Unraveling the nutritional challenges in epilepsy: Risks, deficiencies, and management strategies: A systematic review

Table 1 Quality assessment of randomized controlled trials on vitamin supplementation in epilepsy using the Cochrane risk of bias tool¹

Ref.	Vitamin studied	Sample size (n)	Risk of bias (Cochrane tool)	Main outcome	Statistical findings (P value, 95%CI, etc.)
Holló et al[97], 2012	Vitamin D3	13	Moderate (small sample, no control group)	40% seizure reduction after vitamin D3 supplementation	P = 0.04 (significant reduction in seizure frequency)
Mehvari et al[105], 2016	Vitamin E	65	Low (double-blind, placebo-controlled)	Improved seizure control and EEG findings	P < 0.001 (seizure frequency reduction), P = 0.001 (EEG improvement)
Elmazny et al[96], 2020	Vitamin D	42	Moderate (case-control design)	Lower vitamin D levels correlated with higher seizure frequency	P < 0.001 (vitamin D lower in epilepsy patients), P = 0.004 (seizure frequency correlation)
Nemati et al[59], 2021	Folate (Vitamin B9)	60	Moderate (cross-sectional, no intervention)	Association between low folate and epilepsy in children	Mean folate: 11.60 ± 6.89 nmol/L; correlation with neurodevelopmental delay
Kirik et al[73], 2021	Vitamin B12	26	High (retrospective, small sample)	Seizures in children resolved with vitamin B12 supplementation	No P values reported, high homocysteine levels noted
Portillo et al[75], 2023	Vitamin B12	1 (case report)	Not applicable	Seizures and psychosis improved with B12 supplementation	No statistical data
Specht et al[102], 2020	Vitamin D3 (Neonatal)	403 (cases), 1163 (controls)	Low (large sample, well-controlled)	High neonatal vitamin D levels correlated with increased epilepsy risk	HR adjust 1.86 (95%CI: 1.21-2.86), P trend = 0.004
Leandro-Merhi et al[85], 2023	Vitamin D	93	Moderate (cross-sectional, statistical correlation only)	Low vitamin D associated with worse seizure control in adults	P = 0.048 (seizure control linked to vitamin D levels)

¹This table summarizes the methodological quality and key findings of randomized controlled trials investigating the role of vitamin supplementation in epilepsy. While Vitamin D and Vitamin E showed potential benefits in seizure reduction, findings on Vitamin B12 and Folate are largely observational. Some studies exhibited a moderate-to-high risk of bias, highlighting the need for larger, well-controlled trials to confirm therapeutic efficacy.

EEG: Electroencephalogram; HR: Hazard ratio.

Table 2 Summary of quality assessment and key findings from studies on minerals and epilepsy¹

Ref.	Mineral studied	Sample size (n)	Risk of bias (Cochrane tool)	Main outcome	Statistical findings (P value, 95%CI, etc.)
Baek et al[122], 2018	Magnesium	274 (133 cases, 141 controls)	Moderate (case-control, potential confounders)	Hypomagnesemia more common in febrile seizure patients	OR = 22.12 (95%CI = 9.23-53.02), P < 0.001
Abdelmalik et al[124], 2012	Magnesium	22	High (retrospective, no control group)	Magnesium supplementation reduced seizure frequency	Seizure days reduced (P = 0.021 at 3-6 months, P = 0.004 at 6-12 months)
Guo et al[125], 2023	Magnesium, calcium	44889 (15212 cases, 29677 controls)	Low (mendelian randomization, large sample)	Higher serum magnesium associated with lower epilepsy risk	OR = 0.28 (95%CI = 0.12-0.62), P = 0.002
Abdullahi et al[126], 2019	Magnesium, calcium	90 (40 idiopathic epilepsy, 20 symptomatic epilepsy, 30 controls)	Moderate (case-control, small sample)	Lower serum magnesium and calcium in epilepsy patients	Mg: P = 0.007 (95%CI = -0.189 to -0.031), Ca: P < 0.01
Saghazadeh et al[131], 2015	Magnesium, zinc, copper, selenium	60 studies (Meta-analysis)	Low (large sample, multiple studies)	Altered trace element levels in epilepsy and febrile seizures	Magnesium significantly lower in epilepsy (P < 0.001)
Kheradmand et al[132], 2014	Zinc, copper	70 (35 intractable epilepsy, 35 controlled epilepsy)	Moderate (case-control, small sample)	Zinc deficiency more common in intractable epilepsy	P < 0.05 (71.45% deficiency in intractable vs 25.72% in controlled epilepsy)
Saad et al[133], 2014	Zinc, selenium	80 (40 epilepsy, 40 controls)	Moderate (case-control, small sample)	Lower Zn, Se in epilepsy patients, higher oxidative stress markers	Zn, Se significantly lower (P < 0.001), Plasma MDA higher (P < 0.001)
Chen et al[134], 2019	Zinc	Animal study (Sprague-Dawley rats)	Moderate (preclinical, no human data)	Zinc deficiency worsened seizure-related brain damage	No direct P value reported, hippocampal ZnT-3 and MBP levels altered
Sharif et al[158], 2015	Iron	200 (100 febrile seizure, 100 controls)	Moderate (case-control, single-center)	Iron deficiency more common in febrile seizure patients	45% iron deficiency in seizure group vs 22% in controls (P < 0.05)
Bidabadi et al[159], 2009	Iron	200 (100 febrile seizure, 100 controls)	Moderate (case-control, single-center)	No protective effect of iron deficiency against febrile seizures	OR = 1.175, temperature peak higher in seizure group (P < 0.0001)
Zimmer et al[160], 2021	Iron	Human and animal study	Low (well-controlled, experimental)	Seizures linked to iron accumulation in temporal lobe epilepsy	P < 0.01, iron metabolism changes observed in TLE
Ashrafi et al[168], 2007	Selenium	160 (80 intractable epilepsy, 80 controls)	Moderate (case-control, no intervention)	Serum selenium lower in intractable epilepsy patients	P < 0.05 (lower selenium in epilepsy group)
Omrani et al[175], 2019	Omega-3 fatty acids	50 (randomized clinical trial)	Low (double-blind, placebo-controlled)	Omega-3 reduced seizure frequency and inflammation	P < 0.001 (seizure reduction), lower TNF-α and IL-6
Liang et al[174], 2023	Omega-3 fatty acids	Mendelian randomization	Low (genetic analysis, large sample)	Higher blood omega-3 levels linked to increased epilepsy risk	OR = 1.16 (95%CI = 1.051-1.279, P = 0.003)

¹This table provides an overview of studies investigating the role of various minerals (magnesium, calcium, zinc, iron, selenium) and omega-3 fatty acids in epilepsy and seizure disorders.

MDFA: Methyl-D-aspartate; OR: Odds ratio; TLE: Temporal lobe epilepsy.

Table 3 Summary of quality assessment and key findings from studies on food supplements and seizures¹

Ref.	Supplement studied	Sample size (n)	Risk of bias (Cochrane tool)	Main outcome	Statistical findings (P value, 95%CI, etc.)
Schauwecker et al[189], 2012	Glycemic control	Animal study	Moderate (preclinical, no human data)	Glycemic modulation affects seizure-induced brain injury	Glucose rescue reduced hippocampal pathology (P < 0.001)
Hamerle et al[204], 2018	Alcohol	310	Moderate (retrospective, self-reported)	Alcohol-related seizures linked to heavy consumption	OR = 5.79 for genetic epilepsy, OR = 8.95 for chronic alcohol use
Samsonsen et al[206], 2018	Alcohol	134	Moderate (observational, cross-over design)	Hazardous drinking and sleep deprivation linked to seizures	AUDIT score ≥ 8 in 28% of patients, seizures peaked on Sundays and Mondays
Pelliccia et al[211], 1999	Food allergy	3 (case report)	Not applicable	Seizures improved with cow’s milk elimination	EEG normalized after diet change (no statistical data)
Silverberg et al[212], 2014	Allergic disease	91642 (population-based)	Low (large sample, well-controlled)	Allergies associated with increased epilepsy risk	OR = 1.79 (95%CI: 1.37-2.33) for ≥ 1 allergic disease, OR = 2.69 (95%CI: 1.38-4.01) for food allergies
Gorjipour et al[220], 2019	Hypoallergenic diet	34	Moderate (quasi-experimental, no blinding)	Significant reduction in seizure frequency in children with food allergies	50% seizure-free after 8 weeks, 85% had ≥ 50% reduction (P < 0.001)
Sarlo et al[222], 2023	Low glutamate diet	33	Moderate (non-blinded, small sample)	No significant seizure reduction, but 21% were clinical responders	Clinical response likelihood decreased with age (OR = 0.71, 95%CI: 0.50-0.99, P = 0.04)
Kaufman et al[224], 2003	Caffeine	Case report	Not applicable	Excessive caffeine worsened seizure control	Seizures reduced with caffeine elimination (no statistical data)
Tényi et al[234], 2021	Food intake	100 (596 seizures analyzed)	Low (well-controlled, EEG-monitored)	Food intake significantly precipitated temporal lobe seizures esp. in males	Shorter food-seizure latency linked to less severe seizures (P < 0.05)

¹This table summarizes randomized controlled trials and relevant studies investigating the effects of dietary factors, food allergies, alcohol, caffeine, and glycemic control on epilepsy and seizure disorders.

OR: Odds ratio; EEG: Electroencephalogram.

Table 4 The potential links between various vitamin deficiencies and epilepsy

Vitamin	Role in epileptogenesis	Associated conditions	Causes of deficiency	Treatment/management	Daily recommended dose
Vitamin A	Limited evidence of anti-epileptogenic effects by impacting synaptic plasticity, memory impairment, convulsions	Night blindness, xerophthalmia, weakened immune system, skin changes, and impaired growth and development	Dietary Insufficiency, Malabsorption, poor liver function, rapid growth rates in infancy and childhood	Chronic β-carotene/vitamin A intake; Retinoic acid as potential antiepileptic agent	Infants 0-6 months: 400 mcg/day. Infants 7-12 months: 500 mcg/day. Children 1-3 years: 300 mcg/day.Children 4-8 years: 400 mcg/day. Boys 9-13 years: 600 mcg /day. Girls 9-13 years: 600 mcg/day. Male ≥ 14 years: 900 mcg/day. Females ≥ 14 years: 700 mcg/day
Thiamine (B1)	Essential for nerve function; deficiency linked to seizures; associated with Wernicke's encephalopathy	Wernicke's encephalopathy; chronic alcohol abuse; poor nutrition	Alcoholism, inadequate dietary intake	Thiamine supplementation and addressing the underlying causes	Infants 0-6 months: 0.2 mg/day. Infants 7-12 months: 0.3 mg/day. Children 1-3 years: 0.5 mg/day. Children 4-8 years: 0.6 mg/day. Boys 9-13 years: 0.9 mg/day. Girls 9-13 years: 0.9 mg/day. Teenagers 14-18 years: 1.2 mg/day. Adult men: 1.2 mg/day. Adult women: 1.1 mg/day. Pregnant women: 1.4 mg/day. Breastfeeding women: 1.4 mg/day
Riboflavin (B2)	Important for mitochondrial function; deficiency implicated in riboflavin-responsive epilepsy	Riboflavin-responsive epilepsy; mitochondrial dysfunction	Uncommon in developed countries	Riboflavin supplementation; genetic testing for riboflavin-responsive epilepsy	Infants 0-6 months: 0.3 mg/day. Infants 7-12 months: 0.4 mg/day. Children 1-3 years: 0.5 mg/day. Children 4-8 years: 0.6 mg/day. Children 9-13 years: 0.9 mg/day. Teenagers 14-18 years: Boys: 1.3 mg/day. Girls: 1.0 mg/day. Adult men: 1.3 mg/day. Adult women: 1.1 mg/day. Pregnant women: 1.4 mg/day. Breastfeeding women: 1.6 mg/day
Pyridoxine (B6)	Vital for neurotransmitter synthesis; deficiency linked to pyridoxine-dependent epilepsy	Pyridoxine-dependent epilepsy; rare genetic condition	Genetic mutations affecting pyridoxine metabolism	High-dose pyridoxine supplementation; genetic testing for pyridoxine-dependent epilepsy	Infants 0-6 months: 0.1 mg/day. Infants 7-12 months: 0.3 mg/day. Children 1-3 years: 0.5 mg/day. Children 4-8 years: 0.6 mg/day. Children 9-13 years: 1.0 mg/day. Teenagers 14-18 years. Boys: 1.3 mg/day. Girls: 1.2 mg/day. Adult men: 1.3 mg/day. Adult women: 1.3 mg/day. Pregnant women: 1.9 mg/day. Breastfeeding women: 2.0 mg/day
Folic acid (B9)	Important for DNA synthesis; deficiency may impact neurological health	Elevated homocysteine levels; disruption of neurotransmitter levels	Antiepileptic drugs, inadequate dietary intake	Folate supplementation: Address dietary and drug-related factors	Infants 0-6 months: 65 mcg/day. Infants 7-12 months: 80 mcg/day. Children 1-3 years: 150 mcg/day. Children 4-8 years: 200 mcg/day. Children 9-13 years: 300 mcg/day. Teenagers 14-18 years: 400 mcg/day. Adult men and women: 400 mcg/day. Pregnant women: 600 mcg/day. Breastfeeding women: 500 mcg/day
Vitamin B12	Crucial for nervous system functioning; deficiency associated with seizures	Demyelination, altered neurotransmitter levels	Malabsorption, dietary deficiencies	Vitamin B12 supplementation and addressing underlying causes	Infants 0-6 months: 0.4 mcg/day. Infants 7-12 months: 0.5 mcg/day. Children 1-3 years: 0.9 mcg/day. Children 4-8 years: 1.2 mcg/day. Children 9-13 years: 1.8 mcg/day Teenagers 14-18 years: 2.4 mcg/day. Adults: 2.4 mcg/day. Pregnant women: 2.6 mcg/day. Breastfeeding women: 2.8 mcg/day
Vitamin C	Antioxidant with neuroprotective properties; potential impact on glutamate clearance	Lower levels in patients with epilepsy; neuroprotective effects	Dietary deficiency; oxidative stress	Vitamin C supplementation; antioxidant support	Infants 0-6 months: 40 mg/day. Infants 7-12 mons: 50 mg/day. Children 1-3 years: 15 mg/day. Children 4-8 years: 25 mg per/day. Children 9-13 years: 45 mg/day. Teenagers 14-18 years: Boys: 75 mg/day. Girls: 65 mg/day. Adult men: 90 mg/day. Adult women: 75 mg/day. Pregnant women: 85 mg/day. Breastfeeding women: 120 mg/day
Vitamin D	Regulates calcium levels; potential neuroprotective effects	Vitamin D deficiency is associated with increased seizure risk	Limited sun exposure, dietary deficiency	Vitamin D supplementation, sun exposure, and addressing the underlying causes	Infants 0-12 months: 400 IU/day. Children 1-18 years: 600 IU/day. Adults 19-70 years: 600 IU/day. Adults over 70 years: 800 IU/day. Pregnant and breastfeeding women: 600 IU/day
Vitamin E	Lipophilic antioxidant with neuroprotective and anti-inflammatory effects	Neuroprotective effects; anticonvulsant properties	Deficiency symptoms include neurological issues	Vitamin E supplementation; antioxidant support	Infants 0-6 months: 4 mg (6 IU)/ day. Infants 7-12 months: 5 mg/day. Children 1-3 years: 6 mg/day. Children 4-8 years: 7 mg/day. Children 9-13 years: 11 mg/day. Teenagers 14-18 years: 15 mg/day. Adults (including pregnant and breastfeeding women): 15 mg/day
Vitamin K	Role in gamma-carboxylation of brain proteins; potential anticonvulsant effects	Animal studies show anticonvulsant effects; potential role in brain maturation	Vitamin K antagonist exposure; limited dietary intake	Vitamin K supplementation and addressing underlying causes	Infants 0-6 months: 2.0 mcg/day. Infants 7-12 months: 2.5 mcg/day. Children 1-3 years: 30 mcg/day. Children 4-8 years: 55 mcg/day. Children 9-13 years: 60 mcg/day. Teenagers 14-18 years: Boys: 75 mcg/day. Girls: 75 mcg/day. Adults (including pregnant and breastfeeding women): Men: 120 mcg/day. Women: 90 mcg/day

Table 5 summarizes the relationships between mineral deficiencies and epilepsy, including associated conditions, causes of deficiencies, and management strategies

Mineral deficiency	Mechanisms in epileptogenesis	Associated conditions	Causes of deficiencies	Management strategies
Magnesium	Modulates neuronal excitability by blocking calcium channels. Reduces NMDA receptor activation, lowering neuronal excitability. Prevents excessive calcium influx, mitigating excitotoxicity	Hypomagnesemia is linked to seizures and epilepsy	Inadequate dietary intake, malabsorption, renal disorders, and medications	Magnesium supplementation, dietary changes, addressing underlying health issues
Zinc	Modulates neurotransmission and influences NMDA receptors. Acts as an antioxidant and protects against oxidative stress	Serum zinc concentrations vary in epilepsy; both high and low levels are reported	Dietary insufficiency, malabsorption, genetic factors	Zinc supplementation, balanced diet, investigation into underlying causes
Calcium	Regulates neuronal excitability and neurotransmitter release. Excessive influx to excitotoxicity; deficiency may predispose to seizures	Hypocalcemia or hypercalcemia may impact neurological function	Hormonal imbalances, dietary deficiency, renal disorders, vitamin D deficiency	Dietary changes, calcium supplements, and medical treatment for underlying conditions
Sodium	Essential for generating and propagating action potentials. Dysfunctions in sodium channels can alter neuronal excitability	Dysnatremias can affect neuronal function, but the link to epileptogenesis varies	Dehydration, excessive sweating, kidney disorders, medication side effects	Fluid/electrolyte balance, addressing underlying health issues, medication adjustments
Potassium	Maintains resting membrane potential and influences action potential generation. Changes can affect the neuronal firing threshold	Imbalances can cause neuromuscular issues, but a direct link to epilepsy varies	Dietary insufficiency, renal problems, medications	A balanced diet, potassium supplements, and managing underlying health conditions
Iron	Essential for neurotransmitter synthesis and oxygen transport. Imbalance can lead to oxidative stress and neuroinflammation	Iron deficiency or excess might influence seizure susceptibility but complex relationship	Poor diet, malabsorption, menstrual bleeding, genetic disorders	Iron supplements, dietary modifications, treating underlying conditions
Selenium	Acts as an antioxidant and influences immune function and neurotransmitter systems. Role in GABAergic transmission	Oxidative stress and immune dysregulation linked to epilepsy	Dietary deficiency, soil depletion, absorption issues	Selenium supplementation, balanced diet, addressing absorption issues

NMDA: N-methyl-D-aspartate.

Table 6 The effects of some antiepileptic drugs on the nutritional status of individuals with epilepsy

Drug class/drug	Nutrient affected	Effect on nutrient	Potential side effects and consequences	Recommendations
Enzyme-inducing antiepileptic drugs
Phenytoin (Dilantin)	B1, B2, B3, B6, B12, Biotin, Folic Acid, K, Calcium, Vitamin D	Decreased absorption and metabolism, increased excretion	Nerve damage, fatigue, skin problems, anemia, developmental problems	Supplementation with affected vitamins, calcium and vitamin D, monitoring bone density
Carbamazepine (Tegretol), Oxcarbazepine (Trileptal)	B1, B2, B3, B6, B12, folic acid, calcium, Vitamin D	Decreased absorption and metabolism, increased excretion	Like phenytoin	Similar recommendations as phenytoin
Phenobarbital (Luminal)	B1, B2, B3, B6, B12, Folic Acid, Calcium, Vitamin D	Increased metabolism, decreased absorption	Like phenytoin, it may also cause drowsiness and cognitive problems	Similar recommendations as phenytoin, with additional monitoring for cognitive function
Non-enzyme-inducing antiepileptic drugs
Levetiracetam (Keppra)	B12	Decreased absorption	Anemia, nerve damage, generally well-tolerated, limited impact on nutrition	Supplementation with B12
Lamotrigine (Lamictal)	Bone metabolism	Potential impairment	Bone loss, osteoporosis	Calcium and vitamin D supplementation, monitoring bone density
Topiramate (Topamax)	Weight, Glucose metabolism	Potential increase or decrease, possible impairment	Weight gain or loss, diabetes, altered taste perception	Dietary adjustments, monitoring weight and blood sugar
Valproic acid (Depakote)	Weight, lipid metabolism	Potential increase	Increased risk of weight gain, altered lipid metabolism	Dietary adjustments, monitoring weight
Gabapentin	Weight	Potential increase	Minimal impact on nutrition, some reports of weight gain	Dietary adjustments, monitoring weight
Pregabalin	Weight, appetite	Potential increase	Weight gain, potential alterations in appetite	Dietary adjustments, monitoring weight

Table 7 Showcases the main characteristics of the three primary types of ketogenic diets

Aspect	Classic ketogenic diet	Modified Atkins diet	Medium-chain triglyceride ketogenic diet
Macronutrient ratio	High fat (about 3:1 or 4:1, Fat: Protein + Carbs)	High fat, low carb	High fat, low carb, focused on Medium-Chain Triglyceride
Carbohydrate intake	Extremely low (5%-10% of total daily calories), typically 20-50 g per day	Restricted, liberalized compared to classic, can range from 20-100 g per day	Low, but slightly higher than classic, with a focus on low-glycemic carbs
Protein intake	Moderate (15%-20% of total daily calories), typically 1 g/kg of body weight	Moderate to liberal, like classic ketogenic diet	Moderate: Can be slightly higher than classic ketogenic diet, especially for adults
Fat sources	Emphasizes long-chain triglycerides, from animal and plant sources	Focuses on a variety of fat sources with a mix of long-chain triglycerides and medium-chain triglycerides, with medium-chain triglycerides oil often incorporated	Mainly medium-chain triglycerides
Dietary diversity	Restrictive, emphasizes specific food sources	More flexible in food choices	Limited by sources of medium-chain triglycerides
Implementation complexity	High, requires meticulous measurement and monitoring	Less complex but still requires tracking	Moderate complexity, easier to calculate medium-chain triglycerides
Adherence difficulty	Challenging due to strictness and limited food choices	Moderate, more flexible	Moderate, limited food options with medium-chain triglycerides
Efficacy in seizure control	Often high efficacy, especially in drug-resistant epilepsy, especially in children	Varied may be effective for some, easier to follow for some individuals, and allows for more variety in food choices	Effective for some, especially in certain epilepsies, as it can promote faster ketosis due to medium-chain triglycerides, potentially reducing side effects
Potential drawbacks	More restrictive, can be challenging to follow in the long term	It may not be as effective as classic ketogenic diet for some individuals	It can be more expensive due to the need for medium-chain triglycerides oil
Suitability	Best for children and adults who haven't responded well to medications	It is a good option for individuals who struggle with the strictness of classic ketogenic diet	It can be suitable for both children and adults, depending on individual needs and preferences
Indications	Drug-resistant epilepsy, certain epilepsy syndromes	Epilepsy management	Epilepsy, neurological conditions, fat malabsorption