Epilepsy: Nutrients and Herbs
Abstract
Epilepsy is a common neurological disorder that affects a large global population. While antiepileptic medications provide great relief, nearly 30% of cases remain insufficiently or completely unmanaged. There is a growing interest in the complementary and alternative care and a number of systematic reviews have explored the potential benefits of many herbs. Unfortunately, these reviews focused on preclinical data, comprised of animal and in vitro studies. This review will explore the latest clinical developments in the nutritional and herbal approaches for epilepsy, including Paeonia officinalis, Ganoderma lucidum, Vinpocetine, probiotics, melatonin, omega 3, vitamin E, vitamin D, N-acetylcysteine, and coenzyme q10.
Introduction
Epilepsy is considered to be one of the most common neurological disorders worldwide (Beghi 2020), affecting 0.4 to 1% of the population of all genders, ages, and ethnicities (Kim and Cho 2019). Relapse with epilepsy is characterized by seizures that do not have an identifiable neurological trigger or precipitating factor and thus appear unprovoked. The classification of seizures is based on the onset of the abnormal activity. When seizures originate from one specific location of the brain they are termed as “focal” and if they begin in multiple locations spanning both hemispheres they are “generalized”. Additional terms help to define whether the seizures begin with motor or non-motor symptoms and whether there is a change in awareness. These classifications are useful to describe the way that the seizures present, but do not dictate the mechanism by which they originate. Epilepsy is a disorder that encompasses a wide range of pathophysiological process that can stem from or be promoted by different conditions, including brain trauma/structural, post-stroke, cancers, autoimmune, infectious, metabolic, and genetic.
Management of epilepsy includes the use of antiepileptic drugs (AEDs) comprised of carbamazepine, levetiracetam, phenytoin, sodium valproate, clobazam, and others (Perucca et al 2018). These medications work to increase the seizure threshold and thus make it more difficult for the neurons to produce the synchronous spontaneous activity that results in seizures. Five main mechanisms of action have been frequently cited in the literature. These include: (1) activation of the GABA receptor, (2) inhibition of the AMPA receptor, (3) inhibition of calcium voltage gated channels, (4) inhibition of sodium gated channels, and (5) activation of voltage gated potassium channels. Additionally, oxidative stress and pro-inflammatory states have been observed in patients with epilepsy, but their direct connection to seizure generation is less clear. In certain cases, where the AEDs fail to effectively control the seizures, surgery may be an option. However, this is dependent on the ability to precisely locate the epileptogenic zone. Additionally, there is a lack of clear prognostic outcomes for surgery, which limits the number of patients that are willing to proceed with this option (West et al 2019). Approximately 30% of cases cannot be managed with the AEDs, either due to lack of drug efficacy or due to the severity of adverse effects (da Fonsêca et al 2019). Thus, there is a great need to find alternative treatment options to provide care for these patients. This review will explore the latest clinical developments in the nutritional and herbal approaches for epilepsy.
Paeonia officinalis
In an open label study, 30 pediatric patients with intractable epilepsy were provided with an extract of Paeonia officinalis in addition to their AEDs (Zangooei Pourfard et al 2021). Paeonia was delivered as a hydroalcoholic extract of Paeonia with dose of 20mg/kg administered twice per day. At the end of the study (four weeks), there was a statistically significant decline in seizure frequency, compared to baseline, with 36.7% of the group achieving a greater than 75% reduction in seizures (p<0.005). The mean duration of seizures was also reduced significantly (p<0.05). The greatest benefit appeared to be achieved within the first week of intervention, however, there was a continuous decline in both duration and frequency observed between 3rd and 4th weeks. It is possible that with longer administration there may have been additional benefits, but this needs to be explored in future trials. Adverse events included restlessness and constipation.
Ganoderma lucidum
The reishi mushroom has been used in a diverse range of health conditions and it is of no surprise to find Ganoderma lucidumbeing applied to the treatment of seizures. An observational study reports the adjunct use of Ganoderma lucidum Spore Powder (GLSP) by 18 participants with epilepsy for eight weeks with a statistically significant reduction in seizure frequency compared to baseline (p=0.04) (Wang et al 2018). The GLSP was administered as 1g three times per day in addition to the participants’ regular AED. The seizure frequency was 3.1 per week on average and declined to 2.4 seizures per week by the end of the eight-week period. The most commonly reported adverse events included stomach discomfort and nausea. Preclinical research on GLSP suggests it may inhibit calcium influx or calcium accumulation within hippocampal neurons as well as promote expression of neurotrophin-4. Neurotrophin-4 is a more potent version of the brain-derived-neurotrophic factor (BDNF) which has been observed to increase after seizures (Scharfman 2005). It is not clear whether BDNF promotes epileptogenesis or is elevated as a protective mechanism to heal the damaged induced by the seizures.
Vinpocetine
A double blind randomized controlled study of 87 participants with focal epilepsy compared the impact of adjunct vinpocetine to the use of placebo. All participants were given their regular AEDs and were followed for four weeks to establish a baseline of seizure activity. For the next four weeks they were given titrated doses of either placebo or vinpocetine with the goal of reaching a target dose of 2mg/kg per day. Once this dose was reached, the participants were followed for eight weeks and then reassessed. The use of vinpocetine resulted in significant reduction in seizure frequency compared to placebo (p<0.0001). Of the placebo group, 13% reported a 50% reduction in seizures, while in the vinpocetine group 69% reported a 50% reduction. Adverse events included headaches and diplopia (Garza-Morales et al 2019).
What is vinpocetine? It is a synthetic derivative of a naturally-found compound called vincamine which is first heated to produce apovincamine, and then modified into vinpocetine. This compound is found within Vinca species, including Vinca minor. Vinpocetine has many proposed mechanisms of action. It can block sodium channels, reduce calcium influx, and provide antioxidant activity (Bereczki and Feketa 2008). Additionally, it provides protection against hypoxic induced apoptosis and increases cerebral blood flow, which may be targeting some of the underling mechanisms contributing to seizures.
The dose that was used in this study seems high compared to those reported in some of the literature on the use of vinpocetine in stroke recovery. At 2mg/kg, the current study would be delivering 140mg of vinpocetine per day to a 70kg adult, while the clinical trials reviewed in the systematic review on ischemic stroke ranged from 30-40mg per day (Bereczki and Feketa 2008).
Probiotics and Antibiotics
The importance of the gut microbiome is becoming apparent in an increasing number of neurological disorders. In the case of epilepsy, the hypothesis is that gut dysbiosis may be responsible for reducing the effectiveness of the AEDs (Chatzikonstantinou et al 2021). Microbial studies of the gut of patients with refractory or drug-resistant epilepsy, specifically their stool samples, demonstrate an increase in Firmicutes and decrease in Bacteroides. Animal studies of epilepsy suggest that the widely popular and effective ketogenic diet may be effective at reducing seizures by altering the gut microbiota.
In a prospective clinical study, 45 adult participants with drug-resistant epilepsy were provided with a daily probiotic mixture, in addition to their regular medications, for four months (Gomez-Eguilaz et al 2018). The probiotic mixture contained Streptococcus thermophilus, Lactobacillus acidophilus, L. plantarum, L. paracasei, L. delbrueckii subs bulgaricus, Bifidobacterium breve, B. longus y and B. infantis y CD2. The results demonstrate significant improvement in quality of life as measured by the questionnaire of quality of life in epilepsy and reduction in seizure frequency. Nearly 30% of the participants reported a greater than 50% reduction in seizure frequency.
From a different perspective, another prospective study evaluated the effects of an antibiotic on drug-resistant epilepsy. Ciprofloxacin, a broad-spectrum quinolone, was administered to 23 adult participants for the duration of five days and participants were followed up for a total of 12 weeks to examine the impact. There was significant reduction in seizure frequency (p<0.001) that was observed at the end of the first week and was maintained for the remainder of the study. Additionally, there was an increase in the ratio of beneficial Bacteroidetes to Firmicutes (Cheraghmakani et al 2021).
Melatonin
Melatonin is well known for its benefits in the treatment of insomnia. Seizures and insomnia can often coexist and have a bidirectional relationship. Poor sleep quality or lack of sleep may precipitate increased seizure frequency the next day, and seizures themselves may interfere with sleep quality. Several small clinical studies examined the effects of melatonin on seizure frequency.
A small randomized double-blind study of 10 pediatric participants with epilepsy demonstrated improved sleep latency with the use of 9mg of sustained release melatonin after four weeks compared to placebo. There was no measurable improvement or worsening of seizures during this time, demonstrating safety at a relatively higher dose (Jain et al 2015). Another small study of six pediatric participants with neurological deficit disorders in addition to epilepsy demonstrated a positive impact on seizures when melatonin was provided as an adjunct therapy. All six participants had been consistently taking their respective AEDs and were provided with 3mg of melatonin thirty minutes before sleep for three months. Five out of six parents reported reduction in seizures, particularly during the night, as well as general improvement in communication and daily behaviours (Peled et al 2001). Lastly, a study of 10 pediatric participants with severe epileptic disorder reported better seizure control after one month of nightly supplementation with 3mg of melatonin (Uberos et al 2011).
Melatonin is considered to be a potent antioxidant. Studies on the consequences of epilepsy report higher oxidative stress in unmanaged cases and raise the possibility that epilepsy may be caused or aggravated by increased production of reactive oxygen species (Aguiar et al 2012). A small double-blind study of melatonin in pediatric patients with epilepsy receiving melatonin demonstrated that antioxidant enzymes such as glutathione peroxidase and glutathione reductase are less active in these patients and that melatonin (6-9mg/d) is able to increase their activity (Gupta et al 2004).
Omega-3 Fatty Acids
Adult participants with refractory epilepsy (n=50) were randomized into placebo and omega-3 intervention groups for 16 weeks (Omrani et al 2019). This was a triple-blind study, which included blinding of the patient, neurologist (assessor), and statisticians. The omega-3 capsules were composed of 120mg of DHA and 180mg of EPA and were given twice per day for a total daily dose of 240mg of DHA and 360mg of EPA. The study demonstrated statistically significant improvement in seizure severity (assessed via EEG) (p=0.034), reduction in seizure frequency (p=0.014), reduction in seizure duration (p=0.009) and reduction in TNF-alpha and IL-6 inflammatory markers.
Earlier clinical trials show mixed results with a variety of doses, ranging from 112mg of DHA and 171mg of EPA to 5g of combined EPA with DHA (Schlanger et al 2002, Yuen et al 2005), in terms of seizure frequency. There seems to be consistency with respect to impact on inflammatory cytokines and most studies demonstrate seizure reduction. There are several mechanisms of action that are proposed in relation to epilepsy. These include protection of the GABA inhibitory interneurons, stimulation of antioxidant enzymes such as super oxide dismutase and glutathione peroxidase, as well as reduced inflammation.
Vitamin E
A recent clinical trial on vitamin E demonstrates significant improvement in epilepsy management. The double-blind placebo-controlled trial provided 65 adult participants with epilepsy with 400IU of vitamin E per day as alpha-tocopherol alone for six months in addition to their AEDs. The intervention resulted in statistically significant reduction in seizure frequency (p<0.001) as well as better functioning of the antioxidant enzymes (Mehvari et al 2016). The improvement in seizures may have been due to the improved antioxidant capacity, or due to vitamin E’s ability to promote reduction of excitotoxicity, or its anti-inflammatory effects.
Vitamin D
Deficiency of vitamin D has been observed in a variety of neurological, mood, autoimmune, and many other conditions. Not surprisingly it has also been observed in patients with epilepsy (Teagarden et al 2014). However, when it comes to examining the therapeutic effect of supplementation, the results are mixed. A pilot study (Hollo et al 2012) demonstrates a 40% reduction in mean seizure production after 90 days of supplementation with vitamin D. Participants (n=13) with epilepsy were first assessed for their vitamin D status. Those who had sufficient stores were given a daily maintenance dose of 2,000-2,600IU for the duration of the study. Those with vitamin D levels of <30ng/mL were first given a single oral dose of 40,000-200,000IU of vitamin D and then continued with the daily maintenance dose. Twelve of the thirteen participants were found to be deficient, and six participants were still deficient at the end of the 90-day study, though their levels did improve (Hollo et al 2012).
N-Acetylcysteine (NAC)
The use of NAC in neurology is gaining popularity with a systematic review in 2015 reporting favorable evidence for consideration of the use of NAC in disorders such as Alzheimer’s, bipolar disorder, neuropathies, autism, and many others (Deepmala et al 2015). While the theory behind NAC’s applicability may be positive, there is a lack of clinical trials on this subject in terms of its use for epilepsy. The closest clinical evidence that is available comes from a case report of four siblings with progressive myoclonus epilepsy. The siblings received a combination of antioxidant vitamins and mineral for six months with mild improvement in their symptoms. After the addition of 4-6g of NAC, there was a large decline in seizures which was maintained for the 30 months of continued supplementation (Hurd et al 1996).
Coenzyme Q10
Continuing on the topic of antioxidants, coenzyme Q10 (CoQ10) is also considered an important antioxidant and may be deficient in patients with epilepsy. An observation study examined the serum levels of CoQ10 in 39 participants with epilepsy and compared these to levels from 35 healthy participants. They found that not only were the levels of CoQ10 significantly lower in participants with epilepsy (p<0.001), but they were also correlated with seizure severity and frequency (Simani et al 2020). However, it is unclear whether this is a contributing cause of epilepsy or a consequence. Are the seizures more likely to occur because there is a lack of antioxidant protection and oxidative stress has a direct means of stimulating seizures, or has the body become deficient in antioxidants as a consequence of experiencing frequent seizures which themselves act to produce reactive oxygen species and cause oxidative stress?
Unfortunately, there are no clinical trials that exclusively examine the effect of CoQ10 on seizures. The closest clinical study looked at a combination of vitamins along with CoQ10 on the seizure frequency of adult participants with intractable focal epilepsy (n=30) while taking regular AEDs. This open label study provided participants with a cocktail of 100mg of vitamin B6, 5mg of vitamin B9, 1000IU of vitamin D, 400IU of vitamin E, and 100mg of CoQ10 for six months. There was a significant decline in seizure frequency compared to baseline (p<0.045) with an average decrease of seven seizures per month, as well as 12.5% of the participants reportedly being completely seizure free (Chang 2020).
Conclusion
Several nutrients and herbs have demonstrated significant reduction in seizure frequency when provided in addition to standard antiepileptic drugs. While studies discussed in this review demonstrate the capacity for nutrients and herbs to provide additional benefits to medications, there is a significant need for further clinical trials to examine the maximum potential for these treatments, particularly in patients who are unable to tolerate the antiepileptic drugs. The studies reviewed were fairly small in terms of the number of patients and frequently short in duration. Additionally, the types of medications used and the types of epilepsy were all different in these reports. Further research is crucial as there is an important need for effective management of epilepsy.
References
Aguiar CC, Almeida AB, Araújo PV, de Abreu RN, Chaves EM, do Vale OC, Macêdo DS, Woods DJ, Fonteles MM, Vasconcelos SM. Oxidative stress and epilepsy: literature review. Oxid Med Cell Longev. 2012;2012:795259.
Beghi E. The epidemiology of epilepsy. Neuroepidemiology. 2020;54:185-191.
Bereczki D, Feketa I. Vinpocetine for acute ischaemic stroke. Cochrane Database of Systematic Reviews. 2008;1:CD000480
Chang HH, Sung PS, Liao WC, Chang AYW, Hsiao YH, Fu TF, Huang CY, Huang CW. An Open Pilot Study of the Effect and Tolerability of Add-On Multivitamin Therapy in Patients with Intractable Focal Epilepsy. Nutrients. 2020 Aug 7;12(8):2359.
Chatzikonstantinou S, Gioula G, Kimiskidis VK, McKenna J, Mavroudis I, Kazis D. The gut microbiome in drug-resistant epilepsy. Epilepsia Open. 2021 Jan 13;6(1):28-37.
Cheraghmakani H, Rezai MS, Valadan R, Rahimzadeh G, Moradi M, Jahanfekr V, Moosazadeh M, Tabrizi N. Ciprofloxacin for treatment of drug-resistant epilepsy. Epilepsy Res. 2021 Oct;176:106742.
da Fonsêca DV, da Silva Maia Bezerra Filho C, Lima TC, de Almeida RN, de Sousa DP. Anticonvulsant Essential Oils and Their Relationship with Oxidative Stress in Epilepsy. Biomolecules. 2019 Dec 6;9(12):835.
Deepmala, Slattery J, Kumar N, Delhey L, Berk M, Dean O, Spielholz C, Frye R. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015 Aug;55:294-321.
Garza-Morales S, Briceno-Gonzalez E, Ceja-Moreno H. Extended-release vinpocetine: a possible adjuvant treatment for focal onset epileptic seizures. Bol Med Hosp Infant Mex. 2019;76(5):215-224.
Gomez-Eguilaz M, Ramon-Trapero JL, Perez-Martinez L, Blanco JR. The beneficial effect of probiotics as a supplementary treatment in drug-resistant epilepsy: a pilot study. Benef Microbes. 2018;9(6):875-881.
Gupta M, Gupta YK, Agarwal S, Aneja S, Kohli K. A randomized, double-blind, placebo controlled trial of melatonin add-on therapy in epileptic children on valproate monotherapy: effect on glutathione peroxidase and glutathione reductase enzymes. Br J Clin Pharmacol. 2004 Nov;58(5):542-547.
Hollo A, Clemens Z, Kamondi A, Lakatos P and Szucs A. Correction of vitamin D deficiency improves seizure control in epilepsy: a pilot study. Epilepsy and Behavior. 2012;24:131-133.
Hurd R, Wilder BJ, Helveston WR, Uthman BM. Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine. Neurology. 1996;47(5):1264-1268.
Jain SV, Horn PS, Simakajornboon N, Beebe DW, Holland K, Byars AW, Glauser TA. Melatonin improves sleep in children with epilepsy: a randomized, double-blind, crossover study. Sleep Med. 2015 May;16(5):637-644.
Kim JE, Cho KO. Functional nutrients for epilepsy. Nutrients. 2019;11:1309.
Mehvari J, Motlagh FG, Najafi M, Ghazvini MR, Naeini AA, Zare M. Effects of Vitamin E on seizure frequency, electroencephalogram findings, and oxidative stress status of refractory epileptic patients. Adv Biomed Res. 2016 Mar 16;5:36.
Omrani S, Taheri M, Omrani MD, Arsang-Jang S, Ghafouri-Fard S. The effect of omega-3 fatty acids on clinical and paraclinical features of tractable epileptic patients: a triple blind randomized clinical trial. Clin Trans Med.2019;8:3.
Peled N, Shorer Z, Peled E, Pillar G. Melatonin effect on seizures in children with severe neurological deficit disorders. Epilepsia. 2001;42(9):1208-1210.
Perucca P, Scheffer IE, Kiley M. The management of epilepsy in children and adults. Med J Aust. 2018;208(5):226-233.
Simani L, Rezaei O, Ryan F, Sadeghi M, Hooshmandi E, Ramezani M, Pakdaman H. Coenzyme Q10 Insufficiency Contributes to the Duration and Frequency of Seizures in Epileptic Patients. Basic Clin Neurosci. 2020 Nov-Dec;11(6):765-771.
Scharfman HE. Brain-derived neurotrophic factor and epilepsy – a missing link? Epilepsy Curr. 2005;5(3):83-88.
Schlanger S, Shinitzky M, Yam D. Diet enriched with omega-3 fatty acids alleviates convulsion symptoms in epilepsy patients. Epilepsia 2002;43:103-104.
Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are common in patients with epilepsy. Epilepsy Res. 2014;108(8):1352-1356.
Uberos J, Augustin-Morales MC, Molina Carballo A, Florido J, Narbona E, Muñoz-Hoyos A. Normalization of the sleep-wake pattern and melatonin and 6-sulphatoxy-melatonin levels after a therapeutic trial with melatonin in children with severe epilepsy. J Pineal Res. 2011 Mar;50(2):192-196.
Wang GH, Li X, Cao WH, Li J, Wang LH. A retrospective study of Ganoderma Lucidum Spore Powder for patient with epilepsy. Medicine (Baltimore). 2018;97(23):e10941.
West S, Nevitt SJ, Cotton J, Gandhi S, Weston J, Sudan A, Ramirez R, Newton R. Surgery for epilepsy. Cochrane Database Syst Rev. 2019 Jun 25;6(6):CD010541.
Yuen AW, Sander JW, Fluegel D, Patsalos PN, Bell GS, Johnson T, Koepp MJ. Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav. 2005 Sep;7(2):253-258.
Zangooei Pourfard M, Mirmoosavi SJ, Beiraghi Toosi M, Rakhshandeh H, Rashidi R, Mohammad-Zadeh M, Gholampour A, Noras M. Efficacy and tolerability of hydroalcoholic extract of Paeonia officinalis in children with intractable epilepsy: An open-label pilot study. Epilepsy Res. 2021 Oct;176:106735.