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|Year : 2021 | Volume
| Issue : 4 | Page : 842-846
Involvement of Incomplete Hippocampal Inversion in Intractable Epilepsy: Evidence from Neuropsychological Studies
RM Bhoopathy, B Arthy, SS Vignesh, Smitha Ruckmani, AV Srinivasan
Institute of Neurology, Madras Medical College, Chennai, Tamil Nadu, India
|Date of Web Publication||2-Sep-2021|
Prof. R M Bhoopathy
Institute of Neurology, Madras Medical College, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: The age of onset of seizure, seizure types, frequency of seizure, structural abnormalities in the brain, and antiepileptic medication (polytherapy) causes increased incidence of anxiety and depression in intractable epilepsy patients.
Aim: To compare the anxiety and depression levels in intractable epileptic patients with structural abnormalities [malformations of cortical development (MCD) and incomplete hippocampal inversion (IHI)] and without structural abnormalities.
Materials and Methods: Participants were selected from (239 males and 171 females) intractable epilepsy patients. They were grouped into four groups; Group 1: 51 nonepileptic age-matched controls, Group 2: 41 intractable epilepsy patients without any brain abnormality, Group 3: 17 intractable epilepsy patients with MCD, and Group 4: 30 intractable epilepsy patients with isolated IHI. Neuropsychiatric tools used were Multiphasic Personality Questionnaire and Weschlers Adult Intelligence Scale to assess anxiety, depression, and intelligence. Groups were classified using 1.5T conventional magnetic resonance imaging and hippocampal volumetric studies. Group comparison design was used.
Results: Demographic variables of intractable epilepsy, including seizure types, the frequency of seizure, the age of seizure onset, and antiepileptic drug therapies, did not show significant association between the groups using Chi-square P value. Analysis of variance showed significant anxiety and depression in epileptic patients than the control group (P < 0.01). Post hoc analysis using Tukey's B test showed significant difference in anxiety and depression scores between group value. In group 3 and 4, anxiety scores were significantly different but not depression scores.
Conclusion: The present study concludes high prevalence of anxiety and depression in intractable seizure. Anxiety is observed predominantly when there is IHI along with depression. We emphasize the need to identify IHI in intractable epilepsy and assess anxiety and depression to treat them effectively.
Keywords: Anxiety, depression, epilepsy, incomplete hippocampal inversion, malformations of cortical developmentKey Message: Anxiety and depression were significant in intractable epilepsy. Patients with IHI and intractable epilepsy showed high frequency of anxiety.
|How to cite this article:|
Bhoopathy R M, Arthy B, Vignesh S S, Ruckmani S, Srinivasan A V. Involvement of Incomplete Hippocampal Inversion in Intractable Epilepsy: Evidence from Neuropsychological Studies. Neurol India 2021;69:842-6
|How to cite this URL:|
Bhoopathy R M, Arthy B, Vignesh S S, Ruckmani S, Srinivasan A V. Involvement of Incomplete Hippocampal Inversion in Intractable Epilepsy: Evidence from Neuropsychological Studies. Neurol India [serial online] 2021 [cited 2021 Oct 18];69:842-6. Available from: https://www.neurologyindia.com/text.asp?2021/69/4/842/323886
Anxiety and depression are nonepileptic symptoms that often coexist in individuals suffering from epilepsy.,,,,, The prevalence of anxiety varies from 11 to 25% and that of depression varies from 9 to 40% in persons suffering from epilepsy across various studies when compared to individuals without epilepsy. The prevalence of anxiety and depression are often reported to be higher in patients with drug-resistant epilepsy and temporal lobe epilepsy.,,,,, Depression and anxiety have been also reported to be often associated with suicide, suicidal ideation, suicidal attempts, and stigmatization in individuals with epilepsy.,, Altogether, anxiety and depression in patients with epilepsy affects the quality of life.,,
From a review of the literature, abnormalities of limbic structures, namely, frontal, temporal, and subcortical areas such as basal ganglia and thalamic nuclei have been reported to be involved in depression and anxiety. These structural abnormalities have been observed in individuals with and without epilepsy who present with depression and anxiety. Structural abnormalities in nonepileptic individuals with depression such as hippocampal atrophy,,, changes in amygdala, and structural changes in prefrontal, orbitofrontal, and cingulate gyri, are also noted in the epileptogenic network of temporal lobe epilepsy. Malformation of cortical development (MCD) may be involved in the pathophysiology of depression and anxiety, which were observed in 25 to 40% of patients with intractable epilepsy.
MCDs are microscopic and macroscopic malformations of cerebral cortex due to interruption in cortical development during fetal growth. According to the Barkovich classification, MCDs were classified as malformations due to abnormal neural proliferation, neuronal immigration, and cortical organization.,,, MCDs can coexist with hippocampal abnormalities such as hypoplastic hippocampus, hippocampal sclerosis, incomplete hippocampal inversion (IHI) and enlarged hippocampus. Moreover, IHI is reported to occur in equal proportion of temporal lobe epilepsy (TLE) and MCDs. Although IHI is found in patients with TLE and MCD, there are controversies regarding IHI to be considered as abnormal in patients with epilepsy. Recent studies have reported IHI to be pathological in patients with seizures.,
At present, there are no studies that demonstrate association of anxiety and depression in MCDs and IHI. Hence, the present study aimed to estimate the prevalence of anxiety and depression in patients with MCD and IHI. We also compared the anxiety and depression levels in patients with intractable epilepsy with structural abnormalities (MCD and IHI) and without structural abnormalities.
| » Materials and Methods|| |
Group comparison design was adopted for the present study. Samples were selected based on the magnetic resonance imaging (MRI) findings, volumetric studies, and intelligence quotient (IQ) test scores from 410 individuals (239 males and 171 females) who visited epilepsy clinic at the Rajiv Gandhi Government General Hospital, Chennai. The age range of patients were 18 to 65 years (mean age = 39.43 years), with intractable epilepsy. Based on the detailed clinical history, neurological examination, electroencephalogram (EEG) studies, MRI, and hippocampal volumetric studies, patients were classified into four groups. Group 1 included 51 nonepileptic age-matched controls (25 male and 26 females) with the mean age of 30.8 years. All the subjects in Group 1 did not show any structural abnormalities, including IHI, in conventional MRI and hippocampal volumetric studies. Group 2 included 41 (28 males and 13 females) intractable epilepsy patients without any brain abnormality in conventional MRI (mean age of 32.2 years). Group 3 included 17 (12 males and 5 females) out of 32 intractable epilepsy patients with malformation of cortical development diagnosed based on conventional MRI (mean age of 20.1 years) and IQ scores of ≥70, and Group 4 included 30 intractable epilepsy patients (19 males and 11 females) with IHI diagnosed with MRI and hippocampal volumetric studies (mean age of 33.6 years). The various malformations of cortical development and IHI in Group 3 and 4 are summarized in [Table 1].
|Table 1: Number of patients with malformations of cortical development and incomplete hippocampal inversion|
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Magnetic resonance imaging protocol
All the subjects underwent conventional MRI on a 1.5T, 48 channel System (SeimensAera, Germany) using a head coil (40 element), gradient strength of 45mT, and flow rate of 200 Mt/sec. Axial T1-weighted sequence (T1), axial T2 weighted sequence (T2), and volumetric T1-weighted MRI (3D–SPGR) sequence were included in the MRI protocol. All the images were analyzed by neuroradiologists who detected the MCDs and hippocampal malformations. The criteria for the IHI (malrotation of hippocampus) included abnormal rounded appearance of the head of hippocampus, incomplete rotation, blurry internal structure, changes in shape and size, and vertical orientation of collateral sulcus. Patients who met three out the several criteria for IHI were considered in Group 4.
After neurological examination, MRI, EEG, and hippocampal volumetric studies, all the patients underwent neuropsychological assessment. Weschlers Adult Performance Intelligence Scale III and multiphasic questionnaire (MPQ) were used to assess intelligence, anxiety, and depression by clinical neuropsychologist for all the four groups of patients. All the patients with the intelligence score of ≥70 were included in the study. Selected patients were further assessed with MPQ to measure the anxiety and depression levels. In MPQ questionnaire, the cut-off score for diagnosing anxiety and depression were ≥7 and ≥11, respectively. The anxiety and depression scores were descriptively and statistically analyzed using IBM statistical package for the social sciences software, version 21 (2014).
| » Results|| |
Demographic variables [Table 2] of intractable epilepsy including seizure types, the frequency of seizure, the age of seizure onset, antiepileptic drug therapies, and prevalence of anxiety and depression were analyzed to find the associations between the groups using Chi-square test. Bonferroni corrections were made for multiple comparisons. The results did not reveal any significant association (P > 0.05) between the demographic variables and groups considered in the present study. In epileptic groups, there was no significant association between prevalence of anxiety and depression (P > 0.05). Moreover, demographic variables were not associated with the anxiety and depression scores in epileptic groups.
Out of 51 nonepileptic individuals in Group 1, 2% (n = 1) had anxiety in MPQ. When compared to nonepileptic individuals, epileptic patients had high prevalence of anxiety in Groups 2, 3, and 4. 21.95% (n = 9) in Group 2, 5.8% (n = 1) in Group 3, and 33.3% (n = 10) in Group 4 had anxiety. Among the epileptic patients, anxiety was observed to be highly prevalent in IHI group when compared to MCD and epileptic patients without brain abnormalities, as seen in [Figure 1]. Mean and standard deviation of anxiety and depression scores using MPQ are tabulated in [Table 3]. Analysis of variance (ANOVA) was performed to compare the mean anxiety and depression scores among the four groups. As seen in [Table 4] mean anxiety scores were significantly different between and within the groups (P < 0.01). Post hoc analysis using Tukey B test showed significant difference at P < 0.01 between Groups 1 and 2, 1 and 3, 1 and 4, and 3 and 4.
|Figure 1: Percentage of patients with anxiety and depression across four groups|
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|Table 3: Mean and standard deviation of anxiety and depression scores across four groups|
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Depression was observed in 26% (n = 13) individuals of Group 1, 29.26% (n = 12) patients in Group 2, 41.17% (n = 7) patients in Group 3, and 36.66% (n = 11) patients in Group 4. Among the four groups, Group 3 patients had high prevalence of depression followed by Group 4, Group 2, and Group 1 subjects, as seen in [Figure 1]. ANOVA results [Table] showed significant difference in depression scores within and between the groups (P < 0.01). Post hoc analysis using Tukey B test showed significant difference at P < 0.01 between Groups 1 and 2, 1 and 3, and 1 and 4.
Bivariate analysis using Wilks' lambda and Hotelling's Trace tests showed significant interaction effects between the groups and psychological variables (anxiety and depression) at the level of significance P < 0.01.
| » Discussion|| |
In our present study, control group participants had higher depression than anxiety, which are similar to the prevalence rates of anxiety and depression,, in general population. The prevalence of anxiety in the control group was less when compared to the other studies, which could be due to the variability in diagnostic instruments and sample size. Anxiety and depression in clinical epileptic population were significantly different from nonepileptic patients in the study, which is supported by sufficient evidence from literature.,,,,, In the present study, epileptic groups with and without structural abnormalities of the brain showed anxiety and depression.
Multifactorial interactions such as seizure frequency,, type of seizure,, age of seizure onset, structural abnormalities,,, and antiepileptic drugs, are reported to contribute toward anxiety and depression in epileptic patients. In our intractable epileptic population, seizure-related variables including seizure frequency, type of seizure, and antiepileptic drugs were similar across the epileptic groups. The prevalence of anxiety and depression in epilepsy patients in our study were similar to those of other studies,,,,,, however, we could observe difference between their subgroups. MCD patients showed greater depression when compared to the other epileptic groups. The MCD groups in the study were predominantly focal cortical dysplasias involving structures such as frontal, parietal, and cingulate gyrus and pathways which are involved in depression., Other types of MCDs in this group who were associated with mental retardation were excluded from the study. Higher prevalence of depression in MCD group could also be due to the early age of onset of seizures in this population, which is a significant predictor for depression. Decreased prevalence of anxiety in MCD group could also be due to the focal lesion without much involvement of the amygdala. Anxiety and depression were observed equally in patients with IHI which implies the involvement of hippocampal pathways in re-experiencing fear and depression., There are no studies in literature to support the prevalence of anxiety and depression in MCDs and IHI.
There are growing evidences that IHI is pathological in patients with epilepsy., Recent neuroimaging studies have observed that IHI is prevalent in both epileptic and nonepileptic population. Although controversies exist considering IHI as abnormal in epileptic patients, evidences from literature provide an insight that IHI could be a neural substrate for epilepsy., IHI is often reported to be associated with various malformations in limbic system. In our series of patients, we found that isolated IHI were associated with higher prevalence of anxiety. Because malformed hippocampus may be associated with structural and morphological changes in the limbic system, we expect higher prevalence of anxiety. At present, there are no studies available in the literature to support this viewpoint. However, from the review of literature in anxiety disorders such as generalized anxiety, phobia, panic disorders,, obsessive compulsive disorder, and posttraumatic stress disorder, there is ample evidence that reduction in size and increased activation of amygdala and hippocampus are involved in the the pathophysiology of anxiety.
Although we provide a novel finding in patients with IHI, there are few limitations of the study to support its involvement in the pathophysiology of anxiety and depression. First, we have not estimated the volumes of amygdala in the patients to assess its contribution and role in anxiety. Second, we have investigated for IHI in the control group; however, their imaging findings were negative for IHI. In the present study, comparison of IHI in epileptic and nonepileptic patients was not possible because of the smaller sample size. Further research is required in patients with refractory epilepsy with IHI to establish its role in anxiety and depression.
| » Conclusion|| |
Intractable epileptic patients have significant anxiety and depression. Depression is seen in all groups and anxiety is observed predominantly when there is hippocampal malformation. We emphasize the need to identify IHI in intractable epilepsy and assess anxiety and depression to treat them effectively. This improves the quality of life in epilepsy population.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]