Myasthenia gravis
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Myasthenia gravis
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Myasthenia gravis
- 1. Myasthenia Gravis By Dr Yaqub PGT, Dept. of Pharmacology 1
- 2. Outline • Background • Anatomy • Pathophysiology • Epidemiology • Clinical Presentation • Treatment 2
- 3. Background • The word Myasthenia Gravis is derived from Latin and Greek Myasthenia – weakness Gravis – serious • literally means "grave muscle weakness" 3
- 4. • Myasthenia gravis (MG) - autoimmune disorder - antibodies against AchRs at NMJ • these antibodies attack and destroy AchRs & postsynaptic molecules • leads to impaired signal transduction muscle weakness and fatigability 4
- 5. Anatomy Neuromuscular Junction (NMJ) Components: Presynaptic membrane Postsynaptic membrane Synaptic cleft Presynaptic membrane contains Àch in vesicles ACh attaches to AChR on postsynaptic membrane 5
- 6. 6
- 7. Pathophysiology In MG, antibodies are directed toward the acetylcholine receptor at the neuromuscular junction of skeletal muscles 7
- 8. Antibodies 85% anti- AchR antibodies 65% Hyperplasia 10% Thymomas 15% seronegative 40% Anti-Musk antibodies Others-antititin, RyR, KV1,4 Ab 8
- 10. How do these antibodies act? 1. Blocks the binding of ACh to the AChR. 2. Increases the degradation rate of AChR 3. A complement-mediated destruction Results in: nicotinic acetylcholine receptors postsynaptic membrane folds Widened synaptic cleft 10
- 11. 11
- 12. Epidemiology • Prevalence: 1-7 in 10,000 • Age: BIMODAL PEAK • 20-30 yrs (young women), 50-60 yrs (older men) • < 10% occur in children <10 yrs • Overall F:M = 3:2 • More common in pts with family history of one or the other autoimmune diseases 12
- 13. Clinical Presentation • Fluctuating painless weakness increased by exertion • Worses with repetitive activities and improves with rest Ocular muscle weakness (85%) Asymmetric Ptosis Diplopia is very common 13
- 14. Weakness of face and throat muscles Dysphagia Dysarthria Dysphonia Myasthenic snarls normal during attack 14
- 15. Limb muscle weakness Neck extensors > flexors Upper limbs > lower limbs Dropped head syndrome 15
- 16. • Respiratory weakness Weakness of the intercostal muscles and the diaghram Collapse the upper airway Neuromuscular emergency - mechanical ventilation 16
- 17. Progression of disease Mild to more severe over weeks to months Usually spreads from ocular facial bulbar truncal limb muscles The disease remains ocular in 16% of patients Death rate reduced from 30% to <5% with pharmacotherapy and surgery 17
- 18. Diagnosis 18
- 19. Edrophonium (Tensilon test) • Initial IV dose of 2 mg of edrophonium is given • Observed for objective improvement in muscle weakness • Definite improvement occurs-the test is considered positive & terminated • If no improvement in weakness - the remainder 8mg of the drug is injected 19
- 20. Myasthenic Crisis • Exacerbation of weakness - endanger life • Respiratory failure (diaphragmatic and inter costal muscle weakness) • Cause – intercurrent infection • Cholinergic crisis - excessive anticholinesterase medication 20
- 21. Treatment There are four basic therapies: Symptomatic treatment - acetylcholinesterase inhibitors Rapid short-term - plasmapheresis and intravenous immunoglobulin Chronic long term - immunomodulating treatment - glucocorticoids & immunosuppressive drugs Surgical treatment 21
- 22. 22
- 23. Anticholinesterase Medications • Pyridostigmine is the most widely used • Onset - 15–30 min and lasts for 3–4 h • Dose - 30–60 mg three to four times daily • Frequency of the dose should be tailored to the patient’s individual requirements throughout the day 23
- 24. Neostigmine • Short-acting AChE inhibitor • half-life - 45-60 minutes • Poorly absorbed from the GIT • Should be used only if pyridostigmine is unavailable 24
- 26. Plasmapheresis • Removes AChR Ab from the circulation • Rapidly Improves strength Used for • short-term intervention • Sudden worsening of myasthenic symptoms • Chronic intermittent treatment for refractory cases 26
- 27. • Typically one exchange is done every other day for a total of four to six times • Improvement is noted in a couple of days, but it does not last for more than 2 months. • Complications – hypocalcemia, hypomagnesemia, hypothermia, hypotension & transfusion reactions 27
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- 33. Intravenous Immunoglobulin Therapy • Rapid improvement • Severe myasthenic weakness • Dose is 2 g/kg over 5 days (400 mg/kg per day) • Improvement occurs in ~70% of patients • Adverse reactions include headache, fluid overload, and rarely aseptic meningitis or renal failure 33
- 34. Immunosuppression • Is required in nearly all pts with -late-onset MG -thymoma MG -MuSK-MG • Suppress autoantibody production & its detrimental effects at NMJ 34
- 35. Glucocorticoids • First & most commonly used immunosuppressant • Used when symptoms of MG are not adequately controlled by cholinesterase inhibitors alone • MOA - inhibits MHC expression & IL-1 production IL-2 & IFN γ production 35
- 36. Prednisone – • most commonly used • Decreases the severity of MG exacerbations • Transient worsening might occur initially • Clinical improvement - 2-4 weeks • marked improvement in 40% • Remissions are noted in 30% 36
- 37. Mycophenolate mofetil • Choice for long-term treatment • MOA -prodrug of mycophenolic acid - Inhibits inosine monophosphate dehydrogenase • Lymphocyte proliferation, antibody production and CMI are inhibited 37
- 38. 38
- 39. • Does not kill or eliminate preexisting autoreactive lymphocytes • Clinical improvement may be delayed for 2-6 months • Vomiting, diarrhoea, leucopenia and predisposition to CMV infection, g.i. bleeds are the prominent adverse effects. 39
- 40. Azathioprine • It is a purine analog, reduces nucleic acid synthesis, thereby interfering with T-and B-cell proliferation • Is effective in 70%–90% of patients with MG • When used in combination with prednisone - more effective & better tolerated than prednisone alone • Beneficial effect takes at least 3–6 months to begin 40
- 41. Calcineurin inhibitors • Cyclosporin - Used mainly in patients who do not tolerate or respond to azathioprine • Blocks synthesis of IL-2 cytokine • Dose 4–5 mg/kg per day • Cyclosporine can cause nephrotoxicity, neurotoxicity, hepatotoxicity, hyperlipidemia, hyperuricemia, hyperglycemia, hirsutism and gum hyperplasia 41
- 42. 42
- 43. Tacrolimus • Is ~ 100 times more potent than cyclosporin • It binds to FK 506 binding protein (FKBP) and causes inhibition of helper T cells • Beneficial effect appears more rapidly than that of azathioprine • less nephrotoxicity, hirsutism, hyperlipidemia than cyclosporine • Dose - 0.1 mg/kg per day 43
- 44. 44
- 45. Thymectomy 45
- 46. Thymectomy • Carried out in all patients with generalized MG - aged between puberty and 55 years • Thymoma - Surgical removal is a must - possibility of local tumor spread • up to 85% of patients experience improvement after thymectomy • of these, ~ 35% achieve drug-free remission 46
- 48. Thank you 48
Hinweis der Redaktion
- Myasthenia gravis (MG) is an autoimmune disorder caused by antibodies targeting the neuromuscular junction. In MG, these antibodies bind to the postsynaptic muscle end-plate and attack and destroy postsynaptic molecules. This process leads to impaired signal transduction and, consequently, muscle weakness and fatigability — the hallmark symptoms of MG1–4 . The weakness can be focal or generalized, and usually affects ocular, bulbar and proximal extremity muscles. Respiratory muscle weakness develops only rarely, but can be life-threatening. Weakness is typically symmetrical, except in affected external eye muscles, in which the weakness is usually asymmetrical
- Figure 1 | Neuromuscular junction in myasthenia gravis (MG). a | Normal function of neuromuscular junction, with major components implicated in MG shown. Action potential at the presynaptic nerve terminal causes opening of voltage-dependent Ca2+ channels, triggering release of acetylcholine and agrin into the synaptic cleft. Acetylcholine binds to acetylcholine receptors (AChRs), which promote sodium channel opening, which in turn triggers muscle contraction. Agrin binds to the complex formed by low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific kinase (MuSK), causing acetylcholine receptor (AChR) clustering, which is required for maintenance of the postsynaptic structures of the neuromuscular junction. b | Major pathogenic mechanisms of the AChR antibodies in MG include complement activation at the neuromuscular junction, which causes formation of membrane attack complexes (MACs) on the muscle membrane and destruction of the typical folds in the sarcolemma (1); antigenic modulation that results in internalization and degradation of surface AChRs (2); and binding of AChR antibodies at the AChR ligand binding site (3), which could directly block acetylcholine binding and, consequently, channel opening. Anti-MuSK and anti-LRP4 antibodies have been shown to block the intermolecular interactions of MuSK or LRP4 respectively, and could thus inhibit the normal mechanisms for maintenance of the organization of the neuromuscular junction (4). Antibodies with known pathogenic involvement in MG are shown in red. c | MG treatment can restore function of the neuromuscular junction by increasing the levels of available acetylcholine (acetylcholinesterase inhibitors; green), which improves signal transduction, or by reducing the concentration of autoantibodies (immunosuppressive drugs, plasma exchange/immunoadsorption, B-cell-targeting therapies; red), which alleviates the pathogenic mechanisms described in (b). KV1.4, voltage-gated potassium channel 1.4; RyR, ryanodine receptor. Agrin/MuSK signaling pathway maintains the structural and functional integrity of the postsynaptic NMJ apparatus in the adult muscle cell. Anti-MuSK antibodies affect the agrin-dependent AChR cluster maintenance at the NMJ, leading to reduced AChR numbers.
- Other anti muscle cell protein RyR, titin or KV1.4 Antibodies (e.g., antititin, 10% Thymomas antiryanodine receptor antibodies
- Figure 1 | Neuromuscular junction in myasthenia gravis (MG). a | Normal function of neuromuscular junction, with major components implicated in MG shown. Action potential at the presynaptic nerve terminal causes opening of voltage-dependent Ca2+ channels, triggering release of acetylcholine and agrin into the synaptic cleft. Acetylcholine binds to acetylcholine receptors (AChRs), which promote sodium channel opening, which in turn triggers muscle contraction. Agrin binds to the complex formed by low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific kinase (MuSK), causing acetylcholine receptor (AChR) clustering, which is required for maintenance of the postsynaptic structures of the neuromuscular junction. b | Major pathogenic mechanisms of the AChR antibodies in MG include complement activation at the neuromuscular junction, which causes formation of membrane attack complexes (MACs) on the muscle membrane and destruction of the typical folds in the sarcolemma (1); antigenic modulation that results in internalization and degradation of surface AChRs (2); and binding of AChR antibodies at the AChR ligand binding site (3), which could directly block acetylcholine binding and, consequently, channel opening. Anti-MuSK and anti-LRP4 antibodies have been shown to block the intermolecular interactions of MuSK or LRP4 respectively, and could thus inhibit the normal mechanisms for maintenance of the organization of the neuromuscular junction (4). Antibodies with known pathogenic involvement in MG are shown in red. c | MG treatment can restore function of the neuromuscular junction by increasing the levels of available acetylcholine (acetylcholinesterase inhibitors; green), which improves signal transduction, or by reducing the concentration of autoantibodies (immunosuppressive drugs, plasma exchange/immunoadsorption, B-cell-targeting therapies; red), which alleviates the pathogenic mechanisms described in (b). KV1.4, voltage-gated potassium channel 1.4; RyR, ryanodine receptor.
- AChE, acetylcholinesterase. See text for description of normal neuromuscular transmission. The myasthenia gravis (MG) junction demonstrates a normal nerve terminal; a reduced number of acetylcholine receptors (AChRs) (stippling); flattened, simplified postsynaptic folds; and a widened synaptic space. Diagrams of (A) normal and (B) myasthenic neuromuscular junctions. AChE, acetylcholinesterase. See text for description of normal neuromuscular transmission. The MG junction demonstrates a normal nerve terminal; a reduced number of AChRs (stippling); flattened, simplified postsynaptic folds; and a widened synaptic space. In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. the postsynaptic folds are flattened, or “simplified.” These changes result in decreased efficiency of neuromuscular transmission Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction. The amount of ACh released per impulse normally declines on repeated activity The decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue. The neuromuscular abnormalities in MG are brought about by an autoimmune response mediated by specific anti-AChR antibodies. The anti-AChR antibodies reduce the number of available AChRs at neuromuscular junctions by three distinct mechanisms: (1) Accelerated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the receptors; (2) blockade of the active site of the AChR, i.e., the site that normally binds ACh; and (3) damage to the postsynaptic muscle membrane by the antibody in collaboration with complement. An immune response to muscle-specific kinase (MuSK) can also result in myasthenia gravis, possibly by interfering with AChR
- Occular muscle weakness Asymmetric Usually affects more than one extraocular muscle and is not limited to muscles innervated by one cranial nerve Weakness of lateral and medial recti may produce a pseudointernuclear opthalmoplegia Limited adduction of one eye with nystagmus of the abducting eye on attempted lateral gaze Ptosis caused by eyelid weakness Diplopia is very common Facial muscle weakness is almost always present Ptosis and bilateral facial muscle weakness Sclera below limbus may be exposed due to weak lower lids Bulbar muscle weakness Palatal muscles “Nasal voice”, nasal regurgitation Chewing may become difficult Severe jaw weakness may cause jaw to hang open Swallowing may be difficult and aspiration may occur with fluids—coughing and choking while drinking Neck muscles Neck flexors affected more than extensors Limb muscle weakness Upper limbs more common than lower limbs Respiratory muscle weakness Weakness of the intercostal muscles and the diaghram may result in CO2 retention due to hypoventilation May cause a neuromuscular emergency Weakness of pharyngeal muscles may collapse the upper airway Monitor negative inspiratory force, vital capacity and tidal volume Do NOT rely on pulse oximetry Arterial blood oxygenation may be normal while CO2 is retained
- Drugs that inhibit the enzyme AChE allow ACh to interact repeatedly with the limited number of AChRs in MG, producing improvement in muscle strength. Edrophonium is used most commonly for diagnostic testing because of the rapid onset (30 s) and short duration (~5 min) of its effect. An objective end point must be selected to evaluate the effect of edrophonium, such as weakness of extraocular muscles, impairment of speech, or the length of time that the patient can maintain the arms in forward abduction. An initial IV dose of 2 mg of edrophonium is given. If definite improvement occurs, the test is considered positive and is terminated. If there is no change, the patient is given an additional 8 mg IV. The dose is administered in two parts because some patients react to edrophonium with side effects such as nausea, diarrhea, salivation, fasciculations, and rarely with severe symptoms of syncope or bradycardia. Atropine (0.6 mg) should be drawn up in a syringe and ready for IV administration if these symptoms become troublesome. The edrophonium test is now reserved for patients with clinical findings that are suggestive of MG but who have negative antibody and electrodiagnostic test results. False-positive tests occur in occasional patients with other neurologic disorders, such as amyotrophic lateral sclerosis, and in placebo-reactors. False-negative or equivocal tests may also occur. In some cases, it is helpful to use a longer-acting drug such as neostigmine (15 mg PO), because this permits more time for detailed evaluation of strength.
- Myasthenic crisis is defined as an exacerbation of weakness sufficient to endanger life; it usually consists of respiratory failure caused by diaphragmatic and intercostal muscle weakness. Crisis rarely occurs in properly managed patients. Treatment should be carried out in intensive care units staffed with teams experienced in the management of MG, respiratory insufficiency, infectious disease, and fluid and electrolyte therapy. The possibility that deterioration could be due to excessive anticholinesterase medication (“cholinergic crisis”) is best excluded by temporarily stopping anticholinesterase drugs. The most common cause of crisis is intercurrent infection. This should be treated immediately, because the mechanical and immunologic defenses of the patient can be assumed to be compromised. The myasthenic patient with fever and early infection should be treated like other immunocompromised patients. Early and effective antibiotic therapy, respiratory assistance, and pulmonary physiotherapy are essentials of the treatment program. As discussed above, plasmapheresis or IVIg is frequently helpful in hastening recovery. OVER MEDICATION Too high a dose of cholinergic treatment meds Muscles stop responding to the bombardment of ACh, leading to flaccid paralysis and respiratory failure and LOW BP Cholinergic Sx: hypersecretions / hypermotility STOP all anticholinesterase meds Treat with Atropine (anticholinergic)
- Figure 1 | Neuromuscular junction in myasthenia gravis (MG). a | Normal function of neuromuscular junction, with major components implicated in MG shown. Action potential at the presynaptic nerve terminal causes opening of voltage-dependent Ca2+ channels, triggering release of acetylcholine and agrin into the synaptic cleft. Acetylcholine binds to acetylcholine receptors (AChRs), which promote sodium channel opening, which in turn triggers muscle contraction. Agrin binds to the complex formed by low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific kinase (MuSK), causing acetylcholine receptor (AChR) clustering, which is required for maintenance of the postsynaptic structures of the neuromuscular junction. b | Major pathogenic mechanisms of the AChR antibodies in MG include complement activation at the neuromuscular junction, which causes formation of membrane attack complexes (MACs) on the muscle membrane and destruction of the typical folds in the sarcolemma (1); antigenic modulation that results in internalization and degradation of surface AChRs (2); and binding of AChR antibodies at the AChR ligand binding site (3), which could directly block acetylcholine binding and, consequently, channel opening. Anti-MuSK and anti-LRP4 antibodies have been shown to block the intermolecular interactions of MuSK or LRP4 respectively, and could thus inhibit the normal mechanisms for maintenance of the organization of the neuromuscular junction (4). Antibodies with known pathogenic involvement in MG are shown in red. c | MG treatment can restore function of the neuromuscular junction by increasing the levels of available acetylcholine (acetylcholinesterase inhibitors; green), which improves signal transduction, or by reducing the concentration of autoantibodies (immunosuppressive drugs, plasma exchange/immunoadsorption, B-cell-targeting therapies; red), which alleviates the pathogenic mechanisms described in (b). KV1.4, voltage-gated potassium channel 1.4; RyR, ryanodine receptor.
- Anticholinesterase medication produces at least partial improvement in most myasthenic patients, although improvement is complete in only a few. Pyridostigmine is the most widely used anticholinesterase drug. As a rule, the beneficial action of oral pyridostigmine begins within 15–30 min and lasts for 3–4 h, but individual responses vary. Treatment is begun with a moderate dose, e.g., 30–60 mg three to four times daily. The frequency and amount of the dose should be tailored to the patient’s individual requirements throughout the day. For example, patients with weakness in chewing and swallowing may benefit by taking the medication before meals so that peak strength coincides with mealtimes. Long-acting pyridostigmine may occasionally be useful to get the patient through the night but should never be used for daytime medication because of variable absorption. The maximum useful dose of pyridostigmine rarely exceeds 120 mg every 3–6 h during daytime. Overdosage with anticholinesterase medication may cause increased weakness and other side effects. In some patients, muscarinic side effects of the anticholinesterase medication (diarrhea, abdominal cramps, salivation, nausea) may limit the dose tolerated. Atropine/diphenoxylate or loperamide is useful for the treatment of gastrointestinal symptoms
- Whereas azathioprine (2–3 mg/kg daily) takes 6–15 months to yield an optimal effect, prednisolone exerts its full effect during the first few weeks and months of treatment. Alternate-day dosing and gradual dose increases are widely used in an attempt to avoid adverse effects. Once the optimal improvement has been reached, the dose of prednisolone should be slowly reduced to the lowest effective dose. Two studies have indicated that prednisolone treatment of ocular MG reduces the risk of MG generalization, in addition to the beneficial effect on the ocular symptoms
- It is a purine antimetabolite which has more marked immunosuppressant than antitumour action. The basis for this difference is not clear, but may be due to its selective uptake into immune cells and intracellular conversion to the active metabolite 6-mercaptopurine, which then undergoes further transformations to inhibit de novo purine synthesis and damage to DNA. It selectively affects differentiation and function of T cells and inhibits cytolytic lymphocytes; CMI is primarily depressed. The most important application of azathioprine is prevention of renal and other graft rejection, but it is less effective than cyclosporine; generally combined with it or used in patients developing cyclosporine toxicity. Relatively lower doses (1–2 mg/kg/day) are used in progressive rheumatoid arthritis (see p. 211), and it is frequently employed for maintening remission in inflammatory bowel disease (see p. 685). It may be an alternative to long-term steroids in some other autoimmune diseases as well.
- cyclosporine and tacrolimus are as effective as azathioprine beneficial effect appears more rapidly than that of azathioprine Ca lcineurin inhibitors Calcineurin is required for the activation of NFAT (nuclear factor of activated T cells) which in turn increases the transcription of IL-2 by activated T cells. Cyclosporine and tacrolimu (FK 506) inhibits the activation of NFAT by binding to immunophilins (cyclosporine binds to cyclophilin and tacrolimus binds to FKBP). Net result of administration of cyclosporine and tacrolimus is inhibition of gene transcription of IL-2. These are used as immunosuppressive agents for organ transplantation, GVHD and some autoimmune diseases like rheumatoid arthritis and psoriasis. • Cyclosporine can cause nephrotoxicity, hepatotoxicity, hypertension, hyperkalemia, hyperlipidemia, hyperuricemia, hyperglycemia, hirsutism, gum hyperplasia and neurotoxicity (tremor, headache, motor disturbance and seizures). • Incidence of hyperglycemia and neurotoxicity are more with tacrolimus than cyclosporine. Whereas hirsutism, gum hyperplasia, hyperuricemia and hyperlipidemiaare not caused by tacrolimus. Note: • Tacrolimus is more potent than cyclosporine. • Tacrolimus is a macrolide antibiotic. • Nephrotoxicity is the major indication for cessation or modification of cyclosporine therapy. Hypertension occurs in 50% of renal transplant and almost all cardiac transplant recepients. • Sirolimus aggaravates cyclosporine induced renal dysfunction whereas cyclosporine increases sirolimus induced hyperlipidemia and myelosuppression.
- THYMECTOMY Two separate issues should be distinguished: (1) surgical removal of thymoma, and (2) thymectomy as a treatment for MG. Surgicalremoval of a thymoma is necessary because of the possibility of local tumor spread, although most thymomas are histologically benign. In the absence of a tumor, the available evidence suggests that up to 85% of patients experience improvement after thymectomy; of these, ~35% achieve drug-free remission. However, the improvement is typically delayed for months to years. The advantage of thymectomy is that it offers the possibility of long-term benefit, in some cases diminishing or eliminating the need for continuing medical treatment. In view of these potential benefits and of the negligible risk in skilled hands, thymectomy has gained –widespread acceptance in the treatment of MG. It is the consensus that thymectomy should be carried out in all patients with generalized MG who are between the ages of puberty and at least 55 years. Whether thymectomy should be recommended in children, in adults >55 years of age, and in patients with weakness limited to the ocular muscles is still a matter of debate. There is also evidence that patients with MuSK antibody–positive MG may not respond to thymectomy. Thymectomy must be carried out in a hospital where it is performed regularly and where the staff is experienced in the pre- and postoperative management, anesthesia, and surgical techniques of total thymectomy.
- Algorithm of management