The Management of Seizure Disorders

Prevalence of Seizure Disorders

General US Population:
8% of Americans will experience at least 1 seizure in their lifetime

Recurrence Rates:
23-80% will have a recurrence within 5 yrs

Bimodal distribution
peak onset at newborn-younger age groups, then again in patients > 65

What is the difference between convulsions and seizures?

Convulsion
forceful involuntary contraction or spasm of voluntary muscles the physical manifestation of a seizure in the brain

Seizure
uncontrolled, synchronized electrical discharge of neurons within the brain which interferes with normal function

Epilepsy
chronic disorder diagnosed after 2 or more seizure episodes characterized by paroxysmal, transient disturbances of brain function

Seizure Manifestations
Abnormal firing is the result of changes occurring within these cells:
increased excitability
decreased inhibitory processes interference with normal metabolic processes propagation of abnormal firing along pathways

Kindling Theory

The kindling hypothesis in epileptogenesis. Adapted from Lynch MW et al. Curr Opin Neurol. 1996;9:97-102.

Mechanism of Seizure Spread

Ion channel problems

Decreased inhibition
Reduction in excitation Alteration in extracellular potassium/calcium

Ion Channel Problems

Alteration in neuronal membrane function due to changes in voltage-regulated ion channels in neuronal membranes Lead to excess depolarization or excess action potential firing AEDs may reduce repetitive firing of neurons by producing a use-dependent blockade of sodium channels
carbamazepine, phenytoin, lamotrigine

These allow normal frequency of nerve firing and inhibit abnormally fast rates of discharge by increasing time the inactiviation gate of the sodium channel is closed

Decreased Inhibition
Allows excessive neuronal firing to occur thus acting as a site for genesis and spread of discharge GABA - major inhibitory neurotransmitter in the forebrain GABA opens receptor-operated chloride channels that lead to hyperpolarization and make epileptic firing less likely BDZs, barbiturates, valproic acid

Reducing Excitation
Excitatory neurotransmission is mediated through glutamate or related compounds

NMDA receptor is predominantly involved in high frequency discharges

AEDs which effectively block the NMDA receptor could reduce focal epileptogenesis, slow synchronization of the discharge or slow/block spread of seizure

Extracellular Changes
Extracellular concentrations of potassium and calcium decrease during a seizure Causes greater excitability of neurons and may promote seizure initiation or spread Phenytoin suppresses epileptic discharges in an altered ionic environment, therefore it is more effective in epileptic tissue than in normally functioning brain areas

Seizure Manifestations
Depend on portion of the brain affected Seizures occurring in the frontal or parietal lobe result in manifestations on the contralateral side
R frontal left arm L parietal R face Temporal auditory Occipital visual

Signs and Symptoms of Seizure

Incontinence Movement Disorders Falls Memory Loss Loss of attention Headache Scalds, bruises Tongue laceration Chipped tooth Sensory changes
smell taste sight sound

Differential Diagnosis
Cardiac syncope Transient ischemic attacks Menieres syndrome

Psychiatric disorders

Seizure Precipitants
Conditions that lower the seizure threshold: Head trauma CV Disease Sleep deprivation Stress Hormonal changes
menses, pregnancy, puberty

Metabolic disorders Anatomic abnormalities

Tumors/neoplasm

Genetic traits Infectious processes Medications Alcohol withdrawal

Metabolic Disorders Precipitating Seizures

Hypoglycemia
more likely to occur when Glu < 30mg%

Hyponatremia - Na <115mEq/L
Hypernatremia - Na > 160mEq/L

Hypocalcemia - Ca < 2.5mEq/L

Medications Associated with Seizures

Amphetamines Bupropion Clozapine Cocaine Diphenhydramine Haloperidol Imipenam/cilastin Isoniazid Lithium Loxapine Meperidine Metronidazole Molindone MAO inhibitors PCNs Phenothiazines Pseudoephedrine Theophylline Thioxanthines Tramadol TCAs

Assessment of Seizures
Complete & document ASAP following event First clinical signs Duration of seizure event Order of body parts involved Eye position, pupil size and reactivity Movement type and side involved Breathing pattern Postictal behavior

How are seizures classified?

Clinical & electrophysiologic manifestations Focal point of origin in the brain

Level of consciousness

International Classification of Seizures

Partial Seizures
Simple Partial Seizures Complex Partial Seizures Partial Seizures evolving to Secondarily Generalized Seizures

Generalized Seizures
Absence, Myoclonic, Clonic, Tonic, Tonic-Clonic, Atonic

Unclassified

Partial Seizures
Seizures begin locally Simple Partial
without impairment of consciousness frequency = 10%

Complex Partial
with impairment of consciousness frequency = 35%

Secondarily generalized
partial onset evolving to generalized tonic-clonic frequency = 10%

Generalized Seizures
Bilaterally symmetrical and without local onset
Type Tonic-Clonic (Grand Mal) Absence (Petit Mal) Myoclonic Clonic Atonic Infantile spasms Frequency 30% 10%

Status Epilepticus
Prolonged seizure of any kind without recovery period of consciousness between attacks > 30 minutes of continuous seizure activity Experienced by 1-7% of patients with previously diagnosed epilepsy, may be as high as 42% Causes:
noncompliance with AED therapy, withdrawal of AED therapy metabolic changes

Risk increases with:

stroke, tumor, trauma, infection

Status Epilepticus
Muscular contractions and hypoxia can cause lactic acid release causing sever acidosis, hypotension and shock Excessive heat is generated and may correlate to severity of brain injury Airway obstruction and increase in salivation can cause aspiration pneumonia May result in decrease in cognitive function and prolonged SE may cause neuronal death

Management of Acute Seizure Activity

Protect from injury, move furniture Turn head to side to prevent aspiration Insure adequate airway Loosen restrictive clothing Do Not Place Anything in the Mouth! Get emergency help if seizure persists Document the event

If you witness a seizure ...

Management of Seizures
Define seizure type Assess drug efficacy Consider drug side-effect profile Account for patient-specific factors Consider dosage form availability Compliance Cost $$$

Goal of Therapy
Ideally = eliminate seizures Realistically = control or reduce the frequency, minimize adverse effects, optimize the quality of life When assessing efficacy of regimen consider:
seizure severity frequency reduction duration of seizure-free periods extent of side effects patients acceptance of regimen

Management of Seizures
1. Therapy should be initiated with a single AED based
on seizure type, MOA and adverse effects 2. Dosage should be titrated to optimize seizure control

and minimize side effects

3. If first agent fails, begin another agent from the initial therapy group 4. Alternative agents and polytherapy are reserved for patients who fail monotherapy

Management of Status Epilepticus

CBC, electrolytes IV Glucose, Thiamine Lorazepam 2-4mg Diazepam suppository Phenytoin or Fosphenytoin Phenobarbital Midazolam and Pentobarbital Identify Precipitating Factors

Primary Antiepileptic Agents

Benzodiazepines Clonazepam Diazepam Lorazepam Carbamazepine Oxcarbazepine Ethosuximide..Absence seizure Felbamate Gabapentin.neuropatic pain. Lamotrigine Levetiracetam Phenobarbital Phenytoin Primidone Tiagabine Topiramate Valproic Acid Vigabatrin Zonisamide

AED Based on Seizure Type

Potential MOA of AEDs

AED Contraindications
CBZ - AV heart block, bone marrow depression, blood dyscrasias Felbamate - blood dyscrasias, bone marrow depression, hepatic function impairment Phenobarbital - porphyria Phenytoin - sinus bradycardia, AV block, SA block, Adams-Stokes syndrome Valproic acid - Severe hepatic function impairment

Adverse Drug Reactions with AEDs

ADRs occur frequently with AED therapy (31%)

More common with multi-drug regimens

and higher doses

ADRs may not always correlate with serum

drug concentrations

Adverse Drug Reactions with AEDs

Life-threatening vs. Non-life threatening Toxicity
nystagmus, ataxia, anorexia, GI

CNS Effects
drowsiness, sedation, dizziness may develop tolerance to after first few weeks

Hemotologic
s/s: fever, sore throat, bruising, bleeding CBZ, Phenytoin, Felbamate, Ethosuximide

Hepatotoxicity
Phenytoin, Valproic acid

Drug Interactions with AEDs

Pharmacokinetic: protein-binding interactions
valproate and phenytoin

enzyme induction----P450.GEAR
carbamazepine, phenobarbital, phenytoin, primidone

enzyme inhibition---p450
felbamate, valproate

Pharmacodynamic: additive CNS effects

blurred vision, dizziness, ataxia

Pharmacokinetics of AEDs

Patient Monitoring
Seizure frequency ADRs

Comorbid conditions
Cognitive function

Drug interactions
Serum drug concentrations

When do you measure serum levels?

Titration phase or after dosage adjustmentsphenytoin etc Suspected AED-related toxicity Confirmation of overdose Suspected medication noncompliance Undesired therapeutic response Unstable hepatic function New drug interaction

Serum Concentrations of AEDs

Principles of AED Therapy

Not all patients need to be treated for their lifetime Treat the patient - Not the level Factors associated with good prognosis:
few tonic-clonic seizures prior to the start of AED therapy years seizure-free on AED therapy normal EEG

Considerations in Discontinuation of AEDs

History of patients epilepsy Probability of remaining seizure free Duration since last seizure Risk factors for recurrence Risks of long-term tx with AED Patients concerns of adverse effects Patients concerns of additional seizures

When to consider withdrawal?

Seizure free for 2 to 4 years
Experiencing intolerable side effects

outweighing benefit of therapy

History of single seizure Normal neurologic exam and EEG Those on prophylactic therapy with no h/o seizure

Guidelines for Discontinuation

Avoid abrupt discontinuationtaoper off
Discontinue most toxic drugs first Length of taper?
Medical Research Councils Antiepileptic Drug Withdrawal Study Group suggests to taper over 6 months

Reduce dose in 30 day intervals by 25%

If seizures recur, reinstate the last effective dose

Nonseizure uses of AEDs

Behavioral disturbances Drug withdrawal Mood disorders Pain syndromes Neurogenic Pain Restless legs syndrome Trigeminal neuralgia.Carbamazepine Tremor Migraine prophylaxis

Questions?
Distribute Case #1 Responsible for Questions 1- 9 Meet back for Large Group Facilitation this

afternoon at 3pm.