Myasthenia gravis for students part one
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Myasthenia gravis for MBBS students part one
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Myasthenia gravis for students part one
- 1. Pratap Sagar Tiwari, Lecturer, Internal Medicine, NGMC, Nepal
- 2. PART ONE • Neuromuscular junction • Introduction of MG • Types • Epidemiology • Clinical features PART TWO • Diagnostic approach • Management
- 3. 1. Release of ACh When 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 .
- 4. 2. Activation of ACh receptors The 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.
- 5. 3. Generation of muscle AP The 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.)
- 6. 4. Breakdown of ACh The 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.
- 8. • 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.
- 9. • 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.
- 10. • The majority of patients with AChR antibodypositive 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.
- 11. • 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.
- 12. • Patients who have detectable antibodies to the acetylcholine receptor (AChR) or to the musclespecific 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.
- 13. • 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. 2. Phillips LH. The epidemiology of myasthenia gravis. Semin Neurol 2004; 24:17. Phillips LH 2nd. The epidemiology of myasthenia gravis. Ann N Y Acad Sci 2003; 998:407.
- 14. • 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.
- 15. Presenting 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.
- 16. • 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. 2. Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve 2008; 37:141. 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.
- 17. • 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.
- 18. • End of Part 1
Hinweis der Redaktion
- Release of AChWhen a nerve pulse reaches a synaptic end bulb, it triggers release of the neurotransmitter acetylcholine (ACh) from synaptic vesicles that contain acetylcholine (ACh). ACh then diffuses across the synaptic cleft between the motor neurone and the motor end plate - as shown above.
- 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.(Although the movement of sodium (Na+) ions is mentioned an illustrated, the opening of the ion channel does also allow other cations to pass across the membrane. A cation is a positively-charged ion, which has fewer electrons than protons, is known as a "cation" because it is attracted to cathodes. In the case of a simple description of actions at a neuromuscular junction it is generally sufficient to remember the movement of sodium (Na+) ions .)
- Generation of muscle action potentialThe flow of sodium (Na+) ions across the membrane into the muscle cell generates a muscle action potential. This action potential then travels along the sarcolemma and through the T-Tubules. (Action Potentials and how they are generated and transmitted is a topic usually covered in further detail as part of study of the Nervous System.) Breakdown of AChThe ACh that is released at Step (1.) is only available to take part in step (2.) for a short time before it is broken down by an enzyeme called acetylcholinesterase (AChE). This breakdown of ACh occurs within the synaptic cleft.In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened, or "simplified." These changes result in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction.The amount of ACh released per impulse normally declines on repeated activity (termed presynaptic rundown). In the myasthenic patient, the decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the decremental response to repetitive nerve stimulation seen on electrodiagnostic testing.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 a mechanism involving cross-linking and rapid endocytosis of the receptors; (2) damage to the postsynaptic muscle membrane by the antibody in collaboration with complement; and (3) blockade of the active site of the AChR, i.e., the site that normally binds ACh. An immune response to muscle-specific kinase (MuSK), a protein involved in AChR clustering at neuromuscular junctions, can also result in myasthenia gravis, with reduction of AChRs demonstrated experimentally. The pathogenic antibodies are IgG, and are T cell-dependent. Thus, immunotherapeutic strategies directed against either the antibody-producing B cells or helper T cells are effective in this antibody-mediated disease.How the autoimmune response is initiated and maintained in MG is not completely understood, but the thymus appears to play a role in this process. The thymus is abnormal in 75% of patients with MG; in 65% the thymus is "hyperplastic," with the presence of active germinal centers detected histologically, though the hyperplastic thymus is not necessarily enlarged. An additional 10% of patients have thymic tumors (thymomas). Muscle-like cells within the thymus (myoid cells), which bear AChRs on their surface, may serve as a source of autoantigen and trigger the autoimmune reaction within the thymus gland
- ACh breaks down by AChE and the sequence of events is then repeated with another AP Steps in Contraction Cycle (at level of the sarcomere) The end result of these steps produces an action potential that reaches the terminal cisternae where calcium ions are stored. Calcium ions bind to troponin on the thin filaments and the active site is exposed. Myosin cross-bridge forms and attaches to the exposed active site on the thin filaments. Attached myosin head pivots toward center of sarcomere (M line) ADP and phosphate group are releasedMyosin head binds another ATP molecule and cross-bridges detach Detached myosin head splits the ATP molecule, captures release energy, and is reactivated - Entire cycle is restarted beginning with step 2.
- In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened, or "simplified." These changes result in decreased efficiency of neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction.The amount of ACh released per impulse normally declines on repeated activity (termed presynaptic rundown). In the myasthenic patient, the decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the decremental response to repetitive nerve stimulation seen on electrodiagnostic testing.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: accelerated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the receptors; damage to the postsynaptic muscle membrane by the antibody in collaboration with complement; and blockade of the active site of the AChR, i.e., the site that normally binds ACh. An immune response to muscle-specific kinase (MuSK), a protein involved in AChR clustering at neuromuscular junctions, can also result in myasthenia gravis, with reduction of AChRs demonstrated experimentally. The pathogenic antibodies are IgG, and are T cell-dependent. Thus, immunotherapeutic strategies directed against either the antibody-producing B cells or helper T cells are effective in this antibody-mediated disease.How the autoimmune response is initiated and maintained in MG is not completely understood, but the thymus appears to play a role in this process. The thymus is abnormal in 75% of patients with MG; in 65% the thymus is "hyperplastic," with the presence of active germinal centers detected histologically, though the hyperplastic thymus is not necessarily enlarged. An additional 10% of patients have thymic tumors (thymomas). Muscle-like cells within the thymus (myoid cells), which bear AChRs on their surface, may serve as a source of autoantigen and trigger the autoimmune reaction within the thymus gland
- The thymus contains a small number of "myoid" cells. These cells are distinguished by striations and the presence of acetylcholine receptors (AChR) on their surface and are the only known cells to express intact AChR outside of muscle. In addition, thymic epithelial cells produce unfolded AChR subunits that are hypothesized to prime helper T cells. These "autoimmunized" T cells then attack the AChR on myoid cells and create infiltrating germinal centers in the hyperplastic thymus where deposition of complement is found associated with the myoid cells. The autoimmunization completes as the antibodies in the germinal centers diversify to recognize intact muscle AChR.Thus, all of the elements necessary to produce and promote autoimmunity reside in microenvironments in the hyperplastic thymus
- Similar weakness can also result from mutation of components of the neuromuscular junction, resulting in a group of disorders collectively referred to as "congenital myasthenia". This type of myasthenia is often appreciated at birth. Congenital myasthenia and weakness in newborns that is due to transplacental passage of antibodies from a pregnant woman with myasthenia gravis are presented separately
- There are two clinical forms of myasthenia gravis: ocular and generalized.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.
- Patients who have detectable antibodies to the acetylcholine receptor (AChR) or to the muscle-specific receptor tyrosine kinase (MuSK) are considered to have seropositive myasthenia gravis, while those lacking both AChR and MuSK antibodies on standard assays are considered to have seronegative myasthenia. About half of patients with purely ocular myasthenia are seropositive, compared with approximately 90 percent of those with generalized disease. Another important consideration is that about 10 to 15 percent of patients with myasthenia gravis have an underlying thymoma.
- 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]. The prevalence of the disease has been increasing over the past five decades [3]. This is thought to be due to better recognition of the condition.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.
- The cardinal feature of myasthenia gravis is fluctuating skeletal muscle weakness, often with true muscle fatigue. The fatigue is manifest by worsening contractile force of the muscle, not a sensation of tiredness. Many clinicians think (erroneously) that fatigue without weakness is consistent with myasthenia. Patients present with complaints of specific muscle weakness and not generalized 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. When present, this fluctuation in symptoms is an important feature that can distinguish myasthenia gravis from other disorders that also may present with weakness, such as myopathy or motor neuron disease.
- Presenting symptoms — Although myasthenia can produce weakness in any skeletal muscle group, there are certain presentations that are quite characteristic of myasthenia gravis (table 1).More than 50 % of pts present with ocular symptoms of ptosis and/or diplopia .Of those who present with ocular manifestations, about half will develop generalized disease within two years .About 15 percent of patients present with bulbar symptoms. These include dysarthria, dysphagia, and fatigable chewing.Less than 5 percent present with proximal limb weakness alone.Less common presentations include isolated neck weakness, isolated respiratory muscle weakness, and distal limb weaknessD/DOcular (50 percent): Brainstem and cranial nerve lesions (including Horner's syndrome), thyroid ophthalmopathy, oculopharyngeal muscular dystrophy, chronic external ophthalmoplegia (mitochondrial disease)Bulbar (15 percent): Brainstem and multiple cranial nerve lesions, motor neuron disease, obstructive or malignant lesion of the nasal and oropharynxLimb weakness (<5 percent) :Motor neuron disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and other motor neuropathies, multiple radiculopathies, Lambert-Eaton myasthenic syndrome, myopathiesIsolated neck (uncommon):Motor neuron disease, inflammatory myopathy, paraspinous myopathyIsolated respiratory (rare):Motor neuron disease, acid maltase deficiency, polymyositisDistal limb (rare): Motor neuron disease, CIDP and other motor neuropathies, distal myopathiesOcular muscles — Weakness of the eyelid muscles can lead to ptosis, the degree of which can be quite variable throughout the day. It may switch from one eye to the other over time. The ptosis may start bilaterally and improve in one eye, resulting in unilateral ptosis. In addition, ptosis may start unilaterally and then become bilateral. At times, it may be so severe as to occlude vision.The extraocular muscles are also often involved. This produces binocular diplopia that disappears when the patient closes or occludes one eye. It may be horizontal or vertical. On examination, eye movements are often weak in a pattern that does not conform to the anatomy of one nerve or muscle. They may also be weak in a pattern that simulates another disorder, such as an isolated oculomotor neuropathy, an internuclearophthalmoplegia (INO), or a vertical gaze paresis. The pupils are always spared in myasthenia gravis, helping in the differentiation from other disorders. The ptosis may increase with sustained upward gaze or by holding up the opposite eyelid with the examiner's finger (curtain sign).Bulbar muscles — Muscles of jaw closure are often involved and produce weakness with prolonged chewing (fatigable chewing) . The patient frequently notes that this occurs half-way through a meal.Oropharyngeal muscle weakness produces dysarthria and dysphagia. The quality of speech sounds nasal when there is weakness of the palatal muscles, or it may be of low intensity (hypophonic). These symptoms often worsen with prolonged speech. Dysphagia may be prominent; the patient may be unable to swallow medications or consume adequate food or liquids. Nasal regurgitation, particularly of liquids, may occur due to palatal weakness.Facial muscles — Facial muscles are frequently involved and make the patient appear expressionless. Family members may notice that the patient has "lost his or her smile" as a result of weakness of the orbicularis oris muscle. When attempting to smile, the patient may produce the "myasthenic sneer," where the mid-lip rises but the outer corners of the mouth fail to move. Orbicularis oculi weakness is often easily identified on examination when prying the eyes open during forced-eye closure.Neck and limb muscles — Neck extensor and flexor muscles are commonly affected. The weight of the head may overcome the extensors, particularly late in the day, producing a "dropped head syndrome." Involvement of the limbs in myasthenia produces predominantly proximal weakness similar to other muscle diseases. However, the arms tend to be more often affected than the legs. In addition to proximal muscles, wrist and finger extensors and foot dorsiflexors are often involved. Respiratory muscles — Involvement of the muscles of respiration produces the most serious symptoms in myasthenia gravis. Respiratory muscle weakness that leads to respiratory insufficiency and pending respiratory failure is a life-threatening situation called "myasthenic crisis." It may occur spontaneously during an active phase of the disease or may be precipitated by a variety of factors including surgery, infections, certain medications, or tapering of immunosuppression.
- Most clinicians feel that there are three stages to the disease, although these have been altered considerably by modern immunotherapy.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, medication taper, or other perturbations.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.