Topics Include: Therapies for LGS (Part One) - Pharmacological, presented by Angus A WIlfong, MD and Therapies for LGS (Part 2) - Non-Pharmacological presented by Scott Demarest, MD

2. Therapies for LGS
Part One
Pharmacological
Angus A Wilfong, MD
Baylor College of Medicine
Texas Children’s Hospital
4th International Family & Professional Conference on LGS

3.  Research Funding NINDS
Moody Foundation
Novartis
Acorda
Eisai
Pfizer
UCB
Lundbeck
GW Pharma
 Publication Royalties Up-To-Date
Disclosures

4. Treatment of Epilepsy 2016
 Antiepileptic drugs (AEDs) - >30!
 Epilepsy surgery
 Resective
 Ablative
 Disconnection
 Ketogenic diet
 Neurostimulation
 Vagus Nerve Stimulation (VNS)
 Responsive Neurostimulation (NeuroPace®)
 Deep Brain Stimulation (DBS)

5. Goals of Epilepsy Therapy
 Maximize quality of life
 Having as few seizures as possible
 Having as few adverse effects from
therapy as possible
 Minimize the impact of the “epileptic
encephalopathy”
 Due to a combination of the underlying cause
for the LGS, the seizure burden, and the drugs

6. Basic Principles of Epilepsy Therapy
 Important considerations in choosing the first or the
next best medication to use:
 Efficacy – target most disruptive/dangerous seizure type
 Safety and tolerability - ?need for safety monitoring labs
 Consider comorbidities – weight, mood, behavior
 Formulation – liquid, tablets, chewable tablets, dispersible
tablets, capsules, sprinkle capsules, extended release
tablets/capsules, intravenous solutions
 Route – orally, G-tube
 Number of times per day
 Taste
 Cost - insurance coverage, copays

7. Adverse Effects and Tolerability
 Safety AE’s (idiosyncratic) – 1st month
 hypersensitivity reactions (rash)
 Stevens-Johnson syndrome
 Toxic Epidermal Necrolysis (TENS)
 liver failure
 bone marrow failure (aplastic anemia)
 pancreatitis
 glaucoma
 As a class of medication, FDA considers all AEDs
to have an increased risk for suicidal ideation

8.  Dose-Related AE’s (treatment emergent)
 Depend upon dose, rate of titration, other drugs on board
 sleepy/drowsy/dizzy/double vision (CNS AE’s)
 cognitive/behavioral effects
 GI effects/weight changes
 sleep changes
 cosmetic changes
 endocrine changes
 kidney stones
 bone demineralization
 ataxia/peripheral neuropathy
Adverse Effects and Tolerability

9. Basic Principles of Epilepsy Therapy
 Use scientifically proven therapies first (“on label” for LGS)
 valproic acid
 felbamate
 topiramate
 lamotrigine
 rufinamide
 clobazam
 Attempt to wean off a current AED while adding or shortly
after adding a new AED – try to limit current therapies to
only 2-3 AEDs at a time
 Be aware of drug-to-drug interactions between different
AEDs and other therapies – anxiety, stimulants (ADD),
behavior (neuroleptics), antihistamines

10. Treating LGS is Difficult
 There are typically multiple seizure types, and it is
not uncommon for one AED to work for only one
seizure type
 Seizures in LGS are much more likely to be
refractory to AEDs than the general epilepsy
population
 General epilepsy population – 30-40% intractable
 LGS population – 80-90% intractable and typically have
life-long epilepsy
 High comorbid rates of intellectual disability and
behavior disorders

11. Treatment goals for epilepsy
Kwan P, et al. Epilepsia 2009; doi: 10.1111/j.1528-1167.2009.02397.x Gilliam F. Neurology 2002;58:s9-s19. Wheless JW. Neurostimulation Therapy for Epilepsy. In:
Wheless JW, Willmore LJ, Brumback RA, eds. Advanced Therapy in Epilepsy. Hamilton, Ontario: BC Decker, Inc. 2008. Faught E, et al. Epilepsia 2009;50(3):501-509.
AED Trial 1 Monotherapy
Treatment Goal
• Seizure freedom
Treatment Goal
• Maximize quality of life
• Optimize Long-term seizure control
• Minimize AED side effects
• Maximize adherence
AED Trial 2 Monotherapy
or Polytherapy
Newly Diagnosed Refractory Epilepsy
Epilepsy Surgery
EEG/video monitoring
VNS Therapy
AEDs (Polytherapy)
Ketogenic Diet

12. AEDs 2016
1) phenobarbital
• All generic
2) phenytoin
 Dilantin®/Cerebyx®
3) mysoline
 Primidone®
4) ethosuximide
 Zarontin®
5) carbamazepine
 Tegretol®/Carbatrol®
6) valproate
 Depakene®/Depakote®/
Depakote-ER®/Depacon®
7) felbamate
• Felbatol®
8) gabapentin
• Neurontin®
9) lamotrigine
• Lamictal®/Lamictal-XR®
10) topiramate
• Topamax®/Trokendi-XR®/
Qudexy-XR®
11) tiagabine
• Gabitril®
12) oxcarbazepine
• Trileptal®/Oxtellar-XR®
13) levetiracetam
• Keppra®/Keppra-XR®/
Spirtam®
14) zonisamide
• Zonegran®
15) pregabalin
• Lyrica®
16) rufinamide
• Banzel®
17) lacosamide
• Vimpat®
18) vigabatrin
• Sabril®
19) clobazam
• Onfi®
21) eslicarbazepine
• Aptiom®
20) ezogabine
• Potiga®
22) perampanel
• Fycompa®
23) brivaracetam
• Briviact®

13.  Adjunctive/bridge therapies
 clonazepam – Klonopin®
 clorazepate – Tranxene®
 Rescue therapies – clusters of seizures or
prolonged seizures
 clonazepam - Klonopin®
 clorazepate – Tranxene®
 lorazepam – Ativan®
 diazepam - Valium®
 rectal diazepam - Diastat®
 nasal midazolam – Versed®
 Note: Diastat® is FDA approved for treatment of cluster seizures only and
intranasal Versed® is not FDA approved to treat clusters of seizures or
prolonged seizures
Adjunctive and Rescue AEDs
clusters
prolonged

14.  phenobarbital, primidone, phenytoin, carbamazepine
 Increase cholesterol and triglycerides
 Many drug-to-drug interactions due to induction of hepatic
CYP-450 system
 Impair bone metabolism leading to osteoporosis – need
supplementation with Vitamin D and Calcium
 Impair hormone metabolism – irregular menses
 Sodium channel meds tend to be less effective for LGS
 phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine
 AEDs more likely to aggravate behavior disorders
 phenobarbital, levetiracetam, perampanel
AEDs to Avoid if Possible

15. Valproic Acid (VPA)
 Depakene®/Depakote®/Depakote-ER®/Depacon®
 First broad-spectrum AED to US market 1978 – FDA approved
 Formulations (generic and brand name)
 Liquid (three times daily)
 Capsules (three times daily) and sprinkle capsules (twice daily)
 Tablets (twice daily)
 Extended release tablets (once daily)
 Intravenous solution (three to four times daily)
 Generally considered the “gold standard” for treatment of LGS
 Safety issues are liver toxicity (idiosyncratic and dose-related),
pancreatitis (idiosyncratic), thrombocytopenia (dose-related)
 Generally requires safety monitoring for CBC and liver function
studies

16. Valproic Acid (VPA)
 Tolerability issues are weight gain, hair loss, hormonal
changes
 Behavior – tends to be well tolerated – mood stabilizer.
 Approved by FDA to treat migraine headaches
 Able to “load” orally or IV and get started quickly
 Can be used for status epilepticus
 Drug-to-drug interactions
 lamotrigine – VPA impairs lamotrigine metabolism, so must
decrease dose if adding VPA
 rufinamide – VPA impairs rufinamide metabolism and levels may
increase
 felbamate – impairs VPA metabolism and levels may increase
 cannabidiol (CBD) – impairs VPA metabolism and levels may
increase

17. Felbamate (FBM)
 Felbatol®
 Arrived US market 1993 – FDA approved for LGS
 Formulations (generic and brand name)
 Liquid (three times daily)
 Tablets (three times daily)
 Generally considered one of the most potent of all AEDs
 Safety issues are liver toxicity (idiosyncratic and dose-related)
and aplastic anemia (idiosyncratic) – Black Box from FDA
 Requires very close safety monitoring for CBC and liver function
studies – initially every 1-2 weeks and then monthly for several
months
 Adults are at higher risk – youngest death 14 years old
 All life-threatening toxicity occurred within first year of therapy

18. Felbamate (FBM)
 Tolerability issues are weight loss (may be severe) and
insomnia (may be severe)
 Behavior – tends to be an activator and brightens children up
and can lift some of the “encephalopathy”
 Able to get started fairly quickly
 Drug-to-drug interactions
 Many drug interactions as is both an inducer and an
inhibitor in the P450 system
 Tends to result in higher serum levels of carbamazepine,
phenytoin, and valproic acid

19. Lamotrigine (LTG)
 Lamictal®/Lamictal-XR®
 Arrived US market 1994 – FDA approved for LGS
 Formulations (generic and brand name)
 Tablets (twice daily)
 Chewable tablets and orally disintegrating tablets (twice daily)
 Extended release tablets (once daily)
 Broad spectrum AED with efficacy for most seizure types –
tends to be particularly effective for absence seizures, but may
aggravate myoclonic seizures
 Safety issues are allergic hypersensitivity reactions (rash) –
Black Box warning from FDA for Stevens-Johnson syndrome
and Toxic Epidermal Necrolysis
 Risk factors include age (children>adults), rate of titration (slower
is safer), starting dose (lower is safer), and VPA (increases risk)

20. Lamotrigine (LTG)
 Tolerability issues are dizziness/double vision, insomnia (may
be severe), and rarely aseptic meningitis with headaches
 Behavior – tends to be an activator and brightens children up
and can lift some of the “encephalopathy”. Approved by FDA to
treat depression in Bipolar disease
 Never able to get started quickly and takes the longest of any
AED to reach therapeutic target dosage
 Drug-to-drug interactions
 Most import interaction is with valproic acid that impairs
LTG metabolism and requires lowering the dosage
 Few other drug interactions as is only a mild P450 inducer,
other strong inducers will lower levels and may require a
higher dosage

21. Topiramate (TPM)
 Topamax®/Trokendi-XR®/Qudexy-XR®
 Arrived US market 1996 – FDA approved for LGS
 Formulations (generic and brand name)
 Tablets (twice daily)
 Sprinkle capsules (twice daily)
 Extended release sprinkle capsules (once daily)
 Broad spectrum AED with efficacy for most seizure types,
except for absence seizures
 Safety issues are kidney stones, metabolic acidosis, and acute
glaucoma
 Requires safety monitoring blood work for acidosis

22. Topiramate (TPM)
 Tolerability issues are cognitive slowing, weight loss and
paresthesias (numbness and tingling – orange juice helps)
 Behavior – overall, behavior neutral.
 Approved by FDA to treat migraine headaches
 Not usually able to start quickly due to cognitive effects
 Drug-to-drug interactions
 Few significant drug interactions and none with other AEDs

23. Levetiracetam (LVT)
 Keppra®/Keppra-XR®/Spirtam®(first drug made with 3D printing)
 Arrived US market 1999 – NOT FDA approved for LGS
 Formulations (generic and brand name)
 Liquid (twice daily)
 Tablets (twice daily)
 Extended release tablets (once daily)
 Intravenous solution (twice daily)
 Orally disintegrating tablets (twice daily)
 Broad spectrum AED with particular efficacy for myoclonic
seizures and little efficacy absence seizures
 Safety issues are related to effects on behavior with aggression
 No safety monitoring blood work is needed

24. Levetiracetam (LVT)
 Tolerability issues are mostly related to adverse effects on
behavior with aggression and agitation
 Behavior – negative and can be severe
 Able to “load” orally or IV and can start quickly
 Drug-to-drug interactions
 No significant drug interactions and none with other AEDs

25. Zonisamide (ZNS)
 Zonegran®
 Arrived US market 2000 – NOT FDA approved for LGS
 Formulations (generic and brand name)
 Capsules (once daily)
 Broad spectrum AED with similar efficacy as topiramate,
except works for atypical absence seizures
 Safety issues similar to topiramate with kidney stones and
metabolic acidosis, but no acute glaucoma
 Requires safety monitoring blood work for acidosis

26. Zonisamide (ZNS)
 Tolerability issues are similar to topiramate with cognitive
slowing and weight loss, but no paresthesia
 Behavior – overall, behavior neutral
 Not usually able to start quickly due to cognitive effects
 Drug-to-drug interactions
 Few significant drug interactions and none with other AEDs

27. Rufinamide (RFM)
 Banzel®
 Arrived US market 2008 – FDA approved for LGS
 Formulations (brand name only)
 Liquid (twice daily)
 Tablets (twice daily)
 Broad spectrum AED with efficacy for most generalized seizure
types, except for absence seizures
 Safety issues are cardiac arrhythmias and cannot use if have
familial short-QT syndrome
 Must obtain ECG before taking

28. Rufinamide (RFM)
 Tolerability issues are dizziness, sleepiness, GI upset
 Behavior – tends to be relatively behavior neutral
 Not usually able to start quickly due to dizzy/sedative effects
 Drug-to-drug interactions
 valproic acid impairs rufinamide metabolism and serum
levels may rise
 Few other drug interactions as is only a very mild P450
inducer and inhibitor

29. Clobazam (CLB)
 Onfi®
 Arrived US market 2011 (most of rest of world in early 1980’s)
 FDA approved for LGS
 Formulations (brand name only)
 Liquid (once or twice daily)
 Tablets (once or twice daily)
 Broad spectrum AED with efficacy for most generalized seizure
types, except for absence seizures
 Safety issues are related to it being a benzodiazepine (broadly
in same category as diazepam – Valium®)
 Marked sedative effects if combined with other sedating
medications or alcohol

30. Clobazam (CLB)
 Tolerability issues are similar to, but less severe than other
benzodiazepines with cognitive slowing, sedation, and drooling
 Behavior – overall, behavior neutral, but some children may
become agitated and aggressive
 Not usually able to start quickly due to cognitive and sedative
effects
 Drug-to-drug interactions
 cannabidiol (CBD) – impairs clobazam metabolism and levels may
increase substantially
 Few other significant drug interactions and none with other AEDs

31. Medical Marijuana

32. Courtesy of Fernando Stein MD

33.  Interest in several neurologic conditions – pain,
spasticity, epilepsy
 Fervor in epilepsy community based upon report of
child with Dravet syndrome (CNN – Charlotte’s Web)
 Cannabis contains >80 cannabinoids
 THC - tetrahydrocannabinol
 CBD – cannabidiol
 Thought to have no abuse potential and to have anti-
seizure properties
 Basic science suggested efficacy in animal models
 Several States have approved Medical Marijuana
 First worldwide clinical trial completed in Dravet
syndrome and ongoing in LGS
Medical Marijuana

34. Conclusions
 There are a number of safe and effective
medications available for the management of
seizures associated with LGS
 Management should focus on maximizing quality
of life – as few seizures and as few adverse
effects as possible
 Nonpharmacologic treatments should be
considered early if medications are not working,
especially curative ones if possible
 Exciting and innovative new medical and surgical
treatments are rapidly emerging

35. Thank-you!

37. Non-pharmacologic
Therapies for LGS
Scott Demarest MD
Assistant Professor, Departments of
Pediatrics and Neurology
University of Colorado School of Medicine
Children's Hospital Colorado

38. Disclosures
My epilepsy genetics research is supported by NIH
funding through a K12 mechanism.
No conflicts of interest
I want to thank Drs. Kelly Knupp and Anup Patel who
have provided me with some of these slides

39. Objectives
• Where do non-pharmacologic therapies fit into epilepsy
treatment and LGS?
• What kinds of therapies are these?
• What are the advantages of one therapy over another?
• What is on the Horizon?

40. Goals of Epilepsy Treatment
According to the Epilepsy Foundation, the goal of all
epilepsy treatment is to:
Prevent further seizures
Avoid side effects
Make it possible for people to lead active lives
When Epilepsy is intractable specific treatment goals
should drive care!

41. Intractable Epilepsy Treatment Goals
We always want less seizures and less side effects…
But
These two goals often are in conflict.
Patients and families should define SPECIFIC treatment
goals with their neurologist to help prioritize and
balance treatment and side effects.

42. Medications Are Still the Mainstay of Treatment
Basic principals
• Use a single drug whenever possible
(or as few as possible)
• Start low and go slow

43. Medications
13%
4%
36%
47%
Seizure-free with 1st drug
Seizure-free with 2nd drug
Seizure-free with 3rd or
multiple drugs
Pharmacoresistant epilepsy
Kwan and Brodie 2000
Previously Untreated Epilepsy Patients (n=470)

44. Medications
13%
4%
36%
47%
Seizure-free with 1st drug
Seizure-free with 2nd drug
Seizure-free with 3rd or
multiple drugs
Pharmacoresistant epilepsy
Kwan and Brodie 2000
Previously Untreated Epilepsy Patients (n=470)

45. Medications
13%
4%
36%
47%
Seizure-free with 1st drug
Seizure-free with 2nd drug
Seizure-free with 3rd or
multiple drugs
Pharmacoresistant epilepsy
Kwan and Brodie 2000
Most LGS Patients
Meds are not working well enough.
What else can we try?

46. Medications
13%
4%
36%
47%
Seizure-free with 1st drug
Seizure-free with 2nd drug
Seizure-free with 3rd or
multiple drugs
Pharmacoresistant epilepsy
Kwan and Brodie 2000
≠
Better

47. There are a lot of Meds
Older Medications
(1st
Generation)
Generic Name Year Introduced
Trade
Name
Bromides 1857 —
Phenobarbital 1912 Luminal®
Phenytoin Sodium 1956 Dilantin®
Ethosuximide 1960 Zarontin®
Diazepam 1963 Valium®
Carbamazepine 1968 Tegretol®
Lorazepam 1977 Ativan®
Valproic acid 1978 Depakene®
Divalproex sodium 1983 Depakote®
Carbamazepine 1986 Epitol®
Diazepam 1997 Diastat®
Carbamazepine 1997 Carbatrol®
Phenytoin Sodium 1998 Phenytek®
Newer Medications
(2nd & 3rd Generation)
Generic Name FDA Approval
Trade
Name
Felbamate 1993 Felbatol®
Gabapentin 1993 Neurontin®
Lamotrigine 1994 Lamictal®
Topiramate 1996 Topamax®
Tiagabine 1997 Gabitril®
Levetiracetam 1999 Keppra®
Oxcarbazepine 2000 Trileptal®
Zonisamide 2000 Zonegran®
Pregabalin 2005 Lyrica®
Rufinamide 2007 Banzel ®
Lacosamide 2008 Vimpat®
Vigabatrin 2009 Sabril ®
Clobazam 2011 Onfi ®
Esogabine 2012 Potiga ®
Preampanel 2013 Fycompa®
Eslicarbazepine 2013 Aptiom®
But is there something else to try?

48. So what do we do if meds aren’t working?
We think about:
• Surgery
• VNS
• Ketogenic diet

49. Cannabidiol – lets get this out of the way
This is non-pharma but still a drug
(Actually ~200 drugs if taking an artisanal preparation)
This is not something I recommend, but I do have many
patients taking it.
There is time devoted to this on Sunday

50. Resective Surgery
The first thing I think about
Most patients are not candidates for resection…
But focal lesions in the brain or large lesions mostly on one side of the brain
can cause LGS (or an LGS-like syndrome) and those patients may be a surgical
candidates (PMID – 25284034).
This is important to think about as surgery in this setting is a potential cure
for epilepsy.
These surgeries are a big deal and usually are either a hemispherectomy or
multilobar surgery (though not always).

51. Then what?
Can consider:
• Ketogenic diet
• VNS
• Corpus Callosotomy

52. The Ketogenic Diet
• High fat, low carb, enough protein diet
• This can be done in patients with or
without a Gtube (formula based or
through food)
• Requires the guidance of a dietician
• This diet switches the brain to using
fats for an energy source instead of
sugar
We don’t really understand why this works…

53. Ketogenic Diet
Approximately 50% of patients with LGS respond to the KD with
a >50% reduction in seizures and some patients (23%) may
achieve a >90% reduction (Retrospective – PMID 22443637)
Patients usually admitted to start diet
Some places have patients fast prior to starting diet
Should give it a 3 months trial
Re-evaluate after 1-2 years on treatment

54. Potential Side Effects of the KD
Constipation (Drink lots of water)
Vomiting
Abdominal pain
Decreased energy
High cholesterol
Kidney stones (Drink lots of water)
Slower growth potential
(Probably not if being monitored appropriately)

55. Other Dietary Therapies
Modified Adkins diet
Low-Glycemic index diet
Less restriction
Not been well studied in LGS patients
Could be good options for some to consider

56. Vitamins and Supplements
Vitamin B6 and/or folinic (not folic) acid used for
infants who have a deficiency of this vitamin as a cause
for their seizures
•This is usually the result of specific genetic changes
Other vitamins not clinically proven to help

57. Vagus Nerve Stimulator
The VNS Therapy System consists of
an implanted pacemaker-like
generator and nerve stimulation
electrodes, which deliver
intermittent stimulation to the
patient’s left vagus nerve that sends
signals to the brain

58. Vagus Nerve Stimulator
It is used as add on treatment for drug-resistant epilepsy (including
patients with LGS) who are not suitable candidates for resective
surgery
50% of LGS patients respond to VNS therapy, with at least a >50%
reduction in seizures
Response may improve over time
Appears best for drop attack (atonic) seizures
Recent American Academy of Neurology (AAN) guideline recommends
that VNS be considered for patients with LGS

59. VNS may be considered for seizures in children, for LGS-
associated seizures
Seizure detection by change in heart rate for activation
(Aspire SD)
Longer battery life (now available)
Vagal Nerve Stimulator (VNS)

60. VNS – Side Effects
Site infection
During stimulation: (Typically resolves if turned off)
Hoarseness
Drooling
Cough
Voice alteration
6-23% of patients had worsening behavior or hyperactivity

61. Corpus Callosotomy
Cuts the connection between the two sides of the brain

62. Corpus Callosotomy
There have been a few small studies:
• 60-90% - >50% reduction in seizures
• 50-75% - >90%
• 10-15% seizure free
PMIDs – 2401256, 24912732, 16499762, 25284034

63. Corpus Callosotomy
Side Effects:
~1-5% risk of death from surgical complications

64. Corpus Callosotomy vs VNS
CC is better for Atonic
• 80% vs 55% - >50% reduction in Atonic seizures
• 70% vs 26% - >75% reduction in Atonic seizures
BUT otherwise no difference in efficacy for other seizure types
***You can do one after the other and there is continued ***
improvement in seizures
PMID – 23068970, 26979179

65. Those are the mainstays…
but what else is there?

66. CNS implanted device that would recognize seizure activity and
activate signal to stop it
Potentially more benefit for patients with bilateral mesial temporal
sclerosis or other focal epilepsies
Not clear how helpful this will be for LGS
Recently FDA approved
Not currently approved for children
Responsive NeuroStimulation (RNS)

67. Steroids
• Prednisone and ACTH
have been used
• There are many small
studies that are not high
quality
• Potentially dangerous
side effects
What do we do about the
relapse rate???
PMID: 17951084

68. Steroids
PMID: 26086765

69. Intravenous Immunoglobulin (IVIG)
PMID: 17521345

70. IVIG and Steroids
There are many small LOW quality studies that have
interesting and somewhat promising results.
These treatments are invasive and can be dangerous
(and are expensive – ACTH and IVIG)
We need HIGH quality randomized
control trials!

71. A note on personalized medicine
Probably ~20-40% of patients with LGS are due to
genetic causes
• There are numerous genes
• DNM1, CDKL5, STXBP1, GABRB3, HDAC4, ALG13,
SCN1A, SCN2A, SCN8A… to name a few
The goal is genetic cause specific treatments for
epilepsies like LGS that target the underlying problem
This is just getting started
but this will be a real thing 5-10 years from now

72. Quick review: My approach
You have to try a few meds first but if that does not
work:
1. Think about resective surgery (only chance for cure)
2. What seizure type is the biggest problem?
VNS vs ketogenic diet vs Corpus Callosotomy
3. Can try ALL or some of these…

73. Quick review: My approach
Now we are off the beaten
path:
• Steroids
• IVIG
There are logistical barriers in many cases
AND
There are important side effects to consider

74. Throughout the Journey
We often are trying new medications between some of
these options
Be careful to make one change at a time so you know what helps or hurts!
I keep looking for the cause if it is not known. This is
becoming more and more likely to impact treatment.
Never stop advocating for our kids!
We can make things better!!

75. Thank You
I think we are taking questions at the end