Why stroke patients need more than just aspirin, why the world needs neurologists, and why MS patients need cannabis extracts
Ever wondered if you’re really making a difference as a neurologist? Well, let go of that uncertainty right now. We’ve got the data to prove that the world desperately needs you—and will likely continue to need you for decades to come. But that’s not all. We’re also bringing you new tricks to help your patients avoid stroke, new biomarkers for the condition, and new data on drugs for migraine, Alzheimer’s, and multiple sclerosis.
Psychedelics have a history that’s almost as strange and awe-inspiring as their characteristic trippy effects. Used in spiritual ceremonies throughout ancient history, these eye-opening drugs became the talk of the psychiatric community in the early 1950s, when researchers learned that they held great promise for treating alcoholism and mood disorders alongside psychotherapy. But that great promise was crushed when, in the mid 1960s, prohibitive laws prevented scientists from studying psychedelics. Since the 1990s, though, renewed interest has been building. Now, laws are becoming more flexible, breaking down the dam that has held psychedelic research at bay for decades. A host of trials are currently underway for drugs like MDMA, LSD, psilocybin, ibogaine, and ayahuasca for the treatment of PTSD, among other conditions.
In the News
Have MS side effects met their match? A phase 3 trial is underway to assess the safety and efficacy of nabiximols in treating spasticity associated with multiple sclerosis. The drug, an oral spray that contains cannabidiol (CBD) and tetrahydrocannabinol (THC), is already available in 25 countries, including Canada and most of Europe. Researchers will test it as an add-on therapy for patients with multiple sclerosis who have moderate-to-severe spasticity (ie, muscle stiffness or spasms) who fail to respond to other anti-spastic treatments.
The placebo-controlled trial is expected to enroll more than 400 adults with multiple sclerosis and spasticity, who will be randomly assigned to either nabiximols or placebo. Both will be self-administered as an oral spray in the morning and evening, up to 12 times daily for 12 weeks. This pivotal phase 3 trial is one of five that manufacturer GW Pharmaceuticals is planning to launch assessing nabiximols’ safety and efficacy in multiple sclerosis spasticity. The other four studies—three focusing on the effects of treatment on muscle tone and one on muscle spasm frequency—are expected to open between the end of this year and the middle of 2021. “Given the rigorous studies already conducted on the medicine outside of the US and positive discussions with the FDA, we believe that we have a clear path … [to filing for approval], potentially as soon as next year,” said GW Pharmaceutical’s CEO.
No better reason to be a neurologist. It can get kind of tiring watching people spread disinformation like wildfire and brazenly snub their nose at CDC guidelines for mask wearing and social distancing. But we’re here to tell you that the world needs physicians—and especially neurologists—now more than ever. How do we know? Because, according to a new study published in JAMA Neurology, a large and increasing number of people in the US have neurological disorders, and they need your help.
Systematic analysis of the Global Burden of Disease study shows that in 2017, the three most burdensome neurological disorders were stroke, Alzheimer’s disease and other dementias, and migraine. In different US states, the burden of individual neurological disorders varied widely, from 1.2-fold to 7.5-fold difference. Overall, the absolute numbers of incident, prevalent, and fatal cases and disability-adjusted life-years of neurological disorders across all US states increased from 1990 to 2017, except for traumatic brain injury incidence; spinal cord injury prevalence; meningitis prevalence, death, and disability-adjusted life-years; and encephalitis disability-adjusted life-years. Neurologists, there’s no doubt: The world needs you!
Psyched for psychedelics. The 2020 elections were a big win for science and medicine. Voters in Arizona, Montana, New Jersey, and South Dakota legalized the possession of marijuana, which bodes well for CBD- and THC-based research and therapeutics in those states. But voters in Oregon and Washington, DC, took a vanguard position when they approved ballot measures to decriminalize all drugs and increase access to psilocybin, the compound that gives magic mushrooms their hallucinogenic effects. A new report from Forbes suggests that California, the nation’s most populous state, could follow suit, as State Sen. Scott Wiener (D-San Francisco) quickly said he plans to introduce legislation that would decriminalize psychedelics after the state Legislature reconvenes next month.
“These drugs have been shown to have medicinal value treating depression, PTSD, and other conditions,” Wiener said in a Twitter post. “We need to stop criminalizing drug use & addiction.” If he’s successful in doing so, California would be the first state to remove laws that criminalize psychedelics as part of the lawmaking process, rather than by ballot initiative. As Wiener said, a large pool of studies have shown that psychedelics, including psilocybin, LSD, peyote, ayahuasca, and MDMA, represent a promising therapeutic area for many neuropsychiatric conditions. Now, in some states, the door is open to proving that once and for all.
Beyond COVID-19’s initial acute illness. A new study out this week is bringing us more of something we’re getting disconcertingly used to: Really bad COVID-19 news. Recent data suggests that about one in every five (20%) people diagnosed with COVID-19 went on to be diagnosed with an episode of mental illness and/or insomnia in the 3 months following—a rate higher than people who were sick but were not diagnosed with COVID-19 during the same period. These survivors also experienced a greater risk of dementia after diagnosis.
Researchers arrived at these findings after pooling data from 69.8 million patients in the US. Of these, more than 62,000 were diagnosed with COVID-19 between January 20 and August 1, 2020, and 44,000 had no previous history of mental illness. They compared the mental health outcomes of these patients to those of patients diagnosed with one of six other medical conditions (influenza/other respiratory infections, broken bone, skin infection, kidney stones, and others). All told, patients with confirmed COVID-19 infection had worse outcomes across just about every marker of mental or neurological health the researchers looked at. Roughly 18% of these people were diagnosed with common psychiatric illnesses from 14 to 90 days following diagnosis, which represented a 25% to 50% higher rate of diagnosis compared to any other group of patients. Because the study is observational, it can’t be used to establish a causal link between COVID-19, mental illness, and insomnia, but it falls in line with a growing pool of evidence suggesting as much.
What are the three most debilitating neurological diseases in the US?
According to a recent review in JAMA (you can find it in our second story under In the News), stroke, Alzheimer’s disease and related dementias, and migraines are the most debilitating as measured by disability-adjusted-life-years.
Epigenetic risk factors for ischemic stroke. We know that hypertension is one of the most important causal risk factors for stroke—the second leading cause of death worldwide. We also know that large-scale genome-wide association studies (GWASs) have successfully identified many loci for blood pressure and ischemic stroke (IS), showing that the two diseases share some of the same loci. But we aren’t as clear about which epigenetic risk factors boost rates of blood pressure and ischemic stroke in loci identified by these GWASs. Researchers set out to fill this knowledge gap by detecting DNA methylation for blood pressure (from 317,756 people in the UK Biobank) and ischemic stroke (521,612 people from MEGASTROKE) in Europeans using the summary data-based Mendelian randomization (SMR) method. Then, they selected the most relevant gene to validate the association in 1,207 patients with hypertensive ischemic stroke and 1,269 controls from Chinese populations.
The researchers first identified 173 CpG sites in 90 genes, 337 CpG sites in 142 genes, and 9 CpG sites in seven genes that were significantly associated with systolic blood pressure, diastolic blood pressure, and ischemic stroke, respectively. The methylation level of cg12760995 in CASZ1 was associated with systolic blood pressure, diastolic blood pressure, and IS (OR=0.92) in Europeans. The methylation levels of 17 sites in the promoter of CASZ1 were measured in the Chinese individuals, and 10 of them were significantly associated with ischemic stroke. The higher methylation level of CASZ1 was associated with a lower risk of IS (adjusted OR = 0.97). CASZ1 seemed to be hypomethylated in hypertensive cases, and the level was negatively correlated with BP. The takeaway: CASZ1 methylations were newly identified to be hypomethylated in Chinese patients with hypertensive IS, increasing our understanding of the role of DNA methylations in the pathogenesis of IS.
ALS etiology—it’s pretty metal. Like so many diseases and disorders in neurology, we just don’t know the cause of amyotrophic lateral sclerosis (ALS). But that doesn’t stop scientists from relentlessly pursuing that cause. In a new study published in Annals of Neurology, they may have come a step closer. Previous research has suggested that levels of blood metals could be a risk factor for the disease, but the quality of the evidence wasn’t great. Now, in a nested ALS case-control study, investigators identified cases of ALS through death certificates and analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Next, they measured levels of arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations and estimated ALS risk with logistic regression models.
Comparing the highest with the lowest tertile, cadmium (OR=2.04) and lead (OR=1.89) concentrations suggested associations with increased ALS risk. Zinc, on the other hand, was associated with decreased risk (OR=0.50), and associations for cadmium and lead remained when limiting analyses to noncurrent smokers. The takeaway? This is the first study to compare metal levels before ALS disease onset, minimizing reverse causation. The associations between metal concentrations and ALS suggest that cadmium, lead, and zinc may play a role in ALS etiology. That gets us one step closer to this mysterious disease’s cause.
Earlier Alzheimer’s detection. Earlier biomarkers are better biomarkers, especially when it comes to Alzheimer’s disease, the most burdensome neurological disease in the US. An earlier biomarker may be exactly what Swedish researchers have found in a recent study published in JAMA Neurology. They set out to identify how early in the course of Alzheimer’s disease plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established biomarkers like CSF and positron emission tomography (PET) findings.
The answer? In the cohort study of 490 people with dementia, plasma P-tau217 levels were elevated in amyloid-ß-positive cognitively unimpaired participants before insoluble tau aggregates became detectable by tau-PET. On top of that, modeling approaches predicted that both plasma and CSF P-tau217 increased before tau-PET in the entorhinal cortex followed by more widespread cortical tau-PET changes. All in all, it looks like we can call plasma P-tau217 an early Alzheimer’s biomarker.
The subthalamic nucleus and Parkinson’s disease. A multi-institutional research team (isn’t collaboration great?) has demonstrated an important new fact about our subthalamic nucleus (STN): Hyper-activation and weakened functional connectivity in this important part of our basal ganglia system are both neural markers of sequential memory deficits in de novo Parkinson’s disease. To investigate the neural markers of sequential working memory in Parkinson’s early stages, researchers recruited 50 patients with de novo Parkinson’s and 50 healthy controls in a new study. All participants completed a digit-ordering task in an MRI scanner while their brain activity was recorded.
When the researchers analyzed regional brain activations and inter-regional functional connectivity in the neural network for sequential working memory, they found that poor performance correlated with hyper-activation of the STN and weakened functional connectivity between the STN and striatum. Healthy patients who showed lowered STN activation and more robust STN-striatum connectivity performed more accurately in maintaining sequences. But in patients with de novo Parkinson’s, the STN’s modulatory role was remarkably weakened. But what does all of this mean? The study demonstrates the STN’s modulatory role in sequential working memory and links sequential working memory deficits in de novo Parkinson’s with the STN’s altered functions. That implies that downregulation of the STN activation and upregulation of its functional connectivity could be a potential strategy for enhancing Parkinson’s patients sequential working memory.
For stroke, is aspirin enough? An aspirin a day may help keep strokes at bay, but what if there was a better option? According to a new randomized clinical trial published in JAMA Neurology, there is—aspirin plus ticagrelor. Researchers conducted the trial between January 2018 and December 2019, with a 30-day follow-up, at 414 hospitals in 28 countries, and included 11,016 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk transient ischemic stroke, including 10,803 with modified Rankin Scale (mRS) score recorded at 30 days.
Ischemic stroke was a qualifying event in 2,670 participants with 30-day mRS > 1. Among 11,016 patients, a primary endpoint with mRS > 1 at 30 days occurred in 4% of patients randomized to ticagrelor and 4.7% randomized to placebo. A primary endpoint with mRS 0 or 1 at 30 days occurred in 1.3% and 1.6%. What’s more, the shift analysis of the distribution of mRS following subsequent ischemic stroke showed a significant 23% reduction of the total disability burden. In the end, ticagrelor added to aspirin was superior to aspirin alone in preventing disabling stroke or death at 30 days, effectively reducing the total burden of disability owing to ischemic stroke recurrence, and opening up a new treatment option for neurologists.
Tackling neuropsychiatric symptoms non-pharmacologically. We need drugs to treat neurological disease—badly. But they haven’t been coming as quickly as many have hoped, especially for conditions like dementia. But drugs aren’t the end-all-be-all of medicine—non-pharmacological therapies often work well, too. But just how well do they work for neuropsychiatric conditions? That’s what scientists from the University of Hong Kong set out to discover in a new systematic review and network meta-analysis published in Geriatric Psychiatry.
The researchers conducted a comprehensive search of 10 electronic databases, finding a total of 21 studies involving 1,773 participants with seven studies focused on preclinical dementia and 14 studies focused on mild dementia. Pairwise analysis and network meta-analysis indicated that multimodal interventions were superior to psycho-behavioral educative interventions, cognitive training, and art-based interventions for improving depression. The more crucial design characteristics included those that emphasized skill transferral to daily life, psycho-behavioral content to encourage a positive outlook and self-identify, and disease-specific educational content to improve symptom management. All in all, reviewers found that multimodal interventions with cognitive, psycho-behavioral, and educative components were the most effective for improving depression in patients with preclinical and mild dementia.
Escitalopram and CSF Aß42. Scientists have seen that serotonin signaling suppresses CSF Aß42—the key target group for Alzheimer’s prevention— in animal models of Alzheimer’s disease and in young, healthy human studies. With that in mind, a group of researchers from the University of Pennsylvania wondered if escitalopram, an antidepressant selective serotonin reuptake inhibitor (SSRI), could do the same. In a controlled trial, they used lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, where cognitively normal older adults were assigned to placebo, 20 mg escitalopram for 2 weeks or 8 weeks, or 30 mg escitalopram for 8 weeks.
They found an overall 9.4% greater reduction in CSF Aß42 in escitalopram-treated groups compared with placebo. Positive baseline Aß status was associated with smaller Aß42 reduction compared with negative baseline amyloid status. In sum, the study authors found Class II evidence that short-term longitudinal doses of escitalopram decrease CSF Aß42 in cognitively normal older adults.
New eptinezumab data. The FDA approved eptinezumab—the first intravenous treatment for migraine prevention—back in February based on positive data from two phase 3 clinical trials. Now, more positive data is rolling in, thanks to a new follow-up study published in Headache, in which researchers tested the percentage of patients with a migraine on day 1 after dosing that was specified in the previously published PROMISE-1 and PROMISE-2 trials.
Researchers found that for both studies, all tests for the significance of eptinezumab 100 and 300 mg, from days 1-84 through day 1 alone, achieved nominal significance, indicating that the drug was fully effective beginning on day 1. Over each interval, the treatment effect was comparable to the effect over weeks 1-12. In PROMISE-1, mean changes from baseline in monthly migraine days for the primary endpoint ranged from –3.9 to –4.9, –4.1 to –4.9, and –2.2 to –3.2 for eptinezumab 100 mg, 300 mg, and placebo, respectively. Results were even better in PROMISE-2: –7.2 to –8.0, –7.9 to –8.2, and –4.3 to –5.6, respectively. The bottom line here is that we now have more data to solidify eptinezumab as a neurological treatment—it has a rapid and sustained preventive effect in patients with chronic migraine, with onset of optimal preventive efficacy observed in the day following the initial dose.
New in Patient Management
Additional risk factors for stroke. We all know managing risk factors is crucial for stroke prevention. But the truth is we just don’t know all the risk factors out there. Fortunately, a new study published in the Journal of the American Heart Association is helping buttress our current knowledge with more robust data and uncover new risk factors we can use to help patients decrease their likelihood of suffering from stroke.
From 2014 to 2016, researchers conducted a prospective study from the China National Stroke and Intervention Program comprising 427,318 adults aged ≥ 40 years without stroke at baseline. They found 2,429 cases of first-ever stroke during a median follow up of 2.1 years, which included 2,206 ischemic strokes and 237 hemorrhagic strokes. A Cox regression analysis indicated that age (50 to 59 years vs 40 to 49 years), primary school or no formal education (vs middle school) having > 1 child (vs 1 child), place of living, physical inactivity, hypertension, diabetes, and obesity were all positively associated with the risk of total and ischemic stroke. Surprisingly, being between the ages of 60 and 69 years and living with a spouse or children (vs living alone) were both negatively associated with the risk of total and ischemic stroke. For hemorrhagic stroke, positive associations were seen with a vegetable-based diet, being underweight, being physically inactive, having hypertension, and living in a high-income region. In all, it appears that there’s much more to stroke risk than we knew—and there’s still much more to learn.
Foods for optimal cognitive performance. Medicine isn’t for the faint of heart, or for the dull of mind. That’s why eating with optimal cognitive performance in mind is key for the enterprising physician. But what are the best foods to boost your brainpower, and what measurements should we use to ensure we’re getting the most meaningful benefits from our food? A new report published on our blog, Physician Sense, outlines the best food sources for your brain, based on their ability to improve attention, memory, and problem solving abilities.
When it comes to improving attention, there’s nothing quite like caffeine, which studies have shown can boost attentiveness for simple and complex tasks, and affect the executive control and alerting networks of the brain. Blueberries, for their part, appear to work wonders for memory. Studies have shown that their antioxidant power, derived from polyphenolic compounds in the fruit, has been linked to heightened neural signaling in the parts of the brain associated with memory. They also enhance glucose disposal, which could stave off neurodegeneration. Finally, dietary omega-3 fatty acids contribute to synaptic plasticity and cognition, which can improve problem-solving capabilities—you can load up on these beneficial compounds in cold-water fatty fish like salmon, anchovies, and tuna. How’s that for a little food for thought?
Memory-boosting tricks and treats. How many times have you put down your car keys and instantly forgot where they went? Everyone has a lapse in memory now and then. The good news is that you can do something about it. Your brain’s “memory banks” aren’t restricted by size or function—you can expand and improve your recall. But how?
Want to remember something? Say it out loud. A study published in Memory found that people remember information better when they hear themselves say it. Need to keep quiet? Replay the event in your mind or write it down. Another study found that people build more lasting memories when they replay scenes they just witnessed or transfer them from their imaginary forms into the physical world. Another important point: Focus on the task at hand. A study in Proceedings of the National Academy of Sciences found that people who multitask on smartphones, TV, and laptops perform way worse on simple cognitive memory tasks. Additional tips include staying mindful, taking a hike or a walk, retracing a routine, and—our personal favorite—taking a nap.
Pinning down the prevalence of perinatal stroke. How often is perinatal stroke occurring? Estimates from 2009 cite the incidence at 1 in 1,600 to 5,000 births. But even though it seems like 2009 was just a few short winks ago, 11 (almost 12) years can make quite the difference. Now, a new study published in Pediatrics brings us up to pace with some alarming news: The estimated birth prevalence of term perinatal stroke is higher than previous estimates, at 1:1,100.
To arrive at this ratio, researchers tapped into the Alberta Perinatal Stroke Project, a research cohort established in 2008, with prospective (2008-2017) and retrospective (1990-2008) enrollment leveraging universal health care at a single tertiary care pediatric center. They found that the overall estimated birth prevalence of term-born perinatal stroke was 1:1,100, while it was 1:3,000 for neonatal arterial ischemic stroke (NAIS), 1:7,900 for arterial presumed perinatal ischemic stroke, 1:6,000 for perivenular venous infarction, 1:9,100 for cerebral sinovenous thrombosis, 1:6,800 for neonatal hemorrhagic stroke (NHS), and 1:65,000 for presumed perinatal hemorrhagic stroke. Overall, the apparent birth prevalence of NAIS and NHS increased over time and more males were affected than females were. “This emphasizes the need for further studies to better understand the disease-specific pathophysiology to improve treatment and prevention strategies,” the authors wrote.
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