"Special Issue on Epilepsy & Comorbidities"
Epilepsy and comorbidities: towards unravelling the common underlying mechanisms
Yam Nath Paudel 1, Christos Panagiotis Lisgaras 2, Kheng Seang Lim 3 and Mohd. Farooq Shaikh 1,*
1 Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor, Malaysia.
2 Saul R. Korey Department of Neurology, Laboratory of Developmental Epilepsy, Albert Einstein College of Medicine, Bronx, NY, USA.
3 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
* Correspondence: ; Tel.: +603 5514 4483
Published: 14 October 2018
Keywords: epilepsy; comorbidities; cognitive decline; depression; anxiety;
Epilepsy is a chronic neurological disorder characterized by the rapid occurrence of epileptic seizures affecting approximately 70 million people worldwide [, ]. The quality of life of people with epilepsy (PWE) is challenged by a series of comorbidities that might include neurologic and neuropsychiatric disorders (cognitive decline, depression, anxiety, schizophrenia, and autism) as well as metabolic, cardiovascular and respiratory diseases . Neurobehavioral and other comorbidities might share a reciprocal and complex relationship with epileptogenesis and ictogenesis thus biomarkers of the former might be useful for the prediction of the latter and vice versa . This bidirectional relationship between epilepsy and associated comorbidities has attracted significant attention in recent years as supported by data showing that one half of PWE demonstrate cognitive impairments , 30-50% depressive behavior, 10-25% anxiety disorders  and 5-40% autism or autism spectrum disorder (ASD) . In the past decades, epilepsy-related neurobehavioral comorbidities have been critically discussed, but the current need in unraveling the precise mechanism associated with epilepsy and these neurobehavioral comorbidities is unmet. The precise understanding of the mechanistic pathway underlying these epilepsy-associated comorbid conditions could be instrumental in developing therapeutic interventions that might modify seizure burden and accompanying comorbid conditions.
Much more remained to be learned about the pathophysiology of epileptogenesis , but accumulating evidences suggest that inflammatory cascades might play a crucial role in epileptogenesis [, ]. The role of inflammation in epilepsy is well-documented in the literature and ample of evidence suggest that the same inflammatory pathways might be associated with other comorbid conditions such as cognitive dysfunction [, ], depression [, ], ASD , anxiety  and schizophrenia . But there might be other mechanisms that have been implicated in various epilepsy-related comorbid conditions. For instance, indoleamine 2, 3-dioxygenase (IDO) plays a role in epilepsy-associated depression, as supported by findings reporting that activation of brain IDO contributes to epilepsy-induced depressive-like behavior . Imbalance in neurotransmitters (NT) levels such as norepinephrine, dopamine, and serotonin, γ-aminobutyric acid (GABA) as well as neuroendocrine substances such as adrenocorticotrophic hormone, and neuropeptide Y (NPY) have been hypothesized to play a role in the pathogenesis of anxiety-like behavior in epilepsy [, ]. ASD and epilepsy are hypothesized to be associated with disruption in γ-aminobutyric acid (GABA) neurotransmission affecting the excitation-inhibition signaling balance . Whenever there is a disruption in molecular cascades involved in neuronal development, synaptogenesis, interneuronal function, enhanced protein synthesis in the mammalian target of rapamycin (mTOR) pathways, GABA and glutamate NMDA receptor function, as well as abnormalities in Na+ channel, this disruption might cause both epilepsy and ASD . Moreover, changes in GABAergic activity and some genes, which code for GABAergic receptors and neurexins have been correlated to epilepsy and ASD. Moreover, a product of gene 'SYNGAP' also play an important role for neurotransmission. However, The interplay between genetics, epilepsy, and its comorbidities should not be ruled out . A recent review had shed light on the role of inflammation in epilepsy and related neurobehavioral comorbidities as well as highlighted that anti-inflammatory therapy might be a candidate intervention that might modify ictogenesis and ameliorate associated neurobehavioral conditions [, ]. However, the important question remains unsolved; is inflammation the only underlying mechanism between epilepsy and related comorbidities? This finding does not completely solve the crucial problem, as there might be other mechanisms associated with epilepsy and related comorbid conditions that are not yet explored. Moreover, no experimental and clinical evidence has further substantiated these findings warranting further research in this domain.
Epilepsy and related comorbid conditions, as well as the plausible interplay mechanism, constitutes a novel research arena that deserves to be extensively studied. The scope of this topic is not only limited to unraveling the mechanism associated with epilepsy and related comorbidities, but also extends towards developing suitable animal models for investigating epilepsy and comorbidities as well as identifying potential new biomarkers that would allow for the prediction, diagnosis, and treatment of epilepsy‐related comorbidities . This research topic is of crucial importance as the complex association between epilepsy and comorbid conditions exhibits a greater difficulty in epilepsy treatment and might hinder the outcome of the therapy. The more complicating issues reside in the fact that, epilepsy is not only a single disorder but is a broad range of systemic disorders with shared and common features . Though this research topic will strengthen the state of knowledge of the comorbidities associated with epilepsy, the research in this domain is completely challenging yet interesting. The treatment process of PWE is full of complexity since the main concern still remained unsolved; do these comorbidities associated with epilepsy persist even after epilepsy is resolved?
On top of that, the current research topic will encourage new research avenues and opportunities for further improvement in clinical care and scientific discovery. The research on epilepsy and related comorbidities is utterly crucial and is a current need as the better understanding of the precise mechanisms of comorbidities could help to prevent morbidity and premature mortality of PWE. We are confident that this special issue will provide novel and insightful information to the readers that would spark new research in the field of epilepsy.
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