Myasthenia Gravis can be broken down into two main clinical forms and by several subtypes defined by how the disease is manifesting, by detectable auto antibodies in the patient's serum and, in a certain population, via electrodiagnostic testing where known antibodies are not readily detected. The most commonly detected autoantibodies are against AChR, followed by MuSK and most recently, the latest discovery of Agrin and LRP4.
- Ocular Myasthenia Gravis (OMG) is contained to weakened eye (ocular) muscles that control movement and our eyelids. Pupilary examination is usually normal. Ocular MG can lead to difficulty driving, reading, watching tv and cooking etc., as fluctuating severity and occurrence can cause trouble with focusing problems, eyestrain, double and blurry vision, headaches, strambismus and ptosis ( heavy, drooping eye lid(s), causing limitations in daily activities and quality of life. An estimated 15% of the MG population will be OMG patients. It is generally accepted that patients who begin with ocular symptoms will remain with ocular MG if they do not advance within five years. Roughly 50% of patients who have OMG during their first year of illness will go on to develop more generalized muscle weakness.
- Generalized Myasthenia Gravis (gMG) is a systemic manifestation of the disease where it affects varying combinations of limb, neck, facial, jaw, tongue, throat, vocal chord and diaphragm weakness. This can cause trouble with holding up your neck, chewing, speaking, talking, swallowing, singing, using your hands and arms to bathe, dress, cook, clean, garden, walk, stand, smile, have an animated expression etc...Generalized MG can include ocular weakness, but will also impact other areas of the body. These symptoms can change over time and spread, worsen or sporadically improve.
Antibody Subtypes
- Anti-acetylcholine receptor (AChR) antibodies are seen in an estimated 85% of Myasthenics. These antibodies hinder the action of acetylcholine in three ways: binding, blocking and modulating and comprise a panel of three separate tests. Myasthenics who test positive for AChR antibodies are excluded from the necessity of additional antibody testing.
- Anti-MuSK antibodies to muscle-specific kinase (MuSK), a receptor tyrosine kinase that is essential for neuromuscular junction development, found in 15% of individuals negative for AchR antibodies and up to 40% in the remaining seronegative individuals. One of the more striking differences is the female predominance of patients with MuSK, ranging between series from 78% to 100% women. Individuals with MuSK antibodies are less likely to respond positively to acetycholinesterease inhibitors and thymectomy and have greater pronounced neck, shoulder and respiratory involvement without ocular weakness.
- Striated antibodies are especially useful in the detection and diagnosis of thymoma, notably in patients with the onset of myasthenia gravis under the age of 50. It also holds clinical value as a screening test for MG in older patients who are negative for both AChR and MuSK antibodies. Research also shows these antibodies can be useful in some cases in monitoring patient responsiveness to immunosuppressive therapies.
- LRP4 antibodies attack the LRP4 protein that forms a complex with MuSK, and initiates the activation via Agrin. These processes work together to initialize completed function of the neuromuscular junction. Anti-LRP4 antibodies are found in approximately 9.2% of MG patients who are negative for both anti-AChR and anti-MuSK antibodies.
- Agrin antibodies inhibit the direct construction of the nerve-muscle contact, or synapse,(where MG is manifest) and MuSK, an enzyme on the muscle cell surface, which facilitates a clustering of receptors, activated by acetylcholine. While agrin and MuSK work together, they don't directly communicate, which is where LRP4 comes in. Researchers have recently shown that agrin communicates with LRP4 on the muscle cell surface, then recruits MuSK to join the conversation. Agrin antibodies were first identified in the blood of patients who were double seronegative. They theorize the antibodies diminish signaling between agrin, LRP4 and MuSK and/or stimulate an immune attack against the neuromuscular junction.
Antibody Negative Subtype
- Seronegative patients are classified as those who have negative results in AChR antibody biochemistry (blood work). A seronegative test for MG does not necessarily mean the individual does not have MG, but rather that further testing needs to be completed including MuSK antibodies and electrodiagnostic testing such as RNS, EMG and SFEMG. It is recommended that these patients are ruled out for Lambert Eaton Myasthenic Syndrome, Congenital Myasthenia Syndrome, botulism, cranial nerve damage, mitochondrial disorders, AIDP, motor neuron disease and brainstem ischemia and tested additionally via Tensilon, bedside ice pack and/or curtain testing, as is appropriate. Allow for exclusionary testing to help determine diagnosis when MG specific tests are negative.
- Double sero-negative patients are negative in both AChR and MuSK antibody biochemistry. This does not mean the patient does not have Myasthenia Gravis. It is recommended that these patients are tested for LRP4, striated and Agrin antibodies, in addition to electrodiagnostic testing such as RNS, EMG and SFEMG. It is also important to have ruled out for Lambert Eaton Myasthenic Syndrome, Congenital Myasthenia Syndrome, botulism, cranial nerve damage, mitochondrial disorders, AIDP, motor neuron disease and brainstem ischemia and tested additionally via Tensilon, bedside ice pack and/or "curtain" testing, as is appropriate. Allow for exclusionary testing to help determine diagnosis when MG specific tests are negative. The patient may still have MG in spite of inconclusive data. Double seronegative patients often present and respond to therapeutic treatment similarly as their AChR positive counterparts.
- Triple seronegative patients are negative for AChr, MuSK and LRP4 autoantibodies. Electrodiagnostic testing is especially crucial in this subset, alongside skillful clinical assessment with patient history. It is also important to have ruled out for Lambert Eaton Myasthenic Syndrome, Congenital Myasthenia Syndrome, botulism, cranial nerve damage, mitochondrial disorders, AIDP, motor neuron disease and brainstem ischemia and tested additionally via Tensilon, bedside ice pack and/or "curtain" testing, as is appropriate. Allow for exclusionary testing to help determine diagnosis when MG specific tests are negative. The patient may still have MG in spite of inconclusive data.
- Seronegative patients require an even higher demand of diagnostic skill set than their seropositive counterparts. Patient history alongside changing and fatiguable weakness are key in providing an accurate assessment. These patients often struggle obtaining and maintaining diagnoses and treatment, even after a confirmed diagnosis is in place. Too many in the medical field do not acknowledge lab negative patients and these patients are especially in danger of receiving delayed and poor care.