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MANAGEMENT OF EPILEPSY

Dr. Theresia Christin Department of Neurology University of Sriwijaya

Epilepsy
is a disorder of cerebral cortex characterized by recurrent (periodic and unpredictable) seizures, with more than 24 hours interval and is unprovoked (unknown cause)

Seizures
Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction, resulting from abnormal electrical discharge in cerebral neuronal cells, associated with prolonged depolarisation of cerebral neurons result in motor, sensory or behavioral changes.

ILAE Classification

Epidemiology by Seizure Types


Generalized TC (23%) Complex Partial (36%)

Simple Partial (14%)

Unclassified (3%) Myoclonic (3%) Other Generalized Absence (6%) (8%) Partial Unknown (7%)
Hauser WA. Epilepsia. 1992;33(suppl 4):S10.

First aid for Seizures

First aid for Seizures

First aid for Seizures

Management of Epilepsy
The goal of the therapy is to improve the patients quality of life through:

1.maximize the seizure control 2.minimize drug side effects


Drug choice is based on:

1.Classification of seizures. 2.Patients age & health state 3.Data on efficacy, tolerability, safety and
pharmacokinetics

Classification of Anticonvulsants
Classical Newer
Felbatol (felbamate) Neurontin (gabapentin) 1993 1994

Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid benzodiazepines

Lamictal (lamotrigine)
Topamax (topiramate) Gabitril (tiagabine) Keppra (levetiracetam) Zonegran (zonisamide) Lyrica (pregabalin)

1995
1996 1998 1999 2000 2005

Trileptal (oxcarbazepine) 2000

Ezogabine
Rufinamide, Lacosamide, other

When to Start?

As soon as diagnosis is confirmed


Triggers for seizures can be avoided (alcohol consumption, sleep deprivation, stress, etc) Minimum of 2 attacks in a year The patient and their family has been informed of the therapeutic goal and side effects

How to Start?

Therapy should start as monotherapy accordingly to seizure types and syndromes


Careful titration is a must - START LOW, GO SLOW 2nd AED is added if 1st AED is already titrated to max dose and fail to control seizure

3rd AED is added if 1st and 2nd AED are already titrated to max dose and fail

Anti-Epileptic Drugs (AEDs)


AEDs act to:
- Block the initiation of the electrical discharge from the focal area - Prevent the spread of abnormal electrical discharge to adjacent brain area AEDs prevent depolarisation of neurones by: - Modification of ion conductance (direct membrane stabilisation) - Inhibition of excitatory (glutamergic) activity - Stimulation of inhibitory (GABAergic) transmission.

They do their actions by


- axonal conduction by preventing Na+ influx through fast Na+ channels Example: Carbamazepine, Oxcarbazepine, Phenytoin, Barbiturates, Valproic Acids. Lamotrigine, Felbamate, and Topiramate

- presynaptic Ca+2 influx through type T channels in thalamic neurons


Example: Ethosuximide, Valproic Acids and Lamotrigine

They do their actions by:


- inhibitory tone through 1. 2. 3. 1. Facilitation of GABA-mediated hyperpolarization : Barbiturates and Benzodiazepines. Inhibiting GABA metabolism : Valproic Acid and Vigabatrin or action on the reuptake of GABA : Tiagabine Blockage of AMPA receptors : Lamotigrine and Topiramate

- excitatory effects of glutamic acid

2.

Blockage of NMDA receptors : Felbamate and Phenobarbital

Mechanism of action of AEDs

Classification of Anticonvulsants
Ion Channels#
Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid # For general tonic-clonic and partial seizures Ca++ #: Ethosuximide Valproic acid Zonisamide # For Absence seizures

Enhance Inhibitory aa #

Benzodiazepines Felbamate (diazepam, clonazepam) Barbiturates (phenobarbital) Topiramate Valproic acid Gabapentin Vigabatrin Topiramate Felbamate # Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence

Inhibit Excitatory aa

ILAE GUIDELINES Based on the best evidence available, what is the optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy?

Partial Seizures: Adults Available Evidence

A total of 33 randomized clinical trials (RCTs) and 5 meta-analyses examined initial monotherapy of adults with partial-onset seizures Level A: CBZ, PHT Level B: VPA Level C: GBP, LTG, OXC, PB, TPM, VGB Level D: CZP, PRM Level E: Others

Level F: None

Partial Seizures: Children Available Evidence

A total of 25 RCTs and 1 meta-analysis examined initial monotherapy of children with partial-onset seizures Level A: OXC

Level B: None
Level C: CBZ, PB, PHT,TPM, VPA Level D: LTG,VGB

Level E: Others
Level F: None

Partial Seizures: Elderly Available Evidence

A total of 30 RCTS with elderly participants included which examined initial monotherapy for partial-onset seizures Level A: GBP, LTG Level B: None

Level C: CBZ
Level D: TPM, VPA

Level E: Others
Level F: None

Generalized Tonic Clonic Seizures: Adults Available Evidence

A total of 23 RCTs and 5 meta-analyses examined initial monotherapy of adults with generalized-onset tonic clonic seizures Level A: None

Level B: None
Level C: CBZ,LTG,OXC, PB, PHT,TPM,VPA Level D: GBP,VGB Level E: Others Level F: None

Generalized Tonic Clonic Seizures: Children Available Evidence

A total of 20 RCTs examined initial monotherapy of children with generalized onset tonic clonic seizures Level A: None Level B: None

Level C: CBZ,PB, PHT,TPM,VPA


Level D: OXC Level E: Others Level F: None

Other Types of Seizures and DOC


Absence ( petit mal) DOC* Alternatives: Myoclonic, Atonic DOC Alternatives: Valproic Acid, Lamotigrine Zonisamide, Levetiracetam Valproic Acid, Lamotigrine Phenobarbital, Topiramate, Zonisamide, Levetiracetam Diazepam, I.V, Phenytoin I.V, Phenobarbital I.V, Midazolam I.V Diazepam, rectal or I.V Valproate

Status Epilepticus DOC Febrile Seizures

* DOC = Drug of choice

AED Dosages
AED CBZ PHT VPA PB INITIAL (mg/day) 400-600 200-300 500-1000 50-100 MAINTAIN (mg/day) 400-1600 200-400 500-2500 50-200 DIVIDED DOSE 2-3x 1-2x 2-3x 1x TITRATION 200-300 mg/day per 1-4 weeks 100mg/day per 3-7 days. 500mg/day per 7 days. 30-50mg/day per 10-15 days.

OXC
LVT

600-900
1000-2000

600-3000
1000-3000

2-3x
2x

300mg/day per 1-3 weeks


500-1000mg/day per 2 weeks

AED Dosages
AED INITIAL (mg/day) MAINTAIN (mg/day) DIVIDED DOSE TITRATION

TPM
GBP LTG ZOS PGB

100
900-1800 50-100 100-200 50-75

100-400
900-3600 50-200 100-400 50-600

2x
2-3x 1-2x 1-2x 2-3x

25-50mg/day per 2 weeks


300-900mg/day per 5-10 days 25mg for first 2 weeks. 50mg for next 2 weeks. to target in 1-2 weeks 50-100 per 2 weeks

PHENYTOIN
Adverse Effects: Ataxia and nystagmus. Cognitive impairment. Hirsutism Gingival hyperplasia, Coarsening of facial features. folate dependent megaloblastic anaemia, Osteomalacia, Inhibition of ADH, inhibition of insulin secretionhyperglycemia and glycosuria Hypoprothrominemiacoagulopathy Exacerbates absence seizures.

PHENYTOIN

Fetal hydantoin syndrome include:

cleft lip, cleft palate

congenital heart disease


slowed growth mental deficiency

CARBAMAZEPINE
Adverse Effects : Stupor, coma, respiratory depression, drowsiness, dizziness, vertigo, ataxia, blurred vision, diplopia, bradycardia, skin rashes, GI upsets. Hyponatremia in elderly

SODIUM VALPROATE
Adverse Effects : Elevated liver enzymes Tremor, hair loss, changes in hair growth

Increased appetite weight gain.


Coagulopathy (inhibition of platelet aggregation), Hepatotoxicity. Negative interactions with other antiepileptics. Teratogen: spina bifida

FELBAMATE

Effective against partial seizures but has severe side effects.


Thus, used only for refractory cases. One of the metabolites; ,-unsaturated aldehyde, 2phenylpropenal is chemically reactive, like acrolein covalently linking proteins as well as DNA, it can cause

liver and bone marrow toxicity

GABAPENTIN
Adverse Effects :

Ataxia Dizziness Somnolence Headache Tremor

VIGABATRIN
Adverse Effects :

Depression Psychosis Visual disturbances

LAMOTRIGINE


Presently use as add-on therapy with valproic acid.
Almost completely absorbed T1/2 = 24 hrs Low plasma protein binding Blocks sodium channels, & high voltage Ca+2 channel Adverse effects:

thus its effective in partial, generalized, myoclonic, absence seizures & LennoxGastaut syndrome (LGS).
Approved for use in bipolar disorder

Dizziness

Headache
Diplopia Nausea

Somnolence
Rash

LEVETIRACETAM

Adjunct Rx of refractory Partial Seizure
Unknown mechanism of action but binds to presynaptic vesicle protein

ADVERSE EFFECT Dizziness, sleep disturbances, headache, and asthenia (LACK OF ENERGY)

TIAGABINE

100% bioavailable, highly protein bound. Adverse effects: Dizziness Nervousness Tremor Difficulty concentrating Depression Asthenia Emotional Psychosis Skin rash

T1/2 = 5 -8 hrs
Effective against partial and generalized tonic-clonic seizures.

GABA uptake inhibitor GAT-1.

TOPIRAMATE

Broad spectrum antiseizure activity, also used in migraine

Adverse effects: Somnolence Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20- Fatigue 30 hrs Dizziness blocking of voltage-dependent sodium Cognitive channels slowing Additionally the frequency of Cl- channel Paresthesias opening by binding to GABA receptor. Nervousness High-voltage calcium currents (L-type) are Confusion reduced Urolithiasis Depresses excitatory action of kainate on Weight loss
AMPA receptors. Carbonic anhydrase inhibiter effect Teratogenic in animal models.

ZONISAMIDE

Sulfonamide derivative Orally active half-life 50-60 hrs

Both focal and generalized


Blocks voltage-gated Na+ channels and T-type Ca+2 current,

Mechanism of action

enhancement of GABA-receptor function


somnolence,

Adverse effects:

Ataxia,
hyperthermia (children) Kidney stone

Special Cases: Pregnancy



Seizure is very harmful for pregnant women. Antiepileptic drugs associated with increased (2-3 fold) incidence of birth defects (cleft lip/palate and cardiac defects) Significant risk of neural tube defects, folic acid is recommended to be given for every pregnant women with epilepsy Phenytoin, sodium valproate are absolutely contraindicated and oxcarbamazepine is better than carbamazepine.

Special Cases: Pregnancy



Monotherapy usually better than drugs combination. Experience with new anticonvulsants still not reliable Newborns of mothers receiving phenobarbitone, or phenytoin may develop hypoprothrominemia, heamorrhage prevented by Vit. K

Drugs are secreted in small quantities into breast milk but not usually sufficient to prevent breast feeding (phenobarbitone significantly)

AED DRUG INTERACTIONS


With other drugs: antibiotics anticoagulants cimetidine phenytoin, phenobarb, carb. phenytoin and phenobarb metabolism. displaces pheny, v.a. and BDZs

isoniazid
oral contraceptives salicylates theophyline

toxicity of phenytoin
antiepileptics metabolism. displaces phenytoin and v.a. carb and phenytoin may effect.

VAGAL NERVE STIMULATION (VNS)


VNS requires surgical implant of a small pulse generator with a battery and a lead wire for stimulus. The device is implanted and its lead wires wrapped around the patients vagal nerve.
This treatment was approved in 1997. The device is also approved for treatment of depression. The mechanism of action is unknown. VNS has been effective in treatment of partial onset seizures and has enabled reduction of drug therapy in some cases.

It is an alternative for patients whose conditions have been refractory to multiple drugs and in those who are sensitive to the many adverse effects of antiseizure drugs and those who have difficulty adhering to medication schedules. However, VNS is a costly and invasive procedure.

DEEP BRAIN STIMULATION (DBS)


DBS therapy uses a pacemaker-like device to deliver targeted electrical stimulation to the anterior nucleus of the thalamus.
The therapy is FDA approved with conditions for adjunctive treatment for partial-onset seizures in adults with medically refractory epilepsy. DBS is also FDA approved for treatment of advanced Parkinson disease and essential tremor.