Home Objectives Schedule Lectures Topics Cases Quizzes PDA Refs
MULTIPLE SCLEROSIS
John W. Rose, M.D.
Professor
of Neurology, University of Utah
Lecture Objectives
·
Learn
the clinical features of the disease including the common symptoms,
geographic distribution, and genetic susceptibility.
·
Know
which diagnostic tests aid with the diagnosis of MS.
·
Learn
the immunologic processes in MS and their consequences (demyelination and
axonal damage).
·
Know
the different clinical courses of MS such as relapsing remitting and
secondary progressive MS.
·
Know
the immunomodulatory and immunosuppressive drugs used in the treatment of MS.
Clinical
Features of Multiple Sclerosis
MS is a multifocal disease of the central nervous system.
This disease is typically, characterized by relapses and remissions. However, progressive clinical courses occur and can lead to
rapid accumulation of neurologic damage and clinical disability.
There is no specific diagnostic test for MS.
MRI scans of the brain and spinal cord, evoked potentials or spinal
fluid immunoglobulin abnormalities such as oligoclonal bands may aid the
diagnosis. In most cases the
diagnosis is made on clinical grounds. The
demonstration by history and physical examinations of lesions at different
levels of the central nervous system over time is important.
Sensory disturbances such as numbness and paraethesias are the most
common initial symptoms. Many
other symptoms such as weakness, incoordination, diplopia and loss of vision
(optic neuritis) can occur initially or with subsequent relapses.
Like many disorders with immunologic mechanisms, MS is more common in
females than males. There is a greater incidence of the disease the farther North
one goes in North America and a reverse gradient in the Southern Hemisphere.
Studies of twins with MS have suggested that there are both genetic
susceptibility and environmental factors in the disease.
The concordance in monozygotic twins is 40% compared to 5% in
dizygotic twins. First degree
relatives of an MS patient have approximately a 5% risk of developing MS.
Genetic factors in MS include HLA molecules such as DR2.
Recent studies have again identified potential pathogens associated
with and potentially primarily responsible for MS.
Although many pathogens have been implicated, none has stood the test
of time.
Demyelination,
Remyelination and Axonal Injury in Multiple Sclerosis
The original descriptions of the gross pathology of multiple sclerosis
date back to the 1700s. Carswell
was the first to demonstrate these lesions; however, it was Charcot who put
the lesions of the white matter which he termed sclerosis en plaque, the
demyelination of the white matter within the plaques and the clinical
symptomatology together. Although demyelination was the hallmark of the disease,
Charcot did note that axonal injury could also occur.
Subsequently, the third feature of the disease, perivenular
infiltration by lymphocytes and mononuclear cells was described.
Traditionally, multiple sclerosis is often taught as the classical
demyelinating disease of the central nervous system.
Interestingly, the intensity of the inflammation at the site of the
lesion may determine the type of damage to the myelin and myelin producing
cells also known as oligodendrocytes. These
cells of glial origin may be able to survive several attacks, but they will
eventually undergo cell death by either apoptosis or necrosis.
The cell death may occur as a result of a direct attack by the
lymphocytes or as a result of the products secreted by these inflammatory
cells. Active demyelination can be readily observed in these lesions.
Macrophages and microglia participate in the process of demyelination.
Recent studies with confocal microscopy have however shown that axonal
injury is a significant component of acute inflammatory lesions or active
plaques of MS.
There can be limited remyelination in the central nervous system.
Unfortunately, this is not anywhere near as effective as remyelination
in the peripheral nervous system. Therefore
in MS, it is important to limit damage to the myelin and the axons as well as
reduce the inflammatory response.
Immunology
of Multiple Sclerosis
The immunologic aspects of MS are complex.
Cellular immunology is focused on because of the infiltration of T
cells in the perivascular spaces and the surrounding parenchyma of the brain.
The specific immunopathology of MS needs to be characterized.
Our understanding of the inflammatory response suggests that basic
mechanisms are important, including cell adhesion allowing the infiltration
of lymphocytes and mononuclear cells into the central nervous system as well
as the generation of potentially damaging cytokines and toxic molecules
within the white matter. An
overview is presented in the attached figure 1.
The potential for therapeutic interventions at many levels of the
immune response may be possible. It
is highly likely that multiple mechanisms participate in demyelination and
axonal injury. This may be reflected in the intensity of the inflammatory
process or in different mechanisms in the pathogenesis of the disease.
New
Concepts in the Immunopathogenesis of Multiple Sclerosis
The
lesions of multiple sclerosis are now being characterized in terms of many
more pathologic parameters than previously considered these include degree
and composition of the inflammatory response, oligodendrocyte survival, and
remyelination. Based on these
characteristics the current literature may support as many as 4 types of
active lesions based on biopsy findings.
Pattern I
Pattern II
Pattern III
Pattern IV
Inflammation ----------MŲ >>T-Cells >>B-Cells For All Patterns I-IV--------
Complement negative Positive negative negative
Oligos minor decrease mild decrease Severe decrease Severe decrease
Demyelination
Lesion Edge Sharp Sharp Ill-defined Sharp
Perivenous Positive Positive Negative Plus/Minus
Remyelination Positive Positive negative negative
It
is interesting to speculate on whether more than one type of lesion may be
active at the same time in an individual patient. One study has suggested that each patient will have
lesions of only one Pattern. Treatment
may meet with success or failure in a patient depending on the Pattern of
active lesions being produced by the disease.
Clinical
Course of Multiple Sclerosis
The
clinical course varies considerably. The
course can be divided into a number of types.
There are patients with only rare relapses of their disease and they
are the Benign type.
The most common group of patients has relapses that occur frequently,
one to several times per year, and they are the Relapsing/Remitting
type. Of these patients a
significant number will eventually develop a slow decline and they are then
termed Secondary Progressive MS. Occasional
patients start with a progressive course and never have a relapse, these
patients are the Primary Progressive
type. Patients with both
progression and relapses are termed the Progressive-Relapsing type. The
therapy of MS patients is different depending on the type of clinical course.
Importantly, MRI detects far more disease activity than is clinically
suspected in the MS patients. Therefore,
both the clinical examination and the MRI are used to monitor the patients.
Treatment
with Immunomodulatory and Immunosuppressive Drugs
We now have three immunomodulatory drugs (Betaseron, Avonex and
Copaxone) in use for relapsing and remitting MS and all 3 drugs have their
proponents. There is still much
to be established about each of these medications in terms of initiating
treatment, duration of therapy and determining when to switch therapy.
In general, efficacy of the immunomodulatory drugs is fairly
equivalent. MRI studies support the clinical efficacy of all 3 therapies.
To date we do have one small comparative trial of beta interferon and
glatiramer acetate showing equal efficacy.
Therefore, it is reasonable to offer the choice of the three drugs to
a patient about to start therapy for relapsing and remitting MS.
Considerations which are worth discussing with the patient are 1) the
route, number and reactions to injections 2) the side effect profile and need
for additional medication 3) the need for monitoring bloodwork for patients
on interferon treatment 4) previous medical problems which may be aggravated
by a drug. Preferences are
debatable fortunately if an incompatible medication is chosen it can be
readily replaced. My choices are
often along these lines:
Minimal Disease Often Wait On Treatment
Early Disease C or A or B
Typical Relapsing Course C, A or B
Progressive Relapsing B or A or Immunosuppressive Rx
2nd Progressive Immunosuppressive Rx
Primary Progressive ? Immunosuppressive Rx or C or A
A= Avonex (Beta IFN-1a)
B= Betaseron (Beta IFN-1b)
C= Copaxone (Glatiramer Acetate)
Immunosuppressive Rx= Pulse Solumedrol, Methotrexate, Azathioprine or Mitoxanthrone
References:
Website:
www.medlib.med.utah.edu/kw/ms/
www.medstat.med.utah.edu/kw/ms/
1)
Luchinetti et al. Heterogenity
of multiple sclerosis lesions: implications for the pathogenesis of
demyelination. Annals of Neurology 47: 707-713, 2000.
2)
Johnson et al. Sustained
clinical benefits of glatiramer acetate in relapsing
3)
Jacobs et al. Intramuscular interferon beta-1a therapy initiated
during a first demyelinating event in multiple sclerosis. N Engl J Med
343: 898-904, 2000.
4)
Multiple Sclerosis: Current
Status and strategies for the future. Joy
and Johnston eds, National Academy Press, 2001.
Home Objectives Schedule Lectures Topics Cases Quizzes PDA Refs
Last updated: 10/05/2002 © 2000-2002 John Rose, MD University of Utah School of Medicine