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Psychopathological profile in patients with severe bilateral hippocampal atrophy and temporal lobe epilepsy: evidence in support of the Geschwind syndrome?
Epilepsy & Behavior Epilepsy & Behavior 4 (2003) 291–297 www.elsevier.com/locate/yebeh
Psychopathological profile in patients with severe bilateral hippocampal atrophy and temporal lobe epilepsy: evidence in support of the Geschwind syndrome? L. Tebartz van Elst,a,b E.S. Krishnamoorthy,a D. B€ aumer,a,b C. Selai,a A. von Gunten,a a b N. Gene-Cos, D. Ebert, and M.R. Trimblea,* a
Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK b Department of Psychiatry, Albert-Ludwigs-Universit€at, Freiburg, Germany Received 19 November 2002; revised 25 March 2003; accepted 25 March 2003
Abstract Bilateral symmetrical hippocampal atrophy (BHA) has been implicated as a possible causal element in various neuropsychiatric disorders, in particular depressive disorder and schizophrenia. To test the hypothesis that bilateral symmetrical severe volume loss of the hippocampi is of causal relevance to these psychiatric syndromes rather than an epiphenomenon we assessed the psychopathology in a group of patients with temporal lobe epilepsy (TLE) and very severe bilateral symmetrical hippocampal atrophy and compared it with that of a patient control group. Patients with TLE and hippocampal volumes smaller than three standard deviations below the mean of a control population were identified and compared with a matched patient population with normal hippocampal volumes. Psychopathology was assessed by blinded trained psychiatrists using the Present State Examination and Neurobehavioral Inventory. The prevalence of psychiatric syndromes was high in both patient groups; however, there was no significant difference between the two groups. With use of the more specific Neurobehavioral Inventory a psychopathological pattern reminiscent of the Geschwind syndrome emerged when patients with BHA were characterized by caregivers. While BHA does not result in an increased prevalence of specific psychiatric syndromes, specific symptoms that characterize the Geschwind syndrome like hypergraphia and hyposexuality might be pathogenically related to hippocampal atrophy. Ó 2003 Elsevier Science (USA). All rights reserved. Keywords: Epilepsy; Psychiatry; Geschwind syndrome; Hippocampus; Amygdala; Magnetic resonance imaging volumetry; Neuropsychiatry; Sexuality; Religiosity
1. Introduction Bilateral hippocampal volume loss has been related to different psychiatric disorders like major depressive disorder, posttraumatic stress disorder (PTSD), and schizophrenia [1–3]. In addition, amygdala volume abnormalities have been reported in different psychiatric disorders like depression [4] and schizophrenia [5] and in patients with temporal lobe epilepsy (TLE) associated with various psychiatric syndromes [6–8]. While it has been suggested that volume loss of the amygdala might be associated with hippocampal volume loss represent* Corresponding author. Fax: +44-20-7278-8772. E-mail address: [email protected] (M.R. Trimble).
ing two aspects of a broader pathogenic mechanism of mesial temporal lobe sclerosis, to our knowledge this hypothesis has not yet been tested systematically [9]. The causal relationship between the volumetric abnormalities of these mesial temporal lobe structures and the etiology and pathogenesis of the neuropsychiatric disorders described is not clear. So far only cross-sectional studies are published in the literature, suggesting that in particular bilateral hippocampal atrophy is associated with various psychiatric disorders, in particular affective disorders and schizophrenia. Thus, it remains unclear whether hippocampal volume loss is just a sequel of the given psychopathology possibly indicating chronic hypercortisolemia as one correlate of psychological stress [10] or, alternatively, may play a
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causal role in the development of the psychiatric syndrome. One possible way in which this relationship may be further investigated is by the study of patients with bilateral hippocampal atrophy, to see if the rate of psychopathology in this patient sample is increased compared with a control sample. However, while a link between hippocampal volume loss and generic psychopathology in epilepsy, depression for example, has been investigated, epilepsy-specific psychopathology, which might be closely linked to the epileptic process per se, has not been studied formally in relation to hippocampal volumes. As many patients with epilepsy are investigated at the Institute of Neurology, London, and the linked Centre for Epilepsy at Chalfont St. Peter, Buckinghamshire, and many of these patients display severe and sometimes bilateral atrophy of mesial temporal lobe structures and in particular the hippocampus, the opportunity for us to examine the role of severe bilateral hippocampal atrophy and psychopathology in epilepsy presented itself. The aim of this study was twofold: First, to test the hypothesis that the prevalence of psychiatric disorders like depression and schizophrenia is increased in patients with bilateral volume loss of the hippocampus we investigated the psychopathology of patients with TLE and very severe bilateral atrophy of the hippocampi and compared it with the psychopathology of a matched patient group with hippocampal volumes within the normal range. Second, to assess a possible association between amygdala and hippocampal volume loss, we measured the amygdala of both patient groups and looked for a possible association between amygdala volume abnormalities and psychopathology.
2. Methods 2.1. Patients and patient assessment Approval for this study was obtained from the ethics committee of the National Hospital for Neurology and Neurosurgery. Patients with TLE were recruited from the aforementioned tertiary referral centers. The clinical syndrome of interest was defined as complex partial seizures with semiology, EEG, and MRI findings compatible with TLE. Since 1995 all patients who had been diagnosed at the assessment unit of the Chalfont Centre received a volumetric assessment of the hippocampal volumes as part of the neuroradiological routine assessment. To obtain a very homogenous and well-defined study group we included only patients with very severe and bilateral hippocampal volume loss. Very severe hippocampal atrophy was defined as a hippocampal volume smaller than 3 SD below the mean of a
healthy population. Patients having been diagnosed as suffering from TLE who had very severe and bilateral hippocampal atrophy (BHA) were included in the study group. Patients with TLE and normal hippocampal volumes, i.e., volumes within the range of half a standard deviation above or below the mean, were randomly chosen as a control group. All patients had received a thorough neurological history and examination, as well as EEG investigations and neuropsychological investigations as part of the routine assessment. The diagnosis of TLE was made by expert consultant neurologists who were not involved in this study. We screened the records of all patients who had been diagnosed at the Chalfont Centre between 1995 and 1998 and included all those who met inclusion criteria for our study. Extratemporal or generalized epilepsy, temporal lobectomy, and an IQ lower than 70 served as exclusion criteria. We were in this way able to identify 33 patients with BHA. All these patients and a group of 34 matched control patients with TLE and normal hippocampal volume were contacted, and informed consent was obtained. Qualified neuropsychiatrists (E.S.K., A.v.G.) blinded to group assignment assessed all subjects, using the Present State Examination (PSE) component of the Schedules for Clinical Assessment in Neuropsychiatry, widely considered a gold standard in psychiatric research [11]. Clinical psychiatric diagnosis was made using ICD-10 criteria. In addition, all subjects and their named professional caregivers completed the Neurobehavioral Inventory [12]. The NBI is an expanded and revised version of the scale originally developed by Bear and Fedio [13] and consists of 100 items measuring behaviors and attitudes across 20 domains that are considered relevant to temporal lobe epilepsy. These include the behavioral triad of hyperreligiosity, hyposexuality, and hypergraphia, described by Geschwind as integral features of the syndrome that now carries his name. Other core features of this syndrome include emotional viscosity (stickiness), peculiar ethical concerns, and the proclivity to become angry on slight provocation [14]. True/false responses, for each of the 100 items, are expected, and each subscale is scored by adding up all the ‘‘true’’ responses. A score of 20 or more was chosen as the cutoff criterion. The instrument has been used extensively in tertiary care, and it is the only measure of TLE-specific behavior that is currently available. 2.2. Imaging and measurements MRI images were obtained at the Chalfont Centre for Epilepsy on a 1.5-T GE Signa Horizon scanner (GE Medical Systems, Milwaukee, WI, USA) using a T1-weighted inversion–recovery-prepared volume acquisition (IRSPGR:TI/TR/TE/flip ¼ 450/15/4.2/20; 124 1.5-mm-thick contiguous coronal slices; matrix 256 192,
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24 18-cm FOV). The hippocampal volumes had been measured as part of the routine assessment of patients with TLE at the Chalfont Centre. The reliability of this assessment has been demonstrated and published previously [15]. For quantification of amygdala volumes the images were transferred to a Sun workstation (Sun Microsystems, Mountain View, CA, USA) at the Neuroimaging Laboratory of the Psychiatric Department, University of Freiburg, Freiburg, Germany. Volumetric measurements of the amygdala were performed using the locally developed interactive software program MRreg [16]. Using this software the images were zoomed to a magnification of 4 to outline the amygdala and intensity windowing was set to a level of 80 and width of 140. The amygdala were outlined manually using a mouse-driven cursor following the established protocol described by Watson et al. [17]. The total brain volume was measured by manual segmentation of the cerebrum, cerebellum, midbrain, and pons excluding the rest of the brain stem. The volume of each structure in each slice (the in-slice volume) was calculated by multiplying the number of voxels contained within each trace by the voxel volume, 0:937 0:937 1:5 mm3 , and dividing by the magnification factor. The total volume of each structure was the sum of all in-slice volumes. Amygdala volumes were corrected for total brain size following Cendes et al. [18]. The images of 20 healthy controls were rated twice by one blinded scientist (D.B.) to establish intrarater reliability figures. 2.3. Data analysis Intrarater reliability was assessed by calculating an intraclass correlation coefficient as suggested by Streiner and Norman [19]. 2.3.1. Group comparisons To begin with we analyzed the homogeneity of the two patient groups with respect to age, sex, duration of epilepsy, frequency of seizures, incidence of febrile convulsions, encephalitis, head trauma, status epilepticus, and intelligence using independent-sample t tests and v2 tests. To test our hypotheses we then performed two major group comparisons. First, we compared the amygdala volumes of patients with TLE and bilateral very severe hippocampal atrophy to those with normal hippocampal volumes using independent-sample t tests. To assess the relationship between amygdala and hippocampal volumes we assessed the Pearson correlation between these two parametric variables. We then compared the prevalence of psychopathology between the two patient groups on two levels of complexity. We compared the prevalence of psychiatric diagnoses according to ICD-10 criteria based on PSE assessment. Since it is well known that patients with
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epilepsy often display psychopathological abnormalities that do not fulfill conventional criteria for psychiatric disorders [20,21], we then compared symptoms suggestive of epilepsy-specific psychopathology, based on the domains of the NBI scale. Since both methods of psychiatric assessment result in categorical data, i.e., the presence or absence of a given psychopathological symptom or syndrome, we analyzed these data using contingency tables. A P value of 0.05 was chosen as the criterion of significance. All data were analyzed using SPSS for Windows (Release 7.5.1).
3. Results 3.1. Reliability figures The intraclass correlation coefficient as calculated from repeated measurements of 20 data sets of healthy volunteers was 0.99 for the hippocampi and 0.88 for the amygdala. These compare well with figures published in the literature [6–8,17]. 3.2. Study group comparisons Table 1 summarizes the demographic and clinical findings of the study and control groups. Of the 33 patients with BHA and the 34 control patients we identified, 9 patients with BHA and 14 control patients respectively responded and were assessed by the psychiatrists. Both groups were matched with respect to age, sex, duration of epilepsy, and frequency of complex partial (CS) and secondary generalized (SG) seizures. There were no differences in terms of head trauma, febrile convulsions, and history of encephalitis. Interestingly a history of status epilepticus was increased in patients with bilateral severe hippocampal atrophy, who also had a significantly lower verbal and performance IQ. 3.3. Hippocampal and amygdala volumes The mean hippocampal and amygdala volumes of the two patient groups are summarized in Table 2. Hippocampal atrophy was the group defining criterion. Thus the respective volumes differ significantly. While amygdala volumes on the right-hand side were small both in the hippocampal atrophy group and in the patient control group, there was a significant group difference in left amygdala volume, with the atrophy group displaying smaller amygdalae (see Table 2). We found a significant correlation between hippocampal volumes on both sides and left amygdala volume (right hippocampus/left amygdala: Pearson correlation r ¼ 0:502; P ¼ 0:02; left hippocampus/left amygdala r ¼ 0:542; P ¼ 0:01), while there were no significant correlations between the right
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Table 1 Comparison of study and control groups with respect to demographic and clinical data
Age (years) Sex (female/male) Duration of epilepsy (years) Frequency of CP seizures/month Frequency of SG seizures/month History of encephalitis History of febrile convulsion History of status epilepticus Verbal IQ Performance IQ
TLE and BHAa (n ¼ 9)
TLE and NHV (n ¼ 14)
Significance
35 [7]b 2/7 27 [8] 6.4 [4.3] 1.3 [2.8] 4 3 3 87.6 [9.2] 90.7 [9.0]
40 [9] 7/7 20 [11] 11.6 [18.2] 1.2 [1.4] 2 2 0 98.5 [12.9] 106.8 [13.6]
NS NS NS NS NS NS NS
P 6 0:05, P 6 0:01, P 6 0:001; P values not corrected for multiple comparisons. BHA, bilateral hippocampal atrophy; NHV, normal hippocampal volumes. b SD in brackets. a
Table 2 Cerebral, hippocampal, and amygdala volumes
Total brain volume (cm3 ) Right hippocampal volume (cm3 ) Left hippocampal volume (cm3 ) Right/left ratio Right amygdala volume (cm3 ) Left amygdala volume (cm3 ) a
P 6 0:05, P 6 0:01, SD in brackets.
TLE and hippocampal atrophy
TLE with normal hippocampal volumes
Significance
1628.5 [146.4]a 1.69 [0.26] 1.53 [0.23] 1.1 [0.3] 1.47 [0.34] 1.45 [0.22]
1627.4 [99.1] 3.0 [0.11] 3.0 [0.08] 1.0 [0.03] 1.59 [0.22] 1.74 [0.26]
NS
3.4. Hippocampal atrophy and psychopathology Psychiatric ICD-10 diagnoses generated on the basis of the PSE are summarized for both study groups in Table 3. Overall psychopathology was very high in both patient groups; however, there were no significant differences between the two groups. Table 3 Psychiatric profile in patients with TLE with and without hippocampal atrophya
a
NS NS
P 6 0:001, P values not corrected for multiple comparisons.
amygdala volume and hippocampal volumes (right hippocampus/right amygdala r ¼ 0:164; P ¼ 0:48; left hippocampus/right amygdala r ¼ 0:278; P ¼ 0:22).
Depression OCD Anxiety and panic Somatoform disorder Eating disorder Mania Schizophrenia Other
TLE + HA (N ¼ 9)
TLE without HA (N ¼ 13)
6 0 3 0 1 0 2 3
7 1 5 1 0 0 5 4
Data are numbers of patients suffering from disorders listed (according to PSE). Numbers represent diagnoses and may add to more than the total number of patients due to comorbidity.
3.5. Epilepsy-specific psychopathology measured with the Neurobehavioral Inventory Tables 4A and 4B summarize our findings using the NBI. In the self-rating section of the NBI, the total score was significantly higher in patients with BHA. Significant differences were observed in a cluster of affective symptoms including emotions, fear, guilt, and sadness and regarding the items persistency and physical handicap. In accordance with the self-rating section, caregivers rated patients with BHA significantly higher in dependency. Furthermore there were significant differences in terms of an increased prevalence of hypergraphia and hyposexuality in this patient group.
4. Discussion In summary, our data do not support the hypothesis that BHA results in an increased prevalence of generic psychopathology, for example, depressive or schizophreniform disorders, in patients with TLE. However, we did find a link between BHA and epilepsy-specific psychopathology like affective symptoms in self-ratings and hyposexuality and hypergraphia in caregiver ratings. Based on our findings we cannot confirm the hypothesis that bilateral hippocampal atrophy renders
L. Tebartz van Elst et al. / Epilepsy & Behavior 4 (2003) 291–297 Table 4A Caregiver ratings of the neurobehavioral inventory NBI item
TLE + HA
Total score Cosmic Detail Dependency Destiny Emotions Fear Guilt Hatred Happiness Morals Order Persist Physical Religion Sadness Hyposexuality Serious Suspicion Temper Writing
6 1 7 7 2 1 3 2 1 2 6 5 6 2 1 2 6 1 0 4 7
P 6 0:05, P 6 0:01, multiple comparisons.
TLE + normal hippocampal volumes
Significance
5 1 6 2 1 5 3 3 2 3 6 4 7 6 2 5 3 4 3 7 1
P 6 0:001; P values not corrected for
Table 4B Self-ratings of the neurobehavioral inventory NBI item
TLE + HA
TLE + normal hippocampal volumes
Significance
Total score Cosmic Detail Dependency Destiny Emotions Fear Guilt Hatred Happiness Morals Order Persist Physical Religion Sadness Hyposexuality Serious Suspicion Temper Writing
9 5 8 8 7 8 8 7 5 4 4 8 8 8 5 6 7 6 5 3 7
8 4 9 6 6 6 5 3 4 5 8 7 5 5 3 3 10 8 3 8 6
P 6 0:05, P 6 0:01, multiple comparisons.
P 6 0:001; P values not corrected for
patients more vulnerable to the development of major depression or schizophreniform disorder. Psychopathology in general and depression in particular were very common findings in patients with TLE independent
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of whether they displayed bilateral hippocampal atrophy. Thus it might well be that bilateral hippocampal volume loss reported in psychiatric disorders like depression and schizophrenia is an epiphenomenon of the respective disorder, possibly indicating a state of chronically increased psychological stress [10,22]. On the other hand, BHA was associated with an increased prevalence of affective symptoms like fear, guilt, sadness, and physical symptoms in the self-rating of affected patients with TLE. Interestingly, when looking at the caregiver ratings apart from dependency there were particularly significant differences in hyposexuality and hypergraphia that distinguished patients with BHA from those without. These are symptoms of the Geschwind syndrome [23–25] a rather controversial personality syndrome in epilepsy. Geschwind and Waxman were the first to describe a specific set of personality alterations in epilepsy. In further studies a group of behavioral symptoms (i.e., circumstantiality; intensified preoccupations related to moral, philosophical, religious, or ethical themes; hyposexuality; and irritability) were identified and subsequently referred to as the Geschwind syndrome [14,26]. The existence of this syndrome as a specific personality disorder in epilepsy is not accepted unanimously and has led to considerable debate [27,28]. The evidence for its existence is largely empirical, and following Benson [14], the strongest support so far stems from the many clinicians who have described and attempted to manage patients with epilepsy and these personality features. The only other imaging study we could find that has shown an association between the hippocampus and aspects of the Geschwind syndrome is the case of Kumagasu Minakata, a Japanese genius devoted to natural history and folklore and famous for his immense range of works. Using MRI scans to study his postmortem brain, Murai et al. [29] found evidence of right hippocampal atrophy, which correlated with his history suggestive of temporal lobe epilepsy. Many features of the Geschwind syndrome (the tremendous number of articles; the tendency to write minuscule letters in compact space; the lack of interest in the opposite sex; peculiar ethical concerns; the proclivity to become angry on slight provocation; and notably his extraordinary interest in religious matters) were identified in a detailed study of his diaries. A number of limitations in this study have to be considered in discussing these findings. First, the number of subjects studied, particularly with respect to psychopathology, is rather small. However, to obtain a very homogenous study group we chose a very strict group-defining criterion, i.e., very severe and bilateral hippocampal atrophy. Of the 33 patients with BHA and the 34 control patients we identified, only 9 patients with BHA and 14 control patients respectively responded and were assessed by the psychiatrists. This small turnout
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was partly due to the rigid exclusion criteria we chose to adopt, and also because many of these patients who had been referred from all over the United Kingdom had moved house or did not respond for some other unknown reason. In mitigation, however, the resultant study group is very homogenous and unique, in that it is very difficult to study patients with such a severe bilateral atrophy of the hippocampi. In this study we did not correct for multiple comparisons. However, since psychopathology is measured using many different dimensions (8 for the PSE-generated ICD-10 diagnoses and 2 20 items for the NBI self- and caregiver ratings), many of which are overlapping (as, e.g., the dimensions sadness, emotion, fear, and guilt in the NBI), Bonferroni correction would have resulted in an overcorrection of the findings. At the same time this study is a pilot study in character and therefore we decided not to correct any finding for multiple comparison accepting that all significant results have to be reproduced in a further investigation. As there is a discrepancy between the self-ratings and the caregiver ratings on the NBI questionnaire one might question the validity of these findings. However, this discrepancy is not really surprising on a closer look. Most of the items rated high by patients with BHA and normal by caregivers are symptoms of subjective experience and are difficult for others to assess. On the other hand, caregivers picked up abnormal behavior like hyposexuality or hypergraphia. While in accordance with our clinical experience these symptoms, in particular hypergraphia, sometimes are very striking for relevant others, affected patients do not experience their urge to write and document everything as abnormal or pathological but rather as an adequate behavior. Thus the two scales of the NBI should be regarded as complementary rather than redundant. The neurological and psychiatric assessment was very thorough and the psychiatrists were blind to group assignment when contacting the patients. The imaging protocol and volumetric assessment is part of the routine clinical care at the Chalfont Centre, and its reliability has been proven and published previously [6,7,15]. Since the psychiatric rating was done in a blinded fashion and the neurobehavioral cluster of the symptoms, dependency, hypergraphia, and hyposexuality was obtained from caregivers, there should not be any rating bias. Thus the controversial Geschwind syndrome might occur in a subgroup of patients with TLE with bilateral hippocampal atrophy. However, with our study design we cannot answer the question of whether unilateral severe hippocampal atrophy results in similar psychopathological patterns. Further, as there are other studies linking generic psychopathology such as depression in epilepsy with mesial temporal sclerosis [30], these findings need to be interpreted with caution.
Further research comparing patients with left or right severe hippocampal atrophy to those with BHA is needed to answer this question. In general, a symptomatic rather than a syndromic analysis of disturbed behavior seems to be more appropriate when analyzing a possible relation between psychopathological phenomena and brain pathology.
Acknowledgments This study was supported by the Raymond Way Fund, Institute of Neurology, Queen Square, London (study expenses); the MRI Unit, National Society for Epilepsy, UK (imaging and technical support); Neuroimaging Laboratory, Department of Psychiatry, University of Freiburg, Germany (volumetric and statistical analysis); National Neuroscience Institute, Singapore (E.S.K.—salary support for co-authorship); and Service Universitaire de Psychogeriatrie, Lausanne, Switzerland (A.v.G.—research scholarship). We thank Dr. S. Free, Dr. L. Lemieux, and Dr. J. Duncan for their support of this study.
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[21] Trimble MR, Ring HA, Schmitz B. Neuropsychiatric aspects of epilepsy. In: Fogel BS, Schiffer RB, Rao SM, editors. Neuropsychiatry. Baltimore: Williams & Wilkins; 1996. p. 771–803. [22] Brooke SM, Sapolsky RM. The effects of steroid hormones in HIV-related neurotoxicity: a mini review. Biol Psychiatry 2000;48:881–93. [23] Geschwind N. Behavioral change in temporal lobe epilepsy. Arch Neurol 1977;34:453. [24] Trimble MR, Mendez MF, Cummings JL. Neuropsychiatric symptoms from the temporolimbic lobes. J Neuropsychiatry Clin Neurosci 1997;9:429–38. [25] Trimble MR. Personality disorders and epilepsy. Acta Neurochir Suppl 1988;44:98–101. [26] Waxman SG, Geschwind N. Hypergraphia in temporal lobe epilepsy. Neurology 1974;24:629–36. [27] Blumer D. Evidence supporting the temporal lobe epilepsy personality syndrome. Neurology 1999;53:S9–S12. [28] Devinsky O, Najjar S. Evidence against the existence of a temporal lobe epilepsy personality syndrome. Neurology 1999;53:S13–25. [29] Murai T, Hanakawa T, Sengoku A, et al. Temporal lobe epilepsy in a genius of natural history: MRI volumetric study of postmortem brain. Neurology 1998;50:1373–6. [30] Quiske A, Helmstaedter C, Lux S, Elger CE. Depression in patients with temporal lobe epilepsy is related to mesial temporal sclerosis. Epilepsy Res 2000;39:121–5.
Psychopathological profile in patients with severe bilateral hippocampal atrophy and temporal lobe epilepsy: evidence in support of the Geschwind syndrome? L. Tebartz van Elst,a,b E.S. Krishnamoorthy,a D. B€ aumer,a,b C. Selai,a A. von Gunten,a a b N. Gene-Cos, D. Ebert, and M.R. Trimblea,* a
Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK b Department of Psychiatry, Albert-Ludwigs-Universit€at, Freiburg, Germany Received 19 November 2002; revised 25 March 2003; accepted 25 March 2003
Abstract Bilateral symmetrical hippocampal atrophy (BHA) has been implicated as a possible causal element in various neuropsychiatric disorders, in particular depressive disorder and schizophrenia. To test the hypothesis that bilateral symmetrical severe volume loss of the hippocampi is of causal relevance to these psychiatric syndromes rather than an epiphenomenon we assessed the psychopathology in a group of patients with temporal lobe epilepsy (TLE) and very severe bilateral symmetrical hippocampal atrophy and compared it with that of a patient control group. Patients with TLE and hippocampal volumes smaller than three standard deviations below the mean of a control population were identified and compared with a matched patient population with normal hippocampal volumes. Psychopathology was assessed by blinded trained psychiatrists using the Present State Examination and Neurobehavioral Inventory. The prevalence of psychiatric syndromes was high in both patient groups; however, there was no significant difference between the two groups. With use of the more specific Neurobehavioral Inventory a psychopathological pattern reminiscent of the Geschwind syndrome emerged when patients with BHA were characterized by caregivers. While BHA does not result in an increased prevalence of specific psychiatric syndromes, specific symptoms that characterize the Geschwind syndrome like hypergraphia and hyposexuality might be pathogenically related to hippocampal atrophy. Ó 2003 Elsevier Science (USA). All rights reserved. Keywords: Epilepsy; Psychiatry; Geschwind syndrome; Hippocampus; Amygdala; Magnetic resonance imaging volumetry; Neuropsychiatry; Sexuality; Religiosity
1. Introduction Bilateral hippocampal volume loss has been related to different psychiatric disorders like major depressive disorder, posttraumatic stress disorder (PTSD), and schizophrenia [1–3]. In addition, amygdala volume abnormalities have been reported in different psychiatric disorders like depression [4] and schizophrenia [5] and in patients with temporal lobe epilepsy (TLE) associated with various psychiatric syndromes [6–8]. While it has been suggested that volume loss of the amygdala might be associated with hippocampal volume loss represent* Corresponding author. Fax: +44-20-7278-8772. E-mail address: [email protected] (M.R. Trimble).
ing two aspects of a broader pathogenic mechanism of mesial temporal lobe sclerosis, to our knowledge this hypothesis has not yet been tested systematically [9]. The causal relationship between the volumetric abnormalities of these mesial temporal lobe structures and the etiology and pathogenesis of the neuropsychiatric disorders described is not clear. So far only cross-sectional studies are published in the literature, suggesting that in particular bilateral hippocampal atrophy is associated with various psychiatric disorders, in particular affective disorders and schizophrenia. Thus, it remains unclear whether hippocampal volume loss is just a sequel of the given psychopathology possibly indicating chronic hypercortisolemia as one correlate of psychological stress [10] or, alternatively, may play a
1525-5050/03/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1525-5050(03)00084-2
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causal role in the development of the psychiatric syndrome. One possible way in which this relationship may be further investigated is by the study of patients with bilateral hippocampal atrophy, to see if the rate of psychopathology in this patient sample is increased compared with a control sample. However, while a link between hippocampal volume loss and generic psychopathology in epilepsy, depression for example, has been investigated, epilepsy-specific psychopathology, which might be closely linked to the epileptic process per se, has not been studied formally in relation to hippocampal volumes. As many patients with epilepsy are investigated at the Institute of Neurology, London, and the linked Centre for Epilepsy at Chalfont St. Peter, Buckinghamshire, and many of these patients display severe and sometimes bilateral atrophy of mesial temporal lobe structures and in particular the hippocampus, the opportunity for us to examine the role of severe bilateral hippocampal atrophy and psychopathology in epilepsy presented itself. The aim of this study was twofold: First, to test the hypothesis that the prevalence of psychiatric disorders like depression and schizophrenia is increased in patients with bilateral volume loss of the hippocampus we investigated the psychopathology of patients with TLE and very severe bilateral atrophy of the hippocampi and compared it with the psychopathology of a matched patient group with hippocampal volumes within the normal range. Second, to assess a possible association between amygdala and hippocampal volume loss, we measured the amygdala of both patient groups and looked for a possible association between amygdala volume abnormalities and psychopathology.
2. Methods 2.1. Patients and patient assessment Approval for this study was obtained from the ethics committee of the National Hospital for Neurology and Neurosurgery. Patients with TLE were recruited from the aforementioned tertiary referral centers. The clinical syndrome of interest was defined as complex partial seizures with semiology, EEG, and MRI findings compatible with TLE. Since 1995 all patients who had been diagnosed at the assessment unit of the Chalfont Centre received a volumetric assessment of the hippocampal volumes as part of the neuroradiological routine assessment. To obtain a very homogenous and well-defined study group we included only patients with very severe and bilateral hippocampal volume loss. Very severe hippocampal atrophy was defined as a hippocampal volume smaller than 3 SD below the mean of a
healthy population. Patients having been diagnosed as suffering from TLE who had very severe and bilateral hippocampal atrophy (BHA) were included in the study group. Patients with TLE and normal hippocampal volumes, i.e., volumes within the range of half a standard deviation above or below the mean, were randomly chosen as a control group. All patients had received a thorough neurological history and examination, as well as EEG investigations and neuropsychological investigations as part of the routine assessment. The diagnosis of TLE was made by expert consultant neurologists who were not involved in this study. We screened the records of all patients who had been diagnosed at the Chalfont Centre between 1995 and 1998 and included all those who met inclusion criteria for our study. Extratemporal or generalized epilepsy, temporal lobectomy, and an IQ lower than 70 served as exclusion criteria. We were in this way able to identify 33 patients with BHA. All these patients and a group of 34 matched control patients with TLE and normal hippocampal volume were contacted, and informed consent was obtained. Qualified neuropsychiatrists (E.S.K., A.v.G.) blinded to group assignment assessed all subjects, using the Present State Examination (PSE) component of the Schedules for Clinical Assessment in Neuropsychiatry, widely considered a gold standard in psychiatric research [11]. Clinical psychiatric diagnosis was made using ICD-10 criteria. In addition, all subjects and their named professional caregivers completed the Neurobehavioral Inventory [12]. The NBI is an expanded and revised version of the scale originally developed by Bear and Fedio [13] and consists of 100 items measuring behaviors and attitudes across 20 domains that are considered relevant to temporal lobe epilepsy. These include the behavioral triad of hyperreligiosity, hyposexuality, and hypergraphia, described by Geschwind as integral features of the syndrome that now carries his name. Other core features of this syndrome include emotional viscosity (stickiness), peculiar ethical concerns, and the proclivity to become angry on slight provocation [14]. True/false responses, for each of the 100 items, are expected, and each subscale is scored by adding up all the ‘‘true’’ responses. A score of 20 or more was chosen as the cutoff criterion. The instrument has been used extensively in tertiary care, and it is the only measure of TLE-specific behavior that is currently available. 2.2. Imaging and measurements MRI images were obtained at the Chalfont Centre for Epilepsy on a 1.5-T GE Signa Horizon scanner (GE Medical Systems, Milwaukee, WI, USA) using a T1-weighted inversion–recovery-prepared volume acquisition (IRSPGR:TI/TR/TE/flip ¼ 450/15/4.2/20; 124 1.5-mm-thick contiguous coronal slices; matrix 256 192,
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24 18-cm FOV). The hippocampal volumes had been measured as part of the routine assessment of patients with TLE at the Chalfont Centre. The reliability of this assessment has been demonstrated and published previously [15]. For quantification of amygdala volumes the images were transferred to a Sun workstation (Sun Microsystems, Mountain View, CA, USA) at the Neuroimaging Laboratory of the Psychiatric Department, University of Freiburg, Freiburg, Germany. Volumetric measurements of the amygdala were performed using the locally developed interactive software program MRreg [16]. Using this software the images were zoomed to a magnification of 4 to outline the amygdala and intensity windowing was set to a level of 80 and width of 140. The amygdala were outlined manually using a mouse-driven cursor following the established protocol described by Watson et al. [17]. The total brain volume was measured by manual segmentation of the cerebrum, cerebellum, midbrain, and pons excluding the rest of the brain stem. The volume of each structure in each slice (the in-slice volume) was calculated by multiplying the number of voxels contained within each trace by the voxel volume, 0:937 0:937 1:5 mm3 , and dividing by the magnification factor. The total volume of each structure was the sum of all in-slice volumes. Amygdala volumes were corrected for total brain size following Cendes et al. [18]. The images of 20 healthy controls were rated twice by one blinded scientist (D.B.) to establish intrarater reliability figures. 2.3. Data analysis Intrarater reliability was assessed by calculating an intraclass correlation coefficient as suggested by Streiner and Norman [19]. 2.3.1. Group comparisons To begin with we analyzed the homogeneity of the two patient groups with respect to age, sex, duration of epilepsy, frequency of seizures, incidence of febrile convulsions, encephalitis, head trauma, status epilepticus, and intelligence using independent-sample t tests and v2 tests. To test our hypotheses we then performed two major group comparisons. First, we compared the amygdala volumes of patients with TLE and bilateral very severe hippocampal atrophy to those with normal hippocampal volumes using independent-sample t tests. To assess the relationship between amygdala and hippocampal volumes we assessed the Pearson correlation between these two parametric variables. We then compared the prevalence of psychopathology between the two patient groups on two levels of complexity. We compared the prevalence of psychiatric diagnoses according to ICD-10 criteria based on PSE assessment. Since it is well known that patients with
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epilepsy often display psychopathological abnormalities that do not fulfill conventional criteria for psychiatric disorders [20,21], we then compared symptoms suggestive of epilepsy-specific psychopathology, based on the domains of the NBI scale. Since both methods of psychiatric assessment result in categorical data, i.e., the presence or absence of a given psychopathological symptom or syndrome, we analyzed these data using contingency tables. A P value of 0.05 was chosen as the criterion of significance. All data were analyzed using SPSS for Windows (Release 7.5.1).
3. Results 3.1. Reliability figures The intraclass correlation coefficient as calculated from repeated measurements of 20 data sets of healthy volunteers was 0.99 for the hippocampi and 0.88 for the amygdala. These compare well with figures published in the literature [6–8,17]. 3.2. Study group comparisons Table 1 summarizes the demographic and clinical findings of the study and control groups. Of the 33 patients with BHA and the 34 control patients we identified, 9 patients with BHA and 14 control patients respectively responded and were assessed by the psychiatrists. Both groups were matched with respect to age, sex, duration of epilepsy, and frequency of complex partial (CS) and secondary generalized (SG) seizures. There were no differences in terms of head trauma, febrile convulsions, and history of encephalitis. Interestingly a history of status epilepticus was increased in patients with bilateral severe hippocampal atrophy, who also had a significantly lower verbal and performance IQ. 3.3. Hippocampal and amygdala volumes The mean hippocampal and amygdala volumes of the two patient groups are summarized in Table 2. Hippocampal atrophy was the group defining criterion. Thus the respective volumes differ significantly. While amygdala volumes on the right-hand side were small both in the hippocampal atrophy group and in the patient control group, there was a significant group difference in left amygdala volume, with the atrophy group displaying smaller amygdalae (see Table 2). We found a significant correlation between hippocampal volumes on both sides and left amygdala volume (right hippocampus/left amygdala: Pearson correlation r ¼ 0:502; P ¼ 0:02; left hippocampus/left amygdala r ¼ 0:542; P ¼ 0:01), while there were no significant correlations between the right
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Table 1 Comparison of study and control groups with respect to demographic and clinical data
Age (years) Sex (female/male) Duration of epilepsy (years) Frequency of CP seizures/month Frequency of SG seizures/month History of encephalitis History of febrile convulsion History of status epilepticus Verbal IQ Performance IQ
TLE and BHAa (n ¼ 9)
TLE and NHV (n ¼ 14)
Significance
35 [7]b 2/7 27 [8] 6.4 [4.3] 1.3 [2.8] 4 3 3 87.6 [9.2] 90.7 [9.0]
40 [9] 7/7 20 [11] 11.6 [18.2] 1.2 [1.4] 2 2 0 98.5 [12.9] 106.8 [13.6]
NS NS NS NS NS NS NS
P 6 0:05, P 6 0:01, P 6 0:001; P values not corrected for multiple comparisons. BHA, bilateral hippocampal atrophy; NHV, normal hippocampal volumes. b SD in brackets. a
Table 2 Cerebral, hippocampal, and amygdala volumes
Total brain volume (cm3 ) Right hippocampal volume (cm3 ) Left hippocampal volume (cm3 ) Right/left ratio Right amygdala volume (cm3 ) Left amygdala volume (cm3 ) a
P 6 0:05, P 6 0:01, SD in brackets.
TLE and hippocampal atrophy
TLE with normal hippocampal volumes
Significance
1628.5 [146.4]a 1.69 [0.26] 1.53 [0.23] 1.1 [0.3] 1.47 [0.34] 1.45 [0.22]
1627.4 [99.1] 3.0 [0.11] 3.0 [0.08] 1.0 [0.03] 1.59 [0.22] 1.74 [0.26]
NS
3.4. Hippocampal atrophy and psychopathology Psychiatric ICD-10 diagnoses generated on the basis of the PSE are summarized for both study groups in Table 3. Overall psychopathology was very high in both patient groups; however, there were no significant differences between the two groups. Table 3 Psychiatric profile in patients with TLE with and without hippocampal atrophya
a
NS NS
P 6 0:001, P values not corrected for multiple comparisons.
amygdala volume and hippocampal volumes (right hippocampus/right amygdala r ¼ 0:164; P ¼ 0:48; left hippocampus/right amygdala r ¼ 0:278; P ¼ 0:22).
Depression OCD Anxiety and panic Somatoform disorder Eating disorder Mania Schizophrenia Other
TLE + HA (N ¼ 9)
TLE without HA (N ¼ 13)
6 0 3 0 1 0 2 3
7 1 5 1 0 0 5 4
Data are numbers of patients suffering from disorders listed (according to PSE). Numbers represent diagnoses and may add to more than the total number of patients due to comorbidity.
3.5. Epilepsy-specific psychopathology measured with the Neurobehavioral Inventory Tables 4A and 4B summarize our findings using the NBI. In the self-rating section of the NBI, the total score was significantly higher in patients with BHA. Significant differences were observed in a cluster of affective symptoms including emotions, fear, guilt, and sadness and regarding the items persistency and physical handicap. In accordance with the self-rating section, caregivers rated patients with BHA significantly higher in dependency. Furthermore there were significant differences in terms of an increased prevalence of hypergraphia and hyposexuality in this patient group.
4. Discussion In summary, our data do not support the hypothesis that BHA results in an increased prevalence of generic psychopathology, for example, depressive or schizophreniform disorders, in patients with TLE. However, we did find a link between BHA and epilepsy-specific psychopathology like affective symptoms in self-ratings and hyposexuality and hypergraphia in caregiver ratings. Based on our findings we cannot confirm the hypothesis that bilateral hippocampal atrophy renders
L. Tebartz van Elst et al. / Epilepsy & Behavior 4 (2003) 291–297 Table 4A Caregiver ratings of the neurobehavioral inventory NBI item
TLE + HA
Total score Cosmic Detail Dependency Destiny Emotions Fear Guilt Hatred Happiness Morals Order Persist Physical Religion Sadness Hyposexuality Serious Suspicion Temper Writing
6 1 7 7 2 1 3 2 1 2 6 5 6 2 1 2 6 1 0 4 7
P 6 0:05, P 6 0:01, multiple comparisons.
TLE + normal hippocampal volumes
Significance
5 1 6 2 1 5 3 3 2 3 6 4 7 6 2 5 3 4 3 7 1
P 6 0:001; P values not corrected for
Table 4B Self-ratings of the neurobehavioral inventory NBI item
TLE + HA
TLE + normal hippocampal volumes
Significance
Total score Cosmic Detail Dependency Destiny Emotions Fear Guilt Hatred Happiness Morals Order Persist Physical Religion Sadness Hyposexuality Serious Suspicion Temper Writing
9 5 8 8 7 8 8 7 5 4 4 8 8 8 5 6 7 6 5 3 7
8 4 9 6 6 6 5 3 4 5 8 7 5 5 3 3 10 8 3 8 6
P 6 0:05, P 6 0:01, multiple comparisons.
P 6 0:001; P values not corrected for
patients more vulnerable to the development of major depression or schizophreniform disorder. Psychopathology in general and depression in particular were very common findings in patients with TLE independent
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of whether they displayed bilateral hippocampal atrophy. Thus it might well be that bilateral hippocampal volume loss reported in psychiatric disorders like depression and schizophrenia is an epiphenomenon of the respective disorder, possibly indicating a state of chronically increased psychological stress [10,22]. On the other hand, BHA was associated with an increased prevalence of affective symptoms like fear, guilt, sadness, and physical symptoms in the self-rating of affected patients with TLE. Interestingly, when looking at the caregiver ratings apart from dependency there were particularly significant differences in hyposexuality and hypergraphia that distinguished patients with BHA from those without. These are symptoms of the Geschwind syndrome [23–25] a rather controversial personality syndrome in epilepsy. Geschwind and Waxman were the first to describe a specific set of personality alterations in epilepsy. In further studies a group of behavioral symptoms (i.e., circumstantiality; intensified preoccupations related to moral, philosophical, religious, or ethical themes; hyposexuality; and irritability) were identified and subsequently referred to as the Geschwind syndrome [14,26]. The existence of this syndrome as a specific personality disorder in epilepsy is not accepted unanimously and has led to considerable debate [27,28]. The evidence for its existence is largely empirical, and following Benson [14], the strongest support so far stems from the many clinicians who have described and attempted to manage patients with epilepsy and these personality features. The only other imaging study we could find that has shown an association between the hippocampus and aspects of the Geschwind syndrome is the case of Kumagasu Minakata, a Japanese genius devoted to natural history and folklore and famous for his immense range of works. Using MRI scans to study his postmortem brain, Murai et al. [29] found evidence of right hippocampal atrophy, which correlated with his history suggestive of temporal lobe epilepsy. Many features of the Geschwind syndrome (the tremendous number of articles; the tendency to write minuscule letters in compact space; the lack of interest in the opposite sex; peculiar ethical concerns; the proclivity to become angry on slight provocation; and notably his extraordinary interest in religious matters) were identified in a detailed study of his diaries. A number of limitations in this study have to be considered in discussing these findings. First, the number of subjects studied, particularly with respect to psychopathology, is rather small. However, to obtain a very homogenous study group we chose a very strict group-defining criterion, i.e., very severe and bilateral hippocampal atrophy. Of the 33 patients with BHA and the 34 control patients we identified, only 9 patients with BHA and 14 control patients respectively responded and were assessed by the psychiatrists. This small turnout
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was partly due to the rigid exclusion criteria we chose to adopt, and also because many of these patients who had been referred from all over the United Kingdom had moved house or did not respond for some other unknown reason. In mitigation, however, the resultant study group is very homogenous and unique, in that it is very difficult to study patients with such a severe bilateral atrophy of the hippocampi. In this study we did not correct for multiple comparisons. However, since psychopathology is measured using many different dimensions (8 for the PSE-generated ICD-10 diagnoses and 2 20 items for the NBI self- and caregiver ratings), many of which are overlapping (as, e.g., the dimensions sadness, emotion, fear, and guilt in the NBI), Bonferroni correction would have resulted in an overcorrection of the findings. At the same time this study is a pilot study in character and therefore we decided not to correct any finding for multiple comparison accepting that all significant results have to be reproduced in a further investigation. As there is a discrepancy between the self-ratings and the caregiver ratings on the NBI questionnaire one might question the validity of these findings. However, this discrepancy is not really surprising on a closer look. Most of the items rated high by patients with BHA and normal by caregivers are symptoms of subjective experience and are difficult for others to assess. On the other hand, caregivers picked up abnormal behavior like hyposexuality or hypergraphia. While in accordance with our clinical experience these symptoms, in particular hypergraphia, sometimes are very striking for relevant others, affected patients do not experience their urge to write and document everything as abnormal or pathological but rather as an adequate behavior. Thus the two scales of the NBI should be regarded as complementary rather than redundant. The neurological and psychiatric assessment was very thorough and the psychiatrists were blind to group assignment when contacting the patients. The imaging protocol and volumetric assessment is part of the routine clinical care at the Chalfont Centre, and its reliability has been proven and published previously [6,7,15]. Since the psychiatric rating was done in a blinded fashion and the neurobehavioral cluster of the symptoms, dependency, hypergraphia, and hyposexuality was obtained from caregivers, there should not be any rating bias. Thus the controversial Geschwind syndrome might occur in a subgroup of patients with TLE with bilateral hippocampal atrophy. However, with our study design we cannot answer the question of whether unilateral severe hippocampal atrophy results in similar psychopathological patterns. Further, as there are other studies linking generic psychopathology such as depression in epilepsy with mesial temporal sclerosis [30], these findings need to be interpreted with caution.
Further research comparing patients with left or right severe hippocampal atrophy to those with BHA is needed to answer this question. In general, a symptomatic rather than a syndromic analysis of disturbed behavior seems to be more appropriate when analyzing a possible relation between psychopathological phenomena and brain pathology.
Acknowledgments This study was supported by the Raymond Way Fund, Institute of Neurology, Queen Square, London (study expenses); the MRI Unit, National Society for Epilepsy, UK (imaging and technical support); Neuroimaging Laboratory, Department of Psychiatry, University of Freiburg, Germany (volumetric and statistical analysis); National Neuroscience Institute, Singapore (E.S.K.—salary support for co-authorship); and Service Universitaire de Psychogeriatrie, Lausanne, Switzerland (A.v.G.—research scholarship). We thank Dr. S. Free, Dr. L. Lemieux, and Dr. J. Duncan for their support of this study.
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