A 54-year-old Caucasian female presented to the hospital with a complaint of new-onset double vision for approximately one week. She reported that it was constant and diagonal with both a horizontal and vertical component and worse when looking to the left. She also stated that her friends have been commenting that her left eyelid would droop. When the double vision first started, she went to an urgent care center that sent her to see an ophthalmologist, but that clinician told her that her eye exam was normal and that she needed a neurologist to evaluate her for a stroke. The patient then presented to the emergency department (ED), where a neurologist diagnosed her with a partial third nerve palsy. She was admitted, and the neurologist ordered magnetic resonance imaging of her brain and orbits as well as magnetic resonance angiography of her brain. All testing came back normal, at which point I was consulted.
During her bedside examination, her visual acuity was 20/25 OU. Her extraocular motilities appeared to be full. Her pupils were equal, round and reactive to light with no afferent pupillary defect (APD). Her cover test revealed a right hypertropia worse on left gaze and worse on right head tilt. I also noted an exotropia (Figure 1). External examination showed a variable ptosis of the left upper eyelid that would range from being in the normal position to approximately 50% closed.
Although her right hypertropia was consistent with a right fourth nerve palsy, the additional findings of the exotropia and variable lid ptosis were highly suspicious for myasthenia gravis (MG). She denied dysphagia, dyspnea or any generalized weakness. Her neurological exam was otherwise unremarkable.
The most likely diagnosis, ocular MG, required acetylcholine receptor antibody (binding, blocking and modulating) testing, as well as thyroid labs because thyroid orbitopathy can often cause various ocular motility deficits. In light of her findings, she was discharged with instructions to immediately return to the ED if she developed any swallowing or breathing difficulties before following up with me to review her labs.
The Follow Up
One week later, her labs revealed elevated acetlycholine receptor antibodies. T3, T4, TSH and thyroglobulin were normal; however, her thyroperoxidase was elevated. Her laboratory studies confirmed the diagnosis of ocular MG. She was referred her to neurology for MG treatment and recommended consultation with her internist to evaluate the elevated thyroperoxidase.
|Fig. 1. On this cover test, the patient presented with a right hypertropia worse on left gaze and right head tilt. |
Re-examination three months later revealed some right hypertropia with some exotropia. However, the cover test measurements had significantly improved, and the patient stated that her double vision was essentially resolved. She was prescribed 90mg Mestinon (pyridostigmine, Bausch + Lomb) QID. Her neurologist sent her for a chest CT to rule out a thymoma which was normal, and her internist is currently evaluating her for thyroid dysfunction. She was instructed to follow up with our office in three months.
MG is a rare autoimmune disease with an annual incidence that ranges from 0.04 to 5.00 per 100,000.1 Acetylcholine molecules are released at the neuromuscular junction, bind to the receptors on striated muscle and depolarize the postsynaptic membrane, resulting in muscle contraction. In patients with MG, anti-acetylcholine receptor antibodies block the receptors and cause defective transmission at the neuromuscular junction, leading to muscle weakness.1
Generalized MG involves the bulbar, limb and respiratory muscles. Patients will typically complain of weakness of the involved muscles that worsens during periods of activity and improves with rest. Additionally, symptoms will generally worsen throughout the day. When the muscles in control of swallowing are affected, patients are at risk for choking. Additionally, patients can develop respiratory failure, a life-threatening emergency.2
In ocular MG, symptoms are localized to the extraocular muscles, levator and orbicularis oculi. Patients will typically present with variable lid ptosis and double vision. In patients with ocular MG, 50% to 80% will progress and develop generalized MG, 90% of which evolve over the first two years.1
The clinical and ocular presentations of MG can vary greatly. The extraocular motility deficits can mimic various disorders, including cranial nerve palsies, internuclear ophthalmoplegia, external ophthalmoplegia and thyroid orbitophathy. A suspicion for MG should always be present when examining patients with double vision or ptosis, as many have coined it the “great masquerader.” Often, the clinician will observe variability of the motility and lid deficits during the exam and from visit to visit.
The most common muscles involved in ocular MG are the medial rectus and superior rectus. If a ptosis is present, place an ice pack over the affected lid to observe if the ptosis improves. Cooling may reduce anticholinesterase activity, increasing the amount of available acetylcholine at the neuromuscular junction.1
Clinicians should order laboratory studies looking for anti-acetylcholine receptor antibodies. A positive test result can confirm the diagnosis, but a negative test does not necessarily exclude MG. In approximately 50% of patients with ocular MG and 10% to 15% with generalized MG, testing for these antibodies will give negative results.3,4
Muscle-specific kinase (MuSK) is a protein found in the neuromuscular junction and is essential for each step in the neuromuscular synapse formation.4 In approximately 40% of patients who are seronegative for anti-acetylcholine receptor antibodies, anti-MuSK antibodies will be detectable. Patients who have positive anti-MuSK antibodies are typically middle-aged women, present with facial, neck and respiratory muscle weakness and are at a much higher risk for acute exacerbations.
If serology cannot confirm the diagnosis, the patient should undergo single fiber electromyography, which evaluates the electrical activity when stimulating skeletal muscle. When testing the frontalis or orbicularis muscles, it has a sensitivity of 85% to 100% for ocular MG and a sensitivity of 91% to 100% for generalized MG.1
Additionally, when MG is diagnosed, order a chest computed tomography scan to rule out a thymoma, since it is present in 15% of patients with MG.5
Thyroiditis is also frequently associated with autoimmune disorders such as MG, and patients diagnosed with MG should be evaluated for any thyroid dysfunction.6,7
Therapy depends on the severity of disease. Mestinon, an acetylcholinesterase inhibitor, allows for a greater concentration of acteylcholine at the neuromuscular junction and better neuromuscular transmission.4 In addition to Mestinon, immunosuppressants such as prednisone, azathioprine and cyclophosphamide can help to treat MG. For acute exacerbations, especially when respiratory muscles are involved, treatments such as plasmapheresis and intravenous administration of immunoglobulins are common for crisis intervention. The goal of this treatment is to remove the antibodies targeting the neuromuscular junction.
Because MG commonly causes ocular symptoms such as diplopia and lid ptosis, patients will often present to the optometrist first. In addition to significantly impacting a patient’s daily quality of life, MG can be a fatal disease. It is of the utmost importance to always maintain a suspicion for MG whenever a patient presents with diplopia, ptosis or generalized muscle weakness. Patients often receive an incorrect initial diagnosis, as seen with this case. It is not uncommon to see these patients misdiagnosed with cranial nerve palsies, internuclear ophthalmoplegia or another neurologic disorder. A prompt diagnosis will favor better outcomes, especially in patients with generalized MG that affects their breathing and swallowing.
1. Nair AG, Patil-Chhablani P, Venkatramani DV, Gandhi RA. Ocular myasthenia gravis: a review. Indian J Ophthalmol. 2014;62(10):985-91.
2. Wendell LC, Levine JM. Myasthenic crisis. Neurohospitalist. 2011;1(1):16-22.
3. Peeler CE, De Lott LB, Nagia L, et al. Clinical utility of acetylcholine receptor antibody testing in ocular myasthenia gravis. JAMA Neurol. 2015;72(10):1170-4.
4. Sieb JP. Myasthenia gravis: An update for the clinician. Clin Exper Immunol. 2014:175:408-18.
5.Beydoun SR, Gong H, Ashikian N, Rison RA. Myasthenia gravis associated with invasive malignant thymoma: two case reports and a review of the literature. J Medical Case Reports. 2014;8:340.
6. Lopomo A, Berrih-Aknin S. Autoimmune thyroiditis and myasthenia gravis. Front Endocrinol. 2017;8:169.
7. Lin YP, Iqbal U, Nguyen Pa, et al. The concomitant association of thyroid disorders and myasthenia gravis. Transl Neurosci. 2017;8:27-30.