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.

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.

Preventive treatment positively alters ‘natural history of severe infantile epilepsy’

Article, originally published in Annals of Neurology

Preventive treatment with vigabatrin effectively altered the natural history of seizures among infants with tuberous sclerosis complex, decreasing the risk for and severity of epilepsy, according to results published in Annals of Neurology.

Katarzyna Kotulska, MD, PhD, of the department of neurology and epileptology at the Children’s Memorial Health Institute in Poland, and colleagues conducted the present study as part of the EPISTOP project, a long-term prospective study examining clinical and molecular biomarkers for epileptogenesis in a genetic model of epilepsy/TSC. The trial was conducted from March 2014 through October 2018 at nine sites in Europe and one site in Australia.

In both the RCT and OLT, no patients who received preventive treatment developed infantile spasms compared with four of 13 (31%) patients receiving conventional treatment in the RCT and six of 12 (50%) patients in the OLT, for a statistically significant difference in both the OLT and the pooled analysis (P = .015 and P < .001, respectively). No EPISTOP subject who completed the study developed a severe intellectual disability at the age of 2 years.

“… This EPISTOP study has shown that it may be possible to change the natural history of severe infantile epilepsy through early intervention with antiepileptic therapy,” the researchers wrote.

Precision Medicine: Academic dreaming or clinical reality?

Abstract, originally published in Epilepsia

Precision medicine can be distilled into a concept of accounting for an individual’s unique collection of clinical, physiologic, genetic, and sociodemographic characteristics to provide patient?level predictions of disease course and response to therapy. Abundant evidence now allows us to determine how an average person with epilepsy will respond to specific medical and surgical treatments. This is useful, but not readily applicable to an individual patient. This has brought into sharp focus the desire for a more individualized approach through which we counsel people based on individual characteristics, as opposed to population?level data. We are now accruing data at unprecedented rates, allowing us to convert this ideal into reality. In addition, we have access to growing volumes of administrative and electronic health records data, biometric, imaging, genetics data, microbiome, and other “omics” data, thus paving the way toward phenome?wide association studies and “the epidemiology of one.” Despite this, there are many challenges ahead. The collating, integrating, and storing sensitive multimodal data for advanced analytics remains difficult as patient consent and data security issues increase in complexity. Agreement on many aspects of epilepsy remains imperfect, rendering models sensitive to misclassification due to a lack of “ground truth.” Even with existing data, advanced analytics models are prone to overfitting and often failure to generalize externally. Finally, uptake by clinicians is often hindered by opaque, “black box” algorithms. Systematic approaches to data collection and model generation, and an emphasis on education to promote uptake and knowledge translation, are required to propel epilepsy?based precision medicine from the realm of the theoretical into routine clinical practice.

Study Finds Diet Therapy to be Most Effective Therapy in Children with Myoclonic-Atonic Seizures (Doose Syndrome)

Abstract, originally published in Epilepsia

Objective: Epilepsy with myoclonic-atonic seizures (EMAS) is a rare childhood onset epileptic encephalopathy. There is no clear consensus for recommended treatments, and pharmacoresistance is common. To better assess the clinical phenotype, most effective treatment, and determinants of cognitive and seizure outcomes, three major pediatric epilepsy centers combined data, creating the largest cohort of patients with EMAS ever studied to date.

Methods: Authors performed a retrospective chart review of patients with EMAS who received care at the authors’ institutions.

Results: A total of 166 children were identified. Global developmental delay (>1 domain) was present in 2% of children at onset and 49% during the course of the disease. Afebrile seizures occurred after the age of 2 years in 88%, generalized tonic-clonic seizures in 60%, and drop attack or myoclonic seizures in 30%. At onset, electroencephalography (EEG) found 28% normal, background slowing in 20%, and epileptiform discharges or seizures in 69%. Subsequent EEG found slowing in 62% and discharges or seizures in 90%. Response (>50% seizure reduction) to the first three antiseizure drugs (ASDs) was 26% (levetiracetam, 17%; valproic acid, 31%; other ASDs combined, 26%). Diet therapy was used as a second or third therapy in 19% and ultimately used in 57%; response was 79%, significantly greater than the first three ASDs (P = .005, ?2). Seizure freedom occurred in 57% and was less likely in the case of persistent global developmental delays (P < .001), seizure recorded on subsequent EEGs (P = .027), and failure to respond to diet therapy (P = .005). Development was normal in 47%, and 12% had delays in one domain, which was less likely in the case of global developmental delay after epilepsy onset (P < .001) and failure to achieve seizure freedom (P < .001).

Significance: This large cohort of children with EMAS clarifies areas of variability in practice. Diet therapy is by far the most effective treatment; failure to respond was associated with failure to attain seizure freedom. This therapy should be used early in the treatment in EMAS. This study also identified a bidirectional link between cognitive and seizure outcomes.

Study Highlights the Treatment Burden in Children With Epilepsy and Comorbidities

Abstract, originally published in Epilepsy Research

Objective: We conducted a long-term follow-up of a cohort of children with newly diagnosed unprovoked seizures to assess treatment with antiepileptic drugs (AEDs), neuroleptics, antidepressants and medication for attention deficit hyperactivity disorder (ADHD) with special attention to the impact of comorbidities on the use of such medication.

Methods: Our study cohort comprised 769 children (28 days-18 years), living in Stockholm Sweden, with a first unprovoked seizure identified between 2001 and 2006. Information on neurodevelopmental comorbidities and Cerebral Palsy (CP) at seizure onset was collected from medical records. Information on treatment with AEDs, neuroleptics, antidepressants and ADHD medication was retrieved by linkage to the Swedish National Prescription Registry between 2005 and 2014. The association between comorbidities and drug treatments was assessed by odds ratios (OR) with 95 % confidence intervals (CI), adjusted for age and sex.

Results: Eight years after the index seizure, 31 % of the children were on AEDs, and this was more common among children with any of the comorbidities studied (OR; 4.0 95 % CI 2.9-5.6) compared to those without such comorbidities, and within this group of comorbidities particularly for those with CP (OR; 5.2 95 % CI: 2.9-9.3). Children with neurodevelopmental comorbidity or CP at baseline were more likely to receive neuroleptics (ORs 8 years after the index seizure; 6.9, 95 % CI: 2.4-19.8), antidepressants (OR; 2.3, 95 % CI: 1.0-5.5) and ADHD medication (OR; 3.6, 95 % CI: 1.8-7.2) than children without the studied comorbidities.

Conclusion: Children with seizures in combination with neurodevelopmental comorbidities or cerebral palsy (CP), especially CP, have a more frequent use of antiepileptic drugs, neuroleptics, antidepressants, and ADHD medication up to 13 years following the initial seizure than children without comorbidity. Our data highlight the treatment burden in children with epilepsy and comorbidities.

Epilepsy Research News: November 2020

This month’s research news includes a study that highlights the importance of adherence to antiepileptic drug regimens and controlling seizures to reduce the risk of sudden unexplained death in epilepsy (SUDEP). We also highlight an advancement in understanding and preventing temporal lobe epilepsy, utilizing an animal model.

Additionally, we share a study that highlights the difficulty that can be faced in diagnosing sometimes subtle seizures associated with focal epilepsy, and we present findings on the development of a new tool to help ease what can be a challenging transition from pediatric/adolescent to adult care for individuals with epilepsy.

In other news, a new FDA alert was issued to avoid the use of lamotrigine/Lamictal in people with cardiac conduction disorders, ventricular arrhythmias, or cardiac disease or abnormality.

These studies and the FDA alert are summarized below.

Research Highlights

Preventing SUDEP
Polytherapy, especially the use of three or more antiepileptic drugs, is correlated with a substantially decreased risk for SUDEP according to a nationwide study conducted in Sweden. The study also demonstrated a link between statin use and a decreased risk for SUDEP. “These results provide support for the importance of medication adherence and intensified anti-epileptic drug treatment for patients with poorly controlled generalized tonic-conic seizures in the efforts to reduce SUDEP risks and suggest that comedication with statins may reduce risks,” the researchers wrote.

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Understanding & Treating Temporal Lobe Epilepsy
A team of researchers has found that an amino acid produced by the brain could play a crucial role in preventing cell loss and seizures associated with temporal lobe epilepsy. Utilizing an animal model of temporal lobe epilepsy, the research team found that administration of the amino acid D-serine prevented cell loss characteristic of temporal lobe epilepsy and reduced the number and severity of seizures.

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Focal Epilepsy & Delayed Diagnosis
A new study shows that it can take on average two years for physicians to recognize the early signs of focal epilepsy, particularly in patients with seizures that do not involve uncontrolled movements of their arms and legs. Subtler cases are often not diagnosed until they have progressed to disruptive “motor” seizures, say the study authors, which can cause the unrestrained, whole-body spasms often portrayed in popular culture. Researchers believe the impact of earlier diagnosis in focal epilepsy patients goes beyond more timely treatment of patients; some study participants reported having one or more car accidents before their diagnosis. The researchers estimate that for every 13 early diagnoses, one car accident, equating to an estimated 1,816 annually worldwide, could be prevented.

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Transitioning to Adulthood with Epilepsy
Clinicians at Michigan Medicine have developed an assessment tool to help doctors ensure adolescents and young adults with epilepsy have the skills and confidence they need to take control of seizures and health care. Through a customized screening tool for 16 to 26-year-olds, doctors are effectively able to monitor their patients’ development of knowledge and self-management skills regarding their condition. This tool allows providers to proactively address gaps in readiness that may impact long term health outcomes.

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FDA Alert for Lamotrigine
The FDA has issued a new warning advising against the use of lamotrigine/Lamictal in people with cardiac conduction disorders, ventricular arrhythmias, or cardiac disease or abnormality. People currently taking lamotrigine should consult their healthcare provider. Do not stop taking lamotrigine without talking to your healthcare provider as doing so can cause serious problems.

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Incidence of Potential Adverse Events During Hospital-Based Ketogenic Diet Initiation Among Children with Drug-Resistant Epilepsy

Abstract, originally published in Epilepsia

Objective: Due to the possibility of serious adverse events (AE), patients are commonly admitted to hospital for 3–5 days for ketogenic diet (KD) initiation. This study examined the incidence of potential AE during admission for KD initiation to investigate the possibility of safely initiating a KD at home.

Methods: Children with drug-resistant epilepsy (DRE) who were admitted to hospital for five days for KD initiation were retrospectively studied.

Results: A total of 66 children (59% female) were analyzed. The mean age at the initiation of the KD was 48.0±38.4 months and the mean weight was 14.6±6.3 kilograms. The median number of anticonvulsant medications used at the time of KD initiation was 3. The etiology of the DRE was structural in 4.5%, hypoxic ischemic encephalopathy in 10.6%, genetic/metabolic in 31.8%, acquired in 10.6% and unknown in 42.2%. The potential AE occurred in 28.7% of patients, including hypoglycemia (20%), hypoactivity (6.1%), somnolence (3%), and vomiting (7.6%). A univariate analysis of the clinical characteristics of the AE and no AE groups showed a statistically significant difference in weight (P = 0.003) and age (P = 0.033). The concurrent use of topiramate was found to have a near significant association (P = 0.097) between the groups. The groups’ urine ketone levels on all five days were compared and a statistically significant difference was found on day three (P = 0.026). A statistically significant difference in the serum bicarbonate levels (P = 0.038) was found between the patients taking topiramate and those not taking it.

Significance: The incidence of adverse events during admission for ketogenic diet initiation was found to be low. The adverse events either required no intervention or were easily managed with simple interventions. Thus, it may be possible to initiate a ketogenic diet at home if the parents are adequately prepared and monitored.

New FDA Alert for Lamotrigine

A new FDA alert has been issued for Lamotrigine/Lamictal. If you are taking this drug and have a cardiac condition, especially arrhythmia, there are new warnings, including the potential for sudden death. If you have concerns or questions about using this product, please call your doctor.

Please see the links below for more details:

Characteristics and Treatment Outcomes of Newly Diagnosed Epilepsy in Older People: A 30-Year Longitudinal Cohort Study

Abstract, originally published in Epilepsia

Objectives: To describe the clinical characteristics and evaluate the long-term treatment outcomes in older people with newly diagnosed epilepsy over the past 30 years.

Methods: We included patients newly diagnosed with epilepsy and commenced on antiseizure medications (ASMs) at age 65 years or older between July 1982 and October 2012 at the Western infirmary in Glasgow, Scotland. They were followed up until April 2016 or death. Seizure freedom was defined as no seizure for at least 1 year on unchanged medication at the last follow-up.

Results: A total of 201 patients (median age 73 years, 59% male) were included. The median duration from initial seizure to starting treatment was 8 months (interquartile range: 3.0-24.0 months); 42.2% (85/201) patients had more than five seizures before commencing treatment. Brain imaging showed potentially epileptogenic lesions in 19.7% (38/193) of patients and other abnormalities in 56.5% (109/193); 78.6% patients (158/201) were seizure-free at the last follow-up, of whom 94.9% were taking monotherapy. Concomitant aspirin use (n = 80) was associated with a lower probability of being seizure-free (relative risk 0.82, 95% confidence interval 0.70-0.97; P = .02). The use of second-generation ASMs as the initial monotherapy increased from 31.5% (23/73) before 2000 to 70.3% (90/128, P < .001) from 2000 onward. However, the seizure freedom rates (67.1% vs 55.5%; P = .35) and intolerable adverse-effect rates (16.4% vs 19.5%; P = .45) did not show any significant difference.

Significance: There was often a long interval between seizure onset and the initiation of treatment in older people with new-onset epilepsy, although the majority responded well to antiseizure medication treatment. Brain imaging showed a high rate of abnormalities. Despite the increased use of second-generation antiseizure medications, treatment outcomes in later-onset epilepsy have not improved over time. The possible effect of aspirin on treatment response warrants further investigation.