MGA News Summer 2006

Hope Hospital, Salford
Patient care and research activities.

How did we get here?

For many years, neurologists looked after MG patients in general neurology or muscle clinics in the various Neurology Departments across Greater Manchester. In 2001, these were amalgamated onto a single site, the Greater Manchester Neuroscience Centre at Hope Hospital in Salford. That’s where Dr Mark Roberts and I joined forces soon afterwards – to start a single clinic dedicated to looking after MG patients from the teens onwards. Since then, colleagues across the region have referred patients to us for help in diagnosis and management. We are fortunate in having two experts, Dr Andy Marshall and Dr Hussain Bangash, who carry out nerve stimulation and single-fibre EMG tests to identify faults in electrical transmission from nerves to muscles, tests that are often crucial for diagnosis.

Since then, the clinic has expanded; fortunately, we have the space to see patients on a monthly basis or between clinics on the wards, so that we can tailor their supervision to their individual needs. What’s more, Trainee Specialist Registrars attend the clinic to learn about MG before becoming Consultant Neurologists. We are also very lucky to have the help of Staff Nurse Amanda Woodall who is developing a special interest in myasthenia. In 2005, Amanda and Kate Fraser, MG Nurse in Liverpool, started to run educational Question-and- Answer sessions about myasthenia which are held at Hope Hospital. They have been very popular, despite the quality of the refreshments.

What Research is done here?

The clinic is the focus of much research aimed at improving the care of MG patients and improving our understanding of their condition. Here are some examples:-

(a) To focus on the safety of a ‘Quick-start’ Pyridostigmine (Mestinon®) régime, the ‘246 Study’ was run jointly between neurologists in Liverpool, Birmingham and Manchester. Mestinon® was given at 30 mg twice daily for 2 days, then 30 mg five times daily for 4 days, then 60/30/60/30/60 mg per day for 6 days, then 60 mg five times daily after that. This first-line drug acts by blocking the breakdown of the chemical signaller (ACh) – so giving it a better chance of triggering weak muscles through their ACh receptors. The same ACh also stimulates our ‘automatic’ muscles and glands in the guts, bladder etc; since the receptor is completely different, these functions are not directly affected in MG. But Mestinon® can also make the stomach or bowels over-active, as many of you know too well. Despite a few side-effects, the Quick-start régime was well tolerated by 87% of patients, so we are now more confident in using it when it’s needed.

(b) Mycophenolate mofetil (MMF) (alias Cellcept ®) is a powerful immuno-suppressive drug. It was originally used to control rejection of transplants. Like azathioprine, it slows production of new DNA and so reduces proliferation of cells – a key feature in any active immune response and many autoimmune diseases. As you know, Dr Jackie Palace (in Oxford) showed that azathioprine helped MG patients to reach lower ‘cruising doses’ of steroids in the end. Alas, it can take over 12 months to ‘kick-in’, perhaps because the immune cells turn over more slowly in MG than after transplantation. In early/ small studies, MMF seemed to be effective in MG. What’s more, in Manchester we got the impression that it may start working sooner than azathioprine. If that is confirmed, it might allow earlier tapering of steroid doses, giving less time for their side-effects to build-up. Since no one neurologist can treat enough patients to get a full picture of the pros and cons of any new drug, we have joined a multi-centre study on MMF. All the (MG) patients are started on steroids until their MG has come under control: then some of them are given MMF and others get dummy tablets (placebo). The steroid dose is then reduced – and recorded (of course). The key questions are:- is the final steroid dose any lower in the patients given MMF; is their total steroid consumption lower? Since the steroids are tapered down quite rapidly, we should also be able to tell whether MMF really does kick-in sooner? The study results should be available in the early part of 2007.

(c) As you know from the last two issues of MGA News, our President, Prof. John Newsom-Davis, is masterminding another multi-centre trial; we are one of the 50 centres around the world. The trial aims to test whether thymectomy really does work in MG. The operation came into use in the 1940s – i.e. long before the current demand for hard evidence that such treatments really do work – evidence we still don’t have after all these years (believe it or not). Again, the acid test will be whether it enables patients to cruise on lower total steroid doses. We are starting to recruit patients now: the final results are expected only after about 8 years. (Some wag suggested that the Pensions Agency should use John’s work on the Trial as proof that people shouldn’t retire until they’re at least 80).

(d) Perhaps our most exciting research has been with EN101 (now renamed Monarsen after Mona Soreq who invented the treatment). The results of our pilot study were published in MGA News in Autumn 2003. We also explained there that Monarsen works by turning off the gene responsible for breaking down the ACh; if so, this ‘anti-sense’ alternative to Mestinon® should also soup-up muscle triggering. Indeed, sixteen of the eighteen patients given Monarsen did seem to benefit from it, some quite dramatically, and it didn’t have any obvious side-effects. Interestingly, one of them responded very well to Mestinon® but not at all to Monarsen, so we are not simply testing a ‘space age’ Mestinon®. The study wasn’t set up to compare the two drugs, but we did see hints that some patients found Monarsen more effective: in theory, it might act for longer. To allow definite conclusions, we need a bigger, more controlled study with different doses and comparing it directly with Mestinon®. A second study is scheduled in Manchester for June 2006, and we will be recruiting people with generalised myasthenia, who are taking at least 3 Mestinon tablets® and who have some continuing muscular weakness, to try to answer some of these questions. Everyone on the study will be admitted to hospital overnight to withdraw from Mestinon®, and to start on Monarsen. Everyone will be reviewed once a week for 7 weeks to measure their muscle strength. We would be happy to recruit people with myasthenia from outside Greater Manchester who are prepared to travel.

MGA NEWS Summer 2006

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