Tag Archives: SCN1a

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.

10429450_10152610208453841_6861894890174598213_n

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.

 

Standard
Epilepsy, pain

Cannabidiol: Is there any scientific evidence? Review of some of the novel mechanisms of action in analgesic, anti-epileptic, anti-inflammatory, anti-tumorigenic and anxiolytic effects 

Virginia Thornley, M.D., General Neurologist and Epileptologist

@VThornleyMD

February 16, 2018

Introduction

Cannabidiol (CBD) is the little known medical component without the euphoria used for medical indications such as analgesic, anti-inflammatory, anti-epileptic and anxiolytic effects. In the pathway for endocannabinoids, cannabinoid exerts its therapeutic effects by binding to the CBD1 receptor found in the brains and the nerves exerting their analgesic effects. CBD does not have the same euphoriant effect as THC its counterpart which is better known to the public with much stigma. CBD will need to be 100 times more potent to have the same euphoria as THC making it relatively safe to give without the intoxicating effects. THC or delta-tetrahydrocannabidiol is the main psychoactive component in the marijuana plant, the one finds in the street drugs which has caused such a stigma shadowing the beneficial effects of the plant. Cannabidiol is also thought to work on the 5HT1 receptor giving its anxiolytic properties. This review seeks to understand some of the laboratory research that study the underlying mechanisms for its beneficial actions.

Cannabidiol works on CBD1 receptor and is thought to have an analgesic and anti-inflammatory role in diseases. In many states, it still outlawed to have in possession but growing clinical evidence shows that it can be used in pain syndromes. In the state of Florida there are 10 conditions recognized that can be treated with CBD. It is most commonly used in pain from stage IV metastatic cancer. Cannabidiol has been found to have anti-inflammatory, anti-tumorigenic, analgesic, anti-epileptic and anxiolytic properties.

Analgesic effects

CB1 receptors are found to be expressed in anterior horn cells. The CB2 receptors possibly reduce pain by acting on the neutrophil accumulation and mast cell degranulation which can reduce pain both of these processes increase inflammatory algesia(1).Analgesia has been demonstrated with cannabinoids in visceral inflammation and pain due to peripheral neuropathies, important areas of therapeutic considerations.

Anti-seizure effects

Some of the vast scientific research for cannabinoid is found in the animal models for epilepsy. Cannabinoids exert effects on CB1 and CB2 receptors in the hippocampus where it has a weak affinity(5). CBD1 receptors affect transmission in the synapses through the voltage-gated calcium and potassium channels. There are studies on the effects of CBD in refractory types of epilepsy such as Dravet’s syndrome one of the SCN1a genetic disorders affecting the sodium channel manifesting as severe myoclonic epilepsy. Mechanisms of CBD include 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(7), TRPV1 in addition to voltage-gated voltage-gated potassium and sodium channels. Another study supports the role that cannabinoids may play in shifting the inhibition of glutamatergic effects and GABAergic effects in the hippocampus mediated by CB1 receptors. In the rat model, it was suggested that seizures can upset the balance of these glutamate and GABA systems (4). 15 minutes after an induced seizure, there is increased 2-arachidonylycerol which is a CB1 agonist suggesting cannabinoids act as a negative feedback loop for seizures(4). In addition, it was found there are more CB1 receptors in the hippocampi with induced seizures compared to control suggesting plasticity of the brain with a compensatory increase in CB1 receptors in response to increased seizures(4). CB2 receptors are related to the immune system and are limited in the CNS. Cannabinoids affect calcium homeostasis and may provide its neuroprotective effects. Growing evidence shows case series, case reports and anecdotal reports on patients having fewer seizures on cannabidiol. Large case-controlled clinical randomized trials are needed.

Anti-tumor effects

There appears to be increased cancel cell death, reduced viability and reduced numbers of metastatic cells. In one study, it is found to reduce epidermal growth factor-induced multiplication and chemotaxis of cells in breast cancer. In mouse models, it inhibits macrophage recruitment in tumor-related cells.n It can potentially inhibit metastasis and proliferation and may provide a novel therapeutic option in breast cancer(2).

Anxiolytic effects

It works on the 5HT1 receptor by altering effects on this receptor the exact mechanism is unknown accounting for anxiolytic properties(6).

1383715_10151936144383841_1962894181_n

Anti-psychotic effects

CBD may alter the effects of THC and reduce its psychoactive properties (6).

 

Alternative treatment in opioid use

CBD might also work in place of opioids with the growing epidemic of chronic pain and overuse of opioids, CBD may be an alternative analgesic for chronic pain without the effect of tolerance or sedating properties. CBD was found to reduce the reward effects of morphine and does not have the same properties of tolerance. CBD does not have the same euphoria and THC and works on pain(6).

In summary, it is an exciting time for research in the use of cannabinoids. There are innumerable basic science research studies demonstrating the therapeutic effects at the cellular level. Large randomized clinical trials are still needed to gain information in using cannabinoids in humans.

Introduction/Disclaimer

About

https://neurologybuzz.com/

References

1. Rice, AS, et al, “Endocannabinoids and pain: peripheral and spinal analgesia in inflammation and neuropathy, ” Prostaglandins, Leukotrienes and Essential Fatty Acids, 2002, Feb., 66(2-3)246-256.

2. Elbaz, E. et al, ” Modulation of tumor microenvironment and inhibition of EGF/EGFR pathway: novel mechanisms of Cannabidiol on breast cancer,”Molecular Oncology, 2015, Apr., 9(4):906-919.

3. Welty, W.E., et al, “Cannabinoids: the promises and pitfalls,” Epilepsy Currents, 2014, Sep.-Oct., 14(5):250-252.

4. Wallace, MJ, et al, ” The endogenous Cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy, ” The Journal of Pharmacology and Experimental Therapeutics, 2003, Oct., 307(1):129-137.

5. Gaston, T. et. al, “Pharmacology of cannabinoids in the treatment of epilepsy, ” Epilepsy Behavior, 2017, May, 70:313-318.

6. Volkow, Nora, “The biology and potential therapeutic effects of cannabidiol,” National Institute on Drug Abuse Senate Caucus on International Narcotics Control, 2015, June.

7. 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.

Standard