothesized that a priming of the immune response in the lungs potentially led to a higher risk of MS in those with a genetic susceptibility.

To investigate the influence of exposure to organic solvents on MS risk, researchers analyzed data from a recruited sample of 2,042 Swedish people who had received an MS diagnosis and 2,947 sex- and age-matched healthy controls between April 2005 and December 2013. Participants reported environmental exposures, including organic solvents, painting products, or varnish, and lifestyle factors, like smoking history, in a standardized questionnaire. Blood samples were collected to identify participants who carried one of the two HLA complex genes.

The average age of MS onset was 34 years; 76 percent of MS patients were women; and most cases were relapsing-remitting MS. The majority of cases were recruited within the year after an MS diagnosis. Questionnaires were completed on an average of two years after MS onset.

The findings revealed exposure to organic solvents increased MS risk (OR 1.5, 95% CI 1.2 to 1.8, p=0.0004), along with increasing duration (p= 0.04) and total hours of exposure (p= 0.001).

Participants with different exposure to smoking and exposure to organic solvents, the presence of HLA-DRB1*15, and the absence of HLA-A*02 had a 30-fold increased risk of developing MS compared with non-exposed participants without the genetic risk factors (OR 30.3, 95% CI 11.7–78.3).

The results emphasized these significant interactions have a greater effect together than they do separately.

The researchers reported several limitations, including potential selection and recall bias.

The study received grants from the Swedish Medical Research Council, Swedish Research Council for Health, Working Life and Welfare, Knut and Alice Wallenberg Foundation, AFA insurance, the Swedish Brain Foundation, and Neuro Sweden.

The researchers disclosed financial relationships with Biogen, Genzyme, Novartis, and Merck.

LINK UP FOR MORE INFORMATION:

Hedstrom AK, Hossker O, Katsoulis M, et al. Organic solvents and MS susceptibility: Interaction with MS risk HLA genes​. Neurology 2018; Epub 2018 Jul 3.

Monday, July 16, 2018

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BY CHRISTINE LEHMANN

An analysis of blood pressure data from nearly 1,300 persons in late life found that both higher and declining systolic blood pressure increased the odds of having one or more brain infarcts. In addition, higher mean systolic blood pressure over time was associated with a higher number of Alzheimer's disease tangles in the brain, according to the paper published online July 11 in Neurology.

"While the relationship between high blood pressure and brain infarcts was expected based on previous research including a seminal study published in the July/August 1976 issue of Stroke, we were surprised that a faster decline in systolic blood pressure in late life also increased the odds of having one or more infarcts," lead investigator Zoe Arvanitakis, MD, MS, FAAN, medical director of Rush Alzheimer's Disease Center at Rush University Medical Center in Chicago, told Neurology Today. "The takeaway is that you can't ignore blood pressure even later in life because both increasing and decreasing levels appear to be unhealthy for the brain," said Dr. Arvanitakis.

Previous clinical and neuroimaging research, including a study published in the December 2012 Lancet Neurology, established that hypertension is a risk factor for stroke, but most of the studies involved subjects in mid-life. "Few studies have looked at people in late life to investigate the relationship between a range of blood pressure values and brain pathology," said Dr. Arvanitakis.

Although neuroimaging testing is now more sophisticated than ever, only postmortem assessments can definitively detect microscopic cerebrovascular disease such as infarcts and Alzheimer's pathologies including amyloid plaques and neurofibrillary tangles. "This study extends the knowledge from beyond what's available in the literature currently," said Dr. Arvanitakis.

STUDY DESIGN

This clinical pathologic study funded by the National Institutes of Health was derived from three ongoing prospective studies on aging involving community-based cohorts. In each, blood pressure data were collected at baseline and annually, and a self-reported history of hypertension and medications, including antihypertensives, was recorded annually. They also collected postmortem data on cerebrovascular disease, including different size infarcts and locations of infarcts, large and small vessel diseases (atherosclerosis and arteriolosclerosis), and neuropathological diseases (especially Alzheimer's disease).

The researchers analyzed postmortem data on 1,288 men and women whose mean age at death was 88.6 years; they were followed for a mean of eight years, and up to 24 years.  

"Because late-life blood pressure varies over time, we investigated the role of both mean systolic and diastolic values and changes over time using the slope in late-life blood pressure. We also looked at how these blood pressure measures related to brain pathology," said Dr. Arvanitakis.

The researchers found that that the mean person-specific systolic blood pressure was 134 mmHG (SD=13) and the mean diastolic blood pressure was 71 mmHg (SD=8). Having a higher mean systolic blood pressure and a faster systolic decline over time increased the odds of having one or more brain infarcts. Specifically, a person with a blood pressure of one standard deviation above the mean (147 mmHg) would have a 46 percent increased odds of having one or more infarcts. A higher mean systolic blood pressure was also associated with a higher number of neurofibrillary tangles (p=0.038) but not with amyloid plaques, "both of which are defining pathologic measures of Alzheimer's disease," said Dr. Arvanitakis.

Diastolic blood pressure had a weaker association with infarcts (SD=8) with one standard deviation above the mean resulting in a 28 percent increased odds of having any infarct. The researchers found no relationship between mean and diastolic slope and Alzheimer's disease pathology.

The researchers adjusted for demographics and other factors to examine associations of both systolic and diastolic blood pressure with infarcts, cerebral vessel diseases, and overall and individual measures of Alzheimer's disease pathology, including plaques and tangles. Secondary analyses looked at effects of age, apolipoprotein E4, and variables related to blood pressure such as hypertension, antihypertensive medications, and vascular risk factors and diseases. There was no change in associations but there was an interaction of age with blood pressure, "such that the effect of mean systolic blood pressure on infarcts decreased with aging," said Dr. Arvanitakis.

The main strength of the study is that it looked at the full range of blood pressure values for both systolic and diastolic blood pressure "since these may have differential effects on the brain, as indeed shown by the results," said Dr. Arvanitakis.

The main limitations were a lack of access to midlife blood pressure measurements, and that most subjects were on hypertensive medications and their blood pressure was relatively well controlled. This limited the researchers' ability to observe effects of blood pressure on a wider distribution of values.

EXPERT COMMENTARY

Rebecca F. Gottesman, MD, PhD, professor of neurology and epidemiology in the division of cerebrovascular neurology at Johns Hopkins University in Baltimore, who was not involved with the study, said, "This study confirms that blood pressure is still an important risk factor for silent stroke-like changes in the brain that can cause problems with thinking and memory."

Dr. Gottesman raised several questions about the finding that blood pressure can decline rapidly over time in people in late-life. Is this because this population is sick, on medications, or in preclinical states of Alzheimer's disease? Should clinicians be trying to lower blood pressure with antihypertensives as aggressively in older people or might this practice be harmful?

"The biggest strengths of the study were having both longitudinal and postmortem pathological data and the biggest weakness was the lack of mid-life data to compare with the late-life data in this population," Dr. Gottesman said.

"The results of this larger study add to the body of evidence in the literature reporting associations between late-life elevated and declining blood pressure in both mid and late-life and a risk of micro-infarcts, cortical atrophy and white matter disease burden, as well as clinical cognitive outcomes, including dementia and Alzheimer's disease," Emer McGrath, MBChB, PhD, associate neurologist at Brigham & Women's Hospital of Harvard Medical School in Boston, said in an email to Neurology Today.

Dr. McGrath suggested that reversal causality may explain the association between a rapid decline in blood pressure and increased infarct burden. "In the early stages of dementia/pre-clinical dementia, a decline in observed blood pressure was thought to be due to neurodegenerative effects on hypothalamic and brainstem nuclei that control blood pressure. Brainstem infarcts related to small vessel disease could also lead to a drop in blood pressure by involving brainstem nuclei controlling blood pressure. The development of cardiovascular disease in this older age group could also result in lower blood pressures, reducing systemic and cerebral perfusion."

Charles DeCarli, MD, FAAN, FAHA, director of the Alzheimer's Disease Center at University of California, Davis in Sacramento, said: "This is the first study to look specifically at the relationship between a decline in blood pressure and features of both cerebrovascular disease and Alzheimer's disease in late life. I was struck by the stronger relationship with cerebrovascular pathology than Alzheimer's pathology, which may indicate an association with dementia."

"The association between blood pressure and dementia is clear. Systolic blood pressure is a risk factor for dementia when it's high in mid-to-late life, and low in late-life," he said, citing a study published last December in Neurology.

Dr. DeCarli said a sensitivity analyses would have informed whether the findings, for example, are being driven by the number of people with hypertension.

Dr. Arvanitakis noted that the researchers conducted several sensitivity analyses, which due to space constraints, are only summarized in the paper. She added that there was no change in results when the researchers controlled for a history of stroke, Alzheimer's disease pathology, hypertension, antihypertensive medications, race, and age.

Finally, in response to comments by Drs. DeCarli and Gottesman about the lack of clinical information in the study, Dr. Arvanitakis said: "Our paper is a clinical pathologic study about the relation of annually measured blood pressure to postmortem neuropathology without any clinical diagnosis data and clinically actionable results." She noted that that another paper will address clinical outcomes such as dementia and cognition.

"This highlights the need for more research in this area because we know that pathologies are associated with clinical outcomes including cognitive impairment and dementia," said Dr. Arvanitakis.

LINK UP FOR MORE INFORMATION:

Arvanitakis Z, Capuano AW, Lamar M, et al. Late-life blood pressure association with cerebrovascular and Alzheimer's disease pathology. Neurology 2018; Epub 2018 Jul 11.

Bennett DA, Schneider JA, Arvanitakis Z, Wilson RS. Overview and findings from the religious orders study. Curr Alzheimer Res 2012;9(6):628-645.

Bennett DA, Schneider JA, Buchman AS, et al. Overview and findings from the Rush Memory and Aging Project. Curr Alzheimer Res 2012;9(6):646-663.

Kannel WB, Dawber TR, Sorlie P, Wolf PA. Components of blood pressure and risk of atherothrombotic brain infarction: The Framingham study. Stroke 1976;7(4):327-331.

Gottesman RF, Schneider ALC, Zhou Y, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017: 317(14): 1443-1450.

Gottesman RF, Albert MS, Alonso A, et al. Associations between midlife vascular risk factors and 25-year incident dementia in the atherosclerosis risk in communities (ARIC) cohort. JAMA Neurol 2017;74(10):1246-1254.

McGrath ER, Beiser AS, DeCarli C, et al. Blood pressure from mid- to late life and risk of incident dementia. Neurology 2017; 89(24):2447-2454.

Wednesday, July 11, 2018

BY FAY ELLIS

Neurology Today, the official news source of the American Academy of Neurology, has won a top Clarion Award in the annual editorial competition, in the category, Newspaper Feature Series, for its series on physician burnout.

"At a time when there is increased demand for services and projected professional shortages, the Burnout in Neurology series tackles an issue that threatens to undermine the current and future pipeline of the profession," said Neurology Today Editor-in-Chief Joseph E. Safdieh, MD, FAAN, assistant dean of clinical curriculum and associate professor of neurology at Weill Cornell Medical College. "Our series is unique in that it highlights the concerns regarding burnout in neurology, but also identifies resources and potential solutions to help address the underlying problem."

The Neurology Today award included these articles in the series:

https://journals.lww.com/neurotodayonline/Fulltext/2017/03160/AAN_Survey__Six_out_of_Ten_Neurologists_Report.1.aspx

https://journals.lww.com/neurotodayonline/Fulltext/2017/07200/Burnout_Starts_as_Early_as_Neurology_Residency,.1.aspx

https://journals.lww.com/neurotodayonline/Fulltext/2017/11020/In_Their_Own_Voices__Burnout___What_Neurologists.2.aspx

https://journals.lww.com/neurotodayonline/Fulltext/2017/11160/Wellness__What_Organizations_Are_Doing_About.13.aspx

https://journals.lww.com/neurotodayonline/Fulltext/2017/12070/Wellness__How_Neurologists_in_Independent_and.8.aspx

https://journals.lww.com/neurotodayonline/Fulltext/2017/12210/Wellness__How_to_Measure_Burnout_Where_You_Work.6.aspx

The Clarion awards recognize excellence in clear, concise communications. Recipients represent large and small media organizations, leading corporations, small businesses, as well as nonprofit associations and institutions. For more about the awards from the Association for Women in Communications, see http://www.womcom.org/content.aspx?page_id=22&club_id=903060&module_id=305156.

Tuesday, July 10, 2018

BY KURT SAMSON

While most of the attention surrounding the risk of sports concussion and chronic traumatic encephalopathy has centered on football injuries, a growing body of research indicates that soccer players are also at considerable risk, especially when "heading" balls traveling at high velocities, colliding with opponents, or hitting a goal post.

A fellowship proposal presented at the recent AAN Palatucci Advocacy Leadership Forum (PALF) would encourage a greater role for neurologists in soccer return-to-play (RTP) decisions. PALF is an annual four-day event that aims to help neurologists learn how to become advocates for change at the local, state, and federal levels through legislation, by developing coalitions and helping draft position statements for future legislation.

Studies in soccer players, including those in high school, have found that it is an underrecognized risk, even though the velocity of head hits is just as forceful as being hit in a boxing match or colliding with a football player. It is established that repeated head trauma can result in chronic traumatic encephalopathy (CTE) and lead to serious long-term cognitive issues.

Nikesh Bajaj, DO, a fourth-year neurology resident at University of Illinois Hospital in Chicago, believes that requiring a neurologist's evaluation will help reduce the potential lifelong cognitive consequences that can occur as a result of such impacts.

Neurology Today asked Dr. Bajaj about his PALF proposal to make an impact in this area. Edited excerpts from the discussion appear here.

TELL US ABOUT YOUR PALF PROPOSAL.

My plan is to gather available data of soccer head injuries through research and input from other concerned sports neurologists, including those who may already be involved in professional soccer. I will also look for at least one athlete affected by chronic head injury to be a spokesperson, hopefully a retired US soccer player.

I will also reach out to athletes and their families to garner support for the initiative as well as support from other soccer organizations toward developing a consensus petition to propose to the US Soccer Association and the US Soccer Federation.

A major part of the plan will be developing a network, by computer, phone, and online, to connect with other sports neurologists and informed individuals to become advocates for the initiative. We'll use various methods, including social media as well as considering radio time or on-air broadcasts.

WHAT DO YOU ENVISION AS A GOOD APPROACH TO CONCUSSION IN SOCCER?

For major league soccer, we can follow a model similar to the NFL's and pre-establish a local concussion-trained neurologist to be the primary evaluator for each team. My plan, to start, is not to change all guidelines for all sports at once, but rather starting with requiring leagues to require neurologists in hopes that there will be a gradual trickle-down effect all the way to youth levels.

COULD YOU TELL US WHY YOU ARE FOCUSED ON THIS ISSUE? 

Sports neurology and concussion have been a passion of mine since before I even started medical school. I did my masters in pathology at Boston University and attended a lecture by Dr. Ann McKee, a leader in CTE research in athletes and a major contributor to the field. This was in 2010, and. Dr. McKee showed the histology slides of the brains of deceased football players who had donated their brains to study the issue.

Correlating pathological disease with their sports careers was stunning. Hearing the stories of behavioral changes and suicides, and how it affected their lives and their families after years of sports was shocking. That's when I was inspired to pursue this as a career, which took its shape once I decided on neurology and became involved in health policy as a medical student. I knew I wanted to make a difference in the world of concussion in sports. As a medical student, I wrote a resolution that became the American Medical Association's current policy on concussion. 

WHY IS THIS A GOOD TIME TO ADDRESS THIS ISSUE?

The FIFA World Cup is underway, and while the United States has not qualified for this year's championship games, the sport will receive much more attention than it normally does in the US. This presents an excellent opportunity to take advantage of this to raise awareness of the risk, to take the lead on concussion management, and eventually, implement rules across our leagues to prevent chronic brain injury in our professional and collegiate athletes, especially in younger athletes.

WHAT DOES THE RESEARCH SHOW ABOUT CONCUSSION PREVALENCE AND SEVERITY IN SOCCER PLAYERS?

 While football players sustain the most concussions each year, soccer players are a close second, and among female athletes, soccer accounts for the most concussions. The National Football League already requires that an independent neurotrauma consultant evaluate players before they can return to play, so why shouldn't our professional soccer players receive the same level of care?

DO ANY OTHER COUNTRIES REQUIRE NEUROLOGICAL EVALUATION OF THESE ATHLETES?

Not yet. In fact, concussion management has often been worse on the world stage. For example, just a couple of weeks ago, the Union of European Football Associations (UEFA) Champions League Final occurred which is basically the Super Bowl for Europe. During a game, Liverpool goalkeeper Loris Karius sustained a blow to the head that went unrecognized and went on to make curious mistakes during the match. When Karius was later evaluated at Massachusetts General Hospital he was eventually diagnosed with a concussion. 

A recent study looked at the 2014 FIFA World Cup and found that concussion assessment protocols were not followed in 63 percent of cases where players were involved in head collisions and not assessed by sideline healthcare personnel. This highlights a big problem with concussion management while the entire world is watching. ​

WHAT DO YOU SEE AS MAJOR OBSTACLES?

If we changed all sports guidelines to include neurologists in return-to-play decisions, there would likely be a bottleneck in getting an athlete back on the field. While sports neurology is a relatively new concept, it is a rapidly growing field with at least seven fellowships across the country and growing.

LINK UP FOR MORE INFORMATION:

AAN PALF Leadership Program: http://bit.ly/NT-AAN-PALF

Cusimano MD, Casey J, Jung R, et al. Assessment of head collision events during the 2014 FIFA World Cup Tournament. JAMA 2017;317(24):2548-2549.​

Stewart WF, Kim N, Ifrah CS, et al. Symptoms from repeated intentional and unintentional head impact in soccer players. Neurology 2017;88(9):901-908.

Phalen J, Alosco M, Kiernan P, et al. Chronic encephalopathy in a 24-year-old former soccer player. Neurology 2017;88(16 Supplement).

Grinberg LT, Anghinah R, Nascimento CF, et al. Chronic encephalopathy presenting as Alzheimer's dementia in a retired soccer player. J Alzheimers Dis 2016; 54(1):169-174.​

Monday, July 9, 2018

BY LIZETTE BORRELI

Industry payments to physicians were associated with an increase in prescriptions for repository corticotrophin (H.P. Achtar gel) in the Medicare program, according to a cross-sectional study published online on June 29 in JAMA Network Open.

In the study, 207 out of 235 (88 percent) frequent corticotrophin prescribers received a corticotrophin-related payment from Mallinckrodt Pharmaceuticals.

"Our analysis suggests that every $10,000 spent by Mallinckrodt for payments to physicians is associated with a 7.9% increase in Medicare spending on corticotropin," the researchers, led by Daniel M. Hartung, PharmaD, MPH, an associate professor of pharmacy in the Oregon State University/Oregon Health and Science University College of Pharmacy and an investigator in the Pacific Northwest Evidence-based Practice Center, wrote.

In a separate analysis on corticotrophin (H.P. Acthar Gel) payments and prescribing patterns, CNN found more than 80 percent of doctors who filed Medicare claims in 2018 received money or other perks from Mallinckrodt. According to the CNN report, the rise in Medicare spending coincided with a marketing push by Mallinckrodt to target adults, especially seniors, after it purchased Acthar's previous manufacturer, Questcor, in 2014.  On its website, the drug has been indicated and promoted for systemic lupus erythematosus, proteinuria in nephrotic syndrome, dermatomyositis and polymyositis, rheumatoid arthritis, symptoms of sarcoidosis, and inflammatory conditions of the eye, such as uveitis. It has also been used as a treatment for relapses in multiple sclerosis.

Corticotrophin, a drug best known for treating babies with infantile spasms, has increased dramatically in costs, according to the JAMA Network Open report. For decades, the drug was available for less than $50 per vial and quickly rose to 5-mL vial for a current acquisition cost of $38,392. Despite its very high cost, and lack of evidence that it was better than lower-cost synthetic corticosteroids, corticotrophin continued to experience growth.

In the JAMA Network Open report, researchers examined the link between industry payments to physicians and prescription for repository corticotrophin in a cross-sectional analysis of Centers for Medicare & Medicaid Services 2015 Part D claims and 2015 payment data. A total of 235 physicians, including 65 nephrologists; 59 neurologists; and 111 rheumatologists with more than 10 corticotrophin prescriptions in 2015 were part of the analysis. Researchers manually reviewed the Open Payments physician demographic characteristics record to verify concordance in corticotrophin prescribers identified in the Medicare Part D Public Use Files.

In the 2015 cross-sectional analysis, the median total payment was $189 for most frequent corticotrophin prescribers. Meanwhile, maximum total payments were as high as $56,549 for nephrology, $120,387 for neurology, and $138,321 for rheumatology. Neurologists were the most likely to receive a payment (93.2% vs 78.5% for nephrologists and 91.0% for rheumatologists), had the greatest number of transactions (20 vs 5 for nephrologists and 13 for rheumatologists), and received the highest median total dollar amount over the year ($476 vs $118 for nephrologists and $207 for rheumatologists), the researchers reported.

Mallinckrodt payments were positively associated with greater Medicare spending on corticotropin (β = 1.079; 95% CI, 1.044-1.115; P < .001), with every $10,000 in payments associated with a 7.9 percent increase (approximately $53,000) in Medicare spending on corticotropin.

No associations were identified between corticotrophin-related payments and spending on prescriptions for synthetic corticosteroids.

The researchers concluded these findings suggest financial conflicts of interest may be driving the continued growth of corticotropin use in the Medicare program.

They urge prescribing decisions be made on evidence and be free from undue commercial influence as high-priced therapies are becoming the norm for many conditions.

"[W]e advocate that physicians who receive significant payments from Mallinckrodt disclose this to patients before prescribing corticotropin for them or consider not receiving any payments from Mallinckrodt," the researchers wrote.

The researchers cited several study limitations. Although the findings suggest a casual association between Mallinckrodt payments and corticotrophin prescriptions, the study was cross-sectional and the researchers cannot affirmatively establish the temporal sequence between payments and prescriptions.

Several researchers reported conflicts of interest: Dr. Hartung reported grants from the National Multiple Sclerosis Society during the conduct of the study. Ms. Johnston reported grants from the National Multiple Sclerosis Society during the conduct of the study. Dr. Deodhar reported grants and personal fees from AbbVie, Eli Lilly, Janssen, Novartis, Pfizer, and UCB as well as grants from Sun Pharma outside the submitted work.

LINK UP FOR MORE INFORMATION:

Hartung DM, Johnston K, Cohen DM et al. Industry payments to physician specialists who prescribe repository corticotropin. JAMA Network Open 2018; Epub 2018 29 Jun.