- 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
- Darlington, P.J., Stopnicki, B., Touil, T., Doucet, J.S., Fawaz L., Roberts, M.E., Boivin, M.N., Arbour, N., Freedman, M.S., Atkins, H.L., Bar-Or, A., Canadian MS/BST Study Group. Natural killer cells regulate Th17 cells after autologous hematopoietic stem cell transplantation for relapsing remitting Multiple Sclerosis. Front Immunol. 2018, 9:834
- Donders, R., Bogie, J.F.J., Ravanidis, S., Gervois, P., Vanheusden, M., Maree, R., Schrynemackers, M., Smeets, H.J.M., Pinxteren, J., Gijbels, K., Walbers, S., Mays, R.W., Deans, R., Van Den Bosch, L., Stinnissen, P., Lambrichts, I., Gyselaers, W., Hellings, N. Human Wharton’s jelly-derived stem cells display a distinct immunomodulatory and preregenerative transcriptional signature compared to bone marrow-derived stem cells. Stem Cells Dev. 2018, Jan. 27(2):65-84
- Bose G., Atkins, H.L., Bowman, M., Freedman, M.S. Autologous hematopoietic stem cell transplantation improves fatigue in multiple sclerosis. Mult. Scler. 2018, Sep: 1352458518802544 (epub: ahead of print)
- Sahraian, M.A., Mohyeddin Bonab, M., Baghbanian, S.M., Naser Moghadasi, A. Therapeutic use of intrathecal mesenchymal stem cells in patients with Multiple Sclerosis: a pilot study with booster injection. Immunol Invest 2018, Aug. 29:1-9
- Holloman, J.P., Ho, C.C., Huntley, J.L., Gallicano, G.I. The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis. Am. J. Stem Cells. 2013, Jun. 30, 2(2):95-107
- Nash, R.A., Hutton, G.J., Racke, M.K., Popat, U., Devine, S.M., Griffith, L.M., Muraro, P.A., openshaw, H., Savre, P.H., Stuve, O., Arnold, D.L., Spychala, M.E., McConville, K.C., Harris, K.M., Phippard, D., Georges, G.E., Wundes, A., Kraft, G.H., Bowen, J.D., High-dose immunosuppressive therapy and autologous hematopoeitic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3 year interim report. JAMA Neurol 2015, Feb. 72(2):159-69
This is for informational purposes only not medical advice see your physician.
How can the ketogenic diet help with Multiple Sclerosis?
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- Storoni, M., Plant, G. The therapeutic potential of the ketogenic diet in treating progressive multiple sclerosis. Mult. Scler. Int. 2015. doi 10.1155/2015/681289
- Dupuis, N., Curatolo, N., Benoist, J.F., Auvin, S., Ketogenic diet exhibits anti-inflammatory properties. Epilepsia, 2015. 56(7):e95-98
- DeVivo, D.C., Leckie, M.P., Ferrendell, J.S., McDougal, D.B., Jr. Chronic ketosis and cerebral metabolism. Ann Neurol. 1978, Apr. 394):331-337
Virginia Thornley, M.D. Neurologist, Epileptologist
The endocannabinoid system is found naturally in the brain. It is responsible for the sense of well-being one gets after running a 5-mile course. It does not work through endorphins or adrenaline, as some people may think. It works at the level of the endocannabinoid system. There is a community of CBD producers and consumers and it is in this mysterious world that it is well-known to be used in many medical conditions, still shunned by the majority of the medical community, Congress and even patients in general. The 2 most commonly known are cannabidiol and tetrahydrocannabinol. Cannabidiol has medical properties and has a weak affinity to the CB1 receptor which is predominantly found throughout the central nervous system, which is likely why it is found to work in numerous neurological conditions. Tetrahydrocannabinol (THC) is a well-known cannabinoid most notoriously known for the euphoria of kingpins seen on movies propagated by pop culture. Unfortunately, these connotations overshadow the well-known medicinal benefits. Cannabinoids have been used for centuries even in the B.C. period. It was part of the American pharmacopeia in the 1980’s until it was banned in the 1930’s. Slowly, these products are gaining popularity as a treatment for many medical conditions, primarily neurological because the CB1 receptor is so abundant in the nervous system, due to patients becoming more and more frustrated with the adverse effects and ineffectiveness of conventional treatments. In Europe, a combination of THC and CBD have been used in multiple sclerosis patients since 2010. Animal studies and cell line culture studies demonstrate many potential mechanisms in which CB1 receptors, CBD and THC may be beneficial at the cellular level in many diseases, mechanisms are still being elucidated. It is most commonly used for chronic pain and epilepsy. As with any medication, it may or not be effective for everybody.
How it works–the nitty gritty
Cannabidiol has none of the psychoactive properties as THC. One needs 100 times the amount of CBD to have the same intoxication as THC. Therefore, it works well for those who are reluctant to go this route but who have found conventional medications which do not provide effectiveness, they are simply not cutting it. Because very little is know about its titration, medical marijuana can seem like entering into the world of an apothecary, or such as that found in the medieval days when potions are concocted. Physicians who use it in their treat it similar to a medication and the guidelines are similar start low and go slowly. Tetrahydrocannabinol is more potent and at higher doses works more effectively for pain control and seizures. THC is used at relatively low concentrations in order to effect its medical properties, at higher concentrations one may run into side effects which offsets its medical value. There are different ratios of CBD:THC, different ratios correspond to different symptoms treated. CBD is required in conjunction with THC in order to offset the potential side effects of THC. Tolerance does not build in the system such as that seen with opioids, although if one is medical marijuana naive, the lowest dose possible is ideal. There are no side effects of respiratory depression such as that seen with other medications for pain such as opioids.Consult with your treating physician.
Current legal state of affairs
Currently, there are many states that recognize the medical value of medical marijuana with medical marijuana laws allowing the opening of licensed dispensaries. However, the same cannot be said for the federal law. In some states, the carrying of THC on your person can result in fines and imprisonment. Despite marijuana laws enacted, qualified physicians are at risk for being questioned by authorities, its recommendation and use is not for the faint of heart on the part of physicians and patients. Cannabidiol comes from hemp oil and is not considered illegal. However, anyone who even has 1% hemp oil in their product can still label that product as cannabidiol, which may be the reason why some patients are not getting the full medical effects when bought from the flea market or a vitamin store. Tetrahydrocannabidiol which is more well-known for its recreational use and concomitant psychoactive properties at very high doses is federally illegal in many states. Many states often have registries so patients who require this may obtain an ID and verify they are under the care of a qualified physician. It can take a few months to obtain an ID because many patients are often at the end of their ropes in terms of effectiveness of medications. Many patients wish to come off opioids or do not like the idea of needing higher and higher pain medications for their chronic illnesses. It may serve as a great antidote for the current opioid crisis that is well-documented in the news or overdocumented in the news. Many mothers order products online from other countries to counteract the illegalities of their states in order to help their child who may be using 4 potent anti-epileptic agents and is now like a zombie because of the number of medications. While physicians are leery suggesting anything that is in category 1, its medical value cannot be disputed. There is too much evidence tipping it towards the other side of the scale. As tPA was in its infancy of use and physicians were hesitant using it due to its hemorrhagic adverse effect and is now the standard of care for stroke protocols, medical marijuana will likely find its way back into the pharmacopeia, the amount of medical evidence is far too compelling to ignore.
In short, when used wisely, cannabidiol is a non-intoxicating effective treatment for many medical conditions especially neurologic, as evidenced by thousands of years of history of its use and current animal models, clinical trials and wider clinical experience in Europe. When cannabidiol is combined with low concentrations of THC, the medical effect is even greater with the entourage effect without the stigmatized psychoactive effects that are usually associated with THC.
Sativex has been available in Europe since 2010. It is a combination of tetrahydrocannabinol and cannabidiol at a ratio of 1:1 and has been found to be effective in spasticity resistant to medications in patients with multiple sclerosis. Spasticity is the increased tone seen in the muscles due to abnormalities in the central nervous system such as the white matter lesions seen in multiple sclerosis.
Sativex and medically refractory spasticity in multiple sclerosis
Sativex is a THC:CBD (tetrahydrocannabinol:cannabidiol) preparation taken oromucosally which was approved in European countries for the treatment of medically refractory spasticity in patients with multiple sclerosis. Sativex contains a 1:1 ratio of THC to CBD, where THC interacts with CBD receptors to reduce spasticity while CBD ameliorates the side effects often seen with THC. In one large clinical trial of 1615 patients, 42% showed improvement of spasticity in the first 4 weeks, defined as > or = to 20% reduction in spasticity. The responders were double-blinded and grouped under placebo or THC:CBD, a larger proportion of patients had significant response compared to placebo, > or = to 30% reduction of NRS score for spasticity. 47% had adverse effects including fatigue and dizziness. Reported side effects included psychiatric disturbances, 55 had cognitive (attention problems, cognitive worsening and memory problems) and psychiatric issues (confusion, panic attacks, hallucinations, depression and suicidal ideations). Fatigue, drowsiness, dizziness, gastrointestinal symptoms, mouth discomfort and allergic reactions were other reported side effects. There was no evidence of abuse or addiction in the patients. There were significant side effects deemed unrelated to Sativex including, myocardial infarct, hypertensive crisis (2).
In the original MOVE 2 trial in Italy, in the 322 patients studied, the NRS numerical rating scale decreased by -19.1% from baseline time to 3 months of treatment with Sativex. At visit 3 at 3 months, 24.6% were considered relevant responders to the medication with 30% or more reduction in spasticity. Side effects of >1% included somnolence, dizziness, and fatigue. 41 patients reported side effects 3 were serious side effects of which one was not related (3).
Sativex and studies in Germany, United Kingdom, Switzerland and Spain
Sativex was first approved in Spain and the United Kingdom in 2010 for use in spasticity related to multiple sclerosis. Data were collected to study continued efficacy and safety profiles. 941 patients (761 from the UK, 178 from Germany and 2 from Switzerland) were studied. Data was collected up until January of 2015. A patient registry was set up as per guidelines before new medications are approved. Patients from the UK were 22% of the patients registered in the UK using that medication since 2010. Continuation rates were 1 year for 68% of patients. Among those who stopped it, 30% cited lack of effectiveness and 25% described side effects. Some significant side effects include suicidality in 2% and depression in 6%. There was no evidence of abuse, addiction or misuse. The fatigue was within the known safety margins of the drug. The patients used on average 5.9 +/- 4.9 sprays per day
Sativex and timeline when it is found to be ineffective
In one large study in Italy involving 30 multiple sclerosis centers, the discontinuation profile was studied. Patient data from 30 MS centers were collected from a period of January 2014 to January 2015. 39.5% of patients disconnected treatment with Sativex. Spasticity was studied using the EDSS or expanded disability status scale and the patient NRS numerical rating scale 0-10 for spasticity. Information was collected at baseline (T0), 4 weeks (T1), 3 months (T2) and 6 months (T3).
Spasticity was noted in 1615 patients. 1597 (39.5%) discontinued treatment. Of those, 24.8% did not reach 20% effectiveness using the NRS scale. Reasons of discontinuing include lack of effectiveness 23%, side effects 16.3% and lack of compliance 0.8%, lost to follow-up 0.4%, patient choice 0.3% and unknown reasons 2%. Analysis showed that an increase in the NRS scale by 1 point at baseline time corresponded to a lower rate of discontinuation. While an increase in the NRS scale at timeline 2 or at 4 weeks corresponded with worsening spasticity and a higher non-responder rate. They concluded that Sativex is a good option for spasticity and by 4-6 weeks, patients can be reliably identified as responders or non-responders to avoid the cost burden on the healthcare system (1).
- Messina, et al, “Sativex in resistant multiple sclerosis spasticity: discontinuation study in a large population of Italian patients (SA.FE. study), Public Library of Science PLoS One, 2017, 12(8) e0180651
- Patti, et al, “Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity,” Journal of Neurology, Neurosurgery and Psychiatry, 2016, Sep., 87(9):944-951.
- Trojano, et al, “Effectiveness and tolerability of THC/CBD oromucosal spray for multiple sclerosis spasticity in Italy: first data from a large observational study,” European Neurology, 2015, 74:178-185,https://doi.org/10.1159/000441819
- Fernandez, et al, “THC:CBD in daily practice: available data from UK, Germany and Spain,”European Neurology, 2016, 75 (supp 1);1-3, https://doi.org/10.1159/000444234
Virginia Thornley, M.D., Neurologist
February 25, 2018
Stem cell research is a fast-growing arm of science. Multiple sclerosis is an autoimmune disease where the central nervous system is attacked as foreign. Clinical symptoms depend on the area involved, primarily in the white matter. Scientific research is being more and more directed towards agents and treatment modalities that differ from today’s immunomodulating agents given the potentially devastating side effects of the more efficacious medications. The heavy hitters tend to be more serious adverse effects.
How stem cell administration works
Umbilical cord mesenchymal stem cells may play a significant role in tissue repair and immunomodulatory processes that are important in multiple sclerosis. Stem cells divide into different types of cells which give rise to different tissues. They hold a wealth of potential in repairing damaged tissue as that found in multiple sclerosis. In one study, the mesenchymal stem cells from the umbilical cord were found with low immunogenicity. They can inhibit the multiplication of killer cells, T lymphocytes, and B lymphocytes and can inhibit the maturation of dendritic cells. Mesenchymal stem cells migrate to the site of injury and proliferate to repair damaged tissue.
Different stem cells that can be used in multiple sclerosis
Other types of stem cells are derived from hematopoeitic, embryonic, neural, spermatogonic, adipose, endometrial, Wharton jelly surrounding the umbilical cord and pluripotent-induced stem cells.
Stem cell administration in 2 patients and reduction of abnormal MRI abnormalities
In one study, 2 patients were treated with stem cells. Clinical symptoms were reduced in the 1st patient, they were followed 8 years and found without adverse effects. The 2nd patient progressed and the timing of stem cell administration was shortened resulting in the reduction of symptoms. The number of abnormal foci seen in the MRI of the brain was less suggesting remyelination of damaged tissue within the brain. During illness, the body increases the immunogenicity with amplification of inhibitory co-stimulatory signals. With stem cell administration, this process reduces these destructive immune processes. Umbilical cord mesenchymal cells were found to inhibit IL-17c, HLA-DRB1, and IL-2 thereby protecting against an autoimmune response. The mechanism of action by which the stem cells work favors a remyelination repairing the damaged area(1).
Stem cell research in a study of 20 patients and reduction in disability
In another larger study of 20 patients, mesenchymal stem cell neural progenitor was applied. Results showed 70% had improved muscle strength and 50% improved in bladder symptoms. Improved EDSS (Expanded Disability Status Scale) was noted in 40% of patients, there were some minor adverse effects (2).
Larger clinical randomized case control trials are needed.
- Meng, et al, “Umbilical cord mesenchymal stem cell transplantation in the treatment of multiple sclerosis,” American Journal of Translational Research, 2018, 10(1): 212-223.
- Harris, et al, “Phase I trial of intrathecal mesenchymal stem cell-derived neural progenitors in progressive multiple sclerosis,” EBioMedicine, 2018, Feb., pii.S2352-3964 (18)30051-3 (Epub ahead of print)