New Alzheimer’s drug class on the horizon, recent findings could upend long-established guidelines, and an unconventional way to skirt MS symptoms

Between a brand new class of drugs, revelations about ties to pregnancy, updates on off-label drug use, and a slew of new data on disease-modifying therapies, it was a fast-paced week in the world of multiple sclerosis. We’ll keep you abreast of the latest breakthroughs, plus many more from across the world of neurology—like new findings that fly in the face of long-standing guidelines, promise for portable imaging, and how scientists are moving closer to an explanation for Parkinson’s disease.

Neuro Flashback

Ever wonder what future generations might learn from your years of social media use? Hopefully the world gets as much use from your awkward Myspace and Facebook days as we have from the diaries of Augustus d‘Este, the grandson of British King George III. Sir d’Este, who lived from 1794 to 1848, had the first-ever diagnosable case of multiple sclerosis—all thanks to the meticulous diaries he kept while suffering remitting and relapsing disease from 1822 until the end of his life. It started with blurred vision, which cleared without treatment, then recurred a few years later. Then, he began having episodes of double vision, weakness in his legs, numbness, bladder and bowel problems, and impotence. By 1843, he reported persistent tremors and nighttime spasms. He then relied on a wheelchair, and eventually could not leave his bed prior to his death in 1848. While modern scientists agree his was the first diagnosable case, it would be another 20 years before multiple sclerosis was officially identified by the French neuroscientist Jean-Martin Charcot.

In the News

A neurological disease where higher BMI is actually better for you. Previous studies have suggested something pretty unexpected: higher BMI is better for dementia. The data run counter to the long-standing healthcare-wide credo that high BMI is worse for basically everything. For those wondering if the past studies were flukes, a new study published in The Journal of Clinical Endocrinology & Metabolism finds—once again—that obesity strengthens the protective effect of serum urate on risk of dementia.

To arrive at these findings, researchers analyzed a cohort of more than half a million people derived from the UK Biobank, including individuals aged 37 to 73 years for whom BMI and urate were recorded between 2006 and 2010. Dementia diagnosis was obtained at follow-up using electronic health records. At 8 years of follow-up, 2,138 participants developed dementia. People who were underweight had a 91% increased risk of dementia compared to those who had a healthy weight. The risk of dementia continued to fall as weight increased, as people who were overweight or obese were 19% and 22% less likely to develop dementia than people of healthy weight, respectively. Add that to your (probably short) list of high-BMI silver linings.

Unexpected results from first major study of pregnancy and MS. What’s one of the best ways to skirt multiple sclerosis symptoms? Getting pregnant can delay them by more than 3 years, according to new data from the world’s first major study of multiple sclerosis and pregnancy. First, we have to point out that this finding has huge implications, not only for a greater understanding of multiple sclerosis, but for the future use of hormone therapies to delay the onset of symptoms.

And now, here are the details. The study, led by researchers at the Monash University Department of Neuroscience in Australia, was based on dozens of high-impact multiple sclerosis research studies, including more than 70,000 patients with multiple sclerosis across 35 countries. Results indicated that women who had been pregnant were diagnosed with their first multiple sclerosis symptoms an average of 3.3 years later than women who had never been pregnant. A similar delay in disease onset was seen in women who had carried a baby to term (3.4 years). Study authors speculate that pregnancy could reduce the abnormal overactivity of the immune system that leads to multiple sclerosis. “We don’t know exactly how pregnancy slows the development of MS, but we believe that it has to do with alterations made to a woman’s DNA,” researchers said. They’re now seeking funding for future studies to peel back the layers of this exciting mystery.

Good news for patients using disease-modifying therapies for MS. One of the many tough parts about degenerative disease is maintaining independence. In multiple sclerosis, that means maintaining your ability to move about without canes, crutches, or a wheelchair. Now, new evidence suggests that depending on how they’re used, disease-modifying therapies (DMTs) can help patients maintain significantly longer streaks of independence.

In the study, which was presented at the MSVirtual2020 conference and included real-world data on 1,214 patients with primary progressive multiple sclerosis (PPMS), longer exposure to DMTs delayed disability progression as well as the time until patients with PPMS required the use of a wheelchair. Evidence also suggested that starting treatment with DMTs at a younger age (and shortly after disease onset) could improve patients’ long-term clinical outcomes. Results are intriguing, but future studies are needed to determine the long-term safety of DMTs.       

Epilepsy mortality up, despite mortality due to epilepsy going down. If that sounds a bit confusing, allow us to explain. Between 1999 and 2017, mortality rates in the United States related to epilepsy have shot up significantly. At the same time, epilepsy (and ischemic heart diseases) have declined as the cause of death in people with epilepsy. The data, recently published in the British Medical Journal, points to increases in all-neurologic mortality, epilepsy prevalence, vascular dementia, and Alzheimer’s disease as likely contributors.

How did we get here? Researchers conducted a population-based multiple cause-of-death study, retrospectively reviewing the CDC’s online database to examine cause-of-death data in the US from 1999 to 2017. Primary outcome included change in age-adjusted epilepsy mortality rates over time compared with the mortality rates for all-causes, all-neurologic disorders, stroke, and degenerative dementia. According to the CDC data, epilepsy age-adjusted mortality rates increased by 98.8% during the study period, from 5.83 per million to 11.59 per million. In contrast, all-cause mortality decreased by 16.4%. All-neurologic mortality increased by 81% during the same period. The takeaway: “The increased burden and mortality of all-neurological disorders are likely major contributors to the increase in epilepsy mortality rates,” researchers wrote.

Neuro Trivia

What does the phrase “multiple sclerosis” really mean?

The term “sclerosis” refers to the process of scar formation, so another way to say “multiple sclerosis” could be “many locations of scar tissue.” Other names for multiple sclerosis include encephalomyelitis disseminata and demyelinating disease—both allusions to the fact that the scarring seen in multiple sclerosis is caused by myelin destruction.

Novel Diagnostics

Closer to the cause of Parkinson’s. About 6 million people have Parkinson’s worldwide, making it the second most common neurodegenerative disease. You’d think that by now we’d understand what causes this condition, but here’s the hard truth: We don’t. What we do know is that several molecular mechanisms—including neuroinflammation, mitochondrial dysfunction, dysfunctional protein degradation, and alpha-synuclein pathology—have been identified in Parkinson’s pathology. Now, we’re adding a new mechanism to the mix: brain astrocytes.

In a new study published in Scientific Reports, researchers using induced pluripotent stem cell (iPSC) technology have linked astrocyte dysfunction to Parkinson’s disease pathology, highlighting the role of brain astrocyte cells in Parkinson’s pathology and the potential of iPSC-derived cells in disease modeling and drug discovery. Astrocytes are glial cells—the most abundant type in the human brain. In the study, astrocytes from the brains of Parkinson’s patients produced significantly higher levels of alpha-synuclein, which accumulates in the brain. The discovery opens the door to new perspectives of understanding the role of astrocytes in the pathogenesis of Parkinson’s, the researchers wrote.

New ways to lighten the neurological load after cardiac arrest. When cardiac arrest strikes, just about anything can go wrong. But just how bad will the consequences be, especially neurologically? That can be tough to say, but a new scoring system may make post-cardiac arrest neurologic outcomes easier to predict. It’s called the diffusion-weighted image (DWI) scoring system, and new evidence suggests it can be a valuable tool to get the jump on poor neurologic outcomes before they happen.

To arrive at their conclusion, researchers conducted a prospective single-center observational study between March 2018 and April 2020 involving patients with out-of-hospital cardiac arrest (OHCA) after target temperature management. More than half (54%) of patients were allocated to the good neurologic outcome group and 46% to the poor outcomes group. Between 72 and 96 hours after patients returned to spontaneous circulation, the area under the receiver operating characteristic curve (AUROC) of the overall, cortex, deep grey nuclei, and cortex plus deep grey nuclei scores, white matter, brainstem, and cerebellum were 0.96, 0.96, 0.97, 0.96, 0.95, 0.95, and 0.93 respectively. For 100% specificity to predict poor neurologic outcome, the overall scores of the DWI scoring system had a sensitivity of 81.3%.

Early’ is a relative term when it comes to neurological improvement. How quickly would you want your patients to recover neurologically from an endovascular thrombectomy (EVT)? As quickly as possible, right? Well, even though early neurological improvement (ENI) after EVT is associated with favorable outcomes down the line, scientists had never defined what ENI really means and what it should look like. Until now, that is.

In a new study, researchers enrolled 612 patients with EVT from a multicenter registry as a training cohort. They used a receiver operating characteristic curve to estimate the optimal threshold for ENI at 24 hours of EVT. They found that the optimal threshold for predicting 3-month favorable outcome (modified Rankin Scale 0-2) was an improvement of ≥ 6 points on the National Institutes of Health Stroke Scale (NIHSS) score. Age, blood glucose, recanalization, symptomatic intracranial hemorrhage (sICH), and baseline Alberta Stroke Program Early Computed Tomography Score (ASPECTS) were independently associated with ENI. Altogether, an NIHSS score ≥ 6, as well as age, blood glucose, recanalization, sICH and baseline ASPECTS, may predict the probability of ENI in ischemic stroke patients treated with EVT.

Can loss of a single gene fuel deadly childhood brain cancer? According to new data, that’s all it takes when it comes to atypical teratoid rhabdoid tumors (ATRT), a rare, fast-growing form of brain cancer that usually strikes children 3 years of age and younger, but can also occur in older children and adults. The cause of ATRT is primarily linked to activation of a gene called SMARCB1, which is part of a larger complex that helps regulate gene expression and developmental processes.

Previous research has described that, unlike some cancers, ATRT is predominantly associated with the functional loss of this single gene, which leads to tumor development through changes in how genes are expressed, rather than the combined effect of multiple gene mutations. New research shows that there’s an interaction between the loss of SMARCB1 and neural differentiation pressure, which results in both a resistance to final differentiation and a defect in maintaining normal cell health. “With this new information at hand, our plan is to use our ATRT model and look for therapeutic targets that will cause these tumors to fully differentiate and therefore stop growing, which could prove to be an effective future therapy for ATRT,” researchers noted.

Novel Treatments

Sumifilam rides the pipeline. It’s been ages since a new drug for Alzheimer’s disease has come anywhere near receiving an approval from the FDA. But now, a new drug called sumifilam is inching ever closer to the Promised Land. Last week, its manufacturer, Cassava Sciences, announced encouraging data from a phase 2b study, which showed that sumifilam significantly improved an entire panel of validated biomarkers of disease in patients with Alzheimer’s disease. Big deal, right? Well, it gets even bigger when you account for the fact that the ability to improve multiple biomarkers from distinct biological pathways with one drug has never been shown before.

Sumifilam is the first of a new class of drugs that bind to a protein called Filamin A. In the study, Alzheimer’s patients treated with sumifilam 50 mg or 100 mg twice daily for 28 days showed statically significant improvements in biomarkers of disease pathology, neurodegeneration, and neuroinflammation, vs placebo. What’s more, they showed direct improvements in validated tests of episodic memory and spatial working memory vs placebo. In all, 98% of patients responded to the treatment. The takeaway? It’s time for bigger studies to validate the results. But right now, we can remain excited that the new class of drugs led by sumifilam may help slow disease progression.

A cirrhosis drug—for dementia? It could happen, according to results of joint-effort research between the University of Sheffield and the University of York in the UK. The research team used brain cells from fruit flies and rats to model the neurodegeneration process that occurs in patients with frontotemporal dementia (FTD), a type of dementia with earlier onset (often between ages 45 and 65), and which no available treatments have been able to slow down.

The drug in question—ursodeoxycholic acid—is already approved for primary biliary cirrhosis, and it has very low toxicity. In the current study, researchers found that the drug was effective for treating frontotemporal dementia and motor disease, but it did not rectify the underlying deficits, suggesting that the drug is neuroprotective, but not a cure. While the results are promising, how they might play out in human models is anyone’s guess. Study authors are now embarking on further research to discover how the drug protects neurons and whether more targeted drugs to treat FTD could be developed in the process.

To get more from rituximab, use less. Plenty of physicians are using rituximab as an off-label treatment for multiple sclerosis. If you’re one of them, you should use less—not because it’s only indicated for blood cancers, but because lower doses are safer and just as effective in reducing the frequency of relapses and the number of lesions than higher doses, according to new data presented at the MSVirtual2020 conference.

Analyses reported at the conference were based on data from 303 patients with multiple sclerosis, including 249 who received the high-dose regimen and 54 who received the low-dose regimen. Among those receiving the high-dose regimen, the annual relapse rate (ARR) dropped by 87.5% in the first year of treatment and by 83.3% after three years. A similar trend was seen in patients receiving the low-dose regimen, with ARR dropping by 90.3% in the first year, and by 100% after three years. Those numbers might seem super impressive, but the last result wasn’t statistically significant because it only included 7 patients. Still, when it comes to rituximab for multiple sclerosis, we may soon find that less is more.

Doubts about ozanimod? It may be time to let them go. Three-year data from a phase 3 extension trial of the drug’s oral capsules shows that the capsules continue to safely and effectively prevent relapses and disability progression in people with relapsing forms of multiple sclerosis. Why does this additional data matter? It’s this simple: “Gaining insight into long-term therapeutic outcomes can enable clinicians to identify the most appropriate treatment for multiple sclerosis patients,” the trial’s lead investigator said.

The findings, presented at MSVirtual2020, are from the ongoing DAYBREAK extension study, evaluating ozanimod’s long-term safety and effectiveness in 2,494 patients who previously completed an ozanimod clinical trial. Results have shown that patients’ adjusted annual relapse rate (ARR) was very low (0.11 relapses per year) and that most of the patients were relapse-free at two (79%) and three (75%) years. On the other hand, there were no significant changes in the number of both types of brain lesions after 2 years. Long-term ozanimod was generally well tolerated, although more than 80% of participants reported side effects, including common cold, headache, upper respiratory tract infection, and low counts of immune cells.

New in Patient Management

New evidence that contradicts the guidelines. The American Heart Association and American Stroke Association have similar recommendations when it comes to managing intracerebral hemorrhage (ICH): “For ICH patients presenting with SBP (systolic blood pressure) > 220 mm Hg, it may be reasonable to consider aggressive reduction of BP [blood pressure] with a continuous intravenous infusion and frequent BP monitoring.” Here’s the catch, though. That recommendation is only based on class IIb evidence, indicating that efficacy is not as well-established.

Now, a new study published in JAMA Neurology has found evidence that may lead to an updated recommendation. In a post hoc analysis of a randomized clinical trial, researchers found that in patients with ICH and SBP ≥ 220 mm Hg, there were higher rates of neurological deterioration and no evidence of reducing hematoma expansion at 24 hours or death or severe disability at 90 days in those who underwent intensive SBP reduction. Despite what the guidelines say, study authors cautioned against the use of intensive SBP reduction in patients with initial SBP of 220 mm Hg or more.

A step forward for portable imaging. MRI is a cornerstone of diagnosis of neurological disease. But if you want to run one on a patient, get ready to get tangled in a web of strict, access-controlled environments, rigid safety precautions, and highly-trained professional technicians—not to mention the fact that you have to manage the hassle of transporting the patient to the MRI suite. Wouldn’t it be great if we could just run scans bedside?

That’s no longer a fantasy, thanks to new research published in JAMA Neurology. Between October 30, 2019, and May 20, 2020, researchers at Yale New Haven Hospital in Connecticut ran portable MRIs on 50 patients admitted to the neuroscience or COVID-19 intensive care units. These patients presented with ischemic stroke, subarachnoid hemorrhage, traumatic brain injury, brain tumor, and COVID-19 with altered mental status. Neuroimaging findings were detected in 29 of 30 patients who didn’t have COVID-19, and 8 of 20 patients with COVID-19 demonstrated abnormalities. The portable MRIs caused no adverse complications. In all, the new tech shows the promise of portable MRIs not just in the ICU, but across other settings too, like mobile stroke units and in areas with limited resources.  

Factoring costs into the epilepsy equation. You have a patient with temporal-lobe epilepsy. Drugs aren’t working. What do you do now? You could recommend them for surgery. Studies have shown it is effective, but, like all surgeries, it comes with some serious risks. And what about cost? Can your patient even afford it? As it turns out, surgery might be their best option—for their health and their wallets.

A new study in Neurology finds that epilepsy surgery is cost-effective in surgically eligible patients by virtue of being cost-saving ($328,000 vs $423,000) and more effective (16.6 vs 13.6 quality-adjusted life-years [QALY]) than medical management in the long run. Researchers found that surgical evaluation is cost-effective in patients with drug-resistant temporal lobe epilepsy (DR-TLE) even if the probability of being deemed a surgical candidate is only 5%. “From a societal perspective, surgery becomes cost-effective within 3 years, and 89% of simulations favor surgery over the lifetime horizon,” the authors wrote. “Patients with DR-TLE should be referred for surgical evaluation without hesitation on cost-effectiveness grounds.”

Setting our sights on brain cancer. Glioblastoma is a monster. Not only is it the most common brain tumor in adults, it’s the most aggressive because of its resistance to therapy. Treatment starts with surgery and leads to chemotherapy and radiation, but typically ends in tumor regrowth and death. It’s not an ideal situation, but new research published in Nature Communications could move us closer to improved therapies.

The study, led by researchers at McGill University, suggests that suppression of the OSMR gene can significantly improve the effectiveness of radiation therapy—at least in mouse models. The gene fortifies cancer stem cells’ resistance to therapy by strengthening the mitochondria. But by suppressing OSMR, researchers were able to halt energy production to cancer stem cells, essentially starving them to death. In the mouse models, deletion of the OSMR gene resulted in significant improvement of tumor response to therapy, as well as an extended life span. We’re a long way from human trials, but, if successful, this gene suppression tactic could make a world of difference for patients with glioblastoma, potentially increasing the effectiveness of radiation.

Latest in Journal Summaries

Early indicators of primary brain tumors.

Melatonin for acute treatment of migraine in children and adolescents.

Structural and functional thalamic changes in Parkinson’s with mild cognitive impairment.

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Upcoming Medical Meetings

The following meetings will be entirely virtual:

Headache Conference. October 3, 2020.

145th Annual Meeting of the American Neurological Association (ANA 2020). October 4-9, 2020.

North American Spine Society 35th Annual Meeting (NASS 2020). October 5-6, 2020.

 

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