Psychiatric Comorbidities in Temporal Lobe Epilepsy: Possible Relationships between Psychotic Disorders and Involvement of Limbic Circuits

Kandratavicius, Ludmyla; Lopes-Aguiar, Cleiton; Bueno-Júnior, Lézio Soares; Romcy-Pereira, Rodrigo Neves; Hallak, Jaime Eduardo Cecílio; Leite, João P.

doi:10.1016/j.rbp.2012.04.007

Cited by 53 publications

(45 citation statements)

References 152 publications

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“…Importantly, neurodegenerative conditions such as dementias and Alzheimer' disease (prevalence ratio 6.3 and 8, respectively) and Parkinson' disease (prevalence ratio, 3.2) appear more frequently in people with epilepsy (Gaitatzis et al, 2004; Gaitatzis et al, 2012). A recent study supports a structural basis for psychiatric comorbidities in patients with TLE, pointing to synaptic dysfunction, as well as to aberrant plasticity within hippocampal networks (Kandratavicius et al, 2012). Several studies revealed an association of dentate gyrus (DG) pathological changes with long-term seizure histories and cognitive dysfunction suggesting a compromised regenerative capacity of the DG in a subpopulation of TLE patients (Blumcke et al, 2009; Coras et al, 2010).…”

Section: Glial Activation – a Common Histopathological Finding In mentioning

confidence: 78%

Comorbidities in Neurology: Is adenosine the common link?

Boison

Aronica

2015

Neuropharmacology

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Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the ‘adenosine hypothesis of comorbidities’ implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic ‘comorbidity model’, in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain comorbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.

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Section: Glial Activation – a Common Histopathological Finding In mentioning

confidence: 78%

Comorbidities in Neurology: Is adenosine the common link?

Boison

Aronica

2015

Neuropharmacology

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“…Temporal lobe epilepsy is associated with a number of co-morbidities, including cognitive and memory disturbances [65], autism [66, 67], depression [68–70] and psychosis [71–73]. Behavioral deficits are also common in animal models of epilepsy [74–82].…”

Section: Disrupted Production and Integration Of Adult-generated Gmentioning

confidence: 99%

Hippocampal granule cell pathology in epilepsy — A possible structural basis for comorbidities of epilepsy?

Hester

Danzer

2014

Epilepsy & Behavior

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Temporal lobe epilepsy in both animals and humans is characterized by abnormally integrated hippocampal dentate granule cells. Among other abnormalities, these cells make axonal connections with inappropriate targets, grow dendrites in the wrong direction and migrate to ectopic locations. These changes promote the formation of recurrent excitatory circuits, leading to the appealing hypothesis that these abnormal cells may by epileptogenic. While this hypothesis has been the subject of intense study, less attention has been paid to the possibility that abnormal granule cells in the epileptic brain may also contribute to co-morbidities associated with the disease. Epilepsy is associated with a variety of general findings, such as memory disturbances and cognitive dysfunction, and is often co-morbid with a number of other conditions, including schizophrenia and autism. Interestingly, recent studies implicate disruption of common genes and gene pathways in all three diseases. Moreover, while neuropsychiatric conditions are associated with changes in a variety of brain regions, granule cell abnormalities in temporal lobe epilepsy phenocopy granule cell deficits produced by genetic mouse models of autism and schizophrenia, suggesting that granule cell dysmorphogenesis may be a common factor uniting these seemingly diverse diseases. Disruption of common signaling pathways regulating granule cell neurogenesis may begin to provide mechanistic insight into the co-occurrence of temporal lobe epilepsy and cognitive and behavioral disorders.

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“…Psychiatric comorbidities are frequent in MTLE patients, and in population-based studies, epilepsy has been consistently associated with increased risk of schizophrenia [5]. However, the exact biological substrate behind the association of MTLE and psychiatric comorbidities is unknown [6,7]. We have recently shown neuropathological alterations in the hippocampus of patients with epilepsy and the history of major depression or interictal psychosis, which may indicate that structural changes and neurochemical dysfunctions may underlie psychiatric symptoms in MTLE [8-10].…”

Section: Introductionmentioning

confidence: 99%

Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay

Kandratavicius

Peixoto-Santos

Monteiro

et al. 2015

J Neuroinflammation

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BackgroundDespite the strong association between epilepsy and psychiatric comorbidities, few biological substrates are currently described. We have previously reported neuropathological alterations in mesial temporal lobe epilepsy (MTLE) patients with major depression and psychosis that suggest a morphological and neurochemical basis for psychopathological symptoms. Neuroinflammatory-related structures and molecules might be part of the altered neurochemical milieu underlying the association between epilepsy and psychiatric comorbidities, and such features have not been previously investigated in humans.MethodsMTLE hippocampi of subjects without psychiatric history (MTLEW), MTLE + major depression (MTLE + D), and MTLE + interictal psychosis (MTLE + P) derived from epilepsy surgery and control necropsies were investigated for reactive astrocytes (glial fibrillary acidic protein (GFAP)), activated microglia (human leukocyte antigen, MHC class II (HLA-DR)), glial metallothionein-I/II (MT-I/II), and aquaporin 4 (AQP4) immunohistochemistry.ResultsWe found an increased GFAP immunoreactive area in the molecular layers, granule cell layer, and cornus ammonis region 2 (CA2) and cornus ammonis region 1 (CA1) of MTLEW and MTLE + P, respectively, compared to MTLE + D. HLA-DR immunoreactive area was higher in cornus ammonis region 3 (CA3) of MTLE + P, compared to MTLE + D and MTLEW, and in the hilus, when compared to MTLEW. MTLEW cases showed increased MT-I/II area in the granule cell layer and CA1, compared to MTLE + P, and in the parasubiculum, when compared to MTLE + D and MTLE + P. Differences between MTLE and control, such as astrogliosis, microgliosis, increased MT-I/II, and decreased perivascular AQP4 in the epileptogenic hippocampus, were in agreement to what is currently described in the literature.ConclusionsNeuroinflammatory-related molecules in MTLE hippocampus show a distinct pattern of expression when patients present with a comorbid psychiatric diagnosis, similar to what is found in the pure forms of schizophrenia and major depression. Future studies focusing on inflammatory characteristics of MTLE with psychiatric comorbidities might help in the design of better therapeutic strategies.

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Psychiatric Comorbidities in Temporal Lobe Epilepsy: Possible Relationships between Psychotic Disorders and Involvement of Limbic Circuits

Cited by 53 publications

References 152 publications

Comorbidities in Neurology: Is adenosine the common link?

Comorbidities in Neurology: Is adenosine the common link?

Hippocampal granule cell pathology in epilepsy — A possible structural basis for comorbidities of epilepsy?

Mesial temporal lobe epilepsy with psychiatric comorbidities: a place for differential neuroinflammatory interplay

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