Ayurveda and botanical drugs for epilepsy - Epilepsy & Behavior

Epilepsy & Behavior 52 (2015) 290–296

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Ayurveda and botanical drugs for epilepsy: Current evidence and future prospects Sitaram Jaideep Sriranjini a,⁎, Kumar Sandhya b, Vernekar Sanjeeva Mamta a a b

MS Ramaiah Indic Center for Ayurveda and Integrative Medicine, New BEL Road, MSR Nagar, Bengaluru 560054, India Ramakrishna Ayurvedic Medical College, Ramagondanahalli, Yelahanka, Bengaluru 560064, India

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Article history: Revised 26 May 2015 Accepted 27 May 2015 Available online 2 July 2015 Keywords: Apasmara Ayurveda Epilepsy Whole systems research

a b s t r a c t The understanding of epilepsy has progressed since its earliest impression as a disease associated with paranormal and superstitious beliefs. Landmark advances have been made in deciphering the pathophysiological substrates involved in the disease process, and treatment advances have contributed significantly to ameliorating the seizures. However, disease-modifying agents are yet to be discovered. Ayurveda is a system of medicine that stresses a holistic approach to disease, and treatment is focused on disease modification and symptom management. Herbs form the core of Ayurveda medicine; though many of them have been studied for their anticonvulsant activity, very few actually mention the reference of these herbs in Ayurveda literature. Other therapeutic interventions used in Ayurveda are relatively unexplored, and future research will need to focus on this. The current manuscript briefly discusses the understanding of epilepsy as per Ayurveda and reviews herbs that have been studied for their anticonvulsant activity mentioned in Ayurveda literature. This article is part of a Special Issue entitled “Botanicals for Epilepsy”. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Epilepsy is a chronic neurological disease that, although occurring intermittently, can have lasting changes in the neural circuitry. The disease has a strong propensity for comorbidities including psychiatric and cognitive impairments [1]. Antiepileptic drugs, though effective in symptomatically controlling seizures, do not prevent or reverse the pathological process that underlies epilepsy. Though antiepileptic drugs are generally well tolerated, there still is a need to search for new drugs with fewer side effects and better efficacy [2]. World over, it has been observed that, in cases of chronic conditions, there is a growing tendency to seek other systems of health care. This health-seeking behavior may be complementary or alternative to the existing medical system being used. There are many complementary systems including acupuncture, botanicals, and music therapy, and such systems are being used for epilepsy care. Ayurveda is one amongst a small group of such diverse health-care systems with an inherent holistic theoretical framework of health and disease. Many of the Ayurveda treatments have the potential of not only relieving symptoms but also modifying the pathophysiology of the disease.

⁎ Corresponding author at: MS Ramaiah Indic Center for Ayurveda and Integrative Medicine, Bangalore 560094, India. Tel.: +91 9886492902, +91 22183456. E-mail address: [email protected] (S.J. Sriranjini).

http://dx.doi.org/10.1016/j.yebeh.2015.05.039 1525-5050/© 2015 Elsevier Inc. All rights reserved.

Ayurveda is a functional science and attributes diverse bodily function to three dynamic principles similar to humors (dosha) known as vata (responsible for movement), pitta (responsible for transformation), and kapha (responsible for anabolic activities) [3,4]. Physiology is identified by the harmony in the functioning of these dynamic principles, and pathology is identified by the discordance in their functions affecting the structural elements (dhatu) and the elimination of wastes (mala) [5]. Few aspects of epilepsy as per Ayurveda have been detailed in earlier publications [6,7]. The disease epilepsy is similar to a condition detailed as Apasmara in the earliest Ayurveda literature sometime around 800BCE–400CE including Charaka Samhita, Sushruta Samhita, and Ashtanga Hridaya [3,5,8]. The diagnosis of Apasmara is based on astute observation of the symptomatology, and the main presenting feature of the disease is, as the name defines, ‘loss of consciousness’. Apasmara is due to an aberration of not only the physical bioentities vata, pitta, and kapha dosha but also that of the psychological (manasika) attributes satva (serenity), rajas (passion), and tamas (ignorance). It manifests physical symptoms like alarming movements (bibhatsa cheshta, referring to the involuntary movements during the seizures) and psychological symptoms like perversion of memory and cognition (smriti-buddhi samplava) and temporary loss of consciousness (tamah pravesha). A distinct prodromal (purvarupa) stage of the disease has been elaborated with symptoms of hallucinations — auditory and visual (ashabda shravana and asanti rupa darshana), loss of appetite (anannabhilasha), sweating (sweda), weakness (dourbalya), body ache (angamarda), etc. Apasmara is subclassified based on the predominance

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of the biological entities vata, pitta, and kapha; the intensity and duration of the ictus and the associated symptoms are variable based on this predominance [3]. Treatment of Apasmara is multipronged and includes pharmacologic and nonpharmacologic measures. The exact combination of medication is arrived at after a thorough examination of the subject based on disease factors and host factors. The paroxysmal nature of the disease was recognized, and diverse treatments during an ictus and at other times were advocated. These include therapies like oleation (snehana) and sudation (svedana), cleansing (shodhana) therapies such as emesis (vamana) and purgation (virechana), colonic administration of medicaments (basti), and nasal administration of medicines (nasya) in varied forms. These are complemented with suitable internal medications prepared in different pharmaceutical forms that include freshly prepared juices of herbs (svarasa), pastes (kalka), lipid-based formulations (sneha — oil- or ghee-based preparations), decoctives (kashaya), powders (churna), fermented preparations (asava–arishta), and pills (vati), etc. [3,5,8,9]. Some of the herbal formulations used are Aswagandharishtam [9], Saraswatarishtam [10], Kalyanaka churna, Saraswata churna [11], Brahmi ghrita, Dadhika ghrita, Kalyanaka ghrita, Maha kalyanaka ghrita, Kushmanda ghrita, Panchagavya ghrita, Maha Panchagavya ghrita, Siddarthaka ghrita, Tiktaka ghrita [5], and Mahayogaraja guggulu [10]. Herbomineral/mineral formulations widely prescribed for Apasmara are Manasamitravatakam, Mritasanjeevani gutika [12], Apasmarahara rasa, Apasmarari rasayana [13], Bhootabhairava rasa, Smritisagara rasa, [14], Chaturbhuja rasa [15], Chaturmukha rasa, Chintamani chaturmukha rasa, Tapyadi lauha, Vatakulantaka rasa, Yogendra rasa [9]. As the pathogenesis of Apasmara is attributed to a discordance of the psychological entities too, nonpharmacologic interventions like psychotherapy also form an integral part of treatment. This is referred to as Satvavajaya chikitsa and involves behavioral therapies for the psyche. It aims at harmonizing the functioning of the different components of the psyche including intellect (dhi), fortitude (dhriti), and memory (smriti) of the patient [3,16]. 2. Current evidence for Ayurveda botanicals in epilepsy A cursory literature review was performed using the electronic database PubMed, with the keywords Ayurveda, seizures, epilepsy, anticonvulsant, extracts, and herbs, up to February 2015. The herbs/extracts/ formulations that have been studied for antiepileptic activity in animal/human studies were identified. It was interesting to note that close to 60 different herbs that have been mentioned in Ayurveda literature have been studied for antiepileptic activity. While some of these studies related to the use of the herb in Ayurveda, many did not seem to acknowledge the same. The studies conducted have also been on herbs that may not have been indicated for the specific condition of epilepsy in Ayurveda but, nevertheless, have shown potent antiepileptic activity. The majority of the studies were in animal models, some were ethnobotanical survey studies, and very few were clinical studies in human population. It was also observed that some of the human studies were performed in settings outside India, based on their history of traditional use of the same herb as told in Ayurveda literature. Complementary and alternative medicine use, including Ayurveda, is widely prevalent not only in India but also in the Western countries. The available evidence for Ayurveda botanicals is categorized and described under (1) studies of single herbs/extracts, (2) studies of polyherbal formulations, and (3) clinical studies in human population. 2.1. Studies of single herbs/extracts Some of the main herbs used in Ayurveda for treating Apasmara are discussed in detail. Other herbs that may not have been indicated for Apasmara per se in Ayurveda literature but have been studied for their effect in epilepsy have been summarized in Table 1.

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Table 1 Herbs tested for anticonvulsant activity, described in Ayurveda literature. Sl

Botanical name

Sanskrit name

Reference

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55

Albizia lebbeck (L.) Benth. Aloe vera (L.) Burm.f. Anacyclus pyrethrum (L.) Link. D.C. Anethum graveolens L. Anisomeles malabarica (L.) R.Br. Anthocephalus cadamba Miq. Antiaris toxicaria Lesch. Argyreia speciosa (L.f.) Sweet Asparagus racemosus Willd. Bixa orellana L. Boerhavia diffusa L. Brassica nigra (L.) Andrz. Bryophyllum pinnatum (Lam.) Oken. Butea monosperma (Lam.) Taub. Caesalpinia sappan L. Calotropis gigantea (L.) W.T.Aiton Calotropis procera W.T.Aiton Capparis decidua Edgew. Carum copticum Benth. & Hook.f. Cedrus deodara (Roxb. ex D.Don.) G.Don Cicer arietinum L. Cissus quadrangularis L. Croton tiglium L. Cyperus rotundus L. Delphinium denudatum Wall. Emblica officinalis Gaertn. Ficus carica L. Ficus religiosa L. Glycyrrhiza glabra L. Hibiscus rosa-sinensis L. Hyoscyamus niger L. Indigofera tinctoria L. Marsilea quadrifolia L. Mimosa pudica L. Moringa oleifera Lam. Myristica fragrans Houtt. Nardostachys jatamansi DC. Nigella sativa L. Ocimum sanctum L. Ocimum gratissimum L. Orchis latifolia L. Passiflora incarnata L. Portulaca oleracea L. Pinus roxburghii Sarg. Punica granatum L. Ricinus communis L. Rubia cordifolia L. Sesbania grandiflora Poir. Smilax china L. Solanum nigrum L. Trichosanthes tricuspidata Lour. Vetiveria zizanioides Nash. Vitex negundo L Zingiber officinale Roscoe. Ziziphus jujuba Lam.

Shirisha Kumari Akarakarabha Shatapushpa Gojihva Kadamba Valkala Vriddhadaruka Shatavari Raktabeeja Punarnava Rajakshavaka Pashanabheda Palasha Kuchandana Arka Arka Kareera Yavani Devadaru Chanaka Asthishrinkala Jayapala Musta Nirvisha Amalaki Phalgu Ashwattha Yashtimadhu Japakusuma Parasika yavani Neelini Sunishanna Lajjalu Shigru Jatiphala Jatamamsi Kalajaji Tulasi Vishnupriya Shalabhamishri Krishnakamala Brihatlona Sarala Dadima Eranda Manjishta Agasti Madhusnuhi Kakamachi Kakanasa Usheera Nirgundi Ardraka Badara

[17,18] [19] [20,21] [22,23] [24] [25] [26] [27,28] [29] [30] [31] [32] [33] [18,34] [35] [36] [37] [38] [39] [40] [41] [42] [43,44] [45] [46–51] [52,53] [54] [55,56] [57–61] [18] [62] [63] [64,65] [66] [67,68] [69,70] [71] [72–78] [79,80] [81,82] [83] [84–87] [88] [89] [90] [29,91] [92] [93] [94] [95,96] [97] [98] [99] [100,101] [102]

2.1.1. Acorus calamus L. (Vacha) Vacha has been described as a rasayana (rejuvenation) drug in Ayurveda. It is administered by various routes including oral and nasal and indicated for use in varied pharmaceutical forms. The earliest study was on A. calamus, wherein the effects of acorus oil and its isolated active principles, asarone and β-asarone were assessed on convulsions [103,104]. While acorus oil and asarone had protective effects on convulsions induced by electroshocks or leptazol, β-asarone seemed to facilitate them. Four decades later, a study showed that pretreatment with A. calamus modulated antioxidant enzymes, thereby preventing the development of FeCl(3)-induced epileptogenesis [105]. A more detailed observation by Bhat et al. demonstrated that purifying A. calamus in the classical method as has been described in Ayurveda, i.e. by successively boiling A. calamus in Gomutra (cow's urine), Mundi kwatha

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(decoction prepared from the whole plant of Sphaeranthus indicus L.), Panchapallava kwatha (decoction prepared from a group of five leaves), and Gandhodaka (decoction prepared from a group of aromatic herbs), potentiated the antiepileptic activity [106]. Subsequently, it was demonstrated that the purifying procedure reduced the levels of β-asarone that may contribute to its toxic effect otherwise [107]. It has also been observed that the hydroalcoholic extract of A. calamus when combined with sodium valproate and carbamazepine provided greater protection against seizures [108]. 2.1.2. Bacopa monnieri (L.) Pennell (Brahmi) and Centella asiatica (L.) Urban (Mandukaparni) Brahmi and Mandukaparni are medhya rasayana (neuroprotective) and, widely prescribed for many neurological conditions in Ayurveda. They are very often used for similar indications and instead of each other. Both drugs have been maximally studied for benefits in enhancing learning and memory. Studies of Brahmi for epilepsy in the Caenorhabditis elegans model showed that its active constituent Baccoside A suppressed epileptic-like seizures/convulsions induced by exposure to higher temperature [109]. Matthew and his group have consistently shown that B. monnieri reverses the decrease in GABA receptors in the cerebellum, striatum, hippocampus, and cerebral cortex and associated behavioral and motor deficits in epileptic rats [110–115]. Other studies have also shown that B. monnieri normalizes glutamate-mediated excitotoxicity in epilepsy, evidenced by upregulation of 5-HT2C, NMDA, and IP3 receptors in the cerebellum, hippocampus, and cerebral cortex and associated behavioral, cognitive, and motor changes in epileptic rats [116–118]. Aqueous extract of C. asiatica when administered to PTZ-kindled rats effectively reduced seizure scores and showed improvement on cognitive markers [119], while the ethyl acetate fraction showed additive benefits when given as an adjuvant to conventional AEDs [120]. It is hypothesized that cholinergic modulation may be one of the facets by which C. asiatica brings about antiepileptic activity as was evident by the recovery of acetylcholine and acetylcholinesterase levels in epileptic rats pretreated with different extracts of C. asiatica [121]. The neuroprotective benefits of C. asiatica are also attributed to its ability to directly or indirectly modulate the activities of Na+/K+, Ca2+, and Mg2+ ATPases [122]. 2.1.3. Convolvulus pluricaulis Choisy (shankhapushpi) and Clitorea ternatea L. (aparajita) These 2 herbs are used for almost similar indications in different parts of India as medhya rasayana. Though their effects on enhancing learning and memory have been studied and reviews do mention them as potential drugs for epilepsy [123,124], not many studies are available. Clitorea ternatea reduced the convulsing action of pentylenetetrazol (PTZ) and maximum electroshock (MES) [125], and C. pluricaulis reduced the mean recovery time from MES-induced convulsions at doses of 500 mg/kg and 1000 mg/kg body weight in experimental animals [126]. However, there have also been conflicting reports of C. pluricaulis lowering plasma phenytoin levels and reducing antiepileptic activity in a human study [127]. 2.1.4. Curcuma longa L. (haridra) Curcuma longa has mostly been suggested for nasal administration in Apasmara in combination with other herbs in Ayurveda literature [3]. Curcuminoids extracted from C. longa have shown anticonvulsant activity in different epileptic models [72,128,129]. The mechanisms proposed for its action include as an antoxidant, by enhancing GABAergic inhibition, and via a direct or an indirect activation of adenosine A1 [130–135]. It has further been discovered that, in addition to curcuminoids, bisabolene sesquiterpenoids also promote anticonvulsant activity and need to be studied further [136]. In addition to reducing seizures, curcumin also ameliorates status epilepticus-induced cognitive dysfunction and oxidative damage [137]. It modulates depression-like

behavior and memory impairment in epileptic mice [138]. Agarwal and colleagues reported the benefits of liposome-entrapped curcumin to overcome the poor bioavailability of curcumin [139]. Coadministration of curcumin with subtherapeutic doses of antiepileptic drugs prevented learning and memory deficits and reversed the oxidative stress caused by seizures in kindled rats [140]. It also prevents mitochondrial damage [141]. 2.1.5. Ferula asafoetida L. (Hingu) Hingu is a component of many antiepileptic prescriptions in Ayurveda. It is used in varied forms like lipid-based formulations and as nasal medication [3]. Though an earlier study reported no effect on anticonvulsant activity [142], a later study demonstrated that the hydroalcoholic extract of the gum of F. asafoetida reduces PTZ-induced seizures by an enzyme-mediated antioxidant effect [143]. 2.1.6. Withania somnifera L. (Dunal) (Ashwagandha) Ashwagandha is one of the most preferred rasayana herbs for neurological illnesses in Ayurveda literature. W. somnifera root extract given at doses of 100 or 200 mg/kg, po increased the PTZ seizure threshold and showed similar results when co-administered with GABA or diazepam [144,145]. The root extract and withanolide A restored spatial memory deficit in epileptic rats by inhibiting oxidative stress through enhancing the antioxidant system and restoring altered NMDA receptor density [146]. They also regulated the AMPA receptor function that may have contributed to the motor learning deficit in the cerebellum [147]. 2.1.7. Glycyrrhiza glabra L. (Yashtimadhu) Yashti is another widely used nootropic (medhya rasayana) and forms an integral part of several formulations. The aqueous and ethanolic extracts of G. glabra demonstrated anticonvulsant activity and ameliorated oxidative stress in PTZ-induced seizures [57]. The anticonvulsant activity of the leaves was attributed to compounds of triterpene/sterol class [58]. Glycyrrhizin, the triterpene present in the roots and rhizomes, has potential neuroprotective benefits by its antiinflammatory and antiexcitotoxic effects [59,148]. 2.2. Studies of polyherbal formulations Most of the formulations in Ayurveda are polyherbal in nature, more so in the case of chronic illnesses wherein enhanced potency translates as better effectiveness. Such judicious combinations of herbs ensure that the ill effects of some components of one herb are mitigated by the presence of another, or the therapeutic effect of a herb can be enhanced by the presence of another herb, i.e., a synergism of drugs [149]. It is observed that the bioavailability and bioefficacy of different classes of drugs, such as antibiotics, antituberculosis, antiviral, antifungal, and anticancerous drugs, are enhanced by the addition of herbs at low doses. The oral absorption of nutraceuticals like vitamins, minerals, amino acids, and certain herbal compounds is also increased by such addition [150]. Their mechanism of action is mainly through the absorption process, drug metabolism, and actions on drug targets. Very few polyherbal formulations have been studied for seizure control in epilepsy. Oral administration of Brahmi Rasayan in rats and mice significantly protected against seizures induced by MES and also chemoconvulsions possibly by influencing the GABAergic system in the brain [151]. Mentat, a polyherbal formulation, ameliorated seizures induced by alcohol abstinence [152]. Siotone, another formulation containing Ashwagandha (W. somnifera), Tulasi (O. sanctum), and Shatavari (Asparagus racemosus), protected against PTZ-, MES-, and strychnine-induced convulsions, when given alone and with other AEDs [153]. Unmadnashak ghrita prepared using Ferula narthex (6 g), Gardenia gummifera (6 g), Ellataria cardamom (6 g), Bacopa monneri (6 g), and cow's ghee (clarified butter fat) (76 g) significantly reduced PTZ- and MES-induced convulsions [154]. Another Ayurveda formulation


containing E. officinalis, G. glabra, and cow's ghee slightly prolonged the seizure phases in PTZ-induced seizures [60]. Two different formulations of Hingu (F. asafoetida), Hingusauvarchaladi Ghrita and saptavrita Hingusauvarchaladi ghrita showed anticonvulsant activity in PTZ-induced seizures, though the effect of the latter ghrita was better [155]. Different formulations of Ashwagandha (W. somnifera) have also been studied; they include Ashwagandharishtam and Ashwagandhadi lehyam. Ashwagandharishtam contains Cyperus rotundus, C. longa, Terminalia chebula, A. calamus, Pueraria tuberosa, and G. glabra in addition to W. somnifera. Ashwagandharishtam shortened the flexion phase of MES-induced seizures but had no effect on the tonic extensor phase. Ashwagandhadi lehyam also reduced the seizures in various phases in comparison with phenytoin in MES-induced epileptic rats [156,157]. Saraswatarishtam, containing C. asiatica as its main ingredient, showed significant reduction of MES-induced seizures. Physicochemical evaluation of this formulation also revealed traces of lead, mercury, cadmium, and arsenic within WHO acceptable limits [158]. 2.3. Studies in human populations There are very limited studies that have looked for the effectiveness of Ayurveda treatments in subjects with epilepsy. Though ethnobotanical surveys and CAM use surveys in different populations worldwide indicate a trend for the effective use of Ayurveda as an adjuvant to mainstream health care, rigorous clinical studies are lacking [159–163]. A survey of the indigenous communities of the sub-Himalayan region of Uttarakhand indicated the use of a total of 24 plants belonging to 24 genera and 22 families in 26 formulations to treat epilepsy. Some of the drugs used were Ricinus communis L., Datura stramonium L., B. monnieri L., Allium sativum L., and A. racemosus Willd [29]. It is interesting to note that many herbs mentioned in Ayurveda including Ferula gummosa, Nigella sativa, and Piper longum are widely used even in traditional Iranian medicine for treating epilepsy [72]. Piperine, the active principle of the herbs P. longum L., Piper nigrum L., and Zingiber officinale Roscoe, commonly used together as Trikatu in most Ayurveda preparations, has been studied as an adjuvant to phenytoin and carbamazepine. Piperine, given at a dose of 20 mg with phenytoin (150 mg and 200 mg twice daily) significantly increased the mean plasma concentration of phenytoin at multiple time points in 12 h, while as an adjuvant to carbamazepine (300 mg and 500 mg twice daily), it increased the mean plasma concentration only at higher doses. This indicates the potential of piperine in increasing the bioavailability of conventional AEDs such that side effects of AEDs at high doses may be minimized [164,165]. On the flipside, it must also be noted that there have been sparse reports of herbal drugs like Shankhapushpi (C. pluricaulis) and others reducing plasma phenytoin levels and aggravating seizures [166,167]. 3. Future prospects Although seizures in 70-80% of patients with newly-diagnosed epilepsy respond to AEDs, seizures in 20-30% of them do not respond to AEDs or these patients have adverse effects, significant psychiatric and somatic comorbidities, and increased mortality [2]. The available literature points towards a beneficial effect of herbs used in Ayurveda therapeutics for epilepsy. Although studying single herb extracts/polyherbal formulations has provided valuable insights, the whole-system approach that is the bane of Ayurveda may be a more appropriate evaluation of the effectiveness and efficacy of this health-care system. A whole-system approach consists of a multipronged, personalized management strategy involving pharmacological interventions, panchakarma (detoxification), and modifications in diet and lifestyle [168]. There is growing support for the ‘black-box’ approach, i.e., assessing the entire package of interventions rather than individual components, as efficacy is postulated to depend on the synergistic action of various components [169]. Much has been written about the

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need for newer paradigms for research in Ayurveda and the way forward, and it applies for research on epilepsy too [170–172]. Panchakarma therapies form the mainstay of Ayurveda interventions, and the benefits of these unconventional modes of drug delivery are yet to be elucidated. Different panchakarma modalities have demonstrated significant effects on psychoneuroimmunologic parameters in studies of other neuropsychiatric illnesses like Parkinson's disease, anxiety, stroke, degenerative ataxia, and insomnia. The benefits of cleansing (shodhana) procedures adopted in Ayurveda have been highlighted in comparison with only palliative (shamana) treatment in patients with Parkinson's disease by Nagashayana and colleagues [173]. The other therapeutic modalities studied in these illnesses include Shirodhara (pouring of a steady stream of oil on the forehead), Shirobasti (retention of oil over the scalp), Abhyanga (massage), Svedana (sudation), and Basti (medicated enema) [174–179]. This indicates possible neurotropic activities of Ayurveda therapies which may benefit even in the case of epilepsy. Epilepsy is also associated with a heightened autonomic state, even in the interictal periods and therapies that are known to ameliorate sympathetic activity in other neuropsychiatric illnesses like depression and stroke need to be explored for treating epilepsy as well [180,181]. 4. Conclusion A growing interest in allied systems of health care is being observed worldwide, and it becomes imperative to understand the theories and practice that underlie these systems , because they have very significant potential to contribute to the management of chronic degenerative illnesses. Current antiepileptic management focuses on seizure management, but less importance is given to disease modification, especially in the case of severe epilepsies. An integrative approach that can utilize the benefits of different health-care systems should be explored for its possible impact on epilepsy care for the future. Acknowledgment We would like to sincerely thank Prof. Bhushan Patwardhan, Interdisciplinary School of Health Sciences, University of Pune, Pune 411 007, India for his valuable inputs in the preparation of this manuscript. Conflict of interest None declared. References [1] Rudzinski LA, Meador KJ. Epilepsy and neuropsychological comorbidities. Continuum (Minneap Minn) 2013;19:682–96. [2] Schmidt D, Schachter SC. Drug treatment of epilepsy in adults. BMJ 2014;348:g254. [3] Charaka, Drdhabala, Chakrapanidatta. The Charaka Samhita of Agnivesha. Varanasi: Munshiram Manoharlal Publishers Pvt. Ltd; 1992. [4] Sumantran VN, Tillu G. Cancer, inflammation, and insights from Ayurveda. Evid Based Complement Altern Med 2012;2012:306346. [5] Vagbhata, Arunadatta, Hemadri. Ashtanga Hridaya. Varanasi: Krishnadas Academy; 1995. [6] Manyam BV. Epilepsy in ancient India. Epilepsia 1992;33:473–5. [7] Mishra S, Trikamji B, Singh S, Singh P, Nair R. Historical perspective of Indian neurology. Ann Indian Acad Neurol 2013;16:467–77. [8] Sushruta, Dalhana, Gayadasa. Sushruta Samhita. Varanasi: Krishnadas Academy; 1998. [9] Sen Govinda Das. Bhaishajya Ratnavali. Bombay: Khemraj Srikrishnadas Prakashan; 2001. [10] Sharngadhara. Sharangadhara Samhita. Varanasi: Chaukhambha Surbharati Prakashan; 2013. [11] Bhavamishra. Bhavaprakasha. Varanasi: Chaukhambha Sanskrita Samsthana; 1997. [12] Sharma R, Sharma S. Sahasrayogam. Hyderabad: Dakshina Prakashana; 1989. [13] Haripannaji. Rasayogasagara. Varanasi: Chowkhamba Sanskrit Series Office; 2010. [14] Suresh Babu MS. Yoga Ratnakara. Varanasi: Chowkhambha Sanskrit Series Office; 2006. [15] Bhatt Gopal Krishna. Rasendra Sara Sangraha. Varanasi: Chaukhambha Publications; 2007.

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