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Myasthenia Gravis
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LAY OUT Definition Epidemiology Pathophysiology Clinical Features
Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References This will be the lay out of my presentation
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DEFINITION Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References “It is a fluctuating weakness of certain voluntary muscles, particularly those innervated by motor nuclei of the brainstem, i.e. ocular, masticatory, facial, deglutitional, and lingual”. Myasthenia gravis is the fluctuating weakness of certain voluntary muscles, particularly those innervated by motor nuclei of the brainstem, i.e. ocular, masticatory, facial, deglutitional, and lingual.
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EPIDEMIOLOGY Can occur at any age. In women:20-40 yrs.
In men:40-60 yrs. Familial occurrence: Rare. Spontaneous remission: 20%. 90% no specific cause. Genetic predisposing factor: HLA association. Thymic tumor: 10%. Definition Epidemiology Pathophysiology Clinical Presentation Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Myasthenia gravis can occur at any age. Women are affected more in younger age and males in late fifties. No specific cause is found in 90 percent of the cases.
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EPIDEMIOLOGY Definition Epidemiology Pathophysiology Clinical Features
Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References This chart shows the age wise distribution of myasthenia gravis in both males and females.
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PATHOPHYSIOLOGY Autoimmune response mediated by
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Autoimmune response mediated by specific anti-AChR antibodies. Sero-negative patients may have antibodies directed against other components of the NMJ e.g. MuSK. Pathogenic antibodies are IgG and are T cell dependent, Sensitized T-helper cells. Autoimmune response, the thymus appears to play a role. Myasthenia gravis is an autoimmune response mediated by specific anti acetylcholine receptors antibodies. Sero-negative patients may have antibodies directed against other components of the NMJ e.g. muscle specific kinase (Musk). Pathogenic antibodies are Immunoglobulins G and are T cell dependent, Sensitized T-helper cells. Thymus also appears to play a role in the pathophysiology
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PATHOPHYSIOLOGY Three pathogenic mechanisms:
AChR antibodies bind to acetylcholine binding site and block the receptor AChR antibodies cross-link receptors leading to their internalization and breakdown AChR antibodies bind complement leading to destruction of the muscle endplate (most common mechanism) Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation There are three pathogenic mechanisms associated with this disease. Acetylcholine receptor antibodies bind to acetylcholine binding site and block the receptor Acetylcholine receptor antibodies cross-link receptors leading to their internalization and breakdown Acetylcholine receptor antibodies bind complement leading to destruction of the muscle endplate which is the most common mechanism
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PATHOPHYSIOLOGY Definition Epidemiology Pathophysiology
Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References The differences between myasthenic synapse and normal synapse can be well appreciated from this diagram.
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CLINICAL FEATURES Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Fluctuating weakness of voluntary muscles (fatigability). Worsen after exertion and improve with rest. No abnormality of cognition, sensory function, or autonomic function. Initial symptoms involve the ocular muscles in 60%. Clinical features include Fluctuating weakness of voluntary muscles which worsens after exertion and improves with rest. No abnormality of cognition, sensory function, or autonomic function is seen. Ocular muscles are the first to be involved in most of the cases.
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CLINICAL FEATURES Ocular manifestations:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Ocular manifestations: Ptosis: uni- or bilateral is very common may occur while patients reading, or during long period of driving. Diplopia: Extraocular muscle weakness may also be asymmetrically. Prominent ocular manifestations of this disease are ptosis and diplopia
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CLINICAL FEATURES Definition Epidemiology Pathophysiology
Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Ptosis can be appreciated from the pictures displayed. Pictures taken with consent
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CLINICAL FEATURES Bulbar involvements:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Bulbar involvements: Difficulty in chewing, speaking, or swallowing: initial symptoms in 17% of patients Fatigability and weakness during mastication, Unable to keep jaw closed after chewing. Slurred and nasal speech. Initial symptoms in 17 percent of the cases are difficulty in chewing, speaking, or swallowing. Fatigability and weakness during mastication may also be the complaints along with Slurred and nasal speech.
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CLINICAL FEATURES Weakness: Limb muscles:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Weakness: Limb muscles: Initial symptoms in fewer than 10%. Upper extremities weakness is more common than lower extremities, asymmetrical. Involve proximal muscles than distal. Involve neck muscles: neck flexion weaker than neck extension. Upper extremities weakness is more common than lower extremities, which is asymmetrical and involves proximal muscles more than distal. Neck flexion is weaker than neck extension.
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CLINICAL FEATURES Respiratory insufficiency:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Respiratory insufficiency: The initial presentation is rare, Occurring precipitously in a patient with recent worsening of symptoms. Respiratory insufficiency, though rare, may still be found in some of the cases.
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PRECIPITATING EVENTS Systemic illness.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Systemic illness. Viral upper respiratory tract infection. Receiving general anesthesia. Receiving neuromuscular blocking agents. Pregnancy, menstrual cycle. Extreme heat. Stress. Systemic illness, viral upper respiratory tract infection and general anesthesia are the precipitating factors along with others as displayed.
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PRECIPITATING EVENTS Medications Inducing MG:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Medications Inducing MG: Antibiotics (Aminoglycosides, ciprofloxacin, ampicillin, erythromycin). B-blocker (propranolol). Lithium. Magnesium. Procainamide Some medicines may also induce myasthenia gravis as shown
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CLASSIFICATION Osserman Classification:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Osserman Classification: Grade I: involve focal disease (restricted to ocular muscle). Grade II: generalized disease: IIa: mild . IIb: moderate. Grade III: severe generalized disease . Grade IV: a crisis with life threatening impairment of respiration. Different classifications can be used to classify patients into different clinical classes. Osserman classification is displayed.
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CLASSIFICATION MG Foundation of America Clinical Classification:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References MG Foundation of America Clinical Classification: Grade I: Any ocular muscle weakness. Grade II: Mild weakness affecting other than ocular muscles. IIa: limb and/or axial weakness; less oropharyngeaL involvement IIb: oropharyngeal and/or respiratory weakness. Clinical classification by MG foundation of America is mostly followed which includes grade 1 to 5. Grade 1 is any ocular muscle weakness. Grade 2 is mild weakness affecting muscles other than the ocular muscles.
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CLASSIFICATION Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Grade III: Moderate weakness affecting other than ocular muscles ( a,b). Grade IV: Severe weakness affecting other than ocular muscles ( a,b). Grade V: Defined by tracheal intubation. Grade 3 and 4 involve moderate and severe weakness of the muscles other than the ocular muscles respectively. Grade 5 is defined by tracheal intubation
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DIAGNOSIS Clinical manifestations: chronic intermittent muscle weakness; fatigability. Provocative tests: 1-Physiologic: Look up for several minutes. Counting aloud to 100. Repetitively testing the proximal muscles. Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Diagnosis is made on the basis of clinical manifestations along with provocative, electrophysiological and immunological tests. Provocative tests include physiologic, tensilon and neostigmine test.
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DIAGNOSIS Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Three different serial pictures demonstrate fatigue of eyelid muscles as patient keeps looking up. 1 In physiologic test, the patient is asked to look up for several minutes and Count aloud to 100. Fatigue of eyelid muscles can be appreciated easily as in pictures. 2 3
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DIAGNOSIS 2-Tensilon test: Cardiac monitoring.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References 2-Tensilon test: Using edrophonium chloride: short acting Acetylcholinesterase inhibitor, 10 mg used. A small test dose (2 mg) IV; after 1 min if no improvement and side effect, the remainder given slowly. The effect of edrophonium starts in 30 sec and lasts fewer than 10 min. Tesniolon test is done using 10 mg edrophonium chloride, which is short acting acetylcholine esterase inhibitor. A small test dose of 2 mg is given initially. If no improvement or side effects are seen after one minute, the remaining dose is given slowly. If patient shows any improvement in the interval between 30 sec and 10 minutes, myasthenia gravis is suspected. Cardiac monitoring. Atropine available: 0.6 mg IV.
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DIAGNOSIS 3-Neostigmine test: Longer acting. 1.5 mg IM or 0.5 mg IV.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References 3-Neostigmine test: Longer acting. 1.5 mg IM or 0.5 mg IV. Action begins in mins and lasts up to 3 hours. Neostigmine test may also be done.
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DIAGNOSIS Electrophysiological tests:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References 1-Repetitive Nerve Stimulation Test: 3 Hz is used for 60 sec. Greater than 15% decrement of the amplitude of compound muscle action potential is considered positive. The yield of the test increases if proximal nerves are stimulated. May be abnormal in ALS, peripheral neuropathy. Electrophysiological tests include repetitive nerve stimulation test and single fiber electromyography 2-Single Fiber Electromyography:
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DIAGNOSIS Immunological tests: 1-Antibody to acetylcholine receptor:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References 1-Antibody to acetylcholine receptor: Present in almost all patients with thymoma. Absent in ocular type. Absent in 20% of generalized MG. 2-Sero-negative MG: 70% of SNMG patients have antibody to the muscle-specific receptor Tyrosine Kinase (MuSK). Antibody to acetylcholine receptor and seronegative MG screening are the immunological tests available.
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DIAGNOSIS Ice test: Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Muscles in MG function better at lower temperature. Decreased Acetylcholinesterase activity Increased depolarizing effect of acetylcholine at motor endplates. Applying ice pack on the eyelid during closing for 2 mins. Positive: lid fissure increases by 2 mm or more from baseline. Muscles in MG function better at lower temperature.In ice test, applying ice pack on the eyelid for 2 mins improves the ocular muscle functions.
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DIAGNOSIS Before ice test After ice test Definition Epidemiology
Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Before ice test Difference of muscle tone before and after ice test is visible in the slide. After ice test
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DIAGNOSIS RADIOLOGIC INVESTIGATIONS: X-ray chest.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References RADIOLOGIC INVESTIGATIONS: X-ray chest. Contrast enhanced CT scan chest. X ray chest and contrast enhanced CT scan test can be done to rule out thymus involvement.
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DIFFERENTIALS Myasthenia Gravis Intra Cranial Lesion
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Myasthenia Gravis Intra Cranial Lesion Progressive External Ophthalmoplegia Hyperthyroidism Brainstem gliomas Lambert-Eaton Myasthenic Syndrome Intra Cranial Lesion, Progressive External Ophthalmoplegia, Hyperthyroidism, Brainstem gliomas and Lambert-Eaton Myasthenic Syndrome have to kept in mind when considering a case of myasthenia gravis.
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TREATMENT The goal is to achieve remission.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References The goal is to achieve remission. Symptoms free and taking no medication. By increased neuromuscular transmission. Reduce autoimmunity. Others: having a normal quality of life even if some signs remaining and cholinesterase inhibitors taking. The goal of treatment is mainly to achieve remission by increased neuromuscular transmission and reduced autoimmunity.
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TREATMENT THERAPEUTIC OVERVIEW:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References THERAPEUTIC OVERVIEW: Symptomatic treatments (anticholinesterase agents) Chronic immuno-modulating treatments (corticosteroids and other immunosuppressive drugs). Rapid immuno-modulating treatments (plasma exchange and intravenous immune globulin). Surgical treatment (thymectomy). Treatment involves symptomatic treatment, chronic immunomodulating treatment, rapid immunomodulating treatment and surgical options.
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TREATMENT Definition Epidemiology Pathophysiology Clinical Features
Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References The different treatment options, depending on ocular and general symptoms, may be well understood from the flow sheet.
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TREATMENT 1-Acetylcholinesterase inhibitors
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References 1-Acetylcholinesterase inhibitors Pyridostigmine bromide is used . Starting with 30 mg every 4 to 6 hours; titrated depending on clinical symptoms and patient tolerability. 60 mg Pyridostigmine = 15 mg Neostigmine. Pyridostigmine bromide in a dose of 30 mg may be used every 4 to 6 hours. 60 mg pyridostigmine has the same effect as 15 mg of neostigmine.
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TREATMENT SIDE EFFECTS: Cholinergic crisis
Abdominal cramps and diarrhoea. Increased bronchial secretions and bradycardia. Increased fasciculations and muscle cramps. Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Cholinergic crisis is the main side effect of using acetylcholine esterase inhibitors treatment.
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TREATMENT 2-Immunosuppressive therapy Steroids:
Start on low dose and gradually titrate dose up. Remain on dose for 2 months. Switch to alternate-day therapy. Once, the condition stable, taper downward by 5 mg every month. Azathioprine and cyclosporine are also used. Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Steroids may be used for immunosuppression. Azathioprine and cyclosporine may be used in advanced cases.
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TREATMENT Side effects: Weight gain. Easy bruising and skin fragility.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Side effects: Weight gain. Easy bruising and skin fragility. Cataract. Hypertension. Osteoporosis. Steroid treatment is associated with weight gain, easy bruising, skin fragility and others.
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TREATMENT 3-IV Ig therapy: Dose: 2 g/kg over 2-5 days.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References 3-IV Ig therapy: Dose: 2 g/kg over 2-5 days. Clinical improvement in 1-2 weeks and lasts weeks to months. IV immunoglobulins in a dose of 2g/kg over 2 to 5 days can improve the symptoms in one to two weeks.
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IV Ig: : Side effect profile:
TREATMENT Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References IV Ig: : Side effect profile: Allergic response: low grade fever, chills, myalgia. Diaphoresis, fluid overload, HT. Nausea, vomiting, rash, neutropenia. Headache, aseptic meningitis Hyperviscosity: stroke, MI, ATN (most serious with compromised renal glomerular filtration; DM). The side effect of this treatment are displayed
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TREATMENT 4-Plasmapheresis:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References 4-Plasmapheresis: Double filtration plasma exchange and immuno-adsorption plasmapheresis. To remove the circulating immune complexes and AchR-Ab. Plasmapharesis may also be considered as an option to remove the circulating immune complexes and AchR-Ab
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TREATMENT Complications:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Complications: Complications (catheters): pneumothorax , bleeding, sepsis. Hypotension. Hypercoagulation, hypoalbuminemia. Hypocalcemia, pulmonary embolism. Arrhythmias (frequent exchanges). Low platelets, anemia. Complications associated with plasmapharesis may include hypotension, hypercoagulation and arrhythmias mostly
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TREATMENT 5-Surgical intervention: Mechanisms: Thymectomy.
Performed in any antibody positive patient under 45 yrs with generalized MG.. Mechanisms: Eliminate a source of continued antigenic stimulation. Subside immune response. Correct a disturbance of immune regulation. Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Thymectomy is preferred in any antibody positive patient under 45 yrs with generalized MG..
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TREATMENT Myasthenic crisis: Management: Stop every medication.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Myasthenic crisis: Management: Stop every medication. Assisted ventilation if respiratory support required. Tensilon test to estimate ChE-Inhs requirement. If not improved by medications, IV Ig or plasmapheresis can be used. Myasthenic crisis is a complication which may be managed by stopping every medication and using tensilon test to estimate ChE inhibitors required. IV immunoglobulins or plasmapharesis may also be used if not improved by medications
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TREATMENT MG In Pregnancy:
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References MG In Pregnancy: First trimester and acute post partum period. Pyridostigmine: first line therapy. Second stage of labor affected. Appropriate steps taken in case of maternal fatigue. All infants of myasthenic mothers observed for first hours. Pyridostigmine is the the first line therapy in pregnant myasthenia gravis patients. All infants of myasthenic mothers observed for first hours
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REHABILITATION Strategies emphasize: Patient education.
Definition Epidemiology Pathophysiology Clinical Features Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Strategies emphasize: Patient education. S/S of underdose and overdose of medicines. Instruct on precipitating factors. Diet – semisolid food. Rest, Plan activities. Exercise is not useful. Rehabilitation includes patient education about signs and symptoms of over and under use of medicines. Exercise is not useful to improve the symptoms. Semisolid diet is advised along with rest.
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REFERENCES Definition Epidemiology Pathophysiology Clinical Features
Precipitating events Classification Diagnosis Differentials Treatment Rehabilitation References Téllez-Zenteno JF, Hernández-Ronquillo L, Salinas V, Estanol B, da Silva O (2004). "Myasthenia gravis and pregnancy: clinical implications and neonatal outcome".BMC Musculoskeletal Disorders 5: 42. doi: / PMC PMID Retrieved 10 July 2008 Jaretzki A, Barohn RJ, Ernstoff RM, et al. (2000)."Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America".Neurology 55 (1): 16–23. doi: /WNL PMID Seybold ME (1986). "The office Tensilon test for ocular myasthenia gravis". Arch Neurol 43 (8): 842–3.doi: /archneur PMID This is all from my side. I thank you all for patiently listening. McGrogan A, Sneddon S, de Vries CS (2010). "The incidence of myasthenia gravis: a systematic literature review". Neuroepidemiology 34 (3): 171–183.doi: / PMID Allan H. Ropper, Robert H. Brown Adams and Victor's Principles of Neurology McGraw-Hill Professional; 8 edition (29 March 2005
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