1. Pathology of Epilepsy
Mark Cohen
Department of Pathology
University Hospitals Case Medical Center
January 6th
, 2009

2. 'He was thinking, incidentally, that there
was a moment or two in his epileptic
condition almost before the fit itself (if
it occurred in waking hours) when suddenly
amid the sadness, spiritual darkness and
depression, his brain seemed to catch fire
at brief moments....His sensation of being
alive and his awareness increased tenfold
at those moments which flashed by like
lightning. His mind and heart were flooded
by a dazzling light. All his agitation,
doubts and worries, seemed composed in a
twinkling, culminating in a great calm,
full of understanding...but these moments,
these glimmerings were still but a
premonition of that final second (never
more than a second) with which the seizure
itself began. That second was, of course,
unbearable.'

3. Learning ObjectivesLearning Objectives
• Discuss the Blumcke classification of medial
temporal lobe sclerosis, relating
histopathologic features to surgical outcomes
• Discuss the Palmini classification of cortical
dysplasia, relating histopathologic features to
surgical outcomes
• Define “dual pathology” in temporal lobe
epilepsy, and the relative contribution of
hippocampal and neocortical lesions
• List two additional neuropathologic lesions
which commonly present with epilepsy

4. Pathology of TLEPathology of TLE
5%No Pathology
5%Dual Pathology
25%Focal lesions
65%
Ammon’s Horn
Sclerosis
Blumcke I, Thom M, Wiestler OD. Ammon's horn sclerosis:
a maldevelopmental disorder associated with temporal lobe
epilepsy. Brain Pathol. 2002 Apr;12(2):199-211

7. Wyler grading of HS (1992)Wyler grading of HS (1992)
>50% neuronal loss involving
all hippocampal sectorsGrade 4
>50% neuronal loss CA1, CA3,
and/or CA4; CA2 sparedGrade 3
10-50% neuronal loss in
CA1, CA3, and/or CA4Grade 2
0-10% neuronal loss in CA1,
CA3, and/or CA4Grade 1
AR Wyler, FC Dohan, JB Schweitzer, AD Berry
A grading system for mesial temporal pathology (hippocampal
sclerosis) from anterior temporal lobectomy - J Epilepsy, 1992

10. Blumcke I, et. Al. A new clinico-pathological classification system
for mesial temporal sclerosis.
Acta Neuropathol (Berl). 2007 Mar;113(3):235-244.

11. Blumcke I, et. Al. A new clinico-pathological classification
system for mesial temporal sclerosis.
Acta Neuropathol (Berl). 2007 Mar;113(3):235-244.

13. Blumke classification of MTSBlumke classification of MTS
CA1 preserved, moderate loss in
other sectors (endfolium sclerosis)
MTS type 3 (5%)
Severe CA1 loss, mild loss in
other sectors (CA1-sclerosis)
MTS type 2 (5%)
Severe neuronal loss involving
all sectors (= Wyler grade 4)MTS 1b (50%)
“Classic” – severe CA1 loss,
moderate loss in other sectorsMTS 1a (20%)
Neuronal cell loss within 1st
SD compared to controls
No MTS (20%)
A new clinico-pathological classification system for mesial
temporal sclerosis.
Acta Neuropathol (Berl). 2007 Mar;113(3):235-244.

14. Blumcke type
MTS
Age of initial
precipitating injury
or first seizure
(years)
Excellent outcome
at 1 year post
surgery (%)
Fair outcome at 1
year post surgery
(%)
No MTS 16 60 20
MTS type 1a 2 70 10
MTS type 1b 3 70 10
MTS type 2 6 70 10
MTS type 3 13 30 40

15. Generalized malformations of cortical developmentGeneralized malformations of cortical development
sporadicHME
SPPX2,sporadicPolymicrogyria
Filamin 1FLN 1
PV nodular
heterotopia
DoublecortinDCX
Laminar
heterotopia
PAF-acetylhydrolase
Doublecortin
Reelin
LIS1
DCX(XLIS)
RLN
Lissencephalies
ProteinGenesMalformation
Guerrini R, Dobyns WB, Barkovich AJ. Abnormal development of the
human cerebral cortex: genetics, functional consequences and
treatment options. Trends Neurosci. 2008 Mar;31(3):154-62.

16. Type of cortical
dysplasia
Age at onset of
seizures (years)
Age at surgery (years)
Hemispheric (with
hemimegalencephaly)
0.1 1
Hemispheric (without
hemimegalencephaly)
0.8 3.5
Multilobar 0.7 4.5
Lobar 1.2 5
Focal 1.7 7.5
Cepeda C, et. Al. Epileptogenesis in pediatric cortical dysplasia:
the dysmature cerebral developmental hypothesis.
Epilepsy Behav. 2006 Sep;9(2):219-35

17. MCD pathology by MRI typeMCD pathology by MRI type
00153055
Immature
neurons
8035452045Balloon cells
10253555100
Layer I
neurons
1025806580PMG
7040703590
Cytomegalic
neurons
100909010090
Dysmorphic
neurons
100100100100100WM neurons
FocalLobarMultilobarHemi CDHMEPath (%)

18. Palmini classification
Mild Malformations ofMild Malformations of
Cortical DevelopmentCortical Development
Type I: Ectopic neuronsType I: Ectopic neurons
in/near Layer 1in/near Layer 1
Type 2: NeuronalType 2: Neuronal
heterotopia outside Layer 1heterotopia outside Layer 1
Focal CorticalFocal Cortical
DysplasiasDysplasias
Type IA: Dyslamination +/-Type IA: Dyslamination +/-
mild MCDmild MCD
Type IB: IA + giant orType IB: IA + giant or
immature neuronsimmature neurons
Type IIA: DysmorphicType IIA: Dysmorphic
neuronsneurons sanssans balloon cellsballoon cells
Type IIB: DysmorphicType IIB: Dysmorphic
neuronsneurons avecavec balloon cellsballoon cells
Palmini A, Najm I, Avanzini G, Babb T, Guerrini R, Foldvary-Schaefer N, Jackson G,
Luders HO, Prayson R, Spreafico R, Vinters HV. Terminology and classification of the
cortical dysplasias. Neurology. 2004 Mar 23;62(6 Suppl 3):S2-8

23. • •

24. Dual Pathology: HS + FCDDual Pathology: HS + FCD
• 12 male patients12 male patients
– Age of onset 10 years (<1 – 29)Age of onset 10 years (<1 – 29)
– Age at invasive EEG 30 years (6 – 50)Age at invasive EEG 30 years (6 – 50)
• 113 seizures + interictal data from113 seizures + interictal data from
depth electrodes in HC & subduraldepth electrodes in HC & subdural
electrodes over temporal neocortexelectrodes over temporal neocortex
• 40% of seizures from AHC, 35% from40% of seizures from AHC, 35% from
TN, and 25% from bothTN, and 25% from both
Fauser S, Schulze-Bonhage A. Epileptogenicity of cortical dysplasia in temporal
lobe dual pathology: an electrophysiological study with invasive recordings.
Brain. 2006 Jan;129(Pt 1):82-95

28. Pathologic diagnosis % of cases
Cortical dysplasia (including
Tuberous Sclerosis)
20
Vascular malformations (including
Sturge-Weber disease)
20
Glioneuronal tumors 20
Other gliomas 10
Gliosis 30
52 patients with occipital lobe epilepsy
Binder DK, Von Lehe M, Kral T, Bien CG, Urbach H, Schramm J, Clusmann H.
Surgical treatment of occipital lobe epilepsy.
J Neurosurg. 2008 Jul;109(1):57-69.

31. Rasmussen syndromeRasmussen syndrome
• 45 patients (27F, 18M)45 patients (27F, 18M)
• Age at onset: 7 +/- 3 yearsAge at onset: 7 +/- 3 years
• Age at hemispherectomy: 9.5 +/- 4 yearsAge at hemispherectomy: 9.5 +/- 4 years
• Duration of symptoms: 0.5 – 14 yearsDuration of symptoms: 0.5 – 14 years
Pardo CA, Vining EP, Guo L, Skolasky RL, Carson BS, Freeman JM. The
pathology of Rasmussen syndrome: stages of cortical involvement and
neuropathological studies in 45 hemispherectomies.
Epilepsia. 2004 May;45(5):516-26.

33. RS: Pathologic stagingRS: Pathologic staging
Pan-laminar cavitation &/or gliosis4
Pan-laminar degeneration & gliosis3
Pan-laminar inflammation & gliosis2
Mild focal inflammation1
Normal cortex0

34. Learning ObjectivesLearning Objectives
• Discuss the Blumcke classification of medial
temporal lobe sclerosis, relating
histopathologic features to surgical outcomes
• Discuss the Palmini classification of cortical
dysplasia, relating histopathologic features to
surgical outcomes
• Define “dual pathology” in temporal lobe
epilepsy, and the relative contribution of
hippocampal and neocortical lesions
• List two additional neuropathologic lesions
which commonly present with epilepsy

35. " For several instants I experience a" For several instants I experience a
happiness that is impossible in an ordinaryhappiness that is impossible in an ordinary
state, and of which other people have nostate, and of which other people have no
conception. I feel full harmony in myselfconception. I feel full harmony in myself
and in the whole world, and the feeling isand in the whole world, and the feeling is
so strong and sweet that for a few secondsso strong and sweet that for a few seconds
of such bliss one could give up ten yearsof such bliss one could give up ten years
of life, perhaps all of life.of life, perhaps all of life.
I felt that heaven descended to earth andI felt that heaven descended to earth and
swallowed me. I really attained god andswallowed me. I really attained god and
was imbued with him. All of you healthywas imbued with him. All of you healthy
people don't even suspect what happinesspeople don't even suspect what happiness
is , that happiness that we epilepticsis , that happiness that we epileptics
experience for a second before an attack."experience for a second before an attack."