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Tuesday, September 19, 2017

BY SARAH OWENS

Patients who had a previous ischemic stroke or transient ischemic attack (TIA) and were at high risk of a future stroke or myocardial infarction (MI) derived more of a benefit from the diabetes drug pioglitazone than patients at low risk, according to a study published online in JAMA Neurology on September 18.

Earlier studies have suggested that pioglitazone hydrochloride, an insulin-sensitizing drug, reduces the risk of secondary stroke when added to standard therapies. But researchers have not previously assessed whether high- or low-risk stroke patients are more likely to benefit from the drug – critical information because the drug is also associated with substantial risks, including peripheral edema and bone fractures.

"To our knowledge, our analysis is one of a very few to apply this concept of risk-based treatment selection to the field of stroke prevention, the study authors, led by Walter N. Kernan, MD, professor of medicine at Yale University School of Medicine, wrote.

For the study, researchers conducted a secondary analysis of the Insulin Resistance After Stroke (IRIS) trial, a double-blind, placebo-controlled trial of pioglitazone for secondary stroke prevention. All 3,876 patients, who were enrolled from 179 research sites in seven countries between 2005 and 2013, were insulin-resistant without type 1 or type 2 diabetes and had an ischemic stroke or transient ischemic attack (TIA) within 180 days of trial entry.

The patients were randomized to receive an initial daily dose of 15 mg pioglitazone hydrochloride or placebo. Researchers followed up with the patients every two weeks for three months to determine health events, during which time daily doses were escalated to 45 mg. After three months, the researchers contacted patients every four months for a maximum follow-up of five years.

Based on pretreatment variables associated with stroke and MI risk, the researchers divided the participants into two study populations of equal sizes: those with a high (17.2 percent) and low (6.9 percent) five-year risk of stroke or MI.

After secondary analysis, the researchers found that the five-year risk of stroke or MI was 6 percent in the pioglitazone group versus 7.9 percent in the placebo group. Among patients who were determined to be at higher risk of stroke or MI, the benefit of pioglitazone was greater: The risk of stroke or MI was 14.7 percent in the pioglitazone group versus 19.6 percent in the placebo group – an absolute risk reduction of 4.9 percent, compared to 1.9 percent in the low-risk group.

However, the researchers found no difference in relative risk reduction between the high- and low-risk groups. Also, among patients in the higher-risk group, pioglitazone was found to increase the risk of fractures more than for patients in the low-risk group, although increased weight was observed less often in the high-risk group than the low-risk group.

In any accompanying editorial, Graeme J. Hankey, MD, FRACP, FRCP, professor of neurology at the University of Western Australia in Perth, agreed that the findings "will encourage clinicians to adopt a risk-adapted approach to patient management based on the prognostic factor profile of the patients."

Patients with "perhaps the highest benefit to harm ratio for pioglitazone are those 70 to 79 years of age with a history of coronary artery disease and.or hypertension and/or current smoking," he wrote, while those older than 80 years old who have the highest risk of stroke and MI may have the most to gain from the therapy, but also have the highest risk of bone fracture.

The researchers noted several limitations to their study. Among them, the analysis was not prespecified before the IRIS trial was completed, and the overall number of participants was not great enough to support each subgroup analysis or to eliminate the possibility of error in risk factor selection.

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Thursday, September 14, 2017

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Teshamae Monteith, MD, an assistant professor of clinical neurology and director of the headache division at the University of Miami and a member of the Neurology Now advisory board, chose to stay in Miami when Hurricane Irma barreled through Florida on September 10. And only days later, the neurology clinic is back and running, and she is back at work. Dr. Monteith shared her experiences with Neurology Today Associate Editor Orly Avitzur, MD, MBA, FAAN — why she stayed through the storm and the current conditions as Florida works toward recovery.

WHY DID YOU DECIDE TO STAY?

There were a number of factors that influenced my decision to stay. I have elderly family in the area. I had last-minute home safety work to do, and I had a safe space in my building. I was also aware of the challenges I might face in getting back to work (flooding, airline obstacles, unsafe roadways, etc.). I had a full schedule of chronic migraine patients that often experience severe migraines when botulinum toxin [Botox] is delayed.

WHAT DID YOU DO TO PREPARE?

I live on the 15th floor of a condominium-hotel building, located in an evacuation B zone (near the shoreline). I prepared by getting last-minute balcony repairs, adding a pole to secure the glass door, and by removing everything that could potentially become a projectile. I bought lots of water, canned beans, fruits, vegetables, almonds, nuts butter, and some snacks. I purchased a radio, battery-operated lighting, candles, and charged both my cell phone and laptop. I made sure to wash my laundry, because I didn't know what the water supply would be like after the storm. I also prepared a safe place to sleep away from glass doors during peak wind gusts and tornado alerts. I packed an emergency suitcase with personal identification, important documents, water, fruit and some clothes.

WERE YOU ALONE?

No, I stayed with my sister, mother, stepfather who has parkinsonism, and cat. The staff and building engineers remained on duty for the storm. There were some people in the lobby and many restaurants that remained open. Some residents from Key West docked their boats in the marina before it all started. The ABC local news was reporting outside.  We could no longer leave. The front doors were closed.  I got lots of laundry done but otherwise could not concentrate enough to be very productive.  

 WHAT WAS IT LIKE TO STAY THROUGH THE STORM?

For several days, we sat there glued to the weather programs. I hadn't watched that much television in decades. As grateful as I am for technology, it was an excruciating process to watch the hurricane devastate the Caribbean and slowly march its way up. I saw firsthand the damage that hurricane Andrew caused; the description of Irma in comparison was scary and unreal. I felt both a massive sense of relief when the eye turned west-northwest and great worry for the west coast and the southeast part of the country. For the most part, I kept in contact with friends, family, and some colleagues through text messages, Facebook, and WhatsApp.

I could see the winds flying by initially mostly in parallel.  During the maximum wind gusts in the afternoon, the bay went wild. The glass doors shook, the winds howled, and lightning struck often. The lull was exactly that, a period of calm before the next set of bands appeared. After the storm passed, the bay had an unusual sandy appearance.

WHAT HAD YOUR DEPARTMENT DONE IN PREPARATION BEFORE THE STORM?

Patients received automated messages informing them that the clinic was closing.  It was also announced on social media and through television outlets.  A phone tree was circulated to establish communications within the department.  We were encouraged to stay safe.

WHAT WAS HAPPENING WITH YOUR PATIENTS BEFORE THE STORM HIT?

The hospitals were at near capacity; early discharges, when appropriate, were being encouraged.  Limited shelter was provided for staff at Bascom Palmer Eye Institute (part of the University of Miami Health System). My administrative assistant was fielding extra calls for migraine medications before the storm while trying to hang storm shutters.  One patient, who described having chronic migraine that was worse than her metastatic breast cancer to the spine, utilized the portal daily for several back-up treatments. Another patient needed medications transferred to Colorado before she ran out. While getting water, I found a third patient with three boxes of over-the-counter pain medications.

HAVE YOU BEEN ABLE TO GET TO THE MEDICAL CENTER OR ARE YOU STILL IN YOUR APARTMENT BUILDING?  

There was major flooding in my area. I'm grateful because things could have been much worse. I got out for a walk around the park for the first time on September 11.  Many trees are down but the water from the storm surge has cleared up.  Millions have lost power, and it may be a slow process to reinstate electricity. I got lucky. I did not lose power. Many around me did.  The city has been dark.

WHAT IS HAPPENING AT THE HOSPITAL?

The University of Miami neurology out-patient clinic re-opened on September 13.  We are fully staffed but there are very few patients here. It is not a surprise because trees are down, electricity is out for most, and some of the traffic lights are broken.  The patients had varying experiences with the storm. Two cried in front of me.  It was the suffering from migraine/chronic migraine, and not the storm.

HAVING EXPERIENCED THE HURRICANE, WHAT DID YOU LEARN? WHAT MIGHT YOU HAVE DONE DIFFERENTLY?

Hurricane preparation takes a lot of time, resources, and emotional energy. It's important to become familiar with disaster policies and advisories. Airline flights and essential supplies run out fast and can be expensive. Get plenty of cash because many stores are not taking debit cards and ATM machines run out of money. If your telephone service is connected to the internet, you won't have landline service.  Funds should be saved in preparation for hurricane disasters.  From a clinical perspective, it might be useful if the AAN created a task force to examine best practices in times of disasters. It helps to have a safety plan well before the hurricane season starts. I plan on investing in category 6 impact windows. I will also consider traveling far away if a large-scale direct hit is predicted.

Look for more stories from Hurricane Irma in the days ahead.  


Wednesday, September 13, 2017

BY SUSAN KREIMER

Adjuvant temozolomide chemotherapy following radiotherapy significantly improved survival for patients with newly diagnosed 1p/19q non-co-deleted anaplastic glioma and should comprise the standard of care, the findings of a large international study published in the August 8 online edition of The Lancet suggested.

The absence or presence of the favorable molecular marker — 1p/19 co deletion molecular marker — has long been known to have an impact on survival in patients with anaplastic glioma, the study authors pointed out.

The results from the interim analysis from the CATNON trial — a phase 3, randomized, open-label intergroup study involving 745 patients — warranted immediate release, the researchers said.  

With adjuvant temozolomide, the five-year overall survival rose from 44 percent to 56 percent, and median progression-free survival increased from 19 to 43 months. The survival curves for adjuvant compared with no adjuvant temozolomide widened further with expanding length of follow-up, which implies that overall survival could augment even more with time.

"It really paves the way for using temozolomide instead of a more toxic regimen," Martin J. van den Bent, MD, PhD, the study's principal investigator and head of the neuro-oncology unit at Erasmus MC Cancer Center in Rotterdam, the Netherlands, told Neurology Today.

The international collaboration is the first glioma study to base eligibility on a molecular marker. When it was launched in 2005, patients with anaplastic oligodendrogliomas, which were thought to be responsive to chemotherapy, had shown no survival benefit from treatment with procarbazine, lomustine, and vincristine chemotherapy administered after radiotherapy. In addition, prognosis was much worse in patients with 1p/19q non-co-deleted tumors than in those with 1p/19q co-deleted tumors.

"These so-called anaplastic gliomas are a mixed bag of different tumor types," Dr. van den Bent said, including the anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma or mixed glioma. "But there are two major types of anaplastic gliomas and that has to be defined at the molecular level."

Investigators are carefully examining whether it would be beneficial to combine giving temozolomide alongside radiation therapy. However, before reaching a conclusion, they want to be sure the co-treatment improves outcomes and avoids compounding side effects, Dr. van den Bent added. 

Implications of all the available evidence suggest that the standard of care for 1p/19q non-co-deleted anaplastic glioma should be surgery followed by radiotherapy and 12 four-week cycles of temozolomide given on days one to five, the investigators wrote.

In the current study, researchers tested treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma. Further analysis is underway to evaluate the role of concurrent temozolomide treatment with radiotherapy and the effects of molecular signatures on outcome, Dr. van den Bent said, and additional data are likely to be released next year.

Between Decemer 2007 and September 2015, investigators screened 1,407 patients and randomly assigned 748 to four treatment groups (radiotherapy alone or with 12 cycles of adjuvant temozolomide or radiotherapy with concurrent temozolomide, with or without adjuvant temozolomide). They aimed to answer two questions: whether use of concurrent temozolomide improves overall survival irrespective of treatment with adjuvant temozolomide, and whether administration of adjuvant temozolomide improves overall survival irrespective of concurrent temozolomide.

Eligible patients had newly diagnosed anaplastic glioma without 1p/19q co-deletion, were at least 18 years old, and were taking stable or decreasing doses of corticosteroids. Prior surgery for low-grade glioma was allowed if an anaplastic tumor had been histologically confirmed at the time of progression. Treatment with other experimental agents was not permitted. Radiotherapy had to begin within seven weeks of surgery and within eight days of randomization.

Patients underwent weekly assessments during radiotherapy, every four weeks during adjuvant temozolomide treatment, and every three months after the completion of all treatment. Tumors were evaluated with magnetic resonance imaging at baseline, four weeks after the end of radiotherapy, and every three months thereafter until disease progression.

Treatment was generally well tolerated. Of the 549 patients who were randomized to receive temozolomide, 8 to 12 percent had grade 3-4 toxicity, with the most frequent event being thrombocytopenia (7-9 percent). Adverse events were mainly hematological and reversible. The median follow-up was 27 months (95% CI 25–30).

In the interim analysis, which addresses the second question, investigators reported a significant overall survival benefit with adjuvant temozolomide: The five-year overall survival was 55.9 percent, 95% CI 47.2–63.8 compared with 44.1 percent, 36.3–51.6 without adjuvant temozolomide.

Furthermore, in the treatment groups not given adjuvant temozolomide chemotherapy, 200 (54 percent) of 372 patients had disease progression, compared with 144 (39 percent) of 373 in those who did receive adjuvant chemotherapy.

The study still raises the issue of whether six cycles of temozolomide are sufficient, or whether 12 cycles may lead to better outcomes. In the report, Dr. van den Bent and his collaborators stated that they opted for 12 cycles of adjuvant temozolomide, whereas six cycles of adjuvant temozolomide are recommended for glioblastoma.

"We decided to use 12 cycles to ensure that patients assigned to receive adjuvant chemotherapy without preceding concurrent chemoradiotherapy would have sufficient exposure to temozolomide," they explained. "The role of concurrent temozolomide remains to be clarified. Concurrent radiotherapy and temozolomide improves outcomes in glioblastoma, but it remains unknown whether both concurrent and adjuvant temozolomide are needed for the improvement of outcomes in this disease."

The investigators speculated whether "the risk of late neurotoxic effects might be increased by concurrent administration of temozolomide and radiotherapy." These particular data "will be especially relevant in patients with favorable prognoses," they wrote.

At this point, a follow-up to the report in The Lancet would be immature, the investigators wrote, because 30 percent of patients have died and 46 percent incurred disease progression by the time of the interim analysis.


Look for expanded coverage of the study, including commentary from experts, in an upcoming issue of ​Neurology Today.


Tuesday, September 12, 2017

​BY THOMAS R. COLLINS

In a small, randomized, double-blind, placebo-controlled trial, the glucagon- like peptide-1 (GLP-1) agonist receptor exenatide produced significantly better improvement than placebo on the motor exam portion of the Movement Disorder Society-United Parkinson's Disease Rating Scale (MDS-UPDRS) after 60 weeks, including a 12-week washout period, according to findings published in the August 3 online edition of The Lancet.

Studies involving rodent models have shown that exenatide crosses the blood-brain barrier and has neuroprotective and neurorestorative effects by way of GLP-1agonist receptors at doses that are similar to those already used in type 2 diabetes, bringing about improvements in motor performance, behavior, learning and memory.

Exenatide has also been shown to have a neuroprotective effect in a small, open-label, proof-of concept study with human subjects. But, said study author, Dilan Athauda, MRCP, a clinical research fellow in neurology at University College London, this trial shows a "signal of effect." The size and design of the trial were not enough to say definitively that a neuroprotective effect is at work.

The real test will come in a longer trial, with more centers and more patients, he said.

Independent experts agreed that the results are preliminary, that the trial was too small to show a disease-modifying effect, and that clinicians should not be tempted yet to try exenatide for their Parkinson's patients.

The single-center trial was conducted at the University College London and, researchers said, it was the first double- blind, placebo-controlled trial on exenatide, already approved for diabetes treatment, as a potentially disease-modifying drug in PD. Thirty-two patients were randomized to receive weekly subcutaneous injections of 2 mg of exenatide or weekly placebo injections. Under the trial criteria, patients had to be on dopaminergic treatment with effects that were wearing off, and their disease had to be of moderate severity, with a Hoehn and Yahr stage of 2.5 or less while on treatment.

Patients were given exenatide or placebo for 48 weeks, and then exenatide was withdrawn for 12 weeks.

At their 60-week evaluation, patients were scored on part 3 of the MDSUPDRS: Those who had been taking placebo had worsened by 2.1 points compared to baseline, while those who'd been on exenatide improved by one point.

The difference in the MDS-UPDRS scores — adjusted for baseline differences in disease severity and Hoehn and Yahr stage — was 3.5 points, in favor of exenatide, which was a significant difference, researchers found (p=0.0318).

At 60 weeks, exenatide was undetectable in the blood of the patients and the UPDRS advantage was still there, noted Dr. Athauda.

"Some would say advantages seen at the end of the washout period suggest a disease-modifying effect because the effects are present after you stop the drug and they're washed out of the system," he said.

"However, that's very easily countered by just saying that exenatide could be having long-lasting symptomatic effects. So it's difficult to interpret that in the context of this trial design."

"Parkinson's disease progresses very slowly, so over the course of a year, a three-point advantage is relatively small," Dr. Athauda said. "But one of the important things we're trying to do is to replicate these findings in a much larger population and for a longer period of time. Because if we show that this effect, this three-point advantage, is cumulative — after one year, the difference is three points, but after two years of treatment, it's six points, and three years, it's nine points… then that will be a real effect and we can say we actually altered the progression of Parkinson's disease, and that would really change our approach to how we treat Parkinson's disease."

No significant differences between the exenatide and placebo groups were seen for secondary outcomes, such as the other parts of the MDS-UPDRS on daily living experience and motor complications, and dementia and dyskinesia scales.

"It's important to say that this advantage had a very trivial effect on their day-to-day symptoms, so the patients didn't tend to notice any effects on quality of life or non-motor symptoms," Dr. Athauda acknowledged.

Gastrointestinal symptoms and injection-related reactions were common, though expected, and didn't affect patients' willingness to take the drug, researchers said.

According to the study's disclosure statement, one of the study authors, Nigel H. Greig, PhD, a senior investigator at the National Institute on Aging, is a named inventor on a National Institutes of Health patent that describes the use of GLP-1 receptor agonists in neurodegenerative disorders. According to the statement, all rights to the patent belong solely to the U.S. government.


Look for expanded coverage of this study, including expert commentary, in an upcoming issue of Neurology Today​.


Thursday, September 7, 2017

BY SARAH OWENS

People who sustained a concussion during their adolescent years had an increased risk of developing multiple sclerosis (MS) later in life, and the risk nearly doubled among people who sustained two or more concussions, according to a new study published online on September 4 in Annals of Neurology.

Along with other genetic and environmental factors, head trauma and concussion in sports such as boxing have been proposed as possible triggers of MS pathology. Previous studies have attempted to clarify the association between head trauma and MS risk, but the results were not statistically significant, and all relied upon retrospective reporting of data, which could have limited their accuracy.

The present study, which assessed data prospectively, found a statistically significant association between adolescent concussion and MS risk in a cohort of over 80,000 people with MS and healthy controls. The findings "further emphasise the importance of protecting young people from head injuries," the study authors, led by Scott Montgomery, BSc, PhD, professor of clinical epidemiology and biostatistics at the school of medical sciences at Örebro University in Örebro, Sweden, wrote.

For the study, researchers at Örebro University used ICD codes in the national Swedish Patient and Multiple Sclerosis registers to identify all diagnoses of MS up to 2012 among people born since 1964. They identified 7,292 patients with MS, and matched them individually by sex, year of birth, age, vital status at MS diagnosis, and region of residence (county) to 10 matched controls, yielding an overall study population of 80,212.

They also used hospital inpatient and outpatient records to identify diagnoses of concussion and of upper and lower limb fractures using ICD codes. They classified concussions that took place from birth to age 10 as childhood concussions, and those that occurred from age 10 to 20 as adolescent concussions.

They found that a single concussion during adolescence was associated with a significantly increased risk of MS (adjusted odds ratio [OR], 1.22 (1.05-1.42), 95% CI; p=0.008). Adolescents who sustained two or more concussions had even greater odds of developing MS (adjusted OR, 2.33 (1.35-4.04), 95% CI; p=0.002). There was no association between childhood concussion and MS or between broken bones in either childhood or adolescence and MS.

The findings, the study authors wrote, suggest that head trauma specifically – not just physical injury in general – may raise MS risk. They noted several possible mechanisms that may explain this association, including that such trauma may produce pro-inflammatory cytokines such as interferon-γ, which has been shown to create patterns of nervous system damage that are consistent with MS. But further study will be needed to clarify these mechanisms, they added.

The researchers noted several limitations to their study. Among them, other diagnoses of central nervous system trauma than concussion, and other relevant injuries like spinal cord injury, were excluded. In addition, some cases of head trauma may not have been formally diagnosed and included in the patient registry, which may have affected the risk estimates.

Look for expanded coverage of this study, including commentary from experts, in an upcoming issue of ​Neurology Today.

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