Surgical Pathology of Epilepsy

Mark CohenMark Cohen

Department of PathologyDepartment of Pathology

August 28August 28thth, 2008, 2008

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'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.'

Lecture Outline

Ammon’s Horn/Hippocampal/MTL Ammon’s Horn/Hippocampal/MTL sclerosissclerosis

Malformations of cortical developmentMalformations of cortical development– Classification & subclassification (Palmini)Classification & subclassification (Palmini)– Pathology of extratemporal epilepsyPathology of extratemporal epilepsy

Dual Pathology in TLEDual Pathology in TLE Other epileptogenic lesions Other epileptogenic lesions

(Ganglioglioma, DNT, Rassmussen (Ganglioglioma, DNT, Rassmussen encephalitis)encephalitis)

Pathology 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

Control hippocampus Hippocampal sclerosis

Control hippocampus Hippocampal

sclerosis

CA2CA2

CA1CA1

SubiculumSubiculum

CA3/4CA3/4

Wyler grading of HS (1992)

>50% neuronal loss involving all hippocampal sectors

Grade 4

>50% neuronal loss CA1, CA3, and/or CA4; CA2 spared

Grade 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

Control CA1 Control CA1 (x20)(x20)

Hippocampal sclerosisHippocampal sclerosis

CA1 x4CA1 x4

CA1 x20CA1 x20

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

++0/+3

++++2

++++++1b

+++++1a

CA2-4 lossCA1 lossBlumcke type

MTS: New classification

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 sectors

MTS 1a (20%)

Neuronal cell loss within 1st SD compared to controls

No MTS (20%)

Blumcke I, et. Al. A new clinico-pathological classification system

for mesial temporal sclerosis. Acta Neuropathol (Berl). 2007 Mar;113(3):235-244.

Surgical outcomes at 1 year

15401530MTS type 3

10101065MTS type 2

152070MTS type 1b

5101070MTS type 1a

10201060No MTS

Engle 4Engle 3Engle 2Engle 1Score (%)

Generalized malformations of cortical development

sporadicHME

SRPX2, sporadicPolymicrogyria

Filamin 1FLNAPV nodular heterotopia

DoublecortinDCXLaminar heterotopia

PAF-acetylhydrolaseDoublecortinReelin

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.

Cepeda C, et. Al. Epileptogenesis in pediatric cortical dysplasia: the dysmature cerebral developmental

hypothesis. Epilepsy Behav. 2006 Sep;9(2):219-35

MCD pathology by MRI type

00153055Immature neurons

8035452045Balloon cells

10253555100Layer I neurons

1025806580PMG

7040703590Cytomegalic neurons

100909010090Dysmorphic neurons

100100100100100WM neurons

FocalLobarMultilobarHemi CDHMEPath (%)

Cortical dysplasias (Palmini)

Mild MCDMild MCD– Type I: Ectopic neurons in/near Layer 1Type I: Ectopic neurons in/near Layer 1– Type 2: Neuronal heterotopia outside Layer 1Type 2: Neuronal heterotopia outside Layer 1

Focal Cortical DysplasiasFocal Cortical Dysplasias– Type IA: Dyslamination +/- mild MCDType IA: Dyslamination +/- mild MCD– Type IB: above + giant or immature neuronsType IB: above + giant or immature neurons– Type IIA: Dysmorphic neurons Type IIA: Dysmorphic neurons sanssans balloon balloon

cellscells– Type IIB: Dysmorphic neurons Type IIB: Dysmorphic neurons avecavec balloon balloon

cellscellsPalmini 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

FCD IA

FCD IB

FCD IIA

FCD IIB

Relevance of Balloon cells

CCFUCLA

Pediatric FCD subtypes

Type I Perinatal risk factors

more frequent Lobar

hypoplasia/atrophy common

AHS more frequent Worse outcome

(trend)

Type II More localized ictal

patterns & MRI changes Increased cortical

thickness, abnormal gyral/sulcal patterns, gray/white junction blurring, gray matter signal abnormalities on FLAIR more common

Better outcome (trend)Krsek P, et al. Different features of histopathological subtypes of

pediatric focal cortical dysplasia. Ann Neurol. 2008 Jun;63(6):758-69.

Extratemporal FCD at CCF

Present in 52/135 resections = ~40%Present in 52/135 resections = ~40% Male: Female = 1.0Male: Female = 1.0 Mean age at surgery 15 years (<1 – Mean age at surgery 15 years (<1 –

44 yrs)44 yrs) Mean seizure duration ~10 yearsMean seizure duration ~10 years

Prayson RA, Frater JL. Cortical dysplasia in extratemporal lobe intractable

epilepsy: A study of 52 cases.

Ann Diagn Pathol. 2003 Jun;7(3):139-46

Extratemporal FCD at CCF

10%Coexistent Tumor

10%Coexistent Ischemia

40%Dysmorphic neurons/Balloon cells

60%Increased Layer 1 Neurons

60%Neuronal Cytomegaly

90%Architectural Disorganization

Extratemporal FCD at CCFExtratemporal FCD at CCF

505035%IIB

NANA0IIA

109025%IB

109040%IA

% Worse% BetterPrevalencePalmini

Fauser S, et. al. Factors influencing surgical outcome in patients with focal cortical dysplasia. J Neurol Neurosurg

Psychiatry. 2008 Jan;79(1):103-5

A total of 120 patients with histologically proven focal cortical dysplasias (FCD) were retrospectively analysed for prognostic factors for successful epilepsy surgery. Multivariate data analyses showed that older age at epilepsy surgery, occurrence of secondarily generalised seizures and a multilobar extent of the dysplasia were significant negative predictors. In univariate analyses, longer duration of epilepsy, need for intracranial EEG recordings and incomplete resection of the FCD were factors which significantly reduced the chance of becoming seizure free. Histological subtype of the FCD and age at epilepsy onset had no significant predictive value. These findings strongly suggest early consideration of epilepsy surgery in FCD patients.

Palmini grading: A personal viewPalmini grading: A personal view

IIA IIB

IA IB

Dual 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 from 113 seizures + interictal data from depth electrodes in HC & subdural depth electrodes in HC & subdural electrodes over temporal neocortexelectrodes over temporal neocortex

40% of seizures from AHC, 35% from 40% 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

Dual Pathology: HS + FCD

Quantitative contribution of HC Quantitative contribution of HC correlated strongly with Wyler grade correlated strongly with Wyler grade of HSof HS

FCD subtypes did not affect relative FCD subtypes did not affect relative contribution to ictal activity contribution to ictal activity (including even mMCD)(including even mMCD)

FCD interictal patterns similar to FCD interictal patterns similar to those of extratemporal FCDs those of extratemporal FCDs

What else causes epilepsy?What else causes epilepsy?

Khalsa SS, Moore SA, Van Hoesen GW. Hughlings Jackson and the role of the entorhinal cortex in temporal lobe epilepsy: from patient A to

Doctor Z. Epilepsy Behav. 2006 Nov;9(3):524-31

52 patients with occipital lobe epilepsy

Histopathologic diagnosis

% of cases

FCD (including TS) 20

Glioneuronal tumors 20

Other gliomas 10

Vascular malformations

(including SWD)

20

Gliosis 30Binder 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.

Dysembryoplastic Neuroepithelial Tumor

Ganglioglioma

Rasmussen 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 Age at hemispherectomy 9.5 +/- 4

yearsyears 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.

RS: Pathologic staging

Pan-laminar cavitation &/or gliosis4

Pan-laminar degeneration & gliosis3

Pan-laminar inflammation & gliosis2

Mild focal inflammation1

Normal cortex0

" For several instants I experience a " For several instants I experience a happiness that is impossible in an ordinary happiness that is impossible in an ordinary state, and of which other people have no state, and of which other people have no conception.  I feel full harmony in myself conception.  I feel full harmony in myself and in the whole world, and the feeling is and in the whole world, and the feeling is so strong and sweet that for a few seconds so strong and sweet that for a few seconds of such bliss one could give up ten years of of such bliss one could give up ten years of life, perhaps all of life.life, perhaps all of life.

I felt that heaven descended to earth and I felt that heaven descended to earth and swallowed me.  I really attained god and swallowed me.  I really attained god and was imbued with him.  All of you healthy was imbued with him.  All of you healthy people don't even suspect  what happiness people don't even suspect  what happiness is , that happiness that we epileptics is , that happiness that we epileptics experience for a second before an attack."experience for a second before an attack."