Peripheral neuropathy is a common complication of primary Sjögren syndrome, but central nervous system involvement also occurs and may be the only extraglandular manifestation. Sicca symptoms may also be minimal. Combinations of lesions along with relapses and remissions can suggest multiple sclerosis in the proper clinical setting, making the correct diagnosis elusive.
To report a case of progressive transverse myelopathy with previous optic neuropathy in primary central nervous system Sjögren syndrome (CNS-SS), and to review 17 previously reported cases and the patient's responses to various therapies.
Case report and literature review.
A 63-year-old Hispanic woman with a 10-month history of progressive spastic paraparesis associated with optic neuropathy and a T10 sensory level. Magnetic resonance imaging demonstrated multifocal, contrast-enhancing lesions in the spinal cord. The patient was diagnosed as having CNS-SS because of the presence of sicca symptoms, abnormal serological test results, and salivary gland biopsy results, which fulfilled San Diego criteria for "definite" Sjögren syndrome. She responded to treatment with a combination of prednisone and cyclophosphamide.
Diagnosis of primary CNS-SS requires a high index of suspicion and specialized clinical testing. Treatment with pulse doses of corticosteroids alone may be suboptimal, but results of treatment with a combination of corticosteroids and either cyclophosphamide or chlorambucil have been encouraging.
SJÖGREN SYNDROME (SS) is a chronic autoimmune disorder affecting the exocrine glands that is manifested clinically by keratoconjunctivitis sicca, xerostomia, and multiple abnormalities of cellular and humoral immunity. Systemic disease may also occur, resulting in extraglandular complications, including involvement of the central and peripheral nervous systems.1,2 It is usually considered a disease of older persons, but also can affect younger individuals. Primary SS presents with sicca complex alone, whereas secondary forms occur in conjunction with another connective tissue disorder, most commonly rheumatoid arthritis.1 Peak prevalence is at 40 to 50 years of age, with a female-male ratio of 9:1.2 The use of 2 separately devised classification schema, the San Diego3 and European4 criteria (Table 1), complicates diagnosis and classification. However, both combine objective evidence of the sicca complex, characteristic serum autoantibodies (single-stranded [ss] anti-Ro [ssA-Ro] and ss anti-La [ssB-La] antibodies), and positive results of minor salivary gland biopsy. The European Community Study Group on Diagnostic Criteria for Diagnosis of Sjögren's Syndrome4 recently validated their criteria (sensitivity, 97.5%; specificity, 94.2%).
Clinical diagnosis of SS requires a high index of suspicion, especially when the first manifestations are neurologic. Peripheral neuropathy is well recognized, occurring in about 10% to 35% of patients with primary SS.2 Central nervous system (CNS) involvement in primary SS (CNS-SS) is less common, and its manifestations may be localized (optic neuropathy, hemiparesis, transverse myelitis, and dystonia) or diffuse (encephalopathy and dementia). A combination of lesions and the presence of relapses and remissions often suggests multiple sclerosis.1,5 We report herein 17 cases6- 17 (Table 2) and describe our patient with progressive myelopathy and optic neuropathy, who responded to a combination of prednisone and cyclophosphamide, as previously reported.10
A 63-year-old Hispanic woman presented with paraplegia, preceded by asymmetric sensory symptoms in her legs for 10 months. Urinary frequency and urgency, occasional dysuria, and urinary incontinence developed in the few weeks before admission.
Four months earlier, she had undergone an extensive evaluation. Relevant findings on neurologic examination included spastic paraparesis, worse on the left side and with lower limb hyperreflexia; a sensory level was not present, but hypoesthesia to pinprick was noted in her left buttock and posterior thigh. Plantar responses were flexor. Magnetic resonance imaging (MRI) demonstrated abnormal focal signal intensities on T2-weighted images at the C5-6 and T8-9 levels and on the conus medullaris and cauda equina (Figure 1, A). These same regions were enhanced by the administration of gadolinium on T1-weighted images. Computed tomographic (CT) scanning and MRI of the brain were noncontributory. Initial examination of the cerebrospinal fluid (CSF) showed lymphocytic pleocytosis with 0.011 ×109 cells/L, few atypical lymphocytes, a mildly elevated protein level (0.85 g/L), a nonreactive VDRL test, and absent oligoclonal bands. A second CSF sample had 0.006 ×109 cells/L, a protein level of 0.72 g/L, and normal results of cytologic examination. Serum and urine protein electrophoresis showed no monoclonal gammopathy or elevation of the angiotensin-converting enzyme level, and serum B12 levels were normal. Antibodies to human immunodeficiency virus and human T-lymphotropic virus 1 (HTLV-1) were nonreactive. An antinuclear antibody ratio was mistakenly reported to be less than 1:40. A chest x-ray film was normal. A gallium body scan demonstrated increased activity in the lacrimal glands, regional lymph nodes, and right paratracheal region; chest and abdominal CT studies showed no hilar, mediastinal, or abdominal adenopathy and no evidence of sarcoidosis. The patient was discharged from the hospital and prescribed baclofen therapy.
A, Digitally enhanced T2-weighted magnetic resonance image (MRI) showing abnormal increased signal (arrow) in the cauda equina and conus medullaris. B, Digitally enhanced T2-weighted MRI of cervical spine showing increased signal (arrows) at the C5-7 levels of the cervical cord. C, Digitally enhanced T1-weighted MRI of thoracic spine showing increased signal (arrow) in the thoracic cord. D, Digitally enhanced T1-weighted contrast MRI of the cervical spine demonstrating enhancement of a cervical cord lesion (arrow).
During the next 3 months, her paraparesis progressed to near paraplegia associated with a sensory level at the umbilicus and with left arm paresthesias. On review, the first antinuclear antibody ratio was actually 1:640, and the erythrocyte sedimentation rate was 41 mm/h. Mild sicca symptoms (xerostomia and keratoconjunctivitis) were found on further questioning.
Positive findings on neurologic examination included a left afferent papillary defect, spastic paraplegia with hyperreflexia, crossed adductor responses, ankle clonus, and bilateral Babinski signs. Motor strength was 5/5 (Medical Research Council scale) in the upper extremities and 0/5 in the lower extremities, except for ankle dorsiflexors and plantar flexors, which were 1/5. A T10 sensory level was found, along with decreased anal sphincter tone.
Magnetic resonance imaging of the cervical (Figure 1, B), thoracic (Figure 1, C), and lumbar spine showed multifocal areas of increased T2-signal intensity, enhanced by gadolinium (Figure 1, D), at the C5-7, T3-5, and T8-11 levels and on the conus medullaris. A moderate degree of multilevel cervical spondylosis from posterior osteophytes and protruding discs near the same level of corresponding increased cervical cord signal abnormality was suggested on cervical T2-weighted images (Figure 1, B). However, there was minimal narrowing of the spinal canal at this level of the same region on T1-weighted contrast views (Figure 1, D), and the same areas were markedly enhanced with administration of contrast medium.
A CSF sample had 0.035 ×109 cells/L, a glucose level of 2.9 mmol/L (53 mg/dL), and a protein level of 0.62 g/L. Oligoclonal bands and myelin basic protein were absent, and the IgG index was normal (0.63). A second antinuclear antibody test was positive, with a titer of 1:2560; ssA-Ro antibody was positive with a speckled pattern. Complement C3 was 1.78 g/L (reference range, 0.86-1.84 g/L) and C4, 0.23 g/L (reference range, 0.20-0.59 g/L). Visual evoked potentials were prolonged in the left eye. Examination of a minor salivary gland biopsy specimen showed chronic sialadenitis, with a focus score of 3. The autoimmune serological profile and other test results are given in Table 3. The patient was diagnosed as having CNS-SS because of the presence of sicca syndrome, abnormal serological test results, and the salivary gland biopsy results, which fulfilled the San Diego criteria3 for "definite" SS. The patient received a pulse dose of intravenous methylprednisolone sodium succinate, 1 g/d for 3 days, followed by oral prednisone, 60 mg/d. Rheumatology consultants recommended treatment with intravenous cyclophosphamide, 0.75 g/m2, followed by equal monthly doses for 6 months, along with oral prednisone, 20 mg/d. With treatment, the patient experienced marked improvement in the strength of most of the muscles in her lower extremities, going from 0-1/5 to 3/5 (Medical Research Council scale). Furthermore, sensory complaints, particularly subjective paresthesias in the left upper extremity, slowly abated during the ensuing several weeks.
The occurrence of myelopathy in primary CNS-SS appears to be far from exceptional. In this review, 3 forms of myelopathy occurred: Brown-Séquard syndrome (1 patient),10 acute transverse myelitis (12 patients),6,8,9,12- 18 and progressive myelopathy (5 patients,6,11,14 including ours). Overall, there was a clear preponderance of women (12 [75%] of 16 patients for whom sex was reported), with a mean age of 48.2 years (range, 9-72 years); men were notably younger at diagnosis (mean age, 33.2 years [range, 18-53 years]). All patients presented with paraparesis or paraplegia resulting from lesions at the thoracic or cervicothoracic levels. In one instance,12 the spinal cord lesion was thoracolumbar. Our patient had multifocal MRI lesions at the C5-7, T3-5, and T8-11 levels and on the conus medullaris.
The lesion in the patient with Brown-Séquard syndrome of abrupt onset reported by Ménage and colleagues10 extended from C4 to the bulbomedullary junction. The patient's condition progressed during the next 3 years with partial remissions and exacerbations, and was later accompanied by optic neuropathy and white matter lesions in the centrum semiovale and cerebellum, suggestive of multiple sclerosis.
Acute transverse myelitis appears to be the most common form of spinal cord involvement in CNS-SS (10/18 patients [56%]). Symptoms develop abruptly, with severe neck and interscapular pain followed by sensory and motor deficits below the thoracic level of the lesion. This presentation should be distinguished from nucleus pulposus fibrocartilaginous embolism19 and acute multiple sclerosis.20 The acute transverse myelopathy form of CNS-SS has high mortality, probably due to vasculitis, with 1 instance of rapidly fatal spinal subarachnoid hemorrhage.7 Nonetheless, Konttinen et al9 successfully treated 1 patient with prednisone and plasmapheresis. More recently, Manabe et al18 reported success with intravenous methylprednisolone followed by oral prednisone.
The subacute or chronic form of myelopathy occurred in 5 patients (28%). It usually began with unilateral sensory symptoms below the level of the lesion, sphincteral incontinence, and problems walking, eventually leading to transverse myelopathy and paraplegia. The syndrome was often accompanied by optic neuropathy and other symptoms above the level of the initial lesion in a pattern reminiscent of multiple sclerosis.1,5 Differential diagnosis should also include CNS lupus, spinal dural arteriovenous fistula,21 and HTLV-1 infection.
Infection with HTLV-1 produces a late-onset chronic myelopathy that predominates in women but, in contrast to the current cases, patients present with minimal sensory symptoms.22 In addition, keratoconjunctivitis sicca is the most common form of ophthalmic involvement in HTLV-1 infection,23 occurring in up to 48% of the patients with HTLV-1–associated tropical spastic paraparesis. In half of these patients, results of salivary gland biopsies are also consistent with SS.
The treatment currently recommended for CNS-SS is intravenous corticosteroids plus an immunosuppressive agent. Alexander1 noted that pulse doses of intravenous corticosteroids are only effective in some patients and recommended the addition of cyclophosphamide for 12 months (initial dosage, 0.75 g/m2 monthly, with adjustment to keep the white blood cell count at 3.0 ×109 cells/L after 7-10 days). Wright and colleagues17 recently combined prednisone and chlorambucil, based on the significant effect of this combination on B cells.
This case review illustrates several points. First, sicca symptoms may be so subtle in SS presenting with CNS features that the diagnosis is not entertained. Second, CNS manifestations may essentially be the only extraglandular complication. Third, CNS-SS is usually multifocal, additive, and progressive, with a clinical course of fixed and cumulative deficits. When the spinal cord is involved, deficits are often acute, ie, transverse myelitis. The pathogenesis of CNS-SS appears to stem from an inflammatory ischemic vasculopathy with small vessel angiitis.1,6 However, the presence of antineuronal antibodies may produce paraneoplastic-type lesions.24
In summary, the diagnosis of SS may be difficult and requires a high index of suspicion, autoimmune serological and specialized clinical testing, and minor salivary gland biopsy. Should an improper diagnosis be made, treatment with pulse doses of corticosteroids may be suboptimal. Encouraging results have been obtained with a combined therapy of corticosteroids plus cyclophosphamide or chlorambucil.
Accepted for publication November 9, 2000.
The views and opinions expressed in this article are those of the authors and do not necessarily represent those of the US Air Force or the US Department of Defense.
Corresponding author and reprints: Lt Col Christopher S. Williams, USAF, MC, SFS, Department of Neurology, 59 MDOS/MMCNN, 2200 Bergquist Dr, Suite 1, Lackland Air Force Base, TX 78236-5300 (e-mail: christopher.williams@59MDW.WHMC.af.mil).
Williams CS, Butler E, Román GC. Treatment of Myelopathy in Sjögren Syndrome With a Combination of Prednisone and Cyclophosphamide. Arch Neurol. 2001;58(5):815-819. doi:10.1001/archneur.58.5.815