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COMMENTARY
Year : 2021  |  Volume : 69  |  Issue : 4  |  Page : 962--963

Epilepsy, Phenytoin, and Atherogenic Risk—Current Perspectives

Salvadeeswaran Meenakshi-Sundaram, Muthukani Sankaranarayanan 
 Department of Neurosciences, Apollo Speciality Hospitals, Madurai, Tamil Nadu, India

Correspondence Address:
Dr. Salvadeeswaran Meenakshi-Sundaram
Department of Neurosciences, Apollo Speciality Hospitals, Madurai, Tamil Nadu - 625 020
India




How to cite this article:
Meenakshi-Sundaram S, Sankaranarayanan M. Epilepsy, Phenytoin, and Atherogenic Risk—Current Perspectives.Neurol India 2021;69:962-963


How to cite this URL:
Meenakshi-Sundaram S, Sankaranarayanan M. Epilepsy, Phenytoin, and Atherogenic Risk—Current Perspectives. Neurol India [serial online] 2021 [cited 2021 Oct 24 ];69:962-963
Available from: https://www.neurologyindia.com/text.asp?2021/69/4/962/325320


Full Text



Anticonvulsants are the cornerstones of the management of epilepsy. The morbidity and death related to epilepsy have decreased with the advent of anticonvulsant therapy. Newer anticonvulsants offer advantages in terms of side effect profile and drug interactions which are particularly relevant in the elderly and those with comorbidities, despite higher costs and similar efficacy.[1] The control of seizure may be the primary focus of physicians caring for epilepsy which is achieved with these medications. However other questions also arise. Are seizures the only manifestation of epilepsy? Is the control of seizure sufficient by itself in the management of patients?

Management of epilepsy is multidimensional. While controlling the seizure is the main aim of therapy, epilepsy management also needs consideration of other aspects that include non-seizure manifestations of the underlying disease and nonmedical aspects such as social, cultural, and financial spheres. Of particular importance is the consideration of the metabolic aspects of epilepsy.

Epilepsy and metabolic disturbances are mutually linked to each other. Metabolic disturbances can result in seizure, as is seen with the various metabolic encephalopathies such as uremic or hepatic encephalopathies, or, lead to epilepsy syndromes such as the inborn errors of metabolisms. The latter can present as epilepsy syndromes as with progressive myoclonic epilepsies. Epilepsy can contribute by itself to metabolic derangements as has been widely reported in the literature.

The CYP450 enzyme system comprises a superfamily of hemoproteins that plays an important role in the metabolism of drugs, including anticonvulsants. There are more than 50 human isoforms of the CYP450 enzymes with distinct functions and substrate specificities. Of these, CYP 7A1, 27A1, and 46A1 play key roles in cholesterol elimination, and thus, have potential to serve as targets for achieving cholesterol reduction.[2] Anticonvulsants that induce or inhibit CYP450 enzyme system are thus likely to also influence the lipid profile.

Higher prevalence of diseases such as cerebrovascular and cardiovascular diseases and increased mortality have been noted in patients with epilepsy, especially in those with remote symptomatic epilepsy.[3] The metabolic syndrome or syndrome X as defined by the Adult Treatment Panel III criteria requires the presence of at least three of the following five parameters: abdominal obesity, elevated levels of serum triglycerides, elevated blood pressure, elevated fasting plasma glucose, and low serum levels of high-density lipoprotein cholesterol.[4] Metabolic syndrome was seen in more than half of the people with epilepsy and its prevalence was not associated with a number of antiseizure medications.[5] Of note, valproate has been more often associated with the occurrence of metabolic syndrome than the other anticonvulsants, influenced at least in part by its tendency to induce obesity.[6] Long-term monotherapy with phenytoin, carbamazepine, or valproate has been shown to be associated with dysregulation of vascular risk markers and acceleration of atherosclerosis as measured by carotid intima-media thickness.[7]

Evidence for increased oxidative stress has been demonstrated in patients with epilepsy. High metabolic demand coupled with its rich lipid content, especially polyunsaturated fatty acid, makes the brain particularly vulnerable to oxidative stress. Whether such a phenomenon is related to the occurrence of seizures or is due to anticonvulsant drugs has been a source of debate.[8]

In this journal … et al. (authors) have reported the link between epilepsy and atherogenic risk factors with special focus on phenytoin, a widely used anticonvulsant agent, used extensively due to the price factor and its widespread availability. The authors report the presence of dyslipidemia, oxidative stress, and low-grade inflammation among newly diagnosed epileptic subjects when compared to age-matched non-epileptic healthy subjects, which further increased on treatment with phenytoin for more than 6 months. There was no difference in levels of glycemic indices such as fasting serum glucose and insulin and insulin resistance as assessed by the Homeostatic Model Assessment of Insulin Resistance (HOMA–IR) index among the three groups. While animal and human studies have shown that recurrent seizures itself can promote inflammation and increase oxidative stress, the authors have not commented on the control of seizures in the phenytoin group.[9],[10] What are the implications of this study? Several questions arise.

First, is there a need to routinely monitor for atherogenicity in patients with epilepsy and if so, what age group should we target and what are the markers that should be checked? While the estimation of insulin, leptin, high-sensitive C-reactive protein, and malondialdehyde were are all done as part of this study, for the treating clinician it may be useful to estimate only the fasting blood sugar and lipid profile in patients with epilepsy. Second, to estimate such parameters, should there be any protocol as to when and how often such testing should be done? Third, what measures must be taken to prevent or minimize such a phenomenon? Is there a role for dietary supplements, antioxidants, anti-inflammatory agents, or other measures for achieving such a purpose? What is the role of drugs like statins in such patients? Fourth, is there epidemiological evidence for phenytoin associated with clinical cardiovascular disease? And last, should there be a concern before prescribing these enzyme-inducing anti-seizure drugs in people with epilepsy?

While we do not know the answers to these queries, the authors have raised relevant suggestions that will kindle future studies that may seek answers for some of these pertinent issues.

References

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