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Mood State in Unilateral Temporal Lobe Epilepsy Bruce P. Hermann, Michael Seidenberg, Alan Haltiner, and Allen R. Wyler
The purpose of this investigation was to reexamine the relationship between self-reported depression and laterality of temporal lobe epilepsy and to determine the contribution of associated frontal lobe dysfunc~'o~ ,n predisposing patients to depression. Sixty-four paiients ~th coraple~ p,~'iial 5cizure~ of left (n =- 26) or right (n - 38) temporal lobe origin were administered several self-report measures of mood state (Beck Depression Inventory, Centerfor Epidemiological Studies-Depression scale, Beck Anxiety Inventory), and a test of frontal lobe function [Wisconsin Card Sorting Test (WCST)I. There were no overall differences between the left and right temporal lobe groups on the measures of depression and anxiety. However, the left temporal lobe group exhibited a significant relationship between the degree of associated frontal lobe dysfunction (as indicated ~. increased perseverative responding on the WCST) and dysphoric mood state. For the right temporal lobe group there was a nonsignificant inverse relationship between mood state and indices of frontal lobe dysfunction. These results (1) are consistent with the broader psychiatric literature, which has implicated a relationship between depression and left frontal lobe dysfunction, (2) suggest that previous conflicting reports of depressionlleft temporal lobe epilepsy relationships are due in part to variations in the intactness of frontal lobe function, and (3) suggest that the presence of associated frontal lobe dysfunction may be a consideration in understanding interictal psychopathology in epilepsy.
Introduction Epilepsy is a disorder characterized b~ a s p e c ~ of severity, ran~,ng from ~ d and benign to severe and intractable (Hauser and Hesdorffer 1990). The risk of social psychological disability parallels this spectrum of severity (Edeh et al 1990; Trosfle et al 1989; Zielinski 1986). Research examining psychiatric illness among individu~ with epilepsy is typically conducted at facilities that treat patients from the more severe end of the epilepsy spectrum (Trostle et al 1989). These investigations have consistently reported depression to be a serious and cotnmon interictal psychiatric complication (Altshuler et al 1990; Betts 1981; Currie et al 1971; Dominian et al 1963; Herm~nn and Whitman 1989; Kogeorgos et al 1982; Mendez et al 1986; P e ~ and Mendius 1984;
From EpiCare Center, Baptist Memorial Hospital, Memphis, TN, Depatm~nts of P s y c ~ and Neurosurgery, University of Tennessee, Memphis, TN, Department of Psychology, University of Health Sciences, Chicago ~ School, North Chicago, IL, Semn-~,s-MurpheyClinic, Memphis, TN. Address reprint requests to: Bruce Hermann, Ph.D., EpiCare Center, 910 Madison Avenue, Suke 906, Memphis, TN 38103. Received January 24, 1991; revised June 27, 1991. © 1991 Society of Biological Psychiatry
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Robertson 1989, 1990; Robertson et al 1987; Roy 1979). The significantly elevated mortality in epilepsy due to suicide underscores the seriousness of this psychiatric problem (Barclough 1987; Hawton et al 1980; Matthews and Baratnts 1981; Zielinski 1974). The determinants of interictal depression in epilepsy appear to be multifactorial, encompassing both neurobiological and psychosocial risk factors (Robertson 1990; Hermann and Whitman 1989). Among the potential neurobiological determinants, considerable interest has focused on the significance of the laterality of the interictal temporal lobe spike focus. Some investigations have reported increased depression among patients with a left temporal lobe spike focus (Altshuler et al 1990; Mendez et al 1986; Perini and Mendius 1984), while others have failed to confirm this laterality effect (Hetmann and Whitman 1989; Robertson et al 1987; Trimble and Perez 1980). Although several potential methodological and theoretical reasons might account for these discrepant findings, this investigation will present evidence suggesting that the presence of associated frontal lobe dysfunction interacts with the laterality of seizure focus in determining dysphoric mood state among patients with temporal lobe epilepsy. Converging neurophysiological evidence has indicated that there is pathological involvement of the frontal lobes in a significant proportion of patients with epilepsy of temporal lobe origin. Several findings bear on this point: (1) The area of interictal hypometabolism associated with epilepsy of temporal lobe origin may extend into extratemporal areas, particularly frontal and thalamic regions (Engel et al 1983; Theodore et al 1983; Engel 1990). (2) lntraoperative electrocorticography of patients undergoing anterior temporal lobectomy has revealed considerable epileptogenic activity in frontal lobe regions, which is thought to reflect propagated epileptiform activity from the mesial temporal lobe focus (Abou-Khalil et al 1987; Hermann et al 1988). (3) Invasive (depth electrode) EEG investigations have mapped the spreadof both interictal spikes (Kendrick and Gibbs 1958) and ictal activity (Lieb et al 1989) from the inesial teraporal region and have demonstrated preferential propagation to the medial and orbitofrontal regions (Lieb et al 1989). (4) Neuropsychological evidence of frontal lobe dysfunction (perseverative responding) has been identified in a sizable proportion of patients with temporal lobe epilepsy (Hermann et al 1988). Associated frontal lobe dysfunction among patients with complex partial seizures of unilateral mesial temporal lobe origin may be a significant determinant of depression and dysphoric mood state. Recent investigations of patients with mood disorders following stroke (Robinson and Szetela 1981; Robinson et al 1983, 1984a, 1984b; Starkstein et al 1987), FDG glucose utilization in nonneurological psychiatric patients with depressive illness (Baxter et al 1989; Martinot et al 1990), neurological patients with depressive illness (Mayberg et al 1990), and induction of positive and negative mood state in normal controls (Tomarken et al 1990) have all revealed an association between the degree or laterality of frontal lobe involvement and depressive symptomatology and dysphoric mood. Specifically, among patients with stroke, the frequency and severity of depression has been found to be associated with the proximity of the cortical or subcortical lesion to the left frontal pole (Robinson et al 1984a; Starkstein et al 1987). Reduced glucose metabolism has been found in the left anterior prefrontal cortex among psychiatric patients with major depressive disorder (Baxter et al 1989; Martinot et al 1990). We hypothesize that depression in left ten~poral lobe epilepsy may in part be attributable to the presence of associated frontal lobe dysfunction, and that the conflicting reports of depression and latera!ity of lesion in temporal lobe epilepsy may be due to uncontrolled variability in frontal lobe pathology.
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In this study the integrity of frontal lobe functioning is assessed by performance on a behavioral measure of executive functions, the Wisconsin Card Sorting Test. The capacity to plan, regulate, and self-monitor one's behavior in response to complex and changing environmental feedback is a basic component of the so-called executive functions. executive functions are considered to be among the highest of human cognitive abilities, and are thought to reflect the integrity of the prefrontal cortex (Stuss ~ Benson 1986). Although a variety of signs are considered to reflect a breakdown in these executive abilities, a particularly important marker is perseverative behavior (Stuss ~ Benson 1986). Among the various approaches to the assessment of perseverative behavior, Wisconsin Card Sorting Test (WCST) has been a particularly widely used instrument because it yields specific indices of perseverative behavior (Heaton 1981). Several investigators have found that patients with focal frontal lobe lesions produce s i ~ c a n t l y more perseverative responses than other brain lesion groups on the WCST (Drewe 1974; Milner 1963; Robinson et al 1980). In addition, a recent PET scan study involving normal controls demonstrated an_ association between activation of the dorsolateral prefrontal cortex and WCST performance (Weinberger et al !986). Given this neurophysiolo~cal confirmation of the dependence of WCST performance on prefrontal integrity, the degree of perseverative respending will serve as the ma.~er of associated frontal lobe pathology in the current study. In surnmary, the purpose of the present investigation is to examine the ~lations~p among laterality of temporal lobe lesion, perseverative response set, and self-reported depression in patients with unilateral temporal lobe epilepsy.
Method
Subjects Sixty-four consecutive patients over 16 years of age with intractable epilepsy of ~ a t e r a l temporal lobe origin served as sabjects. These individuals were referred to our epilepsy center because of medication-resistant epilepsy and consideration for suitability for surgical intervention. As such, they underwent intensive neurophysiological investigation, which permitted precise localization of their epileptogenic lesion. The presurgical workup included continuous (24-hr) closed circuit TV/EEG monitoring with scalp electrodes in order to record several of the patients" typical spontaneous seizures for classification of seizure type and preliminary localization of seizure onset. Of the 64 patients, 56 also underwent invasive EEG monitoring with subdural strip electrodes in order to provide precise localization of the epileptogenic lesion (Wyler et al 1984). The eight patients who did not undergo invasive EEG procedures had been determined by the electroencephalographer to show unequivocal localization of ,;eizure onset with scalp electrode monitoring. In each patient undergoing invasive monitoring, six to eight strip electrodes were implanted. The most common electrode placements included bilateral, 6-cm (four-contact) electrodes from lateral to medial under the temporal lobe and a 5-cm (four-contact) electrode placed anterior to posterior along the middle temporal gyms. Both medial and lateral electrodes were introduced through a temporal burr hole. In addition, bifrontal burr holes were made anterior to the coronal suture and just lateral to the m_idline. Through these holes four-contact electrodes were inserted down the interhemispheric fissure toward the corpus callosum and over the lateral frontal lobe. In some cases, a simpler frontal
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lobe examination was accomplished by deleting the frontal burr holes and sliding an eight-contact, 9-cm electrode over the lateral frontal cortex from the temporal burr hole. In all cases, electrodes were implanted bilaterally with attention made to positioning electrodes symmetrically. Immediately following surgery, patients had the electrode positions verified by CT. Generally, three seizures were recorded with invasive EEG procedures. All determinations as to the localization and lateralization of the ictal onset were made independently by the electroencephalographer, blinded to the results of the neuropsychological testing. Patients underwent intracarotid amytal testing to determine cerebral dominance for speech (Blume et al 1973). Both hemispheres were routinely tested i.l all patients. Individuals with anomalous organization of language function (e.g., bilateral speech, right hemisphere speech) were deleted from the subject pool. Patients underwent MRI imaging, and those individuals with underlying structural lesions (e.g., tumors, infarcts, AV malformations) were excluded from consideration. Additional subject inclusion criterion were WAIS-R Full Scale IQ of 70 or greater and a standard score of 70 or greater on the reading section of the Wide Range Achievement Test-Revised. The latter criteria insured that subjects had reading abilities adequate for completion of the self-report inventories. In summary, the final sample consisted of 64 consecutive nonretarded, left-hemispheredominant patients with intractable idiopathic (nonstructural) epilepsy of unilateral temporal lobe origin. Most of the patients (60 of 64) also experienced secondarily generalized seizures as well as complex partial seizures. The results of the EEG monitoring revealed that 26 patients had ictal onset from the left (dominant) temporal lobe, while 38 patients had ictal onset from the right (nondominant) temporal lobe.
Procedure All subjects were seen for neuropsychological evaluation, and for the purposes of this investigation five measures were relevant. Patients were administered the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Wechsler 1981), the Wisconsin Card Sorting Test (WCST) (Heaton 1981), the Beck Dep~sion Inventory (BDI) (Beck et al 1961), the Center for Epidemiological Studies Depression scale (CF.~-D) (Radloff 1977), and the Beck Anxiety Inventory (BAI) (Beck et al 1988b). Patients underwent nem'opsychological evaluation during the week of in-hospital scalp electrode monitoring. Patients were on significantly reduced amounts of their anticonvuisant medications at this time. There was no difference between the left and right temporal lobe groups in the types of medications prescribed, or the proportion on polytherapy. The WCST was administered and scored in accordance with the test manual with one exception. Subjects were allowed to make one unambiguous sort to the previous correct category before perseverative responses were counted. Unless a patient makes such a response there can be no knowledge that the category has changed, and perseverative responses may not h,. fact be perseverative. This alteration in scoring reflects a conservative approach to counting perseverative responses. Because the criteria for determining the presence of perseverative responses on the WCST can be complex, all test protocols were scored by two psychologists and any discrepancies were noted and resolved in accordance with the test manual. Three measures of mood state served as the dependent measures; the BDI, CES-D, and BAI. The BDI and CES-D are self-report indices of depressive symptoms. The BDI is a well-known and fiequently used clinical and research instrument that has been shown
e:oc PS'fCW~TRV
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Table 1. Means and Standard Deviations of Demographic, Cognitive. and Seizm'e Characteristics for the Left and Right TLE Groups~
Age Education Gender FSIQ WCST-CA WCST-PE WCST-PR Over 19 PR Age at seizure onset Duration of seizure disorder
Right Tt.e
Left Tt~
(n = 38)
(n = 26)
29.9 (9.5) 13.2 (2.5) 17 M, 21 F 92.'/(11.3) 4.8 (I.9) 17.9 (20.3) 21.7 (25.4) 20 (52%) 13.1 (10.0) 16.8 (11.5)
32.6 (11.0) 12.4 (2.3) 12 M, 14 F 88.4 (I 1.5) 4.5 (2°0) 18.9 (19.3) 21.8 (23.2) 9 (35%) 11.2 (9.3) 21.4 (! 1.8)
*Allps > 0.10.
to possess excellent psychometric qualities (Beck et al 1988a). The CES-D was developed by the Center for Epidemiological Studies of the National Institute of Mental Health. The scale is composed of 20 items that were deriv~ from other self-report inventories were selected to sample the major components of depressive symptomatology. Instructions ask the subject how often he or she experienced the symptoms (e.g., I felt sad) during the past week. Ratings are made on a 0-3 scale that varies in terms of the frequency of occurrence. Several studies have demonstrated good reliability and vali~ty characteristics fer this scale (Ensel 1986; Hertzog et al 1990; Radloff and Locke 1983; W e i s s ~ et al 1977). The BM is a 21-item self-report inventory developed to measure the severity of ~ e t y symptoms. The respondent is asked to rate how much he or she has been bothered by each symptom during the previous week on a 4-point scale. Items for the B ~ were specifically constructed to avoid confounding with depressive symptoms, and initial study of the instrument indicated good psychometric qualifies and oMy moderate correlation with measures of depression (Beck et al 1988b). The BAI was included in order to determine whether the obtained results were specific to depression, or were related to the presence of a more general dysphoric mood state.
Results Overall Le~ versus Right Temporal Lobe Comparisons Table 1 provides the means and standard deviations for the left and right temporal lobe groups on basic demographic characteristics including age, gender, and education, basic clinical seizure characteristics including age of onset and duration of disorder, and WAISR IQ scores and performance on several indices on the WCST. There were no s i ~ c a n t differences between the left and right temporal lobe groups on any of these demographic, clinical seizure, or cognitive status variables (a!!ps > 0.05). There were also no significant differences in the overall scores on the three mood state measures (BDI, CES-D, BAD between the left and right temporal lobe groups (Table 2). A large proportion of the temporal lobe patients in both groups performed beyond the traditional clinical cutoff point on the perseverative response index. Nine of 26 (35%)
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Table 2. Means and Standard Deviations for Self-Report Mood State Measures for the Left and Right TLE Groups ° Me~,su~ CES.D BDI
BAI
RiOt l].E (a = 38)
Left TLE (a = 26)
14.9 (10.3) 8.1 (8,4~" 9.1 (7.1) e
17.3 (13. !) 9.5 (?.6~ 10.5 (8.5Yr
"All ps > 0.30. q2ES.D : Center for Epidemiological S m d i e s - ~ i o n . BDI = Beck Depression Inventory. BAI = Beck Anxiety Index. cn = 37.
an = 25. "n = 25. sn = 25.
from the left temporal lobe group and 20 of 38 (52%) from the right temporal lobe group obtained 19 or more perseverative responses on the WCST, indicating a clinically significant perseverative tendency in a sizable proportion of both groups.
Predictors of Perseverative Behavior There were significant correlations between the number of perseverative respon.~s and several subject and demographic characteristics including education (r = - 0 . 2 8 , p < 0.05), Full Scale IQ (r = - 0 . 4 6 , p < 0.01), and duration of seizure disorder (r = 0.23, p < 0.05), but not with chronological age (r = 0.11, p > 0.05) or age of onset of seizures (r = - 0 . 1 6 , p > 0.05).
Relationship Between Dysphoric Mood and Perseverative Responding For the left TLE group, increased perseverative responses were associated with increased self-report of depressive and anxiety symptoms. In contrast, for the r i o t T I E group, increased perseverative responding showed a nonsi~ificant tendency to be associated with lowered self-report of symptoms on the mood measures. Figures 1-3 provide a graphic display of the interaction between laterality of seizure focus and WCST persev-
Figure 1. WCST perseverative responses and scores on
/
,e~,ol,,,
r ~. ..............................
"mJllJolmmoll,oa,
20
40
60
80
WCST Perseverations
the Center for Epidemiological Studies-Depression scale for left and right TLE groups. **, p < 0.01; -, left; .... , right.
al
100
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20
Figure 2. WCST perseverr~ive responses ~ ~ on Beck Depression Inventory fo~ left and fight TIE groups. *, p < 0.01; , left; - - , right. ......................
0
0
20
4O
60
80
100
WCST Perseverations
erative response tendency for the BDI, CES-D, and the BAI. For each ~ there is a marked increase in acknowledgment of symptoms with increased perseve~tive responses for the left TLE group, while the pattern is in the opposite direction for the fight TLE group. The means and standard deviations for the left and right temporal lobe groups on hie BDI, CES-D, and BAI are provided in Table 2. The identical pattern of results was found when using clinical cut-off points for the BDI (e.g., over 10 -- "depressed"). The overall proportion of patients scoring in depressed range was the same for the right (38%) and leR (36%) temporal lobe groups. There was again a significant interaction as BDI scores over I0 were associated ~ t h a significantly greater number of perseverative responses for the left but not the right temporal lobe group. General intellectual ability (WAIS-R Full Scale IQ) and duration of epilepsy were both significantly (p < 0.05) correlated with an increased number of perseverative responses on the WCST (r = - 0 . 4 6 and 0.23, respectively, ps < 0.05). Lower IQ and longer duration of epilepsy were associateM with increased perseverative responses. To determine whether the relationship between left temporal lobe epilepsy and dysphoric mood state were specific to WCST perseverative responses, rather than a reflection of general intellectual compromise and/or longer duration of epilepsy, the data were submired to a simultaneous multiple regression procedure. This permitted an examination of the unique variance associated with each of these variables in predicting scores on the mood state measures.
36
"U
27
¢..a
.o r-.
Figure 3. WCST perseverative responses and scores on Beck Anxiety Inventory for left and right TLE groups. *, p < 0.05; ~ , leR; .... , right.
18
< o
'" "......................................
9
0
20
40
60
80
WCST Perseverations
100
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Table 3. Results of Hierarchic~ Regression Analyses on the CES-D, BDI, and BAI° R2 CES-D Duration Main effects FSIQ x laterality WCST x laterality
Multiple R 2 0 .32b
0.01 0.09 0.00 0.17 b O.M b
BDI Duration Main effects FSIQ x laterality WCST x lammlity
0.06 O. !0 0.01 0.10 ~
BAI Duration Main effects FSIQ x laterality WCST x laterality
0.00 0.04 0.02 0.22 c
0.2~
aR2 for duration and main effects ~ | Q , WCST-PR, and la~mdity) ~ Ihe teed (unique + common) incmnmat in variance assessed by hierarchical blockwise entgy. R2 for each ~ term tepcresents its unique variance assessed by simultaneous entry into the regression equation after covaria~es and main effects. 'p < O.OOl. ~p < O.Ol. < o.o5.
Table 3 provides the results for the overall multiple R 2 (amount of total predicted variance) for each of the three mood state measures along with the amount of unique variance accounted for by each of the predictor terms in the regression analyses. For each of the self-report measures of mood state, the overall multiple R2 is statistically significant (all ps < 0.05). Of most interest, on/y the interaction term of the WCST perseverative responses and laterality of seizure focus predicted a significant amount of unique variance on the mood measures. All other predictor variables, including duration, laterality of seizure focus, full-scale IQ, and the interaction term between full-scale IQ and laterality of temporal lobe focus, failed to account for a statistically significant amount of unique variance for any of the self-report mood state measures.
Discussion In the present study, measures of global intellectual ability, perseverative response set, and self-report indices of mood state were administered to a group of patients with complex partial seizures of unilateral left or right temporal lobe origin. There were no overall differences between the gl"oups on any of the measures of depression and anxiety. As anticipated, there was an association between perseverative response set and the mood state measures. Self-reported mood state was determined by an interaction between WCST perseverative response tendency and the laterality of temporal lobe lesion. For patients with left temporal lobe epilepsy there was an increased report of depressive and anxiety symptomatology as a function of the severity of the perseverative response set. In contrast, for patients with right temporal lobe epilepsy, a nonsignificant tendency in the opposite direction was noted--increased perseverative responses were associated with lower endorsement of depression and anxiety. These effects were particularly prominent among
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the most perseverative patients (over 40 perseverative responses). Analyses that these findings remained significant when the effects of other potential c o n f ~ g variables (such as IQ, laterality of TLE, IQ by the laterality of TLE, and d u r " ~ of epilepsy) were also examined. The results were consistent across the three ~ t measures of mood state, which auests to the repficability of the effect. The finding that depression among patients with left temporal lobe epilepsy was associated with an increased perseverative response set, which is suggestive of increasing frontal lobe compromise, is consistent with recent findings from a variety of patient groups. Investigations of post-stroke depression have shown that among left hemisphere stroke patients the incidence and severity of depression is associated with the woximity of the lesion to the left frontal pole (Robinson et al 1983, 1984a, 1987). Although a recent replication attempt was not successful (House et al 1990), these same researcbers have reported a relationship between abnormal emotionalism ( ~ in tearfulness with episodes of crying that were unheralded and not under ~ social control) ~ the proximity of the lesion to the left frontal pole (House et ~ 1989). F~rthermore, two recent investigations of nonneurological patients ~ i ~ depressive disease found ~ glucose metabolism to be decreased in the left anterior prefrontal cortex (Baxter et al 1989; Martinot et al 1990). Therefore, the current findings, which are suggestive of frontal lobe dysfunction contributing to depression in left temporal lobe epilepsy, are consistent with the larger literature implicating frontal lobe involvement in dysphoric ~ state. The findings of the right TILE group are noteworthy for three reasons. First, there was no relationship between self-reported depression and perseverafive response set. M s finding is also consistent with the poststroke depression literature. Robinson and cofieagues reported that the incidence of depression among right hemisphere stroke patients was not associated with frontal involvement, but rather was associated with the distance of the lesion from the frontal pole (Robinson et al 1984a). Heller (1990) has recently discussed the evidence supporting the possibility of two distinct neural systems influencing mood state, a left frontal and a right posterior system. Recent PET investigations have identified right posterior hemisphere activation on select neuropsychological tasks of visual-spatial n! concomitants ability (Hannay et ~.1 1987). Fut&v~ investigation of the neurophysiolog,i~,,, of depression among right TLE patients with these neuropsychological measures may serve to provide additional information about the markers for mood state disruption in right temporal lobe epilepsy. Second, the findings among the right TLE group raise the issue of denial or unawareness of psychological status. Several investigators have reported an increased occurrence of unawareness of cognitive status among patients with right hemisphere focal lesions (McGlynn and Schachter 1989; Anderson and Tranel 1989). McGlynn and Schachter (1989) recently raised the possibility that frontal lobe dysfunction, particularly L¢ right sided, may play an important role in the occurrence of unawareness or underestimation of cognitive impairment among neurological populations. It is conceivable that a similar mechanism is operating at least for some of the subjects in the right TLE group. For example, within the current sample, all seven of the patients obtaining scores of 0 on the BDI were from the right TLE group. However, the current study cannot address the issue of accuracy a,~d awareness since all dependent measures were self-report indices. We are currently engaged in a study that includes measures of emotional status of TLE patients us~_ng ratings by professionals and family members, and this should provide data directly relevant to this point. Third, it should be remembered that there was no overall difference between the left
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and right temporal lobe groups L~.their self-repotted depression or anxiety. This finding is consistent with several previous reports (Hermann and Whitman 1989; Robcdson et al 1987; Trimble and Perez 1980) and would indicate that the presence of depression in temporal lobe epilepsy does not have lateralizing implications. However, within the left and right temporal lobe groups the determinants of self-reported depression appear to differ.
Perseverative Responding in Temporal Lobe Epilepsy Consistent with our previous report (Hermann et al 1988), a large proportion (44%) of patients with epilepsy of invasively verified temporal lobe origin exhibited a degree of perseverative responding on the WCST that fell beyond the tradit~omd c!~ic,~.l ,,u~,,,.."# point (i.e, over 19 perseverative responses). These fLndings therefore indicate that many patients with unilateral excitatory dysfunction of the temporal lobe, medial in most cases, exhibit a significant perseverative response set that has been traditionally considered to be suggestive of frontal lobe dysfunction. The mechanism responsible for this perseverative response set remains unclear. Several possibilities exist. For instance, deficits in executive function may be associated with (1) the spread of temporal lobe hypometabofism into the frontal region, (2) the nature and extent of interictal and/or ictal epileptogenic activity into the frontal lobe~ from the primary temporal lobe focus, (3) the spread of temporal lobe hypometabolism to the thalamus, secondarily affecting the frontal lobes, (4) an inability to activate the frontal regions for adequate WCST performance, or (5) some other reason. Determining the basis for traditional frontal-lobe-like abnormalities among patients with temporal lobe epilepsy remains a challenge for futare investigation. Inconsistent with our previous report is the lack of a laterality effect on the WCST. We previously found increased perseverative responding in the right temporal lobe group. Although the proportion of right temporal patients exceeding the clinical cutoff point exceeded that exhibited by the left temporal lobe group (52% versus 35%), the mean number of perseverative responses was not significantly different. The present investigation benefited from the fact that all petieats were candidates for surgical intervention and therefore underwent continuous 24-hr EF.~3/video monitoring of ictal activity. The vast majority of patients were monitored by invasive F~G procedures, so identification of the side and site of seizure onset was determined with a higher degree of precision than that offered by the interictal scalp EEG procedures that have been used ,,, aetelu,,,,~ ,atzr~tty of tcmporaJ moe focus in the majority of previous investigations.
Methodological Considerations The current findings need to be considered with several points in mind. First, only selfreport measures of depression were examined. Although these measures have shown acceptable overlap with diagnoses from more detailed psychiatric interviews, additional study with alternative diagnostic methods is needed. Further, the mean depression scores for the epilepsy patients were elevated relative to values typically obtained for normal controls, but were below those for patients diagnosed with major depressive disorders (Beck et al 1961; Beck et al 1988a). These observations, together with the fact that the results for the anxiety measure were identical to the depression findings, suggest that dysphoric mood state, rather than major depressive disorder per se, was the object of study.
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Second, some criticisms of the WCST as a measure of frontal lobe (pm~ulatly dorsolateral) function have been raised (Damasio 1985). Some patients with generaliz,.~l neuropathologies and focal but extrafrontal lobe lesions perform poorly on the WCST (Heaton 1981). It is not surprising that frontal lobe fimctions ~ay be ~ by a variety, of conditions given the widespread afferent input into the frontal regions ~ i o 1985; Stuss and Benson 1986). Although poor WCST performance may ~ be guomonic of a focal lesion in the frontal lobe, it may be indicative of compromised frontal lobe functional ability due either to a primary frontal lobe lesion or secondary disruption of the frontal lobe caused by compromise of its afferent network on which it is dependent, its neurochemical regulation, or other factors. WCST performance ~ dependent on activation of the dorsolateral prefrontal cortex as shown by FDG giucose metalmlism (We~:~berger et al 1986): ~nd the ability of that region to respond to challenge of the WCST may be compromised by other than primary frontal I o ~ !esCorts.
Implications for the Epilepsy-Psychopathology Literature As is widely appreciated, the relationship between interictal psychopathology and epilepsy, particularly temporal lobe epilepsy, has been a controversial topic (Stevens 1975). It is a common clinical observation that some patients with temporal lobe ep'depsy are relatively unaffected in the~- personality and behavioral functioning, whereas others present with frank psychiatric disorder or unusual symptomatology. As such, there has been considerable interest in identifying the additional risk factors that are responsible for increased psychiatric risk. Stevens has suggested that given the variability in psychiatric presentation among patients with temporal lobe epil~sy, the presence of some additional factor may account for the presence of emotional or behavioral disorder in affected patients (Robertson 1990; Stevens and Hermann 1981). We speculated previously that concomitant frontal lobe dysfunction may be one such risk factor (Hermann et al 1987), and the results of this investigation would support that perspective. However, issues of d e ~ of disorder, the accuracy of self-report ;z~ relation to observations of others, and the generalizability of these findings to persons with epilepsy in the community will need to be considered.
References Abou-Khalil BW, Siegel GJ, Sackellares JC, et al (1987): Positron emission tomo~aphy smaies of cerebral glucose metabolism in chronic partial epilepsy. Ann Neurol 22:480--486. Altshuler LL, Devinsky O, Post RM, Theodore W (1990): Depression, anxiety, and temporal lobe epilepsy: Laterality of focus and symptoms. Arch Neurol 47:284-288. Anderson SW, Tranel D (! 989): Awareness of disease states following cereb~J infarction, dementia, and head trauma. Clin Neuropsychol 3:327-339. Barclough BM (1987): The suicide rate of epilepsy. Acta Psychiatr Scand 76:339-345. Baxter L, Schwartz JM, Phelps M, et al (1989): Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 46:243-250. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh $ (1961): An inventory for measuring depression. Arch Gen Psychiatry 4:561-568. Beck AT, Steer RA, Gurbin MG (1988a): Psychometric properties of the B~k Depression Inventory: Twenty-five years of evaluation. Clin Psychol Rev 8:77-100. Beck AT, Epstein N, Brown G, Steer RA (1988b): An inventory for measuring clinical anxiety. J Consult Ciin Psychol 56:893-897.
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Betts TA (1981): Depression, anxiety ~ epilepsy. In Reynolds EH, Tfimble MR (eds), Epilepsy and Psychiatry. New York, Churchill Livingstone, pp 60-71. Blume WT, Grabow JD, Darley FL, et al (1973): Intracamtid amobarbital test of language and memory before temporal lobectomy for seizure control. Neuro/ogy 23:812-819. Currie S, Heathfield KWG, Henson RA, Scott DF (1971): Clinical course and prognosis of temporal lobe epilepsy: A survey of 666 ~ . Bm/n 94:173-190. Damasio AR (1985): The frontal lobes. In Heilman KM, Va!enstein E (¢ds), Clinical Neuropsychology. New York: Oxford University Press, pp 339--375. Dominian J, Serafetinides EA, Dewhurst M (1963): A follow-up study of late on~t epilepsy. Br Med J 1:43!-435. Drewe EA (1974): The effect of type and area of brain lesion on Wisconsin Card Sorting Test performance. Cortex 10:159-170. Edeh J, Toone BK, Corney RH (1990): Epilepsy, psychiatric morbidity, and social dysfunction in general practice. Neuropsychiatry Neuropsychol Behav Neurol 3:180-192. Engel ,~Jr (1990): The Hans Berger lecture: Functional explorations of the human brain and their therapeutic impfications. Electroencephulogr Clin Neurophysiol 76:296-316. Engel J Jr, Kuhl DE, Phelps M, Rausch R, Nuwer M (1983): Local cerebral metabolism during partial sei~res. N e o l o g y 33:400-413. Ensel WM (1986): Measuring depression: The CES-D scale. In Lin N, Dean A, Easel W (eds), Social Support, Life Events, and Depression. New York: Academic, pp 51-70. H ~ a y HJ, Falgout JC, Leli DA, Katholi CR, Halsey Jl-l, Willis EL (1987): Focal fight temporooccipital blood flow changes associated with judgment of line orientation. Neuropsychologia 25:755-763. Hauser WA, Hesdorffer DC (1990)- Epilepsy: Frequency, Causes and Consequences. New York: Demos Publications, 1990. Hawton K, Fagg J, Marsack P (1980): Association between epilepsy and attempted suicide. 1 Neurol Neurosurg Psychiatry 43:!68-170. Heaton RK ( 1981): Wisconsin Card Sorting Test. Odessa, FL: Psychological Assessment Resources. Heller W (1990): The neuropsychology of emotion: developmental patterns and implications for psychopathology. In Stein WL, Leventhal B, Trabasso T (eds), Psychological and Biological Approaches to Emotion. ~ s d a l e , NJ: Lawrence Erlbaum Associates. Hermann BP, Whitman S (1984): Behavioral and personality correlates of epilepsy: A review, methodological critique, and conceptual model. Psychol Bull 95:451-497. Hermann BP, Whitman S (1989): Psychosocial predictors of interictal depression. J Epilepsy 2:231237. Hermann BP, Wyler AR, Richey ET (1987): Epilepsy, frontal lobe, and personality. BiolPsychiatry 22:1055-1057. Hermann BP, Wyler AR, Richey ET (1988): Wisconsin Card Sorting Test performance in patients with complex partial seizures of temporal-lobe origin. J Clin Exp Neuropsychol 10:467-476. Hertzog C, Van Alstine J, Usala PD, Huitsch DF, Dixon R (1990): Measurement properties of the Center for Epidemiological Studies Depression Scale (CES-D) in older populations. Psychol Assess 2:64-72. House A, Dennis M, Molyneux A, Warlow C, Hawton K (1989): Emotionalism after stroke. Br Med J 298:991-994. House A, Dennis M, Warlow C, Hawton K, Molyneux A (1990): Mood disorders after stroke and their relation to lesion location: ACT scan study. Brain 1113-1129. Kendrick .IF, Gibbs FA (1958): Interrelations of mesial temporal and orbital frontal areas of man revealed by strychnine spikes. Arch Neurol Psychiatry 79:518-524. Kogeorgos J, Fonagy P, Scott DF (1982): Psychiatric symptom profiles of chronic epileptics attending a neurologic clinic: A controlled investigation. Br J Psychiatry 140:236-243.
Unilateral
TemporalLobe Epilepsy
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Lieb JP, Dashieff RM, Engel J Jr (1989): Role of frontal lobes in ptolg~ation of ~ originating in mesiotemporal regions. Epilepsia 30".664. Martinot J, Hardy P, Feline A, etal (1990): Left prefrontal glucose hypometabofism i n ~ ~ state: A confi:'mafion. Am J Psychiatry 147:1313-1317. Matthews WS, Barabas G (1981): Suicide and epilepsy: A review of the li,emmture.Psychosonmr/cs 22:515-524. Mayberg HS, Starkstein SE, Sadzot B, et al (1990): Selective hypometabolism in the inferior frot~l lobe in depressed patients with ~ , m o n ' s disease. Ann Neurol 28:57--64. McGlynn SM, Schachter DL (1989): Unawareness of deficits in nevaopsychological syndromes, j Clin Ezp Neuropsychol 11:143--205. Mendez MF, Cummings JL, Benson DF (1986): Depression in epilepsy. S i g n i f i ~ nomenology. Arch Neurol 43:766-770.
and phe-
Milner B (1963): Effects of "d~erent brain lesions on card sorting. Arch Neurol 9:90-100. Perini G, Mendius R (1984): Depression and anxiety in complex partial seizures. J Nerv Ment Dis 172:287-290. Radloff LS (1977): The CES-D scale: A self-report depression scale for research in the general population. Appl Psychol Measure 1:385--401. Radloff IS, Locke BZ (1983): The community mental health assessment sur,'ey ~ the CES-D scale. In Weissman MM, Meyers J, Ross CE (eds), Epidemiologic Commurdty Surveys. New York: Pmdist. Robertson MM (1989): The organic contribution to depressive illness in patients with epilepsy. J Epilepsy 2:189-230. Robertson MM (1990): Ictal and interictal depression in patients with epilepsy. In Trimb!e MR, Bolwig TG (eds), Aspects of Epilepsy and Psychiatry. New York: Wiley, pp 213-233. Robertson MM, Trimble MR, Townsend HRA (1987): Phenomenology of depression in epilepsy. Epilepsia 28:364-368. Robinson RG, Szetela B (1981): Mood changes following left hemispheric brain injury. Ann Neurol 9:447-453. Robinson AL, Heaton RK, Lehman RAW, Stilson DW (1980): The utility of the Wisconsin Card Sorting Test in detecting and localizing frontal lobe lesions. J Consult Clin Psychol 48:605614. Robinson RG, Start L, Kub¢~ KL, Price TR (1983): A two-year longitudinal study of poststroke mood disorders: Findings during the initial evaluation. Stroke 14:736-741. Robinson RG, Kubos KL, Start L, Rao K, Price TR (1984a): Mood disorders in stroke patients: Importance of lesion location. Brain 107:81-93. Robinson RG, Starr L, Lipsey JR, Rao K, Price TR (1984b): A two-year longitudinal study of poststroke mood disorders: Dynamic changes in associated variables over the first six months of follow-up. Stroke 15:510-517. Robinson RG, Bolduc PL, Price TR (1987): Two-year longitudinal study of poststroke mood disorders: Diagnosis and outcome at one and two years. Stroke 18:837-843. Roy A (1979): Some determinants of affective symptoms in epileptics. Can J Psychiatry 24:554556. Starkstein SE, Robinson RG, Price TR (1987): Comparison of cortical and subcortical lesions in the production of poststroke mode disorders. Brain 110:1045-1059. Stevens JR (1975): lnterictal clinical manifestations of complex partial se~ares. In Penry JK, Daly DD (eds), Advances in Neurology. New York: Raven. Stevens JR, Hermann BP (1981): Temporal lobe epilepsy, psychopathology, and violence: The state of the evidence. Neurology 31:1127-1132.
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Stuss DT, Benson DF (1986): The Fronta/Lobes. New York: Raven. Theodore WH, Newmark ME, Sato S, et al. (1983): ~ x y g l u c o s e positron emission tomography in refractory complex partial seizures. Ann Neurol 14:42°+,-437. Tomarken AJ, Davidson RJ, Henriques ~ (1990): Resting frontal brain asynunetry predicts affective responses to films. J Pets Sac Psycho159:791-801. Trimble MR, Perez MM (1980): Quantification of psychopadmlogy in adult patients with epilepsy. In Kulig BM, Meinardi H, Stores G (eds), EpiLepsy and Behm,ior '79. IAsse: Swets and Zeitlinger, pp 118-126. Tros~e JA, Hauser WA, Sharbrough FW (1989): Psychological ~ social adjustment to epilepsy in Rochester, Minnesota. Neurology 39:633-637. Wechsler D (1981): Wechsler Adult Intelligence Test---Revised Manual San Antonio, TX: The Psychological Corporation. Weinberger DR, Berman K, Zec RF (1986): Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. Arch Gen Psychiatry 43.'.!14-124. Weissman MM, Sholomskas D, Pottenger M, Pru~ff BA, Locke BZ (1977~,. Assessing depressive symptoms in five psychiatric populations: A validation study. Am J Epidemiol 106:203-214. Wyler AR, Ojemann G, Lettich E, Ward AA Jr (1984): SubduraI strip electrodes for localizing epileptogenic foci. J Neurosurg 60:1195-1200. Zielinski JJ (1974): Epilepsy and mortality rate and cause of death. Epilepsia 15:191-201. Zielinski JJ (1986): Selected psychiatric and psychosocial aspects of epilepsy as seen by an epidemiologist. ~ +Whitman S, Hermann BP (eds), Psychopathology in Epilepsy: Social Dimensions. New York: Oxford University Press, pp 38-65.
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Mood State in Unilateral Temporal Lobe Epilepsy Bruce P. Hermann, Michael Seidenberg, Alan Haltiner, and Allen R. Wyler
The purpose of this investigation was to reexamine the relationship between self-reported depression and laterality of temporal lobe epilepsy and to determine the contribution of associated frontal lobe dysfunc~'o~ ,n predisposing patients to depression. Sixty-four paiients ~th coraple~ p,~'iial 5cizure~ of left (n =- 26) or right (n - 38) temporal lobe origin were administered several self-report measures of mood state (Beck Depression Inventory, Centerfor Epidemiological Studies-Depression scale, Beck Anxiety Inventory), and a test of frontal lobe function [Wisconsin Card Sorting Test (WCST)I. There were no overall differences between the left and right temporal lobe groups on the measures of depression and anxiety. However, the left temporal lobe group exhibited a significant relationship between the degree of associated frontal lobe dysfunction (as indicated ~. increased perseverative responding on the WCST) and dysphoric mood state. For the right temporal lobe group there was a nonsignificant inverse relationship between mood state and indices of frontal lobe dysfunction. These results (1) are consistent with the broader psychiatric literature, which has implicated a relationship between depression and left frontal lobe dysfunction, (2) suggest that previous conflicting reports of depressionlleft temporal lobe epilepsy relationships are due in part to variations in the intactness of frontal lobe function, and (3) suggest that the presence of associated frontal lobe dysfunction may be a consideration in understanding interictal psychopathology in epilepsy.
Introduction Epilepsy is a disorder characterized b~ a s p e c ~ of severity, ran~,ng from ~ d and benign to severe and intractable (Hauser and Hesdorffer 1990). The risk of social psychological disability parallels this spectrum of severity (Edeh et al 1990; Trosfle et al 1989; Zielinski 1986). Research examining psychiatric illness among individu~ with epilepsy is typically conducted at facilities that treat patients from the more severe end of the epilepsy spectrum (Trostle et al 1989). These investigations have consistently reported depression to be a serious and cotnmon interictal psychiatric complication (Altshuler et al 1990; Betts 1981; Currie et al 1971; Dominian et al 1963; Herm~nn and Whitman 1989; Kogeorgos et al 1982; Mendez et al 1986; P e ~ and Mendius 1984;
From EpiCare Center, Baptist Memorial Hospital, Memphis, TN, Depatm~nts of P s y c ~ and Neurosurgery, University of Tennessee, Memphis, TN, Department of Psychology, University of Health Sciences, Chicago ~ School, North Chicago, IL, Semn-~,s-MurpheyClinic, Memphis, TN. Address reprint requests to: Bruce Hermann, Ph.D., EpiCare Center, 910 Madison Avenue, Suke 906, Memphis, TN 38103. Received January 24, 1991; revised June 27, 1991. © 1991 Society of Biological Psychiatry
0006-3223/911503.50
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Robertson 1989, 1990; Robertson et al 1987; Roy 1979). The significantly elevated mortality in epilepsy due to suicide underscores the seriousness of this psychiatric problem (Barclough 1987; Hawton et al 1980; Matthews and Baratnts 1981; Zielinski 1974). The determinants of interictal depression in epilepsy appear to be multifactorial, encompassing both neurobiological and psychosocial risk factors (Robertson 1990; Hermann and Whitman 1989). Among the potential neurobiological determinants, considerable interest has focused on the significance of the laterality of the interictal temporal lobe spike focus. Some investigations have reported increased depression among patients with a left temporal lobe spike focus (Altshuler et al 1990; Mendez et al 1986; Perini and Mendius 1984), while others have failed to confirm this laterality effect (Hetmann and Whitman 1989; Robertson et al 1987; Trimble and Perez 1980). Although several potential methodological and theoretical reasons might account for these discrepant findings, this investigation will present evidence suggesting that the presence of associated frontal lobe dysfunction interacts with the laterality of seizure focus in determining dysphoric mood state among patients with temporal lobe epilepsy. Converging neurophysiological evidence has indicated that there is pathological involvement of the frontal lobes in a significant proportion of patients with epilepsy of temporal lobe origin. Several findings bear on this point: (1) The area of interictal hypometabolism associated with epilepsy of temporal lobe origin may extend into extratemporal areas, particularly frontal and thalamic regions (Engel et al 1983; Theodore et al 1983; Engel 1990). (2) lntraoperative electrocorticography of patients undergoing anterior temporal lobectomy has revealed considerable epileptogenic activity in frontal lobe regions, which is thought to reflect propagated epileptiform activity from the mesial temporal lobe focus (Abou-Khalil et al 1987; Hermann et al 1988). (3) Invasive (depth electrode) EEG investigations have mapped the spreadof both interictal spikes (Kendrick and Gibbs 1958) and ictal activity (Lieb et al 1989) from the inesial teraporal region and have demonstrated preferential propagation to the medial and orbitofrontal regions (Lieb et al 1989). (4) Neuropsychological evidence of frontal lobe dysfunction (perseverative responding) has been identified in a sizable proportion of patients with temporal lobe epilepsy (Hermann et al 1988). Associated frontal lobe dysfunction among patients with complex partial seizures of unilateral mesial temporal lobe origin may be a significant determinant of depression and dysphoric mood state. Recent investigations of patients with mood disorders following stroke (Robinson and Szetela 1981; Robinson et al 1983, 1984a, 1984b; Starkstein et al 1987), FDG glucose utilization in nonneurological psychiatric patients with depressive illness (Baxter et al 1989; Martinot et al 1990), neurological patients with depressive illness (Mayberg et al 1990), and induction of positive and negative mood state in normal controls (Tomarken et al 1990) have all revealed an association between the degree or laterality of frontal lobe involvement and depressive symptomatology and dysphoric mood. Specifically, among patients with stroke, the frequency and severity of depression has been found to be associated with the proximity of the cortical or subcortical lesion to the left frontal pole (Robinson et al 1984a; Starkstein et al 1987). Reduced glucose metabolism has been found in the left anterior prefrontal cortex among psychiatric patients with major depressive disorder (Baxter et al 1989; Martinot et al 1990). We hypothesize that depression in left ten~poral lobe epilepsy may in part be attributable to the presence of associated frontal lobe dysfunction, and that the conflicting reports of depression and latera!ity of lesion in temporal lobe epilepsy may be due to uncontrolled variability in frontal lobe pathology.
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In this study the integrity of frontal lobe functioning is assessed by performance on a behavioral measure of executive functions, the Wisconsin Card Sorting Test. The capacity to plan, regulate, and self-monitor one's behavior in response to complex and changing environmental feedback is a basic component of the so-called executive functions. executive functions are considered to be among the highest of human cognitive abilities, and are thought to reflect the integrity of the prefrontal cortex (Stuss ~ Benson 1986). Although a variety of signs are considered to reflect a breakdown in these executive abilities, a particularly important marker is perseverative behavior (Stuss ~ Benson 1986). Among the various approaches to the assessment of perseverative behavior, Wisconsin Card Sorting Test (WCST) has been a particularly widely used instrument because it yields specific indices of perseverative behavior (Heaton 1981). Several investigators have found that patients with focal frontal lobe lesions produce s i ~ c a n t l y more perseverative responses than other brain lesion groups on the WCST (Drewe 1974; Milner 1963; Robinson et al 1980). In addition, a recent PET scan study involving normal controls demonstrated an_ association between activation of the dorsolateral prefrontal cortex and WCST performance (Weinberger et al !986). Given this neurophysiolo~cal confirmation of the dependence of WCST performance on prefrontal integrity, the degree of perseverative respending will serve as the ma.~er of associated frontal lobe pathology in the current study. In surnmary, the purpose of the present investigation is to examine the ~lations~p among laterality of temporal lobe lesion, perseverative response set, and self-reported depression in patients with unilateral temporal lobe epilepsy.
Method
Subjects Sixty-four consecutive patients over 16 years of age with intractable epilepsy of ~ a t e r a l temporal lobe origin served as sabjects. These individuals were referred to our epilepsy center because of medication-resistant epilepsy and consideration for suitability for surgical intervention. As such, they underwent intensive neurophysiological investigation, which permitted precise localization of their epileptogenic lesion. The presurgical workup included continuous (24-hr) closed circuit TV/EEG monitoring with scalp electrodes in order to record several of the patients" typical spontaneous seizures for classification of seizure type and preliminary localization of seizure onset. Of the 64 patients, 56 also underwent invasive EEG monitoring with subdural strip electrodes in order to provide precise localization of the epileptogenic lesion (Wyler et al 1984). The eight patients who did not undergo invasive EEG procedures had been determined by the electroencephalographer to show unequivocal localization of ,;eizure onset with scalp electrode monitoring. In each patient undergoing invasive monitoring, six to eight strip electrodes were implanted. The most common electrode placements included bilateral, 6-cm (four-contact) electrodes from lateral to medial under the temporal lobe and a 5-cm (four-contact) electrode placed anterior to posterior along the middle temporal gyms. Both medial and lateral electrodes were introduced through a temporal burr hole. In addition, bifrontal burr holes were made anterior to the coronal suture and just lateral to the m_idline. Through these holes four-contact electrodes were inserted down the interhemispheric fissure toward the corpus callosum and over the lateral frontal lobe. In some cases, a simpler frontal
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lobe examination was accomplished by deleting the frontal burr holes and sliding an eight-contact, 9-cm electrode over the lateral frontal cortex from the temporal burr hole. In all cases, electrodes were implanted bilaterally with attention made to positioning electrodes symmetrically. Immediately following surgery, patients had the electrode positions verified by CT. Generally, three seizures were recorded with invasive EEG procedures. All determinations as to the localization and lateralization of the ictal onset were made independently by the electroencephalographer, blinded to the results of the neuropsychological testing. Patients underwent intracarotid amytal testing to determine cerebral dominance for speech (Blume et al 1973). Both hemispheres were routinely tested i.l all patients. Individuals with anomalous organization of language function (e.g., bilateral speech, right hemisphere speech) were deleted from the subject pool. Patients underwent MRI imaging, and those individuals with underlying structural lesions (e.g., tumors, infarcts, AV malformations) were excluded from consideration. Additional subject inclusion criterion were WAIS-R Full Scale IQ of 70 or greater and a standard score of 70 or greater on the reading section of the Wide Range Achievement Test-Revised. The latter criteria insured that subjects had reading abilities adequate for completion of the self-report inventories. In summary, the final sample consisted of 64 consecutive nonretarded, left-hemispheredominant patients with intractable idiopathic (nonstructural) epilepsy of unilateral temporal lobe origin. Most of the patients (60 of 64) also experienced secondarily generalized seizures as well as complex partial seizures. The results of the EEG monitoring revealed that 26 patients had ictal onset from the left (dominant) temporal lobe, while 38 patients had ictal onset from the right (nondominant) temporal lobe.
Procedure All subjects were seen for neuropsychological evaluation, and for the purposes of this investigation five measures were relevant. Patients were administered the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (Wechsler 1981), the Wisconsin Card Sorting Test (WCST) (Heaton 1981), the Beck Dep~sion Inventory (BDI) (Beck et al 1961), the Center for Epidemiological Studies Depression scale (CF.~-D) (Radloff 1977), and the Beck Anxiety Inventory (BAI) (Beck et al 1988b). Patients underwent nem'opsychological evaluation during the week of in-hospital scalp electrode monitoring. Patients were on significantly reduced amounts of their anticonvuisant medications at this time. There was no difference between the left and right temporal lobe groups in the types of medications prescribed, or the proportion on polytherapy. The WCST was administered and scored in accordance with the test manual with one exception. Subjects were allowed to make one unambiguous sort to the previous correct category before perseverative responses were counted. Unless a patient makes such a response there can be no knowledge that the category has changed, and perseverative responses may not h,. fact be perseverative. This alteration in scoring reflects a conservative approach to counting perseverative responses. Because the criteria for determining the presence of perseverative responses on the WCST can be complex, all test protocols were scored by two psychologists and any discrepancies were noted and resolved in accordance with the test manual. Three measures of mood state served as the dependent measures; the BDI, CES-D, and BAI. The BDI and CES-D are self-report indices of depressive symptoms. The BDI is a well-known and fiequently used clinical and research instrument that has been shown
e:oc PS'fCW~TRV
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1~
Table 1. Means and Standard Deviations of Demographic, Cognitive. and Seizm'e Characteristics for the Left and Right TLE Groups~
Age Education Gender FSIQ WCST-CA WCST-PE WCST-PR Over 19 PR Age at seizure onset Duration of seizure disorder
Right Tt.e
Left Tt~
(n = 38)
(n = 26)
29.9 (9.5) 13.2 (2.5) 17 M, 21 F 92.'/(11.3) 4.8 (I.9) 17.9 (20.3) 21.7 (25.4) 20 (52%) 13.1 (10.0) 16.8 (11.5)
32.6 (11.0) 12.4 (2.3) 12 M, 14 F 88.4 (I 1.5) 4.5 (2°0) 18.9 (19.3) 21.8 (23.2) 9 (35%) 11.2 (9.3) 21.4 (! 1.8)
*Allps > 0.10.
to possess excellent psychometric qualities (Beck et al 1988a). The CES-D was developed by the Center for Epidemiological Studies of the National Institute of Mental Health. The scale is composed of 20 items that were deriv~ from other self-report inventories were selected to sample the major components of depressive symptomatology. Instructions ask the subject how often he or she experienced the symptoms (e.g., I felt sad) during the past week. Ratings are made on a 0-3 scale that varies in terms of the frequency of occurrence. Several studies have demonstrated good reliability and vali~ty characteristics fer this scale (Ensel 1986; Hertzog et al 1990; Radloff and Locke 1983; W e i s s ~ et al 1977). The BM is a 21-item self-report inventory developed to measure the severity of ~ e t y symptoms. The respondent is asked to rate how much he or she has been bothered by each symptom during the previous week on a 4-point scale. Items for the B ~ were specifically constructed to avoid confounding with depressive symptoms, and initial study of the instrument indicated good psychometric qualifies and oMy moderate correlation with measures of depression (Beck et al 1988b). The BAI was included in order to determine whether the obtained results were specific to depression, or were related to the presence of a more general dysphoric mood state.
Results Overall Le~ versus Right Temporal Lobe Comparisons Table 1 provides the means and standard deviations for the left and right temporal lobe groups on basic demographic characteristics including age, gender, and education, basic clinical seizure characteristics including age of onset and duration of disorder, and WAISR IQ scores and performance on several indices on the WCST. There were no s i ~ c a n t differences between the left and right temporal lobe groups on any of these demographic, clinical seizure, or cognitive status variables (a!!ps > 0.05). There were also no significant differences in the overall scores on the three mood state measures (BDI, CES-D, BAD between the left and right temporal lobe groups (Table 2). A large proportion of the temporal lobe patients in both groups performed beyond the traditional clinical cutoff point on the perseverative response index. Nine of 26 (35%)
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Table 2. Means and Standard Deviations for Self-Report Mood State Measures for the Left and Right TLE Groups ° Me~,su~ CES.D BDI
BAI
RiOt l].E (a = 38)
Left TLE (a = 26)
14.9 (10.3) 8.1 (8,4~" 9.1 (7.1) e
17.3 (13. !) 9.5 (?.6~ 10.5 (8.5Yr
"All ps > 0.30. q2ES.D : Center for Epidemiological S m d i e s - ~ i o n . BDI = Beck Depression Inventory. BAI = Beck Anxiety Index. cn = 37.
an = 25. "n = 25. sn = 25.
from the left temporal lobe group and 20 of 38 (52%) from the right temporal lobe group obtained 19 or more perseverative responses on the WCST, indicating a clinically significant perseverative tendency in a sizable proportion of both groups.
Predictors of Perseverative Behavior There were significant correlations between the number of perseverative respon.~s and several subject and demographic characteristics including education (r = - 0 . 2 8 , p < 0.05), Full Scale IQ (r = - 0 . 4 6 , p < 0.01), and duration of seizure disorder (r = 0.23, p < 0.05), but not with chronological age (r = 0.11, p > 0.05) or age of onset of seizures (r = - 0 . 1 6 , p > 0.05).
Relationship Between Dysphoric Mood and Perseverative Responding For the left TLE group, increased perseverative responses were associated with increased self-report of depressive and anxiety symptoms. In contrast, for the r i o t T I E group, increased perseverative responding showed a nonsi~ificant tendency to be associated with lowered self-report of symptoms on the mood measures. Figures 1-3 provide a graphic display of the interaction between laterality of seizure focus and WCST persev-
Figure 1. WCST perseverative responses and scores on
/
,e~,ol,,,
r ~. ..............................
"mJllJolmmoll,oa,
20
40
60
80
WCST Perseverations
the Center for Epidemiological Studies-Depression scale for left and right TLE groups. **, p < 0.01; -, left; .... , right.
al
100
atot. PsYCmAT~Y
Unilateral Temporal Lobe Epilepsy
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30
20
Figure 2. WCST perseverr~ive responses ~ ~ on Beck Depression Inventory fo~ left and fight TIE groups. *, p < 0.01; , left; - - , right. ......................
0
0
20
4O
60
80
100
WCST Perseverations
erative response tendency for the BDI, CES-D, and the BAI. For each ~ there is a marked increase in acknowledgment of symptoms with increased perseve~tive responses for the left TLE group, while the pattern is in the opposite direction for the fight TLE group. The means and standard deviations for the left and right temporal lobe groups on hie BDI, CES-D, and BAI are provided in Table 2. The identical pattern of results was found when using clinical cut-off points for the BDI (e.g., over 10 -- "depressed"). The overall proportion of patients scoring in depressed range was the same for the right (38%) and leR (36%) temporal lobe groups. There was again a significant interaction as BDI scores over I0 were associated ~ t h a significantly greater number of perseverative responses for the left but not the right temporal lobe group. General intellectual ability (WAIS-R Full Scale IQ) and duration of epilepsy were both significantly (p < 0.05) correlated with an increased number of perseverative responses on the WCST (r = - 0 . 4 6 and 0.23, respectively, ps < 0.05). Lower IQ and longer duration of epilepsy were associateM with increased perseverative responses. To determine whether the relationship between left temporal lobe epilepsy and dysphoric mood state were specific to WCST perseverative responses, rather than a reflection of general intellectual compromise and/or longer duration of epilepsy, the data were submired to a simultaneous multiple regression procedure. This permitted an examination of the unique variance associated with each of these variables in predicting scores on the mood state measures.
36
"U
27
¢..a
.o r-.
Figure 3. WCST perseverative responses and scores on Beck Anxiety Inventory for left and right TLE groups. *, p < 0.05; ~ , leR; .... , right.
18
< o
'" "......................................
9
0
20
40
60
80
WCST Perseverations
100
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BiOL PSYCHIATRY 1991;30:1205-1218
Table 3. Results of Hierarchic~ Regression Analyses on the CES-D, BDI, and BAI° R2 CES-D Duration Main effects FSIQ x laterality WCST x laterality
Multiple R 2 0 .32b
0.01 0.09 0.00 0.17 b O.M b
BDI Duration Main effects FSIQ x laterality WCST x lammlity
0.06 O. !0 0.01 0.10 ~
BAI Duration Main effects FSIQ x laterality WCST x laterality
0.00 0.04 0.02 0.22 c
0.2~
aR2 for duration and main effects ~ | Q , WCST-PR, and la~mdity) ~ Ihe teed (unique + common) incmnmat in variance assessed by hierarchical blockwise entgy. R2 for each ~ term tepcresents its unique variance assessed by simultaneous entry into the regression equation after covaria~es and main effects. 'p < O.OOl. ~p < O.Ol. < o.o5.
Table 3 provides the results for the overall multiple R 2 (amount of total predicted variance) for each of the three mood state measures along with the amount of unique variance accounted for by each of the predictor terms in the regression analyses. For each of the self-report measures of mood state, the overall multiple R2 is statistically significant (all ps < 0.05). Of most interest, on/y the interaction term of the WCST perseverative responses and laterality of seizure focus predicted a significant amount of unique variance on the mood measures. All other predictor variables, including duration, laterality of seizure focus, full-scale IQ, and the interaction term between full-scale IQ and laterality of temporal lobe focus, failed to account for a statistically significant amount of unique variance for any of the self-report mood state measures.
Discussion In the present study, measures of global intellectual ability, perseverative response set, and self-report indices of mood state were administered to a group of patients with complex partial seizures of unilateral left or right temporal lobe origin. There were no overall differences between the gl"oups on any of the measures of depression and anxiety. As anticipated, there was an association between perseverative response set and the mood state measures. Self-reported mood state was determined by an interaction between WCST perseverative response tendency and the laterality of temporal lobe lesion. For patients with left temporal lobe epilepsy there was an increased report of depressive and anxiety symptomatology as a function of the severity of the perseverative response set. In contrast, for patients with right temporal lobe epilepsy, a nonsignificant tendency in the opposite direction was noted--increased perseverative responses were associated with lower endorsement of depression and anxiety. These effects were particularly prominent among
Unilateral Temporal Lobe Epilepsy
atOLps¥cmAT~v 1991 ~0:A20~ | 21 $
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the most perseverative patients (over 40 perseverative responses). Analyses that these findings remained significant when the effects of other potential c o n f ~ g variables (such as IQ, laterality of TLE, IQ by the laterality of TLE, and d u r " ~ of epilepsy) were also examined. The results were consistent across the three ~ t measures of mood state, which auests to the repficability of the effect. The finding that depression among patients with left temporal lobe epilepsy was associated with an increased perseverative response set, which is suggestive of increasing frontal lobe compromise, is consistent with recent findings from a variety of patient groups. Investigations of post-stroke depression have shown that among left hemisphere stroke patients the incidence and severity of depression is associated with the woximity of the lesion to the left frontal pole (Robinson et al 1983, 1984a, 1987). Although a recent replication attempt was not successful (House et al 1990), these same researcbers have reported a relationship between abnormal emotionalism ( ~ in tearfulness with episodes of crying that were unheralded and not under ~ social control) ~ the proximity of the lesion to the left frontal pole (House et ~ 1989). F~rthermore, two recent investigations of nonneurological patients ~ i ~ depressive disease found ~ glucose metabolism to be decreased in the left anterior prefrontal cortex (Baxter et al 1989; Martinot et al 1990). Therefore, the current findings, which are suggestive of frontal lobe dysfunction contributing to depression in left temporal lobe epilepsy, are consistent with the larger literature implicating frontal lobe involvement in dysphoric ~ state. The findings of the right TILE group are noteworthy for three reasons. First, there was no relationship between self-reported depression and perseverafive response set. M s finding is also consistent with the poststroke depression literature. Robinson and cofieagues reported that the incidence of depression among right hemisphere stroke patients was not associated with frontal involvement, but rather was associated with the distance of the lesion from the frontal pole (Robinson et al 1984a). Heller (1990) has recently discussed the evidence supporting the possibility of two distinct neural systems influencing mood state, a left frontal and a right posterior system. Recent PET investigations have identified right posterior hemisphere activation on select neuropsychological tasks of visual-spatial n! concomitants ability (Hannay et ~.1 1987). Fut&v~ investigation of the neurophysiolog,i~,,, of depression among right TLE patients with these neuropsychological measures may serve to provide additional information about the markers for mood state disruption in right temporal lobe epilepsy. Second, the findings among the right TLE group raise the issue of denial or unawareness of psychological status. Several investigators have reported an increased occurrence of unawareness of cognitive status among patients with right hemisphere focal lesions (McGlynn and Schachter 1989; Anderson and Tranel 1989). McGlynn and Schachter (1989) recently raised the possibility that frontal lobe dysfunction, particularly L¢ right sided, may play an important role in the occurrence of unawareness or underestimation of cognitive impairment among neurological populations. It is conceivable that a similar mechanism is operating at least for some of the subjects in the right TLE group. For example, within the current sample, all seven of the patients obtaining scores of 0 on the BDI were from the right TLE group. However, the current study cannot address the issue of accuracy a,~d awareness since all dependent measures were self-report indices. We are currently engaged in a study that includes measures of emotional status of TLE patients us~_ng ratings by professionals and family members, and this should provide data directly relevant to this point. Third, it should be remembered that there was no overall difference between the left
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and right temporal lobe groups L~.their self-repotted depression or anxiety. This finding is consistent with several previous reports (Hermann and Whitman 1989; Robcdson et al 1987; Trimble and Perez 1980) and would indicate that the presence of depression in temporal lobe epilepsy does not have lateralizing implications. However, within the left and right temporal lobe groups the determinants of self-reported depression appear to differ.
Perseverative Responding in Temporal Lobe Epilepsy Consistent with our previous report (Hermann et al 1988), a large proportion (44%) of patients with epilepsy of invasively verified temporal lobe origin exhibited a degree of perseverative responding on the WCST that fell beyond the tradit~omd c!~ic,~.l ,,u~,,,.."# point (i.e, over 19 perseverative responses). These fLndings therefore indicate that many patients with unilateral excitatory dysfunction of the temporal lobe, medial in most cases, exhibit a significant perseverative response set that has been traditionally considered to be suggestive of frontal lobe dysfunction. The mechanism responsible for this perseverative response set remains unclear. Several possibilities exist. For instance, deficits in executive function may be associated with (1) the spread of temporal lobe hypometabofism into the frontal region, (2) the nature and extent of interictal and/or ictal epileptogenic activity into the frontal lobe~ from the primary temporal lobe focus, (3) the spread of temporal lobe hypometabolism to the thalamus, secondarily affecting the frontal lobes, (4) an inability to activate the frontal regions for adequate WCST performance, or (5) some other reason. Determining the basis for traditional frontal-lobe-like abnormalities among patients with temporal lobe epilepsy remains a challenge for futare investigation. Inconsistent with our previous report is the lack of a laterality effect on the WCST. We previously found increased perseverative responding in the right temporal lobe group. Although the proportion of right temporal patients exceeding the clinical cutoff point exceeded that exhibited by the left temporal lobe group (52% versus 35%), the mean number of perseverative responses was not significantly different. The present investigation benefited from the fact that all petieats were candidates for surgical intervention and therefore underwent continuous 24-hr EF.~3/video monitoring of ictal activity. The vast majority of patients were monitored by invasive F~G procedures, so identification of the side and site of seizure onset was determined with a higher degree of precision than that offered by the interictal scalp EEG procedures that have been used ,,, aetelu,,,,~ ,atzr~tty of tcmporaJ moe focus in the majority of previous investigations.
Methodological Considerations The current findings need to be considered with several points in mind. First, only selfreport measures of depression were examined. Although these measures have shown acceptable overlap with diagnoses from more detailed psychiatric interviews, additional study with alternative diagnostic methods is needed. Further, the mean depression scores for the epilepsy patients were elevated relative to values typically obtained for normal controls, but were below those for patients diagnosed with major depressive disorders (Beck et al 1961; Beck et al 1988a). These observations, together with the fact that the results for the anxiety measure were identical to the depression findings, suggest that dysphoric mood state, rather than major depressive disorder per se, was the object of study.
Unilateral Temporal Lobe Epilepsy
slot. ~tCmA"rR't 1991~30:1205-|2|8
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Second, some criticisms of the WCST as a measure of frontal lobe (pm~ulatly dorsolateral) function have been raised (Damasio 1985). Some patients with generaliz,.~l neuropathologies and focal but extrafrontal lobe lesions perform poorly on the WCST (Heaton 1981). It is not surprising that frontal lobe fimctions ~ay be ~ by a variety, of conditions given the widespread afferent input into the frontal regions ~ i o 1985; Stuss and Benson 1986). Although poor WCST performance may ~ be guomonic of a focal lesion in the frontal lobe, it may be indicative of compromised frontal lobe functional ability due either to a primary frontal lobe lesion or secondary disruption of the frontal lobe caused by compromise of its afferent network on which it is dependent, its neurochemical regulation, or other factors. WCST performance ~ dependent on activation of the dorsolateral prefrontal cortex as shown by FDG giucose metalmlism (We~:~berger et al 1986): ~nd the ability of that region to respond to challenge of the WCST may be compromised by other than primary frontal I o ~ !esCorts.
Implications for the Epilepsy-Psychopathology Literature As is widely appreciated, the relationship between interictal psychopathology and epilepsy, particularly temporal lobe epilepsy, has been a controversial topic (Stevens 1975). It is a common clinical observation that some patients with temporal lobe ep'depsy are relatively unaffected in the~- personality and behavioral functioning, whereas others present with frank psychiatric disorder or unusual symptomatology. As such, there has been considerable interest in identifying the additional risk factors that are responsible for increased psychiatric risk. Stevens has suggested that given the variability in psychiatric presentation among patients with temporal lobe epil~sy, the presence of some additional factor may account for the presence of emotional or behavioral disorder in affected patients (Robertson 1990; Stevens and Hermann 1981). We speculated previously that concomitant frontal lobe dysfunction may be one such risk factor (Hermann et al 1987), and the results of this investigation would support that perspective. However, issues of d e ~ of disorder, the accuracy of self-report ;z~ relation to observations of others, and the generalizability of these findings to persons with epilepsy in the community will need to be considered.
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