MYASTHENIA GRAVIS

 INTRODUCTION:

The first reported case of MG is likely to be that of the Native American Chief Opechancanough, who died in 1664. It was described by historical chroniclers from Virginia as “the excessive fatigue he encountered wrecked his constitution; his flesh became macerated; the sinews lost their tone and elasticity, and his eyelids were so heavy that he could not see unless they were lifted up by his attendants… he was unable to walk, but his spirit rising above the ruins of his body directed from the litter on which he was carried by his Indians”. In 1672, the English physician Willis first described a patient with “fatigable weakness” involving ocular and bulbar muscles described by his peers as “spurious palsy.” In 1877, Wilks (Guy’s Hospital, London) described the case of a young girl after pathological examination as “bulbar paralysis, fatal, no disease found". In 1879, Wilhelm Erb (Heidelberg, Germany) described three cases of myasthenia gravis in the first paper dealing entirely with this disease, whilst bringing attention to features of bilateral ptosis, diplopia, dysphagia, facial paresis, and weakness of neck muscles. In 1893, Samuel Goldflam (Warsaw, Poland) described three cases with a complete description of myasthenia and also analyzed the varying presentations, severity, and prognosis of his cases. Due to significant contributions of Wilhelm Erb and later of Samuel Goldflam, the disease was briefly known as “Erb’s disease” and later for a brief time, it was called “Erb-Goldflam syndrome”.

In 1895, Jolly, at the Berlin Society meeting, described two cases under the title of “myasthenia gravis pseudo-paralytica”. The first two words of this syndrome gradually got accepted as the formal name of this disorder. He also demonstrated a phenomenon, that later came to be known as “Mary Walker effect” after she herself observed and described the same finding in 1938. This was reported as “if you stimulate one group of muscles to exhaustion, weakness is apparent in muscles that are not stimulated; an evidence of a circulating factor causing neuromuscular weakness”

In 1934, Mary Walker realized that MG symptoms were similar to those of curare poisoning, which was treated with physostigmine, a cholinesterase inhibitor. She demonstrated that physostigmine promptly improved myasthenic symptoms. In 1937, Blalock reported improvement in myasthenic patients after thymectomy. Following these discoveries, cholinesterase inhibitor therapy and thymectomy became standard and accepted forms of treatment for MG.

In 1959-1960, Nastuk et al. and Simpson independently proposed that MG has autoimmune etiology. In 1973, Patrick and Lindstrom were able to induce experimental autoimmune MG (EAMG) in a rabbit model using muscle-like acetylcholine receptor (AChR) immunization. In the 1970s prednisone and azathioprine were introduced as treatment modalities for MG followed by plasma exchange that was introduced for acute treatment of severe MG, all supporting the autoimmune etiology.

DEFINITION:

Myasthenia Gravis is a relatively rare an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatigue. Muscle weakness is caused by circulating antibodies that block acetylcholine receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the neurotransmitter acetylcholine on nicotinic receptors at neuromuscular junctions.

ANATOMY:

Detailed view of a neuromuscular junction:

1. Presynaptic terminal
2. Sarcolemma
3. Synaptic vesicle
4. Nicotinic acetylcholine receptor
5. Mitochondrion

PATHOLOGY:

In Myasthenia gravis (MG) antibodies form against nicotinic acetylcholine (ACh) postsynaptic receptors at the neuromuscular junction (NMJ) of the skeletal muscles.The basic pathology is a reduction in the number of ACh receptors (AChRs) at the postsynaptic muscle membrane brought about by an acquired autoimmune reaction producing anti-AChR antibodies.

NMJ findings that influence susceptibility to muscle weakness and MG: EPP generated in normal NMJ is larger than the threshold needed to generate the postsynaptic action potential by a measure of multiple folds. This neuromuscular transmission “safety factor” is reduced in MG patients. Reduction in number or activity of the AChR molecules at the NMJ decreases the EPP, which may be adequate at rest; but when the quantal release of ACh is reduced after repetitive activity, the EPP may fall below the threshold needed to trigger the action potential. This translates as clinical muscle weakness, and when EPP, at rest is consistently below the action potential threshold, it leads to persistent weakness.

CLINICAL FEATURES:

• The usual initial complaint is a specific muscle weakness rather than generalised weakness - frequently ocular (eye) symptoms.
• Extraocular muscle weakness or ptosis is present initially in 50% of patients and occurs during the course of illness in 90% of patients. Patients also frequently report diploplia (double vision).
• The disease remains exclusively ocular in 10 - 40% of patients.
• Rarely, patients have generalised weakness without ocular muscle weakness.

• Bulbar muscle weakness is also common, along with weakness of head extension and flexion.
• Limb weakness may be more severe proximally than distally.
• Isolated limb muscle weakness is the presenting symptom in fewer than 10% of patients.
• Weakness is typically least severe in the morning and worsens as the day progresses.
• Weakness is increased by exertion and alleviated by rest.
• Weakness progresses from mild to more severe over weeks or months, with exacerbations and remissions.
• Weakness tends to spread from the ocular to facial to bulbar muscles and then to truncal and limb muscles.
• About 87% of patients have generalised disease within 13 months after onset.
• Less often, symptoms may remain limited to the extra-ocular and eyelid muscles for many years.

CLASSIFICATION:

Subtypes of MG are broadly classified as follows:

1. early-onset MG: age at onset <50 years. Thymic hyperplasia, usually females,
2. late-onset MG: age at onset >50 years. Thymic atrophy, mainly males,
3. thymoma-associated MG (10%–15%)
4. MG with anti-MUSK antibodies,
5. ocular MG (oMG): symptoms only affecting extraocular muscles,
6. MG with no detectable AChR and muscle-specific tyrosine kinase (MuSK) antibodies.

The most widely utilised classification of MG is the Myasthenia Gravis Foundation of America Clinical Classification

1. Class I: Any ocular muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere
2. Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity
3. Class IIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
4. Class IIb: Predominantly bulbar and/or respiratory muscles; may also have lesser or equal involvement of limb, axial muscles, or both
5. Class III: Moderate weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity
6. Class IIIa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
7. Class IIIb: Predominantly bulbar and/or respiratory muscles; may also have lesser or equal involvement of limb, axial muscles, or both
8. Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity
9. Class IVa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
10. Class IVb: Predominantly bulbar and/or respiratory muscles; may also have lesser or equal involvement of limb, axial muscles, or both (Can also include feeding tube without intubation)
11. Class V: Intubation needed to maintain airway,  with or without mechanical ventilation

DIAGNOSIS:

1. Tensilon (Edrophonium Chloride) Test: Edrophonium chloride is a short-acting acetylcholinesterase inhibitor that prolongs the duration of action of acetylcholine at the NMJ. Edrophonium is administered intravenously and the patient is observed for objective improvement in muscle strength particularly the eyelid ptosis and/or extraocular muscle movement. Only unequivocal improvement in the strength of a sentinel muscle should be accepted as a positive result. Patients must be connected to cardiac and blood pressure monitors prior to injection because of the possible risk of arrhythmia and hypotension. Atropine should be available at the bedside for use if an adverse event like severe bradycardia (heart rate below 37) develops. Side effects from Edrophonium include increased salivation and sweating, nausea, stomach cramping, and muscle fasciculation. Hypotension and bradycardia are infrequent and generally resolve with rest in the supine position. Tensilon test has a sensitivity of 71.5%–95% for the diagnosis of MG.
2. Ice Pack Test: The ice pack test is a nonpharmacological test which could be considered in patients with ptosis when the Edrophonium test is contraindicated. It is performed by placing an ice pack over the eye for 2–5 minutes and assessing for improvement in ptosis.
3. Electrophysiological Tests:The two principal electrophysiologic tests for the diagnosis of MG are repetitive nerve stimulation study and single fiber electromyography.

DIFFERENTIAL DIAGNOSIS:

1. Amyotrophic Lateral Sclerosis
2. Basilar Artery Thrombosis
3. Brainstem Gliomas
4. Cavernous Sinus Syndromes
5. Dermatomyositis/Polymyositis
6. Lambert-Eaton Myasthenic Syndrome
7. Multiple Sclerosis
8. Myocardial Infarction
9. Pulmonary Embolism
10. Sarcoidosis and Neuropathy
11. Thyroid Disease
12. Tolosa-Hunt Syndrome

MEDICAL MANAGEMENT:Management of MG should be individualized according to patient characteristics and the severity of the disease. There are two approaches for the management of MG based on the pathophysiology of the disease. The first is by increasing the amount of Acetylcholine that is available to bind with the postsynaptic receptor using an acetylcholinesterase inhibitor agent, and the second is by using immunosuppressive medications that decrease the binding of acetylcholine receptors by antibodies.

There are four basic therapies used to treat MG:

1. symptomatic treatment with acetylcholinesterase inhibitors,
2. rapid short-term immunomodulating treatment with plasmapheresis and intravenous immunoglobulin,
3. chronic long-term immunomodulating treatment with glucocorticoids and other immunosuppressive drugs,
4. surgical treatment

 

SURGICAL MANAGEMENT:

Surgical treatment is strongly recommended for patients with thymoma. The clinical efficacy of thymectomy in other situations has been questioned because the evidence supporting its use is not solid. Surgical treatment is strongly recommended for patients with thymoma. The benefit of thymectomy evolves over several years. Thymectomy is advised as soon as the patient’s degree of weakness is sufficiently controlled to permit surgery. Patients undergoing surgery are usually pretreated with low-dose glucocorticoids and I V Ig. Thymectomy may not be a viable therapeutic approach for anti-MuSK antibody-positive patients because their thymi lack the germinal centres and infiltrate of lymphocytes that characterize thymi in patients who have anti-AChR antibodies. This supports a different pathologic mechanism in anti-MuSK Ab-positive and anti-AChR Ab-positive MG. Most experts consider thymectomy to be a therapeutic option in anti-AChR Ab-positive gMG with disease onset before the age of 50 years.

PHYSIOTHERAPY MANAGEMENT:

Rehabilitation alone or in combination with other forms of treatment can relieve or reduce symptoms for some people with MG.

MG patients should find the optimal balance between physical activity and rest. It is not possible to cure the weakness by active physical training. However, most MG patients are more passive than they need to be. Physical activity and physical training of low to medium intensity is recommended.

One study showed a clear benefit from a strength training exercise program for a group of patients with mild to moderate MG, concluding "physical training can be carried out safely in mild MG and provides some improvement of muscle force".

Physical exercise is well tolerated in patients with well regulated Myasthenia Gravis. Aerobic exercise and mild strength training can be advised and should be supervised.

Balance strategy training maybe effective in improving balance and more research into this domain has to be done.

General advice for exercise programs for people with MG:

• Aim to strengthen large muscle groups, particularly proximal muscles of shoulders and hips
• Advise patient to do the exercises at their "best time of day" ie. when not feeling tired - for the majority of MG patients this will be morning
• If a patient is taking pyridostigmine, exercise at peak dose ie. 1.5 to 2 hours after taking a dose
• Moderate intensity of exercise only: the patient should not experience worsening of MG symptoms (eg. ptosis or diplopia) during exercise
• General aerobic exercise is also valuable, helping with respiratory function as well stamina

THOSE ABOVE ARE COLLECTED FROM SOME BOOKS AND WEBSITES..

THANK YOU,

 SRIKUMARAN PHYSIOTHERAPY CLINIC & FITNESS CENTER