Epilepsy and SeizuresPart 1: Pathophysiology and Classification of Seizure Types

Jacquelyne S. Cios, MD MSAssistant Professor

Department of Neurology, Division of Epilepsy

Jacquelyne.Cios@osumc.edu

“It is thus with regard to the disease called Sacred: it appears to me to be nowise more divine nor more sacred than other

diseases, but has a natural cause like other affections.”

- Hippocrates, 400 BC

Learning Objectives

Be able to define epilepsy and determine which seizure patients can be diagnosed with epilepsy.

Understand what is a seizure, and be familiar with mechanisms of seizure pathophysiology.

Understand that the classification of epilepsy is by etiology and by localization, and if applicable, by syndrome.

Part 1: Outline

History and epidemiology What is a seizure?

Definition Pathophysiology

International League Against Epilepsy (ILAE) Classification of seizures

2 common syndromes- clinical presentation and electrodiagnostic characterization Mesial temporal lobe epilepsy Childhood absence epilepsy

Quiz - 01 Seizures and Epilepsy

What is epilepsy?

Epilepsy definition Recurrent unprovoked seizures Excludes insulin reactions, alcohol withdrawal etc. Results in

Increased rates of morbidity / mortality Increased rates of cognitive impairment Increased rates of psychosocial dysfunction

Epilepsy since the 1800s

Modern concept of etiopathogenesis: Focus of irritation in brain, John Hughlings Jackson, 1873

Electrical excitability of brain confirmed in animal and human brain by Ferrier, Fritz, Hitzig

Electroencephalography (EEG) developed by Hans Berger, 1920s Helped to localize site of seizure discharged

Treatments Potassium bromides, late 1800s Phenobarbitone, 1912 Phenytoin, 1938

However, stigma continues to the present day

Epidemiology

WHO data: 50 million people worldwide 90% of the affected patients found in developing

countries Prevalence in US: 3 million people or about 1%

But lifetime risk for a single seizure 10% $17.6 Billion/yr in direct and indirect medical cost

Incidence: 300,000 per year Caveat: approx 1/3 of these are children under 5 with febrile

seizures Majority of patients with febrile seizure do not go on to have

epilepsy in adulthood (prevalence all comers, 6%, Annegers et al., 1979)

Incidence of Epilepsy

Quiz - 02 Seizures and Epilepsy

What is a seizure?

Abnormal, hypersynchronous electrical discharge from a focus of hyperexcitable cortical neurons which spreads to contiguous neurons Cortical functions represented by area of spread determine manifestations of

seizure Motor Sensory Oroalimentary Visual and auditory Autonomic Perceptive

Déjà vu Derealization and depersonalization

Seizure triggers: sleep deprivation, stress, menstrual cycle, fever, metabolic derangement, photic stimulation, hyperventilation, drugs, medication non-compliance A small population may have “reflex epilepsy” with triggers such as music or reading

Mechanism

Neuronal injury causes a variety of intracellular changes Neurodegeneration and neurogenesis Axonal sprouting and axonal injury Gliosis Inflammation Angiogenesis Altered extracellular matrix Acquired channelopathies

How might these changes lead to epileptogenesis?

Balance between EPSP and IPSP

Glutamate and its analogues are the principal excitatory neurotransmitters AMPA and NMDA subtypes are found in hippocampus, each

linked to groups of ion channels Patients with epilepsy may have different receptor sensitivity to

each of these neurotransmitters EPSPs may be increased in this population in both amplitude and

duration

The EPSPs generated must surpass a certain threshold for generation of an epileptic seizure Excess hypersynchronous activity spread to a neuronal network

creates a seizure

(Isokawa et al. 1991; Masukawa et al. 1991; Urban et al. 1990;Williamson and Spencer 1995)

Seizure pathophysiology Seizures are characterized by

repetitive burst firing of a group of cortical neurons

Loss of GABA-mediated inhibition of dentate granule cells (of the hippocampus) has been demonstrated in vivo

Contributes to the abnormal firing or spread of it through recruitment of neighboring cells

Goddard et al proposed the theory of kindling in 1967

GABAergic basket cells (inhibitory neurons)

_Granule cells

(repetitive burst firing)

_Mossy cell

death (excitatory neurons)

_

Cellular changes in epilepsy

Pitkanen et al. Epilepsy and behavior 2009

Acquired Channelopathies

Acquired channelopathies can lead to epilepsy Can occur in dendrite, axon, or perisomatic region Can lead to anormal cell-cell transmission, resulting in abnormal

eletrical conduction

Pitkanen et al. Epilepsy and behavior 2009

Role of the Immune System

The role of the immune system has been implicated in pathophysiology

Immune cells mediate the breakdown of the blood-brain barrier Maintains ionic and metabolic homeostasis Excludes circulating cells Facilitates the passage of glucose

Ransohoff et al. Nature 457, 155-156 (8 January 2009) 

Immune mechanisms of epileptogenesis

Injection of pilocarpine, used to create animal models of epilepsy, causes WBC adhesion to endothelial cells Causes leakage of BBB K+ ions and other molecules enter brain (pilocarpine itself crosses the BBB)

CD8+ T cells can recognize pre-infected stromal cells in subarachnoid space (SAS) They attract myeloid cells into the SAS which secrete cytokines Cytokines promote further breakdown of the BBB

Fabene et al, 2008; Kim et al, 2009

Quiz - 03 Seizures and Epilepsy

Terminology

Epilepsy - tendency to recurrent unprovoked seizures Classification of epilepsy

Idiopathic vs. cryptogenic vs. symptomatic epilepsy Partial vs. generalized epilepsy

Both include inherited epilepsy syndromes with known genetics Simple vs. complex seizures

Classification scheme: by etiology

Idiopathic Hereditary tendency May have complex genetics at play Usually generalized epilepsy “Lesion” may be widespread, ie, a channelopathy

Symptomatic Cause is known A focal area of dysplasia d/t a known injury or developmental

anomaly Can be congenital or acquired

Cryptogenic Unknown cause, cause not identified by imaging and/or EEG Frequently normal cognition, normal imaging and interictal EEG

idiopathic symptomatic cryptogenic

EEG Normal or with generalized discharges

Abnormal, usually focal slowing and/ or seizure discharge

Focal discharges or normal

imaging Normal Abnormal, a focus of structural defect or anomaly

Normal

example Patient with no history of head injury or seizures, w/ onset of myoclonic jerks and GTC in early adulthood

Patient with head injury and area of focal scarring or atrophy, w/ seizure origin from that area

Patient with no h/o head injury or other risk factor for sz, but p/w first sz in adulthood

CPS = complex partial seizures

Pitkanen et. al.

Classification scheme: by localization

This is the basis for the International League of Epilepsy classification scheme

Partial Starts in one focal part of the brain Simple

Awareness not impaired Complex

Awareness Impaired Generalized

Primary Absence epilepsy, Juvenile Myoclonic Epilepsy, Lennox Gastaut

Secondarily Generalized Wide anatomical spread of partial seizure

Quiz - 04 Seizures and Epilepsy

Generalized seizure semiology

Generalized Seizures Myoclonic seizure

Brief “lightening like” jerk Absence Seizure

Behavioral arrest with “re-animation” Eye-blinking or staring No post-ictal period

Atonic Seizure Abrupt loss of body tone “head drops or body drops” Wear a helmet and possibly even mouthpiece

Generalized Seizures (cont) Generalized tonic-clonic seizure

Tonic phase Whole body stiffening Vertebral compression fractures Anterior shoulder dislocation Hip dislocation Expel air from lungs against closed glottis “epileptic cry”

Clonic Rhythmic synchronous muscle contraction relaxation cycles

Severe post-ictal period

Prevalance of Seizure Types

In the adult population, the prevalence of seizure types is: Complex partial seizures - 40%  Simple partial seizures - 20% Primary generalized tonic-clonic seizures - 20% Absence seizures - 10% Other seizure types - 10%

Atonic Myoclonic Tonic

ILAE Classification

Axis I – Ictal phenomenology Axis II – Seizure type Axis III – Syndrome Axis IV – Etiology Axis V – Impairment

A few syndromes with single gene etiologyClinical features inheritance Gene affected

GEFS+ (idiopathic) Generalized tonic-clonic seizures (GTC)Febrile seizures

AD with incomplete penetrance

Voltage gated Na channel SCN 1A and SCN1B

Severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome)(idiopathic)

Febrile seizures with onset < 1 yr old, myoclonic, absence, hemiconvulsive and GTC, progressive cognitive deficit

Same as above Same as above

Tuberous sclerosis(symptomatic)

Cortical tubers and giant cell astrocytomas, cutaneous signs

AD TSC1 and TSC2; integrate signaling pathways used in protein synthesis

Autodomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (idiopathic)

Nocturnal frontal lobe seizures with onset around 10 yo

AD with incomplete penetrance

Nicotinic Ach receptor,CHRNA4, CHRNB2

Lennox- Gastaut syndrome

Some epilepsy syndromes are described by their clinico-electrographic features

Does not imply the etiology or localization Could be acquired, symptomatic

Perinatal or early childhood injury, infection or hypoxia Could have inherited origin

Developmental anomaly Inherited degenerative or metabolic condition

Lennox Gastaut syndrome is an example Cognitive delay Multiple seizure types (both partial and primary generalized) EEG pattern of slow spike and wave

Quiz - 05 Seizures and Epilepsy

Thank you for completing this module

Questions? Contact me at:

Jacquelyne.Cios@osumc.edu

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