Bridgepoint Neurology


What is Multiple Sclerosis?





Multiple Sclerosis is a disease of the brain and spinal cord, and can have a great variety of neurological manifesetations, depending on which area of the brain or spinal cord is affected. The disease is caused by a dysfunction of the body's immune system, which normally fights off and eliminates different infectious and foreign substances. However, in multiple sclerosis, the immune system makes a mistake and attacks the brain and spinal cord as if they were a foreign virus or bacteria. Medical sciences does not knows exactly why this happens, or how to prevent it from happening.


Multiple sclerosis has several forms, and the most common form is one in which people with the disease have relapses, or attacks of the disease, which then improve over time. This form is called relapsing-remitting multiple sclerosis. These relapses evolve over hours to days, and can entail varied manifestations, such as loss of vision in one eye, lack of coordination on one side of the body, tingling and weakness of one part of the body, difficulty walking, or even difficulty talking.


Because multiple sclerosis is due to dysfunctional over activity of the immune system, we can treat these attacks with medications that acutely suppress the immune system, most commonly cortico-steroids.


These attacks or relapses can also be prevented, to a significant extent at least, by taking medications on a regular basis that modulate or suppress the immune system. Some of these medications also reduce the accumulation of long term disability or permanent neurologic impairment.



How is multiple sclerosis diagnosed?



To diagnose multiple sclerosis, neurologists take a detailed history to determine if a neurological impairment is consistent with what multiple sclerosis can cause, performs a detailed neurological examination to find evidence of dysfunction of the central nervous system, obtains an MRI of the brain and frequently of the spinal cord as well, and will often have a lumbar puncture performed. There are a large number of conditions than can cause abnormalities on brain MRI, but which are not multiple sclerosis, and some of these conditions are common in the population. It is therefor important to distinguish between these lesions and lesions on brain MRI that are characteristic of multiple sclerosis.

In the lumbar puncture the neurologist is looking for evidence of specific antibodies that are found in the fluid that bathes the brain and spinal cord, the cerebrospinal fluid, but are not found in the blood. This provides evidence of immune system dysfunction that is specific to the central nervous system.



Vitamin D and Multiple SClerosis



Some interesting research has come to light about Vitamin D and multiple sclerosis. Medicine has long known that we need sunlight to make vitamin D, where it is made in our skin after exposure to ultraviolet light. We also know people who are born and live far north of the equator, where there is less direct sunlight, have a higher incidence of multiple sclerosis. In the past few years we have also discovered that a low level of vitamin D in the blood increases the risk of developing multiple sclerosis. Consequently, it is of great interest to people with this disease, as well as the physicians who treat it, if taking vitamin D can reduce their chance of getting any worse. Recent findings suggest it may do just that.


In an experiment in Canada at the University of Toronto and the Montreal Neurologic Institute, in which one group of people with multiple sclerosis were given a high dose of vitamin D supplements (~10,000 units per day of vitamin D3) and the other group received only a placebo, a substantially smaller percentage of the group who received vitamin D got any worse compared to the group that received placebo. In fact, only 8% of the patients taking vitamin D had durable worsening of their multiple sclerosis, as opposed to 38% in the group that did not take vitamin D1. This large dose of vitamin D was completely safe also, in this study as well as in several other large studies2. Still other studies have shown a modest improvement in the mental quality of life and fewer MRI lesions in patients with multiple sclerosis taking vitamin D3 supplements.


Often, multiple sclerosis is preceded by a condition called optic neuritis, in which vision in one eye becomes impaired because the optic nerve gets inflamed. Indeed, around 20% to 50% of people who experience optic neuritis will eventually develop multiple sclerosis. Quite interestingly, of those people who experience an episode of optic neuritis, they are much less likely to develop multiple sclerosis if they start supplementing with vitamin D3, developing multiple sclerosis at only 1/3 the rate of people with optic neuritis who did not take vitamin D3 supplements3.


There have, however, been some other studies that did not clearly show a benefit of vitamin D3 in multiple sclerosis, but most of these studies were either with lower doses of Vitamin D, or longer intervals between doses (monthly as opposed to daily), though one study was with a similarly large dose. Additionally, the highly biologically active form of vitamin D (1,25 dihydroxyvitamin D) is dangerous to take in large quantities because it can cause hypercalcemia.


Given the totality of evidence, including an excellent safety profile, at Bridgepoint Neurology we recommend almost every patient with multiple sclerosis take a similar dose of vitamin D3, approximately 10,000 units a day, unless they have a contra-indication such as hypercalcemia or hyperparathyroidism. Whereas we haven't published our results, it is our impression that patients that take this dose of vitamin D3 have fewer relapses and less worsening. This dose can be obtained over the counter at most pharmacies and grocery stores, but since some brands are not as reliable as others, we do recommend checking vitamin D levels in the blood before and after supplementing. The highly active form of vitamin D (1,25 dihydroxyvitamin D) is not available over the counter. We also recommend all our patients continue to take appropriately selected prescription medications for multiple sclerosis to reduce relapses and disability, because vitamin D is not a substitute for these medications and seems to be additive with them. In fact, in combination with the newer more effective medications for multiple sclerosis, we can expect to see more people with multiple sclerosis maintaining a higher level of function over a longer time frame.

For men, there are also some interesting findings about testosterone levels and how these may influence the course of multiple sclerosis. More can be read about this below.




Testosterone and multiple sclerosis



It is well known that women are more frequently affected by multiple sclerosis than men. This is common in what are termed autoimmune diseases, in which the immune system malfunctions and mistakenly attacks some component of the body. In multiple sclerosis, the immune system attacks the brain and spinal cord in small focal areas, causing what are called multiple sclerosis "lesions". We don't clearly know why this happens in multiple sclerosis or in other autoimmune diseases.


The higher rate of autoimmune disease in women is thought to be due in part to differences in the sex hormones estrogen and progesterone and their effects on the immune system. Interestingly, in men, the male hormone testosterone is frequently low in men diagnosed with multiple sclerosis. In one recent study, as many as 40% of men with multiple sclerosis had low testosterone levels. These low levels were also associated with higher rates of disability from multiple sclerosis. Consequently, at Bridgepoint Neurology we always check testosterone levels in men with MS, and recommend replacement with the assistance of an endocrinologist if it is low.


Can testosterone supplementation slow down the progression of multiple sclerosis? There is some interesting research done at UCLA that suggests it might. In this study, they took men with multiple sclerosis, and measured the rate at which their brain atrophied (shrunk) for six months. It is well known that the brain atrophies in multiple sclerosis, and the extent of this atrophy is a strong predictor for developing physical and intellectual impairments from multiple sclerosis. The group at UCLA then calculated the rate of brain tissue loss over those six months, and then they started these same men on supplements of testosterone for 12 months. Quite interestingly, they found that the rate of brain tissue loss slowed down significantly in the first six months while taking testosterone, and then in the next six months on testosterone there was no brain tissue loss at all. In fact, one area of the brain had an increase in brain tissue after 12 months. Additionally, there was some improvement in certain intellectual functions, specifically processing speed, after 12 months of taking testosterone.


Because of these findings, the group at UCLA is trying to get the National Institutes of Health, the government agency that sponsors medical research in the United States, to sponsor a larger and longer study to better evaluate the benefits and risks of using testosterone in men with multiple sclerosis.


There are a number of associated risks with taking testosterone supplements, including emotional lability, increased thickness of the blood (polycythemia), abnormal liver function tests, prostate disease, testicular atrophy, hyperlipidemia and acne, to name only a few. Therefore, in men with multiple sclerosis who are not clearly testosterone deficient, it is important to better define the benefits and risks in large studies before recommending supplementation.



Which medication Should I take for multiple sclerosis?



Although it is unfortunate to develop multiple sclerosis, there are fortunately now a wide variety of medications that are approved to treat this condition. The tough part is figuring out which one is best for you. At Bridgepoint Neurology, we recommend this be done in close collaboration with your neurologist, but it is helpful to be informed about the various treatment options, including their benefits and risks. Consequently, we provide this guide to the various multiple sclerosis medications, including our perspective on these medications.


The first step in figuring out which medication to use is to figure out what type of multiple sclerosis you have. The most common type of multiple sclerosis is called "relapsing-remitting", and consists of episodes of neurologic worsening (blurry vision, imbalance, incoordination, focal weakness, focal numbness etc.) developing over hours to days, and recovering over a few weeks to a month. This worsening and then recovery is what is call relapsing and remitting. However, the worsening often does not fully recover, and it is estimated that about 50% of the time there is some residual neurologic impairment after a relapse. This is one reason it is important to prevent the relapses, not only to avoid the impairment during the time of the relapse, but also to prevent the permanent neurologic impairments that can occur from an incompletely recovered relapse. Almost all of the medications that are approved for use in multiple sclerosis are for the relapsing remitting type. If this is the type you have, you can skip the next two paragraphs and read the section below: Medications for Relapsing-Remitting Multiple Sclerosis.


After someone has had relapsing-remitting multiple sclerosis for a number of years, often after 15-20 years, they may enter a stage in which there is a slow and gradual worsening of their neurologic function, and this is called "secondary progressive" multiple sclerosis. Unfortunately, treatment options are limited at this stage. The medicine Novantrone has shown some modest effects at slowing this form of multiple sclerosis down, but it is associated with cardiac toxicity and risk of leukemia, which has led most multiple sclerosis specialists to avoid its use. The medication Aubagio, which is approved for relapsing-remitting multiple sclerosis, appeared to be somewhat effective in a subset of people in their studies who had secondary progressive multiple sclerosis, and it has a much better safety profile than Novantrone. At Bridgepoint Neurology, we usually recommend Aubagio for people with the secondary progressive form who are still having relapses.


A small percentage of people with multiple sclerosis, about 15%, begin with a slow and gradual worsening, such as a slowly progressive difficulty walking over several years. This form is known as "primary progressive" multiple sclerosis. The only treatment that has shown effectiveness in reducing the progression in some people with this form of multiple sclerosis is Ocrevus, which was recently approved by the FDA. However, in the clinical studies on Ocrevus, in which at least half of the people in the study were women, there was unfortunately no net benefit in women. Consequently, we only recommend Ocrevus for men with primary progressive multiple sclerosis.


Medications for Relapsing-Remitting Multiple Sclerosis


These are medications for reducing the frequency of relapses and some have been shown to consistently reduce the chance of becoming increasingly disabled. Since a relapse is often debilitating but only temporary, but disability is enduring, we focus on and selecting medications that are both well suited to the individual, and reduce the risk of enduring disability. The sheer number of these medications can confuse anyone who has not studied them extensively.


The current list of FDA approved medications includes:


Avonex

Beta-Seron

Rebif

Copaxone, Glatopa (glatiramer acetate)

Tysabri (Natalizumab)

Gilenya (fingolimod)

Tecfidera (dimethylfumarate)

Aubagio (teriflunomide)

Ocrevus (Ocrelizumab)

Lemtrada (Alemtuzumab)

Plegridy (Pegylated interferon)

Zinbryta (Daclizumab)

Mayzent(Siponimod)


Some of these medication are injections, some are pills, and some are intravenous infusions. On an internet search, you may find other medications for multiple sclerosis listed, but these other medications are to either hasten the speed at which a recovery occurs from a relapse, or to treat other symptoms of multiple sclerosis.


Which of the medications is the most effective? From the available studies, Ocrevus and Lemtrada in our judgement appear to be the most effective, with Tysabri coming in a distant 2nd. All three of these are intravenous infusions, with Ocrevus given once every 6 months, Tysabri once a month, and Lemtrada once a year (but for only 2-3 years). Of these, we recommend Ocrevus the most frequently, because in our judgement it has a better side effect and safety profile than Lemtrada or Tysabri.


However, if someone has been on a different medication for a number of years and has not had any relapses or worsening, and is not having any appreciable side effects or intolerance to that medication, we generally recommend continuing that particular medication. Additionally, we do not recommend Ocrevus for a reproductive aged woman who is considering having children, as the safety of Ocrevus has not been demonstrated in this population. For women with mild multiple sclerosis who are considering further pregnancies, we generally recommend Copaxone, because it has an excellent safety profile and is rated as pregnancy category B, meaning adverse effects have not been seen in animal studies or humans during pregnancy.


Some multiple sclerosis specialists do not like to start with the more aggressive intravenous infusions to treat patients with mild multiple sclerosis, preferring instead to use pills that can be taken by mouth. Some of these specialists reason that we haven't seen the long term effects of using intravenous medications like Ocrevus or Lemtrada, or they have concerns about further suppressing the immune system in more elderly patients with multiple sclerosis that already have some decline in immune system function (due to their age or other condition). Additionally, some insurance companies will not pay for Ocrevus or the other intravenous infusions unless other medications have been tried first. In this case, of the available medications that can be taken by mouth (Gilenya, Tecfidera and Aubagio), we generally recommend Aubagio, since in its clinical trials it has consistently reduced disability, whereas the other pill forms have not consistently shown reductions in disability in their clinical trials. Additionally, there have been some rare but serious infections with the other pills, including disseminated shingles and a brain infection called progressive multi-focal leukoencephalopthy, but not with Aubagio. There is a compound related to Aubagio that has been used in rheumatoid arthritis and has been associated with liver damage, but to date there has not been any serious liver disease with Aubagio. Nevertheless, we do as a precaution check liver function tests prior to starting Aubagio and periodically while taking it.


The injections, including Avonex, Rebif, and Beta-seron were some of the first medications developed for multiple sclerosis, and for some people these have remained effective over a number of years, and in such cases we believe it is reasonable to continue these. Rebif appears at least as effective, possibly more, than any of the pills at reducing disability. However, these injections are frequently difficulty to tolerate and the new medications, especially Ocrevus and Lemtrada, are clearly superior to these injected agents.


At Bridgepoint Neurology, we always give any of these medications for multiple sclerosis in combination with Vitamin D3, unless there is a contra-indication.





What can I expect with multiple sclerosis?



After someone is diagnosed with multiple sclerosis and goes on the internet and reads more about it, the number of different things that can happen can be disconcerting. In the following I hope to provide some context for these risks, including what we currently know about the probability of getting significantly worse with multiple sclerosis over time. Often, being better informed with these numbers, and having a better idea of what to expect, makes living with multiple sclerosis less stressful.

We first have to point out that the prognosis depends on the type of multiple sclerosis. Most people with MS have the relapsing-remitting form, but about 15% have primary progressive MS, which is a more aggressive form of multiple sclerosis. It is also important to keep in mind when we look at studies that show how people have done over 5, 10, 15 or 20 years with multiple sclerosis, that these studies began before the newer and more effective medications for multiple sclerosis came out, so the long term outcomes may be better now. Additionally, we also don't know what new medications or other treatments will be developed for multiple sclerosis in the next 5, 10, or 20 years, and this can also affect the long term outcome in a positive way. Finally, it is important to point out that there is considerable variation in the rate different people with MS will progress over time, and an average number can be quite different than what a number of individuals with the condition will experience over that same time frame.

Most of the studies that look at long term disability in multiple sclerosis have focused on the ability to walk. For one of the largest studies on this topic, looking at over 2,000 people with multiple sclerosis, the following was found. In primary progressive multiple sclerosis, it took an average of 8 years from diagnosis to having impairment in walking that was limiting but not requiring an assistive device it took an average of 9-10 years elapsed before requiring some type of assistive device to walk at least 100 yards and it took an average of 21 years prior to being wheelchair bound. In relapsing-remitting multiple sclerosis, it took an average of 17 years from diagnosis to having impairment in walking that was limiting but not requiring an assistive device it took an average of 22 years before requiring some type of assistive device to walk at least 100 yards and it took an average of 40 years prior to being wheelchair dependent. In the past few years, diagnostic guidelines for multiple sclerosis have changed, and it is being diagnosed earlier in some patients, so the prognosis for such individuals is even better.

A large fraction of people with MS will remain with good function for many years, have productive careers, active family lives and remain physically active. Hopefully, as our treatments for multiple sclerosis improve, even more people with MS will remain physically and cognitively intact for more of their lives.


what can I do besides medication to keep it from getting worse?





Individuals who smoke or who are obese tend to do worse over time with multiple sclerosis, and these are modifiable behaviors. In addition, people with conditions such as high blood pressure and diabetes, which lead to heart disease or stroke, also tend to do worse over time with multiple sclerosis. Consequently, we recommend a diet that reduces the risk of these conditions. Probably the most well studied is the Mediterranean diet, for which there are a number of books, and for which we recommend the "Mediterranean Diet for Dummies" book. A paleolithic diet is also a reasonable and healthy diet, and the Mayo Clinic website provides a reasonable description. Finally, we recommend vitamin D supplementation as discussed above, and checking testosterone levels in men and starting replacement if they are consistently low.



BRIDGEPOINT NEUROLOGY



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