Impact of seizures while driving prior to diagnosis in people with focal epilepsy

Bases B, Barnard S, French JA, Pellinen J; Human Epilepsy Project. Impact of Seizures While Driving Prior to Diagnosis in People With Focal Epilepsy: Motor Vehicle Accidents and Time to Diagnosis. Neurology. 2023 Sep 26;101(13):e1370-e1375. doi: 10.1212/WNL.0000000000207464. Epub 2023 Jun 7. PMID: 37286361; PMCID: PMC10558166.

Abstract

Objectives: To identify the type, frequency, and consequences of seizures while driving (SzWD) in people with epilepsy before diagnosis.

Methods: We performed a retrospective cohort study using the Human Epilepsy Project (HEP) to identify prediagnostic SzWD. Clinical descriptions from seizure diaries and medical records were used to classify seizure types and frequencies, time to diagnosis, and SzWD outcomes. Data were modeled using multiple logistic regression to assess for factors independently associated with SzWD.

Results: 32 prediagnostic SzWD were reported among 23/447 (5.1%) participants. Of them, 7 (30.4%) had more than 1. Six participants (26.1%) experienced SzWD as their first lifetime seizure. Most SzWD were focal with impaired awareness (n = 27, 84.4%). Of participants who had motor vehicle accidents (MVAs), 6 (42.9%) had no recollection. SzWD led to hospitalization in 11 people. The median time from first seizure to first SzWD was 304 days (IQR = 0-4,056 days). The median time between first SzWD and diagnosis was 64 days (IQR = 10-176.5 days). Employment was associated with a 3.95-fold increased risk of SzWD (95% CI 1.2-13.2, p = 0.03), and nonmotor seizures were associated with a 4.79-fold increased risk (95% CI 1.3-17.6, p = 0.02).

Discussion: This study identifies the consequences of seizure-related MVAs and hospitalizations people experience before epilepsy diagnosis. This highlights the need for further research aimed at improving seizure awareness and improving time to diagnosis.

Continuous immunotherapy may help patients with new onset refractory status epilepticus

New research shows that immunotherapy given up to 18 weeks after onset may help some patients who suddenly develop refractory continuous seizures, according to an abstract presented at the AAN Annual Meeting, held in Denver in April.

The researchers reviewed data on 135 patients with new onset refractory status epilepticus (NORSE) over nine years, 74 of whom had cryptogenic new onset refractory status epilepticus (C-NORSE). All patients received first-line immunotherapy, such as steroids, with 83.8 percent returning to “mental functionality" within a median duration of 30 days.

Seventy patients were followed up for one year, and 62 patients for two years. A year after the first treatment, 26 of the 70 patients (37.1 percent) achieved favorable outcomes (mRS 0, 1, and 2), increasing to 31 of the 62 patients (50 percent) after two years.

Some patients did not improve; an unfavorable prognosis was associated with hippocampal atrophy plus extra-limbic lesions observed on a three-month MRI (OR1.295, 95 percent CI 1.086 to 1.544, p=006) and prolonged unconsciousness longer than 60 days. Of the 60 patients who underwent sequential brain MRI imaging, 20 (33.3 percent) exhibited both the extra-medial temporal lobe (MTL) lesion and MTL atrophy, said Yoonhyuk Jang, MD, PhD, a neurologist at Seoul National University Hospital.

Study authors said they were drawn to the research topic because patients with C-NORSE often do not respond to treatment, and researchers were uncertain why some patients responded well to longer immunotherapy treatment and some developed hippocampal atrophy.

Investigators defined "continuous immunotherapy" as an intravenous infusion of steroid and immune globulin for five days, which counted as one session, followed by rituximab or tocilizumab for three months, six months, or a year. To account for the washout period of immunotherapy, Dr. Jang said, patients were considered to have received continuous immunotherapy if the time gap between one session of any immunotherapy and the next session was less than 90 days.

“The only thing we found was that cytokines such as IL-6, CXCL9, MIP-1alpha—those involving innate immunity—had some significant differences among the groups that had hippocampal atrophy or extra limbic lesions," said Dr. Jang.

Dr. Rani Sarkis, MD, MSc, an assistant professor of neurology at Brigham and Women's Hospital, who was not involved in the study, said that because C-NORSE is an uncommon disease, determining the best treatment has been challenging.

“The strength of this study is its prospective data, because you're trying to get outcomes at different time points and determine the longitudinal imaging changes, so those are definitely strengths," he said. “They're not commonly done for a disorder like this; you're usually doing retrospective analyses and struggling to find enough patients."

There was not a lot of information about the timing and the nature of immunotherapy, particularly how to optimize treatment to avoid the risks such as infection, Dr. Sarkis said, adding that he expected that to be provided in a separate abstract.

But Dr. Sarkis said it was helpful to have information doctors could use to counsel patients, like the three-month MRI features associated with an unfavorable prognosis.

​Michael Sperling, MD, FAAN, professor of neurology at Thomas Jefferson University and director of the Jefferson Comprehensive Epilepsy Center, said the findings were consistent with past studies, and that the research needed to clearly define “continuous immunotherapy."

“Usually, after IV therapy in the acute phase, therapy that alters the immune system is prescribed over a period of time. These agents are usually given in pulse fashion if intravenous, though some oral agents might be taken on a daily basis (but the IV drugs are usually preferred when therapy is started, though there are no good, randomized trials that have compared any two therapies)," Dr. Sperling said. He added that even the pulse IV therapies have long-lasting effect —for example, rituximab is given in two doses separated by two weeks, and it then lasts for up to six months.

​“The problem with the immune therapies is that no trials have been conducted to see if they really work in NORSE, or if the improvement is coincidental. We all would like to believe that they improve outcome, but the medical profession has a history of employing ineffective therapies because these treatments made sense, until they didn't."

https://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersAANAnnualMeeting/pages/post.aspx?PostID=200&utm_source=email_marketing&utm_medium=email&utm_campaign=health_hlrp_2024-AdSales-Daily%20Meeting%20eNewsletter-AAN-Neurology-Today-At-The-Meeting-AAN%20Annual%20Meeting-April%2025.01-SEND-ASID1809+SeedList&rid=V_0000000032999587&mkt_tok=NjgxLUZIRS00MjkAAAGStS68RkD6P1U9NGxeXG_x6XfYCX2J4mDuN_dN-cqPrm2dEJjUiFnhUom-qUpuAYcMcFwAVaN24arWdOYfqVSoyGklGMHkU0OzFyMcWVU5xtugrewlURY

Auto-brewery syndrome

A Belgian man has been acquitted of drunk-driving because he has auto-brewery syndrome (ABS), an extremely rare condition whereby the body produces alcohol, his lawyer has said.

Anse Ghesquiere said on Monday that in “another unfortunate coincidence” her client worked at a brewery, but three doctors who independently examined him had confirmed he had ABS.

Belgian media said in the verdict the judge emphasised that the defendant, who was not named in line with local judicial custom, did not experience symptoms of intoxication.

The Bruges police court, which acquitted the man, did not immediately reply to an email requesting comment.

Lisa Florin, a clinical biologist with the Belgian hospital AZ Sint-Lucas, said people with ABS produced the same type of alcohol as found in alcoholic drinks but that they generally felt less of its effects.

People are not born with ABS but can develop it when they already have another intestine-related condition. Patients can present with symptoms consistent with alcohol intoxication such as slurred speech, stumbling, loss of motor functions, dizziness and belching.

https://www.theguardian.com/world/2024/apr/22/belgian-man-whose-body-makes-its-own-alcohol-cleared-of-drunk-driving

See: https://childnervoussystem.blogspot.com/2016/01/pediatric-auto-brewery-syndrome.html

Genes play a very small role in determining left-handedness

I am left-handed

NPR's Ayesha Rascoe speaks with Clyde Francks, a geneticist in the Netherlands, about the latest research into what makes people left or right-handed.

AYESHA RASCOE, HOST:

If you're left-handed, like me, you know you are one of a rare and special breed. Just 10% of the world's population is estimated to be left-handed, but many common conceptions about left-handedness turn out to be wrong, starting with that it's definitely hereditary.

CLYDE FRANCKS: We actually think that most of the left-handedness in the population is not caused by genetic variants.

RASCOE: Clyde Francks is a geneticist and neuroscientist at the Max Planck Institute for Psycholinguistics in the Netherlands. He led a team that just published a paper about left-handedness in the journal Nature Communications.

FRANCKS: It's probably just kind of random fluctuations of chemicals in the very early developing brain in the embryo.

RASCOE: That surprised me. My mother's right-handed, but all of her children are left-handed. We thought being left-handed must have something to do with the genes we inherited. And it's even stranger because we don't all have the same father.

FRANCKS: The heritability of left-handedness is actually quite low. So in studies of twins, it's been measured at about only 25%. So in most people who are left-handed, there will not be a simple genetic explanation just running through the generations in a clear way.

RASCOE: But in the new research, Francks and his team did discover one gene that sometimes has an effect on which hand is dominant.

FRANCKS: What we knew before this study was that there were various common variants in the genome that had very, very tiny effects on the probability of being left-handed. And so what we did in the latest study was a quite different approach. We were looking for variants in the genome that are very rare in the population and are located in the specific parts of the genome that code directly for the proteins that our bodies are made of. And those kinds of genetic variants can actually have quite large effects on human traits when they're present in a small number of people.

RASCOE: The gene they analyzed is called TUBB4B. If someone has a particular variant of this gene, Francks says that person is very likely to be left-handed. But very few people, even very few left-handed people, have this variant.

FRANCKS: They're very rare in the population, so they would only be accounting for about 1 in 1,000 left-handers at most.

RASCOE: It's still very much a mystery why the vast majority of left-handed people are that way. His idea about random fluctuations of chemicals in the embryo is also unproven. But what about this question?

I've also heard that left-handed people are more creative because the left side of the body's controlled by the right side of the brain, and that's the creative side. Is that true?

FRANCKS: Yeah. I mean, I don't think that's true. No.

RASCOE: (Laughter).

FRANCKS: I know that this is - it's a popular thing. That's too simple. The differences between the hemispheres of the brain are much more subtle and complex than that, and each side is doing important things in any particular task that you're doing.

RASCOE: OK, so - but we are very special if we're left-handed. Science has confirmed that, right?

(LAUGHTER)

FRANCKS: Well, 10%, you know? You decide how special that is.

RASCOE: Oh, well, thank you. I appreciate that. I'll take that. Thank you so much. Clyde Francks, a geneticist at the Max Planck Institute for Psycholinguistics in the Netherlands. Thank you so much for joining us.

FRANCKS: Thank you.

https://www.npr.org/2024/04/21/1246163875/genes-play-a-very-small-role-in-determining-left-handedness-research-finds

Schijven D, Soheili-Nezhad S, Fisher SE, Francks C. Exome-wide analysis implicates rare protein-altering variants in human handedness. Nat Commun. 2024 Apr 2;15(1):2632. doi: 10.1038/s41467-024-46277-w. PMID: 38565598; PMCID: PMC10987538.

Abstract

Handedness is a manifestation of brain hemispheric specialization. Left-handedness occurs at increased rates in neurodevelopmental disorders. Genome-wide association studies have identified common genetic effects on handedness or brain asymmetry, which mostly involve variants outside protein-coding regions and may affect gene expression. Implicated genes include several that encode tubulins (microtubule components) or microtubule-associated proteins. Here we examine whether left-handedness is also influenced by rare coding variants (frequencies ≤ 1%), using exome data from 38,043 left-handed and 313,271 right-handed individuals from the UK Biobank. The beta-tubulin gene TUBB4B shows exome-wide significant association, with a rate of rare coding variants 2.7 times higher in left-handers than right-handers. The TUBB4B variants are mostly heterozygous missense changes, but include two frameshifts found only in left-handers. Other TUBB4B variants have been linked to sensorineural and/or ciliopathic disorders, but not the variants found here. Among genes previously implicated in autism or schizophrenia by exome screening, DSCAM and FOXP1 show evidence for rare coding variant association with left-handedness. The exome-wide heritability of left-handedness due to rare coding variants was 0.91%. This study reveals a role for rare, protein-altering variants in left-handedness, providing further evidence for the involvement of microtubules and disorder-relevant genes.

SPATA5L1(AFG2B) mutations

Inspired by a patient

Richard EM, Bakhtiari S, Marsh APL, Kaiyrzhanov R, Wagner M, Shetty S, Pagnozzi A, Nordlie SM, Guida BS, Cornejo P, Magee H, Liu J, Norton BY, Webster RI, Worgan L, Hakonarson H, Li J, Guo Y, Jain M, Blesson A, Rodan LH, Abbott MA, Comi A, Cohen JS, Alhaddad B, Meitinger T, Lenz D, Ziegler A, Kotzaeridou U, Brunet T, Chassevent A, Smith-Hicks C, Ekstein J, Weiden T, Hahn A, Zharkinbekova N, Turnpenny P, Tucci A, Yelton M, Horvath R, Gungor S, Hiz S, Oktay Y, Lochmuller H, Zollino M, Morleo M, Marangi G, Nigro V, Torella A, Pinelli M, Amenta S, Husain RA, Grossmann B, Rapp M, Steen C, Marquardt I, Grimmel M, Grasshoff U, Korenke GC, Owczarek-Lipska M, Neidhardt J, Radio FC, Mancini C, Claps Sepulveda DJ, McWalter K, Begtrup A, Crunk A, Guillen Sacoto MJ, Person R, Schnur RE, Mancardi MM, Kreuder F, Striano P, Zara F, Chung WK, Marks WA, van Eyk CL, Webber DL, Corbett MA, Harper K, Berry JG, MacLennan AH, Gecz J, Tartaglia M, Salpietro V, Christodoulou J, Kaslin J, Padilla-Lopez S, Bilguvar K, Munchau A, Ahmed ZM, Hufnagel RB, Fahey MC, Maroofian R, Houlden H, Sticht H, Mane SM, Rad A, Vona B, Jin SC, Haack TB, Makowski C, Hirsch Y, Riazuddin S, Kruer MC. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss. Am J Hum Genet. 2021 Oct 7;108(10):2006-2016. doi: 10.1016/j.ajhg.2021.08.003. PMID: 34626583; PMCID: PMC8546233.

Abstract

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Grosch S, Kehrer M, Riess O, Bevot A, Haack TB. A further case of AFG2B-related neurodevelopmental disorder with hearing loss and microcephaly allows further clarification of pathogenicity of the variant c.1313T>C, p.(Leu438Pro). Mol Genet Genomic Med. 2024 Jan;12(1):e2310. doi: 10.1002/mgg3.2310. Epub 2023 Oct 30. PMID: 37902276; PMCID: PMC10767672.

Abstract

Background: Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss. We report on a 6 1/2-year-old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly.

Methods: We performed trio exome sequencing on the patient and her parents.

Results: Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B [c.527G>T, p.(Gly176Val) and c.1313T>C, p.(Leu438Pro)] in the patient.

Conclusion: Of note, the change c.1313T>C, p.(Leu438Pro) has been observed in a previously published patient as part of a complex disease allele along with a second homozygous missense change, so the exact contribution of the two alterations to this patient's disease had initially remained unclear. Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient.

Keywords: AFG2B; neurodevelopmental disorder; trio exome sequencing.

Corpus callosotomy in pediatric drug-resistant epilepsy

Fine A. Any Way You Slice It: Corpus Callosotomy in Pediatric Drug-Resistant Epilepsy. Epilepsy Currents. 2024;0(0). doi:10.1177/15357597241242243

Abstract

Objectives:
Corpus callosotomy (CC) is used to reduce seizures, primarily in patients with generalized drug-resistant epilepsy (DRE). The invasive nature of the procedure contributes to underutilization despite its potential superiority to other palliative procedures. The goal of this study was to use a multi-institutional epilepsy surgery database to characterize the use of CC across participating centers.

Methods:
Data were acquired from the Pediatric Epilepsy Research Consortium (PERC) Surgery Database, a prospective observational study collecting data on children 0-18 years referred for surgical evaluation of DRE across 22 U.S. pediatric epilepsy centers. Patient, epilepsy, and surgical characteristics were collected across multiple CC modalities. Outcomes and complications were recorded and analyzed statistically.

Results:
Eighty-three patients undergoing 85 CC procedures at 14 participating epilepsy centers met inclusion criteria. Mean age at seizure onset was 2.3 years (0-9.4); mean age for Phase I evaluation and surgical intervention were 9.45 (.1-20) and 10.46 (.2-20.6) years, respectively. Generalized seizure types were the most common (59%). Complete CC was performed in 88%. The majority of CC procedures (57%) were via open craniotomy, followed by laser interstitial thermal therapy (LiTT) (20%) and mini-craniotomy/endoscopic (mc/e) (22%). Mean operative times were significantly longer for LiTT, whereas mean estimated blood loss was greater in open cases. Complications occurred in 11 cases (13%) and differed significantly between surgical techniques (p < .001). There was no statistically significant difference in length of postoperative stay across approaches. Mean follow-up was 12.8 months (range 1-39). Favorable Engel outcomes were experienced by 37 (78.7%) of the patients who underwent craniotomy, 10 (58.8%) with LiTT, and 12 (63.2%) with mc/e; these differences were not statistically significant.

Significance:
CC is an effective surgical modality for children with DRE. Regardless of surgical modality, complication rates are acceptable and seizure outcomes generally favorable. Newer, less-invasive, surgical approaches may lead to increased adoption of this efficacious therapeutic option for pediatric DRE.

Possible pulmonary benefit With Viltolarsen for Duchenne Muscular Dystrophy

Viltolarsen (Viltepso) was well tolerated by boys and men with Duchenne muscular dystrophy (DMD), with no new safety signals, according to results from the open-label, phase II Galactic53 trial.

The results also suggested a clinical benefit in pulmonary function with the exon-skipping therapy, as measured by percent predicted forced vital capacity (FVC%p) and peak cough flow (PCF), Michelle Previtera, PhD, associate director for medical affairs at NS Pharma, and colleagues reported during a late-breaking poster session at the American Academy of Neurology annual meeting.

Among ambulatory participants on viltolarsen, 90% showed an increase or stabilization in FVC%p from baseline, with a significant overall change at week 49 (least squares mean change 8.3%, P=0.02). Among nonambulatory patients, FVC%p increased for participants receiving viltolarsen, and decreased for the control group (least squares mean change 1.6% vs -3.2%, respectively).

"This is the first data on pulmonary function, so this was really encouraging to see in both the ambulatory and the nonambulatory population, because we haven't studied [it] in the nonambulatory population," Previtera told MedPage Today.

"Combined with previous motor function data, these results suggest an additional treatment benefit of viltolarsen for patients with DMD amenable to exon 53-skipping therapy," Previtera and colleagues reported in the poster.

Duchenne muscular dystrophy is incurable, occurring mostly in boys and caused by mutations in the dystrophin gene, leading to a loss of functional dystrophin and muscle damage. As patients lose muscle strength, pulmonary function is impacted, eventually resulting in assisted ventilation.

Exon-skipping therapies like viltolarsen can cause parts of the mutated gene to be skipped, yielding shortened usable dystrophin, according to Previtera and colleagues. The FDA granted viltolarsen accelerated approval status in 2020, and a confirmatory phase III trial is ongoing to assess clinical benefit for the drug in DMD patients with a confirmed dystrophin gene mutation amenable to exon 53 skipping.

The FDA granted accelerated approval to another exon 53-skipping therapy, golodirsen (Vyondys 53), in 2019. The first exon-skipping treatment granted accelerated approval in DMD was eteplirsen (Exondys 51) in 2016. Both of those products are made by Sarepta Therapeutics, which also received accelerated approval for another exon-skipping therapy, casimersen (Amondys 45), in 2021.

In the latest study, the researchers compared 20 ambulatory and nonambulatory males taking 80 mg/kg of viltolarsen intravenously once weekly to a control group of 48 males from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS), matched for age and ambulatory and steroid status, among other baseline characteristics. Ambulatory males were about 10 years old, and non-ambulatory males were nearly 16.

Nearly all participants on viltolarsen (19 out of 20) experienced mild-to-moderate treatment-emergent adverse events (TEAEs), and four events were considered treatment-related. There were no serious adverse events, discontinuations due to TEAEs, or deaths.

Previtera and colleagues also measured an exploratory endpoint, PCF, in liters per minute (L/min). For ambulatory patients, the mean PCF change from baseline was larger in those on viltolarsen than CINRG DNHS controls. For nonambulatory patients, those on viltolarsen showed a significant mean change from baseline compared to the control group at week 49 (56.7 L/min higher, P=0.01).

In both ambulatory and nonambulatory patients receiving viltolarsen, total and midlevel elbow scores on the performance of upper limb 2.0 measurement remained stable over 49 weeks.

https://www.medpagetoday.com/meetingcoverage/aan/109696