t is difficult to think of an aetiological theory that
sis. Disconcertingly, however, many of the aetio-
logical questions asked over 150 years ago are still
Is the disease due to a vascular defect as
blood vessel in the centre of each plaque, or is it a
defect in the glial tissue as argued by Charcot in 1868
after he viewed and drew the glial and nerve changes
under his microscope? Oppenheim was certain that
multiple sclerosis was caused by environmental toxins.
In the middle of the 20th century interest centred
around the possibility that it was an immunological
disease and, more recently, a genetic disease.
Perhaps the most enduring questions concern a
potential infectious agent. In 1894 Pierre Marie, a
former student of Charcot, argued strongly that infec-
tion was the cause of multiple sclerosis and that those
who disagreed had not read his papers. He did not
know the specific infective agent but was certain that a
treatment would soon be available in the form of a
“vaccine of Pasteur or lymph of Koch.”
aggravate multiple sclerosis but was not the cause.
There was a flurry of reports of virus and spirochete
isolations and transmissions in the early decades of the
20th century, but none stood the tests of time and
reproducibility. Absence of evidence is not evidence of
absence, however, and the infection theory remained
strong because it seemed to best fit the developing sce-
nario. Every new antibiotic and antiviral agent is given
a trial in multiple sclerosis. Viral infections have been
cluster of cases on the Faroe Islands.
Intriguing epidemiological but weak virological
bewildering list of usual suspects including measles,
rabies, scrapie-like agent, Carp agent, paramyxovirus,
coronavirus, Epstein-Barr virus, herpes zoster, herpes
simplex virus, human herpesvirus 6, rubella, mumps,
canine distemper, Marek’s Semliki forest virus, animal
and human retroviruses, and human T cell lymphoma
virus type I.
Although multiple sclerosis was on the
virus infection was being formulated in the 1960s, the
transmission experiments were all negative. Interest-
ingly, Stanley Pruziner, recent Nobel laureate for his
work on prions, does not have multiple sclerosis on his
personal list of possible prion diseases.
Current scientific interest is focused on chlamydia
virus has been under suspicion for over two decades,
and recently it was noted that patients with multiple
sclerosis had an increase in respiratory infections
before the onset of multiple sclerosis and a fivefold
increase over controls in infectious mononucleosis.
this an indication of a specific role for Epstein-Barr
the immune system in patients with multiple sclerosis?
A vascular theory for multiple sclerosis resurfaced
with the development of anticoagulants, replaced in
the 1960s by an interest in dietary therapies, which had
a vascular defect as part of the rationale. Recent work is
again focused on the vascular changes as a basis of the
breakdown of the blood-brain barrier that precedes
the inflammation and demyelination in a multiple scle-
rosis plaque. Proponents of the infection theory would
add that an infection could be the initial event that pre-
cipitates this process.
Over the past century and a half, bolstered by a
body of observations and anecdotes, proponents of
aetiological theories have focused on environmental
toxins, “neuropathic constitution,” physical and emo-
tional stresses, circulating myelinotoxins and lipolytic
enzymes, dietary factors, and vascular thrombosis.
Early writers all noted occasional cases in a family but
dismissed these as coincidental. Recent research is
convincing in showing the risk in siblings and fraternal
twins to be about 2-5%, much higher than in the
normal population, but about 30% in identical twins, a
clear indication of a genetic factor.
But why don’t the
the disease? The conclusion is that multiple sclerosis is
a complex trait, determined by multiple genes and an
environmental factor. Is the other factor an infection?
There has been a reluctance to dispense with any
theory when the answer is still unknown. So a current
popular overarching theory postulates a genetically
predisposed individual who develops a viral infection
that disrupts the vascular relations in the blood-brain
barrier and initiates an immune reaction that
continues as a waxing and waning destructive process
that damages myelin, and perhaps more importantly in
the long term, the axons. But just as a workable and
testable theory has evolved, important work by an
international group implies potentially four pathologi-
cal patterns of multiple sclerosis.
So we must add to
with different disorders with different causes. No one
ever said medicine was simple.
Jock Murray professor
Dalhousie University, Sir Charles Tupper Medical Building, 5849
University Avenue, Halifax NS, Canada B3H 4H7
Competing interests: None declared.
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