Seizuresnanimated With Rational Pharmacotherapy

“ SEIZURES “

Bernardo L. Conde, MD, FPPA, FPNA Professor Departement of Neurology & Psychiatry University of Santo Tomas

Modern Neurobiological Analysis of Epilepsy • Began with John Hughlings Jackson’s work in 1860s • Jackson realized that seizures need not involve loss of consciousness, but could be associated with focal symptoms, such as the jerking of the arm

• First surgical treatment for epilepsy – Victor Horsley in 1886 – Resected cortex adjacent to a depressed skull fracture and cured a patient with focal motor seizure

• The modern surgical treatment for epilepsy dates to the work of Wilder Penfield and Herbert Jasper in Montreal in the early 1950s.

• Medical innovation include – the first use of Phenobarbital by A. Hauptmann – development of EEG by Hans Berger – discovery of Phenytoin by Houston Meritt and Tracey Putnam in 1937

Schematic/Anatomic Neuron

Cell Architecture

Cellular Membrane

NERNST EQUATION

The Resting Membrane Potential

N.E. Potential = -61 x log Concin/Concout Na+ = -61 x 14/142 = -61 x log 0.1 = -61 x –1 = +62

K+ = -61 x 140/4 = -61 x log 35 = -61 x 1.54 = -94

What is Seizure and How does it come about?

Seizure • An occasional excessive and disordered discharge of nerve tissue • Manifestation of transient hypersynchronous abnormal neuronal behavior

SEIZURES • Paroxysmal disorder • Altered neurological function • Abnormal cortical electrical discharge • Beginning and an end • Involuntary

Definition – Seizure – transient manifestation of abnormal hypersynchronous discharges of cortical neurons – Epilepsy – disorder characterized by the occurrence of at least 2 unprovoked seizures – Epileptic syndrome – a disorder consisting of a cluster of signs and symptoms plus its typical EEG

Pathophysiology of Epilepsy • Cellular level – Sodium channels – Calcium channels – Potassium channels

• Synaptic level – Glutamate (excitatory) – GABA (inhibitory)

Mechanism of Seizure Generation Seizure generation Cellular level

Synaptic level

Cations Na+ channels

Inc. influx Na

Ca++ channels (T type channels)

K+ channels

Dec. intracellular K+

Inc. intracellularly Na and water

Increase influx of calcium

Neuronal swelling

Cell hyperexcitability

increase tissue excitability

Neurotransmitters

GABA decrease concentration

Glutamate increase concentration

Hyperexcitable state

Firing thalamic and cortical neurons

SEIZURE

Possible Causes of Seizures in Young People • Infant (0-2 years old)

Genetic Hypoxia Congenital Anomalies

• Child (2-12 years old)

Head trauma Acute Infection

• Adolescent (12-18 years old)

Head trauma Drug and alcohol use/withdrawal

Possible causes of seizures in Adults • Young adults

Head trauma Alcoholism Brain tumor

• Older adults

Brain tumor CVA Metabolic disorders Alcoholism

Why Classify? • Facilitate communication among professionals • Facilitate communication between physician and patient • Aid diagnosis • Rational prescribing of AEDs based on accurate diagnosis of seizure type • Prognosis

International League Against Epilepsy (ILAE) classification of Seizure Type I. Partial seizure A. Simple partial seizure (consciousness not impaired) B. Complex partial seizure (with impairment of Consciousness) C. Partial secondarily generalized

II. Generalized seizures (bilaterally symmetrical and without local onset) A. B. C. D. E. F.

Absence seizures Myoclonic seizures Clonic seizures Tonic seizures Tonic-clonic seizures Atonic seizures (astatic)

III. Unclassified epileptic seizures (inadequate or incomplete data)

The ILAE Classification of Epilepsies and Epilepsy Syndromes Shorvon, 2000

Simple and Complex Partial Seizure

Impaired Consciousness • “The inability to respond normally to exogenous stimuli by virtue of altered awareness and/or responsiveness” • Responsiveness – The ability of the patient to carry out simple commands or willed movements

• Awareness – refers to the patient’s contact with events during the period in question and its recall

PARTIAL SEIZURE

Abnormal flow of electrical discharge from a specific or single focus

Simple Partial Seizures • With motor symptoms – – – – –

Focal motor without march Focal motor with march (Jacksonian) Versive Postural Phonatory (vocalization or arrest of speech)

Simple Partial Seizures • With somatosensory or special sensory symptoms – – – – – –

Somatosensory Visual Auditory Olfactory Gustatory Vertiginous

Simple Partial Seizures With autonomic symptoms • Epigastric sensation • Pallor • Sweating • Flushing • Piloerection • Pupillary dilatation • Apnea • Arrhythmias/bradyarr hythmia • Chest pain • Cyanosis

• Erythema • Genital sensations/orgasm • Hyperventilation • Lacrimation • Miosis/mydriasis • Palpitations • Pilomotor excitation • Tachycardia • Urinary urgency/incontinence • Vomiting

Simple Partial Seizures • With psychic symptoms – Dysphasic – Dysmnesic (déjà vu, jamais vu, memory recall, memory gaps/amnesia) – Cognitive (dreamy states, distortions of time sense) – Affective (fear, anger, sadness, pleasure, sexual emotion, emotional distress – Illusions (macropsia) – Structured hallucinations (music, scenes, visual, auditory, olfactory) – Other (change in reality, depersonalization, feeling of a presence (“as if someone is nearby”), forced thinking, distortion of body image)

Partial Seizures

SEIZURE SPREAD • The spread of seizure activity – Involves normal cortical circuitry – Follows the same pathways as does normal cortical activity – Thalamocortical, subcortical and transcallosal pathways become involved in seizure process

Partial seizure Seizur e focus

Seizur e focus

Spread

Secondary generalization

Primary generalized seizure

What Terminates a Seizure • During the initial 30 seconds, typical of secondarily generalized tonic-clonic seizure, neurons in the involved areas – undergo prolonged depolarization – continuously fire action potentials

• This is associated with the loss of afterhyperpolarization that follows PDS.

What Terminates a Seizure • As the seizure evolves, the neurons begin to repolarize and the afterhyperpolarization reappears.

SIMPLE PARTIAL EPILEPSY

Simple Partial Seizure

Simple Partial Seizure

COMPLEX PARTIAL EPILEPSY • Appears to be in a dream like state. • Unaware or unresponsive to questioning • May perform unusual actions such as picking of clothing's, grimacing, contorting to one side, chewing • Feel confused for several minutes • No recollection of the event

COMPLEX PARTIAL SEIZURES

Complex Partial Seizure

COMPLEX PARTIAL EPILEPSY

PARTIAL EPILEPSY with secondary GENERALIZATION • Starts off as simple seizure which later evolves into generalized seizure

Partial with secondary generalization

Partial with secondary generalization

Generalized Seizures • Begin throughout both hemispheres, more or less simultaneously • Do not have localized onset • Reflect generalized disturbance of cortical function

“Generalized Epilepsy” • May cry out or gasp, fall down, become rigid • Muscle may jerk, breathing becomes shallow • May lose bladder and bowel control • May drool, bite the tongue or lips and may turn blue • Post ictal -maybe confused, drowsy, sleep for a while or have headache

Generalized Seizures • Tonic – clonic seizures • Clonic seizures • Tonic seizures • Atonic seizures (astatic) • Absence seizure • Myoclonic seizures

Generalized Tonic Clonic Seizures

Absence Seizure

Absence Seizure

3hz Spike Wave

Absence Seizure

Myoclonic

Atonic Seizure

FEATURES HELPFUL IN DIFFERENTIATING BETWEEN PSCHOGENIC “SEIZURES”and TRUE EPILEPTIC SEIZURES FEATURE PSYCHOGENIC “SEIZURES” Sex Female Age Adolescence or adult Precipitating Emotional

EPILEPTIC SEIZURES Male or Female

Mostly

Any age early Variable; lack of

FEATURES HELPFUL IN DIFFERENTIATING BETWEEN PSCHOGENIC “SEIZURES”and TRUE EPILEPTIC SEIZURES FEATURE EPILEPTIC SEIZURES PSYCHOGENIC “SEIZURES” Precipitant emotional

Usually none

Precipitant

Occurrence and Circumstances in sleep when alone Common Common Onset

Often and

Usually abrupt may have short aura

Rare Less common Maybe gradual with increasing emotional symptoms

FEATURES HELPFUL IN DIFFERENTIATING BETWEEN PSCHOGENIC “SEIZURES”and TRUE EPILEPTIC SEIZURES FEATURE Vocalization

EPILEPTIC SEIZURES During automatism

Manifestation Stereotyped Phenomenon Usually both tonic and clonic phase clonic

PSYCHOGENIC “SEIZURES” Common during a “seizure” Variable Often tonic clonic or only Amplitude and

frequency during the attack

Injury

Common

Pelvic thrusting Pseudoclonic movements Rare

FEATURES HELPFUL IN DIFFERENTIATING BETWEEN PSCHOGENIC “SEIZURES”and TRUE EPILEPTIC SEIZURES FEATURE

EPILEPTIC SEIZURES Inconsistence Common Tongue Biting Common Consciousness Usually totally lost unresponsive

PSYCHOGENIC “SEIZURES” Rare Rare Maybe

often possible to during Duration of prolonged Seizure often Confusion Drowsiness/sleep

Usually short

communicate an attack Maybe

(but with auto-

Maybe gradual,

matism sometimes)

with emotional display Unusual Unusual

Common Common

COMMON PRECIPATATING FACTORS FOR SEIZURES IN YOUNG PATIENTS • • • • • • • • •

Fever Stress Fatigue Sleep Deprivation Drug abuse Menstrual cycle Photic stimulation Alcohol

FACTORS LOWERING SEIZURE THRESHOLD COMMON • Sleep deprivation • Alcohol withdrawal • Dehydration • Drugs and drug interactions • Systemic infection • Trauma • Malnutrition

OCCASIONAL • Barbiturate withdrawal • Hyperventilation • Flashing lights • Diet and missed meals • Specific “reflex” triggers

CEREBRAL ENERGY METABOLISM IN A SINGLE SEIZURE

• There is rapid and abrupt depletion in the high energy phosphates, ATP and PCR, the ultimate sources of energy used by virtually all metabolic processes in the brain; • There are corresponding rises in the breakdown products; ADP, AMP and creatine along with marked elevations in lactate and the lactate/pyruvate ratio.

PROGNOSIS OF EPILEPSY • THE LONGER THE FOLLOW-UP, THE LOWER THE FINAL REMISSION RATE • THE LONGER SEIZURES REMAIN UNCONTROLLED, THE LESS LIKELY CHANCE FOR REMISSION

RISK OF SEIZURE RECURRENCES • •

HIGHER RECURRENCE IF WITH STRUCTURAL DISORDERS WITH APPROPRIATE TREATMENT COMPLETE SEIZURE CONTROL IS ACHIEVED IN 50-90% OF CASES

RISK OF PERSISTENT SEIZURES • PROGRESSIVE NEUROLOGIC DAMAGE • WORSENING SEIZURES • ADVERSE COGNITIVE AND PSYCHOSOCIAL EFFECTS • CUMULATIVE DRUG TOXICITY

PRINCIPLES OF TREATMENT SEIZURES • Establish the diagnosis and the rule out underlying cerebral pathology; • Classify seizure type, using EEG and clinical criteria; • Select AED of first choice for seizure type

PRINCIPLES OF TREATMENT • Increase dose slowly until end-point is reached: – Complete seizure control – Optimum plasma drug level – Toxic side effects appear

• If poor seizure control gradually withdraw first drug while replacing with second drug of choice for seizure type. • Monotherapy is preferable to polypharmacy

PRINCIPLES OF TREATMENT • If improvement is only partial, other drugs may be necessary; • Adjust gradually (if possible, using plasma levels as a guide) keeping in mind – Pharmacokinetics of each drug – Potential drug interactions

PRINCIPLES OF TREATMENT • Continue treatment to achieve minimum seizure free period of 3 to 5 years; • If best medical therapy is unsuccessful, refer to a neurologist.

SEIZURES • Paroxysmal disorder • Altered neurological function • Abnormal cortical electrical discharge • Beginning and an end • Involuntary

STATUS EPILEPTICUS • SINGLE PROLONGED SEIZURE LASTING MORE THAN 30 MINUTES • FREQUENT SEIZURES; NO RECOVERY OF CONSCIOUSNESS BETWEEN ATTACKS

STATUS EPILEPTICUS • CONVULSIVE STATUS – Generalized Tonic-clonic Seizures – Partial Motor Seizures

• NON-CONVULSIVE STATUS – Absence Status – Complex Partial Status – Partial Sensory Status

CAUSES OF STATUS EPILEPTICUS • Sudden Withdrawal Of Anti- Epileptic Medication • CNS Infections • Others

ANTIEPILEPTIC DRUGSSTATUS EPILEPTICUS 1. Diazepam or lorazepam 2. Phenytoin (Dilantin) 3. Phenobarbital 4. Penthotal drip

- 0.3-0.5 mg/kg/slow IV - 0.5-0.1 mg/kg/slow IV - 18-20 mg/kg/slow IV - 20-25 mg/kg/slow IV - 5mg/kg/slow IV 0.2% in D5W IV

ASSOCIATIONS WITH INTRACTABLE EPILEPSY • STRUCTURAL BRAIN DISEASE – Focal Vs. Diffuse – Static Vs. Progressive

• INEFFECTIVE TREATMENT – Inappropriate AED choice or – Inadequate dose – Drug interactions – Non-compliance

“ Rationalizing Pharmacotherapy in Epilepsy “

Bernardo L. Conde, MD, FPPA, FPNA Professor Departement of Neurology & Psychiatry University of Santo Tomas

FEATURES HELPFUL IN DIFFERENTIATING BETWEEN PSCHOGENIC “SEIZURES”and TRUE FEATURE EPILEPTIC EPILEPTIC PSYCHOGENICSEIZURES “SEIZURES” Sex Female Age Adolescence or adult Precipitating Emotional

SEIZURES

Male or Female

Mostly

Any age early Variable; lack of

FEATURES HELPFUL IN DIFFERENTIATING BETWEEN PSCHOGENIC “SEIZURES”and TRUE EPILEPTIC SEIZURES FEATURE EPILEPTIC SEIZURES PSYCHOGENIC “SEIZURES” Precipitant emotional

Usually none

Precipitant

Occurrence and Circumstances in sleep when alone Common Common common Onset gradual

Often and

Usually abrupt

Less

Rare

Maybe

FEATURES HELPFUL IN DIFFERENTIATING BETWEEN PSCHOGENIC “SEIZURES”and TRUE EPILEPTIC SEIZURES FEATURE

EPILEPTIC PSYCHOGENIC SEIZURES “SEIZURES” During automatism

Vocalization Common during a “seizure” Manifestation Stereotyped Variable Phenomenon Usually both tonic clonic and clonic phase clonic

Often tonic or only Amplitude

and frequency during

COMMON PRECIPATATING FACTORS FOR SEIZURES IN YOUNG PATIENTS

• • • • • • • • •

Fever Stress Fatigue Sleep Deprivation Drug abuse Menstrual cycle Photic stimulation Alcohol

RISK OF SEIZURE RECURRENCES • •

HIGHER RECURRENCE IF WITH STRUCTURAL DISORDERS WITH APPROPRIATE TREATMENT COMPLETE SEIZURE CONTROL IS ACHIEVED IN 50-90% OF CASES

RISK OF PERSISTENT SEIZURES

• PROGRESSIVE NEUROLOGIC DAMAGE • WORSENING SEIZURES • ADVERSE COGNITIVE AND PSYCHOSOCIAL EFFECTS

• CUMULATIVE DRUG TOXICITY

•

PRINCIPLES OF TREATMENT EstablishSEIZURES the diagnosis and the rule out underlying cerebral pathology;

• Classify seizure type, using EEG and clinical criteria; • Select AED of first choice for seizure type

PRINCIPLES OF TREATMENT

• Increase dose slowly until end-point is reached: – Complete seizure control – Optimum plasma drug level – Toxic side effects appear

• If poor seizure control gradually withdraw first drug while replacing with second drug of choice for seizure type. • Monotherapy is preferable to polypharmacy

PRINCIPLES OF TREATMENT • If improvement is only partial, other drugs may be necessary; • Adjust gradually (if possible, using plasma levels as a guide) keeping in mind – Pharmacokinetics of each drug – Potential drug interactions

PRINCIPLES OF TREATMENT • Continue treatment to achieve minimum seizure free period of 3 to 5 years; • If best medical therapy is unsuccessful, refer to a neurologist.

Criteria for starting antiepileptic drug therapy • Diagnosis of epilepsy must be firm • Risk of recurrence of seizures must be sufficient • Seizures must be sufficiently troublesome – – – – –

Types of seizures Frequency of seizures Severity of seizures Timing of seizures Precipitation of seizures

• Good compliance must be likely • Patient has been fully counseled

Selection of An Antiepileptic Drug: Factors to Consider • Control of Seizures • Tolerability • Pharmacokinetic properties • Patient Characteristics • Drug interactions • Cost

Cellular basis of epileptogenesis Astrocyte

GABAergic interneuron Glutamine synthase

Glutamate Transporter GABA-T Ca++ channel

Na+ channel

Glutamate

NMDA receptor

GABA receptor

Non-NMDA receptor

Presynapse

Postsynapse

The “Older” Anticonvulsants Phenobarbital Phenytoin Primidone Ethosuximide Carbamazepine

Dilantin TM Mysoline TM ZarontinTM TegretolTM

1912 1938 1954 1960 1974

Valproate

DepakoteTM

1978

“Old” Drugs that decrease excitation Astrocyte

Ethosuximide

Phenytoin Carbamazepine Ca++ channel

Na+ channel NMDA receptor

Ketamine

Glutamate Non-NMDA receptor

Presynapse

Postsynapse

“Old” Drugs that enhance inhibition GABAergic interneuron

GABA-T

Phenobarbital Benzodiazepines

GABA receptor

Why is there a need for “new” anticonvulsants? • More effective • Different mechanism of action: more selective – Better tolerated: less side effect(s) – Safer

• Better for women: less teratogenicity • Less interactions with other drugs

Newer antiepileptic drugs Felbamate

FelbatolTM

Wallace

Gabapentin

NeurontinTM

Pfizer

Lamotrigine

LamictalTM

GSK

Topiramate

TopamaxTM

Ortho-McNeil

Tiagabine

GabitrilTM

Cephalon

Levetiracetam

KeppraTM

UCB Pharma

Oxcarbazepine TrileptalTM

Novartis

Zonisamide

Elan Pharma

ZonegranTM

Gabapentin (Neurontin) •

US FDA approval early in 1994

•

Molecular structure resembles GABA but it does not bind to the GABAReceptor

•

It increases GABA levels in CNS and reduces glutamate

Gabapentin: Kinetics • Absorption: 60% of 600 mg* • Water soluble • Tmax: 2 - 4 hrs • Half life ~ 6 hrs • Protein binding: 0% • No hepatic metabolism, pure renal excretion • No interactions with other drugs

Gabapentin: Current Usage • It is a very safe and easy to use • Rapid titration • Most new prescriptions are for non epileptic conditions - pain, psychiatric illnesses, sleep disorders • Currently it is almost always used as add-on drug except in certain clinical situations - elderly, porphyria, multidrug allergies

Gabapentin: Side Effects • Most people tolerate the drug very well, most common side effects are drowsiness and ataxia • About 20% of patients gain weight • About 10% of patients become “aggressive” or have behavioral issues • Rash is almost unheard of

Lamotrigine (Lamictal) • US FDA approval 1994 • Phenyltriazine derivative • Inhibits voltage gated Na+ channels

Lamotrigine (Lamictal) • Half life: 24 hours • Broad spectrum of activity

• May be used as monotherapy • Rapidly and completely absorbed • Protein binding is 55%

Lamotrigine • Hepatic conjugation of LTG does not change the clearance of other drugs • Inducers: Carbamazepine, phenobarbital, and phenytoin increase LTG clearance • Valproic acid significantly reduces the LTG clearance

Lamotrigine: Current Usage • Used as anticonvulsant and in bipolar disorder • Effective against multiple seizure types, including absence and in Lennox-Gastaut syndrome • As monotherapy: – Very well tolerated – Not associated with an increased incidence of teratogenicity

Lamotrigine: Current Usage • Initial adult dose is 25 to 50 mg/day with gradual titration upwards to 200 mg-600 mg/day

• If the patient is taking valproic acid, initial adult dose is 25 mg QOD with slow titration up to 200 to 300 mg/day

Lamotrigine: Toxicity • Diplopia, dizziness (common) • Less sedating than many AEDs and is not associated with weight gain or cognitive dysfunction • Organ toxicity is very rare • Incidence of rash is elevated if patient is given high initial doses/rapid titration; with slow titration, the rash rate is lower than either phenytoin or carbamazepine

Lamotrigine discontinuation over one year

Topiramate (Topamax) •

Fructopyranose sulfamate derivative

•

Inhibits voltage gated Na+ channels, enhances GABA activity, and blocks AMPA receptor at higher levels

Mechanisms of Action of Topiramate H2CO3 ↔ H2O + CO2 Inhibition of carbonic anhydrase

TOPIRAMATE

Potentiation of GABA

Antagonism of glutamate Glutamate

Na+ and Ca++ channel blockade GABA

Ca++

Na+

Cl-

X ClInhibition flux

X Excitation inhibited

X X

Excitation inhibited

Shank RP et al. Epilepsia. 2000;41(suppl 1):S3.

Topiramate: Kinetics • Well absorbed • Tmax: 1-4 hrs • Not significantly metabolized, excreted unchanged in urine in monotherapy • Half life ~20 hrs • Protein binding ~15%

Topiramate (Topamax) • Broad spectrum anticonvulsant effective in: – Partial/focal epilepsy – Generalized epilepsy including myoclonic seizures – Lennox-Gastaut syndrome

•

Topiramate: Drug Interactions TPM has no significant effect on CBZ or VPA blood levels

• TPM decreases PHT clearance by <20% in some patients • TPM decreases ethinyl estradiol level (BCP) 33% • PHT, CBZ, PB decrease TPM level up to 50% • VPA has no significant effect on TPM level

Topiramate: Side Effects • Dizziness, ataxia, somnolence, and fatigue are the most common AEs • Weight loss in 25% • Paresthesias in 10% • Nephrolithiasis in 1.5% • Metabolic acidosis • Cognitive symptoms, which may develop insidiously, seen in 10 to 30%, less likely with slow titration

Topiramate: Current Usage • In addition to epilepsy, used for migraine prophylaxis and weight loss • Under evaluation for psychiatric conditions, pain, and neuroprotection • Used as monotherapy and add-on for multiple seizure types

Topiramate discontinuation over one year

Levetiracetam (Keppra) • Related to piracetam (used in Europe) • The mechanism(s) of action largely unknown • In animals: prevents kindling • Inactive in maximal electroshock and pentylenetetrazol seizure models in mice and rats • Inactive in convulsions induced by GABAergic chemoconvulsants in mice

Levetiracetam (Keppra) • US FDA approval 2000 • It is approved for add-on treatment of: • Partial seizures • It does appear to have a broad spectrum of activity against multiple seizure types including myoclonic seizures and generalized epilepsies

• Successfully used as monotherapy • May be rapidly titrated and clinical onset of action is very rapid

Levetiracetam: Kinetics • • • • •

Rapid and complete absorption Low protein binding Clearance is renal not hepatic Half life is approximately 8 hour No drug interactions

Levetiracetam (Pooled data from 3 efficacy studies, n=904) 45 % of patients responding 40 35 30

p < 0.001 *** p < 0.01

**

41

25 32

20

10 5 0

1 3 3 1 Placebo

12 4

22 7

**

***

*** 8 ***

**

LEV 1000 mg Seizure free

***

***

28

15

***

2 NS

LEV 2000 mg

75% responder rate

50% responder rate

LEV 3000 mg

Levetiracetam: Toxicity • Most common side effects are fatigue, drowsiness, ataxia • Weight neutral • No rash • No organ toxicity • About 15% of patients have behavioral changes: – Elderly – Mentally retarded

Levetiracetam: Most common side effects

Somnolenc e Asthenia Headache Infection Dizziness

LEV (n=769)

Placebo (n=439)

14.8%

8.4%

14.7%

9.1%

13.7%

13.4%

13.4%

7.5%

8.8%

4.1%

Levetiracetam: Reason for discontinuation 15% of patients taking levetiracetam 11% of patients taking Placebo

Oxcarbazepine: Metabolism O

OH

N O

NH2

Reduction

Gluc O

N O

NH2

O

O

N NH2

Carbamazepine

N

Conjugation

NH2

MHD

Oxcarbazepine

O

No autoinduction

Oxidation

OH

N O

NH2

Hydrolysis

10, 11-epoxide Schachter S. Exp Opin Invest Drugs. 1999;8(7):1-10.

OH

N O

NH2

Autoinduction

Oxcarbazepine (Trileptal) • • • •

Plasma half-life of MHD 9.3 ± 1.8 hours Anticonvulsant activity similar to CBZ Approved for monotherapy Some patients who “fail” CBZ may do well on OxCBZ • 30% of patients with CBZ rash will have rash with OxCBZ

Oxcarbazepine: Kinetics • • • • • • •

Complete absorption Protein binding 40% (CBZ = 70%) Hepatic glucuronidation, not oxidation No active epoxide No auto-induction Fewer drug interactions than CBZ Induce CYP 3A4: – Other drugs metabolized by CYP3A4 (eg BCPs) may have lower blood levels

Oxcarbazepine: Mechanisms of action •

Probably similar to carbamazepine

•

Block voltage-sensitive Na+ channels

•

Modulation of voltage-activated Ca++ currents

•

No significant interactions with brain neurotransmitters or modulation of receptor sites

•

Increases K+ conductance

Oxcarbazepine: Side Effects • Dizziness and diplopia are fairly common especially if an individual dose is large and taken on an empty stomach • Slow titration reduces side effects • Hyponatremia less common than with CBZ but may occur, especially in the elderly

General Guidelines in AED Management

• Start with single (preferably old) drug appropriate for seizure types and patient; give QD or BID if possible • Educate the patient about the drug, its side effects and interactions, and that it helps to control but not “cure” seizures • Start slow and low: Begin with low dose and slowly increase

Blood Levels in AED Management • “Therapeutic level” is a misnomer! • A “good” level is one in which the patient has no seizures and no side effects • The quoted ranges for PB (20-40 mcg/ml), phenytoin (10-20 mcg/ml), carbamazepine (612 mcg/ml), and valproic acid (50-100 mcg/ml) are rough guides at best

When to Get AED Levels? • After initiation of treatment • After dose changes (up or down) of phenytoin • When there are questions of compliance, toxicity, or drug interactions • When there are breakthrough seizures • Routine every 6 - 24 months • I do it when filling out driver’s forms for BMV

Do we have the ideal anticonvulsant? • • • •

Do we have effective AEDs? Do we have more selective AEDs? Do we have non teratogenic AED? Do we have AEDs that do not interact with other medications? • What next???

Conclusion • New AEDs may represent advances over the old in terms of pharmacokinetics, side effects • Efficacy differences have not been established • Each new AED will be the “magic bullet” for some patients

SEIZURES B. L. CONDE, MD, FPNA, FPPA 2001 June*AUT

Efficacy and tolerability of the new antiepileptic drugs: Treatment of new onset epilepsy

Bernardo L. Conde, MD, FPPA, FPNA Professor Departement of Neurology & Psychiatry University of Santo Tomas

Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society

Background and Justification • Age-adjusted epilepsy prevalence of 6.8/1,000 population • Cumulative incidence through age 74 was 3.1%

In the last 10 years, the following drugs were approved by the US FDA • • • • • • • •

Felbamate Gabapentin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisanide

Prior to 1990s, six major AEDs were available for the treatment of epilepsy • • • • • •

Carbamazepine Phenobarbital Phenytoin Primidone Valproic acid Ethosuximide

• The older drugs, while effective in patients with newly-diagnosed epilepsy share some characteristics: – Phenytoin, carbamazepine, phenobarbital, and primidone are hepatic enzyme inducers

Advantages of older AEDs • • • • •

Broad familiarity Lower cost Known efficacy Wide availability Long term experience

The Analytical Process 1. Literature search (MEDLINE, CURRENT CONCEPTS) for relevant articles published between Jan ’87 – Sept 2001 2. Manual search by panel members covering Sept 2001 – May 2002 3. A manual search for Class I articles are updated to include those published through March 2003 4. Cochrane library search for randomized controlled trials in epilepsy in Sept 2002

Criteria for Selection of Articles 1. Relevance to the clinical questions of efficacy, safety, tolerability or mode of use 2. Human subjects only 3. Type of studies: randomized controlled trials, cohort, case control, observational or case series 4. All languages for randomized controlled trials not available in English 5. Relevant to patients with newly-diagnosed epilepsy

Exclusion Criteria • Articles classified as reviews, metaanalyses and articles related to nonepilepsy uses of AEDs unless adverse reactions are disclosed based on AED mechanism of action

• Total # of articles – 1464 – Gabapentin – 240 – Lamotrigine – 433 – Topiradeate – 244 – Tiogabine – 177 – Zonisamide – 146

• Question 1 – How does the efficacy and tolerability of the new AEDs compare with that of older AEDs in patients with newly diagnosed epilepsy?

Summary of Findings • Efficacy in newly diagnosed patients – GBP is effective in the treatment of newly diagnosed patient epilepsy

– LTG, TPM, & OXC are effective in mixed population of newly diagnosed and generalized tonic-clonic seizures

– At present there is insufficient evidence to determine effectiveness in newly diagnosed patients for TGB, ZNS, & LEV

Recommendation 1. Newly diagnosed epileptic patients maybe initiated in standard AEDs (CBZ, PHY; VPA, PB) or new AEDs (LTG, GBP, OXC, TPM) 2. Choice of AED will depend on individual patient characteristics (Level A)

What is the Evidence that the New AEDs are effective in Refractory Partial Epilepsy as Adjunctive therapy? Refractory Epilepsy • failed 3 or more AEDs • average 3 to 4 seizures a month Bernardo L. Conde, MD, FPPA, FPNA Professor Departement of Neurology & Psychiatry University of Santo Tomas

CONCLUSION • All of the drugs have proved efficacies as add-on therapy in patient with refractory partial epilepsy.

Partial Seizure in Adults • • • • • • •

GBP (600-1800mg/day); LTG (300-500mg/day); LEV (1000-3000mg/day); OXC (600-2400mg/day; TGB (16-50mg/day); TPM (300-1000mg/day) are effective in reducing frequency as adjunctive therapy in refractory partial seizures.

• GBP, LTG, TGB, TPM, OXC AND ZON are more effective at higher doses • and ZON (100-400mg/day) • LEV evidence for a dose response is less clear but more patient responded at 3000mg/day • Side effects and drop-outs increase in a dose dependent manner for all drugs • Slower titration reduces side effects for GBP and TPM

Recommendation • It is appropriate to use GBP, LTG, TGB, TPM, OXC, ZON, LEV as addon therapy in patients with refractory epilepsy

What is the evidence that the new AEDs are effective as monotherapy in patients with refractory partial epilepsy?

Summary of Evidence

(Monotherapy for refractory partial epilepsy) • LTG 500mg/day is superior to 100mg/day of VPA (acting as pseudoplacebo) • OXC 2400mg/day is superior to 300mg/day • TPM 1000mg/day is superior to 100mg/day • There is insufficient evidence at present to determine the efficacy of LEV, TGB or ZON • In one trial, GBP 1200mg and 2400mg were not more effective than a pseudoplacebo dose of 600mg in this population

Recommendation • OXC and TPM can be used as monotherapy in patients with refractory partial epilepsy • LTG can be used (Level B downgraded due to drop-outs) • There is insufficient evidence to recommend use of GBP,LEV, TGB or ZON in monotherapy of refractory partial epilepsy (Level U)

IDIOPATHIC EPILEPSY IN ADULTS What is the evidence that the new AEDs are effective for the seizures seen in patients at the refractory idiopathic generalized epilepsy?

CONCLUSION • Trials for refractory generalized epilepsy has been criticized due to the fact that not all patients were required to have an EEG demonstrating a generalized pattern.

SUMMARY OF EVIDENCE

(Refractory primary generalized epilepsy) • TPM 6mg/kg/day is effective for the treatment of refractory generalized tonic clonic convulsions +/- other seizure types • GBP 1200mg is not effective in refractory GTCS in patients with primary or secondary generalized epilepsy

RECOMMENDATIONS • TPM may be used in the treatment of refractory GTCS in children and adults (Level A) • There is insufficient evidence to recommend GBP, LTG, OXC, TGB, LEV or ZON for the treatment of refractory generalized tonicclonic seizures in adults and children (Level U)

TREATMENT OF REFRACTORY EPILEPSY IN CHILDREN What is the evidence that the new AEDs are effective in refractory partial epilepsy as adjunctive therapy in children? Bernardo L. Conde, MD, FPPA, FPNA Professor Departement of Neurology & Psychiatry University of Santo Tomas

AED

Study Profile

Level of Evidence

Dosing

Result Seizure-Free Reduction

Discontinuat ion Rate

AEs

GBP

247 patient 3-12 year DB, PBO – 12 wks

Class 1

23-35 mg/kg/day

35% EPS↓ 28% 2ºGTCS↓ PBO 12%- EPS ↓ 13%- GTCS↑

GBP – 5% PBO – 2%

Viral infection Fever Hostility Fatigue Weight gain

LTG

199 children 2-16 year PBO – controlled

Class 1

1-3mg/kg (VPA) 1-5mg/kg (PHY; CBZ; PHB) 5-15 mg/kg (enzymeinducing AED)

Responder Rate 45% - LTG 25% - PBO

LTG – 5% PBO – 6%

Ataxia Dizziness Tremor Nausea Asthenia S-J syndrome

AED

TPM

OXC

Study Profile 86 children 2-16 year PBO – controlled 16 wks.

267 children 3-17 year DB; PBO

Level of Evidence Class 1

Dosing

125-400 mg/day Starting dose = 25mg/day

Class 1

30-46 mg/kg/day

Result Seizure-Free Reduction Responder Rate (50% reduction) 39% - TPM 20% - PBO

Discontinuati on Rate None–TPM 2 - PBO

Emotional lability Difficulty concentrating Fatigue Memory deficits Weight loss

OXC – 10% PBO – 3%

Headache Somnolence Vomiting Nausea Rash (4%)

Median reduction 33% - TPM 10.5% - PBO Responder Rate 41% - OXC 22% - PBO Median reduction 35% - OXC 8.9% - PBO

AEs

What is The Evidence That The New AEDs are effective as monotherapy in children with refractory partial seizures? *no monotherapy trials have been performed in this population

CONCLUSION • An NIH consensus conference… partial seizures in children are similar in pathophysiology to those in adults. • An AED with demonstrable efficacy in adults will demonstrate the same efficacy or adjunctive therapy in children >2 years of age.

Summary of Evidence • GBP; LTG; TPM; OXC are effective in reducing seizure frequency as adjunctive therapy in children with refractory partial seizures

What is the Evidence that the new AEDs are effective in children and/or adults with Lennox-Gestaut Syndrome?

CONCLUSION • Patients with Lennox-Gestaut syndrome are difficult to treat and are most susceptible to exacerbation by AEDs. • TPM and LTG appear to be effective in this population and should be considered for use.

SUMMARY OF EVIDENCE • LTG at doses adjusted for weight and VPA use reduces seizure associated with Lennox-Gestaut syndrome. • TPM 6mg/kg/day is effective in reducing drop attacks (tonic-clonic seizures) in patients with LennoxGestaut syndrome.

• To date, there is no Class I or II evidence that GBP, TGB, OXC, LEV or ZON are effective. • In case reports, LTG and GBP worsened myoclonic seizures in some patients.

What Is the Risk of Teratogenicity with new AEDs compared to the old AEDs?

• Category D - drugs (AEDs) with known teratogenicity in both animal and human pregnancies e.g. Phenytoin, Carbamazepine, Valproic Acid

• Category C – drugs (AEDs) with demonstrable teratogenicity in animals but not in humans e.g. newer AEDs

“ Rationalizing Pharmacotherapy in Epilepsy “

Bernardo L. Conde, MD, FPPA, FPNA Professor Departement of Neurology & Psychiatry University of Santo Tomas