Glaucoma, Uncategorized

9Tetrahydrocannabinol and novel mechanisms in reducing intraocular pressure in glaucoma

Virginia Thornley, M.D.,  Neurologist, Epileptologist

February 28, 2018

Introduction

The endocannabinoid system is composed of 3 systems: (the cannabinoid receptors, (2) endocannabinoid transportation system and (3) enzymes that break down the ligands. Two endocannabinoids anandamide (AEA) and 2-arachidonyl glycerol (2-AG) are elevated in response to a wide variety of pathological events. This suggests a compensatory response of endocannabinoids in response to damage or pathology within the system (3). Activation of the endocannabinoid system appears to correlate with cell repair and survival. The G-receptors discovered called CB1 and CB2 trigger transducer signal cascades and influence peripheral central cell functions.

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Cannabidiol in glaucoma

Cannabidiol is becoming a topic of hot debate in pain, anti-tumor effects, epilepsy and in glaucoma.  Glaucoma can result in increased intraocular pressure resulting in damage to the optic nerve at the retinal attachment. There is the narrowing of the visual field and eventual blindness through retinal damage. Cannabinoid receptors have been found in the ocular cells leading to speculation of benefits of cannabinoids in glaucoma.

Mechanism for treating glaucoma

One possible mechanism in ameliorating intraocular pressure is by suppressing N-methyl D-aspartate or NMDA receptor excitability, increasing neural vasculature circulation, suppressing apoptosis and damaging free radicals. Separation of the novels effects appears possible from the toxic side effect through novel technique (2).

Involvement of cannabinoid and their receptors in retinal cells have been well documented in fish cells to primates and more recently in neurodegeneration and neuroprotection. There is a fine balance of biosynthetic and degrading enzymes that influence endocannabinoids and exert neuroprotection during trauma, inflammation, ischemia, and neurotoxicity found in brain damage (4).

THC studies and glaucoma

In a rabbit model, 9THC showed improved penetration to the anterior chamber with reduction of intraocular pressure using a prodrug. THC is an established neuroprotectant and has the possibility of being an effective IOP lowering agent. THC and THC-Val-HS reached the retina choroid(5).

 

In one study of 32 different types of cannabinoids, it was found that certain derivatives of delta 9THC and delta 8THC were more effective at lowering intraocular pressure in glaucoma than the parent derivative cannabidiol (1).

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References

  1. ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
  2. Jarvinen, T., “Cannabinoids in treatment of glaucoma,” 2002, Aug., 95(2):203-20.
  3.  Karanian, et al, “Cannabinoid drugs and enhancement of endocannabinoid responses: strategies for a wide array of disease states,” Current Molecular Med., 2006, Sep., 6(6):677-84.
  4.  Rapino, et al, “Neuroprotection by endocannabinoids in glaucoma and retinal neurodegenerative diseases,” Current Neuropharmacology, 2017, Jul., doi:10.2174 (Epub ahead of print)
  5.  Goutham, et al, ” Development of a 9tetrahydrocannabidiol amino acid dicarboxylate prodrug with improved ocular bioavailablity,” Investigative Ophthalmology and Visual Science, 2017, Apr., 58(4):2167-2179.

 

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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.

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Introduction/Disclaimer

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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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