Neuropathology of epilepsy epilepsy related deaths and sudep

Neuropathology of
epilepsy: epilepsy-related
deaths and SUDEP
Maria Thom
Abstract
Most pathologists will encounter deaths in patients with epilepsy in
their practice, including sudden deaths. A systematic approach to
these post-mortem examinations is required, including gathering rele-
vant clinical details and around the circumstances of death, in order to
correctly categorise these cases. Macroscopic and histological exam-
ination of the brain can reveal (i) the underlying cause of the epilepsy,
as cortical dysplasia or tumours, (ii) sequel of previous seizures,
including hippocampal sclerosis and contusions and (iii) potentially
the cause of death. Sudden and unexpected death in epilepsy
(SUDEP) is still under-reported as a cause of death. Although by defi-
nition there is no structural or toxicological cause of death at post-
mortem, clinical and experimental studies together with neuropatho-
logical findings are beginning to identify alterations in central auto-
nomic regions, including the brainstem, critical for cardio-respiratory
regulation. Neuropathology investigations following post-mortem ex-
aminations form an essential component in the identification of dis-
ease mechanisms in epilepsy-related deaths and their future
prevention.
Keywords epilepsy; post mortem; sudden death neuropathology
Introduction
Epilepsy is a common neurological condition. It may arise from
varied underlying brain pathologies, from neurodevelopmental
disorders in the young, to tumours, stroke and neurodegenera-
tive diseases in adults; it is therefore not a single disease entity.
Furthermore, epilepsy can also be due to a genetic disorder (for
example a neuronal ion channel single gene mutation e ‘chan-
nelopathy’) or indeed idiopathic in which no genetic or structural
cause is found. An epileptic seizure is defined by the ILAE (In-
ternational League Against Epilepsy) as a transient occurrence of
signs and/or symptoms due to abnormal excessive or synchro-
nous neuronal activity in the brain whereas epilepsy is a the
enduring tendency to have recurrent seizures.1
For example, a
single seizure may be secondary to intoxication, infection or
febrile illness and does not amount to a diagnosis of epilepsy.
Seizures can be focal or generalised, both with or without loss of
consciousness. In recurring seizures with focal onset there is
more often an underlying brain pathology.
With advances in the sensitivity of neuroimaging combined
with EEG investigations, structural causes of epilepsy are being
increasingly recognised. Furthermore, with state of the art image
guidance, localised resective neurosurgery is increasingly being
used with good outcomes in drug-resistant patients with focal
seizures.2
While epilepsy surgery is mainly carried out in
specialist centres and specimens reported by a neuropathologist,
the general pathologist will encounter post-mortems in patients
with epilepsy. Neuropathological investigations are mainly
directed to the following questions: (i) Identification of structural
lesions or cellular alterations that caused seizures (epileptogenic
focus), (ii) the secondary effects of seizures on the brain and (iii)
if epilepsy was directly related to the cause of death (Epilepsy
related deaths (ERD)). The latter can include an accident during a
seizure, status epilepticus or sudden and unexpected death in
epilepsy (SUDEP) (Table 1). SUDEP is defined as “Sudden, un-
expected, witnessed or unwitnessed, non-traumatic and non-
drowning deaths in patients with epilepsy, with or without evi-
dence for a seizure, and excluding documented status epilepticus,
where autopsy examination does not reveal a toxicological or
anatomical cause of death”.3
SUDEP is the commonest cause of premature death in adults
with epilepsy and is more common in patients with poorly
controlled generalised convulsive seizures.4
They are typically
unwitnessed deaths, often nocturnal or occurring during sleep
and, by definition, no cause of death is ascertained at post-mor-
tem.5
The mechanisms causing SUDEP are unknown but current
evidence, including from witnessed SUDEP deaths in patients
undergoing investigations on epilepsy monitoring units,6
favour a
centrally mediated depression of cardiac and respiratory regula-
tion. SUDEP affects all ages but peaks in young adults5
and the
incidence is estimated around 1 to 1.2 per 1000 per year in people
with epilepsy amounting to 500 deaths per year in the UK alone.
Historical perspectives of SUDEP and ERD
Pathologists were probably the first to recognise that patients
with epilepsy can die suddenly and unexpectedly (‘mors subita’)
and that following post-mortem remained ‘none the wiser’ as to
the cause of death.7
Indeed, one of the earliest neuropathology
studies by Sommer in 1880 documenting the pathology of hip-
pocampal sclerosis, reveals that several patients had died sud-
denly following a short seizure.8
In the 1980s, Leetsma a forensic
pathologist in the USA, carried out the first systematic studies of
the brain in a large sudden death in epilepsy series, documenting
the incidence of lesional neuropathology.9
In 1997 Nashef and
colleagues in the UK coined the term ‘SUDEP’ and defined the
clinical and pathological criteria. National audits shortly fol-
lowed in the UK in 2002 and highlighted the national scale of
SUDEP as well as the standards of death investigations, autopsy
practice and shortfalls; 87% of examinations were incomplete or
inadequate.10
In view of this, as well as for more accurate
epidemiological categorisation, refined criteria for definite,
probable and possible SUDEP were introduced3
(see Table 1).
For definite SUDEP a complete, negative autopsy is required, in
probable SUDEP the post-mortem investigation was incomplete
but SUDEP still remained the most likely cause of death and for
possible SUDEP a competing cause of death was identified at
post-mortem (examples of this include non-significant coronary
atheroma (50e75% occlusion), mild cardiac hypertrophy and
where the person is found dead in bath but without substantia-
tion of drowning). SUDEP also encompasses cases with short
Maria Thom BSc MB BS FRCPath MD Honorary Consultant in
Neuropathology, Department of Neuropathology, UCL Institute of
Neurology, London, UK. Conflict of interests: none.
NEUROPATHOLOGY
DIAGNOSTIC HISTOPATHOLOGY --:- 1 Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Thom M, Neuropathology of epilepsy: epilepsy-related deaths and SUDEP, Diagnostic Histopathology (2018),
https://doi.org/10.1016/j.mpdhp.2018.11.003

period of survival following resuscitation but without recovery
following a seizure related cardiac arrest; these are also termed
delayed or ‘near-miss’ SUDEP. In instances where the cause of
death is considered to be the combined effect of epilepsy plus a
concomitant condition, the term ‘definite SUDEP plus’ has also
been proposed.3
Approach to the post mortem examination in epilepsy-
related death
In suspected ERD and SUDEP cases, a ‘complete’ post-mortem
examination includes external and full internal examination,
and toxicology, including anticonvulsant levels.10,11
The brain
should be examined by a neuropathologist or personnel with
sufficient neuropathology training. Epilepsy-related and sudden
deaths typically fall under the remit of the coroner. Some of the
practical problems include that full clinical information regarding
the epilepsy history, including investigations carried out during
life, may not be available at the time of the post mortem
(Table 2). Also in an unwitnessed SUDEP there may be a long
post-mortem interval, particularly if the deceased was living
alone or death unwitnessed. Brain retention protocols and
coronial practice varies widely regarding what is permissible
regarding epilepsy-related death investigations, which may
restrict the pathologists examination. The Royal college of pa-
thologists guidance document recommends that retention of the
brain with examination after a period of fixation is advisable to
enable optimum neuropathological examination. It further
specifies a regional block sampling protocol (any lesion or ab-
normality detected, the hippocampus, amygdala, basal ganglia
with insular cortex, watershed frontal cortex, thalamus brain-
stem and cerebellum), taken from both hemispheres as epilepsy
pathology can lateralise (Figure 1). The rationale of this approach
is that through a systematic and histological examination, an
underling unsuspected cause of death, for example vascular
disease, inflammation, infection (meningoencephalitis) or meta-
bolic disorder (e.g. mitochondrial disease), is excluded thus
enabling more stringent SUDEP classification. Samples for toxi-
cology are mandatory in sudden ERD investigations, whereas
other investigations (microbiology, virology, metabolic tests,
genetics etc.) are tailored for a particular case, directed by cir-
cumstances of death, clinical data and post-mortem findings.
Categories of death in patients with epilepsy and post mortem evidence
Category Comments
Epilepsy-related deaths Status epilepticus Clinical or EEG evidence of unremitting convulsive or
partial seizures (or EEG evidence of seizure activity in
non-convulsive status) for >30 min period prior to death.
Aspiration during a seizure Confirmation by histology required in distal airways.
Gastric contents may be displaced in main airways
(trachea and bronchi) in sudden death without true
aspiration
Accidental death PM examination carried out to confirm e.g. drowning,
trauma occurring during a seizure including head injury.
Suicide Patients with epilepsy have increased incidence of
neuropsychiatric disease, depression
As a result of surgical or medical
treatment of epilepsy
Drug reaction/interaction/accidental overdose
Post-surgical complication (rare)
SUDEP -Definite Sudden death in patient with known epilepsy diagnosis
(excluding status epilepticus)
Negative histology, neuropathology and toxicology is
required.
The cause of epilepsy may be identified.
SUDEP e Possible As above but competing cause of death identified at PM
(e.g. cardiac hypertrophy).
SUDEP e Probable As above but the PM examination was incomplete (e.g.
no neuropathology).
SUDEP e Near miss As above but the patient is resuscitated and survived for
a short period without regaining consciousness.
Death from the underlying condition
causing epilepsy
e.g. Alzheimer’s disease, Glioblastoma,
Stroke etc.
PM examination of the brain to confirm underlying
pathology and any potential contribution to the mode of
death (e.g. brain swelling or intra-tumoural
haemorrhage)
Cause of death is unrelated to epilepsy Other cause of death identified.
Epilepsy may be included in part II of the certificate if
indirectly contributing.
Table 1
NEUROPATHOLOGY

Neuropathology findings in SUDEP
It is important to bear in mind that in a SUDEP post mortem the
brain is not always normal even though, by definition, there is no
neuropathological explanation for cause of death. The brain
external surfaces and coverings should be examined in a system-
atic way, being careful to assess for any features associated with
brain swelling as uncal and tonsillar herniation (Figure 2c). Mild
degrees of brain swelling with effacement or fullness of the gyri are
a not uncommon finding in SUDEP (Figure 2a, 2b),12
due to mild
degrees of acute cerebral oedema, but alone are insufficient for a
cause of death. The external surface of brain in epilepsy can also
reveal old contusions (Figure 2g and h), evidence of previous
surgery, vascular malformations (Figure 2j, 2k) and underlying
cortical malformations (Figure 1i) such as polymicrogyria;
photographic documentation is recommended, particularly if the
brain is not being fixed. Other neuropathological causes of sudden
death, such as acute traumatic brain injury or spontaneous
intracerebral haemorrhages (Figure 2d) and meningitis are usually
readily apparent naked eye but should nevertheless be supported
with histology to explore aetiology. More focal or subtle neuro-
pathologies, such as fatal colloid cysts or acute encephalitis
(Figure 2f), require a more careful approach, are better identified
in fixed brains and often necessitate additional confirmatory
immunohistochemistry (See Table 3 for suggested panels).
There is no single neuropathological feature that can cate-
gorically confirm that seizures occurred during life in the absence
of supportive clinical documentation. There are certain pathol-
ogies that have strong associations with epilepsy and some pat-
terns of regional neuronal damage and re-organisation (e.g.
mossy fibre sprouting, see below) are relatively specific for
seizure-related brain injury. Nevertheless, epilepsy is a clinical
diagnosis that requires corroborative EEG findings during life.
Among lesions that are known to highly associate with epilepsy,
published series to date do not suggest that any single pathology
type is over-represented in SUDEP. Indeed the range of pathol-
ogies in SUDEP capture those commonly encountered in surgical
epilepsy series, including hippocampal sclerosis, cortical
Useful clinical information for post-mortem examinations in epilepsy-related deaths
Category Questions to ask
Circumstances of death Witnessed or not Evidence of seizure?
Duration of seizure?
Last seen alive and state of health?
Location and position of body In bed/during sleep?
Prone versus supine?
Evidence for suffocation/airway obstruction?
Death in water, head submerged?
Other evidence Photographs of death scene
Evidence of incontinence?
Vomiting?
Tongue bite/blood around mouth?
Epilepsy history Epilepsy Type of seizures (all)
Age of onset of epilepsy
Frequency of seizures
Nocturnal seizures
Episodes of status epilepticus
Investigations EEG
Genetic or metabolic tests
MRI or other neuroimaging
Cause of epilepsy if know
Treatments Surgery
AEDs
Other e.g. vagal nerve stimulator
Recent history Worsening seizure control?
Drug compliance?
Recent changes in AEDs?
History of seizure-related apnoea?
Other medical history Cardiac Syncopal attacks?
Alcohol, neuropsychiatry Previous suicide attempts?
Family history Epilepsy
Cardiac disease
Inherited cardiac disease or epilepsy
AED ¼ anti-epilepsy drug.
Table 2
NEUROPATHOLOGY

malformations such as focal cortical dysplasia (FCD) and low
grade tumours13
(Figure 3). Focal neuropathological abnormal-
ities are found in w50% of SUDEP autopsies, ranging from 34 to
89% between larger SUDEP series (Table 4). Leestma identified
brain lesions in 60% of SUDEP cases,9
but not all SUDEP studies
have replicated this and there are few published large post-
mortem non-SUDEP epilepsy series for comparison (Figure 3).
Variability in lesion detection in SUDEP may reflect the popula-
tion demographics under study as well as methodological dif-
ferences, for example whether only macroscopically visible or
additional histological pathologies are reported. Indeed audits
have shown that identification and documentation of brain pa-
thology pertaining to epilepsy is highly dependent on the brain
being examined in detail following a period of fixation,14,15
the
number of histological regional samples taken and the depth of
the evaluation, including if immunohistochemistry is performed
as recommended in epilepsy surgical protocols16e18
(Table 3) as
well as the experience and training of the pathologist. Further-
more clinical information of investigations localising the seizure
focus to a specific brain region (e.g. EEG, seizure semiology,
MRI, PET findings) may increase the detection of underlying
pathology, especially as some epilepsy pathologies may be
macroscopically occult, for example, focal cortical dysplasia and
smaller, diffuse cortical tumours.
Regional neuropathology and insights into mechanisms in
epilepsy and SUDEP
Hippocampus and hippocampal sclerosis
Hippocampal sclerosis is one of the commonest pathologies in
larger epilepsy surgical series as well as in post mortems,
particularly in temporal lobe epilepsy when it can be unilateral.
Macroscopically the hippocampus appears reduced in size, pale
and firmer with compensatory dilation of the adjacent temporal
horn of the lateral ventricle. Microscopically regional pyramidal
neuronal loss and gliosis is present in specific subfields (typically
CA1, CA4 and to a lesser extent CA3) (Figure 4). This can be
observed on H&E but more clearly demonstrated with immuno-
histochemistry for neuronal markers such as MAP2, NeuN and
synaptophysin; the gliosis affecting CA1 is confirmed with GFAP
stain (Figure 4). Three subtypes of hippocampal sclerosis are
recognised based on the distribution of neuronal loss between
CA4 and CA117
; in type 1 (w75% of cases) there is neuronal loss
in CA1 and CA4, in type 2 (w20% of cases) neuronal loss is
restricted to CA1 and in type 3 (w5% of cases) there is neuronal
loss in CA4 alone. These subtypes likely reflect different patho-
aetiologies with different patient outcomes following surgery.
The granule cell layer of the dentate gyrus can show patchy
neuronal loss and, in addition, in around 40e60% of sclerosis
Figure 1 Block sampling strategy in suspected SUDEP or other epilepsy related deaths post mortem. Lines indicate approximate coronal
levels for block sampling, following hindbrain removal, as shown in the slices. Sample should be taken of any macroscopic abnormality. The
samples 1e6 are shown only on one hemisphere to illustrate the anatomy, but paired blocks are recommended as good practice. The numbered
blocks correspond to: 1. Vascular watershed region/Frontal watershed regions (F1/2) for assessment of any acute hypoxic/ischaemic damage,
meningitis, encephalitis, chronic neuronal loss (from previous seizures or episodes of status epilepticus e.g. laminar atrophy). 2. Insular cortex/
basal ganglia to assess acute neuronal injury, hypoxic/ischaemic damage, meningitis, encephalitis. 3. Amygdala to evaluate any chronic neuronal
loss or acute neuronal injury, hypoxic/ischaemic damage, limbic encephalitis, chronic astrocytosis. 4. Hippocampus to evaluate any acute
neuronal injury (CA1), hypoxic changes, limbic encephalitis, hippocampal gliosis or sclerosis, malformation or neurodegenerative disease. 5.
Thalamus to evaluate any chronic or acute neuronal injury and any chronic regional gliosis. 6. Temporal cortex (T1/2) to assess for meningeal
inflammation, encephalitis, gliosis, global hypoxic changes, chronic atrophy, traumatic brain injury and any neurodegenerative pathology. 7.
Cerebellar cortex to assess for acute or chronic atrophy (Purkinje cell loss and gliosis), and any inflammation. 8. Medulla to assess for any in-
flammatory disease or acute neuronal injuries. The standard stains that may be useful in analysis in assessment of any identified epilepsy-related
pathologies is included in Table 3. This sampling strategy corresponds to the Royal College of Pathologists guide for epilepsy deaths.
NEUROPATHOLOGY

Figure 2 Macroscopic brain appearances in epilepsy-related deaths and sudden deaths. (a). Fixed brain in patient with SUDEP showing mild
brain swelling and effacement or fullness of the gyri over the hemisphere. (b). Another SUDEP case in a child which has been sliced in sagittal
plane, one hemisphere was frozen and one fixed for histology (shown here) with evidence of effacement of the gyri but not subfalcine herniation.
(c). A further SUDEP case with mild brain swelling and uncal grooving (arrowed) but without tissue necrosis. (d). A sudden death due to a traumatic
subarachnoid haemorrhage following seizure. (e). Sudden death in a patient with epilepsy with an oligodendroglioma (arrowed) showing micro-
cystic changes and mild expansion of the grey matter. (f). Sudden death in patient with recent onset poorly controlled epilepsy where the fresh
brain showed collapse and haemorrhage in CA1 sector of the hippocampus (arrows) and histology confirmed a limbic (autoimmune) encephalitis.
(g). Coronal slices through a fixed brain showing a large old temporal lobe contusion (arrowed) following assault; this patient had a sudden death
but no history of seizures. (h). SUDEP in a patient with epilepsy and history of RTA with a small region of brain injury compatible with an old
contusion (arrows). (i). SUDEP case in patient with early onset of epilepsy and cortical malformation with a microgyric pattern involving both
occipital lobes. On histology this correlated with focal cortical dysplasia (type IIId). (j). Witnessed SUDEP following two seizures in a patient with
refractory epilepsy due to a known arteriovenous malformation showing numerous, tortuous ectatic changes on the meningeal surface and in (k)
abnormal extension of vessels into the underlying parenchyma with cavitation. (l). A SUDEP case on which the brain appeared macroscopically
normal but histology confirmed evidence of a cortical dysplasia.
NEUROPATHOLOGY

cases (all subtypes), shows dispersion or broadening of this cell
layer. Reorganisation or sprouting of the axons of the granule
cells (mossy fibres) is also present in 80e90% of hippocampal
cases, readily demonstrated with immunohistochemistry
including Zinc transporter protein 319
(Table 3, Figure 4). The
constellation of these cellular alteration can aid in the distinction
of hippocampal damage due to epilepsy from other causes of
hippocampal neuronal loss (for example, hypoxic/ischaemic
injury, neurodegenerative causes) encountered at post mortem.
The aetiology of hippocampal sclerosis is generally considered
an acquired process following an early childhood initiating insult
(such as a prolonged febrile seizure), possibly occurring in an
immature hippocampus or predisposed individual. The precise
pathogenesis remains elusive but with its extensive cortical
connections, the hippocampus may represent the vulnerable
‘fuse-box’ in an immature, seizing brain. Hippocampal sclerosis
can also arise in association with a second epileptogenic pa-
thology, such as a cortical malformation, vascular malformation
or tumour (also referred to as a ‘dual pathology’). Hippocampal
sclerosis is a sporadic condition with rare families with both
febrile seizures and TLE reported; some common genetic sus-
ceptibility factors, for example SCN1A gene, are beginning to be
identified through study of large series in addition to epigenetic
modifications as DNA methylation.20
Activation of neuro-
inflammatory pathways has also been proposed as a driving
force in disease progression.
The hippocampus in SUDEP
There is no evidence that hippocampal sclerosis is more preva-
lent in SUDEP. It had been reported in 21% of SUDEP cases15
which compares to 30.5%e45% in other epilepsy post-mortem
series (see Figure 3). Some unexplained deaths in infancy and
childhood may be seizure-induced and unexpected deaths in
young patients with febrile seizures may share similar pathoge-
netic mechanisms to SUDEP. Interestingly hippocampal devel-
opmental lesions have been reported in SIDS series, including bi-
lamination or broadening of the dentate gyrus and incomplete
hippocampal rotation as potential disease biomarkers.21
In a
quantitative MRI study, increased hippocampal volumes in
SUDEP were noted on the right side.22
The limited neuropa-
thology studies of the hippocampus as yet have not identified any
specific or diagnostic surrogate biomarker for SUDEP. In partic-
ular, there is no evidence of increased neuro-inflammation,
including lymphocytic parenchymal infiltrates and HLA-DR
activated microglia in SUDEP compared to control groups.23
Acute ‘eosinophilic’ neuronal change is reported in approxi-
mately half of SUDEP post mortems,15
supported by studies of
neuronal HSP-70, HIF-1a and c-jun expression; these primarily
involving the hippocampus CA1/subiculum region. Although
these could indicate recent seizure induced hippocampal
neuronal injury they are essentially non-specific cytopathic
changes that could be equally caused by hypoxic and/or exci-
totoxic cellular stresses.
Useful histology stains and immunohistochemistry in the assessment of epilepsy-related neuropathologies
Histological stain Application
H&E For many epilepsy PMs this is sufficient to exclude any underlying pathology in regional brain
samples.
Myelin stain (Luxol fast blue) or
Myelin basic protein
Assessment of myelination and cortical lamination
Evaluation of cortical malformations as focal cortical dysplasias
Helpful for anatomical orientation, e.g. in amygdala blocks
Neuronal markers Neurofilaments,
NeuN and MAP2
Highlight abnormal neuronal populations in cortical dysplasias and glioneuronal tumours
Also can aid in the evaluation of regional patterns of neuronal loss (e.g. in mild hippocampal
sclerosis)
Glial markers GFAP Highlights areas of chronic scarring (e.g. fibrillary gliosis in old traumatic brain injury or hippocampal
sclerosis).
Cellular ‘reactive’ gliosis can identify regions with more recent/acute brain injury, but this is a non-
specific reaction.
Inflammatory markers (CD3, CD20,
microglial markers (e.g. CD68, Iba1)
Evaluation of suspected encephalitis (infectious or autoimmune) to look for microglial nodules and
neuronophagia.
Mild degrees of chronic inflammation (eg scattered lymphocytes in the meninges) may be present
following seizures.
Evaluation of tumour type in epilepsy Primary brain tumours e.g. low grade gliomas (WHO grade II) and glioblastoma (WHO grade IV):
GFAP, IDH1, ATRX
In low grade epilepsy associated tumours/glioneuronal tumours (WHO grade I) (e.g.
gangliogliomas): additional neuronal markers, CD34 and BRAF V600E should be considered.
(Tumour immunopanels in post mortem are tailored to diagnostic rather than prognostic markers)
Other panels Based on any pathology type identified on H&E. For example:
Neurodegenerative panels (tau, amyloid beta)
Mossy fibre pathway demonstration in hippocampal sclerosis
Viral markers/PCR if infection suspected
Table 3
NEUROPATHOLOGY

Cortical lesions causing epilepsy e focal cortical
dysplasia and tumours
Cortical lesions more frequently associated with epilepsy in
surgical series include focal cortical dysplasias (characterised by
immature neurones, abnormal cortical laminar architecture and
associated with mutations in the mTOR pathway genes) and
vascular malformations (including cavernomas and arteriove-
nous malformations) (see Figure 2j). For their detailed descrip-
tion please refer to other reviews.18
Any tumour involving the
CNS can cause epilepsy but certain low grade tumours (partic-
ularly gangliogliomas and other glioneuronal tumours), many
harbouring BRAF gene or other MAP-kinase pathway mutations,
are particularly associated with chronic epilepsy. These tumours
form a distinct group from the more conventional and progres-
sive low grade gliomas associated with IDH1/2 mutations. For
further description of common tumour types associated with
epilepsy please refer to other reviews.24
Cortex and other regional pathology in SUDEP
There is no evidence that specific malformations or tumours are
more associated with epilepsy-related deaths or SUDEP. Clinical
studies show that cortical lesions involving brain regions with
known cardio-regulatory or autonomic functions, including the
insular cortex and amygdala, can be associated with SUDEP in
some cases. Experimental, clinical and MRI studies have also
focused on structural and functional abnormalities in the car-
dioregulatory regions of the thalamus, cerebellum and brainstem
that could represent risk factors for SUDEP. There are limited
neuropathology investigations but recent publications highlight
alteration of human respiratory brainstem neuronal populations
in SUDEP, including the serotonergic neurones of the raphe
which regulate breathing in response to hypercapnia25
(Figure 5).
Cardiopulmonary pathology and investigations in SUDEP
Post mortem examination in suspected SUDEP is requisite to
exclude a cardiac cause of sudden death with histology where
appropriate. Following status epilepticus or a convulsive seizure,
stress-induced cardiac changes or Takotsubo cardiomyopathy can
occur. Although an increased incidence of mild cardiac hypertro-
phy and fibrosis have been reported in some epilepsy and SUDEP
series there is conflicting evidence for this.26,27
Nevertheless,
careful consideration is advocated for attributing minor cardiac
pathologies as the underlying cause of death and categories of
possible SUDEP should be considered where there is uncertainty
(Table 1). Furthermore underlying channelopathies and genes
causing long QT syndrome (including KCNQ1, KCNH2, SCN5A,
RYR2, HCN4) can cause both epilepsy and arrhythmias or increase
the risk of seizure-induced arrhythmias and have been linked to
SUDEP (reviewed in5
). Consideration should be given to genetic
testing in suspected cases at post-mortem and the hereditary im-
plications and organ referral to a cardiac specialist as appropriate.
Pulmonary pathology, mainly congestion or oedema, is
frequently reported in 72% of SUDEP post-mortems.27
The
possible pathogenic mechanisms of pulmonary oedema
following seizures include increased sympathetic drive, altered
hydrostatic pressures and increased pulmonary capillary
permeability (‘neurogenic pulmonary oedema’). It is possible
that this, together with central apnoea following a seizure and
impaired arousal during sleep, contributes to the sudden death
(Figure 5).
Figure 3 Comparison of the relative incidence of common epilepsy neuropathologies in surgical series (blue) compared to reports in SUDEP
(red) and non-SUDEP post mortem series (green). Each point for each pathology represents a different series. Adapted from reference 12.
NEUROPATHOLOGY

Pathology studies in SUDEP comparing the relative frequency of documented neuropathology findings
Post mortem SUDEP series
Author and year of study
publication
Period of study Number SUDEP cases
(Age ranges)
Neuropathology: relevent to cause of epilepsy
(%) in series
Neuropathology: sequele of previous
seizures (%) in series
Acute neuropathologyb
(%) in series
Leestma (1984) 1976e1979 66 (10 moe60 ys) CNS tumours (4.5%)
Hippocampal sclerosis (6%)
Brain malformations (6%)
Cerebrovascular disease (3%)
Tuberous sclerosis (1.5%)
Old scars (9%)a
Brain atrophy/hemiatrophy (7.5%)
Old TBI/brain contusions (26%)a
Cerebral oedema (12%)
Leestma (1989) 1983 60 (8 moe83 ys) Cerebrovascular disease (17%) Hippocampal
sclerosis (12%)
Brain malformations (7%)
Vascular malformations (2%) CNS tumour (2%)
Old TBI/brain contusions (11%)a
Scars (20%)a
Cerebellar atrophy (7%)
Earnest (1992) 1982e1987 44 (3e58 ys) e e Cerebral oedema but no
herniation (31.8%)
Antoniuk (2001) 1990e1999 20 (11e50 ys) e e Cerebral oedema (55%)
Black & Graham (2002) 1991e1996 131 (adults) Hippocampal sclerosis (% n/s) Old TBI (n/s)a
Hypoxic-ischaemic brain injury
Shields (2002) 1996e2000 70 (16e71 ys) Hippocampal/cortical atrophy (26%)
Vascular malformation (6%)
Tumour (3%)
Old TBI (59%)a
Inflammation (38%)
P-Codrea (2005) 1998e2000 15 (17e56 ys) Old haemorrhage (n/s)
Focal cortical dysplasia microcephaly
Heterotopia
Old TBI (n/s)
Zhou (2012) 2007e2009 74 (14e63 ys) Cortical malformation (6.8%) Vascular
malformation (4.1%) Hippocampal gliosis
(2.7%) Cortical/hippocampal atrophy (2.7%)
Cerebrovascular disease (2.7%)
Tumours (2.7%)
Tuberous sclerosis (1.4%),
Old TBI (13.5%)
Cerebellar atrophy (5.4%)
Acute neuronal injury (1.4%)
Thom (2016) 2016 145 (2e82 ys) Cortical malformations (15%)
CNS Tumours (6.8%)
Hippocampal sclerosis (21%)
Cerebrovascular accident (6.9%)
Old TBI (17%)
Mild brain swelling (28%)
Acute neuronal injury (55%)
These have been categorised here as (i) those more likely to be relevant to the cause of seizure, (ii) sequel of chronic/previous seizures (iii) acute and more relevant to recent seizures and mechanism of death. TBI ¼ traumatic
brain injury, Ys ¼ years, Mo ¼ months. Studies with details of macro and/or histological findings are included. In some series (n/s) the percentage of cases with pathology type was not specified.
a
These may also be relevant to causing seizures (e.g. post-traumatic epilepsy).
b
Pathology potentially relevant to underlying final mechanism of death, but not sufficient explanation alone for the cause of death.
Table 4
NEUROPATHOLOGY
DIAGNOSTICHISTOPATHOLOGY--:-8Ó2018PublishedbyElsevierLtd.
Pleasecitethisarticleinpressas:ThomM,Neuropathologyofepilepsy:epilepsy-relateddeathsandSUDEP,DiagnosticHistopathology(2018),

Issues with death certification in ERD
Determining cause of death in a patient with epilepsy can be a
challenge since there is often incomplete data (e.g. unwitnessed
deaths, incomplete medical history, and decomposed body),
competing causes of death and a lack of confirmatory anatomic
or toxicological findings. Also because there is often little evi-
dence to determine that a seizure has occurred it is can be
impossible to be certain that epilepsy was the cause of death.
Figure 4 Histopathological findings in hippocampal sclerosis in epilepsy. A surgical case of type 1 hippocampal sclerosis is shown with
neuronal loss in CA1 and CA4 more clearly confirmed with MAP2 neuronal marker and gliosis with GFAP in the same regions. The zinc transporter
3 protein (ZnT3) highlights aberrant sprouting of axons in the dentate gyrus (arrowed).
Figure 5 Diagram of possible pathways and risk factors that could lead to SUDEP.
NEUROPATHOLOGY

Furthermore, terminal ‘seizure-like activity’ can occur in persons
dying of other conditions (stroke, intoxication, hypoxia etc).
Nevertheless, the sudden death of a person with epilepsy is still
most likely to be caused by epilepsy. The wording on death
certificates however, varies widely and despite the increased
recognition of the term SUDEP this is still under-used (or even
the term epilepsy on the certificate), limiting the ability to track
epilepsy-related deaths over time.
Tissue banking and research
Biobanking, including post-mortem tissues, forms an essential
component to further advance our understanding of epilepsy and
SUDEP, including neuropathological changes and germ-line and
somatic molecular genetics. For SUDEP this is the first step in the
process of recognising biomarkers for at-risk patients and intro-
ducing pharmacological disease modifying interventions.28
The
majority next of kin are generally very willing to donate tissue
samples for research when informed and approached. Systematic
collection at specified centres involved in research is supported
by epilepsy commissions including the ILAE12,29,30
and the NIH
Centre for SUDEP Research.31
A
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Practice points
C SUDEP is the commonest cause of death in young adults with
epilepsy.
C Fixation of the brain prior to examination is more likely to identify
pathology relevant to the cause of death or epilepsy.
C Pathology in brain central autonomic networks is the likely cause
of SUDEP rather than any specific lesion.
C Pathology in the hippocampus is frequent in epilepsy with distinct
patterns of neuronal loss and reorganisation but no specific pa-
thology is reported in SUDEP.
C SUDEP is still under-recognised and under-reported as a cause of
death.
NEUROPATHOLOGY

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and medullary raphe in sudden unexpected death in epilepsy.
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Incidence of cardiac ﬁbrosis in SUDEP and control cases.
Neurology 2018; 91: e55e61. https://doi.org/10.1212/WNL.
0000000000005740.
27 Nascimento FA, Tseng ZH, Palmiere C, et al. Pulmonary and
cardiac pathology in sudden unexpected death in epilepsy
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31 Lhatoo S, Noebels J, Whittemore V, Research NCfS. Sudden
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mortality. Epilepsia 2015; 56: 1700e6.
NEUROPATHOLOGY

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