Drug mix-up could put patients in danger, the cognitive cost of high blood pressure, and smartphones are interfering with treatment

Are you reading this on your cell phone? Well, if you’re prone to headaches, you may want to swing open the laptop instead. This week, we’re looking at the link between migraines and phone use, a potentially embarrassing and dangerous drug mix-up, neuroimaging disparities and—as always—so much more.

Neuro Flashback

Old MacDonald is beloved for his jovial little farm, but there’s another MacDonald we’re a bit fonder of. His name was MacDonald Critchley, MD, an internationally known British neurologist who lived a long life with a lengthy list of contributions to the field of neurology. Critchley, who lived to the ripe age of 97, was renowned for his enthralling, lively lectures, which he delivered without notes. He was so animated during his talks that he even considered becoming an actor. Fortunately for neurologists the world over, he stuck to his noble field, manning the chair as president of the World Federation of Neurology from 1965 to 1973, and even playing a part in combatting the rise of fascism when he served in the Royal Navy in World War II.

In the News

You mixed up my antidepressants with WHAT? If you’re taking trazodone to treat your depression, you may want to read this before you continue with your regular dose. The manufacturer AvKARE has issued a voluntary nationwide recall of trazodone and sildenafil, the active ingredient in Viagra, due to a product mix-up.

According to a company announcement, the recall is in effect for one lot of sildenafil 100 mg tablets and one lot of trazodone 100 mg tablets, due to the products being inadvertently packaged together during bottling at a 3rd party facility. While the thought of someone unwittingly popping a sildenafil pill—a treatment for erectile dysfunction—may sound appealing to sketch comedy writers, unintentional consumption of the drug may pose serious health risks to consumers with underlying medical issues. Sildenafil can, for example, interact with nitrates found in some prescription drugs, which can result in blood pressure lowering to dangerous levels. Likewise, the unintentional intake of trazodone can lead to adverse health consequences like somnolence/sedation, dizziness, constipation, and blurred vision.

Smartphones are a real headache. Need another reason to stop spending so much time staring at your phone? A new study has found that smartphone use may be causing an increased need for migraine medications. The cross-sectional study, which was published in Clinical Practice and took place from June 2017 to December 2018, aimed to determine whether smartphone use was associated with the occurrence of new-onset headaches and with increased severity of headaches in patients prone to getting them.

Researchers divided the 400 patients into two groups: Smartphone users and non-smartphone users. While the study found that headache characteristics of both groups were mostly similar, smartphone users were more likely to be taking acute medication and experiencing less relief from it. While longitudinal studies are required to confirm the findings, it appears that smartphones aren’t just destroying our attention spans and increasing our anxiety—they may be giving us headaches, too.

Migraine pain and painkillers. At this point, the dangers of prescription opioids are common knowledge. But despite the association with negative outcomes, opioids are often used—with a prescription or not—to treat migraines. Now, a new cross-sectional analysis has shown that increasing use of prescription opioids is associated with a number of factors—including chronic migraine.

The study, published in Headache, looked at 15,000 individuals who suffered from migraines and who were receiving prescription acute medications, including opioids. Researchers aimed to assess factors associated with the frequency of self‐reported prescription opioid use for the treatment of migraines, including demographic variables, comorbidities, headache characteristics, and patterns of consultation. They found that, compared to non‐opioid users, frequent users were more likely to be male, to smoke, to be obese, to report greater pain interference, to have moderate to severe disability, to have symptoms of anxiety and depression, to use fewer triptans and NSAIDs, and to have poor acute treatment optimization. It’s unclear whether regular opioid use leads to increased migraines, but we now know that those who experience migraines are more likely to use them, increasing the potential for unwanted side effects.

The high cost of high blood pressure. It’s easy for patients to write off high blood pressure. After all, some 108 million Americans—roughly 45% of US adults—have the condition. But there’s a pile of overwhelming evidence that the condition shouldn’t be ignored. Now, new evidence published in Hypertension adds to that pile, suggesting that high blood pressure—at any age—can increase a person’s risk for dementia later in life.

Among the key findings was data suggesting that even slightly elevated blood pressure in middle age or older was linked to faster cognitive decline. “We initially anticipated that the negative effects of hypertension on cognitive function would be more critical when hypertension started at a younger age,” a study author said. “However, our results show similar accelerated cognitive performance decline whether hypertension started in middle age or at older ages.” The news is rough, but it comes with a silver lining: Effectively treating blood pressure at any age in adulthood could reduce or prevent this acceleration.

Neuro Trivia

How much cerebrospinal fluid is contained in the body?

About 100 to 150 mL—right around half of a cup’s worth.

Novel Diagnostics

The science of sleep and Alzheimer’s. Here’s another reason you should be getting more sleep: It may help protect against Alzheimer’s disease (AD). A new study from a team of scientists at the Washington University School of Medicine in St. Louis has identified a protein biomarker for AD that appears to be regulated by the circadian rhythm.

The team had conducted a study in 2018 that indicated how disrupted sleep can accelerate the buildup of amyloid plaques in the brain. The recent study, published in Science Translational Medicine, shows that a brain protein called YKL-40 plays a role in this relationship. While this protein has long served as a biomarker for Alzheimer’s (high levels of it are found in the cerebrospinal fluid of AD patients, and the levels rise as the disease progresses), researchers were previously unaware that it is regulated by sleep cycles. Not only did the team discover that the circadian rhythm controls how much YKL-40 is produced, but they also experimented on mice and found that, without YKL-40, only half the amount of amyloid plaques were present in their brains. Researchers concluded that the protein likely serves as a modulator of microglia, which are immune cells that combat amyloid plaques. When studying 778 human subjects, the team noted that lower levels of YKL-40 was associated with a 16% slower rate of mental decline. So, you heard the scientists: Go to bed!

Six new biomarkers for stroke in AF patients. Biomarkers can offer doctors diagnostic clues, which can be vital when it comes to interventions or treatment—especially in those who have a pre-existing condition. Now, a new study has unveiled six biomarkers associated with ischemic stroke in patients with atrial fibrillation (AF).

The study, which was published in the Journal of the American Heart Association, looked at the connection between 268 plasma proteins and subsequent stroke in two large AF cohorts receiving oral anticoagulation. The groups involved 282 AF patients from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial who have had ischemic stroke or systemic embolism, and 4,124 patients who hadn’t. Over a nearly 2-year follow-up, researchers identified six out of the 268 biomarkers that were strongly associated with subsequent ischemic stroke/systemic embolism in those with AF. These were: Fibrosis/remodeling (matrix metalloproteinase‐9 and soluble suppression of tumorigenesis 2), cardiac dysfunction (NT‐proBNP), vascular calcification (osteopontin), metabolism (sortilin), and mucosal integrity/ischemia (trefoil factor‐3).

New neurotoxicity diagnosis tool. In those with relapsed or refractory hematologic malignant neoplasm, chimeric antigen receptor (CAR) T-cell therapy is known to cause severe neurologic adverse events. These range from encephalopathy and aphasia to cerebral edema and death. Fortunately, researchers are getting closer to being able to diagnose this kind of neurotoxicity, after a new study established a prognostic scoring system to assess the risk of its occurrence.

The study, which was published in JAMA, aimed to identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk. The investigation was carried out at Brigham and Women’s Hospital/Dana Farber Cancer Institute from April 2015 to February 2020, and it involved more than 200 patients receiving CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma. The scoring system that the analysis revealed may help predict which patients are likely to experience CAR T-cell–associated neurotoxicity. As such, it could be used for triage and to guide resource allocation by enabling the early discharge of a large proportion of patients from hospital.

Diagnosis using NGS on the rise. Last week, market research firm Frost & Sullivan announced their 2021 healthcare predictions. One prediction suggested that Next-Generation Sequencing (NGS) testing will emerge as the new standard in diagnostics for a number of cancers. A new study published this week shows that NGS is being used with increasing frequency to diagnose neurodevelopmental disorders, including epilepsy, autism spectrum disorder, and intellectual disability.

A group of genetic researchers recently conducted a systematic review and meta-analysis of the NGS success rate in neurodevelopmental disorder diagnosis. The review, published in Epilepsia, analyzed 103 studies that looked at more than 32,000 individuals. Researchers found that overall diagnostic yield for neurodevelopmental disorder sequencing studies was 23.7%, weighted by the number of cases in each study. The highest diagnostic yield observed was for intellectual disability, followed by epilepsy (24%) and autism spectrum disorder (17.1%). The researchers also analyzed seizure type and diagnostic yield by sequencing technology. While the review had some limitations (for example there were no studies from Africa, Latin America, or India), researchers believe their findings can help to guide policy makers and healthcare providers.

Novel Treatments

Nilotinib not so hot. For years now, researchers have been examining the use of nilotinib, a medication typically used to treat chronic myelogenous leukemia, as a promising treatment for Parkinson’s disease. The drug is thought to help eliminate toxic proteins that build up in the brain in patients with the disease. But a new study has shown that while the drug demonstrates acceptable safety and tolerability in PD, it should not be further tested in PD due to low CSF exposure, lack of biomarker effects, and efficacy data trending negatively.

The study, published in JAMA, aimed to assess the safety of the drug in those with moderately advanced PD and to test its effect on PD disability, pharmacokinetics, CSF penetration, and biomarkers. Over 6 months, the study looked at 76 patients who received a stable regimen of PD medications. Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by a 2-month off-drug evaluation. While the researchers found that both doses of the drug had an acceptable safety profile, they concluded that the resulting low CSF exposure and lack of biomarker effect, combined with the efficacy data trending in the negative direction, indicate that nilotinib may be a dead end for Parkinson’s.

MS drug can be administered quicker. Ocrelizumab, a humanized anti-CD20 monoclonal antibody used to treat those with relapsing or primary progressive multiple sclerosis, is typically administered over 3.5 hours by intravenous infusions. Even when it works, it’s no joy sitting around for hours with a needle stuck in your arm. For your patients who need the treatment, we have good news: The results of a 2017 trial have led to the FDA approving a shorter infusion time that shaves off an hour and a half.

The approval was based on data from the randomized, double-blind phase 3b ENSEMBLE PLUS study, which looked at the frequency and severity of infusion-related reactions of a 2-hour infusion vs the previously approved 3.5-hour infusion time. Participants received the approved initial dosing schedule of two 300-mg infusions 2 weeks apart, followed by subsequent doses of 600 mg infusion over a shorter 2-hour period every 6 months. Reactions were monitored during and 24 hours after the infusion. Researchers found that the frequency of infusion-related reactions was comparable between the 2-hour (24.6%) and 3.5-hour infusion times (23.1%). The majority of these reactions were either mild or moderate, and 98% were resolved without complication. If you have MS patients, this could be a real time-saver.

One step closer for oral AD drug. While Alzheimer’s disease has been the subject of extensive research in the past decades, there haven’t been many major medical breakthroughs in the area. That may be about to change, as Novo Nordisk has announced that it is entering phase 3 of its development of oral semaglutide for treatment of the disease.

The 14-mg oral semaglutide treatment is a once-daily oral formulation of the long-acting GLP-1 analogue semaglutide. The move to enter phase 3 development comes following evaluation of GLP-1 data from preclinical models, real-world evidence studies, post-hoc analyses of data from large cardiovascular outcomes trials, and discussions with regulatory authorities. The phase 3a program will involve roughly 3,700 patients with early AD and is planned for the first half of 2021. It will examine the efficacy and safety of the drug vs placebo over 2 years. With more research, we can only hope that AD will move toward becoming a thing of the past.

Non-invasive nerve stimulation for headaches? Sign me up. Treating migraines remains a tricky problem, but a bioelectronic medicine company has released promising partial results from a study on non-invasive vagus nerve stimulation as a way to alleviate symptoms.

ElectroCore, Inc announced top-line results from its GM-US-10 (PREMIUM II) study, which looked at more than 110 patients over 12 weeks. Despite the early termination of the study in April 2020 due to the COVID-19 pandemic, researchers found various endpoints that showed a statistically significant improvement with nVNS compared to sham stimulation. Patients who were given the company’s gammaCore nVNS had 3.1 fewer migraine days over the final 4 weeks of the double-blind study period, compared to a decrease of 2.3 migraine days in the sham group. Beyond that, roughly 45% of participants using the real treatment had at least a 50% decrease in the number of migraine days, compared to 26.8% for those receiving sham stimulation. The full results of the study are due to be published in early 2021 in a peer-reviewed neurology journal—but the top-line results briefly detailed above are certainly a cause for hope for those afflicted by migraines.

New in Patient Management

Is neuroimaging being used enough? Neuroimaging utilization in patients with headaches in US emergency departments (ED) nearly doubled from 2006-2014. That must be a good thing, right? Well, according to a recently published study, it’s being used more frequently in adults than in children, which could be a cause for concern.

The study, published in Headache, sought to analyze temporal neuroimaging utilization trends for adults and children with nontraumatic headache in US EDs, and to identify factors that may predict neuroimaging use among this population. The retrospective cross-sectional study used the Healthcare Cost and Utilization Project Nationwide Emergency Department Sample database to look at more than 18 million patients with nontraumatic headache symptoms between 2006 and 2014. Researchers found that advanced neuroimaging utilization increased from 18.6% (n=350,777) to 34.8% (n=756,895) among the entire group, and from 18.8% (n=314,646) to 36.5% (n=698,080) in the adult subgroup (+ 94.1%). But in the pediatric subgroup, utilization only increased from 16.9% (n=36,131) to 22.0% (n=58,815). Lower utilization was also found to be associated with weekend ED visits (OR 0.92, 95% CI 0.92–0.93), female sex (OR 0.82, 95% CI 0.81–0.83), and Medicare, Medicaid, or self‐pay (vs private insurance) encounters. Researchers noted that this raises concerns over whether neuroimaging is being preferentially performed.

PD brain stimulation treatment breeds apathy. Apathy and reduced motivation are a common issue for those suffering from Parkinson’s disease—and this is observed particularly often in those undergoing deep brain stimulation of the subthalamic nucleus (STN DBS). Now, a new meta-analysis has uncovered the data to back this up.

The analysis, published in Movement Disorders, trawled PubMed/Medline, SCOPUS, EMBASE, and Web of Sciences electronic databases for relevant articles, eventually selecting 33 studies for inclusion. A total of 1,286 patients, with a disease duration of 11.0 ± 5.8 years, were included in the studies. Researchers found that apathy scores (measured by means of the Apathy Evaluation Scale, Starkstein Apathy Scale, and the Lille Apathy Rating Scale) were significantly higher after DBS than pre‐operatively. Likewise, a significant difference in the severity of apathy was found between those undertaking STN DBS and those using medication only. The results may help inform patients and physicians when it comes to choosing treatment for PD.

Mindfulness for migraines. Every week it feels like a new possible treatment for migraine pain emerges. But a new clinical trial has found one that involves what may be one of your favorite hobbies: Yoga.

The trial looked at the effects of mindfulness-based stress reduction (MBSR), a standardized 8-week program that combines yoga with meditation. Developed in the 1970s, the program sees patients take part in meditation and gentle yoga postures, with the aim of reframing people’s reactions to pain. The trial, which was published in JAMA, looked at 89 patients who were experiencing 4 to 20 migraine days a month. Half were assigned to the MBSR program and half were provided with education on migraines. The entire group continued taking their medication. After 3 months, both groups reported a drop in their number of migraine days. The MBSR group, however, additionally reported lower levels of depression and disability due to migraine pain, and a generally higher quality of life. While more research is required, it does appear that mindfulness can help you manage the pain of migraines more effectively. Namaste!

Breakthrough in post-stroke movement research. The extent to which the brain is damaged and movement is impaired following a stroke varies from patient to patient. Now a team of scientists has found that movement recovery in the aftermath of a stroke depends largely on the integrity of connections between the cerebral cortex and the spinal cord.

The study, published in Stroke, looked at the relationship between movement recovery in the upper limb and the structural and functional state of the motor system. Using transcranial magnetic stimulation and MRI, researchers looked at 35 patients who’d had a stroke more than 6 months prior to the study period. They found that the structural integrity of the corticospinal tract assessed using structural MRI is the best predictor for the upper limb motor recovery. Additionally, the study indicated that using MRI and TMS are equally effective for assessing the condition of the corticospinal tract and can be used interchangeably to assess patients with low levels of recovery. Researchers hope that the results will be used to better understand the processes of recovery after a stroke to craft rehab plans for survivors.

Latest in Journal Summaries

CSF features in COVID-19 patients with neurologic manifestations.

Measuring coping in patients with ALS.

Zuranolone as an oral adjunct to treatment of Parkinsonian tremor.

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Upcoming Medical Meetings

The following meetings are entirely virtual:

Southern Clinical Neurological Society 47th Annual Meeting. January 16-19, 2021.

Mayo Clinic Multiple Sclerosis and Autoimmune Neurology Update 2021 – Livestream. February 5-6, 2021.

The following meeting is scheduled to have an in-person and virtual component:

American Academy of Neurology 73rd Annual Meeting (AAN 2021). San Francisco, CA. April 17-23, 2021.

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