Summary
More than 10,000 researchers and practicing neurologists from around the world gathered at the 62nd Annual Meeting of the American Academy of Neurology (AAN) in Toronto from April 10-17. Nearly 500 presentations related to research efforts to stop multiple sclerosis, to restore function, and to end MS forever. National MS Society grantees were among those presenting novel findings on many different aspects of MS research.
Details
RESEARCH TOWARD STOPPING MS
— Experimental Therapies in the Pipeline
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Alemtuzumab and disease progression: In
previously reported phase 2 studies, treatment with alemtuzumab
(Genzyme Corporation) reduced the accumulation of disability
and the frequency of relapses in 223 people with early
relapsing-remitting MS, compared to Rebif. Those taking
alemtuzumab, an immune-suppressing monoclonal antibody,
experienced adverse events more frequently, including a serious
bleeding disorder and thyroid problems. Four-year follow up
among 176 of these patients shows that a greater proportion of
those in the alemtuzumab group are relapse-free and have not
had sustained disability progression (as measured by a 1- to
1.5-point increase on the EDSS scale, sustained for 6 months).
No additional adverse events were reported. Phase III studies
of alemtuzumab are ongoing, and have completed enrollment.
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Teriflunomide results: Mark Freedman, MD
(University of Ottawa) and colleagues reported on phase II
results of a study in which two doses of oral teriflunomide
(sanofi-aventis), an immune modulator, or placebo, were added
to ongoing Copaxone therapy in 123 people with RR MS. Disease
activity as observed on MRI scans was reduced significantly
more than placebo in both treatment groups. Six people in the
treatment groups had increased liver enzymes. Phase III studies
of teriflunomide are underway in relapsing MS and in people at
high risk for MS.
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Omega 3-fatty acids: Kjell-Morten Myhr, MD,
PhD (University of Bergen) and colleagues randomly assigned 92
people with RR MS to receive omega-3 fatty acids (fish oil) or
placebo (corn oil) capsules daily for 6 months. Thrice weekly
interferon beta-1a was then added on in both groups for another
18 months. MRI scans (taken monthly until month 9 and then at
months 12 and 24) and clinical outcomes were monitored. The
primary outcome was the cumulative number of newly active
(contrast-enhancing) lesions and did not differ between the
groups. There were no differences in relapses or any of the
clinical outcome measures, or of self-reported fatigue or
quality of life measures. This well-designed study showed that
omega-3 fatty acid supplements were safe in this group of
people with MS, but failed to show benefit.
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Mesenchymal (adult) stem cells: Mesenchymal
stem cells derived from the bone marrow potentially have the
ability both to treat immune disorders and promote tissue
repair. Dimitrios Karussis, MD, PhD (Hadassah Medical Center)
and colleagues conducted a study of mesenchymal stem cell
infusion in 15 people with MS and 19 people with the
neurodegenerative disease ALS. No major side effects were
reported during 25 months of follow up; 21 people experienced
infusion-related side effects consisting of transient, mild
fever and headache. An anti-inflammatory immune response
occurred within 24 hours after infusion. There was a trend to
clinical improvement, but the study was not powered to detect
clinical benefit. Larger and longer-term studies are needed to
determine the safety and effectiveness of this strategy.
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Lipoic acid: One approach to stopping MS is to
find a way to protect nervous system tissues from harm. In a
study supported by the National MS Society, Department of
Veterans Affairs and others, Priya Chaudhary, PhD and
colleagues at the Oregon Health & Science University
(Portland, Oregon) investigated the neuroprotective
capabilities of lipoic acid, an antioxidant that previous
studies suggest can benefit mice with MS-like disease in part
by inhibiting immune cells from entering the brain. In an
experimental mouse model of acute optic neuritis, they found
that lipoic acid could reduce damage to myelin and to nerve
fibers, and also reduced inflammation. This group is planning
more research needed to determine whether lipoic acid may
provide benefits for people with MS.
- T cell vaccination: This strategy aims to induce immunity to attacking T cells. Rivka Abulafia-Lapid, PhD (Hadassah Medical Center) and colleagues randomly assigned 26 people with progressive MS to receive either vaccination with their own “deactivated” T cells, or sham injections. They were followed for one year. Disability scores worsened slightly in the sham group and improved slightly in the vaccination group. Annualized relapses were reduced from a mean of 0.82 to 0.06 in the treatment group and remained unchanged in the sham group. MRI results did not differ between the groups. This study provides some preliminary evidence suggesting clinical benefit, but larger, controlled studies are necessary.
— Progressive multifocal leukoencephalopathy (PML)
and natalizumab:
During a plenary session, David Clifford, MD (Washington
University School of Medicine, St. Louis, Mo.), who has studied
and treated PML in non-MS populations and who has served as an
expert consultant to Biogen Idec on this issue, presented
information regarding cases of PML that have occurred in people
taking natalizumab. To date, 46 cases of PML associated with
natalizumab treatment since the drug re-entered the market.
Identification of PML cases in the MS population can only be
pursued through clinical monitoring, particularly for changes in
personality or thinking, or progressive neurological impairments
over weeks to months. He noted that many local labs can’t detect
the JC virus in spinal fluid in suspected cases because it is at
very low levels, and that ultrasensitive JC DNA PCR assay may be
necessary for proper detection. He also noted that although
three-fourths of individuals have survived after this form of
PML, most have been left with serious disability.
It is believed that most adults harbor the virus that causes PML,
apparently controlled under normal circumstances by the person’s
immune responses. As of yet, there is no reliable way to identify
individuals with MS who receive natalizumab and who might be at
increased risk of PML, since it is not certain whether risk is
randomly related to exposure or involves particular risk factors
that are currently unknown. A presentation of a study by Leonid
Gorelik, PhD, and colleagues at Biogen Idec described a new blood
serum test that would detect antibodies to the JC virus, which
causes PML.(The presence of antibodies indicates that a person
has at some point been infected by the virus.) The team has
tested 800 serum samples and has found that this test can
distinguish between people with MS who are negative for
antibodies (about 40 to 50%) and those who are positive (about 50
to 60%). Further work is being undertaken to evaluate the test
prospectively in patients receiving natalizumab to see if a
positive antibody test identifies those at risk for
natalizumab-associated PML. If these studies confirm that only
those with antibodies to JC virus detectable by the test are at
risk of PML, those with negative tests might be considered to
have little risk of the disease. (Abstract S31.003)
— Stopping Relapses
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When is the first MS attack? Olivier Gout, MD
(Foundation Rothschild, Paris, France) and colleagues gave a
self-administered questionnaire to 178 patients during an
initial consultation with a neurologist after experiencing what
was possibly a first neurologic symptom indicative of myelin
damage. The neurologist validated the reported symptoms in a
follow-up visit. The investigators reported that as many as 33%
of the patients had prior symptoms suggestive of demyelination
that went unnoticed, and that almost 70% had previous signs and
symptoms that qualified them for a diagnosis of MS. They
concluded that the questionnaire could facilitate earlier
diagnosis and treatment.
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In vitro fertilization (IVF) and relapses:
Laure Michel, MD (INSERM, Nantes, France) and colleagues from
institutions across France reported on 28 women with MS who had
undergone 64 in-vitro fertilization procedures, finding an
increase in relapses within two months after the procedure. The
increase was linked to both the type of hormones used (LHRH
agonists, not LHRH antagonists) and to the failure of the
procedure. This adds evidence to previous reports showing that
IVF and other fertility procedures may increase the risk of
relapse in women with MS.
- Breastfeeding and relapses: The risk of MS relapse is known to increase during the three months after a woman gives birth. Last year a study from San Francisco suggested that women who exclusively nursed their children were less likely to have a relapse in the year following birth, compared to women who combined nursing with bottle feeding or who chose to resume disease-modifying therapy and not to nurse. In this larger prospective study of 302 pregnancies, Emilio Portaccio, MD (University of Florence, Italy) and co-investigators at 21 MS centers in Italy did not find clear-cut evidence that breastfeeding could protect against postpartum relapses after accounting for other factors such as age, duration of disease, disease activity prior to pregnancy, and disability status. They found that the strongest predictors of relapses following a pregnancy were relapse activity preceding and during pregnancy, and the use of disease-modifying therapies prior to pregnancy, which might represent people with increased MS activity. Further research on the influence of hormonal and immunological events related to pregnancy, and their impact on the course of MS, continues to be an important area of investigation. (Abstract S40.003)
RESEARCH TOWARD RESTORING FUNCTION
— Addressing symptoms
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Sleep disorders and fatigue: Christian P.
Veauthier, MD (Klinikum Stralsund) and colleagues used
polysomnography – a diagnostic tool used in sleep medicine – to
evaluate people with MS and fatigue. They found that 25 of 26
people reporting higher levels of fatigue actually had sleep
disorders, such as insomnia, restless legs syndrome or sleep
apnea. Twelve had two different sleep disorders. In 40 people
with lower levels of fatigue, 20 were diagnosed with mild sleep
disorders. The group urged health care professionals treating
people with MS to evaluate fatigued patients for the presence
of sleep disorders, which are likely to improve with the
appropriate treatments.
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Donepezil for memory problems: Problems with
memory and thinking speed commonly affect people with MS, and
studies have looked at drugs used to treat memory disorders in
Alzheimer’s disease to see if they would help people with MS.
Several years ago, small studies of donepezil (Aricept®, Eisai
Inc. and Pfizer Inc.) suggested modest benefit on some tests of
cognition. In this larger, randomized, placebo-controlled,
prospective trial funded by the National Institutes of Health,
Lauren Krupp, MD (State University of New York, Stony Brook)
and colleagues administered donepezil or inactive placebo to
120 people with all types of MS who had at least a mild memory
deficit. The drug showed no benefit compared with placebo on
cognitive measures or on patients’ own reports of memory
changes. A similar study of another Alzheimer’s drug,
memantine, last year also failed to show benefit. Results
suggest that the mechanisms underlying cognitive impairment in
MS may differ significantly from those in Alzheimer’s
disease.
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Bone health: Nancy Hammond, MD (University of
Kansas Medical Center) and colleagues examined the
questionnaires and bone health exams of 60 women with
relapsing-remitting MS who were recruited into a larger study
on bone health: 53% reported that they did no weight-bearing
exercise; 15% were current smokers; 78% reported current
alcohol use; 41% took some type of calcium supplementation; 45%
subjects took vitamin D supplementation; and 46% reported
exposure to corticosteroids. Based on the results, the
investigators suggest that health care providers advise people
with MS on how lifestyle can impact bone health.
- Omega-3 for depression: Lynne Shinto, MD (Oregon Health & Science University) and colleagues administered 6 grams/day of omega-3 fatty acids (fish oil) or inactive placebo (soybean oil) to 31 people with MS who had mild to moderate depression for three months. Both groups improved on the depression scale; there were no significant differences. However, the omega group did improve significantly more than the placebo group on a measure of cognition (PASAT). Further study is necessary to confirm this finding.
— CCSVI Preliminary Results
- Buffalo CCSVI prevalence study: In February the University at Buffalo Medical Center released preliminary results from an ongoing Combined Transcranial and Extracranial Venus Doppler Evaluation study. Using Doppler criteria developed by Dr. Zamboni, it is designed to evaluate the prevalence of venous obstruction, with a planned enrollment of 1700 consecutively recruited people who have possible and/or definite MS, other neurological conditions, and healthy controls. They are also using MRI of the brain, and in a subgroup, MRI of the veins of the neck to help verify the Doppler results.
was based on the first 500 participants enrolled. Of those, 499
were eligible for statistical analysis: 289 people had MS, most
with the relapsing-remitting form. There were 163 healthy controls,
21 with CIS (first neurological episode, at risk for developing MS)
and 26 with other neurological disease. Doppler scan results were
reported on five specific criteria that affect venous blood flow.
Patients who met at least two of the criteria were considered to
have CCSVI. 56.1% of the MS cohort met the criteria for CCSVI. This
was also true for 22.7% of the healthy controls, and 42.5% of
people with other neurological conditions; abnormalities were less
frequent and less specific than in the original reports of Dr.
Zamboni. The investigators concluded that further blinded studies
are needed to determine the prevalence of CCSVI in MS.
RESEARCH TOWARD ENDING MS FOREVER
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MS Genes on the Web: Understanding how a
person’s genes make them susceptible to developing MS will go a
long way toward finding ways to prevent it. Christina M. Lill,
MD (University of Boulder) and colleagues reported on the new
Web site www.msgene.org, a collection of published genome-wide
MS studies, launched by the International MS Genetics
Consortium and hosted by the Alzheimer Research Forum Web site.
Site developers have systematically summarized over 800 MS
genetic association studies testing over 2000 genetic
variations. They list the strongest associations, which were
exerted by immune system genes such as HLA-related variations,
and IL7R, IL2RA, and CD58. This systematic collection of data
can help to clarify the status of MS susceptibility genes and
to prioritize future genetic studies.
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Vitamin D and kids: Beyond genes, other
factors appear to play a role in the development of MS. Several
studies focused on the potential influence of vitamin D levels
and risk of MS. Researchers at two National MS
Society-supported Pediatric MS Centers of Excellence
(University of California at San Francisco and State University
of New York, Stony Brook) retrospectively analyzed vitamin D
blood serum levels in relation to relapse risk in 110 children
with MS or CIS (having experienced a first neurological episode
but not yet having confirmed MS). They found that low vitamin
D3 levels were independently associated with the risk of
relapse, after accounting for other factors such as age,
gender, ethnicity, duration of MS and use of disease-modifying
therapies. The authors report that every 10ng/ml increase in
vitamin D levels was associated with a 34% decrease in relapse
risk. The investigators appropriately suggest that a
randomized, placebo-controlled, prospective study is needed to
determine whether vitamin D supplementation improves the course
of MS. (Abstract IN2-2.004)
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Vitamin D, milk and mothers to be: Fariba
Mirzaei, MD, MPH, and colleagues at the Harvard School of
Public Health used the ongoing Nurses Health studies to
investigate levels of vitamin D intake – in the form of either
milk or vitamin D supplements – of mothers whose daughters were
enrolled in the nurse study. A questionnaire about their
pregnancy with these daughters was completed by 35,794 mothers.
MS was diagnosed in 199 of the nurses in the study. The
investigators reported that the risk of developing MS among the
daughters was significantly less if their mothers drank four or
more glasses of milk per day, compared to mothers who drank
less than three glasses of milk per month. Those whose mothers
took larger amounts of vitamin D during pregnancy were also
less likely to develop MS than those whose mothers took lower
amounts. This study adds to growing evidence that vitamin D may
reduce the risk of developing MS.
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Vitamin D and immune cells: How might vitamin
D influence disease activity? Looking at one aspect of this
question was a basic laboratory study by Edward Knapp, PhD,
National MS Society Sylvia Lawry Physician Fellow Christopher
Eckstein, MD, and Peter Calabresi, MD (Johns Hopkins
University). Taking specific, active immune T cells (CD4+ T
cells, which tend to drive MS immune attacks) from healthy
participants, the team grew the cells in lab dishes for 72
hours with different concentrations of vitamin D. Then they
sorted the cells and evaluated the types of messenger chemicals
released by them. Compared to T cells that did not have vitamin
D added, they found that vitamin D-treated cells released
significantly less of the messenger chemicals interferon gamma
and interleukin-17, both of which have been implicated in
stimulating inflammation.
MS research today.
With information from the National MS Society (USA).