Sudden Unexpected Death in Epilepsy (SUDEP)

Sudden, unexpected, non-traumatic, non-drowning, witnessed or unwitnessed death, in any individual who has history of epilepsy, excludes documented status epilepticus and post-mortem examination does not reveal any cause (anatomical or toxicological) of death.

Primary Category
Epilepsy
P-Category
Secondary Category
S-Category

Introduction

💡
Sudden, unexpected, non-traumatic, non-drowning, witnessed or unwitnessed death, in any individual who has history of epilepsy, excludes documented status epilepticus and post-mortem examination does not reveal any cause (anatomical or toxicological) of death.
  • It is a diagnosis of exclusion
  • Deaths in the adults and children are comparable in incidence.
Definite SUDEP-PLUS
  • When a patient fulfils definition of SUDEP plus presence of another disease or condition that could have caused death, identified before or after the death.
  • Conditions may be coronary insufficiency without MI or Long QT syndrome without evident ventricular arrhythmias.
Near-SUDEP
  • When a patient fulfils definition of SUDEP plus cardiorespiratory arrest that is reversed by resuscitation efforts with survival > 1hour
  • No structural cause is identified after investigation
Probable SUDEP or probable SUDEP plus
  • When patient fulfils definition of definite SUDEP or SUDEP plus, but there is lack of data on postmortem examination.
Possible SUDEP
  • When SUDEP cannot be ruled out and a competing cause of death is present.
  • Unavailability of postmortem report.
Not SUDEP
  • When a clear alternative cause of death has been identified and it is impossible to classify due to insufficient information.

Epidemiology

Incidence

  • 8-17% deaths in patients with epilepsy are categorized as SUDEP
  • 1 per 1,000 patients in a year in individuals with newly diagnosed epilepsy
  • 1-2 per 1,000 patients in a year in individuals with chronic epilepsy
  • 2-10 per 1,000 patients in a year in individuals with treatment resistant epilepsy
  • In children risk is lower: 0.22 per 1000 children per year per a systematic review sanctioned by AAN and AES, however in a Swedish study, the risk in children was 1.11 per 1000 person-years, indicating that their risk is higher than previously thought and quite comparable to adults.
80% cases of SUDEP are unwitnessed, and patient is most commonly found in prone position on bed.
Study by Lamberts et al. revealed
  • 62% cases happened between midnight and noon
  • 58% cases were sleep related
  • Nocturnal seizures were 2-3 times more common in patients with SUDEP

Risk Factors

Risk factors for SUDEP are classified as direct or indirect factors
  • Most important risk factor is a history of Generalized tonic-clonic seizures
    • Greater the frequency of seizure, greater will be SUDEP risk
      • 1-2 episodes per year increases risk up to 5 fold
      • 3 or more episodes per year increase risk up to 15 fold
  • Risk Factors in children
    • Treatment resistant GTCS
    • Nocturnal Seizures
    • Developmental delay
    • Structural brain abnormalities
    • Dravet Syndrome

Direct Risk Factors
  • Generalized tonic-clonic seizures history
  • Not being seizure free (for 1-5 years)
  • Not adding an AED in medically refractory patients
  • Nocturnal Seizures and postictal respiratory depression
  • Early age onset epilepsy<16
  • Chronic epilepsy more than 15 years
Indirect Risk Factors
  • Excessive use of alcohol
  • Sleep deprivation
  • Lack of supervision
  • Prone position
  • Non-adherence to treatment
 

 

Pathological Findings

Pathological findings in patients with SUDEP observed on autopsy can be
  • Cerebral edema
  • Pulmonary or visceral congestion/edema
  • Cardiac perivascular and interstitial fibrosis
  • Signs of recent seizures such as tongue bites or bruises
  • Sub therapeutic concentration of AEDs

Genetic Association

  • Recently emerged evidence suggests polygenic distribution contribution
  • Various Neurocardiac genes have been identified in patients which encode proteins related to cardiorespiratory system and epilepsy.

Table 2: Genetic association with SUDEP

Gene
Ion Channel Involved
Associated syndrome
SCN1A & 1B
Sodium Voltage-Gated Channel Alpha Subunit 1
Dravet syndrome and epileptic encephalopathy
SCN2A
Sodium Voltage-Gated Channel Alpha Subunit 2
Epileptic encephalopathies
SCN5A
Voltage-Gated Sodium Channel Subunit Alpha Nav1.5
Long QT Syndrome 3
SCN8A
Sodium Voltage-Gated Channel Alpha Subunit 8
Early-infantile encephalopathy
KCNH2
Voltage-Gated Potassium Channel Subunit Kv11.1
Long QT Syndrome 2
KCNJ2
Voltage-Gated Potassium Channel
Long QT Syndrome 7
KCNQ1
Voltage-Gated Potassium Channel Subunit Kv 7.1
Long QT Syndrome 1
CACNA1C
Calcium channel
Long QT Syndrome 8
DEPDC5
DEP Domain-Containing Protein
Genetic cause of focal epilepsy

Mechanisms

Mechanisms resulting in SUDEP in patients with epilepsy are not completely understood.
💫
Among the pathophysiological mechanisms addressed below pulmonary hypoventilation and cardiac arrhythmias are most common resulting in cardiorespiratory arrest-potential mechanism that leads to SUDEP

Cardiac dysfunction

  • Ictal arrhythmias and hypotension has been reported in some patients in the epilepsy monitoring unit. These are characterized by an initial phase of tachycardia and/or tachypnea, followed by bradycardia and asystole, with delayed atonia and subsequent sudden fall. Central apnea also accompanies and there is generalized EEG suppression.
  • Cingulate stimulation during seizure in patients can lead to asystole which is considered as potential SUDEP mechanism.
  • Reduced thalamic–cingulate connectivity causes disruption of the pathways involved in central modulation of cardiorespiratory and blood pressure mechanisms.
  • Seizure-related Takotsubo cardiomyopathy with hemodynamic deterioration and cardiogenic shock has also been proposed as a potential mechanism.

Respiratory dysfunction

  • Seizure spread to the amygdala may cause respiratory depression that contributes to SUDEP.
  • The disruption of posterior thalamus (involved in oxygen sensing and relaying afferent activity essential for breathing) in high-risk patients is of greater concern because of its link with respiratory failure in SUDEP.
  • Postconvulsion central apnea is considered to be a possible SUDEP biomarker

Autonomic dysregulation

  • Heart rate variability (HRV) is indicative of autonomic function
    • About two third of patients experiencing ictal bradycardia or asystole have temporal lobe epilepsy
  • Brainstem atrophy in patients with epilepsy impairs autonomic control and may increase the risk for SUDEP
  • Impaired connectivity between the putamen and cingulate cortex may disrupt vital ANS communications in patients who are at high risk of SUDEP
  • Brainstem arousal system dysfunction
    • Respiratory depression results in hypoxemia which triggers normal arousal function
    • impaired arousal in postictal patients may interfere with brain resuscitation mechanisms thus preventing change of prone position
    • thus airway obstruction due to patient positioning and items on the bed can further deteriorate hypoxemia and may result in death
  • Dysregulation in the neurotransmitter and neuromodulator system
    • defect in midbrain serotonin neurons can impair response to increased CO2 level in blood
    • adenosine surge in prolonged seizure can cause cardiac and respiratory inhibition
    • seizure induced opioids release can cause central hypoventilation

Biomarkers

Postictal EEG suppression

  • Postictal EEG suppression
    • Defined as postictal unilateral or bilateral EEG suppression for >1 second that occurs immediately or within 30 seconds of seizure cessation(amplitude of <10 mV)
    • Linked with unresponsiveness and lack of arousal
    • Preceded by hypoventilation
    • Tends to be most severe in patients with nocturnal seizures
    • Duration of EEG suppression is predictor of SUDEP

Electrocardiographic biomarkers

Interictal cardiac rhythm biomarkers help to identify sympathovagal dysequilibrium
  • Heart rate variability
    • It is difference between the interbeat intervals
    • Reflects reduced parasympathetic activity
Antiepileptic medications also tend to decrease the parasympathetic activity

Neuroimaging biomarkers

  • MRI may reveal
    • Increases grey matter volume in right anterior hippocampus, amygdala and parahippocampus
    • Decreased grey matter volume in posterior thalamus (intervenes in oxygen regulation)
    • Right medial temporal lobe changes
      • May increase autonomic flow resulting in cardiac tachyarrhythmia

Prevention

  • Education of the patient is the most important measure of prevention. Patient should be informed about
    • Risk factors for morbidity and mortality associated with refractory epilepsy
    • Importance of adherence to medical therapy
    • Life style adjustments
    • Avoidance of unhealthy behaviors such as
      • Sleeping in prone position
        • As GTCS in a patient in prone position can result in airway obstruction leading to apnea
        • Changing prone to lateral position may help the patient.
      • Insufficient sleep
      • Excessive drinking
  • Nocturnal supervision
    • May be achieved by availability of a family member in the same room or through video monitoring. Alternatively, the patient can be regularly checked upon at night. However, these practices are not evidence-based.
    • Disadvantages include
      • Increased FP and FN rates
      • Impact on quality of life of the patient
  • Seizure monitoring
    • Early detection of seizure and effective treatment can prevent cardiorespiratory distress to occur that leads to SUDEP
    • Many seizure detecting devices are available
  • Use of airway protection devices
    • Anti-suffocation pillows
      • Latex foam pillows are available that reduce the prone positioning contribution toward postictal apnea.
  • Use of nocturnal listening device
  • SSRIs
    • Decrease risk of apnea and SUDEP in patients
  • Successful epilepsy surgery reduces SUDEP risk
  • Routine electrocardiogram should be done and reviewed to identify factors such as prolonged QT intervals
💫
Therapy adherence to maintain freedom from GTCS is the most important measure to reduce the risk of SUDEP. Adequate counselling, management of expectations from epilepsy treatment, and open communication between physician and patient can potentially help to achieve treatment compliance.
notion image

Counseling

  • Measures should be done to
    • Optimize seizure control and minimize nocturnal seizures
    • Address SUDEP risk factors to increase awareness among healthcare professional and patients
    • Reduce the anxiety about the threat of SUDEP on patients and their families
    • Facilitate use of longer-acting agents to treat epilepsy if indicated
  • Increase awareness of SUDEP within the wider medical community beyond the specialty of neurology
    • Enhance the reporting of SUDEP
    • For SUDEP post mortem examinations to be done to find the cause
  • Encourage research to determine the efficacy of drugs such as SSRIs, adenosine receptor inhibitors and opiates, cardiac pacemakers and ICDs in the prevention of SUDEP
  • Investigate how various methods of nocturnal observation could help reduce the risk of SUDEP.
 

Further Reading

  • Harden, C., Tomson, T., Gloss, D., Buchhalter, J., Cross, J. H., Donner, E., French, J. A., Gil-Nagel, A., Hesdorffer, D. C., Henry Smithson, W., Spitz, M. C., Walczak, T. S., Sander, J. W., & Ryvlin, P. (2017). Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsy Currents, 17(3), 180–187. https://doi.org/10.5698/1535-7511.17.3.180
  • Devinsky, O., Hesdorffer, D. C., Thurman, D. J., Lhatoo, S., & Richerson, G. (2016). Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. The Lancet Neurology, 15(10), 1075–1088. https://doi.org/10.1016/S1474-4422(16)30158-2

Bibliography

  • Bhasin, H., Sharma, S., & Ramachandrannair, R. (2021). Can We Prevent Sudden Unexpected Death in Epilepsy (SUDEP)? Canadian Journal of Neurological Sciences, 48(4), 464–468. https://doi.org/10.1017/cjn.2020.221
  • Coll, M., Oliva, A., Grassi, S., Brugada, R., & Campuzano, O. (2019). Update on the genetic basis of sudden unexpected death in epilepsy. International Journal of Molecular Sciences, 20(8). https://doi.org/10.3390/ijms20081979
  • DeGiorgio, C. M., Curtis, A., Hertling, D., & Moseley, B. D. (2019). Sudden unexpected death in epilepsy: Risk factors, biomarkers, and prevention. Acta Neurologica Scandinavica, 139(3), 220–230. https://doi.org/10.1111/ane.13049
  • Devinsky, O., Hesdorffer, D. C., Thurman, D. J., Lhatoo, S., & Richerson, G. (2016). Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. The Lancet Neurology, 15(10), 1075–1088. https://doi.org/10.1016/S1474-4422(16)30158-2
  • Dibué, M., Spoor, J. K. H., Dremmen, M., von Saß, C. F., Hänggi, D., Steiger, H. J., Ryvlin, P., & Kamp, M. A. (2020). Sudden death in epilepsy: There is room for intracranial pressure. Brain and Behavior, 10(11), 1–11. https://doi.org/10.1002/brb3.1838
  • Ellis, S. P., & Szabó, C. Á. (2018). Sudden unexpected death in epilepsy: Incidence, risk factors, and proposed mechanisms. American Journal of Forensic Medicine and Pathology, 39(2), 98–102. https://doi.org/10.1097/PAF.0000000000000394
  • Harden, C., Tomson, T., Gloss, D., Buchhalter, J., Cross, J. H., Donner, E., French, J. A., Gil-Nagel, A., Hesdorffer, D. C., Henry Smithson, W., Spitz, M. C., Walczak, T. S., Sander, J. W., & Ryvlin, P. (2017). Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsy Currents, 17(3), 180–187. https://doi.org/10.5698/1535-7511.17.3.180
  • Hayashi, K., Jin, K., Nagamori, C., Okanari, K., Okanishi, T., Homma, Y., Iimura, Y., Uda, T., Takada, L., & Otsubo, H. (2019). Sudden unexpected death in epilepsy in the bathtub. Epilepsy and Behavior, 96, 33–40. https://doi.org/10.1016/j.yebeh.2019.04.009
  • Johnson, J. N., Tester, D. J., Bass, N. E., & Ackerman, M. J. (2010). Cardiac channel molecular autopsy for sudden unexpected death in epilepsy. Journal of Child Neurology, 25(7), 916–921. https://doi.org/10.1177/0883073809343722
  • Jones, L. A., & Thomas, R. H. (2017). Sudden death in epilepsy: Insights from the last 25 years. Seizure, 44, 232–236. https://doi.org/10.1016/j.seizure.2016.10.002
  • Kinney, M. O., McCluskey, G., Friedman, D., Walker, M. C., Sander, J. W., & Shankar, R. (2019). Investigative practice into sudden death in epilepsy: A global survey. Acta Neurologica Scandinavica, 139(5), 476–482. https://doi.org/10.1111/ane.13080
  • Li, J., Ming, Q., & Lin, W. (2017). The insula lobe and sudden unexpected death in epilepsy: a hypothesis. Epileptic Disorders, 19(1), 10–14. https://doi.org/10.1684/epd.2017.0890
  • Manolis, T. A., Manolis, A. A., Melita, H., & Manolis, A. S. (2019). Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection. Seizure, 64(December 2018), 65–73. https://doi.org/10.1016/j.seizure.2018.12.007
  • McLean, B., Shankar, R., Hanna, J., Jory, C., & Newman, C. (2017). Sudden unexpected death in epilepsy: Measures to reduce risk. Practical Neurology, 17(1), 13–20. https://doi.org/10.1136/practneurol-2016-001392
  • Pensel, M. C., Nass, R. D., Taubøll, E., Aurlien, D., & Surges, R. (2020). Prevention of sudden unexpected death in epilepsy: current status and future perspectives. Expert Review of Neurotherapeutics, 20(5), 497–508. https://doi.org/10.1080/14737175.2020.1754195
  • Petrucci, A. N., Joyal, K. G., Purnell, B. S., & Buchanan, G. F. (2020). Serotonin and sudden unexpected death in epilepsy. Experimental Neurology, 325, 113145. https://doi.org/10.1016/j.expneurol.2019.113145
  • Ryvlin, P., Nashef, L., Lhatoo, S. D., Bateman, L. M., Bird, J., Bleasel, A., Boon, P., Crespel, A., Dworetzky, B. A., Høgenhaven, H., Lerche, H., Maillard, L., Malter, M. P., Marchal, C., Murthy, J. M. K., Nitsche, M., Pataraia, E., Rabben, T., Rheims, S., … Tomson, T. (2013). Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): A retrospective study. The Lancet Neurology, 12(10), 966–977. https://doi.org/10.1016/S1474-4422(13)70214-X
  • Ryvlin, P., Rheims, S., & Lhatoo, S. D. (2019). Risks and predictive biomarkers of sudden unexpected death in epilepsy patient. Current Opinion in Neurology, 32(2), 205–212. https://doi.org/10.1097/WCO.0000000000000668
  • Saxena, A., Jones, L., Shankar, R., McLean, B., Newman, C. G. J., & Hamandi, K. (2018). Sudden unexpected death in epilepsy in children: A focused review of incidence and risk factors. Journal of Neurology, Neurosurgery and Psychiatry, 89(10), 1064–1070. https://doi.org/10.1136/jnnp-2017-317702
  • Shankar, R., Donner, E. J., Mclean, B., Nashef, L., & Tomson, T. (2017). Seminar in Epileptology Sudden unexpected death in epilepsy ( SUDEP ): what every. 19(1), 1–9.
  • Stewart, M. (2018). An explanation for sudden death in epilepsy (SUDEP). Journal of Physiological Sciences, 68(4), 307–320. https://doi.org/10.1007/s12576-018-0602-z
  • Stöllberger, C., Wegner, C., & Finsterer, J. (2011). Seizure-associated Takotsubo cardiomyopathy. Epilepsia, 52(11), 160–167. https://doi.org/10.1111/j.1528-1167.2011.03185.x
  • Sveinsson, O., Andersson, T., Carlsson, S., & Tomson, T. (2017). The incidence of SUDEP: A nationwide population-based cohort study. Neurology, 89(2), 170–177. https://doi.org/10.1212/WNL.0000000000004094
  • Van Niekerk, C., Van Deventer, B. S., & Du Toit-Prinsloo, L. (2017). Long QT syndrome and sudden unexpected infant death. Journal of Clinical Pathology, 70(9), 808–813. https://doi.org/10.1136/jclinpath-2016-204199
 
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Filzah Faheem MD

Aspiring Neurologist. Research Fellow at AINeuroCare Academy. Epilepsy Sub-section Coordinator.

Ayaz Khawaja MD

Written by

Ayaz Khawaja MD

Assistant Professor with Department of Neurology at Wayne State University, Neurohospitalist and consultant at Harper University Hospital and Karmanos Cancer Institute, and as a Neurohospitalist, consultant and Neurointensivist at Detroit Receiving Hospital.

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