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Friday, September 23, 2016

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BY SARAH OWENS

About one quarter of people who came to the hospital with an acute ischemic stroke within two hours of symptom onset and were eligible to receive intravenous tissue plasminogen activator (tPA) did not receive it, according to a new study of the Get With The Guidelines-Stroke (GWTG) registry published online on September 14 ahead of the print edition of Neurology. Eligible patients were more likely to receive tPA if they were treated at a primary stroke center, while women and minorities were less likely, the study found.

"As has been reported previously, treatment at a primary stroke center is one of the strongest predictors of tPA use," the study authors, led by Steven R. Messé, MD, FAAN, associate professor of neurology at the University of Pennsylvania, wrote. "To improve thrombolysis rates, continued development of systems of care for stroke should remain a high priority."

STUDY METHODOLOGY

For their study, the authors accessed data on stroke treatment from GWTG, an ongoing, voluntary, national registry comprising more than 1,800 hospitals and 2.5 million patient records. They identified all patients in the registry who were admitted to a hospital with acute ischemic stroke within two hours of stroke onset, had no known contraindications to tPA, and were treated within three hours.

FACTORS DETERMINING TPA USE

They found that of 61,698 patients who met those criteria, 75 percent received tPA within three hours. The remaining 25 percent were not treated with tPA. Those who were not treated were more likely to be older, female, black or another nonwhite race, and generally had more vascular risk factors for stroke, including coronary artery disease, diabetes, hypertension, and prior stroke.

In addition, patients who were not treated with tPA were less frequently transported to the hospital by EMS and had a longer delay in door-to-CT time. Hospitals that didn't treat eligible patients with tPA tended to have fewer beds, fewer annual ischemic stroke admissions, and were less likely to be certified as primary stroke centers by the Joint Commission, the independent health care evaluation body that awards certifications in partnership with the American Heart Association/American Stroke Association.

WAYS TO INCREASE TPA USE

The results, the study authors concluded, provide further evidence that becoming certified as a primary stroke center in accordance with GWTG/Joint Commission guidelines may increase rates of tPA use for eligible ischemic stroke patients. Other factors that may help include educating patients and medical staff about vascular risk factors for stroke, increasing use of EMS in transporting patients to hospitals, reducing door-to-CT time, and improving tPA treatment rates for eligible nonwhite and female stroke patients.

The authors noted a number of limitations, including that some patients who were considered eligible were not in fact eligible because their doctors failed to record contraindications, and that patients who were treated after three hours were excluded, even though current guidelines allow for tPA treatment in a three-to-four-and-a-half-hour time window.

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Tuesday, September 13, 2016

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 BY SARAH OWENS

People who had a stroke had a four-fold increased risk of developing depression within two years compared to a control population who did not have stroke, and those who had depression prior to the stroke or who had a severe stroke had an especially high risk, according to a new study published online on September 12 ahead of the print edition of JAMA Psychiatry.

Previous studies have consistently associated stroke with depression, but few have included a control population, and many had small sample sizes or did not examine associations between post-stoke depression and sociodemographic factors or stroke subtype, the study authors noted. The current findings suggest that depression is common after stroke, is related to stroke subtype, and is an independent risk factor for mortality.

"The high rates of depression in patients with stroke indicate that a large number of deaths occurring during rehabilitation may be attributable to this condition," the study authors, led by Terese S. H. Jørgensen, MSc, of Copenhagen University in Denmark, wrote. "[This] suggests that clinicians should remain vigilant concerning this risk, especially in patients with a history of depression and a high number of somatic comorbidities."

For their analysis, researchers analyzed data from seven Danish nationwide registries. They matched 157,243 patients who had a first-time hospitalization for stroke between 2001 and 2011 with a reference population of 160,236 patients. They confirmed depression through a clinical diagnosis or by the filling of a prescription for an antidepressant.

Among those who did not have depression at the start of the study, the researchers found that depression occurred within two years after stroke in 34,346 patients (25.4 percent) in the stroke group and within two years of the start of the study in 11,330 patients (7.8 percent) in the control group, corresponding to a four times greater overall risk of depression after stroke.

More than half of the cases (17,690) of depression in the stroke group occurred during the first three months after stroke, whereas depression occurred within the first three months in less than a quarter of cases (2,449) in the reference group. This corresponded to an eight times greater risk of depression after stroke during this time period, the study authors added.

Patients who had a severe stroke had the highest risk of depression, while patients who had a transient ischemic attack had a three times lower risk of depression compared to those with a stroke diagnosis.

Several risk factors were associated with depression in both the stroke and control populations, including older age; female gender; and a high level of somatic comorbidities, including diabetes and coronary heart disease. However, the relative risk of these associations was higher in the controls than in those who had a  stroke.

Additionally, the researchers found that depression was associated with mortality in both populations, but that depression-related relative mortality was about twice as high in the control group compared to the stroke population. This, the study authors wrote, "suggests different etiologic mechanisms" underlying depression after stroke and depression arising without a known prior somatic illness. A number of theories – including the location of the stroke lesion, vascular depression, inflammation, and neuroplasticity – may explain the differing etiology, but the study was not able to examine those theories, the authors added.

The study authors noted several limitations, including a lack of information on the lesion location, which allows only indirect support for etiologic mechanisms of post-stroke depression. In addition, they pointed out that the antidepressant prescriptions, used to define most cases of depression, could have been for other comorbidities.

Look for more in-depth coverage of this study in an upcoming issue of Neurology Today.

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Wednesday, September 7, 2016

BY SARAH OWENS

Aducanumab, a human monoclonal antibody that selectively targets amyloid-beta (Abeta), appeared to reduce Abeta plaques in patients with prodromal or mild Alzheimer's disease (AD) over a 54-week course of intravenous treatment, according to the results of a randomized, double-blind, placebo-controlled phase 1b trial that were published online on September 1 in Nature.

In a transgenic mouse model of Alzheimer's disease (AD), researchers found that aducanumab entered the brain, binded parenchymal Abeta, and reduced soluble and insoluble Abeta in a dose-dependent manner. The findings add support to the amyloid hypothesis of Alzheimer's neuropathology, they said, which posits that Abeta-related toxicity is a primary cause of Alzheimer's-related neurodegeneration. "Together, the clinical and preclinical data support continued development of aducanumab as a disease-modifying treatment for Alzheimer's disease," they wrote.

For the PRIME study, researchers enrolled 165 patients at 33 sites in the United States between October 2012 and January 2014. The patients had prodromal or mild AD with brain Abeta pathology confirmed by molecular positron emission tomography (PET) imaging. The patients were randomized to receive monthly intravenous infusions of aducanumab at doses of 1, 3, 6, or 10 mgkg-1 or placebo for one year.

The researchers used PET imaging with florbetapir to measure changes in Abeta plaque accumulation in the brain. They found that after 54 weeks of treatment, the mean PET standard uptake value ratio (SUVR) decreased significantly from the baseline score of 1.44 (p<0.001) in the aducanumab group, compared to a minimal change for the placebo group. Additionally, they found that Abeta reduction increased in a dose-dependent manner.

The reductions in Abeta PET SUVR composite scores in patients treated with aducanumab were similar in patients with mild and prodromal forms of Alzheimer's disease, and between apolipoprotein E (ApoE) ε4 carriers and non-carriers, the study authors added.

Administration of aducanumab was also associated with improved clinical outcomes, as measured by a dose-dependent slowing of clinical depression on both the Clinical Dementia Rating – Sum of Boxes scale (a commonly used scale for scaling dementia severity, with scores ranging from 0 to 18 and higher scores indicator greater dementia severity) and the Mini Mental State Examination scale (a 30-point questionnaire that measures cognitive impairment, with lower scores indicating greater impairment).

Common adverse side effects included headache, urinary tract infection, and upper respiratory tract infection. A minority of patients experienced amyloid-related imaging abnormalities, primarily ARIA-vasogenic edema (ARIA-E), with higher doses linked with a higher incidence of ARIA-E, early in the course of treatment. This adverse effect was classified as severe, although no patients were hospitalized.

The study authors speculated that the drug may work by slowing release of soluble Abeta oligomers —which have been hypothesized to be the primary toxic species of Abeta — into the neuropil, limiting their toxic effect on neurons.

The authors noted several study limitations, including the staggered parallel-group design, the small sample size, and the limited region of study (only the United States).

Look for more in-depth coverage of this study in a forthcoming edition of Neurology Today.

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Wednesday, August 31, 2016

BY SARAH OWENS

A significant proportion of child neurologists and neurodevelopmental specialists in the United States are dissatisfied with their compensation and benefits, and they say the workforce is understaffed and growing too slowly to meet projected needs, according to an electronic survey conducted jointly by the American Academy of Pediatrics (AAP) and the Child Neurology Society (CNS).

The results of the survey were published online on August 26, 2016 ahead of the print edition of Neurology.

For their analysis, members of the AAP/CNS Task Force surveyed 523 practicing physicians and 97 trainees. Most of the respondents practiced in academic medical centers and had a primary or secondary subspecialty in child neurology, neurology, and/or neurodevelopmental disabilities; 85.5 percent of them were in active clinical practice.

Among responses, the survey showed that medical school loans placed a considerable financial burden on many respondents — most respondents who took out loans had at least $50,000 in medical school debt. And only about 26.5 percent of those surveyed were positive or extremely positive about their compensation, compared to a larger 42.4 percent who were negative or extremely negative.

A primary concern of the task force was workplace shortages in child neurology. The study authors noted that the number of training positions in child neurology has increased from an average of 80 per year in the 1997-2002 period to 154 positions in 2014, and the number of active members in the CNS has grown steadily since the 1980s. While these numbers might seem encouraging, the authors noted that the compound annual increase in CNS membership was just 3.37 percent, which they considered a slow rate of growth. 

The study authors noted that a decreasing number of child neurologists and neurodevelopmental disabilities specialists are practicing in independent practices – instead, a growing number work at hospitals or academic physician organizations. As a result, the study authors suggest, they may be held to "arduous accountability standards," and they may have reduced leverage in negotiations about salary or their professional environments.

And while nearly half of the respondents reported clinical research activity, less than 10 percent of them conduct basic research, suggesting that the physician-scientist workforce in child neurology is becoming an "endangered species," the task force said. Many child neurologists do not receive the specialized training they want or need; for example, of the 402 respondents who said they managed patients with epilepsy, only 65 percent said they could read an electroencephalogram (EEG), and only 42 percent were formally trained in a neurophysiology or epilepsy fellowship.

Recruitment and mentoring of trainees by current child neurologists, as well as advocacy for recognition of the values of their contributions, are crucial to maintaining growth in the field, the study authors concluded. Additionally, they expressed their hope that programs like the NIH Neurological Sciences Academic Development Award will help foster the growth of early career physician-scientists through grants and career development programs.

The task force noted as a limitation that the 38 percent overall response rate was substantially lower than the response rate, 65 percent, to an earlier (2002) study, which may be related to the fact that  the survey was sent electronically. In addition, they wrote, the fact that a significant proportion of respondents were trained before 1994 may have partially obscured demographic shifts.

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Tuesday, August 30, 2016

BY SARAH OWENS

Intravenous thrombolysis with tissue plasminogen activator (tPA) is safe and effective for treating acute ischemic stroke when administered through a telestroke network within three hours after stroke onset, according to a new systematic review and meta-analysis published online on August 26 ahead of the print edition of Neurology.

"While telestroke has repeatedly proven to convey [stroke] expertise to many rural hospitals worldwide, evidence for efficacy on clinical outcomes is still sparse," the study's authors, led by Jessica Kepplinger, MD, neurologist at Dresden University Stroke Center in Dresden, Germany, wrote. "This meta-analysis confirmed the safety of IVT delivered through telestroke networks."

The researchers conducted a systematic review of seven studies totaling 1,863 patients – including two randomized controlled trials (n=72) and five nonrandomized, observational studies (n=1,791) – that compared telestroke-guided intravenous thrombolysis (IVT) with IVT administered at a stroke center. In order to qualify for the analysis, patients with acute ischemic stroke had to be treated with IV tPA through a hub-and-spoke stroke care network, in which stroke centers (hubs) are connected via telemedicine to hospitals without specialized stroke centers (spokes). The studies measured rates of symptomatic intracerebral hemorrhage after tPA administration, mortality at three months, and functionality at three months; all studies used the modified Rankin scale (a scale from 0 to 6, with higher scores corresponding to greater disability or dependence) to measure functionality.

Rates of symptomatic intracerebral hemorrhage were similar between patients who were treated with telemedicine-guided thrombolysis and patients who received tPA onsite at a stroke center (p=0.978). Additionally, there was no between-group difference in three-month mortality rates (p=0.806) and three-month functional independence scores (p=0.565). The results remained consistent after a sensitivity analysis.

The findings, the study's authors wrote, demonstrate that the "safety and efficacy of IV tPA delivered through telestroke networks is not inferior to tPA administered at specialized stroke centers for treatment of [acute ischemic stroke] in the three-hour time window."

They noted, however, that all available studies restricted IVT to a three-hour time window, "leaving a gap in our understanding" of the safety and efficacy of IVT in an expanded, three-to-four-and-a-half-hour time window.

The study authors noted several limitations, including the small number of included studies and the fact that data from two of the included studies overlapped. They also noted that most of the included studies did not adjust for potential confounders, including stroke severity, age, and onset-to-treatment time, and that the studies varied in their definitions of safety and efficacy outcomes.

In an accompanying editorial, Bart M. Demaerschalk, MD and Steven R. Levine, MD, FAAN praised the results of the study, concluding that "In the right hands, we believe the evidence is in" supporting the use of IV tPA through telestroke networks in a three-hour time window. They noted, however, that much attention has been paid to the efficacy of telemedicine in the diagnosis and decision-making stages of care. "The time has come," they concluded, "to examine remotely managed stroke patients in the intensive care unit, the stroke unit, and the hospital floor."

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