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Epilepsy surgery in children with developmental disabilities
Epilepsy Surgery in Children With Developmental Disabilities Paul M. Levisohn Surgery for treatment of medically uncontrolled epilepsy in children is now widely accepted with reported outcomes similar to those in adults. Epilepsy is reported in 8.8% to 32% of children with mental retardation (MR) and in up to half of children with severe retardation. There has been concern that patients with low IQ will experience unsatisfactory outcomes from epilepsy surgery and not achieve good seizure control. It is appropriate to reassess the prior bias against resective epilepsy surgery in children with MR in view of the changing criteria for potential candidacy for epilepsy surgery in infants and young children. There are three prerequisites for epilepsy surgery: (1) the epilepsy must be medically intractable; (2) the surgery must be feasible, that is, the epileptogenic zone can identified and safely resected; and (3) there is high likelihood of a satisfactory outcome as regards both the epilepsy and the patient's functional status. Patients with MR may have diffuse cerebral dysfunction and diffuse or multifocal epileptogenic regions. Appropriate patient selection is made possible through use of current technology that allows identification of lesions or areas of cerebral dysgenesis, aiding in identification of localized areas of epileptogenesis. Results from various series of patients with MR who have undergone resective surgery for epilepsy have shown that with careful presurgical evaluations, outcomes are similar between patients with normal IQ scores and those with low scores. Surgical protocols specifically for patients with MR and intractable epilepsy are required, including careful definition of desired outcomes. Copyright 9 2000 by W.B. Saunders Company
URGERY FOR treatment of medically uncontrolled epilepsy in children is now widely accepted, with reported outcomes similar to those in adults. However, there is a concern that patients with low IQ will experience poor outcomes from epilepsy surgery and will not achieve good seizure control. In 1972, Falconer I published his experience with surgery for temporal lobe epilepsy in children, expanding the indications for resective epilepsy surgery to include children with intractable temporal lobe epilepsy. Subsequently, many series have been published documenting experience in epilepsy surgery for children, adolescents, and more recently, infants, documenting the efficacy, feasibility, and safety of resective surgery in children, e-12However, Falconer considered patients with low IQs (below 70) as inappropriate candidates for temporal lobectomy, expressing concern regarding "widespread brain damage. ''13 Experience with adolescents and adults with epilepsy and low IQ suggested relatively poorer outcomes in patients with low IQs explained by the belief that mental retardation (MR) reflects diffuse central nervous system (CNS) dysfunction or multifocal sources of the seizures, the converse of appropriate
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From the Children 'S Epilepsy Program, The Children 'S Hospital Denver, CO. Address reprint requests to Paul M. Levisohn, MD, The Children's Hospital, 1056 East 19 th Ave, B 155, Denver, CO 80218. Copyright 9 2000 by W.B. Saunders Company 1071-9091/00/0703-0007510.00/0 doi: l O.l O53/spen.2000.9216 194
substrate for resective surgery, the identifiable single focal lesion. 13,14 Significant developmental delay is still often considered a relative contraindication for resecfive epilepsy. 15 However, surgical treatment of epilepsy is now considered an option even for infants. 16-19 New diagnostic procedures, such as positron emission tomography (PET) scans and single photon emission computed tomography (SPECT), have helped identify appropriate candidates for epilepsy surgery, aiding in localization and directing invasive monitoring. Criteria and protocols for evaluation and surgical treatment of localization related epilepsy have been developed at multiple centers. 15,2~It is appropriate to reassess the prior bias against resective epilepsy surgery in children with mental retardation in view of the changing criteria for potential candidacy for epilepsy surgery in infants and young children. Cognitive and neurobehavioral dysfunction makes standard approaches to evaluation of surgical candidacy difficult. Diagnostic studies, such as intracarotid amobarbital testing (IAT), invasive monitoring, and cortical mapping, are often impossible in patients with significant MR, complicating the process of identifying the epileptogenic focus and functional cortex. Experience with younger children suggests that protocols can be developed for children with mental retardation, leading to effective decision-making and acceptable outcomes. The last several years have seen increasing emphasis on health-related quality-of-life (HRQOL) as an important outcome measure for epilepsy surgery. The development of new criteria for defin-
Seminars in Pediatric Neurology, Vol 7, No 3 (September), 2000: pp 194-203
EPILEPSY SURGERY IN CHILDREN WITH DISABILITIES
ing appropriate neuropsychologic and social indications for epilepsy surgery in the developmentally disabled remains a challenge. EPIDEMIOLOGY AND ETIOLOGY
MR has proven difficult to define. Even the term "mental retardation" is occasionally inappropriately shunned in preference for "learning disability. ''21 The more generic terms developmental disabilities and developmental delays are often used instead of MR, particularly with younger children. The definition of intelligence has proven controversial, and its accurate measurement is complex. In general, developmental disabilities are a heterogeneous group of disorders, onset of which are early in life. They feature disturbances in the ongoing development of cognitive, motor, and social skills. 22 Definitions of MR have emphasized significant difficulties in both general intellectual functioning as measured by standard instruments as well as concurrent deficits in adaptive function. 22 The American Association on Mental Retardation definition requires limitations in at least two areas of adaptive behavior that affect the functioning of an individual within society. 23 In epidemiologic studies, MR is pragmatically defined as measured IQ greater than two standard deviations below the mean, such that 2.5% of the population would be defined as being mentally retarded. The higher prevalence of MR in the socioeconomicaily disadvantaged points out the difficulties in defining MR, reflecting the importance of social and cultural factors in determining intelligence, a factor of importance for children with epilepsy. 24.25 There appear to be no generally accepted measures of adaptive skills. In practice, most studies of MR and epilepsy rely on measured IQ as the "administrative definition" of MR. 26 Measured IQ below 70 is generally accepted as the measure of low intelligence. Prevalence of MR has been estimated at 2.8 to 7.6/1000, though this is below the 2% to 3% rate that would be predicted by IQ measurement alone. 26 The World Health Organization differentiates between "impairment" (defined as a loss or abnormality of psychologic, physiologic, or anatomic structure or function occurring at the organ level) from "disability" (defined as the consequence of impairment in terms of functional performance and activity by an individual)Y Handicaps are further definable as the result of an interaction between an individual with impairment or disability and that
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individual's environment. 27 Disabilities and handicaps are common in children with epilepsy, with various studies having shown additional neurodisorders in one third of children with epilepsy, especially MR and cerebral palsy. 27 In a populationbased study in Goteborg, Sweden, Beckung identified mild MR (IQ 50 to 70) in 22% and severe MR (IQ < 50) in 27% of children with epilepsy. 27 In a similar Finnish study assessing the occurrence of disabilities and handicaps in children with epilepsy, Sillanpaa 28 found the most common comorbid neurologic impairment to be MR, which occurred in 31.4% of an unselected population of Finnish children ages 4 to 15 years with epilepsy. However, differences in methods have resulted in quite variable estimates of the frequency of MR in children with epilepsy. 21 Impaired cognitive, academic, and social functioning occurs more frequently than can be explained by the measured IQs of children with epilepsy. 29 Sillanpaa 28 found speech disorders in 27.5% of children with epilepsy and specific learning disorders in 23.1%. Beckung and Uvebrant 27 found "impairment of perception" in 23% of children with epilepsy without either MR or cerebral palsy (CP). Significant neuropsychoiogic impairment in children with complex partial seizures (CPS) is evident, suggesting generalized cognitive effects of even partial seizures, further impacting the social functioning of children with epilepsy and MR. 30 Various studies have reported the incidence and prevalence of epilepsy in patients with MR, the results varying depending on the population studied and age of ascertainment. Most studies use the standard definition of epilepsy, that is, two or more unprovoked seizures. Epilepsy is reported in 8.8% to 32% of children with MR and in up to half of children with severe retardation. 29 Prevalence is higher in institutionalized patients, those with severe MR (IQ < 50), and those with multiple disabilities. 29,31 Trevethan et a132 reported that 15% of a cohort of 10-year-old children with MR had concurrent epilepsy, 7.2% of those with mild MR and 32% of those with severe MR. In a population of 6- to 13-year-old children, Steffenburg et a133 reported prevalence of active epilepsy and MR of 2.0/1,000. Goulden et a134 reported the cumulative risk of epilepsy in 221 children with MR born between 1951 and 1955 in Aberdeen, Scotland. In children with MR and no other associated disabili-
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ties, the risk of epilepsy was 5.2% by age 22 years. 34 The presence of CP markedly increases the prevalence of epilepsy in patients with MR with a cumulative risk of 38% by age 22 years. 34Zafeiriou et a135 reported a prevalence of epilepsy in children with CP to be 36%, but other studies have reported rates of epilepsy in children with CP as high as 60%. 29,31 An increased prevalence of epilepsy is also reported in children with autistic spectrum disorders, ranging from 6.5% to 30%. 36,37 The etiology of seizures in this group of children is generally believed to reflect the same etiology as the MR, 23,38 the epilepsy arising from a variety of mechanisms related to and specific to individual syndromes. 39 In general, the more severe the epilepsy and the more severe the MR, the more extensive is the underlying cerebral dysfunction and damage. 4~ Most studies of MR and epilepsy have tended to differentiate between prenatal, perinatal, and postnatal causes with prenatal causes further differentiated into acquired versus congenital/genetic causes. 34,41,42 Prenatal causes include abnormalities of cerebral developmental (cortical dysplasia), which are frequently the substrate for seizures in children who undergo surgery for intractable localization-related epilepsy.4345 MR is often present as a result of the cerebral developmental malformations, which are associated with epilepsy. Most of these patients are not candidates for epilepsy surgery, though some will have focal abnormalities that are potentially treatable by surgical removal. Steffenburg et a142 found that 56% of children with MR and active epilepsy had a presumed prenatal origin, of whom 48% had cerebral and "noncerebral maldevelopments," the latter defined as "minor congenital anomalies." Cortical dysplasia and pachygyria were found in six children. "Prenatal and untraceable" causes were more likely to be described in those with mild MR than in those with severe MR, who tended to have perinatal and postnatal causes. 42 This is significant as we consider evaluation of patients with seizures and MR for possible surgically treatable causes.
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abnormalities are likely to result in severe MR as well as intractable seizures, although significant variability is reported. 44 Type I lissencephaly often presents with infantile spasms in association with profound developmental delays. 43 Less-severe cognitive impairment and epilepsy are reported in some patients with band heterotopia. 44 On the other hand, patients with subependymal heterotopia (also known as periventricular and subcortical nodular heterotopia) commonly have seizures and may have normal cognition or mild MR. 44 The syndrome of bilateral perisylvian cortical dysplasia, pseudobulbar palsy, and secondarily generalized seizures is associated with cognitive impairment of variable severity.46 Patients with bilateral schizencephaly may have significant developmental delays and seizures, but those with small unilateral clefts may be asymptomatic or have focal seizures without MR. 43,44 Hemimegalencephaly is a congenital disorder of unknown origin associated with unilateral cerebral maldevelopment and at times associated with contralateral somatic hypertrophy. Parents with hemimegalencephaly often experience intractable epilepsy as well as developmental delay and may be candidates for hemispherectomy. 43,47 Focal cortical dysplasia is the most common form of focal developmental abnormality associated with intractable seizures and is often approachable surgically. 43 MR is a variable feature, less likely to be seen in older patients with milder epilepsy. 44 Other disorders associated with potentially resectable structural lesions, MR and intractable epilepsy include tuberous sclerosis and Sturge-Weber syndrome. Surgical treatment of the epilepsy may be associated with significant improvement in developmental outcome. 48,49Acquired causes, such as perinatal ischemic injury, are less likely to be associated with surgically resectable lesions although perinatal strokes may result in porencephaly and potential treatment by hemispherectomy or multilobar resections. 5~ Hemispherectomy remains the only proven and widely accepted treatment for Rasmussen's encephalitis. 51
Cortical Dysplasia
SEIZURE TYPES AND EPILEPSY SYNDROMES
Cortical dysplasia forms a spectrum of lesions resulting from abnormal development of neocortex. The classification of cortical dysplasia remains confusing for clinicians, with embryology, anatomy, and genetics providing the basis of classification rather than clinical features. 44 Generalized cerebral
In patients with MR, diagnosing epilepsy may present significant difficulties in that an accurate clinical history may be unobtainable. A variety of nonepileptic events may occur that may be misdiagnosed. Video-electroencephalographic recordings may be necessary to define the presence and nature
EPILEPSY SURGERY IN CHILDREN WITH DISABILITIES
of epileptic seizures. 38 In addition, classifying seizures using the International League Against Epilepsy classification is difficult. As with infants and young children, it may not be possible to determine the presence of an aura or of impairment of consciousness. Nevertheless, estimates of the relative prevalence of various seizure types in patients with MR provide evidence of significant numbers of patients with localization-related epilepsy. In a population of 326 institutionalized patients with MR and epilepsy, Mariani et a141 identified 106 (32.5%) with partial seizures of whom 70% experienced secondary generalization. Ninety-three (90%) of the patients with partial seizures had "well-defined brain lesions." Steffenburg et aP 3 defined the characteristics of epilepsy in a population-based study of epilepsy and mentally retarded children in Goteborg. Focal abnormalities were detected in the EEG of 79%. Seventy percent showed evidence of brain lesions on imaging but only 9% showed a unifocal abnormality, and there was not a clear correlation between focality on the EEG and a focal lesion on imaging. There is a well-recognized and all too frequent association between developmental delays and the so-called catastrophic epilepsy syndromes, especially those of infancy. More than 75% of children with West syndrome 52 and 90% of those with Lennox-Gastaut syndrome 53 are severely cognitively impaired. Although resective surgery may be an option for some children with intractable infantile spasms] 7 this is not an option for many who continue to experience intractable epilepsy as well as severe cognitive impairment.
Outcomes of Surgery Falconer I reported on his experience in two adolescents (among 6 patients with childhoodonset temporal lobe epilepsy), advocating early surgery for patients with temporal lobe epilepsy of childhood onset. In 1975, Davidson and Falconer 13 reported outcomes in 40 children 15 years old and younger of whom 23 were seizure-free at followup. This series specifically excluded patients with low IQs for concern that they were likely to have "widespread brain damage." Surgery for treatment of medically uncontrolled epilepsy in children is now widely accepted, with reported outcomes similar to those in adult series. 2,8,~1 However, it remains unclear as to whether low IQ is a significant predictor of poor outcomes regarding seizure
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control. It is generally accepted that the best surgical candidates are those with discrete areas of brain that are epileptogenic and amenable to resection without significant risk of neurologic or functional injury. There remains a concern that patients with MR may have diffuse cerebral dysfunction and will have poorer outcomes because of diffuse or multifocal epileptogenic regions.15 Outcomes in various studies suggest that adult patients with low IQ may be less likely to be seizure-free following epilepsy surgery. However, significant numbers of patients do achieve marked reduction in seizures and many become seizure free. Chelune et a154 evaluated outcomes of temporal lobectomy in 1,034 patients from eight epilepsy centers. All subjects were 16 years or older at the time of surgery. Patients who became seizure-free following surgery had higher preoperative IQ scores than those with continued seizures (two or more seizures postoperatively). Analysis of seizure outcome by standard IQ ranges (MR: 50 to 69; Borderline: 70 to 79; low average: 80 to 89; Average 90 to 109; High Average 110 to 119; Superior 120+) failed to reveal a significant relationship between seizure outcome and IQ. However, analysis by collapsing categories of 50 to 75; 76 to 109; and 110+ resulted in a significantly increased likelihood of continued seizures in those with the lowest IQ scores (32.8%) as opposed to the other two categories, 23.8% and 16.9%, respectively. They conclude, "However, the magnitude of the observed differences and the effect size of these differences were quite small, suggesting that baseline IQ scores alone are apt to be of little clinical utility in predicting success or failure in the case of the individual patient. ''54 Gleissner et ai 55 reported a retrospective analysis of 16 patients with low intelligence (mean IQ = 70, range 47 to 83) who were over 13 years old at the time of focal resective surgery. One-year follow-up data were available in 14 patients. Nine (64%) were seizure-free. Poor outcome was believed to be due to "insufficient resection" of the identified epileptogenic region rather than the presence of multifocal epilepsy. Similarly, there is evidence suggesting that children with MR are less likely to have good outcomes as measured by seizure recurrence postoperatively. Gilliam et al 8 reported outcomes on 33 children who underwent epilepsy surgery at the University of Alabama at Birmingham and The Cleveland Clinic epilepsy centers. Sixty-seven per-
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cent were seizure-free and an additional 9% experienced a >90% reduction in seizures (Engel classes I and II). Five patients had low IQ (Verbal and Performance IQ < 70). Two of these (40%) were seizure-free and one had a >90% decrease in seizure frequency. Szabo et a156 reported on the outcomes in five patients with pervasive developmental disorders, aged 32 months to 8 years of age who underwent epilepsy surgery. Four had temporal lobectomies and one had a multilobar resection. Three (60%) were seizure-free, one had rare staring spells, and one had significant but incomplete improvement (decreased severity and frequency, with sleep-related seizures only). Only one child showed significant neurobehavioral improvement (the child with persistent seizures). One showed mild improvement and one showed deterioration in neurobehavioral function. One was unchanged. Adams et al4 reported outcomes of temporal lobectomy in 44 children under the age of 16 years. When they analyzed outcomes by dividing the patients into two groups, IQ greater than or less than the median IQ of 90, there was a tendency for better outcomes in those with higher presurgical IQ scores, with 76% becoming seizure-free as opposed to 50% in the lower IQ group. In a retrospective review of 64 patients under the age of 18 years who had undergone cortical resection, Gashlan et al7 found no relationship between seizure outcome following surgery and preoperative intellectual function. A sep~ate analysis of temporal as opposed to extratemporal resections suggested that among patients who had temporal resections and g o d seizures outcomes, normal presurgical intellectual functioning was more frequent. Not all series of pediatric patients report MR as a significant risk factor. Wyllie et al z reported surgery outcomes in 136 children operated on at the Cleveland Clinic between 1990 and 1996. Patients with temporal resections had highest IQs (mean IQ score of 84 in children and 96 in adolescents). Extratemporal patients were lower, 69 for children and 78 for adolescents. No statistical difference was found between those who became seizure-free versus those who did not, whether analyzed as a group or by the nature of the resection (temporal, extratemporal/multilobar, or hemispherectomy), though those with extratemporal/multilobar resections did less well than those with temporal resections or hemispherectomies (54% seizure-free versus 78% and 69%, respectively). In an analysis of
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preoperative factors predictive of outcome following temporal lobectomy in 33 children, Goldstein et al5 found that MR was less common in those who were seizure-free than in those who were not, but the difference did not reach statistical significance. In younger children, that is, those 3 years and younger, the issues are complicated by difficulties in obtaining meaningful measure of cognition and by the uncertainty regarding the immature brain's response to epilepsy on the one hand and resective surgery on the other. 17,18,57,58 In a series of infants operated on at Miami Children's Hospital, 80% had moderate or severe MR. 17 However, the value of early surgery to prevent subsequent cognitive decline is one potential rationale for early surgery, though it is not clear that this will necessarily occur. 2 Resective surgery, including hemispherectomy, is advocated for some patients with Sturge-Weber syndrome to prevent progressive cognitive decline. 59 Evidence of developmental delay does not appear to be a contraindication to surgical intervention in children with Sturge-Weber syndrome. 49,6~MR and severe developmental delay have not been considered contraindications to corpus callosotomy for intractable epilepsy in children in multiple series, 61-63 though higher IQ appears to be associated with a better outcome in those operated on before age 13 years. 64 Although the role of surgery in treatment of medically uncontrolled epilepsy in patients with tuberous sclerosis complex remains ill defined, recent series have included patients with significant developmental delay or MR in more than half the cases. 48,65 Two of three patients with profound developmental delay in Baumgartner's series were improved. 65 Finally, hemispherectomy is performed for a variety of disorders including Rasmussen's encephalitis, Sturge-Weber syndrome, hemimegalencephaly, and infantile hemiplegia. 5~ Preoperative cognitive deficits do not appear to predict outcomes, and in fact, improved cognition may be noted in some patients. 66 However, evidence of bilateral abnormalities on PET scan in infants with hemimegalencephaly appears to predict worse outcome. 47 To date, there are little data regarding the efficacy of vagus nerve stimulation in patients with MR, though patients with Lennox-Gastaut syndrome, usually associated with significant cognitive dysfunction, appear to respond as well as patients with other epilepsy syndromes. 67
EPILEPSY SURGERY IN CHILDREN WITH DISABILITIES
PRESURGICAL EVALUATION OF THE CHILD WITH MR
There are three prerequisites for epilepsy surgery68: (1) the epilepsy must be medically intractable, that is, despite appropriate medical therapy, seizures persist; (2) the surgery must be feasible, that is, the epileptogenic zone can identified and safely resected; and (3) there is high likelihood of a satisfactory outcome as regards both the epilepsy and the patient's functional status. The specifics of each criterion may differ between children, particularly younger children, and adults, but the principles remain constant. The alterations reflect, in part, the plasticity of the immature brain both in terms of the potential impact of the epilepsy and the ability to tolerate resection of "eloquent" cortex. 2~ It remains for us to define these three criteria in children with MR.
Intractability The definition of intractability remains vague and must be placed in context of the individual. For the teenager with one complex partial seizure every 3 months, the inability to obtain a drivers license defines intractability. For the patient with MR, intractability requires identifying those factors in the patient's environment that are adversely affected by continuing seizures. For the purpose of epidemiologic study, Steffenburg et a133 chose to define intractability as the occurrence of seizures every day or week for 1 year despite appropriate use of three antiepileptic drugs. In their study, 45% of children with MR and active epilepsy were medically intractable. Marcus 69 defined intractability as one or more seizures per week, present in 21% of patients with MR and epilepsy in an outpatient pediatric neurology clinic. Factors other than frequency clearly impact on the definition, including seizure severity and medication side effects. Only recently have measures of seizure severity and side effects appropriate for children, including children with MR, become available. 7~ Also to be considered is the impact of continuing seizures on cognitive development, especially in the vulnerable young child who already demonstrates evidence of cerebral dysfunction and developmental delay. ~7 The extent to which poorly controlled epilepsy has a social impact, creating more restrictive living and work environment for developmentally delayed children must be considered. Other issues to consider are the risk of
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significant injury, impact of medications on children with limited cognitive reserves, and the increased risk of mortality in patients with MR and uncontrolled epilepsy. 71
Feasibility Modem technology, including magnetic resonance imaging and functional imaging, has altered our ability to identify resectable lesions, 16,72 but noninvasive identification of the epileptogenic focus remains imprecise. The identification of the putative "epileptogenic zone" often requires intracranial monitoring. 73,74 Experience with infants undergoing evaluations for epilepsy surgery suggests that intracranial monitoring with strips and grids is feasible. 17 Children as young as 6 years of age typically can participate in an intracarotid amobarbital test (IAT). 75 Nevertheless, the child with significant MR will often be unable to tolerate even noninvasive video-electroencephalographic monitoring, let alone IAT and intracranial monitoring. The risk of unexpected neurologic deficits must be considered in situations where mapping of eloquent cortex is not possible, given the plasticity of the immature nervous system and the possibility of functional reorganization. 76 Thus, although the presence of MR may indicate diffuse CNS dysfunction, it does not necessarily indicate diffuse or multifocal epileptogenesis. Appropriate patient selection is made possible through use of current technology that allows identification of lesions or areas of cerebral dysgenesis, aiding in identification of localized areas of epileptogenesis. Although functional imaging cannot replace direct recordings of ictal onset from subdural electrodes, it can both eliminate patients with multifocal or diffuse epileptogenesis and guide placement of subdural strip and grids in those with apparent unitary foci. Careful family history will further eliminate patients with genetic epilepsy or inherited disorders that make surgery ill advised, v7
Outcome Control of seizures is the primary objective of epilepsy surgery, and standard outcome measures, such as the widely used Engel outcome measures, are based on the degree to which seizures are controlled.78 Results from various series of patients who have undergone resective surgery for epilepsy have shown that with careful presurgical evaluations, outcomes are similar between patients with
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normal IQ scores and those with low scores. Seizure reduction is the most sensitive measure of efficacy of epilepsy treatment but not the sole measure. 79As Cassell 8~noted in 1975, " . . . there is a distinction between the disease of an organ of the body and the illness of the whole man." Our goal is not only treatment of the disease, that is, epileptic seizures but treatment of the illness, that is, the entire patient. HRQOL is an appropriate outcome measure for epilepsy surgery and several validated measures are now available for adults and adolescents who have undergone surgery for epilepsy. 81,82 Unfortunately, there are few measures of HRQOL for children with disabilities in general 83 and only limited tools for assessing children with epilepsy, especially those with co-existing MR. 8,84 As we consider outcomes of epilepsy surgery in children with MR, it behooves us to recall that the goal of epilepsy surgery is not simply elimination of seizures. The goal is to improve functional outcomes. As Taylor et a185 point out, it is often disappointing to observe that some patients who become seizure-free continue to lead disabled lives. Presurgical expectations play a significant role in perceived outcomes after surgery. As Taylor et al emphasizes " . . . (it is an) unsound assumption that not having seizures will lead to obvious benefits that will be manifest in the way in which life is subsequently lived."85 It is imperative that presurgical expectations be clear before embarking on invasive procedures in patients with MR. Too often, families blame seizures and medications for the entirety of the cognitive difficulties of their child with MR. Unrealistic expectations regarding postoperative functioning even with total seizure control must be anticipated and dealt with early on. The likelihood of continued need for use of antiepileptic drugs postoperatively should be discussed. On the other hand, reduction in seizure severity and frequency or reduction in the amounts of medication required for improved seizure control may be sufficient reasons for pursuing epilepsy surgery for many children with developmental disabilities.
Establishing Protocols In children with MR, evaluation must often be altered in recognition of the child's specific limitations. Neuropsychologic assessment early in the process of evaluation can help tailor the protocols in recognition of each child's developmental level.
PAUL M. LEVISOHN
At the Children's Epilepsy Program of The Children's Hospital, Denver, neuropsychologic testing and psychosocial evaluation often occur at the time of admission to the hospital for phase I (videoEEG) monitoring, as medications are tapered. This allows observation of the child in a setting that will reflect the child's tolerance for hospitalization and the limitations imposed by monitoring.
Phase I Video-EEG Monitoring As with all children who are candidates for resective surgery, ictal recording of typical seizures is required. A parent or caretaker familiar with the child's repertoire of seizures must be in attendance, and review of videotapes with family can often clarify issues regarding seizure semiology. Medication withdrawal before admission is often advisable to shorten the time necessary to record seizures.
IAT Neuropsychologic assessment before IAT can often determine a child's ability to participate in IAT. Modification of standard protocols may be necessary for the child who cannot read. More limited information may be determined, for instance, it may be impossible to ascertain lateralization of memory although language lateralization may be defined.
Invasivo Monitoring Localization of the presumptive epileptogenic zone by intracranial recording and delineating eloquent cortex by cortical stimulation are essential to appropriately plan surgical resection, especially in the absence of a structural lesion. This goal may be elusive in children with significant neurobehavioral and cognitive impairments. Intraoperative stimulation for motor mapping and electrocorticography to map interictal spikes may be the only tolerated intracranial diagnostic procedures in children with MR. Careful evaluation of noninvasive data may allow surgery to proceed but less than ideal outcomes may reflect the increased uncertainty. It is this uncertainty that would appear to be the most significant factor in limiting epilepsy surgery for children with MR, altering patient selection because of an inability to fully evaluate the child. As noted earlier, appropriate evaluations can result in outcomes that parallel those of patients with normal cognition.
EPILEPSY SURGERY IN CHILDREN WITH DISABILITIES
Outcomes Appropriate choice of outcome measures will provide the data on which surgical candidacy can be continuously redefined. At The Children's Hospital, Denver, those measures include a variety of instruments to assess HRQOL as well as impact of the child's illness on the family. No single measure of HRQOL has been found that is appropriate for all children and families. A variety of instruments are being used in the belief that further experience with available instruments will lead to appreciation of which are most sensitive and useful.
Informed Consent When dealing with vulnerable patients, special attention must be paid to informed consent. Increas-
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ingly, assent of a minor child is required before enrollment in clinical trials. Although the legal guardian must consent before treatment of a child may proceed, the process of assent is increasingly accepted as necessary in other situations also. How one obtains assent from a child with MR is unclear. Sensitive and unhurried discussions with the patient, as well as the family, are necessary before procedures that may produce fear, discomfort, pain, and a risk for injury. The information must be presented in a meaningful way at the level that the child can understand. As one 6-year-old with MR noted after temporal lobectomy surgery, "I hope that when you opened my brain, you found all of my seizures and took them all out and that none of them were hiding." Fortunately, for this child with intractable epilepsy and MR, none were.
REFERENCES 1. Falconer MA: Place of surgery for temporal lobe epilepsy during childhood. BMJ 2:631-632, 1972 2. Wyllie E, Comair YG, Kotagal P, et al: Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 44:720-748, 1998 3. Bizzi JWJ, Bruce DA, North R, et al: Surgical treatment of focal epilepsy in children: Results in 37 patients. Pediatr Neurosurg 26:83-92, 1997 4. Adams CBT, Beardsworth ED, Oxbury SM, et al: Temporal lobectomy in 44 children: Outcome and neuropsychological follow-up. J Epilepsy 3:157-168, 1990 (suppl) 5. Goldstein R, Harvey S, Duchowny M, et al: Preoperative clinical, EEG and imaging findings do not predict seizure outcome following temporal lobectomy in childhood. J Child Neurol 11:445-450, 1996 6. Morrison G, Duchowny M, Resnick T, et al: Epilepsy surgery in childhood: A report of 79 patients. Pediatr Neurosurg 18:291-297, 1992 7. Gashlan M, Loy-English 1, Ventureyra ECG, et al: Predictors of seizure outcome following cortical resection in pediatric and adolescent patients with medically refractory epilepsy. Childs Nerv Syst 15:45-51, 1999 8. Gilliam F, Wyllie E, Kashden J, et al: Epilepsy surgery outcome: Comprehensive assessment in children. Neurology 48:1368-1374, 1997 9. Westerveld M, Sass KJ, Chelune GJ, et al: Temporal lobectomy in children: Cognitive outcome. J Neurosurg 92:2430, 2000 10. Munari C, Lo Russo G, Minotti L, et al: Presurgical strategies and epilepsy surgery in children: Comparison of literature and personal experience. Childs Nerv Syst 15:149157, 1999 11. Bourgeois M, Sainte-Rose C, Lellouch-Tubiana A, et al: Surgery of epilepsy associated with focal lestions in childhood. J Neurosurg 90:833-842, 1999 12. Keene DL, Higgins M, Ventureyara ECG: Outcome and life prospects after surgical management of medically intrac-
table epilepsy in patients under 18 years of age. Childs Nerv Syst 13:530-535, 1997 13. Davidson S, Falconer MA: Outcome of surgery in 40 children with temporal-lobe epilepsy. Lancet 1: 1260-1263, 1975 14. Lieb JP, Rausch R, Engel JJr, et al: Changes in intelligence following temporal lobectomy: Relationship to EEG activity, seizure relief, and pathology. Epilepsia 23:1-13, 1982 15. Engel JJr, Shewmon DA: Overview: Who should be considered a surgical candidate, in Engel JJr (ed): Surgical Treatment of the Epilepsies (ed 2). New York, NY, Raven, 1999, pp 23-34 16. Chugani HT, Shewmon DA, Shields WD, et al: Pediatric epilepsy surgery: Pre- and postoperative evaluation with PET. J Epilepsy 3:75-82, 1990 (suppl) 17. Duchowny M, Jayakar P, Resnick T, et al: Epilepsy surgery in the first three years of life. Epilepsia 39:737-743, 1998 18. Sugimoto T, Otsubo H, Hwang PA, et al: Outcome of epilepsy surgery in the first three years of life. Epilepsia 40:560-565, 1999 19. Hwang PA, Gilday DL, Adams C, et al: SPECT studies in epilepsy: Application to epilepsy surgery in children. J Epilepsy 3:83-92, 1990 (suppl) 20. Shewmon DA, Shields WD, Chugani HT, et al: Contrasts between pediatric and adult epilepsy surgery: Rationale and strategy for focal resection. J Epilepsy 3:141-155, 1990 (suppl) 21. Cassidy G, Corbett J: Learning disorders, in Engel JJr, Pedley TA (eds): Epilepsy: A Comprehensive Textbook. Philadelphia, PA, Lippincott-Raven, 1999, pp 2053-2063 22. Shevell MI, Swaiman KF: Global developmental delay and mental retardation, in Swaiman KF, Ashwal S (eds): Pediatric Neurology: Principles and Practice (ed 3). St. Louis, MO, Mosby, 1999, pp 551-560 23. Coulter DL: Epilepsy and mental retardation: An overview. Am J Ment Retard 98:S1-S11, 1993 (suppl) 24. Vining EPG: Psychosocial issues for children with epilepsy. Cleve Clin J Med 56:S-214-$220, 1989 (suppl part 2)
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25. Leonard E, George MRM: Psychosocial and neuropsychological function in children with epilepsy. Pediatr Rehabil 3:73-80, 1999 26. Steffenburg U, Hagberg G, Kyllerman M: Active epilepsy in mentally retarded children. I. Prevalence and additional neuroimpairments. Acta Pediatr 84:1147-1152, 1995 27. Beckung E, Uvebrant P: Impairments, disabilities and handicaps in children and adolescents with epilepsy. Acta Pediatr 86:254-260, 1997 28. Sillanpaa M: Epilepsy in children: Prevalence, disability, and handicap. Epilepsia 33:444-449, 1992 29. Hauser WA, Hesdorffer DC: Epilepsy: Frequency, Causes and Consequences. New York, NY, Demos Publications, 1990 30. Schoenfeld J, Seidenberg J, Woodard A, et al: Neuropsychological and behavioral status of children with complex partial seizures. Dev Med Child Neuro141:724-731, 1999 31. Sillanpaa M: Definitions and epidemiology, in Sillanpaa M, Lennart G, Johannessen SI, et al (eds): Epilepsy and Mental Retardation. Petersfield, UK and Philadelphia, PA, Wrightson Biomedical Publishing, 1999, pp 1-6 32. Trevathan E, Yeargin-Allsopp M, Murphy CC, et al: Epilepsy among children with mental retardation. Ann Neurol 24:321, 1988 (abstr) 33. Steffenburg U, Hedstrom A, Lindroth A, et al: Intractable epilepsy in a population-based series of mentally retarded children. Epilepsia 39:767-775, 1998 34. Goulden KJ, Shinnar S, Killer H, et al: Epilepsy in children with mental retardation: A cohort study. Epilepsia 32:690-697, 1991 35. Zafeiriou DI, Kontopoulos EE, Tsikoulas I: Characteristics and prognosis of epilepsy in children with cerebral palsy. J Child Neurol 14:289-294, 1999 36. Wong V: Epilepsy in children with autistic spectrum disorder. J Child Neurol 8:316-322, 1993 37. Tuchman R, Rapin I: Regression in pervasive developmental disorders: Seizures and epileptiform electroencephalogram correlates. Pediatrics 99:560-566, 1997 38. Iivanainen M: Diagnosing epilepsy in patients with mental retardation, in Sillanpaa M, Lennart G, Johannessen SI, et al (eds): Epilepsy and Mental Retardation. Petersfield, UK and Philadelphia, PA, Wrightson Biomedical Publishing, 1999, pp 62-72 39. Stafstrom CE: Mechanisms of epilepsy in mental retardation: insights from Angelman syndrome, Down syndrome and fragile X syndrome, in Sillanpaa M, Lennart G, Johannessen SI, et al (eds): Epilepsy and Mental Retardation. Petersfield, UK and Philadelphia, PA, Wrightson Biomedical Publishing, 1999, pp 7-40 40. Aicardi J: Epilepsy in brain-injured children. Dev Med Child Neuro132:191-202, 1990 41. Mariani E, Ferini-Strami L, Sala M, et al: Epilepsy in institutionalized patients with encephalopathy: clinical aspects and nosological considerations. Am J Ment Retard 98:$27-$33, 1993 (suppl) 42. Steffenburg U, Hagberg G, Kyllerman M: Active epilepsy in mentally retarded children. II. Etiology and reduced pre- and perinatal optimality, Acta Pediatr 84:1153-1159, 1995 43. Kuzniecky ILI:MRI in cerebral developmental malformations and epilepsy. Magn Reson Imaging 13:1137-1145, 1995 44. Whiting S, Duchowny M: Clinical spectrum of cortical
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dysplasia in childhood: Diagnosis and treatment issues. J Child Neurol 14:759-771, 1999 45. Mischel PS, Vinters HV: Neuropathology. Neurosurg Clin North Am 6:565-579, 1995 46. Kuzniecky R, Andermann F, Guerrini, et al: The epileptic spectrum in the congenital bilateral perisylvian syndrome. Neurology 44:379-385, 1994 47. Rintahaka PJ, Chugani HT, Messa C, et al: Hemimegalencephaly: Evaluation with positron emission tomography. Pediatr Neurol 9:21-28, 1993 48. Avellino AM, Berger MS, Rostomily RC, et al: Surgical management and outcome in patients with tuberous sclerosis. J Neurosurg 87:391-396, 1997 49. Rochkind S, Hoffman HJ, Hendrick EB: Sturge-Weber syndrome: Natural history and prognosis. J Epilepsy 3:293-304, 1990 (suppl) 50. Vining EPG, Freeman JM, Carson BS, et al: Hemispherectomy in children: The Hopkins experience, 1968-1988, a preliminary report. J Epilepsy 3:169-176, 1990 51. Peacock WJ: Hemispherectomy for the treatment of intractable seizures in childhood. Neurosurg Clin North Am 6:549-63, 1995 52. Riikonen R: West's syndrome, in Wallace S (ed): Epilepsy in Children. London, Chapman and Hall Medical, 1996, pp 209-226 53. Aicardi J: Lennox-Gastaut syndrome, in Wallace S (ed): Epilepsy in Children. London, Chapman and Hall Medical, 1996, pp 249-262 54. Chelune GJ, Nangle RI, Hermann BP, et ah Does presurgical IQ predict seizure outcome after temporal lobectomy? Evidence from the Bozeman Epilepsy Consortium. Epilepsia 39:314-318, 1998 55. Gleissner U, Johanson K, Helmstaedter C, et al: Surgical outcome in a group of low-IQ patients with focal epilepsy. Epilepsia 40:553-559, 1999 56. Szabo CA, Wyllie E, Dolske M, et al: Epilepsy surgery in children with pervasive developmental disorder. Pediatr Neurol 20:349-353, 1990 57. Duchowny M, Levin B, Jayakar P, et al: Neurobiologic considerations in early surgery for epilepsy. J Child Neurol 9:2S42-2S49, 1994 (suppl) 58. Resnick T, Duchowny M, Jayakar P: Early surgery for epilepsy: Redefining candidacy. J Child Neurol 9:2S36-2S41, 1994 (suppl) 59. Erba G, Cavazzuti V: Sturge-Weber syndrome: Natural history and indications for surgery. J Epilepsy 2:287-291, 1990 (suppl) 60. Ito M, Sato K, Ohnuki A, et al: Sturge-Weber disease: Operative indications and surgical results. Brain Dev 12:473437, 1990 61. Carmant L, Holmes GL: Commissurotomies in children. J Child Neurol 9:2S50-2S60, 1994 (suppl) 62. Black PM, Holmes G, Lomboso C: Corpus callosum section for intractable epilepsy in children. Pediatr Neurosurg 18:298-304, 1992 63. Gates JR, Ritter FJ, Ragazzo PC, et al: Corpus callosum section in children: Seizure response. J Epilepsy 2:271-278, 1990 (suppl) 64. Lassonde M, Sauerwein C: Neuropsychological outcome of corpus callosotomy in children and adolescents. J Neurosurg Sci 41:67-73, 1997
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65. Baumgartner JE, Wheless JW, Kulkarni S, et al: On the surgical treatment of refractory epilepsy in tuberous sclerosis complex. Pediatr Neurosurg 27:311-318, 1997 66. Brandt J, Vining EPG, Stark RE, et al: Hemispherectomy for intractable epilepsy in childhood: Preliminary report on neuropsychological and psychosocial sequelae. J Epilepsy 3:261270, 1990 (suppl) 67. Frost M, Gates J, Helmers S, et al: Vagus verve stimulation for the Lennox-Gastaut syndrome. (submitted for publication) 68. Aicardi J: Evolution of epilepsy surgery in childhood: The neurologist's point of view. Epileptic Disorders 1:243-247, 1999 69. Marcus JC: Control of epilepsy in a mentally retarded population: Lack of correlation with IQ, neurological status, and electroencephalogram. Am J Ment Retard 98:47-51, 1993 70. Carpay HA, Arts WFM, Vermeulen J, et al: Parentcompleted scales for measuring seizure severity and severity of side-effects of antiepileptic drugs in childhood epilepsy: Development and psychometric analysis. Epilepsy Res 24:173-181, 1996 71. Forsgren L, Edvinnson S-O, Nystrom L, et al: Influence of epilepsy on mortality in mental retardation: An epidemiologic study. Epilepsia 37:956-963, 1996 72. Cascino G: Structural neuroimaging in partial epilepsy: Magnetic resonance imaging. Neurosurg Clin North Am 6:455464, 1995 73. Engel J Jr: Principles of epilepsy surgery, in Shorvon S, Dreifus F, Fish D, et al (eds): The Treatment of Epilepsy. London, Blackwell Science, 1996 74. Jayakar P, Duchowny M, Resnick T: Subdural monitoring in the evaluation of children for epilepsy surgery. J Child Neurol 9:2S61-2S66, 1994 (suppl)
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75. Szabo CA, Wyllie E: Intracarotid amobarbital testing for language and memory dominance in children. Epilepsy Res 15:239-246, 1993 76. Duchowny M: Pediatric epilepsy surgery: The widening spectrum of surgical candidacy. Epileptic Disorders 1:143-151, 1999 77. Degen R, Holthausen H, Wolf P: The genetics of localization-related symptomatic epilepsy: Risk of a family history with seizures in patients who have undergone surgery. J Neuro1244:439-445, 1997 78. Engel JJr: Classification of outcome. J Epilepsy 3:219226, 1990 (suppl) 79. Baker GA, Camfield C, Camfield P, et al: ILAE Commission Report: Commission on outcome measurement in epilepsy, 1994-1997: Final report. Epilepsia 39:213-231, 1998 80. Cassell E: Illness and disease. Hastings Cent Rep 6:2737, 1976 81. Devinsky O: Outcome research in neurology: Incorporating health-related quality of life. Ann Neurol 37:141-142, 1995 (editorial) 82. Vickery BG, Hays R, Engel JJr: Outcome assessment for epilepsy surgery: The impact of measuring health-related quality of life. Ann Neurol 37:158-166, 1995 83. McLaughlin JE Bjornson KF: Quality of life and developmental disabilities. Dev Med Child Neurol 40:435, 1998 (editorial) 84. Hoare P, Russell M: The quality of life of children with chronic epilepsy and their families: Preliminary findings with a new assessment measure. Dev Med Child Neurol 37:689-696, 1995 85. Taylor DC, Neville BGR, Cross JH: New measure of outcome needed for the surgical treatment of epilepsy. Epilepsia 38:625-630, 1997
URGERY FOR treatment of medically uncontrolled epilepsy in children is now widely accepted, with reported outcomes similar to those in adults. However, there is a concern that patients with low IQ will experience poor outcomes from epilepsy surgery and will not achieve good seizure control. In 1972, Falconer I published his experience with surgery for temporal lobe epilepsy in children, expanding the indications for resective epilepsy surgery to include children with intractable temporal lobe epilepsy. Subsequently, many series have been published documenting experience in epilepsy surgery for children, adolescents, and more recently, infants, documenting the efficacy, feasibility, and safety of resective surgery in children, e-12However, Falconer considered patients with low IQs (below 70) as inappropriate candidates for temporal lobectomy, expressing concern regarding "widespread brain damage. ''13 Experience with adolescents and adults with epilepsy and low IQ suggested relatively poorer outcomes in patients with low IQs explained by the belief that mental retardation (MR) reflects diffuse central nervous system (CNS) dysfunction or multifocal sources of the seizures, the converse of appropriate
S
From the Children 'S Epilepsy Program, The Children 'S Hospital Denver, CO. Address reprint requests to Paul M. Levisohn, MD, The Children's Hospital, 1056 East 19 th Ave, B 155, Denver, CO 80218. Copyright 9 2000 by W.B. Saunders Company 1071-9091/00/0703-0007510.00/0 doi: l O.l O53/spen.2000.9216 194
substrate for resective surgery, the identifiable single focal lesion. 13,14 Significant developmental delay is still often considered a relative contraindication for resecfive epilepsy. 15 However, surgical treatment of epilepsy is now considered an option even for infants. 16-19 New diagnostic procedures, such as positron emission tomography (PET) scans and single photon emission computed tomography (SPECT), have helped identify appropriate candidates for epilepsy surgery, aiding in localization and directing invasive monitoring. Criteria and protocols for evaluation and surgical treatment of localization related epilepsy have been developed at multiple centers. 15,2~It is appropriate to reassess the prior bias against resective epilepsy surgery in children with mental retardation in view of the changing criteria for potential candidacy for epilepsy surgery in infants and young children. Cognitive and neurobehavioral dysfunction makes standard approaches to evaluation of surgical candidacy difficult. Diagnostic studies, such as intracarotid amobarbital testing (IAT), invasive monitoring, and cortical mapping, are often impossible in patients with significant MR, complicating the process of identifying the epileptogenic focus and functional cortex. Experience with younger children suggests that protocols can be developed for children with mental retardation, leading to effective decision-making and acceptable outcomes. The last several years have seen increasing emphasis on health-related quality-of-life (HRQOL) as an important outcome measure for epilepsy surgery. The development of new criteria for defin-
Seminars in Pediatric Neurology, Vol 7, No 3 (September), 2000: pp 194-203
EPILEPSY SURGERY IN CHILDREN WITH DISABILITIES
ing appropriate neuropsychologic and social indications for epilepsy surgery in the developmentally disabled remains a challenge. EPIDEMIOLOGY AND ETIOLOGY
MR has proven difficult to define. Even the term "mental retardation" is occasionally inappropriately shunned in preference for "learning disability. ''21 The more generic terms developmental disabilities and developmental delays are often used instead of MR, particularly with younger children. The definition of intelligence has proven controversial, and its accurate measurement is complex. In general, developmental disabilities are a heterogeneous group of disorders, onset of which are early in life. They feature disturbances in the ongoing development of cognitive, motor, and social skills. 22 Definitions of MR have emphasized significant difficulties in both general intellectual functioning as measured by standard instruments as well as concurrent deficits in adaptive function. 22 The American Association on Mental Retardation definition requires limitations in at least two areas of adaptive behavior that affect the functioning of an individual within society. 23 In epidemiologic studies, MR is pragmatically defined as measured IQ greater than two standard deviations below the mean, such that 2.5% of the population would be defined as being mentally retarded. The higher prevalence of MR in the socioeconomicaily disadvantaged points out the difficulties in defining MR, reflecting the importance of social and cultural factors in determining intelligence, a factor of importance for children with epilepsy. 24.25 There appear to be no generally accepted measures of adaptive skills. In practice, most studies of MR and epilepsy rely on measured IQ as the "administrative definition" of MR. 26 Measured IQ below 70 is generally accepted as the measure of low intelligence. Prevalence of MR has been estimated at 2.8 to 7.6/1000, though this is below the 2% to 3% rate that would be predicted by IQ measurement alone. 26 The World Health Organization differentiates between "impairment" (defined as a loss or abnormality of psychologic, physiologic, or anatomic structure or function occurring at the organ level) from "disability" (defined as the consequence of impairment in terms of functional performance and activity by an individual)Y Handicaps are further definable as the result of an interaction between an individual with impairment or disability and that
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individual's environment. 27 Disabilities and handicaps are common in children with epilepsy, with various studies having shown additional neurodisorders in one third of children with epilepsy, especially MR and cerebral palsy. 27 In a populationbased study in Goteborg, Sweden, Beckung identified mild MR (IQ 50 to 70) in 22% and severe MR (IQ < 50) in 27% of children with epilepsy. 27 In a similar Finnish study assessing the occurrence of disabilities and handicaps in children with epilepsy, Sillanpaa 28 found the most common comorbid neurologic impairment to be MR, which occurred in 31.4% of an unselected population of Finnish children ages 4 to 15 years with epilepsy. However, differences in methods have resulted in quite variable estimates of the frequency of MR in children with epilepsy. 21 Impaired cognitive, academic, and social functioning occurs more frequently than can be explained by the measured IQs of children with epilepsy. 29 Sillanpaa 28 found speech disorders in 27.5% of children with epilepsy and specific learning disorders in 23.1%. Beckung and Uvebrant 27 found "impairment of perception" in 23% of children with epilepsy without either MR or cerebral palsy (CP). Significant neuropsychoiogic impairment in children with complex partial seizures (CPS) is evident, suggesting generalized cognitive effects of even partial seizures, further impacting the social functioning of children with epilepsy and MR. 30 Various studies have reported the incidence and prevalence of epilepsy in patients with MR, the results varying depending on the population studied and age of ascertainment. Most studies use the standard definition of epilepsy, that is, two or more unprovoked seizures. Epilepsy is reported in 8.8% to 32% of children with MR and in up to half of children with severe retardation. 29 Prevalence is higher in institutionalized patients, those with severe MR (IQ < 50), and those with multiple disabilities. 29,31 Trevethan et a132 reported that 15% of a cohort of 10-year-old children with MR had concurrent epilepsy, 7.2% of those with mild MR and 32% of those with severe MR. In a population of 6- to 13-year-old children, Steffenburg et a133 reported prevalence of active epilepsy and MR of 2.0/1,000. Goulden et a134 reported the cumulative risk of epilepsy in 221 children with MR born between 1951 and 1955 in Aberdeen, Scotland. In children with MR and no other associated disabili-
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ties, the risk of epilepsy was 5.2% by age 22 years. 34 The presence of CP markedly increases the prevalence of epilepsy in patients with MR with a cumulative risk of 38% by age 22 years. 34Zafeiriou et a135 reported a prevalence of epilepsy in children with CP to be 36%, but other studies have reported rates of epilepsy in children with CP as high as 60%. 29,31 An increased prevalence of epilepsy is also reported in children with autistic spectrum disorders, ranging from 6.5% to 30%. 36,37 The etiology of seizures in this group of children is generally believed to reflect the same etiology as the MR, 23,38 the epilepsy arising from a variety of mechanisms related to and specific to individual syndromes. 39 In general, the more severe the epilepsy and the more severe the MR, the more extensive is the underlying cerebral dysfunction and damage. 4~ Most studies of MR and epilepsy have tended to differentiate between prenatal, perinatal, and postnatal causes with prenatal causes further differentiated into acquired versus congenital/genetic causes. 34,41,42 Prenatal causes include abnormalities of cerebral developmental (cortical dysplasia), which are frequently the substrate for seizures in children who undergo surgery for intractable localization-related epilepsy.4345 MR is often present as a result of the cerebral developmental malformations, which are associated with epilepsy. Most of these patients are not candidates for epilepsy surgery, though some will have focal abnormalities that are potentially treatable by surgical removal. Steffenburg et a142 found that 56% of children with MR and active epilepsy had a presumed prenatal origin, of whom 48% had cerebral and "noncerebral maldevelopments," the latter defined as "minor congenital anomalies." Cortical dysplasia and pachygyria were found in six children. "Prenatal and untraceable" causes were more likely to be described in those with mild MR than in those with severe MR, who tended to have perinatal and postnatal causes. 42 This is significant as we consider evaluation of patients with seizures and MR for possible surgically treatable causes.
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abnormalities are likely to result in severe MR as well as intractable seizures, although significant variability is reported. 44 Type I lissencephaly often presents with infantile spasms in association with profound developmental delays. 43 Less-severe cognitive impairment and epilepsy are reported in some patients with band heterotopia. 44 On the other hand, patients with subependymal heterotopia (also known as periventricular and subcortical nodular heterotopia) commonly have seizures and may have normal cognition or mild MR. 44 The syndrome of bilateral perisylvian cortical dysplasia, pseudobulbar palsy, and secondarily generalized seizures is associated with cognitive impairment of variable severity.46 Patients with bilateral schizencephaly may have significant developmental delays and seizures, but those with small unilateral clefts may be asymptomatic or have focal seizures without MR. 43,44 Hemimegalencephaly is a congenital disorder of unknown origin associated with unilateral cerebral maldevelopment and at times associated with contralateral somatic hypertrophy. Parents with hemimegalencephaly often experience intractable epilepsy as well as developmental delay and may be candidates for hemispherectomy. 43,47 Focal cortical dysplasia is the most common form of focal developmental abnormality associated with intractable seizures and is often approachable surgically. 43 MR is a variable feature, less likely to be seen in older patients with milder epilepsy. 44 Other disorders associated with potentially resectable structural lesions, MR and intractable epilepsy include tuberous sclerosis and Sturge-Weber syndrome. Surgical treatment of the epilepsy may be associated with significant improvement in developmental outcome. 48,49Acquired causes, such as perinatal ischemic injury, are less likely to be associated with surgically resectable lesions although perinatal strokes may result in porencephaly and potential treatment by hemispherectomy or multilobar resections. 5~ Hemispherectomy remains the only proven and widely accepted treatment for Rasmussen's encephalitis. 51
Cortical Dysplasia
SEIZURE TYPES AND EPILEPSY SYNDROMES
Cortical dysplasia forms a spectrum of lesions resulting from abnormal development of neocortex. The classification of cortical dysplasia remains confusing for clinicians, with embryology, anatomy, and genetics providing the basis of classification rather than clinical features. 44 Generalized cerebral
In patients with MR, diagnosing epilepsy may present significant difficulties in that an accurate clinical history may be unobtainable. A variety of nonepileptic events may occur that may be misdiagnosed. Video-electroencephalographic recordings may be necessary to define the presence and nature
EPILEPSY SURGERY IN CHILDREN WITH DISABILITIES
of epileptic seizures. 38 In addition, classifying seizures using the International League Against Epilepsy classification is difficult. As with infants and young children, it may not be possible to determine the presence of an aura or of impairment of consciousness. Nevertheless, estimates of the relative prevalence of various seizure types in patients with MR provide evidence of significant numbers of patients with localization-related epilepsy. In a population of 326 institutionalized patients with MR and epilepsy, Mariani et a141 identified 106 (32.5%) with partial seizures of whom 70% experienced secondary generalization. Ninety-three (90%) of the patients with partial seizures had "well-defined brain lesions." Steffenburg et aP 3 defined the characteristics of epilepsy in a population-based study of epilepsy and mentally retarded children in Goteborg. Focal abnormalities were detected in the EEG of 79%. Seventy percent showed evidence of brain lesions on imaging but only 9% showed a unifocal abnormality, and there was not a clear correlation between focality on the EEG and a focal lesion on imaging. There is a well-recognized and all too frequent association between developmental delays and the so-called catastrophic epilepsy syndromes, especially those of infancy. More than 75% of children with West syndrome 52 and 90% of those with Lennox-Gastaut syndrome 53 are severely cognitively impaired. Although resective surgery may be an option for some children with intractable infantile spasms] 7 this is not an option for many who continue to experience intractable epilepsy as well as severe cognitive impairment.
Outcomes of Surgery Falconer I reported on his experience in two adolescents (among 6 patients with childhoodonset temporal lobe epilepsy), advocating early surgery for patients with temporal lobe epilepsy of childhood onset. In 1975, Davidson and Falconer 13 reported outcomes in 40 children 15 years old and younger of whom 23 were seizure-free at followup. This series specifically excluded patients with low IQs for concern that they were likely to have "widespread brain damage." Surgery for treatment of medically uncontrolled epilepsy in children is now widely accepted, with reported outcomes similar to those in adult series. 2,8,~1 However, it remains unclear as to whether low IQ is a significant predictor of poor outcomes regarding seizure
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control. It is generally accepted that the best surgical candidates are those with discrete areas of brain that are epileptogenic and amenable to resection without significant risk of neurologic or functional injury. There remains a concern that patients with MR may have diffuse cerebral dysfunction and will have poorer outcomes because of diffuse or multifocal epileptogenic regions.15 Outcomes in various studies suggest that adult patients with low IQ may be less likely to be seizure-free following epilepsy surgery. However, significant numbers of patients do achieve marked reduction in seizures and many become seizure free. Chelune et a154 evaluated outcomes of temporal lobectomy in 1,034 patients from eight epilepsy centers. All subjects were 16 years or older at the time of surgery. Patients who became seizure-free following surgery had higher preoperative IQ scores than those with continued seizures (two or more seizures postoperatively). Analysis of seizure outcome by standard IQ ranges (MR: 50 to 69; Borderline: 70 to 79; low average: 80 to 89; Average 90 to 109; High Average 110 to 119; Superior 120+) failed to reveal a significant relationship between seizure outcome and IQ. However, analysis by collapsing categories of 50 to 75; 76 to 109; and 110+ resulted in a significantly increased likelihood of continued seizures in those with the lowest IQ scores (32.8%) as opposed to the other two categories, 23.8% and 16.9%, respectively. They conclude, "However, the magnitude of the observed differences and the effect size of these differences were quite small, suggesting that baseline IQ scores alone are apt to be of little clinical utility in predicting success or failure in the case of the individual patient. ''54 Gleissner et ai 55 reported a retrospective analysis of 16 patients with low intelligence (mean IQ = 70, range 47 to 83) who were over 13 years old at the time of focal resective surgery. One-year follow-up data were available in 14 patients. Nine (64%) were seizure-free. Poor outcome was believed to be due to "insufficient resection" of the identified epileptogenic region rather than the presence of multifocal epilepsy. Similarly, there is evidence suggesting that children with MR are less likely to have good outcomes as measured by seizure recurrence postoperatively. Gilliam et al 8 reported outcomes on 33 children who underwent epilepsy surgery at the University of Alabama at Birmingham and The Cleveland Clinic epilepsy centers. Sixty-seven per-
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cent were seizure-free and an additional 9% experienced a >90% reduction in seizures (Engel classes I and II). Five patients had low IQ (Verbal and Performance IQ < 70). Two of these (40%) were seizure-free and one had a >90% decrease in seizure frequency. Szabo et a156 reported on the outcomes in five patients with pervasive developmental disorders, aged 32 months to 8 years of age who underwent epilepsy surgery. Four had temporal lobectomies and one had a multilobar resection. Three (60%) were seizure-free, one had rare staring spells, and one had significant but incomplete improvement (decreased severity and frequency, with sleep-related seizures only). Only one child showed significant neurobehavioral improvement (the child with persistent seizures). One showed mild improvement and one showed deterioration in neurobehavioral function. One was unchanged. Adams et al4 reported outcomes of temporal lobectomy in 44 children under the age of 16 years. When they analyzed outcomes by dividing the patients into two groups, IQ greater than or less than the median IQ of 90, there was a tendency for better outcomes in those with higher presurgical IQ scores, with 76% becoming seizure-free as opposed to 50% in the lower IQ group. In a retrospective review of 64 patients under the age of 18 years who had undergone cortical resection, Gashlan et al7 found no relationship between seizure outcome following surgery and preoperative intellectual function. A sep~ate analysis of temporal as opposed to extratemporal resections suggested that among patients who had temporal resections and g o d seizures outcomes, normal presurgical intellectual functioning was more frequent. Not all series of pediatric patients report MR as a significant risk factor. Wyllie et al z reported surgery outcomes in 136 children operated on at the Cleveland Clinic between 1990 and 1996. Patients with temporal resections had highest IQs (mean IQ score of 84 in children and 96 in adolescents). Extratemporal patients were lower, 69 for children and 78 for adolescents. No statistical difference was found between those who became seizure-free versus those who did not, whether analyzed as a group or by the nature of the resection (temporal, extratemporal/multilobar, or hemispherectomy), though those with extratemporal/multilobar resections did less well than those with temporal resections or hemispherectomies (54% seizure-free versus 78% and 69%, respectively). In an analysis of
PAUL M. LEVISOHN
preoperative factors predictive of outcome following temporal lobectomy in 33 children, Goldstein et al5 found that MR was less common in those who were seizure-free than in those who were not, but the difference did not reach statistical significance. In younger children, that is, those 3 years and younger, the issues are complicated by difficulties in obtaining meaningful measure of cognition and by the uncertainty regarding the immature brain's response to epilepsy on the one hand and resective surgery on the other. 17,18,57,58 In a series of infants operated on at Miami Children's Hospital, 80% had moderate or severe MR. 17 However, the value of early surgery to prevent subsequent cognitive decline is one potential rationale for early surgery, though it is not clear that this will necessarily occur. 2 Resective surgery, including hemispherectomy, is advocated for some patients with Sturge-Weber syndrome to prevent progressive cognitive decline. 59 Evidence of developmental delay does not appear to be a contraindication to surgical intervention in children with Sturge-Weber syndrome. 49,6~MR and severe developmental delay have not been considered contraindications to corpus callosotomy for intractable epilepsy in children in multiple series, 61-63 though higher IQ appears to be associated with a better outcome in those operated on before age 13 years. 64 Although the role of surgery in treatment of medically uncontrolled epilepsy in patients with tuberous sclerosis complex remains ill defined, recent series have included patients with significant developmental delay or MR in more than half the cases. 48,65 Two of three patients with profound developmental delay in Baumgartner's series were improved. 65 Finally, hemispherectomy is performed for a variety of disorders including Rasmussen's encephalitis, Sturge-Weber syndrome, hemimegalencephaly, and infantile hemiplegia. 5~ Preoperative cognitive deficits do not appear to predict outcomes, and in fact, improved cognition may be noted in some patients. 66 However, evidence of bilateral abnormalities on PET scan in infants with hemimegalencephaly appears to predict worse outcome. 47 To date, there are little data regarding the efficacy of vagus nerve stimulation in patients with MR, though patients with Lennox-Gastaut syndrome, usually associated with significant cognitive dysfunction, appear to respond as well as patients with other epilepsy syndromes. 67
EPILEPSY SURGERY IN CHILDREN WITH DISABILITIES
PRESURGICAL EVALUATION OF THE CHILD WITH MR
There are three prerequisites for epilepsy surgery68: (1) the epilepsy must be medically intractable, that is, despite appropriate medical therapy, seizures persist; (2) the surgery must be feasible, that is, the epileptogenic zone can identified and safely resected; and (3) there is high likelihood of a satisfactory outcome as regards both the epilepsy and the patient's functional status. The specifics of each criterion may differ between children, particularly younger children, and adults, but the principles remain constant. The alterations reflect, in part, the plasticity of the immature brain both in terms of the potential impact of the epilepsy and the ability to tolerate resection of "eloquent" cortex. 2~ It remains for us to define these three criteria in children with MR.
Intractability The definition of intractability remains vague and must be placed in context of the individual. For the teenager with one complex partial seizure every 3 months, the inability to obtain a drivers license defines intractability. For the patient with MR, intractability requires identifying those factors in the patient's environment that are adversely affected by continuing seizures. For the purpose of epidemiologic study, Steffenburg et a133 chose to define intractability as the occurrence of seizures every day or week for 1 year despite appropriate use of three antiepileptic drugs. In their study, 45% of children with MR and active epilepsy were medically intractable. Marcus 69 defined intractability as one or more seizures per week, present in 21% of patients with MR and epilepsy in an outpatient pediatric neurology clinic. Factors other than frequency clearly impact on the definition, including seizure severity and medication side effects. Only recently have measures of seizure severity and side effects appropriate for children, including children with MR, become available. 7~ Also to be considered is the impact of continuing seizures on cognitive development, especially in the vulnerable young child who already demonstrates evidence of cerebral dysfunction and developmental delay. ~7 The extent to which poorly controlled epilepsy has a social impact, creating more restrictive living and work environment for developmentally delayed children must be considered. Other issues to consider are the risk of
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significant injury, impact of medications on children with limited cognitive reserves, and the increased risk of mortality in patients with MR and uncontrolled epilepsy. 71
Feasibility Modem technology, including magnetic resonance imaging and functional imaging, has altered our ability to identify resectable lesions, 16,72 but noninvasive identification of the epileptogenic focus remains imprecise. The identification of the putative "epileptogenic zone" often requires intracranial monitoring. 73,74 Experience with infants undergoing evaluations for epilepsy surgery suggests that intracranial monitoring with strips and grids is feasible. 17 Children as young as 6 years of age typically can participate in an intracarotid amobarbital test (IAT). 75 Nevertheless, the child with significant MR will often be unable to tolerate even noninvasive video-electroencephalographic monitoring, let alone IAT and intracranial monitoring. The risk of unexpected neurologic deficits must be considered in situations where mapping of eloquent cortex is not possible, given the plasticity of the immature nervous system and the possibility of functional reorganization. 76 Thus, although the presence of MR may indicate diffuse CNS dysfunction, it does not necessarily indicate diffuse or multifocal epileptogenesis. Appropriate patient selection is made possible through use of current technology that allows identification of lesions or areas of cerebral dysgenesis, aiding in identification of localized areas of epileptogenesis. Although functional imaging cannot replace direct recordings of ictal onset from subdural electrodes, it can both eliminate patients with multifocal or diffuse epileptogenesis and guide placement of subdural strip and grids in those with apparent unitary foci. Careful family history will further eliminate patients with genetic epilepsy or inherited disorders that make surgery ill advised, v7
Outcome Control of seizures is the primary objective of epilepsy surgery, and standard outcome measures, such as the widely used Engel outcome measures, are based on the degree to which seizures are controlled.78 Results from various series of patients who have undergone resective surgery for epilepsy have shown that with careful presurgical evaluations, outcomes are similar between patients with
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normal IQ scores and those with low scores. Seizure reduction is the most sensitive measure of efficacy of epilepsy treatment but not the sole measure. 79As Cassell 8~noted in 1975, " . . . there is a distinction between the disease of an organ of the body and the illness of the whole man." Our goal is not only treatment of the disease, that is, epileptic seizures but treatment of the illness, that is, the entire patient. HRQOL is an appropriate outcome measure for epilepsy surgery and several validated measures are now available for adults and adolescents who have undergone surgery for epilepsy. 81,82 Unfortunately, there are few measures of HRQOL for children with disabilities in general 83 and only limited tools for assessing children with epilepsy, especially those with co-existing MR. 8,84 As we consider outcomes of epilepsy surgery in children with MR, it behooves us to recall that the goal of epilepsy surgery is not simply elimination of seizures. The goal is to improve functional outcomes. As Taylor et a185 point out, it is often disappointing to observe that some patients who become seizure-free continue to lead disabled lives. Presurgical expectations play a significant role in perceived outcomes after surgery. As Taylor et al emphasizes " . . . (it is an) unsound assumption that not having seizures will lead to obvious benefits that will be manifest in the way in which life is subsequently lived."85 It is imperative that presurgical expectations be clear before embarking on invasive procedures in patients with MR. Too often, families blame seizures and medications for the entirety of the cognitive difficulties of their child with MR. Unrealistic expectations regarding postoperative functioning even with total seizure control must be anticipated and dealt with early on. The likelihood of continued need for use of antiepileptic drugs postoperatively should be discussed. On the other hand, reduction in seizure severity and frequency or reduction in the amounts of medication required for improved seizure control may be sufficient reasons for pursuing epilepsy surgery for many children with developmental disabilities.
Establishing Protocols In children with MR, evaluation must often be altered in recognition of the child's specific limitations. Neuropsychologic assessment early in the process of evaluation can help tailor the protocols in recognition of each child's developmental level.
PAUL M. LEVISOHN
At the Children's Epilepsy Program of The Children's Hospital, Denver, neuropsychologic testing and psychosocial evaluation often occur at the time of admission to the hospital for phase I (videoEEG) monitoring, as medications are tapered. This allows observation of the child in a setting that will reflect the child's tolerance for hospitalization and the limitations imposed by monitoring.
Phase I Video-EEG Monitoring As with all children who are candidates for resective surgery, ictal recording of typical seizures is required. A parent or caretaker familiar with the child's repertoire of seizures must be in attendance, and review of videotapes with family can often clarify issues regarding seizure semiology. Medication withdrawal before admission is often advisable to shorten the time necessary to record seizures.
IAT Neuropsychologic assessment before IAT can often determine a child's ability to participate in IAT. Modification of standard protocols may be necessary for the child who cannot read. More limited information may be determined, for instance, it may be impossible to ascertain lateralization of memory although language lateralization may be defined.
Invasivo Monitoring Localization of the presumptive epileptogenic zone by intracranial recording and delineating eloquent cortex by cortical stimulation are essential to appropriately plan surgical resection, especially in the absence of a structural lesion. This goal may be elusive in children with significant neurobehavioral and cognitive impairments. Intraoperative stimulation for motor mapping and electrocorticography to map interictal spikes may be the only tolerated intracranial diagnostic procedures in children with MR. Careful evaluation of noninvasive data may allow surgery to proceed but less than ideal outcomes may reflect the increased uncertainty. It is this uncertainty that would appear to be the most significant factor in limiting epilepsy surgery for children with MR, altering patient selection because of an inability to fully evaluate the child. As noted earlier, appropriate evaluations can result in outcomes that parallel those of patients with normal cognition.
EPILEPSY SURGERY IN CHILDREN WITH DISABILITIES
Outcomes Appropriate choice of outcome measures will provide the data on which surgical candidacy can be continuously redefined. At The Children's Hospital, Denver, those measures include a variety of instruments to assess HRQOL as well as impact of the child's illness on the family. No single measure of HRQOL has been found that is appropriate for all children and families. A variety of instruments are being used in the belief that further experience with available instruments will lead to appreciation of which are most sensitive and useful.
Informed Consent When dealing with vulnerable patients, special attention must be paid to informed consent. Increas-
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ingly, assent of a minor child is required before enrollment in clinical trials. Although the legal guardian must consent before treatment of a child may proceed, the process of assent is increasingly accepted as necessary in other situations also. How one obtains assent from a child with MR is unclear. Sensitive and unhurried discussions with the patient, as well as the family, are necessary before procedures that may produce fear, discomfort, pain, and a risk for injury. The information must be presented in a meaningful way at the level that the child can understand. As one 6-year-old with MR noted after temporal lobectomy surgery, "I hope that when you opened my brain, you found all of my seizures and took them all out and that none of them were hiding." Fortunately, for this child with intractable epilepsy and MR, none were.
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