The case of a 55-year-old woman diagnosed with overlapping Lambert-Eaton myasthenic syndrome and myasthenia gravis — which tested negative for well-known neuromuscular junction antibodies — could help pave the way for further research into better, target-specific therapies, a study suggests.
Lambert-Eaton myasthenic syndrome (LEMS) and myasthenia gravis (MG) are autoimmune diseases characterized by damage to muscle function. In MG, antibodies against the neuromuscular junction — the site where nerve cells and muscles communicate — cause fatigue and muscle weakness. Often, patients experience oculobulbar weakness, involving the eyes and the muscles innervated by cranial nerves, but normal reflexes. Symptoms tend to improve with rest.
About 80% of MG patients have self-antibodies against the muscle acetylcholine receptor (AChR). Yet, a smaller fraction of patients negative for anti-AChR are positive for antibodies against the muscle-specific tyrosine kinase (MuSK) and components of the neuromuscular junction including agrin and LRP-4 proteins.
LEMS is also a condition that affects the neuromuscular junction. The disease symptoms, such as proximal muscle weakness, are caused by antibodies against the presynaptic voltage-gated calcium channels (VGCCs). Half of LEMS cases result from an underlying cancer, most often small cell carcinoma of the lungs.
When a patient has features of both conditions, the diagnosis is of “myasthenia gravis Lambert-Eaton overlap syndrome” or MLOS.
In this report, researchers describe the case of a 55-year-old African-American woman, a nonsmoker, who experienced severe bilateral hand and leg weakness for two weeks and ptosis (drooping of the upper eyelid) along with double vision for four months. She also experienced constipation and dry mouth. The patient reported that physical activity aggravated her symptoms.
Medical examination showed that she had severe ptosis on both eyes and ophthalmoplegia (a weakness of the eye muscles). She also showed a generalized muscular weakness, accompanied by areflexia (absence of neurological reflexes).
The patient tested positive for edrophonium, a test that measures response to anti-cholinesterase, an indication of MG.
Yet, she was negative for antibodies against AChR and MuSK. She also tested negative for VGCC antibodies, and chest radiological exam showed no signs of cancer.
A repetitive nerve stimulation (RNS) test revealed the patient had a 67.3% decrease in the response of the right abductor digiti-quanti muscle (a muscle which lies along the outer border of the foot), a characteristic of MG; but a 106% increased response after 15 seconds of tetanic contraction (sustained muscle contraction), which matched LEMS features. Nerve conduction tests were normal.
She was negative for LRP-4 and agrin antibodies.
Clinicians decided to treat the patient with pyridostigmine, sold as Mestinon and approved by the U.S. Food and Drug Administration to treat muscle weakness in people with MG. The medication is an acetylcholinesterase inhibitor that works by preventing ACh breakdown so that it stays in the neuromuscular junction longer, strengthening muscle stimulation.
Additional treatment included intravenous (into-the-vein) antibodies, and maintenance dosage of prednisone (a corticosteroid) that mimics an immune-suppressing hormone normally produced by the body. This regimen improved the patient’s symptoms, and her reflexes returned to normal.
The woman’s MLOS diagnosis is the second case reported that tested negative for AChR, MuSK, and VGCC, and the first to be negative for agrin and LRP-4, the researchers said.
“Further studies into the specific pathophysiological [disease mechanism] pathways of the several subforms of seronegative MG, LEMS, and MLOS might help develop new and more antigen-specific therapies,” they said.
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