Professor Paul Maddison and Dr Girija Sadalage look at late onset myasthenia Professor Paul Maddison and his student Dr Girija Sadalage have been investigating why the incidence of myasthenia gravis (MG) in the older population has been steadily increasing over the last 30-35 years. The incidence of myasthenia gravis has been steadily increasing over the last 30-35 years. It is curious that the increase is much steeper in the late onset group as compared to the early onset group. For the purposes of studies, late onset is described as onset over the age of 50 years (LOMG). No clear cause for this disparity has been found to date. Our aim was to describe the signs and symptoms that patients present with in both early onset and late onset myasthenia. We looked at blood samples to see if there is any difference in the immunological profiles. We assessed them clinically and scored them on the MG composite scoring sheet and also collected ‘Quality of Life’ data. Since the start of our study in August 2014 we have recruited 150 patients with myasthenia gravis and 8 patients with Lambert-Eaton myasthenic syndrome (LEMS) making this the largest prospective cohort study in MG to date with 100% recruitment rates in the Trent region. We also have recruits from out of the region who volunteered to participate in the study. Three quarters of our patients were over 50 years of age at diagnosis, in keeping with previously published epidemiological data. We found more females (60%) in early onset myasthenia gravis (EOMG) but the opposite of more males (60%) in late onset myasthenia gravis (LOMG). Around half the patients presented with purely ocular symptoms (defined as ocular symptoms only at 3 months from symptom onset). Ocular presentation was more common (69.23%) in EOMG than in LOMG patients (46.84%). Composite scores (a marker of MG disease severity) were lower at diagnosis (milder disease) in EOMG compared to LOMG patients. Although generalisation rates were similar in EOMG and LOMG (40.74% vs 42%), older patients developed symptoms of generalised myasthenia much more quickly after diagnosis than younger patients. LOMG patients were more likely to need inpatient hospital treatment (36% vs 15%) and the mortality rate was also higher. The dose of steroids (prednisolone) required at second year follow up in both the LOMG and the EOMG groups was significantly less than that required at first year follow up, particularly in patients with ocular myasthenia. Although steroid requirement in generalised myasthenia gravis also fell with time, this was less dramatic and not statistically significant, as might be expected in more severe disease. Continued, ongoing follow-up (which is currently taking place) will be useful to determine if steroid requirements are different in EOMG and LOMG patients, particularly with generalised symptoms. There was an improvement in the MGFA Post Intervention Scores (PIS) over time in patients with generalised MG (but not statistically significant), but not in those with ocular MG and there was no difference here between the LOMG and the EOMG groups. From the results of chest imaging in 137 patients, we found EOMG patients were more likely to have thymic abnormalities (50% vs 13.86%) than older LOMG patients, thymic hyperplasia being much more common in younger patients (61.11%) and thymoma in older patients (78.57%). Antibodies related to myasthenia were present in 95% of patients at initial recruitment and the antibody levels (titres) reduced significantly over time in the patient group as a whole. Interestingly, acetylcholine receptor antibody levels were lower at diagnosis in EOMG patients, compared to LOMG patients, perhaps due to the increased proportion of pure ocular symptoms in this younger group. Of patients who had levels of acetylcholine receptor antibodies measured at diagnosis and again at 12 months (n=91), most (73/91, 80%) had reduced antibody levels on follow-up, both among EOMG (67%) and LOMG (83%) patients. We looked at the lymphocytes (white blood cells) in the blood collected from our patients and compared them with healthy controls and EOMG and LOMG subgroups. The number of regulatory T cells (Tregs) was significantly reduced in patients with myasthenia compared to healthy controls. Regulatory T cells were equally as low in EOMG and LOMG patients, indicating that perhaps similar mechanisms of loss of immune tolerance causing the autoimmune condition of myasthenia are occurring in both young and old patients. Our study has shown that there are clinical and immunological differences between early onset and late onset myasthenia gravis, but both respond well to treatment with an improvement in composite scores and a fall in antibody titres. We are continuing to study this cohort of MG patients with extended follow-up. Blood samples are being analysed to look for viral triggers and predictable markers of generalisation after ocular presentation and future work will hopefully allow us to identify the abnormal white blood cells that are producing acetylcholine receptor antibodies.