A spotlight on epilepsy

In conjunction with International Epilepsy Day, Dr Fong Si Lei, neurologist and current President of the Malaysian Society of Epilepsy, gives an overview and insights on the oft-overlooked disease.

What is epilepsy?
Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological and social consequences of this condition. It is generally classified into focal and generalized epilepsy based on the seizure type ie, focal seizure onset or generalized seizure onset, based on clinical observation and/or electroencephalogram (EEG). In conditions when specific seizure types and EEG patterns are found in patients of specific age groups, these are termed as epileptic syndromes eg, juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE) or juvenile absence epilepsy (JAE).

Some types of epilepsy are rare, such as Lennox-Gastaut syndrome and Dravet syndrome. Lennox-Gastaut syndrome is characterized by a triad of multiple seizure types, characteristic EEG findings (diffuse, slow spike-waves and generalized paroxysmal fast activities), and intellectual disabilities. It is found in 0.1 to 0.28 per 100,000 population, accounting for 2-5 percent of all childhood epilepsies.

Dravet syndrome is a genetic epileptic encephalopathy which begins in the first year of life, giving rise to multiple seizures (myoclonic, clonic, tonic-clonic, atonic, atypical absence), which are refractory to anti-seizure medications. It occurs in 1-in-20,000 to 1-in-40,000 population. Eight out of 10 people with Dravet syndrome have a gene mutation in SCN1A.

Diagnosing epilepsy
Key diagnostics tools are good history taking skills looking into age of onset, presence of developmental progression/intellectual status after seizure onset, family history of epilepsy, history of head trauma, central nervous system infection and significant perinatal events. Home videos or closed-circuit television (CCTV) are also useful to help clinicians to determine seizure types based on the semiology. EEG as mentioned, is helpful to determine the seizure types (focal vs generalized). Brain magnetic resonance imaging (MRI) in epileptic syndrome such as JME, JAE or CAE, or developmental epileptic encephalopathy (DEE) such as Dravet syndrome are usually normal ie, no abnormalities are seen in the scan.

MRI is mandatory to look for the etiology of focal seizures or epilepsy with multiple seizure types. Common lesions are mesial temporal sclerosis, malformations of cortical development (MCDs) such as focal cortical dysplasia, periventricular nodular heterotopia, polymicrogyria and lissencephaly. A high-resolution MRI (at least 3.0 Tesla) with specific sequences such as volumetric T1 and fluid attenuated inversion recovery (FLAIR) sequences can improve the detection of these lesions and allow the clinicians to refer these patients for epilepsy surgery especially in drug-resistant epilepsy. Genetic testing such as targeted genetic panel, whole exome sequencing (WES), and whole genome sequencing (WGS) has improved the diagnostic yield for DEE, which are important for screening of other potentially involved organs, prognostication of patient’s outcome and genetic counseling.

Management and treatment

For both focal and generalized epilepsies, anti-seizure medications are always the first line therapy. However, only up to 60 percent of patients with focal epilepsies could be seizure-free with anti-seizure medication alone. When the epilepsy becomes drug-resistant ie, persistent seizures despite two appropriate and optimum dose of anti-seizure medications, patients should be referred to a centre which provide epilepsy surgery service for further evaluation, including long-term video EEG monitoring, high-resolution brain MRI, positron emission tomography (PET).

Epilepsy surgeries may be considered if these data are concordant. Epilepsy surgeries, which could be done, are individualized based on the etiology of epilepsy and include lesionectomy (for focal cortical dysplasia, cavernoma, brain tumors), or invasive intracranial monitoring such as stereo-EEG, subdural EEG followed by thermocoagulation. For cases who are not candidate for epilepsy surgery (multiple or generalized seizure onset foci), neuromodulation therapies such as deep brain stimulation (DBS), vagus nerve stimulation (VNS) or responsive nerve stimulation (RNS) could be performed.

Epilepsy surgery is often the key towards the goal of seizure freedom in drug-resistant focal epilepsy. Other therapies such as ketogenic diets (including classical ketogenic diet, low glycemic index diet and modified Atkins diet), are usually adjunctive to anti-seizure medication. Newer anti-seizure medications are always being developed to target especially focal epilepsy, and these includes brivaracetam and cenobamate.

Advancements in the treatment of epilepsy
More recent pharmacological advancements are seen in two groups of patients. The first are patients with specific epileptic syndromes, where fenfluramine was approved for Dravet syndrome; and everolimus for tuberous sclerosis. The second are those with focal epilepsy in general, where cenobamate is now available.

Surgery wise, options which are rapidly developing now are (1) minimally invasive MRI-guided laser interstitial thermal therapy (MRgLiTT) and (2) minimally invasive thermocoagulation for ablation epileptic focus eg, periventricular nodular heteropia, hypothalamic hamartoma, and focal cortical dysplasia. Focused ultrasonography (FUS) is also another form of non-invasive treatment to modulate and lower cortical neuronal hyperexcitability in epilepsy patients.

Personalized gene-targeted medicine ie, precision medicine in the epilepsies has gathered much attention in recent years. However, integrating precision medicine into clinical practice is challenging, due to the complexity of genotype-phenotype correlation in epilepsy and the unequal access to genetic testing and counseling. In addition, further validation and determination of common standard for gene-based therapies are still lacking to date. While gene discovery pushes forward new understanding of disease biology and its pathogenesis in epilepsy, large-scale randomized controlled trials for the development of safe, ethical, and equitable gene-based approaches for these rare genetic epilepsies are needed to allow translation of sciences to clinical practice.

A debilitating disease for all
The disease often affects both the patients and their families. Psychosocial challenges faced by the patients and their families include, multi-level stigmatization (personal stigma, institutional stigma and societal stigma), other highly stigmatizing psychiatric comorbidities include major depressive disorders and anxiety disorders. Long-term caregivers to a family member with epilepsy could also face the issue of burnout, major depressive disorders and anxiety. The consequences of these psychosocial issues are low self-esteem, lack of education, unemployment, lower socioeconomic status, divorce, and isolation from the society.

Psychosocial issues could negatively impact the management of people with epilepsy as the problem listed above may cause avoidance of attendance to clinic, denial of concurrent depressive and anxiety symptoms leading to undermanagement of psychiatric comorbidities. Healthcare providers should ensure patients are regularly screened for anxiety and depression with referrals to psychiatrist or psychologist when needed. HCPs should also be supportive to caregivers and patients, especially in return-to-work programme, and encourage them to join societal support groups.

What is on the horizon?
Neuromodulation therapies especially the non-invasive therapies such as transmagnetic stimulation and low-intensity focused ultrasonography, and targeted immunotherapies for immune-mediated epilepsy are rapidly developing research areas in epilepsy.

Takeaway
A successful healthcare system should allow equal access to anti-seizure medications and epilepsy surgeries. The cost of these therapies are the main barrier to improve the treatment gap in people with epilepsy. Special subsidization programme, anti-seizure medication or epilepsy surgery-related cost-reduction policy should be implemented to ensure rare and refractory epilepsy patients have access to affordable anti-seizure medications and necessary intervention.