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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This is info only not medical advice.

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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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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Epilepsy

Ketogenic diet and its variants, modified Atkins diet and medium-chain triglyceride ketogenic diet and control of seizures

Virginia Thornley, M.D, Neurologist, Epileptologist

March 6, 2018

Introduction

In the past decade, different modifications of the ketogenic diet have evolved given the high intolerance to the side effects of the classic ketogenic diet and poor adherence to the strict regimen. Other variants have had similar effects in achieving control of seizures. The ketogenic diet remains a viable treatment option in patients medically refractory to conventional agents and should not be discounted as part of the armamentarium of the epileptologist or neurologist who treats patients with seizures.

 

 

Studies and classic ketogenic diet

In one small trial of febrile related seizures, 7 children with medically refractory febrile infection-related epilepsy syndrome (FIRES)were followed, 6 had less frequent and less severe seizures. On average, 4 antiepileptic agents were weaned (1). FIRES is a febrile related convulsion syndrome that starts during childhood where febrile seizures are thought to induce a cytokine reaction that occurs post-infectiously(2). In one remarkable study of 77 patients with refractory status epilepticus, only one patient had a shortened acute phase in response to ketogenic diet, 2 to anesthesia and 1 in response to IVIG, all other treatment modalities including conventional IV medications failed to shorten the acute phase (6).

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In several case reports of pediatric patients in status epilepticus, the ketogenic diet was used to stop the continuous seizures. In 10 patients in one case series, all 10 pediatric patients were in continuous status epilepticus. 4 patients had focal partial status epilepticus while 6 had generalized status epilepticus. The patients had a mean duration of seizures of 18 days. The mean time for achievement of ketosis was 7 days of which 9/10 patients stopped having continuous seizures during that timeframe(4).

Modified Atkins diet and seizure control

In one study of 14 patients, the modified Atkins diet seemed to be better tolerated than the ketogenic diet. The diet was well-tolerated by 86%. 7 (50%)remained on the diet after 6 months and 36% had a 50% reduction in seizures 21% were seizure free. Strong ketosis appeared to be key in controlling the seizures (5).

Medium chain triglyceride ketogenic diet 

In another variation, the medium-chain triglyceride ketogenic diet, ketones have been challenged as the substrate for control of seizures. It has been shown that medium-chain fatty acids can work through the AMPA receptors where the excitatory neurotransmitter glutamate binds, as the mechanism for controlling seizures and by changing the bioenergetics of the mitochondria (3).

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Introduction/Disclaimer

About

References:

  1. Gofshteyn, et al, “Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome in acute and chronic phases,” Journal of Child Neurology, 2017, Jan.,32(1):35-40.
  2. Gaspard, et al “New onset refractory epilepticus (NORSE) and febrile infection-related epilepsy syndromes (FIRES): state of the art and perspective,” Epilepsia, 2018, Feb., doi:10:1111/epi. 14022 (Epub ahead of print)
  3. Augustin, et al, “mechanism of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorder,” Lancet Neurology, 2018, Jan., 17(1):84-93.
  4. Appavu, et al, “Ketogenic diet treatment for pediatric super-refractory status epilepticus,” Seizure, 2016, Oct., 41:62-65.
  5. Kang, et al, “Use of modified Atkins diet in intractable childhood epilepsy,” Epilepsia, 2007, Jan. 48(1):182-186.
  6. Kramer, et al, “Febrile infection-related epilepsy syndrome(FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children,” Epilepsia, 2011, Nov., 52 (11):1956-1967.

 

 

 

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Epilepsy

Ketogenic diet and its variants modifed Atkins diet, low glycemic index treatment: effectiveness, side effect profile in patients with epilepsy and incidental weight loss

Virginia Thornley, M.D., Neurologist, Epileptologist, February 26, 2018

Doctors first took notice of the ketogenic diet working in patients with epilepsy in the 1920’s. But the exact mechanism remains unclear. One study elucidated that the ketone bodies are one of the reasons why the ketogenic diet works in patients with epilepsy. Ketosis occurs during a natural fasting state. In the ketogenic diet using high fat, the by-products of beta-oxidation of fatty acids which are beta-hydroxyacetate and acetoacetate in the blood do not correlate with patients who are doing better. Medium chain triglyceride fatty acids, which are a part of a variation of the ketogenic diet, are shown to suppress the AMPA receptors which subserve the excitatory neurotransmitter glutamate and may change energy use of the cell through mitochondrial processes (1).

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Ketogenic diet and adverse effects

Some patients have difficulty adhering to the diet which makes it difficult to use. Common side effects because of the high-fat content are diarrhea, constipation, nausea, transient increase in lipemic values. Variations of the ketogenic diet are sometimes used to offset these side effects and reduce the non-compliance.

Some ketogenic 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 (2).

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Effectiveness of the ketogenic diet and ketogenic diet variants

One study summarizing studies on patients using the classic ketogenic diet found that 50% of patients out of 206 had a >50% reduction of seizures using the classic ketogenic diet. Older patients seemed to benefit less. In the modified Atkins diet, seizures were reduced in younger patients with more frequent seizures. Patients tended to drop out because of the side effects, lack of perceived effectiveness and because of the restrictions in the diet. Patients greater than 12 years old were less adherent to the diet (3).

It is possible that the protective effects of the ketogenic diet are related to the medium chain triglyceride fatty acids and not the ketone bodies.

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Introduction/Disclaimer

References

1. Augustin, et al, “Mechanism of action for medium-chain triglyceride ketogenic diet and metabolic disorders,” Lancet Neurology, 2018, Jan., 84-93.

2. McDonald, et al, “Ketogenic diets for adults with highly refractory epilepsy,” Epilepsy Currents, 2017, Nov.-Dec., 17(6):346-350.

3. Payne, et al, “The ketogenic and related diets in adolescents and adults-a review,” Epilepsia, 2011, Oct., 52(11):1941-1948.

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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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