User:Aasj2215/Management of drug-resistant epilepsy

Drug-resistant epilepsy (DRE), also known as refractory epilepsy, intractable epilepsy, or pharmacoresistant epilepsy refers to a state in which an individual with a diagnosis of epilepsy is unresponsive to multiple first line therapies. Based on the 2010 guidelines from the International League against Epilepsy (ILAE), DRE is officially diagnosed following a lack of therapeutic relief in the form of continued seizure burden after trialing at least two antiepileptic drugs (AEDs) at the appropriate dosage and duration. The probability that the next medication will achieve seizure freedom drops with every failed AED. For example, after two failed AEDs, the probability that the third will achieve seizure freedom is around 4%. Drug-resistant epilepsy is commonly diagnosed after several years of uncontrolled seizures, however, in most cases, it is evident much earlier. Approximately 30% of people with epilepsy have a drug-resistant form. Achieving seizure control in DRE patients is critical as uncontrolled seizures can lead to irreversible damage to the brain, cognitive impairment, and increased risk for sudden unexpected death in epilepsy called SUDEP. Indirect consequences of DRE include seizure related injuries and/or accidents, impairment in daily life, adverse medication effects, increased co-morbidities especially psychological, and increased economic burden, etc.

Some clinical factors that are thought to be predictive of DRE include the female sex, focal epilepsy, developmental delay, status epilepticus, earlier age of onset of epilepsy, neurological deficits, having an abnormal EEG and/or imaging findings, genetic predisposition, association with the ABCB1 gene, and inborn errors of metabolism. Especially among pediatric populations there is a growing association between DRE and genetic conditions or developmental disorders such as Lennox-Gastaut or Dravet Syndrome.

There are numerous theories regarding the mechanism of action behind DRE many of which have been studied in human and/or animal models. However, it still remains unclear the exact pathogenesis of this condition.

• Transporter Hypothesis: Changes to transporters in the blood-brain barrier lead to decreased effectiveness of AEDs through decreased drug concentration. These changes could be in the form of increased efflux transporters or less transporters overall.
• Pharmacokinetic Hypothesis: Changes to transporters (increased efflux) peripherally in places like the intestines influence efficacy of AEDs and ability to ultimately reach target sites in the brain.
• Target Hypothesis: Changes to target protein sites of AEDS influence their effectiveness.
• Intrinsic Severity Hypothesis: Refers to the severity of epilepsy and impact increased seizure burden can have on drug efficacy.
• Gene Variant Hypothesis: When AEDs are not as effective due to inherent genetic variability whether in transporters, target sites, and/or the specific kind of epilepsy.
• Neural Network Hypothesis: When increased seizure burden impacts structure of the brain through neural connections which worsens clinical symptoms and reduces drug efficacy.

Diagnostic evaluation

The first step is for physicians to refer their DRE patients to an epilepsy specialist in a comprehensive epilepsy center where further diagnostic work-up can be performed.

Prolonged EEG/Continuous video EEG/ Epilepsy Monitoring Unit monitoring

One of the first steps in management of drug resistant epilepsy is confirming the diagnosis by EEG. Typically patients are admitted to hospital for prolonged EEG monitoring with video technology used to capture clinical events as they occur. Typically patients are taken off their anti-seizure medications in order to characterize the evolution of seizure symptoms and their relation with changes in electrical activity of brain. This is done while simultaneously minimizing the adverse consequences of seizures. Additional maneuvers to provoke seizures are also frequently performed, like sleep deprivation, photic stimulation, and hyperventilation. This study can take anywhere from 1–14 days. The length of the study depends on factors like baseline seizure frequency, the number and type of seizure medications the patient is taking prior to the study, institutional protocols etc. The goal is to record 3-4 typical seizures, though in some cases more or fewer seizures may need to be recorded. After this evaluation some patients may be determined to have non-epileptic causes of their symptoms, eg. syncope, psychogenic nonepileptic seizures, cardiac arrhythmia etc.

For patients who are confirmed to have epilepsy, this testing helps further elucidate the type of epilepsy (generalized vs focal), type of seizures (atonic, absence, GTC, etc.), and can be used for pre-surgical evaluation or to guide further management. Changes on EEG in relation to clinical seizure symptoms is used to determine the likely area of the brain responsible (symptomatic zone) and by extrapolation the area where seizure activity likely starts (seizure onset zone). In some specific cases, prolonged EEG may be done as an outpatient or ambulatory study where the patient goes home with an EEG set-up. This type of monitoring is usually limited to 2–3 days and patients are not taken off their AEDs.

Neuroimaging

MRI of brain is the most common first-line neuroimaging modality to be used in evaluation of a structural cause of epilepsy. A 3 Tesla MRI is generally recommended, as opposed to scanning on lower magnet strengths. MRI for evaluation of epilepsy often include T1 and T2 images that are optimized to appreciate gray-white matter differentiation and oblique coronal images along the axis of hippocampus. Identification of common lesions associated with epilepsy like focal cortical dysplasia, mesial temporal sclerosis, microencephalocele, and heterotopia require thorough review of images by trained clinicians as the changes can be very subtle and easily missed if not specifically evaluated for. Oftentimes, repeat MRI is required to elucidate an etiology to epilepsy and typically an epilepsy imaging protocol is followed to identify these subtle changes. There is ongoing quantitative analysis of standard MRI images to identify subtle lesions and use of stronger magnetic fields, like 7 Tesla MRI, for better delineation of anatomical details. Additionally, not all structural abnormalities seen on MRI correlate with epilepsy and may represent incidental findings.

Positron emission tomography scan (PET) using the ¹⁸F-FDG radiotracer can also be used in evaluation of DRE. Its use in epilepsy evaluation is based on the premise that areas of the brain responsible for seizure onset also have persistent metabolic dysfunction and do not use glucose at the same rate as neurotypical areas of the brain. Specifically, during seizure activity (ictal) one would expect a hypermetabolic state with increased radiotracer uptake on PET scan while in between events (interictal) one would expect a hypometabolic state with lower radiotracer uptake on PET scan. Oftentimes findings on PET scan are often correlated with other diagnostic workup that has already/concurrently been obtained to further localize an epileptogenic area of the brain, particularly in the case of focal epilepsy. Other ligands like ¹¹C-flumazenil, 1¹C-alpha-methyl-L-tryptophan, ¹¹C-methionine, have also been used, mostly on research basis to help identify areas of seizure onset.

Single-Photon Emission Computerized Tomography (SPECT scan) is another radiotracer based imaging technique that uses an oxygen radio-isotope to assess blood flow in the brain. This imaging is performed during inpatient video EEG monitoring in which the tracer is injected into the patient's bloodstream as soon as a seizure start. Areas of the brain associated with seizure onset will have increased blood flow, hence, increased uptake of the tracer if injected at an appropriate time. Imaging is performed after seizure activity is over to assess areas showing a significant increase in blood flow at seizure onset. A major limitation with this technique is the logistics required when injecting the radiotracer and quality of the images produced.

Magnetoencephalography (MEG): A newer non-invasive imaging technique that measures the magnetic field associated with neuronal firing in the brain. While each individual neuron's magnetic field is undetectable, when neurons are firing concurrently, such as during a seizure, the magnetic field generated is detected via MEG. This data provides real time brain mapping and has proven to be extremely effective in pre-surgical planning and localization of epilepsy. MEG is particularly useful in detect more superficial abnormalities and is more sensitive than other imaging modalities.

Neuropsychological testing

Neuropsychological testing involves a series of tests aimed at assessing higher order mental functions like memory, executive function, language, overall IQ, etc. in order to establish baseline cognitive function. If there is poor performance in measures of specific cognitive domains like verbal memory, naming, visuo-spatial orientation; it may point to areas of brain that are dysfunctional and likely related to seizure onset. This testing could also indicate poor performance on most measures and suggest more widespread dysfunction in the brain. Besides helping assess the likely area of seizure onset, this testing can be informative post surgical intervention and/or epilepsy therapy.

Language Lateralization

If epilepsy surgery is being considered, testing is often performed to determine the hemisphere of the brain involved in language and memory function. This helps inform about potential risks to language and memory with surgery. There are two main tests available for this objective: the Wada test and fMRI.

The Wada test has been one of the most commonly used tests around the world since the 1960s. This is an invasive testing technique that requires neurointerventionalists, neuropsychologists, neurophysiologists, EEG technologists, and anesthesiologists. When conducting the wada test, a catheter is threaded from wrist or groin into the carotid artery and finally the middle cerebral artery. An injection of sodium amytal is given to temporarily anesthetize 2/3rd of the cerebral hemisphere on one side. Neuropsychological testing is then done to assess language and memory function of the other hemisphere. Once the patient is fully recovered from the injection on the first side, the catheter is withdrawn and threaded up the contralateral middle cerebral artery with neuropsychological testing repeated. This testing informs the "reserve" for memory and language function in each hemisphere and the potential for impairment with resective surgery on a given side. In some cases additional testing with selective injection of the posterior cerebral artery (that supplies the mesial temporal region including hippoampus) can be done.

The Wada test is increasingly being replaced by the noninvasive fMRI imaging technique. Functional MRI (fMRI) measures the change in blood flow and oxygenation in different parts of the brain in response to an activity. Different tasks or paradigms are presented to a patient while they are in an MRI scanner. These tasks are designed to activate areas involved in different language functions and post processing of the images helps identify areas that are activated during different language tasks.

Pharmacotherapy

While the term drug resistant epilepsy implies ineffectiveness of pharmacologic therapy, recent advances in the pharmaceutical industry have introduced new drugs that have proven to be effective in the management of DRE patients.

Cenobamate

Approved by the FDA in 2019 for treatment of epilepsy in adults, Cenobamate is primarily used to treat patients with focal onset seizures. The mechanism of action of this drug is unclear, but is likely related to the inactivation of Na Channels and action as a GABA modulator. The dosing range for this drug is anywhere from 100-400 mg with a half-life of 55 hours. There have been at least three separate clinical trials involving Cenobamate with results showing a reduction in seizure burden by at least 50% in the experimental groups especially at higher doses of the drug. Of note, Cenobamate can interact with other medications especially other AEDs being taken and as such requires medication titration.

Fenfluramine

This drug was used at high doses as an obesity drug that was later recalled given adverse cardiac effects. Fenfluramine is now approved at lower doses as of 2020 for treatment of seizures in patients 2 years and older with Lennox-Gastaut and Dravet syndrome. Fenfluramine is an amphetamine derivative that acts on GABA and NMDA receptors. Among Dravet and LGS patients, it has been shown to be helpful with most seizure types including atonic, GTC, and tonic. This medication has also been reported to be helpful in behavioral and cognitive symptoms associated with intractable epilepsy. In specific, at higher doses there are reports of patients showing improvement in daily executive functioning and emotional regulation. No adverse cardiac events have been reported with the use of fenfluramine for epilepsy treatment.

Diets

For over 100 years it has been known that a diet with a high fat content and a low carbohydrate content can reduce seizures. Radically curbing carbohydrate intake imitates starvation and forces the body to draw energy from ketone bodies that form when fat is metabolized instead of drawing its energy from sugar. This state is called ketosis and it changes several biochemical processes in the brain in a way that inhibits epileptic activity. On this basis there are several diets that are often recommended to children under 12 years old, but are also effective in adults for DRE management.

Ketogenic diet

The ketogenic diet is the diet that is most commonly recommended by doctors for patients with epilepsy. In this diet the ratio of fat to carbohydrates and proteins is 4:1. That means that the fat content of the consumed food must be around 80%, the protein content must be around 15%, and the carbohydrate content must be around 5%. For comparison the average western diet consists of a carbohydrate content of over 50%. After one year on the ketogenic diet the success rate (seizure reduction over 50%) is between 30 and 50% and the dropout rate is around 45%. Although the ketogenic diet can be very effective, some families report that it's not compatible with daily life given its restrictive nature. It can be especially difficult for adolescents to follow as their autonomy increases. For this reason a fat ratio of 3: 1 instead of 4: 1 can be recommended to make meals more palatable. Side effects of the ketogenic diet include constipation, fatigue, weight loss, and kidney stones (typically after long-term adherence).

MCT-Ketogenic diet

In the 1960s, it was discovered that when medium-chain triglycerides (MCT) are metabolized more ketone bodies are produced than from metabolizing any other fat. This discovery sparked the introduction of the MCT-ketogenic diet, a modification of the ketogenic diet. In the MCT-ketogenic diet, MCT oil is added to ketogenic meals, which allows the carbohydrate content to be increased. The efficacy of the MCT ketogenic diet does not differ significantly from the classic ketogenic diet however not all patients, especially pediatric populations, can tolerate the large amounts of MCT oil required. This diet can also be costly.

Modified Atkins

A modified Atkins diet was coined after the popular Atkins diet with the goal of reducing seizures through ketosis. In this diet, the fat content is slightly lower than in the ketogenic diet at around 60%, the protein content is around 30% and the carbohydrate content is around 10%. Several studies show that the modified Atkins diet is just as effective as the ketogenic diet. Some physicians recommend the modified Atkins diet because they assume that patients will adhere to it on the long-term because it is more compatible with daily life and the meals are more enjoyable.

Low Glycemic Index (LGI)

The aim of the LGI diet is to keep blood glucose levels at a stable state. Rapid fluctuations in glucose levels both high and low is thought to be a trigger for seizures in some patients with epilepsy. This diet permits 40-60 gram of carbohydrates daily but with the goal of a glycemic index of <50. This diet has been studied among pediatric populations as an effective form of management for DRE.