Autonomic Nervous System Dysfunction In Patients With Epilepsy And Its Potential Association With Sudden Unexpected Death In Epilepsy (SUDEP) - Info and Reading Options

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Patients with epilepsy have a higher risk of chronic conditions, including psychiatric comorbidities, lower quality of life, status epilepticus, and worse cognitive function (4–6). Apart from the increased morbidity, Patients who have epilepsy have a higher risk of unnatural premature death compared to the general population (7,8). The leading cause of death in patients with DRE, especially in young adults, with an approximate incidence of 1-6 per 1000 persons per year, is attributed to sudden unexpected death in epilepsy (SUDEP). The mechanisms for SUDEP are still unclear and are presumed to be multifactorial. The three main hypotheses are: respiratory dysfunction, cardiac arrhythmias, and alterations in cerebral blood flow autoregulation (9,14–16). Contributing pathophysiological events implicate broad autonomic dysfunction (17,18). Other factors that could play a role in SUDEP include: comorbidities such as sleep apnea, obesity and cardiovascular conditions, antiseizure medications (carbamazepine), and genetic predisposition (19). Seizures frequently have autonomic manifestations especially when they originate from limbic structures (21,22). The amygdala, anterior and mid cingulate, orbitofrontal cortex, insula, thalamus, hypothalamus, periaqueductal grey matter, parabrachial nucleus, medial prefrontal cortex, hippocampus and medullary regions are part of a central autonomic network (CAN) that regulate responses via the sympathetic and parasympathetic systems (23–27). The cornerstone for preventing SUDEP is achieving seizure freedom, particularly freedom of bilateral tonic clonic seizures. Epilepsy surgery offers the greatest chance of seizure freedom for up to 70% of appropriately selected patients (28,29). When the information obtained during the phase I (non-invasive) evaluation does not allow to proceed directly to surgery, a phase II (invasive) evaluation with intracranial electrodes (SEEG: Stereo electroencephalography, SDG: Subdural grid) is required (29,30). Cortical stimulation is a procedure used as part of the phase II evaluation for epilepsy surgery. It is a non-physiological method based on electrical stimuli that would inhibit or excite specific brain functions (31). The principal objectives of this study are to disclose the eloquent cortex that are areas of the brain associated with critical functions (such as language) and to aid in localizing the epileptogenic network involved in seizure generation (31–34). Cortical stimulation has been used in studies to analyze different physiological responses after stimulating specific structures in the brain in patients with epilepsy. A “breathing modulating network” has being described involving limbic and para-limbic structures (35). Central apnea and oxygen desaturation has been provoked when seizures originate from, or spread to, the amygdala (24). Other studies have shown enhancement of respiration after stimulating the amygdala, anterior cingulate gyrus, anterior insula, temporal pole, and thalamus (36). The subcallosal neocortex has been implicated in lowering the blood pressure during stimulation (37). The dysfunction of these brain structures during or in between seizures has been suggested to be associated with the physiopathology of SUDEP. When resective surgery is not an option, non-curative palliative procedures can also be performed to reduce the seizure burden and improve quality of life of patients and caregivers. In our center, patients with epilepsy are evaluated in the epilepsy monitoring unit (EMU) to assess the burden of their epilepsy and/or to see if they could be candidates for epilepsy surgery. In this scenario we can asses how the autonomic system behaves at baseline, during and/or after seizures. Additionally, for the patients with SEEG we can explore the relationship between stimulating a specific structure within the brain and the autonomic response while the patient undergoes the cortical stimulation study, in addition the normal recording epochs. The study design is a prospective study of patients admitted to our epilepsy monitoring unit (EMU) as part of the standard-of-care to try to control their seizures. We will collect information in regard to their epilepsy. Additionally, a research team member will assess physiological parameters at baseline, during and/or after seizures. Patients who are implanted with depth electrodes, may also choose to participate in the portion of the study where the physiological parameters be assessed during the cortical stimulation, in addition to the other times proposed for the patients admitted for Phase I, including the ones who underwent to previous intervention. All the patients will complete two questionnaires, one related the sleep apnea (Epworth Scale) and one to evaluate autonomic complaints (COMPASS-31). With this project we wish to expand the knowledge of the autonomic system in patients with epilepsy and its potential implications for SUDEP.

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