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Multiple System Atrophy News - January 2005

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  • Pam Bower
    _________________________________________________________ Multiple System Atrophy News - January 2005 _________________________________________________________
    Message 1 of 1 , Jan 5, 2005
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      Multiple System Atrophy News - January 2005

      Table of Contents

      a. Danish MSA Society Website
      b. Free Booklet from NORD: The Physician's Guide to Multiple System

      a. MSA Video Documentary Expected in 2005
      a. Report: 2nd International Meeting on Multiple System Atrophy
      b. Research: Water Helps Low Blood Pressure
      c. Research: "Smart Drug" for Low Blood Pressure
      d. Research: Riluzole improves motor deficits in rat model of
      multiple system atrophy

      4. ODDS & ENDS
      a. Ask the Doctor: What can be done for repeated urinary infections?



      a. Danish MSA Society Website

      From: "Birgit Meister" <birgitmeister@...>


      Dear Pam,

      This is to inform you, that we now have a MSA homepage in Danish.
      The address is http://www.msa-danmark.dk
      We plan to also have a version in English later.
      If you have any suggestions you are more than welcome.

      All the best Hans and Birgit in Copenhagen, Denmark

      b. Free Booklet from NORD: The Physician's Guide to Multiple System





      a. MSA Video Documentary Expected in 2005

      "Sophie's Search for a Cure", a 1-hour video documentary about
      Sophia Dohm, who has MSA, is expected to be completed in 2005. The
      production, announced in this newsletter in 2002, has taken much
      longer than anticipated, and the producers thank the MSA/PSP
      community for their patience. Sophie's Search for a Cure will be
      distributed on DVD and VHS, and hopefully will receive television
      broadcasts and be "streamed" on the internet. Contact information
      will be provided as soon as the video is available.



      a. Report: 2nd International Meeting on Multiple System Atrophy
      Rome, Italy
      June 17-18 2004

      Source: "SMART NEWS" - Summer 2004

      This event was held as a satellite meeting of the 8th International
      Congress of Parkinson's diseases and Movement Disorders. Tim Young,
      Sarah Matheson Trust Clinical Research Fellow, summarizes the key
      presentations made during the meeting.


      Etiopathogenesis of MSA
      by Professor Nick Wood

      In this talk Prof Wood summarized the current situation on genetics
      and MSA. Of course, at present, to make a clinical diagnosis of MSA
      requires the exclusion of a family history. However, this does not
      mean that genetic factors are unimportant in MSA.

      A few conditions in medicine follow simple genetic patterns (e.g.
      with the condition cystic fibrosis, if both parents are carriers of
      the faulty gene, you would expect that, on average, 1 in four of
      their children would be likely to develop cystic fibrosis). However,
      other conditions are more complex (e.g. "X"- linked disorders where
      males are more prone to develop disorders). Most medical conditions
      have even more complex genetic components, for example
      susceptibility to coronary heart disease may be influenced by many
      different genes which influence cholesterol levels, blood pressure

      The protein a-synuclein has been implicated in both Parkinson's
      disease and MSA as it is found to build up in the damaged brain
      areas in these conditions. That excessive a-synuclein itself is
      likely to be important has recently been shown by the discovery of a
      family with an inherited form of Parkinson's disease where there are
      too many genes coding for a-synuclein, resulting in excess of the
      protein.However, inherited forms of Parkinson's only seem to make up
      5-10% of all cases of Parkinson's disease, and a-synuclein gene
      disorders have not yet been associated with MSA.

      There has been recent interest in the newly described condition
      FXTAS (Fragile X associated Tremor/Ataxia Syndrome). This condition
      is caused by a trinucleotide repeat. It is essentially a problem in
      the same part of the DNA which leads to the condition Fragile X
      syndrome in children/young adults, but FXTAS has fewer repeats of
      the trinucleotide. The syndrome was noticed when it was noted that
      the grandfathers of some children with Fragile-X syndrome were noted
      to have a tremor and ataxia (FXTAS). It was initially claimed that
      FXTAS had many similarities with MSA. However, FXTAS also tends to
      produce a peripheral neuropathy (not associated with MSA) and
      autonomic failure is not a prominent feature, unlike MSA. Finally
      the inclusion bodies are a-synuclein negative in FXTAS, and are
      found in the nerve cells themselves rather than in the nerve support
      cells (oligodendroglia) seen in MSA.

      The FXTAS story does at least show that candidate genetic areas or
      genes can emerge which can then be tested for in MSA subjects. The
      improvement of existing MSA DNA banks should help the search for
      such candidate gene defects as and when they are discovered in the

      During subsequent questions it was agreed that 2 areas might help
      target the search for candidate genes:

      • Possible investigations of the 5% of MSA subjects who develop
      symptoms at a young age (40 years or younger); a similar approach
      helped in the discoveries of inherited Parkinson's disease.

      • In Europe/USA the ratio of MSA-P (Predominantly parkinsonian) to
      MSA-C (predominantly cerebellar) is 2:1. In Japan this ratio is 1:2.
      Racial differences in genes occur between Caucasian and Japanese
      populations and may thus provide clues to possible candidate genes.


      Clinical Skills
      by Professor Niall Quinn

      Prof Quinn discussed some of the findings from the history and
      examination, which can point to a possible diagnosis of MSA. In
      particular he emphasised a few points which are not always widely

      • In the history it is important to ask about sleep disturbance-this
      may be present but not appreciated by the patient and so asking the
      partner about this is important. Specifically, REM Behaviour
      Disturbance ("acting out dreams") may be common in MSA, sometimes
      predating the diagnosis of MSA • On examination, classical
      "pillrolling" tremor in the hands is only seen in 9% of MSA, being
      much more common in Parkinson's disease.

      • 50% of MSA patients have pyramidal signs on examination (including
      brisk reflexes elicited with a tendon hammer). These findings are
      also commonly seen in stroke patients, but in MSA these findings are
      NOT associated with significant weakness.


      Autonomic Testing
      by Professor Mathias

      Prof Mathias outlined many of the autonomic tests which are
      routinely used to help diagnose MSA, which have previously been
      discussed in SMarT News.

      Single Photon Emission Tomography (SPECT) & Positron Emission
      Tomography by Dr Sid Gilman and Dr Angelo Antonini

      Angelo & Dr Gilman discussed various aspects of these imaging
      techniques, which use short-lived radioactive injections to
      highlight certain areas in the brain. The specific areas usually
      looked at include the dopamine producing nerves and the receptors
      upon which they act. Whilst the dopamine producing nerves are
      affected in both MSA and PD, the dopamine receptors are especially
      depleted in MSA. SPECT cannot only help differentiate MSA and PD,
      but can help monitor progression in both conditions. It therefore
      provides a means to monitor progression in MSA when designing
      therapeutic trials.

      Dr Gilman also discussed MIBG and 11CHED tracers used in SPECT
      studies of the heart. Recently there has been a lot of interest in
      imaging the heart in PD, as there seems to be selective loss of the
      small sympathetic nerves supplying the heart. Whilst the clinical
      implications of this are not fully understood, diagnostically this
      is useful as this may help differentiate from MSA where these small
      nerves are thought to be preserved. These scans are expensive
      however, are not widely available, and some MSA subjects may also
      show similar changes to those seen in PD (Dr.Gilman is currently
      investigating this aspect).


      Sphincter EMG
      by Dr David Vodusek

      David has several decades of experience in the use of sphincter EMG,
      which can be used to help distinguish MSA from PD and other
      disorders. The rationale behind the test is that Onuff's nucleus, a
      small group of nerves near the base of the spine, which innervates
      the anal and urethral sphincters, is specifically targeted in MSA.
      The resulting damage to the sphincters results in specific changes
      in the muscles of both sphincters as assessed with a very small

      Some of the key points made:
      • Other disorders including PD and previous haemorrhoid/prostate
      surgery can also result in abnormal results
      • Even if the test is initially normal, it can become abnormal
      within the following 2 years in MSA. Therefore re-testing is
      sometimes required after a normal test. If a second test, performed
      2 years after their first, is also normal then a diagnosis of MSA
      would be unlikely.
      • Sphincter EMG testing is now standardised allowing better
      correlation between different centres for this highly specialist
      • Interestingly an abnormal EMG result does NOT necessarily mean
      that the patient will have any symptoms related to the anal or
      urethral sphincters


      Natural History of MSA: Prospective Studies
      The European Multiple System Atrophy Study Group-EMSA-SG
      by Professor Gregor Wenning

      Gregor described the recent validation of the MSA rating scale. Both
      a firm diagnosis and understanding of severity of MSA are clearly
      essential to allow interpretation of any studies of treatment of MSA.

      It is important to know that one is including true MSA patients and
      have a way to decide if the treatment has led to an improvement, or
      at least a slowing of, deterioration. For this reason the validation
      of the MSA rating scale has provided an important tool to help
      assess study results. It is highly likely that any treatment for MSA
      would be most effective if started as early as possible.

      For this reason improved techniques to confidently improve early MSA
      diagnosis are needed. The rate of deterioration in MSA has also been
      studied. This is important to know for therapeutic studies so that
      it can be seen if the intervention results in a slowing of
      deterioration in MSA. An additional element of the European MSA
      study group has been the setting up of an MSA DNA bank.

      There are currently 4 major ongoing studies of possible therapeutic
      intervention in MSA, all of which are nearing completion:

      • Neuroprotection and Natural History in Parkinson Plus Syndromes
      This study is looking at the effects of riluzole. Riluzole is a drug
      which has been recently shown to slightly improve prognosis in Motor
      Neuron Disease. It has many actions including blocking the release
      of the neurotransmitter glutamate. It has been shown in rat models
      of PD to protect against neuronal damage. About 400 patients with
      MSA and 400 with PSP (another Parkinsons plus syndrome) have been
      recruited and given even riluzole or placebo.

      • Growth Hormone Study: Looking at the effects of Growth Hormone
      (GH) injections in a smaller number of MSA patients. The scientific
      background is not as powerful as for riluzole, but results are still

      • Minocycline is an antibiotic which also has antioxidant and
      neuroprotective effects in animal models. This study is looking at
      the effects of minocycline for 48 weeks in MSA, using the Unified
      MSA rating scale as an end-point

      • GDNF is a nerve growth factor which is being studied in MSA after
      having shown improvements in PD. HOWEVER, this treatment requires
      the drug to be infused via a small tube directly into the brain. The
      trial design is that patients receive GDNF or placebo for 0-6 months
      and then all patients receive GDNF for the remaining 6 months. The
      above studies are still on going and so results have NOT been
      reported yet. Results should start to become available in about a
      year. Even if these results do not show an improvement, these
      studies represent an important and exciting step forward in
      MSAresearch as they provide the framework for future therapeutic
      studies to be performed. Future research will not only focus on
      developing new agents to try in studies, but also better ways to
      differentiate MSA from other related conditions at an earlier stage.

      Dr Tim Young, Neurovascular Medicine (Pickering Unit), Imperial
      College London, St Mary's Hospital

      b. Research: Water Helps Low Blood Pressure


      c. Research: "Smart Drug" for low Blood Pressure

      d. Research: Riluzole improves motor deficits in rat model of
      multiple system atrophy

      Riluzole improves motor deficits and attenuates loss of striatal
      neurons in a sequential double lesion rat model of striatonigral
      degeneration (parkinson variant of multiple system atrophy).
      J Neural Transm. 2004 Dec 7

      Scherfler C, Sather T, Diguet E, Stefanova N, Puschban Z, Tison F,
      Poewe W, Wenning GK.

      Department of Neurology, University Hospital, Innsbruck, Austria.

      We investigated neuroprotective effects of riluzole, an anti-
      glutamatergic agent that is FDA approved for disease-modifying
      therapy in amyotrophic lateral sclerosis (ALS), in an established
      double lesion rat model of striatonigral degeneration (SND), the
      neuropathological substrate of parkinsonism associated with MSA (MSA-
      P). Riluzole was administered prior to and consecutively for ten
      days following double lesion placement in the left-sided medial
      forebrain bundle and ipsilateral striatum. Assessment of motor
      behaviour using a flex field system showed a significant reduction of
      motor disturbance in animals with striatonigral lesions treated with
      riluzole compared to lesioned but untreated animals (P<0.001). DARPP-
      32 immunohistochemistry revealed a significant reduction of absolute
      striatal lesion volume in riluzole treated animals compared to
      lesioned but untreated animals (P<0.01). No significant difference
      in count of nigral dopaminergic neurons was found in treated versus
      untreated double-lesioned animals. The results of our study indicate
      that riluzole mediates neuroprotective effects in the double lesion
      rat model of MSA-P. Whether riluzole also protects autonomic and
      cerebellar pathways that are frequently affected in MSA remains to
      be determined. Nonetheless, our study is the first to provide an
      experimental rationale for exploring possible neuroprotective
      effects of riluzole in MSA.


      4. ODDS & ENDS

      a. Ask the Doctor: What can be done for repeated urinary infections?
      Nov 19, 2004


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