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Time for an Epilepsy Moonshot Initiative? -Precision Medicine at AES

                         AES Poster Demonstrates the Increasing Relevance of a Genetic Diagnosis 

                                to the Treatment of Epileptic Children at a Center of Excellence

by John Otrompke

Genetic analysis led to a change in treatment for almost half of the children with epilepsy who received a consultation at Boston Children’s Hospital for whom a firm etiology was lacking, according to a poster presented on Dec. 5 at the 2021 annual meeting of the American Epilepsy Society in Chicago. Treatment was impacted in 45% of individuals, including 36% with an impact on anti-seizure medication choice.

In light of developing knowledge of the disease and emerging therapies, providers should routinely use genetic testing to evaluate children with epilepsy, according to abstract number 2.319, “Genetic Diagnosis in Pediatric Epilepsy Impacts Medical Management,” which was said to be the first study to report on the impact of a genetic diagnosis on the medical management of pediatric epilepsy in a clinical setting.

Pediatric epilepsy is unexplained in about two-thirds of cases, so a genetic diagnosis is especially important for children. Geneticists have determined that epilepsy is a highly variegated disease, with some studies reporting that up to 78% of patients with epilepsy of unknown cause having significant genetic variants.  

“There are over 500 genetic variants implicated in epilepsy, and they’re all very rare,” said Heather Olson, MD, attending physician at Boston Children’s Hospital, and assistant professor of neurology at Harvard Medical School, senior author on the poster. The poster found that in 10% of the patients, genetic testing had an influence on the discussion of participation in ongoing gene-specific clinical trials. 

In some forms, epilepsy is not only a severe, limiting condition, but can even be fatal. For example, some children with the BRAT-1 variant, which is thought to be related to mitochondrial homeostasis, die a few months after birth due to cardiopulmonary arrest.

Nevertheless, genetic testing remains controversial among insurers, with an ICER of around $15,000 per diagnosis.

                                                            About the Study

In the study, researchers examined course-of-treatment and other outcomes for 602 children with epilepsy who received next-generation genetic sequencing at Boston Children’s Hospital between 2012 and 2019. About one-quarter of the children who were tested received a genetic diagnosis. 

“Patients with childhood epilepsy usually receive genetic testing at our hospital when no other cause has been identified,” explained Isabel Haviland, MD, lead author and postdoctoral research fellow at Boston Children’s.

Of the children who received an epilepsy gene assay with or without exome, 152 received a clinical diagnosis of genetic epilepsy, which had an impact on medical management in 110 or 72% of those patients. Of those 110 patients, the choice of anti-seizure medication was impacted in 36% of patients, while 10% were eligible for gene-specific clinical trials or investigational new drug use. Another 3% of the 110 patients were treated off-label.

Of the 152 patients who received a genetic diagnosis, care coordination was impacted in 48%, and vitamin treatment and/or metabolic treatment such as the ketogenic diet was ordered in 7%.

Additionally, genetic testing led to a change in diagnosis in some children. “For two children who initially had a diagnosis of primary mitochondrial disorder, it was found that their epilepsy was in fact due to a genetic cause,” explained Haviland.

One child was found to have a variant in gene PRRT2 and was switched to a different anti-seizure medication, eventually becoming seizure-free.

                               A Diagnosis of Genetic Epilepsy Frequently Determines Treatment

Due to the variegated nature of genetic epilepsy, genetic diagnoses in the children resulted in differential treatment in the form of vitamin supplements, dietary regimens, off-label treatment with already approved drugs, new or experimental treatment with small molecule drugs, or enrollment in gene therapy clinical trials. 

While outright cures are very rare, even something as simple as supplementing the child’s diet with vitamins may partially correct the problem and treat the epilepsy. “For example, vitamin B6 is important for brain development, but some genetic disorders affect its pathway in the brain,” said Haviland.

Another nutritional intervention sometimes used is the ketogenic diet. “This results in changes in not only ketones, but insulin, glucose, and free fatty acids; all of these metabolic changes may have a role in reducing seizure frequency,” she added, noting that initiating the ketogenic diet in a child requires hospitalization.

Some drugs are already approved for the treatment of genetic epilepsy, such as fenfluramine, which was approved in June of 2020 to treat Dravet syndrome, one of the first established epilepsies.

“We recently published a case report  about an individual who had been having monthly seizures, who had to go into the intensive care unit each time. Having now received an accurate genetic diagnosis of Dravet syndrome, the patient is now three years seizure free,” said Olson.

Then there are the genetic epilepsies for which off-label treatments can be used, such as epilepsy with a variant in GRIN2A, a gene involved in brain cell communication, which has been treated with memantine, a drug approved only for Alzheimer’s disease. There are also small molecule drugs under development for some genetic epilepsies. 

“But generally, the only way to cure genetic epilepsy is with a gene therapy that modifies and corrects the variant in the patient’s gene, such as an antisense oligonucleotide (ASO). An ASO is designed just for one child, but these are very few and far between,” explained Olson. 

HIV-Related Dementia Worsens in Patients with Depression and Peripheral Inflammation

 

by John Otrompke

Dementia which occurs in people with HIV can be distinguished from Alzheimer’s disease and warrants different treatment, according to a poster presented at this year’s annual meeting of the American Neurological Association, which took place virtually.

Markers for inflammation found in HIV patients are associated with cognitive decline, whereas amyloid markers were not, according to poster 368, “Peripheral Inflammation and Depressed Mood Independently Predict Neurocognitive Worsening Over.”

“HIV dementia is different from Alzheimer’s because it is one of the few treatable dementias. When patients go on anti-retroviral therapy and achieve suppression, they also get cognitive improvement,” explained Ronald Ellis, MD, PhD, professor at the University of California-San Diego, lead author on the poster.

The researchers measured cognitive decline over 12 years in 191 patients with HIV. Inflammation biomarkers such as interleukin-6, C-reactive protein, and soluble tumor necrosis factor type II were associated with greater neuro-cognitive decline (p=0.02), as was depressed mood at entry (p=0.0004). On the other hand, biomarkers like amyloid beta 42 and solid amyloid precursor proteins (sometimes thought to be associated with Alzheimer’s disease) were not associated with greater cognitive decline in HIV patients.

There are other differences as well, according to Ellis. “Although classic Alzheimer’s proceeds at a more rapid rate, people with HIV develop cognitive problems earlier.”

And while viral suppression is associated with cognitive improvement, it doesn’t restore cognition to normal, he explained. However, researchers have speculated that treatment intensification could actually reverse the decline, he added.

#ANA

#dementia

Black Patients and Women with HIV Suffered Greater Years of Potential Life Lost, according to Study from ID Week

 by John Otrompke

Between 1998 and 2018, women with HIV had a higher risk of mortality and higher premature mortality than other patients, according to a study presented at this year’s Infectious Disease Week conference, which took place online and in San Diego.

The disparity held true notwithstanding generally improved outcomes that occurred across the four treatment eras of the study, according to presentation 53, “Sex and Race Disparities in Premature Mortality among People with HIV: A 21-Year Observational Cohort Study.”

Women experienced 5.5 more adjusted years of life lost, while black subjects experienced nine months more.

“There are a lot of programs for MSM in the South of the United States, so women may be more affected by HIV,” said lead author Rachael Pellegrino, MD, MPH, a physician at Vanderbilt University Medical Center in Nashville and the study’s lead author.

              The findings of the 6,531-person study were concerning, noted Pellegrino, since women made up 20% of the HIV population

Largest Study Finds Reduced Cardiovascular Mortality & Stroke in Regular Coffee-Drinkers

 by John Otrompke

A study in nearly half a million participants found that coffee drinking is associated with a significantly-reduced risk of cardiovascular mortality and stroke, according to an e-poster presented at this year’s on-line meeting of the European Society of Cardiology.

                Researchers found that cardiovascular mortality was reduced by 17% in those who drank up to three cups of coffee per day compared to non-coffee-drinkers, according to the e-poster, “Light-to-moderate coffee drinking associated with health benefits.” (The p value was 0.006).

                “To our knowledge, this was the largest study to systematically assess the cardiovascular effects of regular coffee consumption in a population without diagnosed heart disease,” said study author Dr. Judit Simon, of the Heart and Vascular Centre at Semmelweis University in Budapest, Hungary.

                Researchers examined data from 468,629 participants in the UK Biobank and found a 12% lower risk of all-cause death (p<0.001), and a 21% lower risk of incident stroke (p=0.037), with a median follow-up of 11 years. The average age of participants was 56.2 years and 55.8% of the participants were women.

“The study excluded those with more severe heart disease like myocardial infarction, stroke, and atrial fibrillation, but those with hypertension and diabetes were included,” noted Simon.

Of the UK Biobank population, 30,650 participants underwent an MRI. “In the first 30,000, we checked the volume and ejection fraction, and found positive alterations in the heart structure. The amount the heart pushes out is a healthy alteration,” explained Simon.

The researchers also conducted a sub-analysis evaluating differences associated with the type of coffee consumption, and found improvements in all three outcomes, that is, cardiovascular mortality, stroke, and all-cause mortality, among those who used ground coffee, she added.

My thanks to the European Society of Cardiology for credentialing me to attend the meeting.

Hello potential employers,

I'm gathering momentum! Now, I have been credentialed for the 2021 annual meeting of the American Neurological Association, happening online from Oct. 17-19.

As you know, there has been much interesting news in the dementia space this year. I have been invited to attend a media roundtable with the chairs of the plenary sessions.

Thank you for your interest. 

~John Otrompke

John_Otrompke@yahoo.com

 Dear readers,

I have been credentialed for the 2021 annual Infectious Disease Week meeting, happening online from Sept. 29 through October 3, 2021.

See my 2012 coverage for The Body Pro here and here.

I hope to post additional material regarding important news from the meeting in the next couple of weeks.

Thank you for your interest. 

~John Otrompke

John_Otrompke@yahoo.com