When nerves break down
- View SourceWhen nerves break down
* 05 June 2004
* From New Scientist Print Edition. Subscribe and get 4 free issues.
* Howard Weiner
* Howard Weiner is the Robert L. Kroc Professor of Neurology at
Harvard Medical School and Director of the Partners MS Center at Brigham
and Women's Hospital
THREE years ago a 34-year-old teacher named Janet Brown* attended the
multiple sclerosis centre at the Brigham and Women's Hospital in Boston,
where I had been her neurologist for the previous five years. Janet had
been doing well on one of the newer injectable MS therapies until 12
months previously when she began to have an increasing number of
relapses that affected her speech and walking. She had turned up in a
An MRI scan of Janet's brain showed several areas were inflamed, a key
sign that her immune system was attacking nerve cells, one of the
hallmarks of MS. That day we began treatment with a cancer chemotherapy
drug that suppresses the immune system. After two months, brain scans
showed a lot of improvement. After one year she could walk with a cane
and today her only symptom is a limp.
That same day in 2001, however, I saw another patient, Charles Wilson*,
a 48-year-old investment banker. He had first noticed a problem 10 years
earlier when his usual games of tennis began to make his legs ache. Over
a period of three years, he had gone from playing singles to playing
doubles tennis and then began limping and requiring a cane. He
definitely had MS, yet brain scans revealed little inflammation.
Charles, too, had already been receiving treatment by injection and that
day we also began chemotherapy. But Charles continued to slowly worsen
and now he has to use a wheelchair.
These two cases highlight one of the biggest frustrations with MS - why
the disease takes different forms in different patients. They also help
illustrate important new thinking among neurologists about the molecular
mechanisms behind this condition. For a long time MS has been seen as an
inflammatory disease, in which patients' immune cells attack the myelin
sheath, the "insulation" that covers neurons in the brain and spinal
cord. Based on this idea, scientists have developed drugs that reduce
the inflammation, and these do reduce the frequency of attacks, although
they are not a cure. The new theory says that while the autoimmune
attack on the myelin sheath is important, it also triggers a
self-sustaining process of damage to the neurons themselves. It is this
neuronal degeneration that may be one of the main factors determining
the extent of patients' disability.
This is no academic debate, because if the new theory is right it opens
the door to a host of novel drugs for MS that stop nerves degenerating.
Some are being tested on animals, and others are already licensed to
treat other diseases. The idea that nerve degeneration is at the heart
of MS also has major implications for existing MS drug treatments,
making it vital that they are given as soon as possible, to try to
prevent degeneration from starting.
MS has long held a prominent place in the public consciousness that
belies the fact it is not especially common, affecting about one in a
thousand people. Perhaps this is because it generally strikes people in
the prime of life, between the ages of 20 and 40, and since the
eradication of polio it has become the most common cause of paralysis in
In the past, MS was seen as a single disease. Now it is clear that it is
far more complex, with different subtypes and with the condition
changing character over time. Some patients have a relatively benign
illness with intermittent attacks and minimal symptoms in the first 10
to 30 years (the so-called relapsing-remitting form). In other patients,
though, each attack causes more disability and in about half of all
patients, MS eventually becomes a progressive disease that ultimately
confines many to wheelchairs. Another form of the disease is progressive
from the start and is termed primary progressive MS.
Since MS was first described in the 19th century, various hypotheses
have been put forward about what causes the disease, including viral
infections, environmental toxins, and inherent defects of the brain. But
despite intense efforts, none of these theories has been substantiated,
and the vast majority of neurologists now see MS as an autoimmune
disease - in which the immune system attacks the patient's own body -
like type 1 diabetes or rheumatoid arthritis.
In MS, immune cells called T-cells are believed to leave the bloodstream
and enter the brain and spinal cord, where they attack the myelin sheath
of nerves. With their myelin sheath damaged or destroyed, the neurons
transmit electrical impulses much less efficiently, leading to problems
with balance, walking, vision and sensation.
As recently as this February, researchers in Sydney caused a stir when
they claimed the initial trigger for MS is not autoimmune attack at all
but some other unknown factor. However, their findings were from only
seven patients, in contrast to the extensive evidence supporting the
autoimmune basis. For example, as with other autoimmune diseases, MS
strikes women more often than men, and is commoner in people with
certain variants of immune system genes (the HLA genes).
Regardless of the initial trigger for MS, autoimmune attacks definitely
play an important role in the disease. Imperfect though they are,
existing therapies work by interfering with this process. Injectable
beta-interferons seem to stop certain immune cells getting into the
brain and decrease their production of gamma-interferon, an important
chemical signalling molecule, or cytokine. The other main injectable
drug, glatiramer acetate, causes immune cells to release
anti-inflammatory cytokines and also decreases T-cells' gamma-interferon
response. Finally, certain chemotherapy drugs have been shown to help
patients with aggressive MS by killing or suppressing the T-cells.
But is autoimmune attack the only disease mechanism involved? A growing
number of neurologists think not. The scientific paper that brought this
into focus was published in The New England Journal of Medicine in 1998
by Bruce Trapp, a neuroscientist at the Cleveland Clinic in Ohio. He
reported that in MS patients, not only was there loss of myelin but that
the nerve fibres, or axons, were also damaged. In fact, they were
"transected" or broken in two, and the axons had contracted into balls
Trapp was highlighting a finding described before by other pathologists
but his report, which included striking electron-microscope photographs
of the damaged axons, rekindled a great deal of interest in it. The
study forced a re-evaluation of the exact processes that lead to
disability in MS.
One line of research that supports the importance of axon damage comes
from Alastair Compston's team at Cambridge University. Compston helped
to develop an artificial antibody called Campath (named after the
university's pathology department, where the research was carried out),
which targets a molecule on the surface of T-cells called CD52. Campath
kills T-cells and is used to treat leukaemia, which is a cancer of
T-cells in the blood and bone marrow. But Campath is also an
immunosuppressant and Ilex Oncology, the US biotech firm that makes
Campath, is carrying out trials of the drug in MS patients.
The early studies suggest that Campath is very effective at suppressing
inflammation in MS and halting new attacks. But some patients in the
trials have still experienced a slow worsening of their condition -
despite the absence of inflammation. This seems to suggest that once the
myelin sheath has sustained a certain amount of damage, it sets off a
self-sustaining process of axon degeneration.
What might that degeneration process involve? In the past few years
neuroscientists working in many areas have become increasingly
interested in how the amino acid glutamate can damage neurons. Healthy
neurons use glutamate as a signalling molecule, or neurotransmitter, but
it is possible that higher-than-normal levels can harm both neurons and
the oligodendrocyte cells that make up the myelin sheath. Glutamate
toxicity is thought to play a role in various neurological diseases,
such as stroke, epilepsy and the rare but fatal condition amyotrophic
lateral sclerosis (ALS).
Could it play a role in multiple sclerosis too? One source of excess
glutamate is overexcited neurons, but immune cells also release large
amounts of the chemical when activated. This connection led Cedric
Raine, a neuropathologist at Albert Einstein College of Medicine in New
York, to test compounds that block glutamate receptors on the outside of
cells in animal models of MS. In 2000 he showed that a chemical called
NBQX lessened paralysis and nerve damage in mice (Nature Medicine, vol
6, p 67). It had no effect on brain inflammation, however - like
Campath, only in reverse.
Excitingly, some medicines that are already licensed to treat other
diseases work by blocking glutamate toxicity, suggesting they could be
turned into new treatments for MS. One such drug licensed for use in
ALS, called riluzole, is already being tested in early-stage human
trials in MS, as is a new Alzheimer's disease treatment called memantine.
Much of the degeneration theory is still speculative, and it is unclear
whether this process occurs alone or alongside continuing inflammation.
However, some neurologists think that when a patient switches from
relapsing-remitting to progressive MS, that means degeneration is taking
over from inflammation as the major disease mechanism.
Support for this idea comes from a study led by Christian Confavreux
based in Lyon, France, using a database of 1844 patients (The New
England Journal of Medicine, vol 343, p 1430). This showed that there is
huge variability in the length of time patients spend in the
relapsing-remitting phase, ranging from 1 to 33 years. But once patients
enter the progressive phase, variability is much less, and they take
from 4 to 7 years to reach the wheelchair stage. This finding hints that
the immune attacks cause damage to the axon that, once initiated,
progresses at a predetermined rate.
Neurons working overtime
If the correlation between axon degeneration and progressive MS holds
true, it would explain the different outcomes experienced by my
patients. Janet Brown was still in the relapsing-remitting phase, where
the main determinant of symptom severity is whether there is ongoing
autoimmune attack and inflammation. This process was halted by our use
of a strong immunosuppressant. Charles Wilson, on the other hand, was
experiencing unrelenting progression of his MS, because of axon
degeneration, which would be unaffected by immunosuppressants. Of
course, we still do not understand why the disease progresses
differently in different patients.
We do have a theory, however, about why some patients in the
relapsing-remitting phase do well for many years even though they have
periodic attacks. The brain may be compensating for damage to some
neurons by using others. In support of this hypothesis are findings from
functional MRI scans, which can detect increased blood flow to different
parts of the brain, indicating neuronal activity. One study found that
when MS patients obeyed requests to move their hands in a certain way,
their brain activity was five times that of individuals without MS. It
seems that in MS patients, the brain is working overtime to keep brain
In most patients, however, as more and more damage is done, the brain
can no longer keep up and the hidden damage becomes apparent, resulting
in disability. Nonetheless, there are some fortunate patients with
relatively benign disease who do not become more disabled over time. It
is possible that such patients have higher levels of factors that
protect their nervous system from toxic substances such as glutamate, or
perhaps not much of the toxins are produced in the first place. It may
even be down to certain types of T-cells secreting protective chemicals.
My team at Brigham and Women's Hospital is studying a group of 150
patients with benign MS. We are taking samples of their DNA, carrying
out MRIs, and recording the characteristics of their disease and immune
system in minute detail. The aim is to identify the factors that stop
their disease from progressing in the hope of using this knowledge to
develop new drugs for MS that would keep all patients on such a benign
Does the new understanding of MS mean we will need new animal models of
this disease? It appears not. Although the commonly used model,
experimental allergic encephalomyelitis, is sometimes seen as a poor
representation of human MS, it does appear to involve a degenerative
process after the initial inflammation phase.
The degeneration theory does, however, have important implications for
the use of beta-interferon, glatiramer acetate and the many new
immunosuppressants being developed to reduce inflammation. It is clear
that patients with MS should start treatment as early as possible to
suppress inflammation and prevent the degeneration process from
starting. In some countries such as the UK, this does not yet happen,
mainly because the injectable therapies are expensive, costing several
thousand pounds a year.
Our new understanding of MS will influence how we use existing drugs
then, as well as raising the possibility of a host of new therapies that
block degeneration. I believe that in future, MS patients will receive
strong anti-inflammatory therapy right from the start, followed by the
addition of degeneration-blockers. MS could be turned from a
relentlessly progressive disease that causes permanent pain and
disability into a relatively mild condition that can be kept in check
with the right medicines.
A cure for MS may be some way off - but taming this disease looks within
* Patient names have been changed