Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
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        Anti-Muscle Associated Antibody Tests, blood
      
Muscle biopsy:

In our community hospital, most of our biopsies (several per month) are to prove polymyositis or to help differentiate a myopathy from a neurogenic weakness. Our local neurologists often refer highly elective case situations to the neurology service in Augusta, Ga.

An excellent & comprehensive website with lab test info (including an extensive catalogue of muscle-disease associated antibodies) is at the Washington University (St. Louis, MO) Neuromuscular Disease Center (NDC); a good site with histology photos is HERE...use the drop down menu to find myopathies.

A fairly common myopathy which we will never see biopsied is the autoimmune myopathy, myasthenia. Most commonly, the attack affects extra-ocular muscles (ocular myasthenia) and often progresses to a general involvement (myasthenia gravis). Antibodies cause the effect in at least three ways (see ARUP review HERE). Those who consult on this disease like to see antibodies titered so that responses to treatment can be followed. If the serum antibody against the acetylcholine receptor (AChR) is undetectable, then one screens for anti-MuSK (see ARUP, above). There are inherited & acquired myasthenias (see NDC, above).

By long habit and satisfaction, we have primarily referred our muscle biopsies to the lab of Dr. Andrew Engel at Mayo Clinic. Dr. Roberta Seidman also directs an expert lab at Stonybrook (see below) which can provide services to those who have limited on-site resources (and, they can do EM when/if indicated).

As of 2010, the lines of evidence that can be tapped in muscular disease include EEG, routine lab tests, reference-lab type bichemical tests, western blot tests, genetic tests, serum antibody tests, histological tests from routine H&E & special stains & markers to DIF to EM, enzyme histochemical stains, etc. When patients are not referred to major centers for workup, a major challenge is the obtaining of an array of specimens sufficient to allow a specific diagnosis.

Classification:
Clues to inflammatory (inflammatory cellular presence, especially if appears to be affecting muscle fibers) myopathy muscle disease:
  • clinical & lab: myalgia (muscle aches & pains) & elevated muscle enzymes such as CPK.
  • histological: normal myocyte pattern but with clusters of inflammatory cells.

Clues to neurogenic (nerve-damage-induced) muscle disease:

  • clinical & lab: weakness and/or motor dysfunction & lack of elevated muscle enzymes.
  • histological: myocyte fiber size & shape variation.

Clues to non-inflammatory (e. g., toxic myopathy) muscle disease:

  • clinical & lab: acute = high CPK; chronic = normal or mildly elevated muscle enzymes.
  • histological: injured myocyte cytoplasmic structure (vacuolation; hypereosinophilic myocytes; variable cytoplasmic staining and even ropey degeneration [dense cytoplasmic cords in otherwise-clear myocytes]); macrophages.

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 or CPK) level is the single most important ROUTINE blood test to obtain for the screening 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 (except maybe early dermatomyositis). Myoglobinuria also may reflect myopathy. Either test may be elevated following significant but possibly undisclosed muscular exertion and only represent a very temporary, non-pathological elevation.

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 fluctuating in and out of the normal range & is normal at the test encounter.

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. That is, muscle pathology can be complicated with overlapping features & hence the need for adequate tissue.

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]. Statins can apparently trigger an ongoing injury showing fiber damage for extended periods after they are stopped [L10-8893].
  • Myophagocytosis; macrophages.
  • Regeneration.
  • Rounded atrophic fibers.
  • Fiber hypertrophy and splitting.
  • Increase in internal nuclei.
  • Fibers negative for cytochrome-c-oxidase beyond percentage reasonable for patient's age indicate mitochondrial dysfunction [L09-12896].
  • Fibrosis...maybe first noted focally in perifascicular areas.
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Myositis, glycogen storage diseases, mitochondrial myopathies, and congenital myopathies are 4 important groups of disorders that can be diagnosed by muscle biopsy, as follows:

  • 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). Fibrosis in the biopsy implies chronicity.

    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, no-visible-pathological-change biopsy in a patient who has this disorder is possible, especially early in the course of disease.

    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 antibody (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 [L11-11106].

    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/changes: This atrophy affects the fibers at the periphery of the fascicle [L11-14380] and is believed to be a product of muscle ischemia at the capillary level (fibrosis?[L11-11282]). 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 such as mixed connective tissue disease.

    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 (EM) 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 [L09-12896, L10-5518]. On trichrome, the granular material is red [IMAGE HERE].

    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 (congophilic inclusions), 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.

    Ragged red fibers (muscle myocyte with a hematoxylinophilic periphery) increase with age and appear to relate to mitochondrial dysfunction. And EM might appreciate mitochondrial disease myopathy related to loss of mitochondria.

    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.

  • Storage myopathies:
  • mitochondrial myopathies:
  • congenital myopathies:

References:

  1. A great deal of this outline was based on, or drawn from, the 2005-version excellent web source by Roberta Seidmman, M. D., Director of Neuropathology at Stonybrook University Hospital in Stonybrook, N. Y., her expert analysis being carried in the excellent & highly recommended eMedicine website. http://www.emedicine.com/neuro/topic230.htm
(Karen Xu, M. D. 30 June 2005; latest additions 5 February 2012)
 
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