Inclusion body myositis masquerading as polymyositis: A case study

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Inclusion Body Myositis Masquerading as Polymyositis: A Case Study Andrea J. Boon, MD, Kathryn A. Stolp-Smith, MD ABSTRACT. Boon AJ, Stolp-Smith KA. Inclusion body myositis masquerading as polymyositis: a case study. Arch Phys Med Rehabil 2000;81:1123-6. A case of inclusion body myositis masquerading as unresponsive polymyositis is presented. A 56-year-old woman diagnosed with ‘‘biopsy-proven’’ polymyositis in 1991 was referred to our clinic in 1997 with progressive, painless weakness that was unresponsive to steroid therapy. Further evaluation, including electromyography and review of the original muscle biopsy specimen, found a diagnosis of inclusion body myositis, leading to a change in the patient’s prognosis and management. Inclusion body myositis is frequently mistaken for polymyositis, despite the fact that it is now the most common inflammatory myopathy affecting people older than 50 years. The purpose of this report is to increase awareness of this disease, to enhance early diagnosis, and to ensure appropriate management. We discuss the clinical findings, pathogenesis, and physiatric management, as well as compare this disease with other idiopathic inflammatory myopathies. Key Words: Electromyography; Muscular diseases; Muscle weakness; Myositis, inclusion body; Rehabilitation. r 2000 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

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NCLUSION BODY MYOSITIS (IBM) is a common, acquired, slowly progressive, and disabling inflammatory myopathy that has only been recognized in the past decade. The clinical presentation is quite characteristic compared with other idiopathic inflammatory myopathies, which, in conjunction with the electrodiagnostic, laboratory, and histologic findings, can make the diagnosis quite straightforward if one maintains a high level of awareness. The pathogenesis is uncertain, although there is some evidence for autoimmune, infectious, or degenerative causes. The disease is resistant to treatment with steroid drugs or other immune suppressants, and the prognosis is guarded, with gradual progressive decline. We present a case of unresponsive polymyositis, which was diagnosed as IBM 7 years after initial presentation. An earlier diagnosis might have spared the patient many risks and complications related to the long-term use of high-dose prednisone and azathioprine. CASE REPORT A 56-year-old woman had been diagnosed with ‘‘biopsyproven’’ polymyositis in 1991 after developing painless, bilateral lower limb weakness. There was predominantly proximal muscle involvement with some asymmetry, but no dysphagia, From the Department of Physical Medicine and Rehabilitation, Mayo Clinic and Mayo Foundation, Rochester, MN. Submitted June 22, 1999. Accepted in revised form November 15, 1999. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Kathryn A. Stolp-Smith, MD, Department of Physical Medicine and Rehabilitation, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. 0003-9993/00/8108-5702$3.00/0 doi:10.1053/apmr.2000.5585

rash, or systemic symptoms. The patient reported some muscle atrophy, but she denied fasciculations, muscle cramps, or sensory symptoms. The weakness gradually progressed to involve the upper limbs and trunk, and there was minimal response to high-dose steroids, azathioprine, or methotrexate. Medical history was significant only for hyperlipidemia treated with lipid-lowering agents for several years. The patient presented to our institution in 1997 for further evaluation of progressive weakness, unresponsive to steroid therapy. At that time she was able to ambulate with the assistance of a cane and by maintaining her knees in extension. She needed assistance for transfers from sitting to standing, with stairs, and to get in and out of a car. She had discontinued driving several years earlier because of distal weakness. She lived in a one-level home with her husband and remained independent in basic activities of daily living (ADLs) such as dressing, feeding, and grooming; however, she had difficulty with overhead activities such as washing or combing her hair, which required her to rest often. Her husband assisted with instrumental ADLs, including work around the house, particularly any activities that involved lifting. These difficulties with ADLs had come on insidiously and progressed slowly, but she believed she was gradually becoming more disabled. On examination the patient had 2/5 strength in her quadriceps, ankle dorsiflexors, and long finger flexors bilaterally, with less significant weakness (4/5) in other major muscle groups, including deltoids, shoulder rotators, hip abductors, wrist extensors, and toe flexors. There was marked side-to-side asymmetry, which the patient reported had been present since the onset of symptoms. Facial muscles were intact. Deep tendon reflexes were absent at the knees and symmetrically reduced elsewhere. Plantar responses were downgoing bilaterally. Sensory systems were intact. There was no evidence of a skin rash or any muscle tenderness to palpation. Creatine kinase (CK) levels were mildly increased and had never been more than three times the upper limit of normal. Electrodiagnostic testing at the patient’s initial presentation to our institution showed only occasional fibrillation potentials and mostly small, rapidly recruited motor unit potentials (MUPs). A further trial of higher-dose steroids and azathioprine failed, and when her weakness progressed significantly after a flu-like illness, a repeat electromyogram was done. This time, a more focused examination was performed that specifically included the quadriceps and finger flexor muscles. Frequent fibrillation potentials were noted in the muscles most severely affected clinically, with a mixed population of short, rapidly recruited and large, polyphasic, slowly recruited MUPs. These findings were thought to be most suggestive of IBM in light of the clinical picture and pattern of muscle involvement. Congo red staining had not been performed at the time of the original biopsy, thus precluding definitive diagnosis. During the patient’s evaluation at our institution, it was thought that a second biopsy, with its associated risks, was not indicated, because there was adequate clinical and electrophysiologic evidence to make the diagnosis in the absence of definitive histopathology. The prednisone dose was tapered to zero and the azathioprine was discontinued. The patient had developed significant osteoArch Phys Med Rehabil Vol 81, August 2000

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porosis, likely related to the long-term steroid use, as well as glucose intolerance, which resolved after discontinuing prednisone. At initial follow-up she reported some improvement in her subjective symptoms of weakness and overall well-being (perhaps in part caused by the resolution of some degree of steroid myopathy and weight loss after discontinuing prednisone). She continued to require assistance with transfers and used a cane for ambulation. DISCUSSION IBM is now the most common acquired idiopathic myopathy seen in adults older than 50 years.1,2 It is frequently misdiagnosed, with an average delay to diagnosis from onset of symptoms of 6 years.2 The patient typically presents with insidious onset of slowly progressive weakness, as opposed to a more acute or subacute course that is usually seen in polymyositis. Distal muscles are frequently involved,2 in addition to proximal muscles, and there appears to be selective involvement, with associated weakness and atrophy, of the quadriceps, ankle dorsiflexors, wrist flexors, and the long finger flexors.3-5 The quadriceps reflex is diminished early in the course of the disease,2 with relative preservation of the other reflexes. Dysphagia is prominent, occurring in up to 40% of cases. Other muscles innervated by the cranial nerves are generally spared, although occasionally there can be involvement of the facial muscles. Peripheral neuropathy is present in up to 30% of patients and autoimmune disorders are present in 15%.2 Electrodiagnostic testing is helpful but not diagnostic. Results of nerve conduction studies are generally normal or show evidence of a mild sensory neuropathy. Needle examination reveals frequent fibrillation potentials in the muscles most affected clinically and a mixed population of small and large complex MUPs. Large, polymorphic MUPs are nonspecific and not merely indicative of a neuropathic process, as is commonly believed.6 In the case of IBM, chronic ongoing muscle disease with fiber splitting and regeneration may lead to significant remodeling of the muscle, with resultant reinnervation of muscle fibers by neighboring motor neurons. Another possible cause for such ‘‘neurogenic appearing’’ MUPs in inflammatory myopathies is extension of the inflammation and fibrosis to involve the intramuscular nerve branches in addition to the muscle fibers themselves. Therefore, it is not uncommon to see large, complex MUPs in addition to the low amplitude, rapidly recruited MUPs typically associated with myopathic disease. Other diagnostic tools include measuring CK enzyme levels, which are usually at least 5 to 10 times more than normal in polymyositis4,5 but only mildly increased, if at all, in IBM.2,3 Muscle biopsy is helpful. Diagnostic features include (1) endomysial T-cell infiltrates, with invasion of nonnecrotic fibers; (2) one or more rimmed vacuoles with amyloid deposits per low-power field; and (3) tubulofilamentous cytoplasmic or nuclear inclusions or evidence of amyloid deposition in the muscle fibers after Congo red staining.2,3,7,8 Early on there is an attack on muscle fibers by cytotoxic T lymphocytes, which is less evident later in the disease. Vacuolar degeneration becomes more prominent in the later stages of the disease, as does muscle fiber atrophy, which often resembles that seen in denervation atrophy. Proposed diagnostic criteria for IBM were developed by Mendell and colleagues and presented by Griggs and colleagues9 (table 1). The differential diagnosis for slowly progressive, painless weakness includes other inflammatory myopathies. There are three major classes of inflammatory myopathies—IBM, polymyositis, and dermatomyositis—all of which are clinically, pathogenetically, and histologically distinct. Polymyositis and dermatomyositis typically present acutely or subacutely with Arch Phys Med Rehabil Vol 81, August 2000

predominantly proximal weakness, and in dermatomyositis a rash usually precedes or accompanies the weakness.4,5 CK levels are characteristically increased to more than 10 times normal, and both diseases usually respond to steroids and other immunosuppressants. Other entities that should be considered in the differential diagnosis for this case include iatrogenic myopathies (in this case caused by cholesterol-lowering agents or steroids) and neuromuscular disease such as spinal muscular atrophy, other motor neuron diseases, or multifocal motor neuropathy with conduction block. Endocrinopathies and metabolic disorders such as glycogen storage disease should also be considered. In the absence of sensory symptoms, chronic inflammatory demyelinating polyradiculopathy would be unusual and a vasculitic process usually would be painful. The pathogenesis of IBM is unknown, whereas it is known that polymyositis is a cell-mediated immune response directed at the muscle fibers3,5,10,11 and that dermatomyositis is a humorally mediated microangiopathy.3,5,10-14 There are several theories, including one involving an autoimmune basis, because there is a CD8 T-cell attack on the muscle fibers in IBM, and the disease is sometimes seen in association with autoimmune disorders or monoclonal gammopathies.15,16 However, it is not established whether the inflammatory response is the primary mediator of the disease process or a secondary response. Although viral particles have not been isolated in the inclusion body, there have been case reports of IBM developing after a viral infection, specifically mumps, hepatitis C, and retroviral infections.4,17 A further theory is that the pathogenesis is a degenerative process, because the same amyloid deposits seen in the basal ganglia in Alzheimer disease are found in the rimmed vacuoles in IBM.7,18 There are some cases that appear to evolve from polymyositis or dermatomyositis; however, many authors believe that many cases diagnosed as unresponsive polymyositis are in fact early IBM in which patients present before the development of characteristic histologic features.3 This is the most likely explanation in the case described here. There is a second entity that clinicians should consider: the group of hereditary inclusion body myopathies in which inflammation is not a feature. This includes clinically and genetically distinct myopathies that have proximal and distal weakness (often with prominent hamstring involvement), variable inheritance, and pathologic features of a rimmed vacuolar myopathy without inflammation. This subset of myopathies was previously referred to generically by the term ‘‘distal myopathies,’’ which frequently occur sporadically in familial and ethnic distributions. Many patients have been treated with steroids at some point during the course of their disease. One challenge in evaluating a patient with myopathy is attempting to determine if ongoing weakness is a result of the primary disease process, or is in fact due to steroid myopathy. This is an important distinction, because steroid myopathy is reversible with cessation of the medication, but in an undertreated inflammatory myopathy, increasing the steroid dose may be of substantial benefit. The characteristic clinical pattern in a steroid myopathy is proximal muscle weakness, without any elevation of CK, and the findings on electromyography are usually minimal. Prednisone preferentially affects type II muscle fibers, which are not recruited with the low-level voluntary muscle activation that is typically used in qualitative electromyography.6 Prognosis also differs from that of polymyositis. IBM tends to be slowly but relentlessly progressive, with severe incapacitation over time. There are few studies to date that have looked at long-term outcome, morbidity, and mortality in IBM. Lotz and colleagues2 followed 28 patients for a mean time of 72

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INCLUSION BODY MYOSITIS, Boon Table 1: Proposed Diagnostic Criteria for Inclusion Body Myositis Characteristic Features—Inclusion Criteria Clinical features Duration of illness Age at onset Muscle weakness

Laboratory features Serum creatine kinase Muscle biopsy

Electromyography Family history Epidemiology Diagnosis

Associated Disorders Occurrence Presence of an associated condition Diagnostic Criteria Definite IBM

Possible IBM

⬎6 months ⬎30 years old Must affect proximal and distal muscles of arms and legs and Patient must exhibit at least one of the following features ● Finger flexion weakness ● Wrist flexor ⬎ wrist extensor weakness ● Quadriceps muscle weakness (ⱕ grade 4 MRC) ⬍12 times normal level Inflammatory myopathy characterized by mononuclear cell invasion of nonnecrotic muscle fibers Vacuolated muscle fibers One of the following ● Intracellular amyloid deposits (must use fluorescent method of identification before excluding the presence of amyloid) ● 15 to 18nm tubulofilaments by electron microscopy Must be consistent with features of an inflammatory myopathy (however, long-duration potentials are commonly observed and do not exclude diagnosis of sporadic IBM) IBM can rarely be observed in families This condition is different from inclusion body myopathy without inflammation Requires specific documentation of the inflammatory component by muscle biopsy and Vacuolated muscle fibers Intracellular (within muscle fibers) amyloid 15 to 18nm tubulofilaments IBM occurs widely with a variety of other, especially immune-mediated, conditions Does not preclude a diagnosis of IBM if diagnostic criteria (below) are fulfilled Patients must exhibit all muscle biopsy features including ● Invasion of nonnecrotic fibers by mononuclear cells ● Vacuolated muscle fibers ● Intracellular (within muscle fibers) amyloid deposits or ● 15 to 18nm tubulofilaments None of the other clinical or laboratory features are mandatory if muscle biopsy features are diagnostic Muscle shows only inflammation (invasion of nonnecrotic muscle fibers by mononuclear cells) without other pathologic features of IBM and Patient exhibits characteristic clinical and laboratory features (except muscle biopsy) described above

Abbreviations: IBM, inclusion body myositis; MRC, Medical Research Council. Developed by J. Mendell, R. Barohn, V. Askanas, M. Dalakas, S. DiMauro, A. Engel, G. Karpati, L.P. Rowland. Adapted with permission.9

months. Six patients observed for 15 years or longer became severely incapacitated. One was bedridden after 10 years and died of respiratory and cardiac failure 12 years after onset. Patients are at risk of aspiration pneumonia secondary to dysphagia as well as restrictive lung disease when the abdominal, spinal, and respiratory muscles are involved.17 Therefore, it is prudent to follow up those patients with pulmonary function tests and to emphasize the importance of preventive measures such as chest expansion and thoracic extension exercises. Sphincters are not typically involved, and the presence of such symptoms should prompt a search for a different disease entity. Symptoms are generally unresponsive to steroid agents or immunosuppression, including azathioprine and immunoglobulin therapy. Studies to date have been inconclusive, but the general consensus is that patients should have a 6-month trial of

medication before it is determined that their disease is unresponsive to immunosuppression. Regular stretching and range of motion exercises are an important part of the overall management in patients with IBM to prevent contractures and maintain function wherever possible. There has been one study to date that examined the effect of a supervised progressive resistance training program in IBM patients and, although limited by small sample size, the authors found no deleterious effects in terms of biopsy changes or CK levels and did note strength gains in the muscles least affected.19 In other inflammatory myopathies, submaximal exercise has been shown to be safe and effective,20-22 although eccentric or intense exercise to the point of muscle fatigue is not recommended. The dysphagia commonly seen in IBM is most often related Arch Phys Med Rehabil Vol 81, August 2000

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to upper esophageal dysfunction.2,5 This is similar to that seen in polymyositis, although in polymyositis impaired mobility has been documented in the pharyngeal muscles as well as the upper and lower esophagus.5 Affected patients should undergo a comprehensive swallow evaluation, including videofluoroscopy when indicated. Management includes modification of diet and use of compensatory techniques to enhance swallowing and avoid aspiration.23 In summary, IBM is the most common idiopathic inflammatory myopathy affecting patients aged over 50 years. It affects proximal and distal musculature. There is usually side-to-side asymmetry and prominent involvement of the quadriceps, ankle dorsiflexors, and wrist and finger flexors. Dysphagia is common. The diagnosis should be suspected in a patient with a more insidious onset of painless weakness than is typical of polymyositis, particularly when CK levels are only minimally increased or where there has been no response to steroids at the dose ordinarily considered effective in polymyositis. Electromyography often shows a pattern of increased spontaneous activity, with a mixed population of large and small MUPs. Muscle biopsy can be diagnostic if certain pathologic features are present. The prognosis is more guarded than that for other inflammatory myopathies, and at this time no medication has been shown clearly to be effective. References 1. Sivakumar K, Dalakas MC. Inclusion body myositis and myopathies. Curr Opin Neurol 1997;10:413-20. 2. Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis. Observations in 40 patients. Brain 1989;112: 727-47. 3. Amato AA, Gronseth GS, Jackson CE, Wolfe GI, Katz JS, Bryan WW, et al. Inclusion body myositis: clinical and pathological boundaries. Ann Neurol 1996;40:581-6. 4. Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med 1991;325:1487-98. 5. Griggs RC, Mendell JR, Miller RG. Evaluation and treatment of myopathies. Philadelphia: FA Davis; 1995. 6. Dumitru D. Electrodiagnostic medicine. Philadelphia: Hanley & Belfus; 1995. p. 1031-129. 7. Mendell JR, Sahenk Z, Gales T, Paul L. Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of filaments. Arch Neurol 1991;48:1229-34. 8. Askanas V, Engel WK. Sporadic inclusion-body myositis and hereditary inclusion-body myopathies: diseases of oxidative stress and aging? Arch Neurol 1998;55:915-20.

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9. Griggs RC, Askanas V, DiMauro S, Engel A, Karpati G, Mendell JR, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705-13. 10. Dalakas MC, Sivakumar K. The immunopathologic and inflammatory differences between dermatomyositis, polymyositis and sporadic inclusion body myositis. Curr Opin Neurol 1996;9:235-9. 11. Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann Neurol 1984;16:193-208. 12. Kissel JT, Halterman RK, Rammohan KW, Mendell JR. The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis. Arch Neurol 1991;48:26-30. 13. Emslie-Smith AM, Engel AG. Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol 1990;27:343-56. 14. Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986;314:329-34. 15. Dalakas MC, Illa I, Gallardo E, Juarez C. Inclusion body myositis and paraproteinemia: incidence and immunopathologic correlations. Ann Neurol 1997;41:100-4. 16. Rugiero M, Koffman B, Dalakas MC. Association of inclusion body myositis with autoimmune diseases and autoantibodies [abstract]. Ann Neurol 1995;38:333. 17. Mikol J, Engel AG. Inclusion body myositis. In: Engel AG, Franzini-Armstrong C, editors. Myology: basic and clinical. 2nd ed. Vol. 2. New York: McGraw-Hill; 1994. p. 1384-98. 18. Askanas V, Engel WK. New advances in the understanding of sporadic inclusion-body myositis and hereditary inclusion-body myopathies. Curr Opin Rheumatol 1995;7:486-96. 19. Spector SA, Lemmer JT, Koffman BM, Fleisher TA, Feuerstein IM, Hurley BF, et al. Safety and efficacy of strength training in patients with sporadic inclusion body myositis. Muscle Nerve 1997;20:1242-8. 20. Wiesinger GF, Quittan M, Aringer M, Seeber A, Volc-Platzer B, Smolen J, et al. Improvement of physical fitness and muscle strength in polymyositis/dermatomyositis patients by a training programme. Br J Rheumatol 1998;37:196-200. 21. Hicks JE. Exercise in patients with inflammatory arthritis and connective tissue disease. Rheum Dis Clin North Am 1990;16: 845-70. 22. Escalante A, Miller L, Beardmore TD. Resistive exercise in the rehabilitation of polymyositis/dermatomyositis. J Rheumatol 1993; 20:1340-4. 23. Noll SF, Bender CE, Nelson MC. Rehabilitation of patients with swallowing disorders. In: Braddom RL, editor. Physical medicine and rehabilitation. Philadelphia: WB Saunders; 1996. p. 533-54.