INTRACAROTID AMYTAL TESTING IN THE EVALUATION FOR EPILEPSY SURGERY

 

CONFERENCES
TOPIC: EPILEPSY

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Abstract

The Intracarotid Amytal Procedure, or "Wada" test remains the standard for definitive lateralization of primary speech functions in epilepsy surgery candidates.  Assessment of hemispheric memory capacity during this procedure, originally performed to predict risk of global amnesia following unilateral temporal lobectomy, is increasingly seen as useful for lateralizing seizure onset, predicting seizure outcome, and evaluating risk of cognitive morbidity other than global amnesia.

In this paper we review the literature regarding the use of the Intracarotid Amytal Procedure ("Wada Test") in evaluation for epilepsy surgery.  Although results from various centers utilizing different procedures appear to provide robust findings, the interpretation and validity of findings with respect to predicting cognitive morbidity is not without question.  With respect to memory findings, there is some question about the likelihood of incurring a global amnestic syndrome following unilateral temporal lobe resection and the ability of the Wada test to predict such a low frequency occurrence.  Furthermore, although the assumption is that Wada memory performance is a measure of hippocampal function, the direct evidence of this is sparse.  This calls into question the value of a "lateralizing" memory study (e.g., asymmetry between right and left hemisphere memory performance), especially since many patients demonstrate adequate memory bilaterally.

Controversies regarding language findings are also discussed.  The criteria for defining anomalous representation of language (e.g., right hemisphere dominance or bilateral language) vary from center to center, resulting in significant variability in estimates of the frequency of occurrence.  This is particularly relevant if the Wada is considered the standard against which emerging technologies are compared, such as fMRI.

Based on our review, we conclude that the IAP ("Wada" test) continues to play an important role in evaluation for epilepsy surgical candidates despite the limitations.  Although the specific applications and interpretations continue to evolve, the current knowledge about emerging technologies limit their application in clinical populations at the present time.
 
 

Resumen

El Test de Amital Intracarotideo (TAI) o "Test de Wada" continua siendo el estándar para la lateralización de las funciones lingüísticas primarias, en los pacientes candidatos a cirugía de la epilepsia. Tal y como progresivamente se ha ido comprobando, la valoración de las funciones mnésicas en cada hemisferio durante este procedimiento, originalmente diseñado para predecir el riesgo de amnesia global  tras lobectomía temporal unilateral, esta siendo útil también para la lateralización del foco epiléptico, para predecir la eficacia de la cirugía en el control de las crisis y evaluando los riesgos de morbilidad de otras funciones cognitivas además de la memoria.

En este articulo exponemos un resumen de la literatura relacionada con el TAI (Wada Test) en la evaluación de la cirugía de la epilepsia. Aunque los resultados de los distintos centros utilizando diferentes procedimientos parecen indicar resultados robustos, la interpretación y validez de los hallazgos respecto a la predicción de la morbilidad cognitiva  no esta todavía clara. Respecto a los resultados de memoria, existen ciertas dudas acerca de la probabilidad de incurrir en el síndrome de amnesia global post resección temporal unilateral y la habilidad del Test de Wada para prevenirla, aun cuando esta se produce con una frecuencia muy baja. Es mas, aunque se infiere que la ejecución mnésica, durante el test de Wada, es una medida de la función del hipocampo su evidencia directa es difusa. Esto cuestiona el valor del estudio de la lateralización de la memoria (pej: asimetría entre el hemisferio derecho y el izquierdo en la ejecución de memoria), especialmente cuando muchos pacientes muestran adecuadas ejecuciones mnésicas bilaterales.

Por otro lado, también se comentan las controversias existentes respecto a los hallazgos del lenguaje. El criterio para definir una representación anómala del lenguaje (Pej: dominancia del hemisferio derecho o lenguaje bilateral), varia de centro a centro, resultando una significativa variabilidad en la estimación de la frecuencia de su ocurrencia. Esto es particularmente relevante si el Wada es considerado el estándar comparado con otras tecnologías como la RMf.

Basándonos en nuestra revisión, concluimos que el TAI (Test de Wada) continua jugando un importante papel en la evaluación de los candidatos a cirugía de la epilepsia a pesar de sus limitaciones.
 
 
 

 
The Wada test is used in the evaluation for epilepsy surgery to 1) establish cerebral language representation, 2) identify patients who are at risk for developing a significant post-surgical decline in learning, and 3) to contribute information important for lateralization and localization of seizure onset for surgical decision making.  The procedure involves pharmacologically inactivating the cortex within one cerebral hemisphere for several minutes, during which time the patient is presented with multiple cognitive tasks.  The test is not standardized, and the above goals are emphasized differently at various epilepsy surgery centers.  However, it can also lead to some interpretive confusion when the procedures are poorly defined, and disagreement about the optimal parameters for performing the test.  Comparison of results across centers is also hindered, which limits studies of validity and reliability.  Nonetheless, the variability in the procedure is not completely problematic.  There is greater flexibility in tailoring the specific parameters of the procedure to the needs of the individual patients.  Furthermore, despite the tremendous variability in the procedure both between and even within centers from patient to patient, the results with respect to both language and memory findings appear to be robust.

The Wada test is actually many different procedures.  There is even some disagreement about the proper name for the procedure (Intracarotid Amytal Procedure, or IAP, Intracarotid Sodium Amytal, or ISA/ISAT).  We will use the term "Wada test" in this paper to refer to this procedure in part because of its listing as such in the Current Procedure Terminology (CPT) code book.  The procedure used in Wada testing can vary for virtually every aspect of the test. A recent survey summarized some of the important dimensions on which the Wada test varies (Rausch et al., 1993).  For example, patient selection can vary- some centers have all epilepsy surgery candidates undergo Wada testing, while others limit the procedure to those patients that are suspected of having anomalous language representation based on historical and clinical factors, or those believed to be at risk for severe memory loss.  Some centers inject only the hemisphere targeted for surgery in order to assess function in the unoperated hemisphere, while other centers inject both hemispheres routinely.  Most centers that perform bilateral hemisphere injections conduct both studies on the same day, but there are some centers that perform right and left hemisphere injections on successive days.  Unilateral anesthetization is confirmed behaviorally at some centers (e.g., hemiparesis contralateral to injected hemisphere).  Other centers rely on EEG and/or metabolic studies to confirm hemispheric inactivation.   Other test conditions that vary include drug parameters (e.g.., Amytal or Brevital; dose, dilution, rate of injection).  Each of these factors may impact on the interpretation of the Wada test results, and need to be carefully considered and meticulously reported when describing results.

Technical variations may impact directly on the patientís performance.  However, psychometric factors and administration variability also differs among centers and can have an equally significant impact on interpretation of results.  Most centers perform comprehensive clinical and standardized assessment of language that includes spontaneous expressive language, confrontation naming, repetition, and comprehension. The behavioral stimuli are often not standardized, and may be idiosyncratic between centers.  Interpretation of the results is usually classified in terms of hemispheric dominance (e.g., "Left", "Right", or "Bilateral/Mixed").  However there is some disagreement about what constitutes bilateral speech as well (see discussion below).   Similarly, memory stimuli and presentation methods vary.  Some centers present a series of objects (e.g., Loring et al.,1992) while others rely on presenting drawings of objects and nonsense figures for memory assessment.  The timing of stimulus presentation also varies, and may occur during the period of maximal hemispheric anesthetization in the first 2-3 minutes after injection, or continue for several minutes after the initial injection.  Recall procedures also vary in terms of the timing and method.  Many centers that present real objects for later recall use a forced choice recognition memory procedure (e.g., did I show you this?).  Centers that present drawings of objects may utilize multiple choice recognition format for testing recall.  Again, all of the relevant factors need to be meticulously described in order to allow interpretation of the study and comparison of results among different centers.

With all of this variability in technical and psychometric procedures, how could a test like the Wada be of any clinical or scientific value?  As noted above, despite these differences, validity studies and interpretation of results yields remarkably robust findings.  In the following sections, we discuss some of the major interpretive and validity issues with respect to the Wada test, followed by a selected bibliography of recent references.
 

 
The Wada procedure was originally developed to provide a technique to establish cerebral dominance extra-operatively.  In general, establishing hemispheric dominance is a relatively simple task since patients display recognizable patterns of aphasia following inactivation of the speech dominant hemisphere.  Typically, the dominant hemisphere injection is followed by global aphasia with progressive recovery.  The period of recovery can depend on procedural factors such as dose and rate of injection, but generally recovery is complete within 10-12 minutes following the initial bolus injection if no further Amytal is administered.

The value of language testing during the Wada test is, in part, determined by the consistency of the definition of "Speech" dominance.  As noted above, there is considerable variability in how speech is defined, and the criteria for identifying bilateral or mixed dominance.  In a 1990 survey of 55 epilepsy surgery centers from 10 countries, Snyder et al. reported the range of "Mixed Speech Dominance" was from 0 to 60% of patients, depending on the center.  The criteria employed for determining presence of language in the dominant hemisphere were relatively uniform.  Most epilepsy surgery centers (93%) employ object naming as a criterion for establishing speech in the dominant hemisphere (Snyder, et al., 1990).  In addition, aphasic signs (78%), counting ability (80%), familiar word/phrase repetition (61%) and unfamiliar word/phrase repetition (65%) are common positive language signs.  In contrast, more heterogeneous criteria are used to infer the presence of some speech representation in the nondominant hemisphere, including mouthing appropriately, groaning, singing, object naming, partial phoneme vocalization, serial rote speech, and expression of familiar words.  The result of the variability in definition of "speech" is significant variability in the estimate of occurrence of bilateral or right hemisphere speech.  While this may seem to pose merely a thorny theoretical issue, the clinical implications are also significant.  First, surgical planning is greatly facilitated by confident knowledge of cerebral language representation.  Knowledge of independent or compensatory language in the right hemisphere would suggest less risk of language morbidity following resection of functional language cortex. While there is no single clear definition of what constitutes "speech" or "language" ability in the nondominant hemisphere, when surgical planning includes suspected language areas, confirmation of function with cortical stimulation is indicated.

Second, interpretation of neuropsychological test results may be effected by assumption of mixed, or right hemisphere, dominance for speech.  The effect of atypical language on neuropsychological test results is unclear, and there are no pathognomonic indicators of atypical speech in our standard neuropsychological test batteries.  The literature on "crossed aphasia" (e.g., aphasia following acquired right hemisphere lesion) suggests that the presence of situs inversus, or complete mirror representation of language and spatial dominance occurs, but that it is not a reliable finding.  Alternatively, the crowding literature (which may be more relevant to developmental and/or chronic disorders such as epilepsy) suggests that the effects can be either global or limited, with magnitude of the lesion exerting a significant influence (Loring et al., 1999).

Lastly, emerging technologies such as fMRI tend to be validated against existing procedures like the Wada test.  Early validation of the Wada test was based on comparison of cortical stimulation and outcome following surgery.  Newer technologies tend to be compared and validated against the existing standard, regardless of the flaws inherent in that standard.  Ambiguity in the definition of bilateral speech in the Wada test potentially poses a problem for clinical application of the fMRI.  Lack of confidence in what constitute bilateral speech during the Wada test potentially undermines confidence for interpreting bilateral activation during fMRI language tasks.   This is an increasingly important issue in that fMRI has the potential to provide a noninvasive alternative to the Wada test, but first must be adequately compared to it.  The emerging literature has indicated good concordance in samples that are unambiguously dominant.  However, the agreement is not 100%, and there are case reports of patients that have been ambiguously or incorrectly lateralized with fMRI.
 

Wada memory testing was included in the procedure by Milner to predict whether the hemisphere contralateral to a unilateral seizure focus could sustain memory function following temporal lobectomy.  The rationale and history of this has been well chronicled (see Loring et al., 1992 for review).  Briefly, Milner hypothesized that transient pharmacological deactivation of the hemisphere ipsilateral to planned temporal lobectomy allowed for modeling the effects of surgery.  If the patient could recall the events that immediately followed the injection, it seemed  reasonable to conclude that the contralateral hemisphere could support memory and unilateral temporal lobectomy would not result in severe postoperative amnesia.  The inference is that unilateral anesthetization temporarily incapacitated the hippocampus and that recall for the events that transpired is mediated by the contralateral hippocampus.  This hypothesis has been criticized because the distribution most commonly injected for Wada memory testing (the MCA) does not directly perfuse the hippocampus, and consequently anesthetization cannot be presumed.  However, Wada memory performance has been validated in several different ways.  First, depth record EEG slowing occurs in this region following Intracarotid Amobarbital administration (Adachi et al., 1993).  More recently, HMPAO SPECT studies performed at the time of Amytal injection have demonstrated reduced rCBF to medial temporal structures in the majority of patients (Kim et al., 1999;  de Silva . et al., 1999).  Wada memory performance has also been correlated with hippocampal cell counts (Sass et al., 1991; Saykin et al., 1993), hippocampal sclerosis (Davies et al., 1996) and MRI hippocampal volumes (Loring et al., 1993).  Thus, there is both a structural and functional relationship between Wada memory and the hippocampus.

Another method of validating the Wada memory test is the positive predictive value of the test for the severe post-operative memory impairment it is used to avoid.  This type of criterion related validity is more difficult to achieve with Wada memory testing.  If the test is used to predict this outcome and avoid it, then there will be few instances in which the procedure will be undertaken when the predictor is positive.  Nonetheless, Rausch et al (1993) reported that 6 respondents to their survey reported patients who failed the Wada memory test (i.e., failed to recall events following injection of the hemisphere ipsilateral to subsequent surgery) and went on to demonstrate an amnestic syndrome following unilateral temporal lobectomy.  However, there are also reports of false negatives, that is, patients who pass Wada memory testing who develop amnestic syndromes.  Thus, while there appears to be limited evidence for positive criterion related validity, the sensitivity and specificity of the procedure for accurately predicting the possibility of amnesia following temporal lobectomy may be determined by careful interpretation of additional clinical factors.

More recently, the interpretation of Wada memory testing has evolved to include prediction of lateralized cognitive dysfunction that is associated with a primary seizure focus.  Asymmetry in the hemispheric memory scores shows a strong relationship to side of seizure onset in patients with temporal lobe epilepsy.  In patients with other clinical data that is suggestive of unilateral onset but not conclusive, definite Wada memory test asymmetry may eliminate the need for invasive monitoring before surgery.  In seizure onsets outside the temporal lobe, Wada memory asymmetries occur less frequently, but when they do occur are also predictive of side of seizure onset.

Patients are more likely to have poor memory performance following injection contralateral to a seizure focus if significant hippocampal sclerosis exists.  This relationship is presumably due to the degree of bilateral temporal lobe dysfunction temporarily created by the injection.  Presumably, minimal functional capacity is present in the severely sclerotic hippocampus and consequently, contralateral amobarbital perfusion creates greater bilateral dysfunction with "failed" memory for the events following the injection.  Conversely, injection of the same hemisphere as the sclerotic hippocampus creates no greater deficit than was present at baseline.  However, not all patients with temporal lobe epilepsy "fail" the memory test following injection contralateral to the suspected seizure focus.  Patients with mild sclerosis may demonstrate some memory impairment, but not complete failure, for events immediately following the injection.  Again, presumably the functional capacity of the mildly sclerotic hippocampus is impaired, but still adequate to support some memory. The result is an asymmetry favoring the "normal" hippocampus, but without unilateral failure.  Consequently, it is not necessary to demonstrate memory failure following one injection to confidently interpret memory asymmetry as reflecting unilateral seizure onset.  The degree of asymmetry necessary for interpretation is dependent on the technique for testing memory.
 

Memory Outcome
Wada memory performance is also related to postoperative verbal memory performance.  Patients with symmetrical Wada memory scores tend to be more likely to demonstrate a decline on laboratory measures of verbal memory following left temporal lobectomy.  In contrast, patients with Wada memory asymmetry suggesting left unilateral temporal lobe impairment do not show similar declines in verbal memory following left temporal lobectomy.  The picture is less clear concerning Wada memory test performance and right temporal lobectomy.  As with other studies of memory outcome following right temporal lobectomy, no consistent relationship has been found between Wada memory test performance and visual-spatial memory.  However, this may not necessarily be a reflection of adequacy of the Wada memory test as it is a reflection of the criterion we are using to measure visual-spatial memory following right temporal lobectomy.  If there is no clear relationship between right temporal lobectomy and visual spatial memory outcome, it would be virtually impossible to predict this relationship using the Wada memory test, regardless of itsí efficacy.

Seizure outcome
Evidence of well-lateralized temporal lobe dysfunction increases the likelihood of a good surgical outcome.  Patients with significant volumetric MRI hippocampal asymmetries are more likely to have a good outcome following temporal lobectomy (Loring et al., 1994; Perrine et al., 1995).  Since the presence of hippocampal atrophy is related to postoperative seizure frequency, and because Wada memory asymmetries are related to MRI hippocampal volume asymmetries, the association between Wada memory and seizure outcome would be anticipated.  In one study (Loring et al., 1994) 89% of patients with Wada memory asymmetries were seizure free at one year follow-up.  In contrast, only 63% of the patients without asymmetries were seizure free.  Wada memory asymmetries contribute unique information to outcome prediction, beyond the information provided by other clinical factors.
 

Epilepsy surgery, in particular temporal lobectomy, is increasingly considered an option for children. Assessment of pediatric surgical candidates also includes the Wada language and memory tests.  As noted above, early onset of seizures may be associated with anomalous organization of speech, clouding the interpretation of neuropsychological test results.  Consequently it is necessary to confirm language laterality in pediatric surgical candidates.  Good Wada test results may be obtained in children (Westerveld et al., 1994; Szabo & Wyllie, 1993), but some modifications to the procedure may be needed (Williams & Rausch, 1992).  The rationale for using the invasive procedure for children is essentially the same as adults.  Identification of the language dominant hemisphere may facilitate surgical planning if no language is identified in the epileptogenic hemisphere.  Identification of hemispheric dominance for language can be reliably accomplished in children as young as age 7 years of age (Westerveld et al., 1994) and possibly younger (Williams & Rausch, 1992; Szabo & Wyllie, 1993).  Furthermore, asymmetry in memory function during this procedure indicates lateralized dysfunction that aids in determining side of surgery for pediatric temporal lobectomy candidates (Westerveld, et al, 1994).  Memory testing during the Wada test may also be useful in predicting memory outcome, although this has yet to be demonstrated in children.

The Wada test is well validated for its intended purposes.  At the present time, there is not a more reliable or accurate method of determining hemispheric language dominance or modeling the effects of temporal lobectomy on memory.  However, functional magnetic resonance imaging, or fMRI, holds promise as a noninvasive alternative to Wada language and memory testing.  The potential advantages of fMRI are numerous, and include a more precise map of language distribution within the dominant hemisphere, avoidance of possible complications of Wada testing that are associated with the invasive angiography, minimizing or eliminating the need for subdural grid or intraoperative mapping of language, and exploration of other cognitive functions in relation to language during a single imaging session.  However, there are also some limitations to fMRI as a total replacement for Wada testing.  These include technical differences in the methodology of fMRI and poor current knowledge about the impact of various disease states on fMRI results.  There are significant differences in the way in which fMRI and Wada information are obtained.  Functional MRI relies on cognitive activation paradigms in which the patient performs a cognitive task, analogous to traditional neuropsychological testing, and requiring proper patient motivation and cooperation.  Based upon imaging of activated brain regions during task performance compared with a resting and control states, inferences about brain structures contributing to task performance are made.  All regions in the network involved in successful task performance, either directly or indirectly, should show some degree of activation.  However, since activity relative to a control state is measured, proper control for factors extraneous to the critical function is imperative.  Even when the most rigorous control tasks are used, there is still the risk of attributing function to areas that are active in but not critical to a particular task performance.

The Wada test and fMRI results also answer a different question.  Functional MRI is an activation procedure.  In contrast, the Wada test is a deactivation procedure.  Brain regions are temporarily inactivated by perfusion of Amobarbital, and the effects of drug inactivation on cognitive performance is assessed.  Wada testing addresses the question of whether these tasks can be performed without the contribution of the affected brain regions.  Although a region may be involved in task performance under ordinary circumstances, this region may not be necessary for task performance.  Thus, Wada testing potentially provides a more appropriate technique to model the effects of surgery on post-operative cognitive function.  In addition, the Wada test may be more appropriate for some patients that may be unable to reliably perform an activation procedure while remaining still (e.g., anxiety when placed in the MRI apparatus, patients with limited cognitive resources or attention problems).

Current studies of concordance between fMRI language mapping and Wada language results generally support the validity of fMRI language activation techniques.  Reliable activation of expressive language areas, receptive language areas, and systems involved in reading have been reliably identified.  Furthermore, studies of normal volunteers have generally reported prevalence of atypical speech that is consistent with estimates based on the Wada test.   However, in epilepsy patient populations the concordance with Wada language results is not 100%, and there are some reports of erroneous lateralization in patients, indicating that further study is needed.
There are both technical and theoretical issues to overcome when imaging memory for purposes of surgical planning.  Although there are some recent reports of activation during retrieval tasks, imaging of encoding processes using fMRI is limited, with few reports of consistent, localized hippocampal activation.  Since the hippocampus is critical for encoding and consolidation of memory, this is obviously an area for further work.  There are currently no studies that report on concordance of fMRI with Wada memory test results, or studies that use fMRI to predict memory outcome following temporal lobectomy.

Wada testing of language and memory continues to play a critical role in the evaluation of epilepsy surgery patients.  In many patients, Wada testing measures functional deficits associated with known cerebral lesions, contributes to establishing laterality of seizure onset, and provides some estimate of the risk to memory following temporal lobectomy.  There will continue to be procedural refinement based upon correlations with MRI volumetry, fMRI, and MR spectroscopy. More importantly, prediction of long term cognitive outcome and seizure control is possible with the Wada test, and in conjunction with other neurological, functional, and psychometric assessments, facilitates selection of patients most likely to benefit from surgical treatment of epilepsy.  Eventually, noninvasive measures of brain function, including fMRI will provide much of the same information as that derived from Wada testing.  However, it remains to be established if a procedure that relies on activation can provide comparable date to the Wada test which may provide a more accurate reversible model of the effects of surgery on cognition.  Ideally, advances in fMRI and other imaging techniques will provide a complementary picture that improves on our ability to predict and avoid significant post-operative cognitive deficits.
 

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