NEUROPATHOLOGY FOR MEDICAL STUDENTS
Presented by William I. Rosenblum, MD
CHAPTER 10--MUSCLE PATHOLOGY
The functional and structural integrity of skeletal muscle depend on its nerve supply. Each motor neuron in the spinal cord or brain stem supplies many muscle fibers, usually several hundreds in large muscles. The motor neuron, its axon and the muscle fibers supplied by it, are known as a motor unit.
This image shows a diagram of four motor units. Using certain enzyme histochemical staining techniques, two basic types of fibers are recognized in human skeletal muscle.
Type 1. These fibers are rich in oxidative enzymes and stain darkly by NADH-tetrazolium reductase technique (NADH-TR).
Type 2. These fibers are low in mitochondrial oxidative enzymes, but stain darkly for myofibrillar ATPase.
The image above illustrates an NADH-TR stain showing dark type 1 and pale type 2 fibers. The latter would appear dark in ATPase stain. At least two subtypes are now identified among type 2 fibers using different methods of staining. All of the muscle fibers in a given motor unit are of the same histochemical types, either type 1 or type 2, suggesting that the neuron determines the type of muscle fibers. The fibers of adjacent motor units overlap and intermingle resulting in a characteristic mosaic or checkerboard pattern.
This image diagrammatically illustrates this phenomenon.. The diagnostic investigation of a muscle biopsy specimen includes evaluation of the size, distribution and the relative number of these two major fiber types.
The diseases of muscle are classified into two broad categories:
 NEUROGENIC DISEASES OF MUSCLE
There are a large number of conditions that affect lower motor neurons or their axons such as:
The denervated myofibers become smaller and more angular (may be round in childhood spinal muscular atrophy), but otherwise remain intact. The cross striation usually persists until very late in the process. Since a single motor unit supplies many fibers (graphic on page 4), denervation initially results in randomly scattered atrophic fibers. With further involvement of adjacent motor units, groups or whole fascicles of fibers become atrophic. This is known as group atrophy.
This diagram illustrates atrophic muscle fibers caused by involvement of an isolated motor unit.
The figure below shows H&E image in which small angular fibers are seen in small groups and also intermingled with intact fibers similar to the previous diagram.
This H&E image shows a large group of atrophic fibers [center] next to a group of normal fibers (left), a typical example of group atrophy.
If the denervated muscle fibers are in the vicinity of intact axons, they may become reinnervated by collateral sprouting. Since the motor neuron determines the muscle fiber type, all of the reinnervated fibers are converted to a single histochemical fiber type with loss of the normal checkerboard pattern. This phenomenon is called "type grouping." The image below illustrates typical type grouping in an ATPase stain. Note the area of dark type 2 fibers next to a large area of pale type 1 fibers. Normal checkerboard pattern is lost.
Sometimes, denervated muscles stained with the NADH-TR method show an unstained area surrounded by a dense rim in the central zone of the myofibers. This is known as target fiber. The end stage of denervation is reflected by nearly total replacement of muscle by fibroadipose tissue.
In many disorders in this category, the pathologic changes in the muscle are non-specific. However, these changes, when analyzed in light of the clinical manifestations, are usually helpful in the diagnosis of these disorders. Some of the common myopathic changes are as follows:
A. Necrosis phagocytosis and regeneration: Necrosis of muscle fibers is a common feature in many myopathic conditions especially in the early stages. This is largely responsible for elevated serum enzymes, notably creatine phosphokinase (CPK) in many active myopathic conditions. Necrosis is followed by phagocytosis of the necrotic debris. The phagocytes invade the necrotic fiber and remove the debris. Phagocytosis is illustrated below
In most instances, regeneration of the muscle fibers follows. The regenerating fibers appear slightly bluish in H and E stain and contain large vesicular nuclei with prominent nucleoli frequently occupying the central part of the muscle fibers (image below).
B. Random variation of fiber size: Unlike group atrophy in denervation, atrophic fibers are usually scattered in a random fashion among normal and frequently hypertrophic fibers. Both atrophic and hypertrophic fibers are usually round on cross section (image below). Occasionally the atrophy is seen selectively in type 1 fibers such as in myotonic dystrophy or in type 2 fibers as in a variety of unrelated conditions including disuse atrophy.
C. Nuclear changes: Among several other changes, displacement of the nuclei from the periphery of the fibers to the central zone is significant. This phenomenon is frequently seen in various muscle dystrophy (illustrated in image below, particularly in the lower two fibers).
D. Endomysial fibrosis: Normally a thin rim of endomysial tissue surrounds individual muscle fibers. An excessive production of connective tissue is often seen in many myopathic conditions, notably in dystrophy.
This image above shows almost indiscernible endomysial connective tissue in normal muscle.
The image below shows a large amount of dense collagenous connective tissue around individual muscle fibers that show other myopathic changes. In inflammatory myopathy, a variable number of lymphocytes and other mononuclear cells are seen in the interstitium with or without fibrosis.
E. Fiber splitting: The longitudinal splitting of fibers is identified by noting that the split fibers are enclosed within the same endomysial sheath (image below).
F. Ring fiber: The outermost myofibrils are seen to coil around the longitudinally oriented myofibers. The significance of this phenomenon is unclear, but it may be present in myotonic dystrophy as well as other unrelated conditions (illustrated image below).
G. Vacuolar changes: These are non-specific and are seen in many conditions. Accumulation of glycogen in large amounts may resemble vacuolar changes (image below). The changes mentioned above are seen in various combinations in most myopathies.
The myopathic disorders may be classified in the following categories:
Only a few selected examples will be described.
SPECIFIC MYOPATHIC CONDITIONS
1. MUSCULAR DYSTROPHIES
These are a group of disorders of unknown pathogenesis in which skeletal muscle involvement is the predominant feature. They are usually classified on the basis of mode of inheritance, age of onset, pattern of involvement, etc. Illustrative diseases are described below.
DUCHENNE MUSCULAR DYSTROPHY
This is the most severe type of muscular dystrophy and is transmitted as an X-linked recessive trait. Sporadic cases are also seen. The disease begins in early childhood and progresses relentlessly. The patients usually die during the second or third decade. The myocardium is also involved in some cases. It has been shown recently that Duchenne dystrophy is due to a mutation at Xp 21, a specific locus on the short arm of the X chromosome. This results in diminution of dystrophin, a normal component of muscle cell membranes.
The histologic findings vary with the duration of the disease. In the early stages, there is focal necrosis, phagocytosis and regeneration of myofibers. Subsequently, there is marked variation of the fiber size with increased endomysial fibrosis. Central displacement of sarcolemmal nuclei are common. Eventually, the skeletal muscles are almost totally replaced by fibroadipose tissue.
This image shows focal necrosis and phagocytosis in the early stage.
This image illustrates marked variation of the fiber size.
A higher power of similar changes can be seen in this image.
The late stage is shown in the image above, where muscle is replaced by fibroadipose tissue.
2. INFLAMMATORY MYOPATHY
This disorder of uncertain cause occurs at all ages and includes two major types: polymyositis and dermatomyositis. Several subtypes are recognized on the basis of age, clinical manifestations and other associated conditions. The pathologic changes in all types are basically similar. The characteristic features are shown in the images below.
In early and active stages of the disease, necrosis of myofibers and inflammatory mononuclear cellular infiltrate in the interstitium are characteristic features.
Other non-specific myopathic changes may be present at different stages of the disease. In some patients, particularly children atrophic fibers may be largely confined to the periphery of the fascicles known as perifascicular atrophy
3. METABOLIC AND ENDOCRINE MYOPATHIES
Muscle weakness may be seen in association with certain endocrine disorders. Pathologic changes in these conditions, when present, are mild and non-specific. Several metabolic disorders are recognized in which skeletal muscles are affected. Glycogen storage diseases are important in this category. At least five of the glycogenoses have been shown to involve skeletal muscle. McArdle's disease is an example in which glycogenesis is restricted to the skeletal muscle because of myophosphorylase deficiency.
Pathologic change consists of an excessive accumulation of glycogen in myofibers. In the image below, the vacuolated appearance is due to extraction of glycogen during histologic preparation.
A definitive diagnosis can be made from muscle biopsy specimen by histochemical demonstration of lack of myophosphorylase activity. This image illustrates this feature
The pale-looking half shows no myophosphorylase activity as compared to a normal control in the upper two thirds of the figure.
In some metabolic myopathy, there is an accumulation of neutral fat. In some instances, this is due to a deficiency of carnitine which is essential for the metabolism of fatty acids.
An increased number of abnormal mitochondria are seen in the muscle in some patients with a variety of neuromuscular and other systemic manifestations. The nature of this group of disorders remains to be clarified.
4. CONGENITAL MYOPATHY (illustrated below)
Several types of disorders are included in this class. They are distinguished from one another by characteristic morphologic appearance. Some of these are inherited. They usually share the common manifestation of infantile hypotonia (Floppy Baby) and slowly progressive or nonprogressive muscular weakness.
A. Nemaline (rod) myopathy
It is characterized by the presence of numerous rod-like structures or granules within the myofibers.
This cross section of muscle fiber stained by modified trichrome method shows subsarcolemmal accumulation of abnormal material (image above).
This longitudinal section shows rod-like inclusions breaking up the normal striated pattern of skeletal muscle shown in the rest of the affected fibers. The rod-bodies appear to arise from Z-bands of the muscle (image above).
B. Central core disease
It derives its name from the presence of "cores" in the central zones of many myofibers. The cores are best demonstrated by certain special stains (illustrated in trichrome stained image above), including NADH-TR. In the latter stain, the cores remain unstained.