Myasthenia gravis.

myathenia gravis; diagnosis and treatment

1. MG Efgartigimod By Dr Mohammud Ibraheem

2. INTRODUCTION

3. MG is an autoimmune disease affecting the NMJ causing fatigable ocular, limb,and bulbar muscle weakness. The prevalence is 1 in 5000. MG affects patients of all ages with a peak in younger women and older men. Antibodies against the AChR or the MuSK are found in the majority of patients , but seronegative cases occur in 50 % of purely ocular cases and 20% of generalized cases. Severity varies from mild weakness limited to the ocular muscles (purely ocular MG) to generalized limb and bulbar weakness (generalized MG). In 15%; severe weakness of respiratory muscles causes respiratory failure ( ie , myasthenic crisis).

4. MG is treatable with immunomodulation with corticosteroid , long-term immunosuppressive drugs as azathioprine and mycophenolate mofetil , IV immunoglobulin ( IVIg ), and plasma exchange. Thymectomy improve clinical outcome. Pharmacologic remission is common, and the prognosis is good with a mortality of less than 5%. Treatment should be tailored to the individual patient, and special consideration should be given to women of childbearing age, pregnant women, children , and the elderly when choosing the most suitable immunosuppressant medication.

5. Congenital myasthenic syndromes are very rare genetic diseases and causing ocular, bulbar, and limb muscle weakness of varying severity and usually with an onset early in life. The diagnosis is based on clinical signs and symptoms, a lack of serum antibodies, an abnormal repetitive nerve stimulation test with compound muscle action potential ( CMAP) decrement , and no response to immunosuppressive therapy. Multiple genes encoding proteins expressed at the neuromuscular junction are associated with different subtypes of congenital myasthenic syndromes.

6. EPIDEMIOLOGY the prevalence of MG has been steadily increasing for the past 50 years because of better diagnosis. MG is uncommon disease with approximately 60,000 estimated cases in the US. Prevalence is 20 in 100,000 and varies in different countries. In patients younger than 40, women are more commonly affected with aratio of 7:3, whereas men are more commonly affected among patients older than 50,with aratio of 3:2. More men are now affected than are women, and the majority of MG patients in the US are over age 50. Pediatric MG is very rare.

7. ETIOLOGY MG is immune disease affecting epitopes in the postsynaptic membrane of the neuromuscular junction. The antibody- mediated, T cell dependent immunologic attack on the postsynaptic membrane results in damage of the post synaptic muscle membran causing simplification of the highly folded surface and a reduced number and density of AChRs. Antibodies against the AChR bind alpha subunit of the AChR. Thymic pathology includ: thymoma in 15% of MG thymichyperplasia with lymphofollicularhyperplasia in 65%. antibodies to MuSK are in 1/3 of patients with MG who are AChR seronegativ. MuSK plays a role in the clustering of AChR and in endplate formation and maintenance

8. CLINICAL PICTURE

9. The core clinical feature of MG is fluctuating and fatigable weakness of muscle groups that worsens with exercise and improves with rest. Ptosis , frequently asymmetric and varies during sustained activity. Chronic contraction of the frontalis muscle produces a worried or surprised look. Patients may tilt their head back. Eyelid closure is usually weak Diplopia are the most common presenting symptoms and appear in most cases early in the disease course. the medial rectus is frequently and more severely involved. Ptosis and/or diplopia are the initial symptoms of MG in 85%.

10. OMG is 10%–15% of MG. The diagnosis of OMG may be a challenge as RNS studies and anti-AChR antibodies are often negative, and SFEMG testing may be required . Bulbar weakness resulting in flaccid dysarthria, dysphagia, jaw closure weakness, and facial weakness (weak smile or a “ myasthenic snarl ”). Patients report nasal speech, liquids escaping through the nose; an inability to drink through a straw or to whistle; food getting stuck in the throat.

11. Neck flexion is usually more affected than neck extension, but dropped head syndrome can occur Weakness of limb muscles is usually proximal more than distal and symmetric, but fingers and wrist extension and foot dorsiflexion are also commonly affected. There is difficulty in:: Performing tasks that require the arms to be above the head Getting up from low seats or toilets, walking for prolonged distances, and climbing stairs Selective or predominant weakness of triceps muscles has been described especially in African American patients

12. Patients with anti- MuSK antibody can have atypical clinical presentations, including either: Neck extensor, shoulder, and respiratory muscle weakness Severe oculobulbar weakness, fixed facial muscle weakness , and weakness of the tongue and pharyngeal muscles that respond poorly to treatment . Many MuSK MG patients do not improve with cholinesterase inhibitors, some become worse, and many have profuse fasciculations with these medications

13. MG with anti-ryanodine receptor antibodies positive is associated with more severe, generalized, or predominantly oropharyngeal weakness, and frequent myasthenic crises Focal distal predominant weakness affecting finger flexors or extensors, sometimes asymmetric, and foot drop have also been described

14. Myasthenic crisis occurs in about 15% and is caused by severe weakness of the diaphragm and accessory breathing muscles , causing respiratory failure . It needs to be managed in ICU with ventilatory support and treatment with corticosteroids with IVIg or plasma exchange . Refractory MG is defined by unchanged or worsened symptoms after corticosteroid treatment and at least 2 other immunosuppressants used at adequate doses for an adequate duration or until intolerable side effects occurred.

15. Factors That Worsen MG Surgery Pregnancy and Postpartum Period Heat Stress Viral Infections Bone Marrow Transplantation Medications Antibiotics Aminoglycosides Fluoroquinolones Tetracyclines Sulfonamides Penicillins Nitrofurantoin Telithromycin Magnesium and magnesium-containing medications ( eg , laxatives, antacids) Botulinum toxin Interferon alfa D- Penicillamine Cardiovascular medications Quinidine , quinine Beta-blockers Calcium channel blockers Anesthetics ( eg , methoxyflurane ) Neuromuscular blockers ( eg , succinylcholine) Checkpoint inhibitors ( eg , pembrolizumab )

16. DIAGNOSTIC TESTS

17. Serologic testing: Positive AChR -binding antibodies are very specific for autoimmune MG and are found in 80 % generalized MG, 50% of ocular MG, and in 50% of children with MG. False-positive results are extremely rare and have been found in some patients such as GBS and in patients with thymoma without signs of MG.

18. Istriational antibodies are in 30% of MG and in 80% of patients with thymoma without MG. they are more commonly found in older patients. MuSK antibodies are tested if AChR antibodies are negative ; MuSK antibodies are found in 1\3 of seronegative patients with generalized MG, usually female patients (85 %). In 20 % of patients who are double seronegative (negative AChR and MuSK antibodies), autoantibodies against the low-density lipoprotein receptor related protein 4 (LRP4) is identified.

19. Electrodiagnostic testing 2-Hz to 5-Hz repetitive nerve stimulation studies are more sensitive in generalized than ocular MG. A CMAP decrement greater than 10% is indicative of a neuromuscular transmission defect . Submaximal stimulation, and limb temperature less than 35°C (95°F) during repetitive nerve stimulation testing can affect the validity of the results .

20. Single-fiber EMG , when performed in a weak muscle, is the most sensitive diagnostic test to confirm a neuromuscular transmission disorder (positive in 97% of affected patients). Usually, the extensor digitorum communis muscle is studied first, and if it is normal, a facial muscle ( frontalis or orbicularis oculi) should be tested next. If single-fiber EMG is normal in clinically affected muscles, the diagnosis of MG is excluded .

21. Edrophonium test; IV edrophonium chloride is a acetylcholinesterase inhibitor with a 30sec onset and 5minute duration. Incremental doses starting at 2mg and up to a total 10mg are administered with intervals of 1-2 minutes to observe for improvement or muscarinic SE (sweating , lacrimation, salivation , nausea, vomiting, diarrhea, bradycardia and bronchospasm ) atropine should be available.

22. The ice pack test has a high specificity and sensitivity for distinguishing myasthenic ptosis from other causes of ptosis. An ice pack is applied to the eyelid for 5 minutes, an improvement of palpebral fissure of 2 mm is considered a positive test. Chest CT to rule out thymoma or thymoma recurrence. Thyroid function testing

23. DIFFERENTIAL DIAGNOSIS

24. MG needs to be differentiated from other neuromuscular junction disorders, such as: Lambert-Eaton myasthenic syndrome Congenitalmyasthenic syndromes Botulism Lyme disease Bulbar ALS Brainstem ischemia Acute inflammatory demyelinating polyradiculoneuropathy (AIDP ), such as Miller Fisher syndrome and pharyngeal-cervical-brachial variants.

25. Purely ocular MG needs to be differentiated from mitochondrial disorders , such as chronic progressive external ophthalmoplegia and oculopharyngeal muscular dystrophy . The ptosis in these disorders is usually symmetric, chronically progressive, and non-fatigable or fluctuating.

26. Ophthalmoplegia in chronic progressive external ophthalmoplegia and oculopharyngeal muscular dystrophy, rarely causes significant diplopia because of the slow progression and uniform involvement of intrinsic ocular muscles. Muscle biopsy and DNA testing confirm the diagnosis of chronic progressive external ophthalmoplegia or oculopharyngeal muscular dystrophy .

27. In cases with predominantly bulbar weakness and minimal ocular symptoms , bulbar ALS is the alternative diagnosis: UMN signs and atrophy and fasciculations in the tongue and other muscles distinguish ALS from MG. The dysarthria in MG is flaccid and nasal, while in bulbar ALS is frequently a spastic. One confusing feature is the presence of fasciculations and atrophy of the tongue in some MuSK -positive MG patients.

28. Patients with a primary symptom of generalized fatigue without weakness in specific muscle groups, especially if pain is also present, are usually not affected by MG. Electrodiagnostic evaluation that includes EMG, repetitive nerve stimulation, and single-fiber EMG of affected muscles is very helpful in differentiating the above disorders.

29. TREATMENT

30. The goal in the management of MG is to achieve remission (no signs or symptoms of myasthenic weakness) or minimal manifestations (no subjective symptoms and only mild weakness found on objective neurologic examination that does not interfere with normal function). Plasma exchange and IVIg are used in generalized MG as rapid-onset short-term immunotherapy,

31. Plasma exchange and IVIg are used in generalized MG, for severe acute exacerbations, and preoperatively to optimize the patient’s strength prior to surgery. In refractory patients and in patients who do not respond to or cannot tolerate oral immunosuppressants, IVIg and plasma exchange are used more chronically. Plasma exchange 5 to 6 exchanges of 2 to 3 liters on alternating days, is effective in improving strength in majority of patients with MG and is the treatment of choice in true myasthenic crisis because of its fast onset (usually after the 2nd or 3rd exchange). Plasma exchange is contraindicated in sepsis and hypotension . Complications are related to the central venous catheters and fluid shift or overloa

32. IVIg Dose of 1 g/kg to 2 g/kg divided over 2 to 5 days is used to treat moderate to severe exacerbations and for patients who do not respond to or cannot tolerate any immunosuppressant. Improvement occurs between a few days and 2weeks and usually lasts weeks to months. SE include idiosyncratic reactions (chills, fever, headaches) and aseptic meningitis. Premedication with acetaminophen, diphenhydramine, and hydrocortisone help in preventing or mitigating the side effects. Caution is taken in patients with cardiomyopathy or valve disease and renal impairment due to the risk of volume overload.

33. Pyridostigmine It is acetylcholinesterase inhibitor used for the symptomatic treatment of MG, alone in pure ocular and mild generalized cases or in combination with immunosuppressants in severe cases. The symptomatic effect starts in 30 to 60 minutes and lasts for 3 to 4 hours. The dose should be administered 30 minutes before meals.if dysphagia is the main symptom or every 4 hours while the patient is awake if diplopia is the main symptom. Common side effects include abdominal cramps, diarrhea, and excessive lacrimation

34. Corticosteroids They are the first choice for ocular and generalized MG if require more than pyridostigmine. The dose is 60 mg/d-80 mg/d until improvement occur, but because of the possible risk of short-term exacerbation especially in bulbar weakness, this option is reserved for the inpatient setting whereas in the outpatient setting taper up. In the outpatient, prednisone is started at 10 mg/d-20 mg/d and increased by 5 mg/d every week till improvement. Once improvement is reached, a slow taper should starte on an alternating day schedule and a long term steroid-sparing immunosuppressant added if symptoms recur.

35. Mycophenolate mofetil and azathioprine They are the commonest used immunosuppressants in management of MG. They are the first choice if corticosteroids are contraindicated. Mycophenolate mofetil is an inhibitor of monophosphate dehydrogenase that suppresses cell-mediated immune response and antibody formation. The doses in adults are 2 g/d-3 g/d divided in 2 doses. Side effects include abdominal pain, diarrhea, and nausea. Because of potential leukopenia and anemia, periodic monitoring of complete blood cell counts is performed. The therapeutic effect takes few weeks to 2 months.

36. Azathioprine is a 6-mercaptopurine that blocks nucleotide synthesis and T-lymphocyte proliferation . The dose is 2 mg/kg/d-3 mg/kg/d, and side effects include myelosuppression, toxic hepatitis, idiosyncratic allergic flu-like reaction, and pancreatitis. Monitoring of complete blood cell count and liver enzymes is required. The therapeutic effect takes 4 to 8 months.

37. Rituximab it is a synthetic CD20 antibody given IV. It induce significant improvement and even remission in some patients with severe and refractory generalized MG, especially in MuSK-positive patients. Side effects include hepatitis B virus reactivation, infusion reactions, skin and mouth ulcers, and progressive multifocal leukoencephalopathy. Indications of rituximab CD20 positive B-cell Non Hodgkin lymphoma Chronic lymphocytic leukemia Rheumatoid arthritis Wagener granulomatosis and microscopic polyangitis Pemphigus vulgaris Rasmussen encephalitis

38. Eculizumab It is a complement inhibitor recently approved by the FDA for the treatment of adult patients with AChR-antibody positive generalized MG. Its use is indicated for patients with severe or refractory disease who either have not responded to or are unable to tolerate other immunosuppressants. Because of the risk of meningococcal and other serious bacterial infections, vaccination recommendations should be followed prior to use. Indications of eculizumab paroxysmal noctornal hemoglobinuria hemolytic uremic syndrome MG NMOSD

39. Efgartigimod it is a first in class neonatal Fc receptor antagonist being developed for treatment of autoimmune diseases including MG. The neonatal Fc receptor plays a key role in prolonging the life-span of IgG as it protects them from lysosomal degradation by recycling them back into the circulation In December 2021, IV efgartigimod received the FDA approval for the treatment of generalized MG in adults who are anti AChR antibody positive. The dose is 10 mg/kg ( MAX 1200mg), is administered as a 1h IV infusion once weekly for 4 weeks as one treatment cycle; It is diluted with 0.9% NaCL injection to a total of 125 mL. Patient is monitored for signs and symptoms of hypersensitivity reactions. Subsequent cycles are administered based on clinical evaluation; not less than 50 days after previous cycle. It causes transient decrease in IgG levels so immunization with live or live-attenuated vaccines is not recommended during treatment

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