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Reliability of the sodium amobarbital test for memory
I Epilepsy 1989 ;2 :31-39
© 1989 Demos Publications
Reliability of the Sodium Amobarbital Test for Memory Jeannette McGlone and 'Bonnie H : MacDonald
Two studies were conducted on epileptic patients to examine the reliability of Milner's protocol for testing memory after the unilateral injection of sodium amobarbital into the carotid artery . The first study examined alternate-form reliability in 10 patients who underwent 18 repeat injections of the same hemisphere . Major changes in memory performance from pass to fail or vice versa occurred in 8 of 18 repeat injections . Seven of the eight changes were associated with identifiable variation in external factors (e.g ., technically unsatisfactory first injections or reported deterioration in functioning over time) . Of the eight injections that were technically satisfactory but were repeated tore-ex jmine the initial memory score, seven outcomes remained stable across both 'injections, despite variability I betwee4est-retest conditions . In the second stuffy, data from 70 patients given bilateral injections were analyzed, and no evidence for a practice effect was found when comparing memory scores from the first to the second injection . Whether the left or right side was injected first did not affect memory scores, nor did other variables such as sex, hand preference, or hemisphere injected . As expected, memory functions were more impaired for the injection contralateral than ipsilateral to the major temporal lobe seizure focus . We concluded that reliable results can be obtained from a sodium amobarbital memory protocol, adapted from Milner, which employs a pass/fail criterion based on chance performance . Key Words : Sodium amobarbital-Memory- Reliability .
Milner et al . (1) first adapted the Wada technique (2) of intracarotid sodium amobarbital testing for the purpose of predicting and preventing global amnesia in epileptic patients who were surgical candidates for temporal lobectomy . Milner (3) reasoned that the unilateral action of the drug should produce a generalized memory disorder if "there were a pre-existing lesion in the medial temporal region of the opposite hemiFrom the Epilepsy Unit, University Hospital, London, Ontario, and the 'Department of Psychology, Credit Valley Hospital, Mississauga, Ontario, Canada . This paper was a poster presentation at the annual meeting of the American Epilepsy Society, Baltimore, December 8, 1987. Address correspondence and reprint requests to Dr . J . McGlone at Department of Psychological Services, University Hospital, P.O. Box 5339, Station A, London, Ontario N6A 5A5, Canada .
sphere ." Her research on group data demonstrated that failure to meet criterion on postinjection memory testing was rare but clearly more frequent when patients received the injection contralateral (23%) rather than ipsilateral (1 .7%) to the major seizure focus (p < 0 .001) (3) . Recently, the reliability of the sodium amobarbital test for memory has been questioned . Novelly (4) reported that 12 of 18 patients who failed their first memory test after sodium amobarbital injection ipsilateral to the seizure focus later went on to pass the second memory test . A different protocol was used by Dinner et al. (5), who found that five patients who underwent repeat injections ipsilateral to their seizure focus improved their memory score by 9-66% . Such dramatic improvement in performance from first to second injection of the same side calls into question the test retest reliability of sodium amobarJ EPILEPSY, VOL. 2, NO. 1 , 1989 31
J. McGLONE AND B. H. MacDONALD
bital testing of memory. Reliability is a necessary precondition for establishment of the validity of a psychological test; hence, this retrospective study examined the alternate-forms reliability of an amobarbital protocol adapted from Milner (3) . Two studies were conducted. The first examined whether those few patients who underwent repeat sodium amobarbital testing on the same side obtained similar memory scores . We also included data from repeat injections of the contralateral side, as well as two cases in which there were third injections of the side ipsilateral to the major seizure focus . We calculated changes in the raw scores, but more importantly, we determined whether the pass/fail results of the repeat injections were correlated with the results of the previous injection . Thus, the first study examined alternate-form reliability of the sodium amobarbital memory protocol. The second study examined a larger sample of patients and investigated whether a practice effect was present between injections of different hemispheres .
or laboratory evidence to suspect bitemporal lobe dysfunction. For example, amytals were ordered if there were bilateral temporal EEG epileptiform abnormalities, verbal and nonverbal memory loss, or bitemporal structural lesions visualized on a computed tomography (CT) or magnetic resonance imaging (MRI) scan . In many cases, evidence for possible bilateral temporal lobe dysfunction was derived from several sources, such as in the case of a right-hander with intact verbal memory, defective nonverbal memory, and a clear left temporal lobe seizure focus on ictal EEG skull recordings . Approximately 20-25% of surgical candidates undergo sodium amytal testing in our center . The patient's primary epileptogenic lesion was identified by a combination of ictal recordings, interictal EEG recordings with scalp electrodes, and, rarely, by subdural recordings . As shown in Table 2, most patients received a bolus of 175 mg sodium amobarbital dissolved in 3 .5 ml sterile water . A catheter was placed into the right femoral artery, then navigated up to the designated internal carotid artery . There were 16 second injections, nine on the left side and seven on the right, and two third injections on the left side . The majority of repeat injections (12/18) involved the side ipsilateral to the major seizure focus (Table 2), with the retest interval ranging from 5 days to over 10 years . Table 2 shows that at least one element of the procedure changed in 17 of the 18 repeated injections, and one patient had subdurals implanted between administrations . For these reasons, and because new stimuli were used on repeat injections, the following results offer informa-
Study 1 : Alternate-Forms Reliability Methods In 11 years, 10 of 128 patients (7 .8%) investigated in the Epilepsy Unit at the University Hospital in London, Ontario, underwent repeated sodium amobarbital injections on the same side (Table 1) . In our center, patients were selected for sodium amobarbital testing of memory functions when there was clinical
Table 1 .
Patient A B C D
E F G
H I J
Subject characteristics of patients with repeat sodium amobarbital injections
Major seizure focus°
Etiology"
Sex
RT LT > RT LT > RT LT LT > RT RT > LT LT LT LT > RT LT
NT NT NT NT NT NT T NT NT T
F F M M M M F F M M
Hand preference`
Age (years)
L
R R R L R L
R L R X=
aLT, left temporal; RT, right temporal. IT, tumor; NT, nontumor . 'L, left-handed; R, right-handed .
32 1 EPILEPSY, VOL 2, NO. 1, 1989
Education (grade)
17 32 43 43 27 35 38 22 49 31
12 12 9 9 12 17 8 15 11 13
33 .7
11 .8
Wechsler FSIQ 101 94 76 79 67 111 81 96 77 86 86 .8
Wechsler MQ 110 86 66 76 106 98 80 86 66 86 .0
Reason
LI
RC
LI
D
D
J
Unresponsive Unresponsive Incorrect procedure
Sz
Memory Memory
Memory
RC
RI
LC
LI RC
G
F
F
I I
No
Yes Yes
4 weeks
22 mo 30 mo
No
No
3 mo 4 weeks
Yes
Yes Yes
No
Yes (post) No
Yes (post) Yes (pre)
No
5 days
1 week
Yes
No
Yes
10 yr 4 mo
Yes (pre)
Yes (pre)
Yes (post) No
Yes
No
No
No
No
Memory
No
Yes
4 yr 7 mo
4 mo
Yes
No
2 weeks
4 yr 7 mo
No
Yes
10 yr 4 mo
3 mo
Yes
No
3 weeks 2 weeks
Yes
No
Speech
Change in protocol
5 mo
3 mo
Test-retest interval
125 125
175 175 Yes Yes
140
175
Yes
175
175 No
No ; Sz subdurals Yes; Sz subdurals Yes Yes
175
175'
175" 175
150
150
175
150
175
Phenytoin, 400 Phenytoin, 400
Phenytoin, 200 ; phenobarbital, 60
Phenytoin, 200 ; Phenobarbital, 60
Phenytoin, 400 ; primidone, 750 Carbamazepine, 600 ; nitrazepam, 25 Carbamazepine, 800"; thioridazine, 50" Phenytoin, 300
Carbamazepine, 1,200 ; phenytoin, 200 Carbamazepine, 1,200; phenytoin, 200 Carbamazepine, 600 ; phenytoin, 400 ; phenobarbital, 120
Carbamazepine, 600
175
175
Phenytoin, 300
Carbamazepine, 1,000; phenytoin, 400 Carbamazepine, 1,200"; phenytoin, 450" Carbamazepine, 1,400 ; phenytoin, 300 Carbamazepine, 1,400 ; phenytoin, 300 Carbamazepine, 600; phenytoin, 400; phenobarbital, 120
First
Phenytoin, 400 Phenytoin, 400 ; carbamazepine, 400
Phenytoin, 400 ; phenobarbital, 30
Phenytoin, 400; phenobarbital, 30
Phenytoin, 300
Phenytoin, 400 ; primidone,, 750 Carbamazepine, 604; nitrazepam, 25 Carbamazepine, 600'
Carbamazepine, 800; thioridazine, 50 Carbamazepine, 800; thioridazine, 50 Carbamazepine, 700; phenytoin, 500; primidone, 525
Carbamazepine, 800
Phenytoin, 300
Carbamazepine, 1,200 ; phenytoin, 450 Carbamazepine, 1,000' ; phenytoin, 450' Carbamazepine, 1,400 ; phenytoin, 300 Carbamazepine, 1,400 ; phenytoin, 300 Carbamazepine, 700 ; phenytoin, 500 ; primidone, 525
Second
Seizure medications (mg)
175
150-175
125
125
125'
175
Second
Yes
Yes
Yes
150
175?
Yes
No
175
175
175
175
Yes
Yes
Yes
Yes
175
175
Yes Yes
175
175"
Yes Yes
175
First
No
Strength
Sodium amobarbital dosage (mg)
Yes
No
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Delta
Change in length of drug effect
Parameters of sodium amobarbital injections
°Ll, left ipsilateral; RI, right ipsilateral ; LC, left contralateral ; RC, right contralateral . "Second injection. 'Third injection.
Memory Memory
Memory
LI
E
Memory
LI
Speech
B
D. Speech or memory RI A
C. Functional deterioration E LI Deterioriltion E RC Deterioration J RC Deterioration
B. Environmental factors G LI Memory, glasses LI Panic reH action
LI
C
A. Technically unsatisfactory C LI Sz
Patient
Repeat injection"
Table 2 .
J. McGLONE AND B. H. MacDONALD
tion on alternate-forms reliability rather than testretest reliability. The protocol for speech and memory testing was adapted from Milner (3) . Figure 1 depicts the approximate timing and the content of the typical protocol. The two injections were done on separate days, usually 24 h apart . A rehearsal of the procedure was conducted the day prior to the first injection and again on the next day, minutes before the first injection . For most cases, four different memory items were administered after each injection . These were one object palpated by the patient's nonparetic hand, two line drawings, and one nursery rhyme . The examiner named each while the patient viewed it for 5-10 s . The patients were encouraged to name the items even if they were dysphasic at the time . Recognition memory testing occurred 10-15 min after the injection, when grip strength of the paretic hand had returned to baseline levels and unilateral delta on the EEG had disappeared. Scoring was based on verbatim transcripts taken from video and audio taped records. One point was assigned to a correct recognition (maximum = 4), and this was converted to a percent correct score . There were two foils for the object recognition test (chance = 33 .3%), two foils for the nursery rhyme recognition test (chance = 33 .3%), and five foils for the postinjection picture recognition test (chance = 28 .6%) . Thus, the combined chance performance for the four postinjection stimuli was 31% . Failure was based on a score of 50% or below (i.e ., 2 of 4 correct recognition or less) . False-positive errors were recorded each time a patient said he recognized a foil (object, picture, or rhyme) that had not been presented earlier. The percent correct recognition and false-positive error scores for the 18 repeat injections are found in Table 3 . When falsepositive errors occurred in patients who obtained 75% or more correct recognition, an arbitrary decision was made concerning their passing or failing that particular test .
Results For 10 patients, the first and second injection recognition memory scores (i.e ., 16 of 18 injections in Table 3) were compared using a paired observations t test. The mean first (X= 53 .1% ; SD = 27 .9) and second (X = 61 .4% ; SD = 33 .1) injection scores were not significantly different [t(15) = 0 .93 ; NS] . The total group was then subdivided into four subgroups based on the clinical reason for repeating the injection. Group I : Technically unsatisfactory . Five injections were repeated because they were technically 34
1 EPILEPSY, VOL . 2, NO. 1, 1989
unsatisfactory (see Table 2, Part A) . In one case (C), a seizure was recorded on the EEG at the onset of the second injection . Consequenty, a third injection on the left side was performed (Table 2, Part A) . Both left- and right-sided injections were repeated for another patient (D) who was unresponsive to commands for as long as 15 min after the first left injection; thus, memory testing was precluded during the unilateral effect of the drug . In the fifth case (J), the left injection was repeated because recognition testing began before the unilateral effect of the drug cleared (i .e ., during hemiparesis) . In this group, two repeat injections yielded an improvement in percent recognition, another showed no change, and two declined (Tables 3 and 4) . Ori average (excluding CLI second and third injections), there was an overall mean increase in percent correct recognition from 45 .8% (SD = 41 .7) for the first injection to 62 .5% (SD = 32.3) for the second injection . Three of the five injections yielded a score in the same pass/fail category as the first injections . Group II : Environmental factors . Factors extraneous to the test procedure sometimes produced artificially lowered first injection memory scores (see Table 2, Part B) . One subject (H) experienced a panic reaction, with crying and inattentiveness, during the first injection . Relaxation training was conducted during the test-retest interval to reduce anxiety for the repeat injection . In another instance, the subject was not wearing her glasses for the first injection . Improvement occurred for both these repeat injections, with an increase from a mean score of 50 .0% (SD = 0) to 90 .0% (SD = 14 .1), and both scores changed from a failure to a pass . Group III : Functional deterioration . E's mother noted a decline in his speech over the 4 1/2-year period between injections (see Table 2, Part C) . Although neuropsychological testing revealed no obvious alteration in any aspect of speech or language, sodium amobarbital testing for memory did show a decline from 1982 (pass) to 1986 (fail) category . The second patient (J) underwent surgical removal of a glioblastoma multiform between repeat injections . A left anterior temporal lobectomy had been performed, sparing the hippocampus . Decline over the 10-year interval was evident both on neuropsychological testing and on the repeat right-sided injection memory testing . In this group, memory scores decreased from the first injection (X= 72 .3% ; SD = 4 .6) to the second (X= 33 .3% ; SD = 28 .9) and in all three injections, scores moved from the pass to the fail category .
RELIABILITY OF AMOBARBITAL MEMORY TEST sec
0 C) w cz a
- 240 - Baseline expressive and receptive speech
-
180
-
120 - Baseline memory presentation (2 pictures, - 60
-
1 sentence)
Baseline memory recall
0 --- INJECTION (counting)
----------------------------
Test for responsiveness 60
Figure 1 . University hospital sodium amobarbital protocol (adapted from ref. 3) .
120 1801-
Expressive and receptive speech -Naming -Sequencing Memory presentation-(new object) -Repetition -Modified Token Test -(2 pictures)
0 240
-(nursery rhyme)
V W 300 N O d
360 420
-
Oral fluency
-
Interview
480 540 600
Group IV : Memory or speech . Six cases (eight injections) were repeated to reinvestigate memory performance, because the initial score was lower than expected (see Table 2, Part D) . In another case (A), speech lateralization was being reinvestigated, and the memory protocol was also repeated . As shown in Tables 3 and 4, improvement in the percent recognition memory score occurred for five repeat injections, two cases had no change, and one case declined . Overall (excluding E-LI), the mean memory scores increased from the first injection (X= 50.0% ; SD = 28 .9) to the second injection (X= 64 .7%; SD = 35 .1), but the difference in this small sample was not statistically significant [t(6) = 1 .40 ; p < 0 .25] . More importantly, the performance category of pass/fail remained the same for seven of the eight repeat injections. Application of the Fisher's Exact Test (6) indicated that this result approaches statistical significance (p < 0.07) . The small sample size limits the power of this test and the likelihood of obtaining a statistically significant result (see Addendum) .
Conclusions
Repetition of sodium amobarbital injections is usually conducted on a biased sample, i .e., in those patients whose first injection was technically unsatisfactory, or where the findings were unexpected . Moreover, in our study some aspect of the procedure was altered in virtually every repeat injection . Seizure
Recall and Recognition memory testing - pre-injection stimuli - post-injection stimuli (object, 2 pictures, nursery rhyme)
medications and frequencies changed over the testretest interval; hence, low reliability would be expected due to high error variance . Indeed, significant change between the pass/fail category occurred in 8 of 18 repeat injections; in six of these, external factors clearly appeared to be responsible, e .g., technically unsatisfactory first procedure, reported deterioration of functioning, a panic attack, and corrected vision with glasses. In these cases, error variance due to changing environmental or physiological conditions most likely influenced the lack of congruence in scores. It is also possible that memory scores vary when the dosage of sodium amobarbital differs systematically between the first and second injections . This was not examined in the current study, but it may prove important in understanding the fact that Novelly found better memory performance in 12 of 18 patients who were given a second injection . Novelly's (personal communication) use of a lower dosage on the second injection shortens the unilateral effect of the drug and may specifically alter its anesthetizing effect on the temporal lobe . If the drug effect is less pronounced in the second injection than in the first injection, then the possibility is strong that memory performance may improve accordingly, unless particular attention is given so that memory items are presented earlier in the protocol, before the drug effect wears off. What is remarkable is flat despite variability in test retest conditions, 10 of the repeat injections in
f
EPILEPSY, VOL 2, NO. 1, 1989
35
J. McGLONE AND B. H. MacDONALD the current study yielded similar outcomes on a pass/ fail criterion based on chance performance (Table 4) . In the subgroup where the reason for repeating the procedure was to check on the memory scores, per se, the pass/fail scores remained stable in seven of eight repeat injections. It is also interesting to note that whether improvement occurred in percentage memory scores did not differ according to the side of injection (left = 5/11 ; right = 11/7) or in relation to the seizure focus (ipsilateral = 6/12 ; contralateral = 3/6) . From these preliminary data, we conclude that it is possible to obtain reliable results using the sodium amobarbital procedures and pass/fail criterion suggested originally by Milner (3) . Environmental and physiological error variance, however, contribute to poor reliability of the memory scores . Unstandardized protocols that arbitrarily vary the number of memory items per side and/or have no pass/fail criterion based on chance and protocols that systematically change the drug dosage may yield less reliable results . Table 3 . Percent correct recognition memory of four postinjection items : failure = 50% or less, chance = 31%
Patient
Repeat injection'
First (%) b
Second (%) b
Group I: technically unsatisfactory C LI 100 (2FP) 100 (2FP) C LI 100 (2FPI) 75 (3FP-~ D LI 0 50 D RC 50 25 J LI 33 75 Group II : environmental factors G LI 50 H LI 50 Group III : functional deterioration E LI 75 E RC 75 J RC 67 (1 FP) Group IV : memory or speech A RI 0 B LI 75 (2 FP) E LI 50 (1FP`) G RC 25 F RI 50 F LC 75 I LI 50 I RC 75
80 (4/5 items, 2FP) 100 50 (1FP) 50 0 33 60 (3/5 items) 50 (1FPJ 40 (2/5 items) 100 100 20 (1/5 items) 100 (5/5 items)
Table 4 .
Patient
Side'
Change in memory scores Improved (I), same (S), or deteriorated (D)"
Pass/fail category (FirstSecond)
Group I : technically unsatisfactory C LI S P-P C LI D P-F D U I F-F RC D F-F J LI I F-P Group II : environmental factors G LI I? H LI I
Change (C), or no change (NC)`
NC C NC NC C
F-P F-P
C C
Group III : functional deterioration E LI D P-F E RC D P-F J RC D P-F
C C C
Group IV : A B E G F F I I
memory or speech RI I LI D? LI S RC I RI I LC I LI D RC I
F-F P-P F-F F-F F-P P-P F-F P-P
NC NC NC NC C NC NC NC
"See Tables 2 and 3 for meaning of abbreviations . 'Change in absolute % score : improved, 9 ; same, 2 ; deteriorated, 7 . `Change across pass/fail criterion : change (C), 8 ; no change (NC), 10 .
Study 2 : Practice Effect The aim of the second study was to investigate the possibility of a practice effect due to test familiarity or transfer of training . Dinner et al . (5) have suggested that improvement from the first to the second injection of the same side on their protocol may be due in part to practice effects . Our first study, using a standard protocol and strict a pass/fail criterion, revealed no statistically significant effect of practice per se . We next examined whether memory scores from different injections improved due to repeated exposure to the procedure .
Methods 'U, left ipsilateral ; RI, right ipsilateral; LC, left contralateral ; RC, right contralateral . bFP, false-positive error . Second injection. °Third injection . 36
1 EPILEPSY, VOL 2 , NO. 1, 1989
Subjects . During a 10 1/2-year period, 206 amobarbital injections were carried out on 116 patients, the majority (105) of whom were surgical candidates
RELIABILITY OF AMOBARBITAL MEMORY TEST Table 5 . Characteristics of patients given bilateral sodium amobarbital injections Sex Male Female Handedness Right Left Ambidextrous Locus of major seizure focus Temporal Frontal Temporofrontal Side of major seizure focus Left Right Bilateral
mg sodium amobarbital dissolved in 3 .5 ml sterile water. The remaining 10 received 125 mg, 150 mg, or 200 mg sodium amobarbital . The side injected first was counterbalanced across sex and hand preference groups, with half the subjects receiving the left injection first . The order of injections ipsilateral versus contralateral to the seizure focus was not counterbalanced. Four postinjection stimuli were presented during the effect of the drug, and recognition memory for them was tested about 10 min later . A multiple-choice format was used, with chance performance set at 31% and the maximum memory score for each side set at 100% correct (see Methods, Study 1) .
39 31 48 19 3 65 4 1 34 33 3
Data Analysis
for the control of their medically intractable seizure disorder . Seventy subjects met the criteria of (a) having bilateral injections; (b) being at least 12 years of age; (c) having etiologies other than arteriovenous malformation; and (d) undergoing a technically satisfactory procedure . Hand preference was assessed by requesting that subject demonstrate eight everyday activities, e .g., brushing teeth . If writing and six of seven other activities were performed with the same hand, then the subject was classified as left- or righthanded, accordingly . Otherwise, the classification was ambidextrous . Tables 5 and 6 outline the patient characteristics. Procedure. The main reason for recommending the sodium amobarbital procedures was to test the memory function of each hemisphere . However, speech lateralization was also examined . The protocol was described in Study 1 and Fig . 1 . Two injections of the same dosage were done on separate days, usually 24 h apart . Sixty subjects received a bolus of 175
Table 6 .
Patient characteristics
Parameter Age Age at seizure onset Education Wechsler Full-Scale IQ (W-BII, WAIS, WAIS-R) Wechsler Memory Quotient
X
SD
29.8 years 12.8 years 11 .7 years
11 .2 13 .9 5 .1
Range, 57-121 92.2
16 .3
The difference between memory scores that were ipsilateral vesus contralateral to the major seizure focus was tested by a one-way analysis of variance (ANOVA) on patients with unilateral temporal lobe seizure foci . Three patients with bilateral seizure foci and four patients with frontal lobe foci were not included in the analysis . The effects of practice (first versus second injection) and order of injections (left side injected first versus right side injected first) were tested in three 2 X 2 ANOVAs . An analysis was performed on the entire sample, then on the nontumor subgroup, and finally on the tumor subgroup . Repeated measures were taken on the practice variable in all three analyses. Supplementary analyses were performed to investigate subject variables . A 2 X 2 ANOVA, with sex and side of injection (left versus right) as the independent variables, was performed on memory scores. Repeated measures were taken on the side variable. Another 2 X 2 ANOVA was performed with handedness (left versus right), replacing sex as the betweensubjects variable . Three ambidextrous subjects were not included in the latter analysis .
Results Memory performance and seizure focus . Percent correct recognition memory scores were significantly lower for the side contralateral (X = 62 .0% ; SD = 28 .8) than ipsilateral (X = 77 .1%; SD = 27 .9) to the major temporal lobe seizure focus [F(1,62) = 8 .69 ; p < 0 .005] . Practice effect . Patients did not perform better on memory testing for the second side (X= 65 .1%; SD = 30 .8) than for the first side (X= 72 .6 ; SD = 29.4) injected [F(1,68) = 2 .0; p < 0 .201 . If anything, the direc-
I
EPILEPSY, VOL. 2, NO. 1 , 1989 37
J. McGLONE AND B. H. MacDONALD
Table 7 .
Mean percent correct recognition memory for four postinjection items
Order of injections
Contralateral to seizure focus Ipsilateral to seizure focus
First
Second
X= 63 .6%; SD = 31 .1° X= 79 .1%; SD = 26 .7"
X= 58 .1%; SD = 29 .8 1 X= 73 .6%; SD = 30 .3°
°n = 30 . b n = 37 . tion of the trend was opposite to that expected and may have been due to the fact that more patients received the contralateral injection second (n = 37) than first (n= 30) . However, Table 7 shows that both the contralateral and ipsilateral mean scores declined nonsignificantly from first to second injections . Cavazzuti et al . have suggested that amobarbital memory test results may be atypical for tumor patients (7) ; thus, etiology was investigated in this study . Table 8 shows that no significant practice effect emerged for either the nontumor [F(1,54) = 2 .69 ; p < 0 .15] or the tumor groups [F(1,12) < 1] . It is noteworthy that ipsilateral first versus contralateral first was balanced in the nontumor group (26 ipsilateral second, 27 contralateral second) but not in the tumor group (4 ipsilateral second, 10 contralateral second) . (Three of the nontumor group had bilateral seizure foci .)
Procedural and Subject Variables
There was no effect for order of injections . That is, whether the left or right side was injected first did not alter the memory scores for the entire sample (X = 68 .9% ; SD = 18 .9 versus k= 68 .8% ; SD = 22 .3, respectively) [F(1,68) < 1] . Similarly, no significant main effects for order emerged for the tumor or nontumor subgroups . Practice did not interact with order in any of the above analyses . Neither sex [F(1,68) = 1 .70 ; p < 0 .20] nor handedness [F(1,65) = 1 .42; p < Table 8 . Mean percent correct recognition memory of four postinjection items for nontumor and tumor groups Order of injections Etiology
Nontumor (n = 56)
Tumor (n = 14)
38
First
Second
X= 75 .3%; SD = 28 .0 X= 61 .9%; SD = 33 .5
X= 66 .1%; SD = 31 .2 X= 61 .3%; SD = 29 .9
1 EPILEPSY, VOL . 2, NO. 1, 1989
0 .25] interacted significantly with side of injection . Thus, left or right injection memory scores did not vary according to patients' sex or handedness . Using this protocol, there was no difference between the mean memory scores after a left injection (67 .4%) versus a right injection (70 .4%) [F(1,68) = 0 .5; NS] .
Conclusions As expected, memory performance was poorer for the intracarotid sodium amobarbital injection contralateral to, rather than ipsilateral to, a major seizure focus in the temporal lobe (1,3) . No evidence for a practice effect or for transfer of learning emerged when comparing the side tested first versus the side tested second . If anything, subjects performed slightly worse on the second side injected than on the first, but this difference only approached statistical significance in our nontumor group (p < 0 .15) . Whether the left or right side was tested first did not affect memory scores either indirectly-by interacting with a practice effect-or directly. Other variables of interest such as sex, handedness, or hemisphere of the brain injected (left versus right) did not yield significant effects on memory scores . In the small sample (n = 10) described in Study 1, the mean scores on repeat injections of the same hemisphere increased nonsignificantly, whereas, in the larger sample (n = 70) described in Study 2, there was a nonsignificant drop in mean scores from first to second injection of different hemispheres . These divergent trends raise the possibility that over short intervals (24 h or less), there may be a slight drug effect that negatively affects memory performance . The half-life of sodium amobarbital is 20-25 h, although it can vary (from 14 to 42 h) among individuals (8,9) . Since five half-lives are required for complete elimination of the drug, some of the dosage from the first injection will still be in the system until 5 days have elapsed. Therefore, it would be of interest to investigate whether intervals shorter than 24 h between injections (i .e., 30 min) produce even greater decrement in memory scores from first to second procedures. Of course, this comparison could only be made in centers that randomly ordered the side tested first (i.e., ipsilateral versus contralateral to the major seizure focus) . If future studies are able to demonstrate a detrimental drug effect, then this factor needs to be taken into consideration when interpreting the memory scores as predictors of postoperative global amnesia, especially if nonstandardized protocols are employed that vary the number of items to be remembered and have no pass/fail criterion based on norms or chance performance .
RELIABILITY OF AMOBARBITAL MEMORY TEST
Addendum Three additional cases representing five repeat injections were tested after this paper was accepted for publication . No change in pass/fail status occurred across the first and second injections : Case K : first left injection, 75%; second, 75% Case L: first left injection, 25%; second, 0%; 3FP Case L : first right injection, 100% ; second, 75% Case M : first left injection, 0%; second, 50% Case M : first right injection, 75% ; second, 100% In total, 12 of 13 repeat injections in group IV patients yielded the same outcome (Fisher's Exact Test, p < 0 .02) .
Acknowledgment : The authors wish to thank Alanna Leffley, Lucy Carriere, and Kay Abony-Bencze for their help with data analyses . We are grateful to Bonnie Jamieson for the typing of the manuscript. We thank Dr. R . Glueckauf, Dr . W. Blume, Dr. J . Girvin, and Dr . R. McLachlan for their comments in the preparation of this manuscript and to Dr . A . J . Fox and the members of the Neuroradiology Department for their
cooperation in this procedure . Drs . Y. Parnell and Y . Archibald kindly gave us access to case material .
References 1 . Milner B, Branch C, Rasmussen T . Study of short-term memory after intracarotid injection of sodium amytal . Trans Am Neurol Assoc 1962;87 :224-6. 2 . Wada J. Igaku to Seibutsugaki . Med Biol 1949;14:221-2 . 3 . Milner B . Disorders of learning and memory after temporal lobe - lesions in man. Clin Neurosurg 1972 ;19 : 421-46 . 4 . Novelly RA . Relationship of intracarotid amytal procedure to clinical and neurosurgical variables in epilepsy surgery. I Clin Exp Neuropsychol 1987;9 :33 . 5 . Dinner DS, Luders H, Morris HH III, Wyllie E, Kramer RE . Validity of intracarotid sodium amobarbital (Wada test) for evaluation of memory function. Neurology 1987;37(S) :142. 6 . Ferguson GA . Statistical analysis in psychology and education, 2nd ed . New York : McGraw-Hill, 1959. 7 . Cavazzuti V, Winston K, Baker R, Welch K Psychological changes following surgery for tumors in the temporal lobe . I Neurosurg 1980;53 :618-26 . 8 . Knoben JE, Anderson PO . Handbook of clinical drug data. 5th ed . Hamilton, IL : Drug Intelligence Publications Inc ., 1983 . 9 . McEvoy GK American hospital formulary service drug information 87. Bethesda, MD: American Society of Hospital Pharmacists, 1987.
J EPILEPSY, VOL 2, NO. 1, 1989
39
© 1989 Demos Publications
Reliability of the Sodium Amobarbital Test for Memory Jeannette McGlone and 'Bonnie H : MacDonald
Two studies were conducted on epileptic patients to examine the reliability of Milner's protocol for testing memory after the unilateral injection of sodium amobarbital into the carotid artery . The first study examined alternate-form reliability in 10 patients who underwent 18 repeat injections of the same hemisphere . Major changes in memory performance from pass to fail or vice versa occurred in 8 of 18 repeat injections . Seven of the eight changes were associated with identifiable variation in external factors (e.g ., technically unsatisfactory first injections or reported deterioration in functioning over time) . Of the eight injections that were technically satisfactory but were repeated tore-ex jmine the initial memory score, seven outcomes remained stable across both 'injections, despite variability I betwee4est-retest conditions . In the second stuffy, data from 70 patients given bilateral injections were analyzed, and no evidence for a practice effect was found when comparing memory scores from the first to the second injection . Whether the left or right side was injected first did not affect memory scores, nor did other variables such as sex, hand preference, or hemisphere injected . As expected, memory functions were more impaired for the injection contralateral than ipsilateral to the major temporal lobe seizure focus . We concluded that reliable results can be obtained from a sodium amobarbital memory protocol, adapted from Milner, which employs a pass/fail criterion based on chance performance . Key Words : Sodium amobarbital-Memory- Reliability .
Milner et al . (1) first adapted the Wada technique (2) of intracarotid sodium amobarbital testing for the purpose of predicting and preventing global amnesia in epileptic patients who were surgical candidates for temporal lobectomy . Milner (3) reasoned that the unilateral action of the drug should produce a generalized memory disorder if "there were a pre-existing lesion in the medial temporal region of the opposite hemiFrom the Epilepsy Unit, University Hospital, London, Ontario, and the 'Department of Psychology, Credit Valley Hospital, Mississauga, Ontario, Canada . This paper was a poster presentation at the annual meeting of the American Epilepsy Society, Baltimore, December 8, 1987. Address correspondence and reprint requests to Dr . J . McGlone at Department of Psychological Services, University Hospital, P.O. Box 5339, Station A, London, Ontario N6A 5A5, Canada .
sphere ." Her research on group data demonstrated that failure to meet criterion on postinjection memory testing was rare but clearly more frequent when patients received the injection contralateral (23%) rather than ipsilateral (1 .7%) to the major seizure focus (p < 0 .001) (3) . Recently, the reliability of the sodium amobarbital test for memory has been questioned . Novelly (4) reported that 12 of 18 patients who failed their first memory test after sodium amobarbital injection ipsilateral to the seizure focus later went on to pass the second memory test . A different protocol was used by Dinner et al. (5), who found that five patients who underwent repeat injections ipsilateral to their seizure focus improved their memory score by 9-66% . Such dramatic improvement in performance from first to second injection of the same side calls into question the test retest reliability of sodium amobarJ EPILEPSY, VOL. 2, NO. 1 , 1989 31
J. McGLONE AND B. H. MacDONALD
bital testing of memory. Reliability is a necessary precondition for establishment of the validity of a psychological test; hence, this retrospective study examined the alternate-forms reliability of an amobarbital protocol adapted from Milner (3) . Two studies were conducted. The first examined whether those few patients who underwent repeat sodium amobarbital testing on the same side obtained similar memory scores . We also included data from repeat injections of the contralateral side, as well as two cases in which there were third injections of the side ipsilateral to the major seizure focus . We calculated changes in the raw scores, but more importantly, we determined whether the pass/fail results of the repeat injections were correlated with the results of the previous injection . Thus, the first study examined alternate-form reliability of the sodium amobarbital memory protocol. The second study examined a larger sample of patients and investigated whether a practice effect was present between injections of different hemispheres .
or laboratory evidence to suspect bitemporal lobe dysfunction. For example, amytals were ordered if there were bilateral temporal EEG epileptiform abnormalities, verbal and nonverbal memory loss, or bitemporal structural lesions visualized on a computed tomography (CT) or magnetic resonance imaging (MRI) scan . In many cases, evidence for possible bilateral temporal lobe dysfunction was derived from several sources, such as in the case of a right-hander with intact verbal memory, defective nonverbal memory, and a clear left temporal lobe seizure focus on ictal EEG skull recordings . Approximately 20-25% of surgical candidates undergo sodium amytal testing in our center . The patient's primary epileptogenic lesion was identified by a combination of ictal recordings, interictal EEG recordings with scalp electrodes, and, rarely, by subdural recordings . As shown in Table 2, most patients received a bolus of 175 mg sodium amobarbital dissolved in 3 .5 ml sterile water . A catheter was placed into the right femoral artery, then navigated up to the designated internal carotid artery . There were 16 second injections, nine on the left side and seven on the right, and two third injections on the left side . The majority of repeat injections (12/18) involved the side ipsilateral to the major seizure focus (Table 2), with the retest interval ranging from 5 days to over 10 years . Table 2 shows that at least one element of the procedure changed in 17 of the 18 repeated injections, and one patient had subdurals implanted between administrations . For these reasons, and because new stimuli were used on repeat injections, the following results offer informa-
Study 1 : Alternate-Forms Reliability Methods In 11 years, 10 of 128 patients (7 .8%) investigated in the Epilepsy Unit at the University Hospital in London, Ontario, underwent repeated sodium amobarbital injections on the same side (Table 1) . In our center, patients were selected for sodium amobarbital testing of memory functions when there was clinical
Table 1 .
Patient A B C D
E F G
H I J
Subject characteristics of patients with repeat sodium amobarbital injections
Major seizure focus°
Etiology"
Sex
RT LT > RT LT > RT LT LT > RT RT > LT LT LT LT > RT LT
NT NT NT NT NT NT T NT NT T
F F M M M M F F M M
Hand preference`
Age (years)
L
R R R L R L
R L R X=
aLT, left temporal; RT, right temporal. IT, tumor; NT, nontumor . 'L, left-handed; R, right-handed .
32 1 EPILEPSY, VOL 2, NO. 1, 1989
Education (grade)
17 32 43 43 27 35 38 22 49 31
12 12 9 9 12 17 8 15 11 13
33 .7
11 .8
Wechsler FSIQ 101 94 76 79 67 111 81 96 77 86 86 .8
Wechsler MQ 110 86 66 76 106 98 80 86 66 86 .0
Reason
LI
RC
LI
D
D
J
Unresponsive Unresponsive Incorrect procedure
Sz
Memory Memory
Memory
RC
RI
LC
LI RC
G
F
F
I I
No
Yes Yes
4 weeks
22 mo 30 mo
No
No
3 mo 4 weeks
Yes
Yes Yes
No
Yes (post) No
Yes (post) Yes (pre)
No
5 days
1 week
Yes
No
Yes
10 yr 4 mo
Yes (pre)
Yes (pre)
Yes (post) No
Yes
No
No
No
No
Memory
No
Yes
4 yr 7 mo
4 mo
Yes
No
2 weeks
4 yr 7 mo
No
Yes
10 yr 4 mo
3 mo
Yes
No
3 weeks 2 weeks
Yes
No
Speech
Change in protocol
5 mo
3 mo
Test-retest interval
125 125
175 175 Yes Yes
140
175
Yes
175
175 No
No ; Sz subdurals Yes; Sz subdurals Yes Yes
175
175'
175" 175
150
150
175
150
175
Phenytoin, 400 Phenytoin, 400
Phenytoin, 200 ; phenobarbital, 60
Phenytoin, 200 ; Phenobarbital, 60
Phenytoin, 400 ; primidone, 750 Carbamazepine, 600 ; nitrazepam, 25 Carbamazepine, 800"; thioridazine, 50" Phenytoin, 300
Carbamazepine, 1,200 ; phenytoin, 200 Carbamazepine, 1,200; phenytoin, 200 Carbamazepine, 600 ; phenytoin, 400 ; phenobarbital, 120
Carbamazepine, 600
175
175
Phenytoin, 300
Carbamazepine, 1,000; phenytoin, 400 Carbamazepine, 1,200"; phenytoin, 450" Carbamazepine, 1,400 ; phenytoin, 300 Carbamazepine, 1,400 ; phenytoin, 300 Carbamazepine, 600; phenytoin, 400; phenobarbital, 120
First
Phenytoin, 400 Phenytoin, 400 ; carbamazepine, 400
Phenytoin, 400 ; phenobarbital, 30
Phenytoin, 400; phenobarbital, 30
Phenytoin, 300
Phenytoin, 400 ; primidone,, 750 Carbamazepine, 604; nitrazepam, 25 Carbamazepine, 600'
Carbamazepine, 800; thioridazine, 50 Carbamazepine, 800; thioridazine, 50 Carbamazepine, 700; phenytoin, 500; primidone, 525
Carbamazepine, 800
Phenytoin, 300
Carbamazepine, 1,200 ; phenytoin, 450 Carbamazepine, 1,000' ; phenytoin, 450' Carbamazepine, 1,400 ; phenytoin, 300 Carbamazepine, 1,400 ; phenytoin, 300 Carbamazepine, 700 ; phenytoin, 500 ; primidone, 525
Second
Seizure medications (mg)
175
150-175
125
125
125'
175
Second
Yes
Yes
Yes
150
175?
Yes
No
175
175
175
175
Yes
Yes
Yes
Yes
175
175
Yes Yes
175
175"
Yes Yes
175
First
No
Strength
Sodium amobarbital dosage (mg)
Yes
No
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Delta
Change in length of drug effect
Parameters of sodium amobarbital injections
°Ll, left ipsilateral; RI, right ipsilateral ; LC, left contralateral ; RC, right contralateral . "Second injection. 'Third injection.
Memory Memory
Memory
LI
E
Memory
LI
Speech
B
D. Speech or memory RI A
C. Functional deterioration E LI Deterioriltion E RC Deterioration J RC Deterioration
B. Environmental factors G LI Memory, glasses LI Panic reH action
LI
C
A. Technically unsatisfactory C LI Sz
Patient
Repeat injection"
Table 2 .
J. McGLONE AND B. H. MacDONALD
tion on alternate-forms reliability rather than testretest reliability. The protocol for speech and memory testing was adapted from Milner (3) . Figure 1 depicts the approximate timing and the content of the typical protocol. The two injections were done on separate days, usually 24 h apart . A rehearsal of the procedure was conducted the day prior to the first injection and again on the next day, minutes before the first injection . For most cases, four different memory items were administered after each injection . These were one object palpated by the patient's nonparetic hand, two line drawings, and one nursery rhyme . The examiner named each while the patient viewed it for 5-10 s . The patients were encouraged to name the items even if they were dysphasic at the time . Recognition memory testing occurred 10-15 min after the injection, when grip strength of the paretic hand had returned to baseline levels and unilateral delta on the EEG had disappeared. Scoring was based on verbatim transcripts taken from video and audio taped records. One point was assigned to a correct recognition (maximum = 4), and this was converted to a percent correct score . There were two foils for the object recognition test (chance = 33 .3%), two foils for the nursery rhyme recognition test (chance = 33 .3%), and five foils for the postinjection picture recognition test (chance = 28 .6%) . Thus, the combined chance performance for the four postinjection stimuli was 31% . Failure was based on a score of 50% or below (i.e ., 2 of 4 correct recognition or less) . False-positive errors were recorded each time a patient said he recognized a foil (object, picture, or rhyme) that had not been presented earlier. The percent correct recognition and false-positive error scores for the 18 repeat injections are found in Table 3 . When falsepositive errors occurred in patients who obtained 75% or more correct recognition, an arbitrary decision was made concerning their passing or failing that particular test .
Results For 10 patients, the first and second injection recognition memory scores (i.e ., 16 of 18 injections in Table 3) were compared using a paired observations t test. The mean first (X= 53 .1% ; SD = 27 .9) and second (X = 61 .4% ; SD = 33 .1) injection scores were not significantly different [t(15) = 0 .93 ; NS] . The total group was then subdivided into four subgroups based on the clinical reason for repeating the injection. Group I : Technically unsatisfactory . Five injections were repeated because they were technically 34
1 EPILEPSY, VOL . 2, NO. 1, 1989
unsatisfactory (see Table 2, Part A) . In one case (C), a seizure was recorded on the EEG at the onset of the second injection . Consequenty, a third injection on the left side was performed (Table 2, Part A) . Both left- and right-sided injections were repeated for another patient (D) who was unresponsive to commands for as long as 15 min after the first left injection; thus, memory testing was precluded during the unilateral effect of the drug . In the fifth case (J), the left injection was repeated because recognition testing began before the unilateral effect of the drug cleared (i .e ., during hemiparesis) . In this group, two repeat injections yielded an improvement in percent recognition, another showed no change, and two declined (Tables 3 and 4) . Ori average (excluding CLI second and third injections), there was an overall mean increase in percent correct recognition from 45 .8% (SD = 41 .7) for the first injection to 62 .5% (SD = 32.3) for the second injection . Three of the five injections yielded a score in the same pass/fail category as the first injections . Group II : Environmental factors . Factors extraneous to the test procedure sometimes produced artificially lowered first injection memory scores (see Table 2, Part B) . One subject (H) experienced a panic reaction, with crying and inattentiveness, during the first injection . Relaxation training was conducted during the test-retest interval to reduce anxiety for the repeat injection . In another instance, the subject was not wearing her glasses for the first injection . Improvement occurred for both these repeat injections, with an increase from a mean score of 50 .0% (SD = 0) to 90 .0% (SD = 14 .1), and both scores changed from a failure to a pass . Group III : Functional deterioration . E's mother noted a decline in his speech over the 4 1/2-year period between injections (see Table 2, Part C) . Although neuropsychological testing revealed no obvious alteration in any aspect of speech or language, sodium amobarbital testing for memory did show a decline from 1982 (pass) to 1986 (fail) category . The second patient (J) underwent surgical removal of a glioblastoma multiform between repeat injections . A left anterior temporal lobectomy had been performed, sparing the hippocampus . Decline over the 10-year interval was evident both on neuropsychological testing and on the repeat right-sided injection memory testing . In this group, memory scores decreased from the first injection (X= 72 .3% ; SD = 4 .6) to the second (X= 33 .3% ; SD = 28 .9) and in all three injections, scores moved from the pass to the fail category .
RELIABILITY OF AMOBARBITAL MEMORY TEST sec
0 C) w cz a
- 240 - Baseline expressive and receptive speech
-
180
-
120 - Baseline memory presentation (2 pictures, - 60
-
1 sentence)
Baseline memory recall
0 --- INJECTION (counting)
----------------------------
Test for responsiveness 60
Figure 1 . University hospital sodium amobarbital protocol (adapted from ref. 3) .
120 1801-
Expressive and receptive speech -Naming -Sequencing Memory presentation-(new object) -Repetition -Modified Token Test -(2 pictures)
0 240
-(nursery rhyme)
V W 300 N O d
360 420
-
Oral fluency
-
Interview
480 540 600
Group IV : Memory or speech . Six cases (eight injections) were repeated to reinvestigate memory performance, because the initial score was lower than expected (see Table 2, Part D) . In another case (A), speech lateralization was being reinvestigated, and the memory protocol was also repeated . As shown in Tables 3 and 4, improvement in the percent recognition memory score occurred for five repeat injections, two cases had no change, and one case declined . Overall (excluding E-LI), the mean memory scores increased from the first injection (X= 50.0% ; SD = 28 .9) to the second injection (X= 64 .7%; SD = 35 .1), but the difference in this small sample was not statistically significant [t(6) = 1 .40 ; p < 0 .25] . More importantly, the performance category of pass/fail remained the same for seven of the eight repeat injections. Application of the Fisher's Exact Test (6) indicated that this result approaches statistical significance (p < 0.07) . The small sample size limits the power of this test and the likelihood of obtaining a statistically significant result (see Addendum) .
Conclusions
Repetition of sodium amobarbital injections is usually conducted on a biased sample, i .e., in those patients whose first injection was technically unsatisfactory, or where the findings were unexpected . Moreover, in our study some aspect of the procedure was altered in virtually every repeat injection . Seizure
Recall and Recognition memory testing - pre-injection stimuli - post-injection stimuli (object, 2 pictures, nursery rhyme)
medications and frequencies changed over the testretest interval; hence, low reliability would be expected due to high error variance . Indeed, significant change between the pass/fail category occurred in 8 of 18 repeat injections; in six of these, external factors clearly appeared to be responsible, e .g., technically unsatisfactory first procedure, reported deterioration of functioning, a panic attack, and corrected vision with glasses. In these cases, error variance due to changing environmental or physiological conditions most likely influenced the lack of congruence in scores. It is also possible that memory scores vary when the dosage of sodium amobarbital differs systematically between the first and second injections . This was not examined in the current study, but it may prove important in understanding the fact that Novelly found better memory performance in 12 of 18 patients who were given a second injection . Novelly's (personal communication) use of a lower dosage on the second injection shortens the unilateral effect of the drug and may specifically alter its anesthetizing effect on the temporal lobe . If the drug effect is less pronounced in the second injection than in the first injection, then the possibility is strong that memory performance may improve accordingly, unless particular attention is given so that memory items are presented earlier in the protocol, before the drug effect wears off. What is remarkable is flat despite variability in test retest conditions, 10 of the repeat injections in
f
EPILEPSY, VOL 2, NO. 1, 1989
35
J. McGLONE AND B. H. MacDONALD the current study yielded similar outcomes on a pass/ fail criterion based on chance performance (Table 4) . In the subgroup where the reason for repeating the procedure was to check on the memory scores, per se, the pass/fail scores remained stable in seven of eight repeat injections. It is also interesting to note that whether improvement occurred in percentage memory scores did not differ according to the side of injection (left = 5/11 ; right = 11/7) or in relation to the seizure focus (ipsilateral = 6/12 ; contralateral = 3/6) . From these preliminary data, we conclude that it is possible to obtain reliable results using the sodium amobarbital procedures and pass/fail criterion suggested originally by Milner (3) . Environmental and physiological error variance, however, contribute to poor reliability of the memory scores . Unstandardized protocols that arbitrarily vary the number of memory items per side and/or have no pass/fail criterion based on chance and protocols that systematically change the drug dosage may yield less reliable results . Table 3 . Percent correct recognition memory of four postinjection items : failure = 50% or less, chance = 31%
Patient
Repeat injection'
First (%) b
Second (%) b
Group I: technically unsatisfactory C LI 100 (2FP) 100 (2FP) C LI 100 (2FPI) 75 (3FP-~ D LI 0 50 D RC 50 25 J LI 33 75 Group II : environmental factors G LI 50 H LI 50 Group III : functional deterioration E LI 75 E RC 75 J RC 67 (1 FP) Group IV : memory or speech A RI 0 B LI 75 (2 FP) E LI 50 (1FP`) G RC 25 F RI 50 F LC 75 I LI 50 I RC 75
80 (4/5 items, 2FP) 100 50 (1FP) 50 0 33 60 (3/5 items) 50 (1FPJ 40 (2/5 items) 100 100 20 (1/5 items) 100 (5/5 items)
Table 4 .
Patient
Side'
Change in memory scores Improved (I), same (S), or deteriorated (D)"
Pass/fail category (FirstSecond)
Group I : technically unsatisfactory C LI S P-P C LI D P-F D U I F-F RC D F-F J LI I F-P Group II : environmental factors G LI I? H LI I
Change (C), or no change (NC)`
NC C NC NC C
F-P F-P
C C
Group III : functional deterioration E LI D P-F E RC D P-F J RC D P-F
C C C
Group IV : A B E G F F I I
memory or speech RI I LI D? LI S RC I RI I LC I LI D RC I
F-F P-P F-F F-F F-P P-P F-F P-P
NC NC NC NC C NC NC NC
"See Tables 2 and 3 for meaning of abbreviations . 'Change in absolute % score : improved, 9 ; same, 2 ; deteriorated, 7 . `Change across pass/fail criterion : change (C), 8 ; no change (NC), 10 .
Study 2 : Practice Effect The aim of the second study was to investigate the possibility of a practice effect due to test familiarity or transfer of training . Dinner et al . (5) have suggested that improvement from the first to the second injection of the same side on their protocol may be due in part to practice effects . Our first study, using a standard protocol and strict a pass/fail criterion, revealed no statistically significant effect of practice per se . We next examined whether memory scores from different injections improved due to repeated exposure to the procedure .
Methods 'U, left ipsilateral ; RI, right ipsilateral; LC, left contralateral ; RC, right contralateral . bFP, false-positive error . Second injection. °Third injection . 36
1 EPILEPSY, VOL 2 , NO. 1, 1989
Subjects . During a 10 1/2-year period, 206 amobarbital injections were carried out on 116 patients, the majority (105) of whom were surgical candidates
RELIABILITY OF AMOBARBITAL MEMORY TEST Table 5 . Characteristics of patients given bilateral sodium amobarbital injections Sex Male Female Handedness Right Left Ambidextrous Locus of major seizure focus Temporal Frontal Temporofrontal Side of major seizure focus Left Right Bilateral
mg sodium amobarbital dissolved in 3 .5 ml sterile water. The remaining 10 received 125 mg, 150 mg, or 200 mg sodium amobarbital . The side injected first was counterbalanced across sex and hand preference groups, with half the subjects receiving the left injection first . The order of injections ipsilateral versus contralateral to the seizure focus was not counterbalanced. Four postinjection stimuli were presented during the effect of the drug, and recognition memory for them was tested about 10 min later . A multiple-choice format was used, with chance performance set at 31% and the maximum memory score for each side set at 100% correct (see Methods, Study 1) .
39 31 48 19 3 65 4 1 34 33 3
Data Analysis
for the control of their medically intractable seizure disorder . Seventy subjects met the criteria of (a) having bilateral injections; (b) being at least 12 years of age; (c) having etiologies other than arteriovenous malformation; and (d) undergoing a technically satisfactory procedure . Hand preference was assessed by requesting that subject demonstrate eight everyday activities, e .g., brushing teeth . If writing and six of seven other activities were performed with the same hand, then the subject was classified as left- or righthanded, accordingly . Otherwise, the classification was ambidextrous . Tables 5 and 6 outline the patient characteristics. Procedure. The main reason for recommending the sodium amobarbital procedures was to test the memory function of each hemisphere . However, speech lateralization was also examined . The protocol was described in Study 1 and Fig . 1 . Two injections of the same dosage were done on separate days, usually 24 h apart . Sixty subjects received a bolus of 175
Table 6 .
Patient characteristics
Parameter Age Age at seizure onset Education Wechsler Full-Scale IQ (W-BII, WAIS, WAIS-R) Wechsler Memory Quotient
X
SD
29.8 years 12.8 years 11 .7 years
11 .2 13 .9 5 .1
Range, 57-121 92.2
16 .3
The difference between memory scores that were ipsilateral vesus contralateral to the major seizure focus was tested by a one-way analysis of variance (ANOVA) on patients with unilateral temporal lobe seizure foci . Three patients with bilateral seizure foci and four patients with frontal lobe foci were not included in the analysis . The effects of practice (first versus second injection) and order of injections (left side injected first versus right side injected first) were tested in three 2 X 2 ANOVAs . An analysis was performed on the entire sample, then on the nontumor subgroup, and finally on the tumor subgroup . Repeated measures were taken on the practice variable in all three analyses. Supplementary analyses were performed to investigate subject variables . A 2 X 2 ANOVA, with sex and side of injection (left versus right) as the independent variables, was performed on memory scores. Repeated measures were taken on the side variable. Another 2 X 2 ANOVA was performed with handedness (left versus right), replacing sex as the betweensubjects variable . Three ambidextrous subjects were not included in the latter analysis .
Results Memory performance and seizure focus . Percent correct recognition memory scores were significantly lower for the side contralateral (X = 62 .0% ; SD = 28 .8) than ipsilateral (X = 77 .1%; SD = 27 .9) to the major temporal lobe seizure focus [F(1,62) = 8 .69 ; p < 0 .005] . Practice effect . Patients did not perform better on memory testing for the second side (X= 65 .1%; SD = 30 .8) than for the first side (X= 72 .6 ; SD = 29.4) injected [F(1,68) = 2 .0; p < 0 .201 . If anything, the direc-
I
EPILEPSY, VOL. 2, NO. 1 , 1989 37
J. McGLONE AND B. H. MacDONALD
Table 7 .
Mean percent correct recognition memory for four postinjection items
Order of injections
Contralateral to seizure focus Ipsilateral to seizure focus
First
Second
X= 63 .6%; SD = 31 .1° X= 79 .1%; SD = 26 .7"
X= 58 .1%; SD = 29 .8 1 X= 73 .6%; SD = 30 .3°
°n = 30 . b n = 37 . tion of the trend was opposite to that expected and may have been due to the fact that more patients received the contralateral injection second (n = 37) than first (n= 30) . However, Table 7 shows that both the contralateral and ipsilateral mean scores declined nonsignificantly from first to second injections . Cavazzuti et al . have suggested that amobarbital memory test results may be atypical for tumor patients (7) ; thus, etiology was investigated in this study . Table 8 shows that no significant practice effect emerged for either the nontumor [F(1,54) = 2 .69 ; p < 0 .15] or the tumor groups [F(1,12) < 1] . It is noteworthy that ipsilateral first versus contralateral first was balanced in the nontumor group (26 ipsilateral second, 27 contralateral second) but not in the tumor group (4 ipsilateral second, 10 contralateral second) . (Three of the nontumor group had bilateral seizure foci .)
Procedural and Subject Variables
There was no effect for order of injections . That is, whether the left or right side was injected first did not alter the memory scores for the entire sample (X = 68 .9% ; SD = 18 .9 versus k= 68 .8% ; SD = 22 .3, respectively) [F(1,68) < 1] . Similarly, no significant main effects for order emerged for the tumor or nontumor subgroups . Practice did not interact with order in any of the above analyses . Neither sex [F(1,68) = 1 .70 ; p < 0 .20] nor handedness [F(1,65) = 1 .42; p < Table 8 . Mean percent correct recognition memory of four postinjection items for nontumor and tumor groups Order of injections Etiology
Nontumor (n = 56)
Tumor (n = 14)
38
First
Second
X= 75 .3%; SD = 28 .0 X= 61 .9%; SD = 33 .5
X= 66 .1%; SD = 31 .2 X= 61 .3%; SD = 29 .9
1 EPILEPSY, VOL . 2, NO. 1, 1989
0 .25] interacted significantly with side of injection . Thus, left or right injection memory scores did not vary according to patients' sex or handedness . Using this protocol, there was no difference between the mean memory scores after a left injection (67 .4%) versus a right injection (70 .4%) [F(1,68) = 0 .5; NS] .
Conclusions As expected, memory performance was poorer for the intracarotid sodium amobarbital injection contralateral to, rather than ipsilateral to, a major seizure focus in the temporal lobe (1,3) . No evidence for a practice effect or for transfer of learning emerged when comparing the side tested first versus the side tested second . If anything, subjects performed slightly worse on the second side injected than on the first, but this difference only approached statistical significance in our nontumor group (p < 0 .15) . Whether the left or right side was tested first did not affect memory scores either indirectly-by interacting with a practice effect-or directly. Other variables of interest such as sex, handedness, or hemisphere of the brain injected (left versus right) did not yield significant effects on memory scores . In the small sample (n = 10) described in Study 1, the mean scores on repeat injections of the same hemisphere increased nonsignificantly, whereas, in the larger sample (n = 70) described in Study 2, there was a nonsignificant drop in mean scores from first to second injection of different hemispheres . These divergent trends raise the possibility that over short intervals (24 h or less), there may be a slight drug effect that negatively affects memory performance . The half-life of sodium amobarbital is 20-25 h, although it can vary (from 14 to 42 h) among individuals (8,9) . Since five half-lives are required for complete elimination of the drug, some of the dosage from the first injection will still be in the system until 5 days have elapsed. Therefore, it would be of interest to investigate whether intervals shorter than 24 h between injections (i .e., 30 min) produce even greater decrement in memory scores from first to second procedures. Of course, this comparison could only be made in centers that randomly ordered the side tested first (i.e., ipsilateral versus contralateral to the major seizure focus) . If future studies are able to demonstrate a detrimental drug effect, then this factor needs to be taken into consideration when interpreting the memory scores as predictors of postoperative global amnesia, especially if nonstandardized protocols are employed that vary the number of items to be remembered and have no pass/fail criterion based on norms or chance performance .
RELIABILITY OF AMOBARBITAL MEMORY TEST
Addendum Three additional cases representing five repeat injections were tested after this paper was accepted for publication . No change in pass/fail status occurred across the first and second injections : Case K : first left injection, 75%; second, 75% Case L: first left injection, 25%; second, 0%; 3FP Case L : first right injection, 100% ; second, 75% Case M : first left injection, 0%; second, 50% Case M : first right injection, 75% ; second, 100% In total, 12 of 13 repeat injections in group IV patients yielded the same outcome (Fisher's Exact Test, p < 0 .02) .
Acknowledgment : The authors wish to thank Alanna Leffley, Lucy Carriere, and Kay Abony-Bencze for their help with data analyses . We are grateful to Bonnie Jamieson for the typing of the manuscript. We thank Dr. R . Glueckauf, Dr . W. Blume, Dr. J . Girvin, and Dr . R. McLachlan for their comments in the preparation of this manuscript and to Dr . A . J . Fox and the members of the Neuroradiology Department for their
cooperation in this procedure . Drs . Y. Parnell and Y . Archibald kindly gave us access to case material .
References 1 . Milner B, Branch C, Rasmussen T . Study of short-term memory after intracarotid injection of sodium amytal . Trans Am Neurol Assoc 1962;87 :224-6. 2 . Wada J. Igaku to Seibutsugaki . Med Biol 1949;14:221-2 . 3 . Milner B . Disorders of learning and memory after temporal lobe - lesions in man. Clin Neurosurg 1972 ;19 : 421-46 . 4 . Novelly RA . Relationship of intracarotid amytal procedure to clinical and neurosurgical variables in epilepsy surgery. I Clin Exp Neuropsychol 1987;9 :33 . 5 . Dinner DS, Luders H, Morris HH III, Wyllie E, Kramer RE . Validity of intracarotid sodium amobarbital (Wada test) for evaluation of memory function. Neurology 1987;37(S) :142. 6 . Ferguson GA . Statistical analysis in psychology and education, 2nd ed . New York : McGraw-Hill, 1959. 7 . Cavazzuti V, Winston K, Baker R, Welch K Psychological changes following surgery for tumors in the temporal lobe . I Neurosurg 1980;53 :618-26 . 8 . Knoben JE, Anderson PO . Handbook of clinical drug data. 5th ed . Hamilton, IL : Drug Intelligence Publications Inc ., 1983 . 9 . McEvoy GK American hospital formulary service drug information 87. Bethesda, MD: American Society of Hospital Pharmacists, 1987.
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