Abstract 

Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction resulting in fluctuating, fatiguing weakness.  It can affect people of any age, sex and ethnicity.  It has been observed that the incidence and prevalence of MG in older patients has been increasing.  As a result, the typical myasthenia clinic now has a substantial portion of elderly patients, both newly diagnosed late onset MG (LOMG) and with longstanding early onset MG (EOMG).  The management of these patients brings specific challenges less often seen in younger populations.  The differential diagnoses vary, the risks of treatments can be greater with less evidence supporting their use, and increasing polypharmacy requires particular caution and awareness of possible interactions.  

In this article, we review the approaches and considerations needed when diagnosing and managing the elderly patient with MG. 


Introduction 

Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction.  Clinically, antibodies against the acetylcholine receptor (AChR) or muscle specific kinase (MuSK) are identified in 85% and 5-10% of patients with MG respectively, while others are usually classified as seronegative.  It is a disorder that can be associated with thymoma in 15-20% of the patients with AChR antibodies.   

In western populations, the incidence of MG typically shows two peaks.  One, seen mainly in females, occurs in the 2nd and 3rd decades of life, while the second, in the 6th and 7th decades, affects more men than women.  Nonetheless, the incidence of MG does increase with age until around the 8th decade of life, when it reduces [1]. In parallel to this, the incidence of thymoma-associated MG peaks between the 5th and 7th decades [2]. 

It has been observed that the incidence and prevalence of MG has been increasing for several decades now, and this is particularly noticeable in those with MG presenting after 50 years of age (late onset MG, ‘LOMG’) [3]. This may be the result of an ageing population where people live longer, with better diagnosis and treatment of MG, and other factors yet to be identified.  The result is that a significant cohort of the MG patients treated by the average neurologist are older adults or elderly, with some having had MG presentation before 50 years of age (early onset MG, ‘EOMG’), and others having LOMG.  

The approach to the diagnosis and management of older patients can present different challenges to younger patients and necessitate a flexible approach to management. Here, we outline some of the challenges faced, and possible approaches to tackling them.  

Diagnosis 

Elderly patients often suffer from multiple co-morbidities and are at risk of other conditions that can be a differential for myasthenia gravis, some of which are far more common.  This can make recognising the possibility of MG and subsequent diagnosis difficult.    

The most common presentations of MG are ptosis/diplopia (70%), bulbar (22%), and isolated limb/axial (5.4%) [4]. These can have numerous other causes, particularly in the elderly.  The table on page 13 lists some potential differential diagnoses to consider in the elderly. 

Despite the broad number of differential diagnoses for MG in the elderly, one should not be deterred from investigating. Antibody testing for AChR or MuSK is widely available and both should be checked, including low affinity testing if required. The use of EMG, both to look for evidence of myasthenia gravis with repetitive nerve stimulation/single-fibre EMG, and to investigate alternative diagnoses such as amyotrophic lateral sclerosis is valuable, particularly in uncertain cases. 

Further investigations of possible differential diagnoses such as those in Table 1 should be requested on a case-by-case basis.   

Practically speaking, obtaining antibody results and neurophysiology can take time. As a result, the diagnosis can remain uncertain. In such cases, a trial of an acetylcholine esterase inhibitor (AChE-I) such as pyridostigmine, unless contraindicated, can be a useful indicator of diagnosis and may provide symptomatic relief. However, some patients without MG do report improved weakness with pyridostigmine, while those with MG may not respond, or may even worsen.  Therefore, it is important to interpret any response with caution. If there is a high suspicion of MG, early CT chest, even prior to a positive AChR antibody, can identify an underlying thymoma, thus supporting diagnosis. 

Management    

The management of MG can be broadly viewed as symptomatic, and acute or long-term immunotherapy.  Following the diagnosis, most patients will trial pyridostigmine, with the dose increasing to a dose that is beneficial and tolerated (usually no higher than 360 mg a day). Depending on the response, this may then continue medium- to long-term. While generally safe and well tolerated, AChE-I’s can cause both diarrhoea and increased urinary frequency and urgency. While this is not too problematic in younger patients and can be easily managed with dose reduction or an anti-cholinergic such as propantheline, some caution must be exercised in the elderly, particularly those who may have poor mobility, as the urgency could result in falls as they rush to the bathroom. This is particularly problematic overnight and so evening doses should be minimised where possible.   

In the acute phase, both intravenous immunoglobulin (IVIg) and plasma exchange (PLEX) have equally good evidence in MG, though PLEX seems to be more efficacious in MuSK MG. These should be considered in those with significantly impacted bulbar or respiratory function, or when ophthalmoplegia or limb weakness impact mobility increasing the risk of falls, they can be considered. Which approach is used is largely determined by availability, thromboembolic history and risk, anticoagulation, previous treatment response, venous access, requirement/availability of admission, and patient preference.   

Immunosuppression in the elderly 

The decision to immunosuppress older patients is not to be taken lightly.  Immunosenescence, pharmacokinetic/metabolic changes, comorbidities and polypharmacy mean that the elderly are at increased risk of infection, neoplasm, and other adverse effectswith immunosuppressive treatments. Treatment is complicated by a lack of supportive evidence as, despite an increasing number of older MG patients, the very elderly and those with significant co-morbidities are often excluded from clinical trials [5]. A further challenge is predicting the disease course and response to adverse effects of treatments.  

Long-term management of MG typically involves oral corticosteroids [6]. While usually safe, the clinician must consider the risks in older patients when initiating and deciding on the dose.  While avoiding or using a lower dose of corticosteroid may make achieving remission more difficult, it may be acceptable to tolerate some mild MG symptoms to avoid adverse effects. Some factors that are more pertinent to the elderly are outlined below.  

Osteoporosis and osteonecrosis are well recognised effects of chronic steroid use.  The risk of fractures increases two-fold, with up to 48% of patients aged ≥ 70 years on long-term steroids having at least one vertebral fracture. This increase in risk occurs within 3 months, and is dose dependent, occurring with as little as 5mg prednisolone/day.  Cessation of steroids reduces the risk [7,8].   

A 4-8% increase in weight with 2 years of 5-10mg prednisone (or equivalent) has been reported [8]. This can be more problematic in the elderly who may already have limited mobility, and also for their carers who may find moving and handling more challenging. 

Cardiovascular disease and its associated risk factors increase with age [9]. The use of corticosteroids, even at small doses, further increases the risk of dyslipidaemia, hypertension, diabetes, heart failure, ischaemic heart disease and cerebrovascular disease [10,11]. It is important to consider this when deciding whether to commence corticosteroid therapy, and to liaise with their general practitioner to ensure they are appropriately monitored/treated. 

In approximately 50% of patients using long-term corticosteroids, a proximal myopathy can occur. This can be difficult to diagnose, with investigations often yielding non-specific results.  While there is no evidence that this is more common in the elderly, they may struggle to compensate for any weakness more due to other co-morbidities. Differentiating the weakness of steroid myopathy from that of MG can be challenging, but it should be considered in those with prolonged steroid use who are disproportionately weak in the proximal lower limbs. There is no specific treatment, but improvement can occur on reducing or stopping steroids [12,13].    

Steroid sparing agents are often used in patients requiring long-term, high dose corticosteroids, typically greater than 10-15mg/day of prednisolone or equivalent.  Our experience is that elderly patients require lower doses of immunosuppression and are at increased risk of infection and adverse effects.  While there is very little evidence for immunosuppression in elderly patients with MG, there is data from other specialities [14,15].  

Azathioprine is probably the most used immunosuppressive agent in patients with MG in the UK. A study of patients with inflammatory bowel disease comparing patients >60 years and 18-50 years taking thiopurines (azathioprine or mercaptopurine) showed that 43.4% of the older patients had some kind of adverse effeccts compared to 29.7% in the younger group. They also experienced a higher rate of infection (3.6% vs 2%) and neoplasm (1.5% vs 0.2%).  Other adverse effects included (elderly % vs young %): Myelotoxicity (14 vs 7.6), anaemia (4.3 vs 1.2), leukopenia (10.4 vs 6.1) and hepatotoxicity (9 vs 4.7) [14]. The cumulative probability of thiopurine discontinuation due to any adverse effects reached 37.6% in the elderly compared to 23% in the younger group [14]. With the exception of digestive adverse effects, it was the dose-dependent adverse effects that were more likely in the elderly, suggesting that changes in pharmacokinetics may be relevant.   

Mycophenolate mofetil (MMF) has become increasingly popular in recent years, despite mixed evidence supporting its use [16,17]. There is evidence in MG patients that adverse effects are fewer and better tolerated than azathioprine, though our experience has been that recurrent and opportunistic infections are more likely, particularly in the elderly.  This is supported by evidence in patients with lupus [18-20]. There is rheumatological evidence that the risk of infection is dose dependent [21], and we attempt to keep the dose ≤1500mg/day in older patients if possible. 

Methotrexate is a well-established immunosuppressive agent. In MG, there is evidence of non-inferiority to azathioprine and its efficacy in improving symptoms and reducing steroid-dependence, while being well tolerated by patients who have had to stop azathioprine due to adverse effects [22]. There is good safety and efficacy evidence for patients with rheumatoid arthritis (RA) taking low dose methotrexate (7.5mg/day) [15], though doses used in MG are often higher [22].  The familiarity of general practitioners with methotrexate is also a positive, and while there is little dedicated evidence in older MG populations, its long-standing use in patients with RA, many of whom are elderly, is reassuring, and we are increasingly favouring it in older patients.

Ciclosporin is an effective immunosuppressant but is rarely used in the UK now.  It has an extensive AE profile and interacts with many common medications (see Table 2).  Given the presence of safer alternatives, most MG patients seen on ciclosporin are those commenced on it many years ago.  

Of the newer treatments used in MG, anti-CD20 therapies, most notably rituximab, have been embraced by clinicians the most.  It is most readily used in anti-MuSK MG, where it has shown to be extremely effective [23]. However, it also has a role in anti-AChR MG, and is more effective if given early in the disease course. The RINOMAX trial looking at the use of a single 500mg dose of rituximab in new-onset (<12 months) MG (defined as having at least 2 of: anti-AChR antibody, abnormal RNS/SF-EMG or AChEI response), found that there was a greater chance of minimal manifestation at 16 weeks versus placebo group (71% vs 29%) and less requirement for rescue therapy (4% vs 36%). The mean age of patients receiving rituximab was 67 years, making its finding more relatable to the elderly population.  This is encouraging as lower doses reduce the risk of associated infection and adverse effects.  Furthermore, the infrequent infusions make it an appealing option for those who may already struggle with compliance [24].   

One concern with rituximab is the risk of infection, particularly in association with hypogammaglobulinaemia.  Surprisingly, there is no evidence that older age increases the risk of this.  However, previous or current use of steroids, dose and duration of rituximab use are associated with lower IgG levels [25,26]. It is therefore reassuring that low dose rituximab, used early, before a patient has required long-term steroid use, can be effective. We would encourage clinicians to consider the use of rituximab early in diagnosis as first line therapy in the elderly, though at present NHS England guidance limits its use. This should be reviewed, not only for the elderly, but all patients [27]. 

There has been a recent boom in clinical trials using new therapies, with anti-complement and anti-FcRn inhibitors at the forefront of this.  While at this stage most completed trials have had upper age limits, these may represent a new path to safer treatment of MG in the elderly.  

Polypharmacy 

A major challenge in treating elderly patients is the higher incidence of co-morbidities and associated polypharmacy.  It is well established that some drugs can worsen MG and lists of these are readily available online.  There is, however, less awareness of the interactions of myasthenia treatments with other drugs, many of which are commonly used, particularly in the elderly.  Some of these are outlined in Table 2.

Thymectomy 

The association of the thymus with AChR+ MG has long been established. All patients with AChR+ MG must have thymus imaging, and if an anterior mediastinum mass is found, and is suspected of thymoma, this must be treated as is appropriate.  

The decision to perform thymectomy in patients without thymoma is more challenging. The landmark MGTX trial established that thymectomy in non-thymoma patients resulted in better clinical outcomes and less requirement for prednisone. However, this trial only recruited patients aged 18-65.  As thymic hyperplasia is more common in younger patients, it is standard practice to offer thymectomy to any patient of that age (below 50 years). However, the MGTX trial does show potential benefit in patients up to 65, albeit less so than in younger patients. In older patients up to this age, it is our practice to decide on thymectomy on a case-by-case basis, taking into account imaging, comorbidities and other operative risk factors [29].

Exacerbation of MG, or of symptoms mimicking MG 

MG exacerbation can occur for a variety of reasons.  Furthermore, patients may develop symptoms that mimic those of MG, but which have distinct underlying causes. Identifying these early can prevent deterioration as well as avoiding unnecessary changing of immunosuppression.  Some potential causes of both MG exacerbation and of symptoms mimicking MG are outlined in Table 3.

Conclusion 

The diagnosis and management of myasthenia in the elderly is challenging and often without strong supportive evidence. It is important to exercise extra caution when deciding how to treat elderly patients, and to take into account their comorbidities, polypharmacy and differing physiology. Close monitoring of patients by GP and hospital MDT is advised.  A summary of the key points in this article are shown in Table 4.


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