multiple sclerosis, Uncategorized

The impact of immunomodulating agents used in multiple sclerosis on the risk of cancer

Virginia Thornley, M.D., Neurologist, Epileptologist
June 14, 2019
Introduction
Multiple sclerosis is already an illness where the immune system recognizes the nervous system specifically the white matter tracts as foreign and attacks it. The complex cascade of mechanisms make adequate treatment challenging. Many treatments focus on the inflammatory mechanism with little attention on the degenerative mechanism involved.
Presentation of symptoms come in a wide variety depending on the the location of the multiple sclerosis plaque in the brain.
Patients may have concomitant morbidities which may make treatment challenging.
 
Immunomodulating agents and its impact on cancer
Many of the newer treatments for multiple sclerosis work at the level of the immune system through immunosuppression, the newer ones tend to be very potent. With greater efficacy comes greater risks including the risk of cancer.
Some of the newer medications can potentially increase the risk of cancer. Higher risk of cancer was found in many reports to occur with use of cyclophosphamide, azathioprine and mitoxanthrone. Fingolimod, natalizumab and alemtuzamab  can potentially increase the risk of cancer, these agents lack long-term data and work through the immune system. Dimethyl fumarate, terifluonimide, ocrelizumab, daclizumab and cladribine merit mandatory risk management plans to detect cancer before its use.
Reference
  1. Lebrun, C., Rocher, F., Cancer risk in patients with multiple sclerosis: potential impact of disease-modifying drugs. CNS Drugs. 2018, Oct. 32(10):939-949 doi:10.1007/s40263-018-0564-y
Disclaimer: This is medical information only not medical advice. Please consult your physician
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Uncategorized

Can depression affect the structures of the brain?

Virginia Thornley, M.D., Neurologist, Epileptologist
January 26, 2019
Introduction
The current model for depression is that it is a combination of genetic and environmental factors that come into play.

How traumatic events can change brain structures and function
It has been found that negative influences from childhood can affect the structures in the brain including the amygdala and hippocampus which may relate to mood disorders.
The interaction of genes with exposure to negative childhood experiences was shown to produce abnormal changes in the serotonin transporter and the FKBP5 gene. These play significant roles in the development of depression and other mood disorders (1).
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In another study of 34 patients, it was found that those who had maltreatment during childhood had  a change in autobiographical memory. There was reduced activation in areas controlling positive reactions and increased activation for negative responses. Children who suffered maltreatment were at risk of suffering from depression and post-traumatic stress disorder later on in life (2).
Childhood trauma might affect the stress axis as well as the inflammatory-immune system. The association may be related to a pharmacoresistent state with anti-depressants (1).
Reference
  1. Jaworska-Andryszewska, P., Rybakowski, J.K. Childhood trauma in mood disorders:neurobiological mechanisms and implications for treatment. Pharmacol Rep 2018 Oct. 11;71(1):112-120
  2. Mccrory, E.J., Puetz, V.B., Maguire, E.A., Mechelli, A., Palmer, A., Gerin, M.I., Kelly, P.A., Koutoufa, I., Viding, E. Autobiographical memory: a candidate latent vulnerability mechanism for psychiatric disorder following childhood maltreatment. Br. J. Psychiatry 2017, Oct. 211(4)216-222
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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.

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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.

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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.
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