Prevalence of Primary Sjogren’s Syndrome in Patients with Multiple Sclerosis J. Mir6, MD,” J. L. Petia-Sagredo, MD,t J. Berciano, MD,* S. Insua, MD,? C. Leno, MD,* and R. Velarde, MD$
Sixty-four consecutive patients with clinically or laboratory-supported definite multiple sclerosis (MS) were evaluated prospectively for evidence of primary Sjiigren’s syndrome (SS). This diagnosis was established when a patient had objective keratoconjunctivitis sicca, xerostomia, or both together with positive labial salivary gland biopsy. We found 2 patients (3.1%)with clinical evidence of primary SS. Whether this association is fortuitous or whether there is pathogenetic linkage between MS and primary SS remains to be established. Miro J, Petia-Sagredo JL, Berciano J, Inslia S, Leno C, Velarde R. Prevalence of primary Sjogren’s syndrome in patients with multiple sclerosis. Ann Neurol 1990:27: 582- 5 84
T h e relationship between multiple sclerosis (MS) and primary Sjogren’s syndrome (SS) is controversial. Alexander and associates 111 found that 20 of 200 patients with primary SS had central nervous system manifestations mimicking MS. Noseworthy and colleagues C21 documented dry eyes in 17% of 192 consecutive MS patients, dry mouth in 31%, an abnormal Schirmer’s test in 29%, and autoantibodies other than Ro (SS-A) and La (SS-B) in at least 13%. Although these preliminary results could suggest that a subset of their MS patients may indeed have had primary SS, the authors considered that none of the patients had primary SS. Therefore, w e addressed the question again.
Patients and Methods We studied 64 consecutive patients with clinically or laboratory-supported definite MS [3]. Clinical characteristics are summarized in Table 1. Cerebrospinal fluid (CSF) oligoclonal bands and CSF and serum albumin and IgG concentra-
From the Services of “Neurology, tRheumatology, and SOphthalmology, National Hospital “Marques de Valdecilla,” University of Cantabria, Santander, Spain.
Received Jul 24, 1989, and in revised form Oct 27. Accepted for publication Nov 3, 1989. Address correspondence to Dr Berciano, Service of Neurology, National Hospital “Marques de Valdecilla,” 39008 Santander, Spain.
582
tion were determined in all patients. Oligoclonal bands were visualized by isoelectric focusing Resolve-CSF Kit (Isolab Inc, Akron, OH) and IgG was determined by radial immunodiffusion. CSF and serum albumin and serum IgG were measured by immunoturbidimetry (Behring Lab, Marburg, FRG).We estimated the intra-blood-brain barrier immunoglobulin synthesis with the CSF IgG index and Tourtellotte’s formula [5]. Fifty-one patients (80%)had oligoclonal bands. Increased synthesis of IgG was observed in all 64 cases. HLA typing, multimodal evoked potentials, and brain CT scan were also routinely obtained. MRI study was done in 5 1 patients, and characteristic multifocal white matter lesions were constantly observed. A patient questionnaire for the assessment of sicca syndrome I63 was administered by one of the authors (J. L. P.). We also asked about specific manifestations of other autoimmune diseases (e.g., lupus, rheumatoid arthritis, or scleroderma). Twenty-one patients were treated with azathioprine (2-2.5 mglkglday) and 9 patients with azathioprine and bimonthly pulses of intravenous methylprednisolone. Other medications administered were as follows: carbamazepine (3 patients), baclofen (12 patients), clorimipramine (8 patients), amantadine (8 patients), oxybutynin chloride (12 patients) and colchicine (12 patients). Medication was stopped 48 hours before sicca complex specific tests were performed. Xerophthalmia was evaluated by bilateral Schirmer’s test without local anesthesia and slit lamp examination with rose bengal staining. Schirmer’s test was considered abnormal if less than 5 mm of filter paper was moistened after 5 minutes, and rose bengal staining was considered abnormal with Bijsterveld score 2 4 on a scale of 0-9 [7, 81. Keratoconjunctivitis sicca was considered to be present when the two tests were positive. Xerostomia was evaluated by stimulated sialometry and estimation of the sublingual salivary pool. Xerostomia was considered present when there was loss of the sublingual salivary pool or reduced salivary flow rate (less than 0.1 ml/ min) E93. All biopsies were performed with the same method under local anesthesia. A lateral 1 to 2 cm linear incision was made in the mucosa of the lower lip. After dissection of the margins, some accessory salivary glands were removed and placed in fixative. In each case at least 4 salivary gland lobules were evaluated [lo, 11). Biopsy samples were scored according to the criteria of Chisholm and Mason [lo]. In short, the scale ranges from grade I (normal salivary gland with few lymphocytes) to grade IV ( 2 2 lymphocyte foci/4 mm’). A focus was defined as a cluster of at least 50 lymphocytes. The patients’ sera were tested for the presence of rheumatoid factor (by the latex method, positive at a dilution 2 1 :40), antinuclear antibodies (ANA) (by indirect immunofluorescence with HEP-2 cell line as substrate, positive at a dilution 1)1:40), and Ro (SS-A) and La (SS-B) antibodies (detected by double gel immunodiffusion with calf thymus and human spleen extracts as source of the antigen). In this series the diagnosis of primary SS was considered when the patient had keratocon junctivitis sicca, xerostomia, or both combined with positive salivary gland biopsy grade IV and explicit absence of criteria of other connective tissue diseases 1127.
Copyright 0 1990 by the American Neurological Association
Table 1. Clinical Characteristics (n = 64) Sex ratio (female :male) Age at onset (yr)" Age at admission (yr)" Disease duration (yr)" Course of disease Relapsing = remitting Relapsing = progressive Chronic = progressive Disease severityb 0- 3
3.5-6 6.5-9 Diagnosis certainty Clinically definite Laboratory-supported definite
1:13 29.1 2 8.8 38.6 ? 10.3 n z 7.2
~7 I U.L
20 (31)'
32 (50) 12 (18) 35 (54.6) 17 (26.5) 12 (18) 50 (78) 14 (22)
*
"Mean standard deviation. bDisease severity measured on the Expanded Disability Status Scale
C41. 'Values in parentheses represent percent of total patients.
Results Twenty-one (33%) of 64 patients had symptoms of xerophthalmia. Abnormal Schirmer's and rose bengal tests were observed in 15 and 7 patients, respectively. Only 5 patients had abnormal tests for both. Twenty patients (31%) suffered from oral dryness, but only 1 had an abnormal salivary pool. Sialometry was performed in 45 cases and the result was abnormal in 4; 2 of these 4 had keratoconjunctivitis sicca. Seven cases exhibited xerophthalmia, xerostomia, or both; an additional case had had recurrent parotitis. Biopsy of accessory salivary glands was done in these 8 patients; because of insufficient material, the biopsy was repeated in 1 patient. Four patients had normal salivary glands (grade I), 3 (including the patient with recurrent parotitis) had grade IV biopsies, and 1 patient had scattered lymphoid infiltrates (grade 11).Clinical and laboratory data of these 2 patients with sicca signs and grade IV positive biopsies are summarized in Table 2; serological tests for human immunodeficiency virus were negative in both. None of these patients had manifestations of other autoimmune diseases or extraglandular complications of primary SS. Latex rheumatoid factor, anti-Ro and anti-La autoantibodies were negative for all 64 patients. Three cases
had ANA autoantibodies, titers being 11160 in 2 cases and 1/80 in 1 case. Discussion Of 64 consecutive patients with definite MS, about one-third had symptoms of sicca complex. Only 7 patients, however, had objective evidence of keratoconjunctivitis sicca or xerostomia. Salivary gland biopsies were performed in these 7 patients and in 1 other patient suffering from recurrent parotitis. Histopathological examination revealed positive findings, that is, Chisholm-Mason grade IV, in 3 cases. According to the proposed criteria, 2 of these 3 cases could be considered to have primary SS C127. Furthermore, there were 2 patients with positive Schirmer's test and sialometry but with negative salivary gland biopsies, and 14 patients with one isolated positive sicca test. Although these patients cannot be currently diagnosed as having primary SS, serial examination should be performed to determine if they have incipient SS. The clinical and biological characteristics of these patients with clinical evidence of primary SS are different from those in patients reported by Alexander and associates 11, 131. Our patients are male, with onset of symptoms before 20 years of age. Clinical manifestations and MRI findings always indicated cerebral, cerebellar, brainstem, and spinal cord involvement. In our patients there were consistently 4 or more oligoclonal bands in CSF with increased IgG. Oligoclonal bands did not change after treatment {141. Specific autoantibodies for primary SS were negative. In contrast, in Alexander's series 18 of 20 patients were women, ranging in age from 21 to 50 years (mean 38). Apparently, MRI studies 1157 were performed in only 6 patients, with multiple focal areas of increased signal intensity indistinguishable from those of MS being noted in 5 patients; the sixth patient had negative MRI findings. CSF oligoclonal bands were present in 16 of 18 patients, but only 5 had more than 2 bands. Moreover, oligoclonal bands decreased with therapy [1, 31. Increased IgG index was noted in only 50% of cases. Finally, immunogenetic markers (HLA alloantigens) for primary SS or MS in our patients were different from those in Alexander's series [137. The prevalence of primary SS in the elderly population has been estimated to be between 2 and 5% 121.
Table 2. Clinical and Laboratory Data of Patients.with Primary SS
Case
Sex
Onset (yr)
1 2
M M
18 16
Duration of Symptoms (yr)
3 1
Course of Disease
No. of Oligoclonal Bands IgG Inde?
CSF IgG (mg per day)b HLA
Progressive Remitting
4 7
37 32
1.4 1.8
A9, J37, DR 5,6 A19 B5,7, DR 2
"Normal value, up to 0.8. bNormal value, up to 8.5.
Brief Communication: Mir6 et al: Sjogren's Syndrome in MS
583
In this series of patients with MS, with patients under the predilection age for primary SS, the prevalence of primary SS was 3.1%. Whether this association is fortuitous or whether there is a pathogenetic linkage between primary SS and MS remains to be established.
6. Moutsopoulos HM, Kippel JH, Pavlidis N, et al. Correlative
7. 8.
~
~~~~~~~~
The authors thank John Hawkins for stylistic revision and Marta de la Fuente for secretarial help.
9. 10.
References 1. Alexander EL, Malinow K, LejewskiJE, et al. Primary Sjogren’s syndrome with central nervous system disease mimicking multiple sclerosis. Ann Intern Med 1986;104:323-330 2. Noseworthy JH, Bass BH, Vandervoon MK,et al. The prevalence of primary Sjogren’s syndrome in a multiple sclerosis population. Ann Neurol 1989;25:95-98 3. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231 4. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1442-1452 5. Tourtellotte WW. The cerebrospinal fluid in multiple sclerosis. In: Koetsier JC, ed. Handbook of clinical neurology, v o l 3 (47): Demyelinating diseases. Amsterdam: Elsevier Science Publishers, 1985:79-130
584 Annals of Neurology Vol 27
No 5
May 1990
11.
12.
13.
14. 15.
histologic and serologic findings of sicca syndrome in patients with systemic lupus erythematosus. Arthritis Rheum 1980; 2 3:36-40 Van Bijsterveld OP. Diagnostic tests in the sicca syndrome. Arch Ophthalmol 1969;82:10-14 Hansen BV, Lindgren S, Erikson S , et al. Clinical and immunological features of Sjogren’s syndrome in patients with primary biliary cirrhosis with emphasis on focal sialadenitis. Acta Med Scand 1988;224:611-619 Sreebny LM, Valdini A. Xerostomia A neglected symptom. Arch Intern Med 1987;147:1333-1337 Chisholm D, Mason D. Labial salivary gland biopsy in Sjogren’s disease. J Clin Pathol 1970;26:690-712 Fox RI, Robinson CA, Curd JG, et al. Primary Sjogren syndrome. Proposed criteria for classification. Arthritis Rheum 1986;29:577-585 Moutsopoulos HM, Webber BL, Vlagopoulos TP, et al. Differences in the clinical manifestations of sicca syndrome in the presence and absence of rheumatoid arthritis. Am J Med 1979; 661733-736 Alexander EL. Neuromuscular complications of primary Sjogren’s syndrome. In: Talal N, Moutsopoulos HM, Kassan SS, eds. Sjogren’s syndrome: clinical and immunological aspects. Heidelberg: Springer-Verlag, 1986:61-82 Ebers GC. Ohgoclonal banding in multiple sclerosis. Ann NY Acad Sci 1984;436:206-212 Alexander EL, B e d SS, Gordon B, et al. Magnetic resonance imaging of cerebral lesions in patients with the Sjogren’s syndrome. Ann Intern Med 1988;108:815-823
Sixty-four consecutive patients with clinically or laboratory-supported definite multiple sclerosis (MS) were evaluated prospectively for evidence of primary Sjiigren’s syndrome (SS). This diagnosis was established when a patient had objective keratoconjunctivitis sicca, xerostomia, or both together with positive labial salivary gland biopsy. We found 2 patients (3.1%)with clinical evidence of primary SS. Whether this association is fortuitous or whether there is pathogenetic linkage between MS and primary SS remains to be established. Miro J, Petia-Sagredo JL, Berciano J, Inslia S, Leno C, Velarde R. Prevalence of primary Sjogren’s syndrome in patients with multiple sclerosis. Ann Neurol 1990:27: 582- 5 84
T h e relationship between multiple sclerosis (MS) and primary Sjogren’s syndrome (SS) is controversial. Alexander and associates 111 found that 20 of 200 patients with primary SS had central nervous system manifestations mimicking MS. Noseworthy and colleagues C21 documented dry eyes in 17% of 192 consecutive MS patients, dry mouth in 31%, an abnormal Schirmer’s test in 29%, and autoantibodies other than Ro (SS-A) and La (SS-B) in at least 13%. Although these preliminary results could suggest that a subset of their MS patients may indeed have had primary SS, the authors considered that none of the patients had primary SS. Therefore, w e addressed the question again.
Patients and Methods We studied 64 consecutive patients with clinically or laboratory-supported definite MS [3]. Clinical characteristics are summarized in Table 1. Cerebrospinal fluid (CSF) oligoclonal bands and CSF and serum albumin and IgG concentra-
From the Services of “Neurology, tRheumatology, and SOphthalmology, National Hospital “Marques de Valdecilla,” University of Cantabria, Santander, Spain.
Received Jul 24, 1989, and in revised form Oct 27. Accepted for publication Nov 3, 1989. Address correspondence to Dr Berciano, Service of Neurology, National Hospital “Marques de Valdecilla,” 39008 Santander, Spain.
582
tion were determined in all patients. Oligoclonal bands were visualized by isoelectric focusing Resolve-CSF Kit (Isolab Inc, Akron, OH) and IgG was determined by radial immunodiffusion. CSF and serum albumin and serum IgG were measured by immunoturbidimetry (Behring Lab, Marburg, FRG).We estimated the intra-blood-brain barrier immunoglobulin synthesis with the CSF IgG index and Tourtellotte’s formula [5]. Fifty-one patients (80%)had oligoclonal bands. Increased synthesis of IgG was observed in all 64 cases. HLA typing, multimodal evoked potentials, and brain CT scan were also routinely obtained. MRI study was done in 5 1 patients, and characteristic multifocal white matter lesions were constantly observed. A patient questionnaire for the assessment of sicca syndrome I63 was administered by one of the authors (J. L. P.). We also asked about specific manifestations of other autoimmune diseases (e.g., lupus, rheumatoid arthritis, or scleroderma). Twenty-one patients were treated with azathioprine (2-2.5 mglkglday) and 9 patients with azathioprine and bimonthly pulses of intravenous methylprednisolone. Other medications administered were as follows: carbamazepine (3 patients), baclofen (12 patients), clorimipramine (8 patients), amantadine (8 patients), oxybutynin chloride (12 patients) and colchicine (12 patients). Medication was stopped 48 hours before sicca complex specific tests were performed. Xerophthalmia was evaluated by bilateral Schirmer’s test without local anesthesia and slit lamp examination with rose bengal staining. Schirmer’s test was considered abnormal if less than 5 mm of filter paper was moistened after 5 minutes, and rose bengal staining was considered abnormal with Bijsterveld score 2 4 on a scale of 0-9 [7, 81. Keratoconjunctivitis sicca was considered to be present when the two tests were positive. Xerostomia was evaluated by stimulated sialometry and estimation of the sublingual salivary pool. Xerostomia was considered present when there was loss of the sublingual salivary pool or reduced salivary flow rate (less than 0.1 ml/ min) E93. All biopsies were performed with the same method under local anesthesia. A lateral 1 to 2 cm linear incision was made in the mucosa of the lower lip. After dissection of the margins, some accessory salivary glands were removed and placed in fixative. In each case at least 4 salivary gland lobules were evaluated [lo, 11). Biopsy samples were scored according to the criteria of Chisholm and Mason [lo]. In short, the scale ranges from grade I (normal salivary gland with few lymphocytes) to grade IV ( 2 2 lymphocyte foci/4 mm’). A focus was defined as a cluster of at least 50 lymphocytes. The patients’ sera were tested for the presence of rheumatoid factor (by the latex method, positive at a dilution 2 1 :40), antinuclear antibodies (ANA) (by indirect immunofluorescence with HEP-2 cell line as substrate, positive at a dilution 1)1:40), and Ro (SS-A) and La (SS-B) antibodies (detected by double gel immunodiffusion with calf thymus and human spleen extracts as source of the antigen). In this series the diagnosis of primary SS was considered when the patient had keratocon junctivitis sicca, xerostomia, or both combined with positive salivary gland biopsy grade IV and explicit absence of criteria of other connective tissue diseases 1127.
Copyright 0 1990 by the American Neurological Association
Table 1. Clinical Characteristics (n = 64) Sex ratio (female :male) Age at onset (yr)" Age at admission (yr)" Disease duration (yr)" Course of disease Relapsing = remitting Relapsing = progressive Chronic = progressive Disease severityb 0- 3
3.5-6 6.5-9 Diagnosis certainty Clinically definite Laboratory-supported definite
1:13 29.1 2 8.8 38.6 ? 10.3 n z 7.2
~7 I U.L
20 (31)'
32 (50) 12 (18) 35 (54.6) 17 (26.5) 12 (18) 50 (78) 14 (22)
*
"Mean standard deviation. bDisease severity measured on the Expanded Disability Status Scale
C41. 'Values in parentheses represent percent of total patients.
Results Twenty-one (33%) of 64 patients had symptoms of xerophthalmia. Abnormal Schirmer's and rose bengal tests were observed in 15 and 7 patients, respectively. Only 5 patients had abnormal tests for both. Twenty patients (31%) suffered from oral dryness, but only 1 had an abnormal salivary pool. Sialometry was performed in 45 cases and the result was abnormal in 4; 2 of these 4 had keratoconjunctivitis sicca. Seven cases exhibited xerophthalmia, xerostomia, or both; an additional case had had recurrent parotitis. Biopsy of accessory salivary glands was done in these 8 patients; because of insufficient material, the biopsy was repeated in 1 patient. Four patients had normal salivary glands (grade I), 3 (including the patient with recurrent parotitis) had grade IV biopsies, and 1 patient had scattered lymphoid infiltrates (grade 11).Clinical and laboratory data of these 2 patients with sicca signs and grade IV positive biopsies are summarized in Table 2; serological tests for human immunodeficiency virus were negative in both. None of these patients had manifestations of other autoimmune diseases or extraglandular complications of primary SS. Latex rheumatoid factor, anti-Ro and anti-La autoantibodies were negative for all 64 patients. Three cases
had ANA autoantibodies, titers being 11160 in 2 cases and 1/80 in 1 case. Discussion Of 64 consecutive patients with definite MS, about one-third had symptoms of sicca complex. Only 7 patients, however, had objective evidence of keratoconjunctivitis sicca or xerostomia. Salivary gland biopsies were performed in these 7 patients and in 1 other patient suffering from recurrent parotitis. Histopathological examination revealed positive findings, that is, Chisholm-Mason grade IV, in 3 cases. According to the proposed criteria, 2 of these 3 cases could be considered to have primary SS C127. Furthermore, there were 2 patients with positive Schirmer's test and sialometry but with negative salivary gland biopsies, and 14 patients with one isolated positive sicca test. Although these patients cannot be currently diagnosed as having primary SS, serial examination should be performed to determine if they have incipient SS. The clinical and biological characteristics of these patients with clinical evidence of primary SS are different from those in patients reported by Alexander and associates 11, 131. Our patients are male, with onset of symptoms before 20 years of age. Clinical manifestations and MRI findings always indicated cerebral, cerebellar, brainstem, and spinal cord involvement. In our patients there were consistently 4 or more oligoclonal bands in CSF with increased IgG. Oligoclonal bands did not change after treatment {141. Specific autoantibodies for primary SS were negative. In contrast, in Alexander's series 18 of 20 patients were women, ranging in age from 21 to 50 years (mean 38). Apparently, MRI studies 1157 were performed in only 6 patients, with multiple focal areas of increased signal intensity indistinguishable from those of MS being noted in 5 patients; the sixth patient had negative MRI findings. CSF oligoclonal bands were present in 16 of 18 patients, but only 5 had more than 2 bands. Moreover, oligoclonal bands decreased with therapy [1, 31. Increased IgG index was noted in only 50% of cases. Finally, immunogenetic markers (HLA alloantigens) for primary SS or MS in our patients were different from those in Alexander's series [137. The prevalence of primary SS in the elderly population has been estimated to be between 2 and 5% 121.
Table 2. Clinical and Laboratory Data of Patients.with Primary SS
Case
Sex
Onset (yr)
1 2
M M
18 16
Duration of Symptoms (yr)
3 1
Course of Disease
No. of Oligoclonal Bands IgG Inde?
CSF IgG (mg per day)b HLA
Progressive Remitting
4 7
37 32
1.4 1.8
A9, J37, DR 5,6 A19 B5,7, DR 2
"Normal value, up to 0.8. bNormal value, up to 8.5.
Brief Communication: Mir6 et al: Sjogren's Syndrome in MS
583
In this series of patients with MS, with patients under the predilection age for primary SS, the prevalence of primary SS was 3.1%. Whether this association is fortuitous or whether there is a pathogenetic linkage between primary SS and MS remains to be established.
6. Moutsopoulos HM, Kippel JH, Pavlidis N, et al. Correlative
7. 8.
~
~~~~~~~~
The authors thank John Hawkins for stylistic revision and Marta de la Fuente for secretarial help.
9. 10.
References 1. Alexander EL, Malinow K, LejewskiJE, et al. Primary Sjogren’s syndrome with central nervous system disease mimicking multiple sclerosis. Ann Intern Med 1986;104:323-330 2. Noseworthy JH, Bass BH, Vandervoon MK,et al. The prevalence of primary Sjogren’s syndrome in a multiple sclerosis population. Ann Neurol 1989;25:95-98 3. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231 4. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1442-1452 5. Tourtellotte WW. The cerebrospinal fluid in multiple sclerosis. In: Koetsier JC, ed. Handbook of clinical neurology, v o l 3 (47): Demyelinating diseases. Amsterdam: Elsevier Science Publishers, 1985:79-130
584 Annals of Neurology Vol 27
No 5
May 1990
11.
12.
13.
14. 15.
histologic and serologic findings of sicca syndrome in patients with systemic lupus erythematosus. Arthritis Rheum 1980; 2 3:36-40 Van Bijsterveld OP. Diagnostic tests in the sicca syndrome. Arch Ophthalmol 1969;82:10-14 Hansen BV, Lindgren S, Erikson S , et al. Clinical and immunological features of Sjogren’s syndrome in patients with primary biliary cirrhosis with emphasis on focal sialadenitis. Acta Med Scand 1988;224:611-619 Sreebny LM, Valdini A. Xerostomia A neglected symptom. Arch Intern Med 1987;147:1333-1337 Chisholm D, Mason D. Labial salivary gland biopsy in Sjogren’s disease. J Clin Pathol 1970;26:690-712 Fox RI, Robinson CA, Curd JG, et al. Primary Sjogren syndrome. Proposed criteria for classification. Arthritis Rheum 1986;29:577-585 Moutsopoulos HM, Webber BL, Vlagopoulos TP, et al. Differences in the clinical manifestations of sicca syndrome in the presence and absence of rheumatoid arthritis. Am J Med 1979; 661733-736 Alexander EL. Neuromuscular complications of primary Sjogren’s syndrome. In: Talal N, Moutsopoulos HM, Kassan SS, eds. Sjogren’s syndrome: clinical and immunological aspects. Heidelberg: Springer-Verlag, 1986:61-82 Ebers GC. Ohgoclonal banding in multiple sclerosis. Ann NY Acad Sci 1984;436:206-212 Alexander EL, B e d SS, Gordon B, et al. Magnetic resonance imaging of cerebral lesions in patients with the Sjogren’s syndrome. Ann Intern Med 1988;108:815-823
