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

Our Journey

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

Neuromuscular Junction

1. Release of AChWhen a nerve pulse reaches a synaptic end bulb, it triggers release of the NT ACh from synaptic vesicles. ACh then diffuses across the synaptic cleft between the motor neuron and the motor end plate .

Neuromuscular Junction

2. Activation of ACh receptorsThe motor end plate contains receptors onto which the free ACh binds after diffusing across the synaptic cleft.This binding of ACh to ACh receptors in the motor end plate causes ion channels to open & so allow the sodium (Na+) ions to flow across the membrane into the muscle cell.

Neuromuscular Junction3. Generation of muscle APThe flow of Na+ ions across the membrane into the muscle cell generates a muscle AP. (The flow of Na+ ions causes depolarization at the end-plate region of the muscle fiber. If the depolarization is sufficiently large, it initiates an AP that is propagated along the muscle fiber, triggering muscle contraction.)

Neuromuscular Junction

4. Breakdown of AChThe ACh that is released is only available for a short time before it is broken down by an enzyme called AChE. This breakdown of ACh occurs within the synaptic cleft.

Neuromuscular junction

Myasthenia Gravis• The neuromuscular abnormalities in MG are

brought about by an autoimmune response mediated by specific anti-AChR antibodies.

• The anti-AChR antibodies reduce the number of available AChRs at neuromuscular junctions by three distinct mechanisms:

(1)accelerated turnover of AChRs by rapid endocytosis of the receptors;

(2)damage to the postsynaptic muscle membrane by the antibody.

(3) blockade of the active site of the AChR, i.e., the site that normally binds ACh.

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.

• The majority of patients with AChR antibody-positive myasthenia gravis have thymic abnormalities: hyperplasia in 60-70 % and thymoma in 10-12 % [1].

• Furthermore, the disease often improves or disappears after thymectomy [2].

• As a result, the thymus has been evaluated as a possible source of antigen to drive this autoimmune disease.

1. Drachman DB. Myasthenia gravis. N Engl J Med 1994; 330:1797.2. Vincent A. Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2002; 2:797.

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.

EPIDEMIOLOGY• MG is a relatively uncommon disorder with an annual

incidence of approximately 10 to 20 new cases/million [1]. The prevalence is about 150 to 200 per million [2].

• MG occurs at any age, but there tends to be a bimodal distribution to the age of onset with an early peak in the 2ND & 3RD decades (f predominance) and late peak in the 6TH to 8TH decade (m predominance).

• In neonates, a transient form of myasthenia, called neonatal myasthenia gravis, can occur as a result of the transplacental passage of maternal Ab that interfere with function of the NMJ. Rare, nonimmune mediated forms, collectively referred to as congenital myasthenia gravis, may be the result of mutations that adversely affect neuromuscular transmission.

1. Phillips LH. The epidemiology of myasthenia gravis. Semin Neurol 2004; 24:17.2. Phillips LH 2nd. The epidemiology of myasthenia gravis. Ann N Y Acad Sci 2003; 998:407.

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.

Clinical course • Early in the disorder, the symptoms are

often transient in many patients, with hrs, days, or even weeks free of symptoms.

• The symptoms may even remit spontaneously for weeks or longer.

• The progression of MG usually peaks within a few years of disease onset.

• In a case series from the US of 1976 pts with MG, the maximum extent of weakness was reached within 2 yrs in 82 % of pts [1]. In another retrospective study of 1152 pts in Italy, the maximum extent of the disease was seen by 3 yrs of onset in 77 % [2].

1. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve 2008; 37:141.2. Mantegazza R, Beghi E, Pareyson D, et al. A multicentre follow-up study of 1152 patients with myasthenia gravis in

Italy. J Neurol 1990; 237:339.

Clinical course : Phases in MG• There is an active phase with the most

fluctuations and the most severe symptoms that occurs in the five to seven years after onset. Most myasthenic crises occur in this early period.

• This is typically followed by a more stable second phase. In this phase, the symptoms are stable but persist. They may worsen in the setting of infection, or medication taper.

• In many patients, this is followed by the third phase, in which remission may occur, with the patient free of symptoms on immunotherapy, or even off medications entirely.

• End of Part 1