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Project: Ghana Emergency Medicine Collaborative Document Title: Myasthenia Gravis (Case of the Week) Author(s): Project: Ghana Emergency Medicine Collaborative Document Title: Myasthenia Gravis (Case of the Week) Author(s): Chris Oppong, BSc, MBCh. B License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution Share Alike-3. 0 License: http: //creativecommons. org/licenses/by-sa/3. 0/ We have reviewed this material in accordance with U. S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. These lectures have been modified in the process of making a publicly shareable version. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact open. [email protected] edu with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http: //open. umich. edu/privacy-and-terms-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers. 1

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CASE OF THE WEEK BY CHRIS K. OPPONG, BSc HUMAN BIOLOGY, MBCh. B EMERGENCY CASE OF THE WEEK BY CHRIS K. OPPONG, BSc HUMAN BIOLOGY, MBCh. B EMERGENCY MEDICINE RESIDENT-KATH 3

CASE OF THE WEEK l l A 17 year old female presented to KATH CASE OF THE WEEK l l A 17 year old female presented to KATH ED with a 3 day history of difficulty in swallowing , drooling , dysphasia and shortness of breath. Differential diagnosis? ? 4

l l l Pm. Hx: mother claims she has been treated for chronic tonsillitis l l l Pm. Hx: mother claims she has been treated for chronic tonsillitis recently and has been having non-specific recurrent illnesses which has been managed on OPD basis Drug hx: iv ceftriazone 2 g, iv amoksiklav 1. 2 g Social hx: SHS 3 , boarding house 5

O/E l l l Lethargic Weak respiratory effort Drooling Afebrile Vital signs: Bp-130/95, pulse-105 O/E l l l Lethargic Weak respiratory effort Drooling Afebrile Vital signs: Bp-130/95, pulse-105 bpm. RGV, RR-30 cpm, temp. -36. 8 o. C, Spo 2 -62% room air. GCS m-6, v-5, e-3. any concerns? ? 6

Admission Day 1 UPPER AIRWAY OBSTRUCTION ? cause ABC’s l Normal throat examination : Admission Day 1 UPPER AIRWAY OBSTRUCTION ? cause ABC’s l Normal throat examination : tonsils , soft palate l Consult to ENT l CBC, ABG’s, LFT , RFT, pregnancy test l Chest x-ray, lateral neck x-ray, ECG 7

Lab results l l Wbc-15, Hb-10. 1, ESR-18 ABG- p. H-7. 1, p. Co Lab results l l Wbc-15, Hb-10. 1, ESR-18 ABG- p. H-7. 1, p. Co 2 -42. 9, HCO 3 - 15. 8, p. O 229, Na-149. 4, Cl-111. 4 AST 275, ALT-294 UREA-6. 02, CRT-67, BUN /CRT-42 8

DAY 2 l l ENT consult : acute laryngitis Patient transferred to ENT ward DAY 2 l l ENT consult : acute laryngitis Patient transferred to ENT ward 9

DAY 3 l l Improvement in patients condition on the ward. Feeding again Mother DAY 3 l l Improvement in patients condition on the ward. Feeding again Mother expressed concern to doctors that her condition keeps fluctuating, worse in the evening? ? ? hysteria Ward cover doctor called to see patient who had become restless. 10

Day 4 l l l Better in the morning c/o diffiulty in swallowing Ward Day 4 l l l Better in the morning c/o diffiulty in swallowing Ward cover doctor called in the evening to see patient who had become restless again 11

Day 5 l l l 15: 35 GMT , doctor called to see patient Day 5 l l l 15: 35 GMT , doctor called to see patient who had become unresponsive with a GCS of 8/15 Physician consult; epiglotitis with sepsis+ adrenal insufficiency, requested head CTscan 21: 30 GMT, patient rushed to RED by ENT ward nurses with no cardio respiratory activity and brownish secretions from mouth and nostrils 12

l l CPR Patient revived after 3 cycles and intubated ICU ventilators were malfunctioning l l CPR Patient revived after 3 cycles and intubated ICU ventilators were malfunctioning so patient was kept at RED on the transport ventilator CXR- aspiration 13

Day 6 l l Patient transferred to ICU Physician consult; atypical pneumonia(mycoplasma pneumonia) Rapid Day 6 l l Patient transferred to ICU Physician consult; atypical pneumonia(mycoplasma pneumonia) Rapid HIV test ? positive ELISA-negative 14

Day 7 l l Massive subcutaneous emphysema ? ? barotrauma RT pneumothorax 15 Day 7 l l Massive subcutaneous emphysema ? ? barotrauma RT pneumothorax 15

Source Undetermined 16 Source Undetermined 16

Day 10 Source Undetermined 17 Day 10 Source Undetermined 17

l l Hypopyon Ophthalmology consult Ophthalmologist recognizes patient and discloses he had treated her l l Hypopyon Ophthalmology consult Ophthalmologist recognizes patient and discloses he had treated her for ocular myasthenia gravis MYASTHENIC CRISIS now the working diagnosis 18

Day 18 post admission Patient is still on a ventilator on CPAP l Being Day 18 post admission Patient is still on a ventilator on CPAP l Being treated with pyridostigmine, azathioprine and iv immunoglobulin l Significant improvement, , GCS m-5, e-2 v-Intubated l 19

Myasthenia Gravis 20 Myasthenia Gravis 20

MYASTHENIC CRISIS 21 MYASTHENIC CRISIS 21

Outline l l l l Background Anatomy Pathophysiology Epidemiology Clinical Presentation Work-up Treatment Rehabilitation Outline l l l l Background Anatomy Pathophysiology Epidemiology Clinical Presentation Work-up Treatment Rehabilitation Posey & Spiller, Wikimedia Commons 22

Background l l Acquired autoimmune disorder Clinically characterized by: l l l Weakness of Background l l Acquired autoimmune disorder Clinically characterized by: l l l Weakness of skeletal muscles Fatigability on exertion. First clinical description in 1672 by Thomas Willis 23

Anatomy l Neuromuscular Junction (NMJ) l Components: l l l Presynaptic membrane Postsynaptic membrane Anatomy l Neuromuscular Junction (NMJ) l Components: l l l Presynaptic membrane Postsynaptic membrane Synaptic cleft Presynaptic membrane contains vesicles with Acetylcholine (ACh) which are released into synaptic cleft in a calcium dependent manner ACh attaches to ACh receptors (ACh. R) on postsynaptic membrane 24

Nrets, Wikimedia Commons 25 Nrets, Wikimedia Commons 25

Anatomy l Neuromuscular Junction (NMJ) l The Acetylcholine receptor (ACh. R) is a sodium Anatomy l Neuromuscular Junction (NMJ) l The Acetylcholine receptor (ACh. R) is a sodium channel that opens when bound by ACh l l There is a partial depolarization of the postsynaptic membrane and this causes an excitatory postsynaptic potential (EPSP) If enough sodium channels open and a threshold potential is reached, a muscle action potential is generated in the postsynaptic membrane 26

Pathophysiology l l In MG, antibodies are directed toward the acetylcholine receptor at the Pathophysiology l l In MG, antibodies are directed toward the acetylcholine receptor at the neuromuscular junction of skeletal muscles Results in: l l l Decreased number of nicotinic acetylcholine receptors at the motor end-plate Reduced postsynaptic membrane folds Widened synaptic cleft 27

Pathophysiology l Anti-ACh. R antibody is found in 8090% of patients with MG l Pathophysiology l Anti-ACh. R antibody is found in 8090% of patients with MG l MG may be considered a B cellmediated disease l Antibodies 28

Pathophysiology l T-cell mediated immunity has some influence l Thymic hyperplasia and thymomas are Pathophysiology l T-cell mediated immunity has some influence l Thymic hyperplasia and thymomas are recognized in myasthenic patients* Source Undetermined 29

Epidemiology l l Frequency l Annual incidence in US- 2/1, 000 l Worldwide prevalence Epidemiology l l Frequency l Annual incidence in US- 2/1, 000 l Worldwide prevalence 1/10, 000 Mortality/morbidity l Recent decrease in mortality rate due to advances in treatment l l Risk factors l l l 3 -4% (as high as 30 -40%) Age > 40 Thymoma Sex l F-M (6: 4) l Mean age of onset (M-42, F-28) l Incidence peaks- M- 6 -7 th decade F- 3 rd decade 30

Clinical Presentation l Fluctuating weakness increased by exertion l l Extraocular muscle weakness l Clinical Presentation l Fluctuating weakness increased by exertion l l Extraocular muscle weakness l l Weakness increases during the day and improves with rest Ptosis is present initially in 50% of patients and during the course of disease in 90% of patients Head extension and flexion weakness l Weakness may be worse in proximal muscles 31

Clinical presentation l Progression of disease l l Mild to more severe over weeks Clinical presentation l Progression of disease l l Mild to more severe over weeks to months l Usually spreads from ocular to facial to bulbar to truncal and limb muscles l Often, symptoms may remain limited to EOM and eyelid muscles for years l The disease remains ocular in 16% of patients Remissions l l Spontaneous remissions rare Most remissions with treatment occur within the first three years 32

Clinical presentation l Basic physical exam findings l l l Muscle strength testing Recognize Clinical presentation l Basic physical exam findings l l l Muscle strength testing Recognize patients who may develop respiratory failure (i. e. difficult breathing) Sensory examination and DTR’s are normal 33

Clinical presentation l Muscle strength l l l Facial muscle weakness Bulbar muscle weakness Clinical presentation l Muscle strength l l l Facial muscle weakness Bulbar muscle weakness Limb muscle weakness Respiratory weakness Ocular muscle weakness 34

Clinical presentation l Facial muscle weakness is almost always present l l Ptosis and Clinical presentation l Facial muscle weakness is almost always present l l Ptosis and bilateral facial muscle weakness Sclera below limbus may be exposed due to weak lower lids Cumulus, Wikimedia Commons 35

Clinical presentation l Bulbar muscle weakness l l Palatal muscles l “Nasal voice”, nasal Clinical presentation l Bulbar muscle weakness l l Palatal muscles l “Nasal voice”, nasal regurgitation l Chewing may become difficult l Severe jaw weakness may cause jaw to hang open l Swallowing may be difficult and aspiration may occur with fluids—coughing and choking while drinking Neck muscles l Neck flexors affected more than extensors 36

Clinical presentation l Limb muscle weakness l Upper limbs more common than lower limbs Clinical presentation l Limb muscle weakness l Upper limbs more common than lower limbs Upper Extremities Deltoids Wrist extensors Finger extensors Triceps > Biceps Lower Extremities Hip flexors (most common) Quadriceps Hamstrings Foot dorsiflexors Plantar flexors 37

Clinical presentation l Respiratory muscle weakness l l Weakness of the intercostal muscles and Clinical presentation l Respiratory muscle weakness l l Weakness of the intercostal muscles and the diaghram may result in CO 2 retention due to hypoventilation l May cause a neuromuscular emergency(myasthenic crisis) Weakness of pharyngeal muscles may collapse the upper airway l Monitor negative inspiratory force, vital capacity and tidal volume l Do NOT rely on pulse oximetry § Arterial blood oxygenation may be normal while CO 2 is retained 38

Clinical presentation l Occular muscle weakness l Asymmetric l l Usually affects more than Clinical presentation l Occular muscle weakness l Asymmetric l l 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 § l l Limited adduction of one eye with nystagmus of the abducting eye on attempted lateral gaze Ptosis caused by eyelid weakness Diplopia is very common 39

Clinical presentation l Co-existing autoimmune diseases l Hyperthyroidism l Occurs in 10 -15% MG Clinical presentation l Co-existing autoimmune diseases l Hyperthyroidism l Occurs in 10 -15% MG patients § § l l l Exopthalamos and tachycardia point to hyperthyroidism Weakness may not improve with treatment of MG alone in patients with co-existing hyperthyroidism Rheumatoid arthritis Scleroderma Lupus 40

Clinical presentation l Causes l l Idiopathic Penicillamine l l ACh. R antibodies are Clinical presentation l Causes l l Idiopathic Penicillamine l l ACh. R antibodies are found in 90% of patients developing MG secondary to penicillamine exposure Drugs 41

Clinical presentation l Causes l Drugs l Antibiotics (Aminoglycosides, ciprofloxacin, ampicillin, erythromycin) l B-blocker Clinical presentation l Causes l Drugs l Antibiotics (Aminoglycosides, ciprofloxacin, ampicillin, erythromycin) l B-blocker (propranolol) l Lithium l Magnesium l l l l Procainamide Verapamil Quinidine Chloroquine Prednisone Timolol Anticholinergics 42

Differentials l l l Amyotropic Lateral Sclerosis Basilar Artery Thrombosis Brainstem gliomas Cavernous sinus Differentials l l l Amyotropic Lateral Sclerosis Basilar Artery Thrombosis Brainstem gliomas Cavernous sinus syndromes Dermatomyositis Lambert-Eaton Myasthenic Syndrome l l l Multiple Sclerosis Sarcoidosis and Neuropathy Thyroid disease Botulism Oculopharyngeal muscular dystrophy Brainstem syndromes 43

Work-up l Lab studies l Anti-acetylcholine receptor antibody l l Positive in 74% 80% Work-up l Lab studies l Anti-acetylcholine receptor antibody l l Positive in 74% 80% in generalized myasthenia 50% of patients with pure ocular myasthenia Anti-striated muscle l Present in 84% of patients with thymoma who are younger than 40 years 44

Work-up l Lab studies l Interleukin-2 receptors l l Increased in generalized and bulbar Work-up l Lab studies l Interleukin-2 receptors l l Increased in generalized and bulbar forms of MG Increase seems to correlate to progression of disease 45

Work-up l Imaging studies l Chest x-ray l l l Plain anteroposterior and lateral Work-up l Imaging studies l Chest x-ray l l l 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 46

Work-up l Electrodiagnostic studies l Repetitive nerve stimulation Single fiber electromyography (SFEMG) l SFEMG Work-up l Electrodiagnostic studies l Repetitive nerve stimulation Single fiber electromyography (SFEMG) l SFEMG is more sensitive than RNS in MG l 47

Electrodiagnostic studies: Single-fiber electromyography l Generalized MG l l l Abnormal extensor digiti minimi Electrodiagnostic studies: Single-fiber electromyography l Generalized MG l l l Abnormal extensor digiti minimi found in 87% Examination of a second abnormal muscle will increase sensitivity to 99% Occular MG l l Frontalis muscle is abnormal in almost 100% More sensitive than EDC (60%) 48

Workup Pharmacological testing l Edrophonium (Tensilon test) l l Patients with MG have low Workup Pharmacological testing l Edrophonium (Tensilon test) l l Patients with MG have low numbers of ACh. R at the NMJ Ach released from the motor nerve terminal is metabolized by Acetylcholine esterase Edrophonium is a short acting Acetylcholine Esterase Inhibitor that improves muscle weakness Evaluate weakness (i. e. ptosis and opthalmoplegia) before and after administration 49

Workup Pharmacological testing Before After Source Undetermined 50 Workup Pharmacological testing Before After Source Undetermined 50

Workup Pharmacological testing l Edrophonium (Tensilon test) l Steps l l l 0. 1 Workup Pharmacological testing l Edrophonium (Tensilon test) l Steps l l l 0. 1 ml 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 51

Treatment l l ACh. E inhibitors Immunomodulating therapies Plasmapheresis Thymectomy l Important in treatment, Treatment l l ACh. E inhibitors Immunomodulating therapies Plasmapheresis Thymectomy l Important in treatment, especially if thymoma is present 52

Treatment l ACh. E inhibitor l Pyridostigmine bromide (Mestinon) l l l Starts working Treatment l ACh. E inhibitor l Pyridostigmine bromide (Mestinon) l l l Starts working in 30 -60 minutes and lasts 3 -6 hours Individualize dose Adult dose: § § l Caution § l 60 -960 mg/d PO 2 mg IV/IM q 2 -3 h Check for cholinergic crisis Others: Neostigmine Bromide 53

Treatment l Immunomodulating therapies l Prednisone l l l Most commonly used corticosteroid in Treatment l Immunomodulating therapies l Prednisone l l l 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 § § l l 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 54

Treatment Behavioral modifications l Diet l Patients may experience difficulty chewing and swallowing due Treatment Behavioral modifications l Diet l Patients may experience difficulty chewing and swallowing due to oropharyngeal weakness l If dysphagia develops, liquids should be thickened § l Thickened liquids decrease risk for aspiration Activity l l 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 55

Complications of MG l l l Respiratory failure Dysphagia Complications secondary to drug treatment Complications of MG l l l Respiratory failure Dysphagia Complications secondary to drug treatment l Long term steroid use l l l Osteoporosis, cataracts, hyperglycemia, HTN Gastritis, peptic ulcer disease Pneumocystis carinii 56

Prognosis l l l Untreated MG carries a mortality rate of 2531% Treated MG Prognosis l l l Untreated MG carries a mortality rate of 2531% Treated MG has a 4% mortalitiy rate 40% have ONLY occular symptoms l Only 16% of those with occular symptoms at onset remain exclusively occular at the end of 2 years 57

Rehabilitation l Strategies emphasize l l l Patient education Timing activity Providing adaptive equipment Rehabilitation l Strategies emphasize l l l Patient education Timing activity Providing adaptive equipment Providing assistive devices Exercise is not useful 58

References 1. Delisa, S. A. , Goans, B. , Rehabilitatoin Medicine Principles and Practice, References 1. Delisa, S. A. , Goans, B. , Rehabilitatoin Medicine Principles and Practice, 1998, Lippencott-Raven 2. Kimura, J. , Electrodiagnosis in Diseases of Nerve and Muscle, F. A. Davis Company, Philadelphia 3. Rosenberg, R. N. , Comprehensive Neurology, 1991, Raven Press Ltd 4. O’sullivan, Schmidtz, Physical Medicine and Rehabilitation Assessment and Treatment, pg. 151 -152 5. Grabois, Garrison, Hart, Lehmke, Neuromuscular Diseases, pgs. 1653 -1655 6. Shah, A. K. , www. emedicine. com, Myasthenia Gravis, 2002, Wayne State University 7. Tensilon test pictures http: //www. neuro. wustl. edu/neuromuscular/mtime/mgdx. html 59