ketogenic diet, Uncategorized

Ketogenic diet, modified Atkins diet and what is in them: used in seizure control, can these be a weight loss solution to morbid obesity, a risk factor for cerebrovascular and cardiovascular disease?

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

March 29, 2018

Introduction

Ketogenic diet has been used for seizure control when physicians started to notice a reduction of seizures in patients with a high ketone laden diet. This fell out of favor in the 1920’s with the onset of newer agents. As a side note, weight loss has been noted in those on a ketogenic diet.

Previously, guidelines have recommended a reduction in saturated fat which was thought to be the cause of the growing morbid obesity epidemic. Currently, it has been found that carbohydrates which are rich and refined may contribute towards the obesity epidemic. Sugar-laden sodas, the white bread which has refined flour, pizza batter made out of refined flour, all these food which are popular in theIt is no Western culture contribute to the morbid obesity as it is looming today.

How current culture sets the perfect stage for morbid obesity

The current western diet is about 50% carbohydrates. In addition, physical activity is at an all-time low compared to other eras. The current culture is designed as a sedentary and carbohydrate-rich eating culture. Everything nowadays is rapid pace. There are drive-through banks, drive-through pharmacies. Rather than having to physically go to a shop or order things in person,  many things can be done online or by phone reducing the daily need to exert physical activity. There is less time spent on physical activity compared to 100 years ago. If you go to neighborhoods, sidewalks no longer exist. Unless one lives in an urban environment where you are forced to walk to the bus station or live in cities amenable to walking or biking, the car is the mode of transport. Food is rich in carbohydrate, such hamburger buns, pizza dough, white bread or rolls. It is little wonder that morbid obesity abounds.  Food rich in sugar is abundant in grocery store aisles including donuts, cookies, baking packets. The colorful rich in anti-oxidant fresh fruits and vegetables are usually on the sides of the grocery shops, the food that is actually good for you and you need to take time out of your schedule to cook.

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Living a healthy diet is not just staying active but also eating the proper diet. Food that is closest to their original source are richest in nutrients. In short, the colorful vegetables you have to cook without any of the processing that takes place are the food richest in nutrients and have high anti-oxidant properties. Anti-oxidation is important in helping to combat a wide variety of diseases. Colorful fruits and vegetables are rich in fiber and more difficult to digest, hence, uses up more calories. Those which are high in refined carbohydrates are easily digested and contributes more towards obesity.

Components of the ketogenic diet and ketogenic diet variants

Ketogenic diet variants include modified Atkins diet, low glycemic index treatment, and medium chain diet. The ketogenic diet consists of 4:1 ratio of fat to carbohydrates shifting metabolism to the use of ketone bodies as a source of energy. A lower ratio is sometimes employed called the modified ketogenic diet with a 3:1 or 2:1 ratio of fat to carbohydrates. In the modified ketogenic diet, the palatability is improved and avoids the gastrointestinal symptoms associated with the ketogenic diet such as nausea. With the modified Atkins diet, carbohydrates are restricted to 10-20 grams a day, or a 1-2:1 ratio of protein to fat plus carbohydrates. In the low glycemic index treatment, carbohydrates are limited to 40-60 grams while 50-60% of the diet is fat and 20-30% is from protein. The medium-chain triglyceride diet employs oils as a supplement such as coconut oil. The palatability of these diets improve patient compliance and lessen the side effects of the ketogenic diet. Some patients also used the diets to incidentally lose weight in addition to treating seizures.

Ketogenic diet and evidence it works in losing weight

The ketogenic diet has a carbohydrate component of about 20-50 grams a day. It is not so much the restriction of the carbohydrates but the quality of carbohydrates that are ingested that causes people to shed pounds. High fiber, wheat, and whole grain carbohydrates portend a healthier diet as opposed to just restricting carbohydrates in general. In some clinical studies, it was found that weight loss was higher in those with a low carbohydrate diet compared to a low-fat diet (1).

Will the high fat cause me to have heart disease?

In one study where ketogenic diet was used in glucose transporter deficiency, a pediatric epileptic syndrome with encephalopathy, 10 patients were followed for 10 years. After 10 years on ketogenic therapies, there was no evidence of increased cardiovascular risk. While it is a small study, it shows evidence that eating a low carbohydrate diet did not appear to contribute towards heart disease. Larger clinical trials are needed (3).

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How obesity relates to other diseases

It is not uncommon to see patients who come into the ER or the doctor’s office with a history of hypertension, diabetes mellitus type II, hypercholesterolemia and obesity all related to one common denominator-obesity. Take away the obesity, the bad cholesterol or the LDL values go down, glucose goes down and hypertension resolves. When these risk factors are reduced early enough in your life, the odds of cerebrovascular disease or strokes and cardiovascular diseases or heart attacks vastly diminish. If, however, obesity is long-standing, while it is definitely good to reduce risk factors, once atherosclerosis is present in the blood vessels, there is no magic pill to reverse that.

Early identification and reduction of obesity as a contributor towards many health problems is key. Ketogenic diet may play a role in weight reduction. A small case series did not show any risk of heart disease while on the ketogenic diet long-term, over a span of 10 years. Larger clinical trials are needed to support this.

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Introduction/Disclaimer

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Reference

  1. Giugliano, et al, “More sugar? No thank you! The elusive nature of low carbohydrate diets,” Endocrine, 2018, Mar, 19. doi: 10.1007/s12020-018-1580-X (Epub ahead of print)
  2. McDonald, et al, “Ketogenic diets for adults with highly refractory epilepsy,” Epilepsy Currents, 2017, Nov.-Dec., 17 (6):346-350.
  3. Heussinger, et al, “10 patients, 10 years-Long-term follow-up of cardiovascular risk factors in Glut1 deficiency treared with ketogenic diet therapies: a prospective , multicenter case series,” Clin. Nut., 2017, Nov, pil:S0261-5614 (17)31399-7.

 

 

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Anxiety, Depression, Post-Traumatic Stress Disorder, Uncategorized

Cannabidiol and tetrahydrocannabinol: effectiveness in post-traumatic stress disorder, anxiety and depression

Virginia Thornley, M.D., Neurologist, Epileptologist

March 20, 2018

Post-traumatic stress disorder is the silent disorder that could be affecting the co-worker who sits one cubicle over from you. When one hears of post-traumatic stress disorder, one thinks of traumatizing incidents such as war, abuse or some other devastating event but can occur even in situations such as car accidents or a spouse of many decades suddenly leaving. It is the quiet disorder that if you do not expound on it, nobody really knows about it. Because of the stigma surrounding psychological disorders, often times, help is not sought in a timely manner.

It is often characterized by nightmares waking someone up in the middle of the night or sudden flashbacks when placed in a situation similar to the traumatic event.  Management includes working with a psychiatrist using conventional medications and a psychologist using behavioral therapy. It is not uncommon for a patient to have to go through many different anti-depressants or anxiolytics before one finds the correct drug and titration. But sometimes even the best medications fail to treat someone with Post-traumatic stress disorder adequately. Psychotherapy may be helpful in some patients depending on the patient. In others,  there is less benefit and some dislike the thought of reliving the experience in order to learn coping mechanisms.

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Alternatives include non-pharmacologic measures including relaxation techniques such as doing yoga, Tai Chi or meditation. Exercise can often boost the mood and doing enjoyable activities may help alleviate symptoms without the addition of pharmacologic agents. Doing something one enjoys or taking joy in the simple activities in life such as writing poetry, art therapy, taking up a sport may help alleviate some of the stress. Great tips can be found on Psychiatrist, Dr. Welby’s site found here: https://drmelissawelby.com/exercise-depression-get-started-want-stay-bed/

More and more patients are turning towards alternative measures, finding that conventional medications are not always optimal. Cannabidiol works through the endocannabinoid pathway and modulates its effect through the CB1 receptor which is predominantly found in the nervous system. The CB2 receptor is found mostly in the immune system. In some studies, it was found that cannabidiol may help reduce fearful memory if taken in the conditioning phase so that rather than reacting to the stimulus with fear, the stimulus is then associated with a different reaction and may help mitigate the symptoms of post-traumatic stress disorder through this mechanism (1). In another study, it was found to influence synaptic dendrites and may contribute towards learned memory in the hippocampus (2).

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Cannabidiol interacts with the 5HT-A receptor which is an important receptor in mitigating the symptoms of anxiety. Serotonin works through the 5HT1-A receptors. Some anxiolytics and anti-depressants work through an increase in serotonin which boosts the mood. Cannabidiol itself is known to have a calming effect with none of the euphoria found in THC alone.   Cannabidiol is non-intoxicating and when combined with low dose tetrahydrocannabinol has great medical effects.

In summary, when medications and therapy are found to be ineffective for post-traumatic stress disorder, anxiety or depression, cannabidiol which is non-intoxicating may be an effective therapeutic option alone or in conjunction with low dose THC and should be considered.

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References

  1. Uhernik, et al, “Learning and memory are modulated by cannabidiol when administered during trace fear-conditioning,” Neurobiology of Learned Memory, 2018, Feb., 9, 149:58-76. doi: 10.1016/j.nlm.2018.02.009 (Epub ahead of print)
  2. Lee, et al, “Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorder,” British Journal of Pharmacology, 2017, Oct., 174 (19): 3242-3256. doi: 10.1111/bph.13724. (Epub. 2017 Mar. 9.)
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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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Introduction/Disclaimer

https://neurologybuzz.com/

About

 

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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