Obesity and Metabolic Syndrome in Patients with Epilepsy, their Relation with Epilepsy Control

Abstract

Obesity and metabolic syndrome (MetS) are commonly observed in patients with epilepsy (PWE). Obesity and MetS are not only affecting the physical fitness and quality of life of these patients, rather antiepileptic drugs (AEDs) compliance and seizure control have also been affected. The objective of this review is to search the published literature regarding the prevalence of obesity and MetS in PWE and their relation to the response to AEDs. A comprehensive search using PubMed, Cochrane Databases, and Google Scholar was performed. A supplementary citation search was also conducted by analyzing the reference lists of identified sources. The initial search revealed 364 articles of potential relevance. The studies were analyzed in detail to obtain clinical information relevant to the objectives of the review. Many observational, case control studies, randomized control trials and few review articles were included for critical appraisal and review writing. Epilepsy is associated with MetS and obesity in all age groups. AEDs and lack of exercise are the chief causes while metabolic disturbances such as adiponectin, mitochondrial dysfunction, valproic acid (VPA)-associated insulin resistance, leptin deficiency, and endocrine dysfunction are also addressable factors. Although the risk of drug-resistant epilepsy (DRE) is also higher among obese PWE, the interaction between, MetS, and its components with DRE remain to be fully investigated. Further research is required to elucidate their interplay. Appropriate and careful selection of AEDs without compromising therapeutic efficacy supplemented by lifestyle counseling for exercise and diet should be practiced to avoid weight gain and potential DRE.

INTRODUCTION

Obesity, which is now regarded as a common public health problem throughout the world, is defined as “A chronic, multifactorial disease involving excessive body fat with complex psychological, environmental (social and cultural), genetic, physiologic, metabolic, and behavioral causes and consequences.”[1] While Metabolic syndrome (MetS) is a term used when a few specific interrelated cardiovascular risk factors cluster in an individual that results in a two-fold increased risk of cardiovascular disease.[2]

Obesity-induced metabolic dysfunction, inflammation, and dyslipidemias are attributable factors for the development of certain neurological disorders including Alzheimer's and Parkinson's diseases. Scientific evidence suggests that these obesity-related changes not only cause central nervous system damage but the peripheral nervous system is also directly and indirectly impacted by obesity.[3] Obesity and MetS are also commonly observed in people with epilepsy.[4,5]

The relationship between obesity and MetS in patients with epilepsy (PWE) has been addressed in the current published literature.[6,7] There are several possible mechanisms and contributory factors responsible for increased prevalence of overweight and obesity in epilepsy. These factors are behavioral, social, environmental, and iatrogenic factors.[8,9] Some of the antiepileptic drugs (AED) can also cause weight gain and subsequent metabolic disturbances and considerable changes in plasma lipids and hormonal levels.[10,11,12] Obesity and MetS are not only affecting the physical fitness and quality of life of these patients but medication compliance and seizure control have also been affected. Few studies have suggested that a patient's body mass index (BMI) may also predict AED response in PWE and drug-resistant epilepsy (DRE).[12,13,14] PWE receiving polytherapy regimen and few particular AEDs such as valproic acid (VPA) and pregabalin are more prone to have high BMI, obesity, and DRE.

This review aims to search the published literature for the prevalence of obesity and MetS in PWE and their effect on the response to AEDs. The aim is to supplement the existing published literature on the subject, which is very limited. We also hope that this review will help in finding the role of factors that affect response to AEDs in epilepsy patients, thus guiding future studies regarding novel biomarkers of AED response and prognosis.

METHODS AND ANALYSIS

Search strategy

Data sources

A comprehensive search of the published literature was conducted using the search terms “MetS, obesity, and epilepsy” then “obesity and epilepsy control.” The review was limited to articles written in the English language. The databases searched included PubMed, Cochrane Databases, and Google Scholar. A supplementary citation search was also conducted by analyzing the reference lists of identified sources.

Article screening and criteria

The author first categorized as relevant or irrelevant by screening the abstract. Articles were included the studies focused on epilepsy, MetS, obesity, AED proposed mechanisms and associations, and epilepsy control.

Study selection

The initial search revealed 364 articles of potential relevance.

Data extraction

The author in details analyzed the studies, to obtain the clinical information relevant to meeting the objectives of the review.

Data synthesis

The author grouped articles according to topic and types of studies within each group.

RESULTS

Initially, 364 articles were identified on PubMed [Figure 1]. For greater specificity, only those articles referencing MetS, obesity, and epilepsy control were selected. Articles related to any hormonal or molecular mechanisms associated with these conditions were also included. An electronic search in Cochrane databases resulted in 47 articles. Additional searches on Google Scholar were also performed. Duplicates were excluded. Articles not addressing the question were excluded. This yielded 248 articles. Finally, a total 78 selected articles, specific to the study objectives were selected for this review writing.these selected articles were comprised of observational studies, randomomized control trials and few review articles.

Figure 1.

Flow diagram showing search strategy followed in this review

Table 1 shows the selected studies addressing the prevalence of obesity and MetS, in PWE. The prevalence in different age groups was extracted through large population-based surveys or cross-sectional and case–control studies. Obesity and MetS were reported in PWE of all age groups. Few prospective studies, reviews, and meta-analysis discussed the possible genetic, molecular, and metabolic mechanisms and causes of weight gain leading to MetS and obesity in PWE. Many studies related to the role of AEDs causing weight gain and subsequent metabolic disturbances were identified especially VPA-associated MetS in different age groups, its possible mechanism and comparisons with other AED were elaborated in different prospective, comparative, and randomized control trials.

Table 1.

Metabolic syndrome, obesity- and epilepsy-related studies

Reference	Study type	Number of patients (n)	Patient population	Study objective	Key results (%)	Outcomes and comments
FX Ndayambaje et al., 2021[18]	Cross- sectional, observational	1076	Adult PWE	To assess prevalence of MetS in Rwandan Patients	MetS=30.6 The main risk factors were  VPA (P=0.007) and Sedentary  lifestyle (P=0.025)	High prevalence of MetS in epileptic patients
Vooturi S et al., 2020[17]	Cross- sectional, observational	173	Adult PWE	To assess association of MetS variables with patients QoL	MetS=52.6 Obesity=88.4 More number of women had MetS (47.6 vs. 62.6; P=0.049)	More than half of epileptic patients across all age groups had MetS The number of AEDs and QoL are not associated with MetS
Kadima NT et al., 2013[6]	Health interview survey	26,659	Adult PWE	To assess the prevalence of nonpsychiatric comorbidities in PWE	Obesity=27.5 Over weight=34.5	Prevalence of cardiovascular and metabolic disorders in epileptic patients Obesity is higher in PWE than patients without epilepsy
Claire Hinnel et al., 2010[15]	Community health survey	400,055	Adult population	To assess health-related behaviors and health status between PWE, migraine or diabetes	Obesity in epileptic patients=19.1 Obesity in migrainers=18.0 Obesity in diabetic patients=37.1 Obesity in general population=15.4	Obesity and comorbidities were more likely in all chronic conditions studied compared to the general population
Daniels Z et al., 2009[19]	Case–control	848 Cases: 251 Controls: 597	Children and adolescents patients Healthy control	To assess the frequency and factors associated with obesity with newly diagnosed untreated epilepsy	Obesity and overweight=38.6 Adolescents had higher adjusted BMI Z-scores than younger patients	Obesity is common in children with newly diagnosed untreated epilepsy and correlates with increasing age, idiopathic etiology
Rosemarie Kobauet et al., 2004[16]	Population bases health interview survey	8057	Adult population	To assess behavioral risk factors and comorbidities in adults with epilepsy	Obesity in epileptic patients=34.1 Obesity in adults without epilepsy=23.7	Adults with epilepsy had high rates of obesity and other behavioral risks and complications associated with other chronic disorders

MetS=Metabolic syndrome, VPA=Valproic acid, QoL=Quality of life, BMI=Body mass index, PWE=Patients with epilepsy, AEDs=Antiepileptic drugs

We found few studies addressing the influence of obesity and MetS on epilepsy control and how they increase the risk of developing DRE [Table 2]. Most of these studies were either cross-sectional or case–control. Large-scale randomized control studies are lacking.

Table 2.

Studies addressing the metabolic syndrome, obesity and epilepsy control

Reference	Study type	Number of patients	Study population	Study objective	Key results	Outcome and comments
Man Chen et al., 2021[71]	Case control study	n=1617 Drug responsive epilepsy=1272 Drug resistance epilepsy=345	Adult PWE	To assess effect of overweight and obesity on DRE	Obesity and increased risk of DRE (adjusted OR, 2.339; 95% CI, 1.724–3.171) Obesity and increased risk of DRE in patients on VPA (adjusted OR, 1.79; 95% CI, 1.15–2.80)	No significant increase in the risk of DRE was found to be associated with overweight But Obesity potentially plays a role in DRE
R. Arya et al., 2016[13]	Case control	n=2525 Case=446 Control 2079	Children with childhood absence epilepsy and healthy controls	To assess the role of obesity and overweight as predictors of short term drug responsiveness	Obesity and overweight in cases=33.8% Obesity and overweight in control=25.3% Obese children with Increase BMI Z score on VPA and ETX, in had higher odds of achieving FFF (OR 2.75, 95% CI 1.01–7.46, P=0.047) SF (OR 4.89, 95% CI 1.08–22.11, P=0.040)	Overweight/obesity status or increasing BMI Z score was associated with improved seizure outcomes in those receiving ETX and VPA and worse outcomes in patients on LTG compared to weight-appropriate children with CAE
Rochelly de Azevedo Fernandez et al., 2015[69]	Cross- sectional, observational	n=72	Adult PWE	To assess the nutritional status of epileptic patients	Overweight/obesity=66.7%BMI kg/m2 in Men with controlled seizures: 27.0±3.3 Men with uncontrolled seizures, 28.5±5.2 (P=0.376) Women with controlled seizures=29.2±5.9 Women with uncontrolled seizures=28.4±7.7 (P=0.737)	PWE are having tendency to be overweight and obese There was significant differences between the BMI values of men and women with uncontrolled and controlled epilepsy Seizure control did not appear to be related to nutritional status and intake
Ladino LD, et al., 2014[70]	Cross- sectional, observational	n=100	Adult PWE	To assess the prevalence of obesity and its association with drug-resistant epilepsy	Obesity=38% DRE in obese=55% DRE in nonobese=55%	There is an association between obesity, idiopathic generalised epilepsy, and family history of epilepsy. But No association was found between drug-resistant epilepsy and obesity
Janousek J et al., 2013[12]	Cross- sectional, observational	n=554	Adult PWE	To assess the frequency of obesity in a patient population with epilepsy	Obesity and Overweight=55.2% in sample Overweight in patients with refractory epilepsy (60.4% vs. 49.2%) Obesity in patients with refractory epilepsy (36.9% vs. 24.6%) Obesity in patients treated with polytherapy (37.7% vs. 25%)	Overweight/obesity and obesity rates were higher in patients with refractory than nonrefractory epilepsy Obesity was more common in patients treated with polytherapy than monotherapy

DRE=Drug-resistant epilepsy, BMI=Body mass index, VPA=Valproic acid, ETX=Ethosuximide, FFF=Freedom from failure, SF=Seizure freedom, CI=Confidence interval, OR=Odd ratio, CAE=Childhood absence epilepsy, PWE=Patients with epilepsy, LTG=Lamotrigine

DISCUSSION

Metabolic syndrome, obesity, and epilepsy in different populations and age groups

Different epidemiological studies have identified the prevalence of obesity in the form of weight gain and metabolic disturbances as MetS, in PWE.[15,16] However, the long-term conducted studies addressing the relationship between obesity, MetS, and epilepsy are lacking. Obesity and MetS are reported in PWE of all age groups. Vooturi and Jayalakshmi identified MetS in more than half of PWE in a cross-sectional study.[17] Ndayambaje et al. found that MetS is highly prevalent among PWE in Rwandan.[18] A Brazilian cross-sectional study showed that elderly patients with new-onset epilepsy had concomitant abdominal obesity.[7] In one large US study, 34.1% of adult patients with any type of epilepsy were more obese than patients without having epilepsy 27.5%.[6] in one pediatric age group study, older children with idiopathic epilepsy were found more obese than those without epilepsy and concomitant medications did not affect obesity in this cohort.[19] Similar findings were also observed in a study by Arya et al. the study showed the children with newly diagnosed childhood absence epilepsy (CAE) were overweight and obese, despite being on lower carbohydrate intake and caloric restriction.[13]

Possible mechanisms of metabolic syndrome and obesity in patients with epilepsy

There are several possible mechanisms and causes of weight gain leading to MetS and obesity in PWE [Figure 2]. The main contributory causes are metabolic and AEDs related, simultaneous behavioral, social, and environmental factors are considered as further contributing elements. The best-known genetic epilepsy syndrome related to weight gain is the Prader–Willi syndrome. Preliminary studies with experimental models concluded that recurrent seizure activity itself could create a state of chronic inflammation.[20]

Figure 2.

MetS and obesity in epileptic patients, possible mechanisms. MetS = Metabolic syndrome, MnSOD = Manganese superoxide dismutase

Superoxide dismutase 2 (SOD2) is an enzyme related to antioxidant and anti-inflammatory pathways. While a single gene which encodes manganese superoxide dismutase (MnSOD), is located in chromosome 6q25. Single-nucleotide polymorphisms (Ala16Val (rs4880) of the SOD2 encoding gene have shown to be associated with inflammatory pathways and many metabolic disorders, such as obesity and dyslipidemia.[21] Recently, Kegler et al. have investigated the relationship between SOD Ala16Val SNP with epilepsy. An increased proportion of Ala16Val MnSOD polymorphism (VV genotype) was observed in PWE with simultaneous increased inflammatory markers.[22] Furthermore, it has been observed that adiponectin deficiency and mitochondrial dysfunction are common to epilepsy and type two diabetes mellitus (DM), which predispose people with epilepsy to have both obesity and DM.[23,24] Few other important parameters including insulin resistance (IR) and high leptin levels have also been observed in PWE. These parameters are linked to weight gain, lipid abnormalities, and subsequent atherosclerosis in these patients.[25] Among the social and environmental factors, lack of exercise and AEDs are important and addressable factors. Anxiety, depression, and perceived stigma of epilepsy are the factors leading to a lack of exercise and limited physical activities in these patients.[26] In one of the large surveys related to the health status and behavioral patterns of PWE, it was observed that (34% compared to 23.7%) of PWE were obese, they were found to have low levels of exercise despite good seizure control.[16]

Role of antiepileptic drugs in causing metabolic syndrome, obesity

Weight-related issues are observed with many AED, weight loss is seen in patients taking topiramate, (TPX), lamotrigine (LMG) Felbamate, and zonisamide.[27,28,29]

On the other hand, some of the AEDs can cause weight gain and subsequent metabolic disturbances, associated with significant health risks. Sometimes, cosmetic concerns leading to treatment compliance are also observed. Many studies quantify the risk of weight changes with different AEDs. Carbamazepine (CBZ), phenytoin, and VPA may also directly cause considerable changes in plasma lipid levels, which is a major risk factor for MetS.[12,30]

Antiepileptics associated with weight gain and obesity

Valproic acid

VPA is well known for its highest rates of obesity among all AEDs due to several possible mechanisms. VA-related weight gain and metabolic disturbances have been observed in both pediatric and adult age groups. Egger and Brett[30] reported bodyweight gain in 44% of children with epilepsy treated with VA at a daily dosage of 30–50 mg/kg, however, they did not find any relationship between this weight gain with the type of epilepsy or epilepsy control. In a double-blind study comparing LMG and VA, weight changes in patients on monotherapy were assessed.[31] After 32 weeks of treatment, >10% weight gain was reported in 62% of patients on monotherapy with VPA (12.8 ± 9.3 lb) than LMG-treated patients in whom weight remained stable (1.3 ± 11.9 lb). Weight increased in those treated with VPA by week 10 of this study and continued to increase at the end of the study. In this study, clinical variables such as gender, age, dose, and pretreatment body weight failed to identify those patients at a higher risk for weight gain.[32] In a 1-year study of new-onset seizures comparing CBZ, TPX, and VPA. Patients receiving VPA increased their weight by an average of 2.0–5.0 kg. CBZ was weight neutral.[33]

Valproic acid-induced metabolic syndrome and insulin resistance

VPA-induced metabolic disturbances include lipid abnormalities, hyperinsulinemia, centripetal obesity, disturbed hormonal metabolism leading to hyperandrogenism, and polycystic ovaries.[34] MetS has also been frequently observed in a patient taking VPA [Figure 3]. MetS is characterized by a higher frequency of abdominal obesity and hypertriglyceridemia than diabetes in PWE.[35,36]

Figure 3.

Valproic acid-induced MetS and obesity, possible mechanisms. MetS = Metabolic syndrome

It has also been observed that obese PWE treated with VPA are at higher risk of MetS than individuals who are “simply obese” but otherwise well.[37] However, one study from Estonia, comparing the risk of MetS among VA-treated PWA with the general population, did not find a difference in risk.[38]

Studies in both men and women revealed hyperinsulinemia and weight gain in those PWE who were treated with VPA, while CBZ and oxcarbazine (OXC) do not seem to have any significant effects on serum insulin or lipid levels in men with epilepsy.[10,11,27,39] VPA induces obesity, which could be related to the serum values of leptin and adiponectin.

Few studies showed significantly increased leptin level, hyperinsulinemia with oxidative stress, and a rise in BMI, in PWE who were treated with VPA.[40,41]

Further studies have confirmed that significant weight gain is related to high leptin and insulin levels.[42] The role of serum ghrelin and neuropeptide Y (NPY) level in patients taking VPA has been studied because of its link with obesity and weight gain as well. Ghrelin stimulates food intake and regulates energy homeostasis through activating the expression of the NPY and agouti-related protein in hypothalamic neurons, which plays a key role in obesity pathogenesis.[43] Evidence suggests that antioxidant enzymes are key regulators of inflammation. In one study, decreased concentration of lipid-soluble antioxidants α-tocopherol and α- and β-carotene were observed in PWE who gained weight after 1 year of VPA treatment.[44] VPA-treated patients were also found to have higher concentrations of triglycerides, serum cholesterol, uric acid, and lower levels of high-density lipoprotein cholesterol in a few studies.[42,45,46] While VPA-related metabolic disturbances leading to nonalcoholic fatty liver disease have also been reported in certain studies.[47,48]

Valproic acid and endocrine dysfunction

VPA also affects the metabolism of other hormones. Obesity, acne, hirsutism, and frequent anovulatory cycles are observed due to disturbed steroid hormone metabolism, leading to elevates androgens. It was observed in studies that patients who were receiving were found to have polycystic ovary syndrome with menstrual abnormalities and subsequent weight gain and obesity.[49,50]

Carbamazepine

CBZ therapy-induced weight gain is pointed out in a few studies. In one study up to 25% of patients, receiving CBZ had weight gain.[51,52] Excessive fat deposition; an increase in appetite leading to excessive food intake could be the contributory cause of weight gain. The dietary restriction did not put any effect in one study.[53] The role of leptin and insulin was not associated with CBZ-associated weight gain.[54]

Vigabatrin

Bodyweight gain was also pointed to a consistent finding in most preliminary clinical trials of vigabatrin.[55,56] The same was also reported in European and Canadian studies.[57,58]

Gabapentin

Weight gain with has also been reported with gabapentin,[59,60] the body weight gain observed with the use of gabapentin seems to be related to the prescribed dose.[61,62]

Pregabalin

In one study of PWE, receiving pregabalin mean bodyweight increase was 2.5–4.0 kg (standard deviation ± 4.1 kg).[63] Almost the same findings were observed in studies related to patients, who were being treated with pregabalin for neuropathic pain.[64]

Thus, if epilepsy per se does not cause weight gain or loss, then the three most important factors for weight changes are metabolic disturbances, lifestyle, and AEDs.

Metabolic syndrome, obesity, and epilepsy control

Overweight and obesity are recognized as important modifiers of severity, treatment response, natural history, and prognosis for several chronic diseases.[65,66]

Overweight and obesity being the common comorbidities in PWE also have been assessed in relation to seizure control. Satisfactory seizure control still remains the main concern in PWA as about one-third of PWA have seizures refractory to pharmacotherapy, defined as DRE.[67]

Satisfactory seizure control is considered when the patients being treated for epilepsy had more than 50% reduction in seizure frequency, pre- and post-intervention. Unsatisfactory seizure control is considered for patients who were treated for epilepsy, and received well-tolerated, appropriately chosen, and used, AED schedules (as monotherapies or in combination) yet they did not achieve more than 50% reduction of seizure frequency pre-and post-intervention. This included drug-refractory cases or DRE which were those patients who could not achieve sustained seizure freedom despite receiving at least two AED schedules.[68]

We found few studies addressing the influence of obesity and epilepsy control, and how they increase the risk for developing DRE in these patients [Table 2]. One study, addressing the nutritional status of PWE through their anthropometric profile, found no difference between the BMI values of patients with controlled and uncontrolled epilepsy, concluding that nutritional status is not related to seizure control in PWA.[69] In another study Ladino et al. appreciated the link between obesity, idiopathic generalized epilepsy, and family history of epilepsy, however, they did not find any association between obesity and DRE (55% vs. 55%; P = 0.05).[70] Previously Janousek et al. showed that overweight and obesity rates were higher in patients with DRE than in non-DRE (60.4% vs. 49.2% overweight, 36.9% vs. 24.6% obesity).[12]

Similar to Janousek et al.,[12] one recent case–control study by Chen et al. showed that obesity, but not overweight, was associated with DRE, and the risk of DRE was higher among PWA with obesity than among adults without obesity.[71]

Janousek et al. also observed that obesity was more common in patients treated with polytherapy than those treated with monotherapy (37.7% vs. 25.0%). This means indirectly their seizure was difficult to control.[12]

In a study by Arya, et al., weight gain with better seizure control in the pediatric population, is associated with improved seizure outcomes with nonconventional AED when compared to weight-appropriate children with CAE, authors also concluded about the importance of baseline BMI that may also predict AED response, unrelated to pharmacokinetic differences.[13]

The association of better seizure control with stabilization of BMI/weight loss has been a proposed mechanism for seizure treatment and is thought to be the basis of a ketogenic diet for seizure control.[72] The ketogenic diet is a well-established mode of treatment of epilepsy in children. However, there is less documentation on adults.[73]

Strength and limitations

When interpreting the findings yielded by this review, it is essential to consider its strength and limitations. In this review we tried to address an important medical and social issue, that is being faced by PWE, We identified an ample amount of literature and data pointing towards the strong association of obesity and epilepsy, metabolic changes associated with certain old AEDs were also addressed, however, we could not much address about new AEDs in this regard. We tried to give new insights to the clinician about the relationship between obesity MetS and seizure control but found very few studies in this regard.

CONCLUSIONS

Epilepsy is associated with MetS and obesity in all age groups. Different AEDs and lack of exercise are the chief causes while metabolic disturbances such as adiponectin, mitochondrial dysfunction, VPA-associated IR, leptin deficiency, and endocrine dysfunction are also addressed. Although the risk of DRE is also higher among obese PWA, the interaction between MetS and its components with DRE seizure control remains to be fully investigated. Further research is required to elucidate their interplay. Appropriate and careful selection of AEDs without compromising therapeutic efficacy supplemented by lifestyle counseling for exercise and diet should be practiced to avoid weight gain and protection against DRE.

Clinical points

• A higher prevalence of MetS and obesity is observed in all age groups of PWE

• The risk of DRE is also higher among obese PWA. However, the interaction between, MetS, and its components with DRE seizure control remains to be fully investigated

• When managing PWE, the risk of MetS and obesity should be taken into account along with behavioral, social, and environmental factors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.