An update on determination of language dominance in screening for epilepsy surgery: the Wada test and newer noninvasive alternatives

The intracarotid amobarbital procedure or Wada test has been the gold standard for lateralization of language dominance before epilepsy surgery. It is based on deactivation of language cortex with intracarotid anesthesia. However, it is an invasive test with risks and discomforts, and it also has limitations. There has been great interest in replacing the Wada test with a noninvasive procedure. One alternative, repetitive magnetic stimulation works by deactivating language cortex, but most other promising alternatives are based on brain activation. Functional magnetic resonance imaging (fMRI), 15O-water positron emission tomography, single photon emission computerized tomography, transcranial Doppler, and near infrared spectroscopy detect hemodynamic responses to language cortex activation, while magnetoencephalography more directly measures event-related physiological activation. Some of the techniques also provide localization of language functions, whereas the Wada test is strictly a lateralization method. Based on widespread availability, fMRI will likely be the most widely used alternative.     

Hemispheric lateralization and language skill coherence in temporal lobe epilepsy

Patients with an early onset of temporal lobe epilepsy (TLE) are at an increased risk for language reorganization. It is unknown whether this reorganization involves a full shift of all language skills to the contralateral hemisphere, or whether it can be partial and involve only a subset of language skills. In this study we report dominance concordance patterns for five separate language skills measured during the Intracarotid Amobarbital Procedure (IAP) for 124 TLE patients. We examined whether the language skills show similar or independent lateralization patterns. We compare these patterns in early versus late seizure onset groups with either a left or right temporal lobe seizure focus. The data showed that the rates of atypical representation ranged from 25.8% for reading to 14.5% of the sample for speech. A majority of patients (60%) showing atypical language representation do so on more than one skill. While multiple atypicalities were common, the proportion of patients showing atypical representation on all five skills was strikingly low (5.6% of the total sample). Our data suggest that language systems are not independent and do not shift and reorganize in isolation, and no pairs of skills seem more likely to reorganize than others. There was also evidence that language is not monolithic with all language skills reorganizing together. The latter suggests that the pressures compelling atypical representation may not work equally on all language skills.     

fMRI shows atypical language lateralization in pediatric epilepsy patients

PURPOSE: The goal of this study was to compare language lateralization between pediatric epilepsy patients and healthy children. METHODS: Two groups of subjects were evaluated with functional magnetic resonance imaging (fMRI) by using a silent verb-generation task. The first group included 18 pediatric epilepsy patients, whereas the control group consisted of 18 age/gender/handedness-matched healthy subjects. RESULTS: A significant difference in hemispheric lateralization index (LI) was found between children with epilepsy (mean LI =-0.038) and the age/gender/handedness-matched healthy control subjects (mean LI=0.257; t=6.490, p<0.0001). A dramatic difference also was observed in the percentage of children with epilepsy (77.78%) who had atypical LI (right-hemispheric or bilateral, LI<0.1) when compared with the age/gender/handedness-matched group (11.11%; chi(2)=16.02, p<0.001). A linear regression analysis showed a trend toward increasing language lateralization with age in healthy controls (R(2)=0.152; p=0.108). This association was not observed in pediatric epilepsy subjects (R(2)=0.004, p=0.80). A significant association between language LI and epilepsy duration also was found (R(2)=0.234, p<0.05). CONCLUSIONS: This study shows that epilepsy during childhood is associated with neuroplasticity and reorganization of language function.     

Language lateralization in epilepsy patients: fMRI validated with the Wada procedure

Purpose:  This work examines the efficacy of functional magnetic resonance imaging (fMRI) for language lateralization using a comprehensive three-task language-mapping approach. Two localization methods and four different metrics for quantifying activation within hemisphere are compared and validated with Wada testing. Sources of discordance between fMRI and Wada lateralization are discussed with respect to specific patient examples.
Methods:  fMRI language mapping was performed in patients with epilepsy (N = 40) using reading sentence comprehension, auditory sentence comprehension, and a verbal fluency task. This was compared with the Wada procedure using both whole-brain and midline exclusion–based analyses. Different laterality scores were examined as a function of statistical threshold to investigate the sensitivity to threshold effects.
Results:  For the lateralized patients categorized by Wada, fMRI laterality indices (LIs) were concordant with the Wada procedure results in 83.87% patients for the reading task, 83.33% patients for the auditory task, 76.92% patients for the verbal fluency task, and in 91.3% patients for the conjunction analysis. The patients categorized as bilateral via the Wada procedure showed some hemispheric dominance in fMRI, and discrepancies between the Wada test findings and the functional laterality scores arose for a range of reasons.
Discussion:  Discordance was dependent upon whether whole-brain or midline exclusion method–based lateralization was calculated, and in the former case the inclusion of the occipital and other midline regions often negatively influenced the lateralization scores. Overall fMRI was in agreement with the Wada test in 91.3% of patients, suggesting its utility for clinical use with the proper consideration given to the confounds discussed in this work.     

Extent of initial injury determines language lateralization in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS)

Purpose :  To assess the prevalence and attributes of atypical language lateralization (ALL) in patients with left mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS).
Methods :  We recruited consecutive patients with left MTLE-HS, who had undergone resective surgery and had pathologically proven HS. Based on the Wada test, language lateralization was classified into typical (left hemispheric) or atypical (right hemispheric or codominant). We assessed the attributes of patients with ALL using univariate and multivariate analyses.
Results :  Of 124 patients with left MTLE-HS, 23 (18.5%) had ALL. ALL occurred more frequently in patients with severe initial precipitating injury (IPI), early onset of epilepsy, and a short latent period between IPI and onset of habitual seizures. ALL was more common in patients with bitemporal and extratemporal interictal epileptiform discharges (IEDs) on electroencephalogram (EEG) and extratemporal changes on magnetic resonance imaging (MRI). On multivariate analyses, the age at onset of habitual seizures <6 years, atypical IPI, nonunilateral temporal IEDs, and extratemporal MRI abnormalities independently predicted ALL. The likelihood of ALL was very low (∼1%) when all of these four risk factors were absent, whereas it was very high (>95%), if any three or all four of them were present.
Conclusions :  ALL occurs in one-fifth of patients with left MTLE-HS. ALL is more frequent in those with structural or functional extrahippocampal involvement and early onset of epilepsy interrupting the development of normal language networks. Because ALL is uncommon in those with damage/dysfunction restricted to the hippocampus, the hippocampus itself may have only a limited role in determining language lateralization.     

The utility of the intracarotid Amytal procedure in determining hemispheric speech lateralization in pediatric epilepsy patients undergoing surgery

The usefulness of the intracarotid Amytal (amobarbital) procedure (also called the Wada procedure) in identifying hemispheric language dominance in pediatric patients has not been independently confirmed with intraoperative language mapping techniques. Currently, data are extrapolated from adult studies. To better establish the usefulness of the intracarotid Amytal procedure in identifying hemispheric language dominance in pediatric patients, we reviewed the records of 77 consecutive pediatric patients who underwent sodium amobarbital testing. Among these 77 subjects, 34 underwent intraoperative language mapping, the results of which all completely confirmed the Amytal results. It was also shown that among these pediatric epileptic patients who underwent Amytal testing, there existed not only a strong correlation between left-handedness and atypical speech lateralization (right, bilateral hemisphere), but also between right-sided hemiparesis (i.e., early left-hemisphere injury) and atypical speech.     

Threshold-independent functional MRI determination of language dominance: A validation study against clinical gold standards

Functional MRI (fMRI) is often used for presurgical language lateralization. In the most common approach, a laterality index (LI) is calculated on the basis of suprathreshold voxels. However, strong dependencies between LI and threshold can diminish the effectiveness of this technique; in this study we investigated an original methodology that is independent of threshold. We compared this threshold-independent method against the common threshold-dependent method in 14 patients with epilepsy who underwent Wada testing. In addition, clinical results from electrocortical language mapping and postoperative language findings were used to assess the validity of the fMRI lateralization method. The threshold-dependent methodology yielded ambiguous or incongruent lateralization outcomes in 4 of 14 patients in the inferior frontal gyrus (IFG) and in 6 of 14 patients in the supramarginal gyrus (SMG). Conversely, the threshold-independent method yielded unambiguous lateralization in all the patients tested, and demonstrated lateralization outcomes incongruent with clinical standards in 2 of 14 patients in IFG and in 1 of 14 patients in SMG. This validation study demonstrates that the threshold-dependent LI calculation is prone to significant within-patient variability that could render results unreliable; the threshold-independent method can generate distinct LIs that are more concordant with gold standard clinical findings.     

Functional MRI and Wada determination of language lateralization: a case of crossed dominance

The Wada test has historically been the conventional procedure for determining language lateralization before neurosurgery. However, functional magnetic resonance imaging (fMRI) offers a less invasive alternative to the Wada procedure. Research indicates that the two techniques used together may provide comparable, and sometimes complementary, information that results in improved prediction of postsurgical language ability. We present a case in which use of fMRI in conjunction with Wada testing provided complementary information about language lateralization before neurosurgical resection of a mesial temporal subependymoma for seizure control in a patient with schizencephaly.     

Use of preoperative functional MRI to predict verbal memory decline after temporal lobe epilepsy surgery

Purpose: Verbal memory decline is a frequent complication of left anterior temporal lobectomy (L-ATL). The goal of this study was to determine whether preoperative language mapping using functional magnetic resonance imaging (fMRI) is useful for predicting which patients are likely to experience verbal memory decline after L-ATL.
Methods: Sixty L-ATL patients underwent preoperative language mapping with fMRI, preoperative intracarotid amobarbital (Wada) testing for language and memory lateralization, and pre- and postoperative neuropsychological testing. Demographic, historical, neuropsychological, and imaging variables were examined for their ability to predict pre- to postoperative memory change.
Results: Verbal memory decline occurred in over 30% of patients. Good preoperative performance, late age at onset of epilepsy, left dominance on fMRI, and left dominance on the Wada test were each predictive of memory decline. Preoperative performance and age at onset together accounted for roughly 50% of the variance in memory outcome (p < 0.001), and fMRI explained an additional 10% of this variance (p ≤ 0.003). Neither Wada memory asymmetry nor Wada language asymmetry added additional predictive power beyond these noninvasive measures.
Discussion: Preoperative fMRI is useful for identifying patients at high risk for verbal memory decline prior to L-ATL surgery. Lateralization of language is correlated with lateralization of verbal memory, whereas Wada memory testing is either insufficiently reliable or insufficiently material-specific to accurately localize verbal memory processes.     

Atypical language representation in epilepsy: implications for injury-induced reorganization of brain function

This review addresses language function and reorganization associated with various forms of epilepsy. Longstanding epilepsy, particularly types with onset early in life, may be associated with changes in the representation of language function in the brain. As a result of this reorganization, language function may be relatively spared despite injury to areas of the brain that normally subserve these functions. We examine the changes seen in language function in two types of epilepsy: hemispheric epilepsy of childhood and focal epilepsies. Findings from behavioral studies, intracarotid amytal testing, intraoperative cortical testing, and more recent functional imaging studies are reviewed. Studying changes in the representation of language function seen in some forms of epilepsy provides information about brain plasticity with implications for other neurologic diseases, as well as for the neuroscientific understanding of how and when functional reorganization may occur.     

Risk factors for unsuccessful testing during the intracarotid amobarbital procedure in preadolescent children

PURPOSE: Identification of risk factors for unsuccessful testing during intracarotid amobarbital procedure (IAP) in preadolescent children. METHODS: A pediatric IAP protocol was attempted in 42 candidates for epilepsy surgery (5-12 years old; mean, 10 years) based on the ability to pass a practice test. Language dominance was defined by marked asymmetry until first verbal response and paraphasic errors. Intact hemispheric memory was defined by recall of >/=60% of test items. The odds ratios of baseline variables (age at IAP, Full-Scale IQ, side of disease, age at seizure onset, amobarbital dose) were calculated for various IAP outcomes. RESULTS: IAPs were accomplished in 40 children. Language dominance was established in 25 (62.5%) of 40 patients: all 21 focal resection candidates were left language dominant; four hemispherectomy candidates had intact language after injection of the damaged hemisphere. In 12 (30%) of 40 patients, language testing failed because of agitation or obtundation. Compared with the 21 children with language dominance established by bilateral IAP, these 12 children had lower mean Full-Scale IQ (66.4 vs. 87.9; p = 0.014), and more frequently, the epileptogenic lesion in the left hemisphere (presumed dominant by right-handedness; 78 vs. 33%; p = 0.04). Excluding hemispherectomy candidates (intentionally only one injection), memory testing could not be completed in 13 (36%) of 36 children because of obtundation or agitation. These children were significantly younger than the 23 (64%) of 36 with successful bilateral memory testing (mean age, 107.6 vs. 128.7 months; p = 0. 006). The eight (25%) of 32 children with failing retention scores after ipsilateral injection had lower Full-Scale IQ than did the 24 (75%) patients who passed (mean, 59.6 vs. 81.7 months; p = 0.03). CONCLUSIONS: The IAP successfully established hemispheric language dominance and memory representation for just under two thirds of the preselected preadolescent children. Risk factors for unsuccessful testing included low Full-Scale IQ (especially <80), young age (especially <10 years), and seizures arising from the left hemisphere presumed dominant by right-handedness.     

Functional MRI and Wada studies in patients with interhemispheric dissociation of language functions

Rare patients with chronic epilepsy show interhemispheric dissociation of language functions on intracarotid amobarbital (Wada) testing. We encountered four patients with interhemispheric dissociation in 490 consecutive Wada language tests. In all cases, performance on overt speech production tasks was supported by the hemisphere contralateral to the seizure focus, whereas performance on comprehension tasks was served by the hemisphere with the seizure focus. These data suggest that speech production capacity is more likely to shift hemispheres than is language comprehension. Wada and fMRI language lateralization scores were discordant in three of the four patients. However, the two methods aligned more closely when Wada measures loading on comprehension were used to calculate lateralization scores. Thus, interhemispheric dissociation of language functions could explain some cases of discordance on Wada/fMRI language comparisons, particularly when the fMRI measure used is not sensitive to speech production processes.     

Presurgical functional transcranial Doppler sonography (fTCD) with intravenous echo enhancing agent SonoVue enables determination of language lateralization in epilepsy patients with poor temporal bone windows

Presurgical determination of language lateralization is important for planning and outcome estimation of neurosurgical interventions in patients with drug-refractory epilepsy. Functional transcranial Doppler sonography (fTCD) provides an established measure for language lateralization using the temporal bone windows for continuous recording of the cerebral blood flow velocity (CBFV) in both middle cerebral arteries (MCAs). However, because of insufficient temporal bone windows, fTCD cannot be applied properly in every patient. Here, we established stable and sufficient CBFV signals in both MCAs using continuous intravenous application of echo-enhancing agent SonoVue in 7 of 10 patients with poor temporal bone windows and were thus able to determine language lateralization. We conclude that the application of SonoVue can solve one principal disadvantage of fTCD and improves the applicability of the technique as a presurgical functional language lateralization procedure.     

Unilateral intracarotid amobarbital procedure for language lateralization

PURPOSE: The determination of language dominance as part of the presurgical workup of patients with pharmacoresistant epilepsies has experienced fundamental changes. With the introduction of noninvasive functional magnetic resonance imaging (fMRI), the number of patients receiving intracarotid amobarbital procedures (IAPs) for assessment of language dominance has decreased considerably. However, recent studies show that because of methodologic limitations of fMRI, IAP remains an important tool for language lateralization. The current study examines whether unilateral instead of bilateral IAP is an adequate way to apply IAP with reduced invasiveness. METHODS: We retrospectively examine the predictive value of unilateral IAP for the results of bilateral IAP based on a sample of 75 patients with various types of language dominance. Target parameters are the prediction of the language-dominant hemisphere and the identification of patients with atypical language dominance. For language assessment based on unilateral IAP, we introduce the measure hemispheric language capacity (HLC). RESULTS: Unilateral IAP performed on the side of intended surgery quantifies language capacity contralateral to the intended surgery. It detects atypical (bilateral or right) language dominance in the majority of patients. Experience with a separate series of 107 patients requiring presurgical language lateralization shows that in >80%, bilateral IAPs are redundant. CONCLUSIONS: Unilateral IAP is principally sufficient for language lateralization in the presurgical evaluation of patients with pharmacoresistant epilepsies. Necessity of bilateral IAP is restricted to few indications (e.g., callosotomy). In times of noninvasive language lateralization, we propose unilateral IAP as the method of choice for the verification of doubtful (bilateral) fMRI activation patterns.     

Intracarotid amobarbital (Wada) test for language dominance: correlation with results of cortical stimulation

Eighty-eight patients had bilateral intracarotid amobarbital (Wada) testing to determine hemispheric dominance for language in preparation for epilepsy surgery, as well as unilateral extraoperative cortical electrical stimulation using subdural electrode arrays. In none of the patients with left dominance by Wada testing were language areas found with right-sided stimulation, but two patients with right dominance by Wada testing had language areas mapped on the left side. These findings suggest that left dominance by Wada testing is strong evidence for exclusive lateralization of language function in the left hemisphere, but there is concern about the ability of the Wada test to exclude the possibility of some left-sided language function despite apparent right-sided dominance. Patients with left dominance on Wada testing do not need cortical stimulation before extensive right temporal lobectomy, but we believe that patients with right or bilateral dominance on Wada testing should have cortical stimulation for localization of language areas if extensive left or right temporal or frontal resection is planned.     

Pathology type does not predict language lateralization in children with medically intractable epilepsy

Purpose: We examined potential differences in the effects of pathology type on language lateralization in pediatric epilepsy. Methods: We examined findings from intracarotid sodium amobarbital procedure (IAP/Wada) in a large consecutive sample of children with refractory epilepsy. Subjects were assigned to one of three pathology groups: developmental (n = 28), acquired (n = 26), and tumor (n = 20); groups were compared for language lateralization. Results: Rates of atypical language lateralization did not differ across groups. Greater than half of the subjects with left hemisphere insults and seizure onset before 6 years of age had atypical language lateralization, independent of pathology type. Discussion: Atypical language lateralization may occur in the context of developmental, acquired, and/or tumor pathology.     

Atypical lateralization of language predicts cerebral asymmetries in parietal gesture representations

Humans typically show left-hemisphere dominance both for language and manual gestures. If this reflects a dependence of these behaviors on a common cerebral specialization, then healthy left-handers with atypical organization of language should show a similar pattern for gesture. Consistent with this hypothesis, we report fMRI data indicating that sinistrals (5/15) with bilateral, or right-lateralized, language representations in inferior frontal cortex exhibit a similar atypical pattern in inferior parietal representations of familiar gestures.