​Kembara Xtra - Medicine - Myasthenia Gravis

​Kembara Xtra - Medicine - Myasthenia Gravis 
primary neuromuscular transmission disease that causes varying muscle weakness:  Ocular myasthenia gravis (MG) (15%): eyelid and extraocular muscle weakening  Generalized MG (85%): usually affects the respiratory, bulbar, and proximal limb muscles, as well as the eyes. In the first two years after presenting with ocular symptoms, 50% of patients develop generalized MG.
 Although the onset might be rapid and severe, it usually starts off mildly and intermittently over several years, with 85% of cases reaching their peak severity within 3 years.
 Affected systems include the nervous, hematologic, lymphatic, immune, and musculoskeletal ones.


Epidemiology 
occurs at any age, however the age of onset has a bimodal distribution:
20 to 40 years, with a plurality of women
 Males outnumber women 60 to 80 years old.
Incidence
annual incidence guessed 7 to 23/1,000,000
Prevalence
70 to 320/1 million in the United States; rising during the previous five decades Child Safety Considerations
a temporary neonatal type of MG that affects 10–20% of children delivered to moms with MG. It develops as a result of maternal antibodies crossing the placenta and interfering with the neuromuscular junction's ability to function; it goes away in a few weeks to a few months. Ten to fifteen percent of juvenile MG cases in North America are autoimmune.

Pathophysiology and Etiology 

 Decreased acetylcholine receptor (AChR) activity at the muscle end plates, which results in inadequate neuromuscular transmission autoimmune disease that is caused by antibodies
Almost of MG cases involve antibodies.
- A humoral, antibody-mediated, T-cell-dependent attack on the AChRs or receptor-associated proteins at the postsynaptic membrane of the neuromuscular junction is known as seropositive/antiacetylcholine receptor (anti-AChR) or anti-AChR.
Muscle-specific kinase (MuSKs): 5% of individuals with generalized MG; found in 85% of generalized MG and 50% of ocular MG; frequent thymic abnormalities.
generally women. is a severe type that involves the respiratory and bulbar muscles. Thymic anomalies are uncommon.
- With anti-LRP4, a chemical that interacts with MuSK to form a complex, the majority of seronegative individuals (12–50%) experience minor widespread weakness. - Seronegative MG (SNMG): 5%; possible anti-AChR cell-based assay detection. Additionally recorded shortly after viral infections (measles, Epstein-Barr virus [EBV], HIV, and human Tlymphotropic virus [HTLV]); thymic hyperplasia may be observed. Genetics
Congenital MG syndrome refers to a group of uncommon inherited diseases. This disease is autosomal recessive, not immune-mediated, and is caused by a mutation in a neuromuscular junctional component.
In 5% of cases, a familial tendency is evident.

Risk factors Familial MG
D-penicillamine (drug-induced MG) and several autoimmune conditions

Accompanying Conditions 

Thymic hyperplasia (60% to 70%)
Thymomas (10–15%)
 Thyroid autoimmune disease (3–8%)
DIAGNOSIS
Clinical categorization of the Myasthenia Gravis Foundation of America: Class I: Any ptosis, any eye muscle weakness, and no additional signs of muscular weakening elsewhere. Class II: Any degree of weakness in the eye muscles and minor weakening in other muscles: - Class IIa: mainly axial or limb muscles
Class III: eye muscle weakness of any severity; mild weakness of other muscles: Class IIb: mostly bulbar and/or respiratory muscles Class IIIa: mostly limb or axial muscles Class IIIb: primarily bulbar and/or respiratory muscles Class IV: significant weakening of other muscles in addition to any degree of impairment in the eye muscles - Class IVb: mostly bulbar and/or respiratory muscles (may also incorporate feeding tube without intubation) - Class IVa: primarily limb or axial muscles - Class V: intubation necessary to maintain airway

History 
Fatigability is MG's defining trait.
 Fluctuating weakness, often slight, that gets worse during the day and after using the affected muscles for an extended period of time; may get better with rest Early symptoms are brief, lasting only a few days or a few weeks.
As the condition worsens, asymptomatic intervals shrink and symptoms shift from mild to severe.
Ptosis and/or diplopia are ocular symptoms that are present in more than 50% of individuals. 90% of MG sufferers eventually experience ocular symptoms.
Ptosis may be unilateral, bilateral, or shift from one eye to the other. 15% of patients present with bulbar symptoms. 5% of patients only have proximal limb weakness.


Caution 

respiratory muscle weakness resulting in respiratory insufficiency and impending respiratory failure is known as a myasthenic crisis.

clinical assessment 

Ptosis may get worse if the opposite eyelid is propped up (the "curtain sign") or if you keep looking up.
 "Myasthenic sneer," in which the mouth's corners do not move but the midlip rises Muscle weakness is often symmetrical and proximal.
Testing for muscle fatigability involves using a single muscle repeatedly or for an extended period of time. It's also crucial to evaluate and monitor respiratory function.

Differential diagnosis includes: Thyroid ophthalmopathy; oculopharyngeal muscular dystrophy; myotonic dystrophy; Kearns-Sayre syndrome; chronic progressive external ophthalmoplegia; lesions of the brainstem and motor cranial nerves; botulism; motor neuron disease (such as ALS); Lambert-Eaton myasthenic syndrome; drug-induced myasthenia; congenital mya

Initial test results from the laboratory and imaging
 Anti-AChR antibody (seropositivity range: 74–85%): - 75–85% have generalized myasthenia
- 50% have ocular myasthenia
- Thymoma and MG: 98–10%
- There is little connection between antibody titer and illness severityFalse-positive findings include thymoma without MG, Lambert-Eaton myasthenic syndrome, small cell lung cancer, and rheumatoid arthritis treated with penicillamine. Anti-MuSK antibody is used when MG is suspected and a patient is seronegative for AChR antibodies.
- A direct relationship between disease severity and titer
When there is a suspicion of MG and the patient is seronegative for AChR antibodies, LRP4 and clustered anti-AChR are used.
Testing for autoimmune diseases and the thyroid Chest radiography or CT scans can detect a thymoma. Anti-striated muscle (anti-SM) antibodies are: - Present in 84% of patients with thymoma who are under 40 years old; - Can be present without thymoma in individuals over 40 years old.
 A brain and orbital MRI to rule out other potential reasons of a cranial nerve deficiency Other/Diagnostic Procedures
Tensilon test (edrophonium):
- Edrophonium is no longer available in the United States and many other countries, so it is rarely done. - A successful test demonstrates increased strength within 30 seconds of treatment.
80–90% sensitivity 
- Relative contraindications include cardiac illness and bronchial asthma, particularly in elderly patients.
- Atropine: 0.4 to 0.6 mg IV may occasionally be needed as an antidote; it must be on hand. Ice pack test: Apply an ice pack to a closed eyelid for 60 seconds, then remove it. Then, quickly examine the degree of ptosis. Ice will lessen the ptosis brought on by MG.
- In patients with significant ptosis, sensitivity is 80%
Testing electrophysiology:
- RNS: Repeated nerve stimulation
 Easily accessible and widely employed
 Generalized MG sensitivity 76%; ocular MG 50%
- SFEMG (single-fiber electromyogram):
 Measures the temporal variability of two muscle fibers that are part of the same motor unit (jitter) Sensitivity is 99%.
Technically challenging; restricted availability; usage only when suspected; and negative RNS

65% of patients with MG experience lymphofollicular hyperplasia of the thymic medulla, and 15% develop thymomas.
Immunofluorescence in seropositive patients shows immunoglobulin (Ig) G antibodies and complement on receptor membranes.

Treatment depends on age, gender, and the severity and course of the disease  There are three main strategies: supportive, immunosuppressive, and symptomatic. Most patients should get symptomatic care along with immunosuppressive and/or supportive care; very few should receive a single therapy modality.

First Line of Medicine

Pyridostigmine bromide (Mestinon), an anti-anticholinesterase medication, is the most often given symptomatic therapy. - 60 mg PO TID as a starting dosage with food
Maximum dose: 120 mg every three to four hours; long acting; inconsistent impact; frequent side effects; may require dose decrease or slower dose titration digestive issues, hypotension, syncope, and frequent urination Neostigmine methylsulfate (Prostigmin): - Titrate dosage to clinical requirement; starting dose of 0.5 mg SC or IM every three hours
Beneficial for individuals who are unable to take drugs orally; nevertheless, it may result in excessive salivary secretions, which could make swallowing issues worse.Anti-MuSK patients might not respond well to these drugs.
Next Line
Immunosuppressants: When immunosuppression is required, oral corticosteroids are the first medication of choice.
Prednisone: In up to 50% of people, it may temporarily worsen symptoms.
 If receiving other acute treatment while inpatient, begin with 60 mg/day PO.
Start at a lower dose (10 to 20 mg/day PO) if you're an outpatient, then increase it by 5 mg every 3 to 7 days to get to the lowest effective amount.
 Be wary of corticosteroid long-term adverse effects, which can include osteoporosis, weight gain, fluid retention, gastritis, ulcer development, hyperglycemia, and infection risk (4).
- Azathioprine, 100–200 mg orally daily Commonly used for long-term immunomodulation; comparable efficacy to IVIG and steroids
Prior to starting azathioprine, you can think about testing for thiopurine S-methyltransferase (TPMT) levels.
Benefit might not become obvious for up to 18 months after therapy begins.
When administered as a corticosteroid-sparing medication, prednisolone + azathioprine may be successful.
- 1 g PO or IV BID of mycophenolate
Use caution when administering cyclosporine owing to nephrotoxicity and potential medication interactions.
Treatments for acute immunomodulation
- Plasmapheresis, which involves the bulk removal of 2 to 3 L of plasma three times per week until the rate of improvement reaches a plateau.
 Reduces weakness in practically everyone and lasts for up to three months
Plasmapheresis and Ig show equivalent efficacy in treating moderate to severe MG. Ig: 2 g/kg IV over 2 to 5 days.
- Rapid onset of impact but brief duration of action - Used to treat refractory MG, prevent acute exacerbations brought on by corticosteroids, and increase strength before surgery in cases of rapid MG worsening.
Other immunosuppressant treatments, often employed in patients that are refractory: Rituximab with eculizumab:
Rituximab may be more effective for MG patients with seronegative MuSK-antibody positivity than traditional treatments.
- Cyclophosphamide - Tacrolimus
ALERT
Aminoglycosides, fluoroquinolones, -blockers, calcium channel blockers, neuromuscular blockers, statins, diuretics, oral contraceptives, gabapentin, phenytoin, lithium, and other medications might cause weakness, therefore use cautious when taking them.

Thymectomy is advised for patients with thymic abnormalities; it may also be advantageous for those without thymic abnormalities who are younger than 60 years old, particularly for those who have strong anti-AChR pediatric considerations
 Corticosteroids limited to severe disease Side effects of many medications must be carefully monitored in juvenile patients, especially because some may affect long-term fertility or are thought to be carcinogenic. Infants with severe weakness from transient neonatal myasthenia may be treated with oral pyridostigmine; general support is necessary until the condition clears.

Admission, pulmonary infection management, myasthenic/cholinergic crises, plasmapheresis, and intravenous immunoglobulin

Overall excellent but very varied prognosis
Seronegative patients are more likely to have exclusively ocular disease, while those with generalized SNMG have better outcomes after therapy. Myasthenic crisis is associated with significant morbidity and 4% mortality.

Complications 

respiratory arrest that occurs suddenly; persistent respiratory failure

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