Myasthenia Gravis – Diagnosis, Symptoms, and Treatment

What is Myasthenia Gravis?

Myasthenia gravis is a medical condition characterized by autoantibodies against acetylcholine receptors at the neuromuscular junction, resulting in muscle weakness.  Patients often have involvement of their ocular (eye) and bulbar muscles.  The bulbar muscles are located in the head and are essential for chewing and swallowing.  Symptoms often include double vision, eyelid drooping, slurred speech, and dysphagia (trouble swallowing) due to muscle fatigue – this is notably worse at the end of the day.

Patients may have acute flares of disease referred to as “myasthenic crisis.”  During these episodes, patients have muscle weakness involving the diaphragm, a critical muscle for breathing.  This results in respiratory failure, often requiring ventilatory support.

What Causes Myasthenia Gravis?

Myasthenia gravis is an autoimmune disease characterized by antibodies against acetylcholine receptors at the neuromuscular junction.  Acetylcholine is a neurotransmitter typically released by the terminals of motor neurons when muscle contraction is performed.  Acetylcholine then binds to and activates its receptor located on muscle cells – this allows for nerve conduction and muscle contraction to occur.

In myasthenia gravis, this process is interrupted as antibodies against the acetylcholine receptors lead to their destruction.  Muscle contraction becomes impaired since there are fewer available acetylcholine receptors for acetylcholine binding.  This leads to fatigable muscle weakness – this means that weakness worsens with repetitive muscle use.

Newer studies show that patients with myasthenia gravis also have autoantibodies against muscle-specific receptor tyrosine kinase (MuSK) and other postsynaptic neuromuscular junction proteins.

Patients with myasthenia gravis frequently have abnormalities of the thymus gland, such as thymoma (thymus tumor).  This may be a possible antibody formation source as symptoms of myasthenia gravis often resolve after thymectomy (thymus removal surgery).

How Common is Myasthenia Gravis?

Myasthenia gravis is a relatively uncommon disorder but is the most common form of neuromuscular disease.  The condition typically requires referral to a neurology specialist.

It has a bimodal age distribution with an early peak around age 20-30 in women and a late peak at age 60-80 in men.  Its incidence is approximately 7-23 new cases per 1 million people per year, and its prevalence is around 70-320 cases per 1 million people.  Disease prevalence is on the rise.

Signs and Symptoms

Symptoms of myasthenia gravis often include fluctuating muscle weakness with muscle fatigue.  Muscle weakness is worse with activity and often at the end of the day.

Patients typically have ocular symptoms such as diplopia (double vision) and ptosis (droopy eyelid).  They also frequently develop bulbar symptoms such as trouble swallowing (dysphagia) and slurred speech (dysarthria).  Limb muscles are also occasionally involved, resulting in proximal leg weakness.  The respiratory muscles’ involvement is one of the condition’s most dreaded complications as it can lead to respiratory failure and death – this is called “myasthenia crisis.”

Diagnosis

The diagnosis is suggested based on symptoms and physical examination but typically confirmed with laboratory and imaging studies.

The bedside ice pack test supports the diagnosis.  During this test, your doctor will apply an ice pack over your droopy eyelid – improvement in eyelid ptosis is suggestive of myasthenia gravis.

Sometimes your doctor will perform an edrophonium (Tensilon) test.  During this test, you will receive an infusion of the drug edrophonium and be observed to improve ocular symptoms and signs.  Edrophonium is an acetylcholinesterase inhibitor that increases acetylcholine levels in the neuromuscular junction, thereby improving motor function.

Your doctor will typically test you for acetylcholine receptor antibodies.  If these antibodies are negative, they may perform tests for antibodies against muscle-specific tyrosine kinase (MuSK).

Your doctor may order a brain MRI to rule out a tumor or stroke.  They may also consider performing a lumbar puncture (spinal tap) if the diagnosis remains unclear.  Commonly ordered blood tests include a CMP (comprehensive metabolic panel), CBC (complete blood cell count), and thyroid function tests (TSH, free T4).

Myasthenia Gravis Treatment

The first-line treatment of myasthenia gravis is acetylcholinesterase inhibitors such as Mestonin (pyridostigmine).

Patients who remain symptomatic on Regonol may benefit from immunotherapy.  Agents typically include one or more of the following:

• Glucocorticoids – prednisone, methylprednisolone
• Imuran (azathioprine)
• CellCept (mycophenolate mofetil)
• Neoral (cyclosporine)

Patients with myasthenia gravis and thymoma typically benefit from thymectomy – surgical removal of the thymus.  Patients with a myasthenic crisis resulting in respiratory failure typically require plasmapheresis and IVIG therapy.

References:

1. Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol 2009; 8:475. - https://www.ncbi.nlm.nih.gov/pubmed/19375665
2. Silvestri NJ, Wolfe GI. Myasthenia gravis. Semin Neurol 2012; 32:215. - https://onlinelibrary.wiley.com/doi/pdf/10.1002/pnp.315
3. Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol 2010; 10:46. - https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-10-46