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Epilepsy & Behavior 13 (2008) 263–264

Letter to the Editor

Preventive measures for sudden cardiac death in epilepsybeyond therapies

To the Editor:

We read with interest a very comprehensive review articleentitled ‘‘The Mystery of Sudden Death: Mechanisms forRisks” by Lathers and colleagues [1] published in the Janu-ary issue of Epilepsy & Behavior. Given the dearth of pub-lished data on potential preventive measures to minimizethe risk of sudden unexpected death in epilepsy (SUDEP),we applaud Dr. Lathers and her colleagues for pursuing thistopic, but we also find it necessary to address some purposesregarding their suggestions. Although the availability ofpharmacological treatment of the epilepsies has expanded,antiepileptic drugs are still limited in clinical efficacy. Sev-eral factors (genetic, environmental, and social) can con-tribute to the inefficacy of therapy in people with epilepsy.Among these factors, nutritional aspects such as omega-3fatty acid deficiency may have an interesting role. Substan-tial evidence from epidemiological and case–control studiesindicates that omega-3 reduces the risk of cardiovascularmortality, particularly sudden cardiac death [2]. Followingthis reasoning, as omega-3 fatty acids per se have beenshown to reduce cardiac arrhythmias and sudden cardiacdeaths, it was hypothesized that omega-3 fatty acid supple-mentation in patients with refractory seizures may reduceseizures and seizure-associated cardiac arrhythmias and,hence, SUDEP [3]. With respect to the cardioprotective ef-fects of omega-3, it has long been believed that daily intakeof 3000 to 4000 mg of fish oil supplements or two or threeservings of fatty fish per week is safe and effective in adultsin general, including those with neurological diseases [4]. Itis very important, however, to emphasize that nutritionaltherapy (including omega-3 supplementation) is not a sub-stitute for anticonvulsant medications.

Exposure to low temperatures is considered one of themain risk factors for cardiovascular abnormalities and,hence, sudden death [5]. There are several findings thatmay explain the increase in cardiac events in response tocold temperatures: (1) Support for this notion may be de-rived from the 53% increase in cases of acute myocardialinfarction reported during the winter compared with thesummer [6]. (2) During the winter, increases in hemocon-centration (erythrocyte count, plasma cholesterol, andplasma fibrinogen levels) have been reported, which couldcontribute to arterial thrombosis [7]. (3) Cold weather can in-

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doi:10.1016/j.yebeh.2007.12.014

duce a higher systemic vascular resistance with an increase inblood pressure (thus increasing oxygen demand) [8]. (4) Win-ter temperatures may be associated with the flu season, andan increase in upper respiratory tract infections could placestress on the heart [9]. Taking these data into consideration,our research group recently suggested that cold weathercould be considered a new potential risk factor for suddencardiac death in patients with epilepsy [10].

Finally, several suggestions have been made concerningthe mechanisms behind SUDEP, most involving specula-tions on the possible role of autonomic effects such as car-diorespiratory disturbances. It has been believed thatcardiovascular diseases are often associated with overactiv-ity of the sympathetic nervous system [11], and increases inphysical activity produce beneficial effects on the cardio-vascular system in normal and diseased individuals viaalterations in neural control of the circulation [12]. Theseeffects include reductions in blood pressure and sympa-thetic outflow in humans [13] as well as in animal modelsof exercise training [14]. As morbidity and mortality in car-diovascular disease are often associated with elevations insympathetic nervous system activity [15], the beneficial ef-fects of physical activity are probably related, in part, toreductions in sympathetic activity. A recent study by ourgroup evaluated the heart rate, in vivo (ECG) and in anisolated ex vivo preparation (Langendorf preparation) ofrats with epilepsy [16]. The results showed differences inthe mean heart rate in vivo, but, surprisingly, no differencesin heart rate could be observed in the isolated ex vivo situ-ation, suggesting central nervous system modulation of theheart, which could explain SUDEP [16]. In light of thesefindings, it is very reasonable to think that regular physicalactivity is able to attenuate sympathetic nervous systemactivity, cardiac abnormalities, and hence SUDEP. Fur-thermore, it is clear that premature mortality is increasedin patients with epilepsy, particularly in those with more se-vere seizures [17], and it is generally acknowledged that car-diac abnormalities between seizures is the probable causeof SUDEP [10,17]. As physical activity has been consideredto act as an anticonvulsant [18,19], it can be hypothesizedthat regular physical activity may attenuate the frequencyof seizures and cardiac abnormalities that culminate inSUDEP.

In conclusion, as reported by others [20], clarification ofrisk factors and establishment of the mechanisms of SUDEPare important for establishing preventive measures for SU-

264 Letter to the Editor / Epilepsy & Behavior 13 (2008) 263–264

DEP, and striving for full seizure control is the best we canmanage. However, we also believe that encouraging patientswith epilepsy worldwide to receive nonmedical treatmentswill lead to substantial and public health benefits.

References

[1] Lathers CM, Schraeder PL, Bungo MW. The mystery of suddendeath: mechanisms for risks. Epilepsy Behav 2008;12:3–24.

[2] Calder PC. n-3 fatty acids and cardiovascular disease: evidenceexplained and mechanisms explored. Clin Sci 2004;107:1–11.

[3] Yuen AW, Sander JW, Fluegel D, et al. Omega-3 fatty acidsupplementation in patients with chronic epilepsy: a randomizedtrial. Epilepsy Behav 2005;7:253–8.

[4] Mazza M, Pomponi M, Janiri L, Bria P, Mazza S. Omega-3 fatty acidsand antioxidants in neurological and psychiatric diseases: an overview.Prog Neuropsychopharmacol Biol Psychiatry 2007;31:12–26.

[5] Arntz HR, Willich SN, Schreiber C, Braggemann T, Stern R,Schultheiss HP. Diurnal, weekly and seasonal variation of suddendeath: population based analysis of 24,061 consecutive cases. EurHeart J 2000;21:315–20.

[6] Spencer FA, Goldberg RJ, Becker RC, Gore JM. Seasonal distribu-tion of acute myocardial infarction in the Second National Registryof Myocardial Infarction. J Am Coll Cardiol 1998;31:1226–33.

[7] Neild PJ, Syndercombe-Court D, Keatinge WR, Donaldson GC,Mattock M, Caunce M. Cold-induced increases in erythrocyte count,plasma cholesterol and plasma fibrinogen of elderly people without acomparable rise in protein C or factor X. Clin Sci 1994;86:43–8.

[8] Argiles A, Mourad G, Mion C. Seasonal changes in blood pressure inpatients with end-stage renal disease related with hemodialysis. NEngl J Med 1998;339:1364–70.

[9] Fleming DM, Cross KW, Pannell RS. Influenza and its relationshipto circulatory disorders. Epidemiol Infect 2005;133:255–62.

[10] Scorza FA, de Albuquerque M, Arida RM, Cavalheiro EA. Suddenunexpected death in epilepsy: are winter temperatures a new potentialrisk factor? Epilepsy Behav 2007;10:509–10.

[11] Schlaich MP, Lambert E, Kaye DM, et al. Sympathetic augmen-tation in hypertension: role of nerve firing, norepinephrine reup-take, and angiotensin neuromodulation. Hypertension 2004;43:169–75.

[12] Cornelissen VA, Fagard RH. Effects of endurance training on bloodpressure, blood pressure-regulating mechanisms, and cardiovascularrisk factors. Hypertension 2005;46:667–75.

[13] Pescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA,Ray CA. for the American College of Sports Medicine. AmericanCollege of Sports Medicine position stand: exercise and hypertension.Med Sci Sports Exerc 2004;36:533–53.

[14] Krieger EM, Da Silva GJ, Negrao CE. Effects of exercise training onbaroreflex control of the cardiovascular system. Ann NY Acad Sci2001;940:338–47.

[15] Zoccali C, Mallamaci F, Parlongo S, et al. Plasma norepinephrinepredicts survival and incident cardiovascular events in patients withend-stage renal disease. Circulation 2002;105:1354–9.

[16] Colugnati DB, Gomes PA, Arida RM, et al. Analysis of cardiacparameters in animals with epilepsy: possible cause of sudden death?Arq Neuropsiq 2005;63:1035–41.

[17] Tomson T, Walczak T, Sillanpaa M, Sander JW. Sudden unexpecteddeath in epilepsy: a review of incidence and risk factors. Epilepsia2005;46:54–61.

[18] Arida RM, Vieira AJ, Cavalheiro EA. Effect of physical exercise onkindling development. Epilepsy Res 1998;30:127–32.

[19] Arida RM, Scorza FA, Santos NF, Peres CA, Cavalheiro EA. Effectof physical exercise on seizure occurrence in a model of temporal lobeepilepsy in rats. Epilepsy Res 1999;37:45–52.

[20] Bell GS, Sander JW. Sudden unexpected death in epilepsy. Riskfactors, possible mechanisms and prevention: a reappraisal. ActaNeurol Taiwan 2006;15:72–83.

Fulvio A. Scorza *

Disciplina de Neurologia Experimental,

Universidade Federal de Sao Paulo/Escola,

Paulista de Medicina (UNIFESP/EPM), Sao Paulo, Brazil

E-mail address: scorza.nexp@epm.br

Ricardo M. AridaDepartamento de Fisiologia,

Universidade Federal de Sao Paulo/Escola,

Paulista de Medicina (UNIFESP/EPM), Sao Paulo, Brazil

Esper A. CavalheiroDisciplina de Neurologia Experimental,

Universidade Federal de Sao Paulo/Escola,Paulista de Medicina (UNIFESP/EPM), Sao Paulo, Brazil

Received 21 December 2007; accepted 25 December 2007Available online 1 February 2008

* Corresponding author. Fax: +55 11 55739304.