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Myasthenia Gravis – Clinical Case Discussion

Clinical Presentation of Myasthenia Gravis

A 45-year old previously healthy male patient presented to the medical ward with weakness and fatigue in both arms and legs along with drooping eyelids and double vision. He did not have any difficulty in breathing at the time. However, he later developed difficulty in swallowing solid foods and an impairment in the speech as well.

What could be his medical condition? How can we reach a diagnosis? Let’s break down the clinical scenario step by step to find out.

Differential Diagnosis (DDx) We Had in Mind

After gathering the initial symptoms, we prepared a list of differential diagnosis as to what could be the disease condition behind this particular clinical presentation.

DDx:

Although the patient’s initial presenting symptoms would suggest a diagnosis like MG, we needed examination and investigation findings to come to a final diagnosis and to proceed with a management plan.

What is Myasthenia Gravis?

Myasthenia Gravis is an autoimmune disease affecting the neuromuscular junctions of the nervous system. This is a very rare disease condition and its prevalence is about 4 in 100,000. Usually, it is twice more common in women than in men and a peak of incidence of the disease occurs around age 30 and a second smaller peak occurs in older men.(1)

MG is characterized by muscle weakness that worsens after repetitive usage. This weakness is common in proximal limbs, bulbar and ocular muscles. Patients can present with drooping eyelids, double vision, difficulty in swallowing, impaired speech and even with difficulty in breathing.

Since this is an autoimmune disease condition, the disease pathogenesis is immune-mediated. Antibodies start to form against acetylcholine receptor proteins in the post-synaptic surface at the synapse. These immune complexes of anti-AchR IgG and complement are pathogenic and they start destroying the acetylcholine receptors.

These receptors are responsible for passing the electric signal from one neuron to another with the help of a type of neurotransmitters called acetylcholine. It’s only when acetylcholine binds to a receptor and passes the signal, muscle contraction can be activated. If this neuro-signal transmission process gets disrupted somehow it may jeopardize muscle movement and cause weakness as a result.

Sometimes we find individuals with MG who are AChR antibody-negative. In these individuals, symptoms are caused by the action of antibodies against muscle-specific receptor kinase (anti-MuSK antibodies) in the muscles. However, their clinical presentation will be just the same.

In about 70% of patients below the age of 40 with myasthenia gravis, hyperplasia or enlargement of the thymus has been observed. Besides, in nearly 10% of patients, a thymic tumor is present.

The thymus gland plays an important role in mediating immunity in the body, as it contributes to producing T-lymphocytes that are responsible for attacking pathogenic organisms. Therefore, it seems that there’s an association between MG and the occurrence of MG.

Clinical Findings we wanted to elicit on examination

Although the clinical presentation and examination findings may indicate a diagnosis of MG, it is necessary to carry out investigations to confirm the clinical assumptions and to plan management from there onwards.

What are the investigations we ordered?

Apart from the basic investigations like the full blood count and urine full report to assess the patient’s overall general health status, there are a set of specific investigations that can be utilized to come to a definitive diagnosis of MG.

The specific investigations we ordered include;

How we arrived at a diagnosis

Apart from the initial clinical assessment, we needed a set of specific investigation findings to build up the final diagnosis.

Anti-AChR antibodies are highly specific to MG. In 80-90% of the cases, they become positive. However, in pure ocular MG, only less than 30% of cases will become positive for these anti-AChR antibodies.(2)

The presence of anti-MuSK antibodies would indicate a subgroup of MG which presents with weakness mainly in facial, bulbar and neck muscles.

Furthermore, antibodies to striated muscles may indicate the presence of a thymoma.

Repetitive nerve stimulation can be abnormal in nearly 50-70% of the affected. With repetitive stimulation of the nerve endings, the amount of acetylcholine available at the neuromuscular junction gets depleted. As a result, relatively smaller excitatory postsynaptic potentials are generated.

This is the most sensitive test in diagnosing MG. If the single-fiber test comes negative in a case of muscle weakness, the diagnosis of MG can be excluded.

If the patient is truly suffering from MG, the EMG may show block and jitter.

Mediastinal CT or MRI scan can be used to look for the presence of thymoma in all cases.

When acetylcholine is released from the nerve terminal, if it doesn’t bind with an acetylcholine receptor, it gets destroyed by an enzyme called acetylcholinesterase.

In MG as the number of acetylcholine receptors is quite low. Therefore, the interaction between the neurotransmitters and the receptors is also reduced. Therefore, the acetylcholine molecules freely available at the neuromuscular junction may get readily degraded by the enzyme.

Edrophonium is a short-acting AChE inhibitor that can delay the degradation of the acetylcholine molecules at the synapse. It is also known as tensilon.

When edrophonium is given externally, it gives acetylcholine molecules more time to interact with acetylcholine receptors. Therefore, a transient improvement in muscle weakness occurs.

This test involves giving 10mg of Edrophonium intravenously and observing the improvement in muscle weakness that may last from seconds up to five minutes.  Another similar test with saline is performed as a control. The test is about 80% sensitive, but false positives and false negatives might occur as well.

Since this test may result in bronchospasms and syncope owing to its main component’s anticholinesterase activity, the availability of resuscitation facilities is a must for this test.

Monitoring the vital capacity and other lung function parameters are useful in a case of an emergency situation like the myasthenia crisis.

Putting together the presenting symptoms, clinical examination findings and the investigation findings, a diagnosis of MG could be made.

Now, let’s go into detail about how to treat a patient with Myasthenia Gravis.

The management plan we adopted for the acute management of Myasthenia Gravis

Myasthenia Gravis usually has a fluctuating disease severity. Some may even experience a life-long disease progression.

At the acute stage, the patient might need extra care due to respiratory impairment, dysphagia and nasal regurgitation. Some patients might even need emergency ventilatory support. This situation is also known as the Myasthenia crisis.

It is important to carry out regular, simple tests like monitoring the duration for which the arm can be held out-stretched and measuring the vital capacity to detect any respiratory impairment.

Since unprovoked and unpredictable disease exacerbations can occur at any time, regular monitoring is paramount. Sometimes with the usage of drugs like aminoglycosides and infections, disease exacerbation can occur.

The acute management of MG may include;

Pharmacological Therapy

Medications used to treat MG are mainly of two folds. They include;

The most commonly used medication is Pyridostigmine (60mg), usually 3-16 tablets daily are given. Its duration of action is about 3-4 hours. The necessary dose is determined by the response.

It may help overcome the weakness, but fails at altering the natural progression of the disease.

They inhibit the action of the anticholinesterase enzyme while prolonging the action of acetylcholine.

However, overdose of anticholinesterase may cause severe weakness as well. This is known as the “cholinergic crisis”. In addition, muscarinic side-effects like diarrhoea may also occur. The side-effects can be overcome by using atropine, an anti-muscarinic drug.

The most commonly used immunomodulation therapy is the use of corticosteroids. They are used for patients who do not show improvement after Pyridostigmine or have severe muscle weakness.

With steroids, usually, there is an improvement of about 70%. The steroid dose can be increased depending on the situation and response.

Besides, other immunosuppressant drugs such as Mycophenolate, azathioprine, cyclosporine, cyclophosphamide, and rituximab can be also used as steroid-sparing drugs.

Thymectomy

In a majority of patients with thymus hyperplasia along with positive AChR antibodies, thymectomy may improve the myasthenia condition significantly. Usually, this is about one-third of the affected. Others may enter remission or show no improvement at all.

However, this surgical procedure is not recommended in patients with antibodies to muscle-specific kinase (MuSK), as the pathology would be different in this situation.

Plasmapheresis

This involves the removal of circulating anti-AChR antibodies and immune complexes through the process of plasma exchange. Usually, this is kept as an option for myasthenia crisis and for the severe cases not responding to immunomodulation therapy.

ACE inhibitors are stopped 24hrs before plasma exchange and continued until treatment is completed.

IV Immunoglobulin Therapy

This includes the administration of highly-concentrated antibodies from healthy donors. They interfere with the autoimmune process by binding to autoantibodies that cause MG to remove them from circulation.

How can we manage a Myasthenia Gravis patient in the long-term?

Apart from continuous medical management, the long-term management and follow-up plan for MG must include a rehabilitation program that may help the patient to go back to the activities of daily living with minimum or no weakness or discomfort.

The extensive physiotherapy program may include;

It is important to make patients aware of the fluctuating nature of the weakness. They should be taught how to stay active as much as possible with frequent resting to overcome fatiguability. Sustained exercises should be avoided as much as possible.

Some MG patients may develop difficulty in swallowing because of weakness of the oropharyngeal muscles. Besides, they might find it difficult to chew hard food items like meat due to the weakness of muscles of mastication.

For such individuals, liquid meals can be given until the weakness passes away. However, the liquid diet must be thick enough to prevent nasal regurgitation or frank regurgitation.

Psychological counselling can be given for both the patient and caregivers alike to help them get through the situation.

What would be the prognosis of our Myasthenia Gravis patient?

With proper treatment and follow-up, a majority of MG patients gain the ability to lead normal or near-normal life spans.

About 33.8% of MG patients relapse while nearly 85% of patients with ocular myasthenia may progress into generalized MG.(3)

Patients already having some other forms of autoimmune disorders are more prone to getting a relapse in the future.

Hopefully, our patient will recover without any long-term complications or any relapses!

Conclusion

So, in summary, when a patient presents with generalized muscle weakness with fatiguability, ptosis and double vision or sometimes even with just the eye symptoms alone, there’s a high chance of the condition being Myasthenia Gravis. It is important to carry out timely investigations and interventions for the patients to recover successfully and let them return to their normal or near-normal day to day activities without any long-term complications.

References

1.         Kumar and Clark’s Clinical Medicine – 9th Edition [Internet]. [cited 2021 Feb 13]. Available from: https://www.elsevier.com/books/kumar-and-clarks-clinical-medicine/kumar/978-0-7020-6601-6

2.         Myasthenia Gravis Fact Sheet | National Institute of Neurological Disorders and Stroke [Internet]. [cited 2021 Mar 23]. Available from: https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/myasthenia-gravis-fact-sheet

3.         Wang L, Zhang Y, He M. Clinical predictors for the prognosis of myasthenia gravis. BMC Neurol [Internet]. 2017 Apr 19 [cited 2021 Mar 23];17(1):77. Available from: http://bmcneurol.biomedcentral.com/articles/10.1186/s12883-017-0857-7