Research Highlights from the AAN and CMSC 2018 Annual Meetings

The cascade of research driving advances in multiple sclerosis (MS) continued at the same heightened pace in the first half of 2018. The results of numerous significant studies were reported at the Annual Meeting of the American Academy of Neurology (AAN), held in Los Angeles in April, and the Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC), which took place in Nashville in May. We have summarized some of the most interesting findings from those conferences in this update.

Disease-Modifying Therapies in the Research Pipeline

The treatment options for people with MS are likely to continue to expand in the years just ahead, as several disease-modifying therapies (DMTs) are in late stages of clinical development and/or are under review by the United States Food and Drug Administration (FDA). Five noteworthy studies of such “pipeline” medications are summarized here.

Cladribine and magnetic resonance imaging (MRI) outcomes

Cladribine is an oral medication taken for up to 20 days over a period of two years. It selectively targets the immune system’s B cells and T cells, leading to depletion of those cells followed by a distinct pattern of “reconstitution” as new B cells and T cells are produced. It is approved for use in relapsing-remitting MS (RRMS) in several countries, but is not yet approved for use in the United States.

In the Phase III CLARITY study, cladribine showed efficacy when compared to placebo over the course of two years of use by people with RRMS. A post-hoc analysis of that study’s data examined the impact of cladribine on a subset of individuals who had high disease activity as measured by relapses, MRI findings, and other characteristics.1

The analysis found that the effectiveness of cladribine versus placebo in this subpopulation was comparable to that seen in the overall CLARITY population in terms of reducing MRI markers of disease activity. This includes reducing such MRI markers as cumulative new T1 gadolinium-enhancing lesions and cumulative combined unique active lesions.

This post-hoc analysis did not focus on safety. However, in the CLARITY study from which this analysis’ MRI data were derived, certain adverse events occurred more frequently in the cladribine groups than in participants receiving placebo. These adverse events included lymphocytopenia (21.6 percent in the 3.5-mg cladribine group and 31.5 percent in the 5.25-mg group, versus 1.8 percent in the placebo group), and herpes zoster (eight patients and 12 patients, respectively, versus no patients).2

As clinicians experience continued progress in treating MS overall, an increasing focus is placed on improving outcomes in people with high disease activity. Studies of this type help provide informed treatment strategies for these individuals.

Predictors of opicinumab treatment effect

Opicinumab is a monoclonal antibody that targets LINGO-1, a protein in the central nervous system whose role is to halt myelination (repair of the protective covering of the nerves) and prevent the survival of neurons (nerve cells). The SYNERGY trial assessed various doses of opicinumab, given by intravenous infusion, in combination with interferon beta-1a, over the course of 72 weeks in people with relapsing forms of MS (RMS).

The results showed a sort of “inverted U” effect with more favorable outcomes in the 10 mg/kg and 30 mg/kg dose groups, indicating that other factors may have been involved in how the participants responded. That finding prompted investigators to explore those factors associated with a better response to opicinumab.3 Their post-hoc analysis identified three factors associated with better response to the medication: shorter disease duration (less than 20 years); lower baseline magnetization transfer ratio values in T2 lesions, which may signify lower myelin content in those lesions; and lower baseline diffusion tensor imaging-radial diffusivity values in T2 lesions, a characteristic that may be consistent with greater structural integrity.

Practicing “precision medicine” involves identifying those factors that enable clinicians to give the right medication to the right patient at the right time. As this study shows, that effort may entail drawing on highly technical, and possibly even less understood, biomedical characteristics and concepts in the service of individualizing care.

Ublituximab and central nervous system lesions in relapsing MS

Ublituximab is a monoclonal antibody given by infusion. Like Ocrevus®, ublituximab targets the CD20 molecule. Researchers evaluated 24-week data from a Phase II trial of the medication in people with relapsing forms of MS. Among 31 individuals who had a total of 73 T1 gadolinium-enhancing (Gd+) lesions on MRI at baseline, no T1 Gd+ lesions were found at Week 24.4 Additionally, T2-lesion volume decreased by 8.1 percent from baseline to Week 24, prompting the authors to conclude that ublituximab has “robust efficacy” on MRI endpoints.

Ozanimod in relapsing MS

Ozanimod is an oral, once-daily medication being evaluated for use in RRMS. It is a selective modulator of two types of S1P receptors: S1P1 and S1P5. Data from two Phase III studies, SUNBEAM and RADIANCE Part B, show that ozanimod, given at 1 mg/daily and 0.5 mg/daily, had favorable outcomes relative to Avonex® (interferon beta-1a) – both in terms of annualized relapse rate (ARR) and MRI findings.5 Annualized relapse rate, or ARR, refers to how many relapses a person in a particular study group is likely to have, on average, over a one-year period. For example, if the placebo group in a clinical study had an ARR of “1,” the average person in that group could expect to have one relapse per year.

Ozanimod, given at doses of either 1.0 mg or 0.5 mg, reduced the ARR by 48 percent and 31 percent respectively, compared to interferon beta-1a in the SUNBEAM trial. In these same doses, it also reduced the ARR by 38 percent and 21 percent respectively, compared to interferon beta-1a in the RADIANCE trial. Meanwhile, the adjusted mean number of new or enlarging T2 lesions was reduced by 25 percent to 48 percent in people taking ozanimod versus those receiving interferon beta-1a. Additionally, the individuals taking ozanimod had fewer adverse events overall and fewer adverse events leading to study discontinuation.

Siponimod, relapses, and disability progression in secondary-progressive MS

Siponimod is an oral medication being studied for use in secondary-progressive MS (SPMS). Its mechanism of action is similar to that of Gilenya® (fingolimod), in that it works at the S1P receptor family to block the movement of lymph cells from lymph nodes; however, siponimod appears to interact with fewer of the receptors than Gilenya does – with its primary actions at the S1P1 and the S1P5 receptors, the same receptors that ozanimod targets.

The Phase III EXPAND study showed that siponimod reduced confirmed disability progression (CDP). Investigators analyzed the results of that trial to understand to what extent, if any, this effect was related to a reduction in relapses.6 This information is important to uncover, because it could have implications for the effectiveness of the medication in people who do not experience relapses or who have very infrequent relapses. Using sophisticated statistical analyses, the researchers concluded that, “Siponimod treatment reduces the risk for CDP in both relapsing and non-relapsing SPMS patients. Our analyses suggest that siponimod’s effect on disability is largely independent from the effect on relapses.”

Long-Term Efficacy and Safety of Approved DMTs

Research into the safety and effectiveness of a DMT does not stop when that medication wins approval from the FDA. Several recently reported studies provide ongoing information on approved DMTs or findings from focused analyses of data from those medications’ major Phase III clinical trials. Highlights from several such studies are reported below.

Ocrevus® (ocrelimzumab)

Ocrevus® (ocrelimzumab) was approved by the FDA in 2017 for RMS and PPMS. The medication is administered by IV infusion, with 600 mg given every six months. The safety and efficacy of Ocrevus were assessed in two large clinical trials, OPERA I and OPERA II, in which individuals with relapsing MS received either Ocrevus or Rebif® (interferon beta-1a).

At the end of those trials, study participants were allowed to continue on Ocrevus or switch from Rebif to Ocrevus during a so-called “open-label extension” (OLE) period. A recent analysis found that switching from Rebif to Ocrevus at the start of the OLE period was associated with rapid and significant reductions in disease activity as identified on magnetic resonance imaging (MRI). Patients who changed therapies in the OLE went from having an adjusted number of 0.48 T1 gadolinium-enhancing lesions per scan prior to switching, to an average 0.00 such lesions per scan after one year and two years on Ocrevus.7

Tysabri® (natalizumab)

Tysabri® (natalizumab) is a monoclonal antibody that is administered by IV infusion of a 300-mg dose every four weeks. The medication was approved for use in adults with relapsing MS in 2004. However, Tysabri was voluntarily withdrawn from the market the next year after three cases of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal brain infection caused by the JC virus, were identified in individuals taking the medication. Tysabri became available again in 2006, following implementation of a comprehensive risk-management program, which includes testing potential Tysabri users to see if they have anti-JC virus antibodies.

Now, a team of New Zealand researchers have reported favorable results with administering Tysabri every six weeks rather than every four weeks, noting that they pursued extended-interval dosing with a view toward reducing the risk of PML.8 Those investigators report that after administering Tysabri at six-week intervals to 27 patients for an average of two years, none of the participants had lesions on MRI, and only one reported relapse. No participants were diagnosed with PML. This treatment strategy reflects ongoing efforts across the MS treatment spectrum to balance efficacy and safety to the patient’s maximal advantage.

Aubagio® (teriflunomide)

Aubagio® (teriflunomide) was approved in 2012 for use in relapsing MS. It is an oral medication administered as 7-mg or 14-mg once daily. An analysis of long-term data on patients with relapsing MS who participated in two Phase III trials of the medication and the extensions of those trials found that 74 percent taking the 14-mg dose had stable or improved Expanded Disability Status Scale (EDSS) scores over five years.9 Mean EDSS scores at five years were higher (indicating disease progression) in those who experienced a relapse, compared with those who did not – at 2.70 and 2.43 respectively.

A separate study examined 169 pregnancies in women who took Aubagio during pregnancy.10 Based on findings of teratogenicity – an elevated incidence of birth defects – in animal studies, use of the medication is contraindicated in pregnant women and females of reproductive potential not using effective contraception. Nonetheless, some women have taken the medication shortly before conceiving or while pregnant.

In this study, the final dose of Aubagio was administered pre-conception or in the first trimester in all but four cases. Outcomes were known for 67 of the 169 pregnancies. Two structural abnormalities were reported: one case of congenital hydrocephalus in a full-term pregnancy and one cystic hygroma (a fluid-filled sac resulting from a blockage in the lymphatic system) detected on ultrasound during pregnancy (with the outcome of that pregnancy unknown). Researchers concluded that the current data from pregnancies exposed to teriflunomide show no warning signs of a treatment-related increased risk for birth defects.

Lemtrada® (alemtuzumab)

Lemtrada® (alemtuzumab) is a monoclonal antibody approved for use in RMS in 2014. It is administered by intravenous infusion over four hours for two multi-day treatment courses 12 months apart. Researchers recently analyzed data on 393 individuals who had participated in clinical trials of Lemtrada and then remained on the medication during a longer-term extension study.11

The researchers found that after using Lemtrada for six years, 77 percent of the more than 300 patients studied showed stable or improved Expanded Disability Status Scale (EDSS) scores compared to their baseline scores. Additionally, 43 percent achieved a six-month confirmed disability improvement (CDI), further underscoring the long-term benefits of treatment.

Another analysis examined outcomes in extension-study patients who received re-treatment with Lemtrada due to disease activity after the initial two courses of therapy.12 Among 178 participants who received at least one re-treatment, the annualized relapse rate (ARR) fell from 0.85 (12 months before receiving a third course of Lemtrada) to 0.20 (12 months after the third course). The percentage of individuals with a CDI increased from 4 percent to 14 percent over those two time periods. Researchers concluded, “Patients who were re-treated due to relapse and/or MRI activity after the initial two courses demonstrate continued alemtuzumab [Lemtrada] efficacy after [Course 3] with reduced relapses and stable or improved disability.”

Glatiramer acetate

Glatiramer acetate is an injectable DMT approved for use in relapsing forms of MS. It is available both as a branded medication (Copaxone®) and in generic form from two other companies. In a one-year, placebo-controlled study, administering the medication in a dose of 40 mg/mL three-times weekly reduced the annualized relapse rate (ARR) by 34 percent and MRI disease activity by 34.7 percent relative to placebo.

A new analysis shows that those benefits were sustained for up to five years in people participating in the open-label phase of the study, which was supported by Teva.13 The overall ARR during the entire long-term follow-up period was 0.26 for individuals who started on glatiramer acetate in the placebo-controlled phase of the study, and was 0.32 for those who switched from placebo to glatiramer acetate in the open-label phase. Researchers added that the most common adverse events seen over the long term were generally mild and consistent with the medication’s established safety profile.

Interferon beta-1b

Interferon beta-1b was the first DMT approved for use in MS, and today is available in branded form as Betaseron® and Extavia®. A 23-year observational follow-up study was conducted with 87 patients treated at the Henry Ford Health System in Detroit.14 The study found that 29 percent of individuals used the medication for less than one year, while 18 percent remained on therapy for more than 15 years. Of the individuals who stopped treatment, side effects were the reason cited most often in those who discontinued therapy before five years of use, while lack of efficacy was given as the reason for stopping in those who used the medication for longer periods.

Impact of discontinuing DMTs

A stable disease course on a DMT does not predict continued stability after discontinuing that therapy, regardless of a person’s age.15 Noting that clinicians sometimes recommend stopping DMT therapy as individuals with MS get older, researchers assessed the advisability of this strategy by examining data from the New York State MS Consortium (NYSMSC) database.

Of 135 patients who were considered stable on DMT therapy as determined by minimal change in EDSS score, 35.6 percent saw their EDSS score worsen after stopping their DMT. Age did not affect post-discontinuation course, with 34.1 percent of people age 54 years and younger and 37.7 percent of people age 55 years and older recording unfavorable changes in their EDSS scores after going off a DMT.

Comparative Analyses of Approved DMTs

People with MS and their healthcare providers today face a “welcome dilemma” unimaginable even 20 years ago. With more than a dozen disease-modifying therapies (DMTs) now approved by the FDA for use in adults, patients and clinicians have an opportunity (and challenge) to select the medication likely to best address the each individual’s specific health status and needs. That can be a daunting prospect, particularly because few clinical trials have directly compared one agent with another.

Given the scarcity of such studies, investigators often rely on sophisticated analytical methods – such as propensity scoring and other techniques – to assess the merits of one agent relative to others. Those methods, while useful, typically are considered by physicians to be less authoritative than a head-to-head trial of two agents. This section highlights five recently presented studies that compared agents within the same trial or via analysis of data drawn from different trials or large patient databases. In considering various treatments, however, it is critical to not only look at clinical trial data and other analyses, but also for individuals to talk with their clinician about their specific history and circumstances – in order to individualize their care and achieve an optimal effect.

DMT impact on cognition in patients at increased risk of progressive disease

The OPERA 1 and OPERA 2 trials were identical Phase III studies that compared the effectiveness and safety of Ocrevus® (ocrelizumab) to Rebif® (interferon beta-1a) in people with relapsing MS. Study participants received either 600 mg of Ocrevus every 24 weeks or 44 ug of Rebif three times a week for 96 weeks.

The studies included 186 individuals receiving Ocrevus and 180 receiving Rebif who were considered to be at increased risk of progressive disease based on their Expanded Disability Status Scale (EDSS) and pyramidal Kurtzke Functional Systems scores. Participants completed the Symbol Digit Modalities Test (SDMT) at baseline and during the course of 96 weeks to assess their cognitive function. Over the study period, individuals receiving Ocrevus who were at increased risk for disease progression had a greater mean improvement in SDMT scores than did increased-risk individuals receiving Rebif (6.2 for Ocrevus versus 2.6 for Rebif).16

Assessing DMTs in terms of annualized relapse rates

Annualized relapse rate (ARR) is a measure of a DMT’s impact on disease course in MS. Researchers drew on data from two studies of Plegridy® (peginterferon beta-1a) and two studies of Aubagio® (teriflunomide) to assess the ARR in newly diagnosed individuals starting one or the other of those medications.17

The participants had been diagnosed with relapsing MS within one year of study enrollment and had not taken other DMTs. The investigators used individual patient data from the studies to match analyzed subjects by key baseline characteristics. Their analysis showed that at 108 weeks after treatment initiation, the ARR was numerically lower in newly diagnosed individuals receiving Plegridy than in newly diagnosed Aubagio patients. However, this difference was not statistically significant.

In a separate study, a German network of more than 130 neurologists drew on its database of roughly 25,000 individuals with relapsing-remitting MS (RRMS) to assess various DMTs in terms of ARR.18 The analysis found that Tecfidera® (dimethyl fumarate) had a statistically significant reduction in ARR versus interferon medications. Tecfidera also performed better than the other agents in terms of time to first relapse.

A third study assessed the ARR in people with highly active RRMS who switched to either Tysabri® (natalizumab) or Gilenya® (fingolimod) after inadequate response to DMTs that are considered first-line therapies in Europe. Such medications include interferon medications, glatiramer acetate, Aubagio, and Tecfidera.19

Researchers analyzed data for 897 “patient triplets” or matched sets of individuals who either switched from one first-line therapy to another or from a first-line therapy to Tysabri or Gilenya. The study drew from the MSBase Registry, an international online registry for neurologists studying multiple sclerosis and other neuro-immunological diseases. The analysis found that after switching, individuals moving from a first-line therapy to Tysabri had an ARR of 0.21; those moving to Gilenya had an ARR of 0.30; and those switching from one first-line therapy to another had an ARR of 0.33. The ARR was statistically significantly reduced for Tysabri, with no evidence of difference for Gilenya.

MRI outcomes in those with pediatric-onset MS

Earlier this year, Gilenya® (fingolimod) became the first DMT approved to treat relapsing MS in adolescents and children aged 10 years and older. This medication was approved for use in adults with RMS in 2010.

The Phase III PARADIGMS study compared use of Gilenya to interferon beta-1a for up to two years in 214 individuals aged 10 to 17 years with pediatric-onset MS. At the end of the study, Gilenya reduced the annualized rate of new or newly enlarging T2 lesions by 52.6 percent and the number of gadolinium-enhancing T1 lesions per scan by 66.0 percent compared with interferon beta-1a.20

New Diagnostic Testing

The early recognition of MS and the evidence-based assessment of likely disease course are critical to patients’ and physicians’ ability to engage in shared decision-making on treatment choices and overall wellness strategies. A significant amount of research is being conducted to map the connections between imaging findings or biomarker levels and establishing the diagnosis and predicting the course of MS. Other studies are focused on what measures of physical function may reveal about current and future health status. Several recent studies exploring these issues are highlighted below.

2017 McDonald Criteria apply well to children at MS onset

MRI findings play a key role in the diagnosis of MS, but most research on the significance of imaging results has been focused on adults. Now, a study by investigators from The Children’s Hospital of Philadelphia and other institutions, has found that the 2017 McDonald Criteria are largely applicable to children, as well as adults, when assessing patients at clinical disease onset.21

The researchers assessed more than 2,800 MRI scans from 331 pediatric patients with MS, acquired demyelinating syndrome, and related conditions, and followed those patients’ course over a median of six years. They found that the presence of ≥one T1-hypointense lesions or ≥one periventricular lesions were the MRI features most predictive of MS outcome.

The 2010 McDonald criteria and 2017 version of those criteria had comparable utility in predicting a pediatric patient’s disease course, but the investigators said the 2017 criteria were easier to apply. “Both ‘black holes’ and periventricular lesions at baseline are strong predictors of MS” in children, as they are in adults, the researchers concluded, adding that evidence of new disease activity is required to confirm MS in children who present with acute disseminated encephalomyelitis (ADEM).

Location of brain lesions predictive of walking speed

The presence of MRI-detected lesions in the infratentorial/cerebellar region of the brain is associated with slower walking speed in people with MS, according to a retrospective chart review of 82 individuals.22 A team of Connecticut-based researchers reviewed magnetic resonance images and medical records to determine whether the location of lesions in four areas of the central nervous system – the spinal cord, and the infratentorial/cerebellar, juxtacortical, and periventricular regions of the brain – was associated with mobility and disability in people with MS. No significant relationship was found between number of CNS regions with lesions and Extended Disability Status Scale (EDSS) score or time in performing the Timed 25-Foot Walk test. Similarly, no significant relationship was seen between the presence of lesions in any one region of the CNS and EDSS score.

Higher number of oligoclonal bands correlates with relapses and disease progression

People with relapsing-remitting MS (RRMS) who had 10 or more oligoclonal bands (OCBs) in their cerebrospinal fluid (CSF) samples were far more likely to have relapses and disease progression over the ensuing two years than individuals with RRMS who had <10 OCBs in their CSF samples.23 That was the finding from a retrospective study of 128 people with RRMS on DMT therapy.

Researchers from the University of Pennsylvania also found that in addition to having more relapses and more new lesions on MRI, people with ≥10 OCBs were more likely to begin using an assistive device relative to their counterparts with fewer OCBs. “As OCBs may have greater diagnostic weight going forward, the quantity may be important in guiding selection of DMTs,” the study’s authors noted.

Tapping into a new means of assessing MS subtype and mobility

The number of times a person with MS can tap his or her foot in 10 seconds correlates with MS subtype and with results of mobility measures such as the 25-Foot Walk Test (25FWT). This finding was discovered by researchers from the University of Massachusetts Amherst and related institutions.24

In a study of 30 people with non-progressive MS, 30 with progressive MS, and 17 age- and sex-matched healthy controls, 10-second tap counts distinguished people with MS from healthy controls, and those with progressive MS from their peers with non-progressive MS. Further, slower foot tapping correlated with slower performance on the 25FWT and Timed Up and Go test (TUG).

“The associations between foot tap speed and mobility measures, such as the TUG test and 25FWT, suggest that rapid foot-tapping may be a useful marker for tracking or predicting progression of mobility dysfunction in people with MS, regardless of their ability to ambulate,” the researchers noted.

Various Strategies for Wellness and Symptom Management, Physical Activity and Exercise, Vitamin D, and Reproductive-Health Topics

People with MS often must contend with a wide range of issues affecting their quality of life, overall health status, and general well-being. As the nature and impact of those issues have become better understood in recent years, an array of healthcare professionals – from psychologists and physical therapists to health educators and epidemiologists – are analyzing databases and devising innovative programs to further define and more effectively address challenges involving everything from insomnia to infertility. To follow are highlights of research in these areas. These were reported earlier this year at the Annual Meetings of the American Academy of Neurology (AAN) and the Consortium of Multiple Sclerosis Centers (CMSC).

Laughter – is it really the best medicine?

Well, maybe not the absolute best medicine, but apparently good medicine when it comes to addressing depression in people with MS and other neurologic conditions. Researchers at Evergreen Health in Kirkland, Washington, conducted a prospective, open trial of laughter therapy (LT) for 31 participants: 17 with MS, eight with Parkinson’s disease, two with spinal cord injury, and the remainder with other disorders of the central nervous system.25

After participating in eight, 60-minute laughter therapy classes taught by a certified LT instructor (yes, there is such a thing), participants who completed the course saw an improvement from baseline in their scores on a measure of depression. Scores on a separate measure of anxiety essentially were unchanged from baseline.

“Our findings show that LT may reduce depression and be administered across a variety of neurological deficits, including for people with limited exercise options due to severe disability,” the researchers noted. However, they added that the approximate 50 percent attrition rate – with 14 participants not completing the program – may indicate a potential shortcoming for when the intervention is employed in people with neurological conditions.

Comparing strategies for stress reduction in people with MS

Both mindfulness-based stress reduction (MBSR) and group education on stress reduction can provide short-and long-term benefits to people with MS, according to a randomized study involving 62 adults with MS and Expanded Disability Status Scale (EDSS) scores of ≤8.0.26 Compared to their status at the start of the study, people in both groups experienced significant reductions in stress both eight weeks and 12 months after participating in an MBRS program or group education.

Both groups also saw improvement on a measure of emotional well-being at eight weeks, but that improvement was no longer statistically significant at 12 months. No significant differences were found between the two groups in terms of degree of stress reduction achieved or improvement in emotional well-being, suggesting that both approaches are viable options for addressing the stress and other emotional issues that can be part of living with MS.

Addressing insomnia in MS

Cognitive behavioral therapy (CBT) may improve insomnia symptoms, sleep quality, and fatigue in the roughly 40 percent of people with MS who experience chronic insomnia, according to an ongoing study.27 Seven people have completed the randomized controlled trial thus far, with five participating in a six-week program of CBT for insomnia and two serving as controls.

The CBT group showed a 78 percent improvement from baseline on a measure of insomnia symptoms, compared to a 38 percent improvement in the control group. Similarly, sleep quality improved by 63 percent for people in the CBT group and 32 percent in the control group. Additionally, two measures of fatigue showed improvements of 70 percent and 50 percent, respectively, for people receiving CBT, versus a 37 percent improvement and 20 percent worsening, respectively, for control group members.

Can shared medical appointments enhance wellness in MS?

So much needs to happen in an MS patient’s regular visit with his or her clinician. As a result, education on wellness, managing co-morbidities, and other important topics can get lost in the time crunch.

Two researchers from Cleveland explored whether shared medical appointments, or SMAs, may be a solution to that problem.28 In the typical SMA model, individual appointments for patients are scheduled around a time set aside for group instruction and discussion. In this case, the Cleveland researchers offered a monthly SMA, with group sessions covering topics such as nutrition, therapeutic yoga, and guided imagery.

Thirty-three patients attended at least one SMA, with 45 percent of those participants returning for at least one more SMA, and 36 percent attending three or more sessions. Patient-satisfaction assessments found 75 percent of participants had a favorable view of the value of the information presented and regarding attending future SMAs. Female patients attended preferentially relative to men, noted the researchers, adding that “encouraging wellness interventions at an earlier age and to wider demographics and disability level” may encourage more people with MS to adopt healthy lifestyle practices.

Laying the foundation for ongoing exercise

Becoming physically active is a challenge for people with MS – and for all people, for that matter. Staying active after completing a formal physical therapy or exercise program can be even more of a challenge. However, two New York City physical therapists have reported success in encouraging ongoing physical activity among seven of eight participants in a six-week wellness exercise class (WEC) they conducted.29

All eight of the program’s participants recently had been discharged from outpatient physical therapy. The weekly exercise class that they then entered consisted of 60 minutes of progressive aerobic and resistance training, as well as stretching. Upon completing the six-week class, participants showed improvement from baseline on several measures of the physical and psychological impact of MS. And, in keeping with the adage that success begets success, at a follow-up four weeks after completing the class, seven of the eight class members reported being active in an independent gym program.

The researchers concluded, “Providers should work with physical therapists to assure that, after rehabilitation, affordable opportunities such as group WEC exist to help those with MS have the opportunity to independently engage in an exercise program. This bridge between therapy and discharge could safely enhance adherence to exercise post rehabilitation, and potentially decrease the need for a future prolonged course of PT.”

Research supports maximal strength training for people with MS

Properly supervised maximal strength training (MST) is safe for people with MS and can help improve their strength, balance, and walking speed, according to a team of researchers from Hunter College in New York City.30 Those researchers conducted a pilot study in which nine people with MS (six women and three men) participated in an eight-week program. The twice-weekly sessions involved leg press, knee flexion, and ankle plantarflexion, with weights increased based on participant capability and preference.

At the end of the exercise program, the participants showed significant improvement from baseline in the Six Minute Walk Test and Mini-BESTest. Meanwhile, measures of fatigue and spasticity did not change significantly from the study’s start until its end, suggesting that the strength training did not increase fatigue or spasticity. The researchers noted that while the study is ongoing, the results to date suggest that “MST is a safe and effective intervention, and that [people with multiple sclerosis] can benefit from a higher intensity of intervention than might have previously been thought.”

Physical activity and Vitamin D levels in MS

Time spent in physical activity correlates with higher Vitamin D concentrations in people with MS, according to a study of 23 women and 15 men with multiple sclerosis and an Expanded Disability Status Scale (EDSS) score of ≤4.0.31 Researchers used an activity-monitoring device, patient diaries, and measurement of Vitamin D blood levels to follow patients over a one-month period. The participants did not take Vitamin D supplements before or during the study.

The fact that study participants who were more physically active had higher levels of Vitamin D than those who were not as active – despite the fact that they were not taking the Vitamin D supplements, is intriguing. This is because many MS patients have lower-than-normal Vitamin D levels, and because physical activity has been shown to improve outcomes in MS. The study’s authors noted that alternative pathways leading to the connection between disease progression and Vitamin D levels need to be considered.

Long-term reduction in spasticity seen with intrathecal baclofen therapy

Five years after implantation of a pump to deliver intrathecal baclofen therapy, both ambulatory and non-ambulatory people with MS had significant reductions in spasticity, according to researchers from the Cleveland Clinic Mellen Center and related institutions.32 Those researchers examined the records of 77 individuals (40 ambulatory and 37 non-ambulatory) who had a pump implanted between 2001 and 2014, and for whom at least three years of follow-up data were available.

The patient’s mean age at surgery to implant the pump was 47.1 years; 62 percent of the patients were women. For ambulatory patients, spasticity as measured by the Modified Ashworth Scale (MAS) improved from 14.5 (range 10.8-20.25) at baseline to 2 (range 0-8) after five years on IBT. For non-ambulatory patients, MAS score improved from 24 (range 16.5-26) to 2 (range 0-5) after five years of IBT. Pain scores also improved significantly in both groups.

Dalfampridine, physical therapy, and gait in MS

Physical therapy (PT) has been shown to improve gait speed in people with MS. The medication dalfampridine extended-release (DER) also can increase gait speed in those with MS, but only about 38 percent of individuals experience this benefit. Now, the results of a small study support combining the interventions in people with MS who do not see a 20 percent or greater improvement in their Timed 25 Foot Walk test (T25W) after three weeks on the medication.33

The study involved eight adults with MS. Four of those people had been taking DER for three weeks and did not have a ≥20 percent improvement in T25W at the end of that period. They continued on DER for another six weeks, but also engaged in twice-weekly physical therapy during that period. The other four participants did not receive DER but also engaged in six weeks of twice-weekly PT. Among the DER + PT patients, T25FW results improved by 20.7 percent from Week 3 to Week 9, while the PT-only group had a 6.8 percent improvement in T25W during that period.

Infertility and MS – findings from a large database analysis

Women with MS are more likely to have a diagnosis of infertility, less likely to use infertility medications, and less likely to have a live birth than their age-matched peers without MS.34 Those are the main findings from an analysis of United States’ commercial insurance claims for 117,041 women with MS and more than 1.4 million women without MS.

The analysis, which spanned the period from 2006 through 2015, found that 8.52 percent of women with MS and 8.02 percent of those without MS had a diagnosis of infertility. While that percentage difference is small, the researchers noted that it is statistically significant. Similarly, a significantly lower proportion of women with MS used any fertility treatment relative to women without MS (1.01 percent versus 1.19 percent). Finally, the rate of live births in women on any infertility treatment was 5.00 percent among women with MS, compared with 6.98 percent among those who did not have MS.

Reassuring news on pregnancy and MS

Data from the New York State Multiple Sclerosis Consortium (NYSMSC) provide reassuring news regarding both the incidence of relapses during pregnancy and the near-term effect on infants of maternal use of DMTs in pregnancy.35 Among 109 women who reported a pregnancy after being diagnosed with MS, 48.6 percent had a relapse in the two years before becoming pregnant, but just 11.9 percent reported a relapse during pregnancy. Those relapses were more common in the first and second trimesters than in the third trimester.

Meanwhile, 45.8 percent of the women reported a relapse in the first two years after birth, with most of the relapses occurring in the first year after delivery. Women who had experienced a relapse in the 24 months before pregnancy were more likely than others to have a relapse in the 24 months after birth, while relapse during pregnancy was not associated with postpartum relapse.

Eleven of the women in the analysis were on disease-modifying therapy (DMT) for at least part of their pregnancy, with six continuing to use their DMT through their entire pregnancy. None of those women reported birth problems, and none of their children had been referred for special medical services at age 1 or 2 years.

Hot Topics in MS: Stem Cells, Lipoic Acid, Diet and MS, Obesity and MS, Gut Microbiome, and Medical Marijuana

Research into interventions for MS extends far beyond the important efforts to develop new pharmacologic treatments and to better understand the efficacy and safety profile of currently approved medications. Increasingly, investigators are assessing the impact of diet, the gut microbiome – a key component of the immune system – and various substances as they look for ways to manage symptoms and improve outcomes.

Studies also are exploring the role of two very different types of interventions long used to treat other conditions — medical marijuana and stem-cell transplantation – in MS. This section reviews pertinent findings in these and other areas reported at the 2018 Annual Meetings of the American Academy of Neurology (AAN) and the Consortium of Multiple Sclerosis Centers (CMSC).

When relapses continue while taking a DMT – a role for stem-cell therapy?

An international team of researchers is assessing the role of stem-cell transplantation for individuals with highly active RRMS who continue to have relapses despite taking a DMT.36 At the AAN’s annual meeting, those scientists reported interim results from their Multiple Sclerosis International Stem cell Transplant (MIST) trial.

The study involves 110 individuals with RRMS on a DMT who have had two or more relapses in the past 12 months. Fifty-five patients were randomly assigned to receive stem-cell transplantation, while the other 55 continue to receive the DMT that their treating neurologist deemed best for them. Importantly, the study is employing “non-myeloablative” stem-cell transplantation, meaning that patients can go through a less-demanding pre-treatment regimen than what was first used in stem-cell transplantation and still often used in treating certain types of cancer. The study’s main endpoint is treatment failure, defined as a 1.0 increase in EDSS sustained for six months or more.

After a mean follow-up of three years, 60 percent of patients in the DMT arm had experienced a treatment failure, compared to just 6 percent of those in the stem-cell transplant group. During the first year after transplant, those receiving stem cells saw their EDDS score improve from 3.5 to 2.4, while it worsened in the DMT group from 3.3 to 3.9. Both of those findings were statistically significant. No deaths occurred in the stem-cell transplant group. These results led the researchers to conclude that in people with RRMS who have more than two relapses in a year while on a DMT, stem-cell transplantation is superior to continued use of a disease-modifying therapy.

Meanwhile, a separate, smaller study from a single center suggests that stem-cell transplantation may be a first-line option for the minority of MS patients who have rapidly evolving severe multiple sclerosis (RESMS), also known as highly active relapsing-remitting MS (RRMS). British investigators performed stem-cell transplantation on five men and two women who had not received a disease-modifying therapy (DMT), and who had experienced two or more severe relapses in the 12 months before the procedure. These individuals all had clinical or imaging findings that suggested that their MS would continue to worsen, and all had at least one gadolinium-enhancing lesion seen on MRI associated with their relapses. They ranged in age from 27 to 52 years old, and their median time between symptom onset and treatment was nine months.37

The investigators used each patient’s own stem cells for the procedure. After a median follow-up period of 18 months, none of the participants had experienced a relapse following the transplantation, although one had a single new gadolinium-enhancing lesion six months after treatment. The median Expanded Disability Status Scale (EDSS) score for these individuals improved from a median 5.5 before treatment to 3 at the last follow-up. No serious adverse effects were observed. The investigators concluded that autologous (using the patient’s own cells) hematopoietic (blood-cell producing) stem-cell transplantation is safe and effective for previously untreated patients with rapidly evolving, severe MS.

Lipoic acid

Lipoic acid is a naturally occurring compound that exhibits antioxidant and anti-inflammatory properties. Its potential role as a dietary supplement for people with MS has been the focus of recent research, including a study by investigators from the Oregon Health & Science University and VA Portland Health Care System.38

Those researchers administered 1,200 mg of oral lipoic acid to people with relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), and healthy controls. They then drew blood samples to measure the amount of lipoic acid found in the plasma of all three groups, as well as levels of substances involved in immune system responses. In particular, the investigators wanted to see if taking lipoic acid would stimulate the body’s production of cyclic adenosine monophosphate (cAMP), which plays a role in modulating the immune system.

They found that two hours and four hours after ingesting lipoic acid, the health controls and people with SPMS had increased cAMP levels relative to baseline, while those with RRMS had decreases in cAMP. Also, women with RRMS had lower plasma concentrations of prostaglandin E2, which stimulates cAMP, compared to women with SPMS and women without MS four hours after taking lipoic acid. These findings prompted the investigators to conclude that the differences in the way people with RRMS responded to lipoic acid relative to those without MS or with SPMS may have implications for the efficacy of immunomodulatory agents in RRMS.

Diet and MS

Following a paleolithic diet can help decrease fatigue in MS through changes in people’s lipid profiles, according to a study reported at the AAN annual meeting.39 The paleolithic – or so-called “caveman” diet – focuses on eating meat, fish, nuts, and vegetables available before the advent of processed food.

A one-year study of 18 people with progressive MS found that a comprehensive intervention that included following a paleolithic diet, neuromuscular stimulation, and stress reduction reduced participants’ mean Fatigue Severity Scale (FSS) score from 5.51 at baseline to 3.03 at 12 months. During that time, participants saw their HDL-C (“good cholesterol”) levels increase, their total cholesterol levels decrease, and their body mass index (BMI) fall (BMI is a measure of healthy or unhealthy weight). The researchers concluded, “Lipid profile variables are associated with the improvements in fatigue in progressive MS patients on a modified Paleolithic diet-based multimodal intervention.”

Meanwhile, researchers from Johns Hopkins reported on people with MS who follow a Mediterranean-style diet high in fruits, vegetables, whole grains, seafood and polyunsaturated fats while eating little red meat and drinking in moderation. The researchers found that these individuals appear to have less severe depressive and cognitive symptoms than people with MS who follow a more-traditional American diet.

The researchers had 34 people with MS complete dietary recall surveys and then assessed those people for depression, cognitive impairment, and other known symptoms of MS.40 The investigators noted that the results of this cross-sectional survey need to be validated by interventional studies that could better examine the nature of the relationship seen between diet and the MS symptoms studied.

Other research being conducted at Johns Hopkins is examining how caloric restriction affects the metabolite profiles of people with MS.41 In a six-month study, 19 people with MS who were receiving monthly injections of Tysabri and who had a higher body mass index (BMI) of ≥25 kg/m2 (indicating that they are overweight) chose from one of two calorie-restriction strategies.

The first strategy, chosen by 11 individuals, involved continuous calorie restriction (CCR), with participants consuming 78.6 percent of their daily caloric needs each day. The other approach, chosen by eight participants, entailed intermittent calorie restriction (ICR), with people consuming only 25 percent of their daily caloric needs two days per week, and consuming their full caloric needs on the other days of the week.

Nine of the 11 people in the CCR group and six of the eight in the ICR group completed the study. Researchers are assessing blood samples collected at baseline, three months, and six months to see how the two calorie-restriction approaches influenced the production of metabolites. They note that the results of their analysis may provide new information on how dietary changes affect clinical outcomes in MS.

Obesity and MS

People who are obese at the onset of MS are likely to experience greater functional impairment and higher risk of relapses in the first two years after onset than people with a healthy weight, according to a study of more than 1,500 people with MS.42 Drawing on data for 1,524 participants in the Accelerated Cure Project’s study, researchers found that obesity was associated with a 15-percent increase in the number of impaired functional domains and a 30-percent increase in early relapse activity.

People who were obese also were on average 8-percent older than non-obese patients at the onset of MS. The investigators explain, “These results warrant further investigation into the impact of this proinflammatory phenotype [obesity] in MS.”

Gut reaction? Exploring potential ties between MS and the digestive tract’s microbiome

The mix of bacteria found in the digestive tracts of people with MS or clinically isolated syndrome (CIS) differ from the bacterial milieu found in the gastrointestinal systems of people who don’t have those conditions, two recent studies found.43 Those studies reflect a growing research focus on potential links between MS and the “gut microbiome,” the digestive tract’s bacterial environment, which is known to play a major role in immune-system function.

In the first study, American researchers used sophisticated genetic testing to analyze 42 stool samples from individuals with relapsing-remitting MS (RRMS) or secondary-progressive MS (SPMS), as well as stool samples from 28 healthy donors.43 Compared to the samples from healthy volunteers, stool samples from people with RRMS had a statistically significant greater abundance of several types of bacteria, including Ruminococcus torques, Ruminococcus obeum, and Lactospiraces. Escherichia coli and Oscillibacter also were found more often in people with RRMS than in healthy controls.

Conversely, people who did not have MS had a higher concentration of other bacteria – including bacteroides fragilis and Roseburia – than did study participants with MS. The researchers noted that further, larger studies are needed to determine whether these findings can help pave the way for markers of disease activity or even therapies that target the composition of the gut microbiome.

Meanwhile, Italian investigators found differences in both the stool and blood samples of individuals with clinically isolated syndrome (CIS) – referring to individuals experiencing a symptom of MS, but who have not yet been diagnosed – relative to healthy volunteers.44 They found that butyrate-producing bacteria were more abundant in the healthy volunteers compared to those with CIS. Additionally, the blood of people with CIS had an increased level of a type of white blood cell involved in immune function – T helper (Th) 17 – and fewer T regulatory (Treg) cells producing Interleukin 10, compared to healthy volunteers. The researchers said that both findings indicate that gut microbiome dysfunction or imbalance exists at the earliest stages of MS.

Assessing the impact of medical marijuana on MS

Most people with MS who use medical marijuana (MM), find that the medication helps manage their pain, spasticity, and other symptoms. This is according to two recent small-scale studies.45, 46

In the first study, 14 individuals at the University of Rochester MS Center (13 with MS and one with transverse myelitis) enrolled in the New York State Medical Marijuana Program and completed a survey on their experience with MM.45 Ninety-three percent of these individuals who were certified by the state program to use medical marijuana actually had tried the medication at least once, with 77 percent reporting ongoing use, and 62 percent saying they used MM at least daily.

Seventy-seven percent of participants said MM was helpful in managing their symptoms, 70 percent said that their quality of life improved with marijuana use, and most respondents reported no side effects. Most subjects estimated that they spent between $100 and $300 per month on MM, and cost was cited as a factor in stopping use of MM or using the agent less frequently. 

The second study is being conducted in Colorado, where cannabis use – for any purpose, not just medical reasons – is legal. The experience and beliefs of 25 patients from the Rocky Mountain Multiple Sclerosis Center at the University of Colorado were reported in preliminary findings from the research.46

Fifty-six percent of those participants believe cannabis has a beneficial effect on MS symptoms, while 8 percent think marijuana could entail harm in terms of MS symptoms. Seventy-six percent said they would consider cannabis use to ease their symptoms. Pain was the reason most frequently cited for using cannabis (by 57 percent of respondents), followed by spasticity/muscle tightness (29 percent), and muscle spasms (14 percent).

Slowed thinking was the most commonly reported side effect, cited by 29 percent of participants. Forty-eight percent of survey respondents said that they were not currently using cannabis, with half of those people saying their non-usage was because they did not know enough about the medication.

The authors of the second study noted, “As cannabis becomes more available under the laws of individual states, the results of this ongoing study may have important implications in the future landscape of MS symptom treatment and research exploring the efficacy of cannabis for MS symptom management.”46

For general information or to speak with a trained Client Services Specialist, please call MSAA’s Helpline at (800) 532-7667, extension 154. Questions to MSAA’s Client Services department may also be emailed to

Written by Tom Garry, Medical Writer

Reviewed by Dr. Jack Burks, MSAA Chief Medical Consultant

Edited by Susan Wells Courtney, MSAA Senior Writer


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