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5. Pathology of Muscle Disorders

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
Classification of Myopathies
Inflammatory Myopathies
Muscular Dystrophies
Polymositis (PM)
Dermatomyositis (DM)
Inclusion body myositis (IBM)
Granulomatous myositis
Facioscapulohumeral (FSHD)
Infectious myositis (trichinosis)
Oculopharyngeal (OPD)
Alcohol, Steroid
Congenital Dystrophies
Congenital Myopathies (Metabolic)
Thyroid Disorders
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
▪ The presence of abnormally placed nuclei, such as myotubular myopathy (centronuclear
▪ 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
❑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.
❑ 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 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
❑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
❑Features of Polymyositis as well as cutaneous manifestations
▪ The skin lesions may precede or follow the muscle
▪ 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
Metabolic Myopathies
Metabolic Myopathies
❑Many involved disorders of glycogen
synthesis and degradation and lipid
❖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
▪ 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
▪ 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
❑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)
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.
⮚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.
⮚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.
⮚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
▪ Acetylcholinesterase inhibitors.
▪ Corticosteroids.
▪ Immunosuppressants.
▪ Plasmapheresis.
▪ Intravenous immunoglobulins.
▪ Thymectomy.
❑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
❑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.
▪ 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.