Published online Apr Find articles by Monica Coll. Find articles by Antonio Oliva. Find articles by Simone Grassi. Author information Article notes Copyright and License information Disclaimer. Received Jan 21; Accepted Apr Abstract Epilepsy is a common neurological disorder associated with increased morbidity and mortality. Introduction Epilepsy is a common neurological disorder of the central nervous system characterized by recurrent seizures with or without convulsions [ 1 ]. Classification Definition Definite sudden unexpected death in epilepsy SUDEP Sudden, unexpected, witnessed or unwitnessed, non-traumatic, and non-drowning death that occurs in benign circumstances in an individual with epilepsy, with or without evidence for a seizure, and excludes documented status epilepticus, in which post-mortem examination does not reveal a cause of death.
Definite SUDEP plus Death satisfying criteria for definite SUDEP, if a concomitant condition other than epilepsy is identified before or after death, if the death might have been due to the combined effect of both conditions, and if autopsy or direct observations or recording of the terminal event did not prove the concomitant condition to be the cause of death. Unclassified Incomplete information available; impossible to classify. Open in a separate window. Epidemiology The current incidence of SUDEP remains undetermined, mainly because SUDEP and epilepsy are frequently underreported as possible or certain causes of death by clinicians and medical examiners [ 11 ].
Sudden Unexpected Death in Epilepsy SUDEP Pathophysiology Recent studies have extensively investigated the pathophysiology of SUDEP in different groups, proposing four main mechanisms for SUDEP: cardiac dysfunction, respiratory dysfunction, brainstem arousal system dysfunction, and dysregulation in the neurotransmitter and neuromodulator system [ 28 ].
Future Directions Although considerable progress has been made in SUDEP in recent years, there is much work to be done on the genetic diagnosis of this condition. Conclusions SUDEP is the main cause of epilepsy-related premature mortality, especially in younger populations. Author Contributions Conception: M. Conflicts of Interest The authors declare no conflict of interest.
References 1. Suruchi V. Epilepsy-a comprehensive review. Fazel S. Premature mortality in epilepsy and the role of psychiatric comorbidity: A total population study. Berg A. Mortality risks in new-onset childhood epilepsy. Appleton R. Sudden, unexpected death in epilepsy in children. Nashef L. Unifying the definitions of sudden unexpected death in epilepsy.
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Annegers J. United States perspective on definitions and classifications. Sudden unexpected death in epilepsy: Terminology and definitions. Devinsky O. Lamberts R. Sudden unexpected death in epilepsy: People with nocturnal seizures may be at highest risk.
Purnell B. Flannery R. Sudden unexpected death in epilepsy: Epidemiology, mechanisms, and prevention. Lancet Neurol. Shankar R. Epileptic Disord. Epilepsy J. Dlouhy B. Sudden unexpected death in epilepsy: Basic mechanisms and clinical implications for prevention. Holst A. Epilepsy and risk of death and sudden unexpected death in the young: A nationwide study.
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Even people with well-controlled epilepsy may be at risk for sudden death
Leu C. Manolis T.
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Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection. Bagnall R. Exome sequencing-based molecular autopsy of formalin-fixed paraffin-embedded tissue after sudden death. Langan Y.
Unravelling the mysteries of sudden unexpected death in epilepsy.
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Death satisfying criteria for definite SUDEP, if a concomitant condition other than epilepsy is identified before or after death, if the death might have been due to the combined effect of both conditions, and if autopsy or direct observations or recording of the terminal event did not prove the concomitant condition to be the cause of death. These findings concerning hazards associated with high drug concentrations were limited to CBZ, and no similar associations were evident for PHT. TDM not only provides a more accurate measure of drug exposure in terms of AED plasma concentrations, but data on the use of TDM may also reflect the physician's strategy for monitoring and managing AED therapy.
It was the objective of the present study to investigate both these aspects of treatment with AEDs based on the information that could be obtained from routine use of TDM in our case—control study. Regular controls including TDM may be one way to improve the control of drug therapy and thus enhance compliance The plasma concentration at the last TDM was considered the most relevant measure of drug exposure.
The high seizure frequency and frequent changes of AED dosage during the last year among these patients supported this interpretation. Adjustment for all confounding factors that we could anticipate revealed that only two influenced the increase in SUDEP risk associated with high CBZ levels: number of AEDs concomitantly consumed and number of dose changes.
Both these factors can be seen as markers of a severe and unstable epilepsy, and it is difficult to assess whether high CBZ levels per se represent a risk factor for SUDEP or if it is just a surrogate for a difficult seizure situation. Although adjustments were made for seizure frequency, seizure severity was not included in our model, as it was impossible to assess accurately from the record review. However, the relative risk of SUDEP associated with high CBZ level was enhanced with increasing number of concomitant AEDs used by the patient, to an extent that a synergistic relationship could be suspected Tables 4 and 5.
Conversely, the increase in SUDEP risk was considerably less pronounced if adjustment was made for the number of changes of AED dosages during the observation period Tables 4 and 6. We cannot determine if the risk increase associated with high CBZ concentrations is caused by the drug levels as such, or if high CBZ concentrations merely reflect hazards associated with frequent dose changes.
It is conceivable that a high number of dose changes may be the major risk factor, and that such changes result in marked variations in AED levels over time, and to a greater chance of AED levels outside the therapeutic range. It is also reasonable to assume that hazards associated with dose changes are due to the altered pharmacologic effects that the dose change will induce by increasing or decreasing the drug plasma concentration. The results of our analysis of the interrelationship between frequency of dose changes and drug levels suggest that a high CBZ concentration is itself contributing to the increased SUDEP risk, in particular among patients with frequent dose changes Table 6.
However, such arrhythmias have mainly occurred in the elderly and otherwise predisposed patients, which is not a population at particular risk for SUDEP. It is conceivable that treatment with high plasma concentrations of CBZ induces changes in autonomic cardiac control that make patients more vulnerable to seizures that thus can become fatal.
However, experimental data demonstrate that blood concentrations of PHT decline after death, and postmortem drug levels might thus be unreliable Furthermore, the last TDMs obtained in our patients were not taken in close proximity to death and should rather be regarded as a measure of drug exposure over a time preceding death.
Our results point to a therapeutic dilemma. On the other hand, it might also be important to avoid excessive CBZ concentrations. The role of TDM in this context might thus be to facilitate efforts to optimize dosage rather than just to promote compliance. The study was not designed primarily for comparison of different drugs, and patients taking AEDs other than CBZ and PHT were not included in sufficient numbers to allow analysis. It should also be emphasized that the number of subjects taking PHT and CBZ in our study is rather small, and that the results should thus be interpreted with caution.
Furthermore, although adjustments were made for known potential confounding factors, the difficulty of fully accounting for such factors should be pointed out. However, in such cases, one would anticipate similar patterns for all AEDs. It should finally be acknowledged that a retrospective case—control study such as the present can demonstrate associations but not prove causal relationships. Volume 42 , Issue 5. The full text of this article hosted at iucr. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account.
If the address matches an existing account you will receive an email with instructions to retrieve your username. Epilepsia Volume 42, Issue 5. Free Access. Address correspondence and reprint requests to Dr. Tools Request permission Export citation Add to favorites Track citation.
Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Cases The study population was matched with the National Cause of Death Register by an individual identification number to identify those who had died until December 31, and for whom a diagnosis of epilepsy appeared on the death certificate patients.
Controls For each case, three living controls matched for year of birth, sex, and assessment period were randomly sampled from the study population. AED, antiepileptic drug. Figure 1 Open in figure viewer PowerPoint. Neurology ;—4. Google Scholar. Wiley Online Library Google Scholar. Citing Literature. Volume 42 , Issue 5 May Pages Figures References Related Information. Close Figure Viewer. Browse All Figures Return to Figure.
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