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Neurology News

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

Friday, November 16, 2018

BY LIZETTE BORRELI

Unplanned pregnancy in women with epilepsy was associated with double the risk of spontaneous fetal loss compared to women with epilepsy who planned their pregnancy, according to a retrospective study published online on October 15 in JAMA Neurology.

The rate of spontaneous fetal loss occurred in 35 percent of unplanned versus 16 percent of planned pregnancies among women with epilepsy.

"This analysis adds the finding that unplanned pregnancy may increase the risk of [spontaneous fetal loss] in women with epilepsy and identifies pregnancy planning, maternal age, and interpregnancy interval as significant modifiable variables," the researchers, led by Andrew G. Herzog, MD, MSc, of Beth Israel Medical Center in Boston, wrote.

In an interview with Neurology Today, Kimford J. Meador, MD, FAAN, professor of neurology and neurosciences at Stanford University, and clinical director of the Stanford Comprehensive Epilepsy Center, who was not involved with the study, said the key message from this study and others related to pregnancy in women with epilepsy remains the same: "It's very important for us as clinicians to talk with women who have epilepsy about planning for pregnancy and pregnancy prevention."

Current epilepsy practice guidelines suggest that women with epilepsy should plan their pregnancies to occur when they have achieved "optimal seizure control on the minimum effective dosage of [antiepileptic drugs] and take recommended dosages of folic acid supplement before conception to achieve optimal maternal and fetal outcomes, " the study authors noted.

However, despite these guidelines, 65 percent of pregnancies in women with epilepsy are unplanned.

To evaluate whether planned pregnancy is associated with spontaneous fetal loss in women with epilepsy, the researchers conducted a web-based retrospective survey from 2010 to 2014 completed by 1,144 women in the Epilepsy Birth Control Registry. 

On average, survey respondents were aged 28.5 years; 40 percent had household incomes of $25,000 or less, and minority women only represented 8.7 percent of participants.

Data included pregnancy history, such as the number of pregnancies, number of planned or unplanned pregnancies, AEDs used during pregnancies, and pregnancy outcomes such as live birth, induced abortion, and spontaneous fetal loss, or participants could choose to decline to answer. The researchers included loss of pregnancy before delivery, except for induced abortion, in the spontaneous fetal loss category. The term "unaborted" was used to refer to pregnancies not medically terminated.

AED data included categorizing patients into no therapy, monotherapy, and polytherapy groups. AED use was further subdivided into no AED, enzyme-inducing AED, non–enzyme-inducing AED, enzyme-inhibiting AED, glucuronidated AED, and mixed category groups.

Of the 794 pregnancies that occurred, 530 were unplanned (66.8%) and 264 were planned (33.2%), with 473 live births (59.6%), 141 induced abortions (17.8%), and 180 spontaneous fetal loss (22.7%).

The team concluded that the increased risk of spontaneous fetal loss in unplanned pregnancies in women with epilepsy, and due to the potential that a woman with epilepsy with a history of spontaneous fetal loss may increase the risk of her live-born offspring developing epilepsy, more research is needed.

"[T]he finding warrants prospective investigation with medical record verification of pregnancy outcomes" they wrote.

Study limitations included the reliance on self-reported information not verified by medical records; underreporting due to stigmatized health information, which may have led women to report fewer induced abortions in favor of spontaneous fetal loss despite the survey being anonymous and having the option to decline to answer the question about pregnancy outcome; and the underrepresentation of minority women.

The Epilepsy Foundation and Lundbeck funded the study. Researchers reported relationships with the Epilepsy Foundation and Lundbeck.

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Herzog AG, Mandle HB, and MacEachern DB. Association of unintended pregnancy with spontaneous fetal loss in women with epilepsy: Findings of the Epilepsy Birth Control Registry. JAMA Neurol 2018; Epub 2018 Oct 15.

Wednesday, October 31, 2018

BY LIZETTE BORRELI

Medicinal cannabinoids had limited efficacy in treating certain symptoms in adult patients with multiple sclerosis (MS) but overall were safe compared with placebo, according to a meta-analysis and systematic review published online in JAMA Open Network on October 12.

The cannabinoids produced a mild reduction of subjective spasticity, pain, and bladder dysfunction ([standardized mean differences] SMD of -0.25, -0.17, and -0.11, respectively), compared to placebo. And although cannabinoids were associated with a higher total number of adverse events, the differences were not significant.

MS patients experienced side effects including dizziness or vertigo, dry mouth, fatigue, intoxication, impaired balance or ataxia, memory problems, and sleepiness.

The researchers used both objective assessments and patient self-reports in their analysis. "None of the interventions demonstrated a clear efficacy in the treatment of spasticity when evaluated in a more objective form (ie, the Ashworth and Modified Ashworth scales)" the researchers, led by Mari Carmen Torres-Moreno, PhD, of the Universitat Autònoma de Barcelona, Spain wrote. "To our knowledge, this is the most complete systematic review and meta-analysis of the effect of cannabinoids on MS."

Cannabinoids act as neuromodulators of the endocannabinoid system, the study authors explained. They noted that cannabinoids (nabiximols) are approved in some countries for the symptomatic treatment of MS spasticity and neuropathic pain in cases where medication was deemed ineffective, they noted.

However, systematic reviews and meta-analyses have not shown clear or complete efficacy in treating MS symptoms including spasticity, pain, and bladder dysfunction.

The researchers reviewed 17 clinical trials involving 3,161 adult patients with MS. Clinical trials included assessments of oral cannabis extract—containing tetrahydrocannabinol and cannabiniol from the cannabis sativa plant—oromucosal cannabis extract (nabiximols [Sativex]), dronabinol (Marinol), and nabilone (Cesamet). Dronainol and nabilone are oral synthetic versions of THC.

Overall, the researchers found that cannabinoids performed statistically better than placebo for pain and bladder dysfunction. Subjective reports (from patient reports) were significantly better for cannabinoids, though that was not true for objective measures.

In regard to tolerability, the researchers found an relative risk of 1.72 patient-years (95% CI, 1.46 - 2.02 patient-years) in the total adverse events analysis and 2.95 patient-years (95% CI, 2.14 - 4.07 patient-years) in withdrawals due to adverse events.

The researchers performed further analysis to exclude studies potentially influenced by pharmaceutical industry funding. No differences were found between nabiximols and placebo in efficacy outcomes.

The researchers encouraged further studies on the combination of cannabinoids and other therapies for MS patients to yield more concrete results.

Limitations included the small number of studies assessed and the differences in lengths of treatment. The researchers also cited potential publication bias as several studies were funded by the pharmaceutical industry, especially those involving nabiximols.

The study was partly funded by the Ministerio de Sanidad and MINECO/Instituto de Salud Carlos III.

The researchers reported no conflicts of interest.

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Torres-Moreno MC, Papaseit E, Torrens M, et al. Assessment of efficacy and tolerability of medicinal cannabinoids in patients with multiple sclerosis: A systematic review and meta-analysis. JAMA Network Open 2018; Epub 2018 Oct 12.

Thursday, October 25, 2018

BY LIZETTE BORRELI

Chronic inflammation was associated with an increased risk of early-onset Alzheimer's disease (AD) in carriers of the apolipoprotein E4 (APOE4) gene, according to a population-based cohort study published online in JAMA Network Open on October 19.

Low-grade inflammation — defined by a C-reactive protein (CRP) level of 8 mg/L or higher — was linked to an elevated risk of AD only in APOE4 carriers, especially in the absence of cardiovascular diseases ([hazard ratio] HR 6.63, 95% CI 1.80-24.50, p=0.005).

In addition, APOE4 carriers with chronic low-grade inflammation had an elevated risk of earlier disease onset than APOE4 carriers without inflammation (HR 3.52, 95% CI 1.27-9.75, p=0.009).

Among the elderly, infection and inflammation are common. Previous research reported inflammation triggered AD pathologic characteristics only in mice who carried the APOE4 gene. The APOE4 gene is a major genetic risk factor for late-onset AD, but not all APOE4 carriers develop AD.

The researchers, led by Qiushan Tao, MD, of the department of pharmacology and experimental therapeutics at Boston University School of Medicine, wrote that their findings "may explain why ApoE4 carriers have increased risk for AD at an old age and suggest that treating chronic low-grade inflammation may delay the onset of AD in ApoE4 carriers."

The researchers analyzed data from 2,656 participants of the Framingham Offspring Study (generation 2) — a cohort of children from the Framingham Heart. They defined chronic inflammatory status as having at least two longitudinal serum CRP measurements above pre-specified levels. Typically, a CRP level lower than 3 mg/L is considered normal, but in this study, the researchers defined any CRP measurement above 3 mg/L as low-grade inflammation, using cutoff levels to indicate severity. Participants with only one CRP measurement equal to or higher than 3 mg/L were not considered to have chronic low-grade inflammation.

On average, patients were about 61 years old at their last CRP measurement.

During the 17 years of follow-up, 194 participants developed dementia, 152 of these participants were diagnosed with AD.

The findings revealed APOE4 carriers with low-grade inflammation had an increased risk of overall AD and earlier onset. However, APOE3 and APOE2 carriers with chronic low-grade inflammation did not have the same risk. The researchers noted while APOE2 carriers had higher CRP levels as they aged, it was not tied to AD risk.

Lastly, in a subset of 1,761 participants who underwent brain magnetic resonance imaging, the researchers found the interaction between APOE4 and chronic low-grade inflammation was associated with brain atrophy in the temporal lobe (beta = –0.88, SE = 0.22; p< .001) and hippocampus (beta = –0.04, SE = 0.01; p= .005).

"Our results indicate that chronic low-grade inflammation may play an early role leading to AD in ApoE4 carriers," the researchers concluded.

The team suggested rigorously treating chronic inflammation based on an individual's genetic risk could effectively prevent and treat AD.

Study limitations included the irregularity of CRP assessments, which may have led some cases of sustained inflammatory status to be misclassified or missed, and the inability to prove causality. The Framingham Heart Study cohort lacked ethnic diversity. This means the findings may not be generalizable to non-white populations.

The study was funded by the National Heart, Lung, and Blood Institute and by grants from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging.

The researchers reported no conflicts of interest.

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Tao Q, Ang TFA, DeCarli C, et al. Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers. JAMA Network Open 2018; Epub 2018 Oct 19.

Tuesday, October 23, 2018

BY LIZETTE BORRELI

Gabapentin (Neurontin) was found more effective than pregabalin (Lyrica) in reducing leg pain intensity in adults with chronic sciatica and led to fewer and less severe adverse events, according to a randomized, double-blind, double-dummy crossover trial published online on October 15 in JAMA Neurology.

Researchers said the findings suggest gabapentin should be prescribed before pregabalin to permit optimal crossover.

The study — led by Kelvin Robertson, Bpharm, a doctoral candidate in the department of pharmacy, medical services group at Townsville Hospital, and adjunct senior lecturer at the School of Medicine and Dentistry of James Cook University in Australia — is the first prospective randomized cohort of patients with chronic sciatica to compare the head-to-head efficacy of these drugs, the associated frequency and severity of adverse events, and the impact of pregabalin-gabapentin interchange.

These anticonvulsant drugs are both analogs of gamma-aminobutyric acid (GABA), which modulates calcium channel subunits. The researchers hypothesized that they regulate calcium channels in the nerve cells to decrease the contraction of nerves, lessening neuropathic pain.

Gabapentin and pregabalin are both used to treat chronic sciatica, which lasts for at least three months.

To assess the role of gabapentin and pregabalin in treating chronic sciatica, the researchers recruited 18 adults with chronic sciatica attending a specialist neurosurgery clinic in a large tertiary hospital who had not previously received any of these drugs.

Between March 2016 to March 2018, participants were randomized to receive either gabapentin first, then pregabalin, or vice versa. Participants in the gabapentin group started at 400 mg once daily, which was then titrated up to a maximum of 800 mg three times daily; those who took pregabalin started at 150 mg once daily, and then were titrated up to a maximum dosage of 300 mg twice daily. The patients followed the treatment regimen for eight weeks, followed by a one-week washout period in between.

Patients continued to receive their standard neurosurgical care and took concomitant medications, including analgesics if the dose was stable 30 days prior to the start of the study.

Using the mean visual analog scale (VAS), a 10-point scale that rates leg pain from 0 [no pain] to 10 [worst pain], participants reported their leg pain during the last 24 hours. Both drugs led to a significant mean VAS reduction; gabapentin (7.54 to 5.82; p< .001) and pregabalin (7.33 to 6.38; p= .002). However, when unadjusted mean differences in VAS reduction were compared head-to-head, gabapentin proved superior (1.72 vs 0.94; p= .035).

To measure disability, the researchers administered the Oswestry Disability Index (ODI) questionnaire, in which scores range from 0 to 100, with higher scores indicating greater disability. The frequency and severity of adverse events were measured on a 10-point scale, with 10 being the worse possible score.

Both gabapentin and pregabalin led to a significant reduction in disability as measured by the ODI. But the differences in disability between the two drugs were not significant when unadjusted mean differences were compared head-to-head (p= .63).

A total of 38 adverse events were reported in 67 percent of patients: 81 percent for pregabalin compared with 19 percent (p= .002) for gabapentin (p= .002). This was especially true for patients who received pregabalin first.

Gabapentin was associated with less severe adverse events than pregabalin (4.57 vs 6.35; p= .01). Common adverse effects for both drugs dizziness (13 percent), drowsiness (13 percent), and nausea (11 percent).

The researchers concluded that regardless of whether participants received gabapentin first, or last, gabapentin led to a greater mean VAS score and less adverse events.

It remains unknown why one drug led to more side effects compared to the other, especially since they are structurally similar.

The findings warrant further research with a larger sample to decipher why these drugs led to different outcomes.

Study limitations included the small sample size, the effects of treatment duration, and the restricted doses and study time, which may have led researchers to potentially overestimate adverse events with either drug. Other study limitations included the fact that the participants did not receive the maximal dose of gabapentin that can be prescribed, and the maintenance of background therapies may have affected both the efficacy and the development of adverse events.

The study was funded by a grant from the Townsville Hospital Study, Research, and Education Trust.

The researchers reported no conflicts of interest.

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Robertson K, Marshman LAG, Plummer D, et al. Effect of gabapentin vs pregabalin on pain intensity in adults with chronic sciatica: A randomized clinical trial. JAMA Neurol 2018; Epub 2018 Oct 15.

Wednesday, October 17, 2018

BY LIZETTE BORRELI

A behavioral intervention program that taught stroke patients of different racial/ethnic groups how to lower their blood pressure and prevent a secondary stroke led to a decrease in systolic blood pressure 12 months post-discharge among certain groups, according to a randomized, clinical trial published online on October 8 in JAMA Neurology.

In DESERVE (Discharge Educational Strategies for Reduction of Vascular Events), Hispanic patients who had a mild or moderate stroke or transient ischemic attack (TIA) experienced a 9.9 mm HG greater decrease in systolic blood pressure.

"The SBP [systolic blood pressure] reduction in Hispanic individuals translates to nearly 40% risk reduction for secondary stroke events," the researchers, led by Bernadette Boden-Albala, DrPH, MPH, of NYU College of Global Public Health in New York City, wrote.

The behavioral intervention did not lead to a significant difference in systolic blood pressure among non-Hispanic white or black populations, however.

The randomized trial aimed to investigate whether a behavioral intervention program could improve long-term vascular risk reduction among different racial/ethnic groups who had mild/moderate stroke/transient ischemic attack. The team followed 151 non-Hispanic white, 83 non-Hispanic black, and 180 Hispanic individuals at four New York City hospitals. The patients were randomized to receive either a culturally tailored, skills-based education intervention, or usual care-discharge instructions and American Heart Association pamphlets, from August 2012 to May 2016.

Prior to hospital discharge, patients in the DESERVE arm received an interactive educational session that included a patient-paced workbook and video emphasizing three skills-based thematic areas: patient-physician communication, medication adherence, and accurate stroke risk perception with risk reduction skills.

The DESERVE intervention was designed with community input from African-American and Hispanic community members. Among Hispanic patients, the educational video framed recovery in the context of faith and spirituality, whereas for African-American patients, recovery was framed as a matter of self-determination.

Participants in the DESERVE arm also received follow-up calls from a coordinator at 72 hours, one month, usually right before a neurology appointment, and three months to enhance strategies for patient-physician communication, clarify medication regimens, and provide social support to motivate behavior change.

Health coordinators helped participants identify areas of confusion about their treatment and create a checklist of questions for their doctors. They also helped to reinforce these skills prior to doctor visits through phone calls. The researchers believed this would be a more effective way for patients to achieve control of risk factors.

Researchers measured participants' blood pressure at one-year follow-up. The findings revealed no significant difference in systolic blood pressure reduction between the intervention and the usual care groups (beta 2.5 mm Hg, 95% CI -1.9 to 6.9). However, systolic blood pressure did increase in Hispanic patients in the usual care group. This effect was not observed in other control populations.

The researchers were not sure why Hispanic patients in the DESERVE arm had the most significant reduction in systolic blood pressure.

"We hypothesize that the intervention was beneficial for Hispanic participants because it was based on the needs of patients and was closely evidence based," they wrote.

Recurrent strokes disproportionately affect African Americans and Hispanic patients compared to non-Hispanic white patients, the researchers pointed out.  Persistent racial/ethnic disparities in secondary prevention, mostly due to cultural and behavioral factors not addressed in standard prevention programs, and a lack of integration into community resources, can contribute to failure to comply with secondary stroke prevention, they wrote.

The researchers stressed that their trial was not powered to identify differences in subgroup intervention effects. But, they did conclude culturally tailored, skills-based interventions may help with secondary stroke prevention and address racial/ethnic disparities in stroke. The findings warrant further research to replicate the results.

Study limitations included the inability to identify subgroup differences and distributing health literate and linguistically appropriate educational materials, which may not occur in real-world settings.

The National Institute of Neurological Disorders and Stroke of the National Institutes of Health supported the research.

The researchers reported no conflicts of interest.

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Boden-Albala B, Goldmann E, Parikh NS, et al. Efficacy of a discharge educational strategy vs standard discharge care on reduction of vascular risk in patients with stroke and transient ischemic attack: The DESERVE randomized clinical trial. JAMA Neurol 2018; Epub 2018 Oct 8.