Myasthenia gravisPart twoPratap Sagar Tiwari, Lecturer, Internal Medicine, NGMC, Nepal

Our Journey

PART ONE• Neuromuscular junction• Introduction of MG• Types• Epidemiology• Clinical featuresPART TWO• Diagnostic approach• Management

INTRODUCTION• MG is an autoimmune disorder characterized

by weakness and fatigability of skeletal muscles due to dysfunction of the NMJ.

• These autoantibodies are thought to originate in hyperplastic germinal centers in the thymus where myoid cells expressing AChR are clustered.

Types of MG• In ocular myasthenia, the weakness is

limited to the eyelids and extraocular muscles.

• In generalized disease, the weakness commonly affects ocular muscles, but it also involves a variable combination of bulbar, limb, and respiratory muscles.

Types of MG

• Patients who have detectable antibodies to the acetylcholine receptor (AChR) or to the muscle-specific receptor tyrosine kinase (MuSK) are considered to have seropositive MG, while those lacking both AChR and MuSK antibodies are considered to have seronegative MG.

• About half of pts with purely ocular MG are seropositive, compared with approximately 90 % of those with generalized disease.

• 10-15 % of patients with MG have an underlying thymoma.

CLINICAL FEATURES

• The cardinal feature of myasthenia gravis is fluctuating skeletal muscle weakness, often with true muscle fatigue.

• The weakness may fluctuate throughout the day, but it is most commonly worse later in the day or evening, or after exercise.

• Early in the disease, the symptoms may be absent upon awakening. Often as the disease progresses, the symptom-free periods are lost; symptoms are continuously present but fluctuate from mild to severe.

Presenting symptomsPresenting symptoms

Ocular :50 % (Ref:1)

Bulbar : 15 %

Limb weakness :<5 %

Isolated neck weakness :uncommon

Isolated respiratory :rare

Distal Limb :rare

1. Grob D, Arsura EL, Brunner NG, Namba T. The course of myasthenia gravis and therapies affecting outcome. Ann N Y Acad Sci 1987; 505:472.2. Oosterhuis HJ. The natural course of myasthenia gravis: a long term follow up study. J Neurol Neurosurg Psychiatry 1989; 52:1121.

PART TWO• Diagnostic approach• Management

Physical examinationMuscle fatigability can be tested for many muscles. A thorough investigation includes:• looking upward and sidewards for 30 seconds: ptosis

 and diplopia• looking at the feet while lying on the back for 60 seconds• keeping the arms stretched forward for 60 seconds• ten deep knee bends• walking 30 steps on both the toes and the heels• five situps, lying down and sitting up completely• "Peek sign": after complete initial apposition of the lid

margins, they quickly (within 30 seconds) start to separate and the sclera starts to show

DIAGNOSTIC APPROACH• Bedside Test: I. IcePack TestII. Tensilon Test• Serologic Testing:I. Acetylcholine receptor antibodiesII. MuSK antibodies• Electrophysiologic confirmation:I. Repetitive nerve stimulationII. Single-fiber electromyography

Bedside Test: IcePack Test• Since it is based on the physiologic principle of

improving neuromuscular transmission at lower muscle T, the eyelid muscles are the most easily cooled by the application of ice.

Tensilon Test• Edrophonium chloride is an acetylcholinesterase

inhibitor with rapid onset (30 -45 secs) and short DOA(5-10 min). This agent prolongs the presence of acetylcholine in the neuromuscular junction and results in an immediate increase in muscle strength in many of the affected muscles.

Tensilon Test• To perform the test, a test dose of 0.1 mL of 10

mg/mL edrophonium solution is administered.• If no response and no untoward effects are noted,

remainder of the drug (0.9 mL) is injected. • Sinus bradycardia due to excessive cholinergic

stimulation of the heart is a serious complication; consequently, an ampule of atropine should be available at the bedside or in the clinic room while the test is performed.

Serologic testing: Acetylcholine receptor antibodies & MuSK antibodies

Binding AChR antibodies are are highly specific for MG. These antibodies are present in approximately 80 to 90 % of pt with GMG. Essentially all patients (98 to 100 %) with MG and thymoma are seropositive for these antibodies [1,2].1. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol 2004; 24:31.2. Vernino S, Lennon VA. Autoantibody profiles and neurological correlations of thymoma. Clin

Cancer Res 2004; 10:7270.

Other Antibodies• Antibodies to titin• Antibodies to ryanodine• Striated muscle Antibodies

ELECTROPHYSIOLOGIC tests• Repetitive nerve stimulation (RNS) studies and

single-fiber electromyography (SFEMG) have a diagnostic sensitivity in generalized myasthenia of about 75 percent and 95 percent, respectively [1,2].

1. Oh SJ, Kim DE, Kuruoglu R, et al. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve 1992; 15:720.

2. Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol 2004; 24:31.

Treatment: THERAPEUTIC OVERVIEW 

• Symptomatic treatments (anticholinesterase agents)

• Chronic immunomodulating treatments (glucocorticoids & other immunosuppressive drugs)

• Rapid immunomodulating treatments (plasmapheresis and intravenous immune globulin)

• Surgical treatment (thymectomy)

Symptomatic treatment• Oral anticholinesterase medication: usually

pyridostigmine . • Pyridostigmine has a rapid OOA :15-30 min with

peak action at about 2 hr , and its effects last for 3-4 hr and sometimes longer.

• A common starting dose is 30 mg tid. • When a patient has significant persistent

weakness despite the use of pyridostigmine in sufficient doses, or the side effects preclude effective dosing, then immunotherapy is generally warranted.

CHRONIC IMMUNOTHERAPIES• Glucocorticoids and as well as other agents

azathioprine, mycophenolate mofetil and cyclosporine.

• TThe onset of benefit generally begins within two to three weeks.

• However, a transient deterioration occurs in up to 50% of pts with MG when high-dose glucocorticoids are started, usually occurring 5- 10 days after the initiation .

• For this reason, glucocorticoids are most often started in high doses only in hospitalized patients who are receiving concurrent plasmapheresis or intravenous immune globulin (IVIG) for myasthenic crisis.

Time to onset Time to maximal effect

Symptomatic therapy

Pyridostigmine 10 to 15 minutes 2 hours

Chronic immunotherapy

Prednisone 2 to 3 weeks 5 to 6 months

Azathioprine ~12 months 1 to 2 years

Mycophenolate mofetil

6 to 12 months 1 to 2 years

Cyclosporine ~6 months ~12 months

Rapid immunotherapies

Plasmapheresis 1 to 7 days 1 to 3 weeks

Intravenous immune globulin

1 to 2 weeks 1 to 3 weeks

Surgery

Thymectomy 1 to 10 years 1 to 10 years

RAPID IMMUNOTHERAPIES• The rapid therapies used in MG are also

immunomodulating but are distinct because of their quick onset, transient benefit, and their use in select situations. Both plasmapheresis and intravenous immune globulin (IVIG) start to work quickly (over days), but the benefits are only short term (weeks).

• These therapeutic modalities are used most often in the following situations:

1. Myasthenic crisis 2. Preoperatively before thymectomy or other surgery 3. Periodically to maintain remission in patients with MG

that is not well controlled despite the use of chronic immunomodulating drugs

Plasmapheresis• Plasmapheresis (plasma exchange) directly

removes AChR antibodies from the circulation. • Course of treatment — A typical course of

treatment consists of 5 exchanges (3-5 L of plasma each) over 7-14 days.

• Complications — infection and thrombosis,bleeding, hypotension, cardiac arrhythmias .

Intravenous immune globulin•  IVIG is pooled immunoglobulin from thousands of

donors. • MOA:uncertain. As with plasmapheresis, the effect

of IVIG is seen typically in less than a week, and the benefit can last for 3-6 wks.

• Dose and side effects — The total dose of IVIG is 2 g/kg, usually over two to five days.

• The side effects include headache, chills, dizziness, and fluid retention. Other uncommon complications include aseptic meningitis, acute renal failure, thrombotic events, and anaphylaxis.

Need for thymectomy • In parallel with symptomatic treatment and

immunotherapeutic agents for MG, thymectomy is considered because of its potential longer-term benefit.

• Thymectomy is advocated as soon as the patient's degree of weakness is sufficiently controlled to permit surgery.

• Thymectomy is not routinely suggested in patients over 60 years of age, unless a thymoma is present.

Myasthenic Crisis• Myasthenic crisis is a life-threatening condition,

which is defined as weakness from acquired myasthenia gravis (MG) that is severe enough to necessitate intubation or to delay extubation following surgery [1].

• Severe bulbar (oropharyngeal) muscle weakness often accompanies the respiratory muscle weakness, or may be the predominant feature in some patients. When this results in upper airway obstruction or severe dysphagia with aspiration, intubation and mechanical ventilation are necessary.

1. Bedlack RS, Sanders DB. On the concept of myasthenic crisis. J Clin Neuromuscul Dis 2002; 4:40.

Treatment of myasthenic crisis

Admit to intensive care unit

Measure FVC frequently, as often as every two hours if respiratory status is deteriorating

Electively intubate in the presence of any of the following conditions:

• FVC less than 15 mL/kg body weight

• Declines in serial measurements of FVC approaching 15 mL/kg

• Clinical signs of respiratory distress

• Difficulty handling oral secretions, swallowing, or speaking

Withdraw anticholinesterase medications to reduce airway secretions in patients who are intubated

Begin rapid therapy with plasmapheresis or IVIG to treat myasthenic crises

Begin immunomodulating therapy with high dose corticosteroids (eg, prednisone 60 to 80 mg per day). Consider azathioprine, mycophenolate mofetil, or cyclosporine if steroids are contraindicated or previously ineffective

Initiate weaning from mechanical ventilation when respiratory muscle strength is improving with plasmapheresis or IVIG treatment, as quantified by a FVC >15 mL/kg

Myasthenic Crisis: Prognosis• With advances in therapy and intensive care

management, the prognosis in myasthenic crisis has dramatically improved over the last four decades from a mortality rate of 75 % to the current rate of <5 % [1,2].

1. Juel VC. Myasthenia gravis: management of myasthenic crisis and perioperative care. Semin Neurol 2004; 24:75.

2. Alshekhlee A, Miles JD, Katirji B, et al. Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurology 2009; 72:1548.

ThankyouReferences:1. Uptodate 19.32. Harrison’s Internal medicine 18th ed.3. Davidson’s Practice of Medicine