Tag Archives: epileptic syndrome

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.

IMG_6486_preview

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.



https://neurologybuzz.com/
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

Standard
Uncategorized

Cannabidiol: a large study in the U.S., Netherlands, and Poland shows its efficacy in patients with the epileptic disorder Lennox-Gastaut Syndrome

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

March 31, 2018

Introduction

Lennox-Gastaut Syndrome is an epileptic syndrome starting in childhood characterized by a wide spectrum of seizures and slow spike and wave on EEG. The seizures are characterized by the classic mnemonic “a fall, a jerk and a stare” or atonic seizures, myoclonus and complex partial seizures, although there are many other different types. Slow spike and wave generalized epileptiform discharges of 2.5 Hertz or less on electroencephalogram clinch the diagnosis. Patients are often delayed in development. Controlling seizures, because of the sheer complexity, of the different types is often a medical challenge.

Methods of the study

A new study using cannabidiol, which is the non-psychoactive medical component of the cannabis sativa plant, was carried out with the results recently demonstrating value. It covered 24 sites from the U.S., the Netherlands and Poland and studied seizures in patients medically refractory to medications using cannabidiol as an adjunctive add-on agent.  171 patients were enrolled from April 28, 2015, to October 15, 2015, and were randomly assigned to either the placebo control or the group with cannabidiol. 86 received cannabidiol and 85 were in the placebo group. 14 discontinued treatment in the cannabidiol group and 1 in the placebo group. All patients had at least one dose of treatment. Eligible patients ranged from 2-55 years old. Cannabidiol was given at a dose of 20mg/kg.

463633_10152824046473841_4997560710596062158_o

 

Seizure reduction

The results were startling, there was a reduction of seizures by 43.9% in the cannabidiol group and 21% in the control group. 86% patients had side effects in the cannabidiol group and 69% in the control group on placebo. These included somnolence, pyrexia, diarrhea, reduced appetite, and vomiting. 12 stopped in the cannabidiol group due to adverse reactions considered mild to moderate while 1 withdrew from the placebo group. 1 died due to unrelated causes from the cannabidiol group.

Conclusion

Reviewing this study, perhaps one of my critiques of this study is that the dosage was 20mg/kg in a 14-week study which means that within 14 weeks a patient of 50 kg. would have been ramped up to about 1000mg. In real life practice, medications are titrated more gradually over a period of months before maximum efficacy may be seen and in such a gradual way in order to avoid side effects. Although a large percentage of patients had side effects which were mild to moderate, it is quite possible they may have needed a smaller dose and the dosages were increased more than it was necessary to achieve the beneficial effects seen in the study within a short period of time. Nevertheless, the bottom line is that cannabidiol, a product of the Cannabis sativa plant, shows a reduction in seizures in a patient with Lennox-Gastaut syndrome.

This study concluded that there is some efficacy of cannabidiol in Lennox-Gastaut syndrome, one of the most difficult epileptic syndromes to treat, and was found with only very mild to moderate side effects. An open-label study as an extension to this study is currently ongoing.

Neurologybuzz.com

Introduction/Disclaimer

About

Reference

  1. Thiele, et al,. “Cannabidiol in patients with seizures from Lennox Gastaut Syndrome (GWPCARE4): a randomized, double-blind placebo-controlled phase 3 trial,” Lancet, 2018, Jan., 390 (10125):1085-1096.
Standard