[Primary nasopharyngeal carcinoma with Sjögren's syndrome and positive cerebrospinal fluid Epstein-Barr virus: a case report and literature review].

The study presents an analysis of the diagnostic and treatment protocol for a patient with a first episode of nasopharyngeal carcinoma who also has Sjogren's syndrome and Epstein-Barr Virus (EBV) positive cerebrospinal fluid, as detected through metagenomic next-generation sequencing (mNGS). It reviews existing literature to examine the connections between EBV and various conditions including Sjogren's syndrome, encephalitis or meningitis, and nasopharyngeal carcinoma, emphasizing the importance of EBV positive cerebrospinal fluid. The study focuses on a case from the Eighth Medical Center of the General Hospital of the People's Liberation Army, where a patient was admitted with headaches as the primary symptom on March 3, 2021. This patient had a history of Sjogren's syndrome and was later diagnosed with nasopharyngeal carcinoma. The research involved reviewing both domestic and international databases for cases related to cerebrospinal fluid EBV positive encephalitis or meningitis, and nasopharyngeal carcinoma. It aimed to aggregate data on demographics, initial symptoms, treatment methods, and patient outcomes. Findings suggest that positive cerebrospinal fluid EBV is linked to autoimmune diseases, viral encephalitis or meningitis, and nasopharyngeal carcinoma, albeit infrequently in the context of Sjogren's syndrome. Notably, EBV positive cerebrospinal fluid is commonly associated with recurrent nasopharyngeal carcinoma rather than initial episodes. The study concludes that for patients with an immune condition, exhibiting symptoms like headaches or cranial nerve issues, or in cases where nasopharyngeal carcinoma is suspected, early testing through cerebrospinal fluid mNGS or EBV DNA is recommended. This approach facilitates risk assessment, prognosis determination, and the creation of individualized treatment plans.

Complement genes contribute sex-biased vulnerability in diverse disorders.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Interleukin-1-related activity and hypocretin-1 in cerebrospinal fluid contribute to fatigue in primary Sjögren's syndrome.

BACKGROUND: Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren's syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 ß-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue. METHODS: Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS). RESULTS: Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1ß activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1ß-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores. CONCLUSIONS: The main findings of this study indicate a functional network in which several IL-1ß-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway.

Limbic Encephalitis Associated with Sjögren's Syndrome: Report of Three Cases.

Sjögren's syndrome (SS) may be complicated by neurological manifestations. We herein report three women (age range 26-60 years old) who all presented with limbic encephalitis (LE) as the predominant clinical feature 3 months to 15 years after the diagnosis of SS. The 26-year-old patient also developed acute motor axonal neuropathy one week after autoimmune encephalitis. All three patients showed contrast-enhanced MRI lesions and inflammatory cerebrospinal fluid findings, while not displaying any anti-neuronal antibodies and showing a remarkable response to immunotherapy. SS is often overlooked when the symptoms are mild. Therefore, in LE cases with no identifiable cause, serological screening for rheumatologic disorders is recommended.

Association of hippocampal atrophy with cerebrospinal fluid antibodies against the NR2 subtype of the N-methyl-D-aspartate receptor in patients with systemic lupus erythematosus and patients with primary Sjögren's syndrome.

OBJECTIVE: Cognitive dysfunction is common in both systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (SS). Antibodies against the NR2 subtype of the N-methyl-D-aspartate receptor (anti-NR2 antibodies) cause hippocampal atrophy and cognitive impairment in mice and have been associated with memory impairment in both patients with SLE and patients with primary SS. In addition, a reduced volume of hippocampal gray matter has been demonstrated in both SLE and primary SS. This study was undertaken to investigate whether there is a connection between the presence of anti-NR2 antibodies and hippocampal atrophy in human diseases. METHODS: Fifty patients with SLE and 50 patients with primary SS underwent clinical examination and cerebral magnetic resonance imaging. Anti-NR2 antibodies in cerebrospinal fluid (CSF) were measured, and hippocampal gray matter volumes were compared between patients who were positive for and those who were negative for anti-NR2 antibodies. RESULTS: Patients with anti-NR2 antibodies in CSF had less hippocampal gray matter than patients without these antibodies. No other differences regarding gray matter volumes in other parts of the brain were identified. CONCLUSION: The present findings indicate that anti-NR2 antibodies in patients with SLE and primary SS cause neuronal death manifested as reduced hippocampal gray matter, as has been previously demonstrated in mice with autoimmune disease.

Cerebrospinal Flt3 ligand correlates to tau protein levels in primary Sjögren's syndrome.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is an autoimmune disease affecting the exocrine glands and internal organs including the central nervous system (CNS). The fms-related tyrosine kinase 3 ligand (Flt3L) is a maturation factor essential for brain homeostasis. Blood levels of Flt3L are increased in inflammatory diseases including the inflamed salivary glands in pSS. The present study evaluated the role of Flt3L in the CNS of patients with pSS and in two non-autoimmune conditions, fibromyalgia (FM) and Alzheimer's disease (AD). METHOD: Levels of Flt3L were measured in cerebrospinal fluid (CSF) and serum of patients with pSS (n = 15), FM (n = 29), and AD (n = 39) and related to CNS symptoms and to markers of inflammation and degeneration. RESULTS: Levels of CSF Flt3L in pSS and AD were significantly lower than in FM (p = 0.005 and p = 0.0003, respectively). Flt3L in pSS correlated to tau proteins [total tau (T-tau), r = 0.679; phosphorylated tau (P-tau), r = 0.646] and to a marker for microglia activation, monocyte chemoattractant protein 1 (MCP-1). Similar correlations were present in FM and AD patients. One-third of pSS patients had low levels of CSF Flt3L. This group had decreased levels of amyloid precursor protein metabolites (Aß40 and Aß42) in CSF, which was not seen in FM patients. CONCLUSIONS: This study shows a strong correlation between CSF Flt3L and tau proteins in pSS patients suggesting ongoing degradation/remodelling in the CNS. In pSS patients, low levels of Flt3L were linked to changes in amyloid turnover and may represent processes similar to those in AD.

Longitudinal extensive transverse myelitis--it's not all neuromyelitis optica.

Longitudinal extensive transverse myelitis (LETM) is defined as a spinal cord lesion that extends over three or more vertebrae, as seen on MRI of the spine. The clinical presentation of a patient with LETM is often dramatic and can consist of paraparesis or tetraparesis, sensory disturbances, and gait, bladder, bowel and/or sexual dysfunction. LETM is a characteristic feature of neuromyelitis optica, but such spinal lesions can also occur in various other autoimmune and inflammatory diseases that involve the CNS--such as multiple sclerosis, sarcoidosis or Sjögren syndrome--or in infectious diseases with CNS involvement. Patients with a neoplastic disorder or traumatic spinal cord injury can also present with longitudinal spinal lesions. In this Review, the signs and symptoms that suggest various etiologies and differential diagnoses of LETM are described, and illustrated by educational case studies. The best therapeutic options for patients with each diagnosis are also discussed.

Clinical features of Sjogren's syndrome in patients with multiple sclerosis.

OBJECTIVES: To assess the frequency of clinical features of Sjogren's syndrome (SS) in patients with multiple sclerosis (MS) receiving treatment with disease-modifying drugs (DMDs) or naïve to treatment and the possible association with clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) parameters. METHODS: A multicentre cross-sectional observational study was designed, based on a structured neurologist-administered questionnaire to 440 patients. RESULTS: Twenty-eight of 230 (12%) patients receiving treatment with DMDs (DMDs(+)) and 14 of 210 (6.6%) treatment-naïve patients (DMDs(-) ) showed clinical features of SS. Four primary SS were diagnosed, two of which were DMDs(+) and two were DMDs(-) . Sicca symptoms were significantly associated with higher EDSS scores (P = 0.018), a low frequency of gadolinium-enhanced MRI-positive lesions (P = 0.018) and cerebral disturbances (P = 0.001). CONCLUSIONS: Screening for the clinical features of SS should be performed in patients with MS both receiving treatment with immunomodulatory drugs and without therapy.

Fatigue in primary Sjögren's syndrome--a link to sickness behaviour in animals?

Interleukin-1beta (IL-1beta) is involved in the regulation of sickness behaviour in response to infection and inflammation in animals. Human fatigue can be considered an element of sickness behaviour and is a prominent and often disabling phenomenon in autoimmune diseases such as primary Sjögren's syndrome (PSS). The role of the IL-1 system in the fatigue of patients with PSS was explored. A cerebrospinal fluid (CSF) analysis of IL-1beta, IL-1Ra, and IL-1sRII was performed in 54 PSS patients and 53 control subjects. Fatigue was evaluated in the patients using the Fatigue Severity Scale (FSS) and a fatigue visual analogue scale (VAS); mood was evaluated using the Beck Depression Inventory (BDI). There were higher CSF levels of IL-1Ra pg/mL in PSS patients vs. controls (median 38.4: range 15.4-81.7 vs. 33.7: 7.3-163.1, p=0.026). Fatigue VAS scores were associated with increasing CSF levels of IL-1Ra in PSS patients (R(2)=0.11, p=0.015). In a subgroup analysis of the non-depressed PSS patients (N=37; 69%), the association between VAS scores and IL-1Ra was even stronger (R(2)=0.20, p=0.006). The positive association between VAS scores and IL-1Ra remained significant in a multiple regression analysis adjusting for age and BDI scores. Increased levels of IL-1Ra in the CSF are associated with increasing fatigue in PSS patients, indicating that the activated IL-1 system is a possible biological factor associated with fatigue.

Bilateral optic neuropathy revealing Sjögren's syndrome.

INTRODUCTION: The central nervous system involvement has been reported in 20% of cases of primary Sjogrën's syndrome (SS), a chronic autoimmune disease characterized by a disorder of the exocrine glands secondary to progressive lymphocyte infiltration. Classically described neurological manifestations include sensorimotor deficits, aseptic meningitis or meningoencephalitis, multiple sclerosis-like syndromes and myeolopathies. OBSERVATION: We report here the case of a 53-year-old woman who exhibited rapidly progressive visual loss, disclosing bilateral optic neuropathy, as an uncommon initial symptom of primary SS. Examination of CSF revealed associated aseptic meningitis. Because of the lack of efficacy of the first treatment by intravenous corticosteroids, monthly intravenous cyclophosphamide was quickly introduced. After six months, significant visual recovery was observed. CONCLUSION: Optic neuropathies have been rarely reported as the initial symptom revealing primary Sjogrën syndrome, and bilateral simultaneous lesions remain exceptional.

Cerebrospinal fluid anti-SSA autoantibodies in primary Sjogren's syndrome with central nervous system involvement.

BACKGROUND: Central nervous system involvement in primary Sjogren's syndrome is a matter of controversy, and its diagnosis remains difficult. METHODS: We report 3 patients with primary Sjogren's syndrome and central nervous system involvement in whom we assessed intrathecal immunoglobulin G synthesis and the presence of cerebrospinal fluid anti-SSA and anti-SSB autoantibodies. RESULTS: We found intrathecal immunoglobulin G synthesis and presence of cerebrospinal fluid anti-SSA autoantibodies in all patients, with demonstration for the first time of specific anti-SSA autoantibody intrathecal synthesis in 2 patients. CONCLUSION: We suggest that cerebrospinal fluid anti-SSA autoantibodies could serve as a biomarker for Sjogren's-syndrome-related central nervous system involvement.

Reversible cortical lesions in primary Sjögren's syndrome presenting with meningoencephalitis as an initial manifestation.

We report a 50-year-old woman with primary Sjögren's syndrome (SjS) who initially showed forgetfulness, and later developed disturbance of consciousness. In addition to aseptic meningoencephalitis revealed by cerebrospinal fluid examination and magnetic resonance imaging (MRI), the presence of serum anti-SS-A and anti-SS-B antibodies and inflammatory findings in lip biopsy indicated primary SjS. Fluid attenuated inversion recovery (FLAIR) of MRI revealed well defined small, high signal intensity areas in the cortex involving the subcortical white matter. Corticosteroid therapy resulted in rapid and nearly complete resolution of the cortical lesions with marked improvement of the clinical manifestations. Memory disturbance is a rare initial manifestation in meningoencephalitis associated with SjS. Our patient with SjS showed inflammatory cortical lesions on MRI, which were reversed by corticosteroid therapy.

[Differential diagnosis of chronic inflammatory diseases of the central nervous system. Cerebrospinal fluid diagnosis and immunological parameters]. / Differenzialdiagnose chronisch-entzündlicher Erkrankungen des Zentralnervensystems. Liquordiagnostik und immunologische Parameter.

A number of neurological syndromes may be evoked by involvement of the nervous system due to systemic diseases such as lupus erythematosus, sarcoidosis, Behcet's disease, and Sjogren's syndrome. Because of different treatment strategies, it is important to distinguish between these different diseases. Neither clinical signs nor additional analyses such as serological findings or cerebrospinal fluid analysis are able to differentiate between the diseases with certainty. Nevertheless, diagnosis may finally be made taking all findings together. Here we compare typical clinical and cerebrospinal fluid findings in neurosarcoidosis, neurolupus, neuro-Behcet, and nervous system involving Sjogren's syndrome, with special emphasis on those findings allowing differentiation of the respective diseases.

Immunoglobulins within the central nervous system in primary Sjögren's syndrome.

Cerebrospinal fluid (CSF) and sera from 17 patients with primary Sjögren's syndrome (PSS) with or without clinical evidence of nervous system involvement were studied. Intrathecal IgG synthesis as measured by oligoclonal IgG bands on agarose isoelectric focusing or elevated IgG index in CSF was found in 6 of 8 patients with clinical nervous system involvement but also in 5 of 9 patients without clinical nervous system involvement. Elevated IgM-index in CSF was found in 7 of 8 patients with clinical nervous system involvement and in 6 of 9 patients without clinical nervous system involvement. By immunoblotting, CSF IgG-antibodies against myelin basic protein (MBP) were found in 3 of 12 patients with multiple sclerosis (MS), but in none of the patients with PSS or in the 12 controls. Intrathecal anti-viral IgG-antibodies, as measured by immunoblotting against measles, mumps, varicella or herpes simplex, were found in 8 of 17 patients with PSS, and in 7 of 12 patients with MS, but were not detected in the controls. Our observations support the concept that the central nervous system (CNS) is included in the multiple immunological phenomena of PSS. Interestingly, in some PSS patients intrathecal IgG synthesis occurred without overt clinical nervous system involvement and thus the clinical significance of intrathecal IgG synthesis in PSS is uncertain. The similarities with MS regarding intrathecal antiviral antibody production may be interpreted as the result of polyclonal B-cell activation.

Detection of activated terminal complement (C5b-9) in cerebrospinal fluid from patients with central nervous system involvement of primary Sjogren's syndrome or systemic lupus erythematosus.

We have examined cerebrospinal fluid (CSF) and serum from patients with Sjogren's syndrome (SS) and systemic lupus erythematosus (SLE) for evidence of activation of the terminal pathway of complement. Fluid phase terminal complement complexes (SC5b-9), quantitated by ELISA, were detected in the CSF of 14 of 16 patients with SS and focal central nervous system (CNS) disease. Five of six SS patients without focal CNS disease but with psychiatric disease or cognitive dysfunction had detectable CSF SC5b-9, whereas two other SS patients without focal CNS or neuropsychiatric disease had no detectable CSF SC5b-9. Six of seven patients with SLE or SLE overlap syndrome with CNS involvement had CSF SC5b-9, whereas two patients with SLE without CNS involvement had no CSF SC5b-9. A subset of SS and SLE patients with CNS disease had SC5b-9 detected in CSF but not in serum. SC5b-9 was generally absent from the CSF of patients with noninflammatory CNS diseases. These findings demonstrate intrathecal activation of terminal complement in patients with CNS SS or CNS SLE, and suggest a role for terminal complement activation in the pathophysiology of CNS involvement in both SS and SLE.

Evidence of an immunopathogenic basis for central nervous system disease in primary Sjögren's syndrome.

The pathogenesis of central nervous system complications in primary Sjögren's syndrome (CNS-SS) is unknown. In order to determine whether patients with active CNS-SS have cerebrospinal fluid (CSF) abnormalities indicative of CNS inflammation, CSF analyses from 30 patients with active CNS-SS (SSA) were contrasted with those from 20 SS patients without CNS involvement (SSI) and 20 patients with systemic lupus erythematosus and active CNS disease (SLEA). Elevations of total protein concentration, IgG concentration, IgG to total protein ratio, and IgG index were observed in patients with SSA, but not in those with SSI. Agarose gel electrophoresis results were abnormal, with 1 or more bands, in 25 of 29 SSA patients (86%), but in only 3 of 18 SSI patients (17%). Similar, but less striking, CSF abnormalities were seen in a minority of SLEA patients. Fifteen SSA patients (50%) had transient, mild-to-moderate CSF pleocytosis, while only 1 SSI patient and 2 SLEA patients had similar findings. Cytologic findings were abnormal in 18 SSA patients (60%); these included atypical mononuclear cells, lymphoblastoid cells, and plasma cells. The presence of immunocompetent cells and evidence for the intrathecal synthesis of IgG within the CSF of SSA, but not SSI, patients provide diagnostic parameters which are indicative of active disease and which can be monitored serially during therapy.

Primary Sjögren's syndrome with central nervous system disease mimicking multiple sclerosis.

Central nervous system involvement has occurred in approximately 20% of patients with primary Sjögren's syndrome evaluated at our institution. Characteristically, the neurologic dysfunction is multifocal, involving both the brain and spinal cord, and is recurrent over time. We present the features of 20 patients with primary Sjögren's syndrome and central nervous system involvement whose neurologic findings, evoked potential abnormalities, and cerebrospinal fluid profiles (elevated IgG indices, oligoclonal bands on agarose gel electrophoresis, and mild pleocytosis with reactive lymphoid cells) closely resembled those of multiple sclerosis. In fact, multiple sclerosis was considered the most likely diagnosis in each of these patients before diagnosis of Sjögren's syndrome, and each patient met criteria for definite multiple sclerosis. The clinical effects of corticosteroid treatment during episodes of acute neurologic dysfunction appeared to be beneficial in these patients.

Polymorphous exudates and atypical mononuclear cells in the cerebrospinal fluid of patients with Sjögren's syndrome.

Central nervous system (CNS) complications of Sjögren's syndrome are now well recognized. To determine if any of the pathologic changes in the CNS in patients with Sjögren's syndrome were reflected in the cellular composition of cerebrospinal fluid (CSF), we examined the CSF of 14 patients with Sjögren's syndrome and neurologic symptoms and compared the differential cell counts in those cases with those of 14 control patients with similar neurologic symptoms. Patients with Sjögren's syndrome had polymorphous (mixed) inflammatory exudates in CSF, composed predominantly of lymphocytes, but including variable numbers of plasma cells, neutrophils and erythrocytes. In addition, the CSF of all patients with Sjögren's syndrome contained large, atypical, morphologically distinct mononuclear cells. The mean percentage of these cells in the CSF of patients with Sjögren's syndrome (8.3 +/- 1.9) was significantly higher (p less than 0.001) than that observed in the control patients (0.7 +/- 0.2). These results suggest that involvement by Sjögren's syndrome may be suspected by noting a polymorphous exudate containing characteristic atypical mononuclear cells in CSF obtained by lumbar puncture.