Morano A et al. (2016), Cannabis in epilepsy: From clinical practice to...

XB-ART-54745

Epilepsia Open 2016 Sep 19;13-4:145-151. doi: 10.1002/epi4.12015.

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Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin.

Morano A , Cifelli P , Nencini P , Antonilli L , Fattouch J , Ruffolo G , Roseti C , Aronica E , Limatola C , Di Bonaventura C , Palma E , Giallonardo AT .

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Cannabidivarin (CBDV) and cannabidiol (CBD) have recently emerged among cannabinoids for their potential antiepileptic properties, as shown in several animal models. We report the case of a patient affected by symptomatic partial epilepsy who used cannabis as self-medication after the failure of countless pharmacological/surgical treatments. Clinical and video electroencephalogram (EEG) evaluations were periodically performed, and the serum levels of CBDV, CBD, and Δ9-tetrahydrocannabinol were repeatedly measured. After cannabis administration, a dramatic clinical improvement, in terms of both decrease in seizure frequency and recovery of cognitive functions, was observed, which might parallel high CBDV plasma concentrations. To widen the spectrum of CBDV possible mechanisms of action, electrophysiological methods were applied to investigate whether it could exert some effects on γ-aminobutyric acid (GABA)A receptors. Our experiments showed that, in human hippocampal tissues of four patients affected by drug-resistant temporal lobe epilepsy (TLE) transplanted in Xenopus oocytes, there is decrease of current rundown (i.e., reduction of use-dependent GABAA current) after prolonged exposure to CBDV. This result has been confirmed using a single case of Rasmussen encephalitis (RE). Our patient's electroclinical improvement supports the hypothesis that cannabis could actually represent an effective, well-tolerated antiepileptic drug. Moreover, the experimental data suggest that CBDV may greatly contribute to cannabis anticonvulsant effect through its possible GABAergic action.

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Species referenced: Xenopus
Genes referenced: gabarap was

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Figure 1. (A) EEG recording performed before the introduction of cannabis: the tracing shows a subcontinuous paroxysmal epileptiform activity characterized by discharges of spikes in the left hemisphere with rapid contralateral transmission, followed by a brief voltage attenuation on the left frontocentral and anterior temporal regions, and then by a pseudoperiodic slow spike‐and‐wave activity propagating over the midposterior temporal areas. The clinical correlate consisted of a seizure characterized by intense right perioral myoclonus (*), followed by ipsilateral tonic deviation of the mouth (●), dystonic posturing of the right limbs (♦), and partial consciousness impairment ().The neurological examination showed severe ideomotor slowing and an evident worsening of the preexistent aphasia, with increased difficulty in verbal comprehension and word reaching. (B) EEG recording performed 1 year after the introduction of cannabis: the tracing shows diffuse discharges of spikes, clinically associated with isolated perioral myoclonus (*), and focal theta‐delta activity intermingled with spikes and spike‐and‐waves located on the frontal and anterior and middle temporal regions. An improvement in cognitive and, more specifically, language functions was observed. (C) MRI scan (FLAIR and IR sequences). On the left: MRI scan before surgery, showing the presence of a lesion involving the left insula with concomitant slight hyperintensity and bulging of the mesial temporal area and atrophy of the head of the ipsilateral caudate nucleus. On the right: MRI scan after left temporal lobectomy, showing diffuse white matter alterations and left lateral ventricle dilatation.

Figure 2. (A) Cannabinoids serum levels and electroclinical correlations. B: baseline, defined as the coexistence of subcontinuous motor seizures (right perioral myoclonus, ipsilateral tonic deviation of the mouth, dystonic posturing of the right limbs, and partial consciousness impairment) and severe ideomotor slowing with mixed aphasia; PI: partial improvement, defined as the coexistence of perioral myoclonia, subclinical ictal discharges, and motor aphasia; I: improvement, defined as the persistence of isolated perioral myoclonic jerks and the improvement of language fluency. Plasma concentrations of Δ9‐tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabidivarin (CBDV) were quantified by liquid chromatography tandem mass spectrometry (LC‐MS/MS) according to Ferreiròs et al. with slight modifications. After solid phase extraction (SPE), chromatography was performed on KInetex C18 column (50 × 2.1 mm, 2.6 particle size) with a gradient of 0.01% formic acid in water and 0.01% formic acid in methanol. THC and CBDV were monitored using positive mode electrospray ionization and multiple reaction monitoring (MRM). The transitions were m/z 315 → 193 and 287.2 → 165.2 for THC and CBDV, respectively. The limit of quantification (LOQ) was 0.5 ng/ml for both analyses. (B) Normalized time‐course of the averaged (mean ± SEM) GABA current rundown in oocytes transplanted with hippocampal membranes in control condition (filled symbol) and after 50 nm CBDV application (empty symbol). Data refer to 30 oocytes, 4 patients. In all experiments the holding potential was −60 mV. Current amplitude normalized to the first response of rundown protocol. Inset: Representative GABA current traces in one transplanted oocyte showing the first and sixth response to GABA 500 μm (black bars) before and after 50 nm CBDV application as indicated. Data refer to 4 TLE patients (4 males, mean age 32.7 ± 9.5 years; mean epilepsy onset 12.7 ± 1 years). All patients had mainly complex partial seizures resistant to maximal doses of different antiepileptic drugs and had hippocampal sclerosis (HS) with neuronal loss within all hippocampal subfields, including CA1 and CA4 (HS, ILAE type 1). For the clinical part of the study, informed consent was obtained. For the experiments, TLE tissues with HS were provided by Amsterdam University (AMC) and used in accordance with the Declaration of Helsinki.

References [+] :

Devinsky, Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. 2014, Pubmed