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Rev. bras. psicoter. 2023; 25(3):135-145
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Artigos de Revisao
Transtorno Afetivo Bipolar comórbido à Epilepsia: uma revisão integrativa
Bipolar Disorder comorbid with Epilepsy: an integrative review
Trastorno Bipolar comórbido con Epilepsia: una revisión integradora
Bruna Parussolo Bordona; Anderson Ravy Stolfb; Kleber Francisco Meneghel Vargasa,b
Resumo
A prevalência da epilepsia varia de 1% a 2% globalmente, com taxas mais altas em países em desenvolvimento. Indivíduos com epilepsia enfrentam dificuldades psicossociais devido ao estigma associado à doença. Até 52% das pessoas com epilepsia apresentam comorbidades psiquiátricas, incluindo transtornos ansiosos, depressivos e psicóticos. A fisiopatologia destes transtornos é complexa e multicausal e tem sido bem explorada no meio científico, porém há pouca literatura a respeito da associação entre epilepsia e transtorno afetivo bipolar (TAB). O transtorno afetivo bipolar é caracterizado por períodos de depressão e elação do humor intercalados por intervalos de remissão dos sintomas. Este estudo tem como objetivo analisar a comorbidade do TAB com a epilepsia por meio de uma revisão integrativa. Foram revisados artigos da Medline, PubMed e Scielo com as palavras-chave "epilepsia", "transtorno bipolar" e "comorbidade", sem restrições de data, entre maio e junho de 2022. Foram excluídos textos incompletos, estudos que não discutiam a associação fisiopatológica, crises psicogênicas nãoepilépticas, relatos de caso isolados, artigos envolvendo crianças ou adolescentes, ou focados exclusivamente em manejo farmacológico. Entre 34 artigos, 17 atenderam aos critérios de elegibilidade. A revisão sugere que há uma relação entre a natureza das alterações encontradas nos dois transtornos, com bases fisiopatológicas compartilhadas, como alterações de neurotransmissores e efeito kindling. Diagnosticar a comorbidade é desafiador devido à falta de testes específicos e de sintomas patognomônicos, assim como apresentações clínicas atípicas das doenças. São necessários mais estudos compreender a fisiopatologia desses transtornos e aprimorar o tratamento destes pacientes.
Descritores: Epilepsia; Transtorno bipolar. Comorbidade; RevisãoAbstract
The prevalence of epilepsy ranges from 1% to 2% globally, with higher rates in developing countries. Individuals with epilepsy face psychosocial challenges due to the stigma associated with the disease. Up to 52% of people with epilepsy have psychiatric comorbidities, including anxiety, depressive, and psychotic disorders. The pathophysiology of these disorders is complex and multifactorial, extensively explored in the scientific community. However, there is limited literature on the association between epilepsy and bipolar affective disorder (BAD). BAD is characterized by periods of depression and mood elevation interspersed with symptom remission intervals. This study aims to analyze the comorbidity of BAD with epilepsy through an integrative review. Articles from Medline, PubMed, and Scielo with keywords "epilepsy," "bipolar disorder," and "comorbidity" were reviewed without date restrictions between May and June 2022. Incomplete texts, studies not discussing the pathophysiological association, psychogenic non-epileptic seizures, isolated case reports, articles involving children or adolescents, or focusing solely on pharmacological management were excluded. Among 34 articles, 17 met eligibility criteria. The review suggests a relationship between the nature of changes found in both disorders, with shared pathophysiological bases such as neurotransmitter alterations and the kindling effect. Diagnosing comorbidity is challenging due to the lack of specific tests, pathognomonic symptoms, and atypical clinical presentations of the diseases. Further studies are needed to understand the pathophysiology of these disorders and enhance the treatment for these patients.
Keywords: Epilepsy; Bipolar disorder; Comorbidity; Review
Resumen
La prevalencia de la epilepsia varía del 1% al 2% a nivel mundial, con tasas más altas en países en desarrollo. Las personas con epilepsia enfrentan dificultades psicosociales debido al estigma asociado con la enfermedad. Hasta un 52% de las personas con epilepsia tienen comorbilidades psiquiátricas, incluyendo trastornos de ansiedad, depresivos y psicóticos. La fisiopatología de estos trastornos es compleja y multifactorial, y ha sido ampliamente explorada en la comunidad científica. Sin embargo, hay poca literatura sobre la asociación entre la epilepsia y el trastorno afectivo bipolar (TAB). El TAB se caracteriza por períodos de depresión y elevación del humor intercalados con intervalos de remisión de los síntomas. Este estudio tiene como objetivo analizar la comorbilidad del TAB con la epilepsia a través de una revisión integrativa. Se revisaron artículos de Medline, PubMed y Scielo con las palabras clave "epilepsia", "trastorno bipolar" y "comorbilidad", sin restricciones de fecha, entre mayo y junio de 2022. Se excluyeron textos incompletos, estudios que no discutían la asociación fisiopatológica, crisis psicógenas no epilépticas, informes de casos aislados, artículos que incluían a niños o adolescentes, o que se centraban exclusivamente en el manejo farmacológico. De los 34 artículos, 17 cumplieron con los criterios de elegibilidad. La revisión sugiere que hay una relación entre la naturaleza de los cambios encontrados en ambos trastornos, con bases fisiopatológicas compartidas, como alteraciones en los neurotransmisores y el efecto kindling. Diagnosticar la comorbilidad es desafiante debido a la falta de pruebas específicas y síntomas patognomónicos, así como a presentaciones clínicas atípicas de las enfermedades. Se necesitan más estudios para comprender la fisiopatología de estos trastornos y mejorar el tratamiento para estos pacientes.
Descriptores: Epilepsia; Trastorno bipolar; Comorbilidad; Revisión
Introduction
Epilepsy is conceptually defined as a brain disorder characterized by the persistent predisposition of the brain to generate epileptic seizures and the neurobiological, cognitive, psychological, and social consequences of this condition1. Approximately half of individuals with epilepsy have a comorbid diagnosis of a psychiatric disorder2. Mental disorders associated with epilepsy can be clinically similar to functional disorders but often exhibit distinct characteristics, such as greater severity, atypical presentation, influences of pharmacotherapy used in epilepsy treatment, and temporal relationship with seizures or medication use3. Mood disorders, particularly depression, are the most common psychiatric comorbidities in patients with epilepsy. Studies estimate a prevalence of 4% to 33% in this population, with higher rates found in patients with poor seizure control. Suicide rates in individuals with epilepsy are 10 times higher than in the general population4, and it constitutes one of the leading causes of death in this group5. Similar to depression, anxiety disorders are also more prevalent in people with epilepsy compared to the general population, with estimated prevalence of up to 60% of patients6.
Psychotic episodes in patients with epilepsy can occur in temporal association with seizures (ictal and postictal) or independently of them (interictal), as well as being related to seizure cessation, a phenomenon known as forced normalization. The latter usually occurs after a long period of active disease, is more prevalent in patients with difficult-to-control epilepsy, and exhibits some differences compared to schizophrenia, such as a later onset and a lesser impact on affectivity and social interaction impairment3.
Other psychiatric disorders can also appear comorbidly with epilepsy, such as conduct disorders, personality disorders, attention-deficit/hyperactivity disorder, autism spectrum disorder, intellectual disability, and dementias. Mental disorders caused or exacerbated by the use of antiepileptic medications should also be taken into consideration. Many drugs used in epilepsy treatment have psychiatric side effects, such as topiramate and levetiracetam.
Bipolar disorder (BD) is a chronic and recurrent psychiatric condition characterized by mood swings, with episodes of mania or hypomania and periods of depressive symptoms, interspersed with remission intervals. It was described by Kraepelin in 1899 as manic-depressive psychosis, referring to the course of the disease, with periods of elevated mood and phases of melancholic features7.
BD affects approximately 30 million people worldwide, according to data published by the World Health Organization (WHO) in 20088, and lifetime prevalence rates range between 1% and 2% according to most studies.
Epilepsy and bipolar disorder are two serious and potentially disabling mental health conditions. Although they are distinct pathologies, studies indicate that these conditions can co-occur, affecting the health and wellbeing of individuals suffering from them. However, the nature of this relationship is still not well understood. There is a robust literature on psychiatric disorders related to epilepsy; however, solid references on comorbid bipolar disorder with epilepsy are scarce.
This integrative review aims to survey the existing medical literature on bipolar disorder in individuals with epilepsy: the estimated prevalence, any peculiarities in its clinical presentation, and the pathophysiological basis of this association between the two disorders. It also aims to explore hypotheses as to why bipolar affective disorder is relatively common among psychiatric disorders in the general population but is underdiagnosed in patients with epilepsy, who already have a greater vulnerability and predisposition to the development of psychiatric comorbidities.
Methods
An integrative literature review was conducted to examine the relationship between epilepsy and bipolar disorder. The evaluation was guided by the checklist of quality indicators for integrative review articles. Indicativos de qualidade para artigos de Revisão Integrativa. Full-text online articles containing the keywords "epilepsy," "bipolar disorder," and "comorbidity" as descriptors or main subjects in the abstract were recruited. The articles were originally published in Portuguese, English, or Spanish and were obtained from the databases Medline, PubMed, and Scielo.
There were no date restrictions in the literature search, which was conducted between May and June of the year 2022. The search on PubMed yielded 150 results, on Medline 105 results, and on Scielo, it resulted in only one article. All abstracts of the articles in Portuguese, English, and Spanish were read, and those exclusively related to treatment or therapeutic management, including psychogenic non-epileptic seizures, isolated case reports, as well as articles that did not discuss the physiopathological correlation between the two diseases, were excluded. Studies whose samples consisted of children or adolescents were also excluded.
Out of the 150 articles on PubMed, 30 were selected, and of these, two had to be excluded due to language barriers (one in Russian and the other in Hungarian). After evaluating the 105 results on Medline, 31 were selected; however, 25 of these were already included in the ones selected from PubMed and were thus excluded, and one was inaccessible as it was a printed article, leaving five articles. The single article from Scielo was also included for evaluation.
All articles were then read to elucidate the questions raised by this study in order to fulfill the initial objectives. Among the 34 articles, those exclusively discussing treatment or psychopharmacology, or not covering the physiopathological basis of the association between the two disorders, were excluded, leaving a final selection of 17 articles. The content of the articles' discussions was evaluated, and those that aligned with the proposed review were selected.
All of 17 articles selected was completely read and their content were described in the results session of this study.
Results
Out of the 17 recruited articles, two specifically addressed molecular alterations that could be involved in both conditions (alteration of the pyruvate dehydrogenase complex and neuroinflammation with dysfunction of intercellular channels, such as connexin 43 and pannexin 1)9,10.
Ten articles discussed the direct association between epilepsy and bipolar disorder or its spectrum of presentations11-20.
Four articles explored mood disorders (including bipolar disorder) comorbid with epilepsy21-24, and one study focused solely on psychiatric disorders in patients with temporal lobe epilepsy25.
Discussion
Epidemiology
Most of the analyzed studies estimate a prevalence of comorbid bipolar disorder in epilepsy of up to 10%, with a slight tendency to be more prevalent in men than in women14,15. There is a significant methodological challenge in these studies due to the diagnostic complexity of bipolar disorder itself versus symptoms of the bipolar spectrum. There are presentations such as interictal dysphoric disorder or postictal manic symptoms that are closely correlated with epileptiform activity per se, raising doubts about whether these conditions should be considered part of the bipolar spectrum or not. There is an estimate that the prevalence of "pure" bipolar disorder in patients with epilepsy, excluding these confounding factors, would be around 1.4%, similar to the prevalence in the general population15. The clinical presentation of bipolar disorder in individuals with epilepsy could also be a bias in studies on this topic. Similar to unipolar depression, episodes of bipolar depression and mania in patients with epilepsy can have atypical presentations. A series of case studies have shown that some patients with interictal manic symptoms met diagnostic criteria for manic episodes according to the DSM-IV; however, when compared to patients with type I bipolar disorder, these episodes were less severe and had faster cycling12.
Furthermore, the influence of the temporal lobe in the genesis of manic episodes should be taken into consideration, as they are more frequently observed in individuals with temporal lobe epilepsy. Postictal psychotic episodes often present with grandiose delusions similar to those seen in mood disorders, suggesting that this could be another manifestation of manic symptoms in patients with epilepsy11.
Pathophysiology
There are many similarities between bipolar disorder and epilepsy that suggest a possible correlation or shared pathways in the pathophysiology of these two conditions. The cyclical/episodic presentation, chronic course, response to anticonvulsant drugs, alterations in ion channels and neurotransmitter balance, involvement of second messenger systems (such as G protein, phosphatidylinositol, protein kinase C, calcium, and myristoylated alanine-rich C kinase substrate - MARCKS), neuroinflammation, and mitochondrial dysfunction, as well as the hypothesis of kindling involvement in the genesis of these disorders, are some of the characteristics that raise suspicions regarding a possible bidirectional pathophysiology between the two conditions11.
The kindling effect, extensively studied by Graham Goddard and colleagues26, was described in a 1983 article where he applied the phenomenon to the etiology of seizures. Goddard postulated that small, high-frequency stimuli that were not seizure-inducing, when applied repeatedly, would eventually induce seizures. This model would explain the development of predisposition to recurrent seizures in epilepsy, as well as the pharmacological resistance to anticonvulsant drugs. Applied to bipolar disorder, the kindling effect could explain, for example, the tendency for recurrence of manic episodes and the neuroprogression of the disease16.
The hypotheses regarding alterations in second messenger systems arise from pharmacodynamic studies of anticonvulsant drugs. For example, valproic acid, widely used in the treatment of epilepsy and as a mood stabilizer in bipolar disorder, can increase cell survival factors such as Bcl-2 and brain-derived neurotrophic factor (BDNF) through the activation of second messenger systems19.
Alterations in the cerebral neurochemical balance, with a reduction in inhibitory neurotransmitters (such as GABA) and increased action of excitatory neurotransmitters (such as glutamate), are also observed in individuals with epilepsy and during manic episodes. The therapeutic effect of many anticonvulsant drugs is related to alterations in ion channels (such as sodium channels with carbamazepine) or potentiation of the inhibitory effect of GABA (as seen with the use of clobazam, for example)19.
A study by Campbell and Campbell9 published in Medical Hypotheses raises the possibility of alterations in the conversion of pyruvate to acetyl coenzyme A and consequent impairment of oxidative phosphorylation, resulting in mitochondrial dysfunction involved in the pathogenesis of bipolar disorder. The authors theorize that this mitochondrial dysfunction could be due to a disorder in the pyruvate dehydrogenase complex and mitochondrial carrier protein, leading to a reduction in ATP production, which would result in neuronal destabilization in bipolar disorder and explain the positive effects of the ketogenic diet in the treatment of refractory epilepsy.
Another molecular hypothesis would be neuroinflammation in intercellular channels, such as connexin 43 and pannexin 1, which are related to various neurological disorders: migraine with aura, Alzheimer's disease, Parkinson's disease, autism spectrum disorder, major depressive disorder, and epilepsy. Post-mortem analysis of brains from individuals with bipolar disorder has shown an increase in neuroinflammatory markers and excitotoxicity, which are thought to be responsible for the neuroprogression of the disease, leading to neuronal death, brain atrophy, and cognitive decline10.
Genetics and environmental factors
Genetic inheritance seems to be another factor involved in the etiology of both bipolar disorder and epilepsy13. The diagnosis of epilepsy in individuals with bipolar disorder is about two and a half times higher than in the general population. There is evidence of complex genetic heritability involving different genes, partially shared between the two disorders13,17. In bipolar disorder, due to risky behavior and frequent co-occurrence with substance use disorder, there is also increased exposure to known risk factors for the development of epilepsy, such as head trauma and alcohol abuse, which contribute to the onset of new epileptic episodes27.
Conclusion
Epilepsy is a neurological disorder that affects 1 to 2% of the global population, characterized by recurrent unprovoked seizures. Bipolar affective disorder is a psychiatric disorder present in about 1% of the population, characterized by recurrent mood oscillations between depressive and manic poles, with the possibility of psychotic symptoms in more severe cases. Both disorders are chronic and responsible for reduced quality of life and psychosocial impairment in affected individuals. This study aims to conduct an integrative review of the association between these two pathologies. A literature search was conducted in Medline, Pubmed, and Scielo, and 17 articles were included in this review. The analysis of these data leads us to believe that there is a significant association between the two disorders, with a comorbid prevalence estimated at 1.4% when referring to the diagnosis of bipolar disorder type I, but reaching up to 10% in some studies that examined symptoms of the bipolar spectrum as a whole.
Bipolar disorder in patients with epilepsy seems to have atypical presentations (shorter duration of manic episodes, increased cycling), which can be a barrier to accurate diagnosis, potentially leading to an underestimated number of cases and treatment delays. It may also explain the better response of bipolar patients called rapid cyclers to the use of anticonvulsant drugs.
There appear to be shared pathophysiological bases between the two disorders, such as cyclic/episodic presentation explained by the kindling effect, chronic course, response to anticonvulsant drugs, alterations in ion channels and neurotransmitter balance, involvement of second-messenger systems, neuroinflammation, and mitochondrial dysfunction.
Despite being prevalent among mental disorders in the general population, bipolar disorder seems to be underdiagnosed in patients with epilepsy for various reasons. There is difficulty in the more precise differentiation of its phenomenology and atypical clinical presentations. Additionally, mental illnesses have an intrinsic peculiarity in the construction of their diagnosis, as they lack specific tests, pathognomonic symptoms, or a single etiology. Often, similar symptoms originate from disorders with diverse biological bases, just as similar diagnoses can lead to different symptom profiles and progressions.
Added to this difficulty is the need to think hierarchically about the diagnosis, with so-called somatic-based disorders (such as behavioral changes caused by epileptic focus, for example) taking precedence over functional mental disorders. This does not diminish psychiatric diagnosis or disregard the biological bases of mental illnesses but helps guide clinical reasoning and structure diagnostic investigation, thereby reducing errors in therapeutic management and prognosis that could lead to iatrogenic effects.
Another point that is not extensively discussed in the literature is the "masking" of manic episodes in bipolar disorders by anticonvulsant medications that act as mood stabilizers. The lack of literature on this specific point was the major flaw of the study.
This raises suspicions, at least in part, about the reasons why bipolar disorder seems to be underdiagnosed in patients with epilepsy. Further studies on the subject are necessary to continue elucidating the pathophysiology of these disorders, aiming for better treatment response, improved quality of life for these individuals, and combating the stigma caused by both diseases.
References
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a. Hospital Universitário Maria Aparecida Pedrossian / Universidade Federal de Mato Grosso do Sul, Departamento de Psiquiatria - Campo Grande/MS - Brasil
b. Universidade Federal do Mato Grosso do Sul, Faculdade de Medicina - Campo Grande/MS - Brasil
Autor correspondente
Bruna Parussolo Bordon
brupbordon@gmail.com / E-mail alternativo: anderson_stolf@ufms.br
Submetido em: 26/05/2023
Aceito em: 29/06/2024
Contribuições: Bruna Parussolo Bordon - Coleta de Dados, Conceitualização, Investigação, Redação - Preparação do original; Anderson Ravy Stolf - Redação - Revisão e Edição; Kleber Francisco Meneghel Vargas - Redação - Revisão e Edição, Supervisão.
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