Updates in Epilepsy - PowerPoint Presentation

Slide1

Updates in Epilepsy

Natalie Hendon MD

Virginia Mason Medical Center

February 21, 2015Slide2

Learning ObjectivesSlide3
Slide4

Medical use of cannabis

2700 BCE – Chinese physicians

Treatment of menstrual disorders, gout, rheumatism, malaria, constipation, and absent-mindedness

Medieval times – Islamic physicians

Treatment of nausea, vomiting, epilepsy, inflammation, pain and fever

1800s – Western physicians

Used as a common analgesic

English neurologists Reynolds and

Gowers

used cannabis to treat epilepsy

Late 1800s to mid-1900s

Use limited

Largely ignored in English language epilepsy literatureSlide5

Gowers

W. Epilepsy and other chronic convulsive disorders. London: Churchill; 1881:223Slide6

Cannabidiol (CBD)

Cannabis sativa and sister species Cannabis

indica

have been used for centuries and

millenia

Two major

neuroactive

components

Psychoactive

tetrahydrocannabinol

- 9DTHC

Nonpsychoactive cannabidiolCannabis sativa usually has higher 9

DTHC:CBD ratios than cannabis indicaSativa strains have more psychotropic effects and are more stimulating

Indica

strains more sedatingSlide7

Cannabinoid pharmacology and mechanisms of action

C. sativa produces more than 80

terpenophenolic

compounds called cannabinoids, present in varying concentrations depending on the strain

489 total known constituents, many potentially

neuroactive

Psychotropic effects are due to

9

D

THCSlide8

9

D

THC and the

endocannabinoid

system

9

D

THC activates the

endocannabinoid

system

G-protein coupled cannabinoid (CB) receptors, synthetic and degradating enzymes, and transportersIn CNS, this system influences synaptic communication and modulates eating, anxiety, learning and memory, and growth and development.Slide9

9

D

THC: Mechanism of action

9

D

THC binds to 2 G-protein-coupled cell membrane receptors,

cannabinoid type 1 (CB

1

) and type 2 (CB

2

) receptorsEndocannabinoids - anandamide

and 2-arachidonoylglycerol, CB1 and CB2 endogenous ligands CB1

receptors are found primarily in the brain but also in peripheral tissuesCB1 receptors are present in GABAergic

and excitatory

glutamatergic

neurons

CB

2

receptors are mainly in the immune and hematopoietic cells but can be

upregulated

in other tissues

Main psychotropic effects from CB

1

receptorsSlide10
Slide11

Cannabidiol (CBD)

CBD does not activate CB

1

and CB

2

receptors

Lack of psychotropic

activity

CBD interacts with many non-

endocannabinoid

signally systems as a multitarget

drugAt low concentrations, blocks several important receptors and transporters involved in intra and intercelluar signalling; also enhances activity of 5-HT

1a receptor, a3 and a1 glycine receptor, and other receptors having an effect on intracellular calcium concentrations

At high concentrations, activates receptors involved in cell recycling activities (peroxisomes), altering uptake and degradation of

anandamide

As a result, reduces

psychoactivity

of

9

D

THC

to enhance tolerability and widen therapeutic window

Users of cannabis with high CBD:

9

D

THC ratios are less likely to develop psychotic symptomsSlide12

Nabiximols (

Sativex

TM

)

Patented cannabinoid

oromucosal

spray for MS patients to relieve spasticity, neuropathic pain, overactive bladder and other symptoms

Contain equal amounts CBD and

9

D

THCRelieve spasticity and pain more than

9DTHC aloneCBD’s effects allow patients to tolerate higher amounts of 9D

THCCBD supplements antispastic effects of 9D

THC (local potentiation of glycine signaling, inhibition of

endocannabinoid

degradation, retardation of demyelination through antioxidant/anti-inflammatory mechanismsSlide13

Cannabidiol (CBD)Slide14

CBD and neurology: experimental models

CBD and epilepsy

Other cannabinoids

Cannabichromene

(CBC) and propyl homologs of

9

D

THC (

9

D

THCV) and CBD (CBDV)9D

THCV high affinity for cannabinoid receptors - CB1 antagonist and partial CB2 agonist  Parkinson’s disease model

CBC influences adult neural stem cell differentiationCBDV and to a smaller extent 9D

THCV produce anticonvulsant effects in animal models of epilepsy

Likely via non-

CB

1

/

CB

2

mechanismsSlide15

Cannabinoid effects in preclinical models of seizure and epilepsy

2Slide16

Prior human trials with CBD and epilepsy

Recent Cochrane review identified 4 studies between 1978 and 1990

3

Randomized controlled trials, blinded (single or double) or

unblinded

Not adequately powered

9-15 patients per trial

CBD doses of 200-300mg/day range in adults is usually well tolerated

Failed to provide evidence about CBD efficacy in epilepsy

Failed to provide information on safety of long-term CBD treatmentSlide17

Cannabidiol

and related compounds

CBD is the only non-

9

D

THC

phytocannabinoid

to be assessed in preclinical and clinical studies for acute anticonvulsant effects

Mixed efficacy in some mice models but more promising

One study showed significant anticonvulsant effects with CBD,

9

DTHC, and multiple other derivatives.4CBD recently shown to have acute antiepileptiform/anticonvulsant effects in vitro and in vivo models.

5Less preclinical evidence for chronic epilepsy animal models Slide18

Cannabidiol

(CBD) Pharmacology in Humans

Studies have provided sufficient human data on pharmacology to proceed with dosing and efficacy trials

Multiple potential routes of administration

Aerosolization

or vaporization is promising (peak plasma concentration <10 min with bioavailability 31%) but requires special equipment and cooperation.

6

Oil based capsule – first pass metabolism

Oral-mucosal-sublingual delivery

Prior studies of

nabiximols

oral sprayTransdermalSlide19

Metabolism

Extensive metabolism by the liver

Cytochrome P450 enzymes

Excreted in feces and to a small extent urine

Terminal half life 18-32

hrs

7

Drug-drug interactions

8

Theoretical concerns given that CBD is a potent inhibitor of CYP isozymes

(CYP2C and CYP3A)Many medications are substrates for CYP3A4Repeated administration of CBD may induce CYP2B isozymes in animal models

AEDs valproate, clobazam are metabolized by theseAEDs carbamazepine and phenytoin could reduce CBD levelsSlide20

CBD and Severe Childhood Epilepsies:

Dravet

Syndrome

Severe myoclonic epilepsy of infancy (

Dravet

Syndrome)

SCN1A mutations

P

atients healthy until age 6 months when they present with convulsive status

epilepticus

typically triggered by fever. Further episodes occur and new types of seizures develop.

Refractory to standard AEDs. From year 2 onwards, development of epileptic encephalopathyEarly and effective treatment is crucialCharlotte Figi

9baseline sz frequency of 300+ convulsions per weekbegan treatment with a rare, high CBD strain of cannabis at age 5

After 20 months of treatment, >90% reduction in GTCs with improved encephalopathySlide21

Rare, devastating childhood epilepsy syndrome

Multiple causes – structural, metabolic, genetic, idiopathic

Presents at age 1-8, typically between 3-5

Multiple refractory seizures daily with head trauma from recurrent atonic seizures

Survey of 19 US parents, 12 of whom had children with DS, 5 reported >80% reduction in seizures. 1 LGS parent reported >80% reduction in seizures.

10

Because of the severity of these epilepsies, without good treatment options, these patients may be good candidates for a CBD trial

CBD and Severe Childhood Epilepsies: Lennox-

GastautSlide22

Survey of physicians and patients: marijuana use for epilepsy

11Slide23

Survey was open poll through

Epilepsia

and related affiliates (ILAE, IBE,

Epilepsia

newsletters)

Readers asked to complete the poll

8 questions with open commentary at the end

4 related to articles published in

Epilepsia’s

Controversy in Epilepsy series on the use of medical marijuana and CBD for epilepsy

Sufficient safety and efficacy data to allow use with/without a RxWould responder advise patients with severe epilepsy to try CBD/marijuanaShould pharmacologic grade compounds containing CBD be available for use in epilepsy

4 on whether the reader read the papers and their demographicsSlide24

RespondersSlide25

Wide diversity of opinion on safety

Based on the information [provided in the series], do you believe there are sufficient SAFETY data to allow open nonprescription or prescription use for treating epilepsySlide26

Wide diversity of opinion on efficacySlide27
Slide28

Should pharmacological grade compounds containing CBD be available for use in epilepsy?Slide29

Summary

Minority of

epielptologists

and general neurologists said that there were sufficient safety (34%) and efficacy (28%) data for CBD with or without Rx

Majority of public and patients said sufficient safety (96%) and efficacy (95%) data

General physicians, basic researchers, nurses and other allied health professionals sided with patients – sufficient safety (70%) and efficacy (83%)

One area of agreement – 78% said pharmacologic grade compounds with CBD should be available to

pts

with epilepsySlide30

Potential for adverse health effects

12Slide31
Slide32

Caution urged by epileptologists

Most currently prominent data of cannabis-derivatives in epilepsy is anecdotal

Lack of regulation and standardization in medical cannabis industry

Composition and consistency of products

No controlled data on home use – no data on safety either

Cannabis may have negative effects in the developing brain

Randomized double-blind placebo-controlled trials are requiredSlide33

Neurostimulation

and epilepsySlide34

Rationale

30-40% of patients with partial-onset seizures have intractable epilepsy

Failure to control seizures after 2

sz

medications have been appropriately chosen and used

These patients may be candidates for surgical removal of the seizure focus or

vagus

nerve stimulation (VNS)

Newer approaches to treating medically refractory partial onset seizures include direct brain stimulation

RNS system is a cranially implanted

neurostimulator

that provides responsive stimulation to the seizure focus when the epileptiform activity is detectedGoal of disruption of epileptiform activity before a seizure developsSlide35

Responsive Nerve Stimulation

13Slide36

Randomized, multicenter, double-blinded, sham-stimulation controlled pivotal study

Efficacy and safety of RNS as adjunctive therapy to reduce frequency of seizures in adults with medically intractable partial onset seizures from one or two foci.Slide37
Slide38

Baseline characteristicsSlide39

Study DesignSlide40

Subject dispositionSlide41

Results14Slide42

Mean disabling seizures per monthSlide43

Seizure frequency % change by subject – most recent 3 monthsSlide44

Adverse effectsSlide45

Changes in quality of life scores at 2

yrs

post implantSlide46

Conclusions

Acceptable safety and statistically significant reduction in seizure frequency, which was sustained long-term

Statistically significant greater reduction in seizure frequency during BEP relative to

preimplant

period in treatment group compared to sham.

Reduction of seizures with RNS increased over 1-2

yrs

after implant and was sustained at about 50%

These improvements were NOT related to changes in AEDs

92% completion rate

Clinical meaningfulness of response is demonstrated by improvements in overall quality of life

Safety data demonstrates low risk of implantation esp compared to similar devices, well-tolerated and safe over time

 Provides additional treatment option for medically refractory focal onset epilepsy who are not surgical candidatesSlide47

THANK YOUSlide48

References

Gowers

W. Epilepsy and other chronic convulsive disorders. London: Churchill; 1881:

223.

Devinsky

et al.

Cannabidiol

: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.

Epilepsia

2014;55(6):791-802.

Gloss D et al. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2012;6:CD009270.

Karler et al. Cannabis and epilepsy. Adv Biosci 1978;22-23:619-41.

Jones et al.

Cannabidiol

displays

antiepileptiform

and

antiseizure

effects in vitro and in vivo. J

Pharmacol

Exp

Ther

2010;332:569-577.

Ohlsson

A et al. Single dose kinetics of

cannabidiol

in man. In

Agurell

S et al The Cannabinoids: chemical, pharmacologic, and therapeutic aspects. Orlando: Academic Press, 1984:219-25.

Hawksworth

et al. Metabolism and pharmacokinetics of cannabinoids. London, UK: Pharmaceutical Press 2004.

Harvey DJ. Absorption, distribution, and biotransformation of the cannabinoids Marihuana and medicine. New York: Springer;1999:91-103.

Maa

et al. The case for medical marijuana in epilepsy.

Epilepsia

2014;55(6):783-6.

Oakley JC et al. Insights into pathophysiology and therapy from a mouse model of

Dravet

syndrome.

Epilepsia

2011;52:59-61.

Mathern

et al. Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: Result of

Epilepsia’s

survey.

Epilepsia

2015;56(1):1-6.

Volkow

et al. Adverse health effects of marijuana use. NEJM 2014;370:2219-27.

Heck et al. two year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive

neurostimulation

: final results of the RNS system pivotal

trial.

Epilepsia

2014;55(3):432-41.

Morrell et al. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011;77:1295-1304.