This document provides information on the clinical practice of Lennox-Gastaut Syndrome (LGS), including: 1. LGS is a severe epileptic encephalopathy characterized by multiple seizure types and cognitive decline. It accounts for 5-10% of childhood seizures and has a poor prognosis. 2. Diagnostic criteria include multiple seizure types like tonic seizures, atypical absences, and drop attacks, along with abnormal EEG patterns and cognitive impairment. Diagnosis can be challenging due to overlap with other epilepsies. 3. Treatment involves a sequential approach starting with antiepileptic drugs, and may include therapies like the ketogenic diet, vagus nerve stimulation, and epilepsy surgery if drugs are ineffective

1. 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

3. 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

4. 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.

5. Lennox-Gastaut Syndrome:
Evaluation
• Repeat wake/sleep EEGs (Video-EEG)
• MRI
• Chromosone microarray
• Infant epilepsy genetic arrays

6. 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

7. Lennox – Gastaut Syndrome
Treatment Sequence
OR
Re-evaluate
1st AED
Monotherapy
Polytherapy
Trials
2nd AED
Monotherapy
Epilepsy
Surgery
Vagus Nerve
Stimulation
Ketogenic
Diet
Medications
Consider Other Treatments

8. Anterior & Centromedian
Thalamus & Brainstem Activation
in Lennox-Gastaut Syndrome
Significant activation of brainstem and thalamus
(especially centromedian and anterior thalamus)
associated with epileptiform discharges
in Lennox-Gastaut syndrome.
Siniatchkin M et al. Epilepsia, 2011; 52(4): 766-774.

9. Vagus Nerve Stimulation Therapy
Model 100 Model 101 Model 102 Model 103
Model 105 Model106

10. 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

11. 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.

12. 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).

13. After Six Months of
Centromedian Thalamic Stimulation
7 year old, Lennox-Gastaut Syndrome (Herpes encephalitis)
Improvement takes 3-6 months
Seizure reduction and better performance in daily activities
If discontinued, there is a “carry on” effect

14. 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).

15. 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.

16. 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.

17. 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.

18. 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

19. Antiepileptic Drug Interactions
Why does this patient
have lethargy ?

20. 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)

21. Treatment Strategy for
Lennox-Gastaut Syndrome
Or Clobazam
van Rijckevorsel K. Neuropsychiatry Disease & Treatment, 2008; 4(6): 1001-1019

22. Surgical Evaluation in
Lennox-Gastaut Syndrome
Douglass LM & Salpekar J. Epilepsia, 2014;55 (Suppl 4); 21 – 28.

23. Effective Patient
Management Strategies
• 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
Arzimanoglou A, et al. Lancet Neurol. 2009;8:82-93.
Wheless JW, Constantinou JE. Pediatr Neurol. 1997;17:203-211.

24. 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.

25. Effect of Anti-Epileptic Drugs
on Serum Lipids
4/4/14 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)

26. Effect of Anti-epileptic Drugs
on Serum Lipids
4/4/14 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)

27. 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

28. 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

29. Challenges for LGS Families
• 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
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.

30. ? Questions ?

32. 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

33. 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?

34. CYP2D6 Drug Interactions
Drug Effect on Resulting
Atomoxetine
CYP2D6 serum levels
Carbamazepine Induction
Levetiracetam None No change
Paxil (Paroxetine) Inhibition
Prozac(Fluoxetine) Inhibition

35. CYP2D6 Pharmacogenomics
Ethnic Origin Metabolism Effect on
drug
serum
levels
Caucasian poor
(5-10%)
Chinese poor
(1%)
East African rapid
(up to 29%)
Weinshilbaum R, NEJM, 2003; 348 (6):

36. 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)