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Neurology News

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

Monday, March 18, 2019

BY LIZETTE BORRELI

Individuals with a history of migraine are more at risk of being diagnosed with dry eye disease, according to a new analysis published online March 7 in JAMA Opthalmology.

Results from past studies on the association between migraine and the risk of dry eye disease have been mixed. But in the current retrospective study, researchers found individuals with migraine had a 20 percent higher risk of having dry eye disease than those without migraine.

The association between the two disorders was more pronounced with age, especially for women. For men aged 65 years or over with migraines, the odds of having dry eye disease doubled; women of the same age had a 2.5 times higher risk.

The research team noted that the underlying mechanism behind the association between migraine dry eye disease remains unclear. But they said inflammatory processes may play a significant role in the pathogenesis of both disorders.

They noted that migraine has been associated with increased levels of inflammatory markers and cytokines, such as C-reactive protein and interleukin, and is triggered by neurogenic inflammatory mediators. T-lymphocyte mediated inflammatory changes in dry eye disease "might trigger similar events in neurovascular tissue, leading to the development and propagation of migraine headaches, or vice versa," they wrote.

"Physicians caring for patients with a history of migraine headaches should be aware that these patients may be at risk for comorbid DED [dry eye disease]," said the researchers, led by Omar M. Ismail, of the department of ophthalmology at the University of North Carolina, Chapel Hill.

For their analysis, the researchers examined data from 72,969 individuals (comprising 57.2 percent men; 42.8 percent women), older than 18 years, seen at one of the ophthalmology clinics from the university from May 2008 through May 2018.

Participants responded to queries that would help identify those who had migraine. Of the 72,969 patients, 7.3 percent had been diagnosed with migraine, and 13.2 percent with dry eye disease.

The researchers accounted for confounding factors associated with dry eye disease in this population, including the use of specific medications (tricyclic antidepressants, antihistamines, or diuretics); a history of rheumatoid arthritis, Sjögren disease, or lupus, and a history of cataract or refractive surgery.

When the researchers accounted for age and sex, the odds of having dry eye disease with a diagnosis of migraine was 1.72 times higher than that of patients without migraine.

After they excluded individuals with confounding factors, the odds of having a dry eye disease given a diagnosis of migraine was 1.42 times higher than those without migraine.

The researchers concluded that "female sex and advanced age play an important role in determining the strength of this association."

Study limitations included the retrospective design of the study and the inability to establish whether there's a temporal correlation between migraine and dry eye disease.

The researchers reported no relevant conflicts of interest.

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Ismail OM, Poole ZB, Bierly SL, et al. Association Between Dry Eye Disease and Migraine Headaches in a Large Population-Based Study. JAMA Ophthal 2019; Epub 7 March 2019.

Wednesday, March 13, 2019

BY LIZETTE BORRELI

Traditionally, in the U.S., the evaluation of epilepsy in patients with intractable epilepsy requires a craniotomy to determine eligibility for surgery. Now, the availability of a minimally invasive procedure for seizure location challenges the principal approach for intracranial electroencephalographic (EEG) recordings.

In a retrospective analysis published online on March 4 in JAMA Neurology, the use of stereoelectroencephalography (SEEG) led to better outcomes in patients with intractable epilepsy, compared with subdural electrode (SDE) implantation at one year.

SDE implantation requires a craniotomy that allows for the precise functional mapping of brain surfaces in relation to epileptogenic zones.  With SEEG, depth electrodes are inserted into the brain to specific targets without requiring a craniotomy. SEEG provides the advantage of improved coverage and precise targeting of deeper structures, the authors of the study wrote, making it better at localizing the epilepsy focus in many patients. SDE implantation is associated with an increased risk of hemorrhage, while SEEG has lower complication rates, they pointed out.

In a comparative analysis, a team of researchers evaluated the efficacy, procedural morbidity, and epilepsy outcomes of SEEG and SDE in 239 patients with medically intractable epilepsy who underwent 260 consecutive intracranial EEG procedures to localize their epilepsy. The procedures were performed by a single surgeon at one center from November 2004 to June 2017.

Researchers chose implant type and the locations for implant placement based on the epileptogenic zone implicated by noninvasive data.

The SDE group included 139 SDE implantations in 136 patients; three patients had two distinct SDE implantations and two hospital stays. Six of the 136 patients underwent additional SDE electrode placements during the same hospital stay. A total of 99 cases were lesional by MRI and 44 had hippocampal sclerosis of varying severity.

The SEEG group included 121 cases in 116 patients; five patients had two distinct SEEG implantations in two hospital stays. Six of the 116 patients underwent additional SEEG electrode placements performed during the same hospital stay. In this group, 53 cases were lesional and 22 had hippocampal sclerosis of varying degrees of severity.

The researchers noted a larger proportion of the SDE cases were lesional (p< .001).

The SEEG method was associated with quicker, less painful, and fewer morbid outcomes for patients, compared with SDE implantations.

A significantly greater proportion of SDE cases (91.4 percent) had resection or ablative surgery compared with those who were assessed using SEEG (74.4 percent). And study participants who had SEEG implantation had better outcomes at one year compared with those who underwent SDE implantation (76 percent versus 54.6 percent, p= .003). A total of 64 percent of SEEG cases were seizure free compared to 44.4 percent of SDE cases.

When considering all patients undergoing evaluation, not just those undergoing definitive procedures, favorable outcomes (Engel class I [free of disabling seizures] or II [rare disabling seizures]) for SEEG compared with SDE were similar at one year (47.1 percent vs 42.4 percent; p= .45).

Patients with SEEG and SDE achieved survivor functions for seizure freedom of 58.4 percent and 45.7 percent at year one, respectively.

After year two, 56.6 percent of the SEEG group and 43.6 percent of the SDE achieved these functions.

The study "reveals greater efficacy in seizure localization and therapy of SEEG compared with that of SDE, the current criterion standard," the researchers, led by Nitin Tandon, MD, a professor of neurosurgery at McGovern Medical School, wrote.

They added: "These features of the SEEG method should lower the barrier for surgical candidacy in intractable epilepsy."

Study limitations ranged from the retrospective nature of the analysis to the vastly different complication rates.

Dr. Tandon did not report any relevant conflicts of interest.

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Tandon N, Tong BA, Friedman ER, et al. Analysis of morbidity and outcomes associated with use of subdural grids vs stereoelectroencephalography in patients with intractable epilepsy. JAMA Neurol 2019; Epub 2019 Mar 4.

Monday, March 11, 2019

BY LIZETTE BORRELI

Aspirin is recommended for the prevention of new cardiovascular events for patients with atherosclerosis. However, its efficacy in reducing the risk for myocardial infarction (MI), stroke, or vascular death varies. Now in a new study, researchers found that combining anticoagulant and antiplatelet therapy may be better than either alone for stroke prevention.

Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS), a randomized, double-blind, parallel trial published on February 26 in Circulation found patients with coronary artery or peripheral artery disease, treated with a combination of rivaroxaban plus aspirin—2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin once daily—compared with aspirin alone—experienced a 42 percent reduction in all-cause stroke.

The COMPASS trial, first published in 2017 in the New England Journal of Medicine, focused on the combined rate of cardiovascular death, myocardial infarction, or stroke during an average of 23 months of follow-up. The trial was designed to run up to four years, but it was stopped early after an overwhelming benefit of the combination therapy.

The combination of rivaroxaban 2.5 mg twice daily plus aspirin reduced the rate of cardiovascular death, stroke, or MI by 1.3 percent; patients experienced a 1.2 percent increase in bleeding.

Now, in a secondary analysis, the researchers, led by Mike Sharma, MD, a stroke neurologist in the Population Health Research Institute of McMaster University in Hamilton, Ontario, Canada, focused on the efficacy of rivaroxaban plus aspirin on various measures of stroke among patients with stable coronary artery or peripheral artery disease.

The team drew data from the COMPASS trial, which enrolled 27,395 patients, average age 68 years, with stable coronary or peripheral artery disease at 602 centers in 33 countries.

Participants were randomly assigned to receive aspirin 100 mg once daily (n=9126), rivaroxaban 5 mg twice daily (n=9117), or rivaroxaban 2.5 mg twice daily plus aspirin (n=9152).

The researchers excluded patients who required anticoagulation or had a stroke within one month, previous lacunar stroke, or intracerebral hemorrhage.

During an average 23 months of follow-up, patients in the rivaroxaban plus aspirin group had fewer strokes, compared with those taking aspirin only—83, or 0.9 percent per year versus 142, or 1.6 percent per year, respectively (p<0.0001).

Compared with the aspirin only group, the annualized rate of ischemic/uncertain stroke among patients assigned the combination of rivaroxaban plus aspirin was reduced by almost half: 68, or 0.7 percent per year versus 132, or 1.4 percent per year, respectively (p<0.0001).

No significant differences were found in strokes in the rivaroxaban alone group compared with aspirin.

There were fewer fatal and disabling strokes, defined by a modified Rankin Scale score between 3– 6, in the aspirin plus rivaroxaban group than in the aspirin group only group (p=0.01).

Prior stroke was found to be the strongest predictor of incident stroke (p<0.0001), which was associated with a 3.4 percent per year rate of stroke recurrence with aspirin.

Overall, the researchers concluded "low-dose rivaroxaban plus aspirin is an important new option for efficacious antithrombotic therapy for primary and especially secondary prevention of stroke in patients with atherosclerosis."

They added that the risk reduction for secondary prevention is significant and makes a "compelling case favoring the use of 2.5 mg rivaroxaban twice daily plus aspirin in these patients."

Study limitations included the exclusion of participants with recent stroke, thus, limiting the generalizability of these findings during the early poststroke period. Moreover, the researchers did not systematically collect transient ischemic attacks from sites, opening up the possibility for misclassification of some strokes as transient ischemic attacks. Lastly, imaging for suspected stroke was done at the site and not reviewed centrally.

Dr. Sharma reported grants and personal fees from Bayer, Bristol-Myers Squibb, Daiichi Sankyo, and Portola. Study co-authors reported several conflicts of interest relevant to the study.

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Sharma M, Hart RG, Connolly SJ, et al. Stroke Outcomes in the COMPASS Trial. Circulation2019 Feb 26;139(9):1134-1145.

Thursday, March 7, 2019

BY LIZETTE BORRELI

The link between the levodopa-associated dyskinesia and cognitive decline in Parkinson's disease (PD) has not been well studied. But in a new analysis, researchers reported a relationship between the development of levodopa-induced dyskinesia and longitudinal changes in cognition.

The retrospective cohort study published online on February 22 in Neurology found PD patients who developed levodopa-induced dyskinesia within five years of starting levodopa therapy experienced a faster decline in frontal executive function and global cognitive function than PD patients resistant to levodopa-induced dyskinesia.

The researchers noted that previous neuroimaging studies have shown in vivo evidence of structural abnormalities in PD patients with levodopa-induced dyskinesia, such as increased gray matter density in the prefrontal cortex, which plays a role in cognition. They contend that levodopa-induced changes in the brain could affect cognitive function in these patients.

"[O]ur data suggest that LID [levodopa-induced dyskinesia] may be a risk factor for the development of dementia and cognitive decline in PD rather than a simple comorbid factor that is secondary to longer disease duration or faster progression of disease," the researchers, led by Han Soo Yoo, MD, from the department of neurology at Severance Biomedical Science Institute and the Biostatistics Collaboration Unit at Yonsei University College of Medicine in Seoul, South Korea, wrote.

For their analysis, the researchers recruited 119 patients with PD who had been treated with levodopa for more than five years from the Movement Disorders outpatient clinic in the Yonsei University Health System.  The mean latency from the start of levodopa to levodopa-induced dyskinesia in all PD patients was about five years.

Every three to six months, two movement disorders experts assessed the presence of levodopa-induced dyskinesia through self-reports from the patients and caregivers or by an in-person neurologic examination done by the patient at every visit. Thirty-eight patients had levodopa-induced dyskinesia and 81 reported having no dyskinesia within five years of levodopa administration.

All patients underwent baseline assessments that included neuropsychological tests, brain MRI, and 18F-FP-CIT PET scanning. The researchers found no significant differences at baseline between performance on the neuropsychological tests and the percentage of patients with mild cognitive impairment (MCI).

The researchers adjusted for age, sex, years of education, body mass index, motor severity at baseline, and levodopa increment per year, to compare the rates of cognitive decline and dementia conversion between the groups.

They found PD patients with levodopa-induced dyskinesia showed faster declines in frontal executive function (p=0.002) and global cognitive function (p=0.033).

PD patients with levodopa-induced dyskinesia with MCI had a higher likelihood of converting to Parkinson dementia than those with normal cognitive function (adjusted hazard ratio [HR] 6.08; 95% CI, 1.25 to 29.56), and those with MCI in patients without levodopa-induced dyskinesia (adjusted HR, 4.05; 95% CI, 1.14 to 14.43).

Moreover, those with levodopa-induced dyskinesia had a higher conversion to dementia than their counterparts without levodopa-induced dyskinesia (adjusted HR, 3.94; 95% CI, 1.76 to 8.82).

Based on these findings, the researchers encourage clinicians to monitor PD patients with MCI who develop levodopa-induced dyskinesia early throughout the course of disease, because "it may add another important clinical signal to the known factors associated with cognitive decline."

Study limitations ranged from the use of retrospective reports to determine the onset of levodopa-induced dyskinesia to not measuring levodopa-induced dyskinesia severity and onset together.

A grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health, supported this study.

The researchers reported no relevant disclosures.

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Soo Yoo H, Jong Chung S, Hyun Lee Y, et al. Levodopa-induced dyskinesia is closely linked to progression of frontal dysfunction in PD. Neurology 2019; Epub 2019 Feb 22.

Wednesday, March 6, 2019

BY MARK MORAN

Administering pembrolizumab, a programmed cell death protein 1 (PD-1) monoclonal antibody, prior to surgical resection for recurrent glioblastoma multiforme (GBM) appears to result in better survival than adjuvant therapy after surgery, according to a report published online February 11 in Nature Medicine.

[Pembrolizumab is one of several agents known as checkpoint inhibitors, which work by blocking the receptors that cancer cells use to send signals to T cells. When the signal is blocked, T cells may be better able to distinguish a cancer cell from a healthy cell and launch an attack. Checkpoint inhibitors are designed to block either PD-1 or programmed cell-death ligand (PD-L1), exposing the cancer cell for attack.]

 Study authors and experts who reviewed the report for Neurology Today said immunotherapy prior to surgery, when a significant tumor mass exists, appears to promote cell death processes in the tumor microenvironment as well as systemic anti-tumor immune response not seen in adjuvant therapy after surgery.

"Anti-PD-1 blockade in the neoadjuvant setting in patients with recurrent, resectable glioblastoma appears to provide a survival benefit," study co-author Aaron Y. Mochizuki, MD, a pediatric hematology/oncology fellow at David Geffen School of Medicine at University of California, Los Angeles (UCLA), told Neurology Today.

"This is likely driven by the systemic modulation of the immune compartment, wherein tumor-specific T cell clones after checkpoint release can become activated and expand in response to the large antigenic burden present with the tumor still in place. After surgery, this broader repertoire of tumor-specific T cells can continue to eliminate residual tumor cells."

Dr. Mochizuki explained that T cells in and around the tumor are functionally suppressed by the tumor cells' use of the PD-1 axis, which typically is a mechanism that prevents the immune system from attacking the body's own cells.

"By administering PD-1 blockade, the T cells wake up and recognize the tumor as foreign," he told Neurology Today. "When T cells become activated, they release interferon gamma, which recruits other immune cells to the area and enables tumor-specific T cells to proliferate. We think that checkpoint release prior to surgery is important because you have more tumor cells available that T cells can recognize.

"Surgery is also essential," he continued, "but if you take the tumor out before waking the T cells up, there's not enough cancerous cells left over after for the T cells to recognize and so their typical immune signaling through interferon gamma is not as robust; subsequently fewer other immune cells are recruited, and the immune system's ability to respond to the tumor is not as strong as it could be."

Study Design

The lead study author, Timothy F. Cloughesy, MD, director of the neuro-oncology at the Geffen School of Medicine at UCLA, other UCLA scientists, and investigators included investigators at the Ivy Foundation Early Phase Clinical Trials Consortium. They enrolled and randomized 35 patients—16 to neoadjuvant pembrolizumab and 19 to adjuvant therapy only—between October 2016 and September 2017 at seven institutions. There were no statistically significant differences in age, sex, pre- or post-surgery tumor volume, steroid administration at registration, or other prognostic factors. The extent of resection or the fraction of patients who received a gross total resection was not different between groups.

As of the analysis cutoff date, there have been nine deaths in the neoadjuvant arm and 12 in the adjuvant-only arm. The neoadjuvant arm demonstrated a statistically significant increase in overall survival: Patients in the adjuvant-only group had a median overall survival of 228 days (7.5 months), whereas those in the neoadjuvant arm had a median overall survival of 417 days (13.9 months).

Importantly, Dr. Mochizuki and colleagues were able to demonstrate that the survival benefit was associated with intracellular changes in anti-tumor immunological response and tumor replication processes.

For instance, they analyzed transcriptional changes within patient tumors and found that neoadjuvant PD-1 blockade induces distinct tumoral gene expression changes: Interferon- and T cell–pathway induction was observed in nine of 14 tumors in the neoadjuvant group and five of 15 in the adjuvant-only group. Additionally, three out of 14 tumors in the neoadjuvant group demonstrated positive enrichment of cell cycle/cancer proliferation signatures, whereas this occurred in 11 of 15 tumors in the adjuvant group.

They also found that neoadjuvant PD-1 antibody blockade is associated with increased T-cell density: Seven patients who had neoadjuvant therapy compared with just three who had adjuvant therapy exhibited high CD8 T-cell infiltration, suggesting that neoadjuvant treatment is associated with induction of PD-L1 expression.

Dr. Mochizuki said anti-PD-1 blockade in the neoadjuvant setting is just starting to gain traction. "The risks of immunotherapy are relatively well-known," he said. "Immune-related effects, such as hepatitis, colitis, thyroiditis, are the most concerning, though we can't say for certain at this point whether neoadjuvant administration of PD-1 blockade increases the risk of these adverse events."

Dr. Mochizuki added: "There is certainly still a great deal to learn about the use of neoadjuvant PD-1 blockade in patients with recurrent glioblastoma. As such, we're expanding the trial to include more patients on the neoadjuvant arm. Our findings will need to be replicated in larger studies before this becomes standard of care….Given the dismal prognosis associated with recurrent glioblastoma and the limited number of new treatments over the past several years, we believe that this represents a promising new approach to the disease."

Look for an analysis of the findings in the March 21 issue of Neurology Today.