Tag Archives: GABAergic

cannabidiol, Epilepsy

Scientific and clinical evidence of cannabidiol (CBD) and seizure control: mechanisms, randomized controlled clinical trials, open label trials and animal models

Virginia Thornley, M.D., Neurologist, Epileptologist 

@VThornleyMD

May 22, 2018

Introduction

There are numerous scientific studies that have studied the effect of cannabidiol by itself on seizure control encompassing animal models, longitudinal observational studies, case series and currently randomized double-blinded placebo-controlled clinical trials. It is difficult to ignore the wealth of information regarding the medical value of cannabidiol with a significant role in the treatment of epilepsy.

The endocannabinoid pathway and cannabinoids

The endocannabinoid pathway is found naturally within our system, comprising of receptors, transporters, and endocannabinoids. It is responsible for the sense of well-being one gets after running referred to as the “runner’s high,” and not endorphins, serotonin or noradrenergic neurotransmitters as their molecular sizes are too large to pass through the blood-brain barrier. There are 2 types of receptors, CB1 and CB2 receptors. CB1 is found predominantly within the nervous system and is the receptor on which tetrahydrocannabinol works and it is through this binding where psychoactive properties arise. There are two metabolites within the endocannabinoid pathway, anandamide for which tetrahydrocannabinol (THC) is a phytomimetic and 2-arachidonoyl-glycerol for which cannabidiol is a phytomimetic. Cannabidiol (CBD) acts as an inverse agonist on the CB1 receptor, with a weak affinity. 100 times of cannabidiol is needed to get the same psychoactive properties as tetrahydrocannabinol. When CBD is combined with THC the side effects of paranoia, hyperactivity and agitation become less because it is an inverse agonist of the CB1 receptor. In many animal studies, cannabidiol has anti-inflammatory, anti-oxidative and neuroprotective actions within the nervous system (8).

Mechanisms by which cannabidiol works 

It is thought to modulate the neurotransmitter system. Endocannabinoids are increased as a result if hyperexcitability in the nervous system. CBD can regulate intracellular calcium during hyperexcitability states in the hippocampus in the temporal lobe. CBD can regulate NMDA (N-methyl-D-aspartate) receptor transmission and increase serotonergic 5HT-1A (5-hydroxytryptamine)receptor transmission and reduces GABA, 5-HT1A, and norepinephrine synaptic uptake (9). Cannabidiol is thought to be neuroprotective through its role in controlling intracellular calcium. Excess calcium can activate a cascade of neurochemical events leading to cell degeneration and death through lipases, endonucleases, and proteases. In one study in rat models, there was a suggestion that treatment of seizures was not just at the neurotransmitter level but also modulates the oscillatory nature, neuronal loss and post-ictal lethargy of the status epilepticus model.

Scientific evidence in animal models

Animal studies show that the effectiveness of cannabis is at the level of the CB1 receptor. With the deletion of the CB1 receptors in the forebrain excitatory neurons in the mice model, Kainate-induced seizures were more prominent. The presence of CB1 receptors in the hippocampal gyrus seems to protect against Kainate-induced seizures. Viral-induced CB1 overexpression resulted in less Kainate-induced seizures, CA pyramidal cell 3 cell death. This demonstrates that the presence of the CB1 receptor can limit seizures and reduces gliosis and apoptosis (4).

 

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In animal studies, the CB1 receptors increased 1 week after pilocarpine-induced seizures in the CA1-3 striatum oriens and the dentate gyrus. Patients with temporal lobe epilepsy had reduced Anandamide and increased CB1 receptors suggesting an up-regulation of the CB1 receptor as a homeostatic mechanism in the presence of seizures which can reduce excitatory neurotransmitters (4). This compensatory mechanism may be impaired with long-standing seizures and hippocampal sclerosis and refractoriness to pharmacologic measures.

Case series report

In a small study on patients with tumors with seizures, in 3 patients who were medically refractory were started on cannabidiol (Epidiolex) to treat seizures. 2 out of the 3 had improvement in seizures while all 3 had improvement in the severity in the University of Alabama (2).

Evidence in longitudinal observational studies

In one study of 57 patients, ages 1-20 years old, CBD:THC was given at a ratio of 20:1 with the CBD component of 11.4 mg/kg/day. The patients were followed longitudinally for 3 months with a follow-up time of 18 months. 56% or 26 patients had <50% reduction of seizures. No difference was noted between the causes of the seizure and the type of cannabis used. Younger ages of 10 years old and below had a statistically better outcome compared to an older age. Those with higher doses of CBD of >11.4mg/kg/day had a statistically better outcome compared to 11.4mg/kg/day and below. There were side effects in about 46% of patients leading to stopping the protocol. These studies suggest that cannabidiol enriched treatment may be beneficial in seizure control particularly in the pediatric population.  (1).

Open-label studies

In an open-label trial, 214 patients were studied between the ages 1-30, with pharmacoresistant epilepsy. There were 162 in the safety follow-up of 12 weeks, 137 were in the efficacy analysis. For the safety group, 33 had Dravet syndrome and 31 had Lennox-Gastaut syndrome. The rest had medically refractory seizures from different causes. Side effects were mild to moderate including diarrhea, lack of appetite, somnolence, fatigue, and convulsion. 5 had a cessation of treatment related to adverse effects. Serious events were reported in 48 patients with 1 death unrelated to cannabidiol. 20 had severe adverse effect including status epilepticus. The median number of seizures at baseline was 30 which was reduced to 15 per month with a 36.5% reduction of motor seizures (7).

Evidence in randomized controlled clinical trials 

In a multi-country study was performed on Dravet syndrome and effect of cannabidiol in a randomized double-blind trial of cannabidiol versus placebo and in young adults between the ages of 2-18. Dravet syndrome is an epileptic syndrome involving myoclonic epilepsy during childhood which may progress attributed to an SCN1A gene abnormality. There was a 4 week baseline period followed by a 14 week treatment period. The dosages of cannabidiol were increased gradually to 20mg/kg/day. Those in the cannabidiol group was matched to a placebo control. The endpoints were the percentage of change and Caregiver Global Impression of Change (CGIC). In 23 center in the U.S. and in Europe, 120 patients underwent randomization, mean age was 9.8 years old. 108 completed treatment. The median number of drugs was 3 and the most commonly taken were clobazam, valproate, stiripentol, levetiracetam, and topiramate. The most common type of seizures was generalized tonic-clonic followed by secondary generalized tonic-clonic seizures. 114/118 children presented with developmental delay. Adverse reactions were mild to moderate including somnolence, diarrhea and loss of appetite. Elevated liver enzymes were found in those taking valproate likely related to drug-drug interactions. The reduction of seizures was considered meaningful while no change in non-convulsive episodes was noted. In the cannabidiol group, convulsive seizures reduced from 12.4 seizures to 5.9 per month while the placebo control group had a reduction of seizures from 14.9 to 14.1 which was not statistically significant. A reduction of more than 50% of seizures occurred in 43% of patients in the cannabidiol group and 27% in the control cohort. 3 patients in the cannabidiol group and no one in the placebo group became free of seizures. 62% of caregivers thought the condition improved in the cannabidiol group as opposed to 34% in the placebo group (5).

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Another randomized placebo-controlled trial in Lennox-Gastaut syndrome was done using cannabidiol versus placebo. Lennox-Gastaut Syndrome is characterized by multiple seizure types with a slow spike and wave of 2.5 Hz or slower on EEG.  This study covered 30 clinical trial centers between the ages 2-55 with 2 or more seizures per week over 28 days. 225 patients were randomized with 76 in the group for cannabidiol at 20mg/kg/day, 73 in the cannabidiol group at 10mg/kg/day and 76 in the placebo cohort. The reduction in median of drop attacks was 41.9% in the 20mg cannabidiol group, 37% in the 10mg cannabidiol group and 17.2% in the placebo group which was statistically significant. Side effects were somnolence, diarrhea and poor appetite which was dose-related. 9% had higher liver function tests. The study concluded that addition of cannabidiol of either 10mg/kg/day or 20mg/kg/day in addition to standard anti-epileptic agents resulted in a significant reduction of seizures(6).

Cannabidiol as an add-on adjunct for refractory seizures

In another study in Slovenia, add-on cannabidiol was given to 66 patients who were deemed medically refractory at a dosage of 8mg/kg/day. 32 or 48% of patients experienced fewer seizures of more than 50% reduction. 14 (21%) were seizure free. No patient had to worsen and 15 or 22.7% there was no effect. Patients reported less robust seizures, less recovery time and less time duration of the seizures as positive outcomes. Adverse effects were seen in 5 patients or 0.07% of patients. They concluded that there are some beneficial effects of cannabidiol as an add-on adjunctive treatment in controlling medically refractory epilepsy(3). However, this study focused on cannabidiol as an adjunctive treatment, not as monotherapy.  Regardless, there are some beneficial aspects as evidenced in this study (3).

In summary

There is growing evidence that cannabidiol which is the non-psychoactive component of the Cannabis sativa plant is effective in treating intractable seizures, from the mouse model to randomized controlled clinical trials, which can no longer be ignored. There are mostly mild to moderate side effects involving the gastointestinal and neuropsychiatric system, although severe adverse outcomes include status epilepticus. There were no fatal outcomes associated with the use of cannabidiol. The real question are the long-term side effects and drug-drug interactions which can be studied once the cannabidiol is well-established as a conventional agent in the future.

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Introduction/Disclaimer

https://neurologybuzz.com/

References:

  1. Hausman-Kedem, M., et al, “Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – an observational longitudinal study,” Brain Dev., 2018 Apr., pii:S0387-7604 (18)30112-8 doi: 10.1016/j.braindev2018.03.013. (Epub ahead of print)
  2. Warren, et al, “The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy,” Neurocase, 2017, Oct.-Dec., 23 (5-6):287-291.
  3. Neubauer, D., et al, “Cannabidiol for treatment of refractory childhood epilepsies: experience from a single tertiary epilepsy center in Slovenia,” Epilepsy Behav., 2018 Apr., 81:79-85. doi:10.1016/j.yebeh.2018.02.009. (Epub ahead of print)
  4. Rosenberg, et al, “Cannabinoids and epilepsy,” Neurotherapeutics, 2015, Oct., 12 (4):747-768.
  5. Devinsky, O., et al, “Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome,” New England Journal of Medicine, 2017, 376: 2011-2020.
  6. Devinsky, et al, “Effect of cannabidiol on drop seizures in the Lennox-Gastaut Syndrome,” NEJM, 2018, May,  378:1888-1897.
  7. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open label interventional trial,” Lancet Neurology, 2016, Mar., 15 (3):270-8.
  8. Fernandez-Ruiz, et al, “Prospects of cannabinoid therapies in basal ganglia disorder,” British Journal of Pharmacology, 2011, Aug., 163 (7):1365-1378.
  9. Do Val-da-Silva, et al, “Protective effects of cannabidiol against seizures and neuronal death in a rat model of mesial temporal lobe epilepsy,” Front. Pharmacol., 2017, 8:131.
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Amyotrophic lateral sclerosis

Pluripotent stem cell research and amyotrophic lateral sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist

March 1, 2108

Introduction

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease resulting in muscle weakness and respiratory failure. The mechanisms still remain unclear and there is no cure. Recent interest is growing in stem cell research as a novel treatment for ALS.

Stem cells and ALS

Induced pluripotent stem cells have been studied to identify the mechanism underlying ALS and develop treatments using these models. Using stem cells it is possible to grow a disease in a dish and study the mechanisms. The cells are generated from healthy subjects and patients with neurodegenerative disorders cultivating them to produce different types of neurons. CNS neurons are separated from peripheral neurons. Neurotrophins and other factors are used to accomplish this. It is important that these neurons can produce synaptic connections. In some studies, only a low number will differentiate into the neurons with the desired morphologic features and have the desired physiologic functions. The use of pluripotent stem cells is an important landmark in research because it allows researchers to study the disease of ALS with pluripotent cells capable of differentiating into different types of neurons including upper motor neuron, lower motor neuron cells, astrocytes, oligodendrocytes and allows researchers to understand the different dynamics between the cells in the diseased state (2).

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Potential mechanisms of stem cell treatment in ALS

One mechanism is by changing the somatic cells into neuron-like cells. There are now established ways of forcing transcription factors into changing somatic cells into neuron-like cells expressing neuron-specific proteins. The majority studied had excitatory traits. The most important feature is being able to propagate action potentials and developing dendrites.There are some reports of fibroblasts transforming into GABAergic cells using neurotrophins. Reprogrammed cells could convert into neurons, astrocytes and oligodendrocytes. Some cells cannot convert using genomic insertion which may be a barrier.

Induced pluripotent stem cells can be produced from the patient’s own stem cells. Direct conversion of somatic cells into neural cells is an alternative (1).

Introduction/Disclaimer

References

  1. Csobonyeiova, et al, “Induced Pluripotent Stem cells in modeling and cell-based therapy of amyotrophic lateral sclerosis, ” Journal of Physiology and Pharmacology, 2017, 68(5):649-657.
  2. Guo, et al, “Current advances and limitations in modeling ALS/FTD in a dish using induced pluripotent stem cells,” front. Neuroscience, 2017, Dec., https://doi.org/10.3389/fnin.2017.00671
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Epilepsy, Uncategorized

Dravet syndrome: clinical course, SCN1A genetic abnormality involved and non-pharmacologic options including ketogenic diet and cannabidiol

By: Virginia Thornley, M.D., Epileptologist, General Neurologist

February 20, 2018

Dravet first described the syndrome that now bears his name in 1978. It is now a model for some of the channelopathies seen manifesting as epilepsy.

Clinical course and electroencephalographic manifestations

Dravet syndrome is also known as the severe myoclonic epilepsy in infancy (SMEI). Patients usually have no delay in development prior to the first seizure. It usually starts between 5-8 months of life another report mentions after 2nd year of life and may follow a febrile seizure. It consists of generalized tonic-clonic seizures and myoclonus. The term severe myocolic epilepsy of infancy (SMEI) is a misnomer as some patients with this gene related disorder may not manifest with myoclonus so Dravet syndrome is preferred. Clinical evolution includes an initial presentation of generalized tonic-clonic seizures evolving into multiple seizure types predominantly myoclonus. Complex partial seizures, focal seizures, and atypical absence seizures may be identified. Myoclonus is seen about 2 years of age and eventually disappears. The generalized type of seizures persists into adulthood. The EEG background becomes progressively slower, with poor organization. There is the presence of excessive frontal theta rhythms and discharges consist of spike, spike and wave and polyspike and wave complexes. There is sensitivity to fevers. It is usually associated with cognitive impairment. Lifespan is unclear as case series are not reported on those after 20 years of age (1).

SCN1A gene

Dravet syndrome is found to be one of the SCN1A-related disorders causing seizures. Genetic testing reveals a heterozygous variant of SCN1A. SCN1A encodes Nav1.1 or the alpha subunit of the voltage-gated sodium channel. Seizures related to this channel are channelopathies. Due to the molecular abnormality at the level of the channel, there is hyperexcitability due to the imbalance of excitation versus inhibition because of neuronal dysfunction at the level of the sodium channel. The SCN1A is encoded on chromosome 2q24 which also includes SCN2A and SCN3A. In epilepsy-associated variants which are all found in the Nav1.1 alpha subunit, they are more frequently found in the C-terminus, and some in the N-terminus. In Dravet syndrome, nearly 50% are truncating variants, while others are splice, missense or deletion types of abnormalities.  The pathophysiology is an area under intense investigation but likely due to loss of the excitability of inhibitory function of the GABAergic pathway causing seizures(4).

Non-pharmacologic ways to deal with conditions of Dravet syndrome

Anti-convulsants to avoid

Prescription agents are not discussed as new agents become available year to year. However, there are medications that should be avoided including carbamazepine, lamotrigine, vigabatrin, and phenytoin. Rufinamide is a similar agent to carbamazepine and could theoretically worsen this condition. Sodium channel blockers like these worsen these types of seizure. In Dravet syndrome,  there is an abnormality of voltage-gated sodium channel Nav1.1, where one would think there would be fewer seizures following the thinking that sodium channel blockers are used anticonvulsants. However, with the sodium channel abnormality in SCN1A seizure disorders, there is more inhibition of the GABAergic pathway which keeps seizures in check thus, there are more excitatory neurotransmitters available causing seizures to occur(4).

Ketogenic diet and mechanisms of action

The ketogenic diet has been found to improve the condition. With ketogenesis, instead of glucose being used as a substrate for seizures, there are increased ketones available from a high fatty acid diet in the body meaning less available glucose that helps keep up the metabolism required with energy expenditure used in seizures. The body uses ketones as the fuel source. Ketogenesis occurs with natural fasting when the body breaks down fat through lipolysis. Then, the fatty acids produced undergo beta-oxidation into ketone bodies (acetoacetate, beta-hydroxybutyrate, and acetone) which are used to produce energy ATP (adenosine triphosphate) used by the cells(3). The ketogenic diet mimics this natural process by using a high fat low carbohydrate diet so that instead of glucose the body uses fatty acids which turn into ketones used as a fuel source which is not conducive to seizures.  With ketogenic diet as a therapeutic option, it is key to see a dietician as the diet is strictly high fat. It is based on a tightly regimented all or none principle otherwise it will not work. Most patients eventually find the diet highly unpalatable and may give up. However, if followed faithfully, it may be a viable non-pharmacologic additional option in medically refractory patients with seizures. One study found a 62% reduction rate in Dravet syndrome using the ketogenic diet(2). In the study, the EEG significantly improved and a favorable outcome was seen in those with a shorter duration of the condition and those with generalized tonic-clonic seizures. However, like most studies of rare diseases the number studied was small.

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Other mechanisms proposed include changing the pH of the brain making it less favorable for the production of seizures, direct inhibition of ion channels by ketone bodies, and changes in amino acid metabolism to favoring GABAergic synthesis which is inhibitory to seizures.

Cannabidiol in Dravet syndrome

One study examining the effects of cannabidiol (CBD) on Dravet syndrome postulate mechanisms including increasing excitation of the inhibitory effect of the hippocampus where seizures are propagated.  At low doses, it helps with autism and impaired cognition.  It may exert its effect by working against GPR55. The effects of CBD on neurotransmitters were similar to the GPR55 antagonist suggesting CBD works at the level of this lipid-activating G-protein coupled receptor(5).

Consult with your neurologist.

About

Introduction/Disclaimer

https://neurologybuzz.com/

 

References

1. Akiyama, et al, “Dravet Syndrome: A Genetic Epileptic Disorder,”Acta Med. Okayama, 2012, 66(5):369-376.

2. Dressler, et al, “Long-term outcome and tolerability of ketogenic diet in childhood epilepsy— the Austrian experience,”Seizure, 2010, Sept., 19(17):404-408.

3. Maranano, et al, “The ketogenic diet: uses in seizures and other neurologic illness,” Current Treatment Options in Neurology, 2008, Nov., 10(6)410-419.

4. Miller, et al, “SCN1A-Related Seizure Disorder,” Gene Reviews, 2007, Nov., Updated 2014, May.

5. Kaplan, et al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome,” Proceedings of the National Academy of Science, 2017, Oct.

 

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