eMedicine Specialties > Neurology > Seizures and Epilepsy

Epilepsy in Children with Mental Retardation

Author: Norberto Alvarez, MD, Assistant Professor, Department of Neurology, Harvard Medical School; Consulting Staff, Department of Neurology, Boston Children's Hospital
Contributor Information and Disclosures

Updated: Aug 29, 2007

Introduction

Background

Traditionally the expression mental retardation (MR) was applied to individuals with significant cognitive deficiencies, and psychometric testing was the main instrument used to establish the diagnosis and to determine the degree of mental retardation. Individuals with an IQ between 55 and 70 were considered to have mild mental retardation; those with an IQ between 40 and 54 were in the moderate range; those scoring between 25 and 39 were considered to have severe retardation; and an IQ below 24 was considered to indicate a profound degree of mental retardation. More modern definitions, such as the one presented by the American Association on Mental Retardation, emphasize the importance of functioning in a social context and levels of needed supports. Most of the information presented in this article is based either on the author's personal experience or on published information, and in most instances the expression mental retardation is used in the most traditional context.

Epilepsy is common in children with mental retardation. Although mental retardation is seen commonly as a unique clinical entity, affected individuals do not conform to a homogeneous group. mental retardation is a syndrome that is secondary to many different etiologies. In some cases, mental retardation is associated strongly with epilepsy; in other instances, epilepsy rarely is seen. The frequency and the severity of the epileptic syndrome are related more to the primary cause of mental retardation than to the severity of mental retardation. However, there is a direct relationship between severity of intellectual disability and frequency and severity of chronic epileptic seizures.

Pathophysiology

In patients with mental retardation, the pathophysiology of epilepsy is related to the cause of the brain damage. Some of the basic principles that apply to individuals without mental retardation also apply to those with mental retardation.

Frequency

United States

Less than 1% of the general population has epilepsy. The prevalence of mental retardation is approximately 0.3-0.8%, but 20-30% of children with mental retardation have epilepsy. Approximately 35-40% of children with epilepsy also have mental retardation. Certain generalizations could be misleading because children with mental retardation do not conform to a homogeneous group. Although some data can substantiate general, valid statements for individuals with brain damage, the incidence and prevalence of epilepsy in patients with mental retardation vary. This finding reflects the different etiologies and pathologies that are responsible for mental retardation.

International

Studies in other countries do not show any significant differences when compared with the United States.

Mortality/Morbidity

A high degree of morbidity is associated with epileptic disorders in individuals with mental retardation.

• Accidents are frequent, and fractures are common. Whether long-term use of antiepileptic medications, which might predispose users to osteoporosis, facilitates the occurrence of fractures is not clear.
• The life spans of individuals with mental retardation, cerebral palsy (CP), and/or epilepsy are shorter than those of the general population. Each of these factors might increase the mortality rate. Establishing the role of epilepsy in the increased mortality rate is difficult; however, the 1995 studies of Crichton et al indicate that individuals with epilepsy and CP have a mortality rate that is twice that of individuals with CP and no epilepsy.¹
• The risk of sudden unexpected death is significantly higher in persons with mental retardation when compared with persons without mental retardation.²

Race

Race does not appear to have any role in the incidence of epilepsy in people with mental retardation.

Sex

More males than females have mental retardation; however, with the exception of sex-linked causes of mental retardation such as Rett syndrome in females or fragile X syndrome in males, sex appears to play no role in the expression or severity of the epileptic disorder in individuals with mental retardation.

Age

The age at the first epileptic seizure relates to the cause of mental retardation.

• One study, which included 98 children with mental retardation aged 6-13 years, found that the average age at the time of the first seizure was 1.3 years for the whole group, 0.8 years in children with severe mental retardation, and 3.1 years in those with mild mental retardation.
• Another study including adults with mental retardation found that, of 63 individuals, 41% had a first seizure before the second year of life and 30% had a first seizure between ages 2 and 20 years. The most severe convulsive disorders were seen in children who developed epilepsy at an early age and in those with CP. The epileptic disorders were more benign when the seizures started in adulthood.
• In a group of noninstitutionalized individuals, the prevalence of epilepsy was 20%; epilepsy and mental retardation, 43%; and epilepsy associated with CP, 33%. The epileptic disorders were more severe in individuals with a more severe degree of mental retardation.³

Clinical

History

To facilitate discussion of the subject, the epileptic disorders are presented in relation to discrete pathogenetic entities.

Epilepsy and neurocutaneous syndromes

• Approximately 80% of children with tuberous sclerosis (TS) have some form of epileptic seizures, and mental retardation is seen in 60%. In most instances, the first epileptic seizures are seen before the second year of life and are the presenting sign in most patients.
• Mutations in the tumor-suppressor genes TSC1 or TSC2 lead to the proliferation of the typical hamartomas of the TS complex (TSC). Mental retardation and epileptic seizures are important components of the complex. However, not all of the individuals affected with TSC present with seizures or with mental retardation. In terms of cognitive outcome, individuals with seizure onset after the age of 2.5 years have a better cognitive outcome than those whose seizures started before that age. Also, refractory seizures and the presence of the TSC2 mutation correlate with poor cognitive function.
• The epileptic disorder is often severe and resistant to the treatments available, with a very low remission rate. Multiple seizure types, mental retardation, multifocal abnormal EEGs, and many cortical tubers are poor prognostic indicators. The children with few cortical tubers, normal intelligence, and normal EEG have a better prognosis.
• Various epileptic disorders have been described in children with TS, but infantile spasms, characterized by hypsarrhythmia on the EEG, is the most common presentation in approximately 50% of children with TS. On the other hand, TS is associated with 20-30% of all cases of infantile spasms. As these children age, the epileptic disorder changes; in some children, Lennox-Gastaut syndrome, characterized by a combination of tonic-axial, atonic, atypical absences, and myoclonic seizures, emerges. In older children and in those in whom the first seizure started after the second year of life, complex partial or secondary generalized seizures predominate. In older children and young adults, complex partial seizures are the predominant type.
• EEG findings are abnormal in most instances, with a variety of epileptiform discharges such as multifocal discharges, focal discharges with temporal lobe predominance, hypsarrhythmia, and generalized spike and wave discharges. The prognosis in terms of seizure management is generally poor, and the epileptic disorder tends to remain active for many years in spite of medications.
• An interesting observation is that vigabatrin (GABA-transaminase inhibitor) is particularly effective in the treatment of the infantile spasms in children with TS, much better than other anticonvulsant. This might indicate that the neurophysiological mechanism that leads to the epileptic seizure and the infantile spasm syndrome might be different in children with TS.
• Of individuals with TSC, 25-30% develop intractable seizures. Some of these individuals might benefit from surgery when the epileptogenic areas are well defined. In some of these individuals, the presurgical evaluation is made difficult because of the presence of several tubers distributed in both hemispheres. Tubers are often localized in the grey/white matter border and they have been considered the origin of the epileptic foci; however, if the epileptogenic foci is in the tuber itself or in adjacent areas is not known. In some patients, the seizures remained even after complete surgical removal of the tubers. Not all the tubers are alike, and, even in the same individual, they are different from each other in terms of epileptogenicity. 
  
  Seizures are known to arise from the vicinity of the tubers. Ictal and interictal EEGs might not be enough to identify the tubers and the cortical regions to be excised. In these individuals, more invasive neurophysiologic tests (techniques that have some inherited risks), such as intracranial EEG recording, are indicated. Recently, newer noninvasive neuroimaging techniques, such as magnetoencephalography (MEG), alpha-methyl-L-tryptophan (AMT) positron emission tomography (PET), and diffusion tensor imaging (DTI).¹⁸ fluoro-2-deoxiglucose (FDG) PET coregistered onto the MRI and DTI might help identify the epileptogenic areas in individuals with TSC without the need to use invasive intracranial procedures. Uptake of AMT on PET by the tubers correlates with the epileptogenesis of the tubers.
• Surgery with removal of the epileptogenic tuber should be considered in every individual with TS who does not respond to treatment. Even though the surgical outcomes vary, surgical series showed a marked improvement in a substantial number of children.

Struge-Weber syndrome

• In the Sturge-Weber syndrome, the brain damage responsible for the seizure disorder results from the chronic cortical ischemia secondary to the venous vascular malformations on the meninges. This angiomatosis is usually in the same side as the facial angiomatosis, and rarely occurs on the opposite side or bilaterally.
• The brain damage, which progresses with time, is associated with hemiparesis in 30% of cases and with mental retardation in 50-60%. In general, mental retardation and epileptic seizures are correlated. The epileptic disorder might be seen in the first year of life, even before the child develops hemiparesis. Focal motor seizures contralateral to the side of the hemangioma, which might or might not be followed by secondary generalization, are the most common type of epileptic seizures. EEG results are abnormal, with spike and wave discharges coming from the affected areas.
• In many instances, the epileptic disorder remits or is well controlled with antiepileptic medications. For cases in which the seizures are poorly controlled, surgery for removing the atrophic brain areas is indicated. In children with extensive hemispheric lesions, total hemispherectomy early in life is the best treatment course; this procedure not only improves seizure control, but it also arrests the intellectual deterioration that is associated with the intractable seizure disorder.

Neurofibromatosis I

• Neurofibromatosis I is associated with epileptic seizures in 3-5% of patients. Seizures generally are not a major problem, but given the association of the disease with intracranial tumors, these children require a complete evaluation.

Incontinentia pigmenti

• Incontinentia pigmenti is observed mostly in females, is characterized by seizures, mental retardation, and generalized spasticity in 10-15% of patients.

Autism

• Approximately 20-30% of children and adolescents with autism develop some form of epileptic disorder. The seizures are observed more frequently in patients with more severe mental retardation. In a small group of children with autism and language regression, the regression was associated with the development of epilepsy and/or paroxysmal activity in the EEG. In some cases, the clinical regression improved with steroids and/or anticonvulsant medication.

Rett syndrome

• Rett syndrome is a major cause of severe mental retardation associated with seizures in girls. It is characterized by a progressive mental and growth retardation that starts in infancy.
• The girls develop an autismlike syndrome with stereotyped movements, some of which, especially those in the hands, are considered very typical of the disease. Epileptic seizures are seen in 25-30% of cases, mostly generalized and complex partial. Few seizures consist of infantile spasms or myoclonic epilepsy.
• The stereotypical behaviors are often difficult to differentiate from epileptic seizures. For example, vacant stare and periods of apnea could be misdiagnosed as epileptic events.

Cerebral palsy

• Epileptic seizures occur in 25-50% of children with cerebral palsy (CP). The incidence is related to the severity of the cortical damage. It is higher in those children with quadriplegia, lower in those with congenital hemiplegia, and much lower in children with diplegia and the dyskinetic form of CP.
• The presence of epileptic seizures is generally related to the extent of involvement of the neocortex and the limbic systems. The risk of seizures by the age of 5 years in children with mental retardation alone is around 8%; for children with mental retardation and CP, this figure increases to almost 70%. However, in children with severe CP but without mental retardation (ie, those with mostly white matter involvement), the incidence of epilepsy is the same as in the general population.
• The epileptic disorder might start at any age, but the first epileptic seizures typically are seen during infancy. The seizure disorder is the consequence of the brain abnormalities associated with the CP, but genetic factors are also important in the development of epileptic seizures in these children. Whether seizures in early life produce more neuronal damage is not clear, but clinical studies indicate that early seizures are associated with more cognitive deficiencies; however, severe seizures per se are responsible for progressive cognitive deterioration in children with CP.
• When neurological symptoms progress, suspect another etiology. Practically every type of epileptic seizure has been described in individuals with CP. Generalized tonic and tonic-clonic seizures and partial complex seizures with or without secondary generalization are observed most frequently; myoclonic seizures and atonic seizures are also common. Typical absence seizures are observed less frequently in children with CP. Some syndromes, such as infantile spasms and Lennox-Gastaut syndrome, are particularly frequent in children with CP.

Malformations of cortical development

• This is a group of disorders characterized by a prenatal disruption in neuronal proliferation, migration, or organization. Although these disorders are described together, the clinical manifestations and the etiologies responsible for these deficiencies are very different. In some instances, genetic disorders have been demonstrated; in most cases, however, the etiology remains unrecognized.
• Mental retardation, epilepsy, and other sensory and motor deficiencies frequently are associated in one particular syndrome. The advent of MRI has facilitated the identification of these malformations. Between 20% and 25% of children with intractable epilepsy might have these malformations. Several instances of partial epilepsies are associated with these cortical malformations. For example, the number of heterotopic neurons is increased in the temporal lobe of persons with intractable seizures when compared with controls without epilepsy. Hemimeganencephaly, characterized by enlargement of all or part of a cerebral hemisphere, is associated with mental retardation and usually severe, poorly controlled seizures. Infantile spasm and intractable partial seizure are seen frequently.
• Focal cortical dysplasia is characterized by local neuronal abnormalities, lack of normal lamination in the cortex, abnormal giant neurons, and abnormalities in dendrites and axons. The clinical picture consists of a combination of seizures, usually focal with secondary generalization, that respond poorly to treatment. A mild degree of mental retardation may be noted. These individuals might be good candidates for surgery.
• Congenital bilateral perisylvian syndrome is characterized by the presence of polymicrogyria in the perisylvian area. Epileptic seizures and mental retardation are seen in most of these patients. The clinical seizures are a combination of generalized tonic-clonic seizures, typical and atypical absences, as well as tonic and atonic crisis. The seizures are very resistant to medical treatment, and in some instances, splitting of the corpus callosum is indicated.
• Double cerebral cortex syndrome is characterized by the presence of a heterotopic band of gray matter below the cerebral cortex.
  • Most of these patients have mental retardation, the severity of which is related to the severity of the underlying cortical malformation.
  • The epileptic disorder also varies in severity depending upon the degree of the cortical disorganization.
  • Some patients present with hypsarrhythmia in early life, followed by the Lennox-Gastaut syndrome.
  • Generalized as well as focal seizures also are seen.
  • The treatment is partially effective, and some patients might improve with callosotomy.
• Schizencephaly is a major component in several syndromes.
  • The brain malformation is characterized by clefts in the surface of the brain, usually bilateral, that can be seen in different areas of the brain but are more frequent in the parietal areas. When the disorder is unilateral, the neurological complications might not be important. Clinical abnormalities vary from normal development to severe cognitive impairment and marked CP.
  • The neurological picture and the convulsive disorder are more severe when the malformation is bilateral. The epileptic disorder might be characterized by a predominance of focal seizures with secondary generalization. Infantile spasms are much less frequent, and not all the patients develop seizures. In some cases, the origin of the seizures is in a focal area that, if identified, can be excised.
• Lissencephaly might be the result of abnormalities in chromosome 17. Some cases have X-linked recessive inheritance patterns, and some are seen in association with congenital muscle dystrophies and other syndromes.
  • The cortex is characterized by the paucity or lack of cortical sulci, and malformations are present in the border areas between the white and the gray matter. Patients generally have marked developmental delay, and the seizures are refractory to treatment.
  • Infantile spasms as well as generalized tonic-clonic and complex partial seizures are frequent.

Chromosomal disorders

Several chromosomal disorders are frequently associated with mental retardation and epilepsy. In some instances, specific dysmorphic features might help to establish the diagnosis. Besides the benefits of knowing the precise diagnosis, the identification of these chromosome abnormalities associated with epilepsy might help to identified genes that are involved in the development of epilepsy. The most common ones are discussed here.

• Fragile X syndrome is one of the most common chromosomal abnormalities in males with mental retardation. The children might present with macrocephaly, elongated faces with large forehead, elongated earlobes, and family history of mental retardation (mostly in males). The diagnosis is confirmed by the presence of the FMR-1 mutation. Epilepsy started very early in life with a syndrome that clinical and EEG wise is similar to benign partial epilepsy of infancy with centrotemporal spikes. This is an age-limited process and is not seen in adults. The seizures respond well to antiepileptic treatment.
• Angelman syndrome often results from maternally inherited deletions in chromosome bands 15q11-13 (class I). In rare instances, it is due to other chromosomal abnormalities, including the following:
  • Paternal uniparental disomy, in which both chromosome bands 15q11-13 are inherited from the father (class II)
  • Methylation imprinting abnormalities (class III)
  • Mutation in the UBE3A gene (class IV)
  • Notably, the phenotype is similar in all these different types, although the epileptic disorder varies in severity. Patients with class I have severe intractable epilepsy, mostly myoclonic seizures and atypical absences; atonic, generalized extensor tonic, flexor spasms, and secondary generalized tonic-clonic seizures also have been reported.
  • A study involving 19 individuals with the phenotype of Angelman syndrome and the genotype of deletion of the chromosome 15q11-13 showed that generalized seizures were seen in all of the patients, partial seizures in 10 patients, and all the patients had more than one seizure type. The most common were atypical absences (84%), myoclonus (68%), generalized tonic clonic seizures (63%), simple partial (32%), complex partial (26%), and myoclonic-astatic (11%). The seizures are observed early in life (around age 1 y) at the time in which the phenotype is not clearly expressed; Angelman syndrome is usually diagnosed several years after.
    
    Febrile episodes might be the precipitant of the first seizures and, in general, febrile diseases are associated with worsening of the seizure disorder. Status epilepticus is a frequent complication and the seizures are refractory in most of the patients. Few achieve full seizure free status; however, as the patients get older, the variety of seizures has a tendency to decrease, indicating that the severity of the seizure disorder is age dependent, with more severe seizures in early childhood and infancy. In most instances, the epileptic disorder remains active even in adults.
  • The abnormal movements might be difficult to diagnose as an epileptic event, since they often are not correlated directly with the epileptiform activities.
  • Even though epileptic seizures are common and often uncontrolled in children with Angelman syndrome, few randomized studies of AED in the treatment of these patients have been performed. The information available suggests that VPA, phenobarbital, and benzodiazepines are the most effective in the treatment of seizures in these children. Some data suggest that ethosuximide, alone or in combination with valproic acid, might be effective, mostly in the treatment of the atypical absences. Topamax might be other useful medication. Several reports documented a deterioration in the epileptic disorder with carbamazepine, oxcarbazepine, and vigabatrin. The ketogenic was effective in few patients that were tried.
• Children with Down syndrome present with infantile-spasm–like disorders in early life that usually arrest. In the absence of other congenital malformation, children with Down syndrome, even those with profound mental retardation, do not present with serious epileptic disorders.
• In patients with chromosome 15 inversion-duplication syndrome, a tetrasomy dose effect occurs in the 15q11-13 region (the same involved in Angelman and Prader-Willi syndrome). The syndrome is characterized by profound mental retardation, microcephaly, autistic features, and no obvious dysmorphic features. Epilepsy is severe, starting in the first few months of life, and is characterized by a mix of infantile spasms, atypical absences, tonic and atonic seizures, and an EEG shows hypsarrhythmia. Less severe cases with the first manifestations of epilepsy in adulthood have been reported.
• Wolf-Hirschorn syndrome is associated with chromosome 4p deletion. Partial motor seizures, and myoclonus or atypical absences triggered by eye closing, are usually seen in the first year of life. EEG showed generalized epileptiform discharges, activated by closing the eyes, and multifocal discharges. Dysmorphic features that might lead to the diagnosis are severe mental deficiency, microcephaly, “the Greek warrior helmet nose,” hypertelorism, and large ears. Cardiac malformations are common. Many children die in the first year of life. Valproate acid is useful while carbamazepine might aggravate the seizure disorder.
• In ring chromosome 20 syndrome, the epileptic disorder starts early in childhood and is usually intractable. The seizures are easily triggered by psychological stress and can be diagnosed as nonepileptic events. Periods of confusion associated with epileptiform abnormalities can be prolonged (lasting 20-30 minutes). Interictal EEG tracings can be normal or limited to slow spike wave complexes with some spikes mostly in the frontal regions. The abnormalities are seen in the early stages of sleep and might not be seen later.
• Epileptic disorders can be seen in children with other chromosomal aberrations such as a deletion of the long arm of chromosome 1 and trisomy 9p.

Causes

• In persons with mental retardation, the diagnosis of epilepsy presents unique difficulties. The patients generally are not able to describe the epileptic events, and the physician or someone trained in epilepsy observe the events only rarely. The clinical manifestations often are observed by people (eg, teachers, parents) who are not familiar with epileptic disorders.
• Patients with mental retardation frequently present with behaviors that resemble epilepsy. Examples include the following:
  • Generalized tonic extension crisis in children with severe spasticity, resembling generalized tonic seizures, is observed frequently in response to external stimuli.
  • Gastroesophageal reflux might produce generalized tonic extension (Sandifer syndrome) in some cases.
  • In children with severe quadriplegia, a similar clinical response can be seen as a consequence of chronic constipation or pain.
• Episodes of unresponsiveness frequently are seen in individuals with mental retardation. The patient's behaviors closely resemble absence seizures, ie, the patient is very quiet with the eyes fixed, no expression on the face, and slow responses.
• Stereotyped movements (eg, nodding the head, odd hand postures, complex mannerisms, rocking, spinning, waving or flapping hands) are also a potential cause of misdiagnosis.
• A source of confusion is the frequent association of mental retardation and psychiatric disorders. Self-injurious behavior is common in children who already have an active epileptic disorder. These cases often are referred to the neurologist to rule out seizures of frontal or temporal origin.
• Patients with mental retardation often take psychotropic medications, and some of the adverse effects, such as oculogyric crisis and dystonias, can be confused with epileptic events. Psychotropic medications might decrease the threshold for epileptic seizures, but this is not a contraindication for the use of these drugs in individuals with epileptic seizures and psychiatric disorders when these medications are indicated.
• Suddenly discontinuing antiepileptic medications might be associated with withdrawal seizures.
• In the few studies that evaluated the presence of pseudoseizures in people with mental retardation, 20-30% of individuals who were referred for evaluation of epilepsy had behaviors that resembled seizures but did not have an epileptic origin. The most common behaviors that were mistaken for epileptic seizures were myoclonus, absence spells, temper tantrums, and aggressive behaviors.
• Nonepileptic seizures (pseudoseizures) should always be considered in any individual with drug-resistant epileptic behaviors. In many instances, these behaviors are not epileptic in origin, and the use of antiepileptic medications does not help to control them but does add more side effects. The presence of an active epileptic disorder does not rule out the presence of nonepileptic events because they are frequently seen together. It these cases, it is important to diagnose the nonepileptic events as such in order to avoid unnecessary polypharmacy.

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