1. COMORBITIES
ASSOCIATED WITH
LENNOX-GASTAUT
SYNDROME
NATIONAL LGS MEETING
Cerritos CA May 3,4 2013

2. Michael G. Chez MD
Director Pediatric Neurology and
Epilepsy, Sutter Neuroscience
Instititue
Sacramento, CA
Professional Advisory Board LGS Foundation
No conflicts with today’s lecture

3. History
 William G. Lennox 1884–1960
 Henri Gastaut 1915-1995
 Defined EEG and Clinical Abnormalities of
this disease
 LGS clinically described syndrome is
actually spectrum of causes

4. • DEFINED BY CLINICAL FINDINGS
• HETEROGENOUS/ THEREFORE VARIOUS
CAUSES
• NOT ONE CAUSE SO NOT ALL CASES
RESPOND RESPOND THE SAME
LENNOX GASTAUT SYNDROME

5. Defining LGS
 Incidence: estimate 2:100,000 0.002%
 Approximately 5% of Children with
epilepsy
 20 % prior Infantile Spasms of West
Syndrome

6. Clinical Definition
 Age of onset typically after age 2
 Can be normal before onset
 May rarely start in adolscence or
adult
 Mortality rate ranges from 3% to 7%

7. Clinical Manifestations
 Seizure Onset may be sudden and
progress rapidly if not prior seizure
history (i.e. prior infantile spasms)
 Spectrum of Causes
 Idiopathic 30%
 Lesional 70%
 Syndrome
 Genetics

8. • INJURY TO BRAIN
• GENETICS/ DRAVETS
• OTHER GENETICS FOX,
CDLK, KCNQ2
VARIENT,TSC1,2
• ANGELMANN'S; AICARDI,
TSC RETTS ETC
• De Novo Mutations CNV
• INFECTION
• IDIOPATHIC
LGS ETIOLOGY

9.  LGS defined by
clinical seizure type
and EEG pattern
 Irregular
background
 High amplitude slow
 Slow spike and wave
 Electrodecremental
response spike wave
 Fast “buzz”type
discharges in sleep
LGS DEFINED
EEG FINDING

10. LGS EEG

11.  COMPLICATED REFRACTIVE
MULTIPLE MEDICATIONS
 VARIABLE ETIOLOGY
 UNDERLYING BRAININJURY
 SIDE EFFECTS
 COMPLLAINCE
 PHYSICAL INJURY/CONCUSSION
LGS CLINICAL COURSE

12.  LGS COMORBITIES
LGS COMORBID CONCERNS
MEDICAL ISSUES
ETIOLOGY
ISSUES CONCERN OUTCOME
TREATMENT VARIABILITY
SIDE EFFECTS TREATMENT

13.  TREATMENT LGS
TREATMENT LGS
MEDICATIONS
COGNITIVE EFFECTS
OLD VS. NEW MEDICATIONS

14. LGS SEIZURE and TREATMENT
 LGS Seizure Patterns
 Can Alter Outcome
 Early Intervention
 Drop Attacks/ Atonic Atypical Absence
Worsen
 EtilogyDoose vs. Dravet
 Head Injuries/ Status Epilepsticus
 Atypical Absence

15.  EEG Improvement ususally correlates with
better seizure control and cognitive
outcome
TREATMENT LGS
EEG PATTERN CORRELATES WITH
DEVELOPMENTAL
ARREST EARLY IN COURSE
IF EEG IMPROVES MAY SEE
BETTER OUTCOME

16.  EEG PATTERNS
 Generalized attention
 Focal Memory
AEDS IN LGS
AEDS CAN CAUSE SIDE EFFECTS
EEG PATTERNS CAN AFFECT
ATTENTION (GENERALIZED SPIKE
WAVE)
EEG PATTERNS CAN AFFECT
MEMORY (FOCAL)
ATYPICAL ABSENCE/ STUPOR

17.  Often Polytherapy
 Often mixture mechanisms
 All AEDs inhibitory cortical excitation
AEDS IN LGS
AEDS CAN CAUSE SIDE EFFECTS
EEG PATTERNS CAN AFFECT
ATTENTION (GENERALIZED SPIKE
WAVE)
EEG PATTERNS CAN AFFECT
MEMORY (FOCAL)
ATYPICAL ABSENCE/ STUPOR

18. AED Polytherapy the norm: > 3
AED typical in LGS
 AED sedation
 Mechanisms inhibit learning
 Combination Therapy Sedating
 Behavioral side effects
 Topamax memory, cognitive
 Keppra /Phenobarbitol irritability
 Depakote/ others: attention sedation
 Benzodiazepines muscle tone,oral motor,
sedation

19. If Cortex in LGS less excitable
then local synaptic modeling
less likely to adopt and learn
new connectivity or learning
may be inhibited
 LGS Brain may be less excitable than
normal brain
 Cause vs underlying issue of disease
state?

20. LGS less synaptic potentiation
Less ability to learn or inhibit
defective inhibition/excitation
 Synaptic stability is new area of
neuroscience
 Many genes associated with comorbid
psychiatric conditions exhibit less synaptic
excitation/ inhibition
 Protein scaffolding abnormal Shank Genes
and Rett’s Fragile X etc

21. COMORBID LEARNING
ISSUES IN LGS
 Attention Deficit
 May see with AED and frequent
generalized seizures
 Absence/ atypical absence
 >40% children with epilepsy may have
ADD/ ADHD

22. Atypical Absence
 Prolonged staring
 Slow spike and
wave or polyspike
–wave
 1-3 hz Frequency
 May be refractive
to typical
medications for
absence seizures
 Sometimes worse
benzodiazepines

23. LANGUAGE COMORBIDITY
EARLY ONSET EPILEPSY
Focal Epilepsy Language Regions
Sleep Dysruption
Oral Motor Delay
Etiology
Prior IS Genetics Brain Injury
Auditory Processing Issues
Memory

24. BEHAVIORAL ISSUES LGS
Delayed speech
Delayed impulses
Frontal Lobe Pseudobulbar Affect
Sleep Issues
Aggression
Self-Injury
Autism Features
80% will have autism spectrum features
Worse with poor seizure control

25. PSYCHIATRIC COMORBIDITY LGS
Depression 30-40% epilepsy
Bipolar/ Psychosis 15-25% Epilepsy
Cognitive Decline/ Cognitive Disability
(IQ<70)

26. CASE EXAMPLE LGS GENETIC
denovo mutation 7q21 deletion
This is a case of 3.5 yr old boy with history of autism behavior and
atypical absence seizures who begins drop attacks while starting
valproic acid therapy
Patient found genetic defect on microarray 7q21-
Patient negative for channelopathy screen
Parents negative for mutation
Patient had diagnosis autism pre-treatment and LGS on EEG and
seizures clinically
12 weeks after normal EEG no longer autistic no in regular 1st grade
mild ADHD

27. JP 7q21.3 copy deletion post-
depakote/pre-
felbatol/clobazam

28. JP post felbatol and depakote
4 weeks 7q21.3

29. JP Chromosome 7q21.3
deletion
post-felbatol and clobazam
July 2011 at 8 weeks

30. SCN1A defect Dravet EEG change
high dose clobazam 1mg/kg

31. LGS Pre-Valium/Post-Valium
 2p11- case

32. Variability in LGS Comorbity
TREAT THE PATIENT
EEG TREATMENT CRITICAL
COMORBID MEDICATION ISSUES NEED TO BE CONSIDERED
AED choices should use rational polytherapy: complimentary
mechanisms
Patient comorbid ADHD mood or anxiety, sleep, or other
disorders need to be managed per individual
Early aggressive EEG treatment/ seizure control probably
most effective effort to llimit cognitive outcome especially in
idiopathic cases, but also some genetic subtypes

33. LGS Summary
 Treatment should be aggressive due to
refractory nature of seizures
 Treatment should include
pharmacological, dietary, immune, and
surgical options
 Treatment of comorbid neuropsychological
aspects may improve quality of life
 Thorough Genetic evaluation needed all
cases without clear brain injury like HIE or
stroke /infection