Perspectives of cannabis medical use in convulsions in children

SUMMARY
Introduction: The variety of epileptic syndroms is a touchstone for epileptologists, paediatricians and experts in metabolic diseases. The medical and surgi- cal solutions need a correct identification of the cases and also courage to give the adequate therapy to each child in correpondance with guides and ILAE protocols in use. Objectives: We want to highlight and analyse the mechanism of cannabinoids use in childrens epilepsies and the impact in the psychic processes of the children with epielepsy and the effects on cognition from the point of view of the biopsihosocial well being. Material and methods: We want to illustrate the pediatric use of cannabinoids with the case of a 10 year old boy with efforts of the parents under the attentive surveillance of experts in the domain of the use of cannabinoids in children with the amelioration of the neurologic and psychiatric symptoms of the child. Results: After the introduction of more antiepileptic drugs for myoclonic seizures, the patients ameliorated his seizures under a cannabinoid product introduced very slow, so the attention and cognition of the child improved together with the reduction of the dosis of the usual antiepileptic drugs. Discutions: Innovative, the (re)discovery of the effects of cannabinoids on the nervous system shows that this therapy can bring benefits in some cases, when a legal framework exists to be introduced by the doctors. Parent-groups, with their own efforts can help specialists to gain more experience in the epilepsy expert groups.
Key words: Cannabionids, children, epilepsy, cognition

INTRODUCTION
The incidence of epilepsy in cannadian children population under the age of 14 is 6,9/1000.The use of medical Cannabis undergo much controversy and doctors have a reluctance to use these products, being doubts about the mechansims which lead to epilepsy improvement as also because of some aspects regarding the use of these products in an authorized environment [1]. Cannabis sativa is a medicine plant known from thousand of years ago. There are
80 components of extracts of Cannabinoids the most known are the Δ9-tetrahydrocannabinol (Δ9- THC) and the Cannabidiol [2]. The first uses of this substance dates back from 2700 B.C. from the Chinese medicine [3]. The emperor Shen-Nung, was a farmacist and he described the benefits of Cannabis
in his studies which he wrote 2737 BC [4]. The idea of the use of Cannabis is resumed in 1930, the pharmacopoeia of the United States of those years including also these products. In the last years in 2015 an amendment was made to the state of Tennesee which allow the use of products based on Cannabinoid oils for the treatment of epilepsy with the condition that these oils have in their composition less than 0,9% THC. In this moment there are studies for the use of artisanal products containing cannabinoids but in lower doses and not high purified [3]. THC from Cannabis can vary in concentration in the range from 1-30% and the Cannabidiol content is under the threshold of 0,5% [5]. A researcher which leaned on studying the medicine effects of cannabis was William O Shaughnessy which with his efforts led to the use of Cannabis in the Victorian era. The neurologists
J.R Reynolds and William Gowers have followed his ideeas and studied the use of this substance in the treatment of epilepsies [6]. In turn marijuana contains Cannabis Sativa and Cannabis Indica and is a plant that grows in the free environment and her compositon include about 130 phyto cannnabinoids and 300 non cannabinoid constituents. From the components of this plant the most attention gained the D9-tetrahydro- cannabinol (THC), but importance has also the Cannabidiol which has no psychoactive properties, but is known to have stronger anticonvulsivant properties than the Tetrahidrocannabidiol [7]. Charlotte Figi is a girl for which her parents decided to use medicine canabonoids when whe was at age of 5. This treatment begun to be used in children with resistant epilepsy as an alternative.
PRESENT RESEARCHES
Resistant epilepsy has a general frequency of 28-37%.In the adult patients the use of cannabis is present also for nausea as also for the treatment of the side effects of chimiotherapy. The use of canabis products is known also for chronic pain, and for the treatment of spasticity from the multiple sclerosis complex. Their efficiency is proven also in some sleep disorders in adults or in the La Tourette syndrome [8]. The products derived from Marijuana are known to improve the devastating effects of the epilepsies Lennox Gastaut and Dravet syndrome [2]. In 2017 in Cannada was the Tilray study containing 239 questions and the investigators wanted to see how the patients are integrating in their knowledge
the use of cannabinoid products together with other medications. This questionnaire included questions about the way of administration of this products: oral, vaporization,extracts of cannabinoids mixed with foods, tincture, ointment. The interconditionality of the concomitant use of cannabinoids with alcohol, tobacco was studied as also the use of cannabinoids instead of this products by the users [9].
PATHOPHYSIOLOGY
Endocanabinoids are derived from the arachidonic acid. Neuromodulation induced by these substances influences the emotional responses and has also impact on the behavioral reactivity in social contexts and influences the social interaction. The most important canabionids are Anandamid (N-arachidonoylethanolamine) and 2-arachindonyl glycerol. The receptors to which the canaboids bind are CB-1, they being receptors bind on G protein. This receptors are present not just in the brain but also in the adipose cells, cardiovascular system, in the bones and in the reproductive system but they exist in the periphery in other tissues. They inhibit the adenilat cyclase and the calciu dependent voltage channels and they activate the proteinkinases activated by mitogen and potassium channels are also activated. CB1 has role in the psychic activity and CB2 has role in inflammation and stimulates regeneration [10]. In fact the mechanisms which are auctioning on these channels influence the Gabaergic and Glutamatergic synapses. Other studies show that Δ9 THC can lead to amplification of seizure so this susbstance can have anticonvulsivant but also proconvulsivant effects [1]. Endocanabinoids are retrograde messenger because they are releaed from the postsynaptic neuron and are acting alos on the presynaptic CB1 receptors. This fact leads to a lower neurotransmission from the presynaptic neuron in the synaptic cleft. The transmembranar transport is still subject to controversy the mechanism being not complete elucidated. In the brain CB1 is present in the cortex but also in the hipocamp and amygdala and basal ganglia, cerebellum. The intracellular receptors CB1 are present in the mitochondria and are participate in the signaling of the protein G [2]. In a tertiar medical care center there was a study conducted on 54 children from a total 329 patients which undergone concomitant treatment of seizures with Clobazam and cannabinoid oil products [3].

Epilepsy: Epileptic encephalopathies are forms of epilepsies with frequent seizures with child onset and are accompanied of modified EEG aspects which associates the progressive perturbation of the cerebral functioning with consequences on the child development leading to developmental stagnation and regression [11]. Treatment resistant epilepsies are epilepsies in which seizures cannot be controlled after the use after the international protocols of 4 antiepileptic drugs, including vagal stimulation and cetogene diet [7]. Treatment resistant epilepsies affects 20-30% from the total epileptic patients even if there are a lot of antiepileptic drugs which can treat the seizures and have fewer side effects and have a better drug tolerance and the new farmaceutic forms allow a more easier adimistration of the medication even to the patient in a coma [12]. Table I shows the utilization of cannabinoids in the last years in medicine use.
CLINIC PRESENTATION
Pacient, male gender, 10 years old from urban environment presents in our service for symptoms highlight, being treated in another neurologic service. Mother 26, Father 31, young not inbred, healthy parents. From father sight relatives with epilepsy and from mother sight a relative with psychiatric pathology. Physiological pregnancy, natural delivery, birth weight
=3600 grams, Apgar score =9, Normal development by stages of age but with expressive language development delay. Personal pathological antecedents: Suspicion of encephalitis at the age of 3.History: Seizures in infectious context at the age of 3 around 50 events per day. The child underwent treatment with valproic acid in combination with Levetiracetam. Afterthat Levetiracetam iw withdrawn but at the attempt to introduce Lamotrigine a cutaneous eruption fail to maintain this medication.After one uear from the onset of this kind of epilepsy the combination Acid valproicum with Ethosuximide is used and the childs age was 4,5 years.So the seizure frequency lowers to 30 per day but the clinical picture adds auto and heteroagressivity. Clonazepam is tried for a short period with the modulation of the doses of acidum valproicum and thereby the combination of acidum valproicum and Etosuximidum is used again. At 6,5 years a cure of Synacthen (ACTH) is made associated to the AED treatment described lowering the number of seizures to 15 seizures per day. At the age of 7,5 years the patient presents a new infectious episode with enterocholitis when the frequency of crises raises again to 50 and a new cure of Synacthen without ameliorating as at the precedent cure. In this moment Clobazam is associated.. Diagnostics at the age of 7,5 after more evaluations are: Epileptic encephalopathy, Mental retardation, Delay in expressive language, Hiperkinetic disorder. There are also other treatment associated like folic acid and Omega 3.
Figure 1, 2, 3 reflect the EEG discharges after the onset of seizures at the age of 4 years, reflected with high voltage EEG discharges.
Figure 4, 5 reflects EEG after the introduction of Synacthen, with the persistence of epileptiform discharges but with the frequence reduction and lower voltage of the discharges Through the Test Tru Sight One a mutation in the gene PRODH at the exon of the 13 chromosome, which can be linked to hiperprolinemia in some cases.
DISCUSSIONS
The extracts of the Cannabis oils are more and more available. In 2018 the study of Reithmeier and colab. CARE-Ecare was published in which cannabis oil is used based on Cannabi Sativa which is called ‘CanniMed® Oil 1:20’ and which contains 1mg/mL of Δ9-THC in combination with 20 mg/mL CBD and is packed in 60 ml bottles. It is a phase I study for the children with resistant epilepsy with the age 1-10 years.They took 2 daily doses and the evaluation lasted for 4 months. Each month the dose grown from 2-3 mg/kg/day at the first month afterthat grown at 5-6 mg/kg/day and at the end at 10-12 mg/kg/day [11]. Another study was made with administration of Cannabidiol and Tetrahidrocannabidiol în proportion of de 20:1. The Cannabis oil contain Cannabis enriched with CBD and a start dose of 2–5 mg/kg/ day divided in 3 doses administrated on the same day, this preparate beibg added to the antiepileptic drugs which have not been withdrawn. Subsequent depending on tolerance in some patients the dose was grown to 50 mg/kg of CBD per day. On the other hand THC was not allowed to exceed 0,15-1,35 mg/kg/ day. Slowly with the growing doses of Cannabinoids was tempted the lowering of the antiepileptic drugs for the slow withdrawing of the classic antiepileptic treatment.The patients included in this study were in number of 96 with a median age 9,6 years, the follow up period was in average 15,6 months. Cannabis can be administred also on inhalatory way and the product is called Volcano medic PUFF TTM [7]. There are expert parent groups joining on facebook and forums and changing information about the utilization of canabinoids. There are also many countries like Australia whrer the use of cannabis derived products is very restrictive and that is the cause why the parents of the children which are using cannabis product on other ways than the clssic legal ones for the treatment of their children [12]. In the present the use of CBD take place together with Δ9-THC in a formulation called Sativex® which contains the substances in an equimolar equilibrium, this mixture can be used for the treatment of the symptoms associated to multiple sclerosis [2]. Another mixture containing CBD (Epidiolex®) is in phase III study. This mixture is addressed to patients with faramacoresistant epilepsy like Lennox Gastaut syndrome and Dravet syndrome.The age of persons included in this type of study is 2–55 years. Pacients were administred CBD in doses of 10, 20 mg/kg/day, or placebo two equal doses/day for a 14 weeks period. So the frequence of seizures fell down [2]. When Canabidiol is used associated to known antiepileptic drugs then in 43% of the patients there were a seizure reduction with 50% compared with those who have had the same effect with placebo products. Cannabidiol has also the efect of the inhibition of the specific enzymes of the citocrome P450 generating the modification plasmatic levels of the antiepileptic metabolits like the Clobazam is which has a metabolite is N-desmethylclobazam [12]. A pleading for the use of these products are the experiments on rats which was adminstrated Cannabidiol 200 mg intraperitoneally and the effects were limited for cognitive and motor adverse effects [1]. In epileptic dogs there were given cannabinoid products with chicken aroma and in these cases the seizure frequency reduction was mainly in 89% of the cases [4]. The cannabinoids are used also for the treatment of malignant melanoma which was demonstrated on a murine model [5]. When pain is treated with cannabis derivates they can substitute some medication for pain and the reason of this substitution is a greater tolerance for the cannabinoids and more acceptable adverse effects for the patient. The patients from this study were more female patients (>50%) and their age was greater than 50 years. The replaced medication was opioids in 53% of the cases when the medication was susbstituted or 22% were benzodiazepines. If we take in account the medications which can be taken in the same moment with cannabinoids there are antirheumatic agents, nonsteroid anti-inflammatory medication (Paracetamol, Ibuprofen), inhibitors of Serotonin and Norepinephrine uptake, selective inhibitors of Serotonine reuptake, Gabapentinum and others. The study shows that the use of cannaboinoid products together with medication for pain decreases with 4 points the intensity of the pain measured on a visual
analog scale of 10 points. A combination used was Oxycodone and Cannabis in tigaretts and so the doses of Oxicodone for pain could be lowered. These effects are explained through a mechanism in which the threshold for the pain is raised as also the pain tolerance is raised when we use this combination. The cannabinoids are used for the management of the spasticity. Cannabinoids are also used for the treatment of vomit, nausea, some inflammatory diseases,some appart forms of cancer and sometimes in asthma. Canabionids are useful in glaucoma, spinal cord injuries, hypertension, but also multiple sclerosis. There were made studies on Parkinson disease and Alzheimer [4]. The adverse effects were somnolence, a grade of irritability, the appearance or exacerbation of agressivity, and movement disorders that can appear. Also, were noted depressive status, memory loss and also eating disorders so the weight of the patients can get higher. In some cases a drinking disorder can appear thus leading to liquid imbalance and diarrhea can arise. The picture can be completed by higher seizure frequency. For example the diarrhea is explained through the agonist effect on the D2 receptors [7]. Sedation and respiratory failure can occur also. When cronic intoxication occurs a hyperemtic syndrome to canabinoids is noted. Cannabis has a higher risk at low ages because the brain of the child is developing. The cannabionoid products have a greater impact on thus which have predisposition to psychosis or schizophrenia [9].
Innovative, the (re) discovering of the effects of cannabinoids on the central nervous system can demonstrate that this therapy can give raise to benefits in many cases when there is a legal background for the procedures so it can be introduced by the medical staff.

BIBLIOGRAFIE / BIBLIOGRAPHY :
1. James Huntsman R, Tang-Wai R,Acton B Alcorn J, William Lyon A, David Mousseau D, Seifert B,Laprairie R,Prosser-Loose E, Ondrej Hanuš L. Cannabis for the treatment of paediatric epilep- sy? An update for Canadian paediatricians. Paediatr Child Health. 2018 Sep;23(6):368-373.
2. Schonhofen P, Bristot IJ,Crippa JA, Hallak JEC, Zuardi AW, Par- sons RB5, Klamt F.Cannabinoid-Based Therapies and Brain De- velopment: Potential Harmful Effect of Early Modulation of the Endocannabinoid System. CNS Drugs. 2018 Aug;32(8):697-712
3. Porcari GS1, Fu C2, Doll ED2, Carter EG2, Carson RP3. Effi- cacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center. Epilepsy Behav. 2018 Mar;80:240-246.
4. Kogan L1, Schoenfeld-Tacher R2, Hellyer P1, Rishniw M3. US Veterinarians’ Knowledge, Experience, and Perception Regarding the Use of Cannabidiol for Canine Medical Conditions. Front Vet Sci. 2019 Jan 10;5:338.
5. Simmerman E1, Qin X2, Yu JC3, Baban B4. Cannabinoids as a Potential New and Novel Treatment for Melanoma: A Pilot Study in a Murine Model. J Surg Res. 2019 Mar;235:210-215.
6. Thomas RH1, Cunningham MO2. Cannabis and epilepsy. Pract Neurol. 2018 Dec;18(6):465-471.
7. Hausman-Kedem M, Menascu S, Kramer U. Efficacy of CBD- enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – An observational, longitudinal study. Brain Dev. 2018 Aug;40(7):544-551.
8. Elliott J,DeJean D, Clifford T, Coyle D, Potter B, Skidmore B, Alexander C6, Repetski AE, McCoy B, Wells GA. Cannabis for pediatric epilepsy: protocol for a living systematic review. Syst ematic Rev. 2018 Jul 18;7(1):95.
9. Lucas P, Baron EP, Jikomes N. Medical cannabis patterns of use and substitution for opioids & other pharmaceutical drugs, alcohol, tobacco, and illicit substances; results from a cross-sectional survey of authorized patients. Harm Reduct J. 2019 Jan 28;16(1):9.
10. Poleg S, Golubchik P, Offen D, Weizman ACannabidiol as a suggested candidate for treatment of autism spectrum disorder Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 29. pii: S0278-5846(18)30444-5.
11. Reithmeier D, Tang-Wai R,Seifert B,Lyon AW, Alcorn J,Acton B,Corley S,Prosser-Loose E,Mousseau DD, Lim HJ,Tellez-Zen- teno J, Huh L, Leung E, Carmant L, Huntsman RJ. The protocol for the Cannabidiol in children with refractory epileptic encepha- lopathy (CARE-E) study: a phase 1 dosage escalation study. BMC Pediatr. 2018 Jul 7;18(1):221. Doi: 10.1186/s12887-018-1191-y
12. Suraev A, Lintzeris N, Stuart J, Kevin RC, Blackburn R, Richards E, Arnold JC,Ireland C, Todd L, Allsop DJ, McGregor IS. Com- position and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community. Sci Rep. 2018 Jul 5;8(1):10154.
13. Boehnke KF1, Scott JR2, Litinas E3, Sisley S4, Williams DA2, Clauw DJ2. Pills to pot: observational analyses of cannabis sub- stitution among medical cannabis users with chronic pain.J Pain. 2019 Jan 25. pii: S1526-5900(18)30735-1.
14. Mohiuddin MM1, Mizubuti G1, Haroutounian S2, Smith S3, Campbell F4, Park R1, Gilron I1,5,6. Adherence to Consolidated Standards of Reporting Trials (CONSORT) Guidelines for Re- porting Safety Outcomes in Trials of Cannabinoids for Chronic Pain: Protocol for a Systematic Review. JMIR Res Protoc. 2019 Jan 28;8(1):e11637.
15. Blohm E, Sell P, Neavyn M. Cannabinoid toxicity in pediatrics. Curr Opin Pediatr. 2019 Jan 28.