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Introduction
Epilepsy is common in people with intellectual disabilities (ID) and ID is common in people with epilepsy. The rate of psychiatric disorder is high in the general population of children with epilepsy but is much higher in those with ID. This implies that a great proportion of people who have both ID and epilepsy will require psychiatric services and will be demanding of resources. Because each of the three conditions, namely epilepsy, ID, and psychiatric disorder, covers a wide spectrum, there is a significant variation in the nature and severity of the difficulties encountered. Epilepsy becomes much more prevalent, and is also increasingly likely to be refractory to treatment, as the degree of ID increases. Epilepsy syndromes vary from the relatively benign to the very handicapping, and also vary greatly in the range of associated psychiatric disorders. Many behavioral phenotypes are associated with ID and epilepsy. There is an increasing recognition of the role of genetics in influencing outcome in terms of behavioral phenotype, range of ID, and type of epilepsy. Management of the individual with epilepsy, ID, and psychiatric disorder is influenced not only by the genetic and disease/disorder-related factors but also by situational/environmental factors.
Epidemiology
Sillanpää (1992) revealed ID in 31.4% in an unselected population of children in Finland. Murphy et al. (1995) reported similar results from Atlanta, USA. They estimated the prevalence of epilepsy in 10-year-old children and found that 35% had another developmental disability: ID, cerebral palsy, visual impairment, or hearing impairment. Berg (2008), using a broader criterion of IQ <80, carried out a prospective study of children with newly diagnosed epilepsy: 451 of the children (73.6%) were considered to have normal cognitive function. Russ et al. (2012) analyzed data on 91 605 children in the USA from birth to 17 years of age, including 977 children reported to have a seizure disorder; of the latter, 51% had developmental delay. Sillanpää also studied ID in adults who had childhood-onset epilepsy. He found that learning problems of one type or another were common, occurring in 76%, of whom half had ID (Sillanpää, 2004).
A different approach is to examine the prevalence of epilepsy in people with ID, rather than the prevalence of ID in people with epilepsy.
A number of the classical older studies made it clear that the greater the degree of ID, the higher the prevalence of epilepsy. Some of these studies referred to the risk of having one or more epileptic seizures, rather than the risk of developing established epilepsy. For example, Richardson et al. (1980), in a population of children in the UK, found that one or more epileptic seizures occurred in 4% of those with normal intelligence, 11% in those with borderline intelligence, and 27% in those with ID. They also reported that more severe ID was associated with more frequent seizures at a younger age and over a longer time span. Goulden et al. (1991) in the USA, carried out a prospective cohort study of 221 children with ID in whom 33 (15%) developed epilepsy by the age of 22 years. The cumulative incidence of epilepsy was 9% at 5 years, 11% at 10 years, 13% at 15 years, and 15% at 22 years. In those with severe ID, two or more seizures occurred in 35% and one or more in 44%. Steffenburg et al. (1995) assessed all children with ID from 6 to 13 years in a defined geographical area in Sweden, using patient registers. They identified 378 children, of whom 98 had active epilepsy. Epilepsy had been diagnosed in 15% of those with mild ID and in 45% of those with severe ID. McGrother et al. (2006), in a UK population-based prevalence study, found an epilepsy prevalence of 26%. They also commented that, of these subjects, 68% continued to have seizures despite antiepileptic medication, suggesting that the epilepsy was more difficult to treat in the ID population.
The relationships between epilepsy and ID
Can epilepsy cause ID?
The most dramatic situation in which epilepsy can result in intellectual deterioration is when prolonged status epilepticus causes permanent brain damage. Experienced epileptologists will be aware of several personal cases of young people who have apparently been developing normally until they have a prolonged epileptic seizure, following which they have very significant or even profound ID. However, epidemiological studies have produced mixed results in relation to this. The implication is that some children may have prolonged epileptic seizures without sustaining obvious brain damage (Maytal et al., 1989). However, it is also clear that other children do sustain permanent brain damage and acquire ID after a single prolonged seizure. In the circumstances, the current practice of viewing every prolonged seizure as being a medical emergency appears to be entirely appropriate. Prolonged seizures can occur in a particular epilepsy syndrome, namely Panayiotopoulos syndrome, with an apparently benign outcome (Panayiotopoulos, 2000). However, this should be viewed as an exceptional syndrome.
Can repeated seizures that are not prolonged cause ID?
It appears that some children with severe epilepsy plateau in their development; the result of this is that the mental age remains relatively stationary while the chronological age continues to rise. Consequently, the IQ, because it a quotient, falls; Maria Fowler described such a group of children several years ago (Besag, 1988). The reasons for this “stagnation” of mental age remain unclear. Extensive study of the original group by the author of this chapter (unpublished studies) failed to reveal any unequivocal cause, although there was a suggestion that frequent nocturnal and/or diurnal epileptiform discharges might have been associated with this fall in IQ.
It is important to distinguish between permanent intellectual impairment and what has been termed “state-dependent” intellectual impairment. The latter can result from sedative medication, in which case a medication review is necessary, or it can be caused by the epilepsy itself. The important distinguishing factor of “state-dependent ID” is that it is potentially treatable and reversible. The epileptic phenomena that can result in state-dependent intellectual impairment include very frequent absence seizures, transitory cognitive impairment, frequent localized discharges, frequent hemispheric discharges, postictal state-dependent cognitive impairment and electrical status epilepticus of slow-wave sleep (ESES), or continuous spike-waves in slow-wave sleep (CSWS) (Besag, 2011).
Over recent years, the term “epileptic encephalopathy” has been used. This was defined by the International League Against Epilepsy taskforce (Engel and ILAE, 2001) as “a condition in which the epileptiform EEG abnormalities themselves are believed to contribute to a progressive disturbance in cerebral function.” A number of epilepsy syndromes were listed as providing examples of epileptic encephalopathy, including early myoclonic encephalopathy, early infantile epileptic encephalopathy (Ohtahara syndrome), West syndrome, Dravet syndrome, migrating partial seizures in infancy, myoclonic status in non-progressive encephalopathies, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, and epilepsy with CSWS. The author of this chapter has challenged the term “epileptic encephalopathy,” because it might be taken to imply that there is necessarily some type of permanent brain pathology, which is irreversible. In some cases this may be true; however, in other cases the “encephalopathy” appears to be at least partially reversible. For example, in a report of a series of children with the Landau–Kleffner syndrome (acquired epileptic aphasia) some of the children appeared to recover completely, or almost completely, following the novel surgical procedure of multiple subpial transection (Morrell et al., 1989). What is important is that if the epilepsy itself is causing intellectual impairment in a reversible way, the epilepsy should be treated promptly and effectively, to avoid the possibility of permanent damage (Besag, 2011).
Can ID cause epilepsy?
Intellectual diabilities cannot cause epilepsy. The fact that ID are associated with brain dysfunction increases the probability of epilepsy developing.
Can an underlying disorder result in both ID and epilepsy?
There are several ways in which underlying factors can lead both to epilepsy and ID. Some of these will be discussed here.
Brain trauma
Annegers et al. (1998) surveyed 4541 children and adults with traumatic brain injury involving loss of consciousness, post-traumatic amnesia, or skull fracture. The standardized incident ratio of seizures was 1.5 after mild injuries, 2.9 after moderate injuries, and 17.0 after severe injuries. This study left no doubt about the conclusion that the severity of the brain injury determined the likelihood of subsequent seizures. Because the severity of the brain injury is also linked to the subsequent severity of ID, again, the severity of the ID is likely to be related to the probability of seizure occurrence. In the case of traumatic brain injury, there is a clear-cut cause for both the intellectual impairment and the seizures. In the majority of patients who have both epilepsy and ID, the cause will not be so obvious.
Genetics
Zuberi (2013) commented that epilepsy is now associated with several hundred chromosomal abnormalities. Most of these have not been categorized into a clear clinical phenotype. Many of these disorders are associated with ID and epilepsy together. It would not be unreasonable to describe the variety and number of genetic disorders being identified in people with epilepsy and ID as bewildering. There are, however, some very well-defined syndromes.
Does knowledge of the genetics affect treatment and prognosis? In most cases neither treatment nor prognosis is influenced in a major way by the genetic knowledge, although such information can sometimes be of considerable value in informing genetic counseling. For a small number of genetic syndromes, however, treatment and prognosis can be affected. Most cases of Dravet syndrome (severe myoclonic epilepsy of infancy) are caused by mutations in the SCN1A gene. This is a sodium-channel gene. Antiepileptic drugs that act on the sodium channel tend to make seizures worse in this syndrome. This consequently provides one of the few examples of how knowledge of the genetics might influence treatment. Another example is that of tuberous sclerosis complex, the majority of cases of which are the result of mutations in the hamartin gene on chromosome 9 or the tuberin gene on chromosome 16. The gene abnormality results in cell overgrowth, with tubers in the brain and abnormal cell growth in a number of other tissues, including skin (leading to the characteristic facial fibromas, previously termed “adenoma sebaceum”), kidney, lung, and elsewhere. Both the kidney and the lung disease can be life-threatening. In addition, giant cell astrocytomas may develop and can block the outflow of cerebrospinal fluid (CSF) from the ventricular system, which may lead to hydrocephalus and severe neurological problems. Rapamicin (sirolimus) and the closely related drug everolimus can cause regression in the cell growth with, for example, regression of giant cell astrocytomas (Franz et al., 2006). There is great interest in using these medications to treat the epilepsy itself (Wong, 2010).
Although recent advances in genetics are remarkable, their influence in terms of management remains limited at present. It is interesting to note that the current author made the following comment several years ago: “We have yet to reach the stage at which every epilepsy syndrome has a known gene, perhaps coding for a known channelopathy, allowing the doctor to select the specific, scientifically targeted antiepileptic drug to correct the ion channel defect. Is this what the future holds for the treatment of epilepsy? Time will tell” (Besag, 1999).
Malformations of cortical development
Several malformations of cortical development are associated with the combination of epilepsy and ID (Aronica and Crino, 2014). Localized areas of cortical dysplasia may be amenable to surgical resection, sometimes with improvement not only of the epilepsy but also of cognition and behavior. The extreme example of this is hemimegalencephaly, in which one side of the brain is abnormally large. This malformation sometimes results in a storm of epileptiform electrical discharges from the abnormal side of the brain. Hemispherectomy (removal or disconnection of one half of the brain) can result in seizure freedom, improvement in behavior, and, in at least some cases, improvement of cognition.
Neuronal antibodies
One of the most remarkable advances in the investigation and management of epilepsy has been the discovery of the role of neuronal antibodies, of which the most commonly described are N-methyl-d-aspartate (NMDA) receptor antibodies and voltage-gated potassium-channel complex antibodies. Such antibodies can result in acute deterioration, often with seizures and typically with loss of cognitive skills. Other phenomena, such as mood changes, memory loss, and psychosis can occur (Vincent et al., 2004; Dalmau et al., 2008). Left untreated, some patients will go into coma and die. However, this is a potentially treatable condition, generally responding well to immunotherapy. In general, when managing epilepsy, although it may be possible to control seizures with medication, it is not possible to cure the epilepsy by medical means alone. However, the patient with epilepsy resulting from neuronal antibodies provides an exceptional example of epilepsy that can be cured by medical treatment, namely immunotherapy. Many clinicians may be troubled to reflect on the patients they have seen in the past who almost certainly had an encephalitis caused by neuronal antibodies, which was not diagnosed at the time because the knowledge was not available. This raises the interesting question of whether any person who deteriorates cognitively, in association with seizures or not, deserves to be tested for neuronal antibodies. In the view of the current author, unless there is an obvious cause for the cognitive deterioration, the answer to this question is that they should, indeed, undergo such testing. There is an argument for performing such testing very promptly so that treatment can be instituted before permanent damage occurs.
Why is the combination of epilepsy and ID important?
Refractory epilepsy
Epilepsy in people with ID tends to be more difficult to treat effectively. The probability of achieving seizure control will be less, emphasizing the importance of striking a balance between achieving the best possible seizure control while avoiding adverse effects of medication, notably the cognitive and behavioral adverse effects. For example, the seizures in Lennox–Gastaut syndrome, which is associated with ID, autistic features, and behavioral problems, are generally very refractory to treatment. Because of this, clinicians are tempted to prescribe higher doses and greater numbers of antiepileptic drugs which, in combination with the frequent seizures, impair intellectual abilities to an even greater extent. The general rule when managing epilepsy is to try to avoid polypharmacy. However, it is not uncommon for people with ID and epilepsy to require several antiepileptic medications; when carefully planned attempts are made to tail off any of the antiepileptic medications, the seizures become unequivocally worse, with consequent impairment of the quality of life of the individual. In contrast, it is not unusual to find that when one or more of the antiepileptic drugs is tailed off and discontinued in an individual with epilepsy and ID who is taking polypharmacy, the seizures are no worse and no better. The cognitive and behavioral adverse effects, on the other hand, may be much reduced by this approach. For those antiepileptic drugs that tend to exacerbate psychiatric or behavioral problems, it is particularly important to question whether any antiepileptic drug is improving the situation or making matters worse (Besag, 2001). Some antiepileptic drugs need to be tailed off slowly to decrease the chance of withdrawal seizures; for example, the benzodiazepines and barbiturates.
There are several epilepsy syndromes in which ID is common or even characteristic (Besag, 2004a). Four examples of such syndromes follow.
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