Epilepsy Drugs For Newly Diagnosed Patients: What’s Best?

Summary, originally published in MedPageToday

Valproate (Depakene) emerged as the best first-line choice for generalized epilepsy in a pragmatic study and lamotrigine (Lamictal) as the best first-line treatment for focal epilepsy, British researchers said.

The conclusions came from the phase IV open-label Standard and New Antiepileptic Drugs (SANAD II) study with two parts: a randomized trial of levetiracetam (Keppra) and valproate in newly diagnosed generalized epilepsy patients, and a randomized trial of levetiracetam, lamotrigine, and zonisamide (Zonegran) in newly diagnosed focal epilepsy patients. Results were published in separate papers in The Lancet.

In new patients with generalized or unclassified epilepsy, levetiracetam did not meet non-inferiority criteria compared with valproate in intention-to-treat analysis of time to 12-month remission (HR 1.19, 95% CI 0.96-1.47; non-inferiority margin 1.329), reported Anthony Marson, MD, of University of Liverpool in England, and co-authors. Treatment failure due to inadequate seizure control was more likely with levetiracetam, and a per-protocol analysis that took treatment failure into account found valproate to be superior (HR 1.68, 95% CI 1.30–2.15). Cost-effectiveness based on differences in costs and quality-adjusted life years found valproate to be superior.

“The available evidence now identifies valproate as more clinically and cost effective than both lamotrigine and levetiracetam,” Marson said in a statement. “Levetiracetam has been widely adopted in the U.K. and worldwide as a first-line treatment for focal epilepsy, but this should no longer be the case as it is neither clinically nor cost effective compared to lamotrigine,” he added.

Stiripentol in the Treatment of Adults With Focal Epilepsy: A Retrospective Analysis

Abstract, originally published in Seizure

Objectives: The aim of the present study was to evaluate the safety and efficacy of the add-on treatment of stiripentol (STP) in adult patients with severely pharmacoresistant focal or multifocal epilepsy.

Methods: Data on adult patients treated with STP from March 2007 to July 2020 and with at least one clinical follow-up (FU) were retrospectively reviewed. Data on tolerability, efficacy and concomitant medication were evaluated at baseline, 6 months (5.5 ± 1.6 months (mean ± SD)) and 12 months (13.1 ± 3.9 months (mean ± SD)).

Results: Data of 22 patients (54.5% male, mean age 34.4 ± 17.79 years (mean ± SD), including mean duration of epilepsy 17.6 ± 25.5 years (mean ± SD), median seizure frequency 30 ± 20 (median ± MAD) per month, and 63.6% being severely intellectually disabled, with 3 to 18 previous anti-seizure-drugs (ASD), were collected. After 6 months, 72.7% of the patients were still taking STP, and 31% of the patients were responders, including 13% who were seizure-free. The 12-month retention rate was 54.4 %, the response rate was 36.4% and 13.6% of patients were seizure-free at the 12-month FU. Reasons for discontinuation were increased seizure frequency, hyperammonaemia and encephalopathy.

Conclusion: Stiripentol seems to be a useful option in the treatment of patients with severely pharmacoresistant epilepsy. Prospective trials are necessary to examine the efficacy of stiripentol in adult patients with pharmacoresistant focal epilepsy.

Epilepsy Surgery: Late Seizure Recurrence After Initial Complete Seizure Freedom

Abstract, originally published in Epilepsia

Objective: This study was undertaken to improve understanding of late relapse following epilepsy surgery in pharmacoresistant epilepsy.

Methods: Retrospective comparison was made of 99 of 1278 patients undergoing surgery during 1999–2015 with seizure relapses after at least 2 years of complete seizure freedom with matched controls experiencing continued long?term seizure freedom. Univariate and multivariate analyses were performed.

Results: With a mean follow-up of 9.7 years, mean time to seizure relapse was 56.6 months. In multivariate analysis, incomplete resection based on magnetic resonance imaging (MRI), bilateral lesions on preoperative MRI, and epilepsy onset in the first year of life carried a significantly higher risk of late relapse. In patients with late relapse, additional functional imaging with positron emission tomography had been performed significantly more often. Although the differences were not significant in multivariate analysis, doses of antiepileptic drugs were higher in the relapse group preoperatively and in the first 24 months and complete withdrawal was more frequent in the control group (68% vs. 51%). Regarding seizure frequency, most patients had mild seizure relapse (single relapse seizure or <1/month).

Significance: In our predominantly lesional cohort, complete resection of the MRI lesion is the most important factor to maintain long-term seizure freedom. Two patterns of recurrence were identified: (1) incomplete resected lesions with seizure generation in proximity to the initial resection and (2) epileptogenic networks not detected preoperatively or evolving in the postoperative interval and manifesting with new clinical and diagnostic features.

Valproate Usage in Pregnancy: An Audit From the Kerala Registry of Epilepsy and Pregnancy

Summary, originally published in Epilepsia

Objective: This is an audit of the use of valproate (VPA) during pregnancy in women with epilepsy (WWE).

Methods: We identified all pregnancies exposed to VPA in the Kerala Registry of Epilepsy and Pregnancy between January 2010 and December 2019. Subjects’ past usage of antiepileptic drugs (AEDs), seizure count before and during pregnancy, fetal outcome, and major congenital malformations (MCMs) were abstracted from the registry records. The presumed reason for usage of VPA was deducted from the clinical records.

Results: There were 221 pregnancies (17.75%) exposed to VPA (monotherapy, n = 149) during the audit period. The MCM rate for the completed pregnancies exposed to VPA was higher (n = 20, 10.36%) than that of VPA?unexposed pregnancies (n = 39, 4.96%). The relative risk for MCM with VPA exposure was 2.1 (95% confidence interval = 1.24–3.48, number needed to treat with VPA to result in MCM = 19). Reasons for using VPA during pregnancy (some women had more than one reason) were (1) VPA was the first AED prescribed and was effective (68, 29.06%), (2) other AEDs were ineffective (128, 54.70%), and (3) other AEDs were discontinued due to adverse effects (17, 7.28%). Other reasons (21, 8.97%) were (1) VPA was selected after the epilepsy classification was revised (3, 1.28%), (2) other AEDs were expensive (2, .85%), and (3) patient switched to VPA from other AEDs for unspecified reason (16, 6.83%). VPA was discontinued during pregnancy for 6 (2.71%) persons. Less than 10% of women were tried on lamotrigine or levetiracetam before switching to VPA.

Significance: Nine major congenital malformations per thousand pregnancies can be avoided if valproate is not used in women with epilepsy. Safe and effective antiepileptic drugs as alternatives to valproate are the need of the hour. Professional bodies and regulatory authorities need to implement updated guidelines on antiepileptic drug usage in girls and women.

Metformin Trial Dramatically Reduces Seizures in Tuberous Sclerosis

A team of researchers led by UCL Great Ormond Street Institute of Child Health (ICH) and Great Ormond Street Hospital (GOSH) has found that metformin – a drug commonly used to treat Type 2 diabetes – can successfully reduce symptoms associated with tuberous sclerosis complex (TSC), including reduction in the frequency of seizures and the size of brain tumors.

The study, which also included teams from Royal United Hospitals Bath NHS Foundation Trust (RUH) and University Hospitals Bristol and Weston NHS Foundation Trust, recruited 51 patients with TSC who were randomly assigned a placebo or metformin for one year on a dose similar to that given for Type 2 diabetes.

Throughout the study, the research team wanted to see if metformin, which inhibits the mTOR (cellular growth) pathway, could limit the tumour growth and epilepsy associated with TSC. All patients involved in the study had tumors in the kidney known as renal angiomyolipomas (AML). Of the 51 who took part, 27 patients had tumors in the brain called subependymal giant cell astrocytomas (SEGA) and 21 of them were under assessment for seizure frequency.

Over the course of the year, the team found a 21% reduction in the size of brain tumors of those who were given metformin, compared to a 3% increase in tumor volume for those taking the placebo. Patients with epilepsy and taking metformin saw a 44% drop in the frequency of their seizures, compared to a drop of only 3% for those on the placebo.

Epilepsy Surgery in Africa: State of the Art and Challenges

Abstract, originally published in Epilepsy & Behavior

Objective: Epilepsy is an important public health problem representing 0.6% of the global burden of disease that particularly impacts people living in the lowest income countries where epilepsy incidence may be 10 fold more than in the developed world. The battery of treatments designed to counteract the clinical manifestations of this disease are various and range from a wide spectrum of antiseizure medicationand specific diets, to surgical techniques for resection of the epileptogenic focus. The aim of our study was to describe the State of the art of Epilepsy Surgery (ES) in Africa and examine ways to deal with the high surgical treatment gap.

Methodology: In an observational study, we prospectively disseminated questionnaires via email or directly administered to main epileptologists and neurologists involved in epilepsy care, in key African countries. We also conducted a literature search using PubMed, Google scholar on ES in all the African countries.

Results: We received responses from the majority of African countries, which allowed us to identify 3 levels of care for ES in African countries, a first level that uses ES with invasive presurgical evaluation, a second level that uses ES but without invasive presurgical evaluation, and a third level that does not use ES, and we summarized these results on a map.

Discussion: This paper studied the availability of epilepsy surgery as a treatment modality in several African countries. We aimed to establish optimal pathways for initiating epilepsy surgery with noninvasive Electroencephalography and readily available investigations. This could be achieved through collaboration with epilepsy programs in developed countries directly or by using telemedicine.

Hemispherectomy Outcome Prediction Scale: Development and Validation of a Seizure Freedom Prediction Tool

Abstract, originally published in Epilepsia

Objective: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy.

Methods: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques.

Results: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom.

Significance: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Epilepsy Surgery in Children With Electrical Status Epilepticus in Sleep

Abstract, originally published in Neurosurgery

Objective: Pediatric epilepsy surgery candidates with unilateral congenital or early-acquired brain lesions may present with refractory seizures and generalized electroencephalographic features such as electrical status epilepticus in sleep (ESES). The purpose of our study was to review the clinical presentation, neuroimaging findings, and outcome in a series of children with unilateral brain lesions and ESES undergoing resective surgery for refractory epilepsy.

Methods: A total of 415 consecutive patients younger than 18 years of age undergoing video electroencephalographic evaluation and epilepsy surgery at Cleveland Clinic were reviewed for ESES, an underlying pathological lesion, and outcome after surgery.

Results: Eight patients were included. All patients presented with medically refractory epilepsy, hemiparesis, and developmental delay. The pathogenesis was perinatal infarction in 7 patients and malformation of cortical development in 1 patient. Preoperative electroencephalography demonstrated generalized interictal spikes, electroencephalographic seizures, and ESES in all cases. Age at the time of surgery ranged from 3 to 14 years. Six patients underwent hemispherectomy, and 2 patients underwent focal resection. Six patients became seizure-free after resection. Two patients with functional hemispherectomy continued to have rare seizures, but were much improved. These patients also had perinatal infarctions in the hemisphere contralateral to the resection, possibly indicating a less beneficial outcome. Postoperative electroencephalography demonstrated resolution of generalized interictal discharges and ESES in all. Formal pre- and postoperative neuropsychological testing showed overall improvement of age-equivalent scores.

Conclusion: Children with unilateral brain lesions and seizures may become seizure-free after epilepsy surgery, even if the preoperative electroencephalogram shows generalized ESES. The lesion occurring early in life and the location of the lesion may play a role in the development of ESES. Cognitive impairment may be aggravated by the persistence of ESES. Preliminary developmental data in this small sample suggest that termination of seizures and possibly of ESES by epilepsy surgery may have developmental benefits.

UVA Scientist Developing Gene Therapy to Help Girls With Rett Syndrome

A University of Virginia School of Medicine scientist is developing an innovative gene therapy she hopes will slow disease progression and improve movement, coordination and communication in children with Rett syndrome. The approach also may be useful for battling other genetic disorders involving the X chromosome.

UVA researcher Sanchita Bhatnagar discovered that tiny bits of RNA, called microRNAs, play an important role in Rett, a rare genetic disorder that can impair children’s ability to speak, move and even breathe. Based on that finding, she is seeking to sop up those RNA bits, called microRNA, using absorbent particles called microRNA sponges.

Early work in lab models has produced promising results, and she hopes the approach could lead to a better quality of life for children with Rett.

“We are seeing that lab animals treated with this gene therapy are more mobile. They’re moving faster, they’re smarter,” Bhatnagar said. And if that translates into even modest improvements for children, it could make a big difference, she said: “If we can help a child to move more independently, or improve their ability to communicate, I think for a parent, that’s a big win.”

The Role of Surgery in the Management of Lennox–Gastaut Syndrome: A Systematic Review and Meta-Analysis of the Clinical Evidence

Abstract, originally published in Epilepsia

Lennox–Gastaut syndrome (LGS) is a severe form of childhood onset epilepsy in which patients require multiple medications and may be candidates for palliative surgical intervention. In this meta-analysis, we sought to evaluate the impact of palliative vagus nerve stimulation (VNS), corpus callosotomy (CC), and resective surgery (RS) by analyzing their impact on seizure control, antiepileptic drug (AED) usage, quality of life (QOL), behavior, cognition, prognostic factors, and complications.

A systematic search of PubMed MEDLINE, Scopus, and Cochrane Database of Systematic Reviews was performed to find articles that met the following criteria: (1) prospective/retrospective study with original data, (2) at least one LGS surgery patient aged less than 18 years, and (3) information on seizure frequency reduction (measured as percentage, Engel class, or qualitative comment).

Seizures were analyzed quantitatively in a meta-analysis of proportions and a random-effects model, whereas other outcomes were analyzed qualitatively. Forty studies with 892 LGS patients met the selection criteria, with 19 reporting on CC, 17 on VNS, four on RS, two on RS + CC, one on CC + VNS, and one on deep brain stimulation. CC seizure reduction rate was 74.1% (95% confidence interval [CI] = 64.5%–83.7%), and VNS was 54.6% (95% CI = 42.9%–66.3%), which was significantly different (p < .001). RS seizure reduction was 88.9% (95% CI = 66.1%–99.7%).

Many VNS patients reported alertness improvements, and most had no major complications. VNS was most effective for atonic/tonic seizures; higher stimulation settings correlated with better outcomes. CC patients reported moderate cognitive and QOL improvements; disconnection syndrome, transient weakness, and respiratory complications were noted. Greater callosotomy extent correlated with better outcomes. AED usage most often did not change after surgery. RS showed considerable QOL improvements for patients with localized seizure foci.

In the reported literature, corpus callosotomy appeared to be more effective than vagus nerve stimulation for seizure reduction. Vagus nerve stimulation may provide a similar or higher level of quality of life improvement with lower aggregate risk of complications. Patient selection, anatomy, and seizure type will inform decision-making.