Sign.s of Sjogren synd.Tom.e in a patient with myasthenia ravis Sidkn A, Lindahl G. Signs of Sjogren’s syndrome in a patient with myasthenia gravis.
’
Departments of Neurology and Rheumatology, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden
Acta Neurol Scand 1990: 81: 179-180.
A case of myasthenia gravis (MG) with recurrent submandibular salivary gland enlargement and focal lymphocytic infiltrates in lip salivary glands is described. Though the clinical and close histopathological resemblance with Sjogren’s syndrome (SS), a condition characterized by impaired exocrine function of affected glands, no exocrine disturbance evolved during 3-years follow up. The clinical and histopathological overlap between MG and S S, sharing several immunological characteristics, might be of relevance in further studies on the pathogenesis of the two conditions.
Sjdgren’s syndrome (S S) denotes chronic inflammatory conditions of unknown etiology and pathogenesis, characterized by dryness of eyes and mouth due to decreased tear and salivary secretion, i.e. sicca symptoms. In the lacrimal and salivary glands focal infiltrates of lymphocytes are found. SS occurring in coexistence with another chronic systemic inflammatory disease, such as rheumatoid arthritis, systemic lupus erythematosus or polymyositis is denoted secondary S S (2 O SS), while primary SS (1 O SS) denotes patients lacking concurrent chronic inflammatory diseases. The bases for considering 1’ and 2” SS as separate entities are differences in the prevalence of extraglandular manifestations, such as pulmonary fibrosis, interstitial nephritis, mononeuritis multiplex and hematological disturbances, serological characteristics and association to the major histocompatibility complex (1). Myasthenia gravis (MG) is characterized by weakness and abnormal fatigability in voluntary muscles. The symptoms are referable to disturbances in the neuromuscular transmission where arguments for an immunological pathogenesis are manifold (2), but the basic etiology is still unknown. Non-organ specific autoantibodies, such as anti nuclear antibodies (ANA) are frequent in both S S (1) and MG patients (2) and an association to the HLA alleles B8 and DR3 has been described both in 1O SS (3) and M G (2). Myopathic manifestations as well as muscle biopsy abnormalities have been reported in SS (4, 5). However, a coexistence of SS and M G seems to be scarce (2, 6, 7). The present paper gives the clinical data, course and the histopathological findings in a patient with MG, salivary gland enlargement and transient sicca symptoms.
A. Siden’, G. Lindah12
Key words: myasthenia gravis; Sjogren’s syndrome; salivary glands: lymphocytic infiltrates Dr Ake Siden, Department of Neurology, R54, Huddinge University Hospital, S-141 8 6 Huddinge, Sweden Accepted for publication September 8, 1989
Case report
A 40-year-old Turkish woman was admitted to the Department of Neurology because of fluctuating, but gradually increasing, muscle fatigability and weakness. About 9 months before admission, there had been a successive onset of these symptoms in the neck and masticatory muscles. The voice and extremity functions were also affected after some months. Because of an ESR elevation (50mm/h) and leucopenia (2.5 x 109/L,60% lymphocytes), the patient had been investigated for hematological malignancies or infectious/inflammatory diseases with negative result. At admission, the patient exhibited a generalized muscle fatigability and weakness including the muscles innervated by the cranial nerves. The clinical diagnosis of M G was confirmed by a positive response to edrophonium hydrochloride and typical findings on neurophysiological examination. Antibodies against acetylcholinereceptors were present. After treatment with gradually increased doses of pyridostigmine bromide the patient improved, but developed transient oral sicca symptoms and a swelling below the mandible. An evaluation was performed at the Department of Rheumatology owing to a suspicion of SS. The swelling below the mandible and the sicca symptoms had then disappeared and no complaints referable to extraglandular manifestations of S S were presented. Lacrimal and salivary secretion rates were normal (Schirmer test > 25 mm/5 min, chew-stimulated whole salivary secretion rate 1.8 mL/min) and no keratoconjunctival staining by Rose-Bengal could be demonstrated. Histopathological examination of a lower lip salivary gland biopsy revealed focally arranged, periductal lymphocytic infiltrations, 179
SidCn & Lindahl
~
Grade 4 on a 5-grade scale (0 to 4) suggested by Chisholm and Mason (8), a finding often regarded indicative for S S. Immunohistopathological analysis by an immunoenzymatic peroxidase-anti-peroxidase method earlier described (9), revealed a dominance of CD3 + , CD4 + T “helper” lymphocytes constituting more than 75 % of the infiltrating lymphocytes. The surrounding glandular epithelial cells close to the lymphocytic infiltrates expressed the antigen HLA-DR. Anti-Ig+ B cells and plasma cells were sparse, as were OKM 1 + monocytes/macrophages. The Waaler-Rose test for rheumatoid factor was slightly positive, 1/40. There were no detectable ANA, anti-nDNA or antibodies against mitochondria or smooth muscles. The patient did not express the HLA-antigen B8, DR-typing was not performed. An uneventful transsternal thymectomy was performed 3 months after admission. Histopathological investigation revealed hyperplasia, but no thymoma. Three years after the diagnosis of MG, the patient was taking 840 mg of pyridostigmine bromide per day and her functional capacity was good. She still had recurrent swelling of the submandibular salivary glands about once a month, without developing oral or ocular sicca symptoms. The tear and salivary secretion rates were normal and there was no keratoconjunctival staining by the use of Rose-Bengal.
the coexistence of these 2 disorders is infrequent (2, 6,7). The present case illustrates that histopathological findings in salivary glands, as well as recurrent sialadenitis, might occur in M G patients without evolving S S. However, before conclusions are drawn from a single case, the stimulating muscarinic effects of anticholinesterase drugs have to be considered as possibly camouflaging sicca symptoms and disturb functional testing of the exocrine glands. Inspired by the present observation and to further investigate the prevalence of Sjogren-like histopathology in M G patients, its relation to disturbances of exocrine function and a possible influence of cholinergic treatment on the clinical presentation, a study of 11 M G patients has been performed (1 1). In 8 of the 11, lip salivary gland biopsies showed focal lymphocytic infiltrates identical to those is found in SS. None of these presented any symptoms or signs of sicca, regardless of whether cholinergic drugs were administered or not. In conclusion, salivary glands in MG become infiltrated by lymphocytes in a high frequency without giving rise to symptoms or functional impairment. A pathogenic role of the infiltrating lymphocytes as the cause of the sicca manifestations in SS might be doubted. References
Discussion
S S was earlier defined as the simultaneous presence of sicca symptoms from the eyes and mouth often with a coexisting chronic inflammatory disease such as rheumatoid arthritis (10). Later, it has been suggested that a diagnosis of SS should be based on the presence of objective signs, i.e. decreased tear and salivary secretion rate, keratoconjunctival staining by Rose-Bengal solution and presence of focal lymphocytic infiltrates in the lip salivary gland biopsies (1). Our patient had focal periductal lymphocytic infiltrates in the labial salivary glands, where the immunohistological findings were identical to what has recently been described in SS (9). However, apart from a transient episode, oral or ocular sicca were lacking during 3-years follow up. Thus, in spite of recurrent sialadenitis and the histopathological findings ,the patient could not be classified as SS, neither according to the earlier (10) nor recent (1) criteria. The present observation has several implications for the conception of MG. In both S S (1) and M G (2) patients, an increased incidence of connective tissue diseases have been reported. However, the impression from the literature so far available is that
180
1. MANTHOKPE R, FROST-LARSEN K, ISAGERH, PAKUSE JU. Sjogren’s syndrome. A review with emphasis on immunological features. Allergy 1981: 36: 139-153. 2. OOSTERHUISHJGH. Myasthenia gravis. Edinburgh: Churchill Livingstone, 1984. 3. MOUTSOPOULOS HM, MANNDL, JOHNSONAH, CHUSED TM. Genetic differences between primary and secondary sicca syndrome. N Engl J Med 1979: 301: 761-763. 4. SILBEKBERG DH, DRACHMAN DA. Late-lift myopathy occurring with Sjogren’s syndrome. Arch Neurol 1962: 6: 428-438. 5. DENKOCW, OLD JW. Myopathy in the sicca syndrome (Sjogren’s syndrome), Am J Clin Pathol 1969: 5: 631-637. 6. WOLF SM, ROWLAND LP, SCHOTLAND DL, MCKINNEY AS, HOEFER PFA, ARANOWJR H. Myasthenia as an autoimmune disease: clinical aspects. Ann New York Acad Science 1966: 135: 517-535. 7. DOWNESJM, GREENWOOD BM, WRAYSH. Autoimmune aspects ofmyastheniagravis. Quart J Med 1966: 35: 85-105. 8. CHISHOLM DM, MASONDK. Labial salivary gland biopsy in Sjogren’s disease. J Clin Pathol 1968: 21: 656-660. 9. LINDAHLG, HEDFORSE, KLARESKOG L, FORSUM U. Epithelial HLA-DR expression and T lymphocyte subsets in salivary glands in Sjogren’s syndrome. Clin Exp Immunol 1985: 61: 475-482. 10 BLOCH KJ, BUCHANANWW, WOHL MJ, BUNIM JJ. Sjogren’s syndrome. A clinical, pathological, and serological study of sixty-two cases. Medicine 1965: 44: 187-231. 11. LINDAHLG, LEFVERTA-K, HEDFORSE. Periductal lymphocytic infiltrates in salivary glands in myasthenia gravis patients lacking Sjogren’s syndrome. Clin Exp Immunol 1986: 66: 95-102.
’
Departments of Neurology and Rheumatology, Karolinska Institute, Huddinge Hospital, Stockholm, Sweden
Acta Neurol Scand 1990: 81: 179-180.
A case of myasthenia gravis (MG) with recurrent submandibular salivary gland enlargement and focal lymphocytic infiltrates in lip salivary glands is described. Though the clinical and close histopathological resemblance with Sjogren’s syndrome (SS), a condition characterized by impaired exocrine function of affected glands, no exocrine disturbance evolved during 3-years follow up. The clinical and histopathological overlap between MG and S S, sharing several immunological characteristics, might be of relevance in further studies on the pathogenesis of the two conditions.
Sjdgren’s syndrome (S S) denotes chronic inflammatory conditions of unknown etiology and pathogenesis, characterized by dryness of eyes and mouth due to decreased tear and salivary secretion, i.e. sicca symptoms. In the lacrimal and salivary glands focal infiltrates of lymphocytes are found. SS occurring in coexistence with another chronic systemic inflammatory disease, such as rheumatoid arthritis, systemic lupus erythematosus or polymyositis is denoted secondary S S (2 O SS), while primary SS (1 O SS) denotes patients lacking concurrent chronic inflammatory diseases. The bases for considering 1’ and 2” SS as separate entities are differences in the prevalence of extraglandular manifestations, such as pulmonary fibrosis, interstitial nephritis, mononeuritis multiplex and hematological disturbances, serological characteristics and association to the major histocompatibility complex (1). Myasthenia gravis (MG) is characterized by weakness and abnormal fatigability in voluntary muscles. The symptoms are referable to disturbances in the neuromuscular transmission where arguments for an immunological pathogenesis are manifold (2), but the basic etiology is still unknown. Non-organ specific autoantibodies, such as anti nuclear antibodies (ANA) are frequent in both S S (1) and MG patients (2) and an association to the HLA alleles B8 and DR3 has been described both in 1O SS (3) and M G (2). Myopathic manifestations as well as muscle biopsy abnormalities have been reported in SS (4, 5). However, a coexistence of SS and M G seems to be scarce (2, 6, 7). The present paper gives the clinical data, course and the histopathological findings in a patient with MG, salivary gland enlargement and transient sicca symptoms.
A. Siden’, G. Lindah12
Key words: myasthenia gravis; Sjogren’s syndrome; salivary glands: lymphocytic infiltrates Dr Ake Siden, Department of Neurology, R54, Huddinge University Hospital, S-141 8 6 Huddinge, Sweden Accepted for publication September 8, 1989
Case report
A 40-year-old Turkish woman was admitted to the Department of Neurology because of fluctuating, but gradually increasing, muscle fatigability and weakness. About 9 months before admission, there had been a successive onset of these symptoms in the neck and masticatory muscles. The voice and extremity functions were also affected after some months. Because of an ESR elevation (50mm/h) and leucopenia (2.5 x 109/L,60% lymphocytes), the patient had been investigated for hematological malignancies or infectious/inflammatory diseases with negative result. At admission, the patient exhibited a generalized muscle fatigability and weakness including the muscles innervated by the cranial nerves. The clinical diagnosis of M G was confirmed by a positive response to edrophonium hydrochloride and typical findings on neurophysiological examination. Antibodies against acetylcholinereceptors were present. After treatment with gradually increased doses of pyridostigmine bromide the patient improved, but developed transient oral sicca symptoms and a swelling below the mandible. An evaluation was performed at the Department of Rheumatology owing to a suspicion of SS. The swelling below the mandible and the sicca symptoms had then disappeared and no complaints referable to extraglandular manifestations of S S were presented. Lacrimal and salivary secretion rates were normal (Schirmer test > 25 mm/5 min, chew-stimulated whole salivary secretion rate 1.8 mL/min) and no keratoconjunctival staining by Rose-Bengal could be demonstrated. Histopathological examination of a lower lip salivary gland biopsy revealed focally arranged, periductal lymphocytic infiltrations, 179
SidCn & Lindahl
~
Grade 4 on a 5-grade scale (0 to 4) suggested by Chisholm and Mason (8), a finding often regarded indicative for S S. Immunohistopathological analysis by an immunoenzymatic peroxidase-anti-peroxidase method earlier described (9), revealed a dominance of CD3 + , CD4 + T “helper” lymphocytes constituting more than 75 % of the infiltrating lymphocytes. The surrounding glandular epithelial cells close to the lymphocytic infiltrates expressed the antigen HLA-DR. Anti-Ig+ B cells and plasma cells were sparse, as were OKM 1 + monocytes/macrophages. The Waaler-Rose test for rheumatoid factor was slightly positive, 1/40. There were no detectable ANA, anti-nDNA or antibodies against mitochondria or smooth muscles. The patient did not express the HLA-antigen B8, DR-typing was not performed. An uneventful transsternal thymectomy was performed 3 months after admission. Histopathological investigation revealed hyperplasia, but no thymoma. Three years after the diagnosis of MG, the patient was taking 840 mg of pyridostigmine bromide per day and her functional capacity was good. She still had recurrent swelling of the submandibular salivary glands about once a month, without developing oral or ocular sicca symptoms. The tear and salivary secretion rates were normal and there was no keratoconjunctival staining by the use of Rose-Bengal.
the coexistence of these 2 disorders is infrequent (2, 6,7). The present case illustrates that histopathological findings in salivary glands, as well as recurrent sialadenitis, might occur in M G patients without evolving S S. However, before conclusions are drawn from a single case, the stimulating muscarinic effects of anticholinesterase drugs have to be considered as possibly camouflaging sicca symptoms and disturb functional testing of the exocrine glands. Inspired by the present observation and to further investigate the prevalence of Sjogren-like histopathology in M G patients, its relation to disturbances of exocrine function and a possible influence of cholinergic treatment on the clinical presentation, a study of 11 M G patients has been performed (1 1). In 8 of the 11, lip salivary gland biopsies showed focal lymphocytic infiltrates identical to those is found in SS. None of these presented any symptoms or signs of sicca, regardless of whether cholinergic drugs were administered or not. In conclusion, salivary glands in MG become infiltrated by lymphocytes in a high frequency without giving rise to symptoms or functional impairment. A pathogenic role of the infiltrating lymphocytes as the cause of the sicca manifestations in SS might be doubted. References
Discussion
S S was earlier defined as the simultaneous presence of sicca symptoms from the eyes and mouth often with a coexisting chronic inflammatory disease such as rheumatoid arthritis (10). Later, it has been suggested that a diagnosis of SS should be based on the presence of objective signs, i.e. decreased tear and salivary secretion rate, keratoconjunctival staining by Rose-Bengal solution and presence of focal lymphocytic infiltrates in the lip salivary gland biopsies (1). Our patient had focal periductal lymphocytic infiltrates in the labial salivary glands, where the immunohistological findings were identical to what has recently been described in SS (9). However, apart from a transient episode, oral or ocular sicca were lacking during 3-years follow up. Thus, in spite of recurrent sialadenitis and the histopathological findings ,the patient could not be classified as SS, neither according to the earlier (10) nor recent (1) criteria. The present observation has several implications for the conception of MG. In both S S (1) and M G (2) patients, an increased incidence of connective tissue diseases have been reported. However, the impression from the literature so far available is that
180
1. MANTHOKPE R, FROST-LARSEN K, ISAGERH, PAKUSE JU. Sjogren’s syndrome. A review with emphasis on immunological features. Allergy 1981: 36: 139-153. 2. OOSTERHUISHJGH. Myasthenia gravis. Edinburgh: Churchill Livingstone, 1984. 3. MOUTSOPOULOS HM, MANNDL, JOHNSONAH, CHUSED TM. Genetic differences between primary and secondary sicca syndrome. N Engl J Med 1979: 301: 761-763. 4. SILBEKBERG DH, DRACHMAN DA. Late-lift myopathy occurring with Sjogren’s syndrome. Arch Neurol 1962: 6: 428-438. 5. DENKOCW, OLD JW. Myopathy in the sicca syndrome (Sjogren’s syndrome), Am J Clin Pathol 1969: 5: 631-637. 6. WOLF SM, ROWLAND LP, SCHOTLAND DL, MCKINNEY AS, HOEFER PFA, ARANOWJR H. Myasthenia as an autoimmune disease: clinical aspects. Ann New York Acad Science 1966: 135: 517-535. 7. DOWNESJM, GREENWOOD BM, WRAYSH. Autoimmune aspects ofmyastheniagravis. Quart J Med 1966: 35: 85-105. 8. CHISHOLM DM, MASONDK. Labial salivary gland biopsy in Sjogren’s disease. J Clin Pathol 1968: 21: 656-660. 9. LINDAHLG, HEDFORSE, KLARESKOG L, FORSUM U. Epithelial HLA-DR expression and T lymphocyte subsets in salivary glands in Sjogren’s syndrome. Clin Exp Immunol 1985: 61: 475-482. 10 BLOCH KJ, BUCHANANWW, WOHL MJ, BUNIM JJ. Sjogren’s syndrome. A clinical, pathological, and serological study of sixty-two cases. Medicine 1965: 44: 187-231. 11. LINDAHLG, LEFVERTA-K, HEDFORSE. Periductal lymphocytic infiltrates in salivary glands in myasthenia gravis patients lacking Sjogren’s syndrome. Clin Exp Immunol 1986: 66: 95-102.
