Pathophysiology: Myasthenia Gravis & Restless Leg Syndrome

Editor's Notes

• #2: Christopher Robin Milne, the son of A. A. Milne (author of Winnie-the-Pooh ) and the person on whom Christopher Robin was based, lived with myasthenia gravis for many years (1920-1996).
• #4: The cardinal features are weakness and fatigability.See alsohttp://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm
• #5: Ptosis or diplopia, are the initial symptom of myasthenia gravis in two-thirds of patients. The severity of weakness fluctuates during the day, usually being least severe in the morning and worse as the day progresses, especially after prolonged use of affected muscles.
• #6: There are approximately 36,000 to 60,000 cases in the United States.2011 Maine population estimate: 1,328,188; Bangor: 35,473. The incidence of MG has been increasing over the past few decades due to better diagnosis. Also, better treatment has resulted in longer-survival.
• #7: Symptoms typically not observed until 70% reduction in nACh receptors. Muscle Specific Kinase (MuSK) is a receptor tyrosine kinase.MuSK induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself, and on proteins that bind the cytoplasmic domain of the receptor. Knock-out mice lacking MuSK do not form functional neuromuscular junctions.  Activation of MuSK (by agrin) induce "clustering" of acetylcholine receptors.
• #8: Decreased signaling is not just due to antibody binding.The underlying defect is a decrease in the number of available ACh receptors at neuromuscular junctions due to an antibody mediated autoimmune attack.
• #9: The electric eel (Electrophorus electricus) is an electric fish found in South American capable of generating powerful electric shocks of up to 600 volts which it uses for hunting and self-defense. Paralysis was observed 3 weeks after receptor injections.
• #10: Channel opening occurs when ACh binds to both alpha subunits. This lets cations enter. The majority of MG patients have antibodies against the alpha subunit and the main immunogenic region. Howere, the antibodies in MG patients are diverse and target different parts of the receptor.
• #11: Of the controls, the majority did not have other neuromuscular disease. Alpha bungarotoxin is found in the venom of differetkraites (pronounced “crates”) that are found in SE Asia. Poisoning causes ptosis and diplopia.Iodine-125 (125I) is a radioisotope of iodine which has uses in biological assays because of its long half-life (59 days).
• #12: There is endocytosis of the nACh receptor and morphological changes in the muscle.
• #13: Most MG patients have generalized muscle effects but a subset have only ocular effects. Muscle Specific Kinase (MuSK) is a receptor tyrosine kinase.MuSK induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself, and on proteins that bind the cytoplasmic domain of the receptor. Knock-out mice lacking MuSK do not form functional neuromuscular junctions.
• #14: Reduced or absent reflexes occur with LEM but not generalized MG. Antibodies against P/Q calcium channels results in reduced acetylcholine release. Three quarters of people with LEMS also have disruption of the autonomic nervous system. This may be experienced as a dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension (falls in blood pressure on standing, potentially leading to blackouts).Chest X-ray showing a tumor in the left lung (right side of the image). LEMS have difficulties with lower-extremities and may notice difficulties climbing stairs.
• #15: The type of Myasthenia have different patterns of weakness. AChR is more localized to the eyes. There is more impairment in the tongue, pharnx, and larnx (the medulla or bulbar type) with MuSK and the lower extremities in LEMS.
• #16: Plasmapheresis consists of taking blood from one vein, separating plasma from blood cells using membrane filtration or centrifugation and then returning blood with a plasma substitute into another vein. An alternative method of removing antibodies is immunoabsorption. In this the plasma is passed down an absorbant column, which removes antibodies, and then returned to the patient.
• #17: Rabies vaccine example. There have been 4 RCTs (total patients = 128) and 3 were non-blind!
• #19: Thymoma (thī-mō'mə) is a usually benign tumor of the thymus. Thymectomy has been used for MG since the 1940s. Patients over 50 are less likely to benefit. Some improvement may be seen 6-12 months post-surgery.
• #20: Penicillamine is used as a form of immunosuppression to treat rheumatoid arthritisand is also a metabolite of penicillin. It also  increases urinary copper excretion by chelation [kee-ley-shuhn]. It causes MG but muscle weakness is typically mild and it typically resolves after a couple weeks.
• #21: Sir Thomas Willis (1672):Wherefore to some, when being abed they betake themselves to sleep, presently in the arms and legs, leapings and contractions on the tendons, and so great a restlessness and tossings of other members ensue, that the diseased are no more able to sleep, than if they were in a place of the greatest torture.More recent patient terms for the sensation includes:“soda bubbling in veins”, “the gotta moves”, “crazy legs”, “itching bones”, “shock-like feelings”, and “worms moving”.
• #22: 10% of general U.S. population has symptoms of RLS with daily or severe symptoms in about one-quarter.
• #23: PET ­produces images of the body by detecting the radiation emitted from radioactive substances. These substances are injected into the body, and are usually tagged with a radioactive atom, such as Carbon-11, Fluorine-18, Oxygen-15, or Nitrogen-13.PET detects the gamma rays given off at the site where a positron emitted from the radioactive substance collides with an electron in the tissue. See also http://www.howstuffworks.com/nuclear-medicine1.htmRaclopride is a synthetic compound that acts as an antagonist on D2 dopamine receptors.
• #26: A small study (N=12 RLS, half family history positive) showed a reduction in cerebrospinal fluid ferritin (an index of brain ferritin).Transferrin receptor (TfR) is a carrier protein for transferrin. It is needed for the import of iron into the cell.Transferrin receptor immunoreaction product (blue) is present on most of the brown neuromelanin containing cells in the control brains. The immunoreaction product is found on the soma and extends into a primary process in all cases (e.g., cell at arrow). In the RLS brains, the immunoreaction product for Tf receptor is minimal and immunostained cell processes are rare on the brown neuromelanin cells (e.g., cell at arrow).
• #27: Overall, abnormalities in the cofactor for DOPA synthesis, DOPA uptake, and in dopamine receptor levels have been identified in RLSA cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. Cofactors are "helper molecules" that assist in biochemical transformations.
• #28: 6 trials of Fe (oral or iv) for RLS (N=197) which used different criteria for defining RLS and endpoints. Results for the 4 that used International RLS criteria produced variable results.Current guideline for RLS by the RLS Foundation’s Medical Foundation advisory board recommend iron therapy for patients was a low ferritin (usually less than 20ng/ml) and consideration of iron therapy on a case by case basis, with ferritin levels below 50ng/ml.