Epilepsy is a neurological disorder characterised by two or more unprovoked seizures. The high prevalence and incidence of epilepsy globally, especially in Asia, has remained a big concern over the course of centuries. Patients are usually prescribed the already known anti-epileptic drugs, but even after going through three different generations of anti-epileptic drugs, some people still suffer from drug-resistant form of epilepsy. These patients are usually prescribed a higher dose of anti-epileptic drugs, which results in more adverse effects. That is why new treatment options, like herbal extracts, should be explored for patients who do not respond to the classic anti-epileptic drugs. The current narrative review was planned to explore if herbal extracts can be the future for the treatment of drug-resistant epilepsy.
Keywords: Epilepsy, Herbal extracts, Drug-resistant epilepsy, Anti-epileptic drugs.
Submission completion date: 08-06-2022
Acceptance date: 10-12-2022
Epilepsy is known as a chronic disease of the brain and is characterised by occurrence of two or more unprovoked seizures. There can be several causes of seizures, which are categorised into structural, genetic, infectious, metabolic, immune, and unknown types1. Epilepsy can have neurobiological, cognitive, psychological, and social consequences2. Following stroke and neurodegenerative diseases, epilepsy is known as the third most common neurological disease in elderly population3. Anti-seizure drugs are used as the first line of treatment to control the seizures. Despite the availability of various drugs, one-third of the patients remain refractory to seizures4. The current review, as part of an ongoing research to discover novel drugs and treatment options for such patients, was planned to discuss how herbal treatments can be used for successful treatment of epilepsy with minimum side effects.
Epilepsy and prevalence of epilepsy in Asian countries
Epilepsy is a chronic non-communicable disease of the brain that affects around 70 million people worldwide5 The global incidence and prevalence of epilepsy is 50 in 100,000 and 700 in 100,000, respectively. Approximately 4 billion people (50% of the global population) are part of Asia, and, among them, 23 million people have epilepsy6. The overall prevalence of epilepsy in Pakistan is estimated to be 9.99 per 1,000 population7. The highest prevalence is in people aged <30 years and there is a slight decrease in prevalence in those aged 40-59 years7. A recent review in India showed that among a total of 17,91,541 participants, 5,890 were diagnosed with epilepsy, and the pooled prevalence was 4.7 per 1,000 population8. Another population-based door-to-door survey across Malaysia showed that the prevalence of lifetime epilepsy was 7.8 per 1,000 population9. Overall prevalence of epilepsy in Laos was estimated to be 7.7 cases per 1,000 inhabitants10. Nepal also has a high prevalence, estimated to be around 7.3 per 1,000 population, with a treatment gap of over 80%11. The prevalence rate of epilepsy in Thailand was 7.2 per 1,000 population12. In China, the prevalence rate was reported to be ranging from 0.9 to 8.5 per 1,000, mostly because of cerebrovascular diseases13. It is clear that epilepsy is a genuine concern in Asia, and steps need to be taken to find out novel solutions to provide a better life to epilepsy patients.
Treatment according to the aetiology of epilepsy
Typical treatments are used to treat 6 different types of epilepsy, according to aetiology, as approved by the International League Against Epilepsy (ILAE) (Table 1)1.
Drug resistant epilepsy (DRE) is defined as the persistence of seizures despite at least two syndrome-adapted anti-seizure drugs (ASDs) used at an efficacious daily dose. Seizures are not completely controlled in these patients even after taking ASDs singly or even in different prescribed combinations4. Clinical evidence shows that if two ASDs are ineffective in a patient, the administration of additional ASDs is not likely to be effective14. Such pharmaco-resistance leads to reducing the quality of life of these patients and can enhance mortality and morbidity.
Anti-epileptic drugs (AEDs) have been the main pillar of epileptic treatment for a long time. Until 1993, there were only a few AED choices available. However, up to 17 new approved anti-epileptic drugs are currently available in the market. Yet, the target of these drugs are only the symptoms, and they fail to cure the cause of seizures. Currently available medications work on ion channels, receptors, transporters, and enzymes to restore the balance between the inhibitory and excitatory neurotransmitters15. Although now there are numerous drugs available, almost 50% of the patients do not respond to the first AED prescribed to them, and one-third remain resistant regardless of any addition to the treatment options. It is a known fact that some AEDs are effective in certain seizure types, and that is why knowing the seizure type is of utmost importance before prescribing any AED16.
The final decision of treatment is based on the evaluation of the balance between the expected efficacy and the safety profile of the available AEDs. Clinicians usually make their choices according to the mechanism of action of AEDs, especially in patients who are prescribed with polytherapy17. Some of the common allopathic drugs used in epilepsy are carbamazepine, clonazepam, diazepam, ethosuximide, felbamate, gabapentin, lamotrigine, midazolam, phenobarbital, phenytoin, primidone, topiramate, valproic acid and vigabatrin18. These drugs have different mechanism of actions and are used to treat different types of seizure. For example, phenytoin, which is one of the oldest used AEDs, is mainly used for treating partial and tonic-clonic seizures19, while levetiracetam (LEV) is usually valuable against generalised and partial seizures20.
The mechanism of action of four main classes of AEDs has been established: modulation of voltage-gated ion channels; enhancement of gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission; attenuation of glutamate-mediated excitatory neurotransmission; and modulation of neurotransmitter release via a presynaptic action21.
AEDs are usually classified as older or first-generation, or newer or second- and third-generation drugs22. First generation of AEDs include valproic acid, benzodiazepine, phenobarbital, primidone, carbamazepine, phenytoin and ethosuximide23. The second generation comprises lamotrigine, levetiracetam, topiramate, zonisamide, felbamate, gabapentin, oxcarbazepine, rufinamide and pregabalin. The third-generation AEDs approved in the last few years are lacosamide, eslicarbazepine acetate, perampanel, brivaracetam and cenobamate24. There are several steps taken to treat an epileptic patient (Figure 1).
Potassium bromide was the first drug for epilepsy, followed by the discovery of phenobarbital, phenytoin, trimethadione, ethosuximide, valproate and carbamazepine. Chlordiazepoxide was the first available benzodiazepine, followed by diazepam2] and the process is continuing to date25-30 (Figure 2).
There are numerous options in the market for single or adjuvant therapy, but the administration of these drugs over a long period of time and in higher doses can result in complications, including endocrine, metabolic, and psychiatric disorders, and drug interactions and idiosyncratic reactions in a few cases. The most common side effects of AEDs include dizziness, nausea, and headache. Further adverse effects, such as skin, visual and auditory problems, kidney disorders, liver dysfunction and pancreatitis, have also been reported31. Patients suffering from drug resistance are prescribed with high dose of these AEDs which results in higher chances of side effects. Additionally, the incidence of sudden unexpected death in epilepsy patients (SUDEP) is greater in the drug-resistant form of epilepsy4.
AEDs are now the most common and the most effective treatment option for epileptic patients, among which about 15% spend approximately 2-5 years to find an AED regimen which effectively treats their symptoms, and another 25-30% are resistant to any kind of AEDs and need to be moved towards other treatment options, like vagal nerve stimulation or surgery.
Herbal extracts: a potential treatment for epilepsy
Herbal extracts are emerging as an effective treatment option for patients who do not respond to AEDs. Research on discovering the mechanism of action of anti-convulsant herbal extracts is ongoing. Examples of herbal medications are zingiber officinale, pimpinella anisum, carum carvi, moringa oleifera, lavandula officinalis and gastrodia elata blume (Table 2).
Herbal extracts are known to be more effective, low-cost, safer agent to treat epilepsy, and it is a culturally acceptable treatment option for people living in resource-poor regions32. Previously, it was discovered that few extracts are completely able to prevent the induced seizures at a non-lethal dose and some also worked in combination, showing a synergistic or additive effects with conventional AEDs32. Conventional anti-epileptic drugs are known to have inevitable and undesirable side effects with increasing dosage, but traditional herbal extracts are safer to use and result in better patient compliance33.
Some herbal extracts and their benefits
Zingiber officinale Rosc. (Zingiberacae), which is also known as ginger, is a perennial and herbaceous plant with a long cultivation history. Ginger rhizome is known to be prescribed traditionally as a Chinese herbal medicine34. It has numerous benefits, such as antioxidant, anti-inflammatory, anti-microbial, anti-cancer, anti-obesity, anti-diabetic, anti-nausea, anti-emetic, anti-allergic, neuroprotective, hepatoprotective, cardiovascular protective, and respiratory protective activities34. It has known anti-convulsant effect, which has been proven on pentylenetetrazol (PTZ) model (pro-convulsant model) on rodents and larval zebra fish.
Anise (pimpinella anisum L.) belongs to the apiaceae family and is known to be one of the oldest and commonly used spice plants35. It has a variety of properties, such as diuretic, anti-hypertensive, anti-diabetic, anti-cancer, anti-microbial, analgesic, anti-inflammatory, antioxidant, anti-fungal, anti-viral, muscle relaxant, anti-stress, and, most importantly, neuroprotective, and anti-convulsant effects36.
Carum carvi L., which also belongs to the apiaceae family, is one of the most used medicinal plants in conventional medicine37. Pharmacological potencies of caraway seeds include anti-microbial, analgesic, anti-inflammatory, anti-anxiety, anti-hyperglycemic, and anti-spasmodic properties, and it has also been used to treat dyspepsia, flatulent indigestion, diarrhoea, and hysteria38. Studies have shown that it also has anti-convulsant effects38.
Pimpinella anisum L and Carum carvi L are considered to be safe and are well-tolerated, but they do have an allergic potential39.
Moringa oleifera Lam. which is native to India and is cultivated across the world, is used in traditional phytomedicine and as a rich source of essential nutrients. Its leaves are known to be rich in flavonoids, carotenoids, and ascorbic acid. It has numerous important properties, such as antioxidant, anti-inflammatory, anti-diabetic, anti-cancer, cardioprotective, hypocholesterolemic, hepatoprotective and anti-asthmatic40. Also, it is known to be useful in the treatment of neuro-dysfunctional diseases, such as epilepsy, ischemic stroke, and Alzheimer’s disease. It has been shown to have anti-convulsant and neuroprotective effect41. It is reported that a dose of 14g dried leaf powder daily does not have any side effects42.
Lavandula officinalis (lamiaceae), commonly known as ustu khuddoos, or lavandula, has been used in Iranian traditional medicine for treating nervous disorders like dementia and epilepsy for a long time. Some studies have shown that it has anticonvulsant effects on chemically-induced seizures in animal models. Its mechanism of action includes inhibiting the release of glutamate, enhancing the effects of GABA receptors, blocking the calcium channels, and producing anti-oxidant effect43.
Gastrodia elata Blume (G. elata) herbal plant has been used for numerous conditions, including dizziness, headache, stroke, epilepsy, spasm, amnesia, and others, for centuries. Several studies have demonstrated that the active compounds of Gastrodia elata, p hydroxymethylphenyl-β-D-glucopyranoside (gastrodin) and 4-hydroxybenzyl alcohol (HBA) can improve neurological disorders by crossing the blood-brain barrier44.
Some herbal extracts have a known mechanism of action (Table 3)45.
Future possibilities for treatment of epilepsy
As discussed, one-third of epileptic patients suffer from drug-resistant epilepsy despite receiving higher dose of several anti-epileptics, which results in various side effects46. One animal model which can serve as an excellent model for ongoing research is the rodent model of treatment-resistant epilepsy47. Researchers are now moving towards the lithium pilocarpine model and some herbs, like gastrodia elata, are already being investigated. To further prove the efficacy of these herbs as an anti-convulsant, more research needs to be conducted, especially using the lithium pilocarpine model of epilepsy.
Limitations: Among the herbal extracts that are known to have an anti-convulsant effect, majority of them have been tested on a convulsant or seizure model, or if tested on a true seizure model, they were administered before inducing the seizure. Another problem faced is that the mechanism of action and the active constituents of majority of these herbal extracts are also not known yet.
More research is required to prove the efficacy of herbal extracts on a true model of drug-resistant epilepsy, and to discover their active constituents plus mechanism of action responsible for their effects. This might lead to a new treatment option for patients suffering from drug resistance and to improve the quality of their day-to-day life.
1. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58: 512-21.
2. Beghi E. The Epidemiology of Epilepsy. Neuroepidemiology 2020; 54: 185-91.
3. Beghi E, Beghi M. Epilepsy, antiepileptic drugs and dementia. Curr Opin Neurol 2020; 33: 191-7.
4. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev 2020; 72: 606-38.
5. Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet 2019; 393: 689-701.
6. Trinka E, Kwan P, Lee B, Dash A. Epilepsy in Asia: Disease burden, management barriers, and challenges. Epilepsia 2019; 60 Suppl 1: 7-21.
7. Khatri IA, Iannaccone ST, Ilyas MS, Abdullah M, Saleem S. Epidemiology of epilepsy in Pakistan: review of literature. J Pak Med Assoc 2003; 53: 594-7.
8. Dhiman V, Menon GR, Kaur S, Mishra A, John D, Rao Vishnu MV, et al. A Systematic Review and Meta-analysis of Prevalence of Epilepsy, Dementia, Headache, and Parkinson Disease in India. Neurol India 2021; 69: 294-301.
9. Fong SL, Lim KS, Tan L, Zainuddin NH, Ho JH, Chia ZJ, et al. Prevalence study of epilepsy in Malaysia. Epilepsy Res 2021; 170: 106551.
10. Bounlu M, Auditeau E, Vorachit S, Chivorakoun P, Souvong V, Soukhasem T, et al. Management of epilepsy in Laos: Perceptions of healthcare professionals from Vientiane Capital province and traditional healers in Southern Laos. J Tradit Complement Med 2020; 11: 46-52.
11. Kafle DR, Oli KK. Clinical profile of patients with recurrent seizure in tertiary care hospital in Nepal. Kathmandu Univ Med J (KUMJ) 2014; 12: 202-6.
12. Saengpattrachai M, Srinualta D, Lorlertratna N, Pradermduzzadeeporn E, Poonpol F. Public familiarity with, knowledge of, and predictors of negative attitudes toward epilepsy in Thailand. Epilepsy Behav 2010; 17: 497-505.
13. Ding D, Zhou D, Sander JW, Wang W, Li S, Hong Z. Epilepsy in China: major progress in the past two decades. Lancet Neurol 2021; 20: 316-26.
14. Tang F, Hartz AMS, Bauer B. Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers. Front Neurol 2017; 8: 301.
15. Raut D, Bhatt LK. Evolving targets for anti-epileptic drug discovery. Eur J Pharmacol 2020; 887: 173582.
16. Sunwoo JS, Jo H, Kang KW, Kim KT, Kim D, Kim DW, et al. Survey on Antiepileptic Drug Therapy in Patients with Drug Resistant Epilepsy. J Epilepsy Res 2021; 11: 72-82.
17. Guery D, Rheims S. Is the mechanism of action of antiseizure drugs a key element in the choice of treatment? Fundam Clin Pharmacol 2021; 35: 552-63.
18. Khan AU, Akram M, Daniyal M, Akhter N, Riaz M, Akhtar N, et al. Awareness and current knowledge of epilepsy. Metab Brain Dis 2020; 35: 45-63.
19. Patocka J, Wu Q, Nepovimova E, Kuca K. Phenytoin - An anti-seizure drug: Overview of its chemistry, pharmacology and toxicology. Food Chem Toxicol 2020; 142: 111393.
20. Jarvie D, Mahmoud SH. Therapeutic Drug Monitoring of Levetiracetam in Select Populations. J Pharm Pharm Sci 2018; 21: 149s-76s.
21. Sills GJ, Rogawski MA. Mechanisms of action of currently used antiseizure drugs. Neuropharmacology 2020; 168: 107966.
22. Hakami T. Neuropharmacology of Antiseizure Drugs. Neuropsychopharmacol Rep 2021; 41: 336-51.
23. Perucca P, Scheffer IE, Kiley M. The management of epilepsy in children and adults. Med J Aust 2018; 208: 226-33.
24. Lattanzi S, Trinka E, Zaccara G, Striano P, Russo E, Del Giovane C, et al. Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis. Drugs 2022; 82: 199-218.
25. Rho JM, White HS. Brief history of anti-seizure drug development. Epilepsia Open 2018; 3(Suppl Suppl 2): 114-9.
26. Rogawski MA. Brivaracetam: a rational drug discovery success story. Br J Pharmacol 2008; 154: 1555-7.
27. Trinka E, Ben-Menachem E, Kowacs PA, Elger C, Keller B, Löffler K, et al. Efficacy and safety of eslicarbazepine acetate versus controlled-release carbamazepine monotherapy in newly diagnosed epilepsy: A phase III double-blind, randomized, parallel-group, multicenter study. Epilepsia 2018; 59: 479-91.
28. Mitra-Ghosh T, Callisto SP, Lamba JK, Remmel RP, Birnbaum AK, Barbarino JM, et al. PharmGKB summary: lamotrigine pathway, pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 2020; 30: 81-90.
29. Guignet M, Campbell A, White HS. Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action? Epilepsia 2020; 61: 2329-39.
30. Odi R, Invernizzi RW, Gallily T, Bialer M, Perucca E. Fenfluramine repurposing from weight loss to epilepsy: What we do and do not know. Pharmacol Ther 2021; 226: 107866.
31. Akyüz E, Köklü B, Ozenen C, Arulsamy A, Shaikh MF. Elucidating the Potential Side Effects of Current Anti-Seizure Drugs for Epilepsy. Curr Neuropharmacol 2021; 19: 1865-83.
32. Manchishi SM. Recent Advances in Antiepileptic Herbal Medicine. Curr Neuropharmacol 2018; 16: 79-83.
33. Sharma R, Kabra A, Rao MM, Prajapati PK. Herbal and Holistic Solutions for Neurodegenerative and Depressive Disorders: Leads from Ayurveda. Curr Pharm 2018; 24: 2597-608.
34. Zhang M, Zhao R, Wang D, Wang L, Zhang Q, Wei S, et al. Ginger (Zingiber officinale Rosc.) and its bioactive components are potential resources for health beneficial agents. Phytother Res 2021; 35: 711-42.
35. Mosavat SH, Jaberi AR, Sobhani Z, Mosaffa-Jahromi M, Iraji A, Moayedfard A. Efficacy of Anise (Pimpinella anisum L.) oil for migraine headache: A pilot randomized placebo-controlled clinical trial. J Ethnopharmacol 2019; 236:155-60.
36. Es-Safi I, Mechchate H, Amaghnouje A, Elbouzidi A, Bouhrim M, Bencheikh N, et al. Assessment of Antidepressant-like, Anxiolytic Effects and Impact on Memory of Pimpinella anisum L. Total Extract on Swiss Albino Mice. Plants (Basel) 2021; 10: 1573
37. Es-Safi I, Mechchate H, Amaghnouje A, Jawhari FZ, Al Kamaly OM, Imtara H, et al. An Insight into the Anxiolytic and Antidepressant-Like Proprieties of Carum carvi L. and Their Association with Its Antioxidant Activity. Life (Basel) 2021; 11: 207.
38. Hajlaoui H, Arraouadi S, Noumi E, Aouadi K, Adnan M, Khan MA, et al. Antimicrobial, Antioxidant, Anti-Acetylcholinesterase, Antidiabetic, and Pharmacokinetic Properties of Carum carvi L. and Coriandrum sativum L. Essential Oils Alone and in Combination. Molecules 2021; 26: 3625.
39. SŁowianek M, Majak I, LeszczyŃska J, SmoliŃska B, MaŃkowska D, BuczyŁko K, et al. New allergens from spices in the Apiaceae family: anise Pimpinella anisum L. and caraway Carum carvi L. Cent Eur J Immunol 2020; 45: 241-7.
40. Hassan MA, Xu T, Tian Y, Zhong Y, Ali FAZ, Yang X, et al. Health benefits and phenolic compounds of Moringa oleifera leaves: A comprehensive review. Phytomedicine 2021; 93: 153771.
41. González-Burgos E, Ureña-Vacas I, Sánchez M, Gómez-Serranillos MP. Nutritional Value of Moringa oleifera Lam. Leaf Powder Extracts and Their Neuroprotective Effects via Antioxidative and Mitochondrial Regulation. Nutrients 2021; 13: 2203.
42. Dhakad AK, Ikram M, Sharma S, Khan S, Pandey VV, Singh A. Biological, nutritional, and therapeutic significance of Moringa oleifera Lam. Phytother Res 2019; 33: 2870-903.
43. Liu W, Ge T, Pan Z, Leng Y, Lv J, Li B. The effects of herbal medicine on epilepsy. Oncotarget 2017; 8: 48385-97.
44. Lin YE, Chou ST, Lin SH, Lu KH, Panyod S, Lai YS, et al. Antidepressant-like effects of water extract of Gastrodia elata Blume on neurotrophic regulation in a chronic social defeat stress model. J Ethnopharmacol 2018; 215: 132-9.
45. Aghdash SN. Herbal Medicine in the Treatment of Epilepsy. Curr Drug Targets 2021; 22: 356-67.
46. Mutanana N, Tsvere M, Chiweshe MK. General side effects and challenges associated with anti-epilepsy medication: A review of related literature. Afr J Prim Health Care Fam Med 2020; 12: e1-e5.
47. Ahmed Juvale II, Che Has AT. The evolution of the pilocarpine animal model of status epilepticus. Heliyon 2020; 6: e04557.