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When nerves break down

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    When nerves break down http://www.newscientist.com/article/mg18224505.500;jsessionid=NDFAEBAOIMCF * 05 June 2004 * From New Scientist Print Edition. Subscribe
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      When nerves break down

      http://www.newscientist.com/article/mg18224505.500;jsessionid=NDFAEBAOIMCF

      * 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

      Enlarge image

      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
      wheelchair.

      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
      western countries.

      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
      (see Diagram).

      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
      function normal.

      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
      course.

      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
      our reach.

      * Patient names have been changed
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