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OBJECTIVES: This study aims to determine the current state of CDD diagnosis and epilepsy treatment in an upper-middle-income country. METHODS: Forty-seven families of the Brazilian CDD Association were invited to participate in an online survey to gather information about the diagnosis and treatment of epilepsy. RESULTS: Forty-three families (91.5%) of unrelated patients with confirmed genetic diagnosis of CDD participated. The median age was 7 years (ranging from 1.3-25 years) and the male: female ratio was 1:6. Early and severe epilepsy started during infancy in 74.4%. Seizures occurred daily in 61.9% and 83.7% had clusters of seizures. The mean age of diagnosis was 3.3 years (ranging from 37 days to 16 years), and younger patients had an earlier diagnosis (p < 0.001). Patients were seen by an average of 4.4 physicians (1-15) before the diagnosis. The most relevant obstacles to genetic testing were cost (55.8%) and late requests by physicians (27.9%). At the moment of the assessment, patients received a mean of 3.6 ASMs/day (ranging from 1 to 5). Thirty-four (79.1%) caregivers reported side effects throughout life, including life-threatening events in 16.3%. SIGNIFICANCE: Based on our findings, a sense of urgency for genetic assessment implementation is evident since the delay in the diagnosis with unnecessary use of resources and excessive polytherapy with serious side effects cause a higher burden to the healthcare system, caregivers, and patients. PLAIN LANGUAGE SUMMARY: In this study, we assessed the diagnosis and treatment of patients with genetically confirmed DEE-CDKL5 from the Brazilian Association of CDD with an online survey. Caregivers reported a long delay in the diagnosis associated with cost and late referral to genetic testing, considered the last resource for one-third of the patients. Patients received a high number of ASM, mainly under polytherapy, with serious side effects. Although it is promising that younger patients received earlier diagnosis, public policies for genetic testing are needed to improve CDD patients' care.

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The Psychiatric Pediatric Issues Task Force of the International League Against Epilepsy (ILAE) aimed to develop recommendations for the diagnosis and treatment of anxiety and depression in children and adolescents with epilepsy. The Task Force conducted a systematic review and identified two studies that assessed the accuracy of four screening measures for depression and anxiety symptoms compared with a psychiatric interview. Nine studies met the eligibility criteria for treatment of anxiety and depressive disorders or symptoms. The risk of bias and certainty of evidence were assessed. The evidence generated by this review followed by consensus where evidence was missing generated 47 recommendations. Those with a high level of agreement (≥80%) are summarized. Diagnosis: (1) Universal screening for anxiety and depression is recommended. Closer surveillance is recommended for children after 12 years, at higher risk (e.g., suicide-related behavior), with subthreshold symptoms, and experiencing seizure worsening or therapeutic modifications. (2) Multiple sources of ascertainment and a formal screening are recommended. Clinical interviews are recommended whenever possible. The healthcare provider must always explain that symptom recognition is essential to optimize treatment outcomes and reduce morbidity. (3) Questioning about the relationship between symptoms of anxiety or depression with seizure worsening/control and behavioral adverse effects of antiseizure medications is recommended. Treatment: (1) An individualized treatment plan is recommended. (2) For mild depression, active monitoring must be considered. (3) Referral to a mental health care provider must be considered for moderate to severe depression and anxiety. (4) Clinical care pathways must be developed. (5) Psychosocial interventions must be tailored and age-appropriate. (6) Healthcare providers must monitor children with epilepsy who are prescribed antidepressants, considering symptoms and functioning that may not improve simultaneously. (7) Caregiver education is essential to ensure treatment adherence. (8) A shared-care model involving all healthcare providers is recommended for children and adolescents with epilepsy and mental health disorders. We identified clinical decisions in the management of depression and anxiety that lack solid evidence and provide consensus-based guidance to address the care of children and adolescents with epilepsy.

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PURPOSE: This study evaluated sleep quality, chronotype, and excessive diurnal somnolence in persons with Juvenile Myoclonic Epilepsy (JME) and their possible association with clinical variables. METHODS: This cross-sectional controlled study evaluated 49 consecutive patients (65% females, mean age 27.53 years) with an electroclinical diagnosis of JME and 49 healthy controls (55% females, mean age 28.55 years). The Pittsburgh Sleep Quality Inventory (PSQI) was used to assess sleep quality and the Epworth Sleepiness Scale (ESS) to evaluate excessive daytime sleepiness. The patients' chronotype was evaluated by the Morningness-Eveningness Questionnaire (MEQ). Epilepsy-related factors gathered from the medical chart and personal interview were epilepsy duration, age at onset, frequency of myoclonic (Mcl), generalized tonic-clonic (GTC) and absence (ABS) seizures, pharmacoresponse, and current antiseizure medication (ASM). RESULTS: Persons with JME did not differ from the control group regarding daytime sleepiness (p=0.840); however, the JME group had worse sleep quality (p=0.01) than the controls. Persons with JME presented a more evening chronotype than controls (p = 0.003). The age at onset, epilepsy duration, frequency of Mcl seizure, frequency of GTC seizure, frequency of ABS seizure, and drug response did not predict ESS and MEQ scales. Pharmacoresponsive patients had lower PSQI scores compared with pharmacoresistant patients (p=0.036). CONCLUSION: Persons with JME have worse sleep quality and a more evening chronotype. Notably, pharmacoresistant patients present a worse sleep quality that deserves attention and special care due to the relationship between sleep deprivation and seizure worsening.

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BACKGROUND: Mood disorders are the most frequent psychiatric disorders in patients with temporal lobe epilepsy caused by hippocampal sclerosis (TLE-HS). The pathophysiological mechanisms in common between TLE and mood disorders include abnormalities in the serotonergic pathway. We aimed to evaluate the association between serotonin transporter genetic polymorphisms - 5-HTTLPR and 5-HTTVNTR - and the presence of mood disorders in patients with TLE-HS. METHODS: We evaluated 119 patients with TLE-HS, with and without psychiatric disorder; 146 patients diagnosed with major depressive disorder (MDD), and 113 healthy volunteers. Individuals were genotyped for the 5-HTTLPR and 5-HTTVNTR polymorphisms. RESULTS: No difference was observed between the TLE-HS groups, healthy controls, and MDD without epilepsy. There was a correlation between the 12-allele of the 5-HTTVNTR and the family history of patients with epilepsy with TLE-HS (p = 0.013). CONCLUSIONS: In this study conducted in two Brazilian centers, the serotonin transporter polymorphisms evaluated cannot be associated with depressive disorder in patients with TLE-HS. Still, they do have some influence over some clinical characteristics of epilepsy in TLE-HS. These data may not be reproduced in other populations with distinct ethnic characteristics.

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PURPOSE: This study aimed to determine the presence of anxiety disorder and severity of anxiety symptoms in an extensive series of consecutive patients with JME and its association with epilepsy-related factors. In addition, we evaluated the impact of anxiety and clinical variables on social adjustment. METHODS: We prospectively evaluated 112 (56.2 % females, mean age 27.2 years) patients with an electroclinical diagnosis of JME and 61 (52.4 % females, mean age 29.3 years) healthy controls. Anxiety symptoms were assessed by the State and Trait Anxiety Inventory (STAI). Social functioning was addressed with Self-Report Social Adjustment Scale (SAS). The patient group was also evaluated with a psychiatric interview. RESULTS: Patients with JME presented more severe anxiety symptoms and worse social adjustment compared with controls. The presence of anxiety disorder and the severity of anxiety symptoms was associated with frequent seizures - generalized tonic-clonic seizures (p = 0.008) and drug-resistant epilepsy (p = 0.021). Regarding social adjustment, the severity of anxiety symptoms was associated with lower economic adjustment (p = 0.039), while the presence of anxiety disorder impacted family relationships (p 0.025). The presence of hard-to-control myoclonic seizure was associated with lower scores on work (p = 0.019), leisure activities (p = 0.008), family relationship (p = 0.022) and overall social adjustment (p = 0.038). CONCLUSION: Patients with JME have severe anxiety symptoms and worse social adjustment. Anxiety disorder and symptoms were associated with frequent seizures and drug-resistant epilepsy. Epilepsy-related factors and anxiety impaired distinct aspects of social functioning.

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INTRODUCTION: Decision making (DM) is one aspect of impulsivity that can be defined by the ability to decide between two or more options in a given situation. To date, there are at least two types of DM that differ in the level of uncertainty, and how much information about consequences is provided. In this study, we aimed to evaluate the two domains of DM - under risk and ambiguous - with a comprehensive evaluation in a group of patients with juvenile myoclonic epilepsy (JME), and correlate with patients' characteristics, clinical variables, and neuropsychological evaluation for executive functions. METHODS: We evaluated 35 patients with JME and 39 healthy controls using the Iowa Gambling Task for DM under ambiguity and the Game Dice Task for DM under risk. We assessed the performance in Iowa Gambling Task and Game Dice Task through net scores, safe and risky choices, besides the type of decisions across time. RESULTS: Patients with JME had a higher number of risky choices compared to controls in the Game Dice Task. There was no significant difference between patients and controls in the Iowa Gambling Task. However, patients with higher seizure frequency had worse scores on decks C and D (safe choices) from the Iowa Gambling Task. CONCLUSION: Patients with JME have worse performance on DM under risk. The same was not observed for DM under ambiguity. Epilepsy-related factors and the presence of psychiatric disorders, but not executive dysfunction, were associated with a lower tendency for safe choices. These findings showed a dissociation between DM processes in patients with JME and a tendency to make disadvantageous decisions with measurable risks.

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PURPOSE: Some variants of the brain derived neurotrophic factors (BDNF) gene, namely the Val66Met (rs6265), may contribute the risk for epilepsy development. We aimed to investigate if this polymorphism was associated with the risk for epilepsy development in TLE-HS and its correlation with epilepsy-related factors and the presence of psychiatric disorders. METHODS: We assessed 119 patients with unequivocal TLE-HS and 112 healthy controls. Individuals were genotyped for the polymorphisms of the gene encoding BDNF Val66Met. RESULTS: There was no difference between TLE-HS and healthy controls, for the genotypic distribution (p = 0.636) and allelic distribution (p = 0.471). There was no correlation between Val66Met and epilepsy-related factors and for psychiatric comorbidities (p = 0.888). CONCLUSIONS: Our findings demonstrated that polymorphism Val66Met is not associated with TLE-HS, epilepsy-related factors and psychiatric comorbidities in this selected group of patients.

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In this study, we aimed to evaluate the attentional and executive functions in patients with benign childhood epilepsy with centrotemporal spikes (BCECTS) with and without attention-deficit hyperactivity disorder (ADHD) compared with controls and compared with patients with ADHD without epilepsy. We evaluated 12 patients with BCECTS and ADHD (66.7% boys; mean age of 9.67years); 11 children with non-ADHD BCECTS (63.6% boys; mean age of 11.91years); 20 healthy children (75% boys; mean age of 10.15years); and 20 subjects with ADHD without epilepsy (60% boys; mean age of 10.9years). We used a comprehensive battery of neuropsychological tests to evaluate attentional and executive functions in their broad domains. Patients with BCECTS and ADHD had worse performance in Conners' Continuous Performance Test II (reaction time standard error [p=0.008], variability [p=0.033], perseverations [p=0.044] and in reaction time interstimuli interval [p=0.016]). Patients with ADHD showed worse performance in Trail Making Test B errors [p=0.012]. In conclusion, patients with BCECTS and ADHD had worse executive and attentional performance compared with controls than non-ADHD patients with BCECTS. Regardless of the presence of epilepsy, ADHD also negatively impacted executive and attentional functions but in different executive subdomains compared with patients with epilepsy.

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RATIONALE: Benign Epilepsy of Childhood with Centrotemporal Spikes (BECTS) and temporal lobe epilepsy (TLE) represent two distinct models of focal epilepsy of childhood. In both, there is evidence of executive dysfunction. The purpose of the present study was to identify particular deficits in the executive function that would distinguish children with BECTS from children with TLE. METHODS: We prospectively evaluated 19 consecutive children and adolescents with TLE with hippocampal sclerosis (HS) (57.9% male; mean 11.74years [SD 2.05]; mean IQ 95.21 [SD 15.09]), 19 with BECTS (36.8% male; mean 10.95years [SD 2.33]; mean IQ 107.40 [SD 16.01]), and 21 age and gender-matched controls (33.3% male; mean 11.86years [SD 2.25]; mean IQ 108.67 [15.05]). All participants underwent a neuropsychological assessment with a comprehensive battery for executive and attentional functions. We used ANOVA and chi-square to evaluate differences on demographic aspects among groups (BECTS, TLE-HS, and control groups). Group comparisons on continuous variables were complemented by MANOVA and Bonferroni posthoc comparisons. RESULTS: Patients with BECTS had worse performance than controls in: Matching Familiar Figures Test, time (p=0.001); Matching Familiar Figures Test, time×errors index (p<0.001); Verbal Fluency for foods (p=0.038); Trail Making Test, part B time (p=0.030); Trail Making Test, part B number of errors (p=0.030); and WCST, number of categories achieved (p=0.043). Patients with BECTS had worse performance than patients with TLE-HS on Matching Familiar Figures Test, time (p=0.004), and Matching Familiar Figures Test, time×errors index (p<0.001). Patients with TLE-HS had worse performance than controls on the following tests: Verbal Fluency for foods (p=0.004); Wisconsin Card Sorting Test, the number of categories achieved (p<0.001); and Wisconsin Card Sorting Test, the number of perseverative errors (p=0.028). Patients with TLE-HS had worse performance than patients with BECTS on Digit Backward (p=0.002); and the Wisconsin Card Sorting Test, the number of perseverative errors (p<0.001). CONCLUSIONS: Patients with TLE and BECTS present distinct cognitive profiles. Patients with TLE-HS had worse performance in mental flexibility, concept formation, and working memory compared to BECTS. Patients with BECTS had worse inhibitory control compared to children with TLE-HS. Both TLE-HS and BECTS had a higher number of errors on an inhibitory control test. However, patients with BECTS had a slower mental processing even when compared to patients with TLE-HS. Rehabilitation programs for children with epilepsy must include children with benign epilepsies and must take into account the epileptic syndrome and its particular neurocognitive phenotype.

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Previous studies, using surveys, provided an understanding about how health-care providers address patients with PNES. To date, there is limited information on the management of patients with PNES by tertiary referral centers for epilepsy. In this study, we surveyed 11 Brazilian epilepsy center directors about diagnosis, treatment, education and research on PNES. Respondents reported that patients with PNES represented 10-20% of all adult patients recorded by video-EEG (VEEG). All respondents recognized VEEG as the method to confirm the diagnosis, and 81.8% used this approach for confirmation. Most centers had a standard protocol for diagnosis. None of the centers had a particular protocol to treat PNES, but 90.9% had a uniform treatment approach including therapy and educational measures. Psychotherapy was not easily obtained in nine centers (81.8%). Seven (63.3%) centers reported ongoing research projects with PNES. Five centers referred to an educational PNES program discussing diagnosis, but only one reported an educational program for treatment. This study showed a commitment to PNES diagnosis; however, some gaps remain regarding treatment and training, namely implementing a psychotherapy approach for patients and providing educational curricula for clinicians.

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Knowledge about health systems can promote implementation of more specific and strategic health practices for patients with psychogenic nonepileptic seizures (PNES). For this purpose, we surveyed the current management of PNES (standard medical care [SMC]) by Brazilian League Against Epilepsy members. Respondents reported diagnosing PNES with a mean frequency of 3patients/month. Video-EEG (vEEG) was considered the best method for the diagnosis. Respondents who have vEEG in their facilities refer to vEEG significantly more often than those who have no vEEG (p<0.001). Therefore, South and Southeast Brazil regions referred patients more frequently to vEEG than other regions (p=0.004). Psychotherapy was considered the most effective (92.2%) treatment option, followed by education (75%) and psychopharmacology (70.3%). There were no regional differences considering treatment. The study identified current national diagnostic and treatment practices across the country and identified relevant Brazilian regional differences.

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PURPOSE: Lack of response to anti-epileptic drugs (AEDS) is considered a "red flag" pointing to a diagnosis of Psychogenic Nonepileptic Seizures (PNES). On the other hand, placebo effects are relevant in any medical condition with a complex psychosocial component. We aimed to evaluate the presence and frequency of a placebo response in patients with sole PNES and explore its impact on diagnostic delay. METHODS: We reviewed the medical records of 102 patients referred for video EEG monitoring and diagnosed with PNES. Patients with PNES and epilepsy were excluded. The response to AEDs was analyzed according to patients' reports and medical records. Patients were classified, according to the response to AEDs, in two groups: responders (patients achieving remission) and non-responders. Then, we compared the diagnostic delay from the first event to the final diagnosis between these groups. RESULTS: Forty-seven patients (79.7%) with sole PNES who were using AEDs were identified. Twenty-two patients (46.8%) had reported complete or partial remission of PNES with mean response duration of 7.2 months (SD+9.6 months). The time delay of the diagnosis in the AED responder group was 10.6 years; the delay in non-responders was 5.6 years (p=0.035). CONCLUSION: Patients with sole PNES receiving AEDs can go into PNES remission. A favorable response to AEDs is likely to be interpreted as supporting a diagnosis of epilepsy and is associated with diagnostic delay. Physicians should bear in mind that patients with PNES may be particularly vulnerable to placebo effects.

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In children with temporal lobe epilepsy (TLE), memory deficit is not so well understood as it is in adults. The aim of this study was to identify and describe memory deficits in children with symptomatic TLE, and to verify the influence of epilepsy variables on memory. We evaluated 25 children with TLE diagnosed on clinical, EEG and MRI findings. Twenty-five normal children were compared with the patients. All children underwent a neuropsychological assessment to estimate intellectual level, attention, visual perception, handedness, and memory processes (verbal and visual: short-term memory, learning, and delayed recall). The results allowed us to conclude: besides memory deficits, other neuropsychological disturbances may be found in children with TLE such as attention, even in the absence of overall cognitive deficit; the earlier onset of epilepsy, the worse verbal stimuli storage; mesial lesions correlate with impairment in memory storage stage while neocortical temporal lesions correlate with retrieval deficits.

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In children with temporal lobe epilepsy (TLE), memory deficit is not so well understood as it is in adults. The aim of this study was to identify and describe memory deficits in children with symptomatic TLE, and to verify the influence of epilepsy variables on memory. We evaluated 25 children with TLE diagnosed on clinical, EEG and MRI findings. Twenty-five normal children were compared with the patients. All children underwent a neuropsychological assessment to estimate intellectual level, attention, visual perception, handedness, and memory processes (verbal and visual: short-term memory, learning, and delayed recall). The results allowed us to conclude: besides memory deficits, other neuropsychological disturbances may be found in children with TLE such as attention, even in the absence of overall cognitive deficit; the earlier onset of epilepsy, the worse verbal stimuli storage; mesial lesions correlate with impairment in memory storage stage while neocortical temporal lesions correlate with retrieval deficits.

Em crianças com epilepsia de lobo temporal (ELT) os problemas de memória não são tão bem compreendidos como em adultos. O objetivo desse estudo foi identificar e descrever déficits de memória em crianças com ELT sintomática e verificar a influência de variáveis da epilepsia na memória. Avaliamos 25 crianças com ELT com diagnóstico baseado em aspectos clínicos, eletrencefalográficos e de neuroimagem. Vinte e cinco crianças normais foram comparadas com os pacientes. Todas as crianças foram submetidas à avaliação neuropsicológica para estimar nível intelectual, atenção, percepção visual, dominância manual, e processos de memória (verbal e visual: memória a curto prazo, aprendizado e recuperação tardia). Os resultados nos permitiram concluir que: além de déficit de memória, outros distúrbios neuropsicológicos podem ser encontrados em crianças com ELT, tais como déficit de atenção, mesmo na ausência de déficit cognitivo global; quanto mais precoce o início da epilepsia, pior o armazenamento verbal; lesões mesiais se correlacionam com prejuízo no armazenamento de memória enquanto lesões temporais neocorticais se correlacionam com prejuízos de evocação.

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The phospholipase A2 (PLA2) enzymes have been implicated in several neuropsychiatry disorders and activity alterations have been described in brain and platelet. Since brain tissue is not readily available for the measurement of PLA2 activity, it would be of interest to test directly whether PLA2 activities in both tissues are correlated. We performed this task assessing PLA2 activity in platelets and hippocampus collected simultaneously from 19 patients undergoing temporal lobectomy for treatment of refractory epilepsy. Our findings suggest that total PLA2 activity in platelets may reflect the total activity of the enzyme in the brain (rs=0.59, p=0.008). However in our sample no correlations were found between the subgroups of the enzyme in brain and in platelets. This lack of correlations may be due to different effects of drug treatment on the PLA2 subtypes. In face of the difficulty to obtain brain tissues from living patients, further studies with larger drug-free samples are warranted to clarify whether the use of platelets is a reliable strategy to reflect the subtypes of PLA2 activity in the brain.

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OBJECTIVE: Depression is a frequent psychiatric disorder in children with temporal lobe epilepsy (TLE). However, severity of depressive symptoms (DS) is frequently neglected in these patients. This study aimed to determine severity of DS and global functioning by using quantitative measures and to establish their correlation with patients' demographics and clinical variables. METHODS: 31 children (mean age of 11.8±2.3 years) with TLE were assessed with K-SADS-PL for axis I DSM-IV diagnosis. Severity of DS was measured by Children Depression Rating Scale-Revised - CDRS-R. Global functional impairment was evaluated with Child Global Assessment Scale-CGAS. RESULTS: 25 patients (56% boys; 12±2.3 years) had current DS, moderate or severe in 84% according to CDRS-R T-Score. Severity of DS was not correlated with age (p=0.377), gender (p=0.132), seizure control (p=0.936), age of onset (p=0.731), duration of epilepsy (p=0.602) and the presence of hippocampal sclerosis (p=0.614). Patients had moderate to major functional impairment measured by CGAS (48.7±8.8), being adolescents more impaired than children (p=0.03). Impairment of global functioning was not associated with epilepsy variables (p>0.05). CONCLUSION: Children with TLE had moderate to severe DS early in the course of their disease with a relevant impact on their global functional activities, especially considering adolescents. Epilepsy severity seems not to be correlated to the severity of DS, contradicting the idea of a cause-consequence relationship. More systematic research is needed to better understand the association of depressive disorders in children and adolescents with TLE.

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The combination of lamotrigine and valproate/divalproex sodium has been shown to be effective in the treatment of refractory epilepsy. This study aims to evaluate the pharmacologic properties of using this combination in a pediatric population refractory to antiepileptic drugs, with an extended follow-up. We studied a group of 51 patients, ranging from 4 to 16 years of age. Sixteen patients (31.4%) had generalized epilepsy and 35 (69.6%) had focal epilepsy. The combination was effective in 39 patients (76.5%) in the first year of follow-up and in 36 patients (70.6%) in the second year, with a reduction in drop attacks observed in 22 (88.5%). Adverse effects included rash, leading to discontinuation in four patients (7.8%). Slower introduction of lamotrigine minimizes adverse effects, thereby improving quality of life and adherence to treatment. In addition, therapeutic efficacy is maintained with lower doses of lamotrigine, even after the first year of treatment.

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The relationship between depression and epilepsy has been known since ancient times, however, to date, it is not fully understood. The prevalence of psychiatric disorders in persons with epilepsy is high compared to general population. It is assumed that the rate of depression ranges from 20 to 55% in patients with refractory epilepsy, especially considering those with temporal lobe epilepsy caused by mesial temporal sclerosis. Temporal lobe epilepsy is a good biological model to understand the common structural basis between depression and epilepsy. Interestingly, mesial temporal lobe epilepsy and depression share a similar neurocircuitry involving: temporal lobes with hippocampus, amygdala and entorhinal and neocortical cortex; the frontal lobes with cingulate gyrus; subcortical structures, such as basal ganglia and thalamus; and the connecting pathways. We provide clinical and brain structural evidences that depression and epilepsy represent an epiphenomenon sharing similar neural networks.

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