Etiology/Epidemiology

Western New York has a particularly high rate of MS. Hypotheses have included relative lack of sunshine (Vitamin D) and environmental pollutant exposure. Has the role of pollution been explored, and if so, have specific substances been linked to the risk of developing MS?

Robert Zivadinov, MD, PhD :
The current hypothesis is that MS is caused by an environmental trigger in genetically susceptible individuals. Among the environmental factors that have been linked to MS, lack of vitamin D is certainly one of the most interesting, along with smoking and exposure to the Epstein Barr virus.

In a case-control population study of MS risk factors, we looked very carefully at the potential role of environmental pollutants, particularly among people with occupational exposure to heavy chemicals. None of these factors were found to be associated with a higher risk of developing MS. The only factors clearly linked to a higher risk of developing MS were a family history of MS or other autoimmune disease, lower concentrations of vitamin D, cigarette smoking, or exposure to the Epstein Barr virus. I am not aware of any changes in MS risk factor identification since the publication of that study.

 

We have several MS patients in our practice who are of African-American or Caribbean descent. We’ve noticed that they tend to do worse than white or Hispanic patients. Why is that? How do we treat them when the DMT (interferon or glatiramer acetate) no longer works and the disease progresses?

Howard L. Zwibel, MD :
There is evidence that African-Americans tend to have more active inflammation early in the disease course and greater accumulation of disability early on. The reason for this is not clear, but likely has a genetic basis with possibly a different phenotype of disease presenting in these patients. This does not necessarily apply to West Indian/Caribbean patients. Patients of Caribbean descent who appear to have MS should have human T-lymphotropic 1 (HTLV-1) testing to rule out tropical spastic paraparesis.

African-American patients with MS should be started on a standard disease-modifying regimen (high-dose interferon beta or glatiramer acetate). In view of the data we have in this population, I might monitor these patients more closely, especially if the initial presentation is multifocal (two or more regions of the brain affected). In addition, I would consider moving on to an alternative therapeutic approach if the patient appears to have active disease after 3 to 6 months of treatment, rather than waiting 6 to 12 months. Alternative approaches might involve use of natalizumab, or a course of induction chemotherapy with cyclophosphamide or mitoxantrone.

 

What can I tell newly diagnosed patients (or patients with CIS) who believe they are going to be among those who have a "benign" course of MS?

Kathleen Costello, MS, CRNP, MSCN :
"Benign MS" is a highly misleading term and should not be utilized. The course of MS is highly unpredictable, and only after someone has had a diagnosis of MS for 15 to 20 years can we look back and see if the disease course has been relatively mild. A longitudinal study by Sayao and colleagues followed patients whose MS was diagnosed as "benign," with EDSS scores ? 3 10 years after symptom onset. After another 10 years, however, 36 of these 169 patients (21%) had disease progression such that they required use of a cane, and 45 (23%) had progressed to secondary progressive MS.

In another study involving a cohort of "benign" MS patients, only 15% remained in that category after 20 years of follow-up. (It's important to keep in mind that some of these cases may involve an incorrect diagnosis of MS, explaining the lack of expected progression.)

These studies have not been able to show any predictive indicators for which patients would have disease progression, and such predictors remain elusive in MS. Higher EDSS scores at the time of diagnosis appears to predict a more severe disease course. Ongoing studies searching for prognostic predictors have utilized magnetic resonance spectroscopy, cerebrospinal fluid analysis, and other technologies. It’s important to bear in mind that findings derived from such studies may be applicable to large groups of patients, but may not be relevant to individual patients. Thus it is necessary to remain very cautious about trying to make prognostic predictions in MS.

 

What is the latest on vitamin D and MS? Should we be monitoring blood levels and supplementing if low, and if so, is there an optimum level? Should we be advising our patients to supplement their children’s vitamin D? What ongoing studies are looking at this?

James D. Bowen, MD :
There have been many attempts to explain the greater prevalence of MS at higher latitudes. Factors such as race, HLA distribution, diagnostic bias, various meteorological variables, environmental toxins, socioeconomic status, and various dietary differences including fat content, wheat and dairy have all failed to explain the epidemiology of the disease.

Vitamin D deficiency is one of the factors being investigated in an attempt to explain the geography of the disease. There is general agreement that people with MS, as a group, have low vitamin D levels. Low levels of vitamin D are found in those with established disease and also in military recruits a few years before diagnosis. Populations with low dietary intake of vitamin D have a higher prevalence of the disease. However, it is difficult to determine cause and effect in epidemiological association studies. It is unknown whether the low levels of vitamin D contribute to the cause of MS, whether MS causes the low vitamin D level (through decreased sun exposure due to heat avoidance), or whether there is a third factor which causes both MS and vitamin D deficiency. It is difficult to explain the role of vitamin D deficiency when MS rates appear to be increasing despite widespread vitamin supplementation, when racial groups with darker skin (and lower vitamin D levels) have lower rates of MS, and when MS rates appear to be increasing in the South, including equatorial regions.

Because of the uncertainty about causation, no clear recommendation can be given regarding vitamin D supplementation in those with MS or at risk for the disease. Vitamin D supplementation is relatively inexpensive and has few side effects when used at usual doses. However, it should be viewed only as a supplement and not a substitute for therapies of proven benefit. Therapy should be guided by 25-hydroxyvitamin D levels. In most laboratories, levels above 30 nmol/L are considered normal. However, in one study by Munger et al, MS risk was lowest in those with levels above 100 nmol/L, leading some to recommend supplementation to this level. Levels above 200 nmol/L should be avoided because of the increased risk of renal stones. Cholecalciferol (vitamin D3) is usually started at 1,000 to 3,000 IU/d, with 25-hydroxyvitamin D levels rechecked after two to three months. Large-scale treatment trials will be required to fully understand the role of vitamin D deficiency in MS. Until these are done, the true role of vitamin D in the pathogenesis of the disease will be uncertain.

 

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Imaging/Pathophysiology

What is BDNF, and what are its clinical implications in MS?

Corey C. Ford, MD, PhD :
Brain-derived neurotrophic factor (BDNF) is a protein found in the brain and other compartments that functions as a neural growth factor. BDNF may also confer a degree of neuroprotection in defense of the nervous system from injury.  Both properties are of potential interest in MS but the neuroprotective aspects have attracted the most attention.  With the currently available DMTs providing only partial benefit in reducing inflammation and slowing disability progression in MS, the concept of providing neuroprotection is appealing. Activated T-cells attracted to the central nervous system in MS can express BDNF among many other factors. Some T-cells in patients receiving glatiramer acetate are GA-specific and are able to express anti-inflammatory cytokines of the Th-2 profile.  These GA-specific T-cells may cross the blood/brain-barrier and deliver this immune modulation as part of the drug’s mechanism of action.  Activated GA-specific T-cells have also been shown to secrete BDNF in animal models. If this occurs in MS, it may represent a second important disease-modifying action. It has not been definitively proven that this occurs in humans with MS but is a reason we are interested in BDNF as a neuroprotective protein.

 

What is the connection between MS and gray matter?

Robert P. Lisak, MD :
For many years MS was popularly considered to be a purely demyelinating disease of the white matter with late axonal damage. Current interest in early axonal damage and involvement of the gray matter in MS is, in many ways, a “rediscovery.” The damage to gray matter of the cerebral cortex as well as deep nuclei early in the course of MS may be as great or greater in extent than the damage to white matter. This has been demonstrated in both pathologic examinations and more advanced MRI and spectroscopic techniques. There seem to be three or four patterns of demyelination within the gray matter, at least two of which appear very different from white matter demyelination, suggesting different pathogenic mechanisms and/or differences in how gray matter cells respond to MS pathogenic mechanisms. Additionally, there is clearly gray matter neuronal dysfunction and death in early MS. It is not clear whether the loss of neurons is due entirely to the effects of demyelination on axons downstream from the gray matter neurons, or whether there is direct damage to axons and/or neurons, either in an antigen-specific and/or nonspecific manner (innocent bystander).

 

Will future diagnostic criteria for MS incorporate imaging modalities such as 1H-MRS for our patients? Or is this technology mainly limited to clinical trials?

Jerry S. Wolinsky, MD :
Proton-based MR spectroscopy (1H-MRS) is attractive in that it provides more specific biochemical information than what can be shown on conventional MR imaging. Thus MRS and other advanced imaging technologies may be very useful tools to dissect some of the underlying biochemical changes that can be seen in the brains of individuals with MS on a global, regional or local scale, limited only by the resolution of the technique. For example, this technology has allowed us to discover global changes that result in the loss of N-acetyl aspartate (NAA) in the neuronal compartment. Decreased NAA has been found to correlate with neuronal loss and also with disability in MS. These changes can be seen at the earliest stages of disease. In addition, there are regional and local changes in markers of gliosis and myelin alteration that are typical of lesion formation and repair. It is also likely that changes in specific metabolites over time could be useful secondary outcome measures in clinical trials—eg, to determine if brain NAA levels are better preserved by a therapeutic agent compared to placebo therapy or another drug. Unfortunately, the changes seen with MRS and MRSI lack disease specificity, just as do the findings seen on MRI, that will always limit their diagnostic value at the level of individual cases.

 

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Disease Modifying Therapies

Is there any indication that MS may worsen with menopause in a patient who, up to now, has had limited relapses?

Ben W. Thrower, MD :
Sex hormones such as estrogen, progesterone, and testosterone have the potential to impact MS disease activity. The most striking clinical effect of hormones on MS activity is that seen with pregnancy. The second and third trimesters of pregnancy are associated with a significant reduction in relapse rates. Relapse rates rise again for several months post-partum. This protective effect of pregnancy appears to be largely mediated by the hormone estriol. How hormonal fluctuations related to menses, oral contraceptive use, and menopause affect MS is less clear.

There are no large trials looking at the effect of menopause on MS. Given that estrogens may have anti-inflammatory effects, one would predict that menopause might be associated with disease worsening. If this is the case, the clinical effects are more subtle than those seen with pregnancy and the post-partum state. Small surveys have suggested that some women perceive worsening of their MS with menopause. For example, in a small survey of 19 postmenopausal women with MS, 54% reported a worsening of symptoms with menopause, and 75% of those who tried hormone replacement therapy reported an improvement in symptoms with this therapy.

 

What are some effective approaches for convincing a CIS patient with positive MRI findings to begin disease-modifying therapy? Many patients are in denial, want to use natural remedies, or want to wait until oral therapies are available.

Howard L. Zwibel, MD :
A patient must be willing to accept that CIS is a first attack of MS and understand the potential consequences of delaying therapy before he or she will accept long-term treatment. Educating the patient and family about MS is key, as is presenting data on the benefits of treatment versus the consequences of not treating. We now have robust data supporting the effectiveness of disease-modifying therapy in CIS. Studies such as PreCISe (glatiramer acetate), BENEFIT (interferon beta-1b) and CHAMPS (beta interferon-1a IM) show delays in conversion to clinically definite MS (CDMS) of 43% to 50%. Five-year data from the BENEFIT trial show a continued risk reduction to developing CDMS of 37% among patients on active therapy from the start of the trial versus those who were started on placebo. Ten-year data from the CHAMPION trial showed a diminished risk of 40% among patients treated earlier in the course of CIS.

It may be helpful to discuss with the patients the practical costs of having a relapse. Relapses lead to lost income and absence from work, interfere with parenting and daily functioning, and increase the risk for long-term disability. In a study by Lublin et al examining the placebo arms of early pivotal trials of MS therapies, 42% of patients with relapses had increased EDSS scores of a half-step or more lasting three to six months. Morrow estimated that the cost of a relapse ranged $243 to $12,8700 (2002 dollar value) depending on how the patient was treated. The direct and indirect costs of treating MS are significantly lower in patients with lower disability.

As clinicians, we understand that many people facing CIS are reluctant to use injectable medications, especially as they hold out hope for approval of oral forms of therapy. Some of these therapies, while efficacious, have significant risks not seen with glatiramer acetate or any of the interferons. Careful risk-benefit analysis will be needed as these agents become available and patients request them. On the other hand, we know from the pivotal trials, multiple long-term and comparative studies, and postmarketing data that the interferons and glatiramer acetate do not present significantly increased risk for PML, opportunistic infections, or malignancies.

Unless CIS patients are ready to partner with an MS provider, it is not possible to try to force them. If a patient with CIS refuses to begin therapy, it is important that this person be followed very closely and undergo a follow-up MRI of the brain in three to six months.

 

Should patients with progressive MS continue to remain on disease modifying therapy such as beta interferon or glatiramer acetate? When should one discontinue disease-modifying therapy?

Corey C. Ford, MD, PhD :
The issue of treating progressive MS with disease-modifying therapies (DMTs) like beta interferon or glatiramer acetate is complicated. First, we should try to distinguish between secondary progressive (SPMS) and primary progressive MS (PPMS). There are no proven effective treatments for PPMS, although a subgroup analysis of the glatiramer acetate PPMS trial showed potential benefit in men with this pattern of disease. For SPMS, you must decide whether the patient has moved from a treated relapsing phase to some degree of slow progression, with or without relapses. SPMS with relapses is a reasonable indication for DMT. If a patient was treated with a DMT in the relapsing phase and begins to show progression, it may be useful to continue the therapy and follow this patient over time.  Benefit for interferon beta-1b (IFNb-1b) therapy has been demonstrated in the early SPMS phase. This was shown in the European SPMS trial for IFNb-1b and that agent is approved for SPMS in Europe. If progression continues despite therapy with standard DMT, consideration can be given to using mitoxantrone, which is approved in the US for treating SPMS.

 

When prescribing natalizumab, how do you establish a lack of serum JC virus, if the detection assay reports a "less than 500 copies" result rather than a "zero detection" result? Also, how often do you recommend checking liver function tests in patients receiving natalizumab?

Corey C. Ford, MD, PhD :
The decision to use natalizumab to treat patients with MS incurs an obligation to monitor the patients closely for the possible emergence of progressive multifocal leukoencephalopathy (PML). Currently, clinicians using this drug and centers providing infusion services must be certified by the TOUCH risk management plan provided by Biogen Idec and approved by the FDA. This plan provides a protocol for starting appropriate patients on natalizumab and monitoring them for potential problems. If PML is suspected on clinical and MRI grounds, cerebrospinal fluid studies for JC virus are recommended.  Serum virus titers are less specific and less useful. Low JC virus copy numbers can be seen in serum of normal controls, people with MS, and those with other neurological disorders.  These low serum titers are most likely part of the normal JC virus life cycle and do not appear to predict patients at risk for developing PML while receiving natalizumab.  A laboratory report of “less than 500 copies” may be a statement of the assay sensitivity limits and that titers below 500 may not be statistically different from zero.

Liver toxicity has occurred rarely with natalizumab but can be severe. It is recommended that patients on the drug have quarterly tests of liver transaminases (ALT, AST) and bilirubin. When starting the drug, some providers recommend monthly testing for the first year.

 

What is the most beneficial time frame to initiate natalizumab for a relapsing remitting MS (RRMS) patient? Should there be a failure of two or more other disease-modifying therapies (DMTs) before transitioning, or can failing one DMT be sufficient to initiate natalizumab?

Robert P. Lisak, MD :
There is no definite answer to this question since there are no studies that speak to the issues of a) clinical or imaging predictors of response to natalizumab, glatiramer acetate, or beta interferon (IFN-β); or b) head-to-head studies comparing natalizumab to standard DMTs. In addition, the pivotal study of natalizumab is not contemporary with those of the other agents. Given the long-term data and clinical experience demonstrating that glatiramer acetate is well tolerated and without serious side effects and that with careful monitoring the IFN-β formulations are safe and reasonably well tolerated, one would need a head-to-head study demonstrating unequivocal superiority of natalizumab over the other DMTs to initiate therapy in a patient with RRMS with natalizumab. In addition to the appropriately feared progressive multifocal leukoencephalopathy, which has now been reported in several patients (one of whom was treated with natalizumab as the initial agent), there are concerns about the risk of other opportunistic infections, abnormal liver function, allergic reactions and association with recurrent melanoma in patients with prior tumors and perhaps with premalignant skin lesions. Thus, to date, I have not initiated therapy with natalizumab. In general I do not transition to natalizumab as the second agent but treat with IFN-β if the patient fails or does not tolerate glatiramer acetate or vice versa. Since therapy should be tailored to the individual patient, there might be rare circumstances that might move natalizumab to second agent and rarely to primary agent.

 

For what time period do you think it is safe to administer natalizumab: one year? two years? Are patients being taken off natalizumab at some predetermined point and put back on another disease-modifying therapy (DMT)?

Robert Zivadinov, MD, PhD :
No one knows the safest time period to administer natalizumab. We know that during this second phase of natalizumab marketing, there have been three reported cases of progressive multifocal leukoencephalopathy (PML), all of which developed between 12 and 18 months after therapy was initiated. There is a possibility that PML risk might increase with the duration of therapy but we don’t know that for certain at this time. Immunologic studies have shown a substantial change in the ratio of CD4+ to CD8+ cells in cerebrospinal fluid of natalizumab-treated patients similar to that seen in HIV patients. However, we do not have a marker that tells us which patients are at risk for developing PML.

For MS patients who are treated with natalizumab, there is not an “exit protocol” to my knowledge, unless the patient develops side effects or is unresponsive to the therapy. An estimated 6% to 10% of patients (and possibly more) develop a neutralizing antibody to the drug and become nonresponders. Other reasons for discontinuing therapy are anaphylactic reactions, opportunistic infections, and other immunomodulatory related problems. In our clinical practice, up to one-quarter of patients on this drug are halting the therapy after one year.

There is a risk of a rebound phenomenon in patients who are taken off the drug, in which the increase in disease activity may exceed that which existed pretreatment. It’s important to get patients on another DMT at this point. A one- to two-week washout period is recommended after natalizumab is discontinued before another DMT is started. Some have used plasmapheresis to eliminate natalizumab before a new treatment is started but there are little data on this approach.

 

What do you regard as first-line therapy in newly diagnosed Devic's disease (neuromyelitis optica)?

Howard L. Zwibel, MD :
Clinical suspicion of Devic’s disease, or neuromyelitis optica (NMO), is based on the findings of optic neuritis or a long-segmented cervical cord plaque. In these cases, an NMO antibody titer should be ordered. This titer is positive in only about 70% of cases, however. If NMO is suspected based on the above findings, the patient should be treated even if the antibody test is negative.

There are no FDA-approved therapeutic regimens for this condition. Very recently, rituximab has become first-line therapy for NMO among MS specialists. We don’t have large controlled clinical trials yet, but smaller studies strongly suggest that this drug is highly effective. A standard ritixumab regimen should be used, but this regimen should be repeated after 6 months when treating NMO.

Milder forms of the disease, with milder attacks or a prolonged interval between attacks, may be treated with the combination of azothiaprine and corticosteroids, which has been the standard treatment for several years.

 

When do we anticipate FDA approval of oral disease-modifying therapy for RRMS patients?

Howard L. Zwibel, MD :
There is no question that MS patients would prefer an oral agent over injectable therapy. The concern is sacrificing efficacy, safety, or both for a more convenient dosage form. The current disease-modifying drugs, glatiramer acetate and the interferon beta formulations have demonstrated long-term safety and efficacy. Even if an effective oral agent becomes available, we will not have the benefit of a decade or more of safety data as we do with existing drugs.

Several oral disease-modifying agents for MS are currently under study. Cladribine is an antimetabolite chemotherapeutic agent already on the market for treating hairy cell leukemia. It is in Phase 3 studies and expected to be the first to release results from trials in MS and may be marketed for MS by 2010. Other oral agents in the pipeline include:

• Fingolimod (FTY720) (in Phase 3 trials)

• Fumarate (BG12) (in Phase 3 trials)

• Laquinimod (going into Phase 3 trials)

• Teriflunomide (awaiting Phase 3 trials)

• Estriol, the female hormone associated with pregnancy (awaiting more trials)

As noted, even if any of these agents shows promise in Phase 3 trials, one must consider the risks and benefits of using them in a young RRMS patient, taking into account potential concerns about long-term effects on fertility, cancer markers, and the risk of infections or malignancies. In the future, some of these drugs may be used as combination or add-on therapies with existing medications, but no data are available yet to support this concept.

 

Are disease-modifying therapies recommended for patients with secondary progressive MS?

Howard L. Zwibel, MD :
We have had far more success treating patients with relapsing forms of MS, in which there is a greater inflammatory component and less neurodegeneration. The secondary progressive phase is characterized by less inflammation and more degeneration. Interferon beta-1b has an indication for treatment of secondary progressive disease in patients who continue to have relapses. In addition, mitoxantrone is indicated in worsening MS, indicative of secondary progressive disease.

Compared with the natural history of the disease, we know that we can significantly delay the onset of secondary progressive MS in most patients. For our patients who do progress, we may continue with immunomodulatory therapy, use add-on therapy, or interrupt therapy at times with a course of chemotherapy.

Although our current immunomodulatory drugs act primarily through anti-inflammatory mechanisms, there is evidence that they also may have neuroprotective properties, as seen in recently released findings from the PreCISe trial. The implications of neuroprotective properties of these drugs in secondary progressive disease are not known.

 

Are there any clinical or radiological findings in MS that would steer you toward selection of a particular disease-modifying agent?

Omar A. Khan, MD :
This is a difficult area of research to translate into practice.  Most studies indicate that the presence of multiple gadolinium-enhancing lesions may correlate with clinical relapses in the near future, and that the presence of infratentorial lesions predicts a worse disease outcome in a short period of time.  However, this information becomes more difficult to interpret in an individual patient.  Furthermore, there are no large-scale studies that specifically examine this issue in a randomized, controlled fashion.  Recent head-to-head to studies have indicated that there is no difference in the clinical outcomes between high-dose, high-frequency interferon beta and glatiramer acetate, despite the demonstration of differences in MRI-based outcomes.  In clinical practice, some neurologists tend to treat patients who have multiple gadolinium-enhancing lesions with interferon beta.  This is a reasonable approach in this setting although not backed by any controlled studies.  However, in many instances, MRI scans are obtained weeks to months before the patient is seen in the clinic and it is critical to keep in mind that an MRI scan represents only a snapshot in time.  Therefore, it may be more important to keep in mind the patient’s clinical course.  In the vast majority of treatment-naive MS patients, a treatment choice should be based primarily on the clinical course and other patient-specific factors, including tolerability and adherence.

 

Do we know more now about the mechanisms of action of glatiramer acetate? How does this agent work in MS versus the interferon drugs?

Omar A. Khan, MD :
Over the years, there has been considerable improvement in our understanding of the mechanisms of action of disease-modifying therapies in MS.  Glatiramer acetate works by a variety of mechanisms.  Since the discovery experiments of glatiramer acetate conducted in the 1960s, this agent was originally believed to work primarily as a decoy to myelin basic protein (MBP), but with further research, multiple mechanisms have been identified.  A major mechanism is by generating Th2 biased cells, an effect that can be seen within a month of initiating treatment.  This does not suppress the immune system, which retains its ability to launch immune responses when sensitized by other proteins (eg, tetanus toxoid).  Other mechanisms include generation of glatiramer acetate–reactive CD8+ cells, generation of type II monocytes, upregulation of Treg cells, and most recently depleting B-cells.  It remains unclear whether there is any one dominant mechanism in an individual patient.

In contrast, interferon beta attaches to an interferon receptor at the surface of various cell types, which leads to the initiation of intracellular events activating a set of genes through several steps.  Interferon beta appears to have a predominant effect at the blood-brain barrier (BBB) level by shutting down cellular trafficking across the BBB through a variety of mechanisms, including downregulation of matrix metalloproteinases.  Treatment with interferon beta also leads to the production Th2 cytokines in the periphery, which facilitates an anti-inflammatory milieu.

The differing mechanisms of these agents has led to an important clinical question—whether the combination of interferon beta and glatiramer acetate could lead to enhanced efficacy, or might the interferon potentially diminish glatiramer acetate’s efficacy?  This question is the focus a large randomized multicenter, NIH-funded trial testing a combination of these agents.  This trial is currently approximately 3 years from completion.

 

Are there any tests or clinical signs that may indicate which patients will be suboptimal responders to disease-modifying therapy (DMT) for MS?

Jerry S. Wolinsky, MD :
It would be ideal to have a few simple tests that could be done on a person with MS before starting therapy to indicate whether he or she would respond to that drug in an optimal fashion. This would alleviate the guesswork and avoid what is currently a trial-and-error process of choosing a drug, and then following the patient to determine tolerability and degree of clinical response to the drug. As yet, we still lack adequate descriptions of constitutes a suboptimal response to a given therapeutic agent, let alone understanding the early predictors of a suboptimal clinical response.

For the most part, the results of published major clinical trials on all of the approved DMTs only offer general hints as to what these predictors might be. Fortunately, several recent studies have attempted to approach this using data generated from patients at their own sites. A study by Durelli et al looked at whether the number of active new lesions on MRI over the first year of therapy with interferon beta and the presence of neutralizing antibodies to the drug predicted the overall outcome after two years of therapy. Some strong positive and negative predictors were found that require confirmation.

Another study by Rio et al looked at the relative risk of having a poor clinical outcome after two years on therapy based on findings of a one-year MRI and whether the patient had clinical relapse during the first year of therapy. The authors developed their analysis using odds ratios. This type of approach is appealing because it gives the clinician some near-term idea of how patient will likely respond over time.

What we currently lack are very early predictors of which MS patients have a course that is likely to respond to an immunomodulator, and clear-cut indications to know, within a few months of therapy, whether the drug chosen is having the expected effect on an easily measured blood marker of drug activity. One would then follow up with a more intermediate-term indicator at 6 to 12 months to suggest what the long-term clinical outcome is likely to be. Modern treatment trials are being designed to explore appropriate biomarker screens, and planned secondary and tertiary outcome analyses of these trials could make this a reality. Unfortunately, we are not quite there yet.

 

Some of the applicators for disease-modifying drugs have recently switched to thinner needles. What changes can I expect this to make for patients?

Kathleen Costello, MS, CRNP, MSCN :
A thinner needle has recently been introduced for some of the subcutaneously injected MS medications to reduce the pain associated with the injection. Copaxone (glatiramer acetate) is now supplied with a 29-gauge needle while Betaseron (interferon beta-1b) has a 30-gauge needle. In both cases, your patients do not have to do anything different in the preparation or injection of their dose. I would say that my patients have noticed a reduction in discomfort with the use of thinner needles. Surveys of MS patients have shown that the thinner needles are significantly preferred. We hope that, over time, we would also see a reduction in injection-site reactions with the continued use of thinner needles.

 

Do we have evidence that immunomodulation from interferon therapy may increase the risk of some cancers? Is this concern great enough to warrant further study, and if so, what is being done?

James D. Bowen, MD :
Currently, there is no evidence of increased cancer rates with the use of beta interferons. There are case reports of chronic myeloid leukemia, breast cancer, and melanoma, but the rates of these and other cancers in people who use beta interferons are no different than the general population.

In the initial pivotal studies, there was no increase in cancer rates. However, these studies would only have sufficient power to detect a fairly marked increase in cancers. Extension studies have been conducted with all of the marketed beta interferons, and these also have failed to identify any excess cancers. Again, the populations in these studies are not large enough to detect small increases. The primary mechanism to identify extremely rare events is through postmarketing surveillance.

Since the introduction of the first interferon to the market in 1993, the FDA has collected information on unexpected adverse outcomes from patients receiving the medications. In the 16 years since these drugs came on the market, there has not been any identified increase in cancer rates. Given the large number of patients on these medications, it is reassuring that no excess cancers have been found during this postmarketing surveillance. Similarly, glatiramer acetate is not associated with an excess cancer risk.

Mitoxantrone, an immunosuppressant used to treat secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis, has been associated with an increased rate of leukemia, especially acute myelogenous leukemia. The estimated rate is 0.3%. Also, two cases of malignant melanoma have been reported in patients treated with natalizumab. Despite these two cases, there is no recognized increase in melanoma with natalizumab at present. Further postmarketing surveillance is ongoing, but the extensive and lengthy safety records of interferons and glatiramer acetate are reassuring.

 

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Cognitive Issues in MS

How do I treat the cognitive deficits that are interfering with MS patients’ work and daily living? Are there any drugs shown to improve cognition?

Robert Zivadinov, MD, PhD :
It’s clear that the cognitive deficits in MS are not symptoms per se, but part of the neurodegenerative disease process. One of the most important substrates for cognitive dysfunction in MS is brain atrophy. Based on the region where the atrophy predominates, the patient may develop frontal or parietal cognitive symptoms or problems with short-term memory, concentration, attention, or speech. In addition, gray matter damage may contribute significantly to cognitive dysfunction in MS.

Because of this, it stands to reason that the best drugs for improving cognitive ability are the disease-modifying therapies (DMTs). Early treatment with DMTs may reduce cognitive impairment or slow the progression of cognitive deficits in MS.

There are several agents under investigation for symptomatic management of cognitive problems in MS. We are in the process of conducting a multicenter trial on the acetylcholinesterase inhibitor donepezil, which has been shown to modestly improve memory function in MS patients. Two pilot studies have suggested that the cholinesterase inhibitor physostigmine may help improve memory in MS patients. Other ongoing investigations involve drugs such as amphetamines and amitriptyline. It is important to note that the effects of symptomatic drugs on cognition are short-term and temporary.

 

Do disease-modifying drugs have a proven effect on cognition in MS?

Ralph H. B. Benedict, PhD :
While this question has not been very well studied to date, it stands to reason that if a medication is effective in preventing clinical relapses and lesion burden as measured via brain MRI, then the medication will also delay the onset, or help prevent, the development of cognitive impairment in MS.

Because cognitive changes tend to occur over a long period of time, their usefulness as an endpoint in efficacy studies of MS drugs is limited. In an open-label study of glatiramer acetate-treated patients followed for ten years, most patients with relapsing MS had stable cognitive performance during 10 years of prospective evaluation. Cognitive scores relating to memory and semantic retrieval did not change significantly versus baseline, while attention scores did show decline. Changes during the first two years of observation were predictive of 10-year changes.

Of the disease-modifying drugs currently available, only one, interferon-beta1a, has been studied for an effect on cognition using a controlled research design. As expected, in this study by Fischer et al treated patients showed better cognitive outcomes than placebo patients. There is some evidence for similar findings with interferon-beta1b and natalizumab which, while not formally peer-reviewed, has been presented recently at professional meetings.

Thus, the short answer to this question is yes, but some drugs have been better studied than others on this particular clinical outcome.

 

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Emerging Therapeutic Areas

What is the current status of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis?

Robert Zivadinov, MD, PhD :
Right now, procedures to evaluate and treat CCSVI are still in the early research stages. It is important to emphasize that only through carefully controlled research can we truly understand the effect of venous insufficiency in people with MS and how treatments related to the condition might benefit these patients.

In a small pilot study we conducted jointly with Dr. Paolo Zamboni’s group in Italy, 16 MS patients with severe documented CCSVI were given intravascular treatment with percutaneous transluminal angioplasty (PTA) either immediately or following a 6-month delay. The one-year findings of that study will be presented at the 2010 ECTRIMS meeting in Sweden in October. In this trial, the primary outcomes were change in volume of lesions on MRI and number of MS relapses.

Our group in Buffalo is undertaking a larger placebo-controlled trial (PTA versus a “fake” treatment) in 30 RRMS patients. This study will compare many of the standard outcomes in MS but will also include important quality of life measures such as pain, fatigue, and mobility. This study will soon begin enrolling patients at the University of Buffalo.

 

How is CCSVI related to the pathogenesis of MS, based on what is known right now?

Robert Zivadinov, MD, PhD :
The basic theory behind CCSVI is that blood is not properly draining from the brain and spinal cord. CCSVI can include several different types of venous anomalies, including constrictions external to the vein and intraluminal anomalies. The internal jugular and azygous veins are among those involved.

Vascular abnormalities in patients with MS are not a new concept—they were first identified in the 1800s and have been described since the 1930s. Nor are venous insufficiencies specific to MS. Our studies have found CCSVI in about 25% of normal individuals and about 40% of those with neurologic diseases. It could be that an abnormality of the blood vessels triggers an immune response leading to the inflammation and myelin degradation seen in MS, possibly related to deposits of iron in the brain.

My view at this point is that CCSVI is associated with MS; however it is yet to be determined whether CCSVI is among the risk factors that, along with others, increase a person’s susceptibility to developing this disease. The fact that CCSVI prevalence is about 38% in patients with a first clinical attack of MS and almost 90% in those with secondary progressive MS and a disease history of 20 years suggests to me that venous insufficiency has a high likelihood of affecting people with MS over time.

 

Should people with MS seek diagnosis and/or treatment for this condition?

Robert Zivadinov, MD, PhD :
In my opinion, there is currently no role for “open-label” treatment outside of well-designed research studies. Any vascular procedure carries a certain degree of risk, including risk of morbidity and mortality. Vascular surgical risks may be compounded if a patient travels long distances to undergo a procedure and returns via air travel without adequate recovery time, on anticoagulant therapies, etc.

Clearly, more research is needed to determine the best methods for treating CCSVI in patients who are diagnosed with this condition. A study in California was halted because of deaths in patients whose jugular veins were opened with stents, which are designed for arteries rather than veins. We don’t know at this time whether some form of stenting may be an approach to treatment. At this time we are not recommending stenting.

Research is also needed to determine the best approach to diagnosis and what groups of patients might be screened. Doppler ultrasound is an excellent noninvasive diagnostic method and may be useful for screening purposes, but this must be done by experts with appropriate training in identifying venous anomalies. Selective venography is the gold standard for CCSVI diagnosis but is currently not appropriate for screening purposes because of the invasive aspects, costs, and risks associated with this procedure.

 

What should neurologists tell their patients about CCSVI?

Robert Zivadinov, MD, PhD :
Research to determine how to diagnose CCSVI, how and whether it should be treated, and whether the treatment benefits patients with MS is just getting under way. So the only thing neurologists can do is either wait and see, or send the patients to one of the few centers where studies are being conducted.

I predict the debate about the role of CCSVI in MS may get even hotter as more centers attempt to do Doppler exams on patients without the proper training, thus obtaining negative findings.

On the other hand, we have to understand that people with MS have a right to information and an urgent need for answers to these questions. It was only a few years ago that many people doubted the benefit of stem cell treatments in MS, yet now this is emerging as a feasible option. So we can’t shoot down revolutionary types of treatments that may offer hope for patients. We need to listen to our patients, understand that our existing treatments do not completely manage the daily burden of MS, and keep an open mind to any new approaches that might help these patients. Before any new treatment can be recommended, it must first be examined in rigorous research studies.

 

Some literature has suggested that the “pipeline” drugs such as alemtuzumab or cladribine are not more efficacious in treating MS than the original disease-modifying therapies (interferons, glatiramer acetate). What does this mean?

Robert Zivadinov, MD, PhD :
This theory, which was debated in a recent issue of Neurology, is based on the concept that the newer drugs are being tested in a different MS population with less-advanced disease.

Historical pivotal trials of glatiramer acetate and the first interferons used Poser criteria for entry and resulted in annual relapse rates (ARR) of 0.59 to 0.87 over two years. Using McDonald criteria, trials conducted between 2002 and 2005 such as AFFIRM (natalizumab vs. placebo), BEYOND and BECOME (interferon beta-1b vs. glatiramer acetate), and REGARD (glatiramer acetate vs. interferon beta-1a subcutaneous) resulted in ARR from 0.22 to 0.36. Studies involving emerging therapies such as CLARITY (cladribine vs. placebo) and TRANSFORMS (fingolimod vs. interferon beta-1a) have resulted in ARR 0.14 to 0.33 in the years 2007 to the present. Similar ARR values have been observed with alemtuzumab.

While the emerging therapies clearly have impressive efficacy findings, the patient populations and criteria for entry into the trials are different from those historical pivotal trials. Patients are being treated somewhat earlier in the course of their disease and are exhibiting fewer relapses. Higher MR resolution allows for earlier confirmation of the disease in patients with milder symptoms, and patients with more benign disease are now being recruited. Today, because there are effective treatments, patients with a more aggressive early disease course may be less likely to enter a trial and potentially receive placebo. Finally, because patients are being recruited from a more worldwide population, they may reflect different genetic pools compared with the historical trials. As these newer therapies are approved we will have to be aware of these considerations as well as the increased risk of the more serious adverse events than we have with current therapies, including progressive multifocal leukoencephalopathy (PML), malignancies, and opportunistic infections.

 

Now that cladribine’s application has been denied by the FDA, what is the status of other oral agents might be in line for possible approval in MS?

Fred D. Lublin, MD :
The reason that the FDA did not accept the cladribine filing has not been made public. It is likely that the application will be re-filed. Fingolimod is another oral agent that has completed two Phase III clinical trials and is awaiting regulatory review. Other oral agents in the pipeline and undergoing Phase III testing with FDA “fast-track” status are laquinimod, fumarate, and teriflunomide.

Clinical data from two fingolimod studies (FREEDOMS and TRANSFORMS), and a study of oral cladribine (CLARITY) were published earlier this year in the New England Journal of Medicine. At the recent American Academy of Neurology (AAN) meeting in Toronto, data were presented from a 24-week Phase II study of teriflunomide in combination with glatiramer acetate, suggesting that this regimen was well-tolerated and reduced size and volume of brain lesions in comparison with placebo. Also presented at AAN were early data suggesting that laquinimod may exert some axonal/neuroprotective properties in addition to anti-inflammatory effects.

Thus far, studies of these agents have shown that they significantly reduce relapse rates, rate of disability progression, and MRI measures of disease activity in MS. However, it is important to bear in mind that the results cannot be compared across trials or against results of pivotal trials from older therapies such as beta interferons, due to key differences in trial design and study populations at baseline.

Importantly, immunosuppressive/immunomodulating therapies such as cladribine and fingolimod have been associated with a greater risk of potentially serious adverse effects in comparison to the immunomodulatory therapies currently approved for use in MS. Further studies and more clinical experience are needed for all of these agents to determine where they will fit within our therapeutic options with careful risk-benefit evaluations as part of the patient selection process.

 

Where are we in terms of stem cell research for MS? How can we encourage/help this area of research?

Robert P. Lisak, MD :
There are two types of “stem cell” research related to MS. One, which is currently the subject of non-controlled, non-prospective studies or being offered as a treatment option, is autologous hematogenous stem cell transplantation. This therapy, similar to that used to treat certain hematologic malignancies, was originally proposed to eliminate the abnormal immunologic system of patients with autoimmune/immunopathologically mediated diseases, including MS. The goal of autologous stem cell transplantation would be to allow a new, normal immune system to emerge, hopefully in a setting where it will not meet whatever triggers the patient encountered in the past. Since there is some experimental evidence that such cells given intravenously could access the central nervous system, it was also hoped that such cells might develop into oligodendrocyte or neuronal precursors. Current evidence does not support the concept of the return of a naïve immune system. The major mechanism of action is more likely to be a more pronounced and longer-lasting immunosuppression than is possible with routine doses of immunosuppressive agents. However, definite evidence of a positive therapeutic effect in MS, particularly an enduring effect, is not at hand.

The other approach would be to directly inject one of any of several types of embryonic or adult stem cells (precursor cells), directly into the nervous system, or intravenously in some instances, with the express purpose of providing sources of new cells to develop under the influence of the central nervous system, into cells to provide cells for remyelination as well as neurons/axons. Currently, well-performed controlled studies involve experimental animal models of MS. In many of these models, the therapy seems to work by immunomodulation rather than by supplying cells that can be shown to mature and repopulate areas of an abnormal nervous system.

The medical and scientific community can support legislative and other lobbying efforts and help explain and clarify the issues involved in stem cell research. Since stem cell research, like most biomedical research, is expensive, lobbying for increases in research expenditures by government agencies is also critical.

 

What is the latest status on the use of statins to treat MS?

Jerry S. Wolinsky, MD :
For a variety of reasons, statin drugs such as atorvastatin and simvastatin were thought to be particularly attractive as candidates for therapy in MS, either as monotherapy or in combination with available DMTs. Studies in animal models strengthened the theoretical justification for their use in clinical trials. In an early clinical study in MS, Vollmer et al suggested that simvastatin might reduce the frequency of enhancement in patients with relapsing disease. However, more recently Birnbaum and colleagues questioned whether there might be possible drug–drug interactions between atorvastatin and interferon beta-1a. This may have led to aborting their pilot trial due to an unexpected increase in the frequency of relapses. Newer data suggest that statins may induce aberrant myelin formation by oligodendroglial cells—at least in the artificial culture system that was studied—and may reduce remyelination in animal models. While the last word is far from in, evolving data once again show us that what intuitively seems highly attractive may not be so in reality and that the path of translational medicine can be a bumpy road.

 

What are the potential short- and long-term side effects of oral cladribine therapy in MS?

Kathleen Costello, MS, CRNP, MSCN :
Cladribine is a lymphocyte-depleting drug approved as a chemotherapeutic agent for certain cancers. Preliminary results from Phase III studies of oral cladribine in MS were reported at this year’s American Academy of Neurology (AAN) meeting in April by Gavin Giovannoni, MD, of London. Cladribine was given orally at either 3.5 mg/kg or 5.25 mg/kg in two or four cycles at specific intervals over a 14-month course of study and compared with placebo in patients with early relapsing-remitting MS.

Dr. Giovannoni said cladribine appeared to be "of substantial benefit" in reducing relapse rates in RRMS and “adequately safe,” with fewer side effects observed at the lower dose. The most common treatment-emergent adverse event was lymphopenia, occurring in 22% of patients receiving low-dose cladribine and 32% of those on the higher dose. This is consistent with the drug’s mechanism, which involves reducing levels of circulating lymphocytes by causing them to undergo apoptosis.

Adverse events led to withdrawal of 2.1% of the placebo group and in 5.8% of cladribine-treated patients. Further studies are needed to determine optimal dosage of this drug, according to Dr. Giovannoni.

I believe that this drug may have a place for patients who are injection-phobic and unable to self-inject. However, for patients who are taking an injectable disease-modifying therapy (DMT) and whose MS is stable, I would not recommend switching treatment. If an individual is not responding to an injectable DMT, this will be an alternative.

With any new drug for MS, long-term safety is always going to be in question until more clinical experience is obtained. Although oral drugs for MS have been in demand for some time, their potential safety risks with only 2 years’ data must be weighed against the excellent 10- to 15-year safety records seen with currently used disease-modifying agents.

 

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Ocular manifestations of MS

What role does optical coherence tomography (OCT) of the optic nerve play in the management of MS patients? What type of OCT scan is best for following nerve fiber loss and MS progression? Can OCT be used to monitor drug response in place of—or in conjunction with—serial MRI?

Omar A. Khan, MD :
Optical coherence tomography (OCT) is a highly promising investigative tool in the field of MS.  Currently, the use of OCT is restricted to research settings.  OCT research has developed significantly in the past 5 years, but at this time there is still little utility for OCT in the management of individual patients in clinical practice.  Nonetheless, the following details regarding OCT are worth considering as more data emerge in the future.  New machines that perform OCT provide high-definition data and are highly reliable.  OCT is noninvasive and can be performed in approximately 10 to 15 minutes.  It provides information regarding the integrity of the retinal nerve fiber layer (RNFL), which gives rise to the unmyelinated axon that eventually becomes the myelinated optic nerve.  Therefore, OCT provides a direct insight into axonal injury in MS.  Several preliminary studies have shown that RNFL thickness and the rate of RNFL atrophy correlate with other well-known markers of tissue damage on brain MRI scans, including brain atrophy.  Studies have also demonstrated correlation with clinical disability.  These data make OCT a plausible surrogate marker for monitoring axonal injury and the potential neuroprotective effect of therapies.  However, further work needs to be performed with larger randomized studies to confirm these initial findings.  Instead of replacing MRI-based measures of disease pathology, OCT may complement MRI data.  The utility of serial OCT over a long term and its natural progression in different phenotypes of MS are not clearly known.  As more data emerge in the next few years, it is possible that OCT may become a routinely studied secondary outcome in MS clinical trials.

 

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MS Symptoms

We see a lot of information about depression in MS but relatively little about euphoria and disinhibition. How often do these symptoms occur, and what do you recommend for treatment?

Ralph H. B. Benedict, PhD :
There is a condition that occurs in MS patients called euphoria sclerotica. It consists of two dimensions. The first, euphoria, refers to a frequently elevated mood state that is out of proportion to the patient’s circumstances. The second, eutonia, refers to indifference or lack of awareness of the disease state. Alone, euphoria may not be a problem. After all, there is nothing wrong with a person feeling happy. However, when euphoria is combined with eutonia, as in the classic MS-associated euphoria syndrome, problems may arise. In a study published in 2004, we noted that the frequency of euphoria sclerotica in MS was poorly understood due to poor methodology in prior research. We then used the well-validated Neuropsychiatric Inventory (NPI) by Jeff Cummings, MD, to study the neuropsychiatric status of 75 MS patients and 25 healthy controls. We found the syndrome, as defined by the NPI, in roughly 9% of MS patients studied. In addition to euphoria, behaviors described included disinhibition, impulsivity, and emotional lability. The syndrome is commonly associated with cognitive impairment, personality changes, and brain atrophy in MS patients and is also associated with high levels of caregiver distress. Its cause is probably neuropsychological in origin and could be due to a combination of strategically located brain lesions and premorbid personality traits.

There are no approved medications specifically for treating euphoria sclerotica in MS patients. Based on my clinical experience, I can tell you that many patients respond to antidepressants and anticonvulsant medications, but there is no published literature to support this observation.

 

Can you comment on the use of l-amphetamine for treating MS fatigue in the clinical setting? What is your clinical experience with respect to side effects and addictive potential?

Ralph H. B. Benedict, PhD :
The stimulant effects of this drug have prompted keen interest in its potential for treating fatigue in MS. Previous research has suggested it has a much lower addiction potential than does d-amphetamine.

We have conducted two studies of l-amphetamine in MS. In the first study, 19 patients were given different doses of l-amphetamine about 2 hours prior to cognitive testing, on separate visits to the clinic. The data showed a significant effect of the drug on measures of processing speed. However, in a multicenter, placebo-controlled study by Morrow et al involving 151 MS patients, we failed to replicate this finding. In the latter study, we did find some unexpected effects in the area of memory. The significance of these findings remains unclear. Thus, more research on l-amphetamine will be needed before we can make recommendations for use in MS patients.

In the multicenter trial l-amphetamine was well tolerated, with few patients withdrawing because of adverse effects. Likewise, addiction potential is low compared with other amphetamines. If a reliable effect is established it could be a useful agent for treating the MS population.

 

Are there any clinical factors that increase suicide/suicidal ideation risk in patients with MS?

James D. Bowen, MD :
More than 90% of patients who attempt suicide have a major psychiatric disorder, and 95% of patients who commit suicide have a psychiatric diagnosis. In the general population, there are several factors that increase the risk of suicide. The single strongest predictor is a prior history of attempted suicide, with up to 50% of those who complete suicide having a previous attempt. Psychiatric disorders increase the risk, as do some personality traits. For example, hopelessness is strongly associated with suicide. Impulsivity, especially in young people and those with compromised cognitive function, is also a factor in acting on suicidal thoughts. The combination of hopelessness and impulsivity can be particularly lethal.

In general, suicide rates increase with age, though adolescents have surpassed older adults in the past decade. Women attempt suicide more often, but men succeed more often because they tend to choose more lethal means. Marital status/family support affects risk; those never married have higher risk and those married with children have the lowest. Occupations including police, public safety officers, and physicians are at high risk. Adverse childhood experiences may contribute to suicide, including physical, emotional, and sexual abuse; substance abuse in the home; mentally ill or incarcerated family members; or parents who are separated or divorced.

In MS, up to 15% of all patients die from suicide. The lifetime prevalence rate of depression in MS is 50% and the annual prevalence rate is 20%, yet depression in these patients often goes unrecognized. It is assumed that factors predicting suicide in the general population also apply to those with MS. In a study of veterans with MS, depression severity was the single best risk identifier for suicidal ideation. In addition, MS lesions may directly influence the risk of suicide. Demyelinating lesions and atrophy of the frontal lobes, particularly on the left side, accounted for 42% of the variance in predicting depression in one study of people with MS. Fears that interferons may increase the risk of depression and suicide have not been confirmed in subsequent studies.

It is important that those caring for people with MS recognize depression and assess for suicide risk. Patients at risk should be asked about suicidal thoughts, whether there is a plan for carrying out suicide, and whether there is an intent to follow through with this plan. These patients should be referred for appropriate mental health treatment.

 

Among the large number of new drugs being tested in MS, do any offer new options for treating fatigue?

Francois Bethoux, MD :
I am not aware of any new drugs being tested for MS that specifically target fatigue. There are several components to fatigue in MS. Most people refer to an overwhelming feeling of tiredness that limits a person’s ability to function. There is also fatigability, which refers to the problem of tiring quickly while walking or performing a task.

Fatigue is the most commonly reported symptom by individuals with MS, and a frequent cause of disability. Before concluding that a patient has primary MS fatigue, common causes of secondary fatigue (e.g. anemia, thyroid disorder, medications, depression) must be ruled out. The management of severe MS fatigue must be comprehensive. For example, poor sleep hygiene is a contributing factor that is commonly overlooked. Cooling devices can be used in patients with heat sensitivity; and energy conservation strategies (usually taught by an occupational therapist) can be quite helpful in helping patients use their daily “energy pool” efficiently. Recently, cognitive behavioral therapy has emerged as a promising tool in the management of MS fatigue.

We have good evidence that exercise—particularly aerobic exercise—improves fatigue in MS. As a rehabilitation specialist, I regard this as a first-line approach even before medications for fatigue are tried. However, an exercise program must be tailored to the patient’s ability. Ideally, a physical therapist would design an exercise program that patients can do on their own. By exercising on a regular basis, many patients will see improvement in fatigue.

Several symptomatic medications are used off-label to treat MS fatigue, including amantadine, modafinil, and armodafinil. The use of amphetaminic CNS stimulants is more controversial. Clinical trials of symptomatic medications for MS fatigue have produced conflicting evidence regarding their efficacy. Disease-modifying therapies may indirectly improve fatigue by preventing worsening of MS or decreasing the frequency of relapses.

Dalfampridine is an agent newly approved to improve walking in people with MS. Dalfampridine was not found to be effective on perceived fatigue in early studies. However, because the drug increases walking speed and leg strength, it could help to build physical endurance. Dalfampridine works by blocking potassium channels, increasing conduction of action potentials in demyelinated axons. This drug appears to be effective in both relapsing and progressive MS. It is not expected to help a wheelchair-bound patient recover the ability to walk. While we cannot predict in advance which patients will respond to dalfampridine, efficacy in an individual should be apparent within a few weeks of treatment. There is a risk of seizures associated with this agent, which increases if the medication is taken above the recommended dose. Therefore, patients should be advised to not “double up” on their dose, even if they forgot to take the previous dose. Dalfampridine is contraindicated in patients with a prior seizure disorder or moderate to severe renal impairment, and other forms of 4-aminopyridine should not be taken concomitantly with this drug.

 

Are there any new drugs or approaches to address spasticity in MS?

Francois Bethoux, MD :
While there are currently no new medications for spasticity, there are new developments in the use of existing symptomatic treatments, including oral baclofen, tizanidine, botulinum toxin, and intrathecal baclofen.

Stretching and exercise are first-line approaches to spasticity management that should not be overlooked. Baclofen has been used for many years to treat spasticity in patients with MS, and there is published evidence demonstrating its efficacy. One of the problems with immediate-release baclofen is its short half-life, which leads to the need for multiple doses to cover the daytime and does not ensure control of spasms through the night. Recently, sustained-release formulations of baclofen have been proposed, although to my knowledge none of them has been approved in the United States. Tizanidine is another symptomatic drug commonly used to treat spasticity in MS. Tizanidine is also a short-acting drug, but a capsule formulation, when taken with food, exhibited different pharmacokinetics from the tablet formulation, with delayed and decreased peak plasma levels that could result in reduced side effects.

Two years ago the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology published a review of the evidence supporting the use of botulinum neurotoxin to treat spasticity, and found that this treatment should be offered for adults and children with spasticity, based on Level A evidence. Very recently, the FDA approved onabotulinum toxin A for the treatment of upper extremity spasticity in adults, in a variety of conditions including MS.

Control of spasticity-related symptoms (stiffness, spasms), improved comfort, and improved ease of care are common goals for spasticity management in MS. There is a growing focus on the impact of spasticity management on functional performance, particularly ambulation. For example, there is emerging evidence showing that intrathecal baclofen therapy (baclofen pump), an FDA-approved treatment for severe spasticity refractory to oral medications, can be used in ambulatory MS patients without compromising function. While some MS patients and health care providers may once have viewed the baclofen pump as a “last resort” treatment, it is increasingly considered earlier in the course of the disease. Careful patient selection, risk/benefit ratio evaluation, and goal setting, are key to the success of the therapy.

Some studies suggest that relieving spasticity is not necessarily sufficient to enhance voluntary movement, because of underlying loss of motor control. However, medications such as dalfampridine, and an increasing number of devices, are aiming at restoring or compensating for loss of motor control. For example, a low-cost hip flexion assist orthosis showed promising effects on walking performance in a pilot study conducted in our center. Functional electrical stimulation (FES) devices for active correction of foot drop are currently marketed (but unfortunately not routinely reimbursed).

In summary, the management of spastic paresis from MS has become increasingly complex, and referral to rehabilitation professionals should be considered.

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Sexuality and MS

Are there any medications found to be effective for female sexual dysfunction in MS, specifically loss of libido?

Frederick W. Foley, PhD :
Sexual dysfunction can involve reduced libido (desire), arousal (ability to respond to stimulation), or sensation (such as that caused by nerve damage). Loss of libido can be related to both physiologic and psychological factors. It’s important to do a proper assessment in a woman with MS to determine the likely contributing factors. Some of the common causes of low libido in women with MS include genital numbness, depression, severe fatigue, and side effects from some symptomatic medications. The current disease modifying therapies (DMTs) for MS have not been associated with loss of sexual desire.

Physiologically, testosterone is the sex hormone in both men and women primarily responsible for libido. Currently, the only FDA-approved medication for enhancing libido is supplemental testosterone, but this is appropriate only for those with abnormally low testosterone levels. Low testosterone levels are not caused by MS, but can occur incidentally. If indicated, supplementation can be given orally, by injection, or via a patch. In postmenopausal women, hormone replacement therapy that combines estrogen and a small amount of testosterone is available. Hormone replacement therapies that do not contain testosterone may further suppress libido.

Although not typically associated with MS, other physiologic causes of low libido may include abnormally low thyroid hormone levels, in which case supplementation may help restore sexual desire.

Unfortunately, there are no other approved medications specifically for loss of libido in women with or without MS, representing an important gap in our available treatment options at this time. Among other approved medications, estrogen creams can be applied to the vaginal area to increase blood flow to the genital area, which can improve sexual arousal (but not typically low desire). Phosphodiesterase 5 inhibitors (used for treating erectile dysfunction in men) have some utility for increasing arousal in women, although results in women with MS have been mixed.

Clinical depression is a major cause of sexual dysfunction, including low libido. Proper treatment of depression with psychotherapy and antidepressants can alleviate sexual dysfunction. However, some (but not all) antidepressants can interfere with libido, arousal, and orgasm. In general, antidepressants that affect dopamine pathways in the central nervous system (CNS) cause few sexual side effects, while antidepressants that affect serotonergic pathways in the CNS frequently have sexual side effects. If fatigue is an issue, some stimulants that help decrease fatigue can sometimes improve libido, because they also stimulate dopamine pathways.

A number of alternative and herbal products have been purported to improve sexual function, mainly by increasing arousal. Gingko biloba, L-arginine, damiana leaf, and ginseng are a few of the herbal supplements used as natural aphrodisiacs. As with many herbs, there is fairly little controlled evidence of their efficacy and none of them have been evaluated systematically in people with MS for either safety or efficacy.

Counseling can be effective for managing sexual dysfunction in women with MS, including those with low libido. When possible, counseling should be directed toward the couple rather than the individual. In our work, we have been able to teach women who have MS to increase their receptiveness to sexual signals. Thus, even if the pathways for libido have been compromised, these women can still feel arousal and respond sexually.

 

To what extent is depression a cause of sexual dysfunction in MS? Antidepressant treatment can also cause sexual dysfunction, so isn’t this a double-edged sword?

Frederick W. Foley, PhD :
Depression is a major cause of loss of libido and sexual responsiveness in the general population as well as in those with MS. About 50% of MS patients will experience a major depressive episode—a much higher prevalence than in the general population. At the same time, sexual dysfunction is a common problem among people with MS, even those who are not depressed.

Because of the complexity of this issue, individualized management is key. Appropriate treatment for depression is very important. MS patients with depression have high rates of suicidal ideation and suicide. Depression is also an important cause of poor adherence to disease-modifying therapies for MS.

Clinical trials in MS patients with major depression have shown that both pharmacologic therapy and cognitive behavioral psychotherapy are effective treatment approaches. Interpersonal supportive psychotherapy was not shown to work as well.

If antidepressants are used and the patient is sexually active, it is a good idea to choose one with a lower sexual side effect profile. Selective serotonin reuptake inhibitors (SSRIs), while effective antidepressants, do have a high rate of sexual side effects. In choosing an SSRI, you might try those with a shorter half-life (avoiding extended-release versions) in an effort to reduce sexual side effects. Alternatively, the patient may be prescribed an antidepressant such as bupropion, which works via the dopaminergic system. If patient has history of seizures or anxiety this agent may not be appropriate.

To reiterate: managing depression and sexual side effects, treatment should be highly individualized and lines of communication with the patient must be kept open.

 

Should a practitioner continue to bring up the topic of sexual dysfunction with an MS patient if the patient seems embarrassed or reluctant to discuss the topic?

Frederick W. Foley, PhD :
The brief answer is, no. All MS patients should be asked about sexual function, just as they are asked about gait, bowel, and bladder functioning. In discussions with patients, this topic fits very neatly between bladder and bowel in the review of systems. Studies show that many patients are initially embarrassed to ask about sexuality on their own but may be relieved when the practitioner broaches the subjects in an open and nonjudgmental manner. If patients are truly reluctant to discuss sexuality, that’s okay. The practitioner should reassure these patients that if they change their minds, the topic is open for discussion.

Sometimes the reluctance to initiate a discussion about sexuality actually occurs more on the part of the healthcare provider. In a survey of MS professionals published in the International Journal of MS Care, most respondents said they do ask about sexuality in their assessment of patients with MS. Those who did not cited the following reasons: 1) outside their area of expertise 2) not enough time, 3) uncomfortable with the topic. While those surveyed had high levels of experience with topics related to sexuality, it is possible that a different result might be seen among medical practitioners who were not MS specialists.

 

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Comorbidities

What recommendations do you have for the management of a patient with longstanding MS who has concomitant nephrotic syndrome (receiving prednisone)?

Ben W. Thrower, MD :
The doses of prednisone used to manage nephrotic syndrome may not be high enough to have a significant impact on the patient's MS. If the person has a relapsing form of MS, he or she would likely still need to be on an immunomodulatory agent. Rare cases of nephrotic syndrome have been reported with beta interferons, therefore one could argue that glatiramer acetate may be a better choice if a disease-modifying therapy is to be started. If MRIs are done in the patient with nephrotic syndrome, caution may be warranted due to the risk of gadolinium-induced nephrogenic systemic fibrosis in patients with low glomerular filtration rates.

 

In your opinion, is the H1N1 vaccination safe for those with multiple sclerosis?

James D. Bowen, MD :
The National MS Society and our clinic recommend influenza vaccinations, as well as other routine vaccinations, for people with multiple sclerosis.

Vaccination does not influence the onset of multiple sclerosis. In a study of 440 people with MS published in 2003, the risk of having MS was not influenced by prior immunizations. There was no increase in MS in those receiving vaccinations anytime in the past, within the past one to five years, or within the past year. Vaccinations for hepatitis B, influenza, tetanus, measles, and rubella were studied.

Similarly, vaccination does not cause attacks in those already diagnosed with MS. In a large European study, vaccination in the past one, two or three months was not associated with an increased risk of MS attacks. This study looked at tetanus, hepatitis B and influenza vaccines. In a smaller study of 104 subjects with MS, those who received influenza vaccination had the same rate of MS attacks in the following six weeks as those receiving placebo. There is no evidence that tetanus, hepatitis B, or influenza vaccines cause MS attacks.

Those who are not vaccinated have an increased risk of getting the flu. For most people, this is an inconvenience with no major health consequences. In some cases, a viral infection can trigger an MS attack. Those who do not get vaccinated risk having an MS attack from an infection. However, those with weakness of breathing muscles or swallowing difficulty are at risk of complications from colds, influenza, and pneumonias because of limited coughing ability. People over age 50, those living in group settings, or women in the last six months of pregnancy are also at increased risk.

Interferons (Avonex®, Betaseron®, Rebif®) and glatiramer acetate (Copaxone®) have no adverse effect on vaccination. Natalizumab (Tysabri®) has no know effect on vaccination, but many recommend using only inactivated vaccines for those receiving this medication. People receiving immunosuppressive medications (mitoxantrone, azathioprine, methotrexate, cyclophosphamide, rituximab, IVIG, long-term steroid use) should also be treated with inactivated vaccines rather than live vaccines.

Some vaccines have live but weakened virus. These have no known harm in MS, but nevertheless many experts recommend avoiding them in the setting of MS. This includes nasal influenza vaccines (injected vaccines are acceptable), MMR (measles, mumps, rubella), oral polio and others. In our clinic, we recommend that patients receive routine vaccinations, including influenza vaccinations and H1N1 vaccination.

 

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Progressive Stages of MS

For patients with secondary progressive MS who no longer have relapses, is it wise to stop disease-modifying therapies such as interferon or glatiramer acetate?

Fred D. Lublin, MD :
Available data suggest that once a certain disability threshold has been reached, a common disease progression pathway occurs in both relapsing and progressive forms of the disease. The primary goal of therapy in relapsing disease is to avoid progression to this threshold of disability. However, a major shortcoming of our current state of knowledge in MS is how to determine whether a patient is responding to a disease-modifying therapy (DMT). Unfortunately, validated or even consensus definitions of therapeutic failure or “suboptimal response” are lacking.

Also unknown is the precise role that inflammatory activity plays at the later stages of the disease. It is generally recognized that inflammation is active in the early stages of disease, but recent autopsy studies have revealed the presence of inflammatory cells in the brain tissues of individuals with advanced progressive disease and significant axonal damage.

The disease course in MS is highly variable and often completely unpredictable. A common reason for patients to stop taking a DMT is the perception that they are no longer responding to therapy. In fact, there may be some aspects of disease progression that cannot be affected by any DMT. How long to keep patients on a particular DMT before stopping or switching therapy is part of the shared decision-making process of the healthcare practitioner and the patient. However, if a patient with MS had frequent exacerbations prior to starting a DMT and no longer has relapses while on therapy, is the lack of relapses due to disease progression or to the effect of therapy? In these cases one might reasonably elect to continue the medication unless the patient willing to take a chance on worsening disease if therapy is discontinued.

 

What can we do to encourage MS patients who have advanced to the secondary progressive stage? We advise programs involving exercise, diet, and cognitive support, but there are no specific medications. Aside from medications to treat fatigue, what else can be offered?

Howard L. Zwibel, MD :
Treatment of secondary progressive MS (SPMS) involves a comprehensive multidisciplinary approach with emotional, physical and pharmacologic intervention. Mitoxantrone is approved for secondary progressive MS, but many clinicians are reluctant to use the drug in light of newer data reported at ECTRIMS 2009 on the increased risk of cardiotoxicity and treatment-related leukemia relative to earlier estimates.

Patients who are treated early in the progressive stage may benefit from the use of cyclophosphamide. A small cohort of males with primary progressive MS was shown to benefit from glatiramer acetate treatment in one trial. Among the large number of emerging agents being studied for MS, several are being tested in progressive as well as relapsing-remitting forms of MS. In addition, we are hopeful that fampridine, a potassium channel blocker shown to increase walking speed at all stages of MS, will be approved as a new symptomatic therapy.

A multidisciplinary approach to the care of these patients should ensure that their unmet needs are being considered, including emotional issues, employment factors, use of assistive devices, evaluation of the home, etc. Much of this can be accomplished through the local chapter of the National Multiple Sclerosis Society.