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Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy
Epilepsy & Behavior Epilepsy & Behavior 5 (2004) 522–531 www.elsevier.com/locate/yebeh
Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy Mario F. Dulay,a Bruce K. Schefft,a,b,* Jamison D. Fargo,a Michael D. Privitera,b and Hwa-shain Yehc a Department of Psychology, University of Cincinnati, Cincinnati, OH, USA Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH, USA Department of Neurosurgery, University of Cincinnati Medical Center, Cincinnati, OH, USA
b c
Received 29 December 2003; revised 14 April 2004; accepted 16 April 2004 Available online 25 May 2004
Abstract The relationship between severity of depressive symptoms and performance on three Wechsler Memory Scale-III auditory memory and learning subtests was examined in 84 inpatients diagnosed with medically intractable seizures of left (n ¼ 46, LTLE) or right (n ¼ 38, RTLE) temporal lobe origin. Depressive symptom severity was associated with auditory recall test performance in individuals with LTLE, but not RTLE. Multiple regression analyses indicated that severity of depressive symptoms, hippocampal sclerosis, and naming ability were significant predictors of auditory memory test performance in LTLE; however, hippocampal sclerosis was the only significant predictor of auditory memory in RTLE. Results demonstrate the importance of hippocampal sclerosis, greater self-report of depressive symptoms, and poor naming ability as independent predictors of poor auditory memory and learning abilities. Results suggest that a complex relationship exists among multiple risk factors that combine to influence performance on auditory memory tests as a function of side of seizure focus. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Auditory memory; Wechsler Memory Scale-III; Minnesota Multiphasic Personality Inventory-2; Temporal lobe epilepsy; Depression; Confrontation naming; Hippocampal sclerosis
1. Introduction Depression is the most common psychiatric disturbance diagnosed in individuals with epileptic seizures. In a review of the literature, Hermann and colleagues [1] found the prevalence of Diagnostic and Statistical Manual of Mental Disorders diagnosed major depression to be anywhere between 8 and 48% in patients with epilepsy. Others have reported the prevalence to be anywhere between 11 and 75% [2]. Problems with auditory–verbal memory and learning may contribute to frustration that promotes the existence of chronic depression [3,4]. Conversely, symptoms of depression associated with having a chronic seizure disorder may contribute to auditory memory and learning deficits * Corresponding author. Fax: 1-513-556-1904. E-mail address: scheff[email protected] (B.K. Schefft).
1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.04.007
[5]. Most of the knowledge that neurologists, psychiatrists, and neuropsychologists apply to patients with epilepsy when interpreting the impact of depression on cognition is from clinical research in patients without epilepsy. The impact of depression on auditory memory and learning abilities in depressed individuals without a comorbid neurologic disorder is well documented. Several studies indicate deficits in performance on measures of auditory memory in depressed patients compared with nondepressed controls. These studies report memory deficits in verbal material presented using word-list [6–9], verbal paired-associates [10–12], and story recall [13,14] formats. Results suggest that severity of depression is related to level of memory impairment. However, other studies report no performance differences between depressed patients and nondepressed controls on word-list [7,15], verbal
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paired-associates [16,17], and story recall [10,18,19] tasks. Several studies have assessed the impact of symptoms of depression on auditory memory in patients that traditionally present in neurology clinics. Impairments have been reported in depressed individuals with AlzheimerÕs disease [20–23], multiple sclerosis [24], ParkinsonÕs disease [25,26], stroke [27], and traumatic brain injury [19,28]. Results suggest that greater severity of depression is associated with poorer memory abilities over and above impairment associated with the neurologic condition. Fewer studies have assessed the relationship between level of depression and auditory memory and learning abilities in individuals diagnosed with epileptic seizures; these studies have yielded mixed results [29–33]. Three studies indicated that increased self-report of symptoms of depression was associated with diminished immediate and delayed auditory memory test performance [29–31]; however, other studies found no relationship between depression and poor story recall [33] or recognition memory for words presented verbally [31,32]. Paradiso et al. [31] found that poor story recall ability existed in depressed patients with right temporal lobe epilepsy (RTLE) compared with nondepressed right temporal lobe epilepsy patients and found a similar, but nonsignificant, trend among left temporal lobe epilepsy (LTLE) patients with and without depression. Helmstaedter [30] reported finding a relationship between depressive symptom severity and verbal learning, but only for left temporal lobe epilepsy patients with left temporolateral pathology and left frontal lobe epilepsy. These studies constitute the sum of research performed that assessed the relationship between severity of depressive symptoms and objective auditory memory test performance in patients with epilepsy. Because of these disparate findings, as well as the paucity of research, questions remain regarding whether a relationship exists between depression and auditory memory in individuals with epileptic seizures. The present study assessed the relationship between severity of depressive symptoms and level of auditory memory and learning test performance using subtests from the Wechsler Memory Scale-III (WMS-III) in adults with epileptic seizures of right (RTLE) and left (LTLE) temporal lobe origin [34]. Specific questions addressed included the following: (1) Is performance on the WMS-III auditory memory subtests related to severity of depressive symptoms in patients with epilepsy and, if so, does this relationship differ as a function of side of seizure focus? (2) In comparison with other known predictors of memory ability (e.g., attention ability, naming ability, hippocampal sclerosis), how well does the Minnesota Multiphasic Personality Inventory (MMPI)-defined level of depression predict auditory memory and learning abilities?
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2. Method 2.1. Participants This study represents a retrospective analysis of cross-sectional data collected from a series of consecutive patients who were evaluated for epilepsy surgery at a large university hospital. Eighty-four patients diagnosed with medically intractable epileptic seizures of unilateral temporal lobe origin (46 LTLE, 38 RTLE) were assessed. Seizure lateralization and localization were confirmed on concordance of ictal video/EEG monitoring and MRI findings, with subdural grid or electrode placement in some cases, independent of the neuropsychological evaluation. At least three seizures were typically recorded over a period lasting about a week. Sixty-one percent of the patients were diagnosed with complex partial seizures, 29% with simple partial seizures, and 10% with partial seizures evolving to secondary generalized seizures. Intracarotid sodium amobarbital (Wada) with or without electrocortical mapping data was available on 78% of the patients: 96.2% were left hemisphere language dominant and 3.8% were right hemisphere language dominant. Demographic information and medical history were collected through chart review and self-report during patient interviews. Lifetime history of a diagnosis of depression was based on patient self-report of a previous history of psychotherapeutic or pharmacological treatment for a mood disorder. No patient reported a history of bipolar disorder. All patients were included in the study if they met the following criteria: (a) a Wechsler Adult Intelligence Scale—Revised (WAIS-R) Full Scale Intelligence Quotient >70 [35]; (b) age >17; (c) a valid MMPI or MMPI2 profile [36]; (d) absence of comorbid psychogenic nonepileptic seizures [37]. This resulted in the exclusion of 22 patients. Magnetic resonance images were obtained by the primary neurologist of each patient for investigation of epilepsy etiology. Thirty-two patients were identified as having hippocampal sclerosis (HS+) on MRI, 30 patients were identified as having abnormal findings in addition to or other than HS on MRI (e.g., giant cisterna magna, arteriovenous malformations, meningioma, hippocampal asymmetry with no determination of sclerosis), and 22 patients were identified as being within normal limits on MRI (HS)). Magnetic resonance images were obtained using different devices (0.5, 1.0 and 1.5 T) in different centers. Neuroradiologists, who were blinded to clinical information, interpreted the images. A high-resolution brain epilepsy protocol was followed for all cases. This included sagittal fast-spin echo T2 sequencing, coronal 3D T1 sequencing pre- and postcontrast, and oblique-coronal fluid-attenuated inversion recovery (FLAIR), in addition to axial FLAIR fast-spin echo T2 sequencing and diffusion-weighted imaging
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through the brain. Following contrast, T1-weighted axial, sagittal, and coronal images were also obtained. The diagnostic criteria for HS+ were as follows: (a) asymmetry of the hippocampal formations by visual inspection of the images, and (b) exhibition of increased T2-weighted and FLAIR signal intensity or abnormal enhancement in the hippocampal formations. Volumetric hippocampal measures were not performed in this study. 2.2. Materials All patients received the Logical Memory I (from this point on referred to as immediate story recall), Logical Memory II (delayed story recall; 25- to 35-minute delay), Verbal Paired Associates I (immediate paired-associates recall), Verbal Paired Associates II (delayed paired-associates recall; 25- to 35-minute delay), Word Lists Total (word-list learning; total number of words recalled across four trials), Word Lists II (word-list delayed recall; 25- to 35-minute delay), and Word Lists Recognition Memory (recognition memory) subtests of the WMS-III [34]. In addition, the Auditory Immediate Index (immediate recall index) was calculated by combining the immediate story recall and immediate paired-associates recall scaled scores and converting the information to quotients based on published norms [38]. The Auditory Delayed Index (delayed recall index) was calculated in a similar manner using delayed story recall and delayed paired-associates recall. Other neuropsychological tasks included the Information, Digit Span, Arithmetic, Similarities, Picture Arrangement, Block Design, and Digit Symbol subtests of the WAIS-R [35] and the Boston Naming Test [39]. All tests were administered as part of a larger neuropsychological evaluation and were administered following standardized procedures. The seven WAIS-R subtests were used to generate estimated Intelligence Quotients (Verbal Intelligence Quotient, Performance Intelligence Quotient, Attention/Concentration Deviation Quotient, and Full Scale Intelligence Quotient) based on methods documented elsewhere [40]. Level of severity of depressive symptoms was quantified using the Depression scale of the MMPI or MMPI-2 [41,42]. In 1999, we switched from the MMPI to the MMPI-2. Thus, MMPI scaled scores were converted to MMPI-2 norms [43]. As noted above, patients were excluded if they had an invalid profile. An invalid profile was defined as the following: (a) an Infrequency scale raw score minus a Correction scale raw score of >15 or (b) a Lie scale T score greater than 65. A Depression T score 65 and greater is conventionally used to signify the presence of clinically significant signs of a possible mood disorder. True or false statements from the Depression scale of the MMPI-2 that are indicative of Diagnostic and Statistical Manual of Mental Disorders
(DSM) criteria for a mood disorder reflect the presence of anhedonia, feeling sad, weight loss or gain, loss of sleep or too much sleep, psychomotor agitation or retardation, loss of energy, low self-worth, poor attention or concentration abilities, and feelings of guilt. Previous research indicates that there is acceptable correspondence between the MMPI-2 Depression scale and DSM-diagnosed major depressive disorder and dysthymia [44–47]. Further, recent research suggests that chronic symptoms associated with clinical depression in individuals with epilepsy are validly and reliably screened using the MMPI and MMPI-2 [48,49]. 2.3. Statistical analyses First, a review of the assumptions, demographic data, and seizure data are presented. One-way ANOVAs and v2 analyses were performed to assess possible betweengroup differences on the demographic, seizure, and neuropsychological data. Next, Pearson product-moment correlations between the MMPI-2 Depression scale and the WMS-III auditory memory subtests were calculated for (a) the entire sample, (b) LTLE patients, and (c) RTLE patients. Third, multiple regression analyses were conducted to determine the predictive utility of seizure (seizure frequency, number of antiepileptic medications), cognitive (attention, naming), and mood state (depression) variables in accounting for variance in memory test performance (using the immediate and delayed recall composite indices) for (a) the entire sample, (b) LTLE patients, and (c) RTLE patients. Naming and attentional abilities were included as predictor variables in the regression analyses based on the finding that naming ability is a moderator of auditory memory ability in patients with temporal lobe epilepsy [50], and that poor naming [51] and attentional abilities [52,53] are related to elevated symptoms of depression. Further, seizure frequency and polytherapy are related to memory test performance [54,55]. Fourth, two regression analyses were performed on the smaller sample of individuals with hippocampal sclerosis (HS+, n ¼ 32) and with MRI within normal limits (HS), n ¼ 22) to assess the predictive utility of the presence or absence of hippocampal sclerosis compared with the other predictor variables. Individuals with abnormal magnetic resonance images other than hippocampal sclerosis were excluded from these analyses. The presence or absence of hippocampal sclerosis was used as a predictor variable based on previous research that found that the presence of sclerosis is related to an increased rate of depression [56] and is a predictor of poor auditory memory test performance in individuals with temporal lobe epilepsy [57,58]. Given its biological and theoretical importance, hippocampal sclerosis (HS+, HS)) was entered into block 1 of the regression analysis using the Enter function found on SPSS 10.0. Then, all
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of the other criterion variables found to be significant predictors (in the third analysis) were simultaneously entered into block 2 using the Enter function. Performing the regression analysis in this manner amounted to determining the extent to which other variables predict memory test performance after controlling for the variance in memory test performance associated with the presence or absence of hippocampal sclerosis. Raw scores were used for all analyses. Importantly, age-corrected scaled scores were subsequently used for all analyses (not reported here), with results indicating a similar pattern of findings. A P value of 0.01 was used to define all significant findings to reduce the likelihood of reporting false positives. Adjusted R2 was used to interpret the multiple regression analyses.
3. Results 3.1. Assumptions and descriptive statistics No missing data were encountered. No out of range values, skewed or kurtotic distributions, or outliers were encountered. Table 1 displays the means, standard deviations, and percentages for the demographic, seizure, psychiatric history, and MMPI-2 Depression scale data divided by side of seizure focus. A one-way ANOVA and v2 analyses indicated no significant between-group differences. Twelve of the twenty-three LTLE patients with an MMPI-2 Depression T score >65 had a prior diagnosis of depression. This was 86% of the LTLE patients (12/14) who reported a previous diagnosis of a mood disorder. Nine of the eighteen RTLE patients with an MMPI-2 Depression T score >65 had a prior
Table 1 Demographic, seizure-related, psychiatric history, and MMPI-2 depression scale information divided by side of seizure focusa LTLE (n ¼ 46)
Age Education (years) Age at onset Duration of illness (years) Seizure frequencyb No. of AEDS Sex (male/female) History of depressionc Prior hospitalizationd Depression T score >65e a
RTLE (n ¼ 38)
M
SD
M
39.0 12.2 22.1 16.9 28.2 01.8
10.8 02.8 15.6 14.3 41.2 01.0
38.9 12.6 23.6 14.4 22.9 01.8
16/30 30.4% 13.0% 50.0%
SD 11.4 02.3 14.8 12.7 32.6 00.7 17/21 31.6% 12.2% 47.4%
LTLE, left temporal lobe epilepsy; RTLE, right temporal lobe epilepsy; AEDs, antiepileptic drugs. ANOVA and v2 indicated no significant between-group differences. b Number of seizures per month. c Lifetime diagnosis. d Previous hospitalization for any psychiatric treatment. e MMPI-2 Depression scale.
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diagnosis of depression. This was 75% of the RTLE patients (9/12) who reported a previous diagnosis of a mood disorder. A one-way ANOVA (LTLE, RTLE) was computed for all of the neuropsychological tests and the Depression scale. Results indicated significant between-group differences, with individuals with LTLE performing more poorly (see Table 2) on immediate paired-associates recall (F[1,83] ¼ 7.23, P ¼ 0:009), delayed pairedassociates recall (F[1,83] ¼ 6.04, P ¼ 0:01), word-list learning (F[1,83] ¼ 8.67, P ¼ 0:004), and the naming test (F[1,83] ¼ 9.22, P ¼ 0:003). Further, there was a trend toward significance as defined in the present study (P < 0:01) for the immediate memory index (F[1,83] ¼ 3.93, P ¼ 0:052) and the delayed memory index (F[1,83] ¼ 4.05, P ¼ 0:047). Another one-way ANOVA was conducted comparing the subsample of HS+ (n ¼ 32) to the HS) (n ¼ 22) patients on all of the memory tests and the Depression scale. Results indicated significant between-group differences, with HS+ patients performing more poorly, on immediate story recall (F[1,53] ¼ 12.89, P ¼ 0:001; HS+ mean ¼ 31.8, HS) mean ¼ 42.7); delayed story recall (F[1,53] ¼ 7.55, P ¼ 0:008; HS+ mean ¼ 16.7, HS) mean ¼ 23.6); the immediate memory index
Table 2 Neuropsychological data divided by side of seizure focusa LTLE
IQ measures WAIS-R FSIQ WAIS-R VIQ WAIS-R PIQ WAIS-R ACDQ WMS-III subtests LM I LM II VPA I VPA II WL II WL total Recognition AI AD BNT Depression T scoreb a
RTLE
Group differences
M
SD
M
SD
88.2 88.4 91.0 89.2
12.2 13.4 12.9 12.4
91.8 93.0 91.6 92.8
13.2 13.0 13.3 12.8
ns ns ns ns
34.6 18.6 15.2 04.9 05.5 28.7 21.9 90.9 91.0 45.9 65.7
12.4 09.3 08.4 02.7 03.3 07.3 02.7 17.8 17.0 11.1 14.9
38.1 21.6 19.9 06.2 06.5 33.1 22.7 98.5 97.9 51.8 62.6
11.2 09.3 07.4 02.1 03.4 06.3 01.8 17.2 15.1 05.3 12.4
ns ns P ¼ 0:009 P ¼ 0:010 ns P ¼ 0:004 ns P ¼ 0:052 P ¼ 0:047 P ¼ 0:003 ns
LTLE, left temporal lobe epilepsy; RTLE, right temporal lobe epilepsy; WAIS-R, Wechsler Adult Intelligence Scale—Revised; FSIQ, Full Scale Intelligence Quotient; VIQ, Verbal Intelligence Quotient; PIQ, Performance Intelligence Quotient; ACDQ, Attention/Concentration Deviation Quotient; WMS-III, Wechsler Memory Scale III; LM, Logical Memory; VPA, Verbal Paired Associates; WL, Word Lists; WL total, total for trials 1–4; Recognition, WL Recognition Memory Test; AI, Auditory Immediate Index; AD, Auditory Delayed Index; I, immediate recall; II, delayed recall; BNT, Boston Naming Test. b MMPI-2 Depression scale.
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(F[1,53] ¼ 12.15, P ¼ 0:001; HS+ mean ¼ 86.8, HS) mean ¼ 102.2); and the delayed memory index (F[1,53] ¼ 6.41, P ¼ 0:014; HS+ mean ¼ 88.4, HS) mean ¼ 99.4). Further, there was a trend on immediate pairedassociates recall (F[1,53] ¼ 5.72, P ¼ 0:020), delayed paired-associates recall (F[1,53] ¼ 3.84, P ¼ 0:055), naming ability (F[1,53] ¼ 3.23, P ¼ 0:078), and the Depression scale (F[1,53] ¼ 3.88, P ¼ 0:055). 3.2. Correlations Correlations between the Depression scale and the memory tests with the combined sample and groups divided by side of seizure focus are presented in Table 3. For the combined sample, all correlations between the Depression scale and the recall subtests were statistically significant (correlations between )0.25 and )0.45). The pattern of correlations changed when data were analyzed as a function of side of seizure focus. In patients
Table 3 Correlations between the MMPI-2 depression scale and WMS-IIIa
LM I LM II VPA I VPA II WL total WL II Recognition memory AI AD
Combined sample
LTLE
RTLE
)0.28 )0.29 )0.41 )0.45 )0.25 )0.26 )0.23 )0.35 )0.40
)0.50 )0.46 )0.57 )0.51 )0.35 )0.34 )0.15 )0.57 )0.56
)0.11 )0.01 )0.12 )0.32 )0.14 )0.03 )0.35 )0.02 )0.12
a LTLE, left temporal lobe epilepsy; RTLE, right temporal lobe epilepsy; LM, Logical Memory; VPA, Verbal Paired Associates; WL, Word Lists; WL total, total for trials 1–4; AI, Auditory Immediate Index; AD, Auditory Delayed Index; I, immediate recall; II, delayed recall. * Significant at P < 0:001. ** Significant at P < 0:01. *** Trend approaching significance at P < 0:05.
with LTLE, severity of depression was associated with performance on most of the WMS-III memory subtests. The only test that was not significant or did not approach significance was the recognition memory test. In each case, higher self-report levels of depression were associated with poorer performance on the memory tasks. In patients with RTLE, severity of depression approached significance only for the delayed paired-associates recall (r ¼ 0:32, P ¼ 0:054) and recognition memory subtests (r ¼ 0:35, P ¼ 0:033). Fig. 1 depicts the relationship between the MMPI-2 Depression scale and the immediate recall index with data points separated by side of seizure focus. 3.3. Predictors of memory test performance: total sample Multiple regression analyses were conducted to assess which variables (seizure frequency, number of antiepileptic medications used, attention, naming, and depression) best predict immediate and delayed recall test performance. In the combined sample, naming ability (17.0% of the variance, standardized b ¼ 0:424, P < 0:001) and depression (8.1% of the variance, standardized b ¼ 0:355, P ¼ 0:002) were significant predictors of immediate recall test performance, accounting for a total of 25.1% of the variance. Naming ability (21.7% of the variance, standardized b ¼ 0:476, P < 0:001) and depression (10.9% of the variance, standardized b ¼ 0:343, P < 0:001) were also significant predictors of delayed recall test performance, accounting for a total of 32.6% of the variance. The pattern of results changed when predictor analyses were conducted as a function of side of seizure focus. In patients with LTLE, depression (31.1%, standardized b ¼ 0:571, P < 0:001), and naming ability (11.2%, standardized b ¼ 0:355, P < 0:001) were significant predictors of immediate recall test performance, accounting for a total of 42.3% of the variance. Further, depression (29.3%, standardized b ¼ 0:556,
Fig. 1. Relationship between the MMPI-2 Depression scale and the Immediate Recall composite index with data points separated by side of seizure focus. Solid line, LTLE trend line; dotted line, RTLE trend line.
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Table 4 Predictors of auditory memory test performancea Criterion
Group
Predictor b
Immediate recall
g
Delayed recall
Adjusted R2 (%)
Standardized b
P value
Combined sample
Sclerosis Depressione Namingf
)0.435 )0.395 0.333
0.001 0.002 0.002 Total
18.9 14.6 10.2 43.7
LTLE
Sclerosis Depression Naming
)0.567 )0.492 0.374
0.001 0.003 0.005 Total
32.2 17.9 11.9 62.0
RTLE
Sclerosis
)0.351
0.01
12.3
Combined sample
Naming Sclerosis Depression
0.485 )0.331 )0.327
0.001 0.001 0.005 Total
21.1 11.0 10.0 42.1
LTLE
Sclerosis Naming Depression
)0.543 0.452 )0.400
0.001 0.004 0.007 Total
29.4 17.4 11.8 58.6
RTLE
Sclerosis
)0.392
0.01
15.2
c
d
a
LTLE, left temporal lobe epilepsy; RTLE ¼ right temporal lobe epilepsy. b Auditory Immediate Index of the Wechsler Memory Scale III. c Combined sample ¼ analyses included individuals regardless of side of seizure focus. d Sclerosis ¼ presence or absence of hippocampal sclerosis. e Depression ¼ MMPI-2 Depression scale. f Naming ¼ the Boston Naming Test. g Auditory Delayed.
P < 0:001) and naming ability (15.9%, standardized b ¼ 0:415, P < 0:001) were significant predictors of delayed recall test performance, accounting for a total of 45.2%. However, in patients with RTLE, number of antiepileptic medications used (19.8%, standardized b ¼ 0:469, P ¼ 0:003) and attentional ability (13.9%, standardized b ¼ 0:392, P ¼ 0:006) were significant predictors of immediate recall test performance, accounting for a total of 33.7% of the variance. Attentional ability was the only significant predictor of delayed recall test performance, accounting for 21.7% of the variance (standardized b ¼ 0:488, P < 0:001). Additional regression analyses were conducted replacing the MMPI-2 Depression scale with the presence or absence of a lifetime history of depression for all regression analyses. Results indicated that lifetime history of depression was not a significant predictor of auditory memory test performance in any of the analyses (e.g., all P values for standardized b values >0.70 for both immediate and delayed recall). 3.4. Predictors of memory test performance: samples with and without sclerosis Additional regression analyses were conducted by forcing presence or absence of hippocampal sclerosis into a model as the initial predictor variable. Then other
criterion variables (identified as important variables in the previous section) were entered simultaneously into a model (see Table 4). Analyses were conducted separately on data from the (a) combined sample and (b) by side of seizure focus. In the combined sample, hippocampal sclerosis, depression, and naming ability accounted for 43.7% of the variance in immediate recall test performance and a total of 42.1% of the variance in delayed recall test performance. In patients with LTLE, hippocampal sclerosis, depression, and naming ability accounted for a total of 62.0% of the variance in immediate recall test performance and a total of 58.6% of the variance in delayed recall test performance. In individuals with RTLE, sclerosis was the only significant predictor of immediate (12.3% of the variance) and delayed (15.2% of the variance) recall test performance.
4. Discussion The present study assessed the relationship between depressive symptom severity and level of WMS-III auditory memory and learning test performance in individuals with temporal lobe epilepsy. We extended the findings from previous research by simultaneously taking into consideration side of seizure focus, hippocampal sclerosis, naming ability, and depressive symptoms,
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and by including three different types of auditory memory and learning tests. Greater self-report of depressive symptoms was associated with poorer recall test performance; however, side of seizure focus moderated this relationship. Results demonstrate the importance of hippocampal sclerosis, greater self-report of depressive symptoms, and poor naming ability as independent predictors of poor auditory recall test performance. Results suggest that a complex relationship exists among multiple factors that combine to influence performance on auditory memory and learning tasks in individuals with temporal lobe epilepsy. Results indicated that assessing the relationship between depression severity and auditory memory without taking into account side of seizure focus leads to misleading results. Specifically, the correlations were all significant for the relationship between depression and recall ability for the combined temporal lobe epilepsy data; however, these correlations were artificially inflated because the relationships were actually stronger in the LTLE group (Table 3). For LTLE patients, greater self-report of depressive symptoms was associated with poorer test performance on most recall subtests. For RTLE patients, depression severity was not associated with test performance. Side of seizure focus also moderated what variables predicted recall test performance. Initially, without sclerosis in the prediction analysis, depression and naming ability were significant predictors of memory in patients with LTLE, and attention and number of medications were significant predictors in patients with RTLE. Including hippocampal sclerosis as a predictor variable revealed that it was significantly related to memory test performance in both TLE groups separately. Interestingly, attention and number of medications were no longer significant predictors of memory test performance in individuals with RTLE after sclerosis was entered into the prediction model. Results are consonant with other studies that have reported a relationship between depression severity and auditory memory and learning abilities in patients with epileptic seizures [29–31]. Results of our study are also consistent with research that indicated that depressed patients with a left side stroke perform more poorly on measures of neuropsychological functioning compared with nondepressed patients with a left or right side stroke or depressed patients with a right side stroke [59,60]. Interestingly, recent research found that negative symptoms usually associated with patients with schizophrenia (e.g., affective flattening and avolition) exist in a subset of patients with temporal lobe epilepsy and that these symptoms have a detrimental impact on performance on WMS-III auditory memory and learning subtests [61]. The relationship between depressive symptoms, a focal neurologic condition, and cognitive functioning is a complex process impacted by multiple factors that requires further research to better under-
stand the causal directions of the moderators involved [62,63]. Hippocampal sclerosis was the strongest and most consistent predictor of recall ability regardless of side of seizure focus (Table 4). This finding was supported by the between-group comparisons that revealed that patients with hippocampal sclerosis performed more poorly on auditory memory tests compared with patients without sclerosis. These results are consonant with other studies that indicated that hippocampal sclerosis is associated with poorer auditory memory test performance [57,58,64–69]. In addition to memory impairment, Hermann et al. [58] found that individuals with hippocampal sclerosis performed more poorly on measures of academic achievement, intelligence, language, and visual–spatial functions compared with individuals without hippocampal sclerosis. Our results are consonant with the hypothesis that the hippocampus is important in the processing of episodic memories [70]. Naming ability accounted for variance in auditory memory ability above and beyond that predicted by hippocampal sclerosis and depression. These results are consonant with research that showed that word retrieval difficulties predict reduced memory test performance in patients with epilepsy [50,71,72]. In the present study, between-group comparisons indicated that naming ability was significantly poorer in patients with LTLE than in patients with RTLE, which is consonant with other studies e.g., [73]. Further, a trend approaching significance, with greater naming ability impairment in HS+ patients compared with HS) patients, could also be considered consistent with what others have found e.g., [58,74]. The presence of hippocampal sclerosis is associated with an increased degree of depressive symptoms in individuals with temporal lobe epilepsy, hypothesized to reflect a disruption in the limbic systemÕs role in the regulation of emotion and behavior [56,75–77]. In the present study, severity of depressive symptoms and memory (and, likewise, naming ability and memory) may not be directly related to each other, but rather may reflect a common relationship with the same underlying neuropathology (sclerosis). The relationship between depression and memory may also reflect the fact that individuals with hippocampal sclerosis often have an earlier age at onset of seizures, which is associated with greater cognitive impairments, long-term exposure to antiepileptic medications, and having to emotionally cope for a longer time with intractable seizures [58,78]. To some degree the relationship between depression and memory (as well as between naming and memory) may reflect a common association with sclerosis; however, the present studyÕs results also demonstrate the importance of hippocampal sclerosis, depressive symptom severity, and naming ability as independent predictors of auditory memory test performance.
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One hypothesis that can be used to explain the relationship between depression, naming, and auditory memory proposes that symptoms of depression influence expressive language abilities, which in turn impacts the retrieval of auditory memories. Though speculative, this relationship is probably bidirectional in that frustration associated with poor naming and memory abilities may also increase the likelihood of elevated symptoms of depression. Future research could better differentiate between the direction of these relationships by conducting prospective studies where the symptoms of depression are treated and memory test performance is evaluated before and after treatment [79], or where cognitive remediation is provided for a memory weakness and depression severity is assessed before and after treatment [80]. Further, language deficits could be remediated and the relationship between depression and memory could be evaluated before and after treatment [81,82]. Previous research has used the distinction between recognition memory deficits being suggestive of acquisition and consolidation problems (based on the need for adequate attention/encoding) and delayed recall deficits suggestive of retrieval difficulties, as well as poor acquisition/consolidation problems [82–85]. Using this paradigm to evaluate our results provides support for the hypothesis that retrieval is a mechanism involved with poor memory performance in depressed patients with LTLE [86,87]. This was based on the finding that intact recognition memory was not related to level of depression but that all of the delayed recall measures were to some degree related. Prediction analyses support this supposition because naming ability (which relies highly on the retrieval of lexical and semantic information) was also a significant predictor of memory test performance alongside level of depression. There were several limitations to the present study. First, we cannot say whether or not participants met the DSM diagnosis for a mood disorder at the time of testing. Different findings may result from separate DSM categories of depression, different self-report measures of depression, and different rating scales [82,88]. Of note, our sample of patients with epilepsy reported a similar level of depressive symptoms on the MMPI-2 compared with the only study to look at the relationship between memory and depression in individuals with epilepsy with a DSM diagnosis of major depression [31]. Further, cross-validation may be necessary given the moderate ‘‘variable to sample size’’ ratio (between 1:17 and 1:7 for different analyses). Future studies should also control for the impact of antidepressant medications. Research, however, suggests that clinically significant levels of depression are under recognized and undertreated in patients with medically intractable seizures. For example, even though Paradiso et al. [31] found that 36% of their sample was diagnosed
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with major depression, no patient was receiving psychotherapeutic or psychopharmaceutic treatment for a mood disorder prior to initial evaluation. Another issue was that several patients with LTLE reported low levels of depressive symptoms but performed poorly on auditory memory and learning tasks and there were patients who reported elevated levels of depressive symptoms and performed well on the auditory memory tasks (see Fig. 3). This suggests that it is important to look at patient strengths and weaknesses at an individual level and not rely solely on neuropsychological test results. Other factors such as a personÕs social support network, ability to use coping strategies, level of self-efficacy, and level of health-related quality of life are all possible moderators not controlled for in this study that could have added variability to the findings [73,89,90]. In conclusion, greater severity of depressive symptoms was associated with poorer memory and learning test performance in individuals with LTLE. Further, hippocampal sclerosis, depression, and naming ability were independent predictors of memory test performance, and the predictive utility of these variables differed as a function of side of seizure focus. Results of the present study suggest that a complex relationship exists among multiple factors that combine to influence performance on auditory memory and learning tests. Findings highlight the importance of taking into consideration level of depression and other factors when interpreting performance on auditory memory tests from individuals with temporal lobe epilepsy. Further study of the relationship between depression and memory will improve the accuracy of our assessment of the strengths, weaknesses, and needs of the depressed person with epileptic seizures, as well as lead to more effective treatment.
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Severity of depressive symptoms, hippocampal sclerosis, auditory memory, and side of seizure focus in temporal lobe epilepsy Mario F. Dulay,a Bruce K. Schefft,a,b,* Jamison D. Fargo,a Michael D. Privitera,b and Hwa-shain Yehc a Department of Psychology, University of Cincinnati, Cincinnati, OH, USA Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH, USA Department of Neurosurgery, University of Cincinnati Medical Center, Cincinnati, OH, USA
b c
Received 29 December 2003; revised 14 April 2004; accepted 16 April 2004 Available online 25 May 2004
Abstract The relationship between severity of depressive symptoms and performance on three Wechsler Memory Scale-III auditory memory and learning subtests was examined in 84 inpatients diagnosed with medically intractable seizures of left (n ¼ 46, LTLE) or right (n ¼ 38, RTLE) temporal lobe origin. Depressive symptom severity was associated with auditory recall test performance in individuals with LTLE, but not RTLE. Multiple regression analyses indicated that severity of depressive symptoms, hippocampal sclerosis, and naming ability were significant predictors of auditory memory test performance in LTLE; however, hippocampal sclerosis was the only significant predictor of auditory memory in RTLE. Results demonstrate the importance of hippocampal sclerosis, greater self-report of depressive symptoms, and poor naming ability as independent predictors of poor auditory memory and learning abilities. Results suggest that a complex relationship exists among multiple risk factors that combine to influence performance on auditory memory tests as a function of side of seizure focus. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Auditory memory; Wechsler Memory Scale-III; Minnesota Multiphasic Personality Inventory-2; Temporal lobe epilepsy; Depression; Confrontation naming; Hippocampal sclerosis
1. Introduction Depression is the most common psychiatric disturbance diagnosed in individuals with epileptic seizures. In a review of the literature, Hermann and colleagues [1] found the prevalence of Diagnostic and Statistical Manual of Mental Disorders diagnosed major depression to be anywhere between 8 and 48% in patients with epilepsy. Others have reported the prevalence to be anywhere between 11 and 75% [2]. Problems with auditory–verbal memory and learning may contribute to frustration that promotes the existence of chronic depression [3,4]. Conversely, symptoms of depression associated with having a chronic seizure disorder may contribute to auditory memory and learning deficits * Corresponding author. Fax: 1-513-556-1904. E-mail address: scheff[email protected] (B.K. Schefft).
1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.04.007
[5]. Most of the knowledge that neurologists, psychiatrists, and neuropsychologists apply to patients with epilepsy when interpreting the impact of depression on cognition is from clinical research in patients without epilepsy. The impact of depression on auditory memory and learning abilities in depressed individuals without a comorbid neurologic disorder is well documented. Several studies indicate deficits in performance on measures of auditory memory in depressed patients compared with nondepressed controls. These studies report memory deficits in verbal material presented using word-list [6–9], verbal paired-associates [10–12], and story recall [13,14] formats. Results suggest that severity of depression is related to level of memory impairment. However, other studies report no performance differences between depressed patients and nondepressed controls on word-list [7,15], verbal
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paired-associates [16,17], and story recall [10,18,19] tasks. Several studies have assessed the impact of symptoms of depression on auditory memory in patients that traditionally present in neurology clinics. Impairments have been reported in depressed individuals with AlzheimerÕs disease [20–23], multiple sclerosis [24], ParkinsonÕs disease [25,26], stroke [27], and traumatic brain injury [19,28]. Results suggest that greater severity of depression is associated with poorer memory abilities over and above impairment associated with the neurologic condition. Fewer studies have assessed the relationship between level of depression and auditory memory and learning abilities in individuals diagnosed with epileptic seizures; these studies have yielded mixed results [29–33]. Three studies indicated that increased self-report of symptoms of depression was associated with diminished immediate and delayed auditory memory test performance [29–31]; however, other studies found no relationship between depression and poor story recall [33] or recognition memory for words presented verbally [31,32]. Paradiso et al. [31] found that poor story recall ability existed in depressed patients with right temporal lobe epilepsy (RTLE) compared with nondepressed right temporal lobe epilepsy patients and found a similar, but nonsignificant, trend among left temporal lobe epilepsy (LTLE) patients with and without depression. Helmstaedter [30] reported finding a relationship between depressive symptom severity and verbal learning, but only for left temporal lobe epilepsy patients with left temporolateral pathology and left frontal lobe epilepsy. These studies constitute the sum of research performed that assessed the relationship between severity of depressive symptoms and objective auditory memory test performance in patients with epilepsy. Because of these disparate findings, as well as the paucity of research, questions remain regarding whether a relationship exists between depression and auditory memory in individuals with epileptic seizures. The present study assessed the relationship between severity of depressive symptoms and level of auditory memory and learning test performance using subtests from the Wechsler Memory Scale-III (WMS-III) in adults with epileptic seizures of right (RTLE) and left (LTLE) temporal lobe origin [34]. Specific questions addressed included the following: (1) Is performance on the WMS-III auditory memory subtests related to severity of depressive symptoms in patients with epilepsy and, if so, does this relationship differ as a function of side of seizure focus? (2) In comparison with other known predictors of memory ability (e.g., attention ability, naming ability, hippocampal sclerosis), how well does the Minnesota Multiphasic Personality Inventory (MMPI)-defined level of depression predict auditory memory and learning abilities?
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2. Method 2.1. Participants This study represents a retrospective analysis of cross-sectional data collected from a series of consecutive patients who were evaluated for epilepsy surgery at a large university hospital. Eighty-four patients diagnosed with medically intractable epileptic seizures of unilateral temporal lobe origin (46 LTLE, 38 RTLE) were assessed. Seizure lateralization and localization were confirmed on concordance of ictal video/EEG monitoring and MRI findings, with subdural grid or electrode placement in some cases, independent of the neuropsychological evaluation. At least three seizures were typically recorded over a period lasting about a week. Sixty-one percent of the patients were diagnosed with complex partial seizures, 29% with simple partial seizures, and 10% with partial seizures evolving to secondary generalized seizures. Intracarotid sodium amobarbital (Wada) with or without electrocortical mapping data was available on 78% of the patients: 96.2% were left hemisphere language dominant and 3.8% were right hemisphere language dominant. Demographic information and medical history were collected through chart review and self-report during patient interviews. Lifetime history of a diagnosis of depression was based on patient self-report of a previous history of psychotherapeutic or pharmacological treatment for a mood disorder. No patient reported a history of bipolar disorder. All patients were included in the study if they met the following criteria: (a) a Wechsler Adult Intelligence Scale—Revised (WAIS-R) Full Scale Intelligence Quotient >70 [35]; (b) age >17; (c) a valid MMPI or MMPI2 profile [36]; (d) absence of comorbid psychogenic nonepileptic seizures [37]. This resulted in the exclusion of 22 patients. Magnetic resonance images were obtained by the primary neurologist of each patient for investigation of epilepsy etiology. Thirty-two patients were identified as having hippocampal sclerosis (HS+) on MRI, 30 patients were identified as having abnormal findings in addition to or other than HS on MRI (e.g., giant cisterna magna, arteriovenous malformations, meningioma, hippocampal asymmetry with no determination of sclerosis), and 22 patients were identified as being within normal limits on MRI (HS)). Magnetic resonance images were obtained using different devices (0.5, 1.0 and 1.5 T) in different centers. Neuroradiologists, who were blinded to clinical information, interpreted the images. A high-resolution brain epilepsy protocol was followed for all cases. This included sagittal fast-spin echo T2 sequencing, coronal 3D T1 sequencing pre- and postcontrast, and oblique-coronal fluid-attenuated inversion recovery (FLAIR), in addition to axial FLAIR fast-spin echo T2 sequencing and diffusion-weighted imaging
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through the brain. Following contrast, T1-weighted axial, sagittal, and coronal images were also obtained. The diagnostic criteria for HS+ were as follows: (a) asymmetry of the hippocampal formations by visual inspection of the images, and (b) exhibition of increased T2-weighted and FLAIR signal intensity or abnormal enhancement in the hippocampal formations. Volumetric hippocampal measures were not performed in this study. 2.2. Materials All patients received the Logical Memory I (from this point on referred to as immediate story recall), Logical Memory II (delayed story recall; 25- to 35-minute delay), Verbal Paired Associates I (immediate paired-associates recall), Verbal Paired Associates II (delayed paired-associates recall; 25- to 35-minute delay), Word Lists Total (word-list learning; total number of words recalled across four trials), Word Lists II (word-list delayed recall; 25- to 35-minute delay), and Word Lists Recognition Memory (recognition memory) subtests of the WMS-III [34]. In addition, the Auditory Immediate Index (immediate recall index) was calculated by combining the immediate story recall and immediate paired-associates recall scaled scores and converting the information to quotients based on published norms [38]. The Auditory Delayed Index (delayed recall index) was calculated in a similar manner using delayed story recall and delayed paired-associates recall. Other neuropsychological tasks included the Information, Digit Span, Arithmetic, Similarities, Picture Arrangement, Block Design, and Digit Symbol subtests of the WAIS-R [35] and the Boston Naming Test [39]. All tests were administered as part of a larger neuropsychological evaluation and were administered following standardized procedures. The seven WAIS-R subtests were used to generate estimated Intelligence Quotients (Verbal Intelligence Quotient, Performance Intelligence Quotient, Attention/Concentration Deviation Quotient, and Full Scale Intelligence Quotient) based on methods documented elsewhere [40]. Level of severity of depressive symptoms was quantified using the Depression scale of the MMPI or MMPI-2 [41,42]. In 1999, we switched from the MMPI to the MMPI-2. Thus, MMPI scaled scores were converted to MMPI-2 norms [43]. As noted above, patients were excluded if they had an invalid profile. An invalid profile was defined as the following: (a) an Infrequency scale raw score minus a Correction scale raw score of >15 or (b) a Lie scale T score greater than 65. A Depression T score 65 and greater is conventionally used to signify the presence of clinically significant signs of a possible mood disorder. True or false statements from the Depression scale of the MMPI-2 that are indicative of Diagnostic and Statistical Manual of Mental Disorders
(DSM) criteria for a mood disorder reflect the presence of anhedonia, feeling sad, weight loss or gain, loss of sleep or too much sleep, psychomotor agitation or retardation, loss of energy, low self-worth, poor attention or concentration abilities, and feelings of guilt. Previous research indicates that there is acceptable correspondence between the MMPI-2 Depression scale and DSM-diagnosed major depressive disorder and dysthymia [44–47]. Further, recent research suggests that chronic symptoms associated with clinical depression in individuals with epilepsy are validly and reliably screened using the MMPI and MMPI-2 [48,49]. 2.3. Statistical analyses First, a review of the assumptions, demographic data, and seizure data are presented. One-way ANOVAs and v2 analyses were performed to assess possible betweengroup differences on the demographic, seizure, and neuropsychological data. Next, Pearson product-moment correlations between the MMPI-2 Depression scale and the WMS-III auditory memory subtests were calculated for (a) the entire sample, (b) LTLE patients, and (c) RTLE patients. Third, multiple regression analyses were conducted to determine the predictive utility of seizure (seizure frequency, number of antiepileptic medications), cognitive (attention, naming), and mood state (depression) variables in accounting for variance in memory test performance (using the immediate and delayed recall composite indices) for (a) the entire sample, (b) LTLE patients, and (c) RTLE patients. Naming and attentional abilities were included as predictor variables in the regression analyses based on the finding that naming ability is a moderator of auditory memory ability in patients with temporal lobe epilepsy [50], and that poor naming [51] and attentional abilities [52,53] are related to elevated symptoms of depression. Further, seizure frequency and polytherapy are related to memory test performance [54,55]. Fourth, two regression analyses were performed on the smaller sample of individuals with hippocampal sclerosis (HS+, n ¼ 32) and with MRI within normal limits (HS), n ¼ 22) to assess the predictive utility of the presence or absence of hippocampal sclerosis compared with the other predictor variables. Individuals with abnormal magnetic resonance images other than hippocampal sclerosis were excluded from these analyses. The presence or absence of hippocampal sclerosis was used as a predictor variable based on previous research that found that the presence of sclerosis is related to an increased rate of depression [56] and is a predictor of poor auditory memory test performance in individuals with temporal lobe epilepsy [57,58]. Given its biological and theoretical importance, hippocampal sclerosis (HS+, HS)) was entered into block 1 of the regression analysis using the Enter function found on SPSS 10.0. Then, all
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of the other criterion variables found to be significant predictors (in the third analysis) were simultaneously entered into block 2 using the Enter function. Performing the regression analysis in this manner amounted to determining the extent to which other variables predict memory test performance after controlling for the variance in memory test performance associated with the presence or absence of hippocampal sclerosis. Raw scores were used for all analyses. Importantly, age-corrected scaled scores were subsequently used for all analyses (not reported here), with results indicating a similar pattern of findings. A P value of 0.01 was used to define all significant findings to reduce the likelihood of reporting false positives. Adjusted R2 was used to interpret the multiple regression analyses.
3. Results 3.1. Assumptions and descriptive statistics No missing data were encountered. No out of range values, skewed or kurtotic distributions, or outliers were encountered. Table 1 displays the means, standard deviations, and percentages for the demographic, seizure, psychiatric history, and MMPI-2 Depression scale data divided by side of seizure focus. A one-way ANOVA and v2 analyses indicated no significant between-group differences. Twelve of the twenty-three LTLE patients with an MMPI-2 Depression T score >65 had a prior diagnosis of depression. This was 86% of the LTLE patients (12/14) who reported a previous diagnosis of a mood disorder. Nine of the eighteen RTLE patients with an MMPI-2 Depression T score >65 had a prior
Table 1 Demographic, seizure-related, psychiatric history, and MMPI-2 depression scale information divided by side of seizure focusa LTLE (n ¼ 46)
Age Education (years) Age at onset Duration of illness (years) Seizure frequencyb No. of AEDS Sex (male/female) History of depressionc Prior hospitalizationd Depression T score >65e a
RTLE (n ¼ 38)
M
SD
M
39.0 12.2 22.1 16.9 28.2 01.8
10.8 02.8 15.6 14.3 41.2 01.0
38.9 12.6 23.6 14.4 22.9 01.8
16/30 30.4% 13.0% 50.0%
SD 11.4 02.3 14.8 12.7 32.6 00.7 17/21 31.6% 12.2% 47.4%
LTLE, left temporal lobe epilepsy; RTLE, right temporal lobe epilepsy; AEDs, antiepileptic drugs. ANOVA and v2 indicated no significant between-group differences. b Number of seizures per month. c Lifetime diagnosis. d Previous hospitalization for any psychiatric treatment. e MMPI-2 Depression scale.
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diagnosis of depression. This was 75% of the RTLE patients (9/12) who reported a previous diagnosis of a mood disorder. A one-way ANOVA (LTLE, RTLE) was computed for all of the neuropsychological tests and the Depression scale. Results indicated significant between-group differences, with individuals with LTLE performing more poorly (see Table 2) on immediate paired-associates recall (F[1,83] ¼ 7.23, P ¼ 0:009), delayed pairedassociates recall (F[1,83] ¼ 6.04, P ¼ 0:01), word-list learning (F[1,83] ¼ 8.67, P ¼ 0:004), and the naming test (F[1,83] ¼ 9.22, P ¼ 0:003). Further, there was a trend toward significance as defined in the present study (P < 0:01) for the immediate memory index (F[1,83] ¼ 3.93, P ¼ 0:052) and the delayed memory index (F[1,83] ¼ 4.05, P ¼ 0:047). Another one-way ANOVA was conducted comparing the subsample of HS+ (n ¼ 32) to the HS) (n ¼ 22) patients on all of the memory tests and the Depression scale. Results indicated significant between-group differences, with HS+ patients performing more poorly, on immediate story recall (F[1,53] ¼ 12.89, P ¼ 0:001; HS+ mean ¼ 31.8, HS) mean ¼ 42.7); delayed story recall (F[1,53] ¼ 7.55, P ¼ 0:008; HS+ mean ¼ 16.7, HS) mean ¼ 23.6); the immediate memory index
Table 2 Neuropsychological data divided by side of seizure focusa LTLE
IQ measures WAIS-R FSIQ WAIS-R VIQ WAIS-R PIQ WAIS-R ACDQ WMS-III subtests LM I LM II VPA I VPA II WL II WL total Recognition AI AD BNT Depression T scoreb a
RTLE
Group differences
M
SD
M
SD
88.2 88.4 91.0 89.2
12.2 13.4 12.9 12.4
91.8 93.0 91.6 92.8
13.2 13.0 13.3 12.8
ns ns ns ns
34.6 18.6 15.2 04.9 05.5 28.7 21.9 90.9 91.0 45.9 65.7
12.4 09.3 08.4 02.7 03.3 07.3 02.7 17.8 17.0 11.1 14.9
38.1 21.6 19.9 06.2 06.5 33.1 22.7 98.5 97.9 51.8 62.6
11.2 09.3 07.4 02.1 03.4 06.3 01.8 17.2 15.1 05.3 12.4
ns ns P ¼ 0:009 P ¼ 0:010 ns P ¼ 0:004 ns P ¼ 0:052 P ¼ 0:047 P ¼ 0:003 ns
LTLE, left temporal lobe epilepsy; RTLE, right temporal lobe epilepsy; WAIS-R, Wechsler Adult Intelligence Scale—Revised; FSIQ, Full Scale Intelligence Quotient; VIQ, Verbal Intelligence Quotient; PIQ, Performance Intelligence Quotient; ACDQ, Attention/Concentration Deviation Quotient; WMS-III, Wechsler Memory Scale III; LM, Logical Memory; VPA, Verbal Paired Associates; WL, Word Lists; WL total, total for trials 1–4; Recognition, WL Recognition Memory Test; AI, Auditory Immediate Index; AD, Auditory Delayed Index; I, immediate recall; II, delayed recall; BNT, Boston Naming Test. b MMPI-2 Depression scale.
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(F[1,53] ¼ 12.15, P ¼ 0:001; HS+ mean ¼ 86.8, HS) mean ¼ 102.2); and the delayed memory index (F[1,53] ¼ 6.41, P ¼ 0:014; HS+ mean ¼ 88.4, HS) mean ¼ 99.4). Further, there was a trend on immediate pairedassociates recall (F[1,53] ¼ 5.72, P ¼ 0:020), delayed paired-associates recall (F[1,53] ¼ 3.84, P ¼ 0:055), naming ability (F[1,53] ¼ 3.23, P ¼ 0:078), and the Depression scale (F[1,53] ¼ 3.88, P ¼ 0:055). 3.2. Correlations Correlations between the Depression scale and the memory tests with the combined sample and groups divided by side of seizure focus are presented in Table 3. For the combined sample, all correlations between the Depression scale and the recall subtests were statistically significant (correlations between )0.25 and )0.45). The pattern of correlations changed when data were analyzed as a function of side of seizure focus. In patients
Table 3 Correlations between the MMPI-2 depression scale and WMS-IIIa
LM I LM II VPA I VPA II WL total WL II Recognition memory AI AD
Combined sample
LTLE
RTLE
)0.28 )0.29 )0.41 )0.45 )0.25 )0.26 )0.23 )0.35 )0.40
)0.50 )0.46 )0.57 )0.51 )0.35 )0.34 )0.15 )0.57 )0.56
)0.11 )0.01 )0.12 )0.32 )0.14 )0.03 )0.35 )0.02 )0.12
a LTLE, left temporal lobe epilepsy; RTLE, right temporal lobe epilepsy; LM, Logical Memory; VPA, Verbal Paired Associates; WL, Word Lists; WL total, total for trials 1–4; AI, Auditory Immediate Index; AD, Auditory Delayed Index; I, immediate recall; II, delayed recall. * Significant at P < 0:001. ** Significant at P < 0:01. *** Trend approaching significance at P < 0:05.
with LTLE, severity of depression was associated with performance on most of the WMS-III memory subtests. The only test that was not significant or did not approach significance was the recognition memory test. In each case, higher self-report levels of depression were associated with poorer performance on the memory tasks. In patients with RTLE, severity of depression approached significance only for the delayed paired-associates recall (r ¼ 0:32, P ¼ 0:054) and recognition memory subtests (r ¼ 0:35, P ¼ 0:033). Fig. 1 depicts the relationship between the MMPI-2 Depression scale and the immediate recall index with data points separated by side of seizure focus. 3.3. Predictors of memory test performance: total sample Multiple regression analyses were conducted to assess which variables (seizure frequency, number of antiepileptic medications used, attention, naming, and depression) best predict immediate and delayed recall test performance. In the combined sample, naming ability (17.0% of the variance, standardized b ¼ 0:424, P < 0:001) and depression (8.1% of the variance, standardized b ¼ 0:355, P ¼ 0:002) were significant predictors of immediate recall test performance, accounting for a total of 25.1% of the variance. Naming ability (21.7% of the variance, standardized b ¼ 0:476, P < 0:001) and depression (10.9% of the variance, standardized b ¼ 0:343, P < 0:001) were also significant predictors of delayed recall test performance, accounting for a total of 32.6% of the variance. The pattern of results changed when predictor analyses were conducted as a function of side of seizure focus. In patients with LTLE, depression (31.1%, standardized b ¼ 0:571, P < 0:001), and naming ability (11.2%, standardized b ¼ 0:355, P < 0:001) were significant predictors of immediate recall test performance, accounting for a total of 42.3% of the variance. Further, depression (29.3%, standardized b ¼ 0:556,
Fig. 1. Relationship between the MMPI-2 Depression scale and the Immediate Recall composite index with data points separated by side of seizure focus. Solid line, LTLE trend line; dotted line, RTLE trend line.
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Table 4 Predictors of auditory memory test performancea Criterion
Group
Predictor b
Immediate recall
g
Delayed recall
Adjusted R2 (%)
Standardized b
P value
Combined sample
Sclerosis Depressione Namingf
)0.435 )0.395 0.333
0.001 0.002 0.002 Total
18.9 14.6 10.2 43.7
LTLE
Sclerosis Depression Naming
)0.567 )0.492 0.374
0.001 0.003 0.005 Total
32.2 17.9 11.9 62.0
RTLE
Sclerosis
)0.351
0.01
12.3
Combined sample
Naming Sclerosis Depression
0.485 )0.331 )0.327
0.001 0.001 0.005 Total
21.1 11.0 10.0 42.1
LTLE
Sclerosis Naming Depression
)0.543 0.452 )0.400
0.001 0.004 0.007 Total
29.4 17.4 11.8 58.6
RTLE
Sclerosis
)0.392
0.01
15.2
c
d
a
LTLE, left temporal lobe epilepsy; RTLE ¼ right temporal lobe epilepsy. b Auditory Immediate Index of the Wechsler Memory Scale III. c Combined sample ¼ analyses included individuals regardless of side of seizure focus. d Sclerosis ¼ presence or absence of hippocampal sclerosis. e Depression ¼ MMPI-2 Depression scale. f Naming ¼ the Boston Naming Test. g Auditory Delayed.
P < 0:001) and naming ability (15.9%, standardized b ¼ 0:415, P < 0:001) were significant predictors of delayed recall test performance, accounting for a total of 45.2%. However, in patients with RTLE, number of antiepileptic medications used (19.8%, standardized b ¼ 0:469, P ¼ 0:003) and attentional ability (13.9%, standardized b ¼ 0:392, P ¼ 0:006) were significant predictors of immediate recall test performance, accounting for a total of 33.7% of the variance. Attentional ability was the only significant predictor of delayed recall test performance, accounting for 21.7% of the variance (standardized b ¼ 0:488, P < 0:001). Additional regression analyses were conducted replacing the MMPI-2 Depression scale with the presence or absence of a lifetime history of depression for all regression analyses. Results indicated that lifetime history of depression was not a significant predictor of auditory memory test performance in any of the analyses (e.g., all P values for standardized b values >0.70 for both immediate and delayed recall). 3.4. Predictors of memory test performance: samples with and without sclerosis Additional regression analyses were conducted by forcing presence or absence of hippocampal sclerosis into a model as the initial predictor variable. Then other
criterion variables (identified as important variables in the previous section) were entered simultaneously into a model (see Table 4). Analyses were conducted separately on data from the (a) combined sample and (b) by side of seizure focus. In the combined sample, hippocampal sclerosis, depression, and naming ability accounted for 43.7% of the variance in immediate recall test performance and a total of 42.1% of the variance in delayed recall test performance. In patients with LTLE, hippocampal sclerosis, depression, and naming ability accounted for a total of 62.0% of the variance in immediate recall test performance and a total of 58.6% of the variance in delayed recall test performance. In individuals with RTLE, sclerosis was the only significant predictor of immediate (12.3% of the variance) and delayed (15.2% of the variance) recall test performance.
4. Discussion The present study assessed the relationship between depressive symptom severity and level of WMS-III auditory memory and learning test performance in individuals with temporal lobe epilepsy. We extended the findings from previous research by simultaneously taking into consideration side of seizure focus, hippocampal sclerosis, naming ability, and depressive symptoms,
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and by including three different types of auditory memory and learning tests. Greater self-report of depressive symptoms was associated with poorer recall test performance; however, side of seizure focus moderated this relationship. Results demonstrate the importance of hippocampal sclerosis, greater self-report of depressive symptoms, and poor naming ability as independent predictors of poor auditory recall test performance. Results suggest that a complex relationship exists among multiple factors that combine to influence performance on auditory memory and learning tasks in individuals with temporal lobe epilepsy. Results indicated that assessing the relationship between depression severity and auditory memory without taking into account side of seizure focus leads to misleading results. Specifically, the correlations were all significant for the relationship between depression and recall ability for the combined temporal lobe epilepsy data; however, these correlations were artificially inflated because the relationships were actually stronger in the LTLE group (Table 3). For LTLE patients, greater self-report of depressive symptoms was associated with poorer test performance on most recall subtests. For RTLE patients, depression severity was not associated with test performance. Side of seizure focus also moderated what variables predicted recall test performance. Initially, without sclerosis in the prediction analysis, depression and naming ability were significant predictors of memory in patients with LTLE, and attention and number of medications were significant predictors in patients with RTLE. Including hippocampal sclerosis as a predictor variable revealed that it was significantly related to memory test performance in both TLE groups separately. Interestingly, attention and number of medications were no longer significant predictors of memory test performance in individuals with RTLE after sclerosis was entered into the prediction model. Results are consonant with other studies that have reported a relationship between depression severity and auditory memory and learning abilities in patients with epileptic seizures [29–31]. Results of our study are also consistent with research that indicated that depressed patients with a left side stroke perform more poorly on measures of neuropsychological functioning compared with nondepressed patients with a left or right side stroke or depressed patients with a right side stroke [59,60]. Interestingly, recent research found that negative symptoms usually associated with patients with schizophrenia (e.g., affective flattening and avolition) exist in a subset of patients with temporal lobe epilepsy and that these symptoms have a detrimental impact on performance on WMS-III auditory memory and learning subtests [61]. The relationship between depressive symptoms, a focal neurologic condition, and cognitive functioning is a complex process impacted by multiple factors that requires further research to better under-
stand the causal directions of the moderators involved [62,63]. Hippocampal sclerosis was the strongest and most consistent predictor of recall ability regardless of side of seizure focus (Table 4). This finding was supported by the between-group comparisons that revealed that patients with hippocampal sclerosis performed more poorly on auditory memory tests compared with patients without sclerosis. These results are consonant with other studies that indicated that hippocampal sclerosis is associated with poorer auditory memory test performance [57,58,64–69]. In addition to memory impairment, Hermann et al. [58] found that individuals with hippocampal sclerosis performed more poorly on measures of academic achievement, intelligence, language, and visual–spatial functions compared with individuals without hippocampal sclerosis. Our results are consonant with the hypothesis that the hippocampus is important in the processing of episodic memories [70]. Naming ability accounted for variance in auditory memory ability above and beyond that predicted by hippocampal sclerosis and depression. These results are consonant with research that showed that word retrieval difficulties predict reduced memory test performance in patients with epilepsy [50,71,72]. In the present study, between-group comparisons indicated that naming ability was significantly poorer in patients with LTLE than in patients with RTLE, which is consonant with other studies e.g., [73]. Further, a trend approaching significance, with greater naming ability impairment in HS+ patients compared with HS) patients, could also be considered consistent with what others have found e.g., [58,74]. The presence of hippocampal sclerosis is associated with an increased degree of depressive symptoms in individuals with temporal lobe epilepsy, hypothesized to reflect a disruption in the limbic systemÕs role in the regulation of emotion and behavior [56,75–77]. In the present study, severity of depressive symptoms and memory (and, likewise, naming ability and memory) may not be directly related to each other, but rather may reflect a common relationship with the same underlying neuropathology (sclerosis). The relationship between depression and memory may also reflect the fact that individuals with hippocampal sclerosis often have an earlier age at onset of seizures, which is associated with greater cognitive impairments, long-term exposure to antiepileptic medications, and having to emotionally cope for a longer time with intractable seizures [58,78]. To some degree the relationship between depression and memory (as well as between naming and memory) may reflect a common association with sclerosis; however, the present studyÕs results also demonstrate the importance of hippocampal sclerosis, depressive symptom severity, and naming ability as independent predictors of auditory memory test performance.
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One hypothesis that can be used to explain the relationship between depression, naming, and auditory memory proposes that symptoms of depression influence expressive language abilities, which in turn impacts the retrieval of auditory memories. Though speculative, this relationship is probably bidirectional in that frustration associated with poor naming and memory abilities may also increase the likelihood of elevated symptoms of depression. Future research could better differentiate between the direction of these relationships by conducting prospective studies where the symptoms of depression are treated and memory test performance is evaluated before and after treatment [79], or where cognitive remediation is provided for a memory weakness and depression severity is assessed before and after treatment [80]. Further, language deficits could be remediated and the relationship between depression and memory could be evaluated before and after treatment [81,82]. Previous research has used the distinction between recognition memory deficits being suggestive of acquisition and consolidation problems (based on the need for adequate attention/encoding) and delayed recall deficits suggestive of retrieval difficulties, as well as poor acquisition/consolidation problems [82–85]. Using this paradigm to evaluate our results provides support for the hypothesis that retrieval is a mechanism involved with poor memory performance in depressed patients with LTLE [86,87]. This was based on the finding that intact recognition memory was not related to level of depression but that all of the delayed recall measures were to some degree related. Prediction analyses support this supposition because naming ability (which relies highly on the retrieval of lexical and semantic information) was also a significant predictor of memory test performance alongside level of depression. There were several limitations to the present study. First, we cannot say whether or not participants met the DSM diagnosis for a mood disorder at the time of testing. Different findings may result from separate DSM categories of depression, different self-report measures of depression, and different rating scales [82,88]. Of note, our sample of patients with epilepsy reported a similar level of depressive symptoms on the MMPI-2 compared with the only study to look at the relationship between memory and depression in individuals with epilepsy with a DSM diagnosis of major depression [31]. Further, cross-validation may be necessary given the moderate ‘‘variable to sample size’’ ratio (between 1:17 and 1:7 for different analyses). Future studies should also control for the impact of antidepressant medications. Research, however, suggests that clinically significant levels of depression are under recognized and undertreated in patients with medically intractable seizures. For example, even though Paradiso et al. [31] found that 36% of their sample was diagnosed
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with major depression, no patient was receiving psychotherapeutic or psychopharmaceutic treatment for a mood disorder prior to initial evaluation. Another issue was that several patients with LTLE reported low levels of depressive symptoms but performed poorly on auditory memory and learning tasks and there were patients who reported elevated levels of depressive symptoms and performed well on the auditory memory tasks (see Fig. 3). This suggests that it is important to look at patient strengths and weaknesses at an individual level and not rely solely on neuropsychological test results. Other factors such as a personÕs social support network, ability to use coping strategies, level of self-efficacy, and level of health-related quality of life are all possible moderators not controlled for in this study that could have added variability to the findings [73,89,90]. In conclusion, greater severity of depressive symptoms was associated with poorer memory and learning test performance in individuals with LTLE. Further, hippocampal sclerosis, depression, and naming ability were independent predictors of memory test performance, and the predictive utility of these variables differed as a function of side of seizure focus. Results of the present study suggest that a complex relationship exists among multiple factors that combine to influence performance on auditory memory and learning tests. Findings highlight the importance of taking into consideration level of depression and other factors when interpreting performance on auditory memory tests from individuals with temporal lobe epilepsy. Further study of the relationship between depression and memory will improve the accuracy of our assessment of the strengths, weaknesses, and needs of the depressed person with epileptic seizures, as well as lead to more effective treatment.
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