The classical clinical features of myopathy
include the following:
Weakness, which predominantly affects the proximal muscle groups (eg,
shoulder and limb girdles)
Myalgia, or muscle aching, which is present in some patients with
inflammatory myopathy (muscle pain also is found in some patients with
metabolic diseases affecting muscle and occurs when the energy supply of
the muscle is depleted and lactic acid builds up).
Preservation of muscle-stretch reflexes
Absence of abnormalities of somatosensation
Fluctuation of muscle power can suggest the presence of a metabolic
myopathy.
Fatigability is a term that denotes progressive loss of muscle power
with exertion that improves with rest. This is a defining clinical
feature of myasthenia gravis, a disorder of impaired neuromuscular
transmission. Muscle biopsy typically is not performed for myasthenia
gravis.
In contrast to myopathy, the classic clinical features of peripheral
neuropathy include the following:
Weakness predominantly affecting distal musculature
Decrease of muscle-stretch reflexes, particularly in demyelinating
neuropathies
Fasciculations, when abnormal excitability of the motor neuron is
present
Somatosensory abnormalities
The serum creatine phosphokinase (CK) level is the single most important
blood test to obtain for the consideration of myopathy. A representative
reference range is 24-196 IU/L. The CK level is useful, but not definitive,
in determining whether neuropathy or myopathy is present. Extremely elevated
levels of CK (>800 IU/L) almost always indicate muscle disease. Mildly
elevated levels (200-600 IU/L) can be observed in either entity, and normal
levels are less likely to be found in the patient with myopathy. Myoglobinuria also may reflect myopathy.
The serum aldolase level may be helpful in increasing the suspicion of a
myopathy; because of its longer half-life in serum, it may be elevated in
the setting of myopathy when the CK level is normal.
Neurogenic changes in muscle biopsy
The muscle can show neurogenic changes in disorders that affect motor
neurons, including diseases of the anterior horn cell (eg, motor neuron
disease), motor neuropathy, peripheral neuropathy, and disorders that affect
the intramuscular nerve twigs. One of the common requests accompanying
muscle biopsies is to assist in determining whether the patient has
neuropathy or myopathy.
Neurogenic disorders have the following characteristics in muscle
biopsies:
Angulated atrophic fibers.
Fiber-type grouping.
Group atrophy.
Target fibers.
Nuclear clumps.
When all of these findings are present and no other abnormalities are
found in the specimen, the diagnosis of neurogenic atrophy and reinnervation
is straightforward. Often, the biopsy shows a combination of neurogenic and
myopathic findings. These may represent myopathy that is secondary to the
neuropathic process or a separate primary myopathic process. Often the
pathologist can surmise the correct interpretation on the basis of clinical
findings, but occasionally the truth cannot be determined with certainty.
Many biopsies with inflammation also demonstrate some evidence of neurogenic
change. This may be caused by myogenic denervation, in which the sick muscle
fibers lose their innervation, the inflammatory process overrunning and
entrapping the intramuscular nerve twigs in an innocent-bystander mechanism
or from the concurrence of inflammation of the nerves.
Muscle biopsy in myopathy:
In contrast to the pathologic findings in neuropathy, several findings
are characteristic of myopathic processes, including the following:
Myofiber injury changes &/or necrosis [L07-10540].
Myophagocytosis.
Regeneration.
Rounded atrophic fibers.
Fiber hypertrophy and splitting.
Increase in internal nuclei.
Fibrosis.
Myositis, glycogen storage diseases, mitochondrial myopathies, and
congenital myopathies are 4 important groups of disorders that can be
diagnosed by muscle biopsy.
Myositis
The most common reason for performing a muscle biopsy is to evaluate for
the diagnostic consideration of idiopathic inflammatory myopathy. The
idiopathic inflammatory myopathies are polymyositis, dermatomyositis, and
inclusion body myositis (IBM).
The usual clinical presentation of polymyositis and dermatomyositis is a
subacute course of progressive weakness affecting proximal muscle groups,
occasionally with myalgia, elevated CPK level, and myopathic and irritative
findings on EMG. Many of these patients have serum autoantibodies, some of
which are associated with specific clinical syndromes. Patients with
dermatomyositis usually have characteristic rashes. Dermatomyositis in
adults fairly often is a paraneoplastic syndrome.
Polymyositis:
The following are pathologic features of polymyositis:
The inflammatory infiltrates in polymyositis are predominantly
endomysial, and they are enriched with T-suppressor/cytotoxic (CD8)
lymphocytes. The finding of endomysial lymphoid inflammation is one of
the major diagnostic criteria for polymyositis.
Myofiber necrosis: This can be segmental, affecting only part of a
myofiber.
Myophagocytosis : This is the removal of the dead cellular elements
by macrophages.
Invasion of nonnecrotic myofibers by "autoaggressive lymphocytes": This
is a key diagnostic finding in which T cells attack intact myofibers.
This is believed to be the pathologic correlate of the main factor in
the etiopathogenesis of polymyositis. This represents the fundamental
distinction between inflammation that can occur as a secondary
phenomenon and inflammation that is the primary pathologic process. In
the former case (eg, muscular dystrophy), inflammation is found
associated with fibers that already are degenerating. In polymyositis,
inflammation can be found associated with healthy, intact fibers. Such may lead to serum autoantibodies against muscle antigens. See this
ANA table.
Internal nuclei: These are a nonspecific myopathic finding.
Myofiber atrophy: Atrophic fibers generally are of both myofiber
types and rounded in contour. In some patients with polymyositis, the
atrophy affects primarily type 2 myofibers. Type 2 myofiber atrophy can
develop from administration of steroids.
Regeneration.
Fibrosis: This is a feature of chronic polymyositis.
The distribution of the pathology in polymyositis can be patchy, so
obtaining a normal biopsy in a patient who has this disorder is possible.
A subgroup of patients who are believed to have polymyositis have an
abnormal muscle biopsy that does not show inflammation. These patients
present with a fairly rapidly evolving myopathy with severe weakness. They
tend to have exceedingly high CPK levels, often greater than 20,000 IU/L.
Some of these patients have autoantibodies in their serologic studies, often
anti-signal recognition particle (anti-SRP antibody). The presence of these
autoantibodies is the strongest evidence that this disorder is an
immune-mediated disease. In this group of patients, the disease is resistant
to therapy. Muscle biopsy shows the presence of scattered necrotic fibers,
myophagocytosis, and other nonspecific myopathic findings, but inflammatory
infiltration is absent.
Dermatomyositis:
Pathologic findings in dermatomyositis occasionally can bear a
superficial resemblance to polymyositis, but some important distinguishing
features are present. In many patients, the pathology of dermatomyositis is
strikingly unique.
The following are pathologic features of dermatomyositis:
The infiltrates most often are concentrated in a perimysial
perivascular distribution. More B-lymphocytes and T-helper (CD4)
lymphocytes are present than in polymyositis.
Myofiber necrosis
Perifascicular atrophy: This atrophy affects the fibers at the
periphery of the fascicle and is believed to be a product of muscle
ischemia at the capillary level. It is found somewhat more often in
juvenile dermatomyositis, but can be observed in the adult variant of
this disorder and is found infrequently in other disease processes.
Complement deposition in microvessel walls: The deposition of the
membrane attack complex of complement (C5b-9) is found in the walls of
the microvessels early in the disease process, even before other
pathologic findings are present. This immune attack on vessel walls,
with an immunologic cascade involving humoral immunity, may be the
pathogenetic mechanism of dermatomyositis, according to the research of
Andrew Engel and his colleagues. Treatment eliminates this finding.
Tuboreticular inclusions in endothelial cells: This finding is seen
only at the ultrastructural level and no longer is present after
treatment.
Inclusion body myositis:
IBM is the most common myositis in patients older than 50 years. In
contrast to polymyositis and dermatomyositis, which affect more women than
men, IBM more often affects men. The clinical course of IBM may be more
indolent than the other two forms of myositis, and distal muscles are
involved more often in IBM. IBM [L08-4194] is the inflammatory counterpart of a group
of disorders labeled inclusion body myopathy, which includes a variety of
inherited myopathies, some with characteristic distinctive clinical
presentations (eg, quadriceps-sparing myopathy). These myopathies share many
of the pathologic findings of IBM.
The following are pathologic features of IBM:
Chronic inflammation: The inflammatory process is similar to that of
polymyositis.
Invasion of nonnecrotic myofibers by autoaggressive lymphocytes.
Hypertrophy: The presence of hypertrophy in a myositis should prompt
a consideration of the possibility of IBM.
Atrophy: Occasionally the atrophic fibers in IBM share features with
those of neurogenic atrophy.
Rimmed vacuoles: These appear on H&E as ovoid sarcoplasmic vacuoles
lined by blue granular material. On trichrome, the granular material is
red.
Eosinophilic inclusions: These inclusions are dense and red on H&E,
may be cytoplasmic or nuclear, and may be found within rimmed vacuoles.
They stain positive with stains for Congo red positive beta-amyloid precursor protein,
ubiquitin (by IHC), and other proteins associated with neurodegenerative disease.
Tubulofilamentous inclusions: These are the ultrastructural
counterparts to the eosinophilic inclusions observed by light
microscopy.
Myofiber degeneration, myophagocytosis, internal nuclei, fibrosis.
An occasional eosinophil often can be seen in necrotizing and
inflammatory myopathies. When many eosinophils are present, begin to search
for a specific etiology of the myopathy, such as trichinosis or drug
reaction.
(Karen Xu, M. D. 30 June 2005) |
