cannabidiol in drug resistant pediatric...
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Weeding out the Controversy: Cannabidiol in Drug Resistant
Pediatric Epilepsy
Paige Davies, Pharm.D. PGY1 Pediatric Focused Pharmacy Resident
Seton Healthcare Family [email protected]
September 29, 2017
1
ASCENSION TEXAS
Paige Davies, Pharm.D. PGY1 Pediatric Focused Pharmacy Resident
Seton Healthcare Family
Weeding out the Controversy:
Cannabidiol in Drug Resistant
Pediatric Epilepsy
• The author has no conflicts of interest to disclose.
Conflicts of Interest
2
• Compare and contrast the properties of tetrahydrocannabinol
and cannabidiol
• Evaluate the observational and clinical literature regarding
cannabidiol use
• Discuss cannabidiol’s potential place in therapy for resistant
epilepsy
Objectives
3
• Lifetime prevalence of epilepsy: 10.2 per 1,000 (1%)
• Current epilepsy: 6.3 per 1,000 (0.6%)
Epidemiology of Pediatric Epilepsy
Syndromes
Russ SA, et al. Pediatrics. 2012;129:256-264. 4
• Benign childhood epilepsy with centrotemporal spikes
(BCECTS)
• Childhood absence epilepsy
• Juvenile myoclonic epilepsy
• Lennox-Gastaut syndrome (LGS)
• Dravet syndrome (DS)
• Infantile spasms (IS)
• Myoclonic astatic epilepsy (MAE)
Pediatric Epilepsy Syndromes
Gibbon F. Epilepsy Society. 2013. 5
AED Review
AED: antiepileptic drug 6 Appendix B
Shih. Ther Clin Risk Manag. 2013;9:285-293.
2
• Lennox-Gastaut
syndrome
- Clobazam
- Felbamate
- Rufinamide
- Lamotrigine
- Topiramate
• Dravet syndrome
- Valproic acid
- Topiramate
- Clobazam
- Stiripentol
- Avoid: lamotrigine,
carbamazepine
AEDs in LGS & DS
AED: antiepileptic drug
LGS: Lennox-Gastaut syndrome
DS: Dravet syndrome Hussain S, Sankar R. Semin Pediatr Neurol. 2011;18: 171-178. 7
• 47-85% will become seizure free with 1st AED trial
• 14% will become seizure free with trial of 2nd or 3rd AED
Efficacy of First AED in Newly
Diagnosed Epilepsy
Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.
Kwan P, et al. Pharmacol Therapeut. 2001;90:21-34.
Ma MS, et al. Pediatr Neurol. 2009; 41: 22-26.
Yilmaz U, et al. Seizure. 2014; 23: 252-259. AED: antiepileptic drug 8
0
10
20
30
40
50
60
70
80
90
100
Clobazam Felbamate Rufinamide Lamotrigine Topiramate
Resp
on
der
Rate
%
Efficacy of AEDs in Lennox-Gastaut
Syndrome
VanStraten AF, Ng YT. Pediat Neuro. 2012; 47:153-161. AED: antiepileptic drug 9
0
10
20
30
40
50
60
70
80
90
100
Valproic acid Topiramate Levetiracetam CLB + STP +VPA
Resp
on
der
Rate
%
Efficacy of AEDs in Dravet Syndrome
Dressler A, et al. Epilepsy Research. 2015; 109:81-89.
AED: antiepileptic drug
CLB: clobazam
STP: stiripentol
VPA: valproic acid 10
• Uncontrolled seizures are common in LGS & DS
- LGS: 67% (1 seizure every 3 months for the past year)
- DS: 84% (1 seizure within the past year)
Drug Resistant Epilepsy
Akiyama M, et al. Epilepsia. 2010;51(6):1043-1052
Camfield P, Camfield C. Epilepsia. 2007;48(6):1128-1132..
LGS: Lennox-Gastaut syndrome
DS: Dravet syndrome 11
• Intellectual disability
• Physical injury - Lacerations
- Fractures
- Dental trauma
- Concussions
• Decreased quality of life
• Sudden unexpected death
Potential Consequences of
Uncontrolled Seizure Activity
Camfield C, Camfield P. Seizure. 2015;27:80-83.
Russ SA, et al. Pediatrics. 2012;129:256-264. 12
3
Charlotte Figi
• Diagnosed with Dravet
syndrome at 3 months old
• Baseline of 300+ seizures per
week
• Failed 8 AEDs and the
ketogenic diet
• Collaborated with a company
in Colorado to develop a
cannabis extract, “Charlotte’s
Web Oil”
Maa E, Figi P. Epilepsia. 2014;55(6):783-786. AED: antiepileptic drug 13
Cannabinoids
∆9 tetrahydrocannabinol (THC)
Cannabidiol (CBD)
Pharmacological Actions
• Anticonvulsant
• Analgesic
• Euphoria
• Psychoactive
• Cognitive modulation
• Reduces muscle spasms
• Reduces nausea
• Anticonvulsant
• Analgesic
• Anti-inflammatory
• Antitumorigenic
• Neuroprotective
• Reduces nausea
• Immune modulation
Treated Conditions
• Migraines
• Neuropathic pain
• Nausea
• Parkinson’s
disease
• Multiple sclerosis
• CINV
• Cancer pain
Reddy DS, Golub VM. J Pharmacol Exp Ther. 2016;357:45-55. CINV: chemotherapy induced nausea and vomiting 14
CBD Anticonvulsant
THC CB1 & CB2 Anticonvulsant
& Euphoria
Cannabinoid Mechanism of Action
Block adenosine reuptake,
inhibition of TRP channels,
enhancement of
serotonergic receptors
Devinsky O, et al. Epilepsia. 2014;55(6): 791-802.
Szaflarski JP, Bebin EM. Epilepsy & Behavior. 2014; 41:277-282.
CBD: cannbidiol
CB: cannabinoid receptor
THC: tetrahydrocannabinol
TRP: transient receptor potential 15
• Cannabidiol is the component of marijuana that produces
the “high” people seek when using it recreationally.
- True
- False
Knowledge Check
16
High CBD, Low THC Products
10-83 mg/mL CBD
< 0.3% THC 100 mg/mL CBD
< 0.1% THC
CBD: cannbidiol
THC: tetrahydrocannabinol
Recreational cannabis
3-12% THC 17
2017 Legislative Status of Cannabis in the United States
-
Appendix C
Campbell CT, et al. J Pediatr Pharmacol Ther. 2017;22(3):176-185. 18
4
2017 Legislative Status of Cannabis in the United States
• 2015: SB 339
• Legalized CBD (THC
< 0.5%) for patients with
intractable seizures who
have failed at least 2 AEDs
• Route of administration
other than inhalation
Requirements
- Physician registry
- 3 licensed dispensaries
AED: antiepileptic drug
CBD: cannabidiol
SB: senate bill
THC: tetrahydrocannabinol
Campbell CT, et al. J Pediatr
Pharmacol Ther. 2017;22(3):176-185. 19
Observational Studies:
Surveys of Parental Opinion
on CBD Efficacy
CBD: cannabidiol 20
Observational Studies Survey Age
(years) Epilepsy syndrome (%) CBD dose
(mg/kg/day) LGS DS MAE IS Other
Porter
2013,
n=19
group
2-16 5
68 21 N/A 6 0.5-28
Hussain
2015,
n=117
Online
forums
3-10 21 13 4 39 23 2.9-7.5
Press
2015,
n=75
Calls,
emails
0.5-18 12 17 4 N/A 67 Not reported
Aguirre-
Velazquez
2017,
n=43
Email,
group
0.8-18 47 0 2 19 32 1-6.9
CBD: cannabidiol
DS: Dravet syndrome
IS: infantile spasms
LGS: Lennox-Gastaut syndrome
MAE: myoclonic astatic epilepsy
N/A: not applicable
Aguirre-Velazquez CG. Neurol Res Int. 2017;2017:1-5.
Hussain SA, et al. Epilepsy & Behavior. 2015;47:138-141.
Porter BE, et al. Epilepsy & Behavior. 2013;29:574-577.
Press CA, et al. Epilepsy & Behavior. 2015;45:49-52. 21
Observational Studies Survey Age
(years)
Epilepsy syndrome
(%) CBD dose (mg/kg/day)
Reduction
in seizures,
n (%)
Complete
resolution
of seizures,
n (%)
LGS DS MAE IS Other
Porter
2013,
n=19
group
2-16 5 68 21 N/A 6 0.5-28 16 (84%) 2 (11%)
Hussain
2015,
n=117
Online
forums
(LGS & IS)
3-10 21 13 4 39 23 2.9-7.5
100 (85%)
16 (14%)
Press
2015,
n=75
Calls and
emails to
known pts
0.5-18 12 17 4 N/A 67 Not
reported
43 (57%)
2 (0.3%)
Aguirre-
Velazquez
2017,
n=43
Email,
group
0.8-18 47 0 2 19 32 1-6.9 35 (81%)
7 (16%)
Appendix D
Aguirre-Velazquez CG. Neurol Res Int. 2017;2017:1-5.
Hussain SA, et al. Epilepsy & Behavior. 2015;47:138-141.
Porter BE, et al. Epilepsy & Behavior. 2013;29:574-577.
Press CA, et al. Epilepsy & Behavior. 2015;45:49-52.
CBD: cannabidiol
DS: Dravet syndrome
IS: infantile spasms
LGS: Lennox-Gastaut syndrome
MAE: myoclonic astatic epilepsy
N/A: not applicable 22
Porter Hussain Press Aguirre-
Velazquez
Negative SE
Drowsiness ++ + +
Fatigue + + +
Decreased appetite + + +
Increased appetite ++ ++
GI Symptoms +
Positive SE
Improved mood ++++ ++++ +++++
Improved sleep ++++ +++ + ++++
Improved alertness ++++ ++++ ++ +++++
Decreased self stimulation ++
Observational Studies: Side Effects
Appendix E
Aguirre-Velazquez CG. Neurol Res Int. 2017;2017:1-5.
Hussain SA, et al. Epilepsy & Behavior. 2015;47:138-141.
Porter BE, et al. Epilepsy & Behavior. 2013;29:574-577.
Press CA, et al. Epilepsy & Behavior. 2015;45:49-52.
SE: side effects GI: gastrointestinal
+ 0-20%
++ 21-40%
+++ 41-60%
++++ 61-80%
+++++ 81-100% 23
• Responder: > 50% reduction in seizure frequency
• No difference in responder rates based on seizure types
- e.g. generalized tonic-clonic, focal, absence, myoclonic
• Responder rate between epilepsy syndromes:
- Lennox-Gastaut: 8/9 (89%)
- Dravet: 3/13 (23%)
- Myoclonic astatic epilepsy: 0/3 (0%)
• Responder rate was different between families who had
moved to Colorado for treatment vs. already had
established care in Colorado
- 47% vs 22% (OR 3.16; 95% CI 1.16-8.59)
Press, 2015 - Other findings
Press CA, et al. Epilepsy & Behavior. 2015;45:49-52. 24
5
• Most parents with children using cannabis products to
aide in seizure control believe that it has a beneficial effect
• Bias
- Small sample sizes
- Voluntary response and confirmation bias
- Product and dose not standardized
• Parents know their children best
Observational Studies: Summary
25
• Many parents reported an increase in seizure frequency
with the addition of cannabidiol to their child’s therapy.
- True
- False
Knowledge Check
26
Clinical Trials
27
Epidiolex® Clinical Trials: Trial Characteristics
Design Inclusion
Criteria
Intervention
(mg/kg/day)
Duration Primary Endpoint
Devinsky
2016, n=137
Open label Epilepsy, ≥ 4
motor seizures in 4 weeks
Initial 2-5,
↑ weekly 2-5, max 25-50
12 weeks, titration
not specified
Change in motor
seizure frequency
Devinsky
2017, n=120
R, DB, PC DS, ≥ 1 AED, ≥
4 seizures in 4 weeks
20 titrated over 2
weeks, maintained for 12 weeks
Change in frequency
of convulsive seizures
GW Pharm
Jun 2016, n=171
R, DB, PC LGS,
uncontrolled on ≥ 1 AED
20 titrated over 2
weeks, maintained for 12 weeks
% change in monthly
frequency of drop seizures
GW Pharm
Sep 2016, n=225
R, DB, PC LGS,
uncontrolled on ≥ 1 AED
20 vs 10 titrated over 2
weeks, maintained for 12 weeks
% change in monthly
frequency of drop seizures
LGS: Lennox-Gastaut syndrome
DS: Dravet syndrome
R: randomized
DB: double blind
PC: placebo controlled
Appendix F
Devinsky et al. Lancet Neurol. 2016;15:270-78.
Devinsky et al. N Engl J Med. 2017;376: 2011-20.
GW Pharmaceuticals. Press Releases. 28
Age, yrs.
median (range)
Epilepsy Type Current AED
mean (range)
Failed AED
mean (range)
Devinsky
2016, n=137
10.5
(0.9-26.2)
DS 20%
LGS 19%
Other 61%
3 --
Devinsky
2017, n=120
9.1 (2.5-18) DS 3 (1-5) 4 (0-26)
GW Pharm
Jun 2016, n=171
15 (2-55) LGS 3 6
GW Pharm
Sep 2016, n=225
16 (2-55) LGS 3 7
Epidiolex® Clinical Trials: Patient Characteristics
Appendix G
Devinsky et al. Lancet Neurol. 2016;15:270-78.
Devinsky et al. N Engl J Med. 2017;376: 2011-20.
GW Pharmaceuticals. Press Releases
LGS: Lennox-Gastaut syndrome
DS: Dravet syndrome 29
Pre/ Post
seizure
frequency per
month
CBD reduction in
monthly seizure
frequency
Placebo change
in monthly
seizure
frequency
Responder rate
(≥ 50% decrease in
seizures)
Devinsky
2016, n=137
CBD 30 15.8 36.5% 39% for motor
seizures, 37% for all seizure types
Devinsky
2017, n=120
CBD 12.4 5.9
P 14.9 14.1
38.9% 13.3% CBD 43% vs placebo
27% (OR 2; 95% CI 0.93-4.3; p=0.08)
GW Pharm
Jun 2016, n=171
-- 44% (p< 0.02) 22% --
GW Pharm
Sep 2016 n=225
-- 20- 42% (p< 0.01)
10- 37% (p< 0.01)
17% --
Epidiolex® Clinical Trials: Results
Appendix H
Devinsky et al. Lancet Neurol. 2016;15:270-78.
Devinsky et al. N Engl J Med. 2017;376: 2011-20.
GW Pharmaceuticals. Press Releases LGS: Lennox-Gastaut syndrome
DS: Dravet syndrome 30
6
ADR (%) % Mild- Mod
of CBD ADR
% Severe of
CBD ADR
ADR with ≥ 10% incidence
*all: somnolence, decreased
appetite, diarrhea
Devinsky
2016, n=137
CBD 79% 62.5% 37.5% fatigue, convulsion
Devinsky
2017, n=120
CBD 93%
Placebo 75%
CBD 84%
Placebo 95%
CBD 16%
Placebo 5%
fatigue, convulsion, URTI,
vomiting, pyrexia, lethargy
GW Pharm
Jun 2016, n=171
CBD 86%
Placebo 69%
78% 12%
GW Pharm
Sep 2016, n=225
CBD (20) 94%
CBD (10) 84% Placebo 72%
CBD (20) 88%
CBD (10) 89% Placebo 96%
CBD (20) 6%
CBD (10) 6% Placebo 4%
(20) & (10) URTI
(20) pyrexia, vomiting, nasopharyngitis
10 status epilepticus
Epidiolex® Clinical Trials: ADR
Appendix I
Devinsky et al. Lancet Neurol. 2016;15:270-78.
Devinsky et al. N Engl J Med. 2017;376: 2011-20.
GW Pharmaceuticals. Press Releases
ADR: adverse drug reaction
CBD: cannabidiol
URTI: upper respiratory tract infection 31
• Bias
- All funded by GW Pharmaceuticals
- Questionable application to epilepsy syndromes beyond LGS & DS
- Titration schedules not clearly defined which limits patient application
• 37-44% decrease in monthly seizure frequency
• 37-43% experienced a reduction by > 50%
• High rates of ADRs reported, even in placebo group
• Most ADRs were mild-moderate in nature
Epidiolex® Clinical Trials: Summary
32
• Clinical trials of Epidiolex® in pediatric patients with Lennox-
Gastaut and Dravet syndrome have shown a reduction in
seizure frequency in the interventional arm compared to the
placebo arm.
- True
- False
Knowledge Check
33
Drug-Drug
Interactions
34
• CBD inhibits CYP 3A4 and 2C19
• Significant changes in serum concentrations
- Clobazam
- N-desmethylclobazam
- Eslicarbazepine
- Rufinamide
- Topiramate
Drug-Drug Interactions
Gaston TE, et al. Epilepsia. 2017;XX:1-7. CBD: cannabidiol 35
• Charlotte Figi
- Completely weaned off clobazam after 1 month CBD therapy
• Porter et al.
- 12/19 (63%) were able to discontinue at least 1 AED while on CBD
• Clobazam 5/12 (42%)
• Valproic acid 5/12 (42%)
• Stiripentol 3/12 (25%)
Drug-Drug Interactions: A benefit?
Maa E, Figi P. Epilepsia. 2014;55(6):783-786.
Porter BE, et al. Epilepsy & Behavior. 2013;29:574-577. AED: antiepileptic drug
CBD: cannabidiol 36
7
Other Dilemmas
37
Success of
CBD oil in
reducing
seizures
AED Discontinuation
Belief that
“natural”
products are
safer and
healthier
Abrupt AED
discontinuation
without
physician
knowledge
AED: antiepileptic drug
CBD: cannabidiol 38
• If hospitalized, asked to stop use of CBD oil
• Will this cause the patient’s seizures to become uncontrolled?
• Will the serum concentration of other AEDs decrease
resulting in loss of seizure control?
Unfair Expectations
AED: antiepileptic drugs
CBD: cannabidiol 39
Hope from
positive
results
Extrapolations
Stigma
surrounding
cannabis
products
Initiation of
therapy without
physician
knowledge
• Is this appropriate for anyone with uncontrolled epilepsy?
40
Looking ahead…
• New drug application currently in progress • Expected to be completed in October
• Future plans: • Expanding products to include other cannabinoid products
• Research for other indications
• Autism spectrum disorders
• Rett Syndrome
• Neonatal hypoxic ischemic encephalopathy
• Glioblastoma
• Partial onset epilepsy
41
• Who: LGS or DS patients
• What: add on therapy
• When: after trial and failure of at least 2 AEDs
• How:
- Initiate at 2.5 mg/kg/day divided into 2 doses
- Increase by 2.5 mg/kg/day every 2 days
- Up to a maximum dose of 20 mg/kg/day as tolerated
Clinical Application of Epidiolex®
AED: antiepileptic drug
CBD: cannabidiol
LGS: Lennox-Gastaut syndrome 42
8
Charlotte Figi Today
43
• Dr. Ronda Machen, Pharm.D., RD, BCPPS, BCNSP
• Dr. Carolyn Ragsdale, Pharm.D., BCPS, BCPPS
• Dr. Eimeira Padilla-Tolentino, Pharm.D., PhD
• Dr. Thanhhao Ngo, Pharm.D., BCPPS
THANK YOU!
Acknowledgements
44
ASCENSION TEXAS
Paige Davies, Pharm.D.
PGY1 Pediatric Focused Pharmacy Resident
Seton Healthcare Family
Weeding out the Controversy:
Cannabidiol in Drug Resistant
Epilepsy
9
Appendix A: Abbreviations
AED Antiepileptic drug
ADR Adverse drug reactions
BCECTS Benign childhood epilepsy with centrotemporal spikes
CB1, CB2 Cannabinoid receptor 1 & 2
CBD Cannabidiol
CINV Chemotherapy induced nausea and vomiting
CLB Clobazam
DB Double blind
DS Dravet syndrome
GI Gastrointestinal
IS Infantile spasms
LGS Lennox-Gastaut syndrome
MAE Myocolonic astatic epilepsy
PC Placebo controlled
R Randomized
SB Senate bill
SE Side effects
STP Stiripentol
THC Tetrahydrocannabinol
TRP channels Transient receptor potential channels
URTI Upper respiratory tract infection
VPA Valproic acid
10
Appendix B: AED Review
Appendix C: 2017 Legislative Status of Cannabis in the United States
11
Appendix D: Observational Studies
Appendix E: Observational Studies: Side Effects
12
Appendix F: Epidiolex® Clinical Trials: Trial Characteristics
Appendix G: Epidiolex® Clinical Trials: Patient Characteristics
13
Appendix H: Epidiolex® Clinical Trials: Results
Appendix I: Epidiolex® Clinical Trials: ADR
14
Appendix J: Bibliography
Aguirre-Velázquez C. Report from a Survey of Parents Regarding the Use of Cannabidiol (Medicinal cannabis) in Mexican Children with Refractory Epilepsy. Neurology Research International. 2017;2017:1-5. doi:10.1155/2017/2985729.
Campbell C, Phillips M, Manasco K. Cannabinoids in Pediatrics. The Journal of Pediatric Pharmacology and Therapeutics. 2017;22(3):176-185. doi:10.5863/1551-6776-22.3.176.
Camfield P, Camfield C. Long-term Prognosis for Symptomatic (Secondarily) Generalized Epilepsies: A Population-based Study. Epilepsia. 2007;48(6):1128-1132. doi:10.1111/j.1528-1167.2007.01072.x.
Camfield C, Camfield P. Injuries from seizures are a serious, persistent problem in childhood onset epilepsy: A population-based study. Seizure. 2015;27:80-83. doi:10.1016/j.seizure.2015.02.031.
Devinsky O, Cilio M, Cross H et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55(6):791-802. doi:10.1111/epi.12631.
Devinsky O, Marsh E, Friedman D et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. The Lancet Neurology. 2016;15(3):270-278. doi:10.1016/s1474-4422(15)00379-8.
Devinsky O, Cross J, Laux L et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. New England Journal of Medicine. 2017;376(21):2011-2020. doi:10.1056/nejmoa1611618.
Dressler A, Trimmel-Schwahofer P, Reithofer E et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome – Comparison with various standard antiepileptic drug regimen. Epilepsy Research. 2015;109:81-89. doi:10.1016/j.eplepsyres.2014.10.014.
Fidelia Cascini, Carola Aiello, GianLuca Di Tanna. Increasing Delta-9-Tetrahydrocannabinol (∆-9-THC) Content in Herbal Cannabis Over Time: Systematic Review and Meta-Analysis. Current Drug Abuse Reviews. 2012;5(1):32-40. doi:10.2174/1874473711205010032.
Gaston T, Bebin E, Cutter G, Liu Y, Szaflarski J. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58(9):1586-1592. doi:10.1111/epi.13852.
Gibbon F.Childhood epilepsy syndromes. Epilepsy Society. 2013. Available at: https://www.epilepsysociety.org.uk/childhood-epilepsy-syndromes#.WbHVnU2ouUk.
GW Pharmaceuticals. GW Pharmaceuticals Announces Second Positive Phase 3 Trial Of Epidiolex (Cannabidiol) In The Treatment Of Lennox-Gastaut Syndrome.; 2016. Available at: http://ir.gwpharm.com/releasedetail.cfm?ReleaseID=990804.
GW Pharmaceuticals. GW Pharmaceuticals Announces Positive Phase 3 Pivotal Trial Results For Epidiolex (Cannbidiol) In The Treatment Of Lennox-Gastaut Syndrome.; 2017. Available at: http://ir.gwpharm.com/releasedetail.cfm?ReleaseID=977117.
Hussain S, Zhou R, Jacobson C et al. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox–
15
Gastaut syndrome. Epilepsy & Behavior. 2015;47:138-141. doi:10.1016/j.yebeh.2015.04.009.
Kwan P, Brodie M. Early Identification of Refractory Epilepsy. New England Journal of Medicine. 2000;342(5):314-319. doi:10.1056/nejm200002033420503.
Kwan P, Sills G, Brodie M. The mechanisms of action of commonly used antiepileptic drugs. Pharmacology & Therapeutics. 2001;90(1):21-34. doi:10.1016/s0163-7258(01)00122-x.
Ma M, Ding Y, Ying W, Fang F, Ding C, Zou L. Effectiveness of the First Antiepileptic Drug in the Treatment of Pediatric Epilepsy. Pediatric Neurology. 2009;41(1):22-26. doi:10.1016/j.pediatrneurol.2009.01.010.
Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55(6):783-786. doi:10.1111/epi.12610.
Press C, Knupp K, Chapman K. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy & Behavior. 2015;45:49-52. doi:10.1016/j.yebeh.2015.02.043.
Porter B, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy & Behavior. 2013;29(3):574-577. doi:10.1016/j.yebeh.2013.08.037.
Reddy D, Golub V. The Pharmacological Basis of Cannabis Therapy for Epilepsy. Journal of Pharmacology and Experimental Therapeutics. 2016;357(1):45-55. doi:10.1124/jpet.115.230151.
Russ S, Larson K, Halfon N. A National Profile of Childhood Epilepsy and Seizure Disorder. PEDIATRICS. 2012;129(2):256-264. doi:10.1542/peds.2010-1371.
Shih J, Tatum, Rudzinski L. New drug classes for the treatment of partial onset epilepsy: focus on perampanel. Therapeutics and Clinical Risk Management. 2013:285. doi:10.2147/tcrm.s37317.
Szaflarski J, Martina Bebin E. Cannabis, cannabidiol, and epilepsy — From receptors to clinical response. Epilepsy & Behavior. 2014;41:277-282. doi:10.1016/j.yebeh.2014.08.135.
VanStraten A, Ng Y. Update on the Management of Lennox-Gastaut Syndrome. Pediatric Neurology. 2012;47(3):153-161. doi:10.1016/j.pediatrneurol.2012.05.001.
Yılmaz Ü, Yılmaz T, Dizdarer G, Akıncı G, Güzel O, Tekgül H. Efficacy and tolerability of the first antiepileptic drug in children with newly diagnosed idiopathic epilepsy. Seizure. 2014;23(4):252-259. doi:10.1016/j.seizure.2013.12.001.