Check Your Diagnosis — Patient 6
Mary Ellen Vanderlick, M.D.
Inclusion Body Myositis
This patient was referred for long-standing progressive weakness which was first noticed while climbing stairs, characteristic of proximal lower extremity weakness. Later, he began having difficulty in descending stairs, suggestive of distal weakness. The weakness continued to progress, and eventually involved both upper extremities. The history of the onset and progression of the weakness was most important in this case, because by the time we first saw the patient, he already had diffuse, severe atrophy and weakness, both proximally and distally.
His referring physician had raised the possibility of muscular dystrophy, and more specifically myotonic dystrophy. This diagnosis was suspected because of the patient's neck flexor weakness, complaints of dysphagia, the presence of cataracts and frontal balding, and distal weakness. However, the cataracts and frontal balding should not be considered specific for a diagnosis of myotonic dystrophy. The absence of either action myotonia or percussion myotonia, as well as the negative family history (patient had three healthy brothers), also made this diagnosis less likely. Other muscular dystrophies were considered unlikely because of the distal weakness in finger flexors, the proximal and distal weakness in the legs, the late age of onset, and the absence of a positive family history.
The pattern of muscle weakness was characteristic for an inflammatory myopathy, either polymyositis or inclusion body myositis. Polymyositis was thought to be less likely due to the distal muscle weakness in the upper and lower extremities, a normal sedimentation rate, and the slightly elevated creatine phosphokinase at 489. The pattern of weakness which includes proximal leg and distal hand involvement is most characteristic of inclusion body myositis.
The EMG was surprising since it showed true myotonic discharges with myopathic features consistent with myotonic dystrophy. The muscle biopsy, however, demonstrated myopathic alterations with inflammatory foci, rimmed vacuoles, inclusions which stained for amyloid, and ragged red fibers, all of which were diagnostic of inclusion body myositis. Because of the EMG findings, DNA testing for CTG repeats (diagnostic for myotonic dystrophy) was carried out, and was reported as normal. Thus, the myotonia on the EMG was considered to result from the inclusion body myositis.
The term inclusion body myositis was coined in 1971 to describe patients with chronic polymyositis that also had muscle inclusions. Inclusion body myositis (IBM) may be either sporadic (s-IBM) or hereditary (h-IBM).
Sporadic Inclusion Body Myositis (s-IBM)
S-IBM is the most common muscle disease in patients over age 55. The etiology is unknown, but the prominent inflammatory foci suggest an immune-mediated mechanism. There is a male predominance and weakness occurs in both distal and proximal muscles. The most common clinical presentation is proximal weakness in the legs, and distal weakness in the arms. Involved muscles include the quadriceps, iliopsoas, tibialis anterior, biceps, triceps, and finger flexors. Dysphagia is also a common symptom.
The typical muscle biopsy features in patients with s-IBM include inflammatory foci, rimmed vacuoles, atrophic angular fibers (indicating denervation), and inclusions. The majority of the inflammatory cells are CD8 T-lymphocytes. Mitochondrial alterations, including an increased number of mitochondria, as well as ragged-red fibers, have been described in s-IBM. Serum CPK levels are usually normal to modestly increased.
Hereditary Inclusion Body Myositis (h-IBM)
H-IBM can be inherited either as an autosomal-recessive or autosomal-dominant trait. The genetic defects in h-IBM are not known. The histochemical and ultrastructural abnormalities are similar to s-IBM except that the h-IBMs lack mononuclear-cell inflammation in the biopsy. Because of this, it has been suggested that the term inclusion body myopathy be used instead of inclusion body myositis. Mitochondrial paracrystalline inclusions and mitochondrial DNA deletions are not present in h-IBM. In the h-IBM muscles, there are also decreased amounts of phosphorylated tau and intracellular amyloid.
There are distinctive aspects of IBM pathology. Intracellular amyloid deposits have been demonstrated within the s-IBM vacuolated muscle fibers with Congo red and confirmed with thioflavin-S and cresyl violet. A new method of enhancing Congo red positivity, using fluorescent filters, enables identification of amyloid that would otherwise be missed. Within the vacuolated muscle fibers of IBM, there are abnormal accumulations of prion protein, acetylcholine receptor, and proteins that are typically found in Alzheimer brain (ß-amyloid, N-terminal and C-terminal epitopes of ß-amyloid precursor protein, alpha 1 antichymotrypsin, phosphorylated tau, apolipoprotein E, and ubiquitin). Except for tau, all are found at normal human neuromuscular junctions.
The characteristic ultrastructural finding of IBM is the presence of cytoplasmic twisted tubulofilaments, 15 to 21 nm in diameter. These are paired helical filaments (PHFs) that are similar to that of Alzheimer's disease. Other findings include cytoplasmic clusters of small amyloid-like fibrils, flocculomembranous material, and amorphous material.
An important unanswered question is what triggers this unique muscle pathology. Also unexplained is why patients with IBM are not reported to have Alzheimer's disease, despite the similar pathological changes in muscle and brain respectively. The pathological changes of IBM have been described in oculopharyngeal muscular dystrophy, having in common at least three proteins: ubiquitin, ß-amyloid precursor protein, and phosphorylated tau. Thus, the pathological findings are not specific for IBM.
In IBM, there is evidence of denervation in the muscle biopsy and with EMG. In addition to myopathic units in the EMG, nearly all patients have a definite neurogenic pattern, reflecting recent denervation with fibrillations and positive sharp waves; and previous denervation followed by reinnervation with polyphasics of normal and longer duration and increased amplitude.
There is no established effective treatment for IBM. Steroids as well as other immunosuppressive therapies are usually of limited value. More recently, treatment with IV immunoglobulin has been reported to provide more reproducible benefit, but further studies are needed to validate these observations.
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