Faculdade de Medicina / USP
Sudden death in a patient with epilepsy and arterial hypertension: time for re-assessment

DOI: 10.6061/clinics/2021/e3023, Volume: 76, Issue: null, Pages: 0-0
Article Type: article-commentary, Article History

Table of Contents



Epilepsy is a common severe neurological disease independent of age, race, social class, geographic, or national boundaries (1). Refractory epilepsy patients require the most time, attention, effort, and focus from neurologists due to the frequency and severity of their seizures. Refractory epilepsy is a major cause of disability, comorbidity, stigma, costs, and mortality (2 34-5). Epilepsy has been associated with an increased risk of premature death, particularly among refractory epilepsy patients (2,5,6). Sudden Unexpected Death in Epilepsy (SUDEP) is the most important direct epilepsy-related cause of death, accounting for 10-50% of all deaths (2,5,6). SUDEP is defined as “the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death in patients with epilepsy, with or without evidence for a seizure, and excluding documented status epilepticus, in which postmortem examination does not reveal a toxicological or pathoanatomical cause of death” (7). The incidence of SUDEP is approximately 1 in 4,500 children per year and 1 in 1,000 adults per year (2,8-10). The risk factors and predictors for SUDEP include early adulthood, early onset of epilepsy, long duration of epilepsy, a high number of anti-epileptic drugs (AEDs), and cold temperature (5,9,11,12). Several studies have indicated that the frequency of nocturnal generalized tonic-clonic seizures was the leading clinical risk factor for SUDEP (2,6,13-17). Structural and functional heart changes were documented in epilepsy patients, suggesting the involvement of cardiac arrhythmias and autonomic dysfunction in SUDEP (6,10,12,13,16-20). Moreover, patients with drug-resistant epilepsy were found to have an abnormal resting autonomic function, including reduced heart rate variability, baroreflex sensitivity, and electrodermal activity (19). Seizure control is still the most effective management for SUDEP (2,14,15,21-23). Possible preventive strategies include stress reduction, engaging in physical activity and sports, dietary management (e.g., omega-3 supplementation), supervision at night, and living with a dog (2,14,15,21-23). Due to the complex nature of SUDEP, early identification of the clinical risk factors has remained challenging. Thus, it is important to investigate the pathophysiology of arterial hypertension (AHT) and its implications on SUDEP.

AHT has recently been related to the risk of sudden cardiac death (24). This also applies to epilepsy patients (25). Studies on the mechanism behind AHT and the development of cardiovascular abnormalities and sudden death have inspired studies on the risk of SUDEP in epilepsy patients (26). Epilepsy and AHT are common chronic diseases that can coexist in the same individual (24). The relationship between refractory epilepsy, AHT, and sudden death was observed in the following case. A 42-year-old man with normal neurodevelopment experienced a severe febrile seizure during the first year of life. When he was 11 years old, the patient started having focal or bilateral tonic-clonic seizures. On interictal electroencephalography, epileptiform discharges were recorded in the left anterior temporal lobe projection. In addition, brain magnetic resonance imaging showed left mesial temporal sclerosis (loss of internal architecture of hippocampus and reduced hippocampal volume). Several AED therapies failed to control his seizures, and the patient developed refractory epilepsy. He was also diagnosed with AHT during a routine clinical visit. He was referred to a cardiologist and was prescribed medications, but he did not adhere to his antihypertension treatment (mainly driven by forgetfulness to take medications). Thus, his blood pressure remained poorly controlled. The patient was found dead one Sunday morning. The patient did not have other comorbidities aside from AHT and epilepsy. Postmortem examination was not carried out. His death was clinically classified under probable SUDEP (27).

This case and previous related studies have emphasized several learning points. AHT was involved in the pathophysiology and development of seizures and epilepsy (25). Furthermore, AHT was a predictor of late-onset epilepsy, regardless of vascular damage. It also indirectly promotes cerebrovascular disease, which increases the risk for acute symptomatic seizures or chronic epilepsy (25). Moreover, the coexistence of AHT and epilepsy exposes patients to multiple pharmacological treatments (25). The drug-drug interactions and mechanisms of actions should be considered in AHT patients taking multiple drugs (25). Epilepsy and AHT are common chronic diseases with severe implications for public health (25,28), and patients with AHT and epilepsy have an increased mortality rate and risk of sudden death.

Isolated AHT and elevated pulse pressure are involved in the development of brain complications (29). Thus, AHT increases the risk not only for cerebrovascular morbidity and mortality, but also for cognitive impairment and dementia (29). Since AHT increases the risk of SUDEP, it should be considered a risk factor for developing fatal events in epilepsy. Finally, a task force should be established to assess the state of knowledge on this issue and identify clinical gaps in the diagnosis and treatment of this high‐risk population.


The authors would like to thank Dr. Marly de Albuquerque for clinical support. Our studies are supported by the following grants: FAPESP (Fundação de Amparo è Pesquisa do Estado de São Paulo); CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); FAPEMIG (Fundação de Amparo è Pesquisa do Estado de Minas Gerais).

No potential conflict of interest was reported.


    de Boer   HM , Mula   M , Sander   JW . The global burden and stigma of epilepsy. Epilepsy Behav 2008. 12: 4 540 -6 doi: 10.1016/j.yebeh.2007.12.019

    Scorza   CA , Guimarães-Marques   M , Girão   ERC , Nejm   M , Finsterer   J , Girão   MJBC , . Alcohol and sudden unexpected death in epilepsy: do not pop the cork. Clinics (Sao Paulo) 2020. 75: e1770 doi: 10.6061/clinics/2020/e1770

    Moshé   SL , Perucca   E , Ryvlin   P , Tomson   T . Epilepsy: new advances. Lancet 2015. 385: 9971 884 -98 doi: 10.1016/S0140-6736(14)60456-6

    Jetté   N , Sander   JW , Keezer   MR . Surgical treatment for epilepsy: the potential gap between evidence and practice. Lancet Neurol 2016. 15: 9 982 -94 doi: 10.1016/S1474-4422(16)30127-2

    Laxer   KD , Trinka   E , Hirsch   LJ , Cendes   F , Langfitt   J , Delanty   N , . The consequences of refractory epilepsy and its treatment. Epilepsy Behav 2014. 37: 59 -70 doi: 10.1016/j.yebeh.2014.05.031

    Tomson   T , Nashef   L , Ryvlin   P . Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008. 7: 11 1021 -31 doi: 10.1016/S1474-4422(08)70202-3

    Harden   C , Tomson   T , Gloss   D , Buchhalter   J , Cross   JH , Donner   E , . Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2017. 88: 17 1674 -80 doi: 10.1212/WNL.0000000000003685

    Ellis   SP , Szabó   . Sudden Unexpected Death in Epilepsy: Incidence, Risk Factors, and Proposed Mechanisms. Am J Forensic Med Pathol 2018. 39: 2 98 -102 doi: 10.1097/PAF.0000000000000394


    Scorza   FA , Olszewer   E , Fiorini   AC , Scorza   CA , Finsterer   J . Sudden unexpected death in epilepsy: Rethinking the unthinkable. Epilepsy Behav 2019. 93: 148 -9 doi: 10.1016/j.yebeh.2019.01.002


    May   TW , Israel   CW . Plötzlicher unerwarteter Tod bei Epilepsie (SUDEP): Epidemiologie, kardiale und andere Risikofaktoren [Sudden unexpected death in epilepsy (SUDEP): Epidemiology, cardiac and other risk factors]. Herzschrittmacherther Elektrophysiol 2019. 30: 3 274 -86 doi: 10.1007/s00399-019-00643-0


    Scorza   FA , Colugnati   DB , Pansani   AP , Sonoda   EY , Arida   RM , Cavalheiro   EA . Preventing tomorrow's sudden cardiac death in epilepsy today: what should physicians know about this?. Clinics (Sao Paulo) 2008. 63: 3 389 -94 doi: 10.1590/s1807-59322008000300017


    Szurhaj   W , Leclancher   A , Nica   A , Périn   B , Derambure   P , Convers   P , . Cardiac Autonomic Dysfunction and Risk of Sudden Unexpected Death in Epilepsy. Neurology 2021. doi: 10.1212/WNL.0000000000011998


    Watkins   L , Shankar   R , Sander   JW . Identifying and mitigating Sudden Unexpected Death in Epilepsy (SUDEP) risk factors. Expert Rev Neurother 2018. 18: 4 265 -74 doi: 10.1080/14737175.2018.1439738


    Manolis   TA , Manolis   AA , Melita   H , Manolis   AS . Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection. Seizure 2019. 64: 65 -73 doi: 10.1016/j.seizure.2018.12.007


    Pansani   AP , Colugnati   DB , Scorza   CA , de Almeida   AC , Cavalheiro   EA , Scorza   FA . Furthering our understading of SUDEP: the role of animal models. Expert Rev Neurother 2016. 16: 5 561 -72 doi: 10.1586/14737175.2016.1169925


    Pansani   AP , Ghazale   PP , Dos Santos   EG , Dos Santos Borges   K , Gomes   KP , Lacerda   IS , . The number and periodicity of seizures induce cardiac remodeling and changes in micro-RNA expression in rats submitted to electric amygdala kindling model of epilepsy. Epilepsy Behav 2021. 116: 107784 doi: 10.1016/j.yebeh.2021.107784


    Vitorino   PR , Gomes   KP , Ghazale   PP , da Silva   M , Mendes   EP , Dos Santos   FCA , . Coronary vasodilation impairment in pilocarpine model of epilepsy. Epilepsy Behav 2019. 90: 7 -10 doi: 10.1016/j.yebeh.2018.10.037


    Pansani   AP , Colugnati   DB , Schoorlemmer   GH , Sonoda   EY , Cavalheiro   EA , Arida   RM , . Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats. Epilepsy Behav 2011. 22: 3 442 -9 doi: 10.1016/j.yebeh.2011.07.034


    Sivathamboo   S , Perucca   P . Interictal autonomic dysfunction. Curr Opin Neurol 2021. 34: 2 197 -205 doi: 10.1097/WCO.0000000000000906


    Scorza   FA , Arida   RM , Terra   VC , Cavalheiro   EA . What can be done to reduce the risk of SUDEP?. Epilepsy Behav 2010. 18: 3 137 -8 doi: 10.1016/j.yebeh.2010.04.046


    Maguire   MJ , Jackson   CF , Marson   AG , Nevitt   SJ . Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP). Cochrane Database Syst Rev 2020. 4: 4 CD011792 doi: 10.1002/14651858.CD011792.pub3


    Terra   VC , Sakamoto   AC , Machado   HR , Martins   LD , Cavalheiro   EA , Arida   RM , . Do pets reduce the likelihood of sudden unexplained death in epilepsy?. Seizure 2012. 21: 8 649 -51 doi: 10.1016/j.seizure.2012.06.012


    Pan   H , Hibino   M , Kobeissi   E , Aune   D . Blood pressure, hypertension and the risk of sudden cardiac death: a systematic review and meta-analysis of cohort studies. Eur J Epidemiol 2020. 35: 5 443 -54 doi: 10.1007/s10654-019-00593-4


    Gasparini   S , Ferlazzo   E , Sueri   C , Cianci   V , Ascoli   M , Cavalli   SM , . Hypertension, seizures, and epilepsy: a review on pathophysiology and management. Neurol Sci 2019. 40: 9 1775 -83 doi: 10.1007/s10072-019-03913-4


    Terman   SW , Aubert   CE , Hill   CE , Skvarce   J , Burke   JF , Mintzer   S . Cardiovascular disease risk, awareness, and treatment in people with epilepsy. Epilepsy Behav 2021. 117: 107878 doi: 10.1016/j.yebeh.2021.107878


    Nashef   L , So   EL , Ryvlin   P , Tomson   T . Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia 2012. 53: 2 227 -33 doi: 10.1111/j.1528-1167.2011.03358.x


    Shankar   R , Cox   D , Jalihal   V , Brown   S , Hanna   J , McLean   B . Sudden unexpected death in epilepsy (SUDEP): development of a safety checklist. Seizure 2013. 22: 10 812 -7 doi: 10.1016/j.seizure.2013.07.014


    Rigaud   AS , Seux   ML , Staessen   JA , Birkenhäger   WH , Forette   F . Cerebral complications of hypertension. J Hum Hypertens 2000. 14: 10-11 605 -16 doi: 10.1038/sj.jhh.1001118 is an Open Access article distributed under the terms of the Creative Commons License ( which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited. death in a patient with epilepsy and arterial hypertension: time for re-assessment&author=Fúlvio A. Scorza,Antonio Carlos G. de Almeida,Carla A. Scorza,Josef Finsterer,&keyword=&subject=Comments,