seizure patho physiology
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SEIZURES AND EPILEPSY
David Spencer MDSchool of Pharmacy 2008
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Outline Definitions and e idemiolo
Etiology/pathology
Patho h siolo :
Brief overview of molecular and
cellular basis of epileptogenesis
Evaluation of the patient with
seizures
Seizure types
Epilepsy syndromes
Treatment principles
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Definitions
Seizure: paroxysmal episode ofneurolo ical d sfunction caused b
excessive electrical discharge of CNS
neurons
unprovoked seizures
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nc ence
10% will have a seizure in their lifetime
1% will have epilepsy
, , - , ,
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Etiology: The Elderly
Ramsay et al Neurology. 2004 Mar 9;62(5 Suppl 2):S24-9
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Acquired vs. Genetic Etiologies
Acquired Head trauma
Genetic 200 single gene defects
CNS infections
Stroke
(1% of epilepsy)
Polygenic (Complex Tumors
Vascular malformations
contribute to ~40% of
epilepsy)
diseases
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Genetic Causes of Epilepsy
Gene defects affecting neuronal excitability Ion channel defects
Genes encoding development
Neuronal mi rational disorders
Genes encoding cerebral energy metabolism
Mitochondrial disorders
Genetic Neurodegenerative disorders
Pro ressive m oclonic e ile sies
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Hyperexcitability
Intrinsic membrane properties of neurons
Changes in neural networks
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Hyperexcitability
Intrinsic membrane propertiesof neurons
Changes in ion channels
Number of channels a ng proper es
Voltage dependency
Extrinsic Factors
Concentration of ions
Clearing of ions,
extracellular space
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anne opa es
Generalized epilepsy with
K+ Channel Benign Familial Neonatal
Convulsions
a++ anne Absence epilepsy
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Mechanisms of Epileptogenesis
Hyperexcitability
at o o n tory toexcitatory synapses
transmission (GABA)
Increase in excitatory
(Glutamate)
Complex interactions
Changes inconnectivity
lasticit
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GABA receptor
GABA site
Benzodiazepine
site
Steroid site
Dia ram of the GABA rece tor
From Olsen and Sapp, 1995
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.Epileptogenesis
Acute process initiating a seizure
a , , a , , u ama e
Chronic process converting normal brainnto ep ept c ra n
Changes in gene expression
Changes in receptors, transporters, ion channels Plasticity
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Increased Excitation
Kainic Acid (parenteral or intracerebral)
Causes prolonged seizures/status epilepticus
Model of human temporal lobe epilepsy
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Decreased Inhibition
Pentylenetetrazol (PTZ)
GABA antagonist
Model of absence epilepsy
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Electrical Stimulation
Kindling Repeated subthreshold focal electrical (or chemical)
stimulation of hippocampus or amygdala
Initial applications produce afterdischarges
ncreas ng sever y o c n ca se zures
Spontaneous seizures
Model of Generalized Tonic-Clonic seizures
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Animal Models of Epilepsy
Application of other topical agents Penicillin
Aluminum
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Limitations for Drug Development
Simple acute seizure models show responseof a health not chronicall e ile tic brain
to AEDs
No good models for several seizure types
e ance on ew mo e s pro uces me toodrugs
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Evaluation of the
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Does the Patient Have Epilepsy?
Syncope
Migraine
eep sor er
Psychogenic event
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Description of the Typical Attack
Is there a warning (aura)?
What is the patient like after a typical
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Assess Historical Risk Factors
Birth and developmental history
Acquired brain insults (CNS infection, head
,
Family history of seizures
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Provocative Factors
Sleep deprivation
Physical/emotional stress
ntercurrent ness
Alcohol/drugs
Specific Triggers
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y y
Examinations
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The Laboratory Examination
Serum and urine studies
Ictal
Neuroimaging
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The Laboratory Examination
Serum and urine studies
Ictal
Neuroimaging
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Serum and Urine Studies
Serum Chemistries Na+
Ca2+
Glucose Toxicology Screen
Antie ile tic dru levels
CBC
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The Laboratory Examination
Serum and urine studies
Ictal
Neuroimaging
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Focal Epileptiform Discharge
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EEG: Simple Partial Seizure
Right temporal
seizure
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EEG: Simple Partial Seizure
Continuation ofsame seizure
Right temporal
seizures with
reversal in the
right sphenoidal
electrodes
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Discharge: Absence Seizure
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The Laboratory Examination
Serum and urine studies
Ictal
Neuroimaging
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Cort ca Dysp as a per sy v an)
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CT vs. MRI
70
80
50
60
%
30
40 CT
MRI
Abnormal
10
McLach. Latock Schorner Jabbri Heinz
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Studies
PET
Magnetic Resonance Spectroscopy
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Subtraction Ictal-Interictal SPECT
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Classification of Seizures
Partial Seizures Generalized Seizures
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Types of Seizures: Partial
Simple Partial
Complex Partial
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Simple Partial Seizures (Aura)
Motor
Clonic, Versive, Dystonic
Sensory
Somatosensory, Visual, Auditory, Olfactory, Gustatory
Epigastric rising, Sweating, Flushing, Piloerection,Pupillary Dilatation
Psychic Fear, Dj vu, Jamais vu
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Types of Seizures: Partial
Simple Partial
Complex Partial
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Stereotyped elemental behaviors
Usually occur during impaired
consciousness in complex partial
seizures
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Types of Seizures: Partial
Simple Partial
Complex Partial
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Post-ictal Changes
Transient
generalized tonic-clonic seizures.
,
Todds paralysis transient, post-
cta , oca neuro og ca e c t
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Seizure Types: Generalized
Absence
Generalized Tonic-Clonic
Myoclonic
Tonic Atonic
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Seizure T es
Epilepsy Syndromes
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S i T E il ti S d
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Seizure T e vs. E ile tic S ndrome
A group of signs and symptoms that occur together
and characterize a particular abnormality
se z re ype behavior and EEG pattern during the ictal event.
Seizure type(s)
HistoryEEG (ictal and interictal)
Etiology-Genetics
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Focal-
Generalized
opa c
(Genetic)
Symptomaticor Cryptogenic
es ona
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Epilepsy Syndrome: Example
Symptomatic Localization-related Epilepsy
Onset in early teens
Focal onset seizures
Focal right temporal EEG sharp waves MRI shows right hippocampal sclerosis
Prognosis
Usually refractory to medications Epilepsy surgery is curative in up to 80-90%
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FocalGeneralized
oca za on-re a e
opa c
(Genetic)
Symptomatic(Cryptogenic)
Mesial Temporal
Sclerosis
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Epilepsy Syndrome: Example
Idiopathic Generalized Epilepsy
Onset at puberty X Mix of generalized seizures
Generalized spike/wave on EEG
ormal intellect and neurological exam
Normal MRI
rea men an rognos s
Responds well to monotherapy (VPA or LTG)
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Focal-
Generalized
opa c
(Genetic) Juvenile
MyoclonicEpilepsy
Symptomatic(Cryptogenic)
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Onset in teenage years . .
Generalized tonic-clonic seizures
sence n -
Normal intellect
Family history in ~ 50%
An idiopathic generalized epilepsy syndrome
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Epilepsy Syndrome: Example
Symptomatic Generalized Epilepsy
Onset on childhood
Mix of generalized seizures
Impaired intellect X
Abnormal MRI (multifocal or diffuse abnormality)
Generalized slow spike-wave on EEG
rognos s
Poor: usually refractory to many medications
-
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FocalGeneralized
oca za on-re a e
opa c
(Genetic)
Symptomatic(Cryptogenic) Lennox-Gastaut
Syn rome
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Treatment
Avoid seizure triggers Slee de rivation
Alcohol
Medications
urgery
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Unmasking Photosensitivity
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Individualize Decision!
Estimate risk of recurrence
Overall, 16-62% will recur within 5 years
Abnormal imaging, abnormal neurological exam,abnormal EEG or family history increases relapse risk
Driving?
Working?nd
Reference: First Seizure Trial Group. Randomized Clinical Trial on the efficacy of
antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-
c on c se zure. euro ogy ; , par : - . e erence: am e ,
Camfield C, Dooley J, Smith E, Garner B. A randomized study of carbamazepine
versus no medication after a first unprovoked seizure in childhood. Neurology
1989; 39: 851-852.
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37%
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TREATMENT GOAL
Com lete seizure control
No side effects
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Antiepileptic Drug Choice
Adverse effects Individual circumstances
PharmacokineticsCost Drug Interactions
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Case
17 year old boy with history of headaches
dia nosed with seudotumor cerebri
Headaches resolved
Developed frequent seizures with unusual
escr pt on
Non-Epileptic Seizures
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Seizures
-
Physiologic Psychogenic
- 90%10% -
SyncopeMovement Disorders
Hypoglycemia
ConversionSomatization
DissociativeParasomnias... Factitious...
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Pseudoepilepsy
Pseudoseizures
-
Hysterical seizures Psychogenic seizures
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-Events
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Non-epileptic seizures
Video-telemetry monitoring is the gold
standard for dia nosis
Proves the diagnosis
clear-cut laboratory documentation
.
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Non-epileptic Seizures
Feature Frontal Lobe Non-Epileptic
Arises from sleep ++ -
Brief duration ++ -
Hypermotor activity ++ ++
Postictal confusion +/- +/-
Clustering pattern + +
ssoc a e n ur es
Stereotyped ++ -
-
EEG Change +/- -
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Types of Epilepsy Surgery
Focal Resection Corpus Callosotomy Vagus Nerve Stimulation
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Medically Refractory Seizures
E ile s Sur er ?MRIPET
Video EEGWada Test
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Epilepsy Syndromes
Mesial Temporal Sclerosis
80-90% seizure-free
Other Symptomatic Partial Epilepsies
Without discrete lesion
em sp er c sor ers n ren
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Refractory Epilepsy
26-year-old with complex partial seizures
and secondaril GTC seizures for 8 ears
History of prolonged febrile convulsion
combination trials of antiepileptic meds
: r g t mes a tempora sc eros s
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Mesial Temporal Sclerosis
i l l S l i
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Mesial Temporal Sclerosis
Anterior Temporal Lobectomy
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Selective
A d l hi
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Amygdalohippocampectomy
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A t i T l L b t
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Anterior Temporal Lobectomy
K t i Di t
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Ketogenic Diet
Main experience with children, especially
with multiple seizure types
Anti-seizure effect of ketosis (beta
Low carbohydrate, low protein, high fat
Long-term adverse effects unknown
V l N Sti l ti
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Vagal Nerve Stimulation
Approved for the treatment of refractory
artial seizures in atients over 12 ears old
Palliative
, > 40,000 patients to date
V l N Sti l t
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Vagal Nerve Stimulator
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The Future?
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The Future?
Summary
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Summary
Definitions and epidemiology
Pathophysiology:
va uat on o t e pat ent w t se zures
Seizure types
Epilepsy syndromes