Intermittent explosive disorder in epilepsy

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In the past, few studies have addressed the relationship between different psycho-biological factors like brain pathology, IQ and demographic background, and aggression in epilepsy. While Rodin found more evidence of organic brain disease (Rodin, 1973), and Falconer (1973) reported an increased incidence of mesial temporal lobe sclerosis in aggressive patients with temporal lobe epilepsy (TLE), Herzberg and Fenwick did not find any relationship between specific electroencephalography (EEG) or computerized tomography (CT) pathology and aggression in patients with TLE (Herzberg and Fenwick, 1988). All three studies found a relationship between low IQ and aggression and two reported an association between male sex and aggression (Falconer, 1973; Rodin, 1973).

Since none of these studies used modern magentic resonance imaging (MRI) techniques to assess the relationship between brain pathology and aggressive behaviour in patients with epilepsy, in two recent projects we studied this relationship using quantitative MRI (Tebartz van Elst et al., 2000a,b; Woermann et al., 2000). The aims of our studies were first, to investigate amygdala pathology, and second, to assess cortical abnormalities in patients suffering from TLE and additional affective aggression, specifically IED.

The most common pathology underlying TLE in general is hippocampal sclerosis (HS) often in the context of mesial temporal sclerosis (MTS) (Gloor, 1991;

Margerison and Corsellis, 1966; Wieser, 1983). A radiological in vivo diagnosis of mesial temporal lobe sclerosis is possible by demonstrating atrophy of the mesial temporal lobe structures on Tl-weighted anatomical MRI images and increased signal on conventional spin echo T2 MRI sequences (Duncan et al., 1996; Jackson et al., 1990; Woermann et al., 1998). Since HS seems to be diffuse rather than focal in most of the cases (Kim et al., 1995) an involvement of the amygdala by the pathological process underlying hippocampal sclerosis might be expected, and indeed is reported in the literature (Hudson et al., 1993; Miller et al., 1994). In vivo identification of amygdala sclerosis by measuring the amygdala T2 relaxation time has been reported in patients with TLE (Kalviainen et al., 1997; Van Paesschen et al., 1996). Furthermore amygdala volumetry has been validated as a reliable method (Cendes et al., 1993; Kalviainen et al., 1997; Soininen et al., 1994; Watson et al., 1992).

In our study we hypothesized that, in patients with TLE and intermittent affective aggression, amygdala sclerosis in the context of hippocampal sclerosis would be more common as compared to control patients. Furthermore, we wanted to test if there is an association between aggression on the one hand and hippocampal sclerosis, low IQ, and poor social adjustment on the other hand in patients with TLE.

In a second step we analysed cortical grey matter abnormalities in these patients in order to investigate frontal lobe pathology, since from a phenomenological point of view episodic dyscontrol or IED can be characterized as a hyperarousal-dyscon-trol syndrome.

Amygdala pathology in patients with TLE and IED

Twenty- five patients with TLE and IED diagnosed according to the DSM-IV criteria described above and 25 control patients with TLE without any psychopathol-ogy were recruited from a tertiary referral centre (National Hospital for Neurology and Neurosurgery and the associated Chalfont Centre for Epilepsy). The clinical syndrome of interest was defined as complex partial seizures with a semiology, EEG and MRI findings compatible with TLE. On the basis of the discharge summaries patients with TLE with and without a history of aggression were identified, contacted and seen by a neuropsychiatrist (LTVE). Patients with extratemporal or generalized epilepsy were excluded as were those with a history of mental handicap or psychoses. Patients with TLE with and without a history of IED diagnosed according to DSM-IV criteria were included in the study.

A neurological and psychiatric history and examination were obtained, as well as routine EEG investigations and neuropsychological investigations. Full (FIQ), verbal (VIQ), and performance IQ (PIQ) were measured and patients with a FIQ below 70 were excluded from the study to avoid selection bias. All patients were asked to fill in the Beck Depression Inventory (BDI-13) and the State Trait Anxiety Inventory (STAI). Both questionnaires are self-rating instruments for depression and anxiety respectively (Thomson, 1989«, b). In order to assess aggression, carers were asked to fill in the Social Dysfunction and Aggression Scale (SDAS-21), a well validated and recommended questionnaire (European Rating Aggression Group, 1992; Mak and de Konning, 1995). Twenty healthy volunteers, matched for age and sex were scanned and measured twice in order to assess the reliability of the volumetric measurements.

The MRI images were obtained at the Chalfont Centre for Epilepsy on a 1.5 T GE Signa scanner (GE Medical Systems, Milwaukee, USA) using a T1-weighted inversion-recovery prepared volume acquisition (IRSPGR: TI/TR/TE/flip = 450/15/4.2/20; 12 X 1.5 mm thick contiguous coronal slices; matrix 256 X 192, 24 cm X 18 cm FOV), and a conventional spin echo sequence (TR/TE1/TE2/NEX 2000/30/120/1, 256 X 192 matrix, 24 X 18 cm FOV, 5 mm slices) for computation of T2 values. Volumetric measurements were performed using a locally developed interactive software program MRreg (Lemieux et al., 1998; Moran et al., 1999) following the established protocol described by Watson et al. (1992). The rater (LTVE) was blind to the subject grouping. The amygdala volumes were corrected for total brain size by division by the intracranial volume. Intrarater reliability figures were carefully assessed and proved to be satisfactory. Amygdala atrophy was defined as a volume smaller than 3 standard deviations (SD) below the average amygdala volume of the control group. Amygdala T2 values were measured using DispImage image analysis software (Plummer, 1992) by placing the largest possible elliptic region of interest within the amygdala while avoiding anatomical boundaries. Amygdala T2 signals were defined as pathological if they were greater than 2 SD above the mean of the control population. Details of the methodology have been published elsewhere (Tebartz van Elst et al., 1999, 2000b).

The demographic data of both groups are summarized in Table 7.3. The two patient groups were matched for age, sex, demographic background, duration of epilepsy and seizure severity. There was no significant group difference regarding the history of birth complications, febrile convulsions or status epilepticus. However, the incidence of encephalitic brain disease (Fisher's Exact Test: P = 0.05) and left-handedness (Chi-square Test: P< 0.05) was significantly increased in aggressive patients. There was less right-sided focal EEG abnormality and more bilateral EEG abnormality in the aggressive group compared to nonaggressive patients with TLE. Left- as well as right-sided hippocampal sclerosis was significantly less common in patients with TLE and IED. Other left temporal pathology, including three patients with amygdala pathology (amygdala sclerosis, amygdala glioma, amygdala DNT), two patients with multiple small temporal infarctions and two patients with diffuse left temporal atrophy of unknown origin, was significantly more common in patients with TLE plus IED (see Table 7.4).

Table 7.3. Demographic and historical data of patient groups with temporal lobe epilepsy

(TLE), with TLE and intermittent explosive disorder (IED) or without IED (TLE alone)

(n = 25 in each group)


TLE alone

Age (in years) [range]

30.1 [18-49]

33.8 [19-56]

Sex: f/m



Work: number unemployed



Living: number living independently



Income: number on social support



Social: number living in stable relationship



Therapy: monotherapy - polytherapy



Mean duration of TLE (in years) [range]

22.4 [5-45]

24.5 [7-46]

Mean seizure frequency (estimated frequency

13.4 [0.5-60]

21 [1.5-190]

per month) [range]

Birth complications



Febrile convulsions



Status epilepticus






History of encephalitis



Source: Tebartz van Elst et al. (2000a).

Table 7.4. Radiological MRI pathology on visual assessment

Other left

Overall significance: No Right

Left Bilateral


P = 0.002 pathology hemisphere

hemisphere hemispheres


TLE and IED 10 1



TLE alone 6 8

10 1


Significance **




TLE, temporal lobe epilepsy; IED, intermittent explosive disorder.

Other left temporal pathology: amygdala sclerosis =

: 1, amygdala glioma = 1, amygdala DNT =

1; multiple small temporal infarctions = 2; generalized left temporal atrophy = 2.

Closed test procedure: * = P < 0.5, ** = P < 0.01).

Source: Tebartz van Elst et al. (2000b).

There was no evidence of an increased amygdala T2 relaxation time in the aggressive group. Using the definition of amygdala T2 pathology as a T2 time greater than 2 SD above the mean of the control group, there was no significant group difference in amygdala pathology.

A group comparison did not reveal a significant overall difference in amygdala volumes (right side: aggressive = 1893 mm3, SD = 435 mm3; nonaggressive = 1909 mm3, SD = 231 mm3; left side: aggressive = 1840 mm3, SD = 398 mm3; nonaggressive = 1868 mm3, SD = 290 mm3). However, in the aggressive patients, a subgroup of five patients (20%) showed amygdala atrophy as compared to only one in the nonaggressive group (Chi-square: P = 0.04). Two patients had left-sided amygdala atrophy, two had bilateral atrophy and the only patient who exhibited right-sided amygdala atrophy was left-handed. An increased incidence of encephalitis (Chi-square Test: P <0.05; Fisher's Exact Test: P = 0.1) was the only clinical feature that distinguished patients with amygdala atrophy from those with normal amygdala volumes. Since there was no overlap between the five patients with severe amygdala atrophy and those seven patients with other amygdala pathology, in a total number of 12 out of 25 aggressive patients there was some evidence of amygdala pathology as compared to only one in the nonaggressive group (see Figure 7.1).

There was a highly significant group difference in IQ figures with the verbal IQ (VIQ), the performance IQ (PIQ) and hence the full IQ (FIQ) all being lower in the aggressive group (Table 7.5). The verbal IQ differed more than the performance IQ.

As expected there was a highly significant group difference in the Social Dysfunction and Aggression Scores (SDAS 9, SDAS 21) since this was the criterion for group definition (Table 7.5). There was a significant group difference in BDI and STAI scores with the aggressive group rating much higher in depression (P < 0.05) state (P <0.05) and trait anxiety (P < 0.01).

Cortical abnormalities in patients with TLE and IED

In order to detect possible subtle cortical brain pathology, that was not present on visual assessment of the MRI scans, in a second approach we analysed the same groups of patients using a voxel-by-voxel-comparison of cortical grey matter. After automated segmentation of cerebral grey matter from T1-weighted MRI, the objective technique of statistical parametric mapping (SPM) was applied to study the patient groups described above and comparison made with 35 healthy control subjects (Woermann, 1999). Both TLE patient groups were compared with each other and with the control subjects on a voxel-by-voxel basis for increases and decreases of grey matter. SPM 96 characterizes significant regional differences in image parameters, while allowing for global differences to be taken into account. Details of the methodology are published elsewhere (Woermann, 1999; Woermann et al., 1999). The resulting significant differences through the 3D image space were dis-

Intermittent Explosive Disorder

Amygdala No Amygdala pathology pathology

Figure 7.1. Amygdala pathology in patients with TLE with and without IED. AGG = aggressive.

played collapsed into three orthogonal planes ('glass brain', see Figure 7.2). Regions of significant difference were overlaid on normalized Tl-weighted images to facilitate correlation with anatomy (see Figure 7.3).

In patients with TLE with IED compared as a group with healthy control subjects, reductions of grey matter were found over large areas of the left extratemporal neocortex, maximal in the left frontal neocortex; one maximum difference projection had a Zscore of 5.67 at Talairach coordinates x = 58, y = 36, z = 9 mm (left anterior frontolateral cortex), the other a Zscore of 4.78 in a more posterior left frontal lobe location (Talairach coordinates x = 66, y = 0, z = 28 mm, Figures 7.2 and 7.3). Patients with TLE who did not have IED showed no significant decrease of cortical grey matter compared with control subjects. Patients with TLE with IED also had reduction of left frontal grey matter, compared with patients with TLE without IED, although less marked than when compared with control subjects (Zscore = 3.49 at Talairach coordinates x = 66, y = 2, z = 26 mm). The SPM-based

Table 7.5. Neuropsychological and psychometric parameters



TLE alone

Group comparison

Mean FIQ (SD)

80.6 (8.5)

93.0 (13.9)

** (P <0.000)

Mean VIQ (SD)

81.0 (8.6)

93.8 (14.1)

** (P <0.000)

Mean PIQ (SD)

83.3 (11.8)

94.7 (15.1)

* (P <0.005)

Mean BDI (SD)

8.8 (4.8)

4.2 (5.8)

* (P <0.007)


44.1 (14.9)

32.1 (10.9)

* (P <0.005)


50.1 (10.1)

34.7 (11.6)

** (P <0.000)

Mean SDAS-9 (SD)

14.9 (7.5)

0.4 (0.7)

** (P <0.000)

Mean SDAS-21 (SD)

30.9 (12)

3.1 (4.5)

** (P <0.000)


TLE, temporal lobe epilepsy; IED, intermittent explosive disorder; FIQ, full IQ; VIQ, verbal IQ; PIQ, performance IQ; BDI, Beck Depression Inventory; STAI, State Trait Anxiety Inventory; SDAS, Social Dysfunction and Aggression Scale; SD, standard deviation. * = P <0.5, ** = P <0.01 after Bonferroni correction. Source: Tebartz van Elst et al. (2000a).


TLE, temporal lobe epilepsy; IED, intermittent explosive disorder; FIQ, full IQ; VIQ, verbal IQ; PIQ, performance IQ; BDI, Beck Depression Inventory; STAI, State Trait Anxiety Inventory; SDAS, Social Dysfunction and Aggression Scale; SD, standard deviation. * = P <0.5, ** = P <0.01 after Bonferroni correction. Source: Tebartz van Elst et al. (2000a).

voxel-wise correlation of SDAS scores and automatically segmented grey matter in all patients with TLE showed the left frontal grey matter area as negatively correlated with these scores which expressed social consequences of interictal affective aggression (Z score 3.65 at Talairach coordinates x = 66, y = 2, z = 26 mm). Age, scores of depression and anxiety, IQ measures, or scores of verbal fluency did not significantly correlate with specific decreases in grey matter in all patients with TLE.

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  • mungo bunce
    Is intermittent explosive disorder similar to psychomotor epilipsy?
    2 months ago

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