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Epilepsy is without question a costly and complicated major public health problem1. Also unquestioned is the fact that in addition to recurrent seizures, abnormalities in psychiatric status, cognition, and social-adaptive behaviors represent major sources of disability in children and adults with epilepsy–complications referred to collectively as the neurobehavioral comorbidities of the epilepsies. These comorbidities are not only problems in their own right, but also contribute to well-characterized difficulties in life performance (e.g., education, work, income)2. What has been controversial through the decades is the etiology of and best treatments for these comorbidities.
The goal here is to examine the neurobehavioral comorbidities and their potential mediators. Given that the incidence of epilepsy peaks in childhood and older adult years and the epilepsy is often chronic, coordinating care between pediatric and adult specialists is critical3. Therefore, we address the comorbidities in a lifespan perspective that is clinically useful and scientifically sound, identifying both strengths and limitations of the literature, and pointing to opportunities for intervention to improve the quality of life for both children and adults with epilepsy.
This review will proceed as follows (see Figure 1). First, we define the specific psychiatric, cognitive, and social comorbidities of pediatric and adult epilepsy, their epidemiology, and real life impact (Neurobehavioral Comorbidities). Second, we examine the relationship between epilepsy syndromes and the risk of neurobehavioral comorbidities (Epilepsy Syndromes). Third, we address the lifespan impact of epilepsy on brain neurodevelopment and brain aging and the risk of neurobehavioral comorbidities (Brain Development and Aging), followed by discussion of the overarching impact of broader brain disorders on both epilepsy and neurobehavioral comorbidities (Brain Disorders). Directions of causality are considered, as are the contribution of selected epilepsy-related characteristics (e.g., epileptiform discharges, age of onset, years of epilepsy chronicity, seizure medications). In the final section of the review, we outline clinic-friendly screening approaches for these problems and recommended pharmacological, behavioral, and educational interventions.
The term comorbidity refers to a greater than coincidental presence of two conditions in the same person. Comorbidity does not infer a causal relationship, as co-occurrence of two disorders may arise by chance or share a common underlying mechanism. We focus here on population-and community-based studies, as these findings more representatively document the prevalence of psychiatric, cognitive, and social comorbidities of the epilepsies. This information is then supplemented with findings from specialized epilepsy centers, where typically more details can be provided regarding the nature, range, and correlates of these comorbidities.
The burden of co-morbid psychiatric disorders is clear for both children and adults with epilepsy. Community- and population-based investigations uniformly report an increased prevalence of mood, anxiety, and other psychiatric disorders in epilepsy (Table 1).
In pediatrics, a unique set of unequivocal findings document the fact that psychiatric comorbidity is elevated in children with epilepsy compared to both the general population as well as children with other medical disorders. This elevated comorbidity is evident both in children with so-called uncomplicated epilepsies (normal neurological exam and intelligence, attending mainstream schools), but especially marked in those with complicated epilepsies (epilepsy plus brain lesion)—a set of findings reported in two independent epidemiological studies separated by 30-years.4,5
In adults, a recent United Kingdom population-based investigation involving 7,403 participants characterized the psychiatric burden associated with epilepsy6. After adjusting for confounders, people with epilepsy exhibited significantly elevated odds ratios for social phobia, agoraphobia, generalized anxiety disorder, and depression, as well as all measures of suicidality—these associations were significantly stronger than similar relationships in people with asthma or diabetes and comparable to chronic headache/migraine patients (Supplemental Figure 1).
As might be expected, psychiatric comorbidities in epilepsy are associated with more days of limitation and disability beyond that attributable to the epilepsy itself, and greater health care utilization and cost7. Given this psychiatric burden, it is unfortunate that routine screening is not a standard component of pediatric and adult care, especially in light of the potential lethality associated with depression and the widely documented increased risk of suicidal ideation, attempt, and completion6.
A significant potential complication of any human brain disorder, including epilepsy, is impairment in some aspect of objectively assessed cognition including intelligence, language, visuoperception, learning and memory, executive function, and/or processing speed.
Pediatric epilepsy benefits from several population and community-based investigations (Table 2). These studies indicate an increased prevalence of cognitive abnormalities in children with epilepsy, even those with uncomplicated epilepsies, compared to community- or population-based controls. This literature has also characterized prevalent academic achievement problems with significantly higher rates of school-based interventions (e.g., grade retention, summer school, tutors) and parent characterizations of the struggles of their children at school. We are not aware of a community- or population-based investigation of neuropsychological status in adults with epilepsy, clearly a major omission in this literature, but numerous clinical studies document this point8.
The burden of cognitive abnormality in the epilepsies is obviously significant. Investigations from clinical centers have addressed the details of the presenting cognitive profiles associated with specific epilepsy syndromes-a point to be reviewed later. Given this cognitive burden, cognitive screening should be a routine component of clinical care, a point advocated recently by an international review group9.
In addition to psychiatric and cognitive comorbidities, a germane issue is the negative impact of the epilepsies on real life performance, such as peer-to-peer interactions, marriage, independent living, employment and other facets of a productive life. The prevalence of social comorbidities in childhood onset epilepsies are reported in a nationally representative sample of 91,605 children in the United States (birth to 17 years) from the National Survey of Children’s Health, including 977 children reported by their parents to have been diagnosed with epilepsy. The children with epilepsy exhibited lower social competence (the ability to have productive and mutually satisfying relationships with others), more physical and functional disabilities, and more unmet medical and mental health needs10.
Similarly, real life burdens in adults with epilepsies are reported in community- and population-based studies. Especially important are findings from the 2005 Centers for Disease Control Behavioral Risk Factor Surveillance System11. Among 120,845 persons 18 years of age and older, there were 2,207 with a reported history of epilepsy (active in 919). Persons with epilepsy (and especially active epilepsy) exhibited significantly higher rates of unemployment, lower income (<$25K), less educational achievement, being single, and higher rates of problematic health conditions and lifestyle practices (e.g., obesity, inactivity, smoking). Persons with the most active epilepsy (i.e., seizures within the past 3 months) were most likely to report more mentally and physically unhealthy days and more activity limitations.
The prevalence of neurobehavioral comorbidities in epilepsy across the lifespan have triggered a concerted effort to uncover the potential mediators of these complications, which will inform treatment and prevention. Returning to Figure 1, we now examine the contribution of the type of epilepsy (Epilepsy Syndrome) on the risk of neurobehavioral comorbidities, a longstanding relationship of interest in the comorbidity literature. These studies highlight psychiatric, cognitive, and social impairments that are specific to the type of epilepsy, but also demonstrate some limitations of the syndrome classification approach. Next, we will delineate the impact of disrupted brain development, and accelerated brain aging, as well as broader considerations of intrinsic brain abnormalities on neurobehavioral comorbidities (Brain Development and Aging/Brain Disorder). Finally we will discuss psychosocial mediators of comorbidities.
Therapeutic decisions and the prognosis of epilepsy rely on the accurate identification of specific epilepsy syndromes. Each syndrome consists of a constellation of clinical and laboratory variables (e.g. seizure semiology, age of onset, MRI, signature EEG findings, mode of inheritance) that set it apart from other disorders. Inherent in this assumption is that the core pathophysiology of each epilepsy syndrome governs both the type of manifested seizures and its associated neurobehavioral comorbidities. For decades, the syndromic model has served as the basis to investigate the cognitive and psychiatric domain(s) most at risk (Table 3).
While it is logical to categorize comorbidities based on epilepsy syndromes, much remains to be learned about the distribution of shared versus syndrome-specific cognitive and psychiatric abnormalities given the lack of population-based investigations incorporating standardized, contemporary and comprehensive assessments. In point of fact, clinical evidence suggests that comorbidities do not necessarily respect pathophysiological boundaries. To exemplify this point, we first describe the spectrum of cognitive comorbidities that are unique to and common across selected epilepsy syndromes, followed by a discussion of associated psychiatric comorbidities. Then, we focus on temporal lobe epilepsy (TLE), the most frequent form of focal epilepsy, outlining a broad neuroanatomical basis for observed neurobehavioral comorbidities.
There has been a longstanding interest in the association between epilepsy syndromes and cognitive comorbidities. In Benign Epilepsy with Centrotemporal Spikes (BECTS), a syndrome with disturbances in the Sylvian and Rolandic regions, language problems are anticipated12, but a mild degree of deficit in attention and executive function are also noted13. In juvenile myoclonic epilepsy (JME), a disorder of frontothalamic hyperexcitability, impairments extend beyond attention and executive function to include verbal and visual memory, processing speed, naming and language function14. While the cognitive complications of childhood absence epilepsy (CAE) would be expected to predominantly involve attention given the underlying thalamocortical network derangement15, findings also demonstrate affected linguistic ability, broader executive function, and social competence16. While the cognitive complications of temporal lobe epilepsy (TLE) would be expected to center on memory disturbance given the underlying mesial temporal/hippocampal pathology, more widespread cognitive disorders have been reported including abnormal executive functions, processing speed, language, and other abilities17.
Similarly, the association between epilepsy syndromes and the risk of psychiatric comorbidities has been intensely studied, the best example being a proposed link between TLE and an increased risk for depression and psychosis. While depression and psychosis are known complications of TLE, these psychiatric comorbidities have been documented across a wide range of epilepsy syndromes, including BECTS18, JME19, and CAE20. Further, many of the epilepsy syndromes share broader psychiatric, behavioral, and social problems including Attention Deficit Hyperactive Disorder (ADHD), aggression, conduct problems, unemployment, and social isolation20, 21. This controversy regarding the unique psychiatric vulnerability of TLE, decades long, has been replaced by the view that psychiatric disorders are represented across diverse epilepsy syndromes.
These distributed psychiatric and cognitive abnormalities have been linked to surprisingly widespread neuroanatomical derangements. Such functional-structural relationships are again best characterized in people with TLE. While the link between the degree of hippocampal atrophy and memory deficits are well documented, considerable structural abnormality exists outside of this region, including extratemporal lobes (i.e. frontal, parietal and occipital lobes) as well as subcortical and cerebellar regions and their direct and indirect connections17. Importantly, these anatomical abnormalities are correlated with specific cognitive deficits, both within and beyond the memory domain. For example, decreased integrity of the uncinate fasciculus (a white matter tract between the mesial temporal lobe and the frontal lobe) is related to poorer memory performances22. Likewise, the volume of the corpus callosum and the integrity of the frontostriatal connections are correlated with executive function23, 24. Temporal lobe abnormalities have also been implicated in the neurocircuitry of depression and TLE. For example, the degree of hippocampal atrophy is inversely correlated with the severity and/or duration of depression in TLE with depression 25. Patients with TLE and psychosis had 16–18% larger amygdala volumes, when compared to TLE patients without psychosis26. In parallel with the cognitive literature, widespread functional and anatomical abnormalities are associated with mood disorders in TLE, including orbital frontal cortex27, cingulate gyrus28, 29, subcortical regions28, and brainstem29.
In summary, epilepsy syndromes provide a useful framework for considering the risk and type of comorbidities, but there is variability in comorbidity presentation within and across syndromes suggesting that variable phenotypic presentations are driven by other factors. At present, treating clinicians must be aware that pediatric and adult epilepsy syndromes may be associated with classically unanticipated cognitive, psychiatric, and social complications—this very true even for what have been viewed as uncomplicated epilepsies. A broad assessment of potential cognitive, psychiatric, and social complications is indicated to fully characterize associated comorbidities. It is certainly possible that as more clearly defined phenotypes are identified, more characteristic neurobehavioral profiles and targeted treatment strategies will result.
That children with established and chronic epilepsies exhibit subtle anomalies in brain structure and connectivity has been shown. How these anomalies develop is an important question. In healthy maturing children, gray matter volumes decline with concomitant white matter volume expansion30 (Figure 2A). Against this dynamic backdrop, children with epilepsy exhibit abnormalities in brain structure at or near the time of seizure onset and an altered development trajectory early in the course of epilepsy. At baseline, quantitative MRI studies have revealed enlarged ventricular31 and reduced thalamic volumes32 in new-onset idiopathic generalized epilepsy. Over the prospective two years, children with epilepsy displayed a slowed white matter expansion and altered region-specific patterns of gray matter thinning, compared to age-matched controls33 (Figure 2B). Cross-sectional studies supplement this literature, demonstrating the adverse impact of early-onset epilepsy on brain structure. The posterior corpus callosum appears to be particularly vulnerable, with earlier age of seizure onset consistently linked to reduced white matter volume or microstructural integrity22, 23. Clearly, developmental trajectories in children are divergent from their healthy peers and evident near the time of epilepsy onset, but the link between aberrant brain development and variable cognitive, psychiatrc, and social progress in children with epilepsy is uncertain. Preliminary findings suggest that such a relationship exists. In children with new-onset JME, baseline frontothalamic volume is correlated with deficits in executive function34 and in children with new-onset BECTS, striatal enlargement predicted better executive function performances35. It remains uncertain to what degree an altered course of brain development is linked to reliable deviations in cognitive development, and whether these changes are permanent upon remission of seizures and cessation of treatment.
On the other end of the lifespan, the aging brain faces a different set of challenges with epilepsy36,. Aging-related brain atrophy reflects a myriad of cellular changes including a loss of dendritic spine, as well as accumulation of inflammatory damage37, and beta amyloid and tau protein38 (Figure 2C). These changes likely lead to increased vulnerability to seizure-induced cognitive deficits. Although potential cognitive decline in aging patients with epilepsy is likely very slow, these patients start at a lower baseline cognitive level than healthy subjects and may reach a clinically significant threshold of impairment earlier in life39 (Figure 2D). A particularly relevant question is whether cognitive reserve is associated with differential risks for cognitive impairment in elderly people. Greater cognitive reserve, as measured by factors such as higher intelligence, education attainment or greater occupational complexity, appears to improve or protect cognitive outcome in cross-sectional40 and 4-year prospective controlled studies41 (Figure 2 arrow). In summary, the accumulative effects of normal and pathological aging on brain health may influence the later cognitive outcome of aging persons with chronic epilepsy, but direct examination of these relationships are lacking.
One of the fundamental assumptions in the field is that epilepsy does not occur in a normal brain. Indeed, factors relating to the underlying brain structural abnormalities not only increase the risk for epilepsy, but also for cognitive, psychiatric, and social impairments. Although the associated neurobehavioral comorbidities can be variable, the structural-functional relationships appears to be stronger in lesional epilepsy such as malformation of cortical development (MCD)42 and traumatic brain injury (TBI)43, as compared to epilepsy patients without structural abnormalities. For example, periventricular nodular heterotopia is an MCD associated with both epilepsy and dyslexia. Aberrant cortical to cortical white matter integrity has been found to be correlated with poor reading fluency42, while abnormal connections between the heterotopia and overlying cortex was related to longer seizures duration44. In TBI, the location and extent of injury are often closely related to the risk of developing epilepsy and cognitive complications. The presence of parietal lobe lesions and left insular involvement has been found to be associated with an increased risked of post-traumatic epilepsy and longer epilepsy duration was associated with a decline in full scale IQ43. In summary, the cause of epilepsy and the associated neuropathology often dictate the expression of cognitive comorbidities.
The link between an underlying brain disorder and psychiatric comorbidities has also emerged with evidence (Table 4) suggesting bidirectional relationships between epilepsy and a variety of cognitive, psychiatric, and social comorbidities in both pediatric and adult individuals. That is, psychiatric disorder may follow the onset of epilepsy, but, importantly, may also antedate incident epilepsy and serve as a “risk factor” for epilepsy- this is the case for depression, suicidality, ADHD, psychosis, and schizophrenia. Not only is there clear population-based evidence of shared susceptibilities between epilepsy and specific comorbidities, but family have revealed co-aggregation of cognitive45 and behavioral abnormalities46 in the siblings and/or parents of persons with epilepsy. Whereas these recent observations suggest that an intrinsic brain disorder, including a possible common genetic predisposition, may underlie both psychiatric comorbidities and epilepsy, the influence of environmental factors remains to be clarified. Furthermore it is unknown whether the co-aggregation of comorbidities is associated with similar structural or functional brain derangements, findings that have been demonstrated in other disorders such as siblings of patients with childhood onset schizophrenia47.
One unstated but very clinically relevant implication of the bidirectional view is that neurobehavioral comorbidities may be present at diagnosis, early in the course of the disorder, and even occur prior to epilepsy onset. These effects have indeed been reported, especially in children, where multiple investigations of participants with epilepsy without clinical evidence of brain structural abnormalities have demonstrated a pattern of mild diffuse impairment across multiple cognitive domains, as well as elevated rates of behavioral problems including ADHD, with the suggestion that these problems antedated the first recognized seizure48, 49. Indeed, approximately 25% of children with new onset idiopathic epilepsies required special education services prior to clinical seizure onset50. In adults with new onset epilepsies, cognitive and behavioral disorders have also been reported51. From the clinical standpoint, the imperative would be to screen new onset cases for these issues in order to facilitate early intervention. That said, caveats regarding bidirectional hypotheses include the following: 1) similar bidirectional relationships have been reported for several chronic conditions including stroke, diabetes and cardiovascular disease, inferring a broad and not epilepsy-specific phenomenon52, 2) only a subset of persons with antecedent psychiatric disorders develop epilepsy and similarly a subset of those with new onset epilepsy present with or develop a psychiatric or cognitive comorbiditiy early on, so this relationship may apply to a unique phenotype.
To this point we have focused largely on neurobiological biological mediators. However, the social and psychological impact of epilepsy can be profound. Narratives from people with epilepsy underscore the significant personal impact of exposure to essentially warningless events on the perception of personal control, the potential effect of epilepsy on many critical aspects of life (e.g., work and income, transportation, interpersonal relationships), exposure to real and perceived stigma, and the general fear of seizures53. These and other psychological, social and environmental factors influence the risk of psychiatric commorbities54 and need to be integrated into comprehensive predictive models.
Thus far, we have provided a brief account of the evidence that neurobehavioral comorbidities are influenced by several important factors including the epilepsy syndrome, the divergent effects of epilepsy on neurodevelopmental and aging trajectories, as well as the underlying brain disorder. Questions remain as to the directionality of these relationships. While the number of possible permutations are large, we will focus on selected links that are particularly relevant to clinical practice (Figure 1) – the contribution of core epilepsy characteristics, including epileptiform discharges55, the age of epilepsy onset56 and years of epilepsy chronicity57–59, and the prescribed medications, to neurobehavioral comorbidities.
Interictal epileptiform discharges (IEDs) are abnormal neuronal discharges seen on the electroencephalogram (EEG) as a result of transient synchronous depolarization of neurons, producing trains of action potentials60. Whereas IEDs by definition occur when a patient is not having a seizure, they usually occur close to the seizure focus and are specific indicators of higher seizure risks61. The accumulative literature suggests that these discharges are not merely “harmless” biomarkers of epilepsy but have important behavioral and cognitive consequences. Cognitive deficits are related to the timing, duration, and spatial distribution of IEDs, with more pronounced impairment immediately before and after a prolonged (>3 seconds), generalized IED55. Although the most prominent effects of IEDs are attention and motor speed, transient cognitive impairment is not simply inattention55. Focal discharges have been temporally linked to material specific deficits, depending on the hemisphere (i.e. right-sided discharge associated with spatial memory deficits and left-side discharges related to verbal memory impairment55) and the particular brain region (occipital lobe discharges associated with decreased reaction time when material are presented in the visual field contralateral to the discharges62). However, applying these findings in the clinical setting is not straightforward. First, these cognitive deficits are ephemeral and long-term accumulative effects of IEDs are difficult to establish55. Second, pharmacological treatments to suppress IEDs, in addition to suppress seizures, have their own cognitive side effects (Table 5) and not all seizure medications can suppress IEDs. Finally, even when seizure medications suppress IEDs, corresponding cognitive improvements are not readily detected55, suggesting an effect of the underlying pathological substrate. Whereas the views differ regarding the targeted treatment of IEDs, all views agree that rendering individuals seizure free should be the primary objective, as seizure freedom is associated with reduced IEDs and improved cognition.
In the case of psychoses, the temporal relationship with seizures is particularly relevant (Supplemental Figure 2). Peri-ictal psychoses are more frequently reported than inter-ictal psychoses. In particular, post-ictal psychoses account for approximately 25% of all psychoses of epilepsy. They usually occur after a cluster of secondary generalized tonic-clonic seizures in patients with TLE63. These psychotic episodes are usually brief, last from 1 to 6 days63, and often remit spontaneously within days or weeks. However, they are characterized by mixed mood and paranoid delusions with religious content, with an increased risk of self-harm64. Interictal psychoses are unrelated to seizures and typically develop after several years of active mesial TLE65. Despite their chronic course, differences with schizophrenia are quite striking with low rates of long-term institutionalization, a tendency of psychotic symptoms to attenuate over time, and the paucity of personality and cognitive deterioration66. Understanding these temporal relationships between seizures and psychosis are paramount, as specific types of epilepsy-related psychosis respond to different therapeutic strategies, a point we will elaborate in the treatment section. Finally, it is appreciated that there is an elevated time-limited risk of other psychiatric (e.g., depression) and cognitive (e.g., memory) complications in the post-ictal state that slowly resolve over time. The essential point is that the risk of neurobehavioral comorbidities may be transiently affected by intrinsic features of the disorder, a frequently overlooked consideration.
Although animal models suggest that seizures in the immature brain cause altered brain networks and poor cognition67, direct evidence of such an effect in humans has been elusive. When examining children with established epilepsy, many studies show earlier age of seizure onset to be correlated with poorer cognitive function. Specifically, early-life seizures are related to lower IQ68–70, poor academic performances71 and developmental delay72. However, firm conclusions regarding the impact of early-life seizures on cognition can be confounded by several factors: 1) Many studies are retrospective and cross-sectional in design, 2) Most studies included children with a wide spectrum of epilepsy syndromes including idiopathic and symptomatic as well as focal and generalized epilepsies68, 70, 3) Several investigations drew patients from specialized (e.g. surgical) populations with refractory epilepsy, which is difficult to apply to the general population of persons with epilepsy and uncomplicated epilepsy69, 73, 4) Earlier seizure onset can be highly correlated with longer seizure duration and many studies fail to disambiguate this co-linearity, 5) IQ is the only measure of cognitive outcome in many studies and the degree to which other cognitive domains are at risk remains to be determined.
In prospective studies tracking children from the onset of their epilepsy, some groups report subsets of children to be at risk of cognitive decline, but factors in addition to earlier age of seizure onset also appear to contribute to adverse cognitive outcomes74, 75 and there are mixed findings. Bourgeois and colleagues found that children with a decrement in IQ not only had earlier seizure onset but also had higher baseline IQ, higher incidence of seizure medication toxicity, and more refractory epilepsy74. In contrast, Oostrom and coworkers noted that persistent cognitive deficits were not associated with epilepsy-related factors but rather behavior problems prior to the diagnosis of epilepsy and a maladaptive family environment75. In summary, notwithstanding the small number of prospective investigations and their limitations, early-onset epilepsy appears to impart a greater risk for cognitive impairment than later-onset epilepsy, especially in children who have complicated epilepsy, behavior problems or difficult family environment.
Clinically, it is important to recognize that earlier seizure onset is an important but not sole contributor of neurobehavioral comobridities in children. Apparent from these studies is the need for a multidisciplinary team approach to aggressively control seizures, manage seizure medication toxicity, treat behavioral problems and mediate family environments.
An important controversy is whether patients’ psychiatric status and cognitive abilities decline with increasing duration of epilepsy, a controversial literature that began in 1924 with mixed results59. The disparate findings have been influenced by small sample sizes, heterogeneous epilepsy syndromes, restricted and variable neuropsychological batteries (e.g., IQ and memory), and lack of control groups in many studies. Recent studies have aimed to address some of these shortcomings. One investigation highlighted the differential cognitive trajectories between TLE patients and healthy controls over a prospective 4-year interval41. Whereas control subjects showed broad test-retest improvements over time (practice effects), TLE patients on average exhibited minimal practice effects, suggesting a reduced capacity to learn from prior experience. Note too that within the TLE group, variability in cognitive outcomes existed with abnormal cognitive trajectories in a subset of patients (20–25%), with their abnormal prospective cognitive trajectories predicted by smaller baseline brain volumes, lower IQ, older chronological age, and longer epilepsy duration41.
Although the prospective controlled design is the optimal method to evaluate whether cognitive impairment is progressive, the study’s follow up time is short and the cognitive course over a life span is uncertain. Helmstaedter and Elger used a cross-sectional design to indirectly address this challenge, comparing the age-related regression of memory in 1156 TLE patients and 1000 healthy controls over a wide age span (6–80 years)39. The epilepsy group showed an earlier learning peak (defined as highest performance prior to decline) than the control group, but subsequent age-related declines ran parallel between the groups, with the epilepsy group always performing worse.
Progression is often couched in terms of cognitive decline. Less examined are the progressive psychiatric complications that may occur in the face of chronic epilepsy. Jones et al.76 examined temporal lobe epilepsy patients (n = 48) and healthy controls (n = 69) with structured psychiatric interview at baseline and 4 years later to characterize the course of DSM-IV Axis I disorders. Adjusting for the influence of prior psychiatric history, epilepsy subjects exhibited significantly greater risk of interval episodes of Total Axis I Disorders and Mood Disorders, indicating a poorer prognosis for these comorbidities in the context of chronic epilepsy.
While there may be divergent views regarding the long term psychiatric and cognitive course in chronic epilepsy, all views appear to agree on one important fact, which is that persons with chronic epilepsy appear to enter their elder years at a distinct cognitive disadvantage with what is best characterized as age-accelerated cognitive pathology, a point that was emphasized in the section regarding the impact of epilepsy on the aging brain.
Given the large number of available seizure medications, selecting the appropriate medication becomes a daunting task for clinicians. Although there are clear guidelines as to which medication is efficacious for focal versus generalized epilepsy77, head to head comparisons within this broad classification of epilepsy are rare. In practice, selecting seizure medications depends as much on efficacy as on side effect profile. We, thus, summarized a general consensus on the cognitive and psychiatric side effects of seizure medications (Table 5)78. A few broad trends are noted. Cognitively, drug-induced impairments have been associated with barbiturates, phenytoin, and topiramate while milder cognitive effects are found for lamotrigine and oxcarbazepine. The link between depression and barbiturates, vigabatrin, and topiramate seems to be firmly established, as well as the mood stabilizing properties of carbamazepine, oxcarbazepine, lamotrigine, and valproate. In the majority of cases, a rapid titration of the drug, polypharmacy, a past history of a psychiatric disorder, and limbic system functional or structural abnormalities represent an increased risk for developing drug-induced cognitive and psychiatric complications.
Included in the psychiatric complications is the possible increased suicide risk associated with seizure medications, prompting the United States Food and Drug Administration to issue a warning79. Although this remains a controversial issue as studies on the topic have many confounders including a lack of consideration for past suicide attempts, what is clear is that a subgroup of people with epilepsy are more prone to develop psychiatric adverse event whenever a new seizure medication is introduced. Further, patients with a known history of depression and anxiety disorder experience more seizure medication related side effects than individuals without psychiatric diagnoses80. Therefore, screening for psychiatric comorbidities including suicidal thoughts and ideation with questionnaires such as the adverse event profile (AEP) should commence at the time of epilepsy diagnosis and prior to beginning treatment with seizure medications, with continual surveillance in company with medication titration and change.
The phenomenology of psychiatric disorders associated with epilepsy has been a matter of debate with several implications for diagnosis, treatment and prognosis. Some authors contend that clinical syndromes comorbid to epilepsy are more often than not characterized by atypical features that are poorly reflected by conventional classificatory systems such as the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Classification of Disease (ICD-10)81. However, other studies demonstrate that it is possible to apply standardized criteria in a not negligible proportion of patients76, 82. In general terms, the psychopathological spectrum is likely to be large. On one hand, it is reasonable to hypothesize that patients with epilepsy can experience psychiatric disorders identical to those of patients without epilepsy. However, it is equally reasonable to assume that the underlying brain disorder might influence the expression of mood disorder symptoms, masking some features or emphasizing others. Concerning mood and anxiety disorders, we have reviewed in preceding sections a number of factors that may account for atypical features including: 1) the behavioral changes that may precede or follow seizures; 2) peculiar psychiatric syndromes such as the interictal dysphoric disorder; and 3) the psychotropic effect of seizure medications.
To arrive at a definite diagnosis of a psychiatric syndrome in patients with epilepsy can be difficult. In fact, a number of symptoms, which are recognized as diagnostic criteria, may occur in epilepsy secondary to seizure activity or medication treatment. Moreover, one of the most frequent methodological errors in research studies on the subject is the sole reliance on clinical instruments that use measures or cut off scores that may not be valid in the epilepsy population. At present, very few measures exist that have been developed de novo for the assessment of comorbid psychopathology in epilepsy, using modern techniques of questionnaire development.
Among structured or semi-structured clinical interviews for diagnosis of psychiatric disorders following DSM criteria, Mintzer and Lopez 83 proposed the Epilepsy Addendum for Psychiatric Assessment (EAPA) to be used with the Mini International Neuropsychiatric Interview (MINI); a specific version of the Structured Clinical Interview for Axis I disorders (SCID-I) adapted for patients with epilepsy, named SCID-E, has been developed 84. Other clinical instruments have been developed specifically for patients with epilepsy in order to identify atypical manifestations of mood disorders not usually captured by DSM-based interviews such as the Seizure Questionnaire 85 and the Interictal Dysphoric Disorder Inventory 86. Among self-rating screening instruments for depressive symptoms, the well-known Beck Depression Inventory (BDI) has been validated in patients with epilepsy 87. A six-item, self-report questionnaire, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), was developed for the rapid and objective detection of major depressive episodes in patients with epilepsy. It has been found to be a very practical and user-friendly screening instrument in outpatient epilepsy clinics 88.
Systematic data on treatment strategies for psychiatric disorders in epilepsy remain limited, with clinical practice relying heavily on individual experience. Experts from U.S. 89 and international90 panels advocate that treatment of primary psychiatric disorders outside epilepsy is valuable, if the underlying neurological condition is taken into consideration. In this regard, it is important to point out that it is still unclear whether patients with epilepsy respond equally to psychotropic medications or if they have different remission rates, compared to individuals without epilepsy.
Regarding mood disorders, the general impression is that depression in epilepsy is usually mild to moderate in severity with excellent response rates to adequate treatments. Selective serotonin reuptake inhibitors (SSRIs) (e.g. sertraline 50 mg or citalopram 20 mg) can be reasonably considered first choice, bearing in mind that drug doses need to be adjusted according to clinical response, especially if seizure medications with enzyme inducing properties are co-prescribed91. Fluvoxamine and nefazodone are the only difficult to use compounds because they are inhibitors of metabolic pathways of a number of seizure medications (especially carbamazepine, phenytoin)91.
Regarding psychoses, the treatment of peri-ictal psychoses is related to the treatment of the epilepsy (Figure 3). Neuroleptics can be used for a short period of time in order to reduce morbidity and mortality. Interictal psychoses may require long-lasting antipsychotic drug treatment. In such cases, patients need to be followed up in a psychiatric setting. Dosages should be always tailored to patient’s response because in almost all cases, enzyme inducers reduce the plasma levels of these drugs. In particular, the use of clozapine has to be carefully monitored because its metabolism has a high inter-individual and intra-individual variability and, especially in combination with valporate, interactions are difficult to predict92.
The issue of worsening a patient’s seizures with initiation of psychotropic medications is a special concern for clinicians92. However, for the majority of compounds prescribed at dosages within the therapeutic range, the incidence of seizures is less than 0.5% when other risk factors are excluded. In fact, the “proconvulsive” effect is likely to be dose-dependent, becoming significant for very high dosages. Among antidepressants, SSRIs can be considered reasonably safe while clomipramine and maprotiline are the only drugs that may represent a concern. Among antipsychotics, chlorpromazine and clozapine are considered “proconvulsant” in epilepsy patients. The former may be a concern only at high doses (1000 mg/daily) and the latter at medium and high doses (>600 mg/daily). New compounds are usually well tolerated and can be considered reasonably safe. In particular, olanzapine and quetiapine showed a seizure rate of 0.9% and risperidone an even lower risk of seizures (about 0.3%). Finally, it should be acknowledged that the electroconvulsive therapy is not contraindicated in patients with epilepsy, it is well tolerated and worth considering in patients with very severe and treatment-resistant mood episodes.
Data on psychological therapies for mood and disorders in epilepsy appear promising. In general terms, cognitive behavioral therapy has showed utility in the management of depression in both adults93 and children94.
In addition to psychiatric disorders, cognitive impairment also represents a major source of disability in people with epilepsy, but treatment options are more limited. One of the most practical approaches has been to minimize seizure medication side effects by utilizing a screening questionnaire such as the AEP. Rendering patients seizure free with a single agent at low dose would be the best strategy, as a recent study showed that their AEP was similar to controls95. In patients with refractory epilepsy, a tailored approach to select and adjust medications according to the patient’s individual AEP can reduce cognitive impairment and improve quality of life96.
Although medication adjustments can reduce cognitive deficits, they do not mitigate the underlying pathophysiology. Clearly, cognitive impairment in epilepsy has a distinctive mechanism from neurodengenerative diseases, as treatment with anticholinesterase inhibitor does not improve memory in people with epilepsy97. Recently, memory and cognitive training techniques have been applied to epilepsy and other neurological disorders, encompassing a wide range of strategies, including computer-assisted working memory programs, external aids (i.e. diaries, calendars), and exercises on self-regulation and problem solving activities. Helmstaedter and colleagues examined the impact of cognitive rehabilitation on 55 TLE patients after temporal lobe resection98. Positive effects of training were most evident in verbal learning, with little gain in long-term consolidation. Notably, performance improvements were only found in right TLE patients. These training improvements appears to be nonspecific as Koorenhof and coworkers found that 36% of TLE and 50% of control subjects had gains in memory test performances that were greater than expected from re-test or practice effect99. In summary, applying nonspecific strategies such as memory and attention trainings have produced mixed results and it is unclear why some people improve while others do not. Finally, it is also unclear if memory improvements has long-term benefits and would generalize to other cognitive domains.
Major advances have uncovered potential mediators of psychiatric, cognitive, and social comorbidities, but gaps remain in the early detection and treatment of these disorders. Whereas neurobehavioral comorbidities are present early in the course of epilepsy, standardized diagnostic and therapeutic modules are lacking to provide intervention. Brief, uniform, and clinic-friendly screening tools are needed to identify individuals at risk for neurobehavioral complications and homogenize their access to care. In this regard, the National Institute of Neurological Disorders and Stroke has provided leadership with funding of Neuro-QOL, a project aimed to develop psychometrically sound and clinical relevant quality of life measures in children and adult with neurological disorders100. Some of the instruments such questionnaires on executive function, depression and anxiety could be used to screen for comorbidities. However, the primary goal of these instruments is to facilitate longitudinal studies and large-scale clinical trials and thus the use in the clinical arena will require further validation.
Treatment options for neurobehavioral comorbidities remain to be developed. Aside from seizure medication management, strategies are largely adopted from the psychiatric literature and professional experiences. While similarities exit, distinctions are also present between psychiatric disorders and epilepsy-associated comorbidities. Further complicating the issue is that epilepsy is not a single disorder but encompasses a wide spectrum of complex conditions with shared and unique features. Thus, research is needed to clearly identify biomarkers for specific clinical phenotypes. Once the biological basis of different epilepsies is better understood, large-scale randomized trials are needed to develop epilepsy specific and individualized treatment options.
It is important to understand that epilepsy is a dynamic process in which damage likely invokes compensatory mechanisms. Whether we can harvest these altered neurocircuits to enhance cognitive and psychiatry rehabilitation is unknown, but animal models of TLE have provided considerable insight – early life seizures may lead to functional reorganization of the memory network in which successful performance of memory tasks requires increasing reliance on the frontal lobe, indicating a possible compensation for the dysfunctional medial temporal lobe101. Human imaging studies have revealed similar adaptive changes, demonstrating reduced functional connections within the temporal lobe and enhanced functional connections between the temporal and frontal lobes during working memory tasks in TLE102. Collectively, these studies hold the promise of a targeted intervention, leveraging epilepsy-specific compensatory mechanisms to enhance and accelerate psychiatric and cognitive recovery.
Supplemental Figure 1: Prevalence of psychiatric conditions in people with epilepsy6. Figure modified with permission from Wiley-Blackwell
Supplemental Figure 2: Clinical characteristics of psychoses of epilepsy. The figure depicts the frequency, EEG findings, level of consciousness, risk factors and treatment options for four types of psychosis in people with epilepsy.
Supported by grants from the National Institutes of Health including K23 NS060993 (JJL) and NINDS 2RO1-44351 (BPH). BPH also supported by the Clinical and Translational Science Award (CTSA) program, previously through the National Center for Research Resources (NCRR) grant 1UL1RR025011, and now by the National Center for Advancing Translational Sciences (NCATS), grant 9U54TR000021. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding source played no role in the interpretation of the studies present or the preparation and writing of this review.
Conflicts of Interest
MM has received consultancy fees from Pfizer, UCB Pharma and Janssen
JJL received a speaker’s honorarium from UCB-Pharma.
BPH has no potential conflicts to report.