Epilepsy is rarely a syndrome purely of seizures – rather, it is usually accompanied by other cognitive, behavioral, and emotional changes. These co-morbid conditions have in the past been generally viewed as side effects of seizures, and it has been presumed that they would disappear once seizures were adequately controlled. This view has been challenged in recent years, in part due to increasing awareness that the expression of co-morbid conditions may precede that of seizures and that these conditions do not uniformly resolve if seizures are fully controlled. Thus, it is increasingly recognized that to improve the quality of life for many people with epilepsy, a “cure” must involve more than stopping or preventing seizures, but also must include ameliorating the cognitive, behavioral, and emotional difficulties that can be an equally or more disabling part of this disorder.
Conditions for which epileptic adults are at increased risk relative to the general population include depression, anxiety, sleep disturbances, cognitive impairment, and psychosis. Of the psychiatric disturbances, depression is the most common (although the rates of psychosis and dementia are the most elevated relative to those seen in the general population) [74
]. Cognitive impairments include problems with memory, verbal fluency, attention, executive function, and social perception [77
]. Children with epilepsy show higher rates of ADHD, learning disorders, and behavioral problems, as well as depression and anxiety [83
]. Reductions in IQ are seen in both childhood and adult epilepsy [88
], and mental retardation and autism in Dravet, Lennox–Gastaut, and West syndromes and in epilepsies associated with developmental malformations, Fragile X, and Angelman’s syndrome [89
]. Co-morbid changes can be progressive, both over periods of years and over the course of the life span, and their severity has been correlated with age of onset, seizure frequency and total number of seizures, and increasing age [77
]. Higher IQ appears to be protective [82
The etiologies of behavioral and cognitive impairments in patients with epilepsy are incompletely understood and likely multifactorial. There is little doubt that seizures per se
can contribute to some co-morbid symptoms. There is good evidence that a seizure can cause cognitive deficits that can last for an hour or more after the seizure has stopped [93
], and interictal epileptiform discharges can also be accompanied by cognitive impairment [94
]. Conversely, cognition in patients with long-standing epilepsy is often, but not always, improved when seizures are successfully controlled by medication or surgery [77
]. In addition, animal studies have shown that electrical or chemical induction of seizures causes neural damage and cognitive decline in adult animals [96
] and disrupts normal brain development in young animals [98
]. Seizures can also affect cognition indirectly – through sleep disturbance, for example. With regard to psychiatric co-morbidities, social stigma and other negative interpersonal reactions to epilepsy can impact both self-esteem and social relations, which in turn puts patients at higher risk for emotional disturbances [100
]. For example, the cognitive and behavioral problems of children with epilepsy are significantly exacerbated if their parents’ behavior is destabilized by the child’s diagnosis [101
A second potential source of co-morbidity is anti-epileptic drugs (AEDs), all of which can cause cognitive and psychiatric disturbances. The newer AEDs seem to cause fewer problems than the older ones, but their side effects have also received less systematic study (nine new AEDs have entered the market in the past 15 years). Even with the newer AEDs, significant problems have been observed in some patients. For example, topiramate is associated with relatively high rates of adverse effects, including cognitive impairment, depression and nervousness, and vigabatrin is associated with substantial rates of depression and other psychiatric problems [102
]. Maternal exposure to AEDs during pregnancy can also cause problems in offspring: valproate in particular has been linked to cognitive impairment, developmental delay, and major congenital malformations [107
Finally, epileptic seizures and co-morbid conditions may arise from a common, pre-existing pathology. Genetic defects leading to seizures may also cause other neurological problems, either through a common pathogenic pathway or separate ones. Similarly, stroke and trauma can cause cognitive impairment, mood disturbances, and behavioral problems either together with seizures or without them, suggesting the possibilities of both common and independent pathways for the development of these symptoms. The possibility of common underlying pathology leading to multiple phenotypes receives support from findings that cognitive and psychiatric problems are evident in many patients prior to their first seizure. Studies of past histories of children newly diagnosed with epilepsy indicate higher than normal rates of ADHD, learning disorders, anxiety, depression, learning disabilities and behavioral problems before their initial presentation with seizures [84
]. Adults newly diagnosed with epilepsy were found in three different studies to be 1.7- to 7-fold more likely to have a past history of depression [113
]. Finally, many patients have poor long-term quality-of-life outcomes despite seizure control, suggesting that co-morbid conditions can continue to progress even in the absence of seizures.
Studies in animal models are beginning to provide insights into the cellular and molecular mechanisms underlying the cognitive deficits associated with epilepsy. In adult animals, seizures cause cell death in temporal structures that subserve memory [42
]. In humans, hippocampal neuronal cell death accompanies seizures and predicts the extent of memory loss following seizures [115
]. In neonates, seizures interfere with the development of hippocampal dendrites and the maturation of GABAergic and glutaminergic receptors and scaffolding proteins [55
]. Dendritic loss and/or abnormalities of dendritic development are also seen in humans with epilepsy [116
] as well as in Down syndrome and other forms of mental retardation [118
]. Finally, studies in rodent models of Rett syndrome [119
] and TSC [120
], and in rats with electrically [121
] or chemically [122
] induced seizures, suggest that disruption of long-term potentiation and long-term depression also contribute to learning and memory deficits in epilepsy. Indeed, since both learning and epileptogenesis involve long-term changes in glutaminergic and/or GABAergic transmission at individual synapses, it is not surprising that the development of seizures could be accompanied by the appearance of cognitive deficits.
4.1. Future directions
We need to more precisely characterize the full range of comorbidities in patients with epilepsy. Studies to date suggest that different patterns of co-morbidity occur in different epilepsy syndromes, and even within a single syndrome. For example, a study by Hermann et al. [81
] suggests that at least two discrete syndromes of cognitive impairment exist within temporal lobe epilepsy, which are distinguished by selective deficits in memory versus executive function (as has also been noted for age-related cognitive impairment in the general population). The spectrum of cognitive and/or psychiatric problems in a given patient also depends on factors such as the location and laterality of an epileptic lesion, and the individual’s pattern of speech dominance prior to the onset of epilepsy [79
]. It will be important to further characterize the sleep disturbances that occur in epilepsy, as well as somatic co-morbidities, which include increased rates of back and neck pain, arthritis, heart disease, and sudden unexpected death [76
], and to more fully define the side effects produced by different AEDs. A key ingredient in these endeavors will be to increase physician awareness and recognition of co-morbid conditions.
In searching for potential mechanisms, it will be crucial to understand to what extent the cognitive and psychiatric syndromes seen in epileptic individuals resemble or differ from those seen in the general population. Depression, for example, seems to have a different range of symptoms in epileptic than in non-epileptic patients, with up to 71% of clinically depressed epileptic patients showing atypical patterns of symptoms that don’t meet criteria for any of the DSM IV categories (but which frequently show a waxing and waning course most closely resembling dysthymia) [124
Imaging studies have begun to point to specific structural and functional brain abnormalities associated with epileptic co-morbidities [125
]. Future work should include longitudinal analyses: imaging studies in normal children and those with developmental disorders are now showing that analyzing developmental trajectories may be far more useful in defining affected brain regions and circuits than analysis of single time points [126
]. For example, a particular brain region may appear to under-function in experimental subjects relative to controls at one developmental stage, but over-function at another.
Animal models offer great hope for treatment of epileptic comorbidities, as they will enable characterization of synaptic changes underlying these conditions at the cellular and molecular levels, suggest drug targets, and provide vehicles for testing therapeutics. In examples from other disorders, electrophysiological studies of synaptic deficits in animal models of Down’s syndrome and neurofibromatosis type 1 provided novel targets for potential therapeutics. These in turn were tested and shown to alleviate cognitive deficits in the animal models, and now can be further developed for testing in the human conditions [129
]. Animal models have been reported for seizure-induced learning and memory deficits [122
], ADHD [132
] and depression [133
], but additional models should be developed and procedures for generating them standardized across laboratories.