LGS Foundation 2016 Conference - Friday Morning

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

Research Funding NINDS

Moody Foundation

Novartis

Acorda

Eisai

Pfizer

UCB

Lundbeck

GW Pharma

Publication Royalties Up-To-Date

Disclosures

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)

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

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

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

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

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

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

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

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®

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

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

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

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

Felbamate (FBM) Felbatol®

Arrived US market 1993 – FDA approved for LGS


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

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


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

Lamotrigine (LTG) Lamictal®/Lamictal-XR®




Chewable tablets and orally disintegrating tablets (twice 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)

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


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

Topiramate (TPM) Topamax®/Trokendi-XR®/Qudexy-XR®




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

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


Few significant drug interactions and none with other AEDs

Levetiracetam (LVT) Keppra®/Keppra-XR®/Spirtam®(first drug made with 3D printing)

Arrived US market 1999 – NOT FDA approved for LGS


Liquid (twice 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

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


No significant drug interactions and none with other AEDs

Zonisamide (ZNS) Zonegran®

Arrived US market 2000 – NOT FDA approved for LGS


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

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


Few significant drug interactions and none with other AEDs

Rufinamide (RFM) Banzel®


Formulations (brand name only)

Liquid (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

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


valproic acid impairs rufinamide metabolism and serum

levels may rise

Few other drug interactions as is only a very mild P450

inducer and inhibitor

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

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


cannabidiol (CBD) – impairs clobazam metabolism and levels may

increase substantially

Few other significant drug interactions and none with other AEDs

Medical Marijuana

Courtesy of Fernando Stein MD

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

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

Thank-you!

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

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

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?

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!

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.

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

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)

Medications

13%

4%

36%

47%




multiple drugs



Most LGS Patients Meds are not working well enough.

What else can we try?

Medications

13%

4%

36%

47%




multiple drugs



≠ Better

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?

So what do we do if meds aren’t working?

We think about:

• Surgery

• VNS

• Ketogenic diet

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

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).

Then what?

Can consider:

• Ketogenic diet

• VNS

• Corpus Callosotomy

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…

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

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)

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

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

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

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

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)

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

Corpus Callosotomy

Cuts the connection between the two sides of the brain

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

Corpus Callosotomy

Side Effects:

~1-5% risk of death from surgical complications

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

Those are the mainstays…

but what else is there?

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)

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

Steroids

PMID: 26086765

Intravenous Immunoglobulin (IVIG)

PMID: 17521345

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!

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

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…

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

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!!

Thank You

I think we are taking questions at the end

LGS Foundation 2016 Conference - Friday Morning

Healthcare

Transcript of LGS Foundation 2016 Conference - Friday Morning