Advances in the Surgical Management of Epilepsy: Drug-Resistant Focal Epilepsy in the Adult Patient

ABSTRACT, originally published in Neurologic Clinics

Pharmacoresistant seizures occur in nearly one-third of people with epilepsy. Medial temporal lobe and lesional epilepsy are the most favorable surgically remediable epileptic syndromes. Successful surgery may render the patient seizure-free, reduce antiseizure drug(s) adverse effects, improve quality of life, and decrease mortality. Surgical management should not be considered a procedure of “last resort.” Despite the results of randomized controlled trials, surgery remains an underutilized treatment modality for patients with drug-resistant epilepsy (DRE). Important disparities affect patient referral and selection for surgical treatment. This article discusses the advances in surgical treatment of DRE in adults with focal seizures.

Affordability, availability and tolerability of anti-seizure medications are better predictors of adherence than beliefs: Changing paradigms from a low resource setting

Abstract, originally published in Seizure

Objectives: Anti-seizure medication (ASM) non-adherence contributes to treatment gap and increases mortality and morbidity associated with epilepsy. Beliefs about medications are considered better predictors of ASM non-adherence than clinico-demographic factors. We aimed to look into ASM non-adherence rates among adults with epilepsy (AWE), identify the contributing barriers and determine whether medication beliefs were more powerful predictors than clinico-demographic factors.

Methods: This was a cross-sectional study of AWE receiving ASMs. Participants (n = 304) were assessed by validated questionnaires, for non-adherence (8-item Morisky Medication Adherence Scale) and perceptions of ASMs (Beliefs about Medicines Questionnaire) along with clinico-demographic details.

Results: Our group with high literacy and low-income had a high non-adherence rate (55 %) despite having positive beliefs (Mean necessity-concern differential [NCD] = 2.86). Among the beliefs, ASM non-adherence was significantly associated with ASM-concern (t = 4.23, p < 0.001) and NCD (t = -4.11, p < 0.001). Stepwise multiple linear regression analysis showed that non-adherence was significantly associated with per-capita income (? -0.215, p < 0.001), ASM side effects (? 0.177, p = 0.001), high seizure frequency (? 0.167, p = 0.002), ASM availability (? -0.151, p = 0.004), ASM costs (? -0.134, p = 0.013 and NCD (? -0.184, p = 0.001). NCD accounted for 2.9 % of the variance in non-adherence whereas the other clinico-demographic variables together accounted for 14.6 %.

Conclusion: We describe a paradigm shift in adults with epilepsy with high non-adherence to anti-seizure medications, wherein clinico-demographic variables emerge as better predictors of non-adherence than beliefs. High literacy facilitates the perception of need for anti-seizure medications whereas costs and side effects hamper adherence.

Cognitive decline in older adults with epilepsy: The Cardiovascular Health Study

Abstract, originally published in Epilepsia

Objective: Cognitive decline is a major concern for older adults with epilepsy. Whether and how much faster older adults with epilepsy experience cognitive decline beyond expected age-related cognitive change remain unclear. We sought to estimate and compare rates of cognitive decline in older adults with and without epilepsy.

Methods: The Cardiovascular Health Study is a population-based longitudinal cohort study of 5888 US adults aged 65+. Cognitive function was assessed annually with Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST). We used linear mixed models to estimate average rates of decline in 3MS and DSST scores by epilepsy status (prevalent, incident, or no epilepsy), adjusted for risk factors associated with cognitive decline.

Results: The rate of decline in 3MS was significantly faster in prevalent epilepsy (P < .001) and after incident epilepsy (P = .002) compared with no epilepsy. Prevalent epilepsy and apolipoprotein E gene (APOE) ε4 (ApoE4) had a synergistic interaction, whereby prevalent epilepsy and ApoE4 together were associated with 1.51 points faster annual decline in 3MS than would be expected if prevalent epilepsy and ApoE4 did not interact (P < .001). Older adults with prevalent epilepsy had a significantly lower initial DSST score and faster rate of decline compared to those with no epilepsy (P < .001).

Significance: Faster decline in global cognitive ability seen in this study validates concerns of patients. ApoE4 allele status was an effect modifier of the relationship between cognitive decline and prevalent epilepsy. Further research is warranted to explore biological mechanisms and possible interventions to mitigate cognitive decline.

Testing the ‘seizure scaffold’: What can experimental simulation tell us about functional seizures (seizures that resemble epileptic seizures but are not)?

Abstract, originally published in Epilepsy & Behavior

Introduction: It has been suggested for over 100 years that patterns of neurological symptoms and signs in functional neurological disorders may be shaped at a neural level by underlying ideas or preconceptions how neurological symptoms present. This study used experimental simulation to probe ideas about seizures in healthy volunteers, with a view to compare with features commonly observed in functional and epileptic seizure disorders.

Methods: Sixty healthy volunteers were instructed to simulate an epileptic seizure. The episodes were video-recorded and assessed by three qualified markers for the presence of clinical features commonly observed in functional seizures (FS), epileptic seizures, and syncope.

Results: Simulated seizures were hyperkinetic (83%), hypokinetic (7%), or staring (10%). Fifty-two percent had their eyes open and 45% eyes closed. Tremor was observed in 70%, while clonic jerking was only present in 17%. The majority of volunteers maintained a normal or floppy body posture. Head shaking side-to-side was observed in 38%, while guttural cries, stertorous breathing, tearfulness, and hyperventilation were absent in all volunteers.

Discussion: Our results suggest that simulated seizures not only resemble functional seizures [seizures that resemble epileptic seizures but are episodes of impaired self-control and not associated with epileptic EEG discharges] more closely than epileptic seizures but also show some important differences. Subjective seizure experiences in people with functional seizures, not captured by this experimental simulation, remain a core determinant of semiology.

Effects of valproate (Depakote), lamotrigine (Lamictal), and levetiracetam (Keppra) monotherapy on bone health in newly diagnosed adult patients with epilepsy

Abstract, originally published in Epilepsy & Behavior

Purpose: The aim of this study was to evaluate the effects of valproate (VPA), lamotrigine (LTG), and levetiracetam (LEV) on bone turnover and bone mineral density (BMD) in newly diagnosed adult patients with epilepsy.

Methods: Eligible adult patients who were newly diagnosed with epilepsy were treated with VPA, LTG, and LEV. The chemical indicators of bone metabolism and BMD were measured before treatment and 2 years after treatment with different antiseizure medication (ASM) monotherapies. Then, the differences in these parameters before and after treatment were analyzed.

Results: One hundred twenty-four patients completed the 2 years follow-up; 43 received monotherapy with VPA, 32 received LTG, and 49 received LEV. Serum parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and ?-cross-linked C-telopeptide of type I collagen (?-CTX) levels were elevated in adult patients after 2 years of VPA administration; the serum procollagen I intact N-terminal peptide (PINP) level was noticeably higher in patients after LEV treatment than before treatment. Meanwhile, the BMD of the lumbar spine and femoral neck did not change in patients treated with VPA, LTG, and LEV.

Conclusions: Valproate altered bone turnover in adult patients with epilepsy, while lamotrigine and levetiracetam did not exert harmful effects on bone health in adult patients.

UCB’s VIMPAT® (Lacosamide) CV Now Approved by FDA for Primary Generalized Tonic-Clonic Seizures and Expanded Pediatric Use for People Living With Epilepsy

Press release, originally published on the UCB website

UCB, a global pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved VIMPAT® (lacosamide) CV as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures (PGTCS) in patients four years of age and older and VIMPAT injection for intravenous use in children four years of age and older. PGTCS is a type of seizure that occurs all over the brain, affecting both sides of the brain from the start, causing muscles to stiffen and convulsions to occur for up to a few minutes.

“These approvals underscore UCB’s commitment to people living with epilepsy and our focus on finding solutions for specific unmet needs within the epilepsy community,” said Mike Davis, Head of U.S. Neurology at UCB. “We are pleased that VIMPAT is now available as a treatment option for people living with primary generalized tonic-clonic seizures on their journey to seizure control.”

The PGTCS approval is based, in part, on results of a Phase 3 study recently published in the Journal of Neurology, Neurosurgery & Psychiatry.  Adjunctive treatment with VIMPAT resulted in a significantly lower risk of developing a second PGTCS during the 24-week treatment period, with the corresponding risk reduction being 45% (p=0.001), and a significantly higher rate of freedom from PGTCS during the treatment period compared with placebo (31.3% vs 17.2%, p=0.011).

People living with generalized tonic-clonic seizures have an increased risk of injury and those who experienced three or more in one year had a fifteen-fold increased risk of sudden unexpected death in epilepsy.

“The treatment of primary generalized tonic-clonic (convulsive) seizures is challenging, with about one-third of patients still being refractory while on therapy,” said David Vossler, MD, FAAN FACNS FAES, Department of Neurology, University of Washington, Seattle, USA. “Bolstered by a wealth of data demonstrating the efficacy and safety of VIMPAT, this new indication gives people suffering from PGTCS a chance at freedom from these seizures, which many have never experienced.”

Results from the Phase 3 study showed that VIMPAT was generally tolerated in patients with Idiopathic Generalized Epilepsy (IGE) and PGTCS. The most common adverse reactions (?10%) reported in patients treated with VIMPAT were dizziness (23%), somnolence (17%), headache (14%), and nausea (10%) compared to 7%, 14%, 10%, and 6%, respectively, of patients who received placebo.

Regarding the expanded pediatric population, VIMPAT tablets and oral solution were already approved to treat partial-onset seizures in adults and children four years and older as monotherapy and adjunctive therapy. VIMPAT injection was previously approved for the treatment of partial-onset seizures only in adult patients (17 years of age and older).

In October 2020, The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion for VIMPAT as adjunctive therapy in the treatment of PGTCS in adults, adolescents and children from four years of age with idiopathic generalized epilepsy. Regulatory reviews for use of VIMPAT in the treatment of PGTCS are also underway in Japan and Australia.

Resective Surgery Prevents Progressive Cortical Thinning in Temporal Lobe Epilepsy

Abstract, originally published in Brain

Focal epilepsy in adults is associated with progressive atrophy of the cortex at a rate more than double that of normal ageing. We aimed to determine whether successful epilepsy surgery interrupts progressive cortical thinning.

In this longitudinal case-control neuroimaging study, we included subjects with unilateral temporal lobe epilepsy (TLE) before (n = 29) or after (n = 56) anterior temporal lobe resection and healthy volunteers (n = 124) comparable regarding age and sex. We measured cortical thickness on paired structural MRI scans in all participants and compared progressive thinning between groups using linear mixed effects models. Compared to ageing-related cortical thinning in healthy subjects, we found progressive cortical atrophy on vertex-wise analysis in TLE before surgery that was bilateral and localized beyond the ipsilateral temporal lobe. In these regions, we observed accelerated annualized thinning in left (left TLE 0.0192 ± 0.0014 versus healthy volunteers 0.0032 ± 0.0013 mm/year, P < 0.0001) and right (right TLE 0.0198 ± 0.0016 versus healthy volunteers 0.0037 ± 0.0016 mm/year, P < 0.0001) presurgical TLE cases. Cortical thinning in these areas was reduced after surgical resection of the left (0.0074 ± 0.0016 mm/year, P = 0.0006) or right (0.0052 ± 0.0020 mm/year, P = 0.0006) anterior temporal lobe. Directly comparing the post- versus pre-surgical TLE groups on vertex-wise analysis, the areas of postoperatively reduced thinning were in both hemispheres, particularly, but not exclusively, in regions that were affected preoperatively. Participants who remained completely seizure-free after surgery had no more progressive thinning than that observed during normal ageing. Those with postoperative seizures had small areas of continued accelerated thinning after surgery.

Thus, successful epilepsy surgery prevents progressive cortical atrophy that is observed in TLE and may be potentially neuroprotective. This effect was more pronounced in those who remained seizure-free after temporal lobe resection, normalizing the rate of atrophy to that of normal ageing. These results provide evidence of epilepsy surgery preventing further cerebral damage and provide incentives for offering early surgery in refractory TLE.

Late-Onset Epilepsy Tied to a Threefold Increased Dementia Risk

Literature review, originally published on Neurology Reviews

Late-onset epilepsy is linked to a substantial increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy.

“This is an exciting area, as we are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other cohort studies are finding similar results, including the Veterans’ Health Study and the Framingham Study,” she added.

The researchers found that of 9,033 study participants, 671 had late-onset epilepsy. The late-onset epilepsy group was older at baseline (56.5 vs. 55.1 years) and more likely to have hypertension (38.9% vs. 33.3%), diabetes (16.1% vs. 9.6%), and two alleles of APOE4 genotype (3.9% vs. 2.5%), compared with those without the disorder.

In all, 1,687 participants developed dementia during follow-up. The rate of incident dementia was 41.6% in participants with late-onset epilepsy and 16.8% in participants without late-onset epilepsy. The adjusted hazard ratio of subsequent dementia in participants with late-onset epilepsy versus those without the disorder was 3.05 (95% confidence interval, 2.65-3.51).

Specific ICD-10 Codes for Dravet Ultimately Could Improve Patient Outcomes

Article, originally published by Dravet Syndrome News

Dravet syndrome now has its own global health statistics codes — known as “ICD-10” codes — that potentially could result in improved patient outcomes and enhanced clinical and scientific knowledge of the genetic disorder.

The National Center for Health Statistics has designated what are known as International Statistical Classification of Diseases and Related Health Problems (ICD) codes specifically for Dravet. Before, the disease was lumped in with a broad group of epileptic conditions with different causes and treatment strategies, under the code G40.8.

The dedicated Dravet syndrome codes, which took effect Oct. 1, are expected to make it easier for those in the field to conduct research, determine prevalence and morbidity and mortality rates, and recruit patients for clinical trials. The codes also will help researchers and clinicians to track treatment outcomes and develop protocols for a standard of care.

Examining the impacts of the COVID-19 pandemic on the well-being and virtual care of patients with epilepsy

Abstract, originally published in Epilepsy & Behavior

Objective: The emergence of SARS-CoV-2 (COVID-19) as a novel coronavirus resulted in a global pandemic that necessitated the implementation of social distancing measures. These public health measures may have affected the provision of care for patients with epilepsy. Social isolation may have also adversely affected well-being and quality of life due to informal and formal support networks becoming less accessible. The purpose of this qualitative study was to examine the lived experiences of patients with epilepsy and to see how their quality of life and healthcare has been affected by the COVID-19 pandemic.

Methods: From April 27 to May 15, 2020 we performed remote interviews with 18 participants who had virtual appointments with their healthcare providers and were enrolled in the Calgary Comprehensive Epilepsy Program registry. Interviews were recorded and transcribed, after which transcripts were analyzed and coded into relevant themes using NVivo 12.

Results: Three broad themes emerged throughout the interviews:1) impact of pandemic on informal and formal support systems; 2) impact of pandemic on healthcare provision; and 3) concerns about the impact of the pandemic on personal situations and society in the future. Participants reported anxiety and stress about decreased social engagement and activity cessations. Although face-to-face appointments were preferred, virtual care was well-received. Common concerns about the future included securing employment and burnout from balancing family responsibilities. Some patients also feared they would be stigmatized as society adapted to the situation.

Significance: This study highlights the need for additional research in anticipation of the implementation of remote medicine in the management and treatment of epilepsy. It also highlights the tenacity of those living with epilepsy during difficult periods despite social and familial pressures. Raising awareness during this time about the lives and experiences of epilepsy patients can help challenge misconceptions and stigma in the workplace and wider society.