Understanding Sudden Unexpected Death in Epilepsy

Slideshow

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  How can SUDEP research be enhanced?

  A lot of effort has focused on genetic risk factors, but there is a paucity of data on prevention and intervention.² It is still unclear whether the use of seizure detection devices, antisuffocation pillows, anti-SUDEP measures, and other strategies can help change outcomes and reduce risks. Additionally, there are no models available for predicting risk. In 2014, the Center for SUDEP Research (CSR), a collaborative effort of 14 institutions in the United States and Europe, was founded with the goals of better coordinating research activities; encouraging new research, including in novel strategies to prevent SUDEP; and improving information dissemination.² The hope is that this effort will spur discoveries that can be applied in clinical practice to prevent SUDEP and improve overall outcomes in patients with epilepsy.

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  How is SUDEP defined?

  SUDEP is defined as “a category of death in people with epilepsy occurring in the absence of a known structural cause of death.”⁵ It can be witnessed or unwitnessed and excludes cases related to documented status epilepticus.² For research purposes, SUDEP has been subdivided into several classifications in the literature, with varying definitions. However, in 2012, researchers affiliated with the International League Against Epilepsy sought to unify these definitions to “resolve current ambiguities and to retrieve cases that would not have been further studied if the previous definitions were used.”⁵ The definitions were unified within the following classifications: Definite SUDEP; Definite SUDEP plus; Probably SUDEP/Probably SUDEP plus; Possible SUDEP; Near SUDEP/Near SUDEP plus; Not SUDEP; and Unclassified.

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  How can SUDEP be prevented?

  Currently, there are no evidence-based measures that are proven to prevent SUDEP because it remains a poorly understood entity. However, seizure prevention is essential, as most cases are preceded by a seizure. Educating patients and families about SUDEP, use of seizure alerts, and use of antisuffocation pillows might be beneficial since many cases occur unwitnessed at night.² If a possible SUDEP event is witnessed, recommended anti-SUDEP measures include repositioning the patient from a prone to a lateral position; ensuring the nose, mouth, and airways are clear; performing simple resuscitation; providing auditory and/or tactile stimulation; performing any necessary suctioning of airways; and administering oxygen.²However, even if a seizure is rapidly detected and such measures are promptly undertaken, there are no guarantees that SUDEP will be prevented.

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  Is there a genetic component to SUDEP?

  Certain genetic epileptic encephalopathies have been associated with SUDEP, with Dravet syndrome conferring the highest risk. Patients with this syndrome have a 15 times higher risk of SUDEP than patients with other pediatric epilepsies, with two-thirds of deaths before age 25 attributed to SUDEP in this patient population.² Various individual genetic mutations have been associated with SUDEP in human and animal models, particularly mutations that have also been associated with an increased risk of epilepsy and sudden death from arrhythmias and autonomic dysfunction. However, more recent evidence suggests a complex interaction of multiple genes, rather than a single causal gene, ultimately leads to SUDEP. Comprehensive genomic analysis of a 3-year-old girl with Dravet syndrome who died of SUDEP revealed complex combinations of single nucleotide polymorphisms and copy number variants in genes expressed in both neurocardiac and respiratory control pathways, including SCN1A, KCNA1, RYR3, and HTR2C.⁸ Her living unaffected parents carried some of the same genetic mutations, suggesting certain genetic defects alone are not sufficient to cause obvious disease.

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  How prevalent is SUDEP?

  SUDEP is rare, but its true prevalence remains unknown because it is underreported, underrecognized, and there are no International Classification of Disease (ICD) codes to define it as a distinct clinical entity.² Estimates have ranged from 0.09 to 1.16 per 1000 persons with epilepsy annually to 9 per 1000 persons annually among epilepsy surgery candidates.^6,7 Patients with epilepsy that manifests in early childhood (≤1 year) and never fully remits are reported to have an average cumulative lifetime risk of SUDEP of 8% by age 70.⁷ Risk is reduced with later epilepsy onset, with a lifetime risk of SUDEP of 7.2% and 4.6% in patients with epilepsy manifesting at approximately age 15 and 30, respectively.⁷ The incidence of SUDEP is low in children age 1 to 10 years.⁷ SUDEPs appear to be most prevalent between age 15 and 25.⁷ However, it has been suggested that SUDEP might be misattributed to cardiac and other events in older adults and misclassified as sudden infant death syndrome (SIDS) in infants or as sudden unexplained death in childhood (SUDC) in young children.²

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  Are any SUDEP patient education resources available?

  There has been a paucity of written material for patients regarding SUDEP. To address this lack of patient information, the Epilepsy Foundation and the SUDEP Institute have put together a #DareTo Say SUDEP infographic, which is available on the Epilepsy Foundation website. The infographic provides patients with information on what SUDEP is, its risk factors, seizure risk reduction strategies, and how to speak with physicians and family members about SUDEP. SUDEP Action, a UK-based patient advocacy organization, has also made a variety of downloadable pamphlets on SUDEP available. There are guides for teenagers, adults, and even healthcare professionals. Currently, 90% of patients have been reported to want this information.² Providing this material is essential because modifiable risk factors, such as poor medication compliance, are associated with SUDEP. In addition, several medical malpractice suits have stemmed from physicians not disclosing this epilepsy risk to patients and their families.²

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  Which factors increase the risk of SUDEP?

  Although SUDEP can occur without a recent seizure, it most often occurs after a seizure, particularly a generalized tonic-clonic seizure. Thus, poor control of such seizures is considered the strongest risk factor for SUDEP.² Other risk factors include male sex, sleep deprivation, nonadherence to seizure treatment regimens, alcohol withdrawal, presence of microscopic hippocampal abnormalities, epilepsy onset before age 16, disease duration >15 years, >3 generalized tonic-clonic seizures annually, and young adult age (15-40).² In addition, most SUDEP cases occur during sleep at night (58.5% of cases) and have been associated with lying in a prone position.² Despite awareness of these risk factors, it remains impossible to predict a patient’s individual risk of SUDEP. It has been postulated that this might be because “seizures and SUDEP represent complex systems, in which very simple processes interact in unpredictable and potentially catastrophic ways.”² Regardless, the presence of ≥1 risk factor does not guarantee that SUDEP will occur.

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  What pathophysiological changes are involved in SUDEP?

  The underlying pathophysiological changes that are critically involved in SUDEP remain poorly understood, but cardiac arrhythmia, depressed autonomic function after seizure activity, and seizure-related respiratory failure have been reported in many cases to be part of the final cascade leading to SUDEP.⁹ In some patients, this appears to be triggered by increased levels of various regulatory hormones and neurotransmitters — including epinephrine and norepinephrine — following seizure activity.⁹ However, not all cases of SUDEP occur following a seizure, suggesting that no 1 risk factor, gene, or pathophysiological change leads to SUDEP, but that it likely results from a complex interaction of a combination of factors that can vary by patient.^2,9

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  Are there treatments for SUDEP?

  Currently, there are no pharmacological treatments that prevent SUDEP, and the only drugs associated with reduced SUDEP risk are antiepileptic agents.² Therefore, patients should be counseled on the importance of complying with their antiseizure medications to reduce their risk of SUDEP. Because increased levels of various regulatory hormones and neurotransmitters following seizure activity have been associated with SUDEP, drugs that modify serotonin, adenosine, and other neurotransmitters might eventually be shown to prevent SUDEP, but research is ongoing.²