Neuromuscular junction disorders: Pathology review
AssessmentsNeuromuscular junction disorders: Pathology review
USMLE® Step 1 style questions USMLE
A 65-year-old man comes to his outpatient provider because of a chronic cough for the past 3 months. It is occasionally accompanied by flecks of blood-tinged sputum. Review of systems is significant for weakness in the hips and thighs bilaterally and 15 lbs (6.8 kg) weight loss. Past medical history is notable for hypertension. He only takes hydrochlorothiazide. Social history is notable for a 50-pack-year smoking history. In the office, his temperature is 37.0°C (98.6°F), pulse is 76/min and blood pressure is 157/85 mmHg. Pulmonary examination reveals expiratory wheezing on the left side in 5th intercostal space. A chest radiograph is ordered and reveals the following:
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Laboratory testing reveals a creatinine kinase level of 75 U/L. Which of the following additional examination findings will most likely be present in this patient?
Contributors:Kaia Chessen, MScBMC, Tanner Marshall, MS, Sam Gillespie, BSc, Daniel Afloarei, MD
While doing your rounds, you see Kira, a 23-year-old female who presents with a series of recurrent symptoms that get worse as the day progresses. These include slurring of speech, difficulty swallowing, and double vision. She also mentions that her head feels heavy and is hard to hold up. She also complained that her arms are so weak she can’t even brush her hair. Additionally, she reports severe fatigue and shortness of breath. On examination, sensation and reflexes are normal. Next, you see a 62-year-old man named Jonathan, who presents with a history of leg muscle weakness that prevents him from doing simple things like climbing stairs or standing up, which gets better the more he uses his legs. He also reports shortness of breath, fatigue, dry mouth, impotence, and unintentional weight loss. Examination reveals a severely underweight man with dilated pupils. Reflexes are initially absent, although these are obtainable after a brief period of exercise. Blood tests were obtained, detecting anti-acetylcholine receptor antibodies in Kira and anti-voltage-gated calcium channels antibodies in Jonathan.
Now, both seem to have some type of neuromuscular junction disease. But first, a bit of physiology. In normal neuromuscular function, a nerve impulse is carried down the axon from the spinal cord, to the nerve endings, in the neuromuscular junction, where the impulse is transferred to the muscle cell. Here, the nerve impulse leads to the opening of voltage-gated calcium channels, causing an influx of calcium ions into the nerve terminal, which triggers synaptic vesicle fusion with plasma membrane. These synaptic vesicles contain a neurotransmitter called acetylcholine, which is released into the synaptic cleft. The neurotransmitter then binds to nicotinic acetylcholine receptors on muscle cell membranes and activates a chain reaction in the muscles that ultimately results in their contraction.
Ok, so there are two commonly tested diseases affecting the neuromuscular junction. First we have myasthenia gravis which is the most common. It’s an autoimmune disease that leads to varying degrees of skeletal muscle weakness, especially in women in their 20s and 30s and men in their 60s and 70s. The cause of this odd “bimodal” distribution of age-of-onset is unclear. What’s clear, though, is that the disease is marked by an antibody-mediated type II hypersensitivity. This begins when B cells get inappropriately activated, and they start making antibodies against the nicotinic acetylcholine receptors on the muscle cells. The antibodies bind to these receptors, and once they do that, the receptors are unable to bind acetylcholine. Without acetylcholine, muscles don’t contract as they should when they receive the “contract” signal from the central nervous system.
Anti-acetylcholine receptor antibodies can also activate the classical pathway of the complement. The complement system is a family of small proteins that work in an enzymatic cascade to fight off pathogens. The activation of complement causes inflammation and destruction of the muscle cells, reducing the number of acetylcholine receptors on the muscle cell surface, which impairs contraction even more. Now, a minority of people with myasthenia gravis produces another type of antibody called muscle-specific receptor tyrosine kinase antibody, which attacks proteins inside myocytes instead of nicotinic acetylcholine receptors, and this leads to muscle cells impairment as well.
The trigger for autoantibody production is unknown, but the disorder can be associated with other diseases. For example, myasthenia gravis can present as a paraneoplastic syndrome, which is a condition that arises as a result of cancer elsewhere in the body. The culprit is usually bronchogenic carcinoma or a thymic neoplasm, also called a thymoma, which generates an immune response that results in autoantibody production. Other conditions associated with the disease include hyperthyroidism, thymus hyperplasia, and autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, and pernicious anemia.
Regarding symptoms, the high-yield hallmark of myasthenia gravis is muscle weakness that worsens after periods of activity and improves after rest. Manifestations also fluctuate in intensity over minutes, to hours, to days, and tend to get better in cold weather. Ok, so myasthenia can initially affect the muscles around the eyes, which might be the only signs of disease. When this occurs, the disease is called ocular myasthenia gravis, and it typically evolves into generalized myasthenia after a few years.
These muscles control movement of the eye as well as the eyelids, so because they can’t contract, individuals might develop diplopia or double vision, as well as ptosis, or drooping eyelids. Neck muscles can become weak too, and these individuals might feel their head is heavy and it’s hard to keep upright.
When arm and leg muscles are involved, people might experience difficulties in walking, climbing stairs, and performing simple tasks such as hair combing and brushing their teeth. In other cases, individuals might present with bulbar symptoms, which are caused by weakness in the muscles of the mouth and throat responsible for speech and swallowing. These symptoms can include a change in voice and slurred speech, nasal regurgitation, difficulties chewing, choking, and dysphagia, or difficulty swallowing. Finally individuals often exhibit chronic and severe fatigue.
If certain muscles are affected, people can develop a myasthenic crisis, which is a life-threatening manifestation of the disease. This can occur when there decreased function of the muscles that control breathing, like the intercostal muscles or the diaphragm, which can cause dyspnea and, in time, respiratory insufficiency. Once respiratory insufficiency begins, respiratory failure may occur rapidly. Myasthenic crisis are often due to a supervening infection that reactivates the immune system.
Diagnosis is usually based on suggestive symptoms and the presence of the anti-acetylcholine receptor antibody in the serum. During a physical exam, they might have the milkmaid’s grip sign. This is where the individual is asked to squeeze the hand of the clinician and their handgrip may alternate between weak and normal, which resembles a milking motion. A high yield fact to keep in mind is that sensation and deep tendon reflexes are normal. For lab tests, around a quarter of those affected have no antibodies to acetylcholine receptors in their serum; in these individuals, the muscle-specific receptor tyrosine kinase antibody should be tested.
Single-fiber electromyography, a test that uses repetitive electrical stimuli to assess muscle function, can be performed too, and it usually detects abnormal neuromuscular transmission. Now, sometimes, treatment with long-acting acetylcholinesterase inhibitors like pyridostigmine can lead to a cholinergic crisis due to too much acetylcholine released at the neuromuscular junction which causes overstimulation. Because a cholinergic crisis is almost identical to a myasthenic one, the edrophonium, or Tensilon test can be used to differentiate between them. The test uses injections of edrophonium chloride, an acetylcholinesterase inhibitor, to briefly block the breakdown of acetylcholine and temporarily increases its levels at the neuromuscular junction. In myasthenia gravis, this is enough to overcome the symptoms caused by the decreased number of available receptors, so the weakness will improve. If symptoms get worse, a cholinergic crisis can be suspected.
Thyroid function tests are indicated to rule out associated Graves disease or hyperthyroidism. This is essential, especially in those with ocular myasthenia gravis, where concomitant hyperthyroidism is frequent. Similarly, once myasthenia is diagnosed, CT or MRI of the thorax should be done to check for thymic hyperplasia and thymoma. Those with myasthenia crisis should be evaluated for an infectious trigger and for respiratory muscle weakness by pulmonary function tests. Other high-yield triggers of myasthenia include surgery, pregnancy, and childbirth.
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "Myasthenia Gravis: A Review" Autoimmune Diseases (2012)
- "Recent advances in understanding and managing myasthenia gravis" F1000Res (2018)
- "Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society" Journal of Neurology (2016)
- "Lambert-Eaton Myasthenic Syndrome; Pathogenesis, Diagnosis, and Therapy" Autoimmune Diseases (2011)
- "Lambert-Eaton Myasthenic Syndrome" Neurol Clin (2018)
- "Synaptic Pathophysiology and Treatment of Lambert-Eaton Myasthenic Syndrome" Molecular Neurobiology (2014)
- "Lambert-Eaton myasthenic syndrome (LEMS): a rare autoimmune presynaptic disorder often associated with cancer" J Neurol (2017)