Risk factors for SUDEP
[Part 1: Facts; Tomson T]
Although sudden and unexpected death is 20 times more common among people with epilepsy than in the general population (Ficker et al., 1998; Holst et al., 2013), and SUDEP is a major cause of death in people with epilepsy (Sillanpää & Shinnar 2010), the SUDEP risk varies markedly between epilepsy patients (Tomson et al., 2008). The lowest risk is seen among people with newly diagnosed epilepsy where SUDEP is truly rare. Studies have estimated the risk to be in the order of 1 in 10,000 person years, i.e. one can expect on average one case of SUDEP if 1,000 persons were followed during 10 years after their seizure onset. Greatest risks are found among those with severe chronic epilepsy. As an example, the SUDEP risk has been estimated to 5-10 in 1,000 person years for patients with refractory epilepsy and who are candidates for epilepsy surgery (Tomson et al., 2008).
The risk appears to be lower among children than adults. In children with uncomplicated epilepsy the risk has been estimated to approximately 1 in 10,000 person years, whereas SUDEP can be 7 times more common in children with a more complicated epilepsy (defined as, with known structural brain lesion, intellectual disability, or abnormal neurological examination) (Berg et al., 2013).
Several studies have tried to find factors predisposing to SUDEP (risk factors) that could help explain these pronounced differences in SUDEP risk. Such information is important in order to identify people with particularly high risks, as well as to further our understanding of mechanisms behind SUDEP and for the development of preventive strategies.
Risk factors are usually identified in so called case-control studies that compare different characteristics of cases that have died in SUDEP with those of people with epilepsy who have not suffered SUDEP. A Task Force of the International League Against Epilepsy (ILAE) combined data from four major such case-control studies from the UK, Sweden and US (Hesdorffer et al., 2011, 2012). Altogether 289 SUDEP cases and 958 living epilepsy controls were included in this combined analysis. The risk of SUDEP was found to be 1.4-fold higher in males compared to females, 1.7 fold higher in those with onset of their epilepsy at young age (before 16 years) compared to those with onset between 16 and 60 years, and two fold higher among those with a duration of epilepsy of more than 15 years. The most important risk factor was frequency of generalized tonic-clonic seizures. Compared to people without tonic-clonic seizures, 1-2 such seizures/year was associated with a 3-fold increase in risk, 3-50 seizures/year with an 8-9-fold increase. The risk was almost 15-fold higher for those with > 50 tonic-clonic seizures/year. Other studies have indicated that the SUDEP risk may be 20 times higher among people with epilepsy who continue to have seizures compared with those who are seizure-free.
It appears that night time poses a particular risk. In the largest case control study so far with 154 SUDEP cases (Langan et al., 2005), almost 60% of the SUDEPs seemed to occur during sleep. Having a history of night time seizures was associated with a four-fold increased SUDEP risk (Lamberts et al., 2012). The increased risk with such seizures could be at least partly explained by poorer supervision during nights. Lack of night time supervision was a risk factor in this study: compared with no supervision, having someone sleeping in the same room reduced the risk by more than 50%. Special precautions such as listening devices were associated with a further risk reduction (Langan et al., 2005). These risk factors have however so far been identified in one study only and need to be confirmed or refuted in additional independent studies.
Can treatment with antiepileptic drugs affect the SUDEP risk? It is reasonable to assume that a treatment that aims to control seizures also affects the SUDEP risk as uncontrolled seizures are the major risk factor. The analysis combining data from four case-control studies in fact confirmed that being on treatment with one antiepileptic drug reduced the risk by approximately 50% (Hesdorffer et al., 2012). Some studies have suggested that being on treatment with more than one antiepileptic drug at the same time could be a risk factor when compared to monotherapy (Nilsson et al., 1999). However, such polytherapy was not associated with an increased risk in the combined analysis when seizure frequency was taken into account (Hesdorffer et al., 2012). This indicates that polytherapy is just a marker of more severe epilepsy, and that the antiepileptic drugs in the polytherapy do not themselves increase the risk of SUDEP.
There have been a few individual reports suggesting that some specific antiepileptic drugs, such as carbamazepine or lamotrigine, are associated with greater SUDEP risk than other treatments (Langan et al., 2005; Aurlien et al., 2012). However, this was not confirmed in the combined analysis of the four case-control studies. Frequency of generalized tonic-clonic seizures was the most important risk factors, and when seizure control was taken into account there was no support for differences in SUDEP risk between specific antiepileptic drugs.
Effective drug treatment is therefore likely to reduce the risk of SUDEP. However, antiepileptic medication is fully effective only if taken regularly. Non-adherence to the prescribed treatment is therefore thought to be a risk factor for SUDEP. Studies have used data on irregular or delayed collection of antiepileptic drugs from pharmacies as a measure of non-adherence and reported a 2-3 fold increased mortality in association with periods of irregular intake of antiepileptic drugs (Faught et al., 2008; Ridsdale et al., 2012). However, these studies analyzed overall mortality and not SUDEP specifically. Other studies have analyzed variations in antiepileptic drug concentrations in serum or hair as measure of adherence and non-adherence (George et al., 1998; Opeskin et al., 1999, Williams et al., 2006). Some such studies have reported a more pronounced variability of drug concentration over time among SUDEP victims compared with other persons with epilepsy, suggesting that irregular intake of antiepileptic medication is a risk factor for SUDEP.
Professor of Neurology, Karolinska University Hospital, Stockholm, Sweden
How to cite:
Tomson T. Risk factors for SUDEP. In: Hanna J, Panelli R, Jeffs T, Chapman D, editors. Continuing the global conversation [online]. SUDEP Action, SUDEP Aware & Epilepsy Australia; 2014 [retrieved day/month/year]. Available from: www.sudepglobalconversation.com.
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Faught E, Duh MS, Weiner JR, Guerin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology 2008;71:1572-78.
Ficker DM, So EL, Shen WK, Annegers JF, O’Brien PC, Cascino GD, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology 1998; 51:1270-74.
George JR, Davis GG. Comparison of anti-epileptic drug levels in different cases of sudden death. J Forensic Sci 1998; 43:598-603.
Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52(6):1150-59.
Hesdorffer DC, Tomson T, Benn E, Sander JW, Nilsson L, Langan Y, et al. and for the ILAE Commission on Epidemiology; Subcommission on Mortality. Do antiepileptic drugs or generalized tonic-clonic seizure frequency increase SUDEP risk? A combined analysis. Epilepsia 2012;53:249-52.
Holst A, Winkel B, Risgaard B, Nielsen JB, Rasmussen PV, Haunso S, et al. Epilepsy and risk of sudden unexpected death in the young: a nationwide study. Epilepsia 2013;54:1613-20.
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Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology 2005;64(7):1131-33.
Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T. Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet 1999;353:888-93.
Opeskin K, Burke MP, Cordner SM, Berkovic SF. Comparison of antiepileptic drug levels in sudden unexpected death in epilepsy with death from other causes. Epilepsia 1999;40:1795-98.
Ridsdale L, Charlton J, Ashworth M, Richardson M, Gulliford M. Epilepsy mortality and risk factors for death in epilepsy: a population-based study. Brit J Gen Pract 2011;61(586):e271-e8.
Sillanpaa M, Shinnar S. Long-term mortality in childhood-onset epilepsy. N Engl J Med 2010;363(26):2522-29.
Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7(11):1021–31.
Williams J, Lawthom C, Dunstan F, Dawson TP, Kerr MP, Wilson JF, et al. Variability of antiepileptic medication taking behaviour in sudden unexplained death in epilepsy: hair analysis at autopsy. J Neurol Neurosurg Psychiatry 2006;77:481-84.
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