A 73-Year-Old Man With Subacute Onset of Diplopia

Correct Answer: D. The patient’s diagnosis can best be confirmed by antibody testing.

Discussion. The presented patient had recent onset of visual symptoms and episodes of diplopia and ptosis bilaterally, which suggested systemic causation. His detailed history revealed that although these symptoms were mild or absent upon awakening, they would worsen as the day wore on. An important symptom clue was that his jaw would tire when chewing, suggesting a systematic cause. The signs and symptoms raise the possibility of myasthenia graves, which is the diagnosis here.

Myasthenia is an autoimmune disease that shares similarities to other autoimmune diseases but differs in the antibody targets. Generally, the bimodal age of onset peaks in  in the third to fourth decade, mostly among women. There is a second peak that may occur after 50 to 55 years of age, mainly in men.^1,2 There is a frequent co-existence of a second disorder in 10% to 15% of cases, with Hashimoto thyroiditis being the most frequent. Finally, an accompanying thymoma with myasthenia is seen in 10% of cases.^1,2

The clinical presentation in myasthenia is generally found in the orbital muscles and eyelids, with levator palpebrae being the most frequently effected^1,2 and causing the precise symptoms our patient manifested: drooping eyelids and diplopia. Other symptoms include chewing fatigue, speech, and saliva difficulties, as well as neck weakness. Additionally, myasthenia weakness is somewhat unique, and is sometimes termed "fatigability", meaning it is a progressive weakness with repetitive usage. This explains the worsening symptomatology as the day proceeds.

If the disease progresses, there can be more general muscle involvement elsewhere in the body, the most dangerous of which are the thorax, diaphragmatic, and respiratory muscles. Symptoms in these regions can result in the life-threatening respiratory failure requiring ventilator support. The presenting patient is early in his illness, which makes this unlikely and thus makes answer C, hospital care, not required or currently appropriate.

Two very important negatives in the patient’s clinical presentation are absence of any sensory or pain symptoms and, although diminished, retention of deep tendon reflexes, which exclude Giullian-Barre (answer E). Additionally, ALS does not have ocular involvement, which excludes answer B. Regarding answer A, thyroid eye disease causes what appears to be dropping eyelid (“lid lag”) because there is orbital content pushing the globe outward. This condition, called proptosis, can be detected on exam, but it was not present in this case.

The targets of the autoantibodies are the receptors at the neuromuscular junction of axons and myofibrils, specifically the acetylcholine receptor complex and muscle kinases. These complexes are bound and inactivated by these autoantibodies such that acetylcholine released by axons into the synaptic space has diminished effectiveness in its function of chemically, inducing the myofibrils into activity. The family of autoantibodies includes anticholinergic receptor antibody (anti-Ach R), anti-muscle kinase antibody (anti-musk), and others. The most sensitive (85%) and specific (> 90%) is anti-Ach R in generalized myasthenia and 50% sensitivity in ocular myasthenia.^2,3 Sophisticated repetitive nerve stimulation and elastomyography, which demonstrate classical fatigue potential patterns, are excellent backup tests with strong sensitivity and specificity but are reserved for patients where the easier antibody testing is negative,^2,3 which account for about 10% to 15% of cases.²

The myasthenia gravis diagnosis can be confirmed when a patient with appropriate history and physical examination findings demonstrates the presence of any of the antibodies mentioned or classical fatigue patterns during electro-diagnostics testing. 

Treatment and management. There are two core goals and strategies for treating myasthenia: (1) attain symptom control as quickly as possible to obtain more normal function neurologically, and (2) use immunosuppression against the core autoantibody production and hopefully impact a “complete remission” of some duration.

Acetylcholine esterase inhibitors, which allow for more acetylcholine effectors to be present and remain in the synaptic spaces that overcomes the antibody blocking effect on them is the first order of the day. Pyridostigmine is most used with a 60 mg TID initial dosing. Spacing of 6 hours is important as its effect wanes with time. That said, the beneficial effect is usually very prompt and noticeable, and there is room for upward dose titration if required. When pyridostigmine therapy is not delivering enough efficacy, immunosuppression is required. As is so common in essentially all autoimmune disorders, corticosteroids lead off with the usual 60 mg prednisone or equivalent to a strong clinical response followed by a slow taper to more tolerated and safer chronic dosage, with studies reporting 80% efficacy.^1,4 If this approach is not effective or requires unsafe steroid dosage, a litany of non-steroidal immunosuppressives can be used. The criteria for this iinclude poor steroid response, inability to wean, more than one relapse with prednisone tapering, or contraindications to steroids, e.g.  brittle diabetes mellitus.^1,4 Candidate medications include azathioprine, methotrexate, cyclosporine, tacrolimus, and ritoximab. A recent review noted that the International Myasthenia Group, a group of debating experts, “could not reach a consensus on the role of rituximab” in myasthenia.²

Despite the lack of consensus, based on my personal experience, I believe that rituximab will become a core immunosuppressive in myasthenia as well be used first with corticosteroids at initial diagnosis in generalized cases. Rituximab has excellent efficacy, relative convenience of administration, and a good safety profile now 20+ years into its general autoimmune usage.

Finally, newer biological and monoclonal antibodies are being used in trials and will likely show efficacy, but with what advantages and what degree of added expense remain to be seen.¹ When thymoma is present in myasthenia gravis, it should be removed. Video-assisted thoracic surgery techniques have made this easier and safer and data show improved myasthenia natural history in the 10% of cases with thymoma.⁶

Patient follow-up. The patient was told to inform his primary care physician of the likelihood of the presence of myasthenia gravis as the cause of his symptoms and was quickly referred to a neurologist who shared that opinion. Following additional antibody testing, positivity for Ach R autoantibodies confirmed the diagnosis of myasthenia gravis within 10 days. The patient was placed on pyridostigmine at entry level dosage, 60 mg TID at 6-hour intervals during daytime, and 30 minutes before meals.

The patient noticed a dramatic and prompt improvement almost immediately. He did note some mild return of symptoms in the last hour before next dosage but was functional enough to perform his normal activities. He is driving again and back on the ball field—at his previous level of play. His pyridostigmine is being slowly and gradually up titrated to try for even more efficacy. He knows it is likely that he is placed on some form of immunosuppression soon to attain a remission of the autoimmune core of his illness.

What’s The Take Home? Myasthenia gravis is an autoimmune disease in which a series of autoantibodies have pathological activity against acetylcholine receptors and other molecules involved in normal neuromuscular activity and functions in the neuromuscular synapses. This pathophysiology results in diminished impulse transmission and subsequent muscle fatigue and weakness. The condition has bimodal demographics with a peak in young women and older men.

The classic onset usually involves smaller muscles in the eyelids and extra oculars, with ptosis and diplopia being the most frequent early symptoms and signs. In about half of the cases, this may be the extent of the condition, but in the rest, generalization occurs. Muscle weakness, specifically characterized as “fatiguability,” is the cardinal symptom, specifically weakness on repetitive use and worsening as the day progresses. Importantly, deep tendon reflexes are retained, which helps differentiate myasthenia from other neurological conditions with which it may be confused. The core of confirming the myasthenia diagnosis is antibody testing for specific autoantibodies directed against the neuromuscular function, namely anti-acetylcholine Receptor (Ach R) and anti-muscle kinase (Anti Musk).

Therapy is in two forms. Initially acetylcholine receptor antagonists are used to increase the levels of acetylcholine at synapse sites and thus lessen the antibody interference. Pyridostigmine is the most used and provides prompt symptomatic improvement in almost all cases. Meanwhile, attempts to achieve a lasting remission of the autoimmune process and lowering of antibody levels are needed. The litany of available agents is recognized in their efficacy in other autoimmune diseases (steroids, azathioprine, rituximab, and the newer biological and monoclonal antibodies). There is an interesting relationship of thymoma with myasthenia, and thymectomy is often helpful in these cases.

Finally, the dreaded complication of myasthenia crisis with ventilatory failure, seen in diminishing numbers due to better and more early diagnosis of myasthenia, requires ICU care, ventilation support, and the use of plasmapheresis or plasma exchange transfusion. This complication generally occurs most often later in the course of the illness. Still, with current therapies, the prognosis for symptom relief, autoimmune remission, and overall survival in myasthenia gravis is good.