In general, the prevalence of CNS involvement in pSS varies widely across studies, ranging from 0% to 62% [3]. Several theories have been proposed to explain the variability in these studies, including:

1.Lack of a standardized definition for SS diagnosis across studies [4]. Indeed, some investigators have included persons with secondary SS [4, 5], and it is likely that some of these patients may have lupus with CNS dysfunction [5]. In addition, misdiagnosis of SS may occur; for example, persons with multiple sclerosis presenting with sicca symptoms and possessing positive antinuclear antibodies.

2.Varying definitions of CNS disorders have been employed. As reviewed by Soliotis et al. [5], several studies [6–9] have classified psychiatric and/or cognitive diseases in their definitions of CNS disorders, thus raising the prevalence estimates, sometimes dramatically. The inclusion of mild symptoms such as headache or mood disturbances [4] would also impact prevalence estimates.

3. Generalizability of patient populations also may be an issue, that is, the patient groups investigated may not be directly comparable to one another, and potential confounding factors for cerebrovascular disease are not uniformly addressed [4]. Furthermore, data are often based upon single case reports or small cases series [2]. Finally, referral bias may be present if pSS patients with CNS disease are differentially referred to certain institutions for care compared with pSS patients without CNS disease [5].

According to Govoni et al. [2], the spectrum of CNS involvement in pSS is diverse and involves several major categories of disorders: focal symptoms (e.g., aphasia, seizure disorders); movement disorders/pyramidal tract signs (e.g., brain stem syndrome); diffuse nonfocal symptoms (e.g., acute/subacute encephalopathy, aseptic meningoencephalitis); spinal cord involvement (e.g., transverse myelitis); and other disorders such as optic neuropathy, mood disorders, and MS-like disease. The data on the prevalence of nervous system involvement among patients with SS mirror the experience of other autoimmune disorders [10]. Reliable predictors of CNS dysfunction in patients with pSS do not exist.

20.2Cerebral Lesions

The frequency of cerebral MRI changes varies considerably in studies of pSS patients [8, 11–15]. Populations that include a high proportion of individuals with neurological impairments often display marked abnormalities on MRI, mostly in the periventricular and subcortical white matter [12].

The types of CNS abnormalities reported in patients with pSS vary substantially. MRI studies have revealed a wide spectrum of structural CNS changes, ranging from nonspecific disseminated white matter lesions [1, 6, 13, 16] to pseudotumoral brain lesions [16, 17], extensive spinal cord lesions [6, 16–18], subarachnoid hemorrhage, and brain atrophy [14, 19]. Moreover, correlations between CNS symptoms and abnormalities on MRI have been weak, providing further evidence for the heterogeneity of the underlying pathology [6, 18].

Fig. 20.1 White matter damage in a patient with primary Sjögren’s syndrome. Large lesion on T2-weighted MRI (a) and FLAIR (b, wide arrow) as well as patchy hyperintensities more apparent on FLAIR (b, thin arrows). Because of strong tissue contrast, subtle tissue damage is more clearly revealed on FLAIR (b) than on conventional T2-weighted MRI (a) (With kind permission from Morgen [20], Fig. 1)

Most commonly, pSS patients have been found to exhibit nonspecific disseminated white matter lesions on MRI [1, 13, 16] (Fig. 20.1). These may occur in the absence of focal neurological deficits and be associated with psychiatric disturbances (anxiety and depression) and neuropsychological deficits, predominantly affecting attention, visuospatial abilities, and executive function [6, 16, 19].

Small white matter lesions on T2-weighted MRI have also been detected in pSS patients without measurable CNS symptoms [13]. Because such lesions are common among elderly subjects and pSS tends to occur relatively late in life, their true significance has been difficult to interpret. The risk of white matter damage is increased by factors such as hypertension, diabetes, and hyperlipidemia, which are frequently elevated in the elderly [21]. A controlled investigation would require a large sample size [3].

There is some evidence that pSS patients with nonspecific white matter lesions or without apparent white matter damage on conventional MRI may develop brain atrophy [14, 19]. However, the disease specificity of correlations between cognitive performance and MRI measures of atrophy remains unclear [19].

Another approach to detecting subtle structural CNS abnormalities in pSS patients has been to analyze regional cerebral blood flow with single emission photon emission tomography (SPECT). In a recent case-control study, 99mTc-ECD brain SPECT revealed hypoperfusion predominantly in parietal and temporal cortex in pSS patients compared to control subjects, which in turn was associated with executive dysfunction [22].

Less frequently, pSS patients develop extensive CNS lesions, generally associated with focal neurological deficits. Studies, predominantly of patients recruited in tertiary referral centers, have reported CNS involvement characterized by relapsingremitting neurological deficits and white matter lesions mimicking multiple sclerosis (MS), an autoimmune demyelinating disease [1, 16, 23]. However, cases of focal CNS damage atypical of MS have also been described, for example, a patient with lethal subarachnoid hemorrhage resulting from spinal necrotizing vasculitis [24] or a patient with stroke-like onset of aphasia, anarthria, and hemiparesis caused by a pseudotumoral inflammatory white matter lesion with mass effect [16].

Some pSS patients with recurrent CNS deficits and positive anti-aquaporin 4-antibodies show a characteristic pattern of structural abnormalities on MRI reminiscent of neuromyelitis optica (NMO). Aside from spinal cord and optic nerve lesions, these patients appear to develop brain lesions in specific locations; that is, diencephalic and brainstem lesions adjacent to the third and fourth ventricles, longitudinal lesions of the internal capsule, and large cerebral lesions with a tendency toward cavity formation. The results suggest the importance of testing pSS patients with CNS disease for a possible coexistence of NMO [17, 25].

The pathology of CNS damage in pSS remains elusive and is likely to be heterogeneous. Subtle structural abnormalities indicated by punctate lesions on T2-weighted MRI and regional hypoperfusion in patients with or without discrete abnormalities on MRI presumably involve the dysfunction of small blood vessels [18, 22]. Feasible mechanisms of CNS involvement include different forms of vasculitis (small, medium, or large vessel; antibody or cell mediated, possibly immune complex deposition) and demyelinating inflammatory disease [3, 23, 26]. Whether specific immunological factors indicate a risk of developing CNS lesions has also not been resolved. Investigations of Anti-Ro (SSA) and anti-La (SSB) antibodies, antiphospholipid-antibodies, and rheumatoid factor have yielded inconclusive results [3]. The recently discovered evidence of aquaporin-4 antibodies as a risk factor for severe CNS involvement needs to be confirmed in larger studies [17].

Other autoimmune immune diseases associated with CNS tissue damage include MS and SLE. In these diseases, MRI studies can demonstrate clinical and subclinical tissue damage [27–29]. For example, only 5–10% of contrast-enhancing lesions observed on monthly MRI in MS patients are associated with neurological symptoms [27]. MS patients develop progressive cerebral atrophy early in the course of the disease [30]. In SLE, white matter lesions are associated with higher overall disease activity [29].

In pSS, CNS involvement is generally less marked than in MS and SLE, and MRI lesions often more discrete and interpretation more challenging. In the general population, most individuals over the age of 60 years have at least one white matter hyperintensity on T2-weighted MRI [31]. Since a high proportion of pSS cases have onset between the ages of 40 and 50 [6], it can be difficult to distinguish MRI-abnormalities associated with pSS from changes related to age and cerebrovascular risk factors.

20.3Differential Diagnosis with Multiple Sclerosis, Neuromyelitis Optica, and Antiphospholipid Syndrome

MS is a major cause of disability in young adults that generally presents in those aged 20–40 years [32]. In contrast, SS and its CNS manifestations tend to have onset in later years. The course of MS is variable, but it most often presents with a relapsing, remitting disorder that gradually becomes progressive, leading to an accumulation of disability. MS has been categorized as having the following courses: relapsing remitting, secondary progressive, primary progressive, and relapsing progressive. Common presenting symptoms for MS are vision impairment (specifically, reduced color perception and/or blurred vision resulting from optic neuritis) and sensory abnormalities, for example, the loss of sensation, paresthesias, and dysesthesias of variable distribution. Motor symptoms resulting from pyramidal tract dysfunction and cerebellar involvement may also occur initially and increase over the course of the disease, leading to weakness, loss of dexterity, and spasticity.

Optic neuritis, which eventually involves about half of all patients with MS, can also occur in SS. Typically, visual loss occurs in one eye over a few days. Ocular pain may occur before or during the attack. Significant visual recovery usually occurs over 2 weeks.

In addition to visual loss, diplopia may occur in MS and is most commonly caused by internuclear ophthalmoplegia.

Cerebellar involvement is common in MS but rare in SS. In addition, the urinary tract symptoms differ between these two diseases. In MS, urinary frequency, urgency, and incontinence frequently occur. Urinary incontinence is rare in SS but may result from myelitis. More commonly, SS patients develop irritable bladder symptoms as a result of interstitial cystitis [33].

Up to 70% of MS patients develop cognitive disorders, which may be missed on a standard mental status evaluation [34]. Cognitive disorders have been little studied in SS. MS patients typically develop declines in their ability to deal with complex concepts, impairment of complex reasoning, decreased verbal fluency and processing speed, and decline in episodic memory. Affective disorders are common, and almost three fourths of MS patients experience depression. In SS, the prevalence of depression is about 30% [35]. Both MS and SS patients often have debilitating fatigue. Uhtoff’s phenomenon, a temporary exacerbation of MS manifestations following exercise or body temperature elevation, is not a feature of SS, SLE, or antiphospholipid syndrome.

The diagnosis of MS requires evidence that white matter lesions are distributed in time and space, and the disease cannot be otherwise explained. The McDonald criteria are currently applied for the diagnosis of MS [36]. The diagnosis can be made on clinical grounds alone provided that two or more attacks have occurred and there is objective evidence that two or more areas of the CNS are involved. If objective evidence of MS is lacking or only a single attack has occurred, then investigations are required to substantiate the diagnosis. Relevant tests include MRI, cerebrospinal fluid (CSF) examinations, and visual evoked potentials (VEPs).

Typical MS lesions visualized on MRI are larger than 6 mm in diameter, ovoid, and tend to be oriented perpendicular to the lateral ventricles [37]. T1-weighted images of new lesions enhance with gadolinium initially, reflecting disruption of the blood–brain barrier. The inflammation and edema, which disrupt the blood–brain barrier and produce gadolinium enhancement, resolve within 1 or 2 months. At this stage, T1-weighted images may show low-attention signals known as “T1 black holes” that are thought to represent tissue loss. The CNS lesions on MRI may be indistinguishable from those seen in SS.

The CSF in MS shows a lymphocytic pleocytosis that generally is not more than 50 cells per deciliter. Generally, most of the immunoglobulin is IgG and discrete monoclonal bands of immunoglobulin (oligoclonal bands), not present in the serum, are detected in the CSF of approximately 90% of patients. Such bands may also occur in SLE and SS. An increased CSF IgG index can also be noted in both MS and SS.

VEPs measure sensory conduction velocity within the visual system. The great majority of MS patients, even those without a history of optic neuritis, have abnormal VEPs. Evoked response abnormalities may also occur in SS.

The distinction between SS and MS is accomplished most effectively through a careful history to identify features of SS such as symptoms of oral and ocular dryness, a search for evidence of dry mouth and dry eyes, serological testing for antiRo and anti-La antibodies, and pursuit of biopsy evidence of sialadenitis. CNS SS may be difficult to distinguish from relapsing-remitting MS using the symptoms and signs associated with and the investigations typically performed for relapsingremitting MS.

Neuromyelitis optica (NMO), an autoimmune disease considered to be a subtype of MS in the past but recently classified as separate disease, is characterized by a single event or relapsing attacks of optic neuritis and myelitis. The finding that aquaporin4-antibodies constitute a biomarker of NMO has permitted the definition of additional variants. These include optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem; Asian optic neuritis and/or myelitis with MS-like cerebral involvement; longitudinally extensive myelitis; and optic neuritis associated with systemic autoimmune disease [17, 38]. Contrary to MS, NMO tends to be associated with a pronounced CSF pleocytosis and a lower frequency of oligoclonal band (15–30% vs 85% in MS [38]). A recent case series of pSS patients who developed NMO suggests that there may be a subgroup of SS patients with a disposition toward developing NMO and that a test for aquaporin4-antibodies may help identify these patients even at early stages of CNS involvement [17].

Antiphospholipid syndrome (APS) requires a clinical event (thrombosis or pregnancy loss) and the presence of antiphospholipid antibody [39]. The presence of such antibodies can be documented as anticardiolipin antibodies, anti-b2-glycopro- tein-I antibodies, or by an inhibitor of phospholipid-dependent clotting (i.e., a lupus anticoagulant test). The antibodies must be persistently positive at high levels for 12 weeks or more. A number of features common to patients with the antiphospholipid syndrome are not part of the criteria for diagnosis, namely, livedo reticularis, valvular heart disease, and thrombocytopenia [40].