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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.