Challenging Cases in Multiple Sclerosis

Course Director

Aaron E. Miller, MD

Aaron E. Miller, MD
Professor of Neurology
Medical Director
Corinne Goldsmith Dickinson Center for Multiple Sclerosis
Mount Sinai School of Medicine
New York, New York

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Part 2 of a 2-part series

Dr. Miller provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


Recent advances in the arena of multiple sclerosis care have brought new possibilities for patients with this disease, and present a variety of new challenges for neurologists. With the availability of new disease-modifying therapies and several in the later stages of development, we begin to see a rapidly evolving MS treatment paradigm. In addition, new treatment options are being explored to address MS-associated symptoms, such as spasticity. Tailoring therapy to the individual with MS—both newly diagnosed patients and those who have failed prior therapy—is crucial to optimizing outcomes and ensuring patient safety. In this activity, Dr. Aaron E. Miller offers his perspective on challenging cases in multiple sclerosis submitted by your neurology colleagues.

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What is the best treatment option for a 38-year-old woman who has just been diagnosed with relapsing-remitting MS? She does not have significant disability at this point, and would prefer an oral therapy.

Dr. Miller: In my opinion, there’s not necessarily a best treatment option to recommend to most individual patients, with rare exceptions. The best treatment option is the option of an acceptable, approved disease-modifying therapy that the patient feels comfortable taking.

Now, clearly, most patients would have a preference, from a quality of life point of view, for an oral therapy over an injectable therapy. Nonetheless, some patients prefer the comfort and security of knowing that the injectable agents have been around for a substantial number of years and have an extremely favorable safety profile, and we know that we’re not going to get any surprises with the interferons or glatiramer acetate.

However, if the patient does not want to take an injectable medicine, then there are a number of options. And in every case, I personally discuss all of the available options with patients. We now have eight drugs that are FDA-approved for treatment of relapsing MS.

With regard to those choices, natalizumab is probably our most effective agent. It reduces relapse rates by about 68%, which is substantially more than with any of the other agents (Polman CH et al. N Engl J Med. 2006;354:899-910). Now, one has to have the caveat that natalizumab has not been tested head to head in a clinical trial with any other agent. Nonetheless, I think most MS specialists do believe that it is the most effective agent. Now, natalizumab, of course, carries the concern of the development of PML [progressive multifocal leukoencephalopathy] in patients who have been on the drug for a while and who are infected with JC virus, the causative agent for PML. We now have the ability to obtain JC virus–antibody testing, which absolutely should be done before prescribing this drug. In patients who are antibody-negative, the risk of PML is exceedingly low. The reported figures cite a hypothetical risk of less than 1 in 10,000 (Bloomgren G et al. N Engl J Med. 2012;366:1870-1880). We now test patients at least every 6 months for JC virus. So if a patient is antibody-negative, then natalizumab is an excellent option.

Moving to the oral options, we currently have two FDA-approved options, fingolimod and teriflunomide. And we’re awaiting the expected approval of BG-12.

Fingolimod is a quite effective oral agent and very well tolerated in its once-a-day usage (Kappos L et al. N Engl J Med. 2010;362:387‐401; Khatri B et al. Lancet Neurol. 2011;10:520; Cohen JA et al. N Engl J Med. 2010;362:402‐415). It needs to be avoided in patients with certain cardiac risk factors, and there still is some lingering concern about the potential for unusual infections, or even neoplasms, with prolonged usage (U.S. Food and Drug Administration. Gilenya [fingolimod]: Drug Safety Communication. Accessed January 28, 2013; U.S. Food and Drug Administration. Gilenya [fingolimod] Risk Evaluation and Mitigation Strategy. Accessed January 28, 2013). That’s not because we have seen those signals, but just because of the way the drug works in terms of lowering circulating lymphocyte counts very dramatically.

Teriflunomide is a once-a-day oral agent available in two doses, but generally the 14 mg higher dose will be prescribed, because it’s more effective. This drug appears to be approximately equal in efficacy to the interferons (Genzyme, a Sanofi company. Press Release, December 20, 2011. Accessed January 8, 2013), and by inference to glatiramer acetate. It’s generally well tolerated, and the safety profile is very similar to leflunomide, which is a drug that’s been on the market for over a decade to treat rheumatoid arthritis. So we have a good sense of what to expect with teriflunomide. There are important tolerability and safety considerations when considering this drug (Aubagio [teriflunomide] Prescribing Information. Accessed January 9, 2013). This would certainly not be a good drug to use in a woman of childbearing age who still has some contemplation of pregnancy. Teriflunomide carries a category X pregnancy rating because of the risk of teratogenesis, and so women who use this drug must absolutely be counseled to make sure that they are practicing an effective contraceptive method. Patients considering the use of teriflunomide should also be informed that liver enzymes need to be monitored monthly for the first 6 months. Patients should also know about the possibility of GI side effects—nausea or diarrhea—and the possibility of mild hair thinning. Teriflunomide candidates should also be informed about the need to do an accelerated elimination protocol when they stop teriflunomide, because the drug remains in the body for a very long time, perhaps even as long as 2 years. So generally, patients who come off the drug will take cholestyramine three times a day for 11 days to get rid of all of the teriflunomide.

Finally, if one is having this conversation after the approval of BG-12, one should note that the efficacy of that drug appears to be comparable to that of fingolimod, with approximately a 50% reduction in relapse rate (Fox R et al. New Engl J Med. 2012;367:1087-1097; Gold R et al. New Engl J Med. 2012;367:1098-1107).

Narrator: It should be noted that there is the caveat that these two drugs have not been compared in a head-to-head trial.

Dr. Miller: BG-12 has been tested against glatiramer acetate, but not against the other oral medications, so you have to take that difference in annualized relapse rate reduction with a grain of salt. Again, patients should be informed of the possibility of gastrointestinal side effects—nausea and vomiting in particular—and the possibility of flushing.

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My patient is a 28-year-old male who was diagnosed with MS 12 years ago, and has failed on high-dose β interferons, glatiramer acetate, and natalizumab. He has baseline bradycardia (~50 beats per minute). What is the next step for this patient?

Dr. Miller: This is a very difficult problem, and it’s also a very unusual situation, particularly the failure on natalizumab, if the patient indeed has relapsing-remitting MS. I would be concerned that perhaps this patient has transitioned to the secondary progressive phase of the disease, and it’s not clear at this point that any of our available therapies impacts the insidious progression of the disease. Natalizumab is currently undergoing a trial in secondary progressive MS.

But what options do we have for this patient, who has failed natalizumab and the injectable therapies? Fingolimod is an option. This patient is sort of on the cusp, with his baseline bradycardia of about 50 beats per minute. The drug probably could still be given in someone at that high a level who has no evidence of heart disease, but one would need to be particularly cautious in terms of the monitoring, and discuss the risks of aggravating the bradycardia with the patient.

In terms of transitioning the patient from an injectable therapy to fingolimod, I don’t think any particular precautions or steps need to be done, nor does a long waiting period need to be undertaken. And with regard to that waiting period, it’s particularly important to note that most people now believe that a percentage of patients who come off natalizumab appear to have some rebound activity. That is, an activity of their MS that exceeds what one might expect just from the fact that a patient is not being protected by a drug. And that seems to max out at about 3 to 4 months after discontinuation of natalizumab. So for that reason, if I have a patient that’s coming off natalizumab, going onto another agent, I try to make sure that the new agent is begun very quickly.

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I have a patient with MS who suffers from significant spasticity that greatly diminishes her quality of life. What are some novel strategies for managing spasticity in patients with MS?

Dr. Miller: Spasticity remains a very common and vexing problem for many people with MS. It’s worth talking about a few things with regard to spasticity.

First of all, it’s very important to recognize that spasticity varies a great deal from moment to moment, day to day in patients with MS. And it’s important to get that patient with spasticity to understand some of the things that can aggravate spasticity. For example, a full bladder, constipation, urinary tract infections or other types of infection, all of those things can make spasticity worse. So it’s important for patients to make sure that their bladder and bowel function is optimized and appropriately managed. In particular, skin wounds or decubitus ulcers can result in very marked worsening of spasticity.

The management of spasticity always begins with stretching and exercise, and that’s an important part of the management in all cases of spasticity. So patients should be instructed on proper ways to conduct stretching of those spastic muscles.

In terms of treatment, the mainstay of oral treatment remains baclofen, but it’s important for people to understand that baclofen is often underdosed in patients. Doses of 10 mg three times a day are seldom sufficient to significantly impact a person with prominent spasticity, and one often needs to push the dose much higher. I think the prescribing information may suggest that 80 mg/day is the maximum dose (Baclofen Prescribing Information. Accessed January 10, 2013), but in fact, the dose can be pushed substantially higher if one goes very slowly in raising the dose. The slow titration upward will often prevent the patient from developing side effects such as dizziness or drowsiness. In addition, it’s important the patient understand that you can’t identify a target dose from the get-go, that you have to individualize the therapy.

Once one gets beyond oral baclofen, oral tizanidine is also an effective agent, and it doesn’t have the main concerning side effect of baclofen, which is a sense of weakening the muscles, which may interfere with walking. The main side effect of tizanidine is drowsiness, so that it’s sometimes difficult for patients to tolerate daytime tizanidine. It’s an effective agent for a patient who has spasticity that may interfere with sleep. Many patients, however, will tolerate an adequate dose of tizanidine in the daytime if one increases the dosage very, very slowly, for example, by 2 mg every 4 to 7 days.

Moving beyond the oral therapies, one good option is a baclofen intrathecal pump. This delivers a dose of baclofen directly to the target tissue. By avoiding these large oral doses, much of which gets into the brain and is responsible for the side effects, the baclofen pump can produce very effective reduction in spasticity without causing side effects. This pump is implanted surgically under the abdominal skin, usually requiring an overnight stay. The pump is refilled periodically, through a gasket, essentially, that’s accessed through the skin. Dosages are monitored and programmed by a radiofrequency probe.

The other option that’s often used is treatment with botulinum toxin. Botulinum toxin is particularly useful if one has a focal area of spasticity, such as the elbow or the wrist or an ankle. In my experience, it’s a little bit less helpful when one has very large muscles involved, for example, the quadriceps or the abductor muscles of the legs. Here it requires very large doses of botulinum toxin, and that can be problematic over time. Other physicians, however, have a greater enthusiasm for botulinum toxin, even in those larger muscles.

A lot of interest has been given to the potential role of cannabinoids in the treatment of MS. This is a very difficult subject to evaluate, because when trials have been done with cannabinoids, patients can often, because of the psychogenic effects of the cannabinoids, tell that they’re getting an active agent, and therefore there’s often an improvement in the subjective symptoms associated with spasticity—stiffness and sometimes pain—but it’s much harder to show objective changes in spasticity. There is an oral mucosal spray of a cannabinoid preparation which is available in other parts of the world but is not approved in the United States.

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Expert Perspectives in Multiple Sclerosis

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