multiple sclerosis

Review of literature:  stem cell therapy in multiple sclerosis

Virginia Thornley, M.D., Neurologist, Epileptologist
October 8, 2018
 
Introduction
Stem cell therapy is explored for certain types of cancer such as bone marrow cancer. Its therapeutic options have been experimentally being expanded to other disease such as multiple sclerosis. This seeks to review some of the literature on current research for stem cell therapy in multiple sclerosis. As yet, there are still ongoing research and experiments and is not yet  approved by the FDA as treatment for multiple sclerosis. This seeks to review mechanisms, small studies and experimental studies in multiple sclerosis.
Some mechanisms through which stem cell therapy may help
Natural killer cells are thought to attenuate Th17 cells which are pro-inflammatory after autologous hematopoietic stem cell treatment. It may not have effect on the Th1 cell but it seems to reduce the number of Th17 cells (1).
Comparing Wharton Jelly mesenchymal cell with bone marrow mesenchymal stem cell
One study shows that Wharton Jelly mesenchymal stem cell may be comparable to the gold standard bone marrow stem cell and may be more easily extracted. There is a different gene phenotype and are found to overexpress genes that impact neurotrophic support making it a great candidate for stem cell source in neurodegenerative diseases such as amyotrophic lateral sclerosis or Parkinson’s disease. It was found to cause greater neuronal maturation in neuroblastoma cells compared to bone marrow mesenchymal cells. Genes that influenced adhesion, proliferation and the immune system were found to be greater expressed in Wharton jelly mesenchymal stem cell (2).
 
aHSCT in fatigue
In one small study in 23 patients the use of autologous human stem cell treatment helped with symptoms of fatigue using the FIS or the fatigue impact scale (1). The median score in FIS was reduced by 36% with 4 patients with a complete reduction. Some even had gainful employment and returned to driving, measured with the EDSS or expanded disability status scale(3).
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A pilot study shows mesenchymal stem cell injection slows progression
In a pilot study of 4 patients, 3 had secondary progressive type while 1 was in the relapsing-remitting stage. Autologous bone marrow stem cells were injected and patients were followed for 2 years. Those with secondary progressive type stabilized with no further deterioration while the patient with relapsing remitting type had an attack. None of the MRI tests showed any new plaques or abnormalities(4).
Mesenchymal stem cell treatment is thought to be helpful as a neuroprogenitor and slows the neurodegeneration where standard medications may be ineffective (5).
Hematopoietic cell transplant  for relapsing-remitting multiple sclerosis
In one study of 25 patients looking at high dose immunotherapy and autologous hematopoietic stem cell therapy, peripheral blood stem cell grafts were CD34+ chosen. Immunosuppression was given beforehand. It was found to reduce relapses over a course of 3 years in patients with relapsing-remitting multiple sclerosis without serious adverse effects(6).
In summary
There is growing interest in stem cell therapy as a novel treatment in multiple sclerosis.  Research has shown that Wharton’s jelly from the umbilical cord may have features making it a better therapeutic alternative compared to bone marrow mesenchymal stem cells. So far, small studies have shown promise. Larger human trials are needed.
Reference
    1. 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
    2. 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
    3. 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)
    4. 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
    5. 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
    6. 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.

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multiple sclerosis

Ketogenic diet: can it play a role in treating symptoms of Multiple sclerosis?

Virginia Thornley, M.D., Neurologist, Epileptologist
September 19, 2018
@VThornleyMD
Introduction
Multiple sclerosis has no cure at this current moment. It is unclear what is the exact etiology otherwise there would be a cure. Based on research, genetic and environmental factors play a role. Based on MRI observations, there are inflammatory and degenerative components to the pathogenesis.
 
What is the ketogenic diet and how does it pertain the brain
The ketogenic diet was initially found to be effective in treatment of medically refractory seizures. But the underlying concept might be applied to other diseases as well.
Instead glucose as the energy substrate, ketones are utilized, If the supply of glucose is reduced, the energy source is shifted towards the beta-oxidation of fatty acids into ketone bodies. These ketones become the new source of energy and allows increased ATP formation which is the source of energy in the mitochondria, which is the powerhouse of the cell where energy is formed.
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Different lines of thinking regarding pathogenesis of Multiple Sclerosis
There are lines of thought that Multiple sclerosis can be inflammatory versus neurodegenerative. Because of this many agents are directed towards the autoimmune component of the disease process. It is commonly thought that the autoimmune process results in the neurodegeneration seen on MRI.
As evidenced by the “black holes” seen on MRI after acute attacks, there is evidence there is a neurodegenerative aspect. This other line of thinking suggests that it is a degenerative process that triggers the inflammatory response.
It’s been found  that degenerating axons have abnormal mitochondria.
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Ketogenic diet and inflammation
In one animal study, it was found that the ketogenic diet reduced inflammatory cytokines after 14 days in animals (2).
 
Ketogenic diet and increased ATP
In one animal model with a control group and a group on ketogenic diet, after 3 weeks it was found that those on the ketogenic diet had a higher ATP/ADP ratio which is speculated to contribute towards neuronal stability.

How can the ketogenic diet help with Multiple Sclerosis?
The ketogenic diet reduces the formation of reactive oxygen species. It preserves ATP production when the mitochondria fails. The thought is that the axons start to degenerate once the mitochondria are dysfunctional (1).
In summary
There are no human clinical studies on ketogenic diet and the improvement of multiple sclerosis. Based on pre-clinical studies, there is indication that ketogenic diet may help improve the ATP stores when the mitochondria becomes dysfunctional which may potentially slow neurodegeneration of axons.
The ketogenic diet might reduce inflammation which is thought to be triggered by a neurodegenerative process in Multiple Sclerosis. However, more studies are needed especially human clinical trials. Currently there is not enough evidence to support this based on the available studies as pre-clinical studies do not always correlate in human trials. More studies are needed.

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Reference
  1. 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
  2. Dupuis, N., Curatolo, N., Benoist, J.F., Auvin, S., Ketogenic diet exhibits anti-inflammatory properties. Epilepsia, 2015. 56(7):e95-98
  3. 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
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multiple sclerosis

Review of literature: can the Wahls diet (modified Paleolithic diet) and low saturated fat Swank diet have any effect on multiple sclerosis?

Virginia Thornley, M.D., Neurologist, Epileptologist

September 17, 2018

@VThornleyMD

Introduction

Patients are seeking complementary treatments aside from conventional agents. Agree with it or not, if doctors do not listen to their patients they will seek it elsewhere so it is good to be up to date on the review of literature. While alternative treatments are commonly lacking in evidence based medicine it does not necessarily have to work in opposition with conventional agents. There are studies by Mauskop, (1) a headache specialist who found that 50% of migraineurs are magnesium deficient and magnesium can be a effective preventative agent in selected patients. Instead of being instantly dismissive, review of the literature should be sought to have an evidence-based understanding from a scientific level.

What is the modified Paleolithic diet?

In the modified Paleolithic diet, there is stress on meat, fruit and vegetables, excluding legumes, dairy and grains (2). Night shade vegetables such as tomatoes and eggplants are excluded.

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What is the Swank diet?

Dr. Roy Swank from Norway hypothesized that a diet rich in saturated fat likely caused a faster progression of the disease state in multiple sclerosis relapsing-remitting type. He followed 144 patients for 34 years. The patients consumed less than 20g of saturated fat in their diet and followed. It was observed that the relapses and progression correlated with the amount of saturated fat that was consumed. The greatest benefits were seen in those with mild symptoms at the start of the study. The patients were followed 50 years, however, there were no case controls patients for comparision (3).

Review of literature of the Wahl’s diet on Multiple sclerosis

One study focusing mainly on the dietary component seeks to understand an effect using the randomized controlled clinical trial method. The study is ongoing (2). It seeks to study the anecdotal information that diet low in saturated fat may lessen  the debilitating symptom of fatigue in patients with multiple sclerosis. While there have been anecdotal data, many patients have been found to drop out of the control group because of poor tolerability making results unreliable (2). In addition, the studies available provide a multi-prong approach including factors of stress reduction, exercise and muscle stimulation.

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Multimodal approach: exercise, stress reduction, meditation, massage and diet

One small study of 20 patients demonstrated some benefits of modifying diet, reducing stress and stimulating muscles in relation to multiple sclerosis symptoms.  They found that patients who presented with mild symptoms of progressive multiple sclerosis received some benefit to a multi-prong approach with regard to gait improvement compared to those who were more advanced in their disorder (4).

In summary

To summarize, at present there is insufficient data to support the Wahl’s diet as an effective treatment option based on the available current studies.  However, having said that there has been some anecdotal and very small studies indicating benefits in multiple sclerosis. Randomized controlled clinical trials which are the gold standard in research are ongoing which will be shed more light on its effectiveness.

In the meantime, while there are no completed large randomized controlled clinical trials, these types of diets and modalities are complementary with the current treatment and would do no harm. However, until large randomized controlled clinical trials are completed, it is difficult to ascertain if they are indeed effective and recommend it advocating it as effective.

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Reference

  1. Mauskop, et al, All migraine patients should be treated with magnesium. Journ. Neural Trans. 2012, May, 119(5):575-579
  2. Wahls, T., Scott, M.O., Alshare, Z., Rubenstein, L. Darling, W., Carr, L., Smith, Chenard, C.A., LaRocca, N., Snetselaar. Dietary appraoches to treat MS-related fatigue: comparing the modified Paleolithic (Wahls elimination) and low saturated fat (Swank) diets on perceived fatigue in persons with relapsing-remitting multiple sclerosis: a study protocol for randomized controlled trial. Trial. 2018, Jun. 4, 19(1):309
  3. Swank, R.L., Duggan, B.B., Effect of low saturated fat diet in early and late cases of multiple ssclerosis. Lancet, 1990, Jul., 7, 336 (8706)
  4. Bisht, B., Darling, W., White, E.C., White, K.A., Shivapour, E.T., Zimmerman, M.B., Wahls, T. Effects of a multimodal intervention on gait and balance of subjects with multiple sclerosis: a prospective longitudinal pilot study. Degen. Neurol. Neuromuscul Dis. 2017, Jun. 26, 7:79-93

 

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Medical Practice

Understanding the practical aspects of cannabidiol (CBD) and tetrahydrocannabinol (THC)

 

Virginia Thornley, M.D., Board-certified Neurologist, Epileptologist

@VThornleyMD

July 15, 2018

Introduction 

This serves as medical information for educational purposes only not medical advice. Please consult with your treating  physician.

In contrast to the rest of the blog which is more scientific, this gives more practical information in the day to day workings of recommending medical cannabis. It gives the behind the scenes processes that happens before a patient can even begin to start their medical product. It is not a magic pill but because it is unlawful in Florida, a physician cannot even write it on a prescription pad. It takes one hour or more to evaluate, counsel and go over the registration process when presenting for the first time to a doctor.

For more detailed information and scientific references for specific indications please refer to
https://neurologybuzz.com/

Medical cannabis is one of the most misunderstood and controversial medications in the world. Long suppressed for over a century, it is one of the most misunderstood medications known to mankind despite being used for thousands of years with medical intent.

This is to give a brief basic background of mechanisms, rationale for ratios, combinations, pitfalls of isolates and synthetics and legal implications.

Background

The endocannabinoid system is found naturally in our body. It is responsible for the runner’s high people get. It gives a sense of wellbeing, not endorphins like most people think, those molecules are too large to pass the blood-brain-barrier. There are 2 receptors:(1) the CB1 receptor found mostly in the nervous system and (2) the CB2 receptor which is more abundantly found in the immune system. Anandamide works on the CB1 receptor, tetrahydrocannabinol (THC) is similar to this and works on the CB1 receptor. CBD or cannabidiol is from the cannabis sativa plant and is also a phytocannabinoid. One needs 100 times the CBD to get the euphoria as THC. CBD is not intoxicating, legal and works on a wide variety of symptoms including pain, seizures and anxiety. CBD is similar to 2-arachidonoyl glycerol which is a natural cannabinoid. When the 2 are combined together, CBD will offset side effects of THC including paranoia, hyperactivity and agitation. This is a not known fact to those who self-medicate with pure THC.   Because of this THC is medically recommended in conjunction with CBD. Smoking is illegal and not medically recommended as most people think. https://neurologybuzz.com/2018/04/02/medical-marijuana-vlog-series-part-i-mechanisms-medical-benefits-of-non-intoxicating-cannabidiol-and-tetrahydrocannabinol/

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Pitfalls of self-medication

Sometimes patients self-medicate and smoke pure THC from dubious sources to alleviate symptoms, which is illegal and not medically recommended in Florida.  However, the intoxicating effects are not seen when recommended medically using oral forms, cream or patch. At low doses, as is done when recommended medically, THC is non-euphoric. When THC is combined with CBD the side effects of THC are offset. The dangers of patients who self-medicate is that they do not know where the products are coming from and it can be mixed with potentially dangerous substances that can be potentially fatal. In addition, there are highly potent synthetic illegal cannabinoids known as K2 and spice which at high doses can cause cardiotoxicity and fatalities. Self-medicating with THC from an unknown source is highly discouraged as there may be mold involved with the processing. https://neurologybuzz.com/2018/05/31/the-fatal-effects-and-mechanisms-of-synthetic-cannabinoids-including-jwh-compounds-used-recreationally/

Why is a CBD and THC combination important?

In regulated licensed dispensaries, CBD is combined to offset the side effects of THC allowing better tolerance. THC is not recommended by itself because of side effects including paranoia, agitation and hyperactivity.

CBD by itself

With pure CBD, there are certain medical symptoms that are alleviated.

It is legal. There are many companies with CBD products but it is difficult to know how pure these products are, even if you have a small amount of hemp it can be marketed as CBD hence, its ineffectiveness. Some of the most effective CBD products can be found from Colorado and California, anecdotally. Everything else is hit or miss.

In the state of Florida, there are very few medically beneficial CBD products, it’s trial and error. The purer the form such as full spectrum CBD oil the more expensive it will be because processing organic products are costly. A cheap product will likely not be as pure just because of the huge amount of work that goes into extracting the cannabidiol. In addition, some may have flavors, cutting agents and other agents to dilute it but because it’s unregulated.

Ratios

CBD alone has no psychoactivity but medical value. CBD is combined with THC in order to offset its side effects of paranoia, agitation and hyperactivity.

Time of onset and duration

There are different ways of trying it: vaporizer lasts 1 hour and takes about 10 minutes to get into your system. Because the vaporizer is inhaled into the lungs the onset is the fastest because of the rich supply of blood vessels in the lungs. It is advisable to try the vaporizer at home or at night before setting out to see how it affects you. Oral forms last 6 to 7 hours and takes about 1/2 hour to get into your system. Oral form comes in oil concentrate and tincture. Cream and patch last about 12 hours or longer depending on the preparation. Medical marijuana is NOT recommended by physicians to be smoked. Recreational marijuana by smoking is prohibited and unlawful in Florida. This law varies by state. When different parts of the plant are taken together including the terpenes it gives an entourage effect which is more medically valuable than when components are isolated for its use.https://youtu.be/Ir4rwgF2iNc

Are there any edibles in Florida?

As of July 2018, there are no edibles in the state of Florida. It will take an enormous amount of submitting documentation and providing capital before edibles will be implemented in Florida. The dispensaries are working on this.

Registration process: what to expect in Florida

The process includes an evaluation by a qualified licensed physician. https://neurologybuzz.com/2018/07/12/legalities-and-application-process-in-the-state-of-florida/A qualified physician undergoes a 2-hour course and holds a full medical license in the state of Florida. One is evaluated and if patient meets the stringent criteria, they obtain a registry number. The patient undergoes registration which takes between 2-4 weeks. An e-mail arrives before the card then one is instructed to call the office so that recommendations are placed in the system. Oftentimes, if you don’t hear back in 4 weeks it is advisable to give the registry a call. It may be a misentering of an e-mail causing a delay.

Regulated dispensaries in the Florida

In Florida, there are 13 medical marijuana treatment centers and 43 retail dispensaries as of July 2018. In the state of Florida, patients can only obtain the Cannabis products recommended from their treating physicians from these dispensaries. It is illegal to smoke. There are 4 ways of taking it: oral, vaporizer, cream and patch. It is advisable to visit one of the licensed dispensaries in person so that the exact instructions can be given. Physicians recommend orders which are entered into the system. So long as the product is within the number of mg dispensed and the way it is recommended (oral, vaporizer, cream or patch) patients are at the liberty to change the ratio or dosage so long as it is within the orders.

Once you are registered

An e-mail with the marijuana card number comes before the physical card. It is advisable to call the physician office so the orders are placed then physically visit the dispensary of your choice so specific instructions can be taken. Because this is not a pharmacy, doctors do not have immediate access to the dispensary. One should be aware of which product they are taking before their next checkup. This can be easily accessed through the website of the dispensary.

The orders will expire after 70 days after which there is a processing fee of renewal at the office. The certification for medical marijuana expires after 1 year. One must be re-evaluated by their physician before then.

CBD is purely cannabidiol, it is non-psychoactive and legal. THC at low doses is non-intoxicating. Dispensaries combine CBD and THC to offset side effects.  It is federally illegal. It is advisable to be registered under a medical doctor who is qualified to determine if one meets criteria. Medical cannabis products can only be dispensed from a regulated licensed dispensary. Medical marijuana products outside of the jurisdiction of Florida regulates licensed dispensaries cannot be advocated.

Legal implications of THC

In some states, such as Florida, medical use of cannabis is recognized. THC is still considered federally illegal. Recreational use of cannabis is illegal. Smoking THC is illegal. Physicians cannot prescribe it since it is a schedule 1 drug but can recommend it. Schedule 1 drugs are considered illicit and labeled as having no medical use. A statement before the qualifying course on medical cannabis states that the physician can be questioned at any time by the FBI and authorities.

In other states, medical and recreational use is allowed.

In other states, medical and recreational use is completely banned.

The law also varies regarding cultivation of the cannabis sativa plant.

Countries will vary in their marijuana laws.

The laws change very rapidly. Regulations are changed nearly every month with more documentation required from physician offices including consent, doctors’ notes, patient information with indication. As each month goes by another new document is required for submission from the physician office. There is increasing bureaucracy likely signifying resistance at some upper levels against its use related to economic and political reasons. Dispensaries have an equally challenging time. Even worse are small farms applying for licenses huge amounts of capital and documents are required.

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Legal implications of CBD

CBD is legal throughout the US. Countries may vary in their laws since they both come from the cannabis sativa plant.

FDA approved medications and products approved in Europe with CBD and THC

A medication called Epidiolex for seizures with CBD has recently been approved for seizures. Because it comes from a strain from the cannabis sativa plant, cannabis will need to be deregulated from the schedule I category before Epidiolex can be marketed to the public.

Dronabinol has long been approved for nausea and can only prescribed for patients with cancer with chemotherapy induced nausea. It is a synthetic THC and is FDA approved.

In Europe, the medication Sativex which is a combination of CBD:THC has long been used for spasms in multiple sclerosis. This is not available in the US.

In summary

For patients, it is beneficial to have a working understanding of the different strains, different forms that are available in order to obtain the best benefit.  Dispensaries have a huge breadth of products. It is easier to understand as much as possible before facing the overwhelming number of options. Patients must understand all the legal implications in your state as they change rapidly. It is not only a medication it is affected by state and federal laws that change in a blink of an eye which can affect the patient if they are not aware.  One must be mindful that there are different types of practices recommending medical cannabis. The best practices are those that are an already established practice which added medical marijuana to their repertory. Practices that are solely for medical marijuana may be of dubious quality. There are already horror stories of patients never getting a card after several months and phone calls not being advisef on what to do, being examined in a conference hall. As with any new innovative service, there will be legitimate practices and there will be those who meet the minimum requirement of care and service. http://www.tampabay.com/investigations/2018/05/04/floridas-medical-marijuana-program-is-attracting-troubled-doctors-its-like-the-wild-wild-west/

For doctors recommending, one must be well-versed in understanding the potential side effects, drug interactions, the latest scientific research since these are the only guidelines that are guiding us from a scientific level. Pre-clinical studies cannot be ignored nor studies on synthetics to have a better grasp of understanding how it works. One must have a basic understanding in the effects of the phytocannabinoids which is best taken in combination and not in isolation. Patients come with complex medical problems it is always prudent to do due diligence in understanding as much as possible before recommending a product that was never studied for medical purposes in medical school. Patients will ask tough questions, physicians should understand as much as possible and do their due diligence being up to date on legislations as well as the most recent research. The hard questions will come.

One must also follow the legal implications, current regulations which are frequently updated. It is the physician’s responsibility to understand the mechanisms, be current on the literature because this is a pioneering science. Those recommending right now are trailblazing and should still be mindful of the great role you play in understanding what literature is available and to read voraciously.

Last thoughts

While much is still unknown about CBD, THC and mechanisms, there is great anecdotal data from history and clinical anecdotal experience supporting its benefits. While many traditionally trained physicians scoff at the prospect of introducing alternative treatments, one must bear in mind cannabis was not an alternative medication before it was banned in 1830.

While scientists are working overtime in elucidating the mechanisms to combat diseases such as cancer, one must bear in mind that medical cannabis is beneficial when taken in combination with other terpenes found in the plant and the components are not isolated from each other. THC works best in combination with CBD and with other components from the cannabis sativa plant.

When components are isolated from each other and products become synthetic and manufactured much of the benefits are lost and significant side effects result. https://neurologybuzz.com/2018/05/31/the-fatal-effects-and-mechanisms-of-synthetic-cannabinoids-including-jwh-compounds-used-recreationally/

Once it becomes synthetic and components are isolated, the benefits will be substantially altered.

Now is a optimal time to try the benefits of medical cannabis while it is still all organic and being produced on farms and regulated for its use, unsullied by synthetic forms where the risk of side effects are greater.

While much is still to be learned, for a medicine that can easily cover 5 symptoms in one setting, it is an extraordinary time to be recommending and benefiting from medical cannabis while it is still organically natural and pure.

 

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fibromyalgia

Medical marijuana in fibromyalgia: molecular mechanisms and small randomized controlled trials

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

June 17, 2018

Introduction

Fibromyalgia used to be  a condition denoting excessive pain and was previously questionable as there was no testing that could prove or disprove it. Now, the current thought is that it is attributed to hypersensitivity of the nervous system to pain impulses resulting in multiple points of pain in the body.

Endocannabinoid system in pain modulation

The endocannabinoid system is a major chemical neurotransmitter system that has only come to light as to physiology in the last 20 years. The CB1 receptor is found predominantly in the nervous system on which the endogenous endocannabinoid anandamide exerts its effects. The CB2 receptor is found mostly in the immune system on which 2-Arachidonoylglycerol acts. In the nervous system, cannabinoid receptors are seen in the periaqueductal gray area, ventromedial medulla and dorsal horn of the spinal cord which are areas where pain transmission takes place. This suggests that endocannabinoids play a major role in modulation of pain and can impact pain control through manipulation of this system.

Anandamide and and 2-Arachidonoylglycerol are synthesized on demand. It is released immediately after production. 2-AG is formed from a 2 step process. Anandamide has a low affinity to the TPRV1 receptor (2).

1,2-diacylglycerol (DAG) is  a precursor or 2-AG which is formed by hydrolysis of membrane phosphoinositides. DAG is hydrolyzed by 2-AG hydrolase to form 2-AG. 2-AG may be stimulated by activation of G protein receptor such as glutamate receptors. It activates both CB1 and CB2 receptors. Cannabidiol which is found in the cannabis sativa plant is a natural mimetic of 2-AG. Endogenous 2-AG is found 170 times more than Anandamide in the brain. Exogenous 2-AG suppresses nociceptive stimulus (2). 2-AG activity is potentiated with natural 2-acylglycerols which enhances the effects which does not happen when used alone. This is an entourage effect found in the brain where the combination of substances give a combined resulting effect which does not occur if used alone (2).

Mechanisms in pain modulation

Cannabinoids were found to reduce nociceptive transmission at the level of the pain c-fiber responses in the spinal dorsal horn.

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Randomized controlled trial in fibromyalgia

In one study of 40 patients in a randomized controlled clinical trial, nabilone which is a synthetic cannabinoid was given over a 4 week period. Measures that were evaluated included the visual analog scale for primary outcome and for secondary outcome measure, tender points, secondary outcome measure, Fibromyalgia Impact Questionnaire (FIQ) at weeks 2 and 4 were used. There was statistical difference in treated vs. control groups for pain (P value< 0.02), anxiety (P<0.02 and FIQ (P<0.02). There were more side effects for the treated cohort compared tot he placebo controlled group. This study demonstrates that cannabinoids may be an effective treatment for fibromyalgia (1).

In one paper that reviewed 18 randomized controlled clinical trials of cannabinoids in chronic pain syndromes including fibromyalgia, cannabinoids were found to be an effective type of treatment. Despite the short duration of the trials, pain relief was effective and mild to moderate adverse effects were noted. Larger clinical trials are needed (2).

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  1. Skrabek, et al, “Nabilone for the treatment of pain in fibromyalgia,” J. Pain, 2008, Feb., (9)2:164:173
  2. Lynch, et al, “Cannabinoids for treatment of chronic non-cancer pain: a systemic review of randomized trials,” Br. J. Pharmacology, 2011, Nov., 72(5):735-744
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Tourette's Syndrome

Medical cannabis in Tourette’s syndrome: case reports and a small randomized controlled clinical trial

Virginia Thornley, M.D., Neurologist, Epileptologist
June 11, 2018

@VThornleyMD

Introduction
When one hears Tourette’s syndrome the glorified Hollywood impression young person who shouts obscenities comes to mind. It is composed of complex motor or vocal tics generally preceded by a premonitory urge. Vocal tics may consist of coprolalia and echolalia. Motor tics may involve complex actions including copropraxia or simple motor tics. Obsessive compulsive disorder and other neuropsychiatric conditions are often associated with it.

The underlying problem is thought to be related to an imbalance of the neurotransmitters necessary to maintain the fine coordination necessary to avoid excessive motor activity. When that balance is impaired there is less inhibition of motor loop control resulting in reverberating loops and excess movements involving motor groups including muscles controlling speech and body movements. Because the pathophysiology is not entirely clear, these may be some of the most challenging neurological disorders in terms of treatments from a neurological standpoint.

Background on Cannabinoid Mechanisms
With the advent of medical cannabis used in neurological conditions, new indications are discovered. The mechanism is at the level of the endocannabinoid system already inherent within the system. There are 2 receptors, CB1 and CB2. The CB1 receptor is found mostly within the nervous system. The CB2 receptor is mostly in the immune system but is found in other organ systems to a lesser extent. Tetrahydrocannabinol (THC) is a mimetic of Anandamide which works within the endocannabinoid system and has medical properties. THC interacts with the CB1 receptor which is responsible for psychoactive properties most people are familiar with. It is likely at the CB1 receptor where other neurological symptoms are alleviated since this most abundantly found in the nervous system and many neurological symptoms are ameliorated with medical cannabis. Cannabidiol (CBD), which is non-psychoactive, is a pharmacomimetic of 2-AG or diarachidonylglycerol. It is an non-competitive allosteric modulator of the CB1 receptor which alleviates any side effects from THC when they are combined together (1).

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Clinical Reports
There is one report of a patient treated with nabiximol where there was improvement of tics. There was overall improvement in quality of life and global improvement. There was lessening of premonitory urges. Patients feel the premonitory symptoms are more bothersome. In one study anti-psychotics helped ameliorate the motor tics but did not improve the premonitory symptoms (2). Nabiximol was used in this study where 1 puff contained 2.7mg of THC and 2.5mg of CBD. Assessments included the Yale Global Tic Severity Scale (YGTSS), Tourette’s Syndrome Symptom LIst (TSSL), Modified Rush Video Tic Scale, Premonitory Urge for Tic Scale, Global Clinical Impairment, Visual Analogue Scale for satisfaction for the GTS-Quality of Life. The study showed the best results in the quality of life in terms of alleviating premonitory urges. Larger clinical trials are needed to further this study (2).

In a recent case report, THC (trademark Sativex) was used with success to treat a patient using 10.8mg THC and 10mg CBD daily. Yale Global Tic Severity Scale (YGTSS) and the Original Rush Video Tic Scale were used as measures of evaluation. The results demonstrated effective use of THC in combination with THC for treatment in medically refractory patients (5).

In one single dose, cross over study in 12 patients and a randomized trial in 24 patients spanning 6 weeks was performed (3). The study demonstrated that THC reduces tics without any disruption in cognitive function. Neuropsychological impairment was not seen (3).

In the randomized double blinded placebo-controlled clinical trial of 24 patients, THC of up to 10mg was used in the treated cohort over 6 weeks. Measures used included the Tourette’s Syndrome Clinical Global Impression Scale (TS-CGI), Shapiro Tourette Syndrome Severity Scale (STSS), the Yale Global Tic Severity Scale (YGTSS), Tourette Syndrome Symptom List (TSSL) and the videotape based rating scale. Patients were rated at visits 1 for baseline, visits 3-4 during treatment and visits 5-6 after withdrawal. There was a significant difference between both groups. There was a significant reduction in motor tics, vocal tics and obsessive compulsive disorder. No significant adverse cognitive effects were noted (4).

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More randomized controlled clinical studies are necessary
While there may be a paucity of large clinical trials of the use of medical cannabis in Tourette’s syndrome, tetrahydrocannabinol is a potential therapeutic agent in a neurological disorder where treatment options are very limited and often times unsuccessful. Adverse side effects can preclude treatment using conventional pharmaceutic agents.

While large randomized controlled clinical trials are necessary in providing standard of care, tetrahydrocannabinol has emerged as a potential treatment option used by clinicians who are on the frontlines of treating this debilitating disorder.

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Introduction/Disclaimer

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Reference
1. Laprairie, et al, “Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor,” Br. J. Pharmacology, 2015, Oct., 172(20):4790-4805
2. Kanaan, et al, “Significant tic reduction in an otherwise treatment-resistant patient with Gilles de la Tourette syndrome following treatment with nabiximol,: Brain Science, 2017, Apr., 7 (5):47
3. Muller-Vahl,”Cannabinoids reduce symptoms of Tourette’s syndrome,” Expert Opin Pharmacother., 2003, Oct., 4(10):17-1725
4. Muller-Vahl, “Delta-9-Tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6 week randomized trial,” J. Clin Psychiatry, 2003, Apr., 64 (4):459-65
5. Trainor, “Severe motor and vocal tics controlled with Sativex®,” Australas Psychiatry, 2016, Dec, 24 (6):541-544

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stem cell

Mesenchymal stem cell therapy: a viable non-surgical option in lower back pain treatment

Virginia Thornley, M.D., Neurologist, Epileptologist

June 9, 2018

Introduction

Back pain is one of the most common pain disorders encountered by neurologists, neurosurgeons, orthopedic surgeons and pain specialists in the out-patient setting. It is not uncommon for patients to go through an extensive list of medications, steroid injections, physical therapy and even surgery and still remain in unrelenting pain. There is a growing interest in alternative treatments especially with the opioid crisis looming and restriction of strong pain medications. This seeks to review scientific mechanisms behind the success in stem cell treatment. It recaps clinical data. Despite a scarcity of published huge randomized clinical trials, there is a growing and clamoring need for alternative treatments such as stem cell therapy for patients desperately trying to find alleviation from their pain. Trailblazing physicians are using this treatment option in real life practice with growing results.
Back pain is a very common disorder which is especially prevalent in the elderly after wear and tear of long-term activity in conjunction with the natural degenerative changes that come with the aging process. Normally the intervertebral disc complex can withstand compression and shear forces because of the proteoglycans that bind water molecules. This becomes lost with aging. In degenerative disc disease, there are pro-inflammatory molecules.

Pathogenesis of degenerative disc disease
Within the nucleus pulposus, there is no vascular supply except at the end neural plate, has no nerves and is prone to damage. The nucleus pulposus relies on glycolysis for effective disposal of waste products through the endplates. After decades, the nucleus pulposus no longer has notochordal features and is replaced by small chondrocyte like cells. There is replacement of the collagen type 1 and collagen type 2 loss eventually replaced with fibrocartilaginous material. Eventually with time, the endplates have calcification of the small pores where molecules diffuse (1).

 

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There are anabolic processes involved as well as catabolic processes including involvement of enzymes, inflammatory mediators, proteinases, aggrecanases. Examples include IL-1 and TNF-alpha. because the disc is avascular this creates an environement of poor regenerative responses with harsh conditions (3).

Some patients may have a genetic predisposition to have flawed extracellular matrix where degenerative disc disease may occur more severely than in other people. Cleavage of proteoglycan can occur with enzymes resulting in loss of height and less ability to reduce compressive and shearing forces. In addition, environmental factors including occupational activities, excessive physical activity impacting the spine may contribute towards degenerative disc disease (1).

Alternative treatment: stem cell therapy
In order to address these issues, various treatments have arisen to try to try to halt the cascade leading to degenerative disc disease. This includes implantation of biomolecules to reduce the catabolic process.

 

 

Stem cell research is gaining more traction as a viable alternative for treatment of this debilitating condition. One study looked at the potential of nucleus pulposus-like cells derived from mesenchymal cells in the rabbit model. From these cells, SOX9, ACAN, COL2, FOXF1, and KRT19 genes were expressed(2). Transplanted nucleus pulposus cells were integrated into the intervertebral disc complex. Improved water content, glycosaminoglycan, and cellularity within the complex was noted. There was a suggestion of biosynthesis with the gene expression of SOX9, ACAn, COL4 (2). This animal study demonstrates that there may be value in nucleus pulposus cells derived from mesenchymal cells may lead to clinical studies where stem cells can be used for back pain.

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Injection of mesenchymal stem cells
Injections of mesenchymal stems cells into the disc may reduce the clinical pain and restore disc tissue loss. It may be able to reduce the catabolic microenvirnment (3)

Clinical studies of stem cell use in humans
It appears that stems cells of mesenchymal type derived from adipose or the umbilicus may have the most promise (4).

In one small study of 10 patients, autologous bone marrow mesenchymal cells were were injected in the nucleosus pulposus and followed for a year. After 3 months, there was improvement of pain and disability of 85% of the maximum. After 12 months, there was still high water content within the nucleosus pulposus (5).

Stem cell effects were studied in 2 patients with back pain and leg numbness. Marrow fluid was obtained autologously from the ilium from each patient. Mesenchymal stem cells were cultured in autogenous serum. Fenestration was performed and collagen sponge was applied percutaneously to the affected intervertebral disc complex. After 2 years, the T2 signal was high showing increased disc content in the grafted discs. Clinical symptoms were ameliorated (6).

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Clinical trials
In an open label trial of 26 patients, using the VAS and Oswestbry disability scale, there was reduced pain after percutaneous injection of bone marrow cell concentrate showing autologous mesenchymal stem cells are a viable alternative treatment for back pain (7). They studied the patients through 12 months. Those who received >2000 colony forming fibroblast units/ml had faster and greater pain reduction.

There is one small randomized controlled clinical trial in 24 patients using the Pfirrmann grading scale for degeneration, allogeneic mesenchymal cells were transferred to the clinical cohort. Significant relief of pain was noted compared to the sham group demonstrating that allogeneic transfer may be logistically better than autogenous transfer (8).

 

Possible adverse effects
Concerns include transformation into neoplastic process. This seems to be true with embryonic stem cells which are much earlier seen in the cell lineage. Mesenchymal cells are further down the line as a committed cell type to obviate this. With in vitro culturing, there is concern for cell mutations, but this is less of a concern if it is a same day procedure, autologous and exist as when they were in the body previously. There is concern for extravasation beyond the limit of the disc and if combined with other treatments such as PRP it may promote osteogenesis. In addition, animal models may not replicate the harsh microenvironments of disc pathology where continual torsion and pressure is involved and effects and outcomes might be different (3).

In summary
There is much scientific and animal model data that stem cells remain a viable option for treatment of back pain which is one of the most common problem encountered by neurologists, neurosurgeons, orthopedic surgeons and pain management specialists. While there is much demonstrated in animal studies, clinical trials are still very sparse. This treatment, however, shows promise and despite paucity of clinical trial data, this treatment is gaining traction in practicing clinicians who treat back pain.

Given the failure with medications and even with surgery there is increased interest in alternative treatments including stem cell therapy.

Introduction/Disclaimer

Introduction/Disclaimer

References

1. Rosenberg, et al, “Bedside to bench and back to bedside: translational implications of targeted intervertebral disc therapeutics,” J. Orthop. Translat., 2017, Apr., 10:18-27.
2. Perez-Cruet, et al, “Potential of human nucleus pulposus-like cells derived from umbilical cord to treat degenerative disc disease,” Neurosurgery, 2018, Feb., doi:10.1093/neuros/nyy012
3. Zeckser, et al, “Multipotent stem cell treatment for discogenic low back pain and disc degeneration,” Stem Cell Int., 2016, doi: 10.1155/2016/3908389
4. Knezevic, et al, “Treatment of chronic low back pain – new approaches on the horizon,” J. Pain Res., 2017, May 10, 10:1111-1123
5. Orozco, et al, “Intervertebral dis repair by autologous mesenchymal bone marrow cells: a pilot study,” Transplantation, 2011, Oct., 15, 92 (7):822-8
6. Yoshikawa, et al, “Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of 2 cases,” Spine, 2010, May 15, 35 (11):E475-80
7. Pettiness, et al, “Percutaneous bone cell concentrate reduces discigenic lumbar pain through 12 months,” Stem Cell, 2015, 33(1):146-156
8. Noriega, et al, “Intervertebral disc repair by allogeneic mesenchymal bone marrow cells,” Transplantation, Aug., 2017, 101(8):1945-1951.

 

 

 

 

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