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Friday Morning 10-24-14 Dr. Wheless Clinical Practice of LGS
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Transcript of Friday Morning 10-24-14 Dr. Wheless Clinical Practice of LGS
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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
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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
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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.
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Lennox-Gastaut Syndrome:
Evaluation
• Repeat wake/sleep EEGs (Video-EEG)
• MRI
• Chromosone microarray
• Infant epilepsy genetic arrays
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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
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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
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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.
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Model 100 Model 101 Model 102 Model 103
Vagus Nerve Stimulation Therapy
Model 105 Model106
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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
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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.
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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).
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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)
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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).
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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.
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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.
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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.
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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
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Antiepileptic Drug Interactions
Why does this patient
have lethargy ?
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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)
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Treatment Strategy for
Lennox-Gastaut Syndrome
van Rijckevorsel K. Neuropsychiatry Disease & Treatment, 2008; 4(6): 1001-1019
Or Clobazam
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Surgical Evaluation in
Lennox-Gastaut Syndrome
Douglass LM & Salpekar J. Epilepsia, 2014;55 (Suppl 4); 21 – 28.
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• 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.
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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.
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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)
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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)
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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
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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
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• 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.
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? Questions ?
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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
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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?
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CYP2D6 Drug Interactions
Drug Effect on Resulting Atomoxetine
CYP2D6 serum levels
Carbamazepine Induction
Levetiracetam None No change
Paxil (Paroxetine) Inhibition
Prozac(Fluoxetine) Inhibition
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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
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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)