Neuro-Ophthalmic Manifestations of Primary Sjogren Syndrome
Sjogren syndrome (SS) is an autoimmune exocrinopathy primarily characterized by chronic inflammation of the lacrimal and salivary glands. Periductal lymphocytic infiltration of the exocrine glands results in progressive loss of secretory function, resulting in keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth).  It is the second most common autoimmune rheumatologic disease, with an estimated prevalence of 0.1-4.8%. SS can occur independently as primary SS or as secondary SS when occurring in the setting of other autoimmune connective tissue diseases, most commonly rheumatoid arthritis or systemic lupus erythematosus. It primarily affects middle-aged women, with a female to male ratio as high as 9:1. 
SS is characterized by significant polyclonal B-cell activation that results in various circulating autoantibodies, classically anti-nuclear, anti-Ro, anti-La, and rheumatoid factor. Seropositivity is determined by presence of anti-Ro and anti-La antibodies, which are detected in about 60% and 40% of cases, respectively. Patients with seropositive SS are at higher risk of extraglandular disease manifestations than those with a seronegative status, or no detectable anti-Ro or anti-La antibodies. 
Up to 30-70% of patients with primary SS will develop extraglandular diseases including respiratory manifestations (e.g., dry nose, dry trachea, small airway obstruction, interstitial lung disease, renal manifestations including interstitial nephritis and distal renal acidosis, skin involvement, arthralgias, autoimmune thyroiditis, and gastrointestinal manifestations such as esophageal dysmotility, gastritis, autoimmune hepatitis, and primary biliary cholangitis). The prevalence of neurologic manifestations ranges between 2-60%.  This article will focus on the neuro-ophthalmic manifestations of primary SS.
SS is named after Henrik Sjogren (1899-1986), a Swedish ophthalmologist who first described a triad of keratoconjunctivitis sicca, xerostomia, and polyarthritis in a group of women.  In 1930, he examined a 49-year-old female patient with arthritis and extreme dryness of the mouth and eyes. After presenting the case to the local ophthalmological society, he learned that his older colleagues had not encountered a case with such an unusual combination of symptoms.  After finding reports in the medical literature, he believed his patient was suffering from a systemic disease.  In 1933, with the help of his wife, Maria Hellgren, also an ophthalmologist, he published a study detailing 19 patients with dry eyes, 13 of whom had arthritis. He presented this study as his doctoral thesis, but his work was criticized and failed to land him a teaching position in Stockholm. It was not until an Australian ophthalmologist, Bruce Hamilton, translated his thesis into English in 1943 that his work was recognized. In fact, the English translation of his thesis earned him an international reputation and a professorship at the University of Gothenburg in Sweden. Ultimately, the sicca syndrome that he described would go on to be named in his honor. 
The pathophysiology of SS involves chronic immune system stimulation with involvement of B-cells and T-cells. Excessive B-cell activation results in hypergammaglobulinemia and circulating organ-specific autoantibodies, which includes those specific to cellular antigens of salivary ducts, thyroid tissue, gastric mucosa, erythrocytes, the pancreas, prostate, and neurons. However, non-organ-specific autoantibodies are found in 60% of SS patients and include rheumatoid factor, antinuclear antibodies, and antibodies specific to small RNA-protein complexes, or the anti-Ro/SSA and anti-La/SSB antibodies characteristic of the disease. 
The autoimmune process results in periductal lymphocytic infiltration of the salivary and lacrimal glands. The lymphocytic infiltrate consists of T-cells, B-cells, and plasma cells, with activated T-helper cells being the most abundant cell type. The infiltrate extends to the acinar epithelium, causing enlargement of the salivary and lacrimal glands and glandular damage that results in dry eyes and mouth. 
Patients with SS classically experience dry eyes and mouth. Patients may complain of pruritis, grittiness, soreness, and dryness of the eyes, even though the eyes appear normal. Oral dryness can significantly decrease quality of life as it may cause difficulties with eating and speaking. Reduced salivation can cause oral infection, tooth decay and periodontal disease. 
Involvement of glands in the respiratory tract results in dry nose, throat and trachea. Chronic dry cough may result from tracheal dryness. Inflammatory infiltration of exocrine sweat glands may cause dry skin and involvement of vaginal glands may lead to pruritus, irritation and dyspareunia. Joint involvement usually manifests as an intermittent polyarticular arthropathy of the small joints. Nonerosive arthritis resembling systemic lupus erythematosus (SLE) may occur transiently among patients. Gastrointestinal involvement may result in esophageal dysmotility, presenting as dysphasia and rarely malabsorption. Hepatic involvement occurs in 7% of people and may present with elevated liver function enzymes and primary biliary cholangitis. Renal disease can involve tubulointerstitial nephritis, causing distal renal tubular acidosis, hypercalcinuria or proximal tubule defects. Glomerular lesions my cause hematuria, proteinuria, and renal insufficiency. Some patients may progress to nephrotic syndrome and others may develop renal vasculitis causing hypertension and renal insufficiency. 
Additionally, 5% of patients with SS will develop non-Hodgkin lymphoma. Malignant lymphoproliferation may be an initial presentation of the disease or occur later in its course. Most lymphomas are of B-cell origin and usually occur in extranodal tissues, such as the salivary glands, gastrointestinal tract, thyroid gland, lung, kidney or orbit. Monoclonal proliferation of B-cells may initially present as Waldenstrom macroglobulinemia. 
Diagnosing SS can be difficult because sicca symptoms are very common. Older patients may experience sicca symptoms in part due to age-related atrophy of glandular tissues and use of drugs, such as anti-cholinergics.  No single laboratory test can make the diagnosis of SS. The most widely used diagnostic criteria are those revised in 2002 by the American-European Consensus Group. The established criteria are shown in Table 1.2
Table 1. 2002 Sjogren Syndrome Diagnostic Criteria from the American-European Consensus Group 
|I. Ocular symptoms||Positive response to at least one of three:
1. Daily, persistent, troublesome eyes for more than 3 months
2. Recurrent sensation of sand or gravel in the eyes
3. Use of tear substitutes more than three times per day
|Il. Oral symptoms||Positive response to at least one of three:
1. Daily feeling of dry mouth for more than 3 months
2. Recurrently or persistently swollen salivary glands as an adult
3. Frequent drinking of liquids to aid in swallowing food
|III. Ocular signs||Positive result for at least one of two tests:
1. Schirmer’s test performed without anesthesia (≤ 5 mm in 5 minutes) 2. Rose Bengal score or other ocular dye score (≤ 4 according to van Bijsterveld’s scoring system)
|IV. Histopathology in minor salivary gland biopsy||Focal lymphocytic sialadenitis, with focus score ≥ 1 (a focus is defined as ≥ 50 lymphocytes per 4 mm2 of glandular tissue adjacent to normal appearing mucus acini)|
|V. Salivary gland involvement||Positive result for at least one of three:
1. Unstimulated whole salivary flow (≤ 1.5 ml/15 minutes) 2. Parotid sialography showing presence of diffuse sialectasis (punctate, cavitary, or destructive pattern), without evidence of obstruction in the major ducts 3. Salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer
|VI. Autoantibodies||Presence in the serum of antibodies to Ro (SSA) or La (SSB) antigens, or both|
|Primary SS||Presence of any four of the six items, as long as either item IV (histopathology) or item VI (serology) is positive|
|Secondary SS||In the presence of another connective tissue disease, the presence of item I or item II, plus any two from items III, IV, and V|
|Exclusion criteria||Past head and neck radiation treatment, hepatitis C infection, AIDS, pre-existing lymphoma, sarcoidosis, graft versus host disease, use of anticholinergic drugs (since a time shorter than fourfold the half-life of the drug)|
However, in 2012, the Sjogren International Collaborative Clinical Alliance proposed a new expert consensus consisting of criteria based solely on objective measures. This new set of diagnostic criteria is displayed in Table 2. 
Table 2. 2012 Sjogren’s Syndrome Diagnostic Criteria from the Sjogren’s International Collaborative Clinical Alliance 
|I. Ocular signs||Keratoconjunctivitis sicca with ocular staining score ≥ 3 (preferential use of fluorescein staining or lissamine green staining, but break-up time and unanesthetized Schirmer’s test can also be used).
• Assuming patient is not currently using daily eye drops for glaucoma and has not had corneal surgery or cosmetic eyelid surgery in the last 5 years
|II. History in minor salivary gland biopsy||Focal lymphocytic sialadenitis, with focus score ≥ 1 (a focus is defined as ≥ 50 lymphocytes per 4 mm2 of glandular tissue adjacent to normal appearing mucus acini)|
|III. Autoantibodies||Positive serum anti-Ro/SSA and/or anti-La/SSB or positive rheumatoid factor and anti-nuclear antibody titer ≥ 1:320|
|Classification Criteria||At least two of the three items in order to classify a patient as SS|
|Exclusion Criteria||History of head and neck radiation treatment, hepatitis C infection, AIDS, sarcoidosis, amyloidosis, graft versus host disease, IgG4-related disease|
Overview of Neurologic manifestations
Neurologic disease is one of the most common systemic manifestations of SS.  Peripheral neuropathy is the most common neurological complication of primary SS. Central nervous system (CNS) involvement is less common, accounting for about 2-25% of patients with primary SS. Simultaneous involvement of the CNS and peripheral nervous system (PNS) is also possible. 
Central Nervous System manifestations
CNS manifestations of primary SS can be categorized into focal and diffuse involvement.
The most common CNS manifestation of primary SS is focal encephalic involvement. Focal inflammation can result in loss of sensation, motor weakness, aphasia, dysarthria, seizures, movement disorders and cerebellar symptoms depending on the specific brain region affected. Onset of symptoms is variable. They may be acute, insidious, or even present in a relapsing-remitting pattern characteristic of multiple sclerosis (MS). 
Spinal Cord Involvement
The most common form of spinal cord involvement is acute transverse myelitis. Depending on the specific location of the lesion, possible signs and symptoms include but are not limited to tetraparesis, paraparesis, sphincter weakness, impaired proprioception and Brown-Sequard syndrome.  A rare case of diffuse involvement of anterior horn cells (anterior horn syndrome) has been reported, where a patient presented with flaccid tetraparesis, asymmetric muscle atrophy and diffuse fasciculations.  Another case report described two patients with primary SS who presented with lateral-sclerosis-like upper motor neuron lesions manifesting as progressive spastic quadriparesis.  Spinal cord manifestations may also include chronic progressive myelopathies and neurogenic bladder. Acute and chronic myelopathies are rare in primary SS but are often severe and life-threatening. They generally respond poorly to corticosteroid treatment. However, immunosuppression with cyclophosphamide and glucocorticoids has shown some efficacy in those with progressive myelopathy. 
Primary SS can cause result in both unilateral and bilateral optic neuritis with variable clinical courses. Optic neuritis may occur in the absence of any sicca symptoms as the initial manifestation of primary SS, which can make SS difficult to diagnose without antibody tests for anti-Ro/SSA and anti-La/SSB.  Optic neuropathy can also present asymptomatically.  One study reported seven cases of retrobulbar optic neuropathy in patients primary SS, where four were asymptomatic and diagnosed by visual evoked potentials (VEP).
In a study of 82 patients with primary SS, 13 patients had vision loss from optic neuritis, with one severe case leading to blindness. Optic neuritis presented simultaneously with myelopathy in 2 patients, suggesting neuromyelitis optica. VEP confirmed optic neuritis in the 13 patients with vision loss and identified 12 additional patients with subclinical optic neuritis. Overall, there was an abnormal VEP in 61% of patients tested. Based on the high frequency of optic nerve involvement in the study, the authors recommended systematic screening for SS in patients presenting with optic neuritis.  Another study reported seven cases of retrobulbar optic neuropathy, four of which were asymptomatic and diagnosed by VEP.  The pathogenesis of optic neuritis in primary SS is believed to be due to a combination of demyelination and ischemic vasculitis. 
Cognitive dysfunction is common in primary SS.  The most common cognitive disturbances include attention and memory impairment, including deficits in short-term or long-term memory. Patients may also have executive dysfunction and visuospatial disorders. Magnetic resonance imaging (MRI) is normal in 80% of SS patients with cognitive dysfunction. However, MRI may show subcortical focal lesions in the fronto-parietal region of the brain. Hypoperfusion in areas of the frontal and temporal lobes may be seen on single-photon emission computed tomography (SPECT). 
Aseptic meningitis is a relatively common complication of primary SS and may present with headache, flu-like symptoms, confusion and meningismus with or without fever. Meningeal inflammation may result in cranial nerve palsies, cerebellar symptoms or seizures. Cerebrospinal fluid (CSF) analysis will show aseptic lymphocytic pleocytosis up to 900 cells/μl. 
Multiple Sclerosis-Like Manifestations
10-20% of patients with primary SS will develop CNS lesions analogous to those found in MS, most often in the white matter if the brain and spinal cord. Neurologic symptoms may include limb weakness, aphasia, ataxia and internuclear ophthalmoplegia. Similar to MS, the symptoms may demonstrate a chronic, relapsing-remitting course and CSF analysis will show an increased IgG index and oligoclonal bands. Sicca symptoms in patients with MS-like presentation are slightly intensified compared to those without such presentation.  There have also been reports of primary SS patients testing positive for anti-aquaporin-4 antibodies and developing optic neuritis in conjunction with transverse myelitis mimicking neuromyelitis optica spectrum disorders. 
Peripheral Nervous System
Peripheral neuropathy is the most common neurologic manifestation of primary SS, with 10-32% of patients displaying clinically apparent symptoms. When accounting for subclinical disease, an estimated 20-50% of patients have some form of peripheral neuropathy. About half of all cases of PNS involvement are due to axonal polyneuropathies, the most common PNS lesions. Several different PNS manifestations may occur in primary SS, including axonal polyneuropathies, sensory polyneuropathy, sensorimotor and motor polyneuropathy, sensory ganglionopathy, small-fiber neuropathy, multiple mononeuropathy, cranial neuropathies, autonomic neuropathy, and polyradiculoneuropathy.  Since this EyeWiki chapter focuses on the neuro-ophthalmic manifestations of primary SS, we will focus our discussion of PNS involvement on the cranial neuropathies.
The most common cranial neuropathy in primary SS is a sensory trigeminal nerve lesion followed by facial and oculomotor neuropathies.  Trigeminal neuropathy is usually unilateral and affects the maxillary (V2) branch.  However, bilateral involvement is also possible. Symptoms of trigeminal neuropathy may include numbness, paresthesia, and dysesthesia limited to the nerve region involved.  Motor involvement of the trigeminal nerve has not been reported.  Trigeminal nerve involvement has been reported to be as high as 50% among primary SS patients with cranial nerve manifestations.  Neuropathy of the vestibulocochlear nerve have also been reported.  Multifocal cranial neuropathies in the same patient have been reported, including bilateral cranial nerve VII palsy in one patient, as well as recurrent cranial nerve III and VI involvement in another. Other reported cases have included a patient with cranial nerve III, V, VI, VII, IX, and X involvement, one with cranial nerve V, IX, and X palsies, and another with cranial nerve V, VII, IX, X, and XII palsies. 
Pathophysiology of Neurologic Manifestations
The pathogenesis of neurologic compromise in primary SS is largely unknown. However, several hypotheses have been suggested for both CNS and PNS involvement. Three mechanisms have been proposed for the cause of CNS disease. The first involves direct infiltration of the CNS by mononuclear cells, resulting in inflammatory damage. The second involves vascular injury causing neuropathy. The presence of antineuronal and anti-Ro antibodies may be associated with increased risk of vascular injury. The third suggests that CNS neuropathies are due to ischemia secondary to small vessel vasculitis. Mechanisms proposed for PNS involvement include vascular or peripheral inflammatory infiltrates. Vasculitis of the vasa vasorum has also been suggested as a cause of PNS lesions. Antineuronal antibodies and antibodies against type 3 muscarinic receptors may also be a cause of PNS neuropathy in primary SS. 
The treatment of SS primarily symptomatic and aimed at recognizing and treating disease complications early, particularly damage caused by chronic xerostomia and keratoconjunctivitis sicca. For ocular dryness, frequent administration of tear substitutes replaces moisture. Lubricating ointments and methylcellulose inserts are another treatment option but usually used nocturnally. Temporary occlusion of the puncta with collagen or silicone plugs blocks tear drainage and promotes maintenance of the tear film. Permanent blockage with electrocautery is another option. Moisture retaining goggles or glasses may be worn to reduce eye dryness. Soft contact lenses may be helpful but increase the risk of ocular infection. Blepharitis, a possible complication of keratoconjunctivitis, is treated with application of warm compresses, cleaning the eyelids, and topic antibiotics if necessary. 
When ocular dryness is refractory to the therapy, secretagogues may be used. Pilocarpine and cevimeline are the only two agents approved for use as secretagogues in patients with SS. As muscarinic agonists, they stimulate M3 and M1 receptors on acinar and ductal cells of the salivary and lacrimal glands to increase glandular secretions. Adverse effects of pilocarpine include excessive sweating, nausea, bronchoconstriction, and bradycardia. Therefore, its use is limited in patients with asthma or on beta blockers. As a newer selective muscarinic agonist, cevimeline causes excessive sweating in about half as many patients as pilocarpine. 
Management of oral manifestations include use of saliva substitutes, stimulating saliva secretion, and preventing dental caries and infections due to xerostomia. Frequent dental examination and home administration of oral fluoride is necessary for prevention and management of dental carries. Patients with SS should avoid drugs that reduce salivary production if possible, including diuretics, antihypertensives, antidepressants, and antihistamines. Natural human interferon alfa has also been shown increase saliva production and decrease xerostomia. 
For treatment of systemic disease, nonsteroidal anti-inflammatory drugs (NSAIDs) provide some relief from minor joint symptoms and painful parotid gland inflammation. Disease modifying antirheumatic drugs are not commonly used since erosive arthritis is uncommon. Severe extraglandular manifestations may be treated with corticosteroids. 
Up until now, long-term immunosuppression has not produced desired results. Neither oral cyclosporine or methotrexate have been shown to significantly affect lacrimal or parotid gland flow rates, despite reported improvements in subjective symptoms. Since SS is a chronic, nonfatal disorder and these agents have toxic side effects, immunosuppressants should be used with caution. 
There are no specific guidelines for the treatment of neuropathy in primary SS. Treatment recommendations are primarily anecdotal or based on small retrospective studies. Some patients experience spontaneous remission. Corticosteroids appear to often be effective in treatment of multiple mononeuropathy and multiple cranial neuropathy in patients with primary SS. A number of reports suggest that intravenous immunoglobulin (IVIG) therapy is effective in primary SS-associated sensory ataxic mononeuropathy and small fiber neuropathy. Plasmapheresis, D-penicillamine, and infliximab have shown variable results in neuropathy management. Successful treatment with cyclophosphamide has been reported in patients with myelopathy or multiple mononeuropathy as well as in a patient who had previously failed treatment with pulse methylprednisolone, IVIG, and azathioprine. Rituximab and interferon alpha have also shown some efficacy. Interferon alpha showed improvement in two patients with sensory ataxic neuropathy. In one patient with sensorimotor polyneuropathy, interferon alpha resulted in improvement of neuropathic and sicca symptoms, autoantibody titers, and salivary biopsy findings. 
Primary SS has an overall benign prognosis. Patients generally have modest or clinically insignificant deterioration in glandular and organ-specific function. There is also a low incidence of severe organ involvement. Therefore, in contrast to other connective tissue diseases, primary SS does not significantly affect mortality. 
However, primary SS significantly increases the risk of malignant lymphoma. Severe involvement of exocrine glands, vasculitis, hypocomplementemia, and cryoglobulinemia at the time of diagnosis are associated with increased risk of lymphoma, particularly the extranodal mucosa-associated lymphoid tissue (MALT) type. Therefore, these features identify high-risk patients that require closer monitoring and perhaps more robust therapeutic management during their disease course. MALT lymphoma can occasionally transform into diffuse large B-cell lymphoma which is associated with a worse prognosis. 
In addition to classic salivary and lacrimal gland involvement, primary SS can present with various systemic manifestations. Among them include neuro-ophthalmic manifestations, including both CNS and PNS lesions. Therefore, for patients who present with neuropathy, whether optic neuritis, a cranial nerve palsy, or even lesions suggestive of multiple sclerosis, SS should remain on the differential diagnosis. A thorough history assessing for sicca symptoms and systemic symptoms suggestive of possible SS is warranted in order to avoid misdiagnosis or delay in diagnosis.
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