On the application of cannabis in paediatrics and epileptology

Neuroendocrinology Letters Nos.1/2, Feb-Apr Vol.25, 2004
Copyright 2004 Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
On the application of cannabis in paediatrics Rüdiger Lorenz
D-34537 Bad Wildungen, Brunnenstrasse 54, GERMANY. Correspondence to: Dr. Rüdiger Lorenz, Cannabinoids; children; epilepsy; ion channels; neurodegenerative
disease; posthypoxic state; posttraumatic reaction-olfactory system
Neuroendocrinol Lett 2004; 25(1/2):40-44 NEL251204A02 Copyright Neuroendocrinology Letters www.nel.edu
Abstract
An initial report on the therapeutic application of delta 9-THC (THC) (Dronabinol, Marinol) in 8 children resp. adolescents suffering from the follow-ing conditions, is given: neurodegenerative disease, mitochondriopathy, post-hypoxic state, epilepsy, posttraumatic reaction. THC effected reduced spasticity, improved dystonia, increased initiative (with low dose), increased interest in the surroundings, and anticonvulsive action. The doses ranged from 0.04 to 0.12 mg/kg body weight a day. The medication was given as an oily solution orally in 7 patients, via percutaneous gastroenterostomy tube in one patient. At higher doses disinhibition and increased restlessness were observed. In several cases treatment was discontinued and in none of them discontinuing resulted in any problems.
The possibility that THC-induced effects on ion channels and transmitters may explain its therapeutic activity seen in epileptic patients is discussed. Casuistics
1. In the case of the boy P. G., treatment was begun with delta 9-THC (THC) at the age of 8 years and 9 months and continued until shortly before his death at the age of 9 years and 4 months. Ap-proximately 0.07 mg THC/kg body weight a day was administered in two doses via percutaneous gas-troenterostomy tube. The aim was to lessen the severity of spasticity brought on by neuronal ceroid lipofuscinosis, Jansky-Bielschowsky variant, which was causing the boy to suffer and to make it diffi-cult to care for him. The treatment brought about a noticeable reduction in spasticity. Prior treatment with a combination of baclofen and tetrazepam had been unsatisfactory owing to the degree of spas-ticity. There was no noticeable worsening of the myoclonia symptomatic of the disease. Moreover, the patient's mother observed that the boy seemed more awake. This increased alertness may be ascribed to the discontinuation (without adverse reaction) of meperidine. Following the initiation of treatment, it was observed that the boy turned his head with greater precision towards his mother and laughed when she spoke to him. He seemed happier, although mood swings were also observed. "He would still have a smile on his face when suddenly he would seem to weep". These changes however did not fail to leave their mark on the interaction between mother and son: Sometimes the boy's mother was sadder than previously owing to her awareness that the loss of her increasingly alert son nevertheless was in- Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
Neuroendocrinology Letters Nos.1/2, Feb-Apr Vol.25, 2004 On the application of cannabis in paediatrics and epileptology Copyright 2004 Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
evitable. It is impossible to evaluate the effect of THC he laughs more, is more relaxed". A definite influence treatment on the boy's epileptic seizures owing to the on the epileptic seizures (both focal and primary gen-progression of the disease and modifications made to eralised) was not observed. There was a reduction in his antiepileptic treatment [1].
the severity but not in the frequency of myoclonia.
2. In the case of L. S., a 12 year-old girl with spastic- ity arising from mitochondriopathy, to whom approxi- 6. A 11 year-old girl, S. P., suffered a spinal contu- mately 0.09 mg THC/kg body weight a day orally was sion (Th11-Th12) with total paraplegia following a administered in two doses, the parents reported the traffic accident. She also had a frontal skull fracture following: their child became "more relaxed, more in- and suspected haemorrhaging near the clivus. Owing terested, more alert, more interested in her surround- to the severity of injuries to the abdomen, a subtotal il- ings". L. spent "half an hour investigating her ear, as if eum resection was carried out. Despite psychotherapy, it was the first time she had ever noticed it". Nodding the patient developed an eating disorder - without, spasms and tonic seizures improved considerably. De- however, losing weight. This seemed to indicate post- spite this, a temporary increase in seizure severity was traumatic reaction, although the influence of organic observed.
factors remained difficult to assess. She was given 0.09-0.12 mg THC/kg body weight a day, orally ad- 3. The mother of the 12 year-old girl K. D., who suf- ministered in two doses. During treatment vomiting fers from severe spasticity and seizures as a result of decreased. She said, that she was hungry, ate more and severe hypoxia (foetomaternal transfusion) and who started to drink again. Her weight remained constant. 0.07 mg THC/kg body weight a day orally in two doses The girl became "more accessible, for the first time was given, reported that she became "relaxed, less open to therapy", was no longer on a " ,No- trip", and stiff, completely happy, open to everything". Whereas "emerged from her previously destructive attitude". before initiation of the treatment she did not show She could look others in the eye and was happier. On any reaction when exposed to bad smells (her parents increasing the dosage, the patient demonstrated a high are farmers), after that her mimic behaviour demon- degree of associative thinking and verbal disinhibi- strated, that she would smell. In the case of this child, tion concerning sexual contents. After three months there was also a noticeable reduction in the number of treatment was stopped and there were no symptoms of epileptic seizures, heretofore unsatisfactorily treated withdrawal. Even after discontinuing the medication, with valproic acid. Versive seizures with nystagmus the patient's body weight remained stable and her became less frequent, but when they occurred any mood improved. tonic-clonic seizures were "extreme".
7. The youngest patient, a boy J. H., aged 3 years 4. A 14 year-old girl, A. K., with neuronal ceroid and 10 months became paraplegic as the result of a lipofuscinosis, Spielmeyer-Vogt variant, was given 0.04 traffic accident. During his stay in hospital he became mg THC/kg body weight a day orally in two doses. In considerably withdrawn and ate little. He was given a the case of this patient, the aim is to lessen her gait brief course of treatment using 1 mg THC a day orally disturbance, manifested by problems of initiation of - to good effect. The improvement did not seem attrib-movements and a stiffening over longer distances ("no utable solely to adjusting to the new environment.
ground-covering steps"). L-dopa and amantadine had proved only partially successful: they only improved 8. A 14 year-old boy, M. Ö., suffers from severe id- the initiation. During THC therapy, her gait improved iopathic early infantile grand mal epilepsy with tonic-considerably. The stiffness in the left leg lessened and clonic seizures and falling. Owing to the modification the patient was able to cross the street again. The of antiepileptic treatment, the influence of THC (0.12 problem of starting off was not affected by THC. There mg/kg body weight a day orally given) on the epileptic was another improvement to observe: The girl sud- seizures is impossible to assess. Appetite, playfulness, denly developed initiative (setting the breakfast table and mood improved. An epilepsy clinic claimed the of her own accord and changing her clothes when she boy's restlessness was attributable to the THC medica-wet herself). Her concentration when playing also im- tion. However, restlessness was already present before proved slightly. Despite the progression of the disease, this treatment was established. Therefore, ending the the number of focal seizures that progressed to grand THC medication effected only a slight reduction in the mal seizures was slightly lower.
degree of restlessness. Discontinuation of the medica-tion caused no apparent difficulties.
5. The case of the 13 year-old boy C. D. is character- ised by spasticity, athetosis, myoclonia, and epileptic seizures of uncertain aetiology. He was given 0.14 mg THC/kg body weight a day orally in two doses. His parents reported that: the boy "has become more awake, he speaks more, makes more eye contact, takes part in things more, is more alert. It's great, he's more conscious of everything. For instance, in the past when touching him, he would continue to bite. He is happier, Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
Discussion
result in suffering and obsession and may inhibit au-tonomy. In the patient K.D. reaction upon bad smells The following insights may be derived from the case increased. A similar observation only, as far as I know, has been described by the astronomer Carl Sagan, who experienced with cannabis: "The enjoyment of food 1. THC also is a valuable means of treating children is amplified; tastes and aromas emerge that for some reason we ordinarily seem to be too busy to notice. I am able to give my full attention to the sensation." 2. Effects, side - effects and averaged daily doses of [10]. It may be speculated, that this amplification THC can be summarized as follows: reduced spas- is not only due to changed attention, but is due to ticity (0.09mg/kg body weight a day), improved changes in olfactory system, too. The positron-emis- dystonia within the context of a neurodegenerative sion-tomography study cited above [6] gives hints that disease affecting the basal ganglia (0.04mg/kg body regions of the brain processing olfactory stimuli par- weight a day), increased initiative (0.04 mg/kg body ticipate in improved blood circulation, such as amyg- weight a day), improved posttraumatic reaction dala (again), which is involved in aversive olfactory (0.09 mg/kg body weight a day), increased inter- sensations. An other indication is, that in the bulbus est in surroundings (0.1mg/kg body weight a day), olfactorius of the rat the expression of CB1-receptor anticonvulsive action (0.07 mg/kg body weight a protein has been demonstrated [11]. In contrast to day), aided discontinuation of meperidine (approxi- this hypothesis there has been found no difference in mately 0.07 mg/kg body weight a day), disinhibition olfactory identification tasks between groups of canna- concerning thinking and speaking (0.12mg/kg body bis users, former cannabis users and drug free controls weight a day), slight increase in preexisting rest- [12]. Systematic evaluation seems to be much promis- lessness (0.12mg/kg body weight a day).
ing. There could be applied the sniffin' sticks - method 3. In several of the cases treatment was discontinued [13]. Interestingly, preliminary evidence suggests, that and in none of them this caused any signs of with- cannabinoids are able to improve night vision, another Looking for most suitable dosages of THC in pae- Concerning the antiepileptic effects of cannabinoids diatrics requires further investigation. Optimal doses to this point of time there is no systematic knowledge. seem to be varying greatly according to indication. But there are anecdotal reports even from medieval Thus, when compared to doses recommended for times: Al Badri (1443-1489) reports, that Ali ben treatment of cytostatica-induced emesis (more than Makki had helped the epileptic Zahir ad din Moham- 4mg/kg body weight a day [2]), THC doses applied in med ben Ismail ben al Wakil with music and folia of the described patients were much lower. Side effects of the cannabis plant: the patient had forgot (!) his illness THC in children (mood changes) differ from those in adults (drowsiness, dizziness and in rare cases anxiety) In addition to these clinical observations future [3]. CB1-receptors increase gradually during postnatal insights as well into ion channel and transmitter development, so psychotropic side effects in young mechanisms of epilepsy as into cannabinoid actions children may be minor [4]. The effects of cannabinoids will benefit clinical advances in this area. on the CNS are often biphasic. When administered to rodents, lower doses increased activity, while higher THC can have a proconvulsive and an anticonvul- doses induced sedation and cataleptic behaviour [5]. sive effect. Which one is generated depends on the This observation may explain the increased initiative dose and the type of seizure. It is effective in treat- of A.K., when lower doses (0.04mg/kg body weight ing some forms of partial and generalised convulsive a day) are given. It may be interesting to note, that epilepsies, but it has no effect on other types of partial augmented initiative may be explained by findings epilepsies and petit mal absences [16]. In terms of from positron-emission-tomography revealing im- its antiepileptic effect, cannabidiol, the other major provement in blood circulation to the anterior insula cannabinoid in the cannabis plant, is by far the more and orbitofrontal and temporopolar cortices [6 and interesting substance. It has anticonvulsive properties 7] ). On the other hand, since autistic behaviour was without demonstrating any proconvulsive effect. In diminished by higher doses (0.1mg/kg body weight a animal petit mal absence models, however, it has been day), it may be speculated, that THC counteracted in- found to block the effectiveness of antiepileptic drugs hibitory mechanisms underlying autism.
The following observations are interesting to note: In the patients S.P. and J.H. THC improved Six of the eight patients treated with THC in the posttraumatic reaction consistent with findings, present report suffered from epilepsy. In two of the six that endocannabinoids extinct aversive memories (L.S. and K.D.), the frequency of seizures decreased (demonstrating actions on the basolateral amygdala) considerably upon THC administration. In one patient [8]. There is an ethical discussion, if it is justified, to (A.K.), the frequency of seizures did not increase and extinct memories by drugs [9]. Apart from the ethical severity of seizures remained constant (except for the question, remembering traumatic experiences may last seizure), despite the progression of the principal Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
On the application of cannabis in paediatrics and epileptology disease. In one patient (C.D.), a definite influence of There are no hints, that cannabinoids influence THC on seizure activity could not be assessed. Evalu- AMPA-receptors [30], which play an important role ation of two patients proved impossible: in the case of the first because of marked progression of the princi- It has been demonstrated by electric shock model in pal disease (P.G.), in the second (M.Ö.) because of an mice, that the endogenous cannabinoid system extensive change in the antiepileptic medication. The inhibits the epileptic excitability of the CNS [31]. effect of THC treatment on the epilepsies of L. S. and In this model NMDA-receptors are involved [21]. K. D. was most impressive. Suffering fundamental py- Anandamide reduces glutamate release in rat hip- ruvate dehydrogenase deficiency, L. S. demonstrated pocampal cells. Arachidonic acid and its metabolites, clinical nodding spasms and tonic seizures. EEG the eicosanoids, though produced upon degradation records revealed a left parietotemporal spike-wave of anandamide and 2-arachidonylglycerol [32], and sharp-slow wave focus with generalisation. K. exert different action from that of cannabinoids D. suffered from residual symptomatology following (e.g. decreasing of potassium outward currents via severe postnatal hypoxia. Seizures were to classify as A-channels) [29]. So the arachidonic acid must be versive ones accompanied by nystagmus. EEG records rapidly removed to prevent convulsant effects (and revealed a right temporal sharp-wave and sharp-slow it seems to be reincorporated into membrane phos- wave focus. In the case of both patients, there was a temporary increase in apparent seizure severity. A.K. The potential benefit of HU 211, a synthetic non demonstrated focal initiated grand mal seizures, her psychactive, non CB1-receptor binding cannabinoid EEG records revealed generalised and multifocal spike in catastrophic epilepsies and in status epilepticus should be examined. In brain injury a neurotoxicity reducing effect has been observed [33]. It should be A number of animal experiments may explain the considered, however, that apoptosis of cells belong- ing to an epileptic focus is advantageous for the sur-viving of the surrounding cells [34].
In rat hippocampal neurons, WIN 55.212-2 (WIN are non classical synthetic analogues of cannabinoids) Further effects of THC which can exert influence inhibits N and P/Q-type calcium channels [18] regu- on seizure activity must be taken into account: lated by G proteins. In cats L-type calcium channels the influences of THC on vigilance and sleep structure of cerebral arterial muscle cells are inhibited by CB (reducing REM-sleep) [35], the endocrine system 1 - receptor [19]. Calcium channels play a role in the (increasing melatonin secretion [35], reducing initiation and spread of epileptic activity. According production of gestagenic hormones [36]), and the to new findings L-type calcium channels play an important role in epileptogenesis [20]. In the case of Under cannabinoid influence, the EEG revealed a generalised convulsive seizures non-T - type chan- "desynchronisation" [39]. On examining 8 healthy nels come into play [21]. On the other hand, T -type volunteers other researchers could not establish channels are not inhibited by low cannabinoid con- any change under CBD influence [38].
centrations [22]. These channels play an active role in petit mal absences [21].
Inward leading sodium channels, which initiate depo- Conclusion
larisation, are inhibited by THC in mouse neuro-blastoma cells [23]. Increased sodium conductance THC should be considered in the treatment of is a contributing factor of epileptogenesis. neurodegenerative disease or posthypoxic state or In addition, CB1 receptors mediate an increase of the posttraumatic reaction not only in adults but also in outward current of potassium via A channels in hip- children or adolescents. Hopefully, future studies of pocampal neuron cultures [24], thereby stabilising the anticonvulsive effects of cannabinoids will support the membrane potential of excited cells.
the current assessment and lead to new antiepileptic Glutamate release in rat hippocampal cells is reduced drugs.
[25] by CP54.939, CP55.940 and WIN55.212-2. GABA, which produces an outward current of chloride Acknowledgement
that changes direction at -60 mV, thus preventing the depolarisation threshold from being reached I dedicate this article to Prof. Ester Fride for her [26], is an important transmitter effecting inhi- bition of epileptogenesis. In rat globus pallidus, GABA reabsorption is blocked by nabilon [27]. Glo-bus pallidus neurons are able to generate epileptic activity [28].
Cannabinoids reduce the potassium efflux via M chan- nels in rat hippocampal slices. This fact could play a role in convulsant action of cannabinoids.
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
Neuroendocrinology Letters Nos.1/2 Feb-Apr Vol.25, 2004 Copyright Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
Neuroendocrinology Letters Nos.1/2, Feb-Apr Vol.25, 2004 Copyright 2004 Neuroendocrinology Letters ISSN 0172-780X www.nel.edu
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