AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

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

Section 3 of 10  

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

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). ¹⁸fluoro-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.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Pseudoseizure

WORKUP

Section 5 of 10  

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

Lab Studies

• The following tests are indicated for evaluating children with mental retardation. These usually are requested even in patients who do not have epilepsy.
• • Urine - Amino acids, organic acids, mucopolysaccharides, oligosaccharides, reducing substances, ferric chloride, sodium nitroprusside, and dinitrophenylhydrazine
  • Blood - Amino acids, lactate and pyruvate, ammonia, very-long-chain fatty acids, chromosomal studies
  • Cerebrospinal fluid (CSF) (only in selected individuals) - Lactate and pyruvate quantification

Imaging Studies

• Neuroimaging studies are indicated in almost every patient with mental retardation. Generally, a routine evaluation with CT scanning or MRI is enough for diagnostic evaluation of the mental retardation. More complex evaluation is indicated in those patients who are candidates for surgery.
• MRI is probably the best test for evaluating congenital malformations of the brain and deficiencies in white and gray matter. Recent advances in MRI technology, such as the fluid attenuation inversion technique (FLAIR), fat-suppression short T1 inversion recovery technique (STIR), as well as fast and ultrafast MRI technology, have increased the usefulness of MRI for evaluating the causes of mental retardation to diagnose epileptic disorders.
• CT scanning, which is also useful for the same purposes, is indicated when MRI is not possible.
• Ultrasonography, which has a limited use in evaluating intracranial abnormalities, plays a role in screening the brain and spinal cord in neonates and young infants. It also may help when MRI and CT scanning are unavailable.
• Arteriography and magnetic resonance angiography (MRA) have more limited indications, mostly for preoperative evaluation of intractable seizures.
• Positron emission tomography (PET) scanning and single-photon emission computed tomography (SPECT) studies might be more diagnostically sensitive than MRI in areas of the brain where the metabolic disorder is more important than the structural abnormalities. Such is the case of small cortical dysplasias, which show hypometabolism. These tests are more relevant for presurgical evaluation of patients with intractable seizures.

Other Tests

• The EEG, combined with the clinical picture, is central to the diagnosis of epilepsy. The EEG findings in epileptic disorders are described in other eMedicine articles. This article aims to describe some of the EEG changes that are seen more often or are specifically relevant to individuals with mental retardation.
• • 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.
  • Long-term closed-circuit television videotaping and digitized EEG telemetry (CCTV-EEG) is becoming a standard technique to document the diagnosis and also for presurgical evaluation of patients with intractable seizures.
• In children with seizures and progressive degenerative disorders, the presence of slowing in the background activities and loss of normal patterns in serial EEGs might help in the recognition that the patient's encephalopathic process is not static.
• Findings on serial EEGs, which might help confirm the diagnosis in children with Rett syndrome, are usually normal in the first stages of the disease, even when the child has shown some signs of deterioration. As the disease progresses, the background activity deteriorates and the EEG shows spikes and sharp waves in the central and temporal areas; these waves become more frequent during sleep and have the characteristics of benign centrotemporal spikes. As the child's mental condition deteriorates, the discharges become generalized with pseudoperiodic theta and delta patterns as well as marked slowing of the background.
• In Angelman syndrome, the interictal EEG shows high-voltage theta and delta activity, which is generalized with anterior predominance and, at times, with runs of slow delta activity followed by sharp waves.
  • Spike and slow activity, which is facilitated by eye closure, is seen in the posterior quadrants.
  • In some cases, an almost continuous, myoclonuslike movement involving the face is accompanied by rhythmic 5- to 10-Hz activity.
  • These abnormal activities are exaggerated by drowsiness and sleep.
• Children and young adults with fragile X syndrome have centrotemporal spikes, which are activated by sleep.
• In a few cases of children with autism, clinical regression was associated with epilepsy and/or EEG abnormalities. Centrotemporal spikes with no clinical seizures also have been described. Whether these findings have any relationship with the autistic disorder and whether antiepileptic medications might be useful in those patients with EEG abnormalities but without clear clinical seizures is unclear. The most traditional approach is that children with autistic features, abnormal EEG findings, and no clinical seizures would not benefit from antiepileptic medications. Some recent reports, however, showed that children with autism and no clinical seizures might improve with antiepileptic medications.
• Malformations of cortical development might be associated with defined EEG changes.
  • In some cases of cortical malformations, the EEG background activity might be normal or have minimal changes.
  • The degree of EEG abnormality generally correlates with the severity of the malformation and the severity of the seizure disorder.
  • The EEG findings are not specific or characteristic of any particular condition.
• In cases with hemimegalencephaly, EEG findings include poorly organized background activities plus frequent focal and multifocal spikes and sharp waves as well as burst-suppression patterns, which are mostly over the malformed hemisphere.
• In focal cortical dysplasia, the EEG changes, mostly focal slowing and/or epileptiform activity, are primarily localized to the abnormal cortical area.
• In lissencephaly (and depending on the type of brain abnormality), the EEG might show a hypsarrhythmic type pattern, more often in younger children, or high-voltage continuous diffuse discharges of beta activity in both hemispheres. Generalized discharges at slow frequencies also have been described.

TREATMENT

Section 6 of 10  

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

Medical Care

Seizure disorders are generally more severe in people with mental retardation. The basic treatment principles of epileptic disorders also apply to patients with mental retardation. There are several options for the long-term treatment of epileptic seizures, including antiseizure medications, vagal nerve stimulation, ketogenic diet, and surgery. These options are not mutually exclusive and should be used concurrently in the same individual if needed.

Monotherapy is ideal, and polytherapy should be used only when no other options are available. Starting the treatment with one medication in small doses and increasing in increments weekly or biweekly is the preferred method. Most of the side effects are seen when the full dose of medication is achieved in a short period of time. Titration periods of 4-6 weeks are usually safe in terms of preventing side effects. The only inconvenience is the possibility of a seizure during the titration period; however, in the long-term, whenever possible, start with a low dose and increase the medication slowly.

It is not unusual for people with a first seizure to be seen in the emergency department and be sent home with a full dose of medication. These individuals are more prone to have side effects a few days after the initiation of the therapy. In these cases, the medication should be decreased or even stopped and then restarted later when the signs of intoxication have subsided. Unfortunately, in many instances this is seen as intolerance to the medications or an allergy, which is not the case. Medications that are potentially useful should not be excluded due to side effects that could have been avoided with a slow titration.

In many instances, discontinuing antiepileptic medications is possible after a seizure-free period. The time varies among physicians, but discontinuing medications after 2 years without seizures is usually considered safe. However, in the author's practice, medications may be safely discontinued after 4-5 years without seizures in persons with brain damage. Discontinue antiepileptic medications slowly. In children treated with multiple medications, the author recommends tapering one medication at a time, allowing approximately 6-12 months to discontinue each medication. Withdrawal seizures are not unusual and are not necessarily an indication that the medication being tapered is needed. However, in most instances delaying the tapering of the medications is safer.

Many individuals with brain damage present with paradoxical reactions to medications. Sedation, a common side effect of these medications, is more obvious when the medications are used at maximal dose from the beginning of the therapy. Behavior deterioration or the emergence of new abnormal behaviors can be the result of the use of antiepileptic medications.

In 60-70% of persons without mental retardation, seizures are controlled with the available antiepileptic medications either alone or in combination. In children with mental retardation, the success rate is much lower, around 50% or less in certain subgroups, eg, children with the Lenox-Gastaut syndrome.

Establishing that the patient has epileptic seizures is essential before the initiation of treatment. One of the most serious pitfalls in the treatment of recurrent epileptic seizures is failure to differentiate them from nonepileptic events. Nonepileptic events are a confounding factor in persons with and without mental retardation. The lack of recognition leads to unnecessary treatment in addition to the complications of missing the right diagnosis (eg, syncope, migraine, cardiac arrhythmias, vestibular disorders, sleep disturbances).

Reaching the correct diagnosis requires obtaining an accurate history of the event, performing physical and neurologic examinations, obtaining EEG (including EEG-video monitoring or some form of long-term monitoring if there is any doubt about the diagnosis), and conducting neuroradiologic evaluation in any case of new-onset seizure. Once the diagnosis of epileptic seizure is established, the next step is to determine the type of seizure and if possible the epileptic syndrome. Even though some of the antiepileptic medications are effective in many different types of seizures, some are more useful in certain syndromes. For example, valproic acid, lamotrigine, and topiramate are effective in the Lennox-Gastaut syndrome, while carbamazepine would be a poor choice in this syndrome.

• The mainstay of medical care is the use of antiseizure medications.
• • Until 1993, only a limited number of antiepileptic medications was available to choose from if practicing in the United States. These are recognized today as the old drugs (ie, phenobarbital, primidone, carbamazepine, valproic acid, ethosuximide, acetazolamide, several benzodiazepines such as diazepam, clonazepam, and Tranxene).
  • In the last decade, several antiepileptic medications have been approved in United States; the new drugs include felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide.
  • Other therapeutic options have not been approved in United States but are available in other countries; these include vigabatrin, sulthiame, and clobazam.
• The majority of the new antiseizure drugs recently introduced in United States were approved after studies conducted mostly in persons with intractable seizures of the partial or focal type. In most instances, these medications were used as add-on medications. Few of the new antiepileptic drugs have been evaluated in monotherapy trials. Very few studies have compared these medications with each other.
• • Few studies evaluate these medications in children; however, the pathophysiology of partial seizures in children is similar to the pathophysiology of seizures in adults. Furthermore, each antiseizure medication tested as adjunctive therapy in children older than 2 years with refractory partial seizures has demonstrated the same efficacy as in adults. Although not the ideal situation, studies in adults can indicate efficacy in children.
  • A meta-analysis of randomized controlled trials involving some of the new medications (ie, gabapentin, lamotrigine, topiramate, zonisamide, tiagabine, vigabatrin) showed than when compared with placebo there was no conclusive evidence for a difference in efficacy or tolerability among the drugs.
• Even though more information is needed about these new drugs, some evidence suggests that there are advantages with these new agents.
  • Lamotrigine, topiramate, and zonisamide have broad-spectrum activity and are effective in the treatment of generalized seizures, besides being effective in local-onset seizures. These drugs might help in the treatment of the Lenox-Gastaut syndrome.
  • Gabapentin, lamotrigine, and oxcarbazepine are as effective as carbamazepine in individuals with partial-onset seizures but with fewer side effects.
  • Unlike the old drugs, most of the new antiepileptic drugs do not induce hepatic enzymes. Consequently, the interaction with other drugs is decreased or eliminated. Most of the old drugs enhance the metabolism of oral contraceptives, which might result in unexpected pregnancies. With the exception of felbamate, oxcarbazepine, and topiramate, the new drugs do not interfere with oral contraceptives.
  • The incidence of congenital malformations in the offspring of women with epilepsy is 4-6%, twice that of the general population. Phenobarbital, phenytoin, carbamazepine, and valproic acid are proven teratogenics and should be avoided during pregnancy, mostly in the first trimester. The teratogenic effects are increased with polypharmacy. The teratogenic mechanism is not known but is probably related to folate deficiency. Folate supplementation is recommended in women of childbearing age taking antiepileptic medication.
    • The North American Antiepileptic Drug Pregnancy Registry tracks the incidence of malformations in women with epilepsy taking medication during pregnancy. Data showed that major birth defects were found in 8.8% of the participants on valproic acid, in 6.3% of participants on phenobarbital, and in 1.6% of the control group.
    • The Lamotrigine Pregnancy Registry, which collects information on women exposed to lamotrigine in the first trimester, found an incidence of major birth defects of 1.8%, which is comparable with the general population.
    • Information regarding the other new drugs is lacking.
  • With the exception of felbamate, which has been associated with aplastic anemia and also hepatic failure, the new antiepileptic drugs do not have major severe side effects.
  • The old antiepileptic drugs have been associated with decreased bone mineral content and osteoporosis. This is particularly worrisome in individuals with disabilities, especially if they are nonambulatory. The mechanism in the enzyme inducers is probably related to increased catabolism of vitamin D. However, decreased bone mineral density has also been reported with valproic acid, which is not an enzyme inducer, and also in individuals with normal vitamin D. Whether the new antiepileptic medications might also result in osteoporosis is not clear. Supplementation of the diet with vitamin D might not be sufficient to prevent osteoporosis.
  • Felbamate, topiramate, and zonisamide are associated with weight loss. Valproic acid, carbamazepine, gabapentin, and vigabatrin might result in weight gain. Lamotrigine, levetiracetam, and phenytoin do not affect weight.
  • On the negative side, the new medications are much more expensive than the old ones and there is no evidence of superior cost-effectiveness.
• The evaluation of cognitive deficiencies due to the use of antiseizure drugs is difficult. This task is even more difficult in persons with intellectual disabilities. A large number of studies address this issue. Unfortunately, the findings of many are inconclusive and even contradictory. However, it seems clear that no single drug causes problems in all patients taking that drug, and all the drugs can result in some form of cognitive impairment in some patients. Also, a subgroup of individuals seem to be at higher risk for cognitive impairment, but at the present time there are no markers to identify that subgroup.
  • Very little is known in persons with developmental disabilities because very little research has been conducted in this area.
  • The degree of cognitive impairment is probably related to the total dose of the medication, rather than the type of medication.
  • The effect occurs while the patient is taking the medication, and in most instances, patients return to baseline after the medications is discontinued.
  • Among the old drugs, phenobarbital and the benzodiazepines were considered the most prone to produce some cognitive deficiencies.
  • Among the new drugs, topiramate seems to cause more cognitive problems, while lamotrigine seems to be safer. However, more studies are needed to evaluate the cognitive effects of the new drugs.
  • In general, the cognitive effects are more often seen in polypharmacy. In persons with intractable seizures and multiple medications, cognitive impairment is a limiting factor in the use of antiepileptic medication.
  • In some cases, the use of antiepileptic medications has been associated with improvement in cognitive function and degree of alertness. This could be the result of a positive psychotropic effect of the medications or just more effective seizure control.
  • In general, when these medications are used within standard dose, the cognitive impairment added by the medication is minimal.
• Measuring serum levels of the antiepileptic medications routinely has become an integral part of the treatment of epileptic seizures even though the therapeutic levels often do not correlate with an individual's response. However, titration and determination of the dose of medication should not be done on the basis of the serum levels, and unfortunately this is a common practice. The serum level is more useful when poor compliance is suspected or to evaluate the interactions between medications. Some serum levels might be confusing and might lead to wrong therapeutic decisions. For example, serum levels of total phenytoin in persons also taking valproic acid might be low, while the free phenytoin might be high. There are therapeutic values for the old drugs, but there are no such values for the new drugs, and the benefits of the use of serum levels to determine therapeutic effect of the new drugs is minimal.
• Periodic adjustments of the medications might be needed. No fixed guidelines indicate how to proceed. The author recommends closely examining the number of seizures and side effects. Quality of life is an important issue. In many instances, an aggressive attempt to control the number of seizures with a high dose of antiepileptic medications or polypharmacy might result in a decrease in the quality of life. Seizure control and quality of life should be balanced, and the input of other people who are familiar with the patient should be requested. Guidelines may be established based on clinical criteria rather than blood levels of medication.
  • Dose adjustments have been established under certain conditions. Gabapentin and levetiracetam are not metabolized in the liver and are good drugs in the presence of liver damage. However, because they are excreted through the kidneys, the dose should be decreased in individuals with kidney damage. For these drugs, guidelines based on creatinine clearance have been established.
  • In the presence of kidney insufficiency, the half-life of topiramate, oxcarbazepine, and zonisamide is prolonged. Although guidelines are not established, the dose should be decreased. Blood levels are not necessarily useful but might help to identify changes in the pharmacokinetics of the drug involved.
  • Valproic acid has a recognized liver toxicity and might be dangerous to use in persons with history of viral hepatitis.

Surgical Care

This is a valid option for persons with mental retardation. Consider surgery in every case of epileptic disorder that is resistant to antiepileptic drugs.

• The presurgical evaluation is similar to the one performed in individuals without mental retardation.
• Hemispheric surgery is indicated in individuals with intractable seizures and diffuse hemispheric disease. Anatomic hemispherectomy, the removal of the hemisphere, was the first approach; however, because of complications with other techniques, such as subtotal resection, functional hemispherectomy and hemidecortication were developed. Hemispherectomy has been indicated in cases of Sturge-Weber syndrome, hemimeganencephaly, infantile hemiplegia, cortical dysplasi, Rasmussen encephalitis, and infarction. In general, the results are encouraging, with some series showing complete seizure control in 50-79% of the patients who have undergone operation and in most of these patients the AED was discontinued.
  
  In spite of the improvement in the operative techniques, complications do occur in a small number of individuals. The most common complications are intracranial bleeding and hydrocephalus requiring shunt treatment, and a few cases of postoperative headaches and chronic intracranial hypertension. Contralateral hemiparesis affecting mostly the hand function, but with some preservation of proximal upper limb function, and homonymous hemianopsia are usually present after the operation. The prognosis varies with the etiology of the epileptic disorder. Epileptic disorders secondary to vascular etiology have better prognosis, while malformation of cortical development, hemimegalencephaly, and Rasmussen encephalitis have a worse prognosis. Younger age at time of surgery might improve the prognosis in terms of future development, probably by limiting the effect of the epileptic disorder on the nonoperated hemisphere.
• Focal resections can be useful in patients with cortical focal dysplasias or tuberous sclerosis.
• Callosotomy might be useful in patients with intractable seizure and predominance of the atonic type of seizures. Complete callosotomy seems to be more effective than partial anterior corpus callosotomy. A recent series showed that at least a 75% reduction in seizures occurred in 75% of the total callosotomy patients compared with 55% of the partial callosotomy patients. No prolonged neurologic deficits were observed in either group and treatment for secondary generalized intractable seizures not amenable to focal resection in children. No disconnection syndrome has been described in children with callosotomies performed before the age of 10 years.  
• Multiple subpial transection is to be considered when the seizure foci is in or near eloquent cortex, (eg, in the Landau-Klefner syndrome). This might also be useful in cases with multifocal epileptic foci not amenable to surgical excision.
• Vagal nerve stimulation (VNS) has not been widely used in children with mental retardation and epilepsy, mostly in children with Lennox-Gastaut syndrome in whom this treatment seems to be effective. VNS does not seems to be effective in infantile spasm. Regarding specific seizure types, VNS seems to be more effective in the drop attacks, with some children being seizure-free, and it is also effective, but much less, in individuals with focal epilepsy. At the present time, VNS seems to be indicated in children with drug-resistant epilepsy who are not candidates for surgical resection. Whether VNS would be better that total callosotomy for children with drop attacks is not clear.

Diet

• Ketogenic diet
• • This diet was first used for the treatment of epilepsy in the 1920s. Implementing the diet is difficult as are managing its side effects. At the present, the ketogenic diet is indicated in patients with refractory epilepsy.
  • The ketogenic diet is more effective in children younger than 12 years than in adolescents or adults.
  • Even with advanced dietary techniques the ketogenic diet requires a high level of commitment from the parents and the patients, which limits the use of the diet to a select group of patients.
  • This is an option to be considered in children with refractory epilepsy in whom the antiseizure medications are not effective or are toxic.

Activity

The limitation in activities is similar to that for any other person with epilepsy.

MEDICATION

Section 7 of 10  

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

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

Drug Category: Anticonvulsants

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

Drug Name	Ethosuximide (Zarontin)
Description	First choice in treatment of simple absences. Also effective in treatment of myoclonic seizures as well as atonic-akinetic seizures.
Adult Dose	250 mg PO bid; titrate to 1500 mg
Pediatric Dose	<3 years: Not recommended >3 years: Start with small dose, around 5 mg/kg/d PO; increase slowly; not to exceed 20-25 mg/kg/d
Contraindications	Documented hypersensitivity; blood dyscrasias; renal or hepatic disease
Interactions	Phenytoin, carbamazepine, primidone, or phenobarbital may decrease effects; isoniazid may inhibit hepatic metabolism, increasing toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Blood dyscrasias, which may be fatal, may occur; monitor CBC; caution in hepatic or renal disease; abrupt withdrawal of drug may precipitate absence status

Drug Name	Felbamate (Felbatol)
Description	Can be effective in different types of seizures. Because of severe adverse effects, use is limited to those patients in whom no other medication is effective. Felbamate is particularly effective in Lenox-Gastaut syndrome.
Adult Dose	300 mg PO qid or 400 mg PO tid initially as monotherapy; increase dose gradually by 600 mg q2wk; not to exceed 3.6 g/d
Pediatric Dose	<2 years: Not established 2-14 years: 15 mg/kg/d PO in 3-4 divided doses initially; increase by 15 mg/kg/d qwk to 45 mg/kg/d >14 years: Administer as in adults
Contraindications	Documented hypersensitivity; blood dyscrasia; hepatic dysfunction
Interactions	May increase steady-state phenytoin levels; 40% dose-reduction of phenytoin may be necessary in some patients; phenytoin may double felbamate clearance, resulting in more than 45% decrease in steady-state levels; coadministration of felbamate and phenobarbital may cause increase in phenobarbital plasma concentrations; phenobarbital may reduce plasma felbamate levels; felbamate may decrease steady-state carbamazepine levels and increase steady-state carbamazepine metabolite levels; felbamate may increase steady-state valproic acid levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Associated with marked increase in incidence of aplastic anemia (monitor CBC periodically); marked increase in fatal hepatic failure reported in patients receiving felbamate; perform liver function testing (ALT, AST, bilirubin) before felbamate therapy and at 1- to 2-wk intervals during therapy; discontinue immediately if liver abnormalities detected during treatment

Drug Name	Gabapentin (Neurontin)
Description	Introduced as adjuvant in treatment of partial seizures with and without secondary generalization. Might also be effective in generalized tonic-clonic seizures. Not effective in absence seizures.
Adult Dose	300 mg PO tid recommended initially; increase to 600 mg tid; if necessary and no adverse effects, may increase up to 4000 mg/d Manufacturer recommendations for impaired kidney function: CrCl >60 mL/min, 400 mg PO tid CrCl 30-60 mL/min, 300 mg PO bid CrCl 15-30 mL/min, 300 mg qd CrCl <15 mL/min, 300 mg qod Hemodialysis: supplement dose with 200-300 mg
Pediatric Dose	<12 years: Not established >12 years: Not established; may start with small dose of 300 mg/d PO and increase weekly depending upon tolerance and clinical effect
Contraindications	Documented hypersensitivity
Interactions	Antacids may reduce bioavailability significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe renal disease (use smaller dose in persons with renal insufficiency); drowsiness is dose dependent; dizziness, ataxia, fatigue, and nystagmus may occur

Drug Name	Lamotrigine (Lamictal)
Description	Recently introduced. Effective as adjunct and primary drug in management of partial seizures. Also effective in generalized seizures. Indicated in patients aged 2-12 y with Lennox-Gastaut syndrome.
Adult Dose	<16 years: Not established >16 years: Start with 50 mg PO qd for 2 wk, then 50 mg bid for 2 wk; depending upon tolerance, increase weekly up to 300-500 mg/d; if patient is on valproic acid then use half this dose
Pediatric Dose	Not established; start with small doses of 12.5 mg/d PO and increase slowly at 2-wk intervals
Contraindications	Documented hypersensitivity
Interactions	Acetaminophen increases renal clearance, decreasing effects; similarly, phenobarbital and phenytoin increase metabolism, causing decrease in levels; valproic acid increases half-life
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Several cases of Stevens-Johnson syndrome reported; 1% of children (<16 y) and 0.3% of adults may develop rashes; few deaths related to toxic epidermal necrolysis; should be discontinued at first indication of rash; behavior problems can be induced in persons with brain damage; safety in children <16 y, other than those with Lennox-Gastaut syndrome, has not been established

Drug Name	Levetiracetam (Keppra)
Description	Indicated as adjunctive therapy in treatment of partial onset seizures.
Adult Dose	500 mg PO bid initially; increase by 1000 mg/d q2wk; not to exceed 3000 mg/d Dose change in people with renal damage according to creatinine clearance: CrCl 50-80 mL/min, 500-1000 mg PO q12h CrCl 30-50 mL/min, 250-750 mg PO q12h CrCl <30 mL/min, 250-500 mg PO q12h End stage renal disease on dialysis: 500-1000 mg/d PO; supplement by 250-500 mg after dialysis
Pediatric Dose	<16 years: Not established >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Excreted in breast milk; physicians are encouraged to contact Antiepileptic Drug Pregnancy Registry (888-233-2334) and report women exposed to levetiracetam during pregnancy Caution in renal impairment; major side effects include somnolence, asthenia, incoordination, mild leukopenia (3%), and behavioral changes such as anxiety, hostility, emotional lability, depression and psychosis (1-2%), and depersonalization

Drug Name	Oxcarbazepine (Trileptal)
Description	The pharmacologic activity of oxcarbazepine is primarily by the 10-monohydroxy metabolite (MHD) of oxcarbazepine. May block voltage-sensitive sodium channels, inhibit repetitive neuronal firing, and impair synaptic impulse propagation. The anticonvulsant effect may also occur by affecting potassium conductance and high-voltage activated calcium channels. Drug pharmacokinetics are similar in older children (>8 y) and adults. Young children (<8 y) have a 30-40% increased clearance compared with older children and adults. Children <2 y of age have not been studied in controlled clinical trials.
Adult Dose	300 mg PO bid initially; increase 300 mg/d qwk; 1200 mg/d maintenance dose Renal impairment: CrCl <30 mL/min, 300 mg/d PO initially
Pediatric Dose	<4 years: Not established 4-16 years: 4-5 mg/kg/d PO initially; increase by 5 mg/kg/d qwk; 20-30 mg/kg/d maintenance dose Renal impairment: Initial dose should be lower and increased slowly >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	May decrease levels of dihydropyridine calcium antagonists and oral contraceptives; can reduce serum concentrations of carbamazepine, phenobarbital, phenytoin, and valproic acid; when oxcarbazepine is given in doses >1200 mg/d may increase phenytoin and phenobarbital serum concentrations significantly; oxcarbazepine can reduce serum concentrations of oral contraceptives and make oral contraceptives ineffective; can increase clearance of felodipine; not to be used while nursing
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Can cause cognitive adverse effects (eg, psychomotor slowing, impaired concentration, impaired speech, impaired language); decrease initiation dose by 50% with renal impairment (CrCl <30 mL/min) and increase dose more slowly; oxcarbazepine can cause hyponatremia (sodium <125 mmol/L); among persons with hypersensitivity to carbamazepine, 25-30% have hypersensitivity to oxcarbazepine; rapid withdrawal of oxcarbazepine can cause exacerbation of seizures; observe for side effects and monitor plasma levels of concomitant anticonvulsants during dose titration

Drug Name	Phenobarbital (Barbital, Luminal)
Description	Oldest antiepileptic medication. Effective in partial seizures, generalized tonic, and tonic-clonic seizures. Not effective in absence, atonic akinetic seizures.
Adult Dose	200-260 mg/d PO qd; titrate slowly
Pediatric Dose	1-4 mg/kg/d PO; titrate slowly
Contraindications	Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis
Interactions	Alcohol may produce additive CNS effects and death; may decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients with coagulation parameters stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy); menstrual irregularities also may occur
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema

Drug Name	Phenytoin (Dilantin)
Description	One of oldest antiepileptic drugs. Effective for generalized as well as focal seizures. Not effective in absence seizures, poorly effective in akinetic seizures.
Adult Dose	150-300 mg PO qd
Pediatric Dose	5 mg/kg/d PO initially; increase slowly to 10-15 mg/kg/d
Contraindications	Documented hypersensitivity; sinoatrial block; second- or third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Interactions	Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity Barbiturates, diazoxide, ethanol (long-term ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Rapid IV infusion may result in death from cardiac arrest, marked by QRS widening Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; caution in acute intermittent porphyria and diabetes (may elevate blood glucose); discontinue use if hepatic dysfunction occurs

Drug Name	Primidone (Mysoline)
Description	Effective in generalized tonic, tonic-clonic, or partial seizures. Not effective in absence seizures.
Adult Dose	125 mg PO hs; titrate slowly by increasing q3-4d; usually 250 mg PO tid is enough; not to exceed 2000 mg
Pediatric Dose	50 mg PO hs initially, increase slowly; not to exceed 20-25 mg/kg/d
Contraindications	Documented hypersensitivity; porphyria; severe respiratory disease; marked impairment of liver function; nephritis
Interactions	Alcohol may produce additive CNS effects and death; may decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients with coagulation parameters stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy); menstrual irregularities also may occur
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema

Drug Name	Tiagabine (Gabitril)
Description	Mechanism of antiseizure action unknown. Believed related to ability to enhance activity of GABA, major inhibitory neurotransmitter in CNS. May block GABA uptake into presynaptic neurons, making more GABA available for receptor binding on surfaces of postsynaptic cells and possibly preventing propagation of neural impulses that contribute to seizures by GABA-ergic action. It is indicated as adjunct medication in the treatment of partial seizures. Modification of concomitant antiepilepsy drug doses not necessary, unless clinically indicated.
Adult Dose	4 mg/d PO initially, may increase qwk by 4-8 mg/d; not to exceed 56 mg/d
Pediatric Dose	<12 years: Not established >12 years: 4 mg/d PO initially; may be increased by 4 mg/d qwk; not to exceed 32 mg/d
Contraindications	Documented hypersensitivity; rash; hepatic impairment
Interactions	Cleared more rapidly in patients treated with carbamazepine, phenytoin, primidone, or phenobarbital than in patients who have not received these drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Patients receiving valproate monotherapy may require lower doses or slower dose titration of tiagabine for clinical response; moderately severe to incapacitating generalized weakness has been reported following administration of tiagabine in as many as 1% of patients with epilepsy; weakness may resolve after reduction in dose or discontinuation; should be withdrawn slowly to reduce potential for increased seizure frequency; may result in stupor or spike wave stupor; CNS depression, poor concentration, fatigue, and somnolence may occur; may exacerbate EEG abnormalities; sudden death and status epilepticus reported; adverse reactions include dizziness, asthenia, somnolence, nausea, and abdominal pain

Drug Name	Topiramate (Topamax)
Description	Sulfamate-substituted monosaccharide with broad spectrum of antiepileptic activity that may have state-dependent sodium channel blocking action. Potentiates inhibitory activity of neurotransmitter GABA. May block glutamate activity.
Adult Dose	50 mg PO qd pm for 1 wk; titrate in increments of 50 mg bid qwk; doses >400 mg/d do not improve responses
Pediatric Dose	Not established; start with small dose of 25 mg/d PO and increase q2wk
Contraindications	Documented hypersensitivity
Interactions	On occasions, addition of topiramate to phenytoin may require adjustment of phenytoin dose to achieve optimal clinical outcome; phenytoin, carbamazepine, and valproic acid can decrease levels significantly; reduces digoxin and norethindrone levels; carbonic anhydrase inhibitors may increase risk of renal stone formation, and coadministration should be avoided; coadminister with CNS depressants only with extreme caution because may have additive effect in CNS depression as well as other adverse cognitive or neuropsychiatric events
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Risk of kidney stone formation increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment; open angle glaucoma; hypohidrosis; not necessary to monitor plasma concentrations to optimize therapy (trough plasma concentrations do not correlate with clinical responses)

Drug Name	Valproic acid (Depakene), divalproex sodium (Depakote)
Description	Considered one of main antiepileptic medications. Effective in many different types of seizure disorders, primary or secondary. Particularly effective in treatment of akinetic-atonic seizures and typical and atypical absences. Dosing regimen variable.
Adult Dose	1500-2000 mg PO; 3000 mg or more can be used if tolerated
Pediatric Dose	10-15 mg/kg/d PO initially; may increase to 60 mg/kg/d
Contraindications	Documented hypersensitivity; hepatic disease/dysfunction
Interactions	Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may reduce levels significantly; in children, salicylates decrease protein binding and metabolism; may result in variable changes of carbamazepine concentrations with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels, while either may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
Pregnancy	D - Unsafe in pregnancy
Precautions	Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; at periodic intervals and prior to surgery, determine platelet counts and bleeding times before initiating therapy; reduce dose or discontinue therapy if hemorrhage, bruising, or hemostasis/coagulation disorder occurs Hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness

Drug Name	Zonisamide (Zonegran)
Description	Indicated for adjunctive treatment of partial seizures with or without secondary generalization. Evidence indicates that it is effective in myoclonic and other generalized seizure types as well.
Adult Dose	100 mg/d PO initially for 2 wk; increase by 100 mg/d PO q2wk; not to exceed 400 mg/d
Pediatric Dose	<16 years: Not established >16 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	May cause drowsiness, weight loss, ataxia, nausea, and slowing of mental activity; pediatric patients have an increased risk for oligohidrosis and hyperthermia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May increase serum carbamazepine levels; carbamazepine may increase zonisamide concentrations; phenobarbital may decrease zonisamide levels; not for use in nursing women

FOLLOW-UP

Section 8 of 10  

• Authors and Edito