Comorbidities of epilepsy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_922_16
Source of Support: None, Conflict of Interest: None
In epilepsy management, control of seizures is the prime objective. However, the quality of life is affected by comorbid conditions that include the neurological, neuropsychiatric, and neurobehavioural disorders. These are not only reactive processes to a chronic condition but also have a bidirectional relationship, sharing common underlying pathogenesis. This article besides addressing these issues also explores the therapeutic management. A systematic search of PubMed from Jan 2006 to August 2016 was undertaken using the terms “comorbidities” and “epilepsy.” In addition, articles specifically from India and other original papers were selected based on relevance. In this review, the neuropsychiatric, neurobehavioral (mood disorders, behaviour issues, attention deficits, psychosis), and neurologic [cognitive impairment, migraine, SUDEP-Sudden unexpected death in epilepsy (SUDEP)] comorbidities are covered in relation to epilepsy and its treatment. The incidental disorders such as hypertension, diabetes, and cancer that are mentioned in some reports have not been addressed here. Comorbidities in epilepsy are common but poorly understood and often remain unaddressed. The prevalence of comorbid conditions is considerably higher in epilepsy than seen in the general population and other chronic conditions. There is a wide spectrum of secondary disorders that have a marked impact and significantly increase the burden of the primary epilepsy condition. There is a need to acknowledge, screen, and intervene early in newly diagnosed cases for the optimal management of epilepsy.
Keywords: Cognitive, comorbidities, epilepsy, neurobehavioral, neuropsychiatric, SUDEP
Epilepsy is a common neurological disorder affecting nearly 70 million people worldwide, with 90% residing in developing regions. In India, the prevalence rate varies from 1.2 to 11.9/1000 population among adults.
The unpredictable nature of recurrent seizures and the unconscious state during the attack is extremely frightening for both, the person with epilepsy (PWE) and the caregivers. There is also an additional burden of stigma and skewed societal attitudes that results in anxiety and depression. In addition, independent of these challenges, literature is replete with information regarding several serious comorbid conditions that occur in PWE.
Comorbidity in epilepsy is a condition that occurs in association with epilepsy, and may be a cause of epilepsy or a consequence, and may precede, co-occur, or follow the diagnosis of epilepsy.
A systematic search of PubMed from January 2006 to August 2016 was undertaken using the terms “Comorbidities” and “Epilepsy,” and out of the total 1407 articles, 472 relevant articles were selected. Further, articles from India and other key original papers were also selected at the authors' discretion. In this review, the neuropsychiatric, neurobehavioral (mood disorders, behavior issues, attention deficits, psychosis), and neurologic [cognitive impairment, migraine, sudden unexpected death in epilepsy (SUDEP)] comorbidities are covered in relation to epilepsy and its treatment. The incidental disorders, such as hypertension, diabetes, and cancer, which are mentioned in some reports have not been addressed here.
Prevalence rates of psychiatric comorbidity in adults with epilepsy have varied across studies, ranging from 5.9% to 55%., The variability in the prevalence rates is caused by the different diagnostic methods, ranging from the Structured International Classification of Diseases (SICD) or Diagnostic Statistical Manual (DSM) criteria-based interviews to the unstructured, subjective questionnaire or scale-based surveys that tend to overrate the problems. Furthermore, the type of sample also matters, with a majority of the studies being clinic/institution-based, wherein there is a strong patient selection bias and a more pronounced and higher prevalence of psychopathology reported. In one study, a prevalence rate of as high as 80% was reported in a selected subgroup of patients with temporal lobe refractory epilepsy. Community or population-based studies are more representative as well as less biased and have typically reported relatively lesser numbers.
Among these population studies, the method of ascertainment influences the prevalence rates. The Health Styles Survey  examined self-reported epilepsy, depression, and anxiety in 4345 respondents through a mail survey in the US, and found that people with self-reported epilepsy were twice as likely to report depression and anxiety compared to people who did not report epilepsy.
Using a similar methodology of self-reporting in an epilepsy-specific, 11-item survey of 3488 respondents in the US, the EPIC (Epilepsy Comorbidities) study reported that people with epilepsy are more likely to report neuropsychiatric disorders compared to those without epilepsy (major depression and anxiety in 32.5% and 22.4% people with epilepsy versus 25.6% and 13.9% in people without epilepsy, respectively). This study also found significantly high prevalence of bipolar disorders and attention deficit hyperactivity disorders (ADHD) in people with epilepsy.
On the other hand, in the Canadian Community Health Survey (CCHS) that studied the mental health status of 36984 people using the WHO Composite International Diagnostic Interview (CIDI), the prevalence of major depressive disorders was 17.4% in PWE.
In India, there few adult, population-based epidemiological studies reporting on comorbidities associated with epilepsy; however, in two clinic-based studies from South India, prevalence of psychiatric morbidity was studied in PWE and compared to that in patients with chronic asthma and healthy controls. In both studies, standardized interview protocols, i.e. the Mini International Neuropsychiatric Interview (MINI) and the SCID DSM IV, were used to ascertain psychopathology. Both studies showed significantly increased psychiatric comorbidity associated with epilepsy compared to patients with asthma and normal controls, as well as increased lifetime prevalence rates of psychiatric conditions comparable to the CCHS.,
Overall, across studies, irrespective of the methodology used or the type of sample, there is a clear consensus that the prevalence of psychiatric comorbidity is significantly higher in people with epilepsy compared to other chronic conditions and the general population.,,
Risk factors and mechanisms
Psychiatric comorbidity in epilepsy cannot be regarded as a mere reactive process to a chronic condition. The risk factors identified are biological, pharmacological, and psychosocial. Psychosocial factors include a restricted lifestyle, stigma, and social rejection. In two Indian studies, poor compliance to antiepileptic drugs (AEDs) and AED polytherapy were identified as additional risk factors.,
In terms of the biological mechanisms, it is now increasingly being recognized that epilepsy is a spectrum disorder and that there are complex relationships between epilepsy, neurological and psychiatric disorders, with all sharing common underlying pathologies. There is a bidirectional relationship between epilepsy and psychiatric disorders, implying that either of them can antedate or follow the other, and the modification of one increases the risk for the development of the other. This bidirectional relationship has been reported in a study that showed the risk of unprovoked seizure increase during the two years before and after hospitalization for depression or psychosis.
The most widely studied and reported psychopathology is depression and its bidirectional relationship with epilepsy. Depressive symptoms develop not only after the onset of epilepsy but may also precede the onset of seizures. In a community-based sample of 976 adults with active epilepsy who answered a questionnaire, the depression scores predicted seizure frequency and vice versa.
The mechanism of the bidirectional relationship has been studied in both animal models and human studies. Several animal studies such as the GAERS (Genetic Absence Epilepsy Rats Study) showed that depression and anxiety preceded epilepsy and that there were possible inborn defects that led to a disrupted synaptic transmission of 5 hydroxytryptamine (HT), serotonin and norepinephrine (NE).
Human studies have focused on the relationship between temporal lobe epilepsy (TLE) and major depressive disorders in imaging and genetic studies. The medial temporal lobe and its association with the limbic system, the emotional regulator in the brain, is the target in the positron emission tomography (PET) imaging study, wherein deficit 5-HT1A receptor binding is seen in medial temporal regions in depressive disorders; similar deficits are also seen in patients with TLE.,
In the vulnerable, elderly, and pediatric populations, the presence of comorbidities result in far greater management challenges. In the elderly patients with epilepsy, an increase in the prevalence of psychiatric comorbidities (i.e., depression and anxiety disorders),, and in children, an increase in behavioral problems, have been reported.
Magnitude, spectrum, and risk factors
A large number of studies over a decade have unequivocally demonstrated that children with epilepsy (CWE) have significantly higher neurobehavioral comorbidities compared to the general population and children with other chronic conditions.,
In India, in the only pediatric population-based epidemiological study, screening questionnaires and interviews with caregivers and teachers revealed significant issues impacting the psychological well being of the children and caregivers.
In another Indian study, from a tertiary referral center in Vellore, children with intellectual disability were excluded and yet significant psychopathology in 53% of the CWE was found. In addition, the authors reported an unusual finding of more problems in the high-income groups unlike in the western studies, wherein the low-income groups appeared to have more issues. It was postulated that social support is an important protective factor, and in developing countries, there was greater social support in the low-income groups compared to the nuclear families of the high-income groups.
In a recent study from Mumbai, 222 CWE were compared to a control group of 226 matched children without epilepsy. The Strengths and Difficulties Questionnaire was administered and academic records were examined. The authors found that 39.1% of CWE had behavioral problems as compared to 7.9% children without epilepsy.
The spectrum of behavioral disorders has been studied in several population-based studies. In one of the most comprehensive US national studies, the authors reported significantly increased depression, anxiety, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), developmental delays, and conduct disorders in CWE compared to the general population.
In a recent, prospective, community “Children with Epilepsy in Sussex Schools” (CESS) study in the UK, school children with active epilepsy were evaluated with valid, disorder-specific instruments and DSM IV text revision (TR) criteria and 80% had behavioural, and/or cognitive problems with 40% suffering from intellectual disability (ID) 33% from attention disorders (ADHD), and 21% from autism (ASD).
The significantly higher prevalence of attention disorders reported consistently across studies are of concern because they impact academic learning and school performance.,,, ADHD is characterized by hyperactivity, impulsivity, and inattention, and in CWE, it is the inattention type of disorder that has been frequently observed.
The risk factors for behavioral issues are wide ranging and include the presence of early abnormal developmental trajectories, catastrophic childhood epilepsy syndromes, anti-epileptic drug (AED) polypharmacy, abnormalities in the brain morphology, and early age of seizure onset.
Migraine and epilepsy
Migraine and epilepsy are reported to occur together independent of the seizure type, age of onset, and etiology, and may have a common genetic susceptibility. In a review of 13 studies, the prevalence of epilepsy in patient with migraine ranged from 1–17% with a median of 5.9%, while in another study from India, migraine was observed in 26% among PWE as against 15% in the control group.
Premature mortality in people with epilepsy is well recognized. This could be due to epilepsy causative factors (tumors, cerebrovascular disease) or may be related to the seizures (accidental drowning or road traffic accidents), status epilepticus, or due to comorbid depression leading to suicide. In addition, a small but significant number of people with epilepsy have sudden unexpected death in epilepsy (SUDEP). The incidence of SUDEP varies from 0.1 for 1000 person years in population-based cohorts of newly diagnosed patients, 2–5 per 1000 person years in chronic cases, and up to 9 per 1000 among candidates for epilepsy surgery.
As the term implies, death is unexpected and sudden without any obvious cause. However, it occurs more commonly in young adults with refractory epilepsy having tonic–clonic seizures, on AED polytherapy, and during sleep. It is presumed that a seizure induced cardiorespiratory event is responsible, and in one study, a long-term electrocardiogram monitoring, over several months, detected ictal asystole in 3 out of 20 (15%) patients. It is critical to recognize the existence of SUDEP and to prevent it by managing refractory epilepsy more aggressively.
In addition to SUDEP, there is a growing concern regarding the incidence of suicidality associated with epilepsy. A bidirectional relationship has been suggested wherein there is not only a higher risk of suicide among people with epilepsy but also a five-fold higher risk for developing epilepsy among individuals who exhibited suicidality prior to the onset of epilepsy. The risk of suicide is 2.4 times higher in PWE, 11–12 times higher in those with epilepsy and anxiety or psychosis, and 32 times higher in those with epilepsy and depression. The risk is significantly higher in PWE with TLE  especially in conjuction with exposure to certain AEDs.
Cognitive impairment, although frequent, is often underreported and unaddressed despite its significant impact on the quality of life., Multifactorial causes  include (1) underlying structural brain damage and MRI volumetric anomalies,, (2) seizure duration  and its increased frequency, and (3) effects of AEDs. Certain AEDs also affect the developing fetus of mothers with epilepsy, with the offspring having a lower intelligence quotient (IQ) score.,
In newly diagnosed CWE, impairments may antedate epilepsy, with the early cognitive compromise being further magnified by the onset of epileptogenesis, and later on, by the chronicity of seizures.,,
A pattern of generalized, diffuse cognitive impairment and low intelligence is reported for both idiopathic localization related and primary generalized epilepsies. Domain-specific memory impairment in TLE has been the focus of most studies. However, in TLE, extra-temporal deficits have been found suggesting a more widespread network dysfunction , and the presence of different cognitive phenotypes even in localization-related TLE.
A major concern is whether or not seizures cause progressive cognitive impairment, impacting the life span  and leading to adverse cognitive aging in the later years of life. Longitudinal serial magnetic resonance imaging (MRI) has revealed progressively decreasing volumes in patients with unilateral TLE with continuing seizures. However, the results of other longitudinal studies have yielded mixed results with some reporting a decline,, and others, a stable, long-term functioning., A follow-up evaluation, after 3–8 years, of newly diagnosed patients of the multicenter, randomized clinical trial, SANAD (Standard and New Antiepileptic Drugs) study revealed that, although several cognitive measures remained stable, there was a significant decline in the psychomotor speed and memory. Mood issues impacted test performance; however, due to the heterogeneity in demographics and seizure variables, all risk factors could not be identified.
Of interest is also whether or not cognitive impairments persist even after seizures are controlled. Problems are known to persist if there is an underlying brain damage or developmental encephalopathy. However, even in other types of epilepsy, despite seizure control, certain subtle residual cognitive difficulties remain.,
Epilepsy surgery is regarded as curative, and postoperative seizure freedom and AED stoppage should arrest cognitive decline. However, a systematic review revealed a pooled estimate of 44% risk of verbal memory decline and 34% risk for naming difficulties after left temporal lobe surgery. Factors that predicted memory decline after surgery included dominant temporal lobe resections, preoperative normal memory scores, older age at onset, absence of hippocampal sclerosis, and lack of seizure control after surgery.
The decline in verbal memory after dominant temporal lobe surgery has been consistently reported; however, the percentages vary across studies, and there is limited data regarding long-term outcomes after surgery. In a recent study conducted in India, an improvement as well as decline in a subset of patients after surgery was found, but the decline percentage was less than that reported in western studies., In another study from India, memory improvement was reported after the nondominant lobe resection, in patients who achieved a seizure-free status.
In a longitudinal, prospective, controlled study performed 10 years after temporal lobe surgery, the authors reported an initial verbal memory decline in the first 2 years after dominant lobe surgery; however, subsequently, no further decline was noted in the long term, negating the notion that there may be ongoing progressive decline after surgery.
Multiple psychosocial issues of daily life restrictions, educational, and vocational marginalization, low self-esteem, and stigma are frequently associated with epilepsy, and sometimes persist even after a person becomes seizure free, resulting in what is known as the “burden of normality.”
Overall, cognitive, psychiatric, behavioral, and psychosocial problems occur in all types of epilepsy in varying degrees, in both chronic as well as newly diagnosed patients and are a huge burden for patients and families. Hence, it is now strongly recommended that all newly diagnosed patients be screened and tracked for timely intervention.
A comprehensive epilepsy management must go beyond seizure control and include the addressal of comorbidities to improve the quality of life. It is important to be aware of the different types of comorbidities and the various drugs that can optimize or worsen epilepsy and comorbidity management [Table 1].,, Future research has to be directed at understanding the common pathogonomic pathways to address epilepsy and the comorbidities with the same therapy.
Comorbidities in epilepsy have remained invisible due to poor awareness among patients, families, and treating physicians. The high prevalence of a number of comorbidities in epilepsy complicates the management and significantly increases the burden of epilepsy. The report of the International League Against Epilepsy (ILAE) Commission states that epilepsy should no longer be regarded as benign in view of the large number of comorbidities associated with even relatively uncomplicated epilepsies. The time has come to acknowledge and understand these problems to be able to manage them effectively at the very onset of epilepsy.
We would like to acknowledge the help of Ms Tanvi Dingankar for the PubMed Search.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest