Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 90
Neuropsychology Evaluation – Adults
David W. Loring
William B. Barr
Marla Hamberger
Christoph Helmstaedter
Introduction
Neuropsychological impairments are common in many epilepsy syndromes and are related to clinical factors such as seizure frequency and severity, age of seizure onset, as well as the underlying pathologic substrate. It is beyond the scope of this chapter to provide a comprehensive review of all epilepsy syndromes and their patterns of neuropsychological impairment. However, we will highlight several consistent neuropsychological principles.
As described by Hughlings Jackson, there are significant and independent contributions of both static and dynamic factors that affect brain function, and by extension, neuropsychological abilities. Morphologic or structural lesions are associated with relatively nonmodifiable neuropsychological deficits. In contrast, electroencephalographic (EEG) discharges, seizures, and epilepsy treatment are associated with more dynamic brain changes that, to varying degrees, are modifiable and are under direct physician management. Depending on epilepsy type (idiopathic vs. symptomatic), the relative contributions of specific factors will differ.
Disentangling the stable and dynamic cognitive influences in epilepsy often poses a major challenge because the causes of impaired neuropsychological function are not fully independent of each other. Treatment effects, for example, act on and interact with morphology and epilepsy. Although altered brain structure and function may result in epilepsy, epilepsy and its underpinnings may also alter functional cerebral organization. Finally, at the highest level, epilepsy-related cognitive impairment must be evaluated within the patient’s developmental context. Certain seizure syndromes show peaks at specific developmental stages, and etiology is associated with age at seizure onset. Cognitive profiles vary depending on age of seizure onset, with differences apparent depending on whether epilepsy develops in the maturing brain versus mature brain versus aging brain. However, age of seizure onset may simply reflect the expression of dysfunctional brain maturation.
Epilepsy is often dichotomized according to whether the EEG abnormalities involve the entire cerebrum (generalized epilepsy) or begin focally (partial epilepsy). Generalized epilepsy includes tonic–clonic seizures, juvenile absence epilepsy, and myoclonic epilepsy. Partial epilepsy includes a variety of seizure types including the so called “benign” partial epilepsy (e.g., benign epilepsy with centrotemporal spikes, or BECTS) as well as symptomatic focal epilepsy (e.g., mesial temporal lobe epilepsy and neocortical epilepsy). In this chapter, we describe disease effects on cognition as a function of epilepsy syndromes, age of onset, and epilepsy course. We also discuss the complex issue of whether poorly controlled seizures are associated with progressive cognitive decline. For ease of discussion, we categorize epilepsy subtypes according to whether they are considered to be idiopathic or symptomatic.
Idiopathic Epilepsy
Idiopathic epilepsy, including both generalized and partial epilepsy expression, is characterized by a genetic predisposition and the absence of readily identifiable brain lesions. Although not completely silent behaviorally or cognitively, idiopathic epilepsy is generally easy to treat and is associated with less severe cognitive impairments than are other seizure types. Idiopathic generalized epilepsy (IGE) is characterized by generalized EEG abnormalities involving the entire cerebral cortex, whereas idiopathic partial epilepsy (IPE) is associated with regional EEG abnormalities (e.g., centrotemporal EEG in rolandic epilepsy).
As would be predicted from generalized EEG abnormalities, diffuse and generalized cognitive impairments are present, including deficits in attention, psychomotor speed, visuospatial skills, and nonverbal memory. Language and verbal memory, in contrast, appear unaffected.62,102,107
The epileptiform discharges and cognition are also closely related. Not only does cognitive impairment vary as a function of seizure activity, but cognition may also induce seizures and seizure discharges.92 Although this relationship has been described in patients with symptomatic temporal lobe epilepsy (TLE),50 patients with IGE are particularly likely to show neuropsychological EEG activation. Negative effects of spike-and-wave bursts exist for sensory and executive functions. Therefore, tasks requiring sustained attention are best suited to detect the cognitive effects of EEG changes in IGE.102 Although cumulative attentional effects may ultimately result in diminished level of function when they occur over long periods, decreased IQ is not a primary feature of the disease, with developmental delay and retardation developing from interference with cognitive functions over a long period of time. Absence epilepsy developing in early childhood is generally associated with poorer outcome than juvenile absence epilepsy.
BECTS is a common epilepsy syndrome (10%–15%), beginning between 5 and 9 years of age and extending into adolescence. It has a favorable prognosis, and most patients become seizure-free after puberty. Its neuropsychological prognosis, however, is less benign. During its active phase, neuropsychological deficits may include attention, motor functions, short-term memory, visual and perceptive abilities. Language difficulty relating to the interictal dysfunction of the perisylvian language areas, however, is a major characteristic of BECTS.102 Learning disabilities are common in BECTS,143 although they are not progressive in nature. Although children rapidly improve in most areas following seizure remission, minor problems in executive functions and verbal comprehension persist.80,103 Complete seizure remission is generally needed for a favorable cognitive outcome.
Juvenile myoclonus epilepsy (JME) generally begins between 12 and 18 years of age, and is characterized by neuropsychological and behavioral features associated with
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frontal dysexecutive impairment such as reasoning difficulty, poor concept formation, and decreased mental speed and flexibility.22,64,65,102,130 Of course, frontal lobe dysfunction is not specific for JME. Whether frontal lobe cognitive dysfunction together with personality change (e.g., limited self-control, suggestibility, indifference, rapid mood changes) form a syndrome characteristic of JME merits further study.65 The presence of more focal impairments in addition to generalized slowing is consistent with the view that IGE should no longer be considered purely a “generalized” epilepsy. EEG, histologic, structural and functional imaging studies suggest a specific involvement of frontal lobes, thalamus, and thalamocortical loops in IGE.1,75,100,118,147
In conclusion, a wide range of rather mild impairments may be associated with idiopathic generalized or idiopathic partial epilepsy. Mild generalized impairment and learning difficultly have been observed. These are best understood from the close relationship between active epileptic processes interfering with cognitive networks of lower-order functions, on perceptive and executive functions, and on the interference of epilepsy with critical periods of cognitive development (i.e., before, during, or after language acquisition, or at the time before or during frontal executive function development). Frontal/executive functions are the last to fully develop and therefore may represent a common endpoint for the impairments seen in idiopathic epilepsy. Following epilepsy remission, neuropsychological recovery from active epilepsy-driven impairment can be observed. However, some long-term residual deficits may persist, particularly when epilepsy has significantly interfered with cognitive development.
Focal Symptomatic Epilepsy
In contrast to idiopathic epilepsy, the cognitive profiles of symptomatic epilepsy are more strongly related to epilepsy location and etiology. The temporal lobes and temporomesial structures are particularly vulnerable to seizure development, and TLE accounts for approximately 70% of chronic symptomatic epilepsy. Approximately half of TLE patients have hippocampal sclerosis (HS) or hippocampal atrophy, although whether mesial TLE represents a distinct nosological entity or a syndrome is still a matter of debate.146 Mesial TLE is characterized by impaired declarative memory.57 Patients with earlier seizure onset tend to have lower IQs, reflecting the interference of seizures (and perhaps their treatment with antiepileptic medications) with normal cognitive and brain development.54 Accompanying the IQ with earlier seizure onset is a reduction of total brain volume, including both gray and white matter.54 Memory impairment occurs independent of the age of seizure onset, although the nature of the memory impairment depends on when seizures begin. A more generalized memory impairment occurs with earlier seizure onset, whereas a more focal and material-specific memory impairment that varies according to seizure onset laterality is seen with later seizure onset.43
With later seizure development, left temporal/left temporomesial epilepsy is associated with material-specific impairment of verbal learning and memory. Mesial and neocortical structures differentially contribute to verbal memory, with mesial structures subserving consolidation and retrieval, and neocortical structures being more associated with content processing. Thus, impaired delayed recall is more indicative of mesial rather than neocortical temporal lobe damage.48 Impairment of verbal learning, short-term memory, and naming (i.e., semantic memory) are less specific but also may reflect left inferotemporal or temporolateral lesions.39,40,42,125,126 Naming impairment is associated with hippocampal volume,14 and also related to functional activity reflected by spectroscopy.123 Like memory, the magnitude of naming impairment is strongly associated with seizure onset age.
In contrast to left TLE, right TLE tends affect performance on figural or nonverbal memory tasks.34 However, this relationship is less consistent than that between left TLE and verbal memory,6 an effect that has been attributed to nonverbal memory networks being more bilaterally distributed than verbal memory, covert verbalization during task performance, or the type of test and test materials (abstractness, complexity) used. Consequently, using figural memory tests to infer mesial temporal dysfunction will often falsely lateralize seizure onset. However, false lateralizing figural memory impairment in left TLE may also reflect atypical language dominance or sex differences.43
Even though the area of seizure onset in focal TLE is limited, neuropsychological impairment often extends beyond the seizure onset zone.59,89 These “frontal” deficits imply impaired functional connectivity that is disrupted with a temporal lobe focus, and may be considered to reflect “nociferous cortex” effects, in which the negative effects associated with ongoing seizure discharge impair brain function at some distance from the active seizure focus.134 However, magnetic resonance imaging (MRI) volumetrics have demonstrated prominent disruption in ipsilateral hippocampus and neural connectivity (i.e., white matter volume loss) that extends beyond the temporal lobe, affecting both ipsilateral and contralateral hemispheres.128 TLE patients with secondary generalized seizures are at higher risk of additional general neuropsychological impairment.70
Frontal lobe epilepsy (FLE) is seen in approximately 20% of patients with partial onset seizures, and is associated with a less consistent neuropsychological profile than TLE. In contrast to TLE, in which HS is the predominant morphologic feature, frontal lobe epilepsy is associated with a more heterogeneous array of etiologic factors. Moreover, executive functions mediated by the frontal lobe contribute to most other cognitive functions, resulting in diffuse and nonspecific neuropsychological impairments. Patients suffer from attention problems, problems with working memory, mental flexibility, response inhibition, or planning. Tests of motor coordination appear particularly sensitive to frontal lobe epilepsy. At the highest level, a dysexecutive syndrome may comprise problems with response selection, initiation, execution, and inhibition. No consistent lateralized impairment has been associated with focal left versus right FLE.25,41,129,139
The neuropsychological characteristics of parietal lobe epilepsy and occipital lobe epilepsy have rarely been described in a series using adequate sample sizes. Acute parietal or occipital neuropsychological symptoms become evident in seizure semiology, but in chronic epilepsy (most often those patients exhibiting early lesions or malformations), the classic posterior symptoms of aphasia, alexia, agraphia, acalculia, agnosia, and neglect are very uncommon. Primary or secondary perceptive and sensory problems that may be evident at the beginning of epilepsy are often well compensated for behaviorally. Impairments are diffuse, and, as described with seizure semiology and EEG, often mimic frontal or temporal lobe dysfunction.52,72 Nevertheless, tests of stereognosis or haptic search may be sensitive to parietal lobe epilepsy.71,117
Etiology
Partial epilepsy is associated with a variety of etiologies. Lesions include stationary lesions, such as developmental malformations, HS, or atrophy; traumatic brain injury or vascular malformations; as well as potentially progressive defects such as neoplastic and paraneoplastic tumors, CNS infections, and inflammatory and autoimmunologic processes. Independent of
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seizure effects, these lesions themselves are associated with cognitive impairments that range from mild impairment in circumscribed domains to severe generalized neuropsychological impairment. However, cognitive impairments in symptomatic epilepsy are not lesion specific, but rather differ according to age at lesion onset, differences in functionality of the affected tissues, differences in the course and dynamics of the underlying disease, and finally differences in lesion lateralization and localization.7 Although the lesions themselves are generally not associated with ongoing cognitive function, activation of heterotopic gray matter has been demonstrated using functional MRI (fMRI).66
A major concern is the cumulative effects of chronic epilepsy on the brain and on cognition. Seizures, and in particular severe seizures, may result in significant damage, although this is more of an individual patient concern than a concern across all patients. For example, multiple reports exist describing amnestic syndromes following either status epilepticus or a series of generalized tonic–clonic seizures. The cumulative effect of less severe seizures on cognition, however, is less clear-cut. In a review of 20 longitudinal studies in children and adults, 12 of 20 reported a relationship between duration of poorly controlled seizures and neuropsychological decline, 5 of 20 described mixed results, and 3 of 20 described no relationship.82 For those studies reporting an effect, lower IQ with associated increased seizure frequency, greater performance “improvement” in controls than patients, and more important, neuropsychological declines were associated in nonmemory domains.
Cross-sectional studies of chronic uncontrolled TLE suggest a significant IQ decline after three decades.67 Comparing the age regressions of memory in healthy subjects to those of epilepsy patients puts such a finding into perspective.45 In chronic uncontrolled TLE, memory decline in a longitudinal design is very slow, and individually proceeding cognitive decline can be suggested. Presumably, this applies for chronic focal epilepsy, but it remains unclear whether specific domains are affected or whether decline is diffuse and nonspecific. Impairment may be seen in patients with symptomatic focal epilepsy even prior to the onset of epilepsy, and cognitive impairment may develop from the interference of lesions/epilepsy with brain maturation and cognitive development. The impact of additional lesions and the interaction of aging with preexisting damage appear much more relevant for individual cognitive change than for the accumulation of seizures alone.7,43
Antiepilepsy Drug Effects
Given the many potential influences on cognition for patients with epilepsy, such as age of onset, disease substrate, or seizure frequency and severity, antiepilepsy drugs (AEDs) occupy a unique position because they are under the direct control of the treating physician and his patients. Although the choice of specific AED is guided by seizure type and epilepsy syndrome,61 within seizure/syndrome categories, AED selection is typically based on clinical experience rather than evidence-based practice. Most major AEDs used to treat partial epilepsy have comparable efficacy,76 although many recently introduced AEDs are associated with more favorable tolerability profiles that includes less neuropsychological impairment.73
Because AEDs decrease membrane excitability, increase postsynaptic inhibition, or alter the synchronization of neural networks, they are often associated with neuropsychological side effects including decreased motor/psychomotor speed and attention.96 Adverse AED effects are a significant component of treatment effectiveness. The landmark VA Cooperative study reported that standard AEDs including carbamazepine are associated with significant adverse effects that contribute to initial treatment failure in more than 40% of patients,93 and a separate European trial reported that tiredness was described by more than 50% and sleepiness by more than 35% of patients on phenytoin or carbamazepine monotherapy.4 Adverse AED effects are strongly associated with poor health reported by patients30 and with decreased health-related quality of life.32 After seizure control, the most important aspect of AED treatment is the side effect profile, including problems with cognition, energy level, school performance, childbearing, coordination, and sexual function. Because of side effects, 20% of patients adjusted their AED dosing.27
In young adults, neuropsychological AED profiles are generally comparable for the older-generation AEDs carbamazepine, phenytoin, and valproate, with each AED associated with modest psychomotor slowing accompanied by decreased attention and memory.96 Neuropsychological side effects generally emerge according to a dose-dependent relationship96; however, both quality of life31 and memory may be affected, even when AED blood levels are within standard therapeutic ranges. Central nervous system (CNS) effects of AEDs are reflected by EEG slowing that not only is correlated with short-term neuropsychological decline,119,120 but is also related to poorer neuropsychological outcome following 1 year of treatment.28 With the exception of topiramate87,96,122,135 and possibly zonisamide,2,10 most newer-generation AEDs have more favorable tolerability and neuropsychological profiles than their predecessors.86,97,98,99
Although direct head-to-head comparisons examining the neuropsychological profiles of newer AEDs have not typically included medications thought to have favorable neuropsychological outcomes, some data suggest differences in this regard. For example, in one study, oxcarbazepine was associated with both neuropsychological impairment and EEG slowing in healthy volunteers.121 Thus, some data suggest that important differences may exist among AEDs, even across newer agents considered to have favorable neuropsychological side effect profiles. Several recent Class I healthy-volunteer studies suggested increased risk of cognitive impairment associated with topiramate97,121 Because there may be individuals who are at greater risk for developing cognitive impairment, it may be possible to ultimately predict individuals at increased risk for developing treatment-emergent side effects based on pharmacogenetic or pharmacokinetic patient characteristics.
Subjective Report Versus Objective Performance
In addition to poor performance on memory tests and other neuropsychological measures, epilepsy patients often complain of poor memory.19 Although both subjective and objective memory findings indicate decreased memory, subjective memory ratings and objective memory performance are poorly correlated.8,29,46,108,142 In studies with sufficient sample sizes, statistically significant relationships between objective and subjective performances have been reported, although these correlations are generally small and account for a small portion of the variance. In contrast, subjective memory correlates much more highly with mood.19,23,26,108,109 Depressed or anxious patients tend to rate their memory as poor, whereas patients less burdened by poor mood states rate their memory more favorably. Correlations generally account for approximately half of the variance,5,26 with mood being the single best predictor of subjective memory functioning.23,33,108
The association between subjective memory and mood is informative, yet a large portion of the variance remains to be explained. Most studies show no significant relationship between subjective memory and clinical factors such as sex/gender, chronologic age, seizure-onset age, seizure type, seizure frequency, region of seizure onset, and number of AEDs.23,109 However, memory “complainers” may have a later age of
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seizure onset,19 and a small inverse relationship between age and subjective memory reports has been described.26,33 There is a tendency for patients on polytherapy to report greater cognitive difficulty than do patients on monotherapy,33 although this relationship is well-established using formal neuropsychological measures.96 Although most studies are restricted to TLE patients, those that included both temporal and extratemporal patients document greater reports of memory impairment than in TLE.19 Although some investigators report no influence of seizure laterality,5 others have found significant associations between perceived memory and objective verbal memory in left TLE patients, and with objective nonverbal memory in right TLE patients.12 Although reports exist of a relationship between perceived and objective language performance,12 others have not observed this relationship.5
Ecologic Validity of Objective Measures
Formal neuropsychological measures are established indicators of lateralized or localized cognitive dysfunction.14 However, the modest correlation between subjective and objective results raises questions regarding ecologic validity of conventional memory tests. Neuropsychological memory tests typically require learning and recall of word lists or abstract designs, whereas “everyday memory” typically requires incidental memory for complex events in which the individual is personally involved.49 In two independent studies utilizing memory tests simulating everyday memory demands,23,49 more ecologically valid tests correlated weakly with subjective ratings, but correlated more highly with conventional test performance. Although a small but significant correlation was found between ecologically valid memory performance and subjective report in patients “without” memory impairment,49 the absence of a significant correlation in the “impaired” group may be related to the more restricted performance range.
The demands of various activities differ considerably, and cognitive deficits may be more apparent in high- versus low-demand situations. In one postoperative series, patients staying at home (“low demand”) reported greater subjective complaints than did employed subjects (“high demand”),35 and this corresponded with objective memory performance as well (i.e., weaker objective memory in the low-demand situations). Although patients were self-selected for group assignment, these data suggest that patients with poorer objective memory were in less demanding situations due to their genuine memory deficits, as well as feeling more impaired.
Tip-of-the-tongue (TOT) phenomena or “word finding difficulty” is one of the top three cognitive complaints among epilepsy patients,20 although the relationship between objective performance using confrontation naming tests19 or language composite scores5,108 with patient self-report is low or nil. However, the absence of a stronger relationship may result from language test selection using measures that poorly correlate with word finding difficulty. For example, in a study addressing the ecologic validity of object naming measures, no correlation was found between self-reported word finding difficulty and traditional visual object naming, although a small but significant correlation was noted with auditory description naming, a task developed to better simulate word finding in the context of everyday speech.39
Subjective Memory “Theories”
Several studies suggest that laypersons, (i.e., patients, proxies, and normal controls) have a broader definition of “memory” than do neuropsychologists and neurologists. Specifically, performances on various language tasks, such as word fluency, expressive vocabulary, and naming, correlate significantly with subjective memory ratings.26,46,104 Thus, when people are asked to rate their memory, they often consider language fluency and word finding difficulty as well as declarative memory processes.
The poor relationship between subjective performance ratings and objective test results raises the question of whether impaired deficit recognition (e.g., anosognosia) exists. A problem in assessing subjective memory in a population with genuine memory deficits is that the task is retrospective and, therefore, a memory task itself.46,49 The discrepancy between objective and subjective scores is greater in patients with right hemispheric seizure onset, with a greater tendency in these patients to overestimate their genuine memory abilities.3 This pattern is consistent with the specialized role of the right hemisphere in deficit awareness reported in lesions of other etiologies.
It has been suggested that some patients, unaware of their real memory conditions, exaggerate their memory failures and report this inaccurate self-perception in questionnaires.109 Although epilepsy patients with and without memory complaints obtain comparable scores across a range of neuropsychological measures, the “complaint” group scored significantly higher in neuroticism.142 Thus, both disease-related and personality factors reduce self-awareness, thereby contributing to the discrepancy between subjective complaints and objective performance.
Subjective Change in Postoperative Patients
Whereas pre- (or non-) surgical epilepsy patients tend to “over-report” memory deficits, the prevalence of memory complaints among patients following temporal lobe resection is quite low.13,124 In fact, postoperative patients tend to report improved memory functioning despite evidence of memory decline on objective measures.94,95 Accordingly, most studies report little correlation between changes in objective performance and changes in subjective ratings following surgery. Rather, subjective memory ratings in postoperative patients correlate significantly with seizure outcome (i.e., good seizure outcome associated with improved subjective ratings),58,94,95,124 AED side effects, and, similar to that demonstrated in preoperative patients, with mood94,124 and neuroticism.15 Although a higher prevalence of subjective decline might be expected following left anterior temporal lobectomies (ATL) rather than right ATL given the more consistent objective decline following left surgery,14 subjective complaints do not appear to predict surgical laterality.8,15,94,95,124 Because of the overall poor correspondence between performance and complaints after surgery, postoperative memory complaints might be considered a marker of depression or other mood disorder.124 Nonetheless, there is general agreement that, despite these group findings, individual cognitive complaints should be followed up with both formal mood assessment and neuropsychological evaluation.
Practical Implications
The poor correspondence between subjective report and objective performance suggests caution when drawing conclusions from subjective complaints. This is obviously a concern to the treating physician since, in most cases, the presence or absence of memory complaint is based on questioning the patient, rather than on formal memory assessment. Factors to consider include emotional and psychosocial factors, the
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potentially broader definition of “memory” held by patients and their relatives, the patient’s level of daily cognitive demands, and seizure onset laterality. For postoperative patients, one should additionally consider seizure outcome and AED burden. Each of these factors carries a potential influence on cognitive self-appraisal; distinguishing among them on an individual basis is critical, because each implicates a different treatment approach.
Wada Testing and Functional Imaging
One of the primary goals in the preoperative evaluation is to identify patients who may be at increased risk for developing significant postoperative neuropsychological impairment. Patients undergoing temporal lobe resection in the language-dominant hemisphere are at higher risk for experiencing postoperative memory decline than are those undergoing nondominant ATL, and knowledge about language dominance and memory representation is important to establish the relative risks to memory associated with temporal lobectomy.
The Wada test is one of the major procedures to establish relative memory risk following ATL, although not all epilepsy surgery centers perform this procedure routinely on all ATL candidates.83 Wada testing to assess both language and memory function emerged during the 1950s, when structural and functional imaging was almost nonexistent. Although variability in specific protocols exists, the technique generally involves the introduction of amobarbital (or other anesthetic agent) through a transfemoral catheter into the internal carotid artery, which temporarily anesthetizes the distribution of the anterior and middle cerebral arteries. During the period of hemispheric anesthesia, the patient is presented with language and memory acquisition tasks, with memory tested after the drug effects have worn off. Although the memory component of this task was designed to avoid developing a significant postoperative amnesia, this role has largely been supplanted by current functional neuroimaging using MRI, positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Wada memory results, however, are often used to indicate the risk of significant memory decline that may interfere with a patient’s overall quality of life.85
The Wada test differs from all other approaches to functional assessment, including neuropsychological testing, in that it tests each hemisphere in isolation. By doing so, it helps to disentangle the effects of large-scale distributed brain networks, and it can assess the specific contributions of the anesthetized region and their functional connections to language and memory function. When the hemisphere ipsilateral to a medial temporal lobe focus is anesthetized, the reserve capacity of the contralateral temporal lobe to sustain memory function in isolation is assessed.16 Multiple reports demonstrate the contribution of Wada memory results to memory outcome prediction.18,68,74,77,84,116,133 An aphasia confound occurs when testing memory following dominant hemisphere injection and, because of this confound, a selective procedure for anesthetizing the distribution of the posterior cerebral artery may be used,131 although this approach is associated with a greater risk of stroke and, consequently, is generally not employed routinely.148 Selective procedures involving other vascular distributions may be performed based on clinical indications.38,140
Because the Wada procedure is invasive, fMRI and magnetoencephalography (MEG) are advanced as noninvasive alternatives. Many language fMRI paradigms reliably identify language representation, and the use of fMRI has decreased the frequency of Wada use in some epilepsy centers.44 MEG is an alternative measure of functional imaging that, unlike fMRI, which relies on indirect measures of neural activity based on blood flow changes, is a direct measure of neuronal function. MEG is also a reliable noninvasive measure of language lateralization.105,106
Imaging the medial temporal lobes has proven to be more difficult. However, several reports demonstrate the effectiveness of fMRI related to seizure onset laterality21,37,69 as well as memory outcome following surgery.110,113 As the components needed for successful hippocampal activation continue to be understood,11 it is likely the fMRI will increasingly be used in preoperative epilepsy evaluation, with a corresponding decrease in Wada use.
Postoperative Outcome
Up to 80% of those patients undergoing ATL resection will become seizure-free following surgery,145 although some patients will experience specific declines in memory, language, or some other aspect of cognitive functioning. A literature has now developed demonstrating how results from presurgical neuropsychological testing, combined with demographic variables and other neurodiagnostic findings, can predict patients who are at greatest risk for developing postoperative decline.
One of the earliest findings from neuropsychological studies is that epilepsy surgery results in very little change in IQ.44 The view that patients with lower IQ levels, which can suggest greater generalized brain impairment, do not benefit from surgery has been dispelled by research findings comparing seizure outcomes in both low- and high-IQ groups.36,44 Patients with higher IQ levels and memory performance tend to experience greater cognitive declines following surgery, although they also continue to exhibit a higher level of postoperative functioning than do patients with lower presurgical cognitive performance.51 These results support the model of cognitive reserve that has gained acceptance in the fields of dementia and traumatic brain injury.114,132
The majority of epilepsy surgeries are ATLs that involve resection of areas considered important for normal memory processing; consequently, predicting memory outcome has been emphasized. Different rates of memory decline, ranging from 10% to 60%, following ATL have been reported. The prediction of memory decline has been guided by two basic theoretic approaches. The first model is based on Milner’s101 original observation that material-specific memory deficits in verbal and nonverbal memory are associated with ATL of the left (dominant) and right (nondominant) temporal lobes, respectively. The second approach is based on a more recent model, which predicts that the degree of postoperative memory deficit, as well as seizure outcome itself, will be determined by the “functional adequacy” of the tissue to be resected.16,74 The type of surgical procedure (e.g., “standard” ATL vs. selective amygdalohippocampectomy) and postoperative seizure status also contribute to postoperative cognitive outcome.44
Laterality Effects
Analyses of material-specific memory findings are included in nearly every neuropsychological study of postoperative outcome. The conclusion drawn from recent literature reviews is that strong empirical support exists for the link between surgery on the left temporal lobe and postoperative deficits in verbal memory.78 There is, however, substantially less support for the proposed relationship between nonverbal memory impairment and surgery on the right temporal lobe.78,141
There has been a recent trend moving from group methods of analysis toward predicting the risk of postoperative change in individual patient prediction. To optimize the prediction of individual risk, investigators have been using statistical
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processes, such as the reliable change index (RCI) and standardized regression-based (SRB) methods, to control for the reliability of the instruments, practice effects, and regression to the mean. Studies using this methodology have reported that the risk for postoperative decline in verbal memory ranges from 40% to 60% in patients undergoing left ATL, whereas the risk for decline in patients undergoing right ATL ranges from 10% to 30%.56,91 Significant declines following right ATL are not clearly explained by any simple version of the material-specific memory model. Much less is known about the risk of experiencing a decline in nonverbal memory, a result of methodologic factors and small effect sizes.
Language-dominant ATL has been associated with postoperative naming deficits, although details regarding these deficits are less well known than those associated with memory. Postoperative naming impairment is generally thought to occur in only a minority of patients,14 although at least one study has found naming declines in 40% of a left ATL sample versus none in those patients undergoing right ATL.91 The ability to predict postoperative naming deficits through presurgical language mapping using intraoperative or extraoperative methods has been inconsistent. One multicenter study found that the rate of postoperative naming decline was not influenced by the availability of mapping data.53 Others have found that identification of mapping sites critical for auditory descriptive naming is important for predicting both auditory and visual naming outcome.40
There are no consistent findings demonstrating deficits in visual perceptual or spatial functions associated with right ATL. Surgical procedures conducted on patients with frontal lobe epilepsy and other forms of extratemporal epilepsy have been associated with only mild declines in memory, language, or other cognitive functions unless areas of eloquent cortex are involved specifically.24,47 Laterality effects on cognitive functioning are considered to be less of an issue with pediatric patients than with adults.7
Functional Adequacy Model
The functional adequacy model predicts that less postoperative memory decline, as well as a greater likelihood for seizure reduction, will be observed in patients exhibiting lower levels of presurgical functioning in the mesial temporal lobe ipsilateral to seizure onset.16,74 Functional adequacy is established using both neuropsychological methods as well as measure of structural pathology using preoperative neuroimaging. Most research findings have supported this model, as opposed to the competing “functional reserve” model that suggests postoperative memory is best predicted by the functional and structural integrity of the contralateral temporal lobe.
Presurgical Neuropsychological Performance
Evidence supporting the functional adequacy model was initially provided by the finding that patients with higher memory performance on presurgical testing were more likely to demonstrate significant memory decline following ATL than those with lower presurgical memory performance.63,111 These results are not simply the result of statistical “regression to the mean,” but rather reflect the tendency for the most functional patients at baseline to be more vulnerable to experiencing postoperative memory loss.17 This is a robust pattern of change following ATL, and it has been observed in many independent series.55,133,144
Findings from MRI and Other Studies
Neuropathological studies have consistently demonstrated that memory outcome varies according to the presence of HS ipsilateral to seizure onset.9,14,60 Not only do individuals with severe unilateral HS exhibit lower levels of preoperative memory, but they are also less likely to exhibit memory decline following surgery.127 Similar findings have been observed using MRI measures of hippocampal pathology.137,138 Resection of a relatively nonatrophic left hippocampus generally results in greater memory decline, although memory loss may also occur in some patients with severe presurgical HS.90 Surgery in patients with bilateral hippocampal pathology, however, does not necessarily cause global amnesia, although greater rates of memory decline are seen in patients with bilateral hippocampal atrophy who undergo dominant-hemisphere ATL.90 Normal verbal memory in the presence of hippocampal atrophy may also be associated with significant postoperative memory decline.85 Thus, the functional integrity of the left temporal lobe plays a critical role in predicting memory outcome independent of the presence of structural pathology.81,85
Studies using multiple regression methods have demonstrated that prediction of postoperative outcome is best accomplished using a combination of both functional and structural indices.55,133 The importance of functional adequacy to postoperative change has been demonstrated using both magnetic resonance spectroscopy (MRS) and Wada testing.74,84 fMRI has been shown to be useful for predicting postoperative naming.115 Recent presurgical fMRI studies have demonstrated the ability to predict postoperative memory functions.110,113
Demographic Predictors
Developmental factors, including age at the time of surgery and the stage of cognitive development at the time of seizure onset, are important factors for predicting postoperative cognitive decline. The risk of cognitive decline following surgery appears to be lower in children younger than age 16 years than in adults.79 In contrast, older patients may experience greater memory loss, consistent with a profile of accelerated aging.51 Continuing decline in memory performance may be seen in some individuals 10 years or more following surgery.112 The postoperative deficit in verbal memory in patients who are seizure free is similar to what is observed over time in nonsurgical patients who are continuing to experience seizures, suggesting normal age-related memory decline.51
Age of seizure onset interacts with both functional and structural indices in a manner consistent with the functional adequacy model.16,88 Those with a younger age of onset will have experienced pathology at an earlier stage of development and will have experienced seizures for a longer period of time. This leads to greater neurologic compromise, which is accompanied by more severe and widespread cognitive impairment. However, earlier seizure onset also permits a redistribution of function to other brain areas, which would lead to less deficit following surgery. In contrast, patients developing epilepsy later in life are not as compromised neurologically, because it does not interfere with cognitive development and maturation, and consequently they do not exhibit the same degree of cognitive dysfunction preoperatively. However, surgery involves resection of more functional brain tissue, which increases the likelihood of developing greater cognitive decline postoperatively. Support for these findings coupling age of onset with function was present in some early studies, but at least one recent study has failed to find a link between severe hippocampal pathology, memory decline, and early onset of seizures.88
In general, cognitive deficits become more specific and less reversible with surgery with increasing age. The pattern of findings involving age of onset are generally more consistent for cognitive functions associated with neocortical zones than for those associated with the mesial temporal lobe.44 For example, more severe naming deficits are observed in older patients. Other studies examining demographic factors have suggested
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that women, in general, exhibit less severe cognitive decline following surgery than do men.136
Summary and Conclusions
Patients with epilepsy frequently have some cognitive and neuropsychological impairment. Cognitive difficulty may be due to the underlying brain disorder, specific epilepsy syndrome, AED effects, psychiatric comorbidity, and ongoing effects of active seizure discharges. Although the neuropsychological impairment is related to the location of the active seizure focus in patients with localization-related epilepsy, often more subtle impairments in executive functions may be present in both focal and generalized epilepsy syndromes, including those commonly referred to as “benign.” Because a poor relationship exists between subject performance ratings and formal neuropsychological test results, formal assessment is often necessary to document the presence and extent of cognitive difficulty experienced in individual patients. Cognitive impairments are broadly related to age of seizure onset and seizure duration. Unfortunately, well-established interventions to treat or modulate cognitive difficulty in patients with epilepsy do not exist.
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