Updates in EpilepsyNatalie Hendon MD

Virginia Mason Medical CenterFebruary 21, 2015

Learning Objectives

Medical use of cannabis2700 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 literature

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

Cannabidiol (CBD)Cannabis sativa and sister species Cannabis

indica have been used for centuries and millenia

Two major neuroactive componentsPsychoactive tetrahydrocannabinol - 9DTHCNonpsychoactive cannabidiol

Cannabis sativa usually has higher 9DTHC:CBD ratios than cannabis indicaSativa strains have more psychotropic effects and

are more stimulating Indica strains more sedating

Cannabinoid pharmacology and

mechanisms of actionC. 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 9DTHC

9DTHC and the endocannabinoid system

9DTHC activates the endocannabinoid systemG-protein coupled cannabinoid (CB) receptors,

synthetic and degradating enzymes, and transporters

In CNS, this system influences synaptic communication and modulates eating, anxiety, learning and memory, and growth and development.

9DTHC: Mechanism of action

9DTHC binds to 2 G-protein-coupled cell membrane receptors, cannabinoid type 1 (CB1) and type 2 (CB2) receptors

Endocannabinoids - anandamide and 2-arachidonoylglycerol, CB1 and CB2 endogenous ligands

CB1 receptors are found primarily in the brain but also in peripheral tissues CB1 receptors are present in GABAergic and excitatory

glutamatergic neurons

CB2 receptors are mainly in the immune and hematopoietic cells but can be upregulated in other tissues

Main psychotropic effects from CB1 receptors

Cannabidiol (CBD) CBD does not activate CB1 and CB2 receptors

Lack of psychotropic activity

CBD interacts with many non-endocannabinoid signally systems as a multitarget drug

At low concentrations, blocks several important receptors and transporters involved in intra and intercelluar signalling; also enhances activity of 5-HT1a 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 9DTHC to enhance

tolerability and widen therapeutic window Users of cannabis with high CBD:9DTHC ratios are less likely to

develop psychotic symptoms

Nabiximols (SativexTM)Patented cannabinoid oromucosal spray for MS

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

Contain equal amounts CBD and 9DTHC

Relieve spasticity and pain more than 9DTHC aloneCBD’s effects allow patients to tolerate higher

amounts of 9DTHCCBD supplements antispastic effects of 9DTHC (local

potentiation of glycine signaling, inhibition of endocannabinoid degradation, retardation of demyelination through antioxidant/anti-inflammatory mechanisms

Cannabidiol (CBD)

CBD and neurology: experimental models

CBD and epilepsy

Other cannabinoids Cannabichromene (CBC) and propyl homologs of 9DTHC

(9DTHCV) and CBD (CBDV)9DTHCV 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 9DTHCV produce anticonvulsant

effects in animal models of epilepsy Likely via non-CB1/CB2 mechanisms

Cannabinoid effects in preclinical models of seizure and epilepsy2

Prior human trials with CBD and epilepsy

Recent Cochrane review identified 4 studies between 1978 and 19903

Randomized controlled trials, blinded (single or double) or unblinded

Not adequately powered9-15 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 treatment

Cannabidiol and related compounds

CBD is the only non-9DTHC 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, 9DTHC, and multiple other derivatives.4

CBD recently shown to have acute antiepileptiform/anticonvulsant effects in vitro and in vivo models. 5

Less preclinical evidence for chronic epilepsy animal models

Cannabidiol (CBD) Pharmacology in Humans

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

Multiple potential routes of administrationAerosolization or vaporization is promising (peak

plasma concentration <10 min with bioavailability 31%) but requires special equipment and cooperation. 6

Oil based capsule – first pass metabolismOral-mucosal-sublingual delivery

Prior studies of nabiximols oral sprayTransdermal

MetabolismExtensive 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 CYP3A4 Repeated administration of CBD may induce CYP2B

isozymes in animal modelsAEDs valproate, clobazam are metabolized by theseAEDs carbamazepine and phenytoin could reduce CBD

levels

CBD and Severe Childhood Epilepsies: Dravet Syndrome

Severe myoclonic epilepsy of infancy (Dravet Syndrome) SCN1A mutations

Patients 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 crucial

Charlotte Figi9

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

age 5After 20 months of treatment, >90% reduction in GTCs with

improved encephalopathy

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-Gastaut

Survey of physicians and patients: marijuana use for epilepsy11

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 end4 related to articles published in Epilepsia’s

Controversy in Epilepsy series on the use of medical marijuana and CBD for epilepsySufficient 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 epilepsy4 on whether the reader read the papers and their

demographics

Responders

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 epilepsy

Wide diversity of opinion on efficacy

Should pharmacological grade compounds containing CBD be available for use in

epilepsy?

SummaryMinority 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 epilepsy

Potential for adverse health effects12

Caution urged by epileptologists

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

Lack of regulation and standardization in medical cannabis industryComposition and consistency of products

No controlled data on home use – no data on safety eitherCannabis may have negative effects in the

developing brain

Randomized double-blind placebo-controlled trials are required

Neurostimulation and epilepsy

Rationale30-40% 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 detected Goal of disruption of epileptiform activity before a

seizure develops

Responsive Nerve Stimulation13

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.

Baseline characteristics

Study Design

Subject disposition

Results14

Mean disabling seizures per month

Seizure frequency % change by subject – most recent 3

months

Adverse effects

Changes in quality of life scores at 2 yrs post

implant

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 candidates

THANK YOU

References1. Gowers W. Epilepsy and other chronic convulsive disorders. London: Churchill; 1881:223.

2. Devinsky et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014;55(6):791-802.

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

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

5. Jones et al. Cannabidiol displays antiepileptiform and antiseizure effects in vitro and in vivo. J Pharmacol Exp Ther 2010;332:569-577.

6. 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.

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

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

9. Maa et al. The case for medical marijuana in epilepsy. Epilepsia 2014;55(6):783-6.

10. Oakley JC et al. Insights into pathophysiology and therapy from a mouse model of Dravet syndrome. Epilepsia 2011;52:59-61.

11. 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.

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

13. 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.

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