Neurology News

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

Thursday, November 16, 2017


Intravenous eculizumab was safe and well tolerated, but did not significantly improve symptom severity among patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (MG), according to a study published online on October 20 in The Lancet Neurology.

Additional pre-specified sensitivity and secondary analyses suggested, however, that eculizumab (Soliris) may, in fact, be effective.  The U.S. Food and Drug Administration approved the drug for MG on October 23.

Effective treatments are lacking" for refractory generalized myasthenia gravis, a debilitating disease caused by autoantibody-mediated destruction of the neuromuscular junction that causes severe muscle weakness, the study authors wrote. A previous phase 2 study suggested that the terminal complement inhibitor eculizumab led to meaningful improvements in patients with the disease.

While the current findings showed that eculizumab was well tolerated among a large, international, randomized group of patients, they did not find it improved symptoms compared with patients taking a placebo. The study's analytical approach, which treated any discontinuation for any reason as a negative outcome, "makes it difficult to translate the implications of the study results into clinical practice," the study authors, led by James F. Howard Jr., Distinguished Professor of Neuromuscular Disease and chief of the neuromuscular disorders section at the University of North Carolina School of Medicine, wrote.

For the REGAIN study, researchers at 76 hospitals and specialized clinics in 17 countries across North America, Latin America, Europe, and Asia conducted a phase 3, randomized, double-blind, placebo-controlled trial. Between April 2014 and February 2016, they enrolled 125 patients who were at least 18 years old, had a score of 6 or more on the Myasthenia Gravis-Activities of Daily Living (MG-ADL) scale – a validated scale of symptom severity, with higher scores indicating greater severity – and class II-IV disease per Myasthenia Gravis Foundation of America classifications. All patients had been treated with at least two immunosuppressive therapies or one immunosuppressive therapy plus chronic intravenous immunoglobulin or plasma exchange for 12 months, but had not achieved symptom control.

The investigators randomly assigned the patients 1:1 to receive a 26-week course of either intravenous eculizumab (900 mg on day 1 and at weeks 1, 2, and 3; a 1,200 mg dose at week 4; and a 1,200 mg dose every second week thereafter as maintenance dosing) or matched placebo. Their primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score among randomized patients who received least one dose, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. On this primary endpoint, they found no significant difference between eculizumab and placebo (p=0.0698).

However, additional pre-specified sensitivity and secondary analyses suggested that eculizumab may, in fact, be effective. The drug was generally safe, with no deaths or cases of meningococcal infection during the study period, and well tolerated; some patients in both groups had MG exacerbations (10 percent in the active group and 24 percent in the placebo group) or required rescue therapy (10 percent and 19 percent, respectively).

The reason for the disparity between the primary endpoint analysis and the sensitivity/secondary endpoint analyses of efficacy, and a main limitation of the study, was the researchers' use of the worst-rank analytic method, they wrote. That method automatically assigned patients who discontinued the study to the poor outcome group, regardless of the reason for discontinuation or their disease status at the time of discontinuation, which may have caused the drug to appear less effective in the primary analysis. Therefore, they concluded, despite the results of that analysis, "the data suggest that complement inhibition might be an approach to the treatment of anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis, and should stimulate additional research."

The study was funded by Alexion Pharmaceuticals, which had a role in the study design, study conduct, and data collection, the researchers disclosed. The funder was responsible for the statistical analysis plan and protocol as well as the final clinical study report. All study authors had full access to all the data in the study, were provided final approval of the manuscript, and had the final choice of whether to submit for publication.


Monday, November 13, 2017


Thrombectomy performed between six and 24 hours after the onset of stroke symptoms led to better 90-day outcomes of disability and functional independence among patients with severe stroke deficits, suggesting that substantially more patients may be eligible for thombectomy than previously thought, according to a study published online first on November 11 in The New England Journal of Medicine.

The finding was significant even when the researchers compared endovascular thrombectomy plus standard medical care with standard medical care alone for patients with acute stroke who had last been known to be well six to 24 hours earlier and who had a mismatch between clinical deficit and infarct. The study was led by Raul G. Nogueira, MD, professor of neurology, neurosurgery and radiology at Emory University School of Medicine and director of the neuroendovascular division – Marcus Stroke & Neuroscience Center at Grady Nenorial Hospital in Atlanta.

Previous studies and pooled analyses have shown that, while "the earlier, the better" is true for patients with ischemic stroke undergoing thrombectomy, the procedure can be safe and beneficial for up to six hours after treatment. While information on the benefit of thrombectomy after six hours is limited, the researchers noted, some patients who had a stroke six hours or more prior to hospital presentation and have severe deficits may nonetheless have plenty of brain tissue that can be salvaged with reperfusion.

"On the basis of retrospective studies," the researchers noted, "approximately one third of the patients with occlusion of a proximal anterior cerebral vessel who present within six to 24 hours after the onset of stroke may meet the imaging-based eligibility criteria that were used in this trial."

For the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) study, researchers enrolled 206 stroke patients who had an occlusion of the intracranial internal carotid artery or the proximal middle cerebral artery, had last been known to be well six to 24 hours prior, and who had a mismatch between the severity of clinical deficit and the volume of the infarct, as assessed by diffusion-weighted MRI or perfusion CT. They randomly assigned 107 patients to undergo thrombectomy plus standard care and 99 to receive standard care alone.

The researchers' primary end points were the 90-day mean score for disability on the utility-weighted modified Rankin scale, a 10-point scale of disability or death; and the 90-day rate of functional independence on the six-point modified Rankin Scale, with higher scores indicating more severe disability on both.

They found that the mean score on the utility-weighted mRS at 90 days was 5.5 in the thrombectomy group vs 3.4 in the control group (95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999). The rate of 90-day functional independence was 49 percent in the thrombectomy group vs 13 percent in the control group (adjusted difference, 33 percentage points; 95% credible interval, 22 to 44; posterior probability of superiority, >0.999).

Finally, they found that the rate of symptomatic intracranial hemorrhage was similar between the two groups (6 percent in the thrombectomy group vs 3 percent in the control group, p=0.50). Rates of 90-day mortality were also similar between the two groups (19 percent in the thrombectomy group vs 18 percent in the control group, p=1.00).

The researchers found that the benefit of late thrombectomy was consistent across subgroups defined by age, stroke severity, occlusion site, time to treatment, and type of stroke onset, although the small number of trial participants meant the study had limited power to detect differences between subgroups. Because the trial only enrolled patients with small or medium infarcts, they added, "Our findings may be concordant with previous reports that the extent of tissue injury is a determinant of the risk of symptomatic intracerebral hemorrhage after reperfusion therapy."

In an accompanying editorial, Werner Hacke, MD, PhD, DSc, said the DAWN trial results were "strikingly positive," noting that the researchers' strategy for identifying brain tissue that is ischemic but not yet infarcted "resulted in the highest rates of functional independence ever reported with thrombectomy [60 percent and 71 percent])." However, he noted that for now, the findings do not support "a general liberalization of the time window for thrombectomy or thrombolysis" – only an expansion of the time window for certain patients with severe stroke – and that reducing time to treatment is still paramount.

The researchers noted several limitations to their study, including that some baseline variables that were not used for randomization varied significantly between the thrombectomy and control groups, although the benefit of thrombectomy remained in a post-hoc sensitivity analysis that adjusted for them. Also, they said, only strokes assessed using relatively advanced imaging techniques were included, and "further studies are needed to determine whether late thrombectomy has a benefit when more widely available imaging techniques are used, such as assessment of the extent of hypodensity on non-contrast-enhanced CT."


Friday, November 10, 2017


Glucose dysregulation in the brain was found to be associated with the severity of Alzheimer's disease pathology (AD) and the expression of AD symptoms, according to a study published online on November 8 in Alzheimer's & Dementia.

Insulin resistance and diabetes are known risk factors for AD, the study authors noted, but the precise role of glucose dysregulation in AD pathology, and how it relates to the severity of AD symptoms, is unknown. In addition, the transport of glucose across the blood-brain barrier and into brain tissue occurs largely independent of insulin, making it unclear how glucose may factor in AD.

The current findings suggest that "impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis," the study authors, led by Yang An, PhD, statistician at the Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA) at the National Institute of Health, wrote. "Abnormalities in brain glucose homeostatis may begin years before the onset of clinical symptoms."

The results should lead to future research testing brain glucose dysregulation as a target of disease-modifying interventions in AD, the study authors wrote.

For the study, researchers at the NIA obtained brain tissue samples at autopsy from 47 patients who were enrolled in the autopsy program of the Baltimore Longitudinal Study of Aging, a prospective, ongoing cohort study of community-dwelling volunteer participants in Baltimore, MD. As part of their participation, the participants underwent an extensive biomedical examination and neuropsychological testing every two years; researchers used this information to identify AD diagnoses and severity of AD symptoms.

First, the researchers analyzed the brain tissue samples for total brain glucose concentration. To measure abnormalities in glucose metabolism associated with higher glucose concentrations, they also assessed the ratios of three glycolytic amino acids – serine, glycine, and alanine – to glucose in brain regions vulnerable to AD pathology. Additionally, they used mass spectrometry to quantify the protein levels of the neuronal glucose transporter, GLUT3, and the astrocytic glucose transporter, GLUT1. Lastly, the researchers compared plasma glucose levels measured up to four decades before death with glucose levels in the postmortem brain tissue.

They found that a higher glucose concentration in the postmortem brain tissue, reduced glycolytic flux, and lower levels of GLUT3 were all associated with the severity of AD pathology and the expression of AD symptoms in the participants. In addition, they found that longitudinal increases in fasting plasma glucose levels were associated with higher global brain tissue glucose concentrations.

As an important limitation to their study, the researchers noted that they lacked brain and blood tissue samples from patients with other neurological diseases than AD. Further studies using such tissue samples, they note, could help determine "whether abnormalities of brain glucose utilization are a specific feature of AD pathogenesis or may be shared by other neurodegenerative diseases."

The researchers declared no conflicts of interest.


Thursday, November 9, 2017


Amyloid-beta (Aβ) protein derived from parenchymal tissues circulating in the blood may travel to the brain and accumulate there, triggering neurodegeneration, synaptic dysfunction, and Alzheimer's disease (AD) pathology, according to a a new study of transgenic AD and wild-type mice published online on October 31 ahead of the print edition of Molecular Psychiatry.

The findings challenge the longstanding assumption that Aβ that accumulates in AD is derived from the brain, the researchers wrote. The investigators proposed that that peripheral Aβ metabolism might be involved in AD pathogenesis, as well.

"Our study is the first to reveal that blood-derived Aβ can enter the brain, form the Aβ-related pathologies and induce functional deficits of neurons," the study authors, led by Xian-Le Bu, of the department of neurology and the Centre for Clinical Neuroscience at Daping Hospital in Chongqing, China, wrote. "Our study provides novel insight into AD pathogenesis."

For the study, researchers at the University of British Columbia and several universities in China injected female transgenic mice with a human mutant gene, APPswe/PS1dE9, that results in a high production of Aβ. They randomly paired them with female, age-matched wild-type littermates at nine months old. After placing them in a cage together for one month to allow them to adapt to each other, the researchers performed surgery to establish parabiosis, a condition in which two organisms are surgically attached and share a blood supply, between the transgenic and wild-type mice. They saved an equal number of female, age-matched wild-type mice from parabiosis to serve as controls.

At two, four, eight, and 12 months after parabiosis was performed, the researchers extracted frozen brain tissue from the wild-type mice's left hemispheres and analyzed it for Aβ concentration using a western blot analysis and an enzyme-linked immunosorbent assay. They also tested hippocampal long-term potentiation, thought to underpin learning and memory, to investigate the subsequent impact of blood-derived Aβ on synaptic function.

They found, first, that blood-derived Aβ successfully entered the brain parenchyma of the wild-type mice. After tissue analysis, blood levels of Aβ in parabiotic, wild-type mice were found to be comparable to those of the parabiotic, transgenic mice, but both were significantly higher compared to that of the control wild-type mice. In the western blot analysis, they detected Aβ in the brain homogenates of parabiotic, wild-type mice beginning at four months, and it gradually increased from there. Similarly, the enzyme-linked immunosorbent assay tests demonstrated a significant, time-dependent increase in Aβ in the brain tissue of parabiotic, wild-type mice.

These increased levels of Aβ induced markers of neurodegeneration, the researchers found. They detected significantly increased inflammation in the parabiotic, wild-type mice, as measured by levels of proinflammatory cytokines and reactive astrocytes and microglia. They also found cerebral microhemorrhage and a higher number of microhemorrhage profiles in the wild-type mice's brains. Hippocampal long-term potentiation revealed that synaptic function was "markedly impaired in parabiotic wild-type mice."

Finally, the researchers found that the formation of Aβ plaques was similar in parabiotic, wild-type mice and control transgenic mice, but large Aβ plaques existed in the brain parenchyma of transgenic mice. This difference, they concluded, "suggests that Aβ deposits in brains of [parabiotic, wild-type] mice originated from the blood, whereas Aβ deposits in brains of transgenic mice were mainly produced from brain cells."

The findings, which provide novel insights into AD pathogenesis, could potentially facilitate the  "development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery," the researchers concluded.

The researchers declared no conflicts of interest.


Monday, November 6, 2017


Sodium oxybate, a potent central nervous system depressor, was found effective for treating excessive daytime sleepiness (EDS) and sleep disturbances in patients with Parkinson's disease (PD), according to a small study published online on November 6 in JAMA Neurology.

Few options are available to treat sleep disturbances, including both EDS and disturbances in nighttime sleep, which are common among patients with PD, the study authors noted. They decided to  test sodium oxybate because it has been found effective for treating narcolepsy type 1, and its effectiveness for PD has been tested in a small, open-label trial, which hinted at promising results.

The current findings from a randomized, blinded cohort suggest sodium oxybate "may be a powerful novel treatment option for sleep-wake disturbances in PD," the study authors, led by Fabian Büchele, MD, of the department of neurology at University Hospital Zürich in Zürich, Switzerland, wrote. However, they added, "stringent monitoring [for treatment-related complications] is necessary."

For the study, researchers from the sleep laboratory at University Hospital Zürich enrolled 18 patients with PD and EDS who had a score of at least 10 on the Epworth Sleepiness Scale (ESS), an eight-question, 24-point scale of symptoms of sleepiness, with higher scores indicating greater sleepiness. One patient withdrew consent and three patients were excluded due to a sleep apnea diagnosis, leaving 12 patients in the final study.

The researchers randomized the 12 patients in a 1:1 ratio to one of two treatment sequences: Sodium oxybate followed by placebo, or placebo followed by sodium oxybate. The participants took both medications daily as drinkable solutions at bedtime and 2.5 to four hours later for six weeks, followed by a two- to four-week washout period. Doses were titrated between 3 and 9 g per night according to efficacy and tolerability, with a maximum weekly change of 1.5 g.

The researchers' primary outcome was change of objective EDS, as determined by mean sleep latency in the Multiple Sleep Latency Test (MSLT), an objective measure of how quickly patients fall asleep in a quiet environment during the day. Secondary outcomes included change in subjective ESS scores as well as objective variables of nighttime sleep as measured on polysomnography; all outcomes were assessed at baseline and at six weeks.

At six weeks, the researchers found that, among 12 patients in the intention-to-treat population, sodium oxybate significantly improved EDS objectively (mean sleep latency, +2.9 minutes; 95% CI, 2.1 to 3.8 minutes; p=0.002) as well as subjectively (change in ESS score, −4.2 points; 95% CI, −5.3 to −3.0 points; p=0.001). Overall, eight patients (67 percent) demonstrated a positive, electrophysiologically defined treatment response. In addition, sodium oxybate significantly improved subjective sleep quality and the duration of slow-wave sleep (+72.7 minutes; 95% CI, 55.7 to 89.7 minutes; p<0.001).

However, the drug induced new obstructive sleep apnea in two patients, who were excluded from the final per-procotol analysis (n=10); in this analysis, treatment effects were even more pronounced.

The findings, the researchers concluded, "provide class I evidence for the efficacy of sodium oxybate in treating EDS and nocturnal sleep disturbance in patients with PD." However, noting the small size and short duration of the study and the observed potential adverse effects of the drug, they added, "Special monitoring with follow-up polysomnography is necessary to rule out treatment-related complications and larger follow-up trials with longer treatment durations are warranted for validation."

The main limitation to the study noted by the researchers was the small number of participants, which is sufficient to provide level 1 evidence for efficacy but not for safety, they said.

The study was funded by UCB Pharma, which provided the drug, and the Clinical Research Priority Program Sleep and Health of the University of Zurich. Dr. Büchele received speaker honoraria from Hoffmann-La Roche Pharma. He and the other authors reported no other conflicts.


  • Büchele F, Hackius M, Schreglmann SR, et al. Sodium oxybate for excessive daytime sleepiness and sleep disturbance in Parkinson disease: A randomized clinical trial. JAMA Neurol 2017; Epub 2017 Nov 6.​