Olfactory Bulbectomy Leads to the Development of Epilepsy in Mice

There is a clear link between epilepsy and depression. Clinical data demonstrate a 30–35% lifetime prevalence of depression in patients with epilepsy, and patients diagnosed with depression have a three to sevenfold higher risk of developing epilepsy. Traditional epilepsy models partially replicate the clinical observations, with the demonstration of depressive traits in epileptic animals. Studies assessing pro-epileptogenic changes in models of depression, however, are more limited. Here, we examined whether a traditional rodent depression model—bilateral olfactory bulbectomy—predisposes the animals towards the development of epilepsy. Past studies have demonstrated increased neuronal excitability after bulbectomy, but continuous seizure monitoring had not been conducted. For the present study, we monitored control and bulbectomized animals by video-EEG 24/7 for approximately two weeks following the surgery to determine whether they develop spontaneous seizures. All seven bulbectomized mice exhibited seizures during the monitoring period. Seizures began about one week after surgery, and occurred in clusters with severity increasing over the monitoring period. These results suggest that olfactory bulbectomy could be a useful model of TBI-induced epilepsy, with advantages of relatively rapid seizure onset and a high number of individuals developing the disease. The model may also be useful for investigating the mechanisms underlying the bidirectional relationship between epilepsy and depression.     

Epilepsy in the elderly and depression

Epilepsy is one of the most common neurological problems affecting approximately 1% of the world's population with higher incidence among elderly individuals. Although depression is a common comorbid condition in patients with epilepsy, there is a paucity of information regarding depression in geriatric patients with epilepsy. This study analysed a group of 83 patients affected by different epilepsy phenotypes accompanied by mental disorders, especially depression. Antiepileptic and antipsychotic drug treatment has been evaluated, particularly a positive effect of the new antiepileptics (monotherapy and polytherapy) both on the reduction of seizures and mental disorders.     

Epilepsy Associated Depression: An Update on Current Scenario,Suggested Mechanisms,and Opportunities

Depression is one of the most frequent psychiatric comorbidities associated with epilepsy having a major impact on the patient’s quality of life. Several screening tools are available to identify and follow up psychiatric disorders in epilepsy. Out of various psychiatric disorders, people with epilepsy (PWE) are at greater risk of developing depression. This bidirectional relationship further hinders pharmacotherapy of comorbid depression in PWE as some antiepileptic drugs (AEDs) worsen associated depression and coadministration of existing antidepressants (ADs) to alleviate comorbid depression has been reported to worsen seizures. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) are first choice of ADs and are considered safe in PWE, but there are no high-quality evidences. Similar to observations in people with depression, PWE also showed pharmacoresistant to available SSRI/SNRIs, which further complicates the disease prognosis. Randomized double-blind placebo-controlled clinical trials are necessary to report efficacy and safety of available ADs in PWE. We should also move beyond ADs, and therefore, we reviewed common pathological mechanisms such as neuroinflammation, dysregulated hypothalamus pituitary adrenal (HPA) axis, altered neurogenesis, and altered tryptophan metabolism responsible for coexistent relationship of epilepsy and depression. Based on these common pertinent pathways involved in the genesis of epilepsy and depression, we suggested novel targets and therapeutic approaches for safe management of comorbid depression in epilepsy.

     

<Superscript>123</Superscript>I-ADAM SPET imaging of serotonin transporter in patients with epilepsy and comorbid depression

Background

Purpose of the study was to investigate alterations in midbrain serotonin transporter (SERT) binding in patients with epilepsy and symptoms of depression compared to patients with epilepsy with no symptoms of depression.

Methods

We studied 12 patients with epilepsy (7 patients had focal and 5 had generalized epilepsy syndromes). The presence of self-reported symptoms of depression was assessed using Beck Depression Inventory (BDI) and the Emotional State Questionnaire (EST-Q). The binding potential of the SERT was assessed by performing brain single photon emission tomography (SPET) using the SERT radioligand 2-((2-((dimethylamino)methyl)phenyl)thio)-5-(123)iodophenylamine (¹²³I-ADAM).

Results

Seven patients had BDI and EST-Q subscale scores greater than 11 points, which was interpreted as the presence of symptoms of depression. We found that ¹²³I-ADAM binding was not significantly different between patients with epilepsy with and without symptoms of depression. In addition, ¹²³I-ADAM binding did not show a significant correlation to either BDI or EST-Q depression subscale scores and did not differ between patients with focal vs. generalized epilepsy.

Conclusion

The results of our study failed to demonstrate alterations of SERT binding properties in patients with epilepsy with or without symptoms of depression.

     

Psychiatric Comorbidity,Social Aspects and Quality of Life in a Population-Based Cohort of Expecting Fathers with Epilepsy

Objectives

To investigate psychiatric disorders, adverse social aspects and quality of life in men with epilepsy during partner’s pregnancy.

Method

We used data from the Norwegian Mother and Child Cohort Study, including 76,335 men with pregnant partners. Men with epilepsy were compared to men without epilepsy, and to men with non-neurological chronic diseases.

Results

Expecting fathers in 658 pregnancies (mean age 31.8 years) reported a history of epilepsy, 36.9% using antiepileptic drugs (AEDs) at the onset of pregnancy. Symptoms of anxiety or depression were increased in epilepsy (7.0% and 3.9%, respectively) vs. non-epilepsy (4.6% and 2.5%, respectively, p = 0.004 and 0.023), and so were new onset symptoms of depression (2.0% vs. 1.0%, p < 0.031) and anxiety (4.3% vs. 2.3%, p = 0.023). Low self-esteem (2.5%) and low satisfaction with life (1.7%) were more frequent among fathers with epilepsy compared to fathers without epilepsy (1.3% and 0.7%, respectively, p = 0.01 and 0.010). Adverse social aspects and life events were associated with epilepsy vs. both reference groups. Self-reported diagnoses of ADHD (2.2%) and bipolar disorder (1.8%) were more common in epilepsy vs. non-epilepsy (0.4% and 0.3%, respectively, p = 0.002 and 0.003) and non-neurological chronic disorders (0.5% and 0.5%, respectively, p = 0.004 and 0.018). A screening tool for ADHD symptoms revealed a higher rate compared to self-reported ADHD (9.5% vs. 2.2%, p < 0.001).

Conclusion

Expecting fathers with epilepsy are at high risk of depression and anxiety, adverse socioeconomic aspects, low self-esteem, and low satisfaction with life. Focus on mental health in fathers with epilepsy during and after pregnancy is important. The use of screening tools can be particularly useful to identify those at risk.     

Temporal Lobe Epilepsy: A Clinical Study of 47 Cases

Clinical features of 47 cases of temporal lobe epilepsy are analyzed and treatment of this disorder is outlined. Twenty-four per cent of all cases of epilepsy seen by one of the authors over a two-year period were of this type. Fifteen of these 47 patients had a history of birth injury. Care must be taken to distinguish the symptoms of temporal lobe epilepsy from those of acute anxiety or hysteria and to differentiate the short-lived temporal lobe attack from centrencephalic petit mal.Interictal personality disturbances were identified in 11 of 24 persons with temporal lobe epilepsy, four of 35 with focal epilepsy from all other areas, and one of 17 with centrencephalic epilepsy. Personality deviations most frequently encountered were irritability, aggressiveness, bouts of depression, paranoid tendencies and exhibitionism. Medical or surgical treatment often improves the personality abnormalities concomitantly with control of seizures.     

Maternal care exerts disease‐modifying effects on genetic absence epilepsy and comorbid depression

WAG/Rij rats, a genetic animal model of absence epilepsy with comorbidity of depression, exhibit behavioral depression‐like symptoms and spontaneous generalized spike‐wave discharges (SWDs) in the EEG at the age of 6 to 8 months. The aim of the present study was to test the hypothesis that maternal care is an environmental factor which, along with genetic predisposition, may contribute to the expression of absence seizures and depression‐like comorbidity later in life. To achieve this, a cross‐fostering procedure was used. EEG and behavior in the forced swimming test were analyzed in WAG/Rij and Wistar offspring reared by their own mothers (non‐cross‐fostered), foster mothers of the same strain (in‐fostered) or another strain (cross‐fostered) at the age of 7 to 8 months. Maternal care and forced swimming test behavior were assessed in the dams. WAG/Rij mothers showed depression‐like behavior and reduced maternal care irrespective of litter size and litter composition (own or foster pups) compared with Wistar dams. WAG/Rij offspring reared by Wistar dams with a high level of maternal care exhibited less and shorter SWDs and reduced depression‐like comorbidity in adulthood compared with age‐matched WAG/Rij offspring reared by their own or foster WAG/Rij mothers with a low level of maternal care. Moreover, rearing by Wistar mothers delayed the onset of absence epilepsy in WAG/Rij rats. Adoption by WAG/Rij dams did not change EEG and behavior in Wistar rats. Our study demonstrates that improvement of early care‐giving environment can be used as a disease‐modifying treatment to counteract epileptogenesis and behavioral comorbidities in genetic absence epilepsy.     

Which clinical and experimental data link temporal lobe epilepsy with depression?

The association of temporal lobe epilepsy with depression and other neuropsychiatric disorders has been known since the early beginnings of neurology and psychiatry. However, only recently have in vivo and ex vivo techniques such as Positron Emission Tomography, Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy in combination with refined animal models and behavioral tests made it possible to identify an emerging pattern of common pathophysiological mechanisms. We now have growing evidence that in both disorders altered interaction of serotonergic and noradrenergic neurons with glutamatergic systems is associated with abnormal neuronal circuits and hyperexcitability. Neuronal hyperexcitability can possibly evoke seizure activity as well as disturbed emotions. Moreover, decreased synaptic levels of neurotransmitters and high glucocorticoid levels influence intracellular signaling pathways such as cAMP, causing disturbances of brain-derived and other neurotrophic factors. These may be associated with hippocampal atrophy seen on Magnetic Resonance Imaging and memory impairment as well as altered fear processing and transient hypertrophy of the amygdala. Positron Emission Tomography studies additionally suggest hypometabolism of glucose in temporal and frontal lobes. Last, but not least, in temporal lobe epilepsy and depression astrocytes play a role that reaches far beyond their involvement in hippocampal sclerosis and ultimately, therapeutic regulation of glial-neuronal interactions may be a target for future research. All these mechanisms are strongly intertwined and probably bidirectional such that the structural and functional alterations from one disease increase the risk for developing the other. This review provides an integrative update of the most relevant experimental and clinical data on temporal lobe epilepsy and its association with depression.     

Ferulic Acid Supplementation for Management of Depression in Epilepsy

Neurochemical Research - Neuroinflammation driven altered neurochemical milieu have been reported to play a significant role in pathogenesis of comorbid depression in epilepsy. Most of the...     

Screening for depression disorders in patients with chronic somatic illness

Depression is one of the most common complications in patients with chronic somatic illnesses. Comorbidity of depression with physical illness often remains unrecognized and untreated, additionally aggravating the somatic illness itself, its treatment and prognosis. The aim of this study was to investigate the prevalence of depression in chronic somatic patients suffering from diabetes, epilepsy, asthma, chronic obstructive pulmonary disease (COPD) and hypothyroidism. Patients, who were regularly attending control examinations in neurological and internal medicine out-patient departments, were tested for the presence of depression with Beck Depression Inventory. The sample comprised 2153 chronic somatic patients aged between 18 and 80 years. Out of this total, 228 patients (10.6%) did not complete the study, (5.12%) refused to participate, and (5.5%) of the patients were technical failures. 1925 patients completed the study, and 1383 of them were not depressive. In 542 patients (28.5%) depression was confirmed, being almost twice more frequent in women, 346 (64%) vs. 196 (36%) male. Among these depressed examinees, mild depression was found in 284 (52.4%), major in 186 (34.3%) and severe in 72 (13.3%) chronic somatic patients. The majority of patients were aged over 55 yrs (49%). This population contained the largest number of depressed examinees (49.9%). The prevalence of depression with regard to subgroups shows that (25.6%) of asthma patients were depressed, as well as (26.6%) of those with COPD. These two groups did not present statistically significant differences regarding gender. The depression level of (32.2%) was found in patients with diabetes, of (29.6%) in patients with epilepsy and of (24.2%) among those with hypothyroidism. As for gender, statistically significant difference was found in the last three groups of patients (p < 0.001).     

Rearing by foster Wistar mother with high level of maternal care counteracts the development of genetic absence epilepsy and comorbid depression in WAG/Rij rats

It has been shown for the first time that rearing by a foster Wistar mother with high level of maternal care (MC) counteracts the expression of genetic absence epilepsy (AE) and comorbid depression – reduces the number, duration and index of spike-wave discharges (SWDs) and immobility time in the forced swimming test, as well as exerts substantial effects on morphology and time-frequency dynamics of SWDs in WAG/Rij rats. It is supposed that increases in MC early in development might be used to counteract epileptogenesis and comorbid depression in people genetically predisposed to AE.     

Different emotional disturbances in two experimental models of temporal lobe epilepsy in rats

Affective symptoms such as anxiety and depression are frequently observed in patients with epilepsy. The mechanisms of comorbidity of epilepsy and affective disorders, however, remain unclear. Diverse models are traditionally used in epilepsy research, including the status epilepticus (SE) model in rats, which are aimed at generating chronic epileptic animals; however, the implications of different SE models and rat strains in emotional behaviors has not been reported. To address this issue, we examined the emotional sequelae of two SE models of temporal lobe epilepsy (TLE)--the lithium-pilocarpine (LIP) model and the kainic acid (KA) model--in two different rat strains (Wistar and Sprague-Dawley), which differ significantly in the pattern and extent of TLE-associated brain lesions. We found differences between LIP- and KA-treated animals in tests for depression-like and anxiety-like behaviors, as well as differences in plasma corticosterone levels. Whereas only LIP-treated rats displayed increased motivation to consume saccharin, both SE models led to reduced motivation for social contact, with LIP-treated animals being particularly affected. Evaluation of behavior in the open field test indicated very low levels of anxiety in LIP-treated rats and a mild decrease in KA-treated rats compared to controls. After exposure to a battery of behavioral tests, plasma corticosterone levels were increased only in LIP-treated animals. This hyperactivity in the hypothalamus-pituitary-adrenocortical (HPA) axis was highly correlated with performance in the open field test and the social interaction test, suggesting that comorbidity of epilepsy and emotional behaviors might also be related to other factors such as HPA axis function. Our results indicate that altered emotional behaviors are not inherent to the epileptic condition in experimental TLE; instead, they likely reflect alterations in anxiety levels related to model-dependent dysregulation of the HPA axis.     

Prevalence of mood dysfunction in epilepsy patients in Croatia

Fifty consecutive and consenting epilepsy patients from the Zagreb Epilepsy Center were examined for the presence of depressive symptoms using the Beck Depression Inventory (BDI). This questionnaire has been previously validated for use in the Croatian population. Mean age of the patients was 30.8 +/- 13.5 years, 60.4% were females. Majority of them were employed (72.9%) and single (62.5%), and 35.4% had a university degree. Most of them had complex partial seizures (n=40, 80%), and 6 (12%) were diagnosed with idiopathic generalized epilepsy. Assessment with the BDI showed that 33.3% of patients had recent depressive symptoms: 6.3% had mild depressive symptoms, 8.4% moderate and 18.6% severe depressive symptoms. Three patients (6.4%) attempted suicide in the past, two of them had current suicidal ideation, and all of them were severely depressed. This is the first and preliminary study assessing mood dysfunction in epilepsy patients in Croatia. Increased prevalence of depression in epilepsy patients suggests specific approach and need for early treatment.     

Homer proteins: implications for neuropsychiatric disorders

Homer proteins regulate signal transduction, synaptogenesis and receptor trafficking, in addition to maintaining and regulating extracellular glutamate levels in limbo-corticostriatal brain regions. Converging preclinical observations indicate a potential role for both immediate early gene Homer isoforms and constitutively expressed Homer isoforms in behavioral pathologies associated with neuropsychiatric disorders, such as addiction and/or alcoholism, depression, anxiety, epilepsy and schizophrenia.     

Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence?

This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer's disease and dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.     

Synthesis and evaluation of N-substituted nipecotic acid derivatives with an unsymmetrical bis-aromatic residue attached to a vinyl ether spacer as potential GABA uptake inhibitors

γ-Amino butyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS). A malfunction of the GABAergic neurotransmission is connected to several neuronal disorders like epilepsy, Alzheimer’s disease, neuropathic pain, and depression. One possibility to enhance GABA levels in the synaptic cleft is to inhibit mGAT1, one of the four known plasma membrane bound GABA transporters, which is considered the most important GABA transporter subtype, being in charge of the removal of GABA from the synaptic cleft after a neuronal impulse. Lipophilic derivatives of nipecotic acid like Tiagabine (Gabitril®), an approved drug used in add-on therapy of epilepsy, are known to inhibit uptake of mGAT1 with high subtype selectivity and affinity. We synthesized new N-substituted nipecotic acid derivatives with a vinyl ether spacer and an unsymmetrical bis-aromatic residue, which carries fluorine substituents at various positions of the aromatic ring-system. The new compounds were characterized with respect to their potency and subtype selectivity as mGAT1 inhibitors.     

Subjective Memory Evaluation before and after Temporal Lobe Epilepsy Surgery

Subjective memory (SM), a self-evaluation of memory, in contrast to objective memory (OM) measured by neuropsychological testing, is less well studied in patients with epilepsy. We assessed SM before and after temporal lobectomy. The Frequency of Forgetting 10 scale (FOF-10), developed to evaluate SM in dementia, was given before and one year after temporal lobectomy. Reliability and validity for use in epilepsy were first assessed. Measures of depression (CES-D) and neuroticism (PANAS) were done before and after surgery as well as complete neuropsychological assessment of OM. Correlation analysis between FOF-10 results and all the other variables was implemented. In 48 patients the FOF-10 was reliable and valid showing high internal consistency in all items (Cronbach''s alpha >0.82) and high reproducibility (p<0.01). The FOF-10 also correlated with the memory assessment clinics self rating scale (MAC-S) (p<0.01). FOF-10 scores improved or were unchanged postoperatively in 28 patients (58%) and worsened in 20 (42%). The FOF-10 did not significantly correlate with memory scores from neuropsychological testing but did correlate with perceived word finding difficulty (p<0.001) and postoperative depression (p<0.05). A reduction in number of antiepileptic drugs (AEDs) after surgery distinguished those with improved postoperative SM. No correlation was found between SM and neuroticism, side of surgery or number of seizures. The FOF-10 is a brief and reliable measure of subjective memory in patients with epilepsy. Perceived memory impairment reflects more emotional state, language problems and quantity of AEDs than actual defects in memory function. These results would potentially be useful in presurgical counselling and management of memory issues after temporal lobe surgery.     

Cross sectional study of reporting of epileptic seizures to general practitioners

ObjectiveComparison of reporting of recent epileptic seizures by patients to a doctor and anonymously.DesignCross sectional study of patients with epilepsy by comparison of paired questionnaires.SettingRural and urban general practices in Norfolk. Participants122 patients aged over 16 years and able to self complete a questionnaire who were recruited by 31 general practitioners when attending for review of their epilepsy.Results18 patients failed to report a seizure in the past year to their general practitioner (uncontrolled epilepsy). 40% (24/60) of people with epilepsy who anonymously reported a seizure in the past year held a driving licence, but only six revealed this to their general practitioner. The unemployment rate was 34%, substantially higher than the 9% in the general population. Measures of anxiety, depression, and stigmatisation were higher in patients with uncontrolled epilepsy.ConclusionsA significant proportion of patients with epilepsy underreport their seizures. Recognition of underreporting is important if patients are to benefit from adequate and appropriate treatment. General practitioners'' ability to treat epilepsy is hampered by their role in regulating the rights of epileptic patients to hold a driving licence or access certain occupations.

Key messages

• People with epilepsy may be reluctant to report seizures to their general practitioners as epilepsy affects their eligibility for a driving licence and access to various employment and leisure activities
• In this study about a sixth of patients anonymously reported seizures in the past year which they had not revealed to their general practitioner
• 40% of patients who anonymously reported a seizure in the past year held a driving licence, but only a quarter of these admitted this to their general practitioner
• People who had had seizures in the past year were significantly more depressed and felt more stigmatised than those who had not had a seizure
• Underreporting of seizures has important consequences for treatment, and doctors need to put more effort into explaining this to patients

     

The Recurrent Mossy Fiber Pathway of the Epileptic Brain

The dentate gyrus is believed to play a key role in the pathogenesis of temporal lobe epilepsy. In normal brain the dentate granule cells serve as a high-resistance gate or filter, inhibiting the propagation of seizures from the entorhinal cortex to the hippocampus. The filtering function of the dentate gyrus depends in part on the near absence of monosynaptic connections among granule cells. In humans with temporal lobe epilepsy and in animal models of temporal lobe epilepsy, dentate granule cells form an interconnected synaptic network associated with loss of hilar interneurons. This recurrent mossy fiber pathway mediates reverberating excitation that can reduce the threshold for granule cell synchronization. Factors that augment activity in this pathway include modest increases in [K⁺]_o; loss of GABA inhibition; short-term, frequency-dependent facilitation (frequencies of 1–2 Hz); feedback activation of kainate autoreceptors; and release of zinc from recurrent mossy fiber boutons. Factors that diminish activity include short-term, frequency-dependent depression (frequencies <1 Hz); feedback activation of type II metabotropic glutamate receptors; and the potential release of GABA, neuropeptide Y, adenosine, and dynorphin from recurrent mossy fiber boutons. The axon sprouting and reactive synaptogenesis that follow seizure-related brain damage can also create or strengthen recurrent excitation in other brain regions. These changes are expected to facilitate participation of these regions in seizures. Thus, reactive processes that are often considered important for recovery of function after most brain injuries probably contribute to neurological dysfunction in epilepsy.     

Interaction between N-methyl-D-aspartate receptor antagonists and imipramine in shock-induced depression

In the past few years, literature has accumulated describing manifestation of seizures following administration of certain antidepressants. Such reports are of particular importance because depression is a frequent psychiatric problem associated with epilepsy. Therefore, in the view of the fact that NMDA receptor antagonists have been reported to reduce behavioural deficits and have been shown to be anticonvulsant, it was considered imperative to study their antidepressant effect using shock-induced depression model in mice. Presentation of inescapable foot shock significantly reduced ambulation and rearing in the open field arena and increased immobility duration in the FST. Pretreatment with imipramine, MK 801 and ketamine significantly prevented the effect of shock. Also, the combination of imipramine with either of the NMDA antagonists antagonised the effect of shock. Haloperidol, prazosin and ketanserin pretreatment modified the effect of these agents. These findings suggest an antidepressant effect of the NMDA receptor antagonists, and a complexity of neurotransmitter mechanisms, which are responsible for the occurrence of behavioural effects in shock-induced depression model.