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Myasthenia Gravis - Management
 

Myasthenia Gravis - Management

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  • Positive RNS test features Decrement in CMAP amplitude Size: More than 10% in reduction in CMAP amplitude Measure from 1st to 4th or 5th potential in train Smallest CMAP is often 2nd or 3rd potential in train Post-exercise exhaustion Exercising muscle briefly before testing exacerbates decremental response Occurs rapidly after initial stimulation Post-tetanic potentiation Reduction in decrement in minutes after exercise Occurs after post-exercise exhaustion

Myasthenia Gravis - Management Myasthenia Gravis - Management Presentation Transcript

  • Management of myasthenia gravis Dr s.samuthiravel Prof.Dr.A.GOWRI SHANKAR`S unit
  • Diagnostic work up
    • History
    • Physical findings
    • Laboratory tests
    • Electro physiological tests
    • Pharmacological test
    • Simple bedside test
  • history
    • Changeable diplopia, ptosis
    • patients may also complain of fatigue and fluctuating weakness.
    • The weakness worsens after exertion and typically improves with rest.
    • This pathologic fatigability is the hallmark of MG
  • Physical findings
    • Typical myasthenic facies
  • Physical findings
    • Examination of a patient with MG therefore is directed at muscle strength and demonstrating pathologic fatigability.
    • A few maneuvers that may be used are
    • Asking the patient look up for several seconds (examining for ptosis or extraocular weakness),
    • Counting aloud upto 100 (listening for nasal or slurred speech),
    • By repetitively testing the proximal muscles.(Holding outstretched arms in abduction)
    • Check for vital capacities to asses the respiratory involvement
    • Remainder of the neurologic examinations will be usually normal.
  • lab work-up
    • Anti-acetylcholine receptor antibodies
    • Demonstration of these anti body virtually confirm the diagnosis
    • Most sensitive and highly specific test
    • Positive in 80%-90% of generalized myasthenia and 50%-60% of patients with pure ocular myasthenia
    • the degree of “ positivity” does not correlate with the severity of disease but fall during treatment correlate with clinical improvement
    • Anti MuSK antibodies
    • Present in 40% of AChR-ab negative pts with generalized MG
    • Rarely present in AChR-ab positive pts or in ocular MG pts
    • mostly women, predominently bulbar, facial , neck and shoulder muscle weakness, often predominate with severe disease and respiratory crisis, without significant ocular involvement
    • Anti-striated muscle antibodies
    • found to be present in 30% of MG pts
    • Present in 84% of patients with thymoma who are younger than 40 years
  • Work-up
    • Electrodiagnostic studies
      • Repetitive nerve stimulation
      • Single fiber electromyography (SFEMG)
      • SFEMG is more sensitive than RNS in MG
  • Electrodiagnostic studies: Repetitive Nerve Stimulation
    • Most commonly used, simple and easy to perform
    • Low frequency RNS (1-5Hz)
      • Most common employed stimulation rate is 3Hz
      • Electric shocks are delivered at a rate of 2-3/sec to the appropriate nerve and action potentials are recorded from that muscle
      • In normal individual, the amplitude of the evoked muscle action potentials does not change at this rate of stimulation
  • Electrodiagnostic studies: Repetitive Nerve Stimulation
        • Patients w/ MG
          • AchR’s are reduced and Locally available Ach becomes depleted at all NMJs and less available for immediate release
          • so during RNS EPAP’s may not reach threshold and no action potential is generated
            • Results in a ( decremental response) decrease in the compound muscle action potential
            • Any decrement over 10% is considered abnormal
            • Proximal muscles are better tested than unaffected distal muscles
  • Repetitive nerve stimulation
    • The sensitivity of RNS is 75% in genaralized MG and 50% in ocular MG
    • Several factors can affect RNS results
      • Lower temperature increases the amplitude of the compound muscle action potential
        • Many patients report clinically significant improvement in cold temperatures
      • AChE inhibitors prior to testing may mask the abnormalities and should be avoided for at least 6-24hours prior to testing
  • Electrodiagnostic studies: Single-fiber electromyography
          • It is a selective EMG recording that allows measurement of neuromuscular transmission in individual end plate in situ
          • AP are recorded from two muscle fibres in the same motor unit
            • Time variability of the interpotential interval between two muscle fibers of the same motor unit is called jitter
      • Findings suggestive of NMJ transmission defect
          • Increased jitter and normal fiber density
          • Increased jitter with intermittent blocking
  • Electrodiagnostic studies: Single-fiber electromyography
      • Requires extensive training experience to perform
      • Generalized MG
        • Abnormal extensor digiti communis found in 90%
        • Examination of a second abnormal muscle will increase sensitivity to 99%
      • Occular MG
        • Frontalis muscle is abnormal in almost 100%
        • More sensitive than EDC
  • Workup Pharmacological testing
    • Edrophonium (Tensilon test )
      • Reserved for pt s with clinical feature suggestive of MG, but negative antibodies and electro physiological test
      • Edrophonium is a short acting Acetylcholine Esterase Inhibitor that improves muscle weakness
        • 0.1ml of a 10 mg/ml edrophonium solution is administered as a test
        • If no unwanted effects are noted (i.e. sinus bradychardia), the remainder of the drug is injected
        • Evaluate weakness (i.e. ptosis and opthalmoplegia) before and after administration
        • Rapid improvement of weakness over next 2 mts is positive
        • False positive test - occurs in ALS, poliomyelitis, and some peripheral neuropathies
        • False negative test -also possible where we should consider long acting oral neostigmine and that gives more time for evaluation
      • Require cardiac monitoring, ICU setup is needed
  • Workup Pharmacological testing Before After
  • Simple bedside test
    • Ice pack test –
    • A quick bedside technique for diagnosing MG is the ice test. patient with ptosis, a small cube of ice is placed over the eyelid for about 2 minutes .
    • Improvement of the ptosis after this procedure suggests a disorder of neuromuscular transmission
    • Ptosis due to other conditions will not improve
    • Local cooling improves safety factor of NMJ, possibly by slowing the kinetics of acetylcholinesterese
  • Search for associated condition
    • Certain studies should be performed to exclude other disorders that are in the differential diagnosis.
    • Imaging studies
      • Chest x-ray
        • Plain anteroposterior and lateral views may identify a thymoma as an anterior mediastinal mass
      • Chest CT scan is mandatory to identify thymoma
      • MRI of the brain and orbits may help to rule out other causes of cranial nerve deficits but should not be used routinely
    • Laboratory Studies
    • TFT, ANA, RF,CBC,RFT,LFT and voltage gated calcium channel anti bodies and NCS
    • Measurement of ventilatory function to asses the respiratory impairment in myasthenic pt
  • Treatment
    • Anti cholinesterase medications
    • Immunomodulating therapies
    • Surgical treatment –Thymectomy
    • Plasmapheresis and IVIg
  • AChE inhibitor
    • Inhibit the enzymatic elimination of acetylcholine, increasing its concentration at the post synoptic membrane
    • Gives partial improvement in most myasthenic pts although complete improvement in very few pts
      • Pyridostigmine most widely used
        • Adult dose: - starts with 60mg 4 times daily , increase up to 120 mg 4 times daily
          • Long acting drug can be used at bed time
          • Starts working in 15-30 minutes and lasts 3-6 hours but response varies with individual
        • Caution
          • Check for cholinergic crisis
        • Others: Neostigmine Bromide
        • dose 7.5-30 mg average of 15 mg 6 th hrly
        • 1.5mg im for 2hrly and 0.5mg iv
  • Immunomodulating therapies
      • Glucocorticoid therapy
      • Prednisone is the most commonly used corticosteroid
    • Should be given in a single dose to minimize the side effects
    • Initial dose is 15-25 mg/d, increase by 5mg at 2-3days interval until marked clinical improvement achieved or 50-60mg/day is reached
    • Maintain the same effective dose for 1-3 months, then modify to alternate day regimen over the additional 1-3 months
    • Taper the dose and asses the effective minimum dose
    • Close monitoring is necessary
    • Patients may have transient worsening of MG symptoms during the first 2 to 3 weeks of prednisone therapy.
    • Patients should be warned of these potential adverse effects at the initial stages of therapy and reassured them.
    • Significant improvement is often seen after a decreased antibody titer which is usually 1-4 months
    • Azathioprine
    • The most commonly used drug to treat patients with MG until now .
    • It allows tapering of steroid dosage and reduces some of the adverse effects of steroid therapy.
    • starting dose of azathioprine is 50 mg daily for the first week (test dose), and then the dose is titrated up to a maximum of 2- 3 mg/kg body weight daily in two or three divided doses.
    • The most common adverse effects are neutropenia and liver function abnormalities .
    • Cyclosporine and tacrolimus - Calcineurin inhibitors
    • These agents are usually prescribed for patients who have failed to respond to combination therapy with prednisone and azathioprine and those who cannot tolerate azathioprine.
    • Beneficial effects are more rapid than azathioprine
    • dose –cyclosporine 3-6mg/d and tacrolimus 0.1mg/kg in two divided doses
    • The most important adverse effects are nephrotoxicity and hypertension .
    • Cyclophosphamide — In general, cyclophosphamide is used only in refractory cases
    • Cyclophosphamide therapy may be started at 25 mg daily and gradually increased up to a maximum of approximately 2- 5 mg/kg/day .
    • An increased incidence of hemorrhagic cystitis accompanies the use of this medication in some patients
    • Mycophenolate Mofetil
    • Inhibits the purine synthesis by the de novo pathway and so inhibits the proliferation of lymphocytes ,not other cells
    • Currently is being used as an adjunct to corticosteroids due to relative less side effecs
    • Recent trials in patients with MG have shown this medication to provide significant benefit.
    • The standard daily dosage is 1 g to 2 g in two divided doses.
    • Side effects -occasional diarrhea rarely leucopenia
    • very useful in long-term treatment
    • But high cost.
  • Prophylaxis of the complications of immunosuppression
    • Osteoporosis prevention -Measure bone density before treatment and yearly while on treatment. Start calcium and vitamin D supplements. Bisphosphonates may reduce bone loss associated with the chronic use of glucocorticoids.
    • Cardiovascular risk - Risk factor modification , advice to stop smoking, start an exercise program and manage hypertension.
    • Peptic ulcer prevention -Helicobacter screening and prophylactic treatment with proton pump inhibitors or H2 antagonists .
    • Infection prophylaxis - Use of inactivated vaccines such as influenza is recommended. Live vaccines are contraindicated. A chest X-ray should be performed prior to treatment. More specific testing for tuberculosis may be indicated depending on history and chest X-ray results.
    • Malignancy prevention -Skin cancer rates are increased in patients using azathioprine. A full yearly dermatological survey is recommended. Regular cervical smears are recommended.
    • Eye protection may also limit cataract development .
  • thymectomy
    • Surgical Intervention-introduced by blalock
    • Surgical removal of thymoma- If a patient has a thymoma, it should clearly be removed
    • Thymectomy as a treatment for MG
    • 85% of pts experiences improvement after thymectomy, of these 35% achieves drug free remission
    • Clinical improvement is typically delayed by 6 months to 1 year after surgery, but maximum effect occurs after 3 years and offers the long term benefit.
    • Should be carried out in all pts with generalized MG who are between puberty and 55 years of age.
    • Pts with anti MuSK anti body may not respond
    • Preferred electively and not during acute crisis
    • Transsternal thoracotomy is preferred and allows for maximal exposure to ensure that all thymic tissue is removed at the time of surgery.
  • Plasmapheresis
    • Plasma exchange, or plasmapheresis, is an effective means of therapy but is transient in its response (2-8 wks)
    • Useful when treating patients in myasthenic crises or those in preparation for surgery and at the start of immunosuppressive therapy.
    • The goal of this therapeutic intervention is to remove the circulating immune complexes and AchR-Ab.
    • Patients usually undergo a 2-week course of 5 to 6 exchanges (2-3.5L each).
    • Removed plasma is replaced with albumin and saline
    • Risks involved in this treatment include infection, DVT, fluid imbalance and hypercoagulation.
  • Intravenous Immunoglobulin Therapy
    • The administration of intravenous immunoglobulin (IVIG) serves as an alternate mode of therapy to plasmapheresis.
    • This procedure is especially helpful when vascular access is a problem.
    • Intravenous immunoglobulin is given as a dose of 2 g/kg in divided doses over 2 to 5 days.
    • Intravenous immunoglobulin therapy is a relatively safe treatment method and has few adverse effects, though headache, chills, and fever have been reported in some patients.
    • Other rare adverse events include aseptic meningitis and renal failure.
  • pyridostigmine Good response Age<55,AchR+ thymectomy Good response continue Prednisone+azathioprine Good response Gradualy prednisone Poor response Other immunosuppressive drugs no no yes Flow chart for management of MG
  • Treatment for myasthenic crisis
    • Timely intubation and ventilatory support
    • Withhold ACHE inhibitors
    • Plasmaparisis and IVIg
    • High dose steroids
  • Treatment Behavioral modifications
    • Diet
      • Patients may experience difficulty chewing and swallowing due to oropharyngeal weakness
        • If dysphagia develops, liquids should be thickened
          • Thickened liquids decrease risk for aspiration
    • Activity
      • Patients should be advised to be as active as possible but should rest frequently and avoid sustained activity
      • Educate patients about fluctuating nature of weakness and exercise induced fatigability
  • Complications of MG
    • Respiratory failure
    • Dysphagia
    • Complications secondary to drug treatment
      • Long term steroid use
        • Osteoporosis, cataracts, hyperglycemia, HTN
        • Gastritis, peptic ulcer disease
        • Pneumocystis carinii
  • Prognosis
    • Untreated MG carries a mortality rate of 25-31%
    • Treated MG has < 4% mortalitiy rate
    • 40% have ONLY ocular symptoms
      • Only 16% of those with ocular symptoms at onset remain exclusively ocular at the end of 2 years
      • Currently mortality rate due to MG is zero and most pts leads normal lives
  • future perspectives
    • Targeting specific T cells and B cells , which are programmed to mediate anti-acetylcholine receptor activity is the focus of recent experimental work
    • Non selective removal of the T helper cells
    • Inducing tolerance to self antigens by ingesting them -oral ingestion of anti-AChR-ab has been found to prevent the disease in rat models of MG
  • THANK YOU
  • Lab studies
  • Work-up
    • Lab studies
      • Interleukin-2 receptors
        • Increased in generalized and bulbar forms of MG
        • Increase seems to correlate to progression of disease
  • Workup Pharmacological testing
    • Edrophonium (Tensilon test)
      • Steps
        • 0.1ml of a 10 mg/ml edrophonium solution is administered as a test
        • If no unwanted effects are noted (i.e. sinus bradychardia), the remainder of the drug is injected
        • Consider that Edrophonium can improve weakness in diseases other than MG such as ALS, poliomyelitis, and some peripheral neuropathies
  • Work-up
    • Imaging studies
      • Chest x-ray
        • Plain anteroposterior and lateral views may identify a thymoma as an anterior mediastinal mass
      • Chest CT scan is mandatory to identify thymoma
      • MRI of the brain and orbits may help to rule out other causes of cranial nerve deficits but should not be used routinely
    • The drug is usually started at 5 mg daily and may be increased by 5 mg every 4 to 7 days until a clinical benefit is achieved or 1 mg per kilogram of body weight is reached.
    • Once a therapeutic dose is achieved, the patient should remain on this dose for about 2 months. Then a regimen to switch to alternate-day therapy should be instituted.
    • Once the patient’s condition is stabilized, the dosage may be slowly tapered downward. In general, the dose should be tapered downward by 5 mg every month.
  • Immunomodulating therapies
      • Glucocorticoid therapy
        • Prednisone is the most commonly used corticosteroid
        • Significant improvement is often seen after a decreased antibody titer which is usually 1-4 months
        • No single dose regimen is accepted
          • Some start low and go high
          • Others start high dose to achieve a quicker response
        • Clearance may be decreased by estrogens or digoxin
        • Patients taking concurrent diuretics should be monitored for hypokalemia
    • Figure 2. Repetitive nerve stimulation (3 Hz) of the ulnar nerve at the wrist, recording over the abductor digiti minimi muscle. Maximal decrement is noted at the right of the tracings. (A) Baseline reading; (B) Immediately after 10 seconds of exertion (postexercise facilitation); (C) 1 minute after 60 seconds of exertion (postexercise exhaustion); (D) 2 minutes after 60 seconds of exertion (postexercise exhaustion); (E) 3 minutes after 60 seconds of exertion (postexercise exhaustion); (F) Immediately after 10 seconds of exertion again (postexercise facilitation and repair of the decrement). (Reprinted from Electromyography and Neuromuscular Disorders: Clinical-Electrophysiologic Correlations . Preston DC, Shapiro BE. Neuromuscular junction disorders, p 507, Copyright 1997, with permission from Elsevier.)
  • Prognosis
    • Before 1958 1/3 of MG pts died, 1/3 failed to improve and 1/3 improved spontaneously