Myasthenia gravis and the role of the veterinary nurse

Immune-mediated myasthenia, also known as myasthenia gravis, is a fairly common neuromuscular disease affecting dogs and occasionally cats. The dog breeds most often affected are German Shepherds, Labradors, Golden Retrievers, Akitas, Great Danes and Newfoundlands. The Abyssinian and Somali cat breeds are more predisposed than other feline breeds, but the disease can affect any canine or feline breed (Vercesi, 2021). While there is some literature to support the concept of genetic predisposition for the disease, this is an area that requires further research to confirm (Wolf et al, 2017). Myasthenia gravis can be seen at any age over 3 months, but more commonly occurs between 5 and 7 years of age, and neutered female dogs are at a higher risk than males (Platt and Shelton, 2017).

The aetiology of myasthenia gravis is a disruption to neuromuscular transmission. In a neurologically normal patient, acetylcholine is released from the presynaptic vesicles, which are located in the axon terminal of the motor neuron, where it then binds with receptors on the endplate of the muscle fibre membrane. However, in patients with myasthenia gravis, the receptors are targeted by autoantibodies, so the acetylcholine is unable to bind and therefore the muscles do not get the signal to contract. This causes progressive weakness and fatigue which can occur focally or generalised to the point that the patient becomes non-ambulatory.

Myasthenia gravis can be further categorised into the following:

• Focal myasthenia gravis: focal clinical signs including regurgitation, megaoesophagus and dysphagia, with subtle weakness of the facial muscles
• Generalised myasthenia gravis: associated with severe exercise intolerance and megaoesophagus
• Acute fulminating generalised myasthenia gravis: rapid onset of non-ambulatory weakness, megaoesophagus and respiratory distress.

Initially, affected patients may appear to be moving normally following rest, but they will quickly develop a stiff, choppy gait with progressively shortened strides, until they become too weak to continue. They may then crouch down and rest for a short period of time before being physically capable of moving again. This cycle will likely continue with repeated attempts to move. Feline patients with myasthenia gravis tend to become ‘floppy’ and generally reluctant to walk. A neurological examination of the patient will show that they have normal sensation, spinal reflexes and postural reactions.

Megaoesophagus is a common finding in patients with myasthenia gravis, as the skeletal muscles in the oesophagus are also frequently affected. Therefore, managing the patient's nutrition and preventing regurgitation are mainstays of treatment. Many patients with myasthenia gravis also have facial weakness, which can affect the patient's ability to chew and swallow. Facial weakness can be assessed by repeatedly stimulating the palpebral reflex (gently tapping the medial canthus of the eye to stimulate a blink), which in a patient with myasthenia gravis will cause the reflex to weaken and eventually stop. This will also be accompanied by a lack of menace response (the response that causes the eye to close to protect it from being touched). Some patients may be unable to close their eyes at all at this point and their third eyelids may be protruded.

Myasthenia gravis can be caused by a mediastinal thymoma. It is paraneoplastic in these cases as it is triggered by the thymoma (Romi, 2011). A thymoma is neoplasia of the thymus gland in the thorax. This gland is involved in maturation of the immune system and would normally shrivel up after puppy/kitten hood. Thymomas account for between 15–52% of all myasthenia gravis cases in dogs and cats (Romi, 2011; Hague et al, 2015). Therefore, all patients diagnosed with a cranial mediastinal mass should be tested for acetylcholine antibodies before surgical removal of the mass, as weakness can become apparent post-operatively if myasthenia gravis is present and the tumour is completely removed. This can result in normalisation of the antibodies and thus resolution of the clinical signs.

Diagnosis Antibody titre test

The antibody titre test is a blood test to detect the presence of autoantibodies against the acetylcholine receptors. These antibodies are thought to be present in around 98% of dogs with myasthenia gravis; however, some patients can test negative. The test itself can be costly for patients in the UK as it needs to be sent to a laboratory in the USA and can take weeks for a result to be received (Vercesi, 2021).

Edrophonium test, now replaced by neostigmine test

Neostigmine is injected in a conscious patient and they are then exercised (Cridge et al, 2021). Various routes can be used: intravenous, intramuscular or subcutaneous. The dose is dependent on the route chosen. Following injection, the patient should no longer become weak following exercise. The drug works by prolonging the action of acetylcholine by inhibiting the action of the enzymes that destroy it, and therefore allow the acetylcholine to bind for a longer period of time to the available receptors. The effect is only temporary, but can have a profound impact on muscle strength and allow a previously collapsed patient to run around. Atropine should always be available to counteract any cholinergic side effects such as tremors, salivation, bradycardia, miosis, dyspnoea, vomiting or diarrhoea. Therefore, following the test the patient should be monitored very closely (Brooks, 2022).

Electromyogram

The patient will need to go under general anaesthesia and have needles put in place to deliver a small electrical charge repeatedly to a chosen nerve. The sequential responses of the muscle are recorded by the electromyogram machine. In myasthenia, we typically see that the muscle responses diminish following repeated stimulation.

Muscle biopsies

A sample of muscle is taken and examined. This test is often used to diagnose congenital myasthenia, but is only very rarely done for myasthenia gravis.

Thoracic radiographs

Thoracic radiographs allow for diagnosis of a thymoma as well as megaoesophagus. The radiograph for the detection of megaoesophagus is taken with the patient conscious, this is because sedation and general anaesthesia can cause oesophageal dilationas a result of a build up of gas which can mimic megaoesophagus on a radiograph (Wray and Sparkes, 2006). Often patients with megaoesophagus can get aspiration pneumonia, so radiographs can also be used to assess for this (Brooks, 2022).

Treatment

Anticholinesterase agents (acetylcholinesterase inhibitors)

Pyridostigmine (Mestinon) inhibits the enzyme that breaks down acetylcholine, therefore prolonging the action of acetylcholine at the neuromuscular junction. Side effects can include nausea, cramping and gastrointestinal upset, so dosages are started low and increased gradually until a therapeutic level is achieved.

Immunosuppressive drugs

If Mestinon has insufficient effects, other drugs can be added to the treatment regimen. Corticosteroids are used for immunosuppression to suppress the production of the antibodies responsible for destruction of acetylcholine receptors. There are multiple side effects to giving corticosteroids and they can make myasthenia gravis patients weaker to begin with, so should always be started at a low dose and gradually increased to a high anti-inflammatory or immunosuppressive level. Caution needs to be taken if the patient is likely to develop aspiration pneumonia, as corticosteroids can worsen the risk. Examples of other immunosuppressive drugs used, often in addition to corticosteroids, are ciclosporin, azathioprine or mycophenolate mofetil.

Treatment will last several months and repeat check-ups will be required, including repeat blood testing to measure anti-acetylcholine receptor antibody levels.

Therapeutic apheresis

Therapeutic apheresis was developed at the University of California at Davies in the USA. It separates the patient's blood into its components and removes the fractions contributing to diseases. Therefore, in myasthenia gravis, as the antibodies are found in the plasma, therapeutic plasma exchange can be performed to remove the plasma from the affected patient and replace it with plasma from a healthy donor. This treatment has had extremely successful outcomes, but is very expensive which makes it inaccessible to most (Richmond, 2015).

Nursing considerations

Patients with reduced ambulation and weakness will need regular recumbency care, consisting of turning regularly to prevent pressure ulcers. This should include time spent in sternal recumbency with the head elevated in a neutral position to prevent regurgitation (Richmond, 2015). Urination should be monitored and indwelling urinary catheters used if necessary, particularly if the patient is too weak to mobilise to go out to the toilet, as toileting in the kennel can lead to urine scald and stress to the patient (Vercesi, 2021).

As mentioned previously, megaoesophagus is a common problem in patients with myasthenia gravis. This is because the oesophagus is a skeletal muscle that is stimulated by acetylcholine and, therefore, if weakened, it becomes flaccid, enlarged and ineffective, leading to patients suffering from regurgitation as the food is unable to pass into the stomach. This can lead to weight loss and predispose the patient to aspiration pneumonia because they will inhale food and saliva (Brooks, 2022).

Therefore, nursing measures aimed at managing the patient's nutrition are paramount. Elevated feeding can aid in keeping food in the oesophagus and passing into the stomach by gravity. This involves holding the patient in an upright position and can be achieved by holding the patient upright or ideally through the use of a ‘Bailey chair’ (Figure 1a). In addition to eating in this upright position, the food should be given slowly, ideally in small ‘meatballs’ (Figure 1b) and not be too liquid in consistency. Each meatball should be given one at a time and the patient should be witnessed to swallow before the next one is given. The patient should be kept in the upright position for 15 minutes after eating to allow the food to move to the stomach. Bailey chairs are often well tolerated as patients quickly associate them with the positive experience of being fed (Vercesi, 2021). Water should also be offered in this position and the patient should not be exercised excessively after eating. Some owners report success using doughnut buster collars around their dog's neck to lift the neck when the dog is in a sleeping position, which aids in preventing regurgitation and aspiration when at rest (Figure 1c).

If a patient's regurgitation and hypersalivation are unable to be managed in this way, then a feeding tube can be considered. However, nasogastric and oesophageal tubes still rely on oesophageal function, therefore a percutaneous endoscopically or surgically placed gastrotomy tube (PEG) would be needed. A PEG tube would enable nutritional needs to be met and reduce the risk of aspiration. Nevertheless, placement of a PEG tube requires an anaesthetic which may carry a significant risk in a critical myasthenic patient (Brooks, 2022). An added benefit of a PEG tube, however, is that they can remain in situ for many months, so a patient can be discharged with one in place, provided the owners are taught how to care for the stoma site and how to administer the feed.

Managing the patient's nutrition and reducing the risk of aspiration is paramount because of the high morbidity and mortality rates associated with the condition. A patient with myasthenia gravis should be monitored closely for any signs of the development of aspiration pneumonia. Aspiration causes bronchoconstriction of the airways, causing increased respiratory effort which progresses to consolidation of the lung and is the source of most of the clinical signs (Egleston, 2018). The clinical signs include:

• Fever
• Increased respiratory rate and effort
• Soft cough, crackles or harsh lung sounds on thoracic auscultation
• Hyperaemic or cyanotic mucus membranes
• Bilateral nasal discharge (pus).

If any of these signs are observed, the patient should have a pulse oximeter reading performed. If the oxygen level is less than 93%, then oxygen therapy should be administered via the least stressful means necessary (Egleston, 2018). There is increasing evidence that high-flow oxygen therapy is the most beneficial means of delivering oxygen. This is a method of providing a mix of air and oxygen that has been preheated and humidified (Ramesh et al, 2021). Delivering warm and moist oxygen is most beneficial to a patient with aspiration pneumonia as breathing in warm moist air improves mucociliary function and prevents damage to the cells lining the respiratory system. If these mucosal tissues become dehydrated then mucus is retained, which prevents the clearance of secretions (Ramesh et al, 2021). Unfortunately, high-flow oxygen therapy is only available via a commercially available unit that will not be available in most practices yet, so being aware of the importance of providing humidified air at a high flow rate will enable the veterinary team to provide the best support to these patients.

When in lateral recumbency, there is inadequate expansion of both lungs, increasing the risk of atelectasis, therefore the patient should spend time in sternal recumbency to help prevent this. Respiratory physiotherapy techniques can be used to assist in the removal of fluid. However, postural drainage techniques are contraindicated in a myasthenia gravis patient becasue of the risk of regurgitation, as the head is lowered to enable gravity to assist with drainage in most of these positions (Scott, 2020). Manual respiratory physiotherapy techniques such as percussion (coupage) and vibrations can also be used effectively to remove secretions from patients with aspiration pneumonia (Scott, 2020). However, there are no studies to support the use of coupage alone (Egleston, 2018). Additionally, myasthenia gravis patients with reduced oesophageal and pharyngeal function will be less able to expel the pulmonary and bronchial secretions, so it is absolutely imperative that a suction device is used to rapidly clear the secretions from the oral cavity to prevent airway obstruction (Vercesi, 2021).

Therapeutic exercise is considered superior to chest physical rehabilitation or manual therapy in reducing atelectasis, mobilising and preventing pooling of secretions (Scott, 2020). However, myasthenia gravis patients have reduced ability to exercise, so this can be challenging to incorporate into a treatment plan. Regular physical activity such as going out to toilet can form part of this exercise plan and help to encourage the patient to take deeper breaths and thus help clear secretions. If the patient is unable to walk, then assisted standing will also be beneficial, not only from a respiratory point of view but also to assist with musculoskeletal complications, and improve oxygenation and circulation (Scott, 2020). Physiotherapy is beneficial for any recumbent patient to ensure muscles remain supple and avoid the development of contractures (Vercesi, 2021). Physiotherapy exercises should focus on gradual resistance training, with the aim to strengthen the large proximal muscle groups such as the hips and shoulders. General aerobic exercise is also valuable. However, this is extrapolated from human literature and even in human medicine there is no standardised rehabilitation protocol, but physical training including cardiovascular exercise and strength training alongside balance and respiratory training has been beneficial for human patients with myasthenia gravis (Corrado et al, 2020; Edge-Hughes, 2022).

Nebulisation with sterile saline can be used to keep the airways moist and assist in breaking up secretions in the lung parenchyma (Figure 2). These are readily available as they can be purchased over-the-counter for human use (Vercesi, 2021).

Over time patients may become increasingly weak, to the point they are completely non-ambulatory and recumbent. It is important these patients are monitored closely as all muscles in the body will become fatigued, including those of the respiratory system. Therefore, patients should be monitored closely throughout hospitalisation, in an intensive care setting with constant monitoring including respiration rate and effort, and even blood gas analysis if there are concerns that the patient is not sufficiently ventilating (Vercesi, 2021). If the patient declines, they may need oxygen support or to be placed on a ventilator. It is beyond the scope of this article to discuss the monitoring of a patient on a ventilator, but the veterinary team should be prepared that this level of decline is a possibility and be ready to assist the patient as necessary.

Prognosis

The prognosis for patients diagnosed with myasthenia gravis is generally good unless there is severe aspiration pneumonia as a result of the megaoesophagus, or underlying neoplasia. Often limb muscles respond well to medical treatment, but oesophageal muscles can be resistant to treatment. If the megaoesophagus persists, dogs are at risk of aspiration pneumonia, which can result in frequent hospital admissions. The 1-year mortality rate for dogs with myasthenia gravis has been reported to be as high as 60% (Garosi, 2013).

Myasthenia gravis can be a very serious disease, but with early diagnosis and high levels of care, patients can make a full recovery and dogs and cats can go in full remission (no longer requiring therapy). A mainstay of nursing care is managing the megaoesophagus, but failure to do so can lead to the development of aspiration pneumonia which is often the cause of death or reason for euthanasia in myasthenia gravis patients. Therefore, a good understanding of the commitment and care involved is needed by the veterinary team to be able to provide the best possible care while patients are hospitalised and to be able to coach and support owners managing the disease in their animals at home following discharge.

The future

There are new treatments currently being developed which target the underlying pathophysiological pathway including B cell depletion, complement and T cell inhibition, and neonatal Fc receptor (FcRn) antagonists. These treatments are thought to be much more targeted and thus will have far fewer side effects. However, they are at their infancy in testing and so long-term efficacy and safety are yet to be determined and they are currently very expensive (thousands of pounds for one injection) (DeHart-McCoyle et al, 2023).

The current gold standard test for acetylcholine receptor antibodies is via radioimmunoassay; however, some dogs do not have detectable antibodies despite being highly suspected of having myasthenia gravis, meaning that treatment can become delayed. Sometimes a second radioimmunoassay test becomes positive, so repeating a test a few weeks later after the first can be worthwhile. The reason for negative radioimmunoassay results may be because these dogs have low-affinity antibodies against the acetylcholine receptor antibodies or other neuromuscular junction proteins, which has been shown to be the case in 10–20% of human patients with myasthenia gravis (Leite et al, 2008). Therefore, research is currently being undertaken to develop a test based on cell-based assays to search for the presence of the antibodies in serum in cases where myasthenia gravis is still highly suspected following a negative radioimmunoassay test. This would improve the detection of myasthenia gravis and increase the number of dogs correctly diagnosed, allowing for more prompt and targeted treatment, resulting in a better outcome for the patient (Vanhaesebrouck, 2023). For more information and finding out how to help with the study contact myasthenia@vet.cam.ac.uk.

Conclusions

Myasthenia gravis is a fascinating condition, but it can require life-changing adjustments to be made in owners lives to provide their pets with the care needed to prevent potentially fatal comorbidities such as aspiration pneumonia. Therefore, veterinary nurses are ideally placed to coach and support owners in providing care and being involved in monitoring during hospitalisation. Early diagnosis and treatment lead to better prognosis and it is hoped developing a more reliable way to test for the disease will make this more possible in the future.

KEY POINTS

• Myasthenia gravis is a disruption to neuromuscular transmissions causing severe exercise intolerance and megaoesophagus.
• Diagnosis is typically made by a neostigmine test.
• Antibody titre tests are available but need to be sent to the USA, so can take time to get results and may not pick up every case, therefore a new test based on cell-based assays to search for the presence of the antibodies in serum is being developed.
• Patients can be treated with anticholinesterase agents or immune suppressive drugs.
• Myasthenia gravis patients need stringent nursing care to monitor for progression of the disease to the respiratory system and recumbency care may need to be provided.
• Megaoesophagus is common with myasthenia gravis so prevention of aspiration pneumonia is a corner stone of achieving a positive prognosis and patient outcome.