Academic Half-Day Treatment of Epilepsy Ruba Benini & Abdullah Tawakul July 25 th, 2012.

Academic Half-Day

Treatment of Epilepsy

Ruba Benini & Abdullah TawakulJuly 25th , 2012

Preamble

Epilepsy is the second most common neurological condition after headache

Worldwide prevalence of 1% with a cumulative incidence of 2-4%.

The incidence of epilepsy is highest in the very young and the very old.

Hauser et al., 1996

Preamble

Epilepsy is not a single disease entity but rather an umbrella term used to denote a variety of disorders with different etiologies but with seizures as a common denominator

Port Wine Stain (Sturge-Weber)

Prosencephaly

Mesial Temporal lobe sclerosis

http://dermimages.med.jhmi.edu/images/Sturge_1_010204.jpg

Preamble

Treatment of epilepsy can be broadly divided into:

Medical treatment (anticonvulsants)

Surgical treatment (Focal resections; Hemispherectomy; Callosotomy)

Special diets (Ketogenic diet, Atkinson diet)

Other (Vagal Nerve stimulation, Deep brain stimulation, Transcranial Magnetic Stimulation)

OUTLINE

Approach to a first unprovoked seizure – to treat or not to treatAdult versus Child

Medical TreatmentWhat anticonvulsants are available to you Mechanisms of actionSome important pharmacokinetic properties to keep

in mindSome dos and don’ts

Surgical TreatmentBrief overview

OthersA few words

Scenario

25 year old male, presents to the ER for an episode this morning where he was found on the bathroom floor by his girlfriend after she heard a big bang.

Consult says: r/o seizure.

What is a seizure?What do you want to know?How do you take a seizure

history?

Definitions

What is a Seizure:

• Clinical event characterized by transient neurological signs and/or symptoms (motor, sensory, level of consciousness)

• That arise due to abnormal and excessive discharges from hyperexcitable, synchronized neuronal networks

Scenario



What is a seizure?What do you want to know?How do you take a seizure

history?

Approach to a first Seizure

HISTORY!

HISTORY!

HISTORY!

• Is this really an epileptic seizure or a seizure mimic?

• What type of seizure was it? (Seizure Semiology)

• Can you identify a particular epilepsy syndrome?

• What is the etiology of the seizure?


• Is this really an epileptic seizure or a seizure mimic?

Suggested Reading: Crompton and Berkovic (2009) The borderland of epilepsy: clinical and molecular features of phenomena that mimic epileptic seizures. Lancet Neurology


• What type of seizure was it?

Generalized seizures Focal (Partial) Seizures

•Tonic-clonic (Grand mal)•Absence (Petit mal) •Myoclonic •Tonic •Clonic •Atonic

•Simple partial•Complex partial•Complex partial with secondary generalization

Complex partial seizures Impairment of consciousness Usually originate in frontal or

temporal lobe Maybe preceded by auras May involve automatisms

Simple partial seizures No loss of consciousness May manifest as motor signs,

autonomic symptoms, somatosensory, special sensory symptoms or psychic symptoms


• What type of seizure was it?

Suggested Reading: Berg et al. (2010) Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia.

Definitions

What is an Epilepsy Syndrome:

Clinical entity with relatively consistent clinical features that is defined by seizure semiology, etiology, EEG signature, neurologic status, prognosis and in some cases response to specific anticonvulsants


• What is the etiology?

Back to Scenario



First unprovoked SeizureGeneralized seizure

Patient asks if he has epilepsy?Do you treat?

Definitions

What is Epilepsy:

Chronic condition characterized by recurrent, usually spontaneous, epileptic seizures

Two or more unprovoked seizures

Back to Scenario



First unprovoked SeizureGeneralized seizure

Patient asks if he has epilepsy?Do you treat?

Approach to first unprovoked seizure

• Risk of recurrence after first seizure: 30 to 55% over 2 to 5 years

• Treatment of first seizure reduces risk of recurrence by 50% but does not alter the risk of developing epilepsy

• There is no evidence that delaying treatment alters prognosis (chances for eventual seizure control are not reduced by delaying AED therapy)

Approach to first unprovoked seizure

First unprovoked epileptic seizure

No treatment

Exceptions: Early treatment is justifiable for patients in whom recurrence of seizure would have significant consequences related to driving, working and general safety

Hirtz et al., 2003

Summary of Guideline

1. Treatment with AED is not indicated for the prevention of the development of epilepsy (Level B).

2. Treatment with AED may be considered in circumstances where the benefits of reducing the risk of a second seizure outweigh the risks of pharmacologic and psychosocial side effects (Level B).

OUTLINE





OthersA few words

In epilepsy, there is a pathologic imbalance between inhibitory and excitatory processes

Inhibition

Excitation

Treatment of Epilepsy(Anticonvulsants)

Anticonvulsants control seizures either by increasing inhibition or decreasing excitation

Inhibition

Excitation

• Voltage-gated Na channels

• Voltage-gated Ca channels

• Glutamatergic excitation

• GABAergic transmission

Mechanism of action

Important side-effects

Pharmacokinetics

How do you choose the first drug

Special considerations (pregnancy, etc)


Match the following anticonvulsants

to their mechanism(s) of action

Anticonvulsants(Mechanism of Action)

Phenytoin (Dilantin)

Blocks voltage-gated Na channels

Blocks presynaptic release of neurotransmitter by blocking SV 2A

GABA(A) receptor agonist

Blocks voltage-gated Ca channels

Stabilizes slowly-inactivated voltage-gated Na channels

Blocks NMDA receptors

Blocks AMPA receptors

Blocks GAT-1 and prevents uptake of GABA from synapse

Blocks metabolism of GABA by inhibiting GABA-T

Blocks T-type Calcium channels

Increases intracellular GABA levels

Blocks presynaptic release of neurotransmitter by N-type Ca channels


Phenobarbital














Carbamazepine(Tegretol)













OxCarbamazepine(Trileptal)


Clobazam(Frisium)













DiazepamLorazepamMidazolamClonazepam


Lamotrigine(Lamictal)














Levetiracetam(Keppra)














Lacosamide(Vimpat)









Binds to CRMP-2





Valproic Acid(Epival, Depakene)














Ethosuximide(Zarontin)














Topiramate (Topamax)







Blocks AMPA (non-NMDA) receptors







Vigabatrin(Sabril)














Tiagabine














Gabapentin(Neurontin)













Pregabalin(Lyrica)


Felbamate














Rufinimide













Summary

Panayiotopoulos (2010)

Anticonvulsants: SummaryDrug Mechanism of Action

Phenobarbital Agonist of GABA (A) receptorsAntagonist of N- and L-type voltage-gated Ca channels

Phenytoin Stabilizes inactive state of voltage-gated Na ChannelsInhibit presynaptic release of NT via L-type Ca channels

CarbamazepineOxcarbazepine

Stabilizes inactive state of voltage-gated Na ChannelsInhibit presynaptic release of NT via L-type Ca channels

Valproate Stabilizes inactive state of voltage-gated Na ChannelsIncreases GABA levelsBlocks NMDA glutamate receptorsBlocks T-type voltage gated Ca channels

Ethosuximide Antagonist of T-type voltage-gated Calcium channels

Benzodiazepines (clobazam)

Agonist of GABA (A) receptors

Anticonvulsants: Summary

Drug Mechanism of Action

Lamotrigine Stabilizes inactive state of voltage-gated Na ChannelsIncreases intracellular GABA levelsMay act at N, P/Q type voltage-gated Calcium channels

Vigabatrin Blocks metabolism of GABA through GABA-T

GabapentinPregabalin

Blocks presynaptic release of neurotransmitters via N-type Calcium channelsIncreases intracellular GABA levels

Tiagabine Blocks GAT-1 and prevents uptake of GABA from synapse

Felbamate Blocks NMDA glutamate receptorsEnhances GABA(A) receptor transmissionUnclear effect on voltage-gated Na channels

Levetiracetam

Blocks presynaptic vesicle recycling through SV 2A

Anticonvulsants: Summary

Drug Mechanism of Action

Lacosamide Stabilizes slowly-inactivated Na channelsBinds to CRMP-2

Topiramate Blocks AMPA/Kainate glutamate receptorsBlocks L-type voltage gated Ca channelsUnclear effect on voltage-gated Na channelsMay enhance GABA(A) receptor transmissionWeak inhibitor of carbonic anhydrase

Anticonvulsants and side-effects

Anticonvulsants: Side-effects

Which of the following AED can cause somnolence?

PhenobarbitalValproic acidTopiramateVigabatrinPhenytoinLamictalPrimidoneClobazam

PART I: What makes nerve cells excitable?


Which of the following are side-effects of Topiramate?

1. Blurry vision

2. Metabolic acidosis

3. Paresthesias

4. Ataxia

5. Renal stones

6. Mental slowing with speech and memory disturbance

7. Psychosis

8. Alopecia

9. Weight gain

10.Glaucoma



Which of the following are side-effects of Phenytoin?

1. Blurry vision

2. Metabolic acidosis

3. Paresthesias

4. Ataxia

5. Renal stones

6. Hirsutism

7. Psychosis

8. Osteoporosis

9. Alopecia

10.Weight gain

11.Gum hyperplasia

12.Stevens-Johnson syndrome

13.Blood dyscrasias



Which of the following are side-effects of Valproic acid?

1. Blurry vision

2. Dysfunctional platelets

3. Paresthesias

4. Ataxia

5. Birth defects

6. Hirsutism

7. Psychosis

8. Abdominal pain and other GI symptoms

9. Alopecia

10.Weight gain

11.Liver failure


13.Blood dyscrasias



Which of the following are side-effects of Valproic acid?

1. Blurry vision

2. Dysfunctional platelets

3. Paresthesias

4. Ataxia

5. Birth defects

6. Hirsutism

7. Psychosis

8. Abdominal pain and other GI symptoms

9. Alopecia

10.Weight gain

11.Liver failure


13.Hyperammonemia



Which of the following are side-effects of Carbamazepine?

1. Ataxia

2. SJS

3. Visual field loss

4. SIADH

5. Diplopia

6. Hepatotoxicity

7. Aplastic anemia

8. Paresthesias



Which of the following anticonvulsants cause peripheral visual field defects?

1. Tegretol

2. Phenobarbital

3. Vigabatrin

4. Clobazam

5. Valproic acid

6. Dilantin



Which of the following anticonvulsants cause peripheral visual field defects?

1. Tegretol

2. Phenobarbital

3. Vigabatrin

4. Clobazam

5. Valproic acid

6. Dilantin


Bonus Point: What type of seizures is Vigabatrin used for?


Which of the following anticonvulsant(s) can be used in patients with concomitant psychiatric disorders for mood stabilization?

1. Levetiracetam

2. Phenobarbital

3. Oxcarbazepine

4. Vigabatrin

5. Clobazam

6. Valproic acid

7. Dilantin

8. Lamotrigine



Which of the following anticonvulsant(s) can cause SJS

1. Levetiracetam

2. Phenobarbital

3. Oxcarbazepine

4. Vigabatrin

5. Clobazam

6. Carbamazepine

7. Phenytoin

8. Ethosuximide

9. Valproic acid

10.Felbamate

11.Lamotrigine

12.Lacosamide


Continuum (2010)


Which of the following anticonvulsants

need to be monitored and why?

1. Phenytoin2. Phenobarbital3. Clobazam4. Topamax5. Carbamazepine6. Oxcarbamazepine7. Levetiracetam8. Valproic acid9. Gabapentin10.Pregabalin11.Ethosuximide12.Lacosamide13.Vigabatrin

Anticonvulsants and Pharmacokinetics

Anticonvulsants: Pharmacokinetics

All of the following anticonvulsants are hepatically excreted except:

1. Phenobarbital

2. Oxcarbazepine

3. Carbamazepine

4. Phenytoin

5. Levetiracetam

6. Valproic acid

7. Lamotrigine

8. Lacosamide



Which of the following antoconvulsants decrease efficacy of OCP?

1. Carbamazepine/Oxcarbazepine

2. Phenobarbital

3. Valproic acid

4. Topiramate

5. Vigabatrin

6. Phenytoin

7. Lamictal

8. Primidone



Which of the following antoconvulsants decrease efficacy of OCP?

1. Carbamazepine/Oxcarbazepine

2. Phenobarbital

3. Valproic acid

4. Topiramate

5. Vigabatrin

6. Phenytoin

7. Lamictal (level decreases with OCP use)

8. Primidone


http://basic-clinical-pharmacology.net/chapter%2024_%20antiseizure%20drugs.htm


Anticonvulsants: PharmacokineticsPART I: What makes nerve cells excitable?

Enzyme-Inducers:• Increase rate of

metabolism of drugs metabolized by CYP enzymes

• Results in changes in sex hormone levels and increases clearance of estrogen and progesterone in OCP

• Increase metabolism of Vit D (which is metabolized by liver) → rickets and hypocalcemia in children



Which of the following anticonvulsants will be increased with the concomitant use of erythromycin or clarithromycin?

1. Carbamazepine

2. Phenobarbital

3. Valproic acid

4. Topiramate

5. Vigabatrin

6. Phenytoin

7. Lamictal

8. Primidone



A patient who drinks lots of grapefruit juice presents with toxic levels of which of the following anticonvulsants:

1. Carbamazepine

2. Phenobarbital

3. Valproic acid

4. Topiramate

5. Vigabatrin

6. Phenytoin

7. Lamictal

8. Primidone



A patient who drinks lots of grapefruit juice presents with toxic levels of which of the following anticonvulsants:

1. Carbamazepine (grapefruit inhibits CYP3A4)

2. Phenobarbital

3. Valproic acid

4. Topiramate

5. Vigabatrin

6. Phenytoin

7. Lamictal

8. Primidone



Anticonvulsants (phenytoin, phenobarbital) can generally have the following effect on warfarin:

1. Increase warfarin level

2. Decrease warfarin level



The pharmacokinetics of phenytoin can be described as:

1. Non-linear

2. Linear

3. First-order

4. Zero-order



An ICU patient with multiple medical problems is on IV dilantin for the treatment of status epilepticus. What lab variable do you need to order to ascertain the correct dilantin level?

1. Liver enzymes

2. Albumin

3. CBC

4. Urea

5. Ammonia


Special considerations

Anticonvulsants: Special Considerations

You just diagnosed a 16 year old girl with JME. Which of the following drugs would you not prescibe?

1. Lamictal

2. Levetiracetam

3. Valproic acid


Anticonvulsants: Special ConsiderationsPART I: What makes nerve cells excitable?

Choosing among anticonvulsants

Anticonvulsants: Choosing AEDs

Which of the following are important to consider when choosing an anticonvulsant

1. Age

2. Type of seizure (partial versus generalized)

3. Patient characteristics

4. Co-morbid conditions

5. Cost

6. Side-effect profile


High-level evidence for the efficacy for initial monotherapy of partial seizures exists for which of the following drugs:

1. Phenytoin

2. Lamotrigine

3. Phenobarbital

4. Carbamazepine

5. Oxcarbazepine

6. Topiramate

7. Valproic acid


High-level evidence for the efficacy for initial monotherapy of generalized seizures exists for which of the following drugs:

1. Phenytoin

2. Lamotrigine

3. Phenobarbital

4. Carbamazepine

5. Oxcarbazepine

6. Topiramate

7. Valproic acid


8 year old girl with childhood absence epilepsy, your choice(s) include:

1. Phenytoin

2. Ethosuximide

3. Phenobarbital

4. Lamictal

5. Oxcarbazepine

6. Topiramate

7. Valproic acid


16 year old boy with JME, your choice(s) include all of the following except:

1. Lamictal

2. Carbamazepine

3. Valproic acid

4. Levetiracetam

Anticonvulsants: SummaryPART I: What makes nerve cells excitable?


OUTLINE





OthersA few words

Introduction

Approximately 20% to 30% of all patients with epilepsy will have physically, socially, and medically refractory seizure disorders.

Patients with intractable epilepsy are at increased risk for serious morbidity and mortality.

Introduction

The goals of therapy in patients with medically refractory seizures include:

significantly reducing seizure tendency.

avoiding adverse effects.

permitting the individual to become a participating and productive member of society.

WHEN TO DECIDE DRUG THERAPY HAS FAILED

DRE is now defined as ‘failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom.

less than 5% to 10%, who have not responded to monotherapy with two appropriate antiepileptic drugs (AEDs) or a combination of two drugs will respond to a third drug.

after treatment with multiple AEDS, 11% and 16% became seizure free. It is interesting that 52% of patients treated surgically in one of these studies became seizure free.

Who should be referred for surgery

Surgery outcome

Pre-surgical evaluation

Conclusion Epilepsy surgery is highly effective and has

durable benefits, and improves quality of life.

Despite class I evidence and Clinical Practice Guidelines, epilepsy surgery remains underutilized.

The spectrum of patients who may benefit from epilepsy surgery has expanded considerably including younger and older patients and those without apparent MRI lesions.

Electronic Devices

VNS.

Direct Cortical Stimulation.

Responsive Neurostimulation System.

Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy Trial.

VNSVagus nerve stimulation(VNS) is an approved

treatment for intractable partial epilepsy.

A VNS is a palliative procedure that may reduce seizure tendency.

In clinical trials, seizure frequency was reduced by 25% to 30%, an outcome similar to new AED trials.

Day surgery procedure.

The left vagus nerve is stimulated rather than the right because the right plays a role in cardiac function, and stimulating it could have negative cardiac effects.

Mechanism : Unknown , affect blood flow to different parts of the brain and to affect neurotransmitters, including serotonin and norepinephrine, which are implicated in depression.

common side effects include hoarseness, throat pain, cough, dyspnea and paresthesia.

THE KETOGENIC DIET

The ketogenic diet was developed before all of the anticonvulsants in current use except phenobarbital.

It fell out of favor with the introduction of phenytoin.

Since 1990 ,the ketogenic diet has resurfaced as it is often very effective in patients who have failed numerous drug trials.

patients on the diet often require lower doses of anticonvulsants and become more alert and less dizzy.

Description and Mechanism

The classic diet consists of 4 grams of fat for each gram of protein and carbohydrate consumed.

Mechanism : Unknown ,overall changes in brain protein phosphorylation state and particular examples of altered gene expression have been documented.

Early proposals suggesting that cerebral acidosis or changes in electrolyte concentrations are responsible for the diet’s anti seizure effects

Efficacy

The ketogenic diet is a first-line therapy for patients with seizures associated with certain metabolic disorders.

A number of studies have shown the ketogenic diet to be an effective treatment for medically intractable epilepsy in children.

One of the prospective studies included 51 children from 1 to 8 years of age. At the 12-month follow-up, 10% of the children were seizure free, 22% had a greater than 90% reduction in seizure frequency, and 40% had a greater than 50% reduction.

With adolescents , 45 patients aged 12 to 19 years, 20 patients remained on the diet at 1 year. Seven had a 50% to 90% reduction in seizure frequency, while six had a greater than 90% reduction.

One recent adult study. This study included 11 adults between age of 32 -45.

At 8 months follow-up, three patients had a 90% decrease in seizure frequency, three patients had a 50% to 89% decrease ,and one patient had a less than 50%decrease. 6 patients discontinued the diet. 2 had no change in their seizure frequency .

Side Effects and Precaution

Common adverse effects in adolescent and adult trials Included constipation, hypercholesterolemia, Menstrual irregularities, and weight loss.

Kidney stones occur in 6% to7% of children on the diet.

Because valproate is an inhibitor of fatty acid oxidation and decreases hepatic ketogenesis, Valproate is not recommended.

References:

Deckers et al. Conference Report. Current limitations of antiepileptic drug therapy:a conference review. Epilepsy Research 53 (2003) 1–17.

Joana Guimara˜es, and Jose´ Augusto Mendes Ribeiro. Pharmacology of Antiepileptic Drugs in Clinical Practice. The Neurologist 2010;16:353–357.

Johannessen SI, Landmark CJ. Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67.

Panayiotopoulos CP. A Clinical Guide to Epileptic Syndromes and Their treatment. Second Edition. 2010.

Continuum. Epilepsy. 2010.




Questions??


Seizing hold of seizuresGregory L Holmes & Yezekiel Ben-Ari

Figure 1. Focal seizures result from a limited group of neurons that fire abnormally because of intrinsic or extrinsic factors.(a) In this simplified diagram, II and III represent epileptic neurons. Because of extensive cell-to-cell connections, termed 'recurrent collaterals', aberrant activity in cells II and III can fire synchronously, resulting in a prolonged depolarization of the neurons. (b) This intense depolarization of epileptic neurons is termed the paroxysmal depolarization shift. The prolonged depolarization results in action potentials and propagation of electrical discharges to other cells. The paroxysmal depolarization shift is largely dependent on glutamate excitation and activation of voltage-gated calcium and sodium channels. After the depolarization, the cell is hyperpolarized by activation of GABA receptors as well as voltage-gated potassium channels. Axons from the abnormal neurons also activate GABAergic inhibitory neurons (green) which reduce the activity in cells II and III in addition to blocking the firing of cells outside the seizure focus (cells I and IV). An electroencephalogram (EEG) recorded during this time would show a spike and a subsequent slow wave. When the balance of excitation and inhibition is further disturbed, there will be a breakdown in containment of the epileptic focus and a seizure will occur. (c) A sustained depolarization without repolarization occurs in many cells during the seizure. An EEG would show repetitive spikes during the seizure. By inducing cells to release galanin, an endogenous anticonvulsant that reduces glutamate release, Haberman et al. successfully increased inhibition and thereby reduced seizure susceptibility.

Anticonvulsants: Voltage-gated Na channels

• Blockade/modulation of Voltage-gated Na channels is the most common mechanism of action of most of the AEDs

• Bind and stabilize inactive forms of channel → prevent repetitive neuronal firing

CBZ

PHT

VPA

LTG

Oxcarbazepine

Eslicarbazepine

Lacosamide

?Felbamate

Topiramate

Zonisamide

Rufinamide

Approach to Epilepsy(When to stop treatment)

• Seizure control is possible for most patients with epilepsy

• In a recent study by Brodie et al. (2012, Neurology)• 69% seizure-freedom over 2 years• 61% seizure-freedom over 5 years• 52% seizure-freedom over 10 years

• After many years of seizure-freedom, patient begin to question whether therapy is still necessary

• Desire to discontinue medications:• Side-effects• Cost• Inconvenience• Fear of long-term side-effects

• Risk of recurrence after anticonvulsant discontinuation: 12% to 63% over 2 to 5 years follow-up (majority: 41% or less relapse rate)

Approach to Epilepsy(When to stop treatment)

Academic Half-Day Treatment of Epilepsy Ruba Benini & Abdullah Tawakul July 25 th, 2012.

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Transcript of Academic Half-Day Treatment of Epilepsy Ruba Benini & Abdullah Tawakul July 25 th, 2012.