Inclusion Body Myositis: A Case of Bilateral Extremity Weakness

Abstract

Inflammatory myopathy is a common cause of bilateral muscular weakness in adults. Although not as common as polymyositis, inclusion body myositis (IBM) is a form of inflammatory myopathy characterized by chronic progressive muscle inflammation and often goes undiagnosed and untreated. IBM patients most commonly present with proximal lower extremity weakness and may have normal creatine kinase (CK) levels. A high level of clinical suspicion is required for prompt and accurate diagnosis of IBM, which is diagnosed definitively with a muscle biopsy. The patient described in this case report is a 68-year-old man who initially presented with both bilateral symmetric proximal lower extremity and distal upper extremity weakness. IBM was suspected through history, electromyography, and definitively diagnosed with muscle biopsy. The patient was subsequently initiated on prednisone therapy and physical therapy, with improvement in muscular strength after 2 months. In patients presenting with bilateral extremity weakness and normal CK level, the diagnosis of IBM should be included in the differential diagnosis and muscle biopsy performed for appropriate cases.

Introduction

Inclusion body myositis (IBM) is an inflammatory myopathy characterized by chronic progressive muscle inflammation accompanied by muscle weakness. Although not as common as polymyositis, it is often missed and untreated. It has a prevalence ranging from 5 to 9 cases reported per million adults.¹ It is the most common inflammatory myopathy in individuals over the age of 50 years.² Unlike other inflammatory myopathies, IBM does not respond to treatment as well as polymyositis and has a slowly progressive clinical course, though uncommonly some patients do respond to steroid therapy. Because this is a relatively rare disorder, a high level of suspicion is required for the diagnosis of IBM, which requires a muscle biopsy. Prompt and accurate diagnosis of IBM is essential, both for initiation of management and for patient education regarding the clinical course of this disease. The case reported here is a patient with bilateral symmetric extremity weakness, with subsequent work up including a muscle biopsy revealing the diagnosis of inclusion body myositis. A literature review was conducted using the database search engine PubMed. Key inclusion criteria were peer-reviewed articles published in English with keywords including “inclusion body myositis,” “inflammatory myopathy,” and “weakness.”

Case Report

The patient is a 68-year-old man who was referred to a neurology clinic for further evaluation of a 2-year history of proximal and distal extremity weakness. In 2006, the patient was in his previous state of health until he accidentally dropped a chicken coop onto his right first metatarsal. He was eventually hospitalized and subsequently underwent a right transmetatarsal amputation. The patient over the next two years developed a peculiar painless pronounced inflammation of his phalanges on his hands and feet. It eroded the bone and eventually caused pathologic fractures of the 4th and 5th left fingers. Biopsies taken of the amputated toe in 2006 and the left 5th finger in 2011 showed a multinodular epthelioid granulomatous process with stains negative for fungus, bacteria, and acid-fast bacillus (AFB). According to his primary care physician, the inflammation resolved after a prolonged course of doxycycline.

In 2011, the patient was again taken to the emergency room following a non-traumatic fall. He was in his bathroom when his legs suddenly collapsed. He denied any loss of consciousness, acute pain, or discomfort. He was discharged from the emergency room with no further diagnostic testing.

Since his fall in 2011, he noticed progressive bilateral symmetric weakness in his proximal and distal lower extremities. He reported having difficulties ambulating — initially requiring a cane and subsequently a walker to assist with walking. He also noticed progressive bilateral symmetric weakness in his hands. He had difficulties performing daily tasks such as opening a jar and gripping handheld objects. He denied weakness in his upper proximal extremities, shoulders, facial, and ocular muscles. He also denied myalgia, dysphagia, headache, lightheadedness, vertigo, loss of consciousness, vision and hearing impairment, or sensory loss. His past medical, family, and social history are noncontributory.

On physical and neurologic exam, patient's vital signs were within normal limits. He appeared alert, awake, in no acute distress, and was pleasant and cooperative. His muscle strength was 5/5 bilaterally on arm abduction at the shoulder, elbow extension, and elbow flexion; 4/5 bilaterally on wrist flexion, wrist extension, and finger abduction; and 2/5 bilaterally on hip flexion, knee extension, and foot dorsiflexion. His gait was significant for difficulty standing from a sitting position without assistance, and short steps when walking forward. The rest of his neurologic exam, including cranial nerves, sensation, reflexes, and cerebellum exam, was within normal limits.

Laboratory testing including basic metabolic panel, liver function test, erythrocyte sedimentation rate, uric acid, anti-nuclear antibodies, rheumatoid factors, aldolase, and acetylcholine receptor antibodies were all within normal limits. His total creatine kinase was mildly elevated at 221ng/mL, with normal reference range being <200ng/mL for adult males.

Nerve conduction studies (NCS) were performed and revealed a mild sensory and motor axonal peripheral neuropathy predominant in the lower extremities. Monopolar needle electromyography (EMG) was more consistent with an inflammatory myopathic pattern, demonstrating diffuse denervation potentials with proximal predominance, including the lumbar/thoracic/cervical paraspinal nerves, but without significant fasciculations. Motor units were more neuropathic in nature with large amplitude, long duration, and polyphasic potentials. However, motor unit recruitment was overall normal to increased, and more consistent with a myopathic pattern. The combination of inflammatory myopathic needle EMG with peripheral axonal sensory polyneuropathy on NCS was indicative of IBM.

Biopsy of the left deltoid muscle was performed and pathology slides contained adequate material with extensive maceration type artifacts, which limited the evaluation. On review of pathology slides, small foci of endomysial infiltrates of chronic inflammatory cells were present. Atrophic myofibers were present as scattered single fibers. There was an increased number of myofibers with internally located nuclei. No significant fiber type grouping or predominance was identified. Target/targetois fibers were not identified. Blood vessels were unremarkable. No significant fibrosis or necrosis was identified. The thioflavine S stain for amyloid in paraffin sections of skeletal muscle revealed the presence of rare fluorescent intra-sarcoplasmic inclusions (Figure 1). The Mendell modification of the Congo red stain revealed the presence of rare fluorescent inclusions associated with vacuolar structures within cryo-sections of skeletal muscle (Figure 2).

Figure 1.

Thioflavine S stained skeletal muscle section showing rare fluorescent intra-sarcoplasmic amyloid inclusions.

Figure 2.

Congo red stained skeletal muscle section showing rare fluorescent amyloid inclusions associated with vacuolar structures.

Treatment with prednisone 1mg/kg/day was initiated. The patient was also referred to physical therapy for strength training. In subsequent clinic follow ups, the patient reported improvement in muscular strength in both his lower and upper extremities. He tolerated his prednisone therapy well with no reported side effects. He was also in compliance with his physical therapy sessions and his daily exercises as recommended by his physical therapists. On neurologic exam, his muscular strengths improved, with 3/5 bilaterally on hip flexion, knee extension, and foot dorsiflexion. The rest of his physical and neurologic exam was unchanged.

Discussion

The etiology of IBM is unknown, and there is continuing debate as to whether IBM is primarily a T-cell mediated inflammatory myopathy or a myodegenerative disorder. Pathogenesis likely involves the invasion of CD8+ lymphocytes in endomysium, basophilic rimmed vacuoles within muscle fiber sarcoplasm, and cytoplasmic/intranuclear inclusions containing amyloid beta proteins. The interaction among these various pathological changes remains unknown.³ In this patient, it is likely that a form of chronic infection may be the triggering factor of IBM. Several viruses, including Coxsackieviruses, influenza, paramyxoviruses, cytomegalovirus, Epstein-Barr virus, and HIV have been indirectly associated with IBM.⁴ However, sensitive studies have failed to prove a definitive connection between IBM and these viruses.

IBM is characterized by chronic progressive muscle inflammation and should be suspected in all patients with unexplained progressive muscle weakness. Weakness is initially most common in the proximal lower extremities, which slowly progress to the distal and upper extremities.⁵ Though atypical, initial presentation of IBM patients with bilateral distal and upper extremity weakness has also been reported. Distal extremity weakness occurs in 50% of patients. In patients with distal extremity weakness, about 35% note distal extremity weakness being as severe as or more severe than proximal extremity weakness.⁶ The ocular and facial muscles are often spared, though cases of mild facial weakness have been reported.⁷ Muscle atrophy is common and usually progresses in parallel with weakness.⁸ Myalgia and dysphagia are also seen in approximately 40% of patients.^9,10 In patients with bilateral symmetric weakness in upper or lower extremities, inflammatory myopathies and IBM are amongst the differential diagnoses. In this case, the patient presented initially with both proximal and distal extremity weaknesses. The etiology of his weakness is likely mutlifactorial, since chronic disuse of his extremity as a consequence of his inflammatory condition in 2006 may have further contributed to his extremity weakness, making the diagnosis of IBM more elusive.

Diagnosis of IBM is typically made on the basis of muscle weakness, normal or mildly elevated muscle enzymes, myopathic features seen on electromyopathy, and characteristic findings on muscle biopsy. There is no diagnostic laboratory test for IBM, although a normal or mildly elevated serum creatine kinase may suggest a myopathic process. Serum creatine kinase is elevated in 89% of IBM patients.³ In IBM patients with elevated serum creatine kinase, it is usually elevated <10 times of normal reference limits, differentiating them from patients with more common myopathy like polymyositis. For adult males, this elevation is usually within the range of ∼200 – 2,000ng/mL. In this case, the patient's initial creatine kinase was measured at 221ng/mL.

While electromyography is not diagnostic of IBM, it is often helpful in suspected cases. EMG may also be helpful in identifying highest yield biopsy sites and assessing response to therapy. EMG findings in IBM include diffusely increased insertional activity, spontaneous fibrillations and positive sharp waves (denervation potentials), and complex repetitive discharges typical for all inflammatory myopathic diseases. Low-amplitude/short duration polyphasic motor unit potentials are typical; however, neuropathic findings such as large amplitude and long duration potentials can also be seen in IBM which often complicates the diagnosis. Approximately 35–50% of cases demonstrate findings of peripheral neuropathy on nerve conduction studies. Indeed, mixed findings with features of both myopathic and neurogenic disease are common in IBM.^4,5

Muscle biopsy is necessary for the definitive diagnosis of IBM especially in light of possible long-term treatment for patients. In light microscopy, the endomysial chronic inflammatory infiltrate is similar to polymyositis. Small group fibrous atrophy mimicking neurogenic atrophy and fiber hypertrophy is also common. The important diagnostic feature of IBM is the slit-like vacuoles in the sarcoplasm surrounded by hematoxyphilic granules called the rimmed vacuoles. Sometimes these vacuoles contain eosinophilic inclusions. Rimmed vacuoles have also been noted in rare myopathies such as X-linked myopathy with excessive autophagy and distal myopathy with rimmed vacuoles, but the chronic inflammatory infiltrate is lacking in both conditions. The inclusions of IBM are congophilic, and some of the material associated with them show immunoreactivity to beta-amyloid protein, ubiquitin, and phosphorylated tau. Congophilic amyloid inclusions can usually be seen in sections stained with Congo red or Thioflavin S. Ubiquitin staining is also useful in showing muscle fiber inclusions.

Differential diagnosis for IBM includes polymyositis, dermatomyositis, drug induced myopathies, adult onset muscular dystrophy, and denervating conditions such as amyotrophic lateral sclerosis. Differentiating IBM from the aforementioned diagnoses is important as management, and prognosis varies amongst the different conditions causing muscular weakness. The major pathological features of conditions within the differential diagnosis of IBM are summarized in Table 1.

Table 1.

Pathological features of muscle biopsy in conditions presenting with bilateral muscular weakness

Conditions	Pathological features
Inclusion Body Myositis	Endomysial inflammatory infiltrates Rimmed vacuolated muscle fibers Intracellular amyloid inclusions
Neuropathy*	Angular myofibers Fiber type grouping Target and targetoid fibers
Polymyositis	Endomysial inflammatory infiltrates Muscle fiber necrosis
Dermatomyositis	Complement mediated microangiopathy Destruction of capillaries Perifascicular inflammatory infiltrates
Drug-induced myopathy	Non-specific pathological findings
Adult onset muscular dystrophy	Immunohistochemical staining detecting altered protein expression patterns (ie, immunoperoxidase stain for dystrophin) Molecular genetic studies detecting presence of mutations in specific genes

^*Neuropathy includes motor neuron disease, spinal muscular atrophies, and acquired and hereditary motor and sensory neuropathies

The prognosis for IBM is relatively poor, with many patients requiring assistance with activities of daily living, and becoming wheelchair-bound and eventually bedridden in approximately 15 years.¹⁴ IBM is relatively resistant to standard glucocorticoid therapy. Prednisone treatment at dose level effective for other inflammatory myopathies is generally ineffective in IBM⁶. However, in one retrospective review, prednisone appeared to have some modest clinical benefit in 40% of IBM patients.⁶ Immunosuppressive therapy with methotrexate and azathioprine similarly has shown only minor benefit.⁷ Given limited treatment options, consensus agrees that patients with IBM should be tried on prednisone 1mg/kg/day for 2–3 months, with consideration for addition of methotrexate 7.5mg/week or azathioprine 1.5–2.5mg/kg/day if the patient remains nonresponsive to therapy. This patient responded well to prednisone therapy at the recommended dose of 1mg/kg/day after 2 months of therapy. In addition, he reported great benefit from physical therapy. He will continue to have regular follow ups for assessment of his muscular strength and response to therapy.

Conclusion

In patients with bilateral symmetric distal extremity weakness, IBM should always be part of the differential diagnosis in addition to other myopathic conditions. It is important to make an accurate and definitive diagnosis early on with EMG and muscle biopsy, as IBM is a treatable condition. Goal of therapy should mainly be to prevent further deterioration of muscular strength, and glucocorticoid and immunosuppressive therapy are essential for management. Patients with IBM should be informed of their prognosis, which is a progressive deteriorating course generally ending in immobility in 15 years, with rare cases of muscular strength stabilization or improvement.

Conflict of Interest

None of the authors report a conflict of interest.