Epilepsy

Dravet Syndrome: morphologic abnormalities, role of precision medicine, novel mechanisms for treatment and treatment options

Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD

August 13, 2018


Introduction

Dravet syndrome is characterized by developmental delay and intractable predominantly myoclonic seizures related to an abnormality in the SCN1A gene. The SCN1A gene encodes for sodium channel Nav1.1 which is voltage gated. It is one of the most pharmacologically resistant types of epilepsy syndromes.

Functional and morphological studies

One animal study using SCN1a(E1099x/HET mouse model for Dravet syndrome demonstrated early seizures which reached its maximum at post-natal week 4. There were less GABAergic neurons that expressed the Nav1.1 subunit in the dentate gyrus in the Het mice. There was a reduced number of inhibitory inputs travelling to the dentate gyrus cells in the Het mice. There was an increase in transmissions of excitatory impulses. The dentate gyral cells were noted to be abnormal morphologically with less arborization and a greater number of spines(1). This correlated with the abnormal excitation and reduced inhibition.

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Fenfluramine

Fenfluramine has been revisited as a treatment option for Dravet syndrome. It is metabolized into norfenfluramine. Fenfluramine and its metabolite norfenfluramine uncouples the association of sigma 1 receptor from the NR1 subunit of NMDA receptors (glutamate N-methyl-D-aspartate). Fenfluramine has serotonergic activity at the 5HT2AR receptor in addition to the activity at the sigma 1 receptor which reduces convulsive activity. Fenfluramine influences the cannabinoid type 1 receptor uncoupling with NMDARs which allowed greater restriction of the NMDAR actions (2).

Ketogenic diet

Ketogenic diet should not be discounted as a therapeutic option (3). In a study of 52 patients with pharmacoresistent epilepsy, spike and sharp wave complexes were reduced on the electroencephalograms of 26 patients which was significant (p<0.5). After a treatment of 12 weeks, there was a noticeable effective rate if seizure reduction of 42%. Motor, language and cognition was found to be improved in 23 patients, although the degree of improvement was not thought to be significant. Some adverse reactions included digestive problems and elevated liver enzymes.

Precision medicine

Because Dravet syndrome is related to a de novo loss of function mutation, great interest has been generated towards precision medicine. This involves targeting the genetic abnormality with treatments tailored towards a patient’s particular genetic make-up.

In one study using precision medicine, the selective activation of the Nav1.1 through the venom Hm1a restored the inhibitory mechanism of the neurons that are responsible for causing seizures in the mice model for Dravet syndrome (4). This may be a novel target for a therapeutic option using precision medicine in the treatment of Dravet syndrome.

Summary

In summary, while Dravet syndrome continues to be a devastating neurological disorder, there is research in precision medicine and other novel therapeutic options that can pave the way for more studies in this area.



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Reference

1. Tsai, M.S., Lee, M.L., Chang, C.Y., Fan, H.H., Yu, I.S., You, J.Y., Chen, C.Y., Chang, F.C., Hsiao, J.H., Khorkova, O., Liou, H.H.,Yanagawa, Y., Lee, L.J., Lin, S.W. Functional and structural deficits of the dentate gyrus network coincide with the emerging spontaneous seizures in an Scn1a mutant Dravet syndrome model during development. Neurobiol Dis 2015, May, 77:35-48
2. Rodriguez-Munoz, Maria, Sanchez-Blasquez, Pilar, Garzon, Javier. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018, May, 9(34):23373-23389
3. Qiong, W., Hua, W., Yu, Y., Mei Zhang, J., Yan Liu, X., Ying Fang, X., Hua Yang, F., Jun Cao, Q., Qi, Ying. Ketogenic diet effects on 52 children with pharmacoresistent epileptic encephalopathy: a clinical prospective study. Brain Behav. 2018, May, 8(5):e00973
4. Richards, K.L., Milligan C.J., Richardson, R.J., Jancovski, N., Grunnet, M., Jacobson, L.H., Undheim, EAB, Mobli, M., Chow, C.Y., Herzig, V., Csoti, A., Panvi, G., Reid, C.A., King, G.F., Petrou, S. Selective Nav1.1 activation rescues Dravet syndrome mice from seiuzres and premature death. Proc. Natl. Acad. Sci. U.S.A. 2018, Aug. pii:201804764

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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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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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