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

Friday, April 7, 2017

BY SARAH OWENS

The performance of patients with mild cognitive impairment varied greatly in an analysis of seven randomized controlled trials, according to a new study published in the April 5 online edition of Neurology. Variability in the criteria for enrolling patients, study design, and outcomes assessments may have contributed to the wide-ranging results, the study authors said.  

 "While the studies appeared to be designed in a similar fashion, subtle entry, exit, and procedural differences led to vastly different outcomes for the participants," the study authors, led by Ronald C. Petersen, PhD, MD, wrote. "The implementation of continuous outcome measures rather than clinical states may improve performance of trials," they added, "but clinical meaningfulness needs to be established."

For their study, researchers obtained data on placebo groups from 7 randomized, controlled trials of patients with MCI and collated the data for common measurement instruments. Using the Alzheimer's Disease Assessment Sale-cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and the Clinical Dementia Rating-sum of boxes (CDR-SB), the researchers tracked the performance of patients in the placebo arms and measured their progression to prespecified clinical study endpoints.

They found that although similar criteria for MCI were used in the trials, the implementation of those criteria varied significantly. For example, all studies used the ADAS-cog to measure cognition, but in some studies the patients in the placebo group with MCI had worsening cognition on this scale, while patients in other studies appeared to improve. Results on the MMSE and the CDR-SB "appeared to corroborate the ADAS-cog findings": Some patients appeared to worsen in a predictable manner, but others remained stable or improved.

Additionally, researchers examined the effect of APOE4 carrier status on the results, finding that, as expected, APOE4 carriers had worse cognitive performance on all scales.

The results, the study authors concluded, suggest that minor variations in methodology can lead to significant variations in outcomes among patients in the placebo group, which vastly limits efficacy findings. As for the source of these variations, the researchers suggested that differences in the implementation of instruments like the ADAS-cog in order to characterize participants, and subtle variations in study populations, likely play a role. Differences in language, culture, and the prevalence of comorbidities may also contribute, they noted, adding that future trials should address these issues.

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  • Peterson RC, Thomas RG, Aisen PS, et al. Randomized controlled trials in mild cognitive impairment: Sources of variability. Neurology 2017; Epub 2017 Apr 5.​

Friday, March 31, 2017

BY SARAH OWENS

The combined annual cost of neurological diseases in the United States totals almost $800 billion, and it can be expected to rise rapidly due to an aging population, according to a new summary report published online on March 29 in the Annals of Neurology.

The current report identifies the annual costs associated with different neurological disease types, and projects rising costs over the coming years as the elderly population is expected to double by 2050.

"Given the extraordinary and rapidly growing costs of neurological disorders themselves, a concrete strategy is urgently needed to reduce the burden is neurological disease," the study authors, led by Clifton L. Gooch, MD, professor and chair of neurology at the University of South Florida (USF) Morsani Medical College, wrote.

To assess the total cost burden in the US by disease type, researchers at USF conducted a detailed review of published literature, analyzing the most prevalent and the costliest neurological diseases. They excluded diseases that have mixed etiologies, such as depression and chronic pain, they said, because they would have  pushed cost estimates substantially higher.

For each disease category, they accounted for and extrapolated per-patient costs for care and lost productivity as levels of disability increased.

They found that among the costliest were Alzheimer's disease and related dementias, incurring annual costs of $243 billion for informal and home-based care; chronic low back pain, $177 billion; stroke, nearly $110 billion when accounting for primary costs and indirect costs such as loss of productivity; and traumatic brain injury, $86 billion per year.

Among the steps the study authors suggest to offset these costs was to accelerate translational research in preventive and disease-modifying therapies; this would help delay the onset of symptoms that are costly to treat or manage, they wrote. For example, they noted that deploying efforts to control risk factors for stroke — prescribing antihypertensive and statin therapies had decreased the incidence of stroke. A new treatment delaying Alzheimer's disease by as much as 10 years could potentially save a projected $175 billion dollars annually.

They also encouraged enhanced research into outcomes and comparative effectiveness, which would help eliminate costly and unnecessary research; in particular, they cited the Patient Centered Outcomes Research Initiative (PCORI), as an effective venue for such research, though they acknowledged that it is insufficiently funded to enable meaningful progress, 

Among other nitiatives, the study authors suggested comprehensive tracking of neurological diseases through databases, which could be used to gauge the success of new strategies; and enhanced advocacy efforts on individual, state and federal government levels to urge funding and implementation of these initiatives.

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Wednesday, March 29, 2017

BY SARAH OWENS

Pharmacotherapies, including anticonvulsants, antidepressants, and typical and atypical opioids, are generally more effective than placebo for treating diabetic peripheral neuropathy, according to a new meta-analysis published in the March 24 online edition of Neurology. But these therapies are supported only by low- or moderate-strength evidence, and many available studies have major limitations, including a short duration and/or poorly reported quality of life outcomes.

The last comprehensive review of available treatments for diabetic peripheral neuropathy (DPN) by the American Association of Neuromuscular and Electrodiagnostic Medicine, American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation was released in 2011. It found that pregabalin was "effective" for DPN and that duloxetine and gabapentin, among other treatments, were "probably effective." While the current, updated review found that these and other therapies released since 2011 are effective for DPN, it also identified a number of limitations that should be addressed in future research.

"Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients' quality of life," the study authors, led by Julie M. Waldfogel, PharmD, CPE, clinical pharmacy specialist at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, wrote.

For their study, researchers at Johns Hopkins used PubMed, the Cochrane Database of Systematic Reviews, ClinicalTrials.gov, and other study databases to identify 106 randomized controlled trials published between 2011 and 2016. Two reviewers independently evaluated these studies and graded the strength of evidence.

They found that anticonvulsants, including pregabalin and oxcarbapezine; antidepressants, including duloxetine and serotonin-norepinephrine reuptake inhibitors (SNRIs); atypical opioids, including tramatol and tapentadol; and botulinum toxin were all more effective than placebo at reducing pain in patients with DPN. Among agents found ineffective or for which the evidence was insufficient for reducing DPN pain were dextromethorphan and topical agents like capsaicin.

The study authors noted that many of the studies had major limitations. For example, they did not report specific quality of life values – only whether or not quality of life measures were statistically significant. Additionally, the studies in the analysis were short-term (less than six months), and all drugs deemed to be effective were tested in studies that had a dropout rate of more than 9 percent. Reporting bias and inconsistent or conflicting methods of measuring pain were additional concerns.

The available research, the study authors wrote, "supports the effectiveness of the three drugs approved by the FDA for DPN [duloxetine, pregabalin, and tapentadol]" as well as the effectiveness of other, non-FDA-approved agents like tramatol and botulinum toxin. However, they added, "additional studies evaluating long-term outcomes are needed to better inform clinical decision-making, patient choice, and clinical practice guidelines."

The researchers noted several limitations of their meta-analysis, as well. Among them, the analysis excluded studies that included mixed populations of people with DPN and other neuropathy types, meaning some relevant data may have been missed; and the strength of evidence measures used considered only limitations that were reported in the published studies and may have excluded additional, unreported limitations.

An American Diabetes Association position statement on the management of DPN, which was developed by endrocinologists and neurologists, was published in January in Diabetes Care. Read the Neurology Today story about the statement here.

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Friday, March 24, 2017

BY SARAH OWENS

Over one year of follow-up, neurovascular thrombectomy reduced post-stroke disability and improved health-related quality of life compared to medical therapy alone when performed up to eight hours after the onset of symptoms, according to the results of a new randomized, open-label trial published online on March 16 in The Lancet Neurology.

Current guidelines recommend that thrombectomy, a surgical procedure that recanalizes large-vessel occlusions, be performed on patients with acute ischemic stroke within six hours of symptom onset. The Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) meta-analysis, which pooled the results of five randomized, controlled trials testing the efficacy time window for thrombectomy, found last year that the procedure's benefit lasted up until 7.3 hours. The current study suggests that window may extend up to eight hours – or beyond – and that the benefit is sustained one year later, rather than the 90 days or three months used as a benchmark by many trials.

"Our results provide reassurance to clinicians that the benefit of thrombectomy is sustained long term and validates the hitherto unproven hypothesis of sustained treatment effect used in cost-effective analyses of thrombectomy in acute stroke," the study authors, led by Antoni Davalos, MD, PhD, wrote.

For their study, researchers at four stroke centers in Barcelona, Spain enrolled 206 patients who presented with acute ischemic stroke between November 2012 and December 2014. They randomly assigned the patients to receive either medical therapy alone (n=103) or endovascular thrombectomy (n=103). Patients underwent thrombectomy up to eight hours after the onset of symptoms.

At five days, 90 days, three months, and one year post-stroke, masked investigators assessed a number of outcome measures, including disability, health-related quality of life, functional independence, and cognitive function. All but one (n=205) of the population was available for complete follow-up at one year. At one year, patients in the thrombectomy group had lower disability scores on the modified Rankin scale (a 0 to 6 scale of degree of disability, with higher scores indicating greater disability). Additionally, patients in the thrombectomy group had significantly better health-related quality of life, functional independence, and cognitive function.

The results have several important implications, the study authors noted. Since outcomes remained essentially unchanged from three months to one year, the results provide reassurance of the long-term benefit of thrombectomy, and may also suggest that "outcomes beyond 90 days in acute stroke trials might not be necessary." Further, the treatment effect was similar at five days post-stroke and 90 days post-randomization, which justifies further studies that seek to establish the five-day modified Rankin scale as a surrogate outcome measure.

However, the authors did note several limitations to their study. Among them, their trial was open-label, so patients and investigators were aware of treatment assignments; and the trial was stopped before the formal three-month stopping boundary was reached, although the prespecified 12-month secondary analysis showed that three-month benefits were sustained.

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Thursday, March 16, 2017

BY SARAH OWENS

Eighty-four percent of patients who had an acute ischemic stroke and a history of atrial fibrillation were not receiving guideline-recommended therapeutic anticoagulation before the stroke, according to a new study published online on March 14 in the Journal of the American Medical Association.

Those who did receive adequate anticoagulation before the stroke had better stroke severity scores, lower in-hospital mortality, and better functional outcomes, the study authors found.

The findings, the study authors wrote, demonstrate that there are "potentially preventable strokes in high-risk patients with AF who either were not treated with anticoagulants or did not receive adequate anticoagulation" and "highlight the opportunities for stroke prevention by improving appropriate AF treatment."

Atrial fibrillation (AF) is a substantial, but potentially modifiable, risk factor for stroke, and guidelines recommend treatment for patients with AF with vitamin K antagonists (warfarin) and non-vitamin K antagonist oral anticoagulants (NOACs). Previous studies have suggested these medicines are underused, but they tended to examine treatment patterns for AF only post-stroke. The present study, instead, examines how patients with acute ischemic stroke were treated prior to the event.

"A substantial number of strokes may be due to underuse of or inadequate anticoagulation in AF," the study authors, led by Ying Xian, MD, PhD, assistant professor of neurology and assistant professor of clinical pharmacology at the Duke University Medical Center and Duke Clinical Research Institute, wrote.

For their retrospective, observational study, researchers at Duke analyzed 94,474 patients who were participating in the Patient-Centered Research into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) study. All participants had been diagnosed with AF, had a stroke between October 2012 and March 2015, and had been admitted to hospitals participating in the American Heart Association/American Stroke Association's Get With The Guidelines-Stroke registry program. The research assessed anticoagulant use in the study population at the time of hospital admission.

They found that 7,176 (7.6 percent) of participants were receiving warfarin, and 8,290 (8.8 percent) were receiving NOACs. That left 79,008 patients (83.6 percent) who were receiving no anticoagulation therapy. Moreover, among the 91,155 patients defined as having a high risk of stroke according to their CHA2DS2–VASc score, which is designed to estimate the risk of stroke in patients with AF, 83.5 percent were not receiving adequate therapeutic anticoagulation (either warfarin or NOACs) before their stroke.

Those patients who did receive adequate anticoagulation before a stroke had lower rates of moderate or severe stroke:  15.8 percent (warfarin) and 17.5 percent (NOACs) compared with 27.1 percent [no therapy), 24.8 percent (antiplatelet therapy only), and 25.8 percent (subtherapeutic warfarin). Likewise, patients who received anticoagulation had lower rates of in-hospital mortality: 6.4 percent (warfarin) and 6.3 percent (NOACs) compared with 9.3 percent (no therapy), 8.1 percent (antiplatelet therapy only), and 8.8 percent [subtherapeutic warfarin).

Finally, patients receiving anticoagulation pre-stroke had higher odds of a better functional outcome, defined as a modified Rankin score (a functional scale measuring degree of disability or dependence after stroke, with higher scores indicating worse outcomes) of 0-1 or 0-2 at discharge.

The researchers noted several limitations to their study. Among them, the fact that the study analyzed treatment prior to stroke prevented randomization; the study excluded patients with AF who did not have a stroke, which prevented a case-control design; and some patients did not have available measures of stroke severity or functional outcome.

Look for expanded coverage of this study in an upcoming edition of Neurology Today​.

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