Epilepsy is a chronic brain disease that affects approximately 65 million people worldwide.
Approximately 3% of Australians will experience epilepsy at some point in their lives and over 250,000 Australians are currently living with epilepsy. However, despite the continuous development of antiepileptic drugs, over 30% patients with epilepsy progress to drug-resistant epilepsy.
In childhood, epilepsy is the most frequent chronic neurological condition, with approximately 1 in 150 children being diagnosed with a form of epilepsy during the first 10 years of life. Although 4 in 5 children reach a state of remission at 5 years, the remaining 1 in 5 may experience repeated cycles of relapse and remission or suffer severe drug-resistant of refractory epilepsies[2, 3].
Epilepsy is defined as refractory (or drug-resistant) if seizures persist despite adequate doses of two appropriate first-line antiepileptic drugs (AEDs). Negative consequences of untreated refractory epilepsy include learning and development problems and intellectual disability in children, epilepsy-related injury, increased risk of Sudden Unexpected Death in Epilepsy (SUDEP), increased risk of emotional and behavioural problems, poorer occupational outcomes, and increased risk of side effects to multiple antiseizure medications.
Once epilepsy is drug resistant, the likelihood that it will go away is relatively low. This is particularly true if there is a known structural abnormality of the brain. In order to prevent some of the negative consequences of long-standing, poorly controlled seizures, it is important to be assessed and receive prompt treatment.
Current treatment options
Some people with refractory epilepsy may respond to one or more of the following treatment options:
Resective Epilepsy Surgery (e.g. using laser) to remove the area of the brain that causes the seizures can be performed in people where the area of the brain is clearly identified, provided the area can be removed and the risk is minimal. For some individual cases, the procedure can result in a 50-70% reduction in seizures.
Specific Metabolic Treatment provided a metabolic cause of the seizures can be identified. Examples are treatment with a ketogenic diet for people with GLUT1 deficiency, pyridoxine or pyridoxal-5-phosphate for vitamin-dependent epilepsies, and creatine supplementation for creatine deficiency syndromes.
Genetic variant-specific therapy if a specific gene variant can be identified. For example, in people with SCN1A variants, medications such as oxcarbazepine (Trileptal), carbamazepine (Tegretol) or phenytoin (Dilantin) should be avoided. On the other hand, these medications can be helpful for people with SCN2A and SCN8A variants.
Immunotherapy. In the last decade, the role of inflammatory processes in certain types of epilepsy has been recognised. In these cases, medications that counteract these processes have been used with success. However, they have to be used with caution as they are associated with a variety of adverse events.
Metabolic/Dietary Therapy. The ketogenic diet can be highly effective for some young children, whereas a Modified Atkins Diet or Low Glycemic Index Diet can be effective for older children, teens, and adults. Research is underway to understand how metabolic pathways regulate nerve function, and to find antiepileptic therapies that target metabolic pathways. This work will provide a better understanding of the role of metabolism in epilepsy and could lead to the identification of other potential therapeutic targets.
Vagus Nerve Stimulation (VNS) is a type of neuromodulation performed with a device surgically implanted in the chest. The vagus nerve is part of the autonomic nervous system, which controls functions of the body that are not under voluntary control (such as heart rate and breathing). About 80% of people with epilepsy may have an increase in their heart rate before a seizure, and the device reduces that heart rate.
Deep Brain Stimulation (Responsive Neurostimulation) by placing electrodes in the brain and to reduce seizure frequency. The electrodes change how brain cells or networks work by giving electrical stimulation to brain areas involved in seizures. It is used together with seizure medications.
New and emerging therapies
Some severe paediatric epilepsies such as Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and CDKL5 Deficiency Disorder (CDD) are extremely debilitating due to the early onset of seizures and their lack of response to available treatment options including antiepileptic drugs, the ketogenic diet, high doses of steroids, and neurostimulation therapies. Thus, it has become imperative to look for novel and more effective treatment options.
Direct intracranial drug delivery. Epilepsy can cause alterations of the blood-brain barrier (BBB). These are thought to prevent anti-seizure drugs from entering the brain in sufficient amounts, thereby causing drug-resistant epilepsy. Although it is an invasive procedure, targeted intracranial drug delivery is an attractive approach to sidestep BBB-associated drug resistance. It can also lower the risk of general drug-related adverse effects.
Discovery of new drug targets. Promising research into drug therapy is focusing on various processes that may be involved in seizures. These include targeting specific signalling pathway; using zinc supplementation or melatonin; inhibiting carbonic anhydrase, the complement system or TRPV1; using neuroprotective or anti-inflammatory peptides1, and targeting the gut microbiome with probiotics. However, further research is still needed to evaluate how these therapeutic interventions can be applied safely without causing undesirable side effects, especially in combination with already commonly prescribed AEDs.
Cannabidiol. In June 2018, based on the positive results from several randomised, double-blind, placebo-controlled trials[11-15], the US Food and Drug Administration (FDA) approved a pharmaceutical formulation (Epidiolex®, Epidyolex®) of cannabis plant-derived cannabidiol (CBD) for the treatment of DS and LGS. The medication was approved by the Australian government in 2020, which has also issued a guidance document for the use of CBD formulations in the treatment of epilepsy in paediatric and young adult patients in Australia. Between 1 August 2020 to 16 January 2021, the Therapeutic Goods Administration had approved 279 prescriptions of CBD for epilepsy, of which 35% were for children aged less than 16 years, and 65% for people over the age of 16 years.
These decisions followed growing evidence in animal and human studies that supports the involvement of endocannabinoid system (ECS) in early brain development, as well as in in paediatric epilepsy. Cannabinoids have been shown to play a role in the inhibition of nerve transmission and modulation of neuronal firing rate, primarily through the suppression of glutamate release. In epilepsy, it is believed that glutamate contributes to a state of chronic, altered network activity which results in excessive neuronal firing and alterations in signal transmission. This understanding highlighted the potential for modulation of seizure activity through the use of cannabinoids and led to several clinical trials[11-15]. A recent functional MRI (fMRI) study suggests that CBD also modulates attention control processing in people with treatment-resistant epilepsy by changing the activation of specific areas of the brain.
In clinical trials, the addition of high-dose CBD to standard AEDs reduced the number and severity of seizures by up to 50% and improved quality of life in children with refractory epilepsies[11-15]. However, as with all drug interventions, CBD is not risk free. When used at high doses, adverse events reported in the trials included mild to moderate somnolence, decreased appetite, diarrhoea, and some liver damage, which were reversed when the dose was reduced21. CBD may also interact with other AEDs to increase the risk of side effects[22, 23]. For these reasons, it is critical that all patients who wish to investigate the suitability of CBD or any other treatment for refractory epilepsy, are assessed and closely monitored by a registered medical practitioner.
For more information regarding CBD for epilepsy, visit Cannabis 4 Epilepsy (C4E). For a list of new clinical trials of novel therapies for drug-resistant epilepsy, see ClinicalTrials.gov or the Australia New Zealand Clinical Trial Registry (ANZCTR).
Further information can be obtained freely from Epilepsy Action Australia.
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 Berg AT, Rychlik K. The course of childhood-onset epilepsy over the first two decades: a prospective, longitudinal study. Epilepsia. 2015;56(1):40-8.
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 Epilepsy Foundation. https://www.epilepsy.com/learn/drug-resistant-epilepsy. Accessed 16-03-2021.
 Fei Y, Shi R, Song Z, Wu J. Metabolic Control of Epilepsy: A Promising Therapeutic Target for Epilepsy. Front Neurol. 2020;11:592514.
 Fisher B, DesMarteau JA, Koontz EH, Wilks SJ, Melamed SE. Responsive Vagus Nerve Stimulation for Drug Resistant Epilepsy: A Review of New Features and Practical Guidance for Advanced Practice Providers. Front Neurol. 2020;11:610379.
 Granata T, Marchi N, Carlton E, Ghosh C, Gonzalez-Martinez J, Alexopoulos AV, et al. Management of the patient with medically refractory epilepsy. Expert Rev Neurother. 2009;9(12):1791-802.
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 Holmes M, Flaminio Z, Vardhan M, Xu F, Li X, Devinsky O, et al. Cross talk between drug-resistant epilepsy and the gut microbiome. Epilepsia. 2020;61(12):2619-28.
 Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial. Epilepsia. 2019;60(2):294-302.
 Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391(10125):1085-96.
 Szaflarski JP, Bebin EM, Cutter G, DeWolfe J, Dure LS, Gaston TE, et al. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study. Epilepsy Behav. 2018;87:131-6.
 Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90(14):e1204-e11.
 Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med. 2018;378(20):1888-97.
 FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy [press release]. 2018.
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 Barker-Haliski M, White HS. Glutamatergic Mechanisms Associated with Seizures and Epilepsy. Cold Spring Harb Perspect Med. 2015;5(8):a022863.
 Dale T, Downs J, Olson H, Bergin AM, Smith S, Leonard H. Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder. Epilepsy Res. 2019;151:31-9.
 Allendorfer JB, Nenert R, Bebin EM, Gaston TE, Grayson LE, Hernando KA, et al. fMRI study of cannabidiol-induced changes in attention control in treatment-resistant epilepsy. Epilepsy Behav. 2019;96:114-21.
 Lattanzi S, Trinka E, Russo E, Striano P, Citraro R, Silvestrini M, et al. Cannabidiol as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. Drugs Today (Barc). 2019;55(3):177-96.
 Devinsky O, Thiele EA, Wright S, Checketts D, Morrison G, Dunayevich E, et al. Cannabidiol efficacy independent of clobazam: Meta-analysis of four randomized controlled trials. Acta Neurol Scand. 2020;In Press.
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