Although the number of studies published annually on the Wada test has remained fairly stable over the last decade, there have been a number of significant shifts in the focus of this research. Up until the late 1990s, the majority of published studies focused on the reliability and validity of the procedure, with studies designed to identify the salient procedural and clinical variables that influence Wada test scores, combined with wider efforts to delineate and standardize an optimal procedure.
However, the beginning of the 21st century saw an abrupt switch in emphasis in Wada test research. Following the introduction of functional MRI (fMRI) paradigms for lateralizing language function, Wada test scores have been increasingly employed as the standard against which to validate a proliferation of novel, less invasive methods of mapping cognitive function, including magnetoencephalography (MEG)  and high-density electroencephalography (EEG) recordings .
The worldwide shortage of sodium amytal prompted a quest for alternative available compounds with similar properties. However, the coincidence of this shortage with emerging fMRI paradigms to lateralize language function has prompted many clinicians to reexamine the clinical indications for the Wada test for epilepsy surgery candidates today.
Clinical indications for the Wada test
2008 saw the publication of three multicentre surveys [3,4•,5•] of the ways in which the Wada test is currently employed in the presurgical evaluation of epilepsy surgery patients. In the largest study of its kind to date, Haag et al. [5•] examined 1421 Wada procedures conducted in 16 European centres between 2000 and 2005. Although a Wada test was conducted on a third of all surgical candidates in all participating centres, the survey revealed wide variations in the deployment of the test in individual centres, with frequencies ranging from 8 to 110% of candidates (the latter figure presumably accounting for retests of an initial unreliable result). Interestingly, the primary clinical indications for requiring a Wada test prior to surgery in this survey were concerns about resecting potentially relevant language areas or a mesial temporal lobe resection in the language-dominant hemisphere. The reasons for these language concerns in temporal lobe epilepsy (TLE) patients who undergo tailored resections that spare language areas are unclear . The reliability and validity of the Wada test in assessing memory capacity and postoperative memory decline were not highly rated by the survey respondents. Focusing just on the presurgical evaluation of candidates for TLE surgery, Baxendale et al. [7•] surveyed clinical practice in 92 epilepsy centres in 31 countries. The survey showed results similar to the European study regarding the prevalence of the test in the presurgical evaluation of these patients, with 50% of the respondents reporting that they conducted the test in less than 25% of their surgical candidates.
It is clear from these studies that there has been a significant shift in the role of the Wada test in epilepsy surgery programmes. The majority of epilepsy centres no longer conduct a Wada test on every surgical candidate. The timely study by Loddenkemper et al. [8•] quantifying the invasive nature of Wada procedures with complication rates of up to 10% serves as an important warning for the minority of centres who continue to favour ‘a belt and braces approach’ when it comes to including the Wada test as a routine component of presurgical evaluation for all candidates. The current clinical debate is primarily focused on the identification of patient groups in whom the Wada test may still yield unique and important data in the clinical decision-making process.
Kemp et al.  examined the characteristics of Wada test failures in a multicentre UK study of 141 procedures. They concluded from their clinical audit that right-handed patients with right temporal lesions and good baseline verbal memory function were unlikely to fail the test and would probably not need to undergo the invasive procedure. They also noted that patients with left temporal lobe (LTL) lesions were more likely to fail the test, regardless of their handedness or baseline neuropsychological performance, raising the unanswered questions from the 1990s research on the reliability and validity of the test in this regard. In a debate on current controversies in neurology, Baxendale et al. [4•] attempted to identify patients for whom the risks of a Wada test would outweigh the potential benefits from the evidence base in the literature on postoperative amnesic patients. They argued that as no patient has ever been reported to become amnesic following a temporal lobe resection in whom all other tests (volumetric MRI, T2 relaxometry and baseline neuropsychological function) indicated that the structure and function of the contralateral structures were intact, the risks of a Wada test would outweigh the chances of a postoperative amnesic syndrome in this group. In addition to this clinical and theoretical evidence base, cultural factors may also influence the decision to conduct a Wada test. Helmstaedter  has suggested that a culture of litigation may reflect the increased reliance on the Wada test in North America. However, given the current debate, it is possible that clinicians may be threatened with litigation following a Wada test complication if the clinical indication for the test is poor. In a thoughtful commentary on the ethical and clinical issues raised by changing practices, Loddenkemper [9••] has proposed a useful clinical decision algorithm for the presurgical assessment of language and memory function, omitting Wada testing.
The Wada test as a validation tool
Although the debates surrounding the clinical applications for the Wada test remain unresolved, it continues to be used as the gold standard against which novel language lateralization techniques are judged. With a few exceptions (repetitive transcranial magnetic stimulation was originally introduced in the 1990s as a possible alternative to the Wada test but was poorly tolerated by many patients and often produced discrepant findings when the results were compared with the Wada test), the majority of these techniques rely on the analysis of activation patterns during language tasks rather than on the evaluation of behaviour and cognitive function following cerebral deactivation.
fMRI language paradigms are the most widely used and researched alternative to the Wada test in lateralizing language function [10••], and some have already made the transition from research to clinical tool [10••,11,12], with further refinements such as the real-time fMRI coregistration of the three-dimensional fluid-attenuated inversion recovery sequence showing early promise in the presurgical workup of children .
In a novel evaluation of the value of fMRI in assessing language dominance, Medina et al.  conducted a Bayesian analysis of data in the published literature and compared likelihood ratios of right and left language dominance using fMRI and Wada test data. They found that fMRI paradigms provided valuable data in the assessment of hemispheric language dominance in people with epilepsy.
Although fMRI activations may work well for the majority of patients, concerns have been raised about the reliability of these newer techniques in patients with atypical language representation. The interpretation of bilateral fMRI activation patterns is far from straightforward. The use of different thresholds can lead to different results. Wellmer et al. [14•] found large individual differences in fMRI language activation patterns in patients in whom the Wada test suggested atypical language representation, raising concerns about reliance on such data in a clinical setting. In a timely exploration of neuropsychological underpinnings that may underlie discrepant findings between fMRI and Wada-determined language function, Lee et al.  found an interhemispheric dissociation between speech production and comprehension. The four case studies presented in their paper suggest that speech production capacity is more likely to shift hemisphere (away from the seizure focus) than language comprehension. Interestingly, Wada and fMRI indices of language lateralization were discordant in three of the four cases, although the concordance between the two techniques was greater when speech production scores from the Wada test were discounted in the analyses. As a number of language tasks are often used in fMRI paradigms , resulting in different activations, and occasionally different conclusions regarding lateralization, it should be possible for clinicians to carefully examine the possible functional basis of the discrepancies between Wada and fMRI techniques in individual cases when the information is vital for clinical decision-making, particularly in a surgical setting.
MEG is beginning to show some promise in identifying both frontal and temporal language areas. Although it has yet to make the transition to a clinical tool in the lateralization of language function, the technique shows some promise in larger group studies [1,17]. See also ‘The current status of neuroimaging for epilepsy’ by John Duncan in this issue.
Although fMRI remains the front-runner amongst alternatives to the Wada test in lateralizing language functions, other techniques may be more appropriate for very young children or people with intellectual disabilities who may not be able to cope with the demands of a Wada test or an fMRI paradigm. Near-infrared spectroscopy (NIRS) is noninvasive and more tolerant to movement artefacts than fMRI. Although large-scale studies have yet to be completed, an early pilot of NIRS suggests that it may prove to be a useful alternative technique to investigate language lateralization in children and special populations .
Although it has only been tried on a handful of epilepsy patients in the literature to date, functional transcranial Doppler sonography, in which the blood flow is measured in the bilateral middle cerebral arteries during the performance of a language task, also appears to show good concordance with Wada test language lateralization and may be better tolerated by special populations .
Although structural MRI has proved to be a valuable adjunctive tool in assessing memory functions and functional capacity of the hippocampi and other temporal lobe structures [20–22], reliable structural measures and markers of language dominance in individual patients have yet to be identified . Similarly, asymmetries in event-related potentials (ERPs) have not yet proved to be accurate enough for the language lateralization in individuals for clinical purposes, and concerns have been raised about the reliability of ERPs in patients with epilepsy in whom activations may be subject to interference from the epileptic focus. For a comprehensive review of the current state of play of nine alternatives to the Wada test in lateralizing language function, see the study by Abou-Khalil [10••].
The Wada test and postoperative outcome
Because epilepsy surgery is an elective procedure, predicting postoperative outcome both in terms of seizure control and memory decline is an important part of the presurgical evaluation. The Wada test may provide useful data in respect of both outcome domains although it may not be a significant predictor of postoperative seizure control in patients with normal imaging [24,25]. Care should be taken when using memory scores following the anaesthetization of the language-dominant hemisphere to predict postoperative memory function as they may be inaccurate , and predictions based on these scores may be unnecessarily pessimistic.
In a postoperative follow-up study of 60 left anterior lobe resection patients, Binder et al. [27••] found a number of significant predictors of postoperative memory decline, including good preoperative performance, late age at onset of epilepsy and left hemisphere language dominance, established via the Wada test and fMRI paradigms. The combination of preoperative memory scores, fMRI measures and age at seizure onset accounted for up to 60% of the variance in postoperative outcome. Wada memory indices did not add any additional predictive power. Given the invasive nature of the Wada test, it does not appear to provide sufficiently unique data over and above that provided by noninvasive measures to justify inclusion in a preoperative protocol, solely for the purpose of predicting postoperative outcome.
Amobarbital and other compounds
Although the majority of current Wada test research is focused on defining its role and the quest for less invasive alternatives, some research on the test itself continues. With the worldwide shortage of sodium amytal, a number of centres have switched to using other compounds such as pentobarbital or methohexital. Kim et al.  compared recovery times, EEG parameters and indices of drowsiness and confusion following injections of either amobarbital or pentobarbital. The two compounds did not differ in respect of behavioural or EEG indices of the time taken to recover. Pentobarbital was, however, associated with drowsiness and confusion in fewer patients than amobarbital. In a larger comparison of the occurrence of seizures during a Wada test using amobarbital or methohexital in 760 procedures, Loddenkemper et al.  found a significantly higher risk of seizures in the methohexital Wada group (4.1%) than in the amobarbital Wada group (0.7%), consistent with the experience with methohexital as an anaesthetic, suggesting that methohexital may decrease seizure thresholds and trigger seizures.
The Wada test has proved to be an important tool in the presurgical evaluation of epilepsy surgery patients for over 50 years. In recent years, it has become the ‘gold standard’ against which newer noninvasive methods of language lateralization have been validated. The Wada test was never a uniform procedure, and the many reliability and validity issues associated with the memory component of the Wada test remain unresolved. Caution should be exercised in treating Wada memory scores as the ‘gold standard’ against which newer methods of assessing memory capacity and postoperative prognosis should be measured.
Much debate continues to surround the need for a Wada test in the evaluation of presurgical epilepsy patients. Clinical practice currently varies widely between centres in the proportion of surgical candidates who undergo the test. It is clear from the current literature on the efficacy of noninvasive alternatives in many of the roles that the Wada test has historically fulfilled, that, at the very least, the clinical indications for a Wada test should be determined on a case-by-case basis to ensure that the risk–benefit ratio is appropriate for every patient.
It is appropriate for the last words of this review to be left to Wada himself. In a thoughtful and gracious commentary on some of this recent literature, he published his thoughts and reflections on his test. It was, he explained ‘a youthful exploration that…ultimately matured to stand the test of time’. As regards the future:
With surgical outcome as the gold standard, our accumulated experience has led to a progressive sharpening and sophistication of clinical perception. Any investigation for epilepsy surgery is only a complementary component, the use of which depends on specific circumstances, clinical wisdom and judgement.
Juhn A. Wada [30••].
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 000–000).
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2 Ramon C, Holmes M, Freeman WJ, et al
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3 Kemp S, Wilkinson K, Caswell H, et al
. The base rate of Wada test failure. Epilepsy Behav 2008; 13:630–633.
4• Baxendale SA, Thompson PJ, Duncan JS. Evidence-based practice: a reevaluation of the intracarotid amobarbital procedure (Wada test). Arch Neurol 2008; 65:841–845. Evidence-based and theoretical arguments for the careful selection of patients who should undergo a Wada test as part of their presurgical evaluation.
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. The Wada test in Austrian, Dutch, German, and Swiss epilepsy centers from 2000 to 2005: a review of 1421 procedures. Epilepsy Behav 2008; 13:83–89. A useful survey of the clinical indications for 1421 Wada tests conducted since 2000 in Europe.
6 Helmstaedter C. Commentary on Baxendale et al.
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7• Baxendale S, Thompson PJ, Duncan JS. The role of the Wada test in the surgical treatment of temporal lobe epilepsy: an international survey. Epilepsia 2008; 49:715–720. A snapshot of the prevalence of the Wada test in epilepsy centres across the world and an insight into the ways in which the data is used.
8• Loddenkemper T, Morris HH, Moddel G. Complications during the Wada test. Epilepsy Behav 2008; 13:551–553. A timely reminder of the risks associated with a Wada test.
9•• Loddenkemper T. Quo vadis Wada? Epilepsy Behav 2008; 13:1–2. A thoughtful commentary on the clinical indications for a Wada test with a useful algorithm for clinical decision-making.
10•• Abou-Khalil B. An update on determination of language dominance in screening for epilepsy surgery: the Wada test and newer noninvasive alternatives. Epilepsia 2007; 48:442–455. A comprehensive review of the state of play for the current alternatives vying to replace the Wada test in lateralizing language function.
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12 Kesavadas C, Thomas B, Sujesh S, et al
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14• Wellmer J, Weber B, Weis S, et al
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15 Lee D, Swanson SJ, Sabsevitz DS, et al
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16 Chlebus P, Mikl M, Brazdil M, et al
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17 Merrifield WS, Simos PG, Papanicolaou AC, et al
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18 Gallagher A, Theriault M, Maclin E, et al
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19 Knake S, Haag A, Pilgramm G, et al
. Language dominance in mesial temporal lobe epilepsy: a functional transcranial Doppler sonography study of brain plasticity. Epilepsy Behav 2006; 9:345–348.
20 McConley R, Martin R, Palmer CA, et al
. Rey Osterrieth complex figure test spatial and figural scoring: relations to seizure focus and hippocampal pathology in patients with temporal lobe epilepsy. Epilepsy Behav 2008; 13:174–177.
21 Diehl B, Busch RM, Duncan JS, et al
. Abnormalities in diffusion tensor imaging of the uncinate fasciculus relate to reduced memory in temporal lobe epilepsy. Epilepsia 2008; 49:1409–1418.
22 Pegna AJ, Caldara-Schnetzer AS, Perrig SH, et al
. Is the right amygdala involved in visuospatial memory? Evidence from MRI volumetric measures. Eur Neurol 2002; 47:148–155.
23 Dorsaint-Pierre R, Penhune VB, Watkins KE, et al
. Asymmetries of the planum temporale and Heschl's gyrus: relationship to language lateralization. Brain 2006; 129:1164–1176.
24 Tatum WO, Benbadis SR, Hussain A, et al
. Ictal EEG remains the prominent predictor of seizure-free outcome after temporal lobectomy in epileptic patients with normal brain MRI. Seizure 2008; 17:631–636.
25 Wieshmann UC, Larkin D, Varma T, Eldridge P. Predictors of outcome after temporal lobectomy for refractory temporal lobe epilepsy. Acta Neurol Scand 2008; 118:306–312.
26 Mani J, Busch R, Kubu C, et al
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27•• Binder JR, Sabsevitz DS, Swanson SJ, et al
. Use of preoperative functional MRI to predict verbal memory decline after temporal lobe epilepsy surgery. Epilepsia 2008; 49:1377–1394. An examination of the predictors of postoperative outcome in a large series of LTL patients. The findings suggest that the Wada test adds little to models based on noninvasive measures in the preoperative identification of patients at greatest risk of a postoperative memory decline.
28 Kim JH, Joo EY, Han SJ, et al
. Can pentobarbital replace amobarbital in the Wada test? Epilepsy Behav 2007; 11:378–383.
29 Loddenkemper T, Moddel G, Schuele SU, et al
. Seizures during intracarotid methohexital and amobarbital testing. Epilepsy Behav 2007; 10:49–54.
30•• Wada JA. A fateful encounter: sixty years later – reflections on the Wada test. Epilepsia 2008; 49:726–727. Wise words placing the Wada test in its historical context from the man whose name has been inextricably linked to epilepsy surgery for 60 years.