Lack of Symptom Fluctuations in Patients Linked to Delayed Diagnosis

Yedida Y Bogachkov PhD avatar

by Yedida Y Bogachkov PhD |

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People with myasthenia gravis (MG) who lack or have subtle symptom fluctuations may face a delayed diagnosis of the neuromuscular condition, according to a recent case series.

Given such cases, the researchers suggest that patients who show symptoms reminiscent of the autoimmune disease, even without fluctuations, should be tested for MG-specific antibodies. Such testing is warranted, the team said, to identify unusual MG manifestations and help ensure a timely diagnosis.

The study, “Low Fluctuation of Symptoms May Delay Diagnosis of Myasthenia Gravis: A Case Series,” was published in the journal Neurology and Therapy.

In MG, the body’s immune system creates antibodies that target and attack certain proteins involved in nerve-muscle communication. One of them is acetylcholine receptors, which appear in clusters on muscle-cell membranes.

Fatigue and motor symptom fluctuations — loss of muscle strength in response to exercise or as the day progresses — are characteristic of the disease, and are thought to be related to the loss of neurotransmitter receptors.

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MG diagnosis is often based on both symptoms and their fluctuation, along with the presence of antibodies against neurotransmitter receptors. Often patients with low or no symptom fluctuation have a delayed diagnosis and subsequently, experience lags in treatment, according to the researchers.

This study focused on three MG patients who had no symptom fluctuations and faced such a delayed diagnosis.

The first patient was a 64-year-old male with no significant medical history who was admitted to the hospital after experiencing slowly progressive dysphagia, or difficulty swallowing. A previous exam at an outpatient clinic had raised suspicion of amyotrophic lateral sclerosis (ALS), given that the patient had not experienced symptom fluctuations.

However, electrodiagnostic examinations — tests that look at the speed and degree of electrical activity in muscles and nerves — were not consistent with ALS. A repetitive nerve stimulation test, which often is used to help diagnose MG, was performed and was indicative of this disease.

Physicians treated the patient with neostigmine, used similarly to edrophonium to test for the presence of MG by inhibiting the breakdown of acetylcholine and assessing whether symptoms ease. The medication was administered into the man’s muscles. His difficulties swallowing and speaking were relieved with the neostigmine, consistent with an MG diagnosis.

The patient was treated with oral pyridostigmine (sold as Mestinon, among other brand names) and low-dose oral methylprednisolone, which restored muscle strength and swallowing throughout the rest of his hospitalization.

Acetylcholine receptor antibodies — the most common MG-causing antibodies — were detected at a level of 30.05 nanomoles per liter. Of note, the normal upper limit is less than 0.25 nanomoles per liter (nmol/l).

The second patient was a 79-year-old male who was treated for progressive difficulty speaking and swallowing. He had been previously examined by ear, nose, and throat specialists, as well as by experts on digestive tract disorders, but no diseases were identified.

The man had complained of severe weight loss, but no muscle wasting. An electrodiagnostic examination did not find signs consistent with ALS. However, a repetitive nerve stimulation showed a decrease of greater than 10% in only one nerve/muscle group, indicative of MG.

Blood tests came back positive for acetylcholine receptor antibodies, which were present at levels of 4.92 nmol/l. Additionally, the patient had antibodies against a muscle protein called titin, which often are indicative of a thymoma — a tumor originating in the thymus that is often seen in MG patients. He also was positive for antibodies targeting ryanodine receptors, a type of calcium channels found in muscle cells. Imaging tests showed no signs of thymoma.

This patient also received oral pyridostigmine and methylprednisolone and his symptoms resolved.

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A 62-year-old female, the third patient in the series, had sought treatment for a headache, eyelid drooping on one side, and double vision.

Brain imaging tests indicated the presence of blood clots within the network of veins that sit in cavities behind the eye sockets under the brain. The patient was given anticoagulants to deal with these clots and showed a slight improvement in eye movement.

However, one month later, the woman showed eyelid droopiness on both sides and worsened double vision. A clinical examination revealed decreased eye muscle strength in both eyes due to nerve palsies, or a lack of nerve function.

An electrodiagnostic examination and repetitive nerve stimulation showed no abnormalities. But a neostigmine test suggested the presence of MG. Additionally, the patient had acetylcholine receptor antibodies at a level of 5.96 nmol/l.

She received both pyridostigmine and methylprednisolone, with a resulting gradual improvement of eyelid droopiness in both eyes and of double vision. Imaging also revealed a mass for which she ultimately underwent surgery, and was suggestive of thymoma.

All three patients had regular follow-ups for up to one year. Therapy with corticosteroids, including methylprednisolone, was gradually reduced and stopped for the first and third patients.

The first patient ultimately required corticosteroid reintroduction due to upper limb weakness. Additionally, he had a myasthenic crisis — a medical emergency in which MG affects the muscles that control breathing — one year after diagnosis. He ultimately required the addition of corticoid-sparing immunosuppression.

The second patient remained stable on pyridostigmine and low-dose methylprednisolone.

Researchers noted that electrodiagnostic studies and repetitive nerve stimulation may not be enough to diagnose MG, particularly in patients with ocular forms of the disease. They suggest that cholinesterase inhibitor testing — testing with neostigmine or edrophonium — and testing for acetylcholine receptor antibodies may be more effective for confirming MG and preventing a delayed diagnosis.

“We consider it worthwhile to consider the diagnosis of MG even in patients lacking the characteristic fluctuation of symptoms as this can probably delay the correct diagnosis even further,” the researchers wrote.

“Implementing a protocol of electrophysiologic studies and serologic testing for MG-specific antibodies in cases of patients with chronic motor fatigability but without fluctuations of their symptoms could help identify these atypical presentations as MG,” they conclude.

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