Transcript cannabis-for-pediatric-epilepsy-and-autism

Cannabis Use in Pediatric Epilepsy
John Gaitanis, M.D.
11/5/2016
Learner Objectives
At the conclusion of the session, participants will be able to:
• Distinguish the mechanism of action of
cannabidiol versus THC
• Gain awareness of latest clinical and
basis science studies
• Recognize ethical and legal
responsibilities of physician
Commercial Support
“This activity does not have any commercial
support.”
Cannabis in Pediatric Epilepsy
John Gaitanis, M.D.
April 13th, 2016
Incidence of Epilepsy
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Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in
Rochester, Minnesota: 1935-1984. Epilepsia 1993;34(3):453-68.
Why treat seizures?
•
Lessen the risk of seizure-induced injury
•
Reduce the risk of prolonged seizures
•
Lessen the cognitive effects of frequent seizures
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Improve patient’s overall quality of life
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Prevent sudden unexplained death in epilepsy patients
(SUDEP)
When to treat?
•
Recurrence risk following a first unprovoked seizure
in children ranges between 44% to 64%
– Greatest risk in patients with abnormal neurological
exam, abnormal EEG, or remote symptomatic etiology
– Recurrence risk approximately 25% in patients with
normal exam and normal EEG
•
Should a second seizure occur, the recurrence risk
jumps to 79%
How to Treat?
•
Primary goal is for patient to be seizure and side-effect
free
•
For that reason, top considerations are efficacy and sideeffect profile
•
Other considerations are frequency of dosing, ease of
administration, and cost
•
Medication choices have to be tailored to the individual
patient
Efficacy of AEDs
Monotherapy Monotherapy Monotherapy
1st AED
2nd AED
3rd AED
Newly
diagnosed
epilepsy
n=470
Adjunctive
Therapy
Seizure-free
47%
Uncontrolled
seizures
53%
Seizure-free
13%
Seizure-free
1%
Seizure-free
Uncontrolled
3%
seizures
Uncontrolled
40%
seizures
Uncontrolled
39%
seizures
36%
Kwan P et al. N Engl J Med. 2000;342(5):314-319.
SUDEP
•
Incidence is about 0.35 cases/1,000 person-years
– higher in patients with chronic epilepsy
– highest with severe, refractory seizures
– seizure frequency is the strongest risk factor for SUDEP
•
Responsible for 2% to 17% of all deaths in patients with
epilepsy
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Risk of sudden death is increased in the epilepsy population
by 24 times compared with the general population
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SUDEP and Dravet Syndrome
•
24 patients followed at the Centre Saint-Paul, Marseille
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Five patients (20.8%) died, at a mean age of 24.8 years, one
by status epilepticus, three by sudden unexpected death in
epilepsy (SUDEP), and one of unknown cause
Genton P, Velizarova R, Dravet C. Dravet syndrome: the long-term outcome.
Epilepsia. 2011; 52: 44-9
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Patients with DS have depressed HRV compared to other
types of epilepsy patients and age-matched control group
Delogu AB. Electrical and autonomic cardiac function in patients with Dravet
syndrome. Epilepsia. 2011;52 Suppl 2: 55-8.
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PATIENT HISTORY
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Patient History
•
12 year old girl who first developed seizures at 11 weeks of
age
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During that seizure, she had tonic eye deviation to the right
which lasted for 10 to 15 minutes
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EEG and MRI were normal
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Discharged to home off of medications
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Patient History
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Generalized tonic seizures
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Drop spells
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Episodes of staring and eye lid fluttering
– Multiple seizures daily (mostly drop and staring spells)
– Some seizures triggered by visual stimuli
– Many of her breakthroughs developed when she developed a
febrile illness or was over heated
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Multiple PICU admissions for status epilepticus and aspiration
pneumonia
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Patient History
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Multiple MRIs have been normal
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EEG demonstrates slow spike and slow waves
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Patient had developmental regression after 1 year of age
– Non-verbal
– Cognitive delays
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Patient History
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Treatments
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Carbamazepine (seizures worsened)
Valproic acid (continued seizures)
Topiramate (continued seizures)
Levetiracetam (behavioral side-effects and continued seizures)
Phenobarbital (no improvement)
Lamotrigine (no improvement)
Felbamate (seizure breakthroughs)
Ketogenic diet (no improvement)
Vagus Nerve Stimulator (removed due to lead infection)
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WHAT IF MEDICATIONS FAIL?
Non-Medication Options
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Ketogenic diet
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Vagal nerve stimulation
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Epilepsy surgery
CANNABINOIDS FOR EPILEPSY
Cannabis sativa
•
Medicinal use of cannabis
– Originates in ancient China
– Shen Nung (the‘‘red emperor,’’2838–2698BC), considered the
father of all herbalists, is said to have suggested its use in his
book ‘‘The Herbal’’
•
Used against several ailments in ancient Egyptian, Indian,
Greek and Roman pharmacopeias
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The first record of medical marijuana as a treatment for
epilepsy comes from ancient Indian literature, in which
cannabis has been recognized as a medicine since 1000 B.C.
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The Irish physician William O’Shaughnessy is credited with
introducing the therapeutic use of cannabis to Western
medicine in the 1830s
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William O’ Shaughnessy took a position in Bengal at the
young age of 24.
– “In Cannabis, the medical profession has gained an anticonvulsive remedy of the greatest value.”
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J. R. Reynolds; former British Medical Association President
and personal physician to the royal family, noted in an 1890
publication of The Lancet:
– “there are many cases of so called epilepsy in adults … in which
India Hemp is the most useful agent with which I am acquainted.”
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CNN August 2013
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Charlotte Figi
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Charlotte Figi
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WHAT EXACTLY IS IN IT?
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Cannabis sativa
•
Over 421 chemical compounds
– more than 80 terpeno-phenol compounds named “cannabinoids”
– Not found in other plants
– present in varying relative proportions depending on the plant
THC
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Accounts for most psychoactive effects
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Δ9-THC was isolated and characterized in 1964
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Δ9-THC binds to specific cell membrane receptors named
cannabinoid (CB1 and CB2) receptors
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The discovery of cannabinoid receptors was followed by the
identification of their endogenous ligands termed
“endocannabinoids”
– anandamide
– 2-arachidonoylglycerol
Cannabidiol
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Independent of endocannabinoid system
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Does not exert main effects through cannabinoid receptor-1
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At high levels, may actually block cannabinoid receptor-1
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Binds to TRP family of cation channels
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Decreased release of glutamate
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Anti-oxidant and anti-inflammatory effects
Cannabinoid Receptors
•
Cannabinoid receptor 1 (CB1R)
– presynaptic, G-protein–coupled receptor
– activates voltage-gated calcium channels and enhances
potassium-channel conduction in presynaptic terminals
– endogenous ligands
• 2-arachidonoylglycerol
(2-AG)
• anandamide
– Modulates neuronal excitability
PRE-CLINICAL STUDIES
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Cannabinoid Receptors
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Patients with temporal-lobe epilepsy have significantly lower
levels of anandamide in cerebrospinal fluid
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Tissue from patients undergoing surgery for epilepsy have
lower levels of CB1R messenger RNA
Cannabinoid Receptors
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Cannabinoid receptor-1 blockers cause seizure like
discharges in neuronal cell cultures
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Mice that lack cannabinoid receptor-1 have more severe and
prolonged seizures
Cannabinoid Receptors
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Activation of cannabinoid receptor-1 using THC has reduced
seizures in most animal models.
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In four animal studies, THC had a pro-convulsant effect at
certain doses
CLINICAL STUDIES
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Clinical Trials
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Cunha, Carlini, Mechoulam 1980
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Double-blinded trial of cannabidiol
– 200-300 mg cannabidiol for 4 to 5 months
– 15 medically refractory patients
– 8 patients treated with cannabidiol
•4
patients seizure free
• 3 patients with partial improvement
• 1 no improvement
– 7 placebo patients
•1
showed improvement
Chronic administration of cannabidiol to healthy volunteers and epileptic patients.
Pharmacology. 1980;21(3):175-85
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Clinical Trials
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A 2013 survey of caregivers of 19 children with severe
epilepsy who were receiving cannabidiol-enriched cannabis
extracts
– 2 of the children had become seizure-free
– 8 others had a reduction in the frequency of seizures of 80%
Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched can- nabis use in
pediatric treatment-resistant epilepsy. Epilepsy Behav 2013;29:574-7.
Clinical Trials
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2015 survey of 75 parents whose children were treated with
oral cannabis extracts in Colorado
– parents reported that one third of the children had a reduction in
seizures of more than 50%.
– electroencephalograms were obtained for 8 of these children
before and after the administration of cannabis, and none
showed improvement in background activity
Press CA, Knupp KG, Chapman KE. Parental reporting of response to oral cannabis extracts for
treatment of refrac- tory epilepsy. Epilepsy Behav 2015;45:49- 52
Clinical Trials
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Epidiolex (a purified cannabis extract containing 99%
cannabidiol and less than 0.10% ∆9-THC)
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Produced by GW pharmaceuticals
Epidiolex Phase I
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A preliminary report from this open-label study, initiated by
investigators to assess the safety and dosing of cannabidiol
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Among 137 patients who had received at least 12 weeks of
treatment, the median reduction in the number of seizures
was 54%
Devinsky O, Sullivan J, Friedman D, et al. Epidiolex (cannabidiol) in treatment resistant epilepsy. Presented at the
annual meeting of the American Academy of Neurology, Washington, DC, April 18–25, 2015. abstract
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Epidiolex Phase III—Dravet Syndrome
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14 week treatment period (2 week titration/12 weeks on full
dose of CBD or placebo)
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Median reduction of convulsive seizures
– Epidiolex 39%
– Placebo 13%
– Statistical significance p=0.01
Unpublished
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CBD and THC at 20:1 ratio
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Retrospective study of 74 patients (age range 1-18 years)
with intractable epilepsy resistant to >7 antiepileptic drugs
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CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in
olive oil. The CBD dose ranged from 1 to 20 mg/kg/d
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89% reported reduction in seizure frequency
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13 (18%) reported 75-100% reduction
25 (34%) reported 50-75% reduction
9 (12%) reported 25-50% reduction
19 (26%) reported <25% reduction
Five (7%) patients reported aggravation of seizures which led
to CBD withdrawal
Tzadok et al. (CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.
Seizure. 2016 Feb; 35:41-4
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CBD and THC at 20:1 ratio
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Improvement in behavior and alertness, language,
communication, motor skills and sleep
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Adverse reactions included somnolence, fatigue,
gastrointestinal disturbances and irritability leading to
withdrawal of cannabis use in 5 patients
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Tzadok M CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.
Seizure. 2016 Feb; 35:41-4
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Patient History
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At 10 years of age, she underwent genetic testing, which was
notable for an SCN1A mutation
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She has since been diagnosed with Dravet syndrome
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Patient History
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Patient was started on medical cannabis for epilepsy in 2013
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20:1 CBD to THC ration (ACDC)
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Since starting this treatment
– Improved alertness
– Improved attention and communication
– No observed side-effects
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Seizures improved
– breakthroughs only during her menstrual cycle, but is otherwise
not having seizures
– only one PICU admission since 2013
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ETHICAL CONSIDERATIONS
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Ethical Considerations
•
Potential benefits must outweigh the risks of therapy
– Difficult to establish with limited data
– Requires close observation of seizures and side-effects to evaluate
for improvement/worsening
– Consider prolonged EEG for objective data
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No financial conflict of interest
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Adequate trials of standard therapy to prove patient is refractory
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Consider need for video EEG to confirm seizures
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Reliability of care givers
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Agreement among all care givers
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Involve pediatrician in decision making
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LEGAL CONSIDERATIONS
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23 States plus District of Columbia
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New England States
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Maine 1999
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Vermont 2004
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Rhode Island 2006
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Connecticut 2012
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Massachusetts 2012
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New Hampshire 2013
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Physician Certification
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Physicians are not allowed to “prescribe” cannabis
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They may only “recommend” its use or “advise consideration”
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In 2002, the U.S. Court of Appeals held that the First
Amendment, which protects free speech, allows physicians to
discuss and perhaps recommend medical marijuana use
without punishment
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Massachusetts Requirements
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Massachusetts Requirements
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To be a certifying physician, a physician (MD or DO) must:
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be a Massachusetts-licensed physician;
hold an active full license with no prescribing restrictions;
hold a Massachusetts Controlled Substances Registration; and
have at least one established place of practice in Massachusetts.
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Massachusetts Requirements
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Physician must register with the Medical Use of Marijuana
Online System
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Complete a minimum of 2.0 Category 1CME credits
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Access Administrator
– member of the organization who is responsible for arranging
access to the VG for physicians who are members of that
organization
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Pediatric Certification
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Two Massachusetts licensed certifying physicians (at least
one of whom is a board-certified pediatrician or board-certified
pediatric subspecialist)
– diagnose the qualifying patient as having a debilitating lifelimiting illness (one that does not respond to curative treatments,
where reasonable estimates of prognosis suggests death may
occur within two years)
– If the debilitating medical condition is not life-limiting, both
physicians must determine that the benefits of the medical use of
marijuana outweigh the risks
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A certification can only be made in the course of a bona fide
physician-patient relationship
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Certifying conditions
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Cancer
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Glaucoma
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Positive status for human immunodeficiency virus (HIV)
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Hepatitis C
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Amyotrophic lateral sclerosis (ALS)
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Crohn’s disease
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Parkinson’s disease
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Multiple sclerosis
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Other debilitating conditions as determined in writing by a
qualifying patient’s certifying physician
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Legal Concerns
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Cannabis Use in Patients with Epilepsy and Autism
Subtitle goes here
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Text goes here
– Second level text
• Third
level text
– Fourth level text
» Fifth level text
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J, a 9 year-old boy with autism
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He consistently had 30 to 50 aggressions in a school day,
with a one-time high of 300
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“J had 300 aggressions today”
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“He began to bite and to smack the glasses off my face”
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The teachers were wearing tae kwon do arm pads to protect
themselves against his biting
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For a year, his individual education plan at his special-needs
school was full of blanks, recording “no progress” because he
spent his whole day an irritated, frustrated mess
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Following 2 years of Treatment
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After starting cannabis, he began having days—sometimes
one after another—with zero aggressions
After two years of treatment
“I would call our experiment a qualified success. Not because
cannabis has cured J, who's now 11, or anything near it. But it's
alleviated some of his severest symptoms so that he, my husband,
and I can actually enjoy each other, rather than being held hostage
by his autism in a house full of screams, destruction, and three very
unhappy people”
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AUTISM AND AGGRESSION
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Autism and Aggression
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Among 1,380 children with ASD
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68% of the children had previously behaved aggressively
towards caregivers
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49% towards non-caregivers
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Aggressive behavior has been documented in only 7-11% of
people who have intellectual disability (ID) but not autism
Kanne, S. M., & Mazurek, M. O. (2011). Aggression in children and adolescents with
ASD: Prevalence and risk factors. Journal of Autism and Developmental Disorders,
41(7), 926-937.
Emerson, E., Kiernan, C., Alborz, A., Reeves, D., Mason, H., Swarbrick, R., et al.
(2001). The prevalence of challenging behaviors: A total population study. Research in
developmental disabilities, 22(1), 77-93.
Holden, B., & Gitlesen, J. P. (2006). A total population study of challenging behaviour in
the county of Hedmark, Norway: Prevalence, and risk markers. Research in
developmental disabilities, 27(4), 456-465.
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Autism and Aggression
•
Comparing aggressive behaviors in 23 children with autism
and 23 typically developing children
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Typical children use aggression to achieve social goals, such
as getting attention or avoiding adults’ demands
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Children with autism become aggressive when
– adults interfere with a repetitive behavior
– someone takes away an item they need for a repetitive routine
– trying to escape uncomfortable sensory input
Reese, R. M., Richman, D. M., Belmont, J. M., & Morse, P. (2005). Functional characteristics of
disruptive behavior in developmentally disabled children with and without autism. Journal of
Autism and Developmental Disorders, 35(4), 419-428.
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Autism and Aggression
•
Forty-six placebo-controlled RCTs of pharmacologic
treatments of aggression in youth age 2 to 17 years with ASD
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Compared with placebo, 3 compounds resulted in significant
improvement in ABC-I at the end of treatment.
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Risperidone and aripiprazole were found to be the most
effective, with the largest effect sizes.
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Sedation, extrapyramidal sides effects, and weight gain were
common side-effects
Fung LKPharmacologic Treatment of Severe Irritability and Problem
Behaviors in Autism: A Systematic Review and Meta-analysis. Pediatrics.
2016;137 Suppl 2: S124-35
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Autism and Aggression
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Fifty participants treated with risperidone
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Two thirds of risperidone-treated children (n=33) were
reported calmer, better focused, and less aggressive
– serial social responsiveness scale did not improve over time
Marrus NLack of effect of risperidone on core autistic symptoms: data from a
longitudinal study. J Child Adolesc Psychopharmacol. 2014; 24: 513-8
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Autism and Aggression
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Families dealing with aggressive behavior struggled with
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social isolation
concerns about the safety of people and property
lack of respite care
limited professional supports
families were concerned about being able to find alternate
housing for their child with autism as they aged
Parents described an “unbearable” level of exhaustion, with at
least one mother comparing her situation to being in “jail for
life.”
Hodgetts S. Home Sweet Home? Families’ Experiences With Aggression in Children With Autism
Spectrum Disorders. Focus Autism Other Dev Disabl. 2013; 28: 166-174
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EPILEPSY AND AUTISM
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Epilepsy and Autism
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Epilepsy occurs in 8 to 20% of children with autism
spectrum disorders
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Autism occurs in up to 30% of children with
epilepsy
– It is more common when seizures develop within the first
three years
Epidemiology
•
There are two peaks for diagnosis of epilepsy
– Early (Infantile spasms, Dravet)
– Late (BECTS, primary generalized)
Root Causes
Neurotransmitter Disorders
Fragile X
Fragile X
•
Rat models of Fragile X syndrome
– blockade of cannabinoid receptors
• normalize
hippocampal development
• correct cognitive deficits
• improve seizures
• reduce pain sensitivity.
– Enhancing endocannabinoid signaling
• correct
abnormal synaptic plasticity in the prefrontal cortex
• improvement in hyperlocomotion and anxiety-related behaviors
Busquets-Garcia A, Gomis-Gonzalez M, Guegan T, et al. Targeting the endocannabinoid
system in the treatment of fragile X syndrome. Nat Med. 2013 May;19(5):603–607
Jung KM, Sepers M, Henstridge CM, et al. Uncoupling of the endocannabinoid signalling
complex in a mouse model of fragile X syndrome. Nat Commun. 2012;3:1080
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Growth Factors
m-TOR disorders
• Tuberous
Sclerosis
• Neurofibromatosis
• Cowden
Disease
• Bannayan-Riley-Ruvalcaba
Channelopathies
Immunologic
Role of Inter-ictal spikes?
Awake
Asleep
SIDE-EFFECTS
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Effects on Cognition
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Effects on Cognition
Reference
Meier et al., 2012
Pope et al., 2003
Ehrenreich et al., 1999
Huestegge et al., 2002
Fontes et al., 2011
Solowij et al., 2012
Churchwell et al., 2010
Gruber et al., 2011
Lopez-Larson et al., 2011
Wilson et al., 2000
Becker et al., 2010a
Gruber et al., 2012
Jager et al., 2010
Cognitive
↓ intelligence quotient (IQ)
↓ intelligence quotient (IQ)
↓ attention
↓ visual search
↓ executive functioning
↓ executive functioning
↑ impulsivity
Brain Structure
Brain Function
↓ prefrontal cortex volume
↓ white matter integrity in
prefrontal cortex
↓ superior prefrontal cortex
thickness
↓ total gray matter, ↑ total white
matter
↑ left superior prefrontal cortex
fMRIb blood oxygen level
dependent (BOLD) signal
during working memory task
↓ anterior cingulate fMRIb blood
oxygen level dependent (BOLD)
signal during inhibition task
↑ prefrontal cortex MRIb blood
oxygen level dependent (BOLD)
signal during novel stimuli
presentation in working memory
task
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Psychiatric Effects
Depression
Psychosis
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Questions?
Questions?
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