CME Objectives

Upon completion of this educational activity, participants should be able to:

•Diagnose Lennox-Gastaut syndrome based on techniques, symptoms, and clinical presentation

•Employ treatment options for patients (AEDs, surgery, VNS) with Lennox-Gastaut syndrome, based on individualized care as the patient ages

•Prescribe appropriate AEDs in patients with Lennox-Gastaut syndrome

Introduction

• Lennox-Gastaut syndrome (LGS) is a severe difficult-to-treat epilepsy of childhood onset1,2

– Frequently persists into adulthood

• Well-defined clinical and neurophysiologic features3

• Definition has varied over time resulting in misclassification and overdiagnosis3

• Management in adulthood is problematic due to2

– Intractable seizures

– Complexity of intellectual development issues

– Social effects of intellectual disability/behavioral difficulties

1. Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93.2. Kerr M, et al. Epileptic Disord. 2011;13:S15-26.3. Van Rijkevorsel K. Neuropsych Dis Treat. 2008;4:1001-19.

Definition

LGS Defined by ILAE (2001)

• Childhood onset

• Multiple seizure types

– Common: tonic, atonic, atypical absence

– Rare: focal, myoclonic

• Specific EEG pattern

– Diffuse SSW complexes and bursts of fast rhythms (≥10 Hz) during sleep

• Psychologic abnormalities with psychomotor delay, behavioral disorder, or both

Abbreviations: EEG, electroencephalography; ILAE, International League Against Epilepsy; LGS, Lennox-Gastaut syndrome; SSW, slow spike-wave.Engel J. Epilepsia. 2001;42:796-803.

Varied Definitions of LGS

Abbreviations: IDD, intellectual developmental disorder; ILAE, International League Against Epilepsy; LGS, Lennox-Gastaut syndrome; SSW, slow spike-wave.1. Lennox WG, Davis JP. Pediatrics. 1950;5:626-44.2. Trevathan E, Murphy CC. Epilepsia. 1997;38:1283-8.3. Genton P, et al. Handbook of Clinical Neurology. 2000;73(29) (reviewed in Van Rijkevorsel K. Neuropsych Dis Treat. 2008;4:1001-19).4. Engel J. Epilepsia. 2001;42:796-803.5. French J, et al. Neurology. 2004;62:1261-73.

AuthorChildhood

OnsetIDD

Multiple Seizure Types

Tonic Seizure in

Sleep

Diffuse Slow SSW

Fast Rhythms in

Sleep

Lennox19501 Trevathan 19972 Genton 20003 ILAE 20014 French 20045

Complexities of LGS Definition

• Core seizure types (tonic, atonic, atypical absence) not always present at onset1

• Interictal SSW EEG pattern not always pathognomonic1

• Other seizure types (eg, focal or myoclonic) and other EEG features can occur1

• Many patients do not fit the classic definition

– Elderly patient, started with focal pathology of frontal lobe, evolved into LGS-like disorder (treated as LGS)

Abbreviations: EEG, electroencephalography; LGS, Lennox-Gastaut syndrome; SSW, slow spike-wave.1. Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93.

Epidemiology—Etiology

Epidemiology of LGS

• Accounts for 1%-10% of all childhood epilepsies1

• May evolve from IS and encephalopathic epilepsy

– IS preceded LGS in 39% of cases2

• Annual incidence of LGS: 2 per 100,000 individuals2

• Prevalence ranges from 0.1-0.3 per 1000 individuals2

• Onset <8 years of age (peak 3-5 years)3,4

• More common in males than females4

• Seizures persist throughout life in >80% of cases4

Abbreviation: IS, infantile spasms; LGS, Lennox-Gastaut syndrome.1. Crumrine P. Paediatr Drugs. 2011;13:107-18; 2. Trevethan E, Murphy CC. Epilepsia. 1997;38:1283-8.3. Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93; 4. Van Rijkevorsel K. Neuropsych Dis Treat. 2008;4:1001-19.

LGS Classification

• Symptomatic (~75% of cases)1-3

– Clear underlying cause; significant abnormalities on neuroimaging studies

– Various etiologies: pre- or perinatal insult, infection, various malformations (including dysplasia), brain tumor

– LGS often preceded by other epilepsy syndrome (eg, infantile spasms, focal seizures)

• Cryptogenic/idiopathic (~25% of cases)1,4

– No identifiable etiology; normal neuroimaging studies

Abbreviation: LGS, Lennox-Gastaut syndrome.1.Borggraefe I, Noachtar S. Clin Med Insights Ther. 2010;2:15-24.2.Hancock E, Cross H. Cochrane Database Syst Rev. 2009;CD003277.3.Van Rijkevorsel K. Neuropsych Dis Treat. 2008;4:1001-19.4.Markand ON. J Clin Neurophysiol. 2003;20:426-41.

Clinical and Electrographic Characteristics

Electroclinical Features:“Classic LGS Triad”

Abbreviations: EEG, electroencephalography; LGS, Lennox-Gastaut syndrome.Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93.Borggraefe I, Noachtar S. Clin Med Insights Ther. 2010;2:15-24.

Multiple seizure types

Cognitive impairment

Specific EEG pattern

Complete electroclinical profile may not be fully established at syndrome onset

Multiple Seizure Types

Abbreviations: GTC, generalized tonic-clonic; LGS, Lennox-Gastaut syndrome; ms, millisecond. Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93; Borggraefe I, Noachtar S. Clin Med Insights Ther. 2010;2:15-24.

Seizure Type Features

Tonic • Most common/characteristic seizure type (occurring in 17%-95% of cases)• Prerequisite for LGS diagnosis• Sustained increase in muscle contraction lasting a few seconds to minutes• Observed mainly during sleep

Atypical absence • Second most common seizure type• Term used for any seizure associated with brief loss/lapse of consciousness• Level of consciousness difficult to determine in severely retarded patients

Sudden tonic or atonic falls (“drop attacks”)

• Typically preceded by brief myoclonic jerk• Also observed in other epilepsy syndromes not always evolving to LGS• Presence of “drop attacks” is not diagnostic of LGS

Nonconvulsive status epilepticus*

• Occur in 50%-75% of LGS patients• Subcontinuous atypical absences with varying degrees of consciousness,

periodically interrupted by brief tonic seizures

Myoclonic* • Occur in many generalized epilepsy syndromes (not a defining feature)• Seizure shorter (<100 ms) than tonic events; can also result in falls

Other* • Focal with/without secondary generalization, GTC, unilateral clonic• Normally present in later stages of LGS, but sometimes precede core seizures

Red box = core seizure types in children (childhood onset).*Older LGS patients are more likely to have these seizure types, especially secondarily GTC.

Evolution of LGS Into Adulthood: Seizure Types and EEG

• 50%-75% of adults diagnosed with LGS during childhood no longer display all clinical/EEG features

• Number and types of seizures decrease over time

– Tonic seizures tend to persist, mainly during sleep

– Partial seizures become more apparent

– Seizures are often intractable

• EEG features change in adults

– SSW complexes transitory in many patients

– Paroxysmal fast activity during sleep

Abbreviations: EEG, electroencephalography; LGS, Lennox-Gastaut syndrome; SSW, slow spike-wave.Kerr M, et al. Epileptic Disord. 2011;13:S15-26.

Slow Spike and Wave in Adult LGS

Abbreviation: LGS, Lennox-Gastaut syndrome.Figure courtesy of Dr. Michael C. Smith, Rush Medical Center.

Paroxysmal Fast Activity During Sleep in Adult LGS

Abbreviation: LGS, Lennox-Gastaut syndrome.Figure courtesy of Dr. Michael C. Smith, Rush Medical Center.

3T MRI of Frontal Neuronal Migration Abnormality

Abbreviations: 3T, 3 tesla; MRI, magnetic resonance imaging.Image courtesy of Dr. Michael Stein, Alexius Medical Center (personal communication).

Cognitive Impairment

• Abnormal cognitive development before seizure onset occurs in most LGS patients1

– 20%-60% (symptomatic) have delayed development at LGS onset2

• 30% of patients (cryptogenic) have seemingly normal development before seizure onset2

• By 5 years from LGS onset, 75%-95% of patients have cognitive impairment1,2

• 90% of patients will eventually become intellectually handicapped3

• Psychiatric disorders and behavioral problems may also occur in LGS2

Abbreviation: LGS, Lennox-Gastaut syndrome.1.Borggraefe I, Noachtar S. Clin Med Insights Ther. 2010;2:15-24.2.Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93.3.Van Rijkevorsel K. Neuropsych Dis Treat. 2008;4:1001-19.

Diagnosis and Prognosis

Diagnostic Workup

• Complete medical history

• Detailed physical/neurologic exam

• Family history

• Routine blood work, toxic screening, metabolic monitoring,* serum levels

• EEG (often requires sedation in multiply handicapped)

• Neuroimaging (MRI preferred)

• Video-EEG monitoring

• Video recording of events

*Consider metabolic monitoring in multiply handicapped patients who may not be able to express symptoms.Abbreviations: EEG, electroencephalography; MRI, magnetic resonance imaging.

Diagnostic Considerations

• Late onset of LGS in adolescence or adulthood may occur (albeit rare)

– Late- and childhood-onset LGS have similar EEG features

– Development of cognitive impairment may be less evident with late-onset LGS

• Recognition/diagnosis of LGS in adults often overlooked

– Clinicians not expecting LGS in adulthood

• Important to reassess symptoms and features, and change diagnosis as appropriate

Abbreviations: EEG, electroencephalography; LGS, Lennox-Gastaut syndrome.Kerr M, et al. Epileptic Disord. 2011;13:S15-26.

Prognosis

• Poor long-term prognosis due to uncontrolled seizures1,2

• Refractory epilepsy with multiple seizure types persists in many LGS patients from childhood through adulthood1,3

• Worse prognosis in patients with symptomatic LGS (mainly with preexistent IS/West syndrome), frequent seizures, and repeated status epilepticus episodes4

• High and variable mortality rate5-8

– SUDEP accounts for up to 50% of deaths6

– 3%-7% largely related to accidents7

– 25% due to underlying neurologic conditions8

– Frequent falls with fracture (hip) or closed head injury

Abbreviations: IS, infantile spasms; LGS, Lennox-Gastaut syndrome; SUDEP, sudden unexpected death in epilepsy.1. Markand ON. J Clin Neurophysiol. 2003;20:426-41; 2. Ferrie CD, Patel A. Eur J Paediatr Neurol. 2009;13:493-504;3. Crumrine PK. J Child Neurol. 2002;17:S70-5; 4. Campos-Castelló J. Orphanet Encyclopedia. 2004:1-5. www.orpha.net/data/patho/GB/uk-Lennox.pdf. 5. Van Rijkevorsel K. Neuropsych Dis Treat. 2008;4:1001-19; 6. Sperling MR. CNS Spectr. 2004;9:98-101, 106-9.7. Glauser TA. Epilepsia. 2004;45(S5):23-6; 8. Camfield P, Camfield C. Epilepsia. 2007;48:1128-32.

Treatment of LGS

Goals of Adult LGS Management

• Multidisciplinary care approach

– Control seizures

– Reduce polypharmacy

– Minimize AED-associated toxicities

– Manage behavioral and cognitive comorbidities

– Provide support for social and developmental needs

Abbreviations: AED, antiepileptic drug; LGS, Lennox-Gastaut syndrome.Kerr M, et al. Epileptic Disord. 2011;13:S15-26.

Treatment Approaches

• Pharmacotherapy– Antiepileptic drugs (AEDs)

• Nonpharmacotherapy– Surgery

Vagus nerve stimulation (VNS)

Corpus callosotomy

– Diet Ketogenic

Modified Atkins

Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93.Borggraefe I, Noachtar S. Clin Med Insights Ther. 2010;2:15-24.Kerr M, et al. Epileptic Disord. 2011;13:S15-26.Lemmon ME, Kossoff EH. Curr Treat Options Neurol. 2013;6:189-98.

Current AED Management Guidelines

*May worsen seizures in LGS patients.Abbreviations: AAN, American Academy of Neurology; AED, antiepileptic drug; AES, American Epilepsy Society; EU, European Union; NA+, sodium; NICE, National Institute for Health and Care Excellence; US, United States.Figure adapted from Carmant L, Whiting S. Can J Neurol Sci. 2012;39:702-11.1. French J, et al. Epilepsia. 2004;45:410-23; 2. Wheless J, et al. J Child Neurol. 2005;20:S1-56;3. Wheless JW, et al. Epileptic Disord. 2007;9:353-412; 4. National Institute for Health and Care Excellence (NICE) clinical guideline. 2012. Available at: http://www.nice.org.uk/nicemedia/live/13635/57779/57779.pdf.

LamotrigineTopiramate

Valproic acidTopiramateLamotrigine

Valproic acidTopiramateLamotrigine

Valproic acid

EthosuximideClobazam

ClonazepamLevetiracetam

ZonisamideLevetiracetam

FelbamateLamotrigine

TopiramateRufinamide

AVOID*Carbamazepine

GabapentinOxcarbazepine

PregabalinTiagabineVigabatrin

Expert opinion studies recommend 2 monotherapies prior to polytherapy

AAN/AES20041

US Expert Opinion20052

EU Expert Opinion20073

NICE20124

1st Line

2nd Line

3rd Line

• AEDs that excitability of neurons (eg, levetiracetam, gabapentin) may exacerbate behavioral problems

• NA+ channel blockers (eg, carbamazepine, lamotrigine) can exacerbate gait/balance and produce falls

Median Reduction in Drop Attacks With AEDs in LGS*

*Results are from individual studies. AEDs are listed from left to right by FDA approval date.Abbreviations: AED, antiepileptic drug; FDA, Food and Drug Administration; LGS, Lennox-Gastaut syndrome.1. The Felbamate Study Group. N Engl J Med. 1993;328:29-33; 2. Motte J, et al. N Engl J Med. 1997;337:1807-12;3. Sachdeo RC, et al. Neurology. 1999;52:1882-7; 4. Glauser T, et al. Neurology. 2008;70:1950-8;5. Ng YT, et al. Neurology. 2011;77:1473-81.

Felbamate1 Lamotrigine2 Topiramate3 Rufinamide4 Clobazam5

high dose(1.0 mg/kg/day)

P = .041

P = .002P < .0001

P < .000180

70

60

50

40

30

20

10

0

-10

Active Placebo

Median Reduction in Total Seizure Frequency With AEDs in LGS*

*Results are from individual studies. AEDs are listed from left to right by FDA approval date.Abbreviations: AED, antiepileptic drug; FDA, Food and Drug Administration; LGS, Lennox-Gastaut syndrome.1. The Felbamate Study Group. N Engl J Med. 1993;328:29-33; 2. Motte J, et al. N Engl J Med. 1997;337:1807-12;3. Sachdeo RC, et al. Neurology. 1999;52:1882-7; 4. Glauser T, et al. Neurology. 2008;70:1950-8;5. Ng YT, et al. Neurology. 2011;77:1473-81.

Felbamate1 Lamotrigine2 Topiramate3 Rufinamide4 Clobazam5

high dose(1.0 mg/kg/day)

70

60

50

40

30

20

10

0

-10

P = NS

P < .001

P = .002 P = .0015

P < .0001Active Placebo

Median Reduction in Drop Seizures and Total Seizures With Clobazam

Abbreviation: CLB, clobazam.Ng YT, et al. Neurology. 2011;77:1473-81.

Drop Seizures Total Seizures

P < .0001

P = .0015

P = .0120

P < .0001

P = .0044

P = .0414

80

70

60

50

40

30

20

10

0

70

60

50

40

30

20

10

0PlaceboLow-dose (0.25 mg/kg/d) CLB

Medium-dose (0.5 mg/kg/d) CLBHigh-dose (1.0 mg/kg/d) CLB

Cochrane Review of All RCTs of AEDs in LGS

• Review included 9 RCTs

– No meta-analysis performed due to

Different trial populations, therapies, and outcomes

• Results/Conclusions

– Ideal treatment for LGS remains uncertain

– No study has shown one drug to be highly efficacious

– Rufinamide, lamotrigine, topiramate, and felbamate may be useful as add-on therapy

– Clobazam may be helpful for drop seizures

Abbreviations: AED, antiepileptic drug; LGS, Lennox-Gastaut syndrome; RCT, randomized controlled trial.Hancock EC, Cross JH. Cochrane Database Syst Rev. 2013; Feb 28;2:CD003277.

Common Side Effects of AEDs

AED* Adverse EventsClobazam Somnolence or sedation, pyrexia, upper respiratory tract infection, lethargy

Clonazepam Somnolence, dizziness, upper respiratory tract infection, depression

FelbamateAnorexia, vomiting, insomnia, nausea, dizziness, somnolence, and headache

LamotrigineDizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, and rash

Levetiracetam Asthenia, somnolence, headache, infection

Rufinamide Headache, dizziness, fatigue, nausea, and somnolence

TopiramateParesthesia, anorexia, weight decrease, speech disorder, related speech problem, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, fever

Valproate Nausea, somnolence, dizziness, vomiting, accidental injury, asthenia

Abbreviations: AE, adverse event; AED, antiepileptic drug; IDD, intellectual developmental disorder; LGS, Lennox-Gastaut syndrome.Onfi (clobazam) prescribing information, November 2013; Klonopin (clonazepam) prescribing information, October 2013; Felbatol (felbamate) prescribing information, July 2011; Lamictal (lamotrigine) prescribing information, December 2013. Keppra (levetiracetam) prescribing information, September 2013; Banzel (rufinamide) prescribing information, May 2013; Topamax (topiramate) prescribing information, March 2014; Depakote (divalproex sodium) prescribing information, April 2014.

*LGS population is sensitive to many of these AEDs. Patients with IDD may develop AEs at lower AED doses.

AED Warnings and Precautions

AED Black Box WarningLamotrigine Serious skin rashes, including SJS, TEN,

rash-related death

Felbamate Aplastic anemia, hepatic failure

Valproate Hepatotoxicity, fetal risk, pancreatitis

Key Warnings and PrecautionsAll Suicidal behavior and ideation

Clobazam Serious dermatologic reactions, including SJS and TEN

Topiramate Visual field defects

Abbreviations: AED, antiepileptic drug; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. Onfi (clobazam) prescribing information, November 2013; Lamictal (lamotrigine) prescribing information, December 2013. Felbatol (felbamate) prescribing information, July 2011. Depakote (divalproex sodium) prescribing information, April 2014; Topamax (topiramate) prescribing information, March 2014.

Lamotrigine: Skin Reactions

• Cases of life-threatening serious rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death have been reported

• The rate of serious rash is greater in pediatric patients than adults

• Risk factors include– Coadministration with valproate

– Exceeding the recommended initial dose

– Exceeding the recommended dose escalation

• Lamotrigine should be discontinued at the first sign of rash, unless the rash is clearly not drug related

Lamictal (lamotrigine) prescribing information, December 2013.

Felbamate: Aplastic Anemia and Hepatic Failure

• Aplastic anemia (pancytopenia with bone marrow depleted of hematopoietic precursors) – Incidence associated with felbamate may be >100-fold higher

than the background incidence (~2-5 per million persons)

– Fatality rate is 20% to 30%

• Hepatic failure– Felbamate is associated with acute liver failure leading to liver

transplant or death within 5 weeks of onset

– Felbamate should not be prescribed to anyone with a history of liver dysfunction or active liver disease

• Felbamate should only be used if the benefit is considered to outweigh the risk

Felbatol (felbamate) prescribing information, July 2011.

Valproate: Hepatotoxicity, Fetal Risk, and Pancreatitis

• Hepatotoxicity, including fatalities, usually during first 6 months of treatment– Evaluate high-risk populations and monitor serum liver tests

• Fetal risk, particularly neural tube defects, other major malformations, and decreased IQ– Only use to treat pregnant women if other medications are

unacceptable

– Should not be administered to women of childbearing potential unless essential

• Pancreatitis, including fatal hemorrhagic cases– Discontinue valproate

Abbreviation: IQ, intelligence quotient.Depakote (divalproex sodium) prescribing information, April 2014.

Potential for Drug-Drug Interactions With AEDs

Cytochrome P450

Negligible or no effect

LamotrigineLevetiracetam

Zonisamide

Abbreviations: AED, antiepileptic drug; EH, epoxide hydrolase; UGT, UDP-glucuronosyltransferase.Asconape JJ, et al. Neurol Clin. 2010;28:843-52.

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

OxcarbazepineTopiramateRufinamide

Inhibitors(2C9, UGT, EH)

ValproateFelbamate

Strong or moderate inhibitors (2C19)

Clobazam

Drug Level Monitoring

• Establish “baseline” effective concentrations

• Evaluate potential causes for lack of efficacy– Monitor free AED levels for all highly protein-bound AEDs (VPA, CLB)

– “Fast metabolizers”

– Noncompliance

• Evaluate potential causes for toxicity– Altered drug utilization as a result of physiologic (eg, puberty) and/or

pathologic (eg, renal/liver failure) conditions

– “Slow metabolizers”

– Drug-drug interactions

• Evaluate potential causes for loss of efficacy– Altered drug utilization as a result of physiologic conditions (eg, neonates)

– Change in formulation

– Drug-drug interaction

Abbreviations: AED, antiepileptic drug; CLB, clobazam; VPA, valproate.

Treatment Approaches

• Pharmacotherapy– Antiepileptic drugs (AEDs)

• Nonpharmacotherapy– Surgery

Vagus nerve stimulation (VNS)

Corpus callosotomy

– Diet Ketogenic

Modified Atkins

Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93.Borggraefe I, Noachtar S. Clin Med Insights Ther. 2010;2:15-24.Kerr M, et al. Epileptic Disord. 2011;13:S15-26.Lemmon ME, Kossoff EH. Curr Treat Options Neurol. 2013;6:189-98.

Vagus Nerve Stimulation (VNS)

• Pulse generator implanted subcutaneously and connected to left vagus nerve1

– Stimulation parameters can be programmed

• Approved as adjunctive therapy for patients aged ≥12 years with refractory partial-onset seizures

• Evidence-based guidelines recommend VNS for LGS-associated seizures2

Figure from http://epilepsy.med.nyu.edu/diagnosis-treatment/vagus-nerve-stimulation-vns#sthash.QxsV6OfH.dpbs.Abbreviation: LGS, Lennox-Gastaut syndrome. 1. Sethi NK, et al. The Internet J Neurol. 2008;9.2. Morris GL, et al. Neurology. 2013;81:1-7.

Efficacy and Safety of VNS in LGS

• Safety—Most common AEs (in >20% of patients)– Hoarseness, increased coughing, paresthesia, pharyngitis6

• Efficacy– Possibly effective in achieving seizure frequency reduction in LGS

Author NAge (yrs)

Median Reduction in All Seizure Types (%)

≥50% Seizure Frequency Reduction (%)

Hosain et al, 20001 13 4-44 52 46

Frost et al, 20012 50 5-27 57.9 58

Majoie et al, 20053 12 6-17 20.6 8

Shahwan et al, 20094 9 5-16 -- 77.7

Kostov et al, 20095 30 4-52 60.6 66.7

Abbreviations: AE, adverse event; LGS, Lennox-Gastaut syndrome; VNS, vagus nerve stimulation.1. Hosain S, et al. J Child Neurol. 2000;15:509-12. 2. Frost M, et al. Epilepsia. 2001;42:1148-52. 3. Majoie H, et al. Seizure. 2005;14:10-8. 4. Shahwan A, et al. Epilepsia. 2009;50:1220-8.5. Kostov K, et al. Epilepsy Behav. 2009;16:321-4. 6. Cyberonics, Inc. VNS Therapy System Physician’s Manual, January 2014.

Corpus Callosotomy (CC)

• CC entails sectioning of either anterior two-thirds only or entire corpus callosum1,2

– Partial: better speech preservation

– Complete: better seizure control

• CC effective for treating drop attacks, absence, GTCS2-4

– 61%-85% of patients achieve >80% reduction in drop attacks2,3

• VNS often considered first due to invasive nature and risk of AEs with CC1

Abbreviations: AE, adverse event; GTCS, generalized tonic-clonic seizure; VNS, vagus nerve stimulation.Figure from http://www.gru.edu/mcg/neurosurgery/clinicalprograms/esphoto_gallery.php. 1. VanStraten AF, Ng Y-T. Pediatr Neurol. 2012;47:153-61. 2. Maehara T, et al. Epilepsia. 2001;42:67-71.3. Nei M, et al. Epilepsia. 2006;47:115-22. 4. Asadi-Pooya AA, et al. Epilepsy Behav. 2013;29:285-8.

Outcome After CC According to Preoperative Seizure Type

*Success is defined as seizure reduction >85%, postoperatively.Abbreviations: CC, corpus callosotomy; GTCS, generalized tonic-clonic seizure.Asadi-Pooya AA, et al. Epilepsy Behav. 2013;29:285-8.

100

90

80

70

60

50

40

30

20

10

0

Success rate 24 months after CCSuccess rate 6 months after CC

GTCS(n=13)

Atonic(n=6)

Tonic(n=13)

Myoclonic(n=12)

Absence(n=9)

Drop attacks(n=11)

Prognostic Factors for Success After Corpus Callosotomy

Abbreviations: EEG, electroencephalogram; GTC, generalized tonic-clonic; IQ, intelligence quotient; SW, spike-wave.Asadi-Pooya A, et al. Epilepsy Behav. 2008;13:271-8.

Factor Comments

Seizure type Drop attacks, atypical absences, and GTC seizures respond relatively well; myoclonic seizures respond poorly.

Age Younger age at time of surgery is predictive for improvement in daily function, family satisfaction, psychosocial adjustment, and overall quality of life. Adverse effects of callosotomy are less severe in children.

IQ IQ is a controversial factor. IQ <50 is likely associated with poor outcome.

Ictal EEG Generalized slow SW, electrodecrement, or nonevolving low-amplitude fast activity is associated with better outcome.

Interictal EEG Slow SW activity has been associated with a better outcome, and bilateral independent spikes have been associated with poor outcome.

Postoperative EEG

Decline in synchrony of epileptic discharge is a good prognostic indicator.

Meta-Analysis: CC vs VNS in LGS

• Analysis included 17 VNS and 9 CC studies

• CC more effective than VNS in reducing atonic seizures

– >50% reduction: 80% vs 54%, P < .05

– >75% reduction: 70% vs 26%, P < .05

• Patients who underwent CC more likely to be free of atonic seizures (48% vs 23%, P = NS)

• VNS comparable to CC for all other seizure types (tonic, GTC, complex partial, myoclonic)

Abbreviations: CC, corpus callosotomy; GTC, generalized tonic-clonic; LGS, Lennox-Gastaut syndrome; NS, not significant; VNS, vagus nerve stimulation.Lancman G, et al. Seizure. 2013;22:3-8.

Ketogenic Diet

• Should be considered early in treatment course

• Ketogenic diet consists of meals that are

– 3:1 or 4:1 fat: carbohydrate plus protein grams

• Children admitted to hospital for 3-4 day to begin diet

– Glucose and urine ketones monitored during this time

• Rigid compliance essential

VanStraten AF, Ng Y-T. Pediatr Neurol. 2012;47:153-61.Lemmon ME, Kossoff EH. Curr Treat Options Neurol. 2013;15:519-28.

Efficacy of Ketogenic Diet in LGS

– Results were similar after 12 months

• Limitations

– Treatment noncompliance may be worse with ketogenic diet due to its restrictive and complicated nature

• Efficacy

– Ketogenic diet is efficacious in the treatment of LGS

Author NAge (yrs)

>50% Reduction in Seizure Frequency

>90% Reduction in Seizure Frequency

Freeman et al, 20091 20 1-7.4 65 --

Lemmon et al, 20122 71 4-52 51 23

Abbreviation: LGS, Lennox-Gastaut syndrome.1. Freeman JM, et al. Epilepsia. 2009;50:322-5.2. Lemmon ME, et al. Dev Med Child Neurol. 2012;54:464-8.

Modified Atkins Diet

• Modified version of the traditional ketogenic diet1

• Less restrictive than ketogenic diet1

• Started outside of hospital

• Modified Atkins diet has not been studied in LGS prospectively, but it has been reported as helpful2,3

• Recent retrospective review shows promising results in LGS4

Abbreviation: LGS, Lennox-Gastaut syndrome.1. Lemmon ME, Kossoff EH. Curr Treat Options Neurol. 2013;15:519-28.2. Kossoff EH, et la. Epilepsia. 2006;47:421-4.3. Kossoff EH, et al. Epilepsia. 2008;8:37-41.4. Sharma S, et al. J Child Neurol. 2014. Epub ahead of print.

N>50% Reduction in Seizure Frequency

At 3 months At 6 months At 12 months

25 10/25 (40%) 8/11 (73%) 9/9 (100%)

Comorbidities

Cognition and Behavior

• >90% of patients have moderate to severe cognitive impairment by adulthood

• Cognitive impairment in LGS often associated with behavioral issues

– Hyperactivity, insecurity, aggressiveness, autistic traits

• Adolescents at risk of developing depression

– Depression difficult to recognize in presence of intellectual disability

• In adults, cognition and behavioral issues can affect

– Ability to live independently

– Employment

Abbreviation: LGS, Lennox-Gastaut syndrome.Kerr M, et al. Epileptic Disord. 2011;13:S15-26.

Sleep

• Sleep-cycle disruption due to night-time seizure activity

• Epileptic activity hinders nocturnal long-term potentiation

– Thus, sleep disruption may contribute to cognitive impairment

• Detrimental effects of sleep disruption include

– Behavioral impairment

– Psychological problems (hyperactivity, anxiety, depression)

Kerr M, et al. Epileptic Disord. 2011;13:S15-26.

Physical Impact

• Mobility affected by increased frequency of seizures (mainly drop attacks)1

– Drop attacks are physically demanding, often resulting in injury, including fractures Bone health is important; most AEDs, particularly enzyme-inducing AEDs

(carbamazepine, phenytoin), reduce bone mineral density2,3

• Gait disturbances (variable degrees) present1

– Some patients may require wheelchairs

• Dysphagia due to severe motor and intellectual disability1

– Early development strongly associated with poor long-term seizure prognosis

– Affect patient’s ability to eat and take medication

Abbreviation: AED, antiepileptic drug.1. Kerr M, et al. Epileptic Disord. 2011;13:S15-26; 2. Sheth RD, Harden CL. Epilepsia. 2007;48(suppl 9):39-41.3. Vestergaard P. Acta Neurol Scand. 2005:112:277–86.

Management Considerations

Management of LGS

• Long-term treatment is deceptive– Danger of excessive therapy

• AED combinations may facilitate episodes of nonconvulsive/ tonic status epilepticus– Risk for adverse events

• AED interactions

• Transitory efficacy of benzodiazepines– Utilize alternately/intermittently

• Avoid AEDs such as carbamazepine, oxcarbazepine, and phenytoin that may exacerbate seizures – Many AEDs (such as gabapentin, levetiracetam, phenobarbital,

benzodiazepines) exacerbate behavioral problems

Abbreviations: AED, antiepileptic drug; LGS, Lennox-Gastaut syndrome.Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93.

Management of LGS (cont.)

• Choice of drug to be added may depend on prominent seizure at that time– Felbamate, lamotrigine, rufinamide, topiramate, clobazam indicated for

drop attacks

• Given the evolving nature of LGS, identify seizure pattern changes

• Management of LGS requires multidisciplinary medical and psychosocial team

• Issues to consider beyond seizures– Sleep, cognition, behavior, physical impact

• Be aware of potential side effects of multiple AEDs and medications for comorbid disorders

Abbreviations: AED, antiepileptic drug; LGS, Lennox-Gastaut syndrome.Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93.

Transitioning to Adult Care

Transitioning From Childhood to Adulthood: Dispersed LGS Care Management

Figure from Kerr M, et al. Epileptic Disord. 2011;13:S15-26.

Childhood Adolescence Adulthood

Pediatric

neurologist

Community or other pediatrician

Primary care physician

Neurologist

Psychiatrist

Primary care physician

Learning disability clinic

Teenager clinic?

Challenges of Transitioning

• Improper transitioning may leave patient without specialty care

• Families attached to pediatric practice– Concerns about quality of adult care and accessibility of HCPs

• Cultural issues between pediatric and adult care– Pediatric care = family-centered vs adult care = individual-

centered

– Young people with intellectual disability present unique problems for adult healthcare system Difficult behavior not tolerated in adult offices

Other patients in adult practice may be uncomfortable

Abbreviation: HCP, healthcare provider.Camfield PR, et al. Epilepsia. 2011;52:21-7.

Goals of Transition Process

• Financial and legal matters– Educate about potential health insurance changes as patient

enters adulthood– Establish guardianship before age 18 years– Establish care plan that best denotes interests of patient

• Health issues beyond epilepsy– Reproductive care– Bone health– Care for comorbid, emotional, and behavioral conditions– Educate about safety in home and community

Medical and personal identification

Alarms for alerting care providers if patient should leave home

Risks of abuse

Camfield PR, et al. Epilepsia. 2011;52:21-7.

Goals of Transition Process (cont.)

• Housing and life skills/vocational training

– Educate about options for living environments in adulthood

– Referral to appropriate services

Living environments

Life skills, vocational training

Agencies promoting social development of individuals with intellectual disabilities and epilepsy (eg, Arc)

• Additional education/support resources

– Tutorial on organizing medical records to be shared with multidisciplinary team

– Educate parents about record keeping of medicines and HCPs involved in patient care

Abbreviations: HCP, healthcare provider.Camfield PR, et al. Epilepsia. 2011;52:21-7.

Conclusions

Conclusions

• LGS remains one of the most challenging epileptic encephalopathies despite availability of several new AEDs1

• Long-term outcome regarding seizure control and intellectual development is disappointing and can be taxing for families2

• Management of LGS into adulthood requires global care approach3

– Offers unique challenges regarding recognition and diagnosis

• Total seizure control not necessarily the main concern as management of comorbidities is often a higher priority3

− Coordinate educational and psychosocial needs with medical care

Abbreviations: AED, antiepileptic drug; LGS, Lennox-Gastaut syndrome.1. Arzimanaglou A, et al. Lancet Neurol. 2009;8:82-93. 2. Camfield PR. Epilepsia. 2011;52:3-9.3. Kerr M, et al. Epileptic Disord. 2011;13:S15-26.