Muscle Pathology Dr Abderrahman Ouban Muscle Biopsy • Often necessary for final diagnosis of myopathy • Choose site based on clinical, electrodiagnostic, or imaging features • Avoid “end-stage” fatty muscle • Frozen sections most useful • Routine stains • Histochemistry • Immunohistochemistry Myopathies Classification of Myopathies ACQUIRED Inflammatory Myopathies INHERITED Muscular Dystrophies Polymositis (PM) Dystrophinopathies Dermatomyositis (DM) Limb-Girdle Inclusion body myositis (IBM) Myotonic Granulomatous myositis Facioscapulohumeral (FSHD) Infectious myositis (trichinosis) Oculopharyngeal (OPD) Toxic Alcohol, Steroid Endocrine Distal Congenital Dystrophies Congenital Myopathies (Metabolic) Thyroid Disorders Mitochondrial Adrenal disorders Glycogen & lipid storage Congenital Abnormalities Congenital Abnormalities ❑Group of non-progressive primary diseases of the muscle that presents in infancy with hypotonia and weakness ❑Divided on the basis of the morphological characteristics seen on histochemical study of the muscle as follows: ▪ An enzyme abnormalities causing a histochemically abnormal appearance of the muscle cell ▪ The presence of abnormally placed nuclei, such as myotubular myopathy (centronuclear myopathy) ▪ The disruption of normal muscle fiber structures, typically the sarcomeres, such as central core myopathy ▪ The presence of abnormal inclusions within the muscle fibers, often derived from preexisting structures Inflammatory Myopathies Inflammatory Myopathies ❑Include a heterogeneous group of muscle disorders that have as their hallmark the degeneration of muscle via inflammatory process ❑The inflammatory infiltrate are mainly mononuclear with T cells, B cells, NK cells and macrophages ❑Clinically characterized by proximal muscle weakness and wasting ❑Maybe idiopathic or acquired ❑The major idiopathic forms of inflammatory myopathy include: ▪ Polymyositis ▪ Dermatomyositis ▪ Inclusion body myositis Inflammatory Myopathies Epidemiology ❑2-8 cases per million per year ❑Female : male = 2:1 ❑Bimodal distribution: ▪ 10-15 years (pediatric variant) ▪ 45-60 years ❑Association between malignancy and inflammatory myopathy especially DM & PM ❑Anti-Jo-1 in 30 % PM & DM o anti Jo-1 antibody directed against the antihistidyl–tRNA synthetase. Polymyositis ❑ Autoimmune ❑ Usually insidious onset over 3-6 months ▪ No identifiable precipitant ❑ Symmetrical proximal muscle involvement ❑ Shoulder and pelvic girdle muscles affected most severely ▪ Neck muscles (esp. flexors) involved in 50% of patients ❑ Ocular and facial muscles almost never affected ❑ Distal muscles are spared in majority of patients ❑ Dysphagia & dysphonia may occur ❑ Myocarditis, Interstitial lung disease or Vasculitis Polymyositis ❑ Polymyositis is an idiopathic inflammatory myopathy which is more common in females but does occur in children and males. This is a longitudinal section of paraffin embedded tissue stained with H&E to show the marked chronic inflammatory infiltrate and muscle degeneration. Polymyositis ❑This cross section of frozen muscle material with H&E staining shows phagocytosis of a muscle fiber with numerous macrophages in the center of the cell in this case of polymyositis Dermatomyositis ❑Features of Polymyositis as well as cutaneous manifestations ▪ The skin lesions may precede or follow the muscle syndrome ▪ Type 1 interferon-induced gene products are strongly upregulated in affected muscles ▪ Clinically: o Gottron’s sign - symmetric violaceous erythematous eruption over knuckles o Heliotrope rash - reddish violaceous eruption on upper eyelids +/- edema o Shawl sign – erythematous rash over neck, upper chest and shoulders ✔Associated with malignancy in 20-25% of cases ✔Antibodies against Mi-2: o Anti-Mi-2 antibodies. ... Mi-2 antigen is a component of the nuclesome remodeling-deacetylase (NuRD) complex involved in transcription regulation. o Anti-Mi-2antibodies are strongly associated with dermatomyositis (frequency up to 31%) and have a very high positive predictive value for such disease subset. Metabolic Myopathies Metabolic Myopathies ❑Many involved disorders of glycogen synthesis and degradation and lipid metabolism ❖Pompe Disease ❖McArdle’s Disease Pompe Disease ❑ Autosomal recessive genetic disorder ❑ Various molecular defects in the lysosomal acidglucosidase (GAA) gene, resulting in partial or complete deficiency of GAA activity ❑ This enzyme deficiency results in lysosomal glycogen accumulation in almost all tissues in the body, with skeletal and cardiac muscle most seriously affected ❑ Three phenotypes of the disease depending on how much is left of the GAA activity, <1%, 1-10%, and 1040% of normal ❑ Death if the most severe deficiency (<1%) usually happens before the first year of life from cardiorespiratory failure Neuromuscular Junction Disease Neuromuscular Junction Disease ❑Presentation ▪ A 43-year-old white female presents with a 3-month history of double vision, which gets worse as the day goes by ▪ The patient also reports mild difficulty swallowing and chewing. ▪ However, the patient denies generalized fatigue ▪ On further questioning, the patient notices that when she wakes up, she has no complaints in her eyesight, chewing or swallowing. ▪ Examination reveals a sad-looking patient with bilateral, asymmetric ptosis, with documented weakness of the extraocular and eyelid, facial and palatal muscles. While examining the patient, it was noted that her speech was getting slower and her voice fainter as the interview went along. ▪ When the patient was asked to blink, it was noted that she started fine but after several movements, there was significant bilateral lid lag. NJ Disease Myasthenia Gravis (MG) ▪ An autoimmune disease, characterized as a type II hypersensitivity that involves autoantibodies binding nicotinic acetylcholine (Ach) postsynaptic receptors at the neuromuscular junction (NMJ) of skeletal muscle cells ▪ Reduction in the number of Ach receptors at the postsynaptic muscle membrane brought about by the above mentioned autoimmune reaction. ▪ This reduction will result in a characteristic pattern of progressively reduced muscle strength with repeated use and recovery of muscle strength after a period of rest MG ▪ It has a bimodal peak of incidence with first peak in the third decade and the second peak in the sixth decade. ▪ Myasthenia gravis is the commonest disorder affecting the neuromuscular junction. ▪ In a very large population based study of the epidemiology of myasthenia gravis in Greece, the average annual incidence was found to be 7.40/million population/year (women 7.14; men 7.66), and the point prevalence rate was 70.63/million (women 81.58; men 59.39) Classification of MG ❑Acquired autoimmune ❑Transient neonatal caused by passive transfer of maternal anti-AchR antibodies ❑Drug-induced: D-penicillamine is the prototype of drug induced myasthenia gravis. Symptoms maybe identical to typical acquired autoimmune MG and the antibody to AchR exist. Disease tends to remit following cessation of the drug ❑Congenital myasthenic syndromes (slow channel syndrome and fast channel syndrome) heritable disorders of postsynaptic neuromuscular transmission with characteristic age of onset, pathology, electrophysiology and treatment. Schema of normal neuromuscular junction. B R Thanvi, and T C N Lo Postgrad Med J 2004;80:690-700 Copyright © The Fellowship of Postgraduate Medicine. All rights reserved. Schema of the acetylcholine (ACh) receptor. B R Thanvi, and T C N Lo Postgrad Med J 2004;80:690-700 Copyright © The Fellowship of Postgraduate Medicine. All rights reserved. Schema of neuromuscular junction in myasthenia gravis (note: widened synaptic cleft, reduced number of acetylcholine receptors, and simplification of postsynaptic membrane). Pathology Mechanism B R Thanvi, and T C N Lo Postgrad Med J 2004;80:690-700 Copyright © The Fellowship of Postgraduate Medicine. All rights reserved. IMMUNE PATHOGENESIS OF MYASTHENIA GRAVIS ⮚Role of AChR antibodies ❖Mechanism of destruction of the AChRs by the antibody is brought about by following mechanisms: ❑(A) Antibodies cross linking with the AChR with subsequent accelerated endocytosis and degradation of the AChRs by muscle cells ❑(B) antibody blocking the binding sites of the AChRs ❑(C) complement-mediated destruction of junctional folds of the postsynaptic membrane. IMMUNE PATHOGENESIS OF MYASTHENIA GRAVIS ⮚Seronegative myasthenia gravis • As discussed above, about 10%–20% of patients with myasthenia gravis do not have anti-AChR antibodies and are called seronegative. • It has been shown that these patients have circulating antibodies that are not detectable by the radioimmunoassay for AChR antibodies. • These antibodies are capable of destroying AChRs in culture systems and when transferred to mice, can produce an illness similar to myasthenia gravis. • Recently, Hoch et al have shown that at least some of these seronegative patients have antibodies in their sera that bind to MuSK. • As previously described, MuSK is one of the proteins involved in anchoring and clustering of AChRs at the postsynaptic membrane. • The antibodies that target other components of the neuromuscular junction but are not detectable by the currently available tests may be responsible for the remaining cases of myasthenia gravis. IMMUNE PATHOGENESIS OF MYASTHENIA GRAVIS ⮚Role of thymus ▪ The association of myasthenia gravis and thymoma was noted more than 200 years ago. ▪ Thymic abnormalities are found in nearly 75% of patients with myasthenia gravis. Of these, germinal hyperplasia is noted in 85% and thymic tumours in 15%. ▪ Anti-striated muscle antibodies are found in 90% of patients with myasthenia gravis and a thymoma. ▪ Muscle cell-like cells (myoid cells) are found in thymus that express surface AChRs. These cells are surrounded by the helper T-cells and the antibody-presenting cells. It is postulated that these myoid cells are the source of autoantigen, AChR. ▪ The other hypothesis suggests that myasthenia gravis may be triggered by a molecular mimicry—that is, an immune response to an infectious agent that resembles the AChR. Diagnosis of MG ▪ In patients with a characteristic history it may be easy to make a diagnosis on clinical grounds alone. However, it is important to confirm diagnosis of myasthenia gravis before committing patients to long term treatment. ▪ It should be emphasized that the diagnosis of myasthenia gravis is mostly based on the results of the test for the antibody against AChR and the neurophysiological tests. Diagnostic Tests in MG ▪ Edrophonium (Tensilon test) ▪ Ice test ▪ AchR antibody in serum ▪ Repetitive nerve stimulation ▪ Single fibre electromyography ▪ Anti-MuSK antibodies ▪ Computed tomography/MRI of chest ▪ MRI brain TREATMENT OF MYASTHENIA GRAVIS ▪ Acetylcholinesterase inhibitors. ▪ Corticosteroids. ▪ Immunosuppressants. ▪ Plasmapheresis. ▪ Intravenous immunoglobulins. ▪ Thymectomy. MYASTHENIC CRISIS ❑Myasthenic crisis is an exacerbation of myasthenia leading to paralysis of respiratory muscles that requires an urgent respiratory support. ❑This is usually caused by infections, or an inadequate treatment. ❑Patients should be managed in an intensive care unit. In addition to respiratory support appropriate antibiotics, fluid management, and anticholinesterase therapy are required. ❑Plasmapheresis or intravenous immunoglobulin treatment may be required for prompt control of the disease. PROGNOSIS OF MYASTHENIA GRAVIS ▪ Untreated myasthenia gravis has a 10 year mortality of 20%–30%. However, with modern treatment, the prognosis is excellent with practically zero mortality. ▪ Most patients are able to live normal lives, through taking immunosuppressants for life. ▪ Myasthenia gravis associated with a thymoma, particularly in older patients, carries a poor prognosis.
