Faculty

CME Course Director and Content DevelopmentMichael C. Smith, MDDirector, Rush Epilepsy Center

Professor, Department of Neurological SciencesRush University Medical Center

Chicago, Illinois

Content DevelopmentJohn DeToledo, MD

Professor and ChairDepartment of Neurology

Texas Tech UniversityHealth Sciences Center

Lubbock, Texas

CME Objectives

I plan to incorporate the following objectives into my current practice of medicine:

• Utilize specific diagnostic testing in patients with uncontrolled epilepsy

• Determine seizure type based on symptoms

• Employ treatment options for patients (AEDs, surgery, VNS) with refractory complex partial seizures based on their efficacy and durability

• Prescribe appropriate AEDs in patients with refractory complex partial seizures

Refractory Epilepsy

Definition and Potential Predictors of Refractory Epilepsy

• Definition ─ failure of ≥2 drugs and occurrence of ≥1 seizure/month over 18 months

• Factors that may predict refractory epilepsy– Type of epilepsy

– Underlying syndrome

– Etiology

– History of seizure frequency, density, and clustering

– Environmental factors Trauma

Prior drug exposure

– Genetic factors that influence a drug’s PK/PDPD = pharmacodynamics; PK = pharmacokineticshttp://professionals.epilepsy.com/page/Definition_of_refractory_seizures.html. Accessed May 8, 2011.French JA. CNS Epilepsia. 2007;48:3-7.

Epidemiology

• > 7.5 million people worldwide with refractory epilepsy

• ~ 50% of patients are seizure-free with current antiepileptic drugs (AEDs)

• ~ 33% of patients do not have seizure control with current AEDs

– Of the remaining 67% who do achieve remission, ~ 15% have recurrence of seizures over time

• Patients with refractory seizures incur a cost many times higher than those with controlled epilepsy

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.http://profesionals.epilepsy.com/page/Epidemiology.html. Accessed May 8, 2011. Granata T, et al. Expert Rev Neurother. 2009;9:1791-1802.

Approximately One-Third of Patients Are Refractory to AEDs

Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-339.

Treatment regimen

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Mortality

• Patients with epilepsy have a 2- to 3-fold higher risk of mortality than the general population– Increased risk varies by etiology, seizure type, degree

of seizure control, and extent of coexisting neurological impairment

• Patients with refractory epilepsy have a 4- to 7-fold higher risk of mortality than patients in remission– SUDEP accounts for up to 50% of deaths

– Majority of remaining deaths are caused by accidents, suicide, pneumonia, and cerebrovascular disease

SUDEP = sudden unexplained death in epilepsySperling MR. CNS Spectr. 2004;9:98-101, 106-109.

Impact on Quality of Life

Wheless JW. Epilepsy Behav. 2006;8:756-764.

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Possible Reasons for Refractory Epilepsy

• Errors in diagnosis– Failure to identify a seizure syndrome

– Incorrect seizure classification

– Nonepileptic seizures

• Errors in AED choice or management– Incorrect drug for the seizure type or syndrome

– Inadequate drug dose/timing

– Drug-drug interactions

• Noncompliance– Inadequate patient education

– Too frequent or complex dosing schedule

– Poor tolerability

http://professionals.epilepsy.com/page/Potentially_remediable_causes.html. Accessed May 8, 2011.

Potential Consequences of Refractory Epilepsy

• Accidents and physical injuries

• Brain injury and cognitive impairment

• Psychological disorders

• Social isolation and poor self-image

• Lower educational accomplishment

• Decreased employment

Sperling MR. CNS Spectr. 2004;9:98-101, 106-109.

Diagnosis

Review of Patient’s Medical History

• Careful assessment of history fundamental to clinical diagnosis

• Important in search for etiology– In adults 35 − 64 years, main etiologies are head

trauma, vascular insults, and tumors– In adults > 65 years, main etiologies are

cerebrovascular disease and degenerative disorders

• May allow for identification of possible risk factors

• Seizure calendars or diariesTreiman DM. Neuropsych Dis and Treat. 2010;6:297-308.http://profesionals.epilepsy.com/page/Diagnositic_evaluation.html. Accessed May 9, 2011.

Localization-Related Epilepsy

Simple Partial Complex PartialPartial Onset With

Secondary Generalization

•No impairment of consciousness

•Clinical features reflect localization of seizure focus

•Engage portions of opposite hemisphere

•Some impairment of consciousness

•Spread from cortical focus to diencephalon and opposite hemisphere

•Complete impairment of consciousness

•Generalized tonic-clonic convulsions

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.

Clinical Semiology of Complex Partial Seizures

• Dependent upon location of cortical seizure focus

Temporal Lobe Frontal Lobe Occipital Lobe Parietal Lobe

• Aura, viscerosensory sensations, oro-alimentary automatisms

• Postictal confusion with gradual recovery

• Commonly nocturnal• Abrupt onset and short

duration, with little/no postictal confusion

• Explosive or bizarre behavior possible

• Visual hallucinations, forced blinking/ eyelid flutter

• Sensory alterations, visuospatial disorientation, apraxias

• Ipsilateral eye movement possible

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.

Common Characteristics of CPS

• Temporal lobe most common site of origin (~80%); parietal lobe least common

Neurologic Examination

• To identify – Presence of abnormalities, even subtle,

to add support that events are epileptic seizures

– Potential lateralizing abnormalities for predicting location of epileptic focus

• Can be augmented by – Detailed history of seizure semiology– Video recordings of the seizures

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.

Neuroimaging — MRI

• Most sensitive and specific imaging technique for partial-related epilepsy

• Resolution improved by introduction of increasingly powerful magnets– T1- and T2-weighted

imaging

– FLAIR

FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imagingTreiman DM. Neuropsych Dis and Treat. 2010;6:297-308.Image courtesy of Dr. Travis Stoub, High Resolution Epilepsy Protocol, Rush University Medical Center (personal communication)

MRI

Identifying Malformations of Cortical Development With 3T MRI

3T = 3 TeslaImage courtesy of Dr. Michael Stein, Alexius Medical Center (personal communication)

Neuroimaging — Nuclear Medicine

• Positron emission tomography (PET) — metabolic activity

• Single-photon emission computed tomography (SPECT) — ictal and interictal blood flow

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.Image courtesy of Dr. Marvin Rossi, Rush University Medical Center (personal communication)

Ictal SPECTInterictal SPECT

Neuroimaging — SISCOM

• Subtraction ictal SPECT coregistered to MRI (SISCOM) — improved the power of SPECT

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.Image courtesy of Dr. Marvin Rossi, Rush University Medical Center (personal communication)

SISCOM

EEG Monitoring

• Determine seizure type

• Finding epileptiform discharges not essential for diagnosis– Recording off medication can

precipitate seizure

• Advantages of recording 30 minutes of sleep in an EMU– Increases likelihood of

observing interictal spikes

– Recorded behavior can be correlated to EEG changes

• Almost all patients evaluated in an EMU have refractory seizures

EMU = epilepsy monitoring unitTreiman DM. Neuropsych Dis and Treat. 2010;6:297-308.http://profesionals.epilepsy.com/page/Diagnositic_evaluation.html. Accessed May 9, 2011.Image courtesy of Elaine Wylie’s Principles of Epilepsy

EEG: complex partial seizure

MEG Detection of Structural Abnormality Not Previously Seen on MRI

MEG = magnetoencephalographyImage courtesy of Dr. Michael Stein, Illinois MEG Center Alexian Brothers Medical Center

Common Diagnostic Errors

• It is essential to consider diagnostic errors in every case

• Disorders commonly misdiagnosed as epilepsy– Psychogenic nonepileptic seizures– Syncope– REM sleep behavior disorder

REM = rapid eye movementhttp://professionals.epilepsy.com/page/Wrong_diagnosis.html. Accessed May 9, 2011.

Diagnosis and Implications of Epilepsy in the Elderly

• Symptoms of epilepsy in the elderly differ from younger patients– Elderly often present with vague symptoms: confusion,

altered mental status, memory loss

• Lack of clinical signs in the elderly may lead to delayed diagnosis and treatment

Waterhouse E, et al. Cleve Clin J Med. 2005;72(Suppl 3):S26-S37. Garnett WR. Ann Pharmacother. 2005;39:1852-1860.

Parameter Young Elderly

Number of seizure types Multiple Singular

Most common seizure type Tonic-clonic Complex partial

Seizure frequency High Low

Postictal state Brief Prolonged

Injury potential Low High

Treatment

Overview of Treatment Approaches for Refractory Partial Seizures

Pharmacologic– Classic AEDs– New AEDs

Nonpharmacologic– Surgery

– Ablative therapy Gamma Knife

radiosurgery

Laser-induced thermal ablation

– Electrical stimulation Vagus nerve stimulation

Deep brain stimulationa

– Ketogenic diet Modified Atkins diet

a. Not approved by United States Food and Drug Administration.Treiman DM. Neuropsychiatr Dis Treat. 2010;6:297-308.Régis Y, Roberts DW. Stereotact Funct Neurosurg. 1999;72 Suppl 1:11-21.Tovar-Spinoza Z, et al. Childs Nerv Syst. 2013 Jun 4. Epub ahead of print.Granata T, et al. Expert Rev Neurother. 2009;9:1791-1802.http://www.epilepsy.com/epilepsy/treatment_atkins_diet. Accessed June 8, 2011.

Pharmacologic Treatment Approaches

Currently Approved AEDs for Partial-Onset Seizures

Classic AEDs

– Phenobarbital

– Phenytoin

– Primidone

– Carbamazepine

– Valproate

Newer AEDs

– Felbamate

– Gabapentin

– Lamotrigine

– Topiramate*

– Tiagabine

– Levetiracetam

– Oxcarbazepine*

– Zonisamide

– Pregabalin

– Lacosamide

– Vigabatrin

– Clobazam†

– Ezogabine (retigabine)

– Perampanel

– Eslicarbazepine

*Extended-release formulations available.†Approved for Lennox-Gastaut syndrome.NOTE: Drugs are listed in order of approval in United States except extended-release formulations. Treiman DM. Neuropsychiatr Dis Treat. 2010;6:297-308; Onfi [package insert]. Deerfield, IL: Lundbeck Inc.; 2011; Potiga [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013; Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012. Oxtellar XR [package insert]. Rockville, MD: Supernus Pharmaceuticals, Inc.; 2012.

Factors to Consider When Choosing an AED

Adverse reactions AED(s)

Hirsutism, gum hyperplasia Phenytoin

Alopecia, tremor Valproate

Weight gain Valproate, gabapentin, pregabalin

Weight loss Felbamate, topiramate, zonisamide

Hyponatremia Carbamazepine, oxcarbazepine

Teratogenicity Valproate

Hypersensitivity All AEDs

Other factors AED(s)

Once-daily dosing possible Phenobarbital, phenytoin, topiramate, zonisamide, extended-release AEDs

Time needed for dose escalation Lamotrigine, zonisamide

Formulary status/cost* All AEDs

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.

*A drug that is not affordable is neither safe nor effective

Efficacy of Classic AEDs in Patients With Partial Seizures

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Mattson RH, et al. N Engl J Med. 1985;313:145-151.

Newer AEDs as Add-on Therapy in Patients With Refractory Epilepsy

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NOTE: Patient follow-up in these studies varied, but maximum follow-up period studied was 3 months. 1. French JA , et al. Neurology. 2004;62:1261-1273. 2. Nadkarni S, et al. Neurology. 2005;64(suppl 3):S2-S11.

Tiagabine1,2

Efficacy of Felbamate in Patients With Refractory Complex Partial Seizures

• Eligible patients (N = 56) had ≥ 4 seizures/month on phenytoin and carbamazepine– Mean age = 31 years– Gender = 32 male; 24 female

Leppik IE, et al. Neurology. 1991;41:1785-1789.

Seizure frequency

Mean

P valueFelbamate Placebo

Over 8 weeks 34.9 40.2 ─

Reduction over 8 weeks 4.95 - 0.36 0.046

Percent reduction 4.24 - 19.14 0.018

Truncated percent reduction 7.60 - 9.90 0.007

Efficacy of Pregabalin in Patients With Refractory Complex Partial Seizures

French et al Arroyo et al Beydoun et al

French JA, et al. Neurology. 2003;60:1631-1637.Arroyo S, et al. Epilepsia. 2004;45:20-27.Beydoun A, et al. Neurology. 2005;64:475-480.

Doses (mg/day)given as 2 divided doses

Doses (mg/day)given as 3 divided doses

Doses (mg)

Efficacy of Lacosamide in Patients With Refractory Complex Partial Seizures

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40%

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Placebo LCS 200

LCS 400

LCS 600

Placebo LCS 400

LCS 600

Placebo LCS 200

LCS 400

* * *

*P < .05 vs placebo

Ben-Menachem E, et al. Epilepsia. 2007;48:1308-1317Chung S, et al. Epilepsia. 2010;51:958-967Halasz P, et al. Epilepsia. 2009;50:443-453.

Ben-Menachem et al Chung et al Halasz et al

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Efficacy of Vigabatrin in Patients With Refractory Complex Partial Seizures

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VGB 3 g/day

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* * P ≤ .0001 vs placebo

Dean et al French et al

Dean C, et al. Epilepsia. 1999;40:74-82. French JA , et al. Neurology. 1996;46:54-61.

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Efficacy of Ezogabine in Patients With Refractory Complex Partial Seizures

Placebo EZG 600 mg/d

EZG 900 mg/d

EZG 1200 mg/d

Placebo EZG 1200 mg/d

Placebo EZG 600 mg/d

EZG 900 mg/d

0%

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10%

15%

20%

25%

30%

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Porter RJ, et al. Neurology. 2007;68(15):1197-1204.French JA, et al. Neurology. 2011;76(18):1555-1563Brodie MJ, et al. Neurology. 2010;75(20):1817-1824.

Porter et al Brodie et alFrench et al

Efficacy of Perampanel in Patients With Refractory Complex Partial Seizures

French JA ,et al. Neurology. 2012;79(6):589-596. French JA, et al. Epilepsia. 2013;54(1):117-125. Krauss GL, et al. Neurology. 2012;78(18):1408-1415.

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Placebo PML 8 mg/d

PML 12 mg/d

Placebo PML 8 mg/d

PML 12 mg/d

Placebo PML 2 mg/d

PML 4 mg/d

PML 8 mg/d

0%

5%

10%

15%

20%

25%

30%

35%

40%

21%

26%

35%

10%

31%

18%

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23%

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*

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French et al Neurology

Krauss et alFrench et alEpilepsia

*

Placebo ESL 400 mg/d

ESL 800 mg/d

ESL 1200 mg/d

Placebo ESL 400 mg/d

ESL 800 mg/d

ESL 1200 mg/d

Placebo ESL 800 mg/d

ESL 1200 mg/d

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

1%

19%

33% 33%

16%

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Efficacy of Eslicarbazepine in Patients With Refractory Complex Partial Seizures

Ben-Menachem et al Elger et al Gil-Nagel et al

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Ben-Menachem E, et al. Epilepsy Res. 2010;89:278-285.Elger C, et al. Epilepsia. 2009;50:454-463.Gil-Nagel A, et al. Acta Neurol Scand. 2009;120:281-287.

* **

*

*

*

Safety of AEDs

• Drug tolerability important in selecting an AED

• AEDs commonly associated with cognitive, behavioral, or sedative side effects– Complicate use – Negatively impact quality of life

• Side effects more common with classic AEDs

Asconape JJ, et al. Neurol Clin. 2010;28:843-852.

Most Common Side Effects of AEDs

Asconape JJ, et al. Neurol Clin. 2010;28:843-852.

Newer AEDs– Cognitive impairment– Diplopia, blurred vision– Dizziness, ataxia– Drowsiness– Fatigue– Headache– Hyponatremia– Metabolic acidosis– Mood swings, irritability– Nausea– Nephrolithiasis– Oligohidrosis– Paresthesia– Weight gain or loss

Classic AEDs– Confusion– Diplopia, blurred vision– Dizziness, ataxia– Drowsiness– Fatigue– Headache– Irritability– Nausea– Neutropenia– Osteopenia– Rash– Thrombocytopenia– Tremor– Weight gain

Incidence of AEs in Adults With Partial-Onset Seizures Treated With Adjunctive Ezogabine

AEs in Adults With Partial-Onset Seizures Treated With Adjunctive Ezogabine

Adverse Event Placebo(n = 427)

600 mg/d (n = 281)

900 mg/d (n = 273)

1200 mg/d (n = 259)

(%)

Dizziness 9 15 23 32

Somnolence 12 15 25 27

Fatigue 6 16 15 13

Confusional state 3 4 8 16

Vertigo 2 8 8 9

Tremor 3 3 10 12

Abnormal coordination 3 5 5 12

Diplopia 2 8 6 7

Attention disturbance <1 6 6 7

Memory impairment 3 3 6 9

Asthenia 2 4 6 4

Blurred vision 2 2 4 10

Gait disturbance 1 2 5 6

Aphasia <1 1 3 7

Dysarthria <1 4 2 8

Balance disorder <1 3 3 5

AE = adverse event.Potiga [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013; FDA Safety Alert. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm349847.htm Accessed July 9, 2012.

• Other reported adverse reactions include:– Urinary retention

– Neuropsychiatric symptoms

– QT interval effect

– Skin discoloration

– Retina pigment changes, with potential vision loss

Incidence of AEs in Adults With Partial-Onset Seizures Treated With Perampanel

AEs in Adults With Partial-Onset Seizures Treated With Perampanel in Phase 3 Trials

AE = adverse event.Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012

Adverse Event Placebo(n = 442)

4 mg/d (n = 172)

8 mg/d (n = 431)

12 mg/d (n = 255)

(%)

Dizziness 9 16 32 43

Somnolence 7 9 16 18

Fatigue 5 8 8 12

Irritability 3 4 7 12

Falls 3 2 5 10

Nausea 5 3 6 8

Ataxia 0 1 3 8

Balance disorder

1 0 5 3

Gait disturbance 1 1 4 4

Vertigo 1 4 3 5

Weight gain 1 4 4 4

• Other reported adverse reactions include:– Neurologic effects

– Falls

• Black box warning for serious psychiatric and behavioral reactions including aggression, hostility, irritability, anger and homicidal ideation

Incidence of AEs in Adults With Partial-Onset Seizures Treated With Eslicarbazepine

AE = adverse event.Elger C, et al. Epilepsia. 2009;50:454-463.Hufnagel A, et al. Epilepsy Res. 2013;103:262-269.

Adverse Event

Placebo(n = 102)

400 mg/d

(n = 100)

800 mg/d

(n = 98)

1200 mg/d

(n = 102)

(%)

Dizziness 2 4 14 14

Headache 6 5 9 11

Diplopia 0 2 7 11

Somnolence 2 6 9 10

Vertigo 1 2 2 6

AEs in Adults Treated With AdjunctiveEslicarbazepine in a Clinical Study

• In a long-term safety study, additional reported adverse reactions (occurring in ≥5% of patients) included:– Diastolic blood pressure

increase

– Abnormal coordination

– Vomiting

– Nausea

– Nasopharyngitis

– Diarrhea

– Back pain

– Blurred vision

Extended-Release Formulations of Oxcarbazepine and Topiramate

Extended-Release Oxcarbazepine

• 38% and 43%* median percent reduction in seizure frequency for 1200- and 2400-mg doses, respectively, vs 29% for placebo (*P < .01 vs placebo)

• The most frequently reported adverse events (>5% of patients): dizziness, somnolence, diplopia, headache, vomiting, fatigue, balance disorder, tremor, asthenia

Extended-Release Topiramate

• Indicated as initial monotherapy in patients age ≥10 years with partial-onset or primary generalized tonic-clonic seizures– Adjunctive therapy in patients

age ≥6 years with partial-onset or primary generalized tonic-clonic seizures or Lennox-Gastaut syndrome

• Available in 25-, 50-, 100-, and 200-mg doses

• Generally well tolerated, with no serious or severe adverse events

Oxtellar XR [package insert]. Rockville, MD: Supernus Pharmaceuticals, Inc.; 2012; Trokendi XR Tentative Approval Letter. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/201635Orig1s000ltr.pdf. Accessed July 6, 2013; Braun T, et al. Neurology. 2013;80(Meeting Abstracts):P04.212.

Potential for Drug-Drug Interactions With AEDs

Cytochrome P450

Negligible or no effect

Ezogabine (retigabine)GabapentinLacosamideLamotrigine

LevetiracetamPerampanelPregabalinTiagabineVigabatrin

Zonisamide

Asconape JJ, et al. Neurol Clin. 2010;28:843-852; Onfi [package insert]. Deerfield, IL: Lundbeck Inc.; 2011; Potiga [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013; Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012.

Mild inducers (3A4) or inhibitors (2C19)

OxcarbazepineTopiramateClobazam

Inhibitors(2C9, UGT, EH, 2D6)

ValproateFelbamateClobazam

Inducers(1A2, 2C, 3A4, UGT)

PhenytoinCarbamazepinePhenobarbital

Primidone

Black Box Warnings of AEDs

http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/index.cfm. Accessed May 14, 2011; Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012; Potiga [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013.

AED Black box warning

Phenytoin Stevens-Johnson syndrome

Carbamazepine Serious dermatologic reactions and HLA-B*1502 allele, aplastic anemia, and agranulocytosis

Valproate, divalproex Hepatotoxicity, teratogenicity, pancreatitis

Lamotrigine Serious skin rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death

Felbamate Aplastic anemia and hepatic failure

Vigabatrin Vision loss

PerampanelSerious or life-threatening psychiatric and behavioral adverse reactions, including aggression, hostility, irritability, anger, and homicidal ideation

Ezogabine Retinal abnormalities and potential vision loss

Key Warnings and Precautions

All Suicidal behavior and ideation

ILAE Guidelines for EpilepsyClass of study

Seizure type or epilepsy syndrome I II III Level of efficacy and effectiveness evidence

Adults with partial-onset seizures

4 1 34 Level A: CBZ, LEV, PHT, ZNSLevel B: VPALevel C: GBP, LTG, OXC, PB, TPM, VGB

Children with partial-onset seizures

1 0 19 Level A: OXCLevel B: NoneLevel C: CBZ, PB, PHT, TPM, VPA, VGB

Elderly adults with partial-onset seizures

1 1 3 Level A: GBP, LTGLevel B: NoneLevel C: CBZ

Adults with generalized-onset tonic-clonic seizures

0 0 27 Level A: NoneLevel B: NoneLevel C: CBZ, LTG, OXC, PB, PHT, TPM, VPA

Level A = at least 1 randomized controlled trial (RCT) or meta-analysis of RCTs showing superiority (class I) or 2 RCTs or meta-analyses showing noninferiority with 21-30% margin (class II); level B = 1 class II RCT or meta-analysis; level C = at least 2 RCTs showing noninferiority with >30% margin (class III).CBZ = carbamazepine; GBP = gabapentin; ILAE = International League Against Epilepsy; LEV = levetiracetam; LTG = lamotrigine; OXC = oxcarbazepine; PB = phenobarbital; PHT = phenytoin; TPM = topiramate; VGB = vigabatrin; VPA = valproic acid; ZNS = zonisamide.NOTE: AEDs with level A or B evidence of efficacy should be considered for first-line monotherapy.

Glauser TA, et al. Epilepsia. 2013;54:1-13.

Strategies for Optimizing AED Use

• Verify diagnosis and classification; determine etiology if possible

• Match choice of AED to seizure type(s) and to a patient’s specific characteristics

• Use monotherapy if possible

• Use polytherapy if necessary

• When adding an AED start low and go slow, but push to maximum tolerated dose if necessary

• Consider changing timing of dosing to reduce toxicity

• Use pharmacokinetic principles to fine-tune dose

• Adjust dose for drug-drug interactions

• Do not give up

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.

AEDs — Current Limitations and Future Perspectives

• Current limitations– Antiseizure activity, but lack

antiepileptogenic properties– Considerable side effects, acute and chronic– Rationale for polypharmacy mainly based on

empirical evidence

• Future perspectives– Shift to using models that identify disease-

modifying agents– Shift to delivering drug directly into the brain

Boon PA. Seizure. 2011;20:357-358.

Nonpharmacologic Treatment Approaches

Nonpharmacologic Treatment Approaches

• Surgery

• Electrical stimulation– Vagus nerve stimulation– Deep brain stimulation

• Ablative therapy– Gamma Knife radiosurgery– Laser-induced thermal ablation

• Ketogenic diet– Modified Atkins diet

Granata T, et al. Expert Rev Neurother. 2009;9:1791-1802.Régis Y, Roberts DW. Stereotact Funct Neurosurg. 1999;72 Suppl 1:11-21.Tovar-Spinoza Z, et al. Childs Nerv Syst. 2013 Jun 4. Epub ahead of print.http://www.epilepsy.com/epilepsy/treatment_atkins_diet. Accessed June 8, 2011.

Surgery

Epilepsies That May Benefit

• Mesial temporal lobe epilepsy

• Frontal lobe epilepsy

• Lesional partial epilepsy– Focal encephalomalacia

– Tumor

– Vascular malformation

– Congenital developmental anomaly

• Neocortical cryptogenic epilepsy

Available Interventions

• Resection of the seizure focus

• Multiple subpial transection when seizure focus is in eloquent cortex

• Destruction of seizure focus by gamma knife/lasera

• Corpus callosotomy

a. Gamma knife is not FDA approved.Engel J, et al. Epilepsia. 2003;44:741-751; Wiebe S, et al. New Engl J Med. 2001;345:311-318; Zimmerman R and Sirven J. Mayo Clin Proc. 2003;78:109-117; Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308. Asadi-Pooya AA, et al. Epilepsy Behav. 2008;13:271-278.

Surgical Evaluation

• Candidates undergo extensive evaluation– EEG to determine seizure origin

– Neuroimaging tests to support EEG

• High probability of success if following conditions are true– Area of seizure onset is consistently and repeatedly

from same brain region

– Implicated region can be safety removed without creating intolerable deficits

• In ideal candidate, success rates are 70% ─ 90%

http://professionals.epilepsy.com/page/Surgical_evaluation.html. Accessed May 15, 2011.Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.

Predictors of Surgical Outcome

• Lesional vs nonlesional epilepsy

• Temporal vs extratemporal epilepsy

• Presence of hippocampal sclerosis or lack thereof

• Postoperative EEG

Rudzinski LA , Meador KJ. Neurol Clin Prac. 2011;76:S20-S25.

Vagus Nerve Stimulation (VNS)

• For treatment of patients who failed to respond to ≥ 3 AEDs and for whom surgery is not possible

• Pulse generator implanted subcutaneously and connected to left vagus nerve– Stimulation parameters can

be programmed

• Precise mechanism of action unknown

Sethi NK, et al. The Internet J Neurol. 2008;9.

Clinical Efficacy of VNS

• > 50% reduction in seizure frequency in most patients

• In a long-term prospective study, mean seizure reduction at 1 ─ 6 years, respectively, was 14%, 25%, 29%, 29%, 43%, and 50%

• In an open-label, retrospective study, overall reduction in mean monthly seizure frequency was 51% and responder rate was 59%

• In a retrospective analysis of a randomized trial, 6 of 7 nonresponders had > 50% reduction in seizures after current was increased

Sethi NK, et al. The Internet J Neurol. 2008;9.

Adverse Events and Contraindications of VNS

• Adverse events– Dyspnea, increased coughing, laryngismus,

pharyngitis, nausea, throat pain, dysphagia, and hoarseness of voice

– Affects respiration during sleep and can worsen sleep apnea

• Contraindications– Short-wave diathermy, microwave diathermy, and

therapeutic ultrasound

– Switch off VNS device prior to MRI

– Avoid machines that generate strong electric or magnetic fields

Sethi NK, et al. The Internet J Neurol. 2008;9.

Deep Brain Stimulation

• SANTE study– 3-month double-blind phase — 40.4% reduction in seizures

in stimulated group vs 14.5% in control group; P = .002

– 2-year follow-up — 54% had ≥ 50% reduction in seizure rate and 14 patients were seizure-free for ≥ 6 months

– Approved in Europe and Canada; not FDA approved

• RNS System (by NeuroPace) – Cranially implanted responsive neurostimulator (RNS)

– Significant in seizures with RNS (n=97) vs sham (n=94) -37.9% vs -17.3%, P = .012

– FDA approved for treatment of adults with partial-onset seizures not controlled with ≥2 AEDs

Lega BC, et al. Neurobiology of Disease. 2010;38:354-360.Fisher R, et al. Epilepsia. 2010;51:899-908.Morrell M, et al. Neurology. 2011;77:1295-304.

Ketogenic Diet for Children With Refractory Epilepsy

• High-fat, low-protein, low-carbohydrate diet effective in children with refractory epilepsy– > 50% of children have a > 50% reduction in

seizure frequency– 10% − 15% become seizure-free

• In the “classic” diet, 90% of calories are derived from fat

• Production of ketone bodies may diminish hyperexcitability of neurons and improve seizure control

http://professionals.epilepsy.com/page/Non_pharmacologic_therapies.html. Accessed May 18, 2011.

Ketogenic Diet for Adults With Refractory Epilepsy

• Very limited studies in adults

• Data from small prospective studies (9 − 12 patients each) demonstrate that 22% − 33% have > 50% reduction in seizure frequency

• Larger, randomized studies needed to further support potential efficacy in adults with refractory epilepsy

Klein P, et al. Epilepsy Behav. 2010;19:575-579.

Modified Atkins Dietfor Refractory Epilepsy

• Modified version of ketogenic diet– “Modified Atkins”: allows less carbohydrates

than traditional Atkins with higher fat intake

• Initial studies in children and adults showed– 50% seizure reduction after 6 months in about

two-thirds of patients– Many patients able to reduce medications

• Potential side effects: weight loss, increased cholesterol level, and kidney stones

• Blood and urine monitoring every 3 months

• Urine ketones tested once or twice weeklyhttp://www.epilepsy.com/epilepsy/treatment_atkins_diet. Accessed June 8, 2011.

Summary and Conclusions

Summary and Conclusions

• Affects 7.5 − 10 million people worldwide

• Approximately one-third of patients have uncontrolled seizures

• Several treatment strategies– Pharmacologic: AEDs– Nonpharmacologic: surgery, electrical

stimulation, herbal treatment, ketogenic diet

• Increased understanding of epileptogenesis should improve diagnosis and treatment so more patients can be seizure-free

Treiman DM. Neuropsych Dis and Treat. 2010;6:297-308.