神经内科学：Myasthenia Gravis lecture

Ten year-old girl started to feel some tingling in both feet 6 days ago, after 1-2 days started to have the same feeling in both hands and around the mouth, this tingling sensation never ascended or expanded but is still present. almost 3 days prior to admission started to feel weak, specially with tasks like standing up from a sitting position. No fever, cough, diarrhea, rash, known tick bites, sick contact, recent vaccination had mild abdominal pain in the past week. breathing and swallowing OK.CASE 1: 10 year-old girl with progressive muscle weakness Visible Bells phenomenon, orbicularis oculi strength 2 Motor: Biceps 4 b/l, tri 4 b/l, wrist flexion 4+ b/l, wrist extension 4 b/l, Hip flexion 2 b/l, knee extension 4+ to 5 b/l, knee flexion 4 b/l, ankle dorsiflexion 4 b/l, plantar flexion 5 Reflexes: Deep tendon reflexes biceps 2 on right, 0-1 on left, triceps 2, brachioradialis 0, knees 0, ankles 0 Sensory: grossly intact for soft touch, vibration Proprioception intact Wide stance on gaitNeurologic ExamuDiagnosis?uFurther test?uTreatments?CASE 2: 35 years old woman with progressive muscle weakness A 35 years old woman presented with progressive muscle weakness for the last 2 months. She has also noticed intermittent drooping of both of her eye lids, and progressive facial muscles weakness while speaking. She also complaints of weakness and tiredness while climbing the stairs of her office, she has difficulty while typing a lengthy official replies to their clients. continued Her general physical examination revealed a pulse of 82/min. BP 120/80 mmHg. Temp. 98 F and Resp. rate 16/min. with drooping of both eyelids. Her laboratory investigations revealed positive anti-choline receptor antibody. Rest of laboratory workup was unremarkable. uDiagnosis?uFurther test?uTreatments? Case 3u4 years old boy presents to clinic with chief complaint of toe walking and falling. The parents also state that he has trouble with stairs and running. Sat alone at 8 months, walking by 15 months.uOn physical exam he demonstrates walking up legs with hands in order to rise from seated position on floor. Calves are prominent.uDiagnosis?uFurther test?uTreatments?uCase1: AIDP (GBS)uCase2: Myasthenia GravisuCase 3: Duchenne Muscular DystrophyA doctor clinical thinkinguLocationuCharacteristicsuDiagnosis uDifferential diagnosisNerves systemuMotor system (Pyramidal system, Extra-pyramidal system)uSensation systemuVegetative systemMotor systemuCortexuCorticospinal tractsuAnterior horn cellsuPeripheral motor nervesuNeuromuscular junctionsuMusclesThe Neuromuscular Junction: a Specialized form of synaptic transmission: communication between neurons and musclesDisorders of Neuromuscular JunctionGuohua Zhao, M.D.Department of Neurology, 2nd Affiliated Hospital, Zhejiang University School of MDisorders of Neuromuscular JunctionuMyasthenia gravisuLambert-Eaton syndromeuNeonatal myasthenia gravisuCongenital myasthenia gravisuMyasthenic weakness due to antibiotics and other drugsMyasthenia GravisHistoryA detailed history often reveals evidence of early, unrecognized myasthenic features:uIntermittent diplopiauFrequent purchases of new glasses to correct blurry vision, difficulty focusing and/or early onset of convergence insufficiency of a need for prism correctionuUse of dark glasses to reduce diplopia or hide drooping eyelidsHistory continued.uAvoidance of certain foods that become difficult to chew and swallowuCessation of activities that require prolonged use of muscle activityMyasthenia GravisMyasthenia gravis is a disease of skeletal muscle acetylcholine receptors. The chemical transmitter, acetylcholine (ACh) is unable to bind to the receptors (AChR) on the postsynaptic membrane to transmit the nerve impulse to muscle fibers to produce a muscle contractionEpidemiology Frequency Worldwide prevalence 1/10,000 Mortality/morbidity Recent decrease in mortality rate due to advances in treatment 3-4% (as high as 30-40%) Risk factors Age 40 Thymoma Sex F-M (6:4) Mean age of onset (M-42, F-28) Incidence peaks- M- 6-7th decade F- 3rd decade Causes Idiopathic AchR antibody Drugs Antibiotics (Aminoglycosides, ampicillin, erythromycin) B-blocker (propranolol) Lithium Magnesium Procainamide Verapamil Quinidine Chloroquine Prednisone AnticholinergicsEtiology End plate from a normal control and a patient with MG. The terminal axon contains abundant presynaptic vesicles, but postsynaptic are wide and there are few second folds. ControlMGPathophysiology T-cell mediated immunity has some influence Thymic hyperplasia and thymomas are recognized in myasthenic patients*Myasthenia GravisClinical ClassificationI. Ocular aloneIIa.Mild generalizedIIb.Moderately severe generalized plus usually some bulbar involvementIII. Acute severe over weeks-months with severe bulbar involvementIV. Late severe with marked bulbar involvementClinical Presentation (1) Fluctuating weakness increased by exertion Weakness increases during the day and improves with rest Extraocular muscle weakness Ptosis is present initially in 50% of patients and during the course of disease in 90% of patients Head extension and flexion weakness Weakness may be worse in proximal musclesClinical presentation (2) Progression of disease Mild to more severe over weeks to months Usually spreads from ocular to facial to bulbar to truncal and limb muscles Remissions Spontaneous remissions rare Most remissions with treatment occur within the first three yearsClinical presentation (3) Basic physical exam findings Muscle strength testing Recognize patients who may develop respiratory failure (i.e. difficult breathing) Sensory examination and deep tendon reflexes are normalClinical presentation (4) Muscle strength Ocular muscle weakness Facial muscle weakness Bulbar muscle weakness Limb muscle weakness Respiratory weaknessClinical presentation (5) Facial muscle weakness is almost always present Ptosis and bilateral facial muscle weaknessCumulus, Wikimedia CommonsClinical presentation (6) 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 fluidscoughing and choking while drinking Neck muscles Neck flexors affected more than extensorsClinical presentation (7) Limb muscle weakness Upper limbs more common than lower limbsUpper ExtremitiesDeltoidsWrist extensorsFinger extensorsTriceps BicepsLower ExtremitiesHip flexors (most common)QuadricepsHamstringsFoot dorsiflexorsPlantar flexorsClinical presentation (8) Respiratory muscle weakness Weakness of the intercostal muscles and the diaghram may result in CO2 retention due to hypoventilation May cause a neuromuscular emergency(myasthenic crisis) Weakness of pharyngeal muscles may collapse the upper airway Do NOT rely on pulse oximetry Arterial blood oxygenation may be normal while CO2 is retainedClinical presentation (9) Co-existing autoimmune diseases Hyperthyroidism Occurs in 10-15% MG patients Rheumatoid arthritis Scleroderma LupusDifferentials Amyotropic Lateral Sclerosis Brainstem gliomas Cavernous sinus syndromes Dermatomyositis Lambert-Eaton Myasthenic Syndrome Multiple Sclerosis Sarcoidosis and Neuropathy Thyroid disease Oculopharyngeal muscular dystrophy Brainstem syndromesWork-up (1) Lab studies Anti-acetylcholine receptor antibody 80% in generalized myasthenia 50% of patients with pure ocular myasthenia Anti-striated muscle antibody Present in 84% of patients with thymoma who are striateyounger than 40 yearsAcetylcholine Receptor Antibodiesu The AChR Ab tit varies widely among patients with similar degrees of weakness.u The amount of Ab in the serum does not predict the severity of the disease in individual patientsu Worthwhile to repeat test when initial values normalThe Presence of AChR Antibody is not diagnostic for MG, also present in:uSystemic lupus erythematosusuInflammatory neuropathyuAmyotrophic lateral sclerosisuRheumatoid arthritis in patients taking D-penicillamineuIn cases of thymoma without MGWork-up (2) 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 routinelyWork-up (3) Electrodiagnostic studies Repetitive nerve stimulation (RNS) Single fiber electromyography (SFEMG) SFEMG is more sensitive than RNS in MGA typical decrementing response to repetitive nerve stimulation in myasthenia gravis. The amplitude of the initial response is normal, and the decrement is maximal in the fourth response. Thereafter, the responses increase somewhat, giving a U-shaped envelope to the train of responses.Repetitive nerve stimulationWorkup (4) Edrophonium (Tensilon test) Ach released from the motor nerve terminal is metabolized by Acetylcholine esterase Edrophonium is a short acting Acetylcholine Esterase Inhibitor that improves muscle weakness Before AfterTreatment AChE inhibitors Immunomodulating therapies Plasmapheresis Thymectomy Important in treatment, especially if thymoma is presentTreatment (1) AChE inhibitor Pyridostigmine bromide (Mestinon) Starts working in 30-60 minutes and lasts 3-6 hours Individualize dose Adult dose: 60-960mg/d PO 2mg IV/IM q2-3h Caution Check for cholinergic crisis Others: Neostigmine BromideTreatment (2) Immunomodulating therapies Prednisone Most commonly used corticosteroid in US 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 Patients taking concurrent diuretics should be monitored for hypokalemiaImmunoglobulin Safe Quick Expensive Short termTreatment (3)Treatment (4)Behavioral modifications Diet Patients may experience difficulty chewing and swallowing due to oropharyngeal weakness If dysphagia develops, liquids should be thickened 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 fatigabilityMyasthenic crisis Respiratory insuficiency paralysis of respiratory muscles Assisted ventilation required Affect 15-20% myasthenic patients Females : males = 2 : 1 Average age: 55 yearsClinical features Respiratory tract infection, pneumonia ( 38%) Respiratory failure 99% Oropharyngeal or ocular weakness 86% Arms and legs weakness 76%Complication of crisis Ateletatic pneumonia (40%) Hypotension Cardio-respiratory arrest Pneumothorax Treatment ICU is required for assisted ventilation Cardiopulmonary monitoring Plasmapheresis (5 sessions) or IvIg 0.4g/kg in five consecutive days Antithrombotic treatment Antibiotics Respiratory rehabilitationOutcome Duration of intubation : 13 days Duration of hospitalization : 35 days Tracheostomy 40% Mortality 4% Complications of MG Respiratory failure Dysphagia Complications secondary to drug treatment Long term steroid use Osteoporosis, cataracts, hyperglycemia Gastritis, peptic ulcer disease Pneumocystis cariniiFactors that Aggravate MG Emotional stress Systemic illness e.g. viral Thyroid disease, hyper or hypothyroidism Pregnancy Menstrual Cycle Increase in body temperature DrugsDisorders of Neuromuscular JunctionuMyasthenia gravisuLambert-Eaton syndromeuNeonatal myasthenia gravisuCongenital myasthenia gravisuMyasthenic weakness due to antibiotics and other drugsLambert-Eaton Myasthenic Syndrome (LEMS)u Disorder of the neuromuscular junction in which antibodies are made against presynaptic voltage-gated calcium channelsu Symptoms include proximal muscle weakness, fatigue and autonomic dysfunctionu Annual Incidence = 0.48 per million population u There is a high association with malignancyu Underlying cancer may be previously unrecognizedTreatment for LEMSMyastenia Gravis vs. LEMSBoth are acquired autoimmune disorders characterized by defective neuromuscular transmissionLEMSMGAntibodies against voltage-gated Ca channelsAntibodies about acetylcholine receptorsUsually starts at extremities and moves upUsually starts at eyes and moves down Autonomic dysfunction presentNo autonomic dysfunctionDiplopia and dysphagia uncommonDiplopia and dysphagia commonWeakness improves with activity Weakness worsens with activity Associated with SCLCAssociated with thymoma LEMS and Malignancy non-SCLC neuroendocrine carcinomas lymphosarcoma malignant thymoma Breast CA Stomach CA Colon and Rectal CA Prostate CA Bladder CA Kidney CA Gallbladder CA Basal cell carcinoma LeukemiaThe overwhelming majority of cancers associated with LEMS are SCLC. Other malignancies include Laboratory Workup Antibodies to voltage-gated calcium channels (VGCCs) have been reported in 75-100% of LEMS patients who have small cell lung cancer (SCLC) and in 50-90% of LEMS patients who do not have underlying cancer. Disorders of Neuromuscular JunctionuMyasthenia gravisuLambert-Eaton syndromeuNeonatal myasthenia gravisuCongenital myasthenia gravisuMyasthenic weakness due to antibiotics and other drugsMG in Pregnancy Many mothers get worse 1st trimester and better 2nd and 3rd trimester. Up to 10% of infants born to mothers with MG will have Transient Neonatal Myasthenia. Weak cry, poor muscle tone, difficulty breathing etcInterventions Depending on severity Supportive care Administration of plasma exchange and anticholinesterase drugs to the infant may be useful in hastening recovery from neonatal myasthenia.Disorders of Neuromuscular JunctionuMyasthenia gravisuLambert-Eaton syndromeuNeonatal myasthenia gravisuCongenital myasthenia gravisuMyasthenic weakness due to antibiotics and other drugsCongenital myasthenia gravis Inherited defects in components of the presynaptic, synaptic, or postsynaptic junctional apparatus. Clinically, these disorders are distinguished by neonatal onset,fluctuating and sometimes progressive weakness that may be quite severe, sometimes pronounced muscle hypotrophy, persistent ptosis, and seronegativity for anti-AChR and anti-MuSK antibodies. Moreover, heritability is suggested by familial occurrence of the disorders among siblings.Disorders of Neuromuscular JunctionuMyasthenia gravisuLambert-Eaton syndromeuNeonatal myasthenia gravisuCongenital myasthenia gravisuMyasthenic weakness due to antibiotics and other drugsMyasthenic weakness due to antibiotics and other drugs Many drugs may cause a myasthenic syndrome or a worsening of myasthenia gravis by their action on pre- or postsynaptic structures. Presence of hepatic or renal disease that allows excessive accumulation of the causative agent.Antibiotics Aminoglycoside (neomycin, kanamycin, colistin, streptomycin, polymyxin B, and certain tetracyclines)impair transmitter release by interfering with calcium-ion fluxes at nerve terminals. Quinolone antibiotics affect both pre- and postsynaptic activityAnticholinesterase agents Insecticides and nerve gasescause paralysis by binding to cholinesterase and blocking the hydrolysis of ACh.Naturally occurring environmental neurotoxins Known to act at the neuromuscular junction and to induce muscle paralysis of a pattern like that of myasthenia gravis. Venoms of certain snakes, spiders, and ticks are commonThanks!