A Review on Treatments for Seizures and Epilepsy

Abstract

Epilepsy is one of the most common neurological diseases and is characterized by two or more unprovoked seizures due to excessive electrical discharges in brain cells. The main treatments for epilepsy are antiepileptic drugs, surgery, and ketogenic diet. The latter two are particularly for patients with drug-resistant epilepsy. Despite numerous studies and clinical trials done to investigate these therapies, the effectiveness, safety, and mechanisms of many therapies remain controversial and unclear. This review focuses on the effectiveness, adverse effects, and proposed mechanisms of some most commonly used treatments for epilepsy.

 

Introduction

According to World Health Organization, epilepsy affects 50 million people worldwide, making it one of the most common neurological diseases (1). It is defined by two or more unprovoked seizures and creates substantial burdens on households (1). Epilepsy can result from structural, genetic, infectious, metabolic, immune and other deficiencies (1, 2, 3), while seizures are caused by excessive electrical discharges in a group of brain cells (1). Different types of therapies have been developed to prevent and treat epilepsy and seizure. The first treatments were surgeries which were first performed in 1831, followed by the discovery of antiepileptic drugs in the 19th and 20th centuries (4). In the early 20th century, ketogenic diet was introduced as a diet full of fats and low in proteins and carbohydrates (4). More recently, neurostimulation and complementary therapies are developed, but the latter may require more studies to establish their therapeutic effects (4). In general, the newly developed drugs have better drug-drug interaction and lower risk of teratogenicity, but they have not improved the overall efficacy and tolerability of drug treatment for epilepsy and require further studies (5). Furthermore, surgery and ketogenic diets are usually used for drug-resistant epilepsy, which according to the International League Against Epilepsy, may be defined as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (6).

 

Treatments

Medication

For the majority of people with epilepsy, initial therapy consists of pharmacological treatment with one or more of the established antiepileptic drugs (7). Generally, their mechanisms of action involve ion channel inhibition, GABA receptor activation, and/or glutamate receptor inhibition. The majority of antiepileptic drugs target voltage-gated ion channels, and a few also attenuate voltage-dependent, low-threshold T-type calcium currents in thalamocortical neurons, thereby interrupting the thalamic oscillatory firing patterns associated with spike-wave seizures, and others modulate N-type, L-type, P-type, and high voltage-activated calcium currents (7). GABA is one of the main neurotransmitters in the brain, and its receptors control the opening of chloride channels, which leads to chloride influx and thus inhibition of action potential (8). Epileptic drugs such as tiagabine inhibit neuronal and glial uptake of GABA, and vigabatrin increases the synaptic concentration of GABA by inhibition of GABA-aminotransferase, thereby activating chloride channels and preventing depolarization (8). In addition, second-generation drugs such as felbamate are found to limit glutamate-mediated excitatory neurotransmission by preferentially binding to the NR2B subunit of the NMDA receptor and reduces sustained repetitive firing in mouse spinal cord neurons and provides neuroprotective functions (7).

Carbamazepine

Carbamazepine is one of the first-line medications for epilepsy and is effective against partial seizures while may have more adverse effects when treating other types of seizures. One clinical trial showed that carbamazepine is as effective as valproate for the treatment of generalized tonic-clonic seizures but provides better control of complex partial seizures and has fewer long-term adverse effects (9). The results for the patients who completed the trial at 12 months were collected: for patients with generalized tonic-clonic seizures, seizure rate/month for patients treated with carbamazepine and valproate was 0.2±1.0 and 0.2±0.6, respectively; for patients with complex partial seizures, seizure rate/month for patients treated with carbamazepine and valproate was 0.9±3.0 and 2.2±8.2, respectively (9). Potentially serious effects such as rash, platelets counts below 100,000 per cubic millimeter, and third-degree heart block were observed in the carbamazepine group, while rash (rarely), platelets count below 8000 per cubic millimeter, transient pancreatitis with pain, nausea, and vomiting after 18 and 36 months that required hospitalization were observed valproate group (9). Other less serious systemic effects such as weight gain and loss of hair occurred more often with valproate, and neurological effects were similar with both medications (9). In general, at 12 months, the valproate recipient had worse overall status in the group of complex partial seizures and both seizure groups combined but not in the group with tonic-clonic seizures (9). However, there were also studies showing that carbamazepine could exacerbate epilepsy in children and adolescence. In one study, among the twenty-six patients, twenty-two had increases in seizure frequency, eight had increases in individual seizures, and eleven had onset of new seizure types, most often tonic-clonic (10). In addition, twelve patients had two changes, and one patient had all three changes in seizure activity (10). Furthermore, epileptic syndromes such as childhood absence, frontal-lobe, and severe myoclonic epilepsy of infancy worsened with carbamazepine therapy in some patients (10). Therefore, caution is needed when prescribing carbamazepine to a child or adolescence with absence or mixed seizures (10). One proposed mechanism behind the aggravation of absence seizures by carbamazepine is that carbamazepine acts at the ventrobasal complex of the thalamus via GABAA receptor-mediated mechanism and is demonstrated in a study with rats, but this mechanism is believed to be different from its primary antiepileptic action (11).

 

Ethosuximide

Ethosuximide is used in controlling absence seizures and is frequently used together with carbamazepine for mixed-seizure disorders, and its deposition can be altered by carbamazepine (13, 14). In a double-blind, randomized controlled clinical trial that compared the efficiency, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy, the freedom-from-failure at month 12 was 45% for ethosuximide, 44% for valproic acid, 21% for lamotrigine, and treatment failure increased between week 16-20 with the fewest increase in ethosuximide group (12). At 16-20 weeks persisted until month 12, ethosuximide and valproic acid had no intolerable events compared to lamotrigine, but the valproic acid cohort experienced a higher rate of adverse events, indicating that ethosuximide may be the optimal drug for initial empirical monotherapy in childhood absence epilepsy (12). In addition, drugs interact with each other when they are applied together. When applied with carbamazepine, plasma samples collected in six normal subjects that took ethosuximide for 28 days and carbamazepine from days 11 to 27 showed that the mean steady-state concentrations of ethosuximide declined by 17% from day 10 to day 28, meaning that carbamazepine can affect ethosuximide kinetic parameters (13). Furthermore, a study done by Sherwin A L, Robb J P, and Lechter M showed that monitoring of plasma ethosuximide increases the effectiveness of therapy by the recognition of noncompliance and the individualization of drug requirements (14). By monitoring the plasma ethosuximide levels and making appropriate adjustments over 2.5 years, there was a reduction of absence seizures in 48% of previous patients with uncontrolled attacks, and practical control increased from 64% to 81% (14). Therefore, regular monitoring of plasma ethosuximide levels may improve the effectiveness of treatment of patients of absence seizures and lead to optimal individualization of drug requirements (14).

Oxcarbazepine

Oxcarbazepine is used as a first-line and add-on treatment for patients with partial seizures with or without secondarily generalized seizures and generalized tonic-clonic seizures without partial onset (15). It is shown to have similar efficiency as phenytoin in a double-blind, randomized, parallel-group comparison with 5-18 years old patients (15). The results were that 61% in the oxcarbazepine group and 60% in the phenytoin group were seizure-free during the 48 weeks, and 82.3% in the oxcarbazepine group and 89.4% in the phenytoin group had least one adverse experience including ataxia, dizziness, gum hyperplasia, hypertrichosis and nervousness (15). Because of the high incidence of seizure and epilepsy in the elderly, the safety and tolerability of oxcarbazepine in the elderly were accessed in two cohorts of 18-64 years old and 65 years and older patients. Approximately 81% in the elderly group experienced at least one treatment-emergent adverse event during therapy with oxcarbazepine compared with 87% in the adult group (16). In the elderly group, no adverse events were reported at an incidence greater than 20%, while in the adults group, only vomiting was slightly more frequent in the elderly group, but with no statistically significant difference (16). Therefore, oxcarbazepine may be safe to use in elderly patients.

 

Surgery

Epilepsy surgery is a major treatment for drug-resistant epilepsy. Different mechanisms of drug-resistant epilepsy have been proposed, and the two most widely supported are transporter and target hypotheses. The transporter hypothesis suggests that overexpression of multidrug transporters such as efflux transporters at the blood-brain barrier may lead to an increased efflux of drugs, leaving intracellular drug concentration low, and thus low efficiency (17). Target hypothesis suggests that alterations in the properties of antileptic drug targets, such as compositional changes in voltage-gated ion channels and neurotransmitter receptors, result in decreased drug sensitivity and thus lead to refractoriness, but the evidence so far has only been reported for carbamazepine (18). Others also hold the view that due to the complexity of the brain, Inflammation processes, glia functional alterations, and altered intercellular communication related to gap junctions, as well as other documented changes in drug-resistant epileptic brains may together contribute to drug resistance (19).

 

There are different types of surgeries for different types of epilepsies. Resective surgery is the removal of parts of the brain where seizures begin and are gradually recognized to be the major treatment choice for drug-resistant epilepsy; palliative surgery is a conservative treatment that blocks the epilepsy discharge diffusion pathway through surgical operation; neurostimulation includes vagus nerve stimulation, deep brain stimulation, and responsive stimulation, all of which involve the implantation of a device that monitors the patient’s conditions and delivers stimulations to stop seizures (20). Neurostimulation is based on the fact that cells have membrane potential and generate voltage gradient that influences transport mechanisms and thus affect cellular activities (21). Sufficient energy levels induce a depolarization or hyperpolarization of cells; much smaller energy levels result in cellular excitement, which leads to a tissue response (21). The efficiency and safety of neurostimulation depend on endogenous and exogenous diffusion in the epileptogenic network (22). However, the exact mechanism behind neurostimulation is unknown and requires further research (22).

 

Many clinical trials have proved the significant role that surgery plays in the treatment of epilepsy. For example, in a randomized, controlled trial of surgery for temporal-lobe epilepsy, surgery is shown to be superior to prolonged medical therapy: at one year, the cumulative proportion of patients who were free of seizures impairing awareness was 58% in the surgical group and 8% in the medical group, and 4 people (10%) had adverse effects of surgery while 1 person in the medical group died (23). A review of two clinical trials concludes that in general, epileptic surgery is more likely than continued medical treatment to result in a seizure-free outcome but may be less effective when there were extratemporal lesions, the epilepsy was not associated with a structural lesion, or both (24).

 

Ketogenic diet

Ketogenic diet is another treatment for patients with drug-resistant epilepsy. The classic ketogenic diet consists of a high-fat and low-protein and carbohydrate diet, and the production of ketone bodies from oxidation of fat in the liver act as the primary source of metabolic energy (25). Variants of the classic diet include Atkins diet, low glycemic index treatment, and fasting/calorie restriction limit carbohydrates (26). Several mechanisms of ketogenic diet and its variants’ action on epilepsy have been proposed. First, inhibition of glycolysis by 2-Deoxy-d-glucose, a glucose analog, results in acute antiseizure and chronic antiepileptogenic actions in several experimental models, which suggests that carbohydrate depletion may have antiseizure effects (26). Second, these diets improve mitochondrial function and thus metabolism by reducing reactive oxygen species production and activating ATP-sensitive potassium channels, which causes less depolarization of the cell and fewer impulses being produced (26). Third, the ketogenic diet might inhibit mammalian target of rapamycin activity, but this mechanism is controversial: in one study, rapamycin did not protect against acute seizures though the ketogenic diet was highly protective (26). Finally, the relationship of ketones’ contribution to seizure control is unclear, suggested by controversial studies of β-hydroxybutyrate or acetoacetate concentrations and seizure control (26).

 

Ketogenic diet is suggested to be effective in treating drug-resistant epilepsy by short-term clinical trials, but it has complications with different degrees of seriousness especially in the long-term. For example, a 3-month trial in children between 2 and 16 years old showed that the mean percentage of baseline seizures was significantly lower in the diet group (62.0%) than in the controls (136.9%); 38% in the diet group had greater than 50% seizure reduction compared with 6% controls; 7% in the diet group had greater than 90% seizure reduction compared with no controls (27). However, ketogenic diets also have complications. In this study, the most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger (27). However, because of the short duration of this study, there were no serious complications observed. In another study carried out from July 1995 to October 2001 regarding intractable epilepsy, patients developed complications, both early-onset ones such as dehydration, gastrointestinal disturbances, hypertriglyceridemia, hypercholesterolemia, and various infectious diseases, and late-onset ones such as osteopenia, renal stones, and cardiomyopathy (28). Although most of these complications were transient and successfully managed, 17.1% of patients ceased the diet because of various serious complications, and 3.1%  ofpatients died (28). Therefore, although most complications of ketogenic diet can be improved, there could be more serious and even life-threatening diseases induced.

 

Conclusion

Treatments for epilepsy include antiepileptic drugs, surgery, and ketogenic diet. Although many studies have demonstrated their effectiveness, others exposed their weaknesses such as exacerbation of epilepsy and serious complications in the long term. In addition, many mechanisms behind these treatments remain unclear, and the current proposals are controversial. Therefore, there is still room for improvement in therapies for epilepsy and further research in their mechanisms at a cellular level.

 

References                                                                                                       

1.      Epilepsy [Internet]. Who.int. 2021 [cited 13 August 2021]. Available from: https://www.who.int/news-room/fact-sheets/detail/epilepsy.

2.      Nadkarni S, Jung P. Spontaneous Oscillations of Dressed Neurons: A New Mechanism for Epilepsy? Phys Rev Lett. 2003;91(26):3–6.

3.      Wei F, Yan L M, Su T, He N, Lin Z J, Wang J, et al. Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy. Neurosci Bull. 2017;33(4):455–77.

4.      Magiorkinis E, Diamantis A, Sidiropoulou K, Panteliadis C. Highights in the History of Epilepsy: The Last 200 Years. Epilepsy Res Treat. 2014;2014:1–13.

5.      Chen Z, Brodie M J, Kwan P. What has been the impact of new drug treatments on epilepsy? Curr Opin Neurol. 2020;33(2):185–90.

6.      Kwan P, Arzimanoglou A, Berg A T, Brodie M J, Hauser W A, Mathern G, et al. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069–77.

7.      White H S, Smith M D, Wilcox K S. Mechanisms of Action of Antiepileptic Drugs. Int Rev Neurobiol. 2007;81(06):85–110.

8.      Czapiński P, Blaszczyk B, Czuczwar S J. Mechanisms of action of antiepileptic drugs. Current Topics in Medicinal Chemistry 2005, 5, 3-14.

9.      Hattson R H, Joyce M D, Chamber B S, JosephF, Collins Sc D. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults. Psychosomatics. 1993;34(5):464.

10.   Horn C S, Ater S B, Hurst D L. Carbamazepine-exacerbated Epilepsy in Children and Adolescents. Pediatric Neurology. 1986;2(6):340–5.

11.   Liu L, Zheng T, Morris M J, Wallengren C, Clarke A L, Reid C A, et al. The Mechanism of Carbamazepine Aggravation of Absence Seizures. 2006;319(2):790–8.

12.   Glauser T A, Cnaan A, Shinnar S, Hirtz D G, Dlugos D, Masur D, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: Initial monotherapy outcomes at 12 months. Epilepsia. 2013;54(1):141–55.

13.   Warren J W, Benmaman J D, WannamakerB B, Levy R H. Kinetics of a carbamazepine-ethosuximide interaction. Clin. Pharmacol. Ther. 1980;646–51.

14.   Sherwin A L, Robb J P, Lechter M. Improved Control of Epilepsy by Monitoring Plasma Ethosuximide. Arch Neurol. 1973;28(3):178–81.

15.   Guerreiro M M, Vigonius U, Pohlmann H, De Manreza MLG, Fejerman N, Antoniuk SA, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res. 1997;27(3):205–13.

16.   Kutluay E, McCague K, D’Souza J, Beydoun A. Safety and tolerability of oxcarbazepine in elderly patients with epilepsy. Epilepsy Behav. 2003;4(2):175–80.

17.   Koubeissi M. Neuropathology of the blood-brain barrier in epilepsy: Support to the transport hypothesis of pharmacoresistance. Epilepsy Curr. 2013;13(4):169–71.

18.   Tang F, Hartz A M S, Bauer B. Drug-resistant epilepsy: Multiple hypotheses, few answers. Front Neurol. 2017;8(JUL):1–19.

19.   Margineanu D G, Klitgaard H. Mechanisms of drug resistance in epilepsy: Relevance for antiepileptic drug discovery. Expert Opin Drug Discov. 2009;4(1):23–32.

20.   Sheng J, Liu S, Qin H, Li B, Zhang X. Drug-Resistant Epilepsy and Surgery. Curr Neuropharmacol. 2017;16(1):17–28.

21.   Watson T. The role of electrotherapy in contemporary physiotherapy practice. Man Ther. 2000;5(3):132–41.

22.   Sunderam S, Talathi S S, Lyubushin A, Sornette D, Osorio I. Challenges for emerging neurostimulation-based therapies for real-time seizure control. Epilepsy Behav. 2011;22(1):118–25.

23.   Rees D G. A randomized controlled trial of surgery for glue ear. Essent Stat Med Pract. 2019;345(5):85–108.

24.   Jobst B C, Cascino GD. Resective epilepsy surgery for drug-resistant focal epilepsy: A review. JAMA - J Am Med Assoc. 2015;313(3):285–93.

25.   De Lima P A, De Brito Sampaio L P, Teixeira Damasceno N R. Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy. Clinics. 2014;69(10):699–705.

26.   Danial N N, Hartman A L, Stafstrom C E, Thio L L. How does the ketogenic diet work? Four potential mechanisms. J Child Neurol. 2013;28(8):1027–33.

27.   Neal E G, Chaffe H, Schwartz R H, Lawson M S, Edwards N, Fitzsimmons G, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol. 2008;7(6):500–6.

28.   Kang H C, Chung D E, Kim D W, Kim H D. Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia. 2004;45(9):1116–3.

Resources by Judy Zhu