1.
Sudden Unexpected Death in
Epilepsy (SUDEP):
Heart vs. Brain
Terence J. O’Brien, MD, FRACP
Department of Neuroscience, Central Clinical School,
Monash University
Department of Neurology
Alfred Health

2.
Lucia’s story
• 13 year old, healthy, developmentally normal girl.
• PH of congenital cardiac disease – VSD (spontaneously healed), ASD.
• 3 years of brief episodes in bright sunlight with arrest of activity, eyes
flickering, and head nods.
• Mother described as “mini-fits”. Not diagnosed.
• 28 March 2020 had single GTCS in the context of mild “viral illness” and
staying up late on electronic devices.
• Assessed by paediatrician as a “provoked seizure”. No further investigations or
treatment organised. Advised to avoid excessive screen time and late nights.
• 3rd April, 22:30 mother saw on iPad talking to friends in bed.
• Mother said “goodnight” and told her “not to stay up too late”.
• Next morning found face down in bed, cold and purple and not breathing.
• An ambulance was called, she was unable to be revived.
• After post-mortem examination, Coroner determined “unascertained
cause of death”.
• Definite SUDEP Plus

3.
The stone-cutter, Jan Sanders van HemessenSaint Valentin, Bartholomäus Zeitbloom
Epilepsy: The Sacred Disease

4.
• A group of neurological diseases characterized
by an ongoing predisposition to recurrent,
spontaneous seizures.
• No age, racial, social, gender or
geographical boundaries.
•The most common serious chronic neurological
condition:
• Globally 50M people affected.1
• Australia 143K active epilepsy.2
• Annual economic cost $12.3 billion AUD.2
• Commonly accompanied by serious medical
and psychiatric comorbidities.
• Major cause of disability, psychosocial
disadvantage, stigma.
• Increased mortality.
Saint Valentin, Bartholomäus Zeitbloom
1Epilepsy: a public health imperative, WHO 2019.
2Deloitte Access Economics report. February 2020.
Epilepsy: A major global health problem

5.
• Standardized mortality ratio (SMR) >3.0 vs. general population.1
• Higher in drug resistant epilepsy.
• Die from a variety of causes e.g. accidental injury, drowning,
asphyxia, status epilepticus, suicide.
• Sudden unexpected death in epilepsy (SUDEP)
• People with epilepsy have 24 - 40x increased risk of dying suddenly.
• Particularly young people – mean age 35 years.
Epilepsy: A potentially life threatening
condition
1Nightscales R, et al. Neurology 2020

6.
Nashef L. et al., Epilepsia 2012 Feb;53(2):227-33
Nashef unified classification of SUDEP
1. Definite SUDEP :
a
Sudden, unexpected, witnessed or unwitnessed, nontraumatic and non-drowning death,
occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and
excluding documented status epilepticus (seizure duration ≥30 min or seizures without recovery in between), in
which postmortem examination does not reveal a cause of death
1a. Definite SUDEP Plus :
a
Satisfying the definition of Definite SUDEP, if a concomitant condition other than
epilepsy is identified before or after death, if the death may have been due to the combined effect of both
conditions, and if autopsy or direct observations/recordings of terminal event did not prove the concomitant
condition to be the cause of death
2. Probable SUDEP/Probable SUDEP Plus :
a
Same as Definite SUDEP but without autopsy. The victim should have
died unexpectedly while in a reasonable state of health, during normal activities, and in benign circumstances,
without a known structural cause of death
3. Possible SUDEP :
a
A competing cause of death is present
4. Near‐SUDEP/Near‐SUDEP Plus : A patient with epilepsy survives resuscitation for more than 1 h after a
cardiorespiratory arrest that has no structural cause identified after investigation

7.
• Commonest epilepsy-related cause of premature death, and 2nd
leading neurological cause of lost patient life-years
• Otherwise healthy, commonly young (mean age 35 years), with fewer other
reasons to die.
• Incidence:
• Well controlled epilepsy 0.4-2/1,000 per year.
• Drug resistant epilepsy 4-9/1,000 per year.
• Cumulative incidence of up to 10% over 10 years.
• Estimated >100 deaths a year in Australia (>3,000 in the US)
Shorvon S, Tomson T. Lancet 2011; Sillanpaa M, Shinnar S. N Engl J Med 2010;
Thurman DJ, et al. Epilepsia. 2014
SUDEP Importance

8.
• NCIS cases for the ACT over 13 years (2001-13) were searched to identify
all deaths where epilepsy or seizures were mentioned.
• 75 epilepsy related deaths.
• 31 (41.3%) epilepsy or seizures were not listed in the cause of death.
• 53 (70.6%) fulfilled the unified definition of SUDEP (37 Definite SUDEP)
• 22 (41.5%) identified as SUDEP
• 20 (37.7%) epilepsy/seizures/convulsions not mentioned in COD
SUDEP: Commonly not recognized by coroner

9.
SUDEP: Commonly not recognized by medical
examiner
• Of the 220 SUDEP cases with a COD determined by an Medical Examiner,
only 33% (n = 73) listed the final cause of death as SUDEP.
• Particularly low when there was a potentially contributing COD (SUDEP
Plus) or competing COD (possible SUDEP).

10.
Societal Impact of Epilepsy
• Life table modeling with 2017 data from the Australian Bureau of Statistics, the Australian National
Health Survey, and the World Bank.
• Model the productivity and mortality outcomes that working age (15–69 year old) Australians with
epilepsy experience up to the age of 70 years.
• Assumed that 70% of cohort members achieved seizure-free status.
• Epilepsy costs working-age Australians:
• 14,053 excess deaths, 78,143 years of life lost (YLL)
• 146,202 productivity-adjusted life-years (PALYs)
• A lost GDP of A$32.4 billion (US$22.1 billion).
If seizure freedom in the epilepsy cohort improved by 5% from its current baseline of
70%, i.e. up to 75% there would be:
● A$533 million (US$364 million) reduction in direct healthcare costs for epilepsy,
● Prevention of 811 excess deaths,
● 3,961 years of life gained,
● 17,438 PALYs saved, equating to A$3.9 billion (US$2.6 billion) in GDP retained
over the working lifetime of this cohort.

11.
Adapted from P. Kwan, PhD Thesis 2000
20
15
10
5
0
1840 1860 1880 1900 1920 1960 1980 2000
Calendar year
Antiepileptic drugs
Bromide
Phenobarbital
Phenytoin
Ethosuximide
Primidone
Benzodiazepines
Sodium Valproate Vigabatrin
Zonisamide Lamotrigine
Gabapentin
Felbamate
Topiramate
Fosphenytoin
Tiagabine
Oxcarbazepine
Levetiracetam
Pregabalin
Lacosamide
1940
Perampanel
Brivaracetam
Anti-Seizure Medications (ASMs)/Anti-epileptic
Drugs (AEDs)

12.
1st monotherapy (47%)
2nd monotherapy (13%)
3rd monotherapy (1%)
Polytherapy (3%)
Uncontrolled epilepsy
(36%)
Outcome of Newly Diagnosed Epilepsy
Seizure-free = 64% (1982 – 1997; n=470)
Kwan P, Brodie MJ. N Engl J Med 2000;342:314–9

13.
Outcome of Newly Diagnosed Epilepsy
Seizure-free = 64% (1982 – 2012; n=1,795)
1st schedule (45.7%)
2nd schedule (11.6%)
3rd schedule (4.35%)
4th schedule (1.17%)
5th schedule (0.56%)
Uncontrolled
epilepsy (up to
11th schedule)
36.2%
6th schedule (0.33%)
7th schedule (0.06%)
Chen Z, et al. Unpublished data

14.
7
eFIGURE 1
A. All AED prescriptions (N=1,795)
Chen Z, et al. JAMA Neurology 2018;75:279-286
Established AEDs Newer AEDs
Shift in Antiepileptic Drug Use over Time –
Glasgow Experience

15.
Chen Z, et al. JAMA Neurology 2018;75:279-286
No Change in Probability of Seizure Freedom
Over Time

16.
• The outcome most consistently shown to be associated with
improved quality of life in patients treated either medically or
surgically.
• Uncontrolled seizures/drug resistant epilepsy:
• Increased incidence of injury
• Greater medication burden
• adverse effects, financial cost
• Increased psychiatric co-morbidities
• Socio-economic disadvantage
• driving, work, stigma
• Reduced quality of life
• Increased incidence of death
• accidental, SUDEP
Drug Resistant Epilepsy - The importance of
achieving seizure freedom

17.
• Drug-resistant seizures.1
• Polytherapy with AEDs
• Intellectual or neurological impairment
• Higher seizure frequency
• Convulsive seizures.1
• 27x increased risk if GTCS in last 12 months.2
• Nocturnal seizures.1
• 15x increased risk. 2
• Inadequate treatment.1
• Untreated 2
• Subtheraputic AED levels.
• Medication non-adherence
• Unattended/living alone.1
• 5x increased risk. 2
• Substance abuse and alcohol dependence.2
• Psychiatric Comorbidities.3
Risk factors for SUDEP
1 Harden C, et al. Neurology 2017; 2 Sveinsson O, et al., Neurology 2020; 3 Tao G et al., 2020 – submitted

18.
• Cardiac:
• Seizure induced cardiac arrhythmia
• Genetic cardiac channelopathy creating vulnerability
• Acquired cardiomyopathy from effect of chronic epilepsy
• Respiratory
• Airway obstruction
• Neurogenic pulmonary oedema.
• Brain
• Post-ictal generalised cerebral “shutdown” resulting in
secondary, ultimately terminal, cardiorespiratory dysfunction.
Likely all three are involved, but contributions may vary in different
patients
Causes of SUDEP: Heart, Respiratory or Brain

19.
• 160 Units in Europe, Israel, Australia, and New Zealand; retrospective
audit of deaths, resuscitations & asystole during video-EEG
monitoring.
• Purpose was to provide insights into the cardiorespiratory mechanisms
resulting in SUDEP.
Ryvlin P, et al. Lancet Neurol 2013
Mortality in Epilepsy Monitoring Unit Study
(MORTEMUS)

20.
• 16 cases of SUDEP (11 monitored):
• Incidence 5.1 per 1000 patient-years, 1.2 per 10,000 monitoring admissions.
• 9 cases near-SUDEP:
• Combined incidence 7.9 per 1000 patient-years
• All post-ictal, all at night.
• Post-GTCS for all SUDEP, 7/9 near SUDEP.
• 14/16 cases prone position.
• >50% medication withdrawal in at least 19/25
Ryvlin P, et al. Lancet Neurol 2013
Mortality in Epilepsy Monitoring Unit Study
(MORTEMUS)

21.
• Characteristic pattern in the 10 SUDEPs with cardiorespiratory data:
– Post-GTCS rapid breathing  central apoea and severe bradycardia with
generalised suppressed EEG  terminal apnoea (1/3)/transient recovery
(2/3) terminal apnoea  terminal asystole
Seizure
Central Cerebral
Shut Down
Respiratory
Hypopnoea
Cardiac
Bradycardia
Terminal
Apnoea
Terminal
Asystole
Mortality in Epilepsy Monitoring Unit Study
(MORTEMUS)
Ryvlin P, et al. Lancet Neurol 2013

22.
• Not all patients who experience SUDEP have had recent or any GTCS, and
SUDEP may occur independent of seizures.
• Patients with chronic epilepsy have an increased rate of cardiac
electrophysiological and structural abnormalities that could predispose to
a malignant arrhythmia.
• Ion channel mutations resulting in genetic epilepsy, often expressed in
the heart:
• Dual brain and heart channelopathy phenotype.
• During seizures there is a profound autonomic “storm” of aberrant
sympathetic and parasympathic inputs:
→ Major acute changes in rhythm, rate and function.
• Potential to trigger an arrhythmia in those with underlying functional or structural cardiac
pathology.
→ Potential to result in long term functional and structural changes.
• Increased vulnerability to increase arrhythmogenic stimuli.
Does underlying cardiac electrophysiological
dysrhythmia result in some cases of SUDEP?
Lhatoo SD, et al. Epilepsia 2016

23.
• In 185 patients with chronic treatment resistant epilepsy significant
cardiac abnormalities found on ECGs in up to 39%.1
• Atrial fibrillation, junctional escape rhythm, and ST-segment elevation,
early repolarization, prolonged QTc.
• Increased in patients with longer duration of epilepsy, frequent GTCS and
acquired aetiology.
• 2-3x increased risk of sudden cardiac arrest with VF.2
1Lamberts et al. JNNP 2014; 2Bardai et al, PLoS One 2012
Interictal cardiac changes in people with
epilepsy

24.
RMH Study (Sivathamboo S et al., AES 2019): 3/31 (9.7%) chronic drug resistant patients had serious cardiac arrhythmias:
• 2x sinus arrest with ventricular asystole, 1x ventricular tachycardia (VT)

25.
Postictal atrial fibrillation (PIAF): A potential biomarker
for severe autonomic dysfunction and SUDEP?
• 43 yr. old man with 21 year history of drug resistant focal
epilepsy with frequent GTCSs admitted for VEM monitoring.1
• >12-hour PIAF following the first of two back-to-back GTCSs.
• 26 months later died of SUDEP (found dead in bed).
• Van der Lende et al., 2/3 patients with PIAF subsequently died of
SUDEP.2
• PIAF may indicate increased SUDEP risk by suggesting possible,
undetected cardiac disease, severe autonomic dysfunction, and
at risk of fatal arrythmia.
1. Nightscales et al., Neurology Clinical Practice 2021 (in Press)
2. Van de Lende et al., J Neurol Neurosurg Psychiatry 2016 Jan;87(1):69-74
16:40:00
PIAF reverts to sinus
rhythm
4:44:40
Onset of postictal EEG
attenuation resembling
PGES
4:45:45
PIAF onset and
stertorous breathing
C D
4:39:58
S1 EEG onset
(left temporal)
B
4:44:14
S1 terminates
4:46:33
S2 EEG onset (right
temporal)
4:52:40
S2 terminates

26.
Cardiorespiratory and autonomic dysfunction
following GTCS
• Examined peri-ictal cardiorespiratory and autonomic function in 157
seizures (18 convulsive and 139 nonconvulsive) from 70 consecutive
patients who had a seizure captured on concurrent VEM and PSG.
Sivathamboo S et al., Epilepsy and Behavior 2020 DOI:https://doi.org/10.1016/j.yebeh.2020.107271
HeartRateVariability
PGES = Post-Ictal
Generalised
EEG Suppression

27.
Heart Rate Variability (HRV): A potential
clinically applicable biomarker of SUDEP risk
• Deranged HRV may reflect central autonomic dysregulation
• Multicenter, case-control study on 31 patients admitted for VEM
2003 – 2014 who subsequently died of SUDEP.
• 56 epilepsy controls, and 60 healthy controls.
• Time-domain and frequency-domain components of HRV from 5 min
interictal electrocardiogram recordings in sleep and wakefulness.
Increased percentage of Low Frequency Power (LFP) in
wakefulness was associated with an increased latency to SUDEP,
where each 1% incremental reduction to LFP percentage,
corresponded to a 4·2% decrease in the latency to SUDEP
Sivathamboo S, Friedman D, Laze J, Nightscales R, Chen Z, Kuhlmann L,
Devore S, Macefield VG, Kwan P, D’Souza W, Berkovic SF, Perucca P,
O’Brien TJ, Devinsky O, on behalf of the MS-BioS study group (In
submission)

28.
• Many of the ion channels important in modulating neuronal
electrophysiological firing properties, established “epilepsy genes”, are
also important in modulating cardiac electrophysiological firing
properties.
• Sodium channels (e.g. SCN1A, SCN5A*), potassium channels (e.g. KCNQ1*, KCNH2
(HERG)*), T-type calcium channels (e.g. Cav3.2), HCN channels (e.g. HCN2*, 4*).
→ Long QT syndrome, increased ventricular arrhythmias
*Mutations in these genes found in ≈10% of SUDEP patients (Tu et al., Brain
Pathology 2010, 2011)
• Potential to result in dual phenotype of epilepsy and cardiac dysrhythmia,
predisposing to SUDEP?
Genetic ion channel mutations causing both
epilepsy and cardiac dysrhythmia?

29.
Powell KP, et al. Epilepsia 2014
Can chronic epilepsy cause an acquired
cardiac channelopathy?
Chronically epileptic vs. age- and sex-
matched non-epileptic rats
In-vivo: ECG Recordings In-vitro: Perfused-Isolated Heart
Preparations
1. Cardiac
Electrophysiology
2. Post-mortem
measurement of
HCN mRNA &
protein levels
QRS
Complex
ST
Interval
QT Interval
ECG parameter Treatment In vivo Ex vivo
Heart rate (bpm)
Saline 314.2 ± 7.07 264.6.6 ± 4.8
Post-SE 337.0 ± 11.75 276.2 ± 4.0
sdRR (ms)
Saline 0.28 ± 0.03 3.9 ± 0.2
Post-SE 0.41 ± 0.09 5.2 ± 0.5*
QRS interval (ms)
Saline 11.49 ± 0.39 12.7 ± 0.4
Post-SE 13.05 ± 0.75 12.4 ± 0.3
QTc interval (ms)
Saline 128.8 ± 3.18 115.6 ± 3.7
Post-SE 169.0 ±13.60** 130.6 ± 5.2*
ST interval (ms)
Saline 44.86 ± 1.23 37.2 ± 1.4
Post-SE 58.55 ± 5.06** 46.7 ± 2.6**

30.
Powell KP, et al. Epilepsia 2014
Can chronic epilepsy cause an acquired
cardiac channelopathy?
Acquired TLE Model (Post-KA SE)
RelativeHNCproteinexpression
RelativeHNCproteinexpression
Ih
de-activate
Ih
activate
It
inactivate
It
activate
(McCormick and Pape,
1990)

31.
Chronically epileptic rats post-KA SE have
cardiomyopathy and cardiac fibrosis
Powell KP, et al. under submission
Echocardiograms Post-Mortem Histology

32.
• The most important modifiable risk factor is to control the
seizure, particularly GTCS.
• Primary goal of epilepsy management is to achieve as
complete a seizure control as possible:
• Medical treatment (anti-epileptic drugs): complete seizure control in
60-70%
• If appropriate for epilepsy syndrome, adequate dose and patient has good
adherence.
• Surgical treatment:
• The only realistic prospect for complete seizure control in patients with drug
resistant epilepsy.
• In “ideal” surgical candidates long term seizure free rates 60-80%
• Does effective treatment for epilepsy reduce risk of death?
Prevention of SUDEP

33.
Does AED treatment reduce the risk of
SUDEP?

34.
• Faught E. et al., Neurology 2008:
• On the basis of Medicaid prescription data for 33,658 patients with
epilepsy over a decade in 3 US states & classified quarters as being
“adherent” (MPR ≥0.80) 74% or “non-adherent” (MPR <0.80) 26%.
• During “Non-adherent” periods had:
• Higher incidence of ED visits (50%), hospital admissions (86%), MVA
injuries (108%) and fractures (21%).
• Increased risk of mortality (hazard ratio 3.32 (95% CI 3.11–3.54) after
multivariate adjustments for confounders.
Poor medication adherence is associated with
increased mortality (& morbidity)

35.
J Neurol Neurosurg Psychiatry 2010;81:716
Patients with ongoing seizures 4.9 (95% CI 1.2 to 20.3) times as likely to
die as who remained seizure free.
Successful epilepsy surgery is associated with
decreased mortality

36.
Neurostimulation
• Neurostimulation treatments (e.g. VNS, DBS, RNS) are
increasingly being used to reduce seizure frequency and severity
in people with drug resistant epilepsy who are not suitable for
resective epilepsy surgery.

37.
• Supervision at night:
• Found to be protective (OR: 0.4, 95% CI: 0.2 to 0.8) when shared the same bedroom or special
precautions such as a listening device were employed (OR: 0.1, 95% CI: 0.0 to 0.3).1
• O2 administration and repositioning after GTCS
• Educating persons who live with patients how to perform the appropriate first-aid responses to
seizure
• e.g. repositioning and protecting the airway after a tonic-clonic seizure.
• Devices remain unproven:
• Cardiac or oxygen monitoring devises.
• Anti-suffocation pillows.
• ECG & Holter monitor to detect prolonged QT or other serious cardiac arrhythmias.
• Discuss SUDEP and relationship to adequate treatment with patients and their
families
Other potential preventive methods
1. Langan Y et al., Neurology 2005;
Sveinsson et al., Neurology 2020

38.
• Few medical practitioners, including neurologists, routinely discuss
the risk of SUDEP unless specifically asked.1
• Most patients and families want to be provided information
regarding SUDEP.
• Families of SUDEP victims angry at not being told of the risk.
• UK guidelines (NICE, SIGN) recommend all patients with epilepsy
and their families be provided with information about sudden,
unexpected death in epilepsy
• Allows informed decision regarding treatment, adherence and nocturnal
supervision.
Informing patients and families about the risk
of SUDEP
1 Strzelczyk A. et al., Epilepsia 2016

39.
SUDEP: Raising awareness

40.
SUDEP: Raising awareness

41.
SUDEP: Raising awareness

42.
• SUDEP is an important cause of premature death in people with
epilepsy.
• The mechanism likely involves a combination of central,
respiratory and cardiac mechanisms.
• The biggest risk factor is lack of seizure control
• especially nocturnal GTCS
• The incidence can likely be reduced by effective medical or
surgical treatments.
• Further research to identify biomarkers of individual risk, and
develop more effective preventive measures are urgently needed.
• It is important to discuss SUDEP with patients and families with
epilepsy,
• Raise community awareness
SUDEP: Key points

43.
Acknowledgments
Funders:
• Department of Neuroscience,
CCS, Monash University
– Shobi Sivathamboo
– Kim Powell
– Piero Perucca
– Patrick Kwan
– Emma Braine
– Pragati Sharma
– Janine Liu
• Baker Institute
– Vaughan Macefield
• New York University
• Orrin Devinsky
• Dan Friedman
• Juliana Laze
• The Department of Medicine, RMH,
University of Melbourne
– Russell Nightscales
– Gerard Tao, Clarisa Auvrez
– Paul Sparks
• The Department of Medicine, Austin
Health, UoM
– Sam Berkovic
• The Department of Medicine, St.
Vincents Hospital, UoM
– Wendyl D’Souza
– Mark Cook
• The Department of Physiology, UoM
– Lea Delbridge,
– Claire Curl