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Monday, May 23, 2016


Ticagrelor, a new antiplatelet agent, may not be superior to aspirin at reducing the risk of stroke, myocardial infarction, or death over a period of 90 days in patients who have experienced acute cerebral ischemia, according to a study published in the May 10 online edition of the New England Journal of Medicine.

Noting that aspirin offers limited benefit in the secondary prevention of ischemic stroke, researchers hypothesized that "more intensive antiplatelet therapy through a different mechanism of action may be more effective." Ticagrelor reversibly binds and inhibits the P2Y12 receptor on platelets and is direct-acting.

Led by Claiborne Johnston, MD, FAAN, dean of the Dell Medical School at the University of Texas at Austin, the SOCRATES (Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes) trial was designed to compare the effectiveness of ticagrelor with aspirin in reducing the rate of stroke, myocardial infarction, or death over a period of 90 days.

The researchers enrolled 13,199 patients in 674 centers in 33 countries who had a "nonsevere ischemic stroke or high-risk transient ischemic attack," which was not considered to be cardioembolic in cause, and for which they did not receive IV or intra-arterial thrombolysis. Study participants were randomly assigned to double-blind treatment with either ticagrelor or aspirin in a 1:1 ratio. Treatment began within 24 hours of diagnosis and continued for 90 days.

Researchers found that during 90 days of treatment, 442 of the 6,589 patients (6.7 percent) treated with ticagrelor experienced the primary endpoint – stroke, myocardial infarction, or death – compared to 497 of the 6,610 patients (7.5 percent) treated with aspirin. The results were not statistically significant, the study authors noted.

Despite the negative results on the primary outcome, Dr. Johnston and his co-investigators noted that there were some signals within subgroups suggesting that further study of ticagrelor could be warranted. In particular, they found no signs of increased hemorrhage or other safety issues in the ticagrelor arm of the study. Major bleeding occurred in 0.5 percent of patients treated with ticagrelor and in 0.6 percent of patients treated with aspirin; intracranial hemorrhage occurred in 0.2 percent and 0.3 percent, respectively, and fatal bleeding in 0.1 percent and 0.1 percent.

Notably, the study's authors found that there was a high risk of stroke in the first two weeks after an acute ischemic attack, with particularly high event rates in the first two days. This finding, the study's authors say, contradicts "some studies [that] have suggested that the risk of stroke after transient ischemic attack has decreased in recent years."

The study's authors cited several limitations of their study. They noted that while the trial aimed to test monotherapy ticagelor and aspirin, approximately one-third of the patients were taking aspirin at the time of the qualifying event, and since the antiplatelet effects of aspirin typically last several days, the individuals randomized to ticagrelor were essentially receiving dual antiplatelet therapy for the first few days. The study authors also noted that they had limited enrollment to patients who were at especially high risk for stroke, so these patients may have already undergone vascular interventions or other treatments. Finally, the study authors pointed out that the primary end-points of transient ischemic attack (TIA) were lower than expected, so it was possible that some of the enrolled patients had nonischemic conditions that mimicked a TIA.

Look for expanded discussion and commentary on the trial in the June 9 issue of Neurology Today.



Wednesday, May 18, 2016


Citing a number of "unmet needs" in rehabilitative stroke care, a new guideline from the American Heart Association and the American Stroke Association said the best evidence supports offering stroke patients these among other services: a formal fall prevention program during hospitalization, a balance training program, assessments for calcium and vitamin D supplementation for stroke survivors living in long-term care facilities, and speech and language therapy for individuals with aphasia.

The impetus for the evidence-based guideline, which was published online May 4 ahead of the June print issue of Stroke, was a "lack of clear guidelines regarding the efficacy of various interventions," guideline author Joel Stein, MD, Simon Baruch professor and chair of the department of rehabilitation and regenerative medicine at Columbia University College of Physicians and Surgeons, professor and chief of the division of rehabilitation medicine at Weill Cornell Medical College, and physiatrist-in-chief at New York-Presbyterian Hospital, told Neurology Today. A comprehensive guideline is particularly necessary because of the increasing array of therapeutic interventions for stroke, Dr. Stein said.

One of the guideline's most important new recommendations is that patients who have residual deficits after a stroke should receive a functional assessment from a clinician with expertise in rehabilitation, Dr. Stein said. Currently, "some people who have a stroke are not necessarily evaluated by an expert, especially if their symptoms are relatively mild. This can lead to rehabilitation at a lesser level of intensity than is appropriate, or for not as long as required, or that is not as focused on their specific needs as they deserve."

The guideline authors pointed out that stroke care in the US has become very heterogeneous, and is best when delivered by a multidisciplinary team that includes stroke neurologists, physiatrists, nurses, physical and occupational therapies, speech-language pathologists, as well as psychologists, nutritionists, social workers, and others.

The panel conducted computerized searches of available medical literature, including systematic reviews through 2014, and organized data and studies using the joint American Heart Association/American College of Cardiology classification system — dividing findings by level of certainty, the class of each trial, and the level of evidence.

It found that between 1996 and 2003 the proportion of patients who had not been referred for any post-acute rehabilitation increased from 26 to 31 percent. One analysis of 2006 Medicare data found the level had increased to 42 percent.

The guideline authors noted that stroke "has been managed medically as a temporary or transient condition," and that a comprehensive approach was needed to ensure a continuum of care, including social reintegration, health-related quality of life, and self-efficacy.

Dr. Stein also stressed the importance – noted for the first time in this guideline – of recognizing post-stroke depression. "It's extraordinarily common after a stroke – estimates range up to 40 percent for people who have significant depression after stroke. And there's an attitude that [depression] is an unavoidable consequence of stroke. That's very unfortunate, because, in fact, it's very disabling to be depressed; people withdraw socially, they are less active, and their mobility deteriorates. But this type of depression responds well to standard treatments for depression."

The guideline also includes an analysis of inpatient and outpatient rehabilitation treatment; in particular, it emphasizes the importance of impatient rehabilitation for patients with significant deficits. "This guideline, for the first time, clearly states that patients who qualify for inpatient rehabilitation facility care, which is high-level hospital rehabilitation, and who have access to it, really should receive that type of care in preference to lower levels of rehabilitation," said Dr. Stein. Inpatient rehabilitation offers the added benefit that it "supports strong teamwork among caregivers," Dr. Stein added. For patients who receive outpatient stroke treatment, it's important to have a physician who serves as "a central command center for a caregiving team to make sure that referrals go to physical therapy, occupational therapy, speech therapy, psychology, psychiatry, et cetera, as appropriate," said Dr. Stein.

Above all, communication and coordination are "paramount" in achieve the best possible outcomes for people who have suffered a stroke, the study's authors concluded. Without such coordination, they added, "isolated efforts to rehabilitate the stroke survivor are unlikely to achieve their full potential."

Look for a more in-depth analysis of the stroke rehabilitation guideline in the June 9 issue of Neurology Today.


Monday, May 9, 2016


The US Food and Drug Administration (FDA) has approved pimavanserin, a non-dopaminergic atypical antipsychotic, to treat symptoms of psychosis associated with Parkinson's disease, according to an April 29 announcement.

Parkinson's disease-associated psychosis, which includes hallucinations and delusions, can occur in as many as 50 percent of patients with Parkinson's disease at some time during the course of their illness, according to the FDA.

Pimavanserin is a selective serotonin 5-HT2a inverse agonist. The drug exerts its effects by blocking serotonin 5-HT2A receptors in the neocortex that are associated with symptoms of Parkinson's disease, including visual hallucinations and delusions.

In its approval notice, the FDA cited the results from the six-week, randomized, double-blind, placebo-controlled phase 3 trial that enrolled 199 adults with Parkinson's disease. Among findings, the study found Parkinson's patients showed significantly fewer features of psychosis — hallucinations, delusions, and behavior changes — compared to those taking a placebo, as measured by the Scale for the Assessment of Positive Symptoms adapted for Parkinson's disease (SAPS-PD).

In addition, the drug did not worsen the primary motor symptoms of Parkinson's disease and did not cause significant adverse effects. The most common adverse events recorded in patients were urinary tract infections (12 percent in the placebo group compared to 14 percent in the pimavanserin group) and falls (9 percent in the placebo group compared to 11 percent in the pimavanserin group). Ten recipients of pimavanserin discontinued participation in the study due to an adverse events, while two people taking the placebo dropped out.  [Read the Neurology Today article about the phase 3 trial here.]

In an accompanying editorial in the Lancet, Susan Fox, MB ChB,  associate professor of neurology at the University of Toronto in Canada, commented that "further studies will be needed to determine relative efficacy of pimavanserin and clozapine or quetiapine." However, she noted that the study "opens up a new therapeutic avenue in treatment of Parkinson's disease psychosis," and that pimavanserin "might help prevent progression to more bothersome symptoms" in patients with Parkinson's disease.

Wednesday, May 4, 2016


Patients who had a transient ischemic attack (TIA) or minor stroke and were treated at a clinic specializing in TIA were less likely to have a recurrent stroke one year later compared to historical cohorts, according to a study published in the April 21 issue of the New England Journal of Medicine. The lower risk may be explained by better and faster implementation of secondary stroke prevention strategies in contemporary TIA clinics, said the study's authors.

The researchers analyzed data on 4,789 patients in, a patient registry encompassing 61 specialized stroke care sites in 21 countries. Enrollees had experienced a TIA or a minor stroke within the previous seven days and were treated at sites with a "dedicated system for the care of patients with TIA" and "a yearly volume of at least 100 patients during the previous 3 years." Follow-up occurred at one, three, and 12 months after the qualifying event and every 12 months thereafter for 5 years, at which points patients were evaluated for "clinical events, medical treatment, and main risk factors" for stroke, including blood pressure and a lipid profile.

Researchers found that at one year after TIA or minor stroke, a total of 274 primary outcomes (major fatal or nonfatal cardiovascular outcomes) had occurred, corresponding to an event rate of 6.2 percent, and that the overall estimate of the risk of stroke was 5.1 percent. The risk of recurrent stroke was 1.5 percent at two days, 2.1 percent at seven days, and 3.7 percent at 90 days after symptom onset. These risks, noted the study's authors, were "less than half" of those observed in historical cohorts.  For example, the risk of stroke and other vascular events at 90 days in the historical cohorts was 12 to 20 percent, as compared with 3.7 percent in the TIAregistry group.

The findings also confirmed that three variables were "independently associated with one-year stroke risk": a patient's ABCD2 score, which factors age, blood pressure, clinical findings, duration of symptoms, and presence or absence of diabetes; brain imaging; and status of large-artery atherosclerosis. Patients with an ABCD2 score of 6 or 7, who showed multiple infarctions on brain imaging, or who had large-artery atherosclerosis each had "more than a doubling in the risk of stroke."

The results, say the study's authors, show that prompt and targeted treatment of TIA and minor stroke in specialized TIA clinics or dedicated stroke care delivery units is associated with a reduced risk of recurrent stroke. The findings may be explained by "better and faster" implementation of secondary stroke prevention strategies at specialized stroke clinics, including "immediate initiation of antiplatelet drugs, oral anticoagulation in the event of atrial fibrillation, urgent revascularization inpatients with critical carotid stenosis, and other secondary prevention measures such as treatment with statins and blood-pressure–lowering drugs."

Furthermore, the study's authors noted that registered patients showed "good adherence to treatment recommendations," suggesting that "the risk observed during the follow-up was the risk that remained after treatment of risk factors."

The authors noted several limitations of the study, including that sites were chosen "on the basis of the existence of a TIA clinic or dedicated care for patients with TIA." The study was also biased "toward more specialized stroke physicians." However, the study's authors refute the notion that their study cohort was simply healthier than historical cohorts: "More than two thirds of the cohort had an ABCD2 score of 4 or more, and the risk that we obscured was low in each stratum of the ABCD2 score."

In an accompanying editorial, Ralph L. Sacco, MD, FAAN, chairman of neurology, and Tatjana Rundek, MD, PhD, professor of neurology, epidemiology, and public health, both at the University of Miami, noted additional study limitations. They noted that the study was "not a randomized trial" and "there was no comparison group to assess whether specialized units performed better than nonspecialized units."

However, the editorial authors said the results were "striking" and showed that "urgent care for patients with a TIA or minor stroke in specialized TIA clinics or dedicated care delivery units with stroke specialists undoubtedly works." As a result, they concluded, the study should "prompt health care providers and policymakers" to "deliver the most effective care not only to patients with acute stroke, but also to those with a TIA or minor stroke."

Look for more discussion about the study in the May 19 issue of Neurology Today.


Thursday, April 28, 2016


Credit: Michael Polydefkis​


In a case-control longitudinal study, investigators at the Johns Hopkins University reported that patients with small fiber neuropathy (SFN), irrespective of cause, experienced progressive axon loss during two to three years of follow-up, with many developing large fiber dysfunction.

Moreover, they found that SFN, which is associated with painful attacks that begin in the hands and legs, causes damage along the entire length of sensory nerve fibers, rather than just at the longest ends of the fiber first.

The findings, which were published in the April 11 online edition of JAMA Neurology, challenge the conventional thinking about SFN pathogenesis, which posits that the longest nerves degrade first.

In order to measure the natural course of SFN, the researchers tested and monitored 62 people, including 52 people with predominant SFN and 10 healthy controls, over the course of three years. Of those with SFN, 25 people had idiopathic SFN, 13 people had prediabetes or impaired glucose tolerance-associated SFN, and 14 people had diabetes-related SFN. Researchers took biopsies of patients' skin from three locations – the distal leg, the distal thigh, and the proximal thigh – at a baseline visit and at a follow-up appointment three years later.

Among their results, they observed that intraepidermal nerve fiber density (IENFD) "decreased over time in all patients at a similar rate" and that the "decrease in IENFD was similar across the three sites in all three groups of patients." The mean yearly rates of IENFD change over time at the distal leg, distal thigh, and proximal thigh were –1.42, –1.59, and –2.8 fibers per millimeter, respectively, which the study's authors say "indicate comparable rates of decrease across biopsy sites."

In addition, the data suggest that SFN is most damaging to people with diabetes and prediabetes compared with people who have idiopathic SFN. Nerve fiber density was "lower in all sites at baseline in patients with [diabetes and prediabetes] compared with [patients with idiopathic neuropathy]," the researchers reported, noting that people with diabetes and prediabetes who had SFN are "more likely to develop large fiber involvement" than those with idiopathic SFN.

"[Small fiber neuropathy] signals the beginning of nerve deterioration that with time involves other types of nerve fibers and becomes more apparent and dramatically affects people's quality of life," said the study's lead author, Michael Polydefkis, MD, FAAN, professor of neurology at the Johns Hopkins University School of Medicine and director of the Cutaneous Nerve Lab, in a news release about the study. "The results of this new study add urgency to the need for more screening of those with [prediabetes] and faster intervention."

In an accompanying editorial, John T. Kissel, MD, FAAN, chair of the department of neurology at The Ohio State University Wexner Medical Center, and Gordon Smith, MD, FAAN, professor of neurology at the University of Utah, wrote that the study had several strengths, including an "impressive" duration of material collection — 8 years — and the inclusion of a comparison group of healthy control participants who showed no decrease in IENFD.

However, they noted that the study had a number of important limitations. Among them, they cited the small sample size and "the fact that the data were collected at a single major peripheral nerve center." They also pointed out that the IENFD values measured were "surprisingly high," which could indicate that the study population "had greater disease severity, was uniquely vulnerable to progression, or that there was some unrecognized bias in the sample." These weaknesses, according to the authors of the editorial, challenge "the central conclusion that SFN may not be length dependent."​