AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

People with mental retardation do not conform to a homogeneous group. Frequency, characteristics, and prognosis of the epileptic disorder in these individuals are strongly related to the cause of mental retardation. Identification of the cause of mental retardation facilitates understanding of the epileptic disorder. Thus, it makes more sense to discuss epilepsy in individuals with mental retardation in the context of well-defined clinical entities. (See Epilepsy in Children with Mental Retardation where a similar approach has been presented.)

However, some general principles applied to this group of individuals. First, epilepsy is the most common comorbid medical condition in persons with developmental disabilities. Second, approximately 1% of the general population has epilepsy; this rate is similar to the prevalence of mental retardation. However, 26% of children with mental retardation also have epilepsy, 37% of children with epilepsy also have mental retardation, and 50% of people with mental retardation and cerebral palsy have epilepsy. The incidence of epilepsy is related to the severity of the intellectual impairment. The rate is around 20% in persons with mild intellectual impairment and can be as high as 50% in those with severe-to-profound intellectual disability. The epileptic disorders are usually complex, involving more than 1 seizure type and being more difficult to treat than disorders in the general population.

The patient’s prognosis is related to the degree of neurologic involvement. Full seizure control is least frequently achieved in individuals with severe intellectual and motor deficits. Because freedom from seizures might be difficult to achieve in many of these individuals, the success of the antiepileptic therapy should not be measured on the number of seizures alone. Aggressive treatment to achieved full control might result in adverse effects that limit the patient’s quality of life.

The rate of sudden, unexpected death is higher in individuals with mental retardation and epilepsy than in the general population; however, the reason is unclear.

For more information, see Medscape's Epilepsy Resource Center.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Neurocutaneous syndromes - Tuberous sclerosis
• • Tuberous sclerosis complex is an autosomal dominant disorder with a predominance of around 1 case in 6000-10,000 population. Two genes, TSC1 and TSC2, are associated with the complex. In a good number of cases, the tuberous sclerosis is the result of spontaneous genetic mutations.
  • The clinical manifestations are protean, and many systems are involved. Abnormal neurologic disorders include autism, mental retardation, seizures, and behavior disorders.
  • Cortical and subependymal tubers, astrocytomas, neural migration disorders, and hamartomas, among other entities, are frequently seen in persons with tuberous sclerosis.
  • Most of the reported studies refer to mainly children, approximately 80% of whom have some form of epileptic seizures; mental retardation affects 60%.
  • In childhood, infantile spasms (ie, hypsarrhythmia) are the most common presentation. As children age, the epileptic disorder changes and, in some, evolves into Lennox-Gastaut syndrome. In older children and young adults, complex partial seizures are the predominant type.
  • With the exception of typical absences, all types of epileptic seizures have been described in persons with tuberous sclerosis.
  • EEGs are abnormal in most instances, with a variety of epileptiform discharges.
  • Hypsarrhythmia is seen in mostly children (and not in adults) and characterized by generalized spike-and-wave discharges and multifocal discharges (which are focal with temporal-lobe predominant). Tuberous sclerosis is the most frequent cause of infantile spasms.
  • In general, the prognosis in terms of seizure management is poor. The epileptic disorder tends to remain active for many years despite medication.
  • Vigabatrin, a medication not available in United States, have been reported to be effective in the treatment of infantile spasms in children with tuberous sclerosis.
  • Surgery might be an option in selected cases. Because affected individuals usually have many different lesions, determining the active lesion is difficult. However, when it is identified, surgical excision might be effective in achieving a free-seizure state for some patients. A systematic review of the literature regarding postsurgical outcome in patients with tuberous sclerosis showed that selective surgery resulted in seizure freedom in 57% of the patients who had undergone operation and improvement in seizure frequency by greater than 90% in another 18% who had undergone operation.¹ These results are encouraging. Patients with tuberous sclerosis and intractable seizures should be considered candidates for surgery.
• Neurocutaneous syndromes - Sturge-Weber-Dimitri syndrome
• • The brain damage responsible for the seizure disorder is the result of chronic cortical ischemia secondary to venous vascular malformations on the meninges. This angiomatosis is usually on the same side as the facial angiomatosis and rarely on the contralateral or bilateral.
  • Brain damage progresses with time and is associated with hemiparesis in 30% of cases and mental retardation in 50-60%. Hemisensory deficits are most common in adults.
  • In general, mental retardation and epileptic seizures are correlated.
  • Focal motor seizures contralateral to the side of hemangioma, which might or might not be followed by secondary generalization seizures, are the most common type of epileptic seizures.
  • EEG findings are abnormal, with spike and wave discharges coming from affected areas. Poorly organized background and excessive slowing are frequently observed in damaged areas.
  • In many instances, the epileptic disorder remits or is well controlled with antiepileptic drugs (AEDs).
  • When seizures are poorly controlled, surgical removal of atrophic areas of the brain is indicated.
  • Most surgeries are performed in childhood. For many years, adults with mental retardation were not considered candidates for surgery; however, some adults with this syndrome may benefit from surgery.
• Neurocutaneous syndromes - Neurofibromatosis I
• • Only about 3-5% of patients have associated epileptic seizures.
  • Generally, epilepsy is not a major problem but, given the association with intracranial tumors, these patients require close follow-up when seizures are poorly controlled.
• Cerebral palsy
• • Epileptic seizures are frequently observed in children and adults with cerebral palsy. The incidence is related to the severity of brain damage; it could be as high as 70% in those with the hemiplegic form and 15-20% in those with the diplegic and dyskinetic forms of cerebral palsy. Cerebral palsy is the most common disorder in which mental retardation is associated with epilepsy.
  • In general, the presence of epileptic seizures is related to the extension of involvement of neocortex and the limbic system.
  • Cumulative risk for epilepsy in young adults (aged 22 y) with mental retardation is reported as 15% or 5.2% in those with no disability, increasing to 38% in those with cerebral palsy. The highest risk of 66% is observed in patients who had a postnatal injury.
  • Epileptic disorders might start at any age; however, in most instances the first epileptic seizures are seen during infancy.
  • Seizure disorders are the consequence of brain abnormalities associated with cerebral palsy; however, genetic factors are also important in the development of epileptic seizures.
  • Whether seizures in early life produce more neuronal damage than seizures later in life is not clear, but clinical studies reveal clearly that early seizures are associated with more cognitive deficiencies.
  • However, exceptionally severe seizures per se are responsible for progressive cognitive deterioration in patients with cerebral palsy. If progression of neurological symptoms is observed, then another etiology should be suspected.
  • Practically every type of epileptic seizure has been described in people with cerebral palsy. Generalized tonic, tonic-clonic, and partial complex seizures with or without secondary generalization are observed most frequently. However, myoclonic seizures and atonic seizures also are seen frequently. Typical absences are the least frequent type of seizure disorder in children with cerebral palsy. Some syndromes, such as Lennox-Gastaut, are particularly frequent in adults with cerebral palsy.
  • Most intractable seizure disorders in adults with mental retardation are associated with cerebral palsy.
• Malformations of cortical development
• • This group of disorders is characterized by a congenital deficiency in neuronal proliferation, migration, or organization. These disorders are described in the chapter Epilepsy in Children with Mental Retardation.
  • The advent of MRI has facilitated identification of these malformations, and as many as 20-25% of children with intractable epilepsy are believed to have these malformations. Most published articles describe these disorders in children; however, the same conclusions should apply for adults.
  • A retrospective evaluation of MRIs obtained in 303 patients with epileptic seizures, aged 12-41 years, demonstrated that 4.3% had migrational disorders. Among the people with mental retardation, the incidence was 13%.
  • In some cases, the first manifestation of epileptic seizures associated with these malformations occurred in adulthood.
• Autism
• • Approximately 20-30% of children and adolescents with autism develop some form of epileptic disorder.
  • Seizures are observed frequently in autistic patients with severe mental retardation.
  • In a small group of children with autism and language regression, the regression was associated with development of epilepsy or paroxysmal activity in the EEG.
  • In some cases, the clinical regression improved with steroids or anticonvulsant medication.
  • A prospective study involving 120 individuals with an autism diagnosis, mostly limited to persons with moderate to severe degree of mental retardation (individuals with Asperger syndrome were not included) that were observed for a period of 13-22 years showed that the lifetime occurrence of epilepsy was around 38%. Epilepsy was more often seen in females and in those with a severe degree of mental retardation. The presence of epileptic seizures was associated with poor social functioning, poor employment record, the persistence of the autistic features throughout their whole life, and more dependency for activities of daily living. In most instances, the epileptic disorder started in early life and in one third of individuals, the first seizure was already present before age 2 years. In a few individuals, however, the epileptic disorder started after age 18 years.²
• Chromosomal disorders
• • Fragile X syndrome, one of the most common chromosomal abnormalities in males with mental retardation, is associated with focal seizures of rolandic type. This is an age-limited process and not seen in adults. Seizures respond well to antiepileptic treatment. Follow-up of patients into adulthood reveals the transformation of partial seizures into generalized seizures.
  • Rett syndrome is the most common condition associated with mental retardation in girls. It is characterized by progressive mental and growth retardation. The infant has normal development until age 6-18 months and then has progressive deterioration in functions with marked regression and loss of skills. A peculiar hand movement, even though not diagnostic, is very characteristic of the disease. Other clinical features include deceleration of the head growth, loss of motor skills, mental retardation, autonomic dysfunction with particular changes in the respiratory patterns, and hyperventilation followed by apneas.
  • • This syndrome is well described in children in whom epileptic seizures, in many instances refractory to treatment, are seen (50-90% of cases); in most instances starting in this starts in infancy, as early as in third month of life, and by the age of 10 years, 70-80% of the patients that would have developed seizures already have them. Very few individuals will have the first seizure in adulthood.
    • The seizures are mostly generalized and complex partial. In a small number of individuals, seizures consist of infantile spasms or myoclonic epilepsy.    
    • The risk of seizures is higher in those patients who never walk and in those who present with developmental delay in the first 10 months of life.
  • • Less information is available in adults than children because, in some cases, the epileptic disorder improves with age.
    • Cases of seizures that are difficult to control are also reported.
    • Diagnosis of Rett syndrome is possible by sequencing the MECP2 gene on the X chromosome. Sequencing detects 99% of mutations. Some of these mutations (pR294X, pR255X and C terminal mutations) might be associated with lower seizure rate.³
    • Use of this new diagnostic test helps define clinical manifestations of Rett syndrome in women. Many women with mental retardation of unknown etiology might have atypical Rett syndrome.
    • Many epileptic medications have been used in these patients. A recent study suggest that carbamazepine was the most effective drug and it was recommended as first choice. Sulthiame (a drug not approved in the United States) and valproic acid were also effective.
  • • Besides improving seizure control, topiramate might also improve the respiratory abnormalities frequently present in this syndrome.
  • Epileptic seizures in adults in their late 40s with Down syndrome are seen as an expression of Alzheimer disease, which occurs with greater frequency in individuals with Down syndrome than in the general population. See Alzheimer Disease in Individuals With Down Syndrome.
  • • Generalized tonic-clonic seizures are mostly isolated events. Status epilepticus is sometimes seen, but myoclonus is the most common manifestation.
    • In advanced cases, myoclonic seizures are almost constant. These seizures are difficult to control with medication. External stimulation frequently elicit these seizures.
    • EEG findings are normal at the beginning of the disease; however, as the disease progresses, background activity slows generally. Frontal intermittent delta activity can be seen in many cases. In advanced stages, EEG is poorly organized, with predominance of slow theta and mostly delta activity.
    • Photomyoclonic response develops in many cases.
  • Angelman syndrome, in most instances, is the result of deletions in chromosome band 15q11-13 inherited from the mother (class I). In rare cases, it is due to other chromosomal abnormalities. Examples are paternal uniparental disomy, in which both chromosome bands 15q11-13 are inherited from the father (class II), methylation imprinting abnormalities (class III), and mutation in the UBE3A gene (class IV).
  • • The observation that the phenotype is similar in all types of Angelman syndrome is interesting; however, the epileptic disorder varies in severity.
    • Patients with class I syndrome have severe, intractable epilepsy (mostly myoclonic seizures and atypical absences), but atonic, generalized extensor tonic, flexor spasms, and secondary generalized tonic-clonic seizures have also been reported.
    • Abnormal movements might be difficult to diagnose as an epileptic event; in many instances, these are not directly correlated with epileptiform activities.
    • Background activity in the EEG tends to be normal in adults; however, paroxysmal activities do persist.
    • Epileptic disorder in adults with Angelman syndrome may be resistant to AEDs.
    • Severity of the epilepsy does not correlate to the particular molecular diagnosis.
    • The severity of the epileptic disorder improved after age 8.5 years.
    • Valproic acid and clonazepam can be effective treatment.

Causes

Differential diagnosis of adults with mental retardation who have epileptic seizures is, in general, no different from the differential diagnosis in individuals without mental retardation. That is, concomitant disorders such as trauma, tumors, and infections should be considered. However, diagnosis of epilepsy in persons with mental retardation presents unique difficulties that are discussed here.

• Nonepileptic events
• • Probably the most common and unrecognized pitfall in diagnosing the cause of seizures in patients with mental retardation is related to the high incidence of nonepileptic events (pseudoseizures) in this population. Nonepileptic events have been documented in 30-40% of individuals with mental retardation referred for evaluation of epilepsy.
  • Studies performed in adults with mental retardation and epilepsy identified the following as potential sources of diagnostic confusion: nonepileptic myoclonus; movement disorders or tonic reflex posturing, with or without gastroesophageal reflex; sleep disorders (eg, obstructive sleep apnea, restless leg syndrome); and stereotyped behaviors, including self-injurious behavior.
• Comorbidity with psychiatric disorders
• • Psychiatric disorders are seen in 30-40% of individuals with mental retardation. Some manifestations of psychiatric disorders might be confused with epileptic events. On the other hand, psychiatric disorders, mostly in individuals with a severe and profound degree of mental retardation, might be misdiagnosed as epileptic events.
  • Dual effects of some AEDs, which also are effective in psychiatric disorders, add to the confusion.
  • Psychotropic medications might decrease the threshold for epileptic seizures. Some of the adverse effects of psychotropic medications might resemble seizures (eg, myoclonus). Some of these medications might predispose to postural hypotension and syncopal attacks.
• Characterization of epileptic seizures
• • Characterization of epileptic seizures and epileptic syndromes in this population is very difficult. Most of the time, patients are not able to describe the epileptic crisis. In most instances, the crisis is observed by persons (teachers, parents) who are not familiar with epileptic disorders; only in exceptional situations does the physician or someone trained in epilepsy see the clinical event.
• • Short-lasting epileptic events, or epileptic seizures manifested mostly by subjective symptoms, are very difficult to diagnose in this population.
• • Frequently, more than a single seizure type is seen in the same person. In patients with intractable seizures, Lennox-Gastaut syndrome is predominant; symptomatic generalized epilepsy and partial epilepsies also are frequent. Partial complex seizures are not infrequent and are probably more frequent than generalized absence seizures.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Malformations of cortical development
Autism
Fragile X syndrome
Rett syndrome
Angelman syndrome
Complex partial status epilepticus
EEG in sleep disorders
Myoclonus

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Several tests are indicated in evaluation of children with mental retardation.
• • Urine should be examined for amino acids, organic acids, mucopolysaccharides, oligosaccharides, reducing substances, ferric chloride, sodium nitroprusside, and dinitrophenylhydrazine.
  • Blood should be examined for amino acids, lactate and pyruvate, ammonia, and very-long-chain fatty acids.
  • CSF should be tested for lactate and pyruvate quantification (not a routine test).
  • Chromosomal studies should be performed.
• These tests are usually requested even in those patients who do not have epilepsy.
• With adults patients, do not assume that these tests have already been performed.

Imaging Studies

• Neuroimaging studies are indicated in practically every patient with mental retardation, because many adults born before these tests were introduced into medical practice did not have a neuroradiologic evaluation. When seizures are a problem, these tests are indicated.
• MRI is probably the best test for evaluation of congenital malformations of the brain as well as deficiencies in white and gray matter. If the patient is cooperative, this is the best test for evaluation purposes.
• CT scan is also useful for the same purpose and is indicated when MRIs cannot be obtained.
• Arteriograms and magnetic resonance angiography have more limited indications, mostly in preoperative evaluation of patients with intractable seizures.
• Positron emission tomography (PET) and single photon emission CT (SPECT) studies might be more sensitive than MRI for diagnosis of areas of the brain where metabolic disorder is more important than structural abnormalities (eg, small cortical dysplasias that show hypometabolism). These tests are most relevant in presurgical evaluation of patients with intractable seizures.

Other Tests

• EEG combined with the clinical picture is central to the diagnosis of epilepsy. This subject is discussed in Epilepsy in Children with Mental Retardation; EEG findings in epileptic disorders are described in other articles (see Differentials).
• EEG combined with the clinical picture is central to the EEG changes observed in persons with mental retardation and epilepsy are, in general, similar to the ones observed in individuals with epilepsy without mental retardation.
• Some syndromes, such as hypsarrhythmia and Lennox-Gastaut, which have particular EEG features, are seen more often in individuals with mental retardation.
• Some EEG patterns, such as electrical status epilepticus of slow-wave sleep (ESES), also known as continuous spike-wave discharges during slow-wave sleep (CSWS), are associated with intellectual impairment; however, the cause of deterioration is not clear and might not be related to EEG changes.
• Long-term closed-circuit television videotaping and digitized EEG telemetry (CCTV-EEG) is becoming a standard technique for documenting the diagnosis of epilepsy; it is particularly useful in diagnosis of nonepileptic events and in presurgical evaluation of patients with intractable seizures. These techniques require full cooperation from the patient and might be difficult to perform in some cases. Deep sedation, which is often needed, might limit the usefulness of CCTV-EEG.
• Sleep deprivation and special hats embedded with electrodes facilitate the recording of routine EEGs.

TREATMENT

Section 6 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Medical Care

The same basic principles that guide the treatment of epileptic disorders in persons without mental retardation also apply to persons with mental retardation.

Monotherapy is the ideal treatment, and polytherapy should be used only when no other options are available. Several AEDs can be used as the first drug in the treatment of epileptic disorders. No final guidelines are available to determine the first drug to use in any particular patient, but the American Academy of Neurology (AAN)/American Epilepsy Society (AES), the International League Against Epilepsy (ILAE), and the United Kingdom's National Institute for Clinical Excellence (NICE) have published guidelines for the use of AEDs in persons who develop epilepsy. These guidelines are evidence-based and reflect published studies. The guidelines of the 3 organizations do not have major differences. For example, in newly diagnosed partial seizures, the AAN/AES recommend starting with one of the established drugs such as carbamazepine, phenytoin, phenobarbital, or valproic acid or some of the newer drugs such as oxcarbazepine, lamotrigine, gabapentin, or topiramate. The ILAE recommend phenytoin and carbamazepine and consider oxcarbazepine, gabapentin, lamotrigine, phenobarbital, topiramate, and vigabatrin as possible efficacious. A panel of experts in pediatric epilepsy recommended oxcarbazepine and carbamazepine as first choice in complex partial seizures and valproate as the first choice in cases of symptomatic myoclonic and generalized tonic-clonic seizures, except in very young children.

The present data show that the available AEDs have certain differences, but the data do not clearly established a predominance of any drug for the treatment of epilepsy in people with developmental disabilities. However since the new AEDs might improve seizure control in patients resistant to the old medications, the new medications should be used as add-on in cases of refractory epilepsy.

Unfortunately, few have studied these new drugs in persons with developmental disabilities.

Studies done in individuals with refractory epilepsy, selected not on the basis of the presence or absence of mental retardation, showed that adding new AEDs to the regimen of people who were resistant to the treatment with conventional drugs, resulted in an improvement of the seizure control. In some of these individuals, the new drugs were added after 4-6 prior AEDs failed. The studies showed that 12-17% of the patients with intractable seizures become seizure free after the addition of a new drug. Also, in many individuals was a 50-90% reduction in the number of seizures. The conclusion is that in persons with intractable seizures, continue to try AEDs; however, long-term polytherapy should be avoided. Then lack of response to initial therapy with 1 or 2 AEDs, which is an indication of poor prognosis, should not lead to the conclusion that other medications should not be tried. Also, the continuous substitution of AEDs lead to more improvements.

Unfortunately, identifying the individuals who will most likely go on remission is difficult, but it seems that the results were more encouraging in those individuals who were exposed to fewer than than 5 drugs, in those in whom the epileptic disorder was less than 10 years old, and in those with idiopathic epilepsy.

Those patients who failed the first drug because of excessive side effects has a better change of seizure control with the second drug that dose in whom the first drug failed because the drug was not effective.

Failure of successive drugs might be related to cross tolerance.

The choice of first drug depends of the type of seizure and on the physician's familiarity with the medication. The new AEDs (topiramate, oxcarbazepine, lamotrigine, zonisamide, gabapentin, levetiracetam, tiagabine) are not necessarily better than previous drugs (phenobarbital, primidone, ethosuximide, phenytoin, carbamazepine, valproic acid) in terms of seizure control; however, their adverse-effect profile might be improved for some patients.

• AED options
• • With few exceptions (ethosuximide and the benzodiazepines) most of the available AEDs are effective in the treatment of simple and complex partial seizures. Carbamazepine is probable the drug of choice of most neurologists for this type of seizures.
  • Valproic acid, topiramate, zonisamide, lamotrigine are effective in the treatment of generalized seizure disorders. Valproic acid is probably the first choice of most neurologists.
  • Felbamate has proved to be useful in the treatments of seizures in persons with the Lennox-Gastaut syndrome. However, the drug can lead aplastic anemia; therefore, its use has been reduced markedly.
  • Topiramate and lamotrigine might be good choices for the treatment of the Lennox-Gastaut syndrome, mostly to treat the drop attacks. Lamotrigine might exacerbate myoclonic seizures in some individuals.
  • Levetiracetam has also been used with success in the Lennox-Gastaut syndrome, reducing both myoclonic and atonic seizures, but it is less effective in the control of the tonic seizures.
  • Ethosuximide is effective in the treatment of absence seizures and might be the first choice in patients with only absence seizures. However, it is not effective in cases with generalized tonic clonic seizures.
  • Lamotrigine and valproic acid are effective in the treatment of the absences seizures.
• Starting AED therapy 
• • In general, seizure disorders are most severe in people with mental retardation. Therefore, these patients tend to be overmedicated. Starting the treatment with 1 medication in small doses and increasing the dose on a weekly or biweekly basis is better than overmedicating patients from the start.
  • Sedation, a common adverse effect of AEDs, is most obvious when the medications are used at maximal doses from the beginning of therapy.  
• Therapeutic response 
• • About 40-50% of individuals with new epileptic seizures become seizure free with the first AED used, another 15% are seizure free with the second AED, and only few patients in whom 2 AEDs in monotherapy fail improve with a third AED.
  • The combination of 2 AEDs is effective in few of the individuals resistant to monotherapy; therefore, this practice is indicated in very few patients.
  • The hope is that new AEDs might have a major effect on severe cases, though findings from recent clinical studies do not seem to support this expectation. However a small number of individuals with intractable seizures have shown marked improvement, even achieving seizure-free status.
  • Identifying the individuals who are completely resistant to AEDs is difficult, but the past treatment history might help. The seizure-free rate achieved with the addition of new AEDs decreases as the number of drugs tried increases, which is related to the number of AEDs previously used. The rate is reduced to zero after 6 AEDs failed to control the seizures; however, a small group of 16% can still show improvement after the addition of a new AED even after the failure of up to 5 drugs.
  • When a patient's seizures are not fully controlled after 2 trials of monotherapy, surgery should be considered.
  • Even in people with brain damage, epilepsy may remit; AEDs can be withdrawn in many individuals. No definite criteria are available yet, but the best candidates for medication withdrawal are those with late-onset epilepsy, few seizures, long (>2 y) seizure-free periods, low blood levels of AEDs, and normal EEGs.
• Adverse reactions and precautions
• • Many individuals with brain damage present with paradoxical reactions to medications.
  • • Behavior problems might emerge after the initiation of an AED. Barbiturates are well known for aggravating behavioral disturbances; however, negative behavior changes have been described with most of the AEDs, including the new ones.
    • In some cases, successful treatment with marked reduction of epileptic seizures might be associated with a release of abnormal behaviors.
    • In other cases, negative behavioral changes might be the result of poorly recognized but treatable adverse effects. For example, diplopia induced by phenytoin or carbamazepine; abdominal distress caused by valproate; and sedation, a common sequela of all AEDs, might cause a syndrome of pseudoretardation.
  • Bone disorders associated with the chronic used of AEDs was initially described in persons with developmental disabilities living in institutions. At present, bone disorder is a risk factor that is also present in people who do not live in institutions and who do not have developmental disabilities.
  • • The related bone disorders observed with long-term use of AEDs appear to be a heterogeneous group of disorders. The common factor is reduced bone mineral density leading to osteoporosis and increasing the patient's susceptibility to fractures.
    • The cause is not clear, enzymatic induction of vitamin D might play a role; however, it does not seem to be the only factor.
    • Decreased bone mineral density have been reported with phenytoin, phenobarbital, primidone, carbamazepine (all enzymatic inductors of the CYP450 system in the liver) and also with valproic acid (inhibitor of this system). This adverse effect has not been fully evaluated with the new AEDs.
    • Persons that do not ambulate, for example individuals with cerebral palsy, might be more sensitive to this effect than people who walk because the lack of ambulation predisposes patients to decalcification of the bones.
    • Even though osteoporosis is present in both sexes, women with developmental disabilities are at higher risk. For causes that are not clear, Down syndrome seems to be an independent risk factor for osteoporosis.
  • Persons with developmental disabilities tend to have a sedentary life and to gain weight. Some AEDs (carbamazepine, gabapentin, valproate, vigabatrin,) are associated with weight gain, whereas other medications (topiramate, zonisamide, felbamate) are associated with weight loss. These factors might be important in choosing the best medication.
  • Metabolic acidosis is associated with the use of topiramate, acetazolamide, and zonisamide. The 3 drugs are inhibitors of the carbonic anhydrase.
  • Topiramate might produce mild hyperchloremia and decrease bicarbonate levels. This effect is observed even with small doses.
  • Chronic angle glaucoma has been described in individuals taking topiramate. Renal stones are most frequent in individuals receiving topiramate, acetazolamide, and/or zonisamide. These 2 adverse effects may be difficult to diagnose in people with developmental disabilities.
  • Practically all the AEDs, with the exception of gabapentin and levetiracetam, resulted in balance deterioration, even at therapeutic doses in some cases. The effect is dose dependent. This is very important since poor balance leads to fractures secondary to falls. Worth mentioning is that in persons with epilepsy, most of the falls are not necessarily related to seizure activity.
• Special considerations: Late-onset seizures and recurrence
• • Individuals with developmental disabilities are living longer lives than before. Therefore, the incidence of new-onset epileptic disorders is high in individuals older than 60 years.
  • In most instances, the epilepsy is related to a new condition. Most commonly, the epileptic disorder is characterized by focal onset seizures with or without generalization.
  • These individual deserve complete neurologic evaluation. Most often, the cause of the seizure is related to a cerebrovascular accident. Brain tumors, head trauma, and Alzheimer disease are other frequent causes of late-onset seizures.
  • These seizures might have a high risk of recurrence; however, they might not be difficult to treat. In general, monotherapy, even at low doses, is enough to prevent recurrence of the seizures.

Surgical Care

Surgery is a valid option for persons with mental retardation; it should be explored in every individual with an epileptic disorder resistant to AEDs. At present, most neurologists would recommend surgical evaluation of any individual in whom 2 or at the most 3 trials with AED monotherapy have failed. Presurgical evaluation is similar to that performed in individuals without mental retardation. Finding a well-localized area of seizure activity is key to surgical success. For this purpose, imaging techniques and long-term EEG monitoring are necessary. These techniques might not be available outside large medical centers.

• Imaging studies and EEG monitoring
• • MRI and CT are part of routine evaluation. However, in many instances, a well-defined epileptogenic focus might not be detected, and functional neuroimaging techniques might be needed to demonstrate physiologic disturbances.
  • SPECT is used to measure cerebral blood flow during ictal and nonictal conditions.
  • SISCOM, or subtraction ictal SPECT coregistered to MRI, might help to localize the seizure focus in patients with normal MRIs.
  • PET, used to measure cerebral metabolism, provides information superior to that of SPECT. However to be useful, PET should be done within few minutes of the ictal event. This requirement limits the usefulness of PET in evaluating patients with epilepsy.
  • Magnetic resonance spectroscopy (MRS) might reveal areas of structural brain damage, as well as metabolic and neurotransmitter disturbances in the brain.
  • Computerized EEG and magnetoencephalography can also help to locate the origin of the epileptic discharge in the brain.
  • Some individuals might require intracranial placement of electrodes for EEG monitoring.
• Surgical options
• • Patients undergoing focal cortical resections inside or outside the temporal areas have the best postsurgical prognosis, with 70-80% of the patients having marked improvement or becoming seizure-free.
• • Outcome studies in patients with temporal lobectomy demonstrated that the risk of continuous seizures after the operation was highest in those with a lower preoperative intelligence quotient (IQ). However, the magnitude of IQ difference was small. In addition, more than one half the patients with a score of 50-69 remained seizure free. The presence of structural lesions was more important than IQ in predicting seizure recurrence.
• • Anatomic or functional hemispherectomy is indicated for individuals who present with severe pathology in 1 hemisphere. For example, patients with severe cases of Sturge-Weber syndrome might benefit from this operation. In well-selected cases, the seizure-free rate could be as high as 50-60%.
  • Corpus callosotomy, or splitting of the corpus callosum, has indications mostly limited to individuals who do not have a well-defined focus and who present with symptomatic, generalized seizure disorders (eg, Lennox-Gastaut syndrome). This type of surgery might reduce the number of atonic and or tonic seizures. Patients might not be seizure free, but the reduced number of seizures and accidents plus the possibility of reduced doses and drugs result in cognitive improvement in many patients.
• Vagal nerve stimulation (VNS)
• • VNS was approved by the US Food and Drug Administration (FDA) in 1997 for use as an adjunctive therapy for epileptic seizures. VNS has been extensively used in United States and in other countries to treat refractory seizures.
  • VNS is considered a safe technique with minimal adverse effects.
  • Several studies have showed that VNS is effective in reducing epileptic seizures in people with developmental disabilities. Specific studies have been performed in adults and children with Lennox-Gastaut syndrome, tuberous sclerosis, Rett syndrome, and other developmental disabilities with mental retardation.
  • • The cumulative evidence suggests a positive effect in decreasing the burden of seizures and improving quality-of-life measurements.
    • In few cases, seizure control was complete, but approximately half of all individuals treated with VNS had a 50% decrease in the number of seizures, and in many patients the postictal period was shorter.
    • The number of AEDs needed to control the seizures are usually decreased after the VNS.
    • Caregivers reported that the patients with VNS were more alert, had positive mood changes, and were more verbal after the implantation of the VNS.
• • The present evidence suggests that VNS is a treatment option to be considered in individuals with developmental disabilities and difficult-to-control seizures.
  • At the present time, determining valid predictors of positive outcome has not been possible.
• • The most frequent adverse effects are usually mild and have no major effect on the patient's quality of life; they include throat pain, hoarseness, coughing, and respiratory distress.

See Medscape CME activity, Surgery Insight: Surgical Management of Epilepsy.

Diet

A ketogenic diet, which is effective in children with mental retardation, has not been tried extensively in adults.

Activity

Limitation in activities should be similar to that for any other person with epilepsy. However, given their increased frequency of associated sensory and motor deficiencies, patients might require additional protection (eg, helmets).

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Anticonvulsants

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Periodic follow-up is not different from that offered to individuals without mental retardation; however, visits to the neurologist may be more frequent than they otherwise are because of the severity of the epileptic disorder. The following are some special considerations:
• • Avoid polypharmacy; most patients can be treated with monotherapy. Balance adverse effects with therapeutic effects. Full control of seizures might not be the best goal in some individuals.
  • Consider decreasing AEDs in patients who remain seizure free. Even patients with severe disruption of brain architecture and abnormal EEG in infancy might have spontaneous remission of seizures. For example, children with multilobar polymicrogyria with frequent seizures and ESES might be seizure-free when adults.
  • In many instances, seizures are induced by sleep. In these cases, sedation, one of the most common side effects of AEDs, might increase the number of seizures. Decreasing the medication might be enough to control seizures better.
  • Suspect nonepileptic events in patients with refractory seizures, especially if the EEG is consistently normal or shows no epileptiform activity. The presence of bona fide epileptic seizures does not exclude nonepileptic events.
  • Blood levels of AEDs are not necessarily the best indicators of adverse effects. CNS depressant effects of AEDs are additive. Polypharmacy might be associated with CNS depression even if drug levels are not in the toxic range.
  • Paradoxical behavioral reactions are well known with phenobarbital; however, they can be induced by other AEDs. Behavior problems induced by lamotrigine, gabapentin and, less frequently, valproic acid are known.
  • Cognitive deficiencies due to overmedication might be subtle.
  • Evaluation and treatment of persons with multiple handicaps, especially if they are in institutions, by epilepsy specialists results in a better seizure control.
• The incidence of fractures in adults with mental retardation and epilepsy is almost twice that in a similar population without epilepsy. Fractures are reported in all ages, but the peak age range is 40-49 years; they are more frequent in women than in men. In a few instances, the origin of the fracture is related to an epileptic event. Most fractures with unknown causes occur in severely retarded individuals.
• • Factors that might influence the incidence of fractures include chronic use of antiepileptic and psychotropic medications, osteoporosis aggravated by immobility, being bedridden, old age, vitamin D deficiency, and poor exposure to sun. Ensure that patients receive enough vitamin D and calcium.
• • Training persons involved in patients’ care in proper lifting techniques might prevent many fractures, especially in bedridden individuals.

Transfer

• Uncontrolled seizures should not be an impediment for deinstitutionalization of individuals with mental retardation.
• With appropriate medical services, even individuals with a profound degree of mental retardation can be moved from institutions to community settings.

Prognosis

• Generalizations are somewhat misleading because mental retardation is not a uniform category.
• Studies performed in children with and without mental retardation showed that the natural evolution of the disorder includes remission of seizures by the second decade of life in some cases. Causes of this remission are not clear, but it might be associated with developmental changes in neurotransmitter systems.
• Children with mental retardation and seizures starting in early life have a rate of remission of seizures of around 30% by the age of 18 years, lower than in children with normal IQ, in whom it might be as high as 70%.
• Several studies show that it is possible to discontinue AEDs in adults with mental retardation.
• Good candidates for withdrawal of AEDs have the following characteristics:
• • Seizure free for at least 2 years
  • Normal neurologic findings (excluding mental retardation)
  • Normal EEG findings at the time of withdrawal
  • Historically low frequency of seizures
  • Seizure free with low blood levels of AEDs

Patient Education

• People with mental retardation are, in many instances, dependent on others for services.
• Parents, legal guardians, and other caretakers should be educated in several issues. The following are some relevant issues:
• • Recognition of epileptic events
  • Importance of compliance
  • Prevention of accidents
  • Recognition of adverse effects
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Epilepsy.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Physicians should be familiar with sociocultural tendencies that set limits on the services provided to people with mental retardation.
• Mental retardation should not be considered a valid reason to withhold treatment. For example, if surgery is indicated, withholding treatment because the person has mental retardation, besides being unethical, could be considered malpractice and could create liability issues for the treating physician.

MULTIMEDIA

Section 10 of 11