Overview of myasthenic crises Dr. Sonal Dodhiya
Physiology of neuromuscular junction • The nerve terminates at the ‘pre-synaptic membrane’,which is separated by a ‘junctional/synaptic cleft’ from the ‘post synaptic membrane’ of the muscle. • The pre-synaptic membrane has Ach filled vesicles. • The post synaptic membrane has Ach nicotinic receptors.
Physiology of muscle contraction Discharge of motor neuron. Release of Ach at motor end plate. Binding of Ach to nicotinic Ach receptors. Generation of EPP. Generation of action potential in muscle fiber. Contraction of the muscle.
Myasthenia Gravis Myas-Greek for muscle Asthenia-Greek for weak Gravis-latin for very severe Neuromuscular disease leading to fluctuating muscle weakness and fatiguability. Autoimmune disorder where in antibodies are directed against nicotinic Ach receptors. Patient becomes symptomatic when receptors have reduced to <30% of normal.
Pathophysiology of MG • Myasthenia gravis occurs when the immune system makes antibodies that damage or block many of the muscle's acetylcholine (ACh) receptors on the surface of muscle cells. • This prohibits ACh from binding to the damaged receptors and acting on the muscle, which reduces muscle contractions, leading to weakness and fatigue.
Classification after Ossreman & Genkins • Adult MG Group I: Ocular (20%) Group IIA: Mild generalized (30%) Group III: Acute fulminating (11%), rapid onset, early respiratory involvement, high mortality. Group IV: Late Severe (9%), > 2 years after onset. • Transient Neonatal MG: 1/6 born to MG mother. Last a few weeks. • Congenital Myasthenic Syndrome.
The Myasthenia Gravis Foundation of America Clinical Classification • Class I: Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere . • Class II: Eye muscle weakness of any severity, mild weakness of other muscles . • Class IIa: Predominantly limb or axial muscles • Class IIb: Predominantly bulbar and/or respiratory muscles • Class III: Eye muscle weakness of any severity Moderate weakness of other muscles • Class IIIa: Predominantly limb or axial muscles • Class IIIb: Predominantly bulbar and/or respiratory muscles
The Myasthenia Gravis Foundation of America Clinical Classification • Class IV: Eye muscle weakness of any severity, severe weakness of other muscles. • Class IVa: Predominantly limb or axial muscles • Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation) • Class V: Intubation to maintain airway
Myasthenic crisis • Definition: Life-threatening condition , defined as weakness from acquired myasthenia gravis that is severe enough to necessitate intubation or delayed extubation following surgery. • Severe bulbar weakness that produces dysphagia and aspiration often complicates the respiratory failure. • American classification stage V
Patient presentation • Slack facial muscles,expressionless face. • Unable to support his head. • Nasal voice quality • Limp body • Absent gag-risk of aspiration.
Respiratory distress • Pt. unable to generate adequate ventilation &clear bronchial secretions-UTMOST CONCERN • Inability to cough leads to accumulation-rales.ronchi&wheez may be auscultated • Patient may have evidence of pneumonia(fever,cough,dyspnea,consolidation)
Predisposing factors • Non compliance with the medications • Infections • Physiologic stress • Emotional stress • Drugs
Drugs predisposing to myasthenic crisis • Macrolides, fluoroquinolones, aminoglycosides, tetracycline, and chloroquine. • Beta-blockers, calcium channel blockers, quinidine, lidocaine, procainamide, and trimethaphan. • Miscellaneous - Diphenylhydantoin, lithium, chlorpromazine, muscle relaxants, levothyroxine, adrenocorticotropic hormone (ACTH), and, paradoxically, corticosteroids oral contraceptives.
Assessment of patient in crises • Confirmation of the diagnosis of myasthenia gravis • A search for potentially treatable triggers • Withdrawal of any offending drugs • Determination of whether the patient needs intubation or swallowing restrictions.
Differential diagnosis • Other NMJ disorders-cholinergic crisis,eaton-lambert syndrome,botulism,OP poisoning. • Myopathies secondary to electrolyte abnormalties or acid maltase deficiency • Neuropathies –Guillain-barre syndrome and motor neuron disease • Central lesions including cervical cord or brain stem compression by an expanding mass.
Diagnosis of myasthenic crisis ANTIBODY TITRE: • Anti-Ach receptor Ab • MuSK Ab(antibodies to muscle-specific receptor tyrosine kinase) • Antibodies to striated muscle(StrAb)
Diagnosis contd. • Tensilon test(edrophonium): give in incremental doses.start with 2mg,observe for 45 to 60 sec,followed by dose of 3 & 5mg obs for 1 to 2 mins following each dose patients are given Atropine sulphate 0.6mg im/iv to counter act the nicotinic side-effects of edroohonium postive means unequivocally improvement of weakness mild to moderate improvement has been seen in patients with-brain stem lession,occulomotor palsy due to cerebral artery aneurysm,diabetic abducens paresis & normal contral subjects.
Diagnosis contd. • Electro physiology:repetitive stimulation at 3 hertz • Single fiber EMG • HRCT Chest to rule out thymoma
Cholinergic crisis • Most confusing differential diagnosis • Due to excess cholinesterase inhibitors(pyridostigmine,neostigmine,physostigmine) • Resembles organophosphate poisoning • Excessive stimulation of Ach causes flaccid muscle paralysis - clinically indistinguishable from myasthenic crisis
Cholinergic crisis • Bronchospasm with wheezing,respiratory failure,diaphoresis,and cyanosis. • Miosis and SLUDGE syndrome(salivation,lacrimation,urinary incontinence,diarrhea,GI upset and hyper motility,emesis)may mark cholinergic crisis • Deep tendon reflexes are preserved.
Treatment of myasthenic crisis • Admit to intensive care unit • Measure FVC frequently,as often as every two hours if respiratory status is deteriorating • Electively intubate if: - FVC <15ml/kg body weight - declines in serial measurements of FVC approaches 15ml/kg - declines in serial measurements of NIF approaches 25cm of water - clinical signs of respiratory distress - difficulty handling oral secretions,swallowing,or speaking
Treatment contd. • Withdraw anticholinesterase medications to reduce airway secretions in patients who are intubated. • Begin rapid therapy with plasmapheresis or IVIG to treat myasthenic crises. • Begin immunomodulating therapy with high dose corticosteroids(eg,prednisolone 60 to 80 mg per day). • Consider azathioprine,mycophenolate mofetil,orcyclosporine if steroids are contraintraindicated or previously ineffective. • Initiate weaning from ventilation when respiratory muscle strength improving with plasmapharesis or IVIG,as quantified by a FVC>15ml/kg&NIF>30cm of water.
Contraindications of PE • Related to extracorporeal line and anticoagulation • - precarious hemodynamics (cardiogenic shocks) • - unstabilized angina pectoris • - pericardial effusion (heparin) • Related to immunosuppression • - non controlled infectious diseases (septicemia)
Immediate Side effects of PE • Related to extracorporeal line and anticoagulation • - vagus nerve syndrome, low or high blood pressure. • - venous puncture hazards, air embolism. • - excessive bleeding, allergy or thrombocytopenia induced by heparin, citrate poisoning with hypocalcaemia manifestations (headache-cramps-swarming-tetanus rarely cardiac arrhythmia). • Related to replacement fluids : • - chills-fever • - nausea-vomiting, diarrhea (albumin)
Delayed complications of PE • Impaired hemostasis : • - hypocoaguable state 8-12 hours after session • - hypercoaguable state 24-72 hours by rebound effect (antithrombin 3 synthesis delayed) • -> THROMBOSIS RISK increased especially when other promoting conditions (inflammation, confinement to bed) • Preventive heparin treatment with normal coagulation tests objective is the rule in these conditions. • Immunosuppression : • Particular sensitivity to bacterial infections (humoral immunity deficiency) • Transfusion related infection : • Has not been reported since the exclusive use of viro-inactivated, heat treated (Albumin) or artificial substitutes.
Undesirable effects from IVIG occur in less than 5% of patients. The most common adverse effects occur soon after infusions and can include headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension. If this happens during an infusion, the infusion should be slowed or stopped. If symptoms are anticipated, a patient can be premedicated with antihistamines and intravenous hydrocortisone. • IVIG can induce reactions in patients with IgA deficiency. This occurs in 1 in 500-1000 patients. Serious anaphylactoid reactions occur soon after the administration of IVIG. Anaphylaxis associated with sensitization to IgA in patients with IgA deficiency can be prevented by using IgA-depleted immune globulin. The presence of IgG anti-IgA antibodies is not always associated with severe adverse reactions to IVIG.4 • An uncommon but potentially irreversible adverse event is acute renal failure. From June 1985 to November 1998, the US Food and Drug Administration received 120 reports worldwide, 88 in the United States, of renal injury. Acute renal failure with IVIG therapy occurs with the sucrose-stabilized formulation, but not with the D-sorbitol–stabilized formulation.
IVIG is associated with rare cases of thrombosis. It has caused disseminated intravascular coagulation, transient serum sickness, and transient neutropenia. • risk One study reported 7 patients who had thromboembolic events while being treated with IVIG.22 Four patients had strokes or transient ischemic attacks, 1 had an inferior wall myocardial infarction, 1 developed deep venous thrombosis, and 1 had a retinal artery infarct. The age range of the patients was 57-81 years, and most had underlying risk factors such as hypertension, hypercholesterolemia, atrial fibrillation, history of vascular disease and stroke, and deep venous thrombosis. Three patients received multiple IVIG infusions before developing the thromboembolic complications. Therefore, clinicians should be vigilant about the possibility of thromboembolic complications with each IVIG infusion and should be especially judicious with the use of IVIG in patients with underlying factors.
Life-threatening human parvovirus B19 infection and hepatitis C have been transmitted by IVIG. • Severe cutaneous vasculitis has been reported following an intravenous infusion of gammaglobulin in a patient with type II mixed cryoglobulinemia. • IVIG can precipitate acute myocardial infarction. • Aseptic meningitis is a rare but well-recognized complication of IVIG therapy. It manifests as fever, neck stiffness, headache, confusion, nausea, and vomiting. • IVIG therapy can result in postinfusion hyperproteinemia, increased serum viscosity, and pseudohyponatremia. • IVIG should not be given to patients with sensitivity to thimerosal. • IVIG has caused eczematous dermatitis and alopecia. • Complement consumption associated with an eczematous cutaneous reaction has been noted during infusions of high doses of IVIG. • Orbach et al noted encouraging reports on the efficacy of IVIG in different types of glomerulonephritis (mainly lupus nephritis) resistant to conventional therapy, but the exact success rate and clinical indications remain undetermined. However, the issue of IVIG treatment and renal function is a 2-edged sword because nephrotoxicity can be a serious rare complication of IVIG therapy. Products containing sucrose as a stabilizer are mainly associated with such injury through the mechanism of osmotic nephrosis. Preexisting renal disease, volume depletion, and old age are risk factors for such toxicity