Contribution of the µ-opioid receptor system to affective disorders in temporal lobe epilepsy: A bidirectional relationship?

OBJECTIVE: Affective disorders are frequent comorbidities of temporal lobe epilepsy (TLE). The endogenous opioid system has been implicated in both epilepsy and affective disorders, and may play a significant role in their bidirectional relationship. In this cross-sectional study, we investigated the association between µ-opioid receptor binding and affective disorders in patients with TLE. METHODS: Nine patients with TLE and depression/anxiety underwent 11 C-carfentanil positron emission tomography (CFN PET) and neuropsychiatric assessment, including the Hospital Anxiety and Depression Scale and the Positive and Negative Affect Schedule. The normalized CFN PET scans were compared with those of 26 age-matched healthy controls. Correlation analyses with affective symptoms were performed by region of interest-based analysis focusing on the limbic circuit and orbitofrontal cortex. RESULTS: We observed widely reduced CFN binding potential (BP) in bilateral frontal lobes and striata in patients with TLE compared to healthy controls. In the TLE group, more severe anxiety and negative affect were associated with decreased CFN BP in the posterior cingulate gyrus. SIGNIFICANCE: In patients with TLE, interictally reduced binding in the opioid system was associated with higher levels of anxiety and negative affect. We speculate that seizure-related agonist-driven desensitization and downregulation of opioid receptors could be a potential underlying pathomechanism.

Postictal Psychosis in Epilepsy: A Clinicogenetic Study.

OBJECTIVE: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterized postictal psychosis, which comprises about one quarter of epilepsy-related psychoses, and has unknown causation. METHODS: We conducted a case-control cohort study including patients diagnosed with postictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile, and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis; 49 had postictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with postictal psychosis; univariate associations with a p value < 0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated. RESULTS: Cases were more likely to have seizure clustering (odds ratio [OR] = 7.59, p < 0.001), seizures with a recollected aura (OR = 2.49, p = 0.013), and a family history of psychiatric disease (OR = 5.17, p = 0.022). Cases showed predominance of right temporal epileptiform discharges (OR = 4.87, p = 0.007). There was no difference in epilepsy duration, neuroimaging findings, or antiseizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of postictal psychosis cases (n = 58) were significantly higher than in 1,366 epilepsy controls (R2  = 3%, p = 6 × 10-3 ), but not significantly different from 945 independent patients with schizophrenia (R2  = 0.1%, p = 0.775). INTERPRETATION: Postictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (postictal psychosis) in a common disease. ANN NEUROL 2021;90:464-476.

Cognitive behavior therapy for comorbid dissociative seizures in patients with epilepsy.

OBJECTIVES: The main aim of this study was to assess the effectiveness of cognitive behavior therapy (CBT) for comorbid dissociative seizures (DS) in patients with epilepsy. METHODS: We conducted a retrospective case note review of 14 patients with epilepsy who underwent outpatient CBT for DS in a tertiary neuropsychiatry service. The diagnosis of DS was confirmed by neurologists clinically and/or following video-telemetry electroencephalogram (EEG). We evaluated the outcome of the CBT treatment with respect to frequency of DS, measures of depression, anxiety, and social functioning. RESULTS: Measures of depression and anxiety significantly reduced following CBT treatment. Overall, frequency of DS reduced following CBT treatment but did not reach statistical significance. SIGNIFICANCE: This study provides evidence that CBT can be effective in reducing depression and anxiety in patients with both epilepsy and DS. Anxiety and depression are likely to be associated with DS. Further research in larger samples and longitudinal studies are recommended to evaluate the long-term efficacy of CBT in this patient group.

Factors affecting seizure outcome after epilepsy surgery: an observational series.

IMPORTANCE: Surgical treatment can bring seizure remission in people with focal epilepsy but requires careful selection of candidates. OBJECTIVES: To determine which preoperative factors are associated with postoperative seizure outcome. DESIGN: We audited seizure outcome of 693 adults who had resective epilepsy surgery between 1990 and 2010 and used survival analysis to detect preoperatively identifiable risk factors of poor seizure outcome. RESULTS: Seven factors were significantly associated with increased probability of recurrence of seizures with impaired awareness postsurgery: MRI findings (eg, HR adjusted for other variables in the model 2.5; 95% CI 1.6 to 3.8 for normal MRI compared with hippocampal sclerosis), a history of secondarily generalised convulsive seizures (2.3; 95% CI 1.7 to 3.0 for these seizures in the previous year vs never), psychiatric history (1.3; 95% CI 1.1 to 1.7), learning disability (1.8; 95% CI 1.2 to 2.6) and extratemporal (vs temporal) surgery (1.4; 95% CI 1.02, 2.04). People with an older onset of epilepsy had a higher probability of seizure recurrence (1.01; 95% CI 1.00, 1.02) as did those who had used more antiepileptic drugs (1.05; 95% CI 1.01 to 1.09). Combinations of variables associated with seizure recurrence gave overall low probabilities of 5-year seizure freedom (eg, a normal MRI and convulsive seizures in the previous year has a probability of seizure freedom at 5 years of approximately 0.19). CONCLUSIONS AND RELEVANCE: Readily identified clinical features and investigations are associated with reduced probability of good outcome and need consideration when planning presurgical evaluation.

De novo psychogenic nonepileptic attacks after adult epilepsy surgery: an underestimated entity.

We retrospectively assessed all patients in a large cohort of patients with epilepsy surgery at the National Hospital for Neurology and Neurosurgery (NHNN) over 12 years, to identify patients with postoperative psychogenic nonepileptic attacks (PNEA). Twenty-nine patients (23 women) were identified of a total of 790 patients, a frequency of 3.7%. Female gender and presurgical psychiatric diagnosis, other than psychosis, were significant risk factors for PNEA development. In female patients with a preoperative psychiatric diagnosis the chance of developing PNEA after epilepsy surgery was 8.5%. PNEA developed between 2 weeks and 10 years after epilepsy surgery, independently of outcome of epileptic seizures. In most cases, PNEA differed from the present or past epileptic seizures, and motor symptoms were the most common manifestations. Seizures after epilepsy surgery should be carefully evaluated. Physicians should consider the possibility of PNEA, especially in female patients with preoperative psychiatric comorbidity developing "atypical" seizures with motor manifestations postoperatively, even many years after epilepsy surgery.

Predicting and preventing psychopathology following temporal lobe epilepsy surgery.

Less than 3% of temporal lobe epilepsy (TLE) surgical outcome studies have investigated the psychiatric sequelae and morbidity associated with surgery. This is disproportionate to the extent of the problem. Variable prevalence rates have been reported for post-surgical depression, anxiety, and interictal psychosis. Until recently, very few studies distinguished de novo postoperative presentations from pre-existing conditions, making it difficult to accurately assess the impact of TLE surgery on psychiatric morbidity. Predictors of de novo postoperative presentations have proved elusive. This current review summarizes the findings from a systematic literature review of the psychiatric morbidity associated with TLE surgery including newly published follow-up data from our own series of 280 surgical patients. A framework for future research, possible pathophysiological mechanisms, and translational models are also discussed.

Predictors of psychiatric and seizure outcome following temporal lobe epilepsy surgery.

PURPOSE: Neurosurgery is an effective therapy for selected individuals with medically refractory temporal lobe epilepsy (TLE). De novo psychopathology may complicate the postsurgical outcome. Our aims were to identify predictors of de novo psychiatric and seizure outcome following TLE surgery. METHODS: Medical records of 280 patients who underwent TLE surgery were reviewed. Preoperative and postoperative psychiatric diagnoses were identified, in addition to information on seizure recurrence and neuropsychological status. Logistic regression analysis was used to identify predictors of having a de novo psychiatric diagnosis and remaining seizure-free within 4 years following surgery. KEY FINDINGS: One hundred five patients (38%) had significant psychiatric problems within 4 years following TLE surgery. Fifty-one patients (18%) developed de novo psychopathology; half of cases presented within 6 months and 90% of psychopathologies persisted 6 months or longer. A preoperative history of secondary generalized tonic-clonic seizure(s) (SGTCS) was an independent predictor of de novo psychopathology (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.14-6.59, p = 0.02). From patients with available seizure data, 49% (127 of 258) remained seizure-free for 4 years after surgery. Patients with a history of SGTCS (OR 0.47, 95% CI 0.25-0.90, p = 0.02) and those with a preoperative psychiatric diagnosis (OR 0.53, 95% CI 0.28-0.98, p = 0.04) were significantly less likely to remain seizure-free. SIGNIFICANCE: De novo psychopathology is a significant complication of TLE surgery. Inclusion of neuropsychiatric assessments in the presurgical evaluation may lead to increase in the power of prognostic models used to predict the neurologic outcome of TLE surgery.

Cortical abnormalities and their cognitive correlates in patients with temporal lobe epilepsy and interictal psychosis.

PURPOSE: To determine whether cortical abnormalities are more severe and widespread in patients with temporal lobe epilepsy (TLE) and interictal psychosis (IP) compared to those with TLE only (NIP) and healthy controls (HC), and to explore the associations between cortical parameters (area, thickness and volume), psychotic symptoms, and cognitive performance. METHODS: Twenty-two patients with IP (9 male; 10 hippocampal sclerosis, HS), 23 TLE nonpsychotic (NIP) patients (11 male; 13 HS) matched for duration of epilepsy and 20 HC participated. Surface-based morphometry (SBM) was used to measure cortical parameters. Cognition was examined in IP and NIP patients. Associations between cortical parameters and cognition were examined using linear mixed models adjusted by age, gender, and brain volume. KEY FINDINGS: IP patients had an earlier onset of epilepsy, more status epilepticus, and worse cognitive performance than NIP patients. In IP patients, cortical thickness was reduced in the inferior frontal gyrus (IFG), and their current IQ was associated with decreases in area, but not thickness, in regions of the frontotemporal cortex. SIGNIFICANCE: IP likely reflects the interplay of psychosis-related genetic factors and the cumulative effects of seizure activity on the brain. Cortical thinning in the IFG, a region implicated in schizophrenia, is likely to be related to seizure activity, whereas changes in IQ, associated with reductions in area of frontotemporal cortex, may be related to the presence of psychosis.

Long-term seizure, psychiatric and socioeconomic outcomes after frontal lobe epilepsy surgery.

OBJECTIVE: Resective surgery for selected individuals with frontal lobe epilepsy can be effective, although multimodal outcomes are less established than in temporal lobe epilepsy. We describe long-term seizure remission and relapse patterns, psychiatric comorbidity, and socioeconomic outcomes following frontal lobe epilepsy surgery. METHODS: We reviewed individual data on frontal lobe epilepsy procedures at our center between 1990 and 2020. This included the presurgical evaluation, operative details and annual postoperative seizure and psychiatric outcomes, prospectively recorded in an epilepsy surgery database. Outcome predictors were subjected to multivariable analysis, and rates of seizure freedom were analyzed using Kaplan-Meier methods. We used longitudinal assessment of the Index of Multiple Deprivation to assess change in socioeconomic status over time. RESULTS: A total of 122 individuals with a median follow-up of seven years were included. Of these, 33 (27 %) had complete seizure freedom following surgery, with a further 13 (11 %) having only auras. Focal MRI abnormality, histopathology (focal cortical dysplasia, cavernoma or dysembryoplastic neuronal epithelial tumor) and fewer anti-seizure medications at the time of surgery were predictive of a favorable outcome; 67 % of those seizure-free for the first 12 months after surgery never experienced a seizure relapse. Thirty-one of 50 who had preoperative psychiatric pathology noticed improved psychiatric symptomatology by two years postoperatively. New psychiatric comorbidity was diagnosed in 15 (13 %). Persistent motor complications occurred in 5 % and dysphasia in 2 %. No significant change in socioeconomic deciles of deprivation was observed after surgery. SIGNIFICANCE: Favorable long-term seizure, psychiatric and socioeconomic outcomes can be seen following frontal lobe epilepsy surgery. This is a safe and effective treatment that should be offered to suitable individuals early.

Disrupted White Matter Integrity and Structural Brain Networks in Temporal Lobe Epilepsy With and Without Interictal Psychosis.

Background: Despite the importance of psychosis as a comorbidity of temporal lobe epilepsy (TLE), the underlying neural mechanisms are still unclear. We aimed to investigate abnormalities specific to psychosis in TLE, using diffusion MRI parameters and graph-theoretical network analysis. Material and Methods: We recruited 49 patients with TLE (20 with and 29 without interictal schizophrenia-like psychosis) and 42 age-/gender-matched healthy controls. We performed 3-tesla MRI scans including 3D T1-weighted imaging and diffusion tensor imaging in all participants. Among the three groups, fractional anisotropy (FA), mean diffusivity (MD), and global network metrics were compared by analyses of covariance. Regional connectivity strength was compared by network-based statistics. Results: Compared to controls, TLE patients showed significant temporal and extra-temporal changes in FA, and MD, which were more severe and widespread in patients with than without psychosis. We observed distinct differences between TLE patients with and without psychosis in the anterior thalamic radiation (ATR), inferior fronto-occipital fasciculus (IFOF), and inferior longitudinal fasciculus (ILF). Similarly, for network metrics, global, and local efficiency and increased path length were significantly reduced in TLE patients compared to controls, but with more severe changes in TLE with psychosis than without psychosis. Network-based statistics detected significant differences between TLE with and without psychosis mainly involving the left limbic and prefrontal areas. Conclusion: TLE patients with interictal schizophrenia-like psychosis showed more widespread and severe white matter impairment, involving the ATR, IFOF and ILF, as well as disrupted network connectivity, particularly in the left limbic and prefrontal cortex, than patients without psychosis.

Frontal lobe dysfunction as a predictor of depression and anxiety following temporal lobe epilepsy surgery.

OBJECTIVE: Predictors of psychiatric outcome following TLE surgery have proved elusive and represent a current challenge in the practice of TLE surgery. This prospective study investigated whether frontal lobe dysfunction is predictive of poorer psychiatric outcomes. METHODS: Forty-nine unilateral TLE surgical patients were assessed using the Beck Depression Inventory-Fast Screen (BDI-FS) and Beck Anxiety Inventory (BAI) preoperatively and 6 and 12 months postoperatively. Measures of intellectual function, semantic knowledge, memory and executive function were completed preoperatively, at 6 and 12 months following surgery. RESULTS: Preoperatively, 33 (67%) patients had minimal depressive symptoms, 8 (16%) were mildly depressed, 2 (4%) were moderately depressed, and 6 (12%) reported severe depressive morbidity. Twenty-three (47%) patients reported minimal anxiety, 18 (37%) were mildly anxious, 6 (12%) were moderately anxious and 2 (4%) patients reported severe anxiety symptoms. A mixed-model repeated-measures analysis was performed on the BDI-FS and BAI scores, adjusting for pertinent covariates identified in univariable analyses. At a year following TLE surgery, anxiety symptoms significantly improved but depressive morbidity did not. Indicators of frontal lobe dysfunction moderated the magnitude and direction of mood change. Specifically, pre-surgical cognitive measures of frontal lobe dysfunction predicted increased depression and anxiety symptoms following surgery. There was no relationship between preoperative BDI-FS or BAI scores and seizure outcome at 12 months or change in affective morbidity and seizure outcome. SIGNIFICANCE: This is the first longitudinal study to provide evidence that specific pre-surgical cognitive and behavioural indices of frontal dysfunction are predictive of poorer psychiatric outcome following TLE surgery. In addition, our findings highlight the potential utility of a dysexecutive behavioural rating scale (DEX) as an assessment tool in epilepsy. Examination of executive functioning in pre-surgical evaluations may lead to an increase in the power of prognostic models used to predict the psychiatric outcome of TLE surgery.

A magnetization transfer imaging study in patients with temporal lobe epilepsy and interictal psychosis.

BACKGROUND: Findings from previous neuropathological and neuroimaging studies in patients with epilepsy and interictal psychosis have been inconclusive, and both focal and widespread brain abnormalities have been reported. Thus, further investigation with advanced in vivo magnetic resonance imaging (MRI) techniques, such as magnetization transfer imaging, capable of detecting more subtle brain abnormalities, is warranted. METHODS: Twenty patients with temporal lobe epilepsy and interictal psychosis were compared with 20 nonpsychotic patients. Patients were matched with respect to conventional MRI findings. Each group comprised of 10 patients with hippocampal sclerosis (6 left, 4 right) and 10 patients without focal lesions on MRI. A voxel-based analysis was used for the group comparisons. RESULTS: Voxel-based analysis revealed significant reductions of magnetization transfer ratio (an index of signal loss derived from magnetization transfer imaging) in the left superior and middle temporal gyri in the psychotic patients for the subgroup of patients with no focal lesions on MRI. There were no significant volumetric differences between the psychotic and nonpsychotic patients. CONCLUSIONS: Focal cortical magnetization transfer ratio abnormalities in the left temporal lobe unrelated to volume changes can be demonstrated in some temporal lobe epilepsy patients with interictal psychosis. Our findings might reflect subtle neuropathological abnormalities that are undetected by conventional MRI.

A neuropsychological study of patients with temporal lobe epilepsy and chronic interictal psychosis.

PURPOSE: To characterize the pattern of cognitive deficits in patients with temporal lobe epilepsy (TLE) and interictal (schizophrenia-like) psychosis and to examine the relationship between neuropsychological deficits and Magnetization transfer imaging. METHODS: Twenty patients with TLE and interictal psychosis were compared to 20 non-psychotic TLE patients. Patients were matched with respect to premorbid IQ, age and conventional MRI findings. A battery of neuropsychological tests was administered. The neuropsychological tests which showed significant group differences were used for correlational analysis with magnetization transfer ratio (MTR) which provides a quantitative measure of macromolecular structural integrity. RESULTS: Patients with interictal psychosis were significantly more impaired on executive and semantic memory tasks than the non-psychotic TLE group. Vocabulary test scores correlated significantly with MTR reduction in the left fusiform gyrus in the psychotic but not the non-psychotic group. DISCUSSION: In this study, patients with TLE and interictal psychosis were more cognitively impaired than non-psychotic TLE patients. Our findings suggest that the cognitive deterioration in these patients may occur as the illness progresses and the causes for this are probably multifactorial. Our study also provides further evidence that MTR may be useful in investigating structural correlates of cognitive impairment.

Neuropsychiatric systemic lupus erythematosus: a diagnostic challenge.

A 58-year-old woman presented to neuropsychiatric services with increased frequency of confusional episodes and intermittent psychotic symptoms. She had a 19-year history of atypical epileptic seizures and cognitive decline. Detailed review of history and clinical investigations revealed that she had accumulated sufficient features to meet diagnostic criteria for systemic lupus erythematosus (SLE). She had previously had lymphopenia and a malar rash; she had positive antinuclear, anti-Ro (anti-Sjögren's-syndrome-related antigen A) and anti-SM (anti-Smith Antibody) antibodies, and elevated erythrocyte sedimentation rate. The seizures, cognitive impairment and psychosis were attributable to neuropsychiatric SLE. Treatment with immune-modulating therapy, cyclophosphamide, resulted in significant improvement in subjective and objective clinical presentation. Neuropsychiatric SLE should be considered a potential differential diagnosis for patients presenting with seizures, psychotic symptoms or cognitive decline. A detailed clinical evaluation with review of the medical history and appropriate laboratory analyses allows this diagnosis to be made, and appropriate treatment to be initiated.

Neural correlates of de novo depression following left temporal lobe epilepsy surgery: a voxel based morphometry study of pre-surgical structural MRI.

PURPOSE: To investigate cerebral grey matter (GM) volumetric abnormalities in temporal lobe epilepsy (TLE) patients who develop de novo depression following TLE surgery using voxel-based morphometry (VBM). METHODS: We retrospectively examined pre-surgical grey matter (GM) volumes in 30 patients with TLE due to unilateral left-sided hippocampal sclerosis using 1.5-T MRI scan, which were segmented with optimised VBM parameters and normalised to a sample template using DARTEL, with SPM8 software. Voxel-wise GM differences between patients that developed de novo post-surgical depression (n=5) were compared with patients with no pre- or postoperative psychiatric diagnoses (n=25), using independent samples t-tests with age, gender and secondary generalised tonic-clonic seizures (SGTCS) as covariates (p<.001, unc). KEY FINDINGS: Reduced preoperative bilateral GM in orbitofrontal cortices (OFC) and ipsilateral cingulate gyrus and thalamus were significantly associated with the development of de novo depression within 4 years postoperatively. Further analyses revealed no differences in seizure freedom (ILAE 1 vs 2-6) or postoperative memory decline between the groups. SIGNIFICANCE: Although the development of postoperative de novo depression following TLE surgery is likely to be multi-factorial, our results suggest that bilateral OFC and ipsilateral cingulate gyrus and thalamic atrophy in left-sided TLE patients may play a modulatory role. Abnormalities in these areas have also been implicated in primary mood disorders. Prospective neuroimaging studies with larger cohorts are warranted to replicate these results, and further elucidate the neural correlates of de novo depression.

Postictal psychosis in temporal lobe epilepsy: risk factors and postsurgical outcome?

PURPOSE: Postictal psychosis (PIP) occurs in ∼7% of patients with temporal lobe epilepsy (TLE). The aims of this study were to identify risk factors that may predispose patients to developing PIP and determine whether the severity of PIP predicts postsurgical outcome. METHODS: We compared 20 patients with a history of TLE+PIP to 60 age-matched TLE patients without any psychiatric history (TLE-only), with respect to pre-surgical clinical and neuropsychological variables. Group differences in postsurgical psychiatric, histopathological, cognitive and seizure outcomes were also examined. KEY FINDINGS: TLE+PIP patients were significantly less likely to have localised ictal epileptiform activity than the TLE controls (p=0.05) and were significantly more likely to have a positive family psychiatric history than TLE controls (p=0.04). Other pre-surgical clinical and neuropsychological variables did not distinguish between the groups. Patients with two or more PIP episodes had significantly increased odds of developing de novo psychopathology within 4 years of surgery, after controlling for comorbid pre-surgical psychiatric status and a history of SGTCS (OR: 9.11, 95% CI: 1.53-54.10, p=0.02). A history of PIP did not significantly predict other postsurgical outcomes (seizure freedom (ILAE=1) or cognitive outcome). SIGNIFICANCE: Our results suggest that more widespread or diffuse brain abnormalities as reflected by pre-surgical EEG findings and positive genetic determinants may contribute to the development of PIP. Furthermore, patients with recurrent PIP episodes who undergo TLE surgery are at increased risk of developing de novo psychiatric disorders, particularly mood disorders. This has implications for pre-operative counselling and highlights a need for postsurgical psychiatric monitoring for these patients.

Diffusion tensor imaging findings and their correlation with neuropsychological deficits in patients with temporal lobe epilepsy and interictal psychosis.

PURPOSE: To examine frontotemporal white-matter integrity in patients with temporal lobe epilepsy (TLE) and interictal psychosis. METHOD: Patients with TLE and interictal psychosis (IP; n = 20) were compared with age-matched TLE patients without psychosis (NIP; n = 20). Patients had either no focal lesions or hippocampal sclerosis on conventional MRI. Complete diffusion tensor imaging (DTI) data were available in 18 IP and 20 NIP patients. A region-of-interest (ROI) approach was used to determine the DTI measures, fractional anisotropy (FA) and mean diffusivity (MD), in the middle frontal and middle temporal gyri. The relation between the DTI measures and neuropsychological tests previously identified as impaired in the IP group was examined. RESULTS: The IP group had significantly lower FA values in both frontal and temporal regions and significantly higher MD in bilateral frontal regions. We found that performance on some neuropsychological tests was significantly related to frontotemporal FA reductions. CONCLUSIONS: Our findings suggest that subtle abnormalities in the frontotemporal white matter of patients with interictal psychosis may be undetectable on conventional MRI. These abnormalities may contribute to the cognitive deficits detected in these patients.