Which of the following is most accurate in the context of lateralization of language?

Unilateral Amytal Hemispheric Anesthesia (Wada Test)

The Wada test is employed in many patients prior to surgery for refractory epilepsy. Sodium amytal is injected into the internal carotid artery to induce a temporary state of hemianesthesia during which language and memory function of the unaffected hemisphere are tested. The memory function of the temporal lobe to be removed can be tested during contralateral hemianesthesia. Memory impairment then indicates temporal lobe dysfunction and provides indirect support for it being the seizure focus.

Much of the hippocampus is supplied by the posterior cerebral circulation and it is unclear if medial temporal structures are adequately anesthetized by intracarotid injection. Crossflow into the contralateral hemisphere may also complicate interpretation. Exametazime (HMPAO) injected through the arterial catheter clearly defines the distribution of amytal and has revealed crossflow not seen on angiography (63). Alternatively, it can be given intravenously shortly after the amytal to define the extent of cerebral suppression. Intravenous injection should be delayed for 30 seconds after the clinical effects of the amytal become apparent (64). A 25% or more reduction of regional brain activity is then seen and test results can be interpreted with knowledge of the location and extent of the amytal effect (64,65).

Wada Testing

The intracarotid amytal, or Wada, test is a method in which sodium amytal is injected into the internal carotid artery (ICA), temporarily anesthetizing the brain in the territory of that ICA. Following confirmation of clinical effect by the onset of contralateral hemiparesis and EEG changes, a battery of behavioral tests is administered. Wada testing was initially developed to lateralize language dominance in patients undergoing electroconvulsive therapy, but has long been used for language lateralization in preoperative patients.50 The Wada test was subsequently modified to test lateralization of memory and to assess the risk of postoperative amnesia in patients undergoing temporal lobectomy for medial temporal lobe epilepsy.51 The spatial resolution of the Wada test is usually hemispheric. However, Wada testing has been employed in a more highly localized manner with selective catheterization, for instance, to investigate function of the mesial temporal structures in epilepsy patients.52

Wada testing is limited in that the examiner has only a few minutes to test each hemisphere. The test is invasive, carrying a 0.6–1% risk of stroke.53 Agitation or obtundation can preclude cognitive testing in some individuals. Because of its invasive nature, Wada testing is not readily repeatable. Technically, the test may potentially be confounded by cross flow between hemispheres, resulting in anesthesia of both hemispheres from a unilateral injection. Furthermore, despite the Wada test being the gold standard historically, noninvasive functional imaging may provide better predictive efficacy in the contemporary era.54,55 Increasingly, fMRI is substituted for Wada testing for the preoperative determination of language and memory lateralization.56–60 MEG also shows promise in high correlation with Wada testing for language lateralization and presents a viable alternative in some centers.61

Current Use of the Wada Test

There are generally three purposes for which the Wada test is used in major surgical centers today. First, it allows for the identification of the language dominant hemisphere in patients being considered for neurosurgical intervention. This not only allows for planning the extent to which cerebral tissue can be resected, but also permits the preoperative prediction of postoperative memory impairment (Chelune, Naugle, Lüders, Sedlak, & Awad, 1993) in patients undergoing temporal lobe resections. Second, the Wada test allows the clinician to directly assess memory functioning by simulating the functional disruption of critical memory circuits within the brain. As a result, one can evaluate the memory capacity of the cerebral hemisphere contralateral to the side of injection. The third purpose for the Wada test, specifically for individuals planning to undergo epilepsy surgery, is to help substantiate the presumed hemispheric seizure onset as determined by other invasive and noninvasive procedures designed to lateralize and localize epileptogenic tissue (scalp or invasive electroencephalogram (EEG), structural and functional radiography, video EEG telemetry, magnetoencephalogram (MEG), etc.).

Although the Wada test is considered to be an invasive procedure, which carries a small degree of risk (e.g., stroke, cerebral embolism, infection, etc.), it remains an important component of the workup for many comprehensive surgical epilepsy centers. Despite this, there has been some evidence that suggests less invasive procedures, such as functional magnetic resonance imaging (fMRI) and functional magnetoencephalography for language localization can give similar information and should replace the use of Wada testing in some instances (Binder, 2011). Others have suggested that preoperative neuropsychological testing is sufficient to predict postoperative memory decline when combined with the results of other studies (EEG, structural MRI findings) and demographic and other information (age of seizure onset, chronological age, etc.) (Baxendale, Thompson, Harkness, & Duncan, 2006; Stroup et al., 2003). Likely as a result of these less invasive studies, the use of the Wada test has declined in epilepsy centers across Europe and North America, despite an increase in the number of surgeries performed. In one survey, only 12% of epilepsy centers reported the use of the Wada test on all epilepsy surgical candidates (Baxendale, Thompson, & Duncan, 2008). In contrast to current usage, 85% of centers performed the Wada test on all surgery candidates in 1993 (Rausch et al., 1993). Despite this, the Wada test is still considered the gold standard for lateralizing language function, and in a worldwide survey of 92 epilepsy surgery centers nearly half of all centers reported routinely utilizing the Wada test during presurgical workup of epilepsy surgery candidates (Baxendale et al., 2008). In the United States, the number of centers routinely performing the Wada test is even higher as ~50% of epilepsy surgery centers there report routine use of the Wada test on 75% or more of their patients (Baxendale et al., 2008). Currently, at our own center, we use a combination of neuropsychological testing, fMRI, and Wada studies to predict the risk of temporal lobe epilepsy patients. Specifically, if the patient is right-handed and is to undergo a right temporal lobectomy they will receive presurgical neuropsychological testing and fMRI. If they are found to have right hemisphere language dominance, they are then referred for a Wada procedure. Left temporal lobe epilepsy patients nearly always undergo a Wada procedure in lieu of fMRI given their presumed left hemisphere language dominance.

Prediction of Language Outcome

It could be argued that neither the Wada test nor cortical stimulation mapping constitute an ideal ‘gold standard’ against which to judge fMRI language maps. Both these tests have recognized limitations, and both differ sufficiently from fMRI in terms of methodology and level of spatial detail that it is probably unreasonable to expect strong concordance with fMRI maps. A more meaningful measure of the validity of fMRI language maps is how well they predict postoperative language deficits. The purpose of preoperative language mapping, after all, is to assess the risk of such deficits and (in the case of cortical stimulation mapping) to minimize their severity. If fMRI can predict postoperative language deficits as well as, or better than, the Wada test, then what need is there to compare fMRI directly with the Wada?

Sabsevitz et al. (179) assessed the ability of preoperative fMRI to predict naming decline in 24 consecutively encountered patients undergoing left anterior temporal lobectomy (ATL). fMRl employed a semantic decision versus sensory discrimination protocol. All left ATL patients also underwent Wada testing and intraoperative cortical stimulation mapping, and surgeries were performed blind to the fMRI data. Compared to a control group of 32 right ATL patients, the left ATL group declined postoperatively on the 60-item Boston Naming Test (p < 0.001). Within the left ATL group, however, there was considerable variability, with 13 patients (54%) showing significant declines relative to the control group and the remainder no decline. A laterality index based on fMRI activation in a temporal lobe region of interest was strongly correlated with outcome (r = −0.64, p < 0.001), such that the degree of language lateralization toward the surgical (left) hemisphere was related to poorer naming outcome, whereas language lateralization toward the nonsurgical (right) hemisphere was associated with less or no decline (Fig. 10.4). Of note, an LI based on a frontal lobe ROI was considerably less predictive (r = −0.47, p < 0.05), suggesting that an optimal LI is one that indexes lateralization near the surgical resection area. The fMRI temporal lobe LI showed 100% sensitivity, 73% specificity, and a positive predictive value of 81% for predicting significant decline. By comparison, the Wada language LI showed a somewhat weaker correlation with decline (r = −0.50, p < 0.05), 92% sensitivity, 43% specificity, and a positive predictive value of 67%.

These results suggest that preoperative fMRI could be used to stratify patients in terms of risk for language decline, allowing patients and physicians to more accurately weigh the risks and benefits of brain surgery. It is crucial to note, however, that these results hold only for the particular methods used in the study and may not generalize to other fMRI protocols, analysis methods, patient populations, or surgical procedures. Future studies should not only confirm these results using larger patient samples but also test their generalizability to other protocols.

Wada test

The goals of the intracarotid amobarbital procedure, or Wada test, include language and memory lateralization (Baxendale, 2000). In epilepsy patients, atypical language lateralization, i.e., right hemispheric or bilateral representation, is more likely than in normal controls (Helmstaedter et al., 1997b; Springer et al., 1999). The determinants for atypical language dominance include early injuries, lesions adjacent to speech cortex, and finally the epileptic process per se. Thus, early left hemispheric injuries occurring before the age of 5years result in an interhemispheric reconstitution of language functions to the right hemisphere (Rasmussen and Milner, 1977), while later injuries – when language becomes gradually lateralized – cause contralateral language reorganization more seldom (Springer et al., 1999). In mesial TLE, left-sided speech occurred in 76% of left-sided and in 100% of right-sided patients. Atypical language representation was also associated with a higher spiking frequency and sensory auras, representing an ictal involvement of lateral temporal structures and indicating the influence of interictal and ictal epileptic activity on language lateralization (Janszky et al., 2003b).

The rationale of the Wada memory test consists of anesthetizing mesial temporal structures, which should simulate the potential mnestic effects of the proposed surgery in a crude way (Baxendale, 2000). Injection of the hemisphere contralateral to the epileptogenic zone usually results in impaired memory performance owing to the functional deficit of the affected temporal lobe. The functional status of the diseased temporal structure is also referred to as “functional adequacy” and can be considered as a marker of the functional deficit zone of the ipsilateral temporal lobe. If the temporal lobe which is planned to be resected supports significant memory function (i.e., high functional adequacy), a greater memory decline should be anticipated because functionally intact tissue is removed. Anesthetization of the hemisphere ipsilateral to the epileptogenic zone, on the contrary, tests the functional integrity of the contralateral “healthy” temporal lobe, also referred to as “functional memory reserve.” A poor performance after ipsilateral injection thus would indicate an extension of the functional deficit zone to the contralateral temporal lobe and also would suggest poor memory performance after surgery. Both functional adequacy and functional reserve are therefore important predictors for postoperative memory performance (Loring and Meador, 2001). Patients with a strong asymmetry of memory performance, i.e., impaired memory ipsilateral to the epileptogenic focus and intact memory contralaterally, are those at the lowest risk for postoperative memory decline. In the case of symmetric Wada scores, functional adequacy will determine memory decline in patients with bilaterally good performance, whereas functional reserve will be decisive in patients with bilaterally poor performance. Especially in left TLE, high functional adequacy poses a major risk for postoperative memory decline. The highest risk for postoperative memory decrease is present in patients with unexpected asymmetry on Wada test performance, i.e., better performance after contralateral injection (Loring and Meador, 2001). Some patients may fail the Wada memory component without developing a significant memory decline after surgery (Loring et al., 1990), whereas others pass the Wada test and still experience a significant postoperative memory loss (Rausch et al., 1993; Kirsch et al., 2005). Nevertheless, failure of the Wada memory component can be considered as a risk factor for postoperative memory decline and always has to be viewed in the context of the results of other investigations (Loring and Meador, 2001).

3.10. CHALLENGES AND FUTURE DIRECTIONS

So one might ask: what is the future of the Wada test? Will it be replaced by functional imaging for determination of language lateralization? Certainly, fMRI is a safer technology than IAT, but does it afford less risk of language loss postoperatively? Data suggest a high concordance rate between fMRI and IAT, but mostly in cases of left hemisphere language dominance. Unfortunately, if concordance rates are examined separately for persons with right, left, and mixed hemispheric language representations, fMRI struggles to accurately define language representation in persons with right and mixed dominance. It is possible that functional imaging will surpass the accuracy of IAT in determining language lateralization (it already provides important information about intrahemispheric language mapping); however, it will require the establishment of a standardized protocol. While researchers may achieve this goal, they will be hard pressed to replace the one most impressive feature of the IAT: glimpsing into the patient's future by inflicting a temporary lesion.

The Wada Test: Determining Whether Speech Mapping Is Required

Because the speech cortex is a unilateral structure, preoperative identification by a Wada test of the hemisphere containing it may be required.57 The Wada test is advocated as a preliminary to operations in the vicinity of the Sylvan area in left-handed and ambidextrous patients, and also in the right-handed patient if any doubt exists as to which cerebral hemisphere is dominant for speech. The test is performed by intracarotid amytal injection. This results in immediate speech disruption, contralateral hemiparesis, and maintenance of consciousness when the injected carotid supplies the speech-dominant hemisphere. The nondominant hemisphere is identified by speech preservation and contralateral hemiparesis after carotid amytal injection.57

Common Complications

Traditionally, patients with left sided temporal lobe epilepsy underwent a sodium amobarbital intracarotid injection (Wada test) to establish their memory and language laterality. However, earlier data suggested that the test can be useful in predicting patients who will have poor post-resection cognitive outcome.22 Recent data and more experience with temporal lobectomies suggest that the a positive Wada test may not preclude good memory outcomes after temporal lobe epilepsy.23 Indeed, the test is now rarely utilized by most epilepsy centers.24

Efficacy of surgery for drug-resistant temporal lobe epilepsy has been established in a randomized clinical trial.15 These results are confirmed by long-term follow up studies. Between 50 to 60% of patients achieve a seizure free outcome in large series with up to 90% achieving a substantial decrease in seizure frequencies.12,25

Nervous system

Intracarotid injection of sodium amobarbital has been used in exploring cerebral language dominance in a procedure known as the Wada test [35–37]. It has also been used to lateralize abnormal foci in temporal lobe epilepsy [38]. Secobarbital has also been used instead of amobarbital [39].

Of 92 patients who were given intracarotid amobarbital, five developed severe changes in affect and behavior, ranging from prolonged coma to an extended confusional state [40]. Severe behavioral disturbances were more likely to occur in those with left frontal structural lesions when amobarbital was injected into the right hemisphere and patients with structural lesions of the anterior regions of the right hemisphere had no evidence of similar behavioral complications.

Seizures have been described after intracarotid injection of barbiturates, including methohexital and amobarbital. A retrospective chart review of 760 intracarotid amobarbital and methohexital tests showed that 16 patients (2.1%) had seizures [41]. In three the seizures occurred before the injection. Of the other 13, 4 of 538 patients (0.7%) followed injection of amobarbital and nine of 222 (4.1%) followed methohexital injection. The authors suggested that methohexital was more likely to cause seizures than amobarbital.

There is a small risk of carotid dissection after intracarotid amobarbital administration. A retrospective chart review of 435 consecutive procedures showed that three patients had had carotid dissections; their mean age (51 years) was higher than the average age of 432 patients without dissection (32 years) and all had face or neck pain [42].

A patient with a right temporal tumor who was given intracarotid amobarbital developed transient global amnesia [43].

Occasional deaths have been reported during intracarotid amobarbital testing [44], including the case of a 38-year-old man who had a right middle cerebral artery stroke, not having been at risk by Centers for Medicare and Medicaid Services criteria or invasive procedures nor having risk factors for embolic stroke [45].

In 56 patients who underwent intracarotid amobarbital infusion, there was reduced anesthetization in two and very rapid recovery in nine; 10 of the 11 were taking a medication with some carbonic anhydrase-inhibitory effects—topiramate (n = 7), zonisamide (n = 2), hydrochlorothiazide (n = 1), and furosemide (n = 1) [46]. Of 40 who were not taking a carbonic anhydrase inhibitor only one recovered early and that patient had recently stopped taking topiramate. The authors suggested that failure of anesthetization during intracarotid amobarbital infusion is associated with a possible interaction of amobarbital and carbonic anhydrase. This has been confirmed in an archival review of 81 patients, of whom 69 had conclusive findings; all of the other 12 in whom anesthetization failed were taking carbonic anhydrase-inhibitors at the time of the procedure [47]. The implication is that intracarotid amobarbital infusion should not be performed until at least 8 weeks after withdrawal of a carbonic anhydrase inhibitor [48].

In 26 individuals who drove after taking butalbital, the presence of which in the blood was confirmed and quantified, in concentrations of 1.0–30 mg/l, neurological impairment included horizontal and vertical nystagmus, lack of convergence, poor motor coordination, and balance and speech problems, similar to the effects of alcohol [49].

When 17 healthy adults took pentobarbital 100, six developed up-beat, gaze-evoked, vertical nystagmus 12 hours later, three had nystagmus 36 hours later, and none had it 60 hours later [50]. Other barbiturates have occasionally been reported to cause different types of nystagmus [51] and thiopental-induced nystagmus has been used to test brain function in patients with central dizziness [52]. However, different types of vestibular nystagmus do not help in localizing pathological lesions [53].

Intracarotid Amytal Test (Wada Test)

Juhn A. Wada developed the intracarotid amytal test in 1949 for patients with psychosis undergoing evaluation for unilateral electroconvulsive shock therapy. The Wada test was initially used solely to lateralize language function and later expanded to include assessment of memory function. In 1959, the Wada test was used for the lateralization of memory and language function in order to establish language dominance and predict postsurgical functional deficits. The Wada test's modern usage also includes localization of potential epileptogenic zones.

The Wada test examines language and memory function in each hemisphere of the brain. Sodium amobarbital is injected into an internal carotid artery, thereby unilaterally inactivating anterior midhemisphere function for several minutes. Multiple language and memory tasks are subsequently performed in order to assess language and memory function of the active, noninjected hemisphere.

The Wada test is currently used to help localize potential epileptogenic zones and predict postsurgical deficits. For patients with epilepsy of mesial temporal onset, ipsilateral unilateral memory dysfunction demonstrated on Wada serves as a confirmatory test for localization. Furthermore, the results of the Wada test can help predict the likelihood of a decline in memory function after anterior temporal lobectomy.