Version May 2024
INTRODUCTION — Sjögren's disease (SjD) is a chronic autoimmune inflammatory disease characterized by diminished lacrimal and salivary gland function. The clinical manifestations of SjD, however, include both exocrine gland involvement and extraglandular disease features, among which are an array of syndromes affecting the peripheral and central nervous systems (PNS and CNS) [1-4]. SjD occurs in a primary form not associated with other diseases and a secondary form that overlaps with other rheumatic conditions, most commonly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).
The neurologic manifestations of SjD and their diagnosis and treatment will be reviewed here. The pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of both exocrine and the other extraglandular manifestations are discussed separately:
●(See "Pathogenesis of Sjögren’s disease".)
●(See "Clinical manifestations of Sjögren's disease: Exocrine gland disease".)
●(See "Diagnosis and classification of Sjögren’s disease".)
●(See "Overview of the management and prognosis of Sjögren's disease".)
●(See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy".)
●(See "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease".)
●(See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations".)
PATHOGENESIS — Many immune-related mechanisms have been postulated to underlie the neurologic disease of SjD; these vary, depending upon the neurologic syndrome, and generally parallel the pathogenic factors that appear to underlie the neurologic manifestations of systemic lupus erythematosus (SLE). These mechanisms include:
●Small-vessel vasculopathy or frank vasculitis [5-8]
●Dorsal root ganglionitis [9,10]
●Cryoglobulinemia [11]
●Demyelination [12]
●Myelitis [13]
●Antineuronal antibodies [14-16]
●Antibody-mediated autonomic dysfunction [17-19]
The immunologic profile of SjD patients with neurologic involvement, compared with those without, varies depending upon the type of lesion. In a French study of 120 consecutive primary SjD patients, the 7 with sensorimotor neuropathy had a higher frequency of markers of monoclonal B-cell proliferation (mixed cryoglobulins, abnormal free light chain ratio, monoclonal gammopathy, and lymphoma) compared with those without peripheral neuropathy [20]. By contrast, the 20 with nonataxic sensory neuropathy had a lower frequency of antinuclear antibodies, Ro/SSA and La/SSB antibodies, rheumatoid factor, and hypergammaglobulinemia. In a Chinese study of 205 primary SjD patients, the titers of anti-Ro/SSA antibodies were significantly higher in the 40 patients with neurologic involvement compared with those without [21].
The pathophysiology in SjD of fatigue and mild cognitive dysfunction are not known but have been thought to be multifactorial, including pain [22], depression [23], immune-mediated endothelitis [24-27], and antibodies directed against N-methyl-D-aspartate receptor subtype NR2 (anti-NR2) and elevated heat shock protein 90a [28,29].
An analysis of these mechanisms is complicated by a complex differential diagnosis of the neurologic manifestations. As examples, the attribution of specific neurologic manifestations to SjD is confounded by a higher prevalence of neurodegenerative and cerebrovascular disease in the generally older-adult population affected by SjD, the frequent overlap of SjD with other systemic rheumatic diseases (such as SLE) that can also affect the nervous system, and the coincidence of SjD with autoimmune neurologic conditions, such as neuromyelitis optica spectrum disorder (NMOSD). As in any systemic rheumatic disease, infection and adverse effects of medications can have neurologic manifestations and must be included in the differential diagnosis.
EPIDEMIOLOGY — Estimates of the prevalence of neurologic involvement in SjD vary widely as a result of referral bias, disparate diagnostic criteria, differences in the thoroughness with which neurologic manifestations are sought, and whether these manifestations are clinically overt or asymptomatic [30]. Abnormal fatigue is present in the majority (prevalence estimated to be as high as two-thirds of patients) and significantly limits quality of life [31,32]. In a French cohort study of 392 patients with primary SjD, neurologic manifestations were present in 19 percent (peripheral in 16 percent and central in 4 percent) [33]. A Chinese cohort study of 205 patients with primary SjD reported similar findings [21]. In the French study, the annual incidence of new neurologic manifestations was 3.6 percent per year [33]. Neurologic manifestations may precede sicca symptoms in 33 to 93 percent of patients [7,34,35].
Peripheral neuropathy is likely the most common neurologic complication and was identified in 2 to 25 percent of three large primary SjD patient cohorts [20,36,37].
The frequency of central nervous system (CNS) involvement in SjD has long been controversial, and estimates vary widely [30,38]. In some studies, 20 to 25 percent of patients with primary SjD had CNS manifestations, ranging from diffuse symptoms to focal lesions that mimic multiple sclerosis [6]. By contrast, other groups have found a much lower prevalence of CNS disease in SjD [5,39,40]. There is also disagreement regarding whether cerebral white matter lesions on magnetic resonance imaging (MRI) are more prevalent in SjD patients [41,42] and whether they correlate with clinical manifestations of the disease or with age and cerebrovascular risk factors [43].
PERIPHERAL NERVOUS SYSTEM DISORDERS — SjD is associated with a complex array of peripheral nervous system (PNS) abnormalities [7,44]. Overlap may occur among the different forms of peripheral neuropathy. The relative frequency of these syndromes varies widely among case series.
Neuropathic symptoms precede the diagnosis of SjD in most patients, although many have other signs or symptoms of SjD. (See 'Evaluation for Sjögren's disease in patients with neurologic disease' below.)
Symptoms of neuropathy alone do not accurately identify neuropathy, which implies injury to peripheral nerves [45]. SjD patients may have fibromyalgia with neuropathic symptoms but without neuropathy. In addition, many patients will have subclinical disease (findings on electrodiagnostic studies) without symptoms [46]. The clinical diagnosis of neuropathy requires the combination of neuropathic symptoms with findings on examination (such as diminished reflexes, loss of sensation, or weakness) and supportive studies, such as electromyography/nerve conduction studies (EMG/NCS) and skin biopsy (intraepidermal nerve fiber density count).
Axonal sensory and sensorimotor polyneuropathy — Among the neuropathic syndromes in SjD, axonal sensory and sensorimotor polyneuropathies predominate, at least in some case series, with approximately equal frequency [20,36,37]. These neuropathies involve large myelinated fibers (which mediate proprioception, vibration, and touch, in addition to motor function), in contrast to the small-fiber sensory neuropathies (discussed below), which involve only unmyelinated and small myelinated fibers and mediate temperature and pain sensation. (See 'Small-fiber neuropathy' below.)
●Clinical features and findings on evaluation – Affected patients initially develop symptoms of a distal sensory neuropathy with distal paresthesia [47]. Examination demonstrates distal sensory deficits, including those of light touch, proprioception, and vibratory sensation. Weakness is generally mild when present, with involvement of toe flexors and extensors. Deep tendon reflexes may be diminished or absent, particularly in the Achilles tendon.
In contrast to small-fiber sensory neuropathy, sensorimotor neuropathy is associated with more severe extraglandular disease, low C4 complement levels, and cryoglobulinemia [47].
●Evaluation – Patients with symptoms and signs suggesting neuropathy generally undergo EMG/NCS to characterize the neuropathy. Nerve conduction velocities are relatively preserved, while sensory nerve action potentials (SNAPs) have reduced amplitude; compound muscle action potentials (CMAPs) may or may not be reduced [48,49].
Other causes of axonal polyneuropathy should be excluded. (See "Overview of polyneuropathy", section on 'EMG with axonal physiology'.)
A subset of these patients have a vasculitic neuropathy such as that associated with cryoglobulinemia. Clues that a vasculitic neuropathy may be present in a patient with an apparent polyneuropathy include asymmetric involvement on examination and electrodiagnostic studies, rapid onset, or stepwise progression of the neurologic deficits. Epineural and perivascular lymphocytic infiltrates have been observed in nerve biopsies [5,50,51]. Patients with findings suspicious for a vasculitic neuropathy need an expedited evaluation, often including a combined nerve and muscle biopsy for definitive evidence of vessel inflammation [52].
The axonal large-fiber neuropathies may coexist with a small-fiber sensory neuropathy, with diminution in intraepidermal nerve fiber density [53]. (See 'Small-fiber neuropathy' below.)
●Treatment – Treatment is predicated upon the severity and manifestations of the neuropathy and other systemic manifestations of the vasculitis (if present).
For patients with predominantly sensory symptoms, the initial treatment is usually symptomatic, as described for small-fiber neuropathy [47,54]. (See 'Small-fiber neuropathy' below.)
Patients with sensorimotor polyneuropathy and those who have an inadequate response to symptomatic therapy may be treated with immunosuppressive agents, such as a tapering course of glucocorticoids (starting at 0.5 to 1 mg/kg/day), coupled with a conventional synthetic disease-modifying antirheumatic drug (DMARD; eg, azathioprine 1 to 2 mg/kg/day). However, the clinical response is often disappointing [55,56].
For vasculitic neuropathy such as that associated with cryoglobulinemia, more intensive immunosuppression is required, generally with glucocorticoids and rituximab or cyclophosphamide. We also treat patients with a severe and progressive sensorimotor neuropathy, especially with motor involvement, even when the presence of cryoglobulins or vasculitis has not been confirmed. The treatment response appears to be better in patients with necrotizing vasculitis or cryoglobulins; however, clinical relapse is common [52,55].
Small-fiber neuropathy
●Clinical features – Small-fiber neuropathy presents as a painful sensory neuropathy. The initial symptoms are painful dysesthesias in the distal portions of the limbs, most often in the lower extremities. The pain is often described as burning, shock-like, or prickly [57,58] and is associated with allodynia (pain with nonpainful stimuli) and hyperalgesia (exaggerated response to painful stimuli). In the majority of patients, the spread of dysesthesias occurs over months to years to involve more proximal regions, including the trunk and the face [7].
Affected patients most commonly have a distal and symmetric distribution of burning paresthesia, most likely due to a dying-back axonopathy [53]. However, some patients may have an asymmetric and patchy "non-length-dependent" distribution, not confined to the distal extremities [47]. This may represent a dorsal root ganglionitis affecting unmyelinated or thinly myelinated neurons [59]. In one study, high-resolution magnetic resonance neurography demonstrated abnormalities of the dorsal root ganglia in 5 of 10 SjD patients with proximal neuropathic pain [60].
Examination usually demonstrates loss of pinprick and temperature sensation. Functions mediated by large nerve fibers, including muscle strength, light touch and vibratory sensation, proprioception, and deep tendon reflexes, are preserved [7].
Autonomic symptoms may also occur in this form of neuropathy, including alterations in sweating, micturition, pupillary accommodation, or bowel function.
SjD patients with small-fiber sensory neuropathy have a lower prevalence of anti-Ro/SSA antibodies and are more commonly male when compared with those without [58].
●Evaluation and diagnosis – There are no electrophysiologic abnormalities in patients with small-fiber neuropathy unless there is a concomitant large-fiber neuropathy [53,61].
The diagnosis is most often based on a significantly decreased density of epidermal nerve fibers in a skin biopsy from an affected region. The distribution of abnormal nerve fiber density in skin biopsies obtained in proximal and distal sites of the same limb can help differentiate length- versus non-length-dependent neuropathies [58]. (See "Skin biopsy for the evaluation of peripheral nerve disease".)
Other diagnostic modalities include quantitative sensory testing for thermal sensations, orthostatic blood pressure measurements, laser-evoked potentials, sympathetic skin response, and electrochemical skin conductance, but these are available primarily in specialized centers and are not required in routine clinical practice [62].
A small-fiber neuropathy can have multiple etiologies in addition to or instead of SjD. In a population-based study of Olmsted, Minnesota, the overall prevalence of this neuropathy was 13.3 per 100,000, and SjD accounted for 2 percent of cases. Other causes included diabetes mellitus (15 percent), amyloidosis (2 percent), Fabry disease (1 percent), and post-viral (1 percent) [63]. Seventy percent of the cases were classified as idiopathic.
●Treatment – Treatment for small-fiber sensory neuropathy is symptomatic and is similar to that for other causes of small-fiber sensory neuropathy except that in patients with SjD, medications with anticholinergic side effects are avoided [64]. These treatments are described in detail separately. (See "Management of diabetic neuropathy", section on 'Pain management'.)
•For pain relief, we generally initiate therapy with the anticonvulsant calcium channel alpha 2 delta ligands (gabapentin, pregabalin). To avoid somnolence and other troublesome side effects, we gradually titrate the doses of these medications upward over three to four months. The serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine, duloxetine) are also effective and particularly useful in those patients with coexisting depression [54].
•Tricyclic antidepressants (eg, amitriptyline, nortriptyline, desipramine) should generally be avoided, if possible, in SjD patients due to their anticholinergic side effects, but may occasionally be tolerated when introduced at a low dose and titrated slowly [54].
•Intravenous immune globulin (IVIG) has been reported to be effective for severe or treatment-refractory cases in small series and reports [7,65-67]. Prednisone is generally ineffective [7]. Small studies evaluating rituximab in painful sensory neuropathy have had disappointing results [55]. In our experience, patients with a small-fiber neuropathy whose area of numbness on clinical examination enlarges subacutely over weeks may be more responsive to immunomodulatory therapy compared with patients with a very slowly progressive neuropathy.
Sensory ataxic neuronopathy — Sensory ataxic neuronopathy is a rare yet devastating form of PNS disease, occurring in less than 5 percent of SjD patients [54], although in some series, it makes up a larger proportion of neuropathic syndromes [7]. This distinctive neuropathy is related to a dorsal root ganglionitis [9,10]. In patients with SjD, the initial symptoms often precede the diagnosis of SjD by years [50].
Small-fiber sensory neuropathy and sensory ataxic neuronopathy may occur together [7] and have a common pathogenesis (see 'Small-fiber neuropathy' above). In an autopsy study of two primary SjD patients, one with painful sensory neuropathy and the other with sensory ataxic neuronopathy, CD8+ lymphocytic infiltration of the dorsal root ganglia and reduction of dorsal root ganglion neurons were observed in both [59]. Thus, both of these clinical syndromes may arise from a dorsal root ganglionitis, with variable involvement of large and small neurons.
Autonomic neuropathy is also commonly seen in patients with sensory ataxic neuronopathy [68]. (See 'Autonomic neuropathy' below.)
●Clinical features – The initial symptom of a sensory neuronopathy is asymmetric paresthesia in the digits of the foot or hand that progresses over months to years to include the limbs, trunk, and face [7,50]. The subjective sensory symptoms can remain asymmetric or multifocal.
There is prominent loss of kinesthesia and proprioception, leading to gait ataxia, pseudoathetosis of the fingers and toes, and difficulties finding the limbs in space [9]. On examination, Romberg test is positive and generalized areflexia is typically present. There may be a slight reduction in pain and thermal sensation, but strength is preserved [68,69].
●Evaluation and diagnosis – Evaluation of patients with this clinical syndrome includes EMG/NCS to characterize the neuropathy and MRI of the spine to exclude polyradiculopathy. On NCS, CMAPs are preserved while SNAPs are absent or have a markedly low amplitude [7]. Both sensory and muscle nerve conduction velocities are typically preserved. Somatosensory evoked potentials can be absent [7]. On MRI of the spine, T2-weighted images may reveal hyperintensity of the dorsal columns, related to sensory ganglionic neuron injury or axonal degeneration [7,69].
Patients with sensory neuronopathy should be evaluated for paraneoplastic syndrome and infections that can also cause this syndrome. In contrast to these conditions, in SjD, cerebrospinal fluid (CSF; if obtained) typically has normal to mildly elevated protein levels with normal cell counts [51]. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Subacute sensory neuronopathy'.)
Peripheral nerve biopsies are characterized by a marked decrease in the number of large myelinated fibers and a milder decrease in other types of fibers [7]. There may also be epineural and perivascular inflammation and, less commonly, chronic vasculitis of arterioles in the epineural space. Biopsies of the sensory ganglion, when reported, have been notable for a marked CD8+ T-lymphocytic infiltrate with neuronal cell death [51].
●Treatment and prognosis – This rare and disabling form of neuropathy is often difficult to treat. Patients with advanced disease may become wheelchair users.
IVIG is suggested as a first line of treatment [70]. Early institution of IVIG has been associated with some benefit [71,72]. In a series of five patients, marked improvement with IVIG was seen in four [71]. A second series reported a variable response to IVIG (2 g/kg), with two patients improving, three stabilizing, and four worsening [65]. Other series have reported less successful outcomes with IVIG, with improvement in only 3 of 13 patients in one series and 1 of 6 patients in another series [7,73]. Delayed therapy has been postulated to lead to poor therapeutic response [54] and may account in part for these conflicting reports of response to IVIG.
Plasmapheresis is an alternative to IVIG, but there are less data supporting its use in this condition [74].
Glucocorticoids are a widely reported therapeutic modality, often in conjunction with other immunosuppressive agents, but many patients do not respond to this treatment [7,61,73,75].
Mycophenolate mofetil (MMF) at a dose of 2 grams per day has also been reported to be an effective treatment in one series [73] but not another [76].
Several reports have documented success with rituximab [76,77], while others, in the absence of cryoglobulinemia or vasculitis, have been disappointing [55].
Other therapies with some anecdotal reports of efficacy include hydroxychloroquine, cyclophosphamide, tacrolimus, azathioprine, d-penicillamine, infliximab, and interferon alpha [9,73,78,79].
Multiple mononeuropathy — Multiple mononeuropathy (also called mononeuritis multiplex) occurred in 3 percent of 102 primary SjD patients in one study [37].
The initial symptoms of multiple mononeuropathy include the acute onset of paresthesia or painful dysesthesia in the distal limbs. Subsequently, motor and sensory symptoms occur episodically and extend to multiple nerve distributions, primarily in the limbs. The sudden onset and mononeuritis multiplex pattern are suggestive of a vasculitic neuropathy and are described in detail separately. (See "Clinical manifestations and diagnosis of vasculitic neuropathies", section on 'Multiple mononeuropathy'.)
This form of neuropathy can be associated with cryoglobulinemia accompanying SjD.
In patients with multiple mononeuropathy, EMG/NCS is consistent with axonal damage involving multiple individual nerves in an asymmetric fashion. Nerve and muscle biopsy is required to confirm the diagnosis of vasculitic neuropathy unless vasculitis is confirmed by biopsy of other involved organs. Biopsy of affected nerves often shows axonal degeneration and a perivascular inflammatory infiltrate, suggesting an underlying vasculitic cause in many cases [5]. However, lymphocytic neural infiltration without vasculitis has been noted in some patients [50]. (See "Clinical manifestations and diagnosis of vasculitic neuropathies", section on 'Nerve/muscle biopsy'.)
The treatment of vasculitic multiple mononeuropathy is described separately (see "Treatment and prognosis of nonsystemic vasculitic neuropathy"). In patients with SjD, both cyclophosphamide and rituximab have been reported to be associated with high response rates in small case series [36,50,55].
Trigeminal neuropathy — The characteristic feature of trigeminal neuropathy is numbness or paresthesia restricted to the trigeminal region. Usually one side of the face is affected; however, bilateral involvement appears to be more common in SjD compared with idiopathic trigeminal neuralgia [7,80,81]. While trigeminal neuralgia in other clinical settings is typified by sharp attacks of facial pain with cutaneous triggers, trigeminal neuropathy in patients with SjD primarily presents as persistent numbness in the face. Another potentially distinguishing feature is that trigeminal nerve dysfunction in SjD is caused by damage to the gasserian ganglion, thus sparing the ophthalmic division and thereby preserving the corneal reflex. One case report describes masseter and temporalis muscle weakness in a patient with SjD and trigeminal nerve involvement [82]. (See "Trigeminal neuralgia", section on 'Clinical features'.)
The evaluation and differential diagnosis of trigeminal neuralgia is described separately. (See "Trigeminal neuralgia", section on 'Evaluation and diagnosis' and "Trigeminal neuralgia", section on 'Differential diagnosis'.)
Carbamazepine and oxcarbazepine may provide symptom relief of pain [83,84]. Treatment for painful cranial neuropathies can also follow similar strategies to those used for painful peripheral neuropathies, as described for patients with small-fiber neuropathy as well as for patients with idiopathic trigeminal neuralgia, although, as with small-fiber neuropathy, medications with anticholinergic side effects should be avoided in patients with SjD. (See "Trigeminal neuralgia", section on 'Medical treatment'.)
Immunosuppressive therapy is not typically prescribed specifically for this syndrome, although in one series, one of three patients treated with prednisone appeared to respond to treatment [7].
Autonomic neuropathy — The prevalence of autonomic neuropathy is difficult to estimate. In studies of peripheral neuropathies in SjD, it is the rarest to occur in pure form [7,47]. However, mild autonomic dysfunction is common in SjD, and is seen in up to half of patients when evidenced by abnormal cardiovascular reflex testing, delayed gastric emptying, urinary bladder dysfunction, and the quantitative sudomotor axon reflex test [47,70,85]. Many of these findings may be from autonomic dysfunction rather than progressive destruction of autonomic nerves.
This form of autonomic neuropathy may occur in association with a sensory ataxic neuropathy [9] or pure small-fiber sensory neuropathy (the small-fiber nerves mediate autonomic function in addition to perception of pain and temperature). Of note, many clinical factors, including concurrent medications and general deconditioning, influence autonomic testing results, which should be interpreted in the overall context of patient's clinical history.
●Clinical manifestations – Clinically overt autonomic neuropathies are manifested by orthostatic hypotension, fixed tachycardia, hypohidrosis or anhidrosis of the trunk and limbs, abdominal pain, constipation, diarrhea, and Adie's pupil (a dilated pupil that is poorly reactive to light but does react slowly to accommodation); these are similar to signs seen in diabetic autonomic neuropathy. These signs are described in detail separately. (See "Diabetic autonomic neuropathy".)
Autonomic dysfunction may also contribute to the decreased lacrimation and salivation of the sicca complex [86]. (See "Pathogenesis of Sjögren’s disease".)
●Treatment – The management of autonomic neuropathy is primarily symptomatic. The treatment options for orthostatic hypotension due to autonomic neuropathy may include fludrocortisone acetate, sympathomimetic agents such as midodrine, or beta blockers. (See "Treatment of orthostatic and postprandial hypotension".)
Visceral autonomic motor dysfunctions such as impaired gastric motility or bladder involvement have clinical similarities to those found in diabetic patients, and similar treatments have been proposed and are described separately. (See "Diabetic autonomic neuropathy of the gastrointestinal tract" and "Diabetic autonomic neuropathy", section on 'Genitourinary autonomic neuropathy'.)
Patients with severe forms of autonomic neuropathy have been treated with IVIG [65] or rituximab [55,65,87,88]. The response is often mixed, and complete resolution is unusual.
Multiple cranial neuropathies — Some patients present with multiple nerve syndromes: as many as six cranial nerves may be involved in an individual patient [7]. The cranial nerves most commonly affected are VII (Bell palsy); VIII (resulting in neural deafness and vestibular dysfunction); and III, IV, or VI (resulting in diplopia). The acute onset of a cranial neuropathy should prompt concern for a vasculitic neuropathy, particularly when it is associated with multiple mononeuropathies in the extremities [54].
Hearing may also be affected in a significant proportion of patients, although many cases are subclinical [89]. In a study of 30 SjD patients, 14 (46 percent) had sensorineural hearing loss on audiometric testing, compared with only 2.5 percent of the controls. Five of the 14 SjD patients had clinically apparent hearing loss [90].
While patients with SjD may develop impaired smell and taste, these deficits are believed to result from the effects of salivary hypofunction rather than a cranial nerve syndrome [70].
Patients with this presentation should undergo contrast-enhanced MRI and CSF evaluation. The differential diagnosis depends in part on the pattern of nerves involved, but includes other structural disease of the brain stem as well as meningitic processes such as chronic infections and cancer.
Multiple cranial neuropathies in SjD may respond to glucocorticoids [7].
Demyelinating radiculoneuropathy — This disorder has been described in a few patients with SjD and is characterized by sensory and motor dysfunction restricted to the spinal roots or proximal spinal nerve trunk [7,37,91,92]. The CSF protein concentration is usually elevated, but pleocytosis is absent. EMG/NCS demonstrate prolonged latencies consistent with a demyelinating neuropathy. These small case series have also noted gadolinium enhancement in the dorsal spinal roots on spinal MRI as well as evidence of demyelination on sural nerve biopsy in a few patients. These clinical features are similar to those of chronic inflammatory demyelinating polyneuropathy (CIDP), and it is unclear whether these are concurrent autoimmune disorders or whether this syndrome is an SjD disease manifestation. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis".)
IVIG has been reported to be effective for treatment of this syndrome in patients with SjD, and IVIG regimens are used for the treatment of patients with CIDP without SjD [7]. The management of CIDP, including the use and dosing of IVIG for this syndrome, is discussed separately. (See "Chronic inflammatory demyelinating polyneuropathy: Treatment and prognosis".)
CENTRAL NERVOUS SYSTEM DISORDERS — In many patients, the neurologic symptoms affecting the central nervous system (CNS) precede the onset of other signs and symptoms of SjD [50].
Focal or multifocal demyelination/inflammation — SjD has been associated with demyelinating disorders in case reports and series. Any part of the brain or spinal cord can be affected in patients with SjD. The pattern is generally one of multifocal recurrent episodes, often separated by long disease-free intervals, resulting in an insidious progressive neurologic deficit [50]. In most patients, these demyelinating disorders fulfill criteria for multiple sclerosis or neuromyelitis optica spectrum disorder (NMOSD) and can be considered associated with SjD rather than a specific SjD manifestation [30].
The range of CNS findings has been defined in several series of primary SjD patients [50,93,94] and is described below. The most common forms of CNS involvement are focal/multifocal, diffuse, and spinal cord.
Clinical syndromes
●Asymptomatic MRI lesions – In SjD, there is an increased prevalence of nonspecific T2-weighted white matter hyperintensities on MRI of the brain, usually in the absence of focal neurologic signs or symptoms [41,43]. In the absence of localizing findings, these white matter lesions occur at similar rates between SjD patients and age- and sex-matched controls [42] and correlate more with age and cardiovascular risk factors, such as hypertension and hyperlipidemia, than the underlying disease [95].
●Optic neuritis – Optic neuritis presents with monocular vision loss and eye pain and may be the presenting symptom or a later complication in patients with SjD-associated demyelinating syndromes [96-99]. The presentation, differential diagnosis, and evaluation of patients presenting with optic neuritis are described separately. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis".)
●Transverse myelitis – Spinal cord involvement in SjD can take the form of an acute transverse myelopathy or a longitudinally extensive (greater than three vertebral segments) myelopathy. The latter form of myelopathy is usually located in the cervical spinal cord, in contrast to idiopathic transverse myelitis, which is most often located in the thoracic spinal cord [100].
•NMOSD – In patients with SjD, transverse myelitis is often associated with antibodies to aquaporin-4 (AQP4) and falls within the spectrum of neuromyelitis optica spectrum disorders (NMOSD) [12,101]. In a review of published cases of longitudinally extensive myelitis associated with SjD, approximately 89 percent (17 of 19 patients) had positive AQP4 antibody [101]. Patients with SjD and AQP4 antibody behave like patients with conventional NMOSD in terms of relapse frequency and imaging findings in the brain and spine [70]. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)
•Other causes – Myelitis associated with a longitudinal T2-hyperintense lesion in the cervical spinal cord was reported in four SjD patients, each without AQ4 or myelin oligodendrocyte (MOG) antibodies [102]. Cerebrospinal fluid (CSF) neurofilament light chain levels, a measure of neuroaxonal damage, were elevated in these patients compared with controls, and two patients demonstrated intrathecal synthesis of anti-SSA/Ro antibodies.
Progressive spastic paraparesis in a patient with SjD was associated with presence of anti-Ma2/Ta antibody without underlying cancer [103].
The clinical syndrome and differential diagnosis of transverse myelitis are described in detail separately. (See "Transverse myelitis: Etiology, clinical features, and diagnosis".)
●NMOSD – One case series describes 12 SjD patients (all with positive anti-Ro/SSA and anti-La/SSB antibodies) who had relapsing and remitting CNS symptoms and brain involvement, characteristic of NMOSD [12]. These included lesions adjacent to the third and fourth ventricles (10 patients), longitudinal lesions from the internal capsule to the brainstem (eight patients), large and confluent cerebral and cerebellar lesions of >3 cm in length (eight patients), and cavity formation (seven patients). The AQP4 antibody was found in six of eight patients in whom it was tested.
Several findings have supported the concept that NMOSD is not a direct manifestation of SjD, but rather an overlap of two distinct autoimmune diseases [104-106]. These include the high specificity of AQP4 antibodies for NMO, similarities in antibody profile between SjD patients with and without NMOSD, and similarities in CNS lesions between NMOSD patients with and without SjD.
NMOSD is described in detail separately. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis".)
●Multiple sclerosis-like presentations – Since multiple sclerosis is also a common disorder affecting patients with the same demographics as SjD, comorbid multiple sclerosis has to be considered in SjD patients developing demyelinating CNS lesions. Whether there is a linkage between the two diseases has been controversial without large series to substantiate claims. In patients with primary progressive multiple sclerosis, higher than background prevalence of SjD has been found [107]. Others have suggested that patients with SjD-associated myelopathy may instead be misdiagnosed with multiple sclerosis [108]. Advances in MRI brain sequences have allowed for detection of central veins through brain lesions. Multiple sclerosis lesions generally have a significantly higher frequency of veins traversing centrally through the lesions ("central vein sign") when compared with SjD; it is uncertain whether this is a reliable tool to distinguish SjD from multiple sclerosis [109].
●Other focal presentations – Some patients with SjD present with focal brain lesions that may result in motor or sensory deficits, seizures, or cerebellar syndromes.
Focal demyelinating symptoms and their differential diagnosis are described separately. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Clinically isolated syndrome' and "Manifestations of multiple sclerosis in adults".)
Chorea has been described as a presenting symptom of SjD [110,111].
Evaluation — Management of demyelinating disease requires careful consideration of the likely etiology. White matter lesions on MRI may be a reflection of comorbid conditions, including aging, hypertension, and hyperlipidemia, rather than an autoimmune lesion, given that the majority of SjD patients are middle aged and older [95].
Alternative diagnoses such as multiple sclerosis or NMOSD have to be excluded before attributing symptoms and findings to SjD. We suggest that patients with these syndromes be evaluated according to their syndrome presentation, regardless of whether they have a diagnosis of SjD or not. Typically this evaluation includes neuroimaging, CSF evaluation, and in some patients, serologic testing as well. These evaluations are described in detail separately:
●(See "Transverse myelitis: Etiology, clinical features, and diagnosis", section on 'Initial evaluation'.)
●(See "Evaluation and diagnosis of multiple sclerosis in adults".)
Treatment — Acute attacks of demyelination are typically treated with intravenous pulse methylprednisolone, 1 gram daily for three to five days [112,113]. Plasmapheresis is utilized for patients whose neurologic disease does not respond to glucocorticoids [114] (see "Treatment of acute exacerbations of multiple sclerosis in adults"). In patients with severe attacks of NMOSD, there are limited data to suggest improved outcomes if plasmapheresis is started early as adjunctive therapy with glucocorticoids. (See "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis", section on 'Acute attacks'.)
The distinction of NMOSD from SjD-related myelopathy may not be feasible, and presumptive therapy for NMOSD is thus recommended, particularly in the setting of positive AQP4 antibodies. Remission may be maintained with eculizumab, rituximab, azathioprine, or mycophenolate mofetil (MMF) [112,113]. If AQP4 antibodies are negative, long-term immunosuppression may rely on mycophenolate, azathioprine, or rituximab in lieu of eculizumab, similar to treatment of other patients with antibody-negative NMOSD. (See "Neuromyelitis optica spectrum disorder (NMOSD): Treatment and prognosis".)
Similarly, for other demyelinating syndromes, the indications for chronic immunomodulatory treatment mirror those used in patients without SjD. (See "Optic neuritis: Prognosis and treatment", section on 'Disease-modifying therapy' and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults" and "Transverse myelitis: Treatment and prognosis", section on 'Recurrent idiopathic TM'.)
Cognitive dysfunction — Changes in cognitive function with poor memory and concentration are commonly reported by SjD patients, often using the term "brain fog." The severity of these symptoms can range from subtle cognitive impairments to frank dementia [94,115-117].
In most cases, the symptoms are relatively mild; the specificity of this mild encephalopathy to SjD as opposed to any disabling chronic medical illness needs to be evaluated further [117]. One series of 431 consecutive primary SjD patients describes six with a recurrent subacute encephalopathy, characterized by memory loss, cognitive dysfunction, visual disturbances, and reduced performance in concentration and attention [94]. Each had small punctate hyperintense white matter lesions on MRI, but no focal neurologic signs. In other reports, abnormalities on objective neuropsychiatric testing have included reduced psychomotor processing, verbal reasoning, memory, attention, and concentration ability [23,27,118-120], but some studies have failed to show consistent differences between primary SjD patients and controls [23]. Fatigue and depression may have a role in the genesis of this cognitive dysfunction [120].
Other case series also report that MRI studies are normal or have minor nonspecific abnormalities [27]. Regional areas of cortical hypoperfusion on single-photon emission computed tomography (SPECT) were reported in one series of patients with SjD-associated cognitive dysfunction [27].
SjD should not be assumed to be the cause of cognitive dysfunction [117]. Patients should be evaluated for thyroid dysfunction, vitamin B12 deficiency, sleep disturbances, affective disorders, and medication side effects. Neuroimaging and CSF analysis should be reserved for patients with severe symptoms and/or objective evidence of impairment in one or more cognitive domains, as assessed in the clinical interview and with the aid of a screening tool, such as the Folstein Mini-Mental State Examination. The evaluation of patients with cognitive impairment is described in detail separately. (See "Evaluation of cognitive impairment and dementia", section on 'Evaluation'.)
For indolent manifestations such as psychiatric changes or mental fog, monitoring with supportive therapy is appropriate. (See "Mild cognitive impairment: Prognosis and treatment", section on 'Treatment'.)
One case report documented improvement of SjD-related dementia with high-dose glucocorticoid therapy [115]. This patient had normal brain MRI, CSF, and angiography but had perivascular inflammation on brain biopsy. Immunosuppression in SjD patients with dementia should only be pursued after alternative and more common causes of dementia have been excluded and/or an inflammatory process is documented. Neuropsychiatric testing should be performed before and after a glucocorticoid trial to ensure objective improvement has occurred prior to initiation of glucocorticoid-sparing therapy.
Meningoencephalitis — Meningoencephalitis has been reported in a few cases. The largest case series described five patients, four of whom had recurrent episodes [121]. All presented with fever, myalgias, meningismus, and delirium. CSF had leukocytosis (ranging from 33 to 900 cells/microL with variable neutrophilic or lymphocytic predominance), mildly elevated protein, and an elevated CSF immunoglobulin G (IgG) index. Vasculitis involving veins, arterioles, and small arteries was documented in skin or muscle biopsies of three of the five patients, but cerebral angiography failed to show changes indicative of medium-sized vessel vasculitis.
A separate series of recurrent meningoencephalitis cases described intracranial angiographic changes suggestive of vasculopathy and biopsies consistent with vasculitis [26]. Subacute aseptic meningitis with diffuse leptomeningeal enhancement has also been reported [122,123].
Patients with SjD who present with meningoencephalitis require thorough CSF evaluation to exclude infectious causes. (See "Aseptic meningitis in adults".)
Spontaneous recovery without treatment has been reported. Treatment with glucocorticoids alone or in conjunction with cyclophosphamide has been reported as successful in case series and isolated case reports [121,124-126]. One reported case improved markedly following plasmapheresis [127].
Autoimmune encephalitis — Encephalitis associated with antibodies to neuronal proteins and synaptic receptors, including anti-Ma2 and anti-N-methyl-D-aspartate receptor, has been reported rarely in SjD [128,129]. Autoimmune encephalitis is described separately. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)
Other associations — Some studies find that headache is more prevalent in patients with SjD than controls [24,130-132]. However, studies have differed as to the strength of this association as well as the most common headache type (eg, migraine, tension headache). At present, we evaluate and treat patients according to their headache type. (See "Evaluation of headache in adults".)
Psychiatric disorders (in particular, affective disorders [depression and anxiety]) are common in SjD patients and may contribute to neurologic symptoms, particularly cognitive impairment. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Psychiatric disorders'.)
Rare cases of motor neuron disease have been described in patients with SjD [133-135].
SUPPORT FOR TREATMENT APPROACHES — The treatment approach to neurologic manifestations of SjD is based upon clinical practice guidelines, case series, limited clinical trial data for a few agents, our clinical experience, expert opinion, and indirect evidence from the use of these agents in other autoimmune rheumatic disorders. (See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Therapeutic rationale and evidence overview' and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Efficacy of specific therapeutic agents'.)
EVALUATION FOR SJÖGREN'S DISEASE IN PATIENTS WITH NEUROLOGIC DISEASE — Neurologic symptoms precede a diagnosis of SjD in most cases, up to 93 percent in one series [7,34,35]. However, many of these patients will have symptoms of dry eyes, dry mouth, or other features of SjD, which should raise suspicion for this disorder. (See "Diagnosis and classification of Sjögren’s disease", section on 'Symptoms of dry eyes and mouth'.)
For most of these neurologic syndromes, SjD is not among the first tier of diagnoses being considered, but SjD should be suspected in patients with persistent symptoms of dry eyes and/or mouth, parotid gland enlargement, or an unexplained increase in dental caries and in those in whom a cause is not identified after initial testing.
The evaluation can include serologic testing for anti-Ro/SSA and anti-La/SSB antibodies, rheumatoid factor, and antinuclear antibodies; testing for hyperglobulinemia; and an ophthalmologic evaluation. The latter should be performed by an expert in eye disease and typically includes Schirmer testing, a slit-lamp examination, and ocular surface staining. Some patients may require formal testing of salivary function, a labial salivary gland biopsy, and/or imaging studies to confirm a diagnosis of SjD. Among patients who present with neuropathy, the Schirmer test for dry eye and salivary gland biopsy appear to have higher sensitivity than serologic testing [7]. The evaluation and diagnosis of SjD are described in detail separately. (See "Diagnosis and classification of Sjögren’s disease".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sjögren's disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Sjögren's disease (The Basics)")
●Beyond the Basics topics (see "Patient education: Sjögren's disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Clinical presentation and evaluation for SjD – Sjögren's disease (SjD) can cause peripheral nervous system (PNS) and brain abnormalities. (See 'Epidemiology' above.)
•Peripheral neuropathy affects approximately 10 percent of patients.
•Estimates of central nervous system (CNS) involvement vary quite widely, and the nature and frequency of CNS manifestations remain controversial.
Neurologic symptoms frequently precede the diagnosis of SjD. The presence of sicca symptoms may point to a diagnosis of SjD and should prompt a formal evaluation for this disease. (See 'Evaluation for Sjögren's disease in patients with neurologic disease' above.)
●Peripheral nervous system disease – SjD is associated with a variety of PNS abnormalities. Overlap may occur among the different forms of peripheral neuropathy. The relative frequency of these syndromes varies widely among case series. (See 'Peripheral nervous system disorders' above.)
•The evaluation of the neuropathy is tailored to the clinical syndrome, but often includes electrophysiologic studies: electromyography (EMG) and nerve conduction studies (NCS) that help to confirm the syndrome. Skin and/or nerve biopsies and other evaluations are recommended in specific syndromes.
•Recommended treatment approaches are based upon anecdotal evidence of efficacy and/or studies in patients with similar syndromes occurring in diseases other than SjD.
Immunotherapy for peripheral nerve disease is typically limited to patients with disabling symptoms, symptoms not responsive to symptomatic therapies, and/or those with a documented vasculitic component.
●CNS demyelination – Demyelinating disorders are sometimes seen in patients with SjD. Any part of the brain or spinal cord can be affected; in particular, a number of patients with neuromyelitis optica spectrum disorders (NMOSD) have been described. It is not clear whether SjD is the cause of the demyelination or if this represents an autoimmune diseases association. (See 'Focal or multifocal demyelination/inflammation' above.)
A diagnostic evaluation should be undertaken that is similar to that for patients who have one of these syndromes without a history of SjD. Similarly, we suggest treatment approaches similar to those for patients with these syndromes outside the context of SjD. These are described in individual topic reviews. (See 'Focal or multifocal demyelination/inflammation' above.)
●Cognitive impairment – While commonly reported by SjD patients, it is unclear to what extent complaints of poor memory and concentration are specific to SjD as opposed to other disabling chronic medical illnesses. Patients with cognitive impairment should be fully evaluated for other causes. (See 'Cognitive dysfunction' above and "Evaluation of cognitive impairment and dementia".)
●Meningoencephalitis – Meningoencephalitis is a rare complication of SjD and generally has a benign prognosis, with spontaneous recovery or resolution with glucocorticoids or other short-term immunotherapy. (See 'Meningoencephalitis' above.)
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