friday morning 10-24-14 dr. wheless clinical practice of lgs

Clinical Practice of

Lennox-Gastaut Syndrome (LGS)

James W. Wheless, M.D.

Professor and Chief of Pediatric Neurology

Le Bonheur Chair in Pediatric Neurology

University of Tennessee Health Science Center

Director, Neuroscience Institute &

Le Bonheur Comprehensive Epilepsy Program

Le Bonheur Children’s Hospital

Memphis, TN USA

Lennox-Gastaut Syndrome:

Diagnostic Criteria

Multiple Seizure Types- Tonic Seizures

Atypical absences

Tonic/Atonic drop attacks

Non-convulsive status epilepticus

Abnormal EEG

• Interictal slow spike –waves

• Paroxysmal Fast rhythms (non-REM sleep)

Cognitive Impairment

• Intellectual slowing/regression

• Behavioral problems

Bourgeios BFD et al. Epilepsia, 2014; 55 (Suppl. 4): 4-9

Lennox-Gastaut Syndrome

• A severe epileptic encephalopathy characterized by:

1. Multiple seizure types, and

2. Cognitive decline

• Accounts for 5-10% of children with seizures.

• Prognosis is poor:

1. 5% of children die

2. 80-90% continue with seizures into adulthood

3. Almost all have cognitive and behavior problems.

Bourgeois BFD et al. Epilepsia, 2014; 55 (Suppl. 4): 4-9.

Lennox-Gastaut Syndrome:

Evaluation

• Repeat wake/sleep EEGs (Video-EEG)

• MRI

• Chromosone microarray

• Infant epilepsy genetic arrays

Lennox-Gastaut Syndrome:

Diagnostic Challenges¹

• Not all patients display the characteristics triad of features,

especially at onset.

• Significant overlap exists between LGS and other early-

onset epileptic encephalopathies.

• Drop attacks occur in Doose Syndrome, Dravet

Syndrome, West Syndrome, Atypical benign partial

epilepsy of childhood.

• 28% (29/103) misdiagnosed as LGS²

¹Bourgeois BFD et al. Epilepsia, 2014; 55 (Suppl. 4): 4-9

²Beaumanoir A. Electroencephalogr Neurophysiol, 1982; 35 (Suppl.): 85-99

OR

Re-evaluate

1st AED

Monotherapy

Polytherapy

Trials

2nd AED

Monotherapy

Epilepsy

Surgery

Vagus Nerve

Stimulation

Ketogenic

Diet

MedicationsConsider Other Treatments

Lennox – Gastaut Syndrome

Treatment Sequence

Anterior & Centromedian Thalamus & Brainstem Activation

in Lennox-Gastaut Syndrome

Siniatchkin M et al. Epilepsia, 2011; 52(4): 766-774.

Significant activation of brainstem and thalamus (especially centromedian and anterior thalamus)

associated with epileptiform discharges in Lennox-Gastaut syndrome.

Model 100 Model 101 Model 102 Model 103

Vagus Nerve Stimulation Therapy

Model 105 Model106

VNS Therapy: Lennox-Gastaut Syndrome

Author, Year N Responder Rate or Median %

(>50% ) (Sz Reduction)

Hornig G W, 1997 6 83% with > 90%

Lundgren J, 1998 4 50%

Parker APJ, 1999 9 34%

Hosain S, 2000 13 46%

Majoie HJM, 2001 16 25%

Frost M, 2001 46 43%

Benifla M, 2006 10 40%

Rychlicki F, 2006 8 33%

Rossignol E, 2009 5 80%

Shahwan A, 2009 9 78%

Kostov K, 2009 30 60.6%

Cersosimo R, 2011 46 65%

Elliott RE, 2011 24 52.15

1 Hornig GW et al, Southern Med J, 1997; 90(5): 484-88. 2 Lundgren J et al, Epilepsia, 1998; 39(8): 809-813

3 Parker APJ et al, Pediatrics, 1999; 103: 778-782. 4 Hosain S et al, J Child Neurol, 2000; 15: 509-512

5 Majoie HJ et al, J Clin Neurophysiol, 2001; 18(5): 419-428. 6. Frost M et al, Epilepsia, 2001; 42(9): 1148-1152

7 Benifla M et al, Childs Neuro Syst, 2006; 22: 1018-1026. 8. Rychlicki F et al, Seizure 2006; 15: 483-490

9 Rossignol E et al, Seizure, 2009; 18: 34-37. 10 Shahwan A et al, Epilepsia, 2009. 11. Kostov K et al, Epil &

Behav, 2009;16:321-324. 12. Cersosimo RO et al. Epileptic Disord, 2011; 13(4): 382-388. 13.Elliott RE et al. Epil

& Behavior, 2011; 20: 57-63

AAN Guideline Update: VNS

1. Use of VNS in children with epilepsy?• N = 481, responder rate 55%

• Seizure free rate 7%

• Recommendation: Use in partial or generalized epilepsy.

2. Use of VNS in patients with Lennox-Gastaut Syndrome?• N = 113, responder rate 55%

• Recommendation: Use in Lennox-Gastaut Syndrome.

3. Does VNS improve mood?• Recommendation: In adults, improvement in mood may be an

additional benefit.

Morris GL III et al. Neurol, 2013; 81 (16): 1453-1459.

Centromedian Thalamic Stimulation in

Lennox-Gastaut Syndrome

Level IV

Velasco A L et al, Epilepsia, 2006; 47(7): 1203-

1212

N = 13 (ages 4-22 years)

Bilateral stimulation

130 Hz, 0.45 MS, 400-600 micro A, 1 min. on, 4 min.

off

Overall 80% seizure reduction (18 mo. follow-up),

2/13 seizure-free (p < 0.0001) for GTC and Atypical

Abscence Seizures

Significant improvement in ability scale (p < 0.04).

After Six Months of

Centromedian Thalamic Stimulation

Improvement takes 3-6 months

Seizure reduction and better performance in daily activities

If discontinued, there is a “carry on” effect

7 year old, Lennox-Gastaut Syndrome (Herpes encephalitis)

Lennox-Gastaut Syndrome:

Future Research Opportunities

• Need for an animal model

- Test polytherapy combinations of medicines

- Test earlier use of non-pharmacologic therapies

- Test treatments directed at the encephalopathy (not

directly targeting seizures).

Challenges for Patients

• Some patients with LGS use helmets with

face guards to maximize protection – Sometimes patients will not tolerate helmets with face guards

• Even when helmets are tolerated, often

they– Are uncomfortable

– Are not "cosmetically acceptable”

– Do not fully protect from injury

Morita DA, Glauser TA. Lennox-Gastaut syndrome.

Pediatric Epilepsy: Diagnosis and Therapy. New York, NY: Demos Medical

Publishing, LLC; 2008:307-322.

Treatment of Convulsive Seizures & Drop Attacks

Associated with Lennox-Gastaut Syndrome:

Take Home Points

• Most children start with medical treatment, but often

need other, non-medicine treatments.

• Have a plan to make up for a missed medicine dose.

• All reasonable treatments should be tried to eliminate or

reduce these seizure types, as they lead to injury.

• Continually re-evaluate treatments, to eliminate ones no

longer working, and try new options.

• Have appropriate equipment at home to deal with

seizure emergencies.

• Constantly monitor for side-effects of treatment, use

therapies with fewer known long-term side-effects.

• Eliminate any seizure triggers.

Lennox-Gastaut Syndrome:

Treatment Suggestions

• Target most dangerous or frequent seizure type

(review at each visit)

• Avoid sedation

• Always ask: “Can I remove a medicine (If adding

a medicine)?”

• Avoid taking more that 2 to 3 medicines.

• Exhaust “proven” treatments for LGS before

considering other options.

• Evaluate drug interactions.

Antiepileptic Drug Interactions

Hepatic Inhibition

16 year old female, Lennox-Gastaut Syndrome

Treatment: Topiramate-XR 200 mg BID;

Clobazam 20 mg BID

Fluoxetine (Prozac) begun for mood regulation

Over 1 week, increasing lethargy

Antiepileptic Drug Interactions

Why does this patient

have lethargy ?

AN INHIBITOR IS

NOT ALWAYS AN INHIBITOR

ISOZYME INVOLVED

CLOBAZAM (ONFI) CYP3A4, CYP2C19

SERTALINE (ZOLOFT) INHIBITS: CYP2C9, UGT

PEROXETINE (PAXIL®) INHIBITS: CYP2D6

FLUVOXAMINE (LUVOX) INHIBITS: CYP2C19, 3A4, 2D6

CITALOPRAM (CELEXA) NO CYP EFFECT

ESCITALOPRAM (LEXAPRO) NO CYP EFFECT

FLUOXETINE (PROZAC®) INHIBITS: CYP3A4, 2D6, 2C9

VENLAFAXINE (EFFEXOR) INHIBITS: CYP2D6 (weak)

Treatment Strategy for

Lennox-Gastaut Syndrome

van Rijckevorsel K. Neuropsychiatry Disease & Treatment, 2008; 4(6): 1001-1019

Or Clobazam

Surgical Evaluation in

Lennox-Gastaut Syndrome

Douglass LM & Salpekar J. Epilepsia, 2014;55 (Suppl 4); 21 – 28.

• Multidisciplinary assessment

• Vigorous interventions aimed at– Minimizing seizures

– Minimizing potential for injury

– Maximizing a patient’s potential

• Development of rational management plan for each patient– Exploration of various medical modalities

– Recognition and management of behavioral problems

Effective Patient

Management Strategies

Arzimanoglou A, et al. Lancet Neurol. 2009;8:82-93.

Wheless JW, Constantinou JE. Pediatr Neurol. 1997;17:203-211.

Lennox-Gastaut Syndrome:

Medications to Avoid

1. Phenobarbital, primidone, phenytoin, carbamazepine

- All cause elevations in cholesterol and triglycerides,

producing a not “heart healthy” profile.

- All induce CYP450 enzymes, producing complex drug

interactions.

- All can have negative affects on Vitamin D levels and

bone health.

- All affect hormone metabolism

2. Some medications rarely worsen some seizure types.

Mintzer S et al. Ann Neurol, 2009; 65 (4):448-456.

Chuang YC et al. Epilepsia, 2012; 53(1): 120-128.

Mintzer S. Curr Opin Neurol, 2010; 23(2): 164-169.

Effect of Anti-Epileptic Drugs

on Serum Lipids4/4/14 6/2/14 6/20/14

Cholesterol

(<200 mg/dL) 229 (H) 176 (Nl) 146 (Nl)

Triglyceride

(<150 mg/dL) 607 (H) 224 (H) 145 (Nl)

HDL Cholesterol

(40-60 mg/dL) 24 (L) 24 (L) 20 (L)

LDL Cholesterol

(<100 mg/dL) 140 (L) 113 (H) 103 (H)

Phenytoin Stopped Off

Clobazam On On

Valproate On On

Perampanel On On

On

On

On

(H)

Effect of Anti-epileptic Drugs

on Serum Lipids4/4/14 6/2/14 6/20/14

Cholesterol

(<200 mg/dL) 229 (H) 176 (Nl) 146 (Nl)

Triglyceride

(<150 mg/dL) 607 (H) 224 (H) 145 (Nl)

HDL Cholesterol

(40-60 mg/dL) 24 (L) 24 (L) 20 (L)

LDL Cholesterol

(<100 mg/dL) 140 (L) 113 (H) 103 (H)

Phenytoin Stopped Off

Clobazam On On

Valproate On On

Perampanel On On

On

On

On

(H)

Lennox-Gastaut Syndrome:

Chronic Disease Management

1. Routinely assess well being

2. Modified barium swallow

3. Bone health (DXA, Vitamin D levels)

- Supplemental Vitamin D, Calcium

4. Maintain mobility (+ encourage mobility)

5. Promote good sleep hygiene

6. Assess safety issues

- Seizure emergency treatment

- Home equipment (O2, suction, seizure monitor)

7. Assess mood and treat

8. Find a meaningful “life”, after school.

9. Transition to adult physicians

Lennox- Gastaut Syndrome:

Management Issues

• Need multi-discipline assessment

1. Rehabilitation (P.T., O.T., S.T.)

2. Social Work

3. Nutrition- dietary, vitamins

4. Orthopedics

5. Sleep Specialist

6. Behavior Management

• Parent support

1. Respite

2. Guardianship/ Disability

• Parents of patients who have refractory epilepsy face special challenges– Possibility of frequent injuries

– Psychosocial stress for patient, parents, and siblings

– Need for modified or specialized educational settings

• Difficulties are further heightened for patients with LGS and their families – Need for constant supervision

– Delays to diagnosis

– Gaining access to specialists

Challenges for LGS Families

Austin JK, Santilli N. Quality of life in children with epilepsy.

Pediatric Epilepsy: Diagnosis and Therapy.

New York, NY: Demos Medical Publishing, LLC; 2008:839-841.

? Questions ?

AED Drug Interactions:

12 year old male (40 Kg)• Attention disorder for 7-8 years

Complex partial seizure disorder for 3 years

• Current medicine

– Carbamazepine 200 mg tid

– Atomoxetine HCl (Strattera) 25 mg am & noon

(1.25mg/kg/day)

• Current status

– Intermittent seizures for last 8 months

– Attentional disorder well controlled

AED Drug Interactions:Case Study (cont’d)

• Seizure medicine changed• Carbamazepine weaned over 4 weeks

• Levetiracetam initiated simultaneously and increased

to 750 mg bid (37mg/kg/day)

• Follow-up visit (2 months later)• No seizures

• Last 3-4 weeks – behavior problems– Mood swings, irritable, agitated

– Insomnia, poor appetite

What do you tell the parents?

CYP2D6 Drug Interactions

Drug Effect on Resulting Atomoxetine

CYP2D6 serum levels

Carbamazepine Induction

Levetiracetam None No change

Paxil (Paroxetine) Inhibition

Prozac(Fluoxetine) Inhibition

CYP2D6 Pharmacogenomics

Ethnic Origin Metabolism Effect on

drugserum

levels

Caucasian poor(5-10%)

Chinese poor(1%)

East African rapid(up to 29%)

Weinshilbaum R, NEJM, 2003; 348 (6): 529

AED Drug Interactions:Case Study (cont’d)

• Decision• Decrease atomoxetine to 25mg q am (.62mg/kd/day)

• Follow-up• Continues seizure-free

• Behavior better, but with residual problems

• Plan• Decrease atomoxtine to 18mg q am (.45 mg/kg/day)

• Follow-up• Seizure-free, attention disorder improved

(Poor metabolizer of P-450 2D6 isoenzyme)