Acute sarcoid myositis with coexisting sensory neuropathy; Pulmonary sarcoidosis
This 73 year old, African-American woman presented with a disabling proximal, symmetric weakness of several weeks in duration. Neurological examination revealed sensory deficits in the distal lower extremities and in the distribution of the lateral femoral cutaneous nerve bilaterally. In addition, she had mild chronic symptoms of pulmonary insufficiency, and a history of a glucocorticoid-responsive pulmonary disorder in the past. Radiographic findings of interstitial infiltrates and hilar fullness, together with restricted lung volumes, severe limitation of diffusion capacity on pulmonary function testing, hypercalcemia and elevated angiotensin-converting enzyme levels in the serum strongly suggested pulmonary sarcoidosis. Elevation of creatine kinase (CK) and aldolase levels, together with myopathic findings on electromyography, suggested the possibility of a sarcoid myopathy, which was supported by the finding of noncaseating granulomas on muscle biopsy. Although granulomatous myopathy can be seen in other conditions such as in association with inflammatory bowel disease, tuberculosis, Wegener's granulomatosis and thymoma, the patient's history, examination findings, and results of laboratory screens did not suggest any of these disorders. Thus, sarcoidosis involving multiple organ systems would best account for the muscle biopsy findings, abnormal laboratory values and restrictive lung disease.
The patient was treated with oral corticosteroids with resultant improvement of her weakness. Within one week of starting daily prednisone treatment, she was able to stand without assistance. She was ambulating with a walker after two weeks of physical therapy. Two years after her initial neurologic evaluation, she can ambulate independently, but uses a wheelchair for longer distances. Her lower extremity pain, however, did not completely remit, although some benefit was derived from gabapentin treatment.
Sarcoidosis is a systemic inflammatory disorder of unknown cause, characterized by the pathological hallmark of the noncaseating granuloma. The clinical picture of sarcoidosis has a myriad of presentations, ranging from asymptomatic disease to progressive multiorgan failure. The illness may be self-limited or chronic, with episodic relapses and remissions. Because the lungs are nearly always involved, most patients report acute or insidious respiratory problems, which may be accompanied by symptoms affecting other organs (Newman et al., 1997).
The most common form of myopathy associated with sarcoidosis is chronic, frequently asymptomatic, and most likely to occur in postmenopausal women (Kobayashi et al., 1994). In contrast, our patient presented with an acute granulomatous myositis, which may be the least common form of muscle involvement in sarcoidosis, as to our knowledge, only twenty such acute cases have been reported in the literature. Patients with acute sarcoid myositis experience rapidly progressive proximal muscle weakness that may mimic polymyositis or dermatomyositis. Myalgias and tender muscles are common, and erythema nodosum or acute polyarthritis may also occur (Ost et al., 1995). The serum CK level is typically elevated, but usually not more than 2000 U/L. However, in one reported severe case, the CK was elevated to 12,565 U/L (Takuma et al., 2000). Most patients with acute sarcoid myositis are less than 40 years old, and our patient's case possibly may be the oldest reported to date.
Sarcoid myopathy may also present with diffuse atrophy or even occasional pseudohypertrophy. In some cases of progressive, symmetrical weakness associated with sarcoidosis, the serum CK may be normal, although granulomatous inflammation is demonstrated on muscle biopsy. A nodular form of sarcoid myopathy has also been described with palpable nodes, which less commonly leads to muscle pain or impaired muscular function (Levine et al., 1997; Stjernberg et al., 1981). Of note, incidental noncaseating granulomas have been found in muscle biopsy specimens from as many as 25-75% of asymptomatic sarcoid patients without clinical evidence of muscle disease (Stern et al., 1985; Chapelon et al., 1990). Given the significant numbers of granulomas observed on muscle biopsy, and the dramatic clinical improvement seen with steroid therapy, we believe that the granulomas in this patient are unlikely to have been incidental.
In one study of patients with granulomatous myopathy, those associated with sarcoidosis were more likely to present with predominantly proximal, symmetric weakness, severe disability with ambulation, and frequent positive response to corticosteroid treatment, compared to patients with granulomatous myopathy due to causes other than sarcoidosis (Mozaffar et al., 1998). Dysphagia and female gender were common in patients both with and without sarcoidosis, and the average age of patients in this study was 55 years. Isolated sarcoid myopathy without systemic sarcoidosis has only rarely been reported (reviewed in Berger et al., 2002).
Symptomatic muscle involvement is seen in less than 1% of patients with systemic sarcoidosis, but the incidence appears to be higher in patients with other neurological manifestations (Chapelon 1990; Oksanen 1986). Differentiation from other inflammatory myopathies can be difficult, but any evidence of systemic sarcoidosis strongly supports the diagnosis. The serum creatine kinase is sometimes elevated (reviewed in Gallapalli and Phillips, 2002) along with increased levels of angiotensin-converting enzyme levels.
Neurological presentations are uncommon but not rare in patients with sarcoidosis, affecting 5-16% of patients in clinical studies and 15% in pathologic studies (Chapelon et al., 1990; Lower et al., 1997). The facial nerve is most frequently affected, but disease may involve other cranial and peripheral nerves, meninges, the hypothalamus, and the pituitary gland (Stern et al., 1985). Of interest is our patient's previous history of sudden unilateral deafness of unknown cause several years prior to her development of myositis. In retrospect, this history would not be inconsistent with neurosarcoidosis.
Inclusion criteria suggested for diagnosis of neurosarcoidosis include a compatible clinical and radiographic picture, presence of noncaseating granulomas on histologic examination, and absence of exposure to organic or inorganic material capable of inducing granulomas (Chapelon et al., 1990). Peripheral neuropathy is a less common manifestation of neurosarcoidosis, seen in 15-18% of patients with neurologic involvement (Chapelon et al., 1990; Oksanen 1986). Most commonly, a symmetric axonal sensorimotor neuropathy is seen. Histologic studies reveal noncaseating granulomas or inflammatory changes in the epineural and perineural spaces, which lead to perangiitis, panangiitis, and axonal degeneration (Oh, 1978, Galassi et al., 1984). Other presentations of sarcoidosis involving peripheral nerves include mononeuritis multiplex, polyradiculopathy, and rarely Guillain-Barre syndrome (Scott, 1993). Nerve damage could potentially occur from a granulomatous vasculitis, direct compression from granulomata, local inflammation, or direct injury by the causative agent of sarcoidosis (Galassi et al., 1984). Rarely, granulomata in the endoneurium may result in neuropathy with a primarily demyelinating picture (Nemni et al., 1981). Symptomatic myopathy may occur in 7-12% of patients with neurosarcoidosis (Delaney, 1977; Stern et al., 1985; Wiederholt and Siekert, 1965).
At the time of this patient's admission, a nerve biopsy was not performed, given that the results were unlikely to change the medical management of her sarcoidosis. To date, the cause of the patient's sensory neuropathy has not been determined, although the nerve conduction findings of an axonal process would be more consistent with a diagnosis of neurosarcoidosis.
We considered the possibility that the patient's monoclonal gammopathy of undetermined significance (MGUS) also may have contributed to her neuropathy. A relationship between peripheral neuropathy and monoclonal proteins is well described in the literature (Gorson, 1999; Vital, 2001). Neuropathy associated with MGUS typically presents with sensory symptoms, as well as imbalance and gait ataxia. Electrodiagnostic studies may show mixed demyelinating and axonal features, which may be indistinguishable from findings in chronic inflammatory demyelinating polyneuropathy (Gorson, 1999). Monoclonal proteins are found in 3% of the general population over the age of 70 (Axelsson et al., 1966), and thus the M-spike in MGUS may be coincidental and unrelated to a neuropathy.
More importantly, we considered whether the exacerbation of the patient's symptoms may have heralded the transformation of her MGUS into a more aggressive plasma cell disorder such as plasmacytoma or multiple myeloma, which may occur in up to 25% of patients followed over time (Kyle, 1992). In this patient, however, decreasing total amounts of monoclonal IgG kappa protein (a stable fraction of the total protein), normal skeletal roentgenograms and bone scan, and absence of systemic features more consistent with multiple myeloma make the diagnosis of an aggressive plasma cell disorder unlikely. She continues to be periodically screened for this possibility.
Response to steroid treatment is often dramatic in patients with acute sarcoid myositis (Ost et al., 1995). Although no prospective trials have been published to our knowledge, Ost and coworkers (1995) recommended treatment with prednisone 1 mg/kg as a starting dose, as relapses with lower doses were not uncommon. An extended course of steroid treatment is often required, as the course of disease may be unpredictable (Jamal et al., 1988; Ost et al., 1995). In patients who respond insufficiently to steroid monotherapy, methotrexate (7.5 to 15 mg per week) may provide benefit or allow reduction of the steroid dose (Kaye et al., 1995). Whereas acute or subacute sarcoid myopathy is steroid-responsive, the more typical chronic, atrophic myopathy associated with sarcoidosis does not appear to respond well to immunotherapy. Asymptomatic muscle involvement of sarcoidosis does not warrant treatment (Currie, 1988). Serum ACE and calcium levels have been shown to normalize with steroid treatment in some patients and may be useful to follow as markers of disease activity (Berger et al., 2002).
Well-controlled studies demonstrating efficacy of steroid therapy for neurosarcoidosis are lacking. However, oral corticosteroids, 40 to 80 mg per day, are the recommended first line of therapy for persistent peripheral neuropathy, cranial neuropathy and intracranial lesions (Sharma and Sharma, 1991), and clinical improvement may be observed with such empiric treatment.
The optimal treatment for neuropathy associated with MGUS has not been determined. Patients with IgG and IgA monoclonal paraproteins and neuropathy may improve with corticosteroids, intravenous immune globulin, or plasma exchange (reviewed in Gorson, 1999). The efficacy of plasma exchange has been demonstrated in a randomized, placebo-controlled trial (Suarez and Kelly, 1993). However, many responding patients have a clinical and electrodiagnostic picture more consistent with a chronic inflammatory demyelinating polyradiculoneuropathy, as opposed to the presentation in our patient. Given our patient's relatively mild symptoms attributed to her sensory neuropathy, and modest electrodiagnostic findings of distal polyneuropathy, expectant management for this process was opted while she received steroid therapy for her myositis.
Portions of this case were previously presented, by Drs. Steven Lovitt, Melvin Kong, and Yadollah Harati, at the "Unusual Diagnostic and Management Problems in Neuromuscular Disease" seminar of the American Academy of Neurology annual meeting, April 15, 2002. Dr. Lovitt has joined the faculty of the University of Texas at San Antonio, TX. We also thank Dr. Larry Rice, of the Hematology-Oncology Division of the Department of Medicine, Baylor College of Medicine, for discussions regarding this patient's case.
-- Dennis R. Mosier, M.D., Ph.D.
Email comments: