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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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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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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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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Simple Partial

Complex Partial


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Stereotyped elemental behaviors

Usually occur during impaired

consciousness in complex partial

seizures


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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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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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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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i l l S l i


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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

Seizure Patho Physiology

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