http://neurology.medscape.com/medscape/cno/2001/WCNCME/Story.cfm?story_id=2315
XVII World Congress of Neurology
Day 1 - June 17, 2001
Patricia K. Coyle, MD, Syed Rizvi,
MD, MBBS
The 17th World Congress of Neurology included a wealth of presentations about multiple sclerosis (MS). The scope of information provided a truly global perspective on the investigations into the pathophysiology, epidemiology, and management of MS.
MS Main Theme
The day-long MS Main Theme section
involved 10 presentations comprising a broad spectrum of topics ranging
from genetic epidemiology to rehabilitation, and included a case discussion.
Genetics
Dr. D.A.S. Compston, from Cambridge,
UK, discussed the genetics of MS.[1] He noted that there are genes associated
with increased disease risk, as well as disease severity, and reviewed
a number of candidate genes involving immune/inflammatory, trophic, and
CNS factors. MS shows genetic heterogeneity, so linked genes are likely
to differ between distinct MS subgroups. It will be critical to identify
and examine meaningful subsets for gene analysis.
Immunopathology
Dr. H. Lassman,[2] from Vienna, Austria,
reviewed his work on immunopathologic heterogeneity in MS, which focuses
on the pathology of active brain plaques based on degree of inflammation,
presence of antibody/activated complement, oligodendrocyte loss, and remyelination.
These observations have been made on a relatively small dataset; many of
the brain samples came from patients with an atypical presentation. This
raises concern about the ultimate generalization of this cut-and-dry 4-pattern
division.
His presentation stimulated a provocative
discussion about whether ischemic injury could be a critical factor in
the distal oligodendrogliopathy pattern III. Axon damage occurs during
active demyelination, most likely due to a release of toxic factors by
macrophages, the most plentiful cell population within active lesions.
Axon damage also occurs in chronic inactive plaques, which show no remyelination,
implying 2 distinct mechanisms.
Dr. H. Wekerle,[3] from Munich, Germany
reviewed the immunopathogenesis of MS. In addition to discussing the role
for autoreactive T cells, local glia, macrophages, and myelin-specific
B cells, he emphasized the growing appreciation of the importance of neurons,
which help to regulate local immune reactions within the central nervous
system (CNS) microenvironment.
A related study[4] evaluated the
role of apoptosis (programmed cell death) in removing autoreactive T cells.
Activated T cells were examined in cerebrospinal fluid (CSF) and serum
of patients with MS, patients with other neurologic disease, and healthy
controls. CSF T cells from MS patients showed much higher levels of survivin
(an antiapoptosis protein). Survivin levels were also elevated (although
less marked) in peripheral blood T cells of patients with MS. These findings
were interpreted to indicate impaired apoptosis in MS, which could play
a role in allowing an ongoing immune attack against the CNS.
Axonal Conduction
Dr. K. Smith,[5] from London, UK,
discussed the role of axonal conduction in MS. Axonal conduction can be
impaired by demyelination, inflammation, or degeneration of the axon itself.
Inflammatory factors such as nitric oxide, the pentapeptide QYNAD, and
ion channel antibodies can produce reversible conduction block. Conduction
block can be circumvented by insertion of sodium channels into the axolemma
and development of internodal excitability. When demyelination is severe,
or when axons degenerate, permanent conduction loss occurs. Axon structure
and function is an exciting area that will provide a new therapeutic target
for development over the next few years.
Animal Models, Imaging Techniques,
Future Therapies
Others in this Main Theme section
discussed the mouse model of Pelizaeus-Merzbacher disease, which involves
mutations in the proteolipid protein gene;[6] newer magnetic resonance
imaging (MRI) techniques (MR spectroscopy, magnetization transfer imaging,
diffusion-weighted and diffusion-tensor imaging), which allow detection
of microscopic changes in normal appearing brain tissue;[7] and creative
healthcare services.[8]
Dr. J. Kesselring[9] from Valens,
Switzerland, emphasized the beneficial role of rehabilitation in MS and
reviewed several studies which showed that physical exercise programs could
improve both physiologic and psychologic measures. The final 2 papers focussed
on current and future disease-modifying therapies.[10,11] The emphasis
on early treatment of MS is increasing, even in the European community.
Dr. J. Noseworthy,[11] from Rochester, Minnesota, covered a wide range
of new approaches to MS that are under evaluation. He also considered the
difficulty of performing blinded placebo-controlled trials in an era of
accepted and widely used therapeutics.
Drug Therapies
The EVIDENCE Study
Does the amount and frequency of
interferon (IFN) beta-1a dosing affect efficacy? Results of the Evidence
for Interferon Dose-effect: European-North American Comparative Efficacy
(EVIDENCE) study,[12] a comparative head-to-head trial of 2 interferon
beta-1a products (high-dose Rebif, 44 mcg given subcutaneously 3 times
a week vs Avonex 30 mcg given intramuscularly once a week), were reported
during the Late-Breaking News Section on Friday.
This ongoing study involves 56 centers
(36 in the US) and 677 relapsing MS patients (443 from the US). The study
runs 48 weeks, however, the primary outcome (proportion of relapse-free
patients) and main secondary outcome (number of combined unique active
T1- and T2-weighted contrast lesions on brain MRI) involved assessment
at 24 weeks (6 months). Although patients and treating physicians were
not blinded to treatment (this was felt to be impractical), the primary
outcome was determined by a blinded evaluating physician, and all MRI readings
were blinded. Therefore, both the primary and main secondary outcomes are
based on blinded assessments.
At 6 months, the proportion of relapse-free
patients was 74.9% in the Rebif arm vs 63.3% in the Avonex arm (P = .005),
a 32% relative reduction in the proportion of Rebif treated patients with
relapses. Patients treated with Rebif had 27% fewer relapses (P = .022),
47% fewer steroid treated relapses (P = .004), and a 37% longer duration
to first relapse (P = .001). Combined unique brain MRI lesions averaged
0.8 new lesions per scan in the Rebif-treated group compared with 1.2 new
lesions per scan with Avonex (P < .0001). The proportion of active MRI
scans was 24% in the Rebif group vs 37.3% in the Avonex group (P < .001).
Both drugs were well tolerated. Although the Rebif-treated group had more
injection-site reactions and laboratory abnormalities in liver enzymes
and white blood cell counts, virtually all of these were mild reactions.
This is the largest head-to-head
comparison of 2 MS disease-modifying therapies. The study provides convincing
evidence that high-dose/frequently dosed IFN beta-1a is superior to low-dose/infrequently
dosed IFN beta-1a.
Steroids
In a small study of approximately
80 patients with relapsing MS, half were treated with regular pulses of
intravenous methylprednisolone,[13] and half received steroids only at
the time of clinical relapse. MRI was examined at baseline and after 5
years. The group who received regular steroids (total steroid dose about
3.5 times that of the control group) showed less brain atrophy and T1-weighted
holes on MRI and less disease progression. There was no effect on T2-weighted
lesions or relapses. This is a surprising observation. The investigators
suggest that pulse steroids may exert a protective effect to limit atrophy.
This hypothesis is consistent with an observation made by National Institutes
of Health (NIH) investigators that acute treatment with steroids is associated
with less reduction in magnetization transfer ratios within acute lesions.
Of course the study arms were fairly small, and only 2 MRI scans were done.
This is not as convincing as a study involving frequent MRI scans. Nonetheless,
it raises intriguing questions about novel steroid benefits for MS.
Other Drugs
A small study[14] of 15 MS patients
reported that treatment with a potassium-channel blocker 4-aminopyridine
10 mg intramuscularly twice daily for 1 month resulted in improvement in
cognitive function. Controlled-release oral forms of 4-aminopyridine are
being evaluated.
Results indicated no reductions in
MRI lesion formation with valaciclovir, although a trend toward benefit
was found in a subgroup of MS patients with very high MRI activity. The
researchers concluded that this observation should be pursued, even though
overall study results did not indicate a role for antiviral therapy in
MS. Thus far, there has been no convincing data to support use of routine
antivirals in MS.
Markers of Disease
CSF Markers
Several studies examined CSF levels
of axon components, including actin, tubulin, and neurofilament protein.[16,17]
Levels of axon components in MS patients were elevated compared with control
CSF samples, and more elevated in patients with longer-duration MS and
more disabled patients with progressive MS. These are cross-sectional studies,
with fewer than 100 MS patients evaluated. Larger numbers of patients and
longitudinal (multiple time point) studies are needed to validate whether
axonal markers in CSF have real predictive value for future MS course,
or can be used as markers for disease severity.
T-Cell Responses
Weissert and colleagues[18] from
Tuebingen, Germany, examined T-cell reactivity to various peptides of myelin
oligodendrocyte glycoprotein (MOG) in MS patients and controls. T cells
from control patients showed stronger and broader ranges of reactivity
compared with T cells from MS patients. MOG may be an important antigen
target in MS, so further studies are needed to determine whether the T-cell
responses of MS patients to this myelin component are truly altered.
Evoked Potentials
Drory and associates,[19] from Tel
Aviv, Israel, reported on the use of somatosensory-evoked potentials (SSEPs)
and visual-evoked potentials to follow disease progression in MS. Patients
were analyzed at 2 time points, separated by about 20 months. Tibial nerve
SSEP latencies as well as median nerve SSEP amplitude and latencies showed
significant changes over time, but no relationship to Expanded Disability
Status Scale (EDSS) except for changes in median nerve SSEP latency.
The investigators suggested that
SSEP responses could be used to assess disease progression. However, the
data were not convincing. Further studies using much more frequent time
points and better correlations with disease features (including MRI) would
be needed to make a case for use of evoked potentials as a severity marker.
Epidemiology
MS in Libya
An interesting study from Libya reported
on newly diagnosed MS cases identified from September 1994 to December
1997.[20] MRI was used to support the diagnosis, and diagnosis was made
within 1 year of initial symptoms in 80% of cases. Several interesting
features emerged. There was a slightly lower female predominance in Libya
than in North America (1.4:1 vs >2:1, respectively). Almost half of patients
presented with a multiphasic syndrome, and more than 25% of patients were
considered to have severe disease; 35% had a progressive form of the disease.
This study suggests that MS is more
common than previously realized in this population, and may take a more
severe course. It will be important to determine whether genetic features
can distinguish Libyan from North American MS patients.
Race and Optic Neuritis
In a study that tracked outcomes
of optic neuritis based on race -- whites and blacks in the Optic Neuritis
Treatment Trial (ONTT) --[21] blacks experienced more severe vision loss
and higher EDSS at 5 years. A study from Martinique confirmed that French
African-Caribbean MS patients are more likely to suffer severe vision loss
after optic neuritis.[22] Deficits of these patients were compared with
those of patients in the American ONTT. Only growing up in France was associated
with better outcome, suggesting that environmental factors played a role
in outcome.
Late-onset MS
An interesting report[23] from Germany
described 15 patients with onset of MS at age 60 or later. They made up
less than 0.01% of a consecutive MS inpatient population. Compared with
younger MS patients, this older-age-onset group was more likely to have
female predominance (6:1 vs 2:1); primary progressive subtype (93% vs 28%);
and initial paraparesis (87% vs 33%). Older-age onset of MS is considered
a poor prognostic feature. Surprisingly, almost half of patients showed
only very gradual worsening rather than a more severe course.
Specific Symptoms
Dysphagia
A study from Belgium investigated
dysphagia (difficulty with swallowing/chewing) in MS patients.[24] Among
308 consecutive patients, 19% suffered ongoing dysphagia problems, while
an additional 5% had experienced transient difficulties. Most affected
patients were at higher EDSS/disability ranges. Among very disabled patients
(EDSS 8 to 9), 65% noted dysphagia. Early symptoms included changes in
eating habits (93%), and coughing or choking during eating (59%). Formal
swallowing assessment (manofluoroscopy) was helpful to document problems
and guide therapeutic recommendations.
Premenstrual Worsening
In a small study[25] involving 28
women with MS (mean age, 40 years; mean disease duration, 8 years), 78%
had premenstrual worsening of leg weakness, pain, and nocturia, as detected
by a daily questionnaire. This study adds to a small but growing literature
reporting fluctuations in MS symptoms related to the menstrual cycle. This
small but prospective study should be pursued in a larger patient population.
Cognitive Changes
An interesting functional MRI (fMRI)
study[26] evaluated 21 patients with early relapsing MS and 22 matched
controls. They were given a cognitive test to assess processing speed (the
paced auditory serial addition test [PASAT]). Different control areas were
activated in the MS group (frontal cortex areas 44 and 819) vs controls
(frontal cingulate gyrus area 32). Despite this change, there were no significant
cognitive differences between the 2 groups.
The investigators interpreted this
as an example of brain plasticity in the MS patients, with cognitive function
transferred to more intact brain areas. It also suggests a subtle cognitive
disturbance even in those with very early, mild MS. fMRI offers a unique
tool to evaluate MS, since it allows cortical circuitry to be examined
in response to both cognitive and physical tasks.
Pain
Pöllman and associates,[27]
from Berg, Germany, presented information on pain in MS. They interviewed
158 consecutive inpatients to determine whether they had experienced significant
pain problems within the past year. A total of 97 patients (61%) had noted
problems, including multiple pain syndromes. In 12% of patients pain was
rated as their worst MS symptom. Syndromes included migraine headache (23%),
dysesthesia of a limb (21%), back pain (18%), and painful leg spasms (11%).
Most patients felt their physicians did not adequately diagnose and treat
their problem. This study confirms pain as an important symptom in MS,
and highlights that it is not optimally managed.
References
Lycke and associates,[15] from Sweden
and Denmark, reported on a phase II trial of valaciclovir in relapsing
MS. Valaciclovir, an antiviral agent with broad anti-herpes virus activity,
was given at a dose of 1000 mg 3 times daily for 24 weeks. Seventy patients
were randomized to receive active drug or placebo. The main outcome measure
was total number of active brain MRI lesions.
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