Sudden Unexpected Death in Epilepsy (SUDEP)

Authors:

Filzah Faheem MD,

Ayaz Khawaja MD

Introduction

• 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.

• 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

• When patient fulfils definition of definite SUDEP or SUDEP plus, but there is lack of data on postmortem examination.

• When SUDEP cannot be ruled out and a competing cause of death is present.

• Unavailability of postmortem report.

• 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.

• 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

• 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

Pathological Findings

• 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

Mechanisms

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

• Heart rate variability
• It is difference between the interbeat intervals
• Reflects reduced 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

• First step is to identify the patients who are at risk of developing SUDEP by using
• SUDEP safety checklist
• 10-min risk assessment tool used in the clinics to access patients at risk
• It includes 17 risk factors
• Available on mobile devices too
https://apps.apple.com/gb/app/epsmon-epilepsy-self-monitor/id988418313
• SUDEP Risk Inventory (SUDEP-7)
• Includes seven validated risk factors associated with SUDEP
• Score range from 1-7 with mean value of 3.4

• 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

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

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• 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

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• 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

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• https://apps.apple.com/gb/app/epsmon-epilepsy-self-monitor/id988418313

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