Practical Considerations in Epilepsy Neurostimulation

Abstract found on Wiley Online Library

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues.

Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death from epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7-10?years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with co-morbidities such as severe mood or sleep disorders, may influence choice of modality. Programming has evolved – DBS is typically initiated at lower current/voltage than used in the pivotal trial while charge density is lower with RNS, but generalizable optimal parameters are yet to be defined. Non-invasive brain stimulation is an emerging stimulation modality, although currently not widely used.

Clinical practice has evolved from those established in pivotal trials. Guidance is available for clinicians wishing to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

CURE Epilepsy Discovery: Identifying Human Brain Regions that Regulate Breathing as Eventual Targets for Direct SUDEP Intervention

Key Points:

CURE Epilepsy Award grantee Dr. Nuria Lacuey and her team sought to identify specific parts of the brain essential for regulating breathing, a fundamental function whose failure following a seizure is primarily responsible for Sudden Unexpected Death in Epilepsy (SUDEP).
The team recruited patients who were being evaluated for epilepsy surgery and who formally agreed to enroll in a study that had them perform various breathing exercises while having different areas of their brain electrically stimulated with varying intensities.
Quantitative analyses of the data revealed that four specific areas of the cortex of the brain affected the patients’ breathing responses, depending on the strength and frequency of the electrical stimulation. Two of these areas resulted in enhanced respiratory activity.
Additional data from more patients is needed, but Dr. Lacuey hopes to use these valuable results to develop a device that will stimulate critical areas of the brain following seizures to enhance breathing and avoid its cessation, thereby preventing SUDEP.

Deep Dive:

SUDEP is the most frequent cause of death among people with drug-resistant epilepsy [1,2]. Although different biological processes may contribute to SUDEP, the most prominent appears to be a phenomenon known as central apnea, a condition in which breathing repeatedly stops and starts, usually while sleeping, during or immediately after a severe seizure [3,4]. There is compelling evidence that breathing irregularities are an underlying cause of SUDEP. Research to date has almost exclusively concentrated on the role of an area of the brain called the brainstem [5], which ultimately connects higher cortical regions of the brain to the spinal cord. Although the brainstem plays a crucial role in maintaining respiratory activity, it may not be the only contributing area. Indeed, areas of the cortex have also been implicated [6], but the specific roles different areas of the cortex play in modulating breathing is unclear. Most importantly, there are currently no strategies for directly improving respiratory function during the dangerous period between seizure-induced central apnea and death.

One possible approach would be to electrically stimulate specific areas of the brain to maintain respiratory function during this critical period. As a first step, it is vital to assess the role of specific areas of the brain and what intensity and frequency of the electrical current might have beneficial or detrimental effects on breathing. Developing such an innovative method requires a detailed understanding of the relationship between brain electrical activity and breathing responses, specifically how brain regions are structurally and functionally linked through their neuronal connections, collectively known as the connectome [7,8].

Research on this approach was conducted by Dr. Lacuey and her team in the Department of Neurology at the University of Texas Health Science Center in Houston, TX. Nineteen patients who suffered from drug-resistant epilepsy and who were being evaluated for epilepsy surgery consented to be enrolled in the study [9]. Pinpointing the exact seizure focus without damaging surrounding healthy tissue necessitated placing electrodes directly on the brains of these patients and then, electrically stimulating various brain regions for clinical mapping.

Electrodes were implanted in seven brain regions common to all 19 participants, and thus, these were the regions selected for comprehensive investigation. The goal was to ascertain whether electrical stimulation of each of these seven regions would affect breathing responses and, if so, whether the resulting respiratory activity would be enhanced or inhibited. Equally important was to determine the stimulation intensity as well as frequency necessary to elicit such responses. Electrical stimulation was carried out at a current of 1-10 milliamps (mA) and a frequency of 50 Hertz for 0.2 milliseconds [9].

Quantitative analyses of the data showed that electrical stimulation affected breathing responses in four of the seven different brain regions tested. Stimulation of two of these regions, specifically within the frontal portions of areas called the temporal lobe and cingulate gyrus, promoted breathing enhancement at a relatively low current (less than 3 mA) but not at the higher electrical current conditions tested [9]. Future experiments will require a larger group of patients, finer mapping of the identified brain regions, and exploration of brain regions other than the seven examined in the current study. Subsequent experiments will also include an evaluation of electric current and frequency as well as how any observed changes in respiratory control interact with the breathing mechanisms of the brainstem.

The fact that electrical stimulation of four cortical regions affected respiration, and that two of these areas enhanced breathing is an exciting finding. Significantly, this CURE Epilepsy funded research supports the idea that an implantable device capable of electrically stimulating pre-identified cortical regions of the brain to enhance breathing at critical times to prevent SUDEP may eventually be possible.

Literature Cited:

Jones, L.A. & Thomas, R.H. Sudden unexpected death in epilepsy: insights from the last 25 years. Seizure 2017; 44: 232-236.
Devinsky, O. et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088.
Vilella, L. et al. Postconvulsive central apnea as a biomarker for sudden unexpected death in epilepsy (SUDEP). Neurology 2019; 92(3): e171-e182.
So, E.L., Sam, M.C., & Lagerlund, T.L. Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident. Epilepsia 2000; 41(11): 1494-1497.
Patodia, S. et al. The ventrolateral medulla and medulla raphe in sudden unexpected death in epilepsy. Brain 2018; 141(6): 1719-1733.
Herrero, J.L. Breathing above the brain stem: volitional control and attentional modulation in humans. J. Neurophysiol. 2018; 119(1): 145-159.
Bethlehem, R.A.J. et al. Brain charts for the human lifespan. Nature 2022; 604(7906): 525-533.
Fan, Q. et al. Mapping the human connectome using diffusion MRI at 300 mT/m gradient strength: Methodological advances and scientific impact. Neuroimage 2022; 254:118958.
Ganne, C. et al. Limbic and paralimbic respiratory modulation: from inhibition to enhancement. Epilepsia 2022; Epub

A Pioneering Study Discovers an Underlying Cause for Infantile Spasms and Points to a Novel Therapy

Article published by Texas Children’s Hospital

Featuring the research of former CURE Epilepsy grantee Dr. John Swann

Infantile spasm (IS) is a severe epileptic syndrome of infancy and accounts for 50% of all epilepsy cases that occur in babies during the first year of life. Current treatment options for this disorder are limited and most affected infants grow up to have developmental delays, intellectual disabilities and other types of severe epilepsy. A groundbreaking study, conducted in the laboratory of Dr. John Swann, director of the Gordon and Mary Cain Pediatric Neurology Research Foundation labs, investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and professor at Baylor College of Medicine, has found that the levels of insulin growth factor -1 (IGF-1) and its downstream signaling are reduced in the brains of both IS patients and animal models. Furthermore, they found that the administration of an IGF-1 analog to an IS animal model successfully eliminated spasms and abnormal brain activity. This exciting study, published in the Annals of Neurology, has the potential to transform the treatment landscape for babies with infantile spasms.

Dr. Swann is a leading expert in epilepsy research and a few years back, his team’s pioneering discoveries resulted in an FDA-approved treatment for severe epilepsy among tuberous sclerosis patients. He and his team have had a longstanding interest and experience in studying infantile spasms, an epileptic disorder diagnosed in roughly 2500 babies in the United States each year.

Antidepressant Use During Pregnancy Not Linked to Epilepsy in Children

Article published by NewsWise

A new study suggests that antidepressant use by mothers during the first trimester of pregnancy does not increase the chances of epilepsy and seizures in babies. The research is published in the May 11, 2022, online issue of Neurology, the medical journal of the American Academy of Neurology.

“The findings of this study are very important,” said study author Ayesha Sujan, PhD, of Indiana University in Bloomington, Indiana. “Pregnancy can be a trying time, and the addition of depression, anxiety, and other mental health conditions can add to this burden. These findings may provide reassurance to women and their doctors considering the risks and benefits to medication.”

The study looked at over 1.7 million children born in Sweden over a 17-year period. Researchers identified more than 24,000 children who had been exposed to antidepressants during the first trimester of pregnancy and compared them to those who were not exposed.

While the authors found a higher prevalence of neonatal seizures and epilepsy among exposed children compared to unexposed children, after adjusting for factors in the mothers associated with an increase in the risk of seizures in their newborn, they found no link between antidepressant use by mothers during the first trimester and a child’s risk of seizures or epilepsy.

Efficacy, Safety, and Economic Impact of Diazepam Suppositories with As-Needed Acetaminophen for Prevention of Seizure Recurrence During the Same Fever Episode in Children with Suspected Simple Febrile Seizures

Abstract found in PubMed

Objective: To evaluate the efficacy, safety, and economic impact of diazepam suppositories with as-needed acetaminophen in comparison with as-needed acetaminophen alone for prevention of seizure recurrence during the same fever episode in suspected pediatric simple febrile seizures (SFS).

Methods: This single-center, prospective, observational study was conducted from July 29, 2019 to February 15, 2021 at a children’s hospital. Children aged 6 months to 60 months presenting to the emergency department with suspected SFS were included. Participants receiving both diazepam suppositories and as-needed acetaminophen were compared with those receiving as-needed acetaminophen alone. The primary outcome was seizure recurrence during the same fever episode. The secondary outcomes included the incidence of central nervous system (CNS) pathologies, adverse events, and medical costs.

Results: Of the 316 participants, 228 (72.2%) had their first febrile seizure. Diazepam (0.3-0.5 mg/kg for up to two doses) was administered to 88/316 patients (27.8%). The outcomes were available for 306 patients. The recurrence rate was 3.5% (3/85) in the patients receiving diazepam with as-needed acetaminophen and 12.2% (27/221) in the patients receiving as-needed acetaminophen alone (relative risk: 0.29 [95% CI: 0.09-0.93]; P=0.03). The adjusted odds ratio of diazepam administration against recurrence was 0.23 (95% CI: 0.07-0.78; P=0.02). None of the patients had a CNS pathology. No severe adverse events occurred although mild ataxia was observed significantly more often in the patients receiving diazepam and as-needed acetaminophen (29.4% vs 18.7%, P=0.04). The median medical cost was US Dollars 199 (IQR: 86-244) for the group receiving both medications and US Dollars 202 (IQR: 114-242) for the group receiving as-needed acetaminophen alone.

Significance: Compared with as-needed acetaminophen alone, diazepam with as-needed acetaminophen may reduce seizure recurrence more during the same fever episode without severe adverse events or additional costs in children with suspected simple febrile seizures.

Fenfluramine Seems Effective for Lennox-Gastaut Syndrome

Article published by Medical Xpress

Among patients with Lennox-Gastaut syndrome (LGS), the percentage reduction in the frequency of drop seizures is greater with fenfluramine versus placebo, according to a study published online May 2 in JAMA Neurology.

Kelly G. Knupp, M.D., from the Children’s Hospital Colorado in Aurora, and colleagues examined the efficacy and safety of fenfluramine in patients with LGS (aged 2 to 35 years) from 65 sites in North America, Europe, and Australia. Participants were randomly assigned to receive a 0.7- or 0.2-mg/kg/d dose of fenfluramine or placebo (87, 89, and 87 patients, respectively).

The researchers found that the median percentage reduction in frequency of drop seizures was 26.5, 14.2, and 7.6 percentage points in the groups receiving the 0.7- and 0.2-mg/kg/d dose of fenfluramine and placebo, respectively. The trial met its primary efficacy end point, with a ?19.9 percentage point estimated median difference in drop seizures from baseline for the 0.7-mg/kg/d dose of fenfluramine versus placebo. More patients in the group receiving the 0.7-mg/kg/d dose of fenfluramine achieved a 50 percent or greater response versus placebo (25 versus 10 percent). Generalized tonic-clonic (GTC) seizure was the subtype that seemed most responsive to fenfluramine, with reductions in frequency of 45.7 and 58.2 percent in the groups receiving the 0.7- and 0.2-mg/kg/d doses of fenfluramine and a 3.7 percent increase in the placebo group.

Long-Term Seizure Outcomes in Patients with Autoimmune Encephalitis: A Prospective Observational Registry Study Update

Article published by Wiley Online Library

SUMMARY

Objective: To update and evaluate long-term seizure outcomes in patients with autoimmune encephalitis (AE) based on a large cohort study with long follow-up.

Methods: In this prospective observational registry study, we analyzed data from patients with AE mediated by common types of neuronal surface antibodies (anti-NMDAR, anti-LGI1/Caspr2, anti-GABABR). All patients were recruited from the Department of Neurology at the West China Hospital between October 2011 and June 2019, and data were collected prospectively on their demographic and clinical characteristics, treatment strategy, and seizure outcomes with a median follow-up of 42 months (range 6–93 months). Potential risk factors associated with seizure recurrence were also assessed.

Results: Of 320 AE patients, 75.9% had acute seizures, among whom more than 90% of patients had their last seizure within 12 months of disease onset. During our follow-up, 21 (9.3%) patients experienced seizure recurrence. Patients with anti-GABABR encephalitis had a higher cumulative incidence of seizure recurrence than those with anti-NMDAR (log-rank P = 0.03) or anti-LGI1/Caspr2 encephalitis (log-rank P = 0.04). Among patients with anti-NMDAR encephalitis, women had a significantly higher cumulative incidence of seizure recurrence than men (log-rank P = 0.01). Interictal epileptiform discharges (IEDs) or seizures captured on continuous EEG in the acute phase were identified as potential risk factors for seizure recurrence (P=0.04; P=0.007). Among 163 patients with ? 24 months of follow-up, five (3.1%) showed persistent seizures and required ongoing anti-seizure medications (ASMs) despite aggressive immunotherapy.

Significance: Seizure recurrence occurred in a small number of patients and chronic epilepsy occurred in 3.1% of patients during prolonged follow-up. Across all types of autoimmune encephalitis, risk factors for seizure recurrence were interictal epileptiform discharges or seizures captured on EEG in the acute phase; for anti-NMDAR encephalitis, female sex was also a risk factor.

Neurostimulation in People with Drug-Resistant Epilepsy: Systematic Review and Meta-Analysis from the ILAE Surgical Therapies Commission

Abstract found on Wiley Online Library

SUMMARY

Objective: Summarize the current evidence on efficacy and tolerability of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) through a systematic review and meta-analysis.

Methods: We followed the PRISMA reporting standards and searched Ovid Medline, Ovid Embase, and the Cochrane Central Register of Controlled Trials. We included published randomized controlled trials (RCT) and their corresponding open-label extension studies, as well as prospective case series, with ? 20 participants (excluding studies limited to children). Our primary outcome was the mean (or median when unavailable) percentage decrease in frequency, as compared to baseline, of all epileptic seizures at last follow-up. Secondary outcomes included proportion of treatment responders and proportion with seizure freedom.

Results: We identified 30 eligible studies, six of which were RCTs. At long-term follow-up (mean 1.3 years), five observational studies for VNS reported a pooled mean percentage decrease in seizure frequency of 34.7% (95% CI: -5.1, 74.5). In the open-label extension studies for RNS, the median seizure reduction was 53%, 66%, and 75% at two, five, and nine years of follow-up, respectively. For DBS, the median reduction was 56%, 65%, and 75% at two, five, and seven years, respectively. The proportion of individuals with seizure freedom at last follow-up increased significantly over time for DBS and RNS while a positive trend was observed for VNS. Quality of life was improved in all modalities. The most common complications included hoarseness, cough and throat pain for VNS and implant site pain, headache, and dysesthesia for DBS and RNS.

Significance: Neurostimulation modalities are an effective treatment option for drug resistant epilepsy, with improving outcomes over time and few major complications. Seizure reduction rates among the three therapies were similar during the initial blinded phase. Recent long-term follow-up studies are encouraging for RNS and DBS but are lacking for VNS.

Research Offers New Hope for People Living with Seizures

Article published in Medical Xpress

A research collaboration involving the University of Otago could change the lives of people living with seizures.

Researchers from Otago and Okinawa Institute of Science and Technology Graduate University have developed a new system that uses specialized sound waves (above the frequency that we can hear) or light (above the wavelength that we can see) to release medication into specific areas of the brain to stop seizure activity.

Otago lead researcher Professor John Reynolds says this novel new way of delivering drugs could be an effective solution, and a life-changer for some patients with epilepsy.

“The sound waves can be applied from outside the head to target an area where epileptic seizures can start, and will release the drug from tiny biological packages circulating in the blood stream as they pass through the area, to suppress the seizure activity,” he says.

A device would be connected to the head of the patient, and drug-containing liposomes—a drug delivery vehicle—will be injected into the blood stream. These liposomes will float around, but not change the brain unless activated.

“The device could then be triggered by the person when they sense an aura that a seizure is coming on, or automatically by a system that detects seizure brain waves, activating the liposome to release the drug to stop the seizure from developing,” Professor Reynolds says.

FDA Approves Ztalmy® (Ganaxolone) for CDLK5 Deficiency Disorder (CDD)

Exciting update! The FDA has approved a new therapy to treat seizures for CDLK5 deficiency disorder (CDD), a rare epilepsy caused by mutations in the CDKL5 gene. The drug, Ztalmy® (ganaxolone), manufactured by Marinus Pharmaceuticals, is now approved to treat seizures associated with CDD in patients 2 years of age and older. This medication is the first FDA-approved treatment specifically for CDD. It is expected to be available to patients in July 2022.

To learn more about this new drug treatment, please read here.