epilepsy and seizures part 1: pathophysiology and classification of seizure types jacquelyne s....
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Epilepsy and SeizuresPart 1: Pathophysiology and Classification of Seizure Types
Jacquelyne S. Cios, MD MSAssistant Professor
Department of Neurology, Division of Epilepsy
“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
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