A diet drug for neurological disorders, Sanofi’s drug scandal, and vaccines cause…meningitis?
Groundhog Day. Valentine’s Day. President’s Day. The shortest month of the year is packed with so many causes for celebration—including new, groundbreaking research in the neurosciences. For instance, researchers have discovered that aggressive tumor resection in patients with glioblastoma can significantly improves survival outcomes. In other news, the short-term use of an asthma drug may help decrease the risk of Parkinson disease. And, intriguingly, researchers are taking another look at a previously disgraced diet drug—this time as a treatment for Dravet syndrome. Read on for more exciting neurological findings for the week.
The power of dreams. Nearly 100 years ago, in 1921, Otto Loewi, MD, discovered the chemical transmission of nerve impulses. Remarkably, the basis for Dr. Loewi’s discovery came to him in a dream. According to Dr. Loewi, he awoke immediately following the dream, ran to his lab, and performed a simple experiment on a frog heart. This experiment led to his discovery that the primary language of communication between nerve cells is chemical rather than electrical. He ultimately discovered that acetylcholine was an endogenous neurotransmitter. For his discoveries, Dr. Loewi received the Nobel Prize in Medicine—jointly with lifelong friend and colleague Sir Henry Dale—in 1936. Never give up on your dreams, literally!
In the News
Congratulations are in order. John J. Ngai, PhD, has been named the director of the NIH’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Launched in 2013, the BRAIN Initiative seeks to revolutionize the understanding of the brain and brain disorders. Dr. Ngai will oversee the long-term strategy of the BRAIN Initiative, as well as day-to-day operations. Dr. Ngai spent over 25 years as a faculty member of the University of California at Berkeley. He served as the director of Berkeley’s Neuroscience Graduate Program and Helen Wills Neuroscience Institute. Dr. Ngai was also the previous co-chair of the NIH’s BRAIN Initiative Cell Census Consortium Steering Group. He has received numerous awards, including the McKnight Endowment Fund for Neuroscience, Pew Charitable Trusts, and awards from the Sloan Foundation.
Legal woes. French drug manufacturer Sanofi is being investigated over valproic acid (Depakine in France, Depakene in the US), an antiepileptic drug that was found to cause birth defects and slow neurological development of the fetus when taken during pregnancy. Sodium valproate is the active molecule in Depakine and has been marketed for the treatment of epilepsy and bipolar disorder since 1967. It’s also featured on the WHO’s list of essential medicine and is prescribed in over 100 countries.
Sanofi became aware of the risks of fetal malformation—due to Depakene use during pregnancy—in the 1980s. In 2003, Sanofi became aware of the drug’s effects on fetal neurological development, including the risk of autism and learning difficulties. Between 2006 and 2014, an estimated 425-450 infants suffered congenital birth defects or were stillborn due to Depakene exposure, according to the IGAS, France’s social affairs inspection agency. In 2013, the FDA warned that sodium valproate should not be taken during pregnancy. In 2016, the Paris prosecutor launched a preliminary investigation into the authorization and marketing of Depakene after the IGAS criticized Sanofi and health authorities for their slow response to the risks related to the drug and its derivatives. In a current statement, however, Sanofi said that the indictment will allow the drug manufacturer to defend itself, and “prove it has always complied with its duty to inform and been transparent.” We’re not judging, we’ll leave that to the courts.
Meningeal menace. Meningitis rates among kids and adults have changed very little since the introduction of pneumococcal conjugate vaccines (PCVs)—PCV7 and PCV13—despite their high efficacy in reducing pneumonia and other infections caused by Streptococcus pneumoniae. The reason for the stagnation in improvement may lie with the vaccines themselves. Specifically, PCVs may be linked to the emergence of new strains of pneumococcal bacteria that cause meningitis, according to a new study. Researchers found that the widespread use of vaccines has resulted in the emergence of a broad diversity of replacement non-PCV type strains, which cause meningitis that is at least as severe as the types targeted by PCV7 and PCV13. Because almost all cases of pneumococcal meningitis can lead to permanent neurologic sequelae or death, the researchers have called for new PCVs that target all of the pneumococcal strains that colonize the nose and throat.
Got sick days? Although relatively short, cluster headaches are incredibly painful. About 1 in every 1,000 people in the United States have cluster headaches, and they are more common in men. Now, Swedish researchers have shown that people who suffer from cluster headaches could miss twice as many days of work as people who don’t suffer from these types of headaches.
Via analyzing data from two Swedish National registries, researchers identified 3,240 people aged 16-64 years who had been treated for cluster headaches in a hospital or by a specialist. Matching these individuals to 16,200 reference controls from the total population, they found that the average number of sick days resulting in absence for those with cluster headaches was approximately 16 vs 7 for those without. When adding days taken for disability, those with cluster headaches averaged 63 sick and disability days compared with 34 among those without. And the differences in sick days were also significant between women and men. Specifically, women with cluster headaches took twice as many sick days as men (24 vs 12, respectively). Furthermore, those who had less education also took more sick and disability days. Remember to talk with your patients who suffer from cluster headaches to determine whether it may be affecting their work productivity. Chances are, it is.
What percentage of the brain is made up of fat?
A full 60% of the brain is made up of fat. Therefore, not surprisingly, it is considered the fattiest organ in the body. Because it’s built on fat—but runs on glucose—the brain needs dietary fats to function properly. Good fats—ie, mono- and polyunsaturated fats—can be found in foods like extra virgin olive oil, avocados, coconut oil, nuts, seeds, and oily fish. Including good fats in your diet can also protect against neurodegenerative disorders like Alzheimer disease, as well as heart disease, cancer, and depression. Avocado toast, anyone?
Biomarker brilliance. In kids with CNS demyelinating disorders and encephalitis, a new biomarker may speed both diagnosis and treatment. Researchers found that the myelin oligodendrocyte glycoprotein (MOG) antibody may be associated with this group of CNS conditions, including neuromyelitis optic spectrum disorders and acute disseminated encephalomyelitis. MOG antibodies damage the myelin sheath, which can result in vision loss, muscle weakness, and pain.
In their study, researchers identified 116 children with CNS demyelinating disorders and encephalitis who tested positive for MOG antibodies. Following appropriate treatment, 85% of these patients had complete or almost complete recovery. This research is groundbreaking because this group of CNS disorders can mimic conditions like multiple sclerosis, which can make accurate diagnosis and treatment difficult. Complicating matters is that up to 50% of encephalitis cases have no clear cause. Although recognition of MOG antibody-associated syndromes in kids has increased, the full range of diseases linked to MOG antibodies is still unknown. Based on these recent findings, it may be a good idea to test for MOG antibodies in pediatric patients with suspected encephalitis after excluding infectious causes.
What body type are you? Body type may have particular relevance in patients with spinal muscular atrophy. Here’s how: Researchers studied 88 children aged 1-10 years who had spinal muscular atrophy (SMA) type I or II. All underwent anthropometric measurements and dual-energy X-ray absorptiometry to assess fat mass, lean mass, fat-free mass, fat mass and fat-free mass indices, and motor function assessments. All children had a higher fat mass percentage than referenced values. Researchers also found that motor function was moderately correlated with BMI, fat mass index, and lean-mass index, but weakly correlated with fat-free mass index, lean-mass index, and lean mass:fat mass ratio. They concluded that body composition may be a potential biomarker for spinal muscular atrophy, although further studies are needed.
Immunologic sleuthing. Researchers have discovered that interleukin-17 (IL-17) may be a viable therapeutic target for multiple sclerosis (MS) and other autoimmune diseases, including psoriasis and rheumatoid arthritis. The immunological basis for MS is not clear. However, in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]), researchers from Trinity College Dublin showed that T cells secreting IL-17 damage the myelin sheath. They found that IL-17 may play a role in priming the disease-causing immune response that causes damage to the myelin sheath in EAE and MS. Specifically, IL-17 may mobilize and activate immune cells in the lymph nodes, which then move to the CNS and cause the nerve damage typical of these disease states. Their results also suggest that agents that block IL-17 might not need to cross the blood-brain barrier to be effective in treating MS. In early clinical trials, antibody-based drugs that block IL-17 have shown promise in treating relapsing-remitting MS. Here’s to the hope that you will soon have another option for treatment of MS.
Fen-Phen revisited. Could a disgraced old diet drug find new life as a neurological agent? Maybe. Researchers have just found that fenfluramine may benefit patients with Dravet syndrome—previously known as severe myoclonic epilepsy of infancy. Fenfluramine—an amphetamine derivative—was an anti-obesity drug (Fen-Phen) that was withdrawn from the market in 2001 due to its association with cardiac valve injury and pulmonary hypertension.
In a small, double-blind, placebo-controlled, observational study, researchers randomized 119 patients with Dravet syndrome to receive either fenfluramine (0.2 mg/kg/d or 0.7 mg/kg/d) or placebo. Both doses of fenfluramine effectively reduced the incidence of convulsive seizures and were generally well tolerated, with a median reduction of 74.9% in the 0.7-mg group and 42.3% in the 0.2-mg group, compared with 19.2% in the placebo group. Furthermore, no cardiac abnormalities or pulmonary arterial hypertension occurred during the 14-week trial period. Although the long-term safety and efficacy of fenfluramine need further study, the drug may one day be an important new treatment option for patients with Dravet syndrome.
A disappointing finish. Solanezumab and gantenerumab are two investigational drugs with the potential to slow memory and cognitive decline in those in the early stages of a rare, inherited form of Alzheimer disease (AD) called dominantly inherited AD or autosomal dominant AD. Both drugs were designed to target and neutralize amyloid beta in the brain. According to initial results from a phase 2/3 trial, however, neither drug met the study’s primary endpoint: slowing of cognitive decline as measured by cognitive and memory tests.
Researchers enrolled 194 participants who were followed for up to 7 years. All participants came from families that carry a genetic mutation that causes early-onset Alzheimer dementia. Furthermore, participants demonstrated very mild symptoms of memory loss and cognitive decline at baseline or were expected to develop symptoms of dementia within 15 years of enrolling in the study. Although neither solanezumab nor gantenerumab slowed decline, researchers are now conducting analyses of the participants’ brain scans, serum samples, and CSF samples to better understand how AD develops and how it can be stopped. They are hopeful that their results will help inform future clinical trials in AD. If at first you don’t succeed, try and try again!
Be aggressive. Be-be-aggressive! Great news for your patients with glioblastoma: By removing the surrounding tissue as aggressively as the core of the tumor, you may more than double survival rates. Researchers from the University of California, San Francisco, and colleagues recently uncovered this benefit to removing the “non-contrast enhancing tumor” in a new study. Their results could bring about a paradigm shift for neurosurgeons, for whom total tumor resection was, until now, the goal. Researchers included 761 patients with newly diagnosed glioblastoma. In a subgroup of 62 patients with IDH-mutant tumors or IDH-wild-type tumors who underwent resections, they found that each patient had a median of 100% of contrast-enhancing tumor and 90% of non-contrast-enhancing tumor. Their results were compared with those of 212 patients who underwent more modest resection of the non-contrast enhancing tumor. Survival rates doubled in the aggressive resection group vs the modest resection group. Aggressive resection = longer survival but with a caveat: Safe aggressive resection depends on the use of techniques like intraoperative brain mapping to ensure that functional areas of the brain are preserved during surgery.
New in Patient Management
Brain activity maps drug response? Neural signatures may reveal which patients with depression are more likely to respond to treatment with antidepressants, according to a recent study funded by the National Institute of Mental Health. This finding is important because although antidepressants are widely prescribed, they have modest efficacy compared with placebo. For their study, researchers developed a new machine learning algorithm to analyze EEG data called SELSER (Sparse EEG Latent SpacE Regression). They theorized that the algorithm might identify neural signatures of response to treatment with antidepressants. The researchers used SELSER to assess data from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care (EMBARC) study, in which patients with depression were randomized to either sertraline or placebo for 8 weeks. Specifically, SELSER was applied to pre-treatment EEG data from the participants. In all, SELSER reliably predicted patient response to sertraline based on alpha waves (recorded when participants had their eyes open). Moreover, SELSER’s predictive ability was shown to be superior to conventional models that used either EEG data or individual level data, such as symptom severity and demographics. New test that goes above and beyond diagnostic testing in predicting patient responses? Check!
PTSD and alpha-band synchrony. Combat-exposed veterans with post-traumatic stress disorder (PTSD) have increased alpha-band synchrony during non-REM sleep in the left fronto-, left centro-, and inter-parietal brain regions compared with their peers without PTSD, according to recent study results. These changes in alpha synchrony could help clinicians distinguish PTSD. One of the hallmarks of PTSD is disturbed sleep. Although previous researchers have shown that people with PTSD have different brain activity than those without, the overall evidence of such an association has been mixed.
In this study, researchers studied 2 consecutive nights of EEG recordings from 78 combat-exposed male veterans—31 of whom had PTSD. They analyzed differences in 90 synchrony pairs and found larger synchrony of alpha-band pairs in those with PTSD. This makes sense because alpha synchrony in the front-parietal networks is linked with vigilance. Thus, in people with PTSD, increased alpha synchrony during non-REM sleep may be associated with disturbed sleep due to hypervigilance.
Bronchodilators for what? Previously, researchers reported a link between salbutamol use and decreased risk of Parkinson disease (PD). Salbutamol is a short-acting, selective ß2-adrenergic receptor agonist used in the treatment of asthma and chronic obstructive pulmonary disease. To further investigate this association, researchers of a more recent study analyzed data from 2,430,884 people ≥ aged 50 years from the United Kingdom Clinical Practice Research Datalink. They found that those who had used ß2 agonists at least once had a 17% decreased rate of PD compared with those who never used it. But—importantly—this association was limited to early short-term use, and disappeared after more than 2 years of cumulative duration of use. Thus, the researchers concluded that the association between ß2 agonist use and decreased PD risk may be due to reverse causality rather than any biological effects these drugs could have on the risk of PD.
Spinal vs general. In patients with Parkinson disease (PD), the use of spinal anesthesia for any surgical procedure may cause fewer perioperative complications, according to a recent small study. This runs counter to the general preference of anesthesiologists to use general anesthesia in these patients. General anesthesia, however, may not only mask neurological symptoms intraoperatively and exacerbate them postoperatively, but it may also interact with the drugs specifically used to control PD.
In this retrospective study, researchers identified patients with PD admitted because of a hip fracture. Among the eight patients (mean age: 73.2 years) who underwent hip fracture surgery, six received spinal anesthesia, and four received general anesthesia. In the postoperative period, 75% of patients who received general anesthesia developed a complication compared with no patients who received spinal anesthesia. Mean hospitalization for those who received spinal anesthesia was also shorter compared with hospitalization in those who received general anesthesia (5.8 vs 9 days, respectively). Small study, but…maybe rethink the anesthesia approach in your PD patients?
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Upcoming Medical Meetings
International Stroke Conference 2020, in Los Angeles, CA, February 18-21, 2020
North American Spine Society’s (NASS) Evidence & Technology Spine Summit, in Park City, UT, February 19-22, 2020
5th Annual Americas Committee for Treatment and Research in Multiple Sclerosis Forum (ACTRIMS 2020), in West Palm Beach, FL, February 27-29, 2020
American Society for Experimental Neurotherapeutics (ASENT) 2020 Annual Meeting , in Bethesda, MD, March 2-5, 2020