Pathology of the dominant hemisphere

The cognitive manifestations of epilepsy often reflect the region of pathology from which seizures arise. For example, language and memory impairment can be observed in temporal lobe epilepsy, and executive function impairment is often found in frontal lobe epilepsy. However, recent frameworks challenge this classic “lesion model” given evidence of significant heterogeneity of cognitive, behavioral, and neuroimaging presentations across patients (44). For example, executive function impairment can also be observed in temporal lobe epilepsy. In addition, even in focal epilepsies such as temporal lobe epilepsy, neuroimaging abnormalities often extend beyond the epileptogenic zone. Therefore, a new and expanded model views epilepsy as a network disorder and offers a new taxonomy based on cognitive and behavioral phenotyping to better understand individual patient outcomes.

One major organizing principle of cognitive impairment in seizure disorders is the distinction between pathology of the language-dominant (typically left) and language-nondominant (typically right) hemispheres. As such, determining whether such impairment exists is a key goal of presurgical neuropsychological assessment.

Hemispheric dominance and handedness. Handedness is strongly correlated with hemispheric language dominance, and as such provides an estimate of the language-critical hemisphere. In both left- and right-handed healthy individuals, the left hemisphere is most commonly language dominant; in right handers, incidence of left hemisphere dominance is usually estimated at around 93% (51), whereas this drops to around 70% in left-handed individuals (52).

Atypical language dominance in epilepsy. In epilepsy, the rates of atypical language dominance are higher than in healthy controls (31), likely due to early reorganization caused by the epileptic focus, though the relationship between handedness and pathology is far less determined (36). About one fourth of individuals with epilepsy have been reported to have their language organized atypically in the brain (15). The most common predictors of atypical language distribution in the brain are left-handedness, a left hemisphere lesion (69), early seizure onset (99), presence of pathology (eg, hippocampal sclerosis) (78), greater seizure frequency (99), and epileptic activity (08). One study found that a combination of left-handedness and left hemisphere pathology predicted greatest likelihood of atypical language dominance (95). Several studies (though with smaller samples) suggest that bilingualism may be associated with more bilateral language activation on fMRI (70), in particular in left hemisphere epilepsy (94). Therefore, taking bilingual status into account during presurgical language lateralization is important given the possibility of atypical language dominance.

Given that interpretation of cognitive data rests on a probabilistic assumption that the left hemisphere supports language, when definitive statements are to be made about risk to cognitive decline (eg, during presurgical planning) it is essential to confirm hemispheric language dominance. This can be done using measures such as clinical fMRI of language (16), magnetoencephalography (76), intracarotid sodium amytal (Wada) testing (53), and active or passive cortical stimulation mapping (06), which can be performed extra- or intraoperatively.

Impairment of language in epilepsy. The nature of language impairment in epilepsy reflects the region or network from which seizures arise. Our understanding of the brain regions involved in language--and the deficits accompanying their impairment--has rapidly evolved with the advent of noninvasive imaging (eg, PET, DTI, fMRI, MEG). Historic models of language function centered on the contributions of Paul Broca and Carl Wernicke, describing a fundamental relationship between “expressive” language and the posterior inferior frontal gyrus (Broca’s area), and between “receptive” language and the posterior superior temporal gyrus (Wernicke’s area) (83). Overwhelming evidence has supported modification of this model to reflect the contributions made by a range of other regions (21; 61). Rapidly growing evidence strongly suggests that complex cognitive functions (such as language) engage networks that dynamically interact with one another, rather than single cortical areas (60). This evidence, coupled with the growing consensus of epilepsy as a network-level disorder, suggests that epilepsy likely affects language networks rather than single regions (07).

Epilepsy patients seem to have altered functional and structural (ie, white matter) connectivity for language. The magnitude of altered connectivity has been linked to earlier seizure onset as well as longer seizure duration (98; 99). Altered connectivity for language has even been reported in children with new onset benign childhood epilepsy using resting state fMRI. More specifically, the pediatric patients had a higher amplitude of low frequency fluctuation in the right Broca’s region and a lower amplitude of low frequency fluctuation in the fusiform gyrus bilaterally (26). Damage to language-related white matter bundles has been also shown to affect language both pre- and postoperatively (50; 19).

Deficits in manipulating the sounds of speech (phonological processing) can suggest dominant hemisphere pathology. Spoken words (eg, the word “epilepsy”) can be broken into syllables. Syllables are groupings of a vowel sound with or without surrounding consonants (eg, “e/pi/lep/sy”), and can be further separated into basic and distinctive sound units; phonemes (eg, “e/p/i/l/e/p/s/i”). Phonological paraphasic errors occur in conversation when patients substitute phonemes in spoken words (eg, saying “manguage” for “language”). Such errors are seen following impairment through a range of regions within the language system, including Broca’s and Wernicke’s areas, and the angular and supramarginal gyri.

Deficits in reading can also indicate dominant hemisphere pathology. In the same way that words can be broken down to the level of phonemes, written words can be broken into “orthographs.” Inferior parietal cortex, and particularly the angular and supramarginal gyri, are particularly important in mapping these written representations of language with their spoken equivalents (orthography-phonology mapping). Intraoperative stimulation of the dominant angular and supramarginal gyri impairs reading ability and results in paraphasic errors (85). Deficits are most apparent when patients are pronouncing orthographs alone or in unfamiliar groupings; therefore, it is better to test for deficits than to rely on subjective report. Deficits are best elicited through tasks requiring patients to vocalize single (eg, /a/, /f/, /th/) or multiple (eg, “qop,” “sigtrav”) orthographs.

Posterior temporo-occipital cortex, and in particular a region of the fusiform cortex known as the “visual word form area,” is also critical in the processing of word forms, and lesions in this area can result in alexia and agraphia (93). Of direct relevance, epileptogenic pathology in this area can completely disrupt the ability to read and write a given language (56).

Impaired naming, or “word-finding difficulties,” is very common in temporal lobe epilepsy, in particular (62), and indicates impairment of the language-dominant hemisphere and can reflect damage to an area of cortex critical in associating information about an item (semantic knowledge, visual imagery) with the item’s name. Subjectively, such patients with naming difficulties report hesitation in spontaneous speech and difficulty with rapid word retrieval in conversation. In the clinic, this manifests as hesitation in conversation and a tendency to provide (often imprecise) synonyms for words (ie, circumlocution, or “talking around the word”). For instance, instead of saying “I use the bus to get to work” a patient may alternately report “I use the… [pause] that vehicle… [pause] the big vehicle with lots of people… the bus to get to work.” Such deficits are typically less prominent in individuals with higher baseline cognitive function who can often fluently substitute semantically-related alternatives for words that can’t be retrieved; for instance, “I use the [brief hesitation] public transit to get to work.” An area of inferior-lateral temporal cortex usually called the basal temporal language area (BTLA) is critical for this process (33; 01). In a large study, it was shown that resection of this area, which falls predominantly within the fusiform gyrus, predicts around half of the variation in language (naming) decline after surgery in the dominant temporal lobe (18; 50).

Selective impairment of the ability to write in the presence of preserved language in a seizure disorder can indicate damage to the dominant frontal or temporo-occipital regions. Specifically, stimulation of cortex in Exner’s area, a region of the posterior middle frontal gyrus rostral to the motor strip’s hand area (35), can selectively disrupt the ability to translate orthography into written language without impairing oral language or motor movements (84). Clinically, highly focal lesions here can manifest as alexia and agraphia (02). This area can also be mapped using fMRI and direct stimulation (84; 13).

Impaired continuation of speech. Epilepsy patients with acute supplementary motor area damage, which can follow a seizure or the growth of a tumor within this region, may exhibit a dwindling aphasia. That is, sentences gradually fade shortly after they are initiated so that the person falls silent after speaking a few words. This reflects the supplementary motor area’s critical role in sequencing motor movements (82). Such impairment is typically transient as the contralateral supplementary motor area can support function lost by ipsilateral supplementary motor area damage, and the extent of damage to this area corresponds with functional deficits (27). Note that these deficits or related deficits can be enduring if callosal fibers are lesioned with the dominant supplementary motor area (34).

Damage to Broca's area, in the posterior third of the inferior frontal gyrus, can manifest in multiple ways. At the broadest level, insult to Broca’s area can result in word-sequencing deficits such that patients produce nonfluent, halting speech that is lacking in function words (agrammatism). For instance, the sentence “The cat sat on the mat” may be produced as “cat… mat… sitting”. Alternatively, a patient may describe their visit to the doctor “Um… Friday, Friday… visit… Mum… I visit… doctor and ah… heart… check heart.” Patients with Broca’s aphasia may also experience difficulty comprehending sentences that involve complex syntactic structures. For instance, those with Broca’s aphasia make errors when asked a question in the passive voice with noncanonical word order (object-verb-subject), such as “The Pistons were defeated by the Celtics. Which team won?” In contrast, they are able to answer the question when the active voice is used (canonical word order: subject-verb-object), for example, “The Celtics defeated the Pistons, which team won?” (73). That is, comprehension of semantics at the single-word level remains intact, but processing utterances relying on syntactic movement is lost. In line with this, Broca’s area is also engaged during silent reading, which does not involve overt speech production (22). Further, distinct regions within Broca’s area are now known to be preferentially engaged in semantic (anterior region; pars orbitalis), syntactic (medial region; pars triangularis), and phonological processing (posterior region; pars opercularis) (20; 39). Concurrently, these subregions are functionally coupled, which means that they are activated in parallel and not sequentially (29).

In contrast, damage to Wernicke’s area in the posterior component of the superior temporal gyrus impairs the selection of language content. An excellent reconceptualization of this area has highlighted the anatomy of this area, which has long been defined differently by various authors (17). The posterior superior temporal gyrus and supramarginal gyrus in the dominant hemisphere appears critical for retrieving and ordering the sounds of speech. Patients with lesions in Wernicke’s region, then, may offer responses to questions with the correct grammatical structure but incorrect content. In an error of selection, a patient may offer the word "dog" rather than “cat” (semantic paraphasia) or, if phonological processing is disturbed, “cot” or “cap” (phonological paraphasia). With extreme impairment, this may happen to the point where sentences become unintelligible (eg, “The cat sat on the mat” becomes “The animal walked on the green door”). Further, sequencing may be disturbed at a more fundamental level and interfere with phoneme selection. Here speech can become jargonistic; instead of “the cat sat on the mat,” the individual with aphasia may say “atat it mit mat mat at.” Such impairment is more likely to include more posterior temporal or inferior parietal pathology.

Ictal aphasia. Although all the forms of language impairment discussed above can be enduring, there may be transient phenomena that occur only during a seizure (ie, “ictally’”) (100). Depending on seizure focus, different types of language impairments have been reported during ictal aphasia. For example, seizure activity in the basal temporal regions of the left-dominant hemisphere has been associated with jargon aphasia (fluent but highly incoherent language production accompanied by disrupted language comprehension). The transient language impairments can be helpful in assessing seizure focus (97).

Pathology of the nondominant hemisphere

When pathological processes predominantly affect the nondominant hemisphere, especially posterior aspects, visuospatial function is typically affected (104). Patients may report a range of deficits on tasks requiring judgment of spatial relationships. For instance, they may misjudge the boundaries of a vehicle when parking; they may be clumsy when picking up or using items; or they may have difficulties completing hobbies that require fine visual discrimination (eg, knitting, tool use). Any such difficulties must be differentiated from primary issues with motor function or object agnosia. In the clinic, deficits may not be readily observable but can be inferred from reported behavior (eg, misjudgments of the edges of furniture and awkwardness when navigating). Difficulties in copying a line drawing can readily reveal significant visuospatial deficits, though again it is important to rule out more basic problems like difficulties in visual or motor function. On neuropsychological assessment, tasks sensitive to visuospatial deficits range in difficulty and demands--from simple judgments of line position (eg, judgment of line orientation task) or the ability to reassemble the cut-up pieces of a line drawing, as in a puzzle (eg, Hooper Visual Organization Test) (46) to the ability to reason using complex visual stimuli at the most complex level (eg, matrix reasoning task of the Wechsler Adult Intelligence Scale IV) (106). An alternative to the hemispheric material-specific hypothesis, the response bias model, holds that regardless of material content, the left hemisphere is more prone to errors of omission, whereas the right is prone to errors of commission; there is evidence that both models independently correlate with lesion laterality (41).

Although language impairments are not commonly reported in patients with right hemisphere epilepsy, individuals with right-lateralized focus have been found to display deficits in discourse. By discourse we understand the ability to select information that is contextually relevant and integrate it to infer the meaning correctly (54). Prior research on patients with damage to the right hemisphere suggests that this hemisphere is engaged with discourse. When the ability to process discourse is disrupted, functional communication can be impaired (89).

Memory

Material-specific memory impairment (temporal lobe epilepsy). Impairment of memory is a cardinal cognitive sign of mesial temporal lobe damage. Bihippocampal lesions are associated with a dense impairment of the ability to recall richly spatial, temporal, and personal memories (episodic memories) while the ability to learn new semantic information is preserved (103). More importantly, in presurgical patients, the fact that unilateral temporal lobe impairment is associated with impairment of memory for specific types of material (ie, the theory of material specificity such that verbal and visual memory are processed by the left and right medial temporal lobe, respectively) is the cornerstone of neuropsychological assessment in epilepsy (64; 67). This theory has been modified somewhat with accumulating evidence (88) to reflect the statement that verbal memory performance is an index of dominant temporal lobe integrity, whereas nonverbal memory reflects more bilateral mesial temporal function.

Deficits in memory for verbally presented material can manifest as trouble recalling past conversations, material that has been read, details from the news, or movie plots. Nonverbal memory deficits often manifest in difficulties remembering one’s way around familiar routes (eg, the way to the store) or places (the family home) or in difficulties navigating a new environment (eg, a new home or suburb). In neuropsychological assessment, the central sign of dominant mesial temporal impairment is a deficit in the formation of novel, arbitrary associations (87). The ability to learn semantically unrelated word pairs is commonly assessed (eg, “apple-silver”) (Wechsler Memory Task IV: Verbal Paired Associates). Such verbal associations preferentially rely on the mesial temporal lobe, whereas recollection of semantically related word pairs (eg, “walk-run”) tends to tax the lateral temporal cortex in the dominant hemisphere (108). Other dominant memory measures that rely on lateral temporal structures include tests of memory for verbal passages, such as the Logical Memory subtest of the Wechsler Memory Scale IV.

A nonlateralizing indication of mesial temporal lobe impairment is failure to learn more with repetition. For instance, while a patient may be told a shopping list of 15 items by their partner five times, they may only ever be able to recall six of the items at most. This indicates an inability to learn beyond the capacity of one's short-term memory (approximately synonymous with “working memory”), a process more heavily dependent on the frontal lobes.

Executive contributions to memory. Specific patterns of memory deficits may indicate impairment of the executive functions. Impaired executive function is associated with a number of forms of brain insult but is most typically associated with damage to the frontal lobes. The executive skills are a set of functions used to plan, organize, and monitor behavior. They are engaged in memory tasks in a number of ways.

Executive dysfunction can interfere with strategy use in memory. For instance, when learning a long list of items to be bought from the supermarket, they will be better remembered if items of different types are grouped (for instance; fruit and vegetables; meats; dairy and so forth). Patients with executive dysfunction are less likely to use this strategy and may focus on a stimulus detail at the expense of broader organizational characteristics. Such patients can benefit from cueing, which orients them to the organizing principles of the material. These patients may perform poorly on spontaneous recall but may dramatically improve when cued (ie, asked what meats, vegetables, and dairy items they needed to get). These category cues provide explicit structure, so performance improves once the executive requirements of the task are diminished.

Patients with executive difficulties may also find it hard to distinguish learned items from new items, particularly when these items share features. This is because during the retrieval of information it is necessary not only to activate representations of stored material but also to inhibit or suppress other salient but unrelated material. Patients with executive deficits can have difficulties engaging inhibition. For instance, if an individual who needed to collect butter, milk, and cheese from the supermarket is later asked if they needed to collect these three items, they may say yes to each of them, but when then asked if they also needed to get eggs and yogurt, they assent to these items as well (ie, “false alarms”). On formal neuropsychological testing, this is assessed by tests of recognition where, after a person has had an opportunity to recall information they attempted to learn earlier, they are given a list of both old, learned items and new items and asked which they encountered previously. The relationship between the number of endorsed items that were (“hits”) and were not (“false alarms”) presented gives an index of discriminability, which can indicate executive deficits. Patients with executive dysfunction may have higher rates of “false alarms” than expected.

Attending to and organizing incoming information is another frontal lobe function that if impaired can impact memory. This is particularly noticeable when the incoming information exceeds working memory capacity; in these cases, tests that include repetitions of stimuli may be more easily performed than those in which the information is heard just once. Patients with frontal lobe impairments may fail to engage efficient strategies such as chunking or organizing semantically, relying instead on inefficient serial learning strategies.

Other markers of frontal lobe impacts on memory include interference effects. Examples of interference are worse performance on a second word list compared to the first trial of a previously presented word list; an early plateau or inverted learning curve, where multiple attempts to retrieve from the same list result in increased difficulty with recall; and release from proactive interference occurs when there is a break in time or a distraction that results in better performance. At times patients with proactive interference can perform as well or better after a delay compared to immediate recall, particularly on word lists with multiple presentations.

It is also possible that individuals with more severe executive difficulties may confabulate when relying on memory. Here, families may note that when the patient is asked about daily events they “make things up.” Such patients typically take key elements of events and combine these with other information. For instance, when asked what items they were going to get from the supermarket, the patient may respond “milk, cheese, eggs... And then I had to go to the bakery to get bread and some cakes, because you like cakes, and after that I had to go to the drug store...”

Cognitive phenotypes and ongoing research. Most of our understanding of the relationship between neural impairment and cognition in epilepsy has proceeded, historically, from our general knowledge of brain-behavior relationships, case studies, and data from small samples. This has recently been replaced by a move towards multi-site studies with many hundreds of patients that can identify cognitive phenotypes (80; 62) or derive and then independently validate patient-specific algorithms for predicting cognitive decline (24; 25). One notable contribution reexamined cognitive profiles previously shown to exist in temporal lobe epilepsy, which is the most common form of epilepsy (62). The study with over 2000 temporal lobe patients identified four main cognitive phenotypes: (1) generalized impairment across all cognitive domains (10% to 22% of patients), (2) single-domain impairment (most commonly of memory and language) in 26% to 29% of patients, (3) bi-domain impairment in 14% to 19% of patients, and (4) no cognitive impairment in 30% to 50% of patients. These broad phenotypes were also observed in a Spanish-speaking monolingual sample, showing cross-cultural applicability (81).

Clinical variables modifying the cognitive presentation

A number of variables affect the nature of cognitive impairment seen in epilepsy. One of these is the age at which seizures commenced. When seizure onset occurs early in life, as a general rule, it is more likely that cognitive functions, eg, localization of language and verbal memory to the left hemisphere, will be disturbed.

The precise age at which neural insult occurs is also important when considered in light of a child's neural, cognitive, and psychosocial development. When seizures commence at a critical developmental point (for instance, during language development), the course of development can be disturbed. A study investigated a vast range of pediatric epilepsy syndromes (eg, temporal lobe epilepsy, absence seizures, juvenile myoclonic epilepsy) (47). The authors reported a high degree of common language impairments (eg, poor vocabulary performance) shared across the epileptic groups when compared to healthy controls. Deficits may not initially be apparent but may appear as children subsequently fail to acquire expected functions (“growing into deficits”). It is also important to note that insults to the brain actually have a multiplicative impact, not simply a cumulative one (“double hazard” model) (03). That is, consecutive negative events tend to have disproportionately greater impact on an individual. The effects of a head injury, ADHD, or chronic malnutrition will disproportionately influence a child who is already suffering a seizure disorder.

The age of onset is closely linked to the duration of time during which regular seizures have been occurring. The longer seizures continue, the greater the impact on cognition (38) and accelerated brain aging (37). For example, earlier onset of epilepsy and longer seizure duration has been associated with disrupted functional connectivity within the temporal lobes, which might explain deficits in naming in individuals with temporal lobe epilepsy (98). Other key seizure variables are the number of lifetime generalized tonic-clonic seizures, a larger load of antiepileptic drugs, and the number of episodes of uncontrolled seizures (status epilepticus) (38).

Another variable affecting cognitive impairments in individuals with epilepsy is seizure location. For instance, children with frontal lobe epilepsy have been shown to have more problems with executive function as well as more widespread neuropsychological deficits than children with temporal lobe epilepsy. Compared to healthy controls, children with temporal lobe epilepsy had poorer performance on verbal knowledge tasks, tasks evaluating inhibition, and shifting in daily life (102).

Antiseizure medications (ASMs). Antiseizure medications (previously known as anti-epileptic drugs or AEDs) can be associated with significant cognitive side effects. Those side effects are not only subjective but also objectively quantifiable, although individuals’ responses to these medications can differ (75).

Perhaps most notable among these are older antiseizure medications. These include sodium valproate/valproic acid, phenytoin, carbamazepine, and phenobarbital in particular, all of which can impact attention, processing speed, and memory retrieval. More recent medications (eg, felbamate, tiagabine, levetiracetam, lamotrigine, gabapentin, vigabatrin, oxcarbazepine, zonisamide) appear to have less significant cognitive effects. An exception is topiramate, which can cause significant impairment of memory, reaction speed, and language (naming), as shown in a randomized, double-blind study showed (55). These effects are marked at higher doses and can be ameliorated with good titration. Another study showed that use of topiramate is associated with up to 50% worse performance in verbal fluency than gabapentin and lamotrigine (57). Phenytoin and carbamazepine have been associated with impairments in verbal memory recall (65). One study found up to 11% of patients on topiramate described intolerability of cognitive side effects and ultimate discontinuation of the drug, with phenytoin and zonisamide a close second and third (04). Recent fMRI studies indicate that both topiramate and zonisamide altered functional connectivity in networks essential for higher cognitive processes including language (105). Cognitive effects should be carefully considered when interpreting neuropsychological profiles in patients with epilepsy. Finally, cognitive deficits are more pronounced in individuals treated with multiple antileptic drugs (polytherapy) than in those treated with a single antileptic drug (monotherapy) (75).

Psychiatric comorbidities and cognition. Psychological factors may have very significant effects on cognition and can alter the presentation of localizing cognitive impairments. Symptoms of anxiety and depression result in reduced attention, working memory, and processing speed in addition to other deficits (30). Patients with epilepsy have very high rates of both anxiety and depression (107); these symptoms may in turn affect their cognitive profiles; for example, finding memory impairments that may suggest localized, mesial temporal deficits, when in fact the impairments may result from poor encoding due to reduced attention and concentration secondary to depression or anxiety. One study found that patients with early seizure onset had impaired autobiographic memory that was linked to younger onset of epilepsy, reduced working memory, and more frequent seizures (79). In contrast, patients with late seizure onset also had deficits in their autobiographic memory but those were associated with depression and lesion presence (as identified by MRI) (79). For these reasons, neuropsychological testing should include comprehensive psychological evaluation and consideration of psychiatric comorbidities.

Postsurgical declines in cognition

Epilepsy surgery can be highly effective in reducing seizures for medication-resistant epilepsy but comes at a risk of cognitive decline due to resection (eg, anterior temporal lobectomy) or laser ablation of structures critical for cognition (eg, the hippocampus). Pooled estimates suggest verbal memory decline in about 44% of patients undergoing left hemisphere resections of medial temporal lobe structures, in contrast to 20% decline after right-sided surgeries (91). In the same systematic review, naming decline was observed in 34% of left-sided resections.

For the most common form of surgery for focal (ie, temporal lobe) epilepsy, Busch and colleagues derived and then validated (in a separate sample) a simple nomogram (ie, a risk stratification calculator) for predicting naming decline after a temporal lobe resection (24). Using a worksheet provided by Busch and colleagues (also available as an online calculator), the risk of moderate or greater naming decline on the Boston Naming Test can be calculated simply using (1) side of surgery (dominant or nondominant), (2) age at seizure onset, (3) age at surgery, (4) education, and (5) sex. In a follow-up study, Busch and colleagues developed a similar nomogram for prediction of verbal memory decline on RAVLT or logical memory (25). Variables used in prediction of verbal memory decline included surgery side (dominant or nondominant), baseline performance, patient’s education level, and, in some cases, whether the hippocampus was resected or not.

Diagnostic workup

Neuropsychological assessment. A primary goal of preoperative neuropsychological evaluation is to identify potential discrepancies in cognitive deficits and seizure localization results including EEG, MEG, and MRI. Neuropsychological assessment ideally starts from a standardized battery then is tailored to the patient’s clinical complaint and the referral question. It will typically include an assessment of premorbid cognitive function against which impairment can be identified (eg, the Test of Premorbid Function; TOPF). An assessment of global intellectual function is then necessary (eg, Wechsler Adult Intelligence Scale IV [WAIS] or Wechsler Abbreviated Scale of Intelligence II [WASI II]). This allows identification of global impairment, which is more common in significant developmental delay, generalized tonic clonic seizures, or status epilepticus, or with a long duration of regular seizure occurrence. Components of the WAIS provide measures of attention and working memory (digit span) and processing speed (coding). Assessment of language functioning should include a range of tasks to assess the different skills detailed above. This may include assessment of naming ability using both visually (eg, Boston Naming Test) and auditorily presented stimuli (eg, Boston Diagnostic Aphasia Inventory [BDAE] 3 Auditory responsive naming) or the Auditory Naming Test (42). The BDAE also contains a series of measures examining reading and auditory comprehension, expression, and repetition. The Woodcock Johnson III contains a particularly nice measure of orthography-phonology mapping (“Word Attack”) sensitive to angular or supramarginal impairment. Assessment of spatial function may include basic tasks in which line orientation is judged (Judgment of Line Orientation task) and visuoconstructional tasks (eg, Hooper Visual Organization Test). Memory assessment should include both verbal and nonverbal measures per those listed above (Wechsler Memory Scale IV: Verbal Paired Associates, Logical Memory & Visual Reproduction; Rey Complex Figure; California Verbal Learning Test-3).

Psychosocial and psychological assessment. Psychological and psychosocial assessment is a critical part of the presurgical evaluation. A significant proportion of epilepsy patients have comorbid psychological conditions. Depression is found in 20% to 55% of patients with epilepsy and is the most frequent comorbid psychiatric diagnosis in epilepsy (101) followed by anxiety (90), ADHD (43), and psychosis (28). Up to 6% of individuals with epilepsy, especially temporal lobe epilepsy, have a comorbid psychotic illness and have almost an 8-fold risk of psychosis (28). Postictal psychosis was found to be more common under particular circumstances including a heightened genetic predisposition to schizophrenia and was more prevalent with right temporal lobe discharges (23).

Thirty-two percent of all deaths in epilepsy are from suicide (71). A large multisite study found that the presence of presurgical psychiatric history (eg, depression, anxiety, chronic pain), as well as divorced status were risk factors for postsurgical increases in depression (32).

Together this highlights the importance a comprehensive risk assessment presurgically as well as underscoring the need for both presurgical and postsurgical management of psychiatric symptomatology. Mental health care for individuals with epilepsy remains challenging due to the lack of standardized procedures and integrated mental health specialists. In a study, over 60% of patients with epilepsy suffering from a psychiatric comorbidity were not receiving care for their mental health (63).

Quality of life and surgical outcome. A commonly used standardized instrument to assess real-life impact of epilepsy and surgical outcome is the Quality of Life in Epilepsy (QOLIE) (68), which measures multiple domains including social, cognitive, emotional, medication side-effects, energy/fatigue, and seizure worry. There is strong evidence that appreciation of the likelihood of adverse cognitive outcomes following surgery can result in superior outcomes, in part due to having realistic expectations of the potential changes is cognition postoperatively.in cognition postoperatively. Thus, there is a need for tailored preoperative counseling to reflect the likely risk/benefit ratio of surgical resection (11). Careful assessment of potential areas of cognitive decline can help plan postoperative interventions and set up realistic expectations for quality of life. A theoretical review highlights a framework for cognitive “prehabilitation” (eg, using intact functions to establish compensatory strategies) as well as rehabilitation in epilepsy, which is greatly lacking in comparison to research on assessment of cognition (10).

Invasive assessment. More direct mapping of cognitive function is essential to evaluate the assumptions underlying the assessment (namely that the left hemisphere represents language) and to quantify the likelihood of postsurgical impairment in memory and language.

fMRI is an invaluable noninvasive method for mapping cognitive function presurgery, most commonly for language. A number of authors have argued that clinical fMRI has now matured to the point that it can replace Wada testing for the purposes of language lateralization (16). Indeed, many centers have replaced the Wada test with fMRI for language lateralization. However, using fMRI for language lateralization in epilepsy remains an issue of ongoing debate, especially given the consequences of incorrectly localizing language (59). For instance, a study showed that in a series of 229 consecutive patients at a comprehensive epilepsy center, language lateralization by fMRI and Wada was discrepant in 42 instances (48). There were unfortunately no significant predictors of discordance. Moreover, they subsequently showed that when fMRI and Wada testing was discordant, fMRI more accurately predicted language decline (48). Although this demonstrates fMRI can replace Wada testing for language lateralization, it is notable that this is only true in the presence of a highly standardized and reproducible form of language fMRI, and that many epilepsy programs likely do not currently have access to this (14). Although it is not currently feasible, our ability to localize specific regions within the dominant (and nondominant) hemisphere is an area where fMRI will be particularly valuable, and efforts are currently under way to validate it for this purpose.

With respect to memory, there is currently no widely accepted, clinically validated protocol for lateralizing memory function, though there is a growing literature on memory activation paradigms in epilepsy (77; 92). A practice guideline summary by the American Academy of Neurology found lower evidence (ie, Class C) for establishing the laterality of verbal memory function (96).

Magnetoencephalography (MEG), though not as widely available as fMRI, appears to have a similar ability to lateralize language functions (109).

Direct electrocortical stimulation mapping (ESM) with superficial grids or depth electrodes (phase 2) is typically completed if it is highly likely an epileptogenic focus in eloquent cortex. This involves a craniotomy followed by installation of one or more grids of electrodes and/or depth electrodes over the relevant cortex before the craniotomy is closed and the patient returns to ward. A neuropsychologist then evaluates cognitive function with tasks appropriate for the relevant region (eg, naming, reading, etc.) while an electrophysiologist systematically stimulates different electrodes through the grid. The results are then correlated with the precise location of the electrodes as determined by imaging. This can be distressing for patients--the occurrence of one or more seizures is virtually inevitable--but can be an invaluable means of determining whether a resectable seizure focus exists. In the past decade, there has been a growing interest in adding stereo-electroencephalography with electrocortical stimulation mapping, a technique that can help target sulci and deep brain structures, such as the hippocampus or insula (86; 05). There has also been some recent focus on the fact that, in electrocortical stimulation mapping, considering neural activity both distal and remote to the site of stimulation through the variation of polarity during stimulation can improve our understanding of seizure propagation and, potentially, the clinical effects of resection (09).

If grid mapping is not feasible, awake intraoperative mapping provides one final option for mapping cognition. Here the patient is awakened in surgery following craniotomy, and cognitive function is directly evaluated as in grid mapping but with the neurosurgeon directly stimulating cortex either prior to or during resection. Again, this can be an invaluable method so long as it is tolerable to the patient but is frequently complicated by epileptic activity during stimulation. Nonetheless, direct cortical stimulation remains the gold standard to determine the location of brain regions critical for cognitive functions, particularly language (45).

Invasive mapping of other functions such as memory is an emerging area of research. Several case studies showed the utility of testing memory during stimulation of depth electrodes implanted in the hippocampus—ie, an “electric Wada,” which predicted postsurgical outcomes (49; 12). However, more studies are needed to develop optimal paradigms and clinically validate this approach.