versão impressa ISSN 0004-282X
Arq. Neuro-Psiquiatr. vol.67 no.3b São Paulo set. 2009
VIEWS AND REVIEWS
Epilepsy and sudden unexpected death in epilepsy? Eat more fish! A group hypothesis
Epilepsia e morte súbita? Coma mais peixe! A hipótese de um grupo
Roberta M. CysneirosI; Vera C. TerraII; Hélio R. MachadoII; Ricardo M. AridaIII; Marly de AlbuquerqueIV; Carla A. ScorzaIV; Esper A. CavalheiroIV; Fulvio A. ScorzaIV
IPrograma de Pós-Graduação em Distúrbios do Desenvolvimento do Centro de Ciências Biológicas e da Saúde da Universidade Presbiteriana Mackenzie, São Paulo SP, Brasil
IICentro de Cirurgia de Epilepsia (CIREP), Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo SP, Brasil
IIIDepartamento de Fisiologia, Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), São Paulo SP, Brasil
IVDisciplina de Neurologia Experimental, Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), São Paulo SP, Brasil
Epilepsy is the commonest serious neurological disorder and individuals with epilepsy are at higher risk of death than the general population and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures play a potential role. The ultimate goal of SUDEP research is to develop methods to prevent it and nutritional aspects such as omega-3 fatty acid deficiency may have an interesting role in this scenario. Omega-3 fatty acids reduce the risk of cardiovascular mortality and are important for treating or preventing some neurological diseases, including epilepsy. A dietary modification or nutritional supplements increasing the ingestion of omega-3 fatty acids may help to ''save the brain".
Key words: epilepsy, sudden death, omega-3.
A epilepsia é uma das doenças neurológicas sérias mais comuns e está associada a um maior risco de morte do que o observado na população geral e a morte súbita em epilepsia é uma importante causa de morte relacionada à epilepsia. Os potenciais patomecanismos da morte súbita em epilepsia são desconhecidos, mas é bastante provável que arritmias cardíacas durante ou entre as crises tenham um papel preponderante. O objetivo final das pesquisas em morte súbita em epilepsia é o desenvolvimento de métodos que levem à sua prevenção e aspectos nutricionais, como a deficiência de ômega-3 pode ter um papel interessante neste contexto. A suplementação com ômega-3 reduz o risco de mortalidade de origem cardiovascular e é importante no tratamento e prevenção de algumas doenças neurológicas, incluindo a epilepsia. A modificação dietética ou a suplementação nutricional aumentando a ingesta de ômega-3 pode ajudar a "salvar o cérebro".
Palavras chave: epilepsia, morte súbita, ômega-3.
SUDDEN UNEXPECTED DEATH IN EPILEPSY: GENERAL VIEW
Epilepsy is the commonest serious neurological disorder1. Approximately, 3 percent of persons in the general population will have epilepsy at some point in their lives1. Unfortunately, individuals with epilepsy are at higher risk of death than the general population and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death2. Some risk factors for SUDEP have been proposed, however, SUDEP is mainly a problem for patients with chronic uncontrolled epilepsy2. Additionally, potential pathomechanisms for SUDEP are unknown, but it is very probable that cardiac arrhythmias during and between seizures play a potential role2,3. Thus, while admitting the deficiencies in our current knowledge, the ultimate goal of SUDEP research is to develop methods to prevent it. Following these reasoning, nutritional aspects such as omega-3 fatty acid deficiency may have an interesting role in this scenario.
ÔMEGA-3, EPILEPSY AND SUDDEN UNEXPECTED DEATH IN EPILEPSY
Polyunsaturated fatty acids are present at high levels in the brain4. The 04 polyunsaturated fatty acids are designed eicopentanoic acid (EPA) and decosahexanoic acid (DHA), which are n-3 fatty acids (omega-3); and dihomogammalinolenic acid (DGLA) and arachidonic acid (AA), which are n-6 fatty acids (omega-6), comprise over 10% (w/w) of the dry weight of the brain4,5. In fact the brain, dietary consumption of the long-chain omega-3 fatty acids, commonly found in fish (fish oil) (Figure), is certainly a good way to improve the development of the brain (from the composition of cell membranes to cerebral function) and all omega-3 fatty acids reduce the risk of cardiovascular mortality (with an especially potent effect on sudden cardiac death) and are important for treating or preventing some neurological diseases, including epilepsy3,6. Thus, as cardiovascular abnormalities during and between seizures are directly related to a high frequency of SUDEP2,3, a possible relationship between omega-3 fatty acids, epilepsy, and SUDEP should be considered. Along these lines, several experimental studies have been shown that omega-3 fatty acids reduce neuronal excitability and may be useful in the nonpharmacological treatment of patients with epilepsy3-9. Very recently, our group was the first to demonstrate that chronic treatment with omega-3 fatty acids promotes neuroprotection and leads to prominent positive plastic changes in the hippocampal formation of rats with epilepsy3. From a clinical point of view, the first randomized, placebo-controlled parallel group study of omega-3 supplementation in patients with chronic epilepsy showed only a transient effect on seizure frequency that was not confirmed by other research group, but additional trials are required3,10. These results did not totally confirm that omega-3 fatty acids reduce the frequency of epileptic seizures in patients with intractable epilepsy; however, they established the safety of omega-3 supplementation in people with epilepsy10. Quite interesting, there is now great interest in epilepsy prevention, and recent work has shown that early treatment may block changes in the expression of ion channels11. In these lines, n-3 fatty acids may be used for the prevention of SUDEP3,10, as omega-3 fatty acids per se have been shown to reduce cardiac arrhythmias and sudden cardiac deaths, it is reasonable to think that omega-3 fatty acid supplementation in patients with refractory seizures may reduce seizures, seizure-associated cardiac arrhythmias and hence SUDEP3,10,12.
Yes, fish is excellent for us. However, it is very important to remember that some kinds of fish contain contaminants that we'd rather not be eating. As we know, the major risk of fish consumption is its content of methylmercury13. Considering the potential health risk of methylmercury consumption, an interesting question could be evaluated: Are we totally safe eating fish? It is clear that the concentration of methylmercury in fish is increased in predatory fish than non-predatory fish14. Thus, the best seafood choices are those with non predatory characteristics (Table)13-15.
In sum, a number of different dietary modifications and nutritional supplements may help prevent seizures or improve other aspects of health in patients with epilepsy. However, it is very important to emphasize that nutritional therapy (including omega-3 supplementation) is not a substitute for anticonvulsant medications. Overall, our research group strong believes that fish is one of the most important foods we can choose for cardiovascular and brain health. The type of fish and seafood, the frequency of consumption, and the meal size are essential issues in the balance of benefits and risks of a regular consumption16. Concerning the cardioprotective effects of omega-3, it has long been believed that a daily intake of 3000 to 4000 mg of fish oil supplements or 2 to 3 servings of fatty fish per week are safe and effective in adults in general, included those with neurological diseases17. On the other hand, for individuals who want a diet with zero methylmercure but would like to enjoy the benefits of omega-3 fatty acids, there are always fish oil supplements or intake of foods such as walnuts or oils (flax, canola and soybean)16,18. Neurologists should ''save the brain" and prescribe fish again!
1. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003;349:1257-1266. [ Links ]
2. Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7:1021-1031. [ Links ]
3. Scorza FA, Cysneiros RM, Arida RM, Terra-Bustamante VC, de Albuquerque M, Cavalheiro EA. The other side of the coin: beneficiary effect of omega-3 fatty acids in sudden unexpected death in epilepsy. Epilepsy Behav 2008;13:279-283. [ Links ]
4. Ohara K. The n-3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007;31: 469-474. [ Links ]
5. Calon F, Cole G. Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot Essent Fatty Acids 2007;77:287-293. [ Links ]
6. Bourre JM, Paquotte P. Seafood (Wild and Farmed) for the elderly: contribution to the dietary intakes of iodine, selenium, DHA and vitamins B12 and D. J Nutr Health Aging 2008;12:186-192. [ Links ]
7. Leaf A, Kang JX, Xiao YF, Billman GE, Voskuyl RA. The antiarrhythmic and anticonvulsant effects of dietary N-3 fatty acids. J Membr Biol 1999;172:1-11. [ Links ]
8. Das UN. Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how? Prostaglandins Leukot Essent Fatty Acids 2000; 63:351-362. [ Links ]
9. Leaf A. The electrophysiologic basis for the antiarrhythmic and anticonvulsant effects of n-3 polyunsaturated fatty acids: heart and brain. Lipids 2001;36(Suppl):S107-S110. [ Links ]
10. DeGiorgio CM, Miller P. n-3 fatty acids (eicosapentanoic and docosahexanoic acids) in epilepsy and for the prevention of sudden unexpected death in epilepsy. Epilepsy Behav 2008;13:712-713. [ Links ]
11. Cereghino JJ. The major advances in epilepsy in the 20th century and what we can expect (hope for) in the future. Epilepsia 2009;50:351-357. [ Links ]
12. Yuen AW, Sander JW. Is omega-3 fatty acid deficiency a factor contributing to refractory seizures and SUDEP? A hypothesis. Seizure 2004;13:104-108. [ Links ]
13. Smith KM, Sahyoun NR. Fish consumption: recommendations versus advisories, can they be reconciled? Nutr Rev 2005;63:39-46. [ Links ]
14. Jeejeebhoy KN. Benefits and risks of a fish dietshould we be eating more or less? Nat Clin Pract Gastroenterol Hepatol 2008;5:178-179. [ Links ]
15. No authors listed. Fish: friend or foe? In addition to heart-healthy omega-3 fats, seafood can carry mercury and other toxins. For most people, the benefits of eating fish far outweigh the risks. Harv Heart Lett 2007;17:4-6. [ Links ]
16. Domingo JL. Omega-3 fatty acids and the benefits of fish consumption: is all that glitters gold? Environ Int 2007;33:993-998. [ Links ]
17. Mazza M, Pomponi M, Janiri L, Bria P, Mazza S. Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview, Prog Neuropsychopharmacol Biol Psychiatry 2007;31:12-26. [ Links ]
18. Jeejeebhoy KN. Benefits and risks of a fish dietshould we be eating more or less? Nat Clin Pract Gastroenterol Hepatol 2008;5:178-179. [ Links ]
Received 1 April 2009, received in final form 13 July 2009. Accepted 5 August 2009.
Financial support: FAPESP, CInAPCe-FAPESP, INCT/MCT and CNPq.
Dr. Fulvio Alexandre Scorza - Rua Botucatu 862 - 04023-900 São Paulo SP - Brasil. E-mail: email@example.com