Abstracts

SYMPTOMATIC MUSCLE INVOLVEMENT IN NEUROSARCOIDOSIS

A clinicopathological study of 5 cases

Rosana Herminia Scola¹ 1 Neuromuscular Disease Section, Division of Neurology and Department of Internal Medicine, Hospital de Clínicas, Federal University of Paraná, Curitiba PR, Brazil: Associate Professor of Medicine; 2 Tenured Professor of Medicine, 3 Medical Students who are PIBIC/CNPq Research Scholarship Holders, 4 Neurology resident. Partly financed by a grant from CNPq (Brazil) , Lineu Cesar Werneck² 1 Neuromuscular Disease Section, Division of Neurology and Department of Internal Medicine, Hospital de Clínicas, Federal University of Paraná, Curitiba PR, Brazil: Associate Professor of Medicine; 2 Tenured Professor of Medicine, 3 Medical Students who are PIBIC/CNPq Research Scholarship Holders, 4 Neurology resident. Partly financed by a grant from CNPq (Brazil) , Daniel Monte Serrat Prevedello³ 1 Neuromuscular Disease Section, Division of Neurology and Department of Internal Medicine, Hospital de Clínicas, Federal University of Paraná, Curitiba PR, Brazil: Associate Professor of Medicine; 2 Tenured Professor of Medicine, 3 Medical Students who are PIBIC/CNPq Research Scholarship Holders, 4 Neurology resident. Partly financed by a grant from CNPq (Brazil) , Priscila Greboge³ 1 Neuromuscular Disease Section, Division of Neurology and Department of Internal Medicine, Hospital de Clínicas, Federal University of Paraná, Curitiba PR, Brazil: Associate Professor of Medicine; 2 Tenured Professor of Medicine, 3 Medical Students who are PIBIC/CNPq Research Scholarship Holders, 4 Neurology resident. Partly financed by a grant from CNPq (Brazil) , Fábio Massaiti Iwamoto⁴ 1 Neuromuscular Disease Section, Division of Neurology and Department of Internal Medicine, Hospital de Clínicas, Federal University of Paraná, Curitiba PR, Brazil: Associate Professor of Medicine; 2 Tenured Professor of Medicine, 3 Medical Students who are PIBIC/CNPq Research Scholarship Holders, 4 Neurology resident. Partly financed by a grant from CNPq (Brazil)

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology characterized by the accumulation of T lymphocytes and monocytes in the involved organs, noncaseating granulomas and disorganized architecture of the normal tissue. In some cases Schaumann and asteroid bodies are seen as well¹. Commonly it affects young adults of both sexes and presents bilateral hilar adenopathy, pulmonary infiltration, and ocular, cutaneous and reticuloendothelial system involvement ². Nervous system involvement occurs in less than 10% of the patients with sarcoidosis. However, the incidence of subclinical and undiagnosed neurosarcoidosis is much higher^{2, 3}. Neurosarcoidosis has a predilection for the base of the brain, but any portion of the central nervous system (CNS) or peripheral nervous system may be affected ^{2, 4}. The diagnosis of neurosarcoidosis is facilitated in patients with multisystem sarcoidosis who develop neurological features that include cranial nerve palsies, granulomatous meningitis, hypothalamic and pituitary lesions, spinal cord involvement, progressive multifocal leukoencephalopathy, peripheral neuropathy and myopathy^{2, 5}. Furthermore, any of the above-mentioned neurological presentations can occur without evidence of pulmonary or other systemic features of sarcoidosis hindering the diagnosis ^{2, 6}.

Asymptomatic muscle involvement commonly happens in patients with sarcoidosis varying from 50 to 80% of cases and it is evidenced by an inflammatory process including granulomatous formation in muscle biopsy ⁷. Muscle involvement with clinical repercussion is a rare condition and it has already been described in less than 0,5% to 2,3% of the patients diagnosed as being afflicted by sarcoidosis ^8,9.

We describe the clinical course and the histopathological findings in 5 patients with a clinical diagnosis of neurosarcoidosis, who underwent muscle biopsy due to the presence of muscle weakness during the course of the disease.

METHOD

Records were searched for patients with a previous clinical diagnosis of neurosarcoidosis who were submitted to muscle biopsy due to muscle weakness, from 1976 to 2000. Seven patients presented the criteria, but two of them had been hospitalized before 1980 and the records could not be accessed. The patients were appraised in the Neuromuscular Disorders Service of the "Hospital de Clínicas" of the "Universidade Federal do Paraná" in Curitiba-Brazil. All clinical records bearing these diagnoses were then individually reviewed and the following data were obtained from all patients: (1) demographic: age at diagnosis, sex; (2) dates of disease onset (first symptom); (3) clinical information relevant to sarcoidosis, including data from clinical history focused on chief complaints, and general/neurological physical examination, which analyzed proximal and distal muscle strength, tonus and reflexes in upper and lower limbs; (4) laboratory values of erythrocyte sedimentation rate (ESR) and levels of serum muscle enzymes, creatine kinase (CK), lactate dehydrogenase (LDH), aldolase (ALD), aspartate aminotransferase (AST) and alanine aminotransferase (ALT); (5) chest radiograph; (6) needle electromyographic (EMG) and (7) histopathological findings in fresh-frozen muscle biopsy, which was submitted to the following staining and histochemical reaction: hematoxilin-eosin, modified Gomori trichrome, oil red O, PAS, cresyl violet, sirus red, NADH-tetrazolium reductase, ATPases pH 4.3, 4.6, 9.4, myophosphorylase, non-specific esterase, alkaline phosphatase, acid phosphatase, succinic dehidrogenase and cytochrome c-oxidase ^{10, 11}.

A case was included if the diagnosis of neurosarcoidosis with muscle involvement was accepted after the clinical records had been reviewed. Presence of granuloma or a typical chest x-ray with bilateral hilar lymphadenopathy besides signs and symptoms of neural system involvement were enough to consider a case neurosarcoidosis. Any muscle complaint at the time of diagnosis was considered a clinical muscle involvement. On this way, patients presenting muscle weakness during the treatment with steroids or after use it before the diagnosis were not included in the study. Any feature suggesting another disease excluded the case.

RESULTS

All five patients were female. The mean age of the patients at the time the disease was diagnosed was 40 years, varying from 17 to 53. Table 1 shows the signs and symptoms the patients presented in the course of the disease. All patients reported proximal muscle weakness and only one patient failed to report distal weakness. Myalgia was a complaint of three of the five patients. All patients presented normal values of serum muscle enzymes.

Table 2 shows the results of electromyographic-nerve conduction velocity (EMG-NCV), evidencing a heterogeneity of patterns. Electromyography was normal in one patient. A myopathic pattern was shown in two patients and denervation patterns in two other patients.

The histochemical analysis of the muscle biopsies is shown in Table 4. One biopsy was entirely normal. Noncaseating granuloma (Figs 1, 2) was found in four patients and one presented vasculitis in the biopsy. Type 2 fiber atrophy was present in four patients, whereas type 1 fiber atrophy was found in two. Two patients presented endomysial fibrosis in the biopsy.

All patients received prednisone at the beginning of the treatment in initial doses that varied from 40 to 80 mg/day. Aspects of the treatment and of the course of the disease are shown in Table 3. Two patients thoroughly recovered by taking only prednisone. One patient had an azathioprine addition to the prednisone regime, with an excellent result. Another patient started to use azathioprine after interrupting prednisone due to side effects such as osteoporosis; however, the disease continued following a progressive course. One patient had a methotrexate addition to prednisone for 3 months, with a complete remission of the symptoms.

DISCUSSION

Muscle involvement in patients with sarcoidosis is relatively common. Fifty to 80% of patients with sarcoidosis present granulomas in muscle biopsies, despite the absence of signs and symptoms ^{7, 12}. It seems that most patients with sarcoidosis and muscle involvement by granulomatous inflammation have relatively few signs and symptoms related to muscle disease ⁸.

Significant and symptomatic muscle involvement in sarcoidosis is rare and was noted in 0,5 to 2,3% of patients ^{1, 8, 9, 13}. Myopathy can be the initial manifestation of sarcoidosis, but when the diagnosis is confirmed, signs and symptoms of other systems are usually present. Three clinical types of sarcoid myopathy have been described: acute myositis, chronic myopathy and palpable nodules ^{1, 9, 13-15}.

Palpable nodules is the least common type of symptomatic muscle involvement in sarcoidosis and it can cause pain and stiffness with cramps. Weakness is not common during the active phase; however, it may appear later if contractures occur. Acute myositis, another infrequent type of muscle involvement in sarcoidosis, can be clinically indistinguishable from acute polymyositis ^{8, 15}. Symptoms include proximal muscle weakness, fever and myalgia. Electromyographic studies show unspecific myopathic patterns and creatine kinase values are generally high¹⁴.

Chronic myopathy has been the most frequently reported type of sarcoid myopathy, occurring mainly in older women, and is typically a slow progressive symmetrical weakness involving proximal muscles of the extremities, trunk and neck, that often go on to become muscle atrophy. Distal muscle involvement may be secondary to peripheral neuropathy, which has been well documented in sarcoidosis ¹³. Muscle enzymes are usually normal and a myopathic pattern is observed in electromyographic studies. Remissions and exacerbations are noted during the course of the disease^14,15.

The five patients presented a diversity of electromyographic findings, such as normal, myopathic and neuropathic patterns. Most other clinical studies confirm such electromyographic heterogeneity, which is explained by the fact that the EMG had been done during different phases of the disease, including the treatment, when the regeneration of muscle fibers occurs, and by the fact that usually there are mutual muscle and nerve injuries in sarcoidosis^{2, 13}.

The five reported patients present different clinical manifestations, but they share the same insidious muscle involvement. All cases involve women and four of them are past the age of 40. The only case in which granuloma was not found coincides with the patient less than 40 years old. The fact that granuloma was not found in muscle biopsy does not rule out the clinical diagnosis of sarcoidosis and this situation has been related to the sampling and the time when the patient is submitted to the procedure ¹³.

Most patients have improved by using prednisone monotherapy with a minimum initial doses that varies from 20 to 80 mg/day in the literature ^{2, 13}. Prednisone at a dose of 1 mg/Kg is probably a suitable initial dose, since several patients treated with lower doses subsequently suffered relapses ⁹. In acute myopathy the response to corticosteroids is good and the course is usually benign. On the other hand, in chronic myopathy the response is unpredictable. Excellent results have been obtained in certain cases, while in others there has been no responses to corticosteroids ^{13, 15, 17}. In those patients who fail to respond to prednisone therapy and whose conditions continue to deteriorate, other drugs such as cyclophosphamide, cyclosporine, azathioprine and mainly methotrexate should be tried ^{2, 17}.

Received 27 October 2000, received in final form 12 February 2001. Accepted 14 February 2001.

Dra. Rosana Herminia Scola - Serviço de Doenças Neuromusculares, Hospital de Clínicas da UFPR - Rua General Carneiro 181 / 3° andar - 80069-155 Curitiba PR – Brasil. FAX ++55 41 264 3606. E-mail: scola@hc.ufpr.br

Publication Dates

History