Search

Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.

Zika virus (ZIKV) infection during pregnancy is associated with microcephaly, a congenital malformation resulting from neuroinflammation and direct effects of virus replication on the developing central nervous system (CNS). However, the exact changes in the affected CNS remain unknown. Here, we show by transcriptome analysis (at 48 h post-infection) and multiplex immune profiling that human induced-neuroprogenitor stem cells (hiNPCs) respond to ZIKV infection with a strong induction of type-I interferons (IFNs) and several type-I IFNs stimulated genes (ISGs), notably cytokines and the pro-apoptotic chemokines CXCL9 and CXCL10. By comparing the inflammatory profile induced by a ZIKV Brazilian strain with an ancestral strain isolated from Cambodia in 2010, we observed that the response magnitude differs among them. Compared to ZIKV/Cambodia, the experimental infection of hiNPCs with ZIKV/Brazil resulted in a diminished induction of ISGs and lower induction of several cytokines (IFN-α, IL-1α/β, IL-6, IL-8, and IL-15), consequently favoring virus replication. From ZIKV-confirmed infant microcephaly cases, we detected a similar profile characterized by the presence of IFN-α, CXCL10, and CXCL9 in cerebrospinal fluid (CSF) samples collected after birth, evidencing a sustained CNS inflammation. Altogether, our data suggest that the CNS may be directly affected due to an unbalanced and chronic local inflammatory response, elicited by ZIKV infection, which contributes to damage to the fetal brain.

Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFNα in healthy donors, viral infection, and complex and monogenic interferonopathies. IFNα protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFNα levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFNα protein indicated disease-specific mechanisms. Measurement of IFNα attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation., (© 2017 Rodero et al.)

HIV-associated neurocognitive disorders (HANDs) continue to be common and are associated with increased morbidity and mortality. However, the underlying mechanisms in the combination antiretroviral therapy (cART) era are not fully understood. Interferon alpha (IFNα) is an antiviral cytokine found to be elevated in the cerebrospinal fluid (CSF) of individuals with advanced HIV-associated dementia in the pre-cART era. In this cross-sectional study, we investigated the association between IFNα and neurocognitive performance in ambulatory HIV-infected individuals with milder impairment. An eight-test neuropsychological battery representing six cognitive domains was administered. Individual scores were adjusted for demographic characteristics, and a composite neuropsychological score (NPT-8) was calculated. IFNα and CSF neurofilament light chain (NFL) levels were measured using enzyme-linked immunosorbent assay (ELISA). There were 15 chronically infected participants with a history of significant immunocompromise (median nadir CD4+ of 49 cells/μl). Most participants were neurocognitively impaired (mean global deficit score of 0.86). CSF IFNα negatively correlated with three individual tests (Trailmaking A, Trailmaking B, and Stroop Color-Word) as well as the composite NPT-8 score (r = -0.67, p = 0.006). These negative correlations persisted in multivariable analyses adjusting for chronic hepatitis B and C. Additionally, CSF IFNα correlated strongly with CSF NFL, a marker of neuronal damage (rho = 0.748, p = 0.0013). These results extend findings from individuals with severe HIV-associated dementia in the pre-cART era and suggest that IFNα may continue to play a role in HAND pathogenesis during the cART era. Further investigation into the role of IFNα is indicated.

Neurological manifestations have been reported in Kikuchi-Fujimoto disease (KFD). Characteristics of brain lesions are not defined. In addition, no biological indexes are known to help clinicians along the diagnosis process. The authors describe encephalitis associated with KFD. Brain MRI, positron emission tomography (PET) scan and a large biological assessment including interferon α (INF-α) level measurement in cerebrospinal fluid (CSF) were performed. A 39-year-old man with chronic headaches developed diplopia, slow ideation and behavioural disturbances. MRI showed brain lesions particularly in the pontine region and internal temporal lobes with enhancement of the perivacular space and the walls of the lateral ventricle. The IFN-α level was increased in the CSF without viral infection. Cervical and mediastinal adenitis were evident as a hypermetabolic focus on a PET scan, and biopsy confirmed the diagnosis of KFD. The encephalitis spontaneously remitted. The authors characterised brain lesions especially related to KFD in association with increased of IFN-α level in the CSF.

Objective: To assess the utility of interferon-α (IFN-α) in serum and cerebrospinal fluid (CSF) as a biomarker of disease activity in central neuropsychiatric systemic lupus erythematosus (cNPSLE)., Methods: Serum and CSF samples were drawn at hospitalization in 34 patients with cNPSLE, 16 surgical SLE, 4 primary neuropsychiatric conditions, and 25 with nonautoimmune conditions, except in 44 non-NPSLE patients in whom only serum was studied. Six months later, serum/CSF and serum samples were taken in 20 cNPSLE and 35 non-NPSLE patients, respectively. SLE activity was assessed at hospitalization, and 6 months later in cNPSLE and non-NPSLE patients. IFN-α was detected by Luminex technology., Results: The mean ± SD age of patients with cNPSLE was 31.4 ± 12.2 years, which was similar across the study groups (p = 0.46). Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores among cNPSLE, non-NPSLE, and SLE-surgical patients were 15.3 ± 8.2, 12.4 ± 8.2, and 3.8 ± 1.5, respectively. IFN-α levels in serum were higher in cNPSLE than in nonautoimmune patients (p = 0.02), but were similar to non-NPSLE and SLE-surgical groups. In CSF samples, IFN-α levels were higher in cNPSLE than in nonautoimmune patients (p = 0.03), and were nonsignificantly higher than in SLE-surgical and primary neuropsychiatric patients. Six months later, serum levels of IFN-α did not vary from baseline values despite a significant decrease in SLEDAI-2K score in cNPSLE and non-NPSLE patients. IFN-α levels in the CSF of patients with cNPSLE also remained stable. Among specific cNPSLE syndromes, CSF IFN-α levels were significantly higher among patients with acute confusional syndrome., Conclusion: IFN-α does not seem to represent a useful biomarker of cNPSLE syndromes; its utility in specific cNPSLE manifestations merits further investigation.

Aicardi-Goutières syndrome is a rare encephalopathy of mutational origin characterized by increased levels of interferon alpha in cerebrospinal fluid. The aim of this study was to explore the influence of different Aicardi-Goutières syndrome genotypes on the clinical course of patients, seeking to identify specific gene expression profiles able to explain Aicardi-Goutières syndrome phenotype differences. We detected the occurrence of Aicardi-Goutières syndrome mutations in 21 patients and compared microarray gene-expression data of cerebrospinal fluid lymphocytes with clinical variables. The levels of interferon alpha in cerebrospinal fluid were high in all patients; we found differences in the expression of genes encoding for Toll-like receptor, endogenous RNases, T lymphocyte activation, angiogenesis inhibition, and peripheral interferon alpha production. These results indicate that further to interferon alpha production in the central nervous system, a variety of other pathogenic mechanisms is activated in Aicardi-Goutières syndrome to various degrees in different patients, thus explaining the interindividual difference in Aicardi-Goutières syndrome course.

Patients with lupus have a continuous production of IFNα and display an increased expression of IFNα-regulated genes. The reason for the ongoing IFNα synthesis in these patients seems to be an activation of plasmacytoid dendritic cells (pDCs) by immune complexes (ICs), consisting of autoantibodies in combination with DNA-containing or RNA-containing autoantigens. The mechanisms behind the activation of pDCs by such ICs have to some extent been elucidated during the last years. Thus, interferogenic ICs are internalized via the FcγRIIa expressed on pDCs, reach the endosomes and stimulate Toll-like receptor (TLR) 7 or 9, which subsequently leads to IFNα gene transcription. Variants of genes involved in both the IFNα synthesis and response have been linked to an increased risk to develop lupus. Among these genes are interferon regulatory factor 5 (IRF5), which is involved in TLR signaling, and the signal transducer and activator of transcription 4 (STAT4) that interacts with the type I interferon receptor. Produced IFNα may at least partially be responsible for several of the observed alterations in the immune system of lupus patients and contribute to the autoimmune disease process, which will be discussed in the present review. How produced IFNα can contribute to some clinical manifestations will briefly be described, as well as the possible consequences of this knowledge in clinical practice for disease monitoring and therapy.

Aicardi-Goutières syndrome (AGS) is a rare interferon (IFN)-related encephalopathy with onset during the first year of life. AGS, is clinically characterized by progressive microcephaly, bilateral basal ganglia calcification, cerebral atrophy, cerebrospinal fluid (CSF), lymphocytosis, delayed development of psychomotor abilities with pyramidal-extrapyramidal syndrome and mimics congenital viral infections. Microarray analysis examining the expression of 18 880 human genes has been applied to the CSF lymphocytes of 20 AGS cases (age 4.5 +/- 4.4 years, mean +/- standard deviation) characterized by high IFN-alpha levels in CSF and 20 matched controls (age 4.4 +/- 4.3 years, mean +/- standard deviation). Gene-expression data reveal significant differences between AGS cases and controls for all controls and 18 AGS cases. The two AGS cases unclassified as compared with controls were both older than 7 years. AGS cases presented upregulation of genes involved in IFN-dependent pathways and lymphocyte functions, paralleled by the downregulation of genes encoding for angiopoietic activities. The cystatin F and DNAJ genes, having a negative feedback on IFN pathways, underwent a progressive age-related increase in their expression. These gene-expression signature parallels a progressive attenuation of clinical symptoms with age. Obtained results provide evidence that exposure to IFN-alpha is harmful for developing brain.

Aicardi-Goutières syndrome is an autosomal recessive encephalopathy characterised by acquired microcephaly, basal ganglia calcifications, leukodystrophy, cerebral atrophy, chronic cerebrospinal lymphocytosis, and raised titres of interferon alpha in the cerebrospinal fluid. The disease onset is generally within the first months of life. We here report a case of Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy following satisfactory psychomotor development up to the age of 16 months. This case highlights the importance of considering Aicardi-Goutières syndrome in the differential diagnosis of an unexplained leukoencephalopathy and the possibility of later onset of the disease.

Aicardi-Goutières syndrome (AGS) is a genetically determined encephalopathy usually inherited as an autosomal recessive trait. The syndrome can be caused by mutations in the AGS1 gene encoding the exonuclease TREX1, or in any of the AGS2, AGS3, or AGS4 genes that encode the three subunits of the human ribonuclease H2 (RNaseH2) complex. Typically, AGS has an early onset, usually manifesting by the age of 4 months. We describe a female infant in whom the onset of the neurological symptoms of AGS occurred after the age of 12 months, and her younger brother who was identified to be affected by AGS at the age of 8 months on the basis of the presence of non-neurological features alone. This paper is important in providing a detailed description of the late-onset presentation of AGS in patients with proven pathogenic mutations and highlights the occurrence of both chilblains and abnormal neuroimaging many months before the onset of neurological features. Our paper also considers the possible value of immunomodulatory therapy in AGS.

Objective: Acute confusional state (ACS) is an uncommon but severe central nervous system (CNS) syndrome in systemic lupus erythematosus (SLE) defined by clinical manifestations. To develop useful and reliable diagnostic tools for ACS, we evaluated the association of cerebral spinal fluid (CSF) tests with ACS and their predictive values for the diagnosis of ACS in SLE., Methods: We performed a prospective study using a cohort of 59 patients with SLE and compared those with and without ACS. Associations between ACS and each CSF test [interleukin 6 (IL-6), IL-8, interferon-alpha, IgG index, and Q-albumin] were statistically evaluated. Each patient underwent all CSF evaluations., Results: ACS was diagnosed in 10 patients (ACS group), SLE-related CNS syndromes except ACS in 13, and no CNS syndromes in 36 (non-CNS group). CSF IL-6 levels in the ACS group were significantly higher than those in the non-CNS group (p < 0.05). A positive IgG index (p = 0.028) was significantly associated with ACS. No other test showed a significant association with ACS. The positive and negative predictive values for the diagnosis of ACS in SLE were 80% and 85% for elevated CSF IL-6 levels (> or = 31.8 pg/ml), and 75% and 83% for the IgG index, respectively., Conclusion: No single CSF test had sufficient predictive value to diagnose ACS in SLE, although CSF IL-6 levels and the IgG index showed statistical associations with ACS. Use of CSF tests combined with careful history and clinical examinations is recommended for proper diagnosis of ACS in SLE.

This study examined children with an acute encephalopathy illness for evidence of viral infection, disordered blood-brain barrier function, intrathecal immunoglobulin synthesis, and interferon (IFN) production, and related their temporal occurrence to outcome. A prospective study of 22 children (13 males, 9 females; age range 1mo to 13y, median 2y 4mo), recorded clinical details, with serum and cerebrospinal fluid (CSF) analysis near presentation and then on convalescent specimens taken up to day 39 of the neurological illness. Outcome was assessed with standard scales between 18 months and 3 years after presentation. A history consistent with viral infection was given in 17 children but laboratory evidence of viral infection was found in only 7 (7/17). In 18 out of 21 children, an elevated CSF:serum albumin ratio indicative of impairment of the blood-CSF and blood-brain barriers was detected at some stage of the illness. In 14 of the 15 children with a raised immunoglobulin G index, and in 12 of the 14 children where the CSF was positive for oligoclonal bands, this was preceded by, or was observed at the same time as, an abnormal albumin ratio. Sixteen children (16/18) had elevated IFN-alpha levels in serum, or CSF, or in both. We conclude that these findings indicate an initial disruption of the blood-brain barrier followed by intrathecal antibody production by activated lymphocytes, clonally restricted to a few antigens. This is the first in vivo study to show this as an important pathogenetic mechanism of encephalitis in children. Poor outcome was associated with young age, a deteriorating electroencephalogram pattern from grade 1 to grade 2, and the degree of blood-brain barrier impairment, particularly when prolonged, but not with Glasgow Coma Scale score. The persistence of IFN-alpha was associated with a good prognosis.

Aicardi-Goutières syndrome (AGS) is an early-onset progressive encephalopathy characterized by calcifications of the basal ganglia, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis, and/or a raised level of CSF interferon (INF)-alpha. We report a female with mitochondrial respiratory chain deficiency fulfilling the criteria of AGS. Disease onset was in the first year of age with seizures and psychomotor regression. To date, at 4 years of age, she presents a severe encephalopathy, increased INF-alpha in the CSF, and calcifications of basal ganglia on computerized tomography. Cerebral magnetic resonance imaging showed bilateral and symmetric hypersignal of the posterior white matter. A complex I deficiency of the mitochondrial respiratory chain was found in skeletal muscle, which was associated with a complex IV deficiency in cultured skin fibroblasts. The question of whether this oxidative phosphorylation deficiency is primary or secondary in AGS is open to debate. We suggest giving consideration to systematic evaluation of the mitochondrial respiratory chain in skeletal muscle and skin fibroblasts of other AGS patients.

A case of Aicardi-Goutières syndrome is described in a family with index cases. The diagnosis was made prenatally based on high fetal blood concentration of interferon alpha. The biological measurement could be of interest for further diagnosis of other cases., ((c) 2006 S. Karger AG, Basel)

Aicardi-Goutières syndrome is a rare progressive encephalopathy characterized by a typical clinical picture, bilateral basal ganglia calcifications, leukodystrophy and brain atrophy, lymphocytosis, and elevated interferon-alpha in the cerebrospinal fluid. Among the cases described to date, variability in the clinical expression or in the cerebrospinal fluid abnormalities has been reported. We present a case with a delayed diagnosis at the age of 8 years, when brain computed tomography was done because there was no first image from the age of 8 months, when the disease started. Symmetric basal ganglia calcifications were visualized and led to purposeful investigation of the cerebrospinal fluid. It revealed an interferon-alpha titer of 103 IU/mL, which, together with the progressive brain damage and disease course, was crucial for the diagnosis. This rare finding of long-term highly elevated interferon-alpha in the cerebrospinal fluid is discussed with respect to the clinical course.

Described are the outcomes of 11 Italian patients with Aicardi-Goutières syndrome. Neurologic symptoms progressed in the first year of life and stabilized by the end of the second year in 10 patients. White matter abnormalities remained stable; cerebral atrophy was stable in four patients and progressive in two. Calcifications increased (in number and size) in two of six patients. Serial CSF and serum interferon-alpha measurements (three patients) showed reduced CSF interferon-alpha levels.

Aicardi-Goutieres syndrome is a familial progressive early onset encephalopathy with basal ganglia calcifications, chronic CSF lymphocytosis and high level of interferon-alpha in CSF. Cutaneous necrotic lesions and the neuropathological aspect of microangiopathy and microinfarctions suggest a vascular process in relation to elevated interferon-alpha. A genetic defect in the regulation of its synthesis may be the causal factor of the disorder.

Unlabelled: IFN-alpha detection is useful in some clinical circumstances, but its use has never been validated in young infants with viral infections., Objective: The authors wanted to determine it there was any difference in the assessment of IFN-alpha production between infants under or over six months of age., Patients and Method: A series of 233 children with identified common viral infections who had been assessed for IFN-alpha production was retrospectively analyzed. The viral infections were enteroviral meningitis (n =103), respiratory syncytial virus infections (n =60), and rotavirus gastroenteritis (n =70). Data collected from the group of infants under six months of age (n =105) was compared to that of the older children (n =128). Qualitative and quantitative values of interferon-alpha were determined for each group., Results: Interferon-alpha was detected in very young infants (81.9% of cases) as often as in the older age group (80.3% of cases), for any of the three viral infections (P =0.3-0.63). The mean level of interferon-alpha production detected was not lower in the youngest group, and even higher in the group under six months of age with enteroviral meningitis., Conclusion: Interferon-alpha detection in very young infants is efficient and may be useful to differentiate between viral and bacterial infection particularly when the etiological diagnosis appears uncertain.

Background: Japanese encephalitis virus (JEV), the mosquito-borne flavivirus, annually causes an estimated 35,000-50,000 encephalitis cases and 10,000-15,000 deaths in Asia, and there is no antiviral treatment. The role played by the immune response in determining the outcome of human infection with JEV is poorly understood, although, in animal models of flavivirus encephalitis, unregulated proinflammatory cytokine responses can be detrimental., Methods: We studied the innate, cellular, and humoral immune responses in 118 patients infected with JEV, of whom 13 (11%) died., Results: Levels of interferon (IFN)- alpha , the proinflammatory cytokine interleukin (IL)-6, and the chemokine IL-8 were all higher in the cerebrospinal fluid (CSF) of the nonsurvivors than of the survivors (P=.04, P=.006, and P=.04, respectively), as were both the IL-6 : IL-4 ratio in CSF (a marker of the balance of pro- and anti-inflammatory cytokines) and the level of the chemokine RANTES (regulated on activation, normally T cell expressed and secreted) in plasma (P=.03). In contrast, levels of immunoglobulin (Ig) M and IgG in CSF and of IgM in plasma were higher in the survivors (P=.035, P=.003, and P=.009, respectively). Levels of IFN- gamma and nitric oxide did not vary with outcome., Conclusions: During JEV infection, elevated levels of proinflammatory cytokines and chemokines are associated with a poor outcome, but whether they are simply a correlate of severe disease or contribute to pathogenesis remains to be determined.

Aseptic meningitis is a frequent diagnosis in emergency departments. Nevertheless, viral investigations are not carried out currently and the viral etiology in adult population has not been studied extensively. We conducted a prospective study including all consecutive patients undergoing lumbar puncture during a 15 months period in an adult emergency department. Bloody and purulent cerebrospinal fluid (CSF) were excluded. The main tests undertaken were: CSF genomic amplification by the polymerase chain reaction (PCR) for neurotropic viruses and serum and CSF interferon-alpha (IFN-alpha) measurements. Among 194 patients included, 45 had and 149 did not have aseptic meningitis. Of 45 patients with aseptic meningitis, 10 had alternative non-virological final diagnosis, and 35/45 were presumed to have neurological disorders of viral origin. Patients (27/35) completed virological analysis: 21/27 (78%) had either positive viral PCR (enterovirus: 8 patients, Varicella zoster virus (VZV): 5, Epstein-Barr virus (EBV): 2, herpes simplex virus (HSV): 1, human herpes virus 6: 1) or only raised serum or CSF IFN-alpha (4 patients). Overall, 59% of patients with a positive viral PCR had either CSF or serum raised IFN-alpha. Twentyone patients without meningitis had either positive viral PCR (enterovirus: 3 patients) or only high serum IFN-alpha level (18 patients). In the setting of aseptic meningitis diagnosed in an adult emergency department, viruses are the most common agents encountered, with enterovirus and VZV as the two main etiological agents. Current CSF viral genome amplification and IFN-alpha measurement are informative and could be useful to confirm the viral origin of various neurological disorders, although the sensitivity and specificity of IFN-alpha measurement for the diagnosis of viral infection need further confirmation., (Copyright 2004 Wiley-Liss, Inc.)

Aicardi-Goutières syndrome (AGS) is a progressive encephalopathy with onset in the first year of life and a recessive autosomal pattern of inheritance. The syndrome is characterised by acquired microcephaly, basal ganglia calcifications, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis and raised interferon-alpha (INF-alpha) in the CSF. AGS is diagnosed on the basis of a clinical picture characterised by microcephaly and by the onset of encephalopathy associated with severe psychomotor delay, spasticity and extrapyramidal signs. CT is very important in the diagnosis of AGS, demonstrating clearly the presence of calcifications at basal ganglia level: these are often bilateral and symmetrical. CT scan and MRI reveal leukodystrophy and progressive cerebral atrophy. A raised level of INF-alpha in the CSF constitutes a marker of the syndrome: this level, which falls with age, is higher in the CSF than in the serum, suggesting intrathecal synthesis. Differential diagnosis in AGS is carried out to exclude the presence of other neurological and endocrinological pathologies characterised by the presence of intracranial calcification; considering the white matter abnormalities, it is necessary to exclude forms of leukodystrophy associated with metabolic defects, known or otherwise. One fundamental aspect that remains to be clarified is the aetiopathogenetic mechanism underlying AGS: the most well-founded hypotheses are reported. There does not exist, to date, any causal therapy for AGS, although genetic studies, particularly those focusing on interferon-regulating genes, may well provide some therapeutic indications.

The objective was to study the occurrence of autoantibodies and cytokines in serum and cerebrospinal fluid (CSF) in neuropsychiatric systemic lupus erythematosus (NPSLE). In total, 28 consecutive patients with NPSLE and 16 systemic lupus erythematosus (SLE) patients without neuropsychiatric involvement (non-NPSLE) were studied. IFN-alpha, IL-6, IL-10, soluble terminal complement complex (TCC), anti-ribosomal P protein antibodies (anti-P) and anti-cardiolipin antibodies (aCL) were measured in serum and CSF by immunoassays. Analyses of white blood cell differential count, CSF-albumin/serum-albumin ratio, IgG-index in CSF and isoelectric focusing in serum and CSF were also performed. CSF specimens from 23 healthy individuals were used as controls. IFN-alpha was elevated in the CSF of 5 of 28 NPSLE patients compared to three of 14 among the non-NPSLE patients. IL-6 was elevated in CSF in three of 26 NPSLE patients. Normal concentration of IL-10 was found in CSF in all 27 NPSLE-patients analysed. IFN-alpha in serum was elevated in 18 of 28 NPSLE patients. No distinct clinical phenotype was related to elevated cytokine concentration in serum or CSF. One patient with cerebral involvement complicated by progressive multifocal leukoencephalopathy displayed a very high IFN-alpha concentration in serum. High concentration of TCC was present in CSF from only one patient with systemic vasculitis and focal cerebral symptoms. In conclusion, the results of this study suggest that the diagnostic value of serum and CSF concentrations of IFN-alpha, IL-10, IL-6 and TCC is limited in unselected neuropsychiatric SLE, probably due to the heterogeneity of NPSLE pathogenesis.

An 18-year-old woman who presented with photosensitivity, butterfly rash and acute visual disturbance was diagnosed as SLE with retinopathy. The level of IFN-alpha in the cerebrospinal fluid (CSF) was markedly elevated. Her visual acuity recovered with high-dose prednisolone therapy. IFN-alpha in the CSF also reduced to within the normal range. The mechanism causing lupus retinopathy is not clearly understood. Although the association between lupus retinopathy and a high level of IFN-alpha has not been reported, the injection of IFN-alpha is known to frequently cause retinopathy in hepatitis patients. We discuss the possibility of IFN-alpha causing retinopathy in SLE patients.

The International Aicardi-Goutières Syndrome Association (IAGSA) was founded in 2000, its aim being to collect and analyse all available information on this rare syndrome (whose true incidence is not known) in order to increase knowledge of the pathology and the number of reported cases. We analysed the clinical, neuroradiological and biological characteristics of 21 new Aicardi-Goutières syndrome subjects (seven observed directly and 14 on whom we gathered detailed clinical information) and compared our findings with data in the literature. The main clinical symptoms (pyramidal and extrapyramidal symptoms, psychomotor delay, microcephaly) and neuroradiological features (basal ganglia calcification, atrophy, white matter alterations) observed show a greater homogeneity in our subjects than in the literature cases, which indicates an improvement in the diagnostic accuracy of Aicardi-Goutières syndrome. Other symptoms, such as feeding difficulties and irritability are less frequent, but characteristic and present early (even at onset of the disease). In the literature, doubts are expressed as to whether lymphocytosis and/or raised interferon-alpha in cerebrospinal fluid are crucial for a diagnosis of Aicardi-Goutières syndrome. Our data suggest that they are, and in particular that an important role is played by raised interferon-alpha. The clinical course seems to show different stages: early onset, rapid progression, severe deterioration, stabilization. Our follow-up seems to indicate a trend not necessarily towards a worsening, but instead towards a stabilization or even a slight improvement of the clinical picture.

Little is known about the presence of dendritic cells in the human CNS. To investigate the occurrence of dendritic cells in the CSF, paired blood/CSF samples from patients with multiple sclerosis, acute optic neuritis, Lyme neuroborreliosis, other inflammatory neurological diseases and non-inflammatory neurological diseases were examined using flow cytometry. Almost all CSF samples contained myeloid (lin-CD11c+HLA-DR++CD123(dim)) and plasmacytoid (lin-CD11c-HLA-DR+CD123(high)) dendritic cells. In non-inflammatory neurological diseases, dendritic cells of either subset only constituted up to 1% of CSF mononuclear cells. Myeloid CSF dendritic cells were elevated in optic neuritis, neuroborreliosis and other inflammatory neurological disorders, while plasmacytoid dendritic cells were elevated in all neuroinflammatory conditions studied, with especially high numbers in neuroborreliosis. Numbers of CSF dendritic cells correlated with the common parameters of CNS inflammation. The myeloid dendritic cells in CSF expressed higher levels of HLA-DR, CD86, CD80 and CD40 than those in blood, whereas expression of these molecules by plasmacytoid dendritic cells was equal in blood and CSF. Both CSF and blood dendritic cells expressed the chemokine receptor CCR5. This is the first demonstration that dendritic cells are present in human CSF and that plasmacytoid dendritic cells are present in a non-lymphoid compartment. Myeloid and plasmacytoid dendritic cells in CSF may contribute to orchestration of the local immune responses.

Mechanisms involved in the pathogenesis of the AIDS-dementia complex are still unclear. The dichotomy between a small number of HIV-infected cells in the brain and their marked dysfunction could be related to a cellular amplification and/or activation of cerebral viral load by several cytokines. This link between cytokines and viral load could play a role in the generation of the clinical dementia syndrome. We have studied cerebral levels of transforming growth factor-beta1 and interferon-alpha, both in the mild and severe AIDS-dementia complex and also compared these cytokines with HIV RNA load in patients with different degrees of dementia. Our data indicate that production of different cytokines characterized the expression of clinical dementia. In the mild AIDS-dementia complex, there was a significant inverse correlation between interferon-alpha and transforming growth factor-beta1 (r = - 0.743; p < 0.001), and HIV-RNA was present in inverse proportion to transforming growth factor beta1 (r = - 0.751; p < 0.001). In patients with severe AIDS-dementia, transforming growth factor-beta1 was undetectable, while interferon-alpha level were higher than in mild AIDS dementia and correlated positively to cerebral HIV-RNA. No significant difference was evident between these cytokines in the serum of ADC patients and in the control samples. Our study suggests that a relationship is possible between productive HIV infection in the cerebral nervous system and a heterogenous and different expression of the immune response via a complex interaction of cytokines with a differential modulation of the dementia phenotype.

Background: In meningitis without germs, the existence of an inflammatory syndrome leads toward a bacterial etiology while the detection of interferon-alpha (IFN-alpha) in the cerebrospinal fluid (CSF) argues for a viral meningitis. The coexistence of the inflammatory syndrome and the presence of IFN-alpha in the CSF makes this differentiation difficult. The reported case yields the picture and begs the question on the diagnostic approach and the required therapeutic attitude., Case Report: A six-week-old infant, exclusively breast-fed, was hospitalized for fever. The examination showed an important inflammatory syndrome and meningeal attempt with a cellularity at 94/mm3 with 53% polymorphonuclear neutrophils, contrasting with normal proteinorrhachia and glycorrhachia. The IFN-alpha in the CSF was present at 4 UI/mL while the bacteriological culture and the viral search by PCR were negative. The clinical and biological worsening within the first 36 hours, in spite of the parenteral dispensation of a triple antibiotic therapy (amoxicillin, ceftriaxone, netilmicin), then a favorable clinical and biological response after adjunction of vancomycin, led toward a pneumococcal meningitis with reduced sensitivity to beta-lactams. The maternal antibiotic therapy by amoxicillin and its presence in the maternal milk favored the hypothesis of a decapitated bacterial meningitis., Conclusion: In the presence of a meningitis without germs, the coexistence of a sizable inflammatory syndrome and the detection of IFN-alpha in the CSF must be considered as an unusual phenomenon and motivate the pursuit of antibiotic therapy until viral identification.

The aim of this work was to study the role of HIV replication and the role of endogenous secretion of interferon-alpha in the pathogenesis of AIDS Dementia Complex (ADC). To accurately establish the diagnosis of ADC, 39 consecutive HIV-positive patients who presented with immune and intellectual deficiency underwent an extensive neurological evaluation. This included magnetic resonance imaging, neuropsychological testing and a lumbar puncture. The levels of HIV-1 RNA were measured in the cerebrospinal fluid (CSF) and blood by HIV Monitor (Roche Diagnostics) and those of interferon-alpha by an in-house biological assay. The diagnosis of ADC was established in 22 cases, which included nine out of the ten patients who had a high CSF viral load (above 4 log HIV-1 RNA copy per ml). Patients receiving highly active antiretroviral therapy had low viral loads in blood and CSF. In all 22 ADC patients, viral load in the CSF correlated with the staging of ADC (r=0.46, P=0.03), the CSF level of interferon-alpha (r=0.42, P=0.05) and with the bicaudate ratio (r=0.43, P=0.06), a measure of cerebral atrophy in the region of the caudate nucleus. No correlation was observed between CSF and plasma HIV-1 RNA. These results show that HIV may play a role in the neurological impairment of ADC patients possibly in part through the deleterious effect of interferon-alpha on the central nervous system and that highly active combination therapy should reduce or prevent these complications.

Aicardi-Goutières syndrome (AGS) is a severe progressive familial encephalopathy, which is usually diagnosed shortly after birth. Using the principle of homozygosity mapping, genome-wide screening of five consanguineous families was performed to search for a homozygous region shared by all affected individuals. A total of 364 markers with an average spacing of 9.9 cM were genotyped, but no homozygous region common to all affected individuals could be found. Regions of homozygosity in affected sibs could only be identified within each family individually. This may reflect genetic heterogeneity, possibly related to clinical heterogeneity, since several syndromes are clinically difficult to distinguish from AGS. Involvement of a small number of genes and/or of an external factor, such as infection, may also explain the absence of a homozygous region common to all affected individuals.

Twenty-seven patients with familial encephalopathy with calcification of the basal ganglia and chronic cerebrospinal fluid (CSF) lymphocytosis (Aicardi-Goutières syndrome) are reviewed. In 19 children, the onset was within the first 4 months of life. Most patients had normal head circumference at birth, but 21 developed microcephaly between 3 and 12 months. Neuroimaging showed severe and progressive brain atrophy in all patients. The extent and intensity of the calcification was variable even in the same sibship. CSF lymphocytosis persisted beyond 12 months of age in 7 children. High levels of interferon-alpha were found in serum and CSF in 14 patients. The higher CSF levels suggest intrathecal synthesis. Tubuloreticular inclusions related to the presence of interferon were found in 4 additional children. The 19 patients still alive (6 older than 10 years) are profoundly disabled. However, the syndrome may present with individual variations in severity, rapidity of evolution, and imaging features. Neuropathological examination in 2 patients failed to detect significant inflammatory lesions and showed only foci of necrosis and wide-spread demyelination. This study supports an autosomal recessive inheritance for this syndrome. The high level of interferon-alpha is not explained but may play a role in the pathogenesis of the disorder.

The Aicardi-Goutières syndrome (AGS) is an autosomal recessive progressive encephalopathy associated with basal ganglia calcification, white-matter abnormality, cerebro-spinal fluid (CSF) pleocytosis and elevated CSF interferon alpha (IFN alpha). Two brothers of consanguineous parents who presented in the first year with developmental delay are reported. The first boy is normocephalic with spastic diplegia and normal I.Q. Tests in the second year of life showed punctate calcification of the basal ganglia and subcortical white matter and CSF pleocytosis. At 9 years clinical and imaging features are unchanged and CSF including IFN alpha is normal. The second boy at 21 months has dystonic cerebral palsy, slight fall-off in head growth and cognitive delay. Imaging abnormalities are more severe than those in the brother, CSF examination reveals pleocytosis and marked increase in IFN alpha. Detailed metabolic and viral studies were negative in both cases. Although the clinical course is not progressive, it is suggested that the brothers have AGS and represent the mild end of the spectrum of the disorder. CSF examination (including IFN alpha), should be performed early in children with an apparently static encephalopathy and brain calcification, as typical abnormalities decrease or disappear with age.

Neopterin is synthesized mainly by monocytes/macrophages and is considered to be a marker for activation of the cellular immune system. In patients with bacterial or aseptic meningitis, elevated neopterin levels in cerebrospinal fluid (CSF) have been demonstrated. We studied the time courses of CSF and serum neopterin in children with meningitis. The CSF neopterin levels on admission were significantly higher in patients with bacterial meningitis (82.4 +/- 37.0 nmol/L) than in those with aseptic meningitis (32.3 +/- 22.1 nmol/L) or in those with non-pleocytotic CSF (6.9 +/- 4.4 nmol/L). The CSF neopterin levels in the patients with bacterial meningitis were remarkably increased (234.5 +/- 100.2 nmol/L) one day after admission, but the serum neopterin levels were not increased. There was no correlation between CSF neopterin levels and CSF cell count or CSF protein, nor between serum neopterin levels and serum C-reactive protein or peripheral leukocyte count. But the CSF neopterin levels one day after admission were related to the period of positive serum C-reactive protein. CSF neopterin levels in patients with bacterial meningitis were increased one day after admission. The levels in two patients with high levels of CSF IFN-gamma and TNF-alpha were remarkably increased. All patients with bacterial meningitis had received treatment with antibiotics and dexamethasone. It has been reported that TNF-alpha enhances the effect of IFN-gamma for neopterin release by macrophages in vitro and that dexamethasone has the same effect on IFN-gamma as TNF-alpha. The present study suggests that elevation of CSF neopterin in bacterial meningitis results from monocytes/macrophages costimulated with IFN-gamma, TNF-alpha and dexamethasone used in treatment.

Previous studies in patients receiving interferon-alpha (IFN-alpha) therapy and patients with systemic lupus erythematosus have demonstrated that elevated cerebrospinal fluid (CSF) levels of IFN-alpha are associated with cognitive dysfunction. We measured IFN-alpha levels in CSF and blood by ELISA in human immunodeficiency virus (HIV)-positive patients with (n = 21) and without (n = 23) dementia and HIV-negative controls (n = 48). IFN-alpha was significantly elevated in the CSF of HIV-positive patients with dementia compared to those without dementia and controls. An increasing amount of IFN-alpha in the CSF was correlated with the clinical parameter of increasing Memorial Sloan Kettering scores; although these correlations were not statistically significant, they further suggest an association of increased CSF IFN-alpha with neurocognitive dysfunction in AIDS. Immunocytochemical staining of brains demonstrated IFN-alpha-positive macrophages and astrocytes in frontal cortex and white matter and IFN-alpha mRNA was detected by reverse transcriptase-polymerase chain reaction, further indicating that IFN-alpha is made by cells within the brain and suggesting that the significant increases of IFN-alpha protein found in the CSF of patients with HIV-associated dementia complex are derived from intrinsic brain cells such as macrophages and astrocytes. Increased local production of IFN-alpha during HIV infection may contribute directly or indirectly to the pathogenesis of HIV-associated dementia.

Aicardi-Goutières syndrome (Mendelian inheritance in man Catalog No *225750) is an autosomal recessive encephalopathy which causes developmental arrest, intracerebral calcification, and white matter disease in the presence of chronic cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid interferon-alpha (IFN-alpha). Diagnosis requires the presence of progressive encephalopathy with onset shortly after birth, and characteristic clinical neurological and neuroimaging signs together with chronic CSF lymphocytosis. The syndrome has superficial resemblance to the neurological sequelae of congenital infection, thus a rigorous search for microbiological and serological evidence of embryopathic infections should be carried out in each case.

Concentrations of interferon gamma (IFN-gamma) in the lumbar cerebrospinal fluid (CSF) of 30 children (mean age, 27 months) being treated for stage III (16 children) and stage II (14 children) tuberculosis meningitis (TBM) were determined by ELISA. Nine children with stage III TBM and six with stage II TBM received prednisone (4 mg/kg). Concentrations of IFN-gamma in 73 CSF specimens (18 from the first week of therapy, 20 from the second, 19 from the third, and 16 from the fourth) were determined. The mean concentrations were 780 pg/mL in the first week of therapy and 554 pg/mL, 529 pg/mL, and 269 pg/mL in the second, third, and fourth weeks, respectively. Tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) concentrations in 56 specimens from 23 of these same children were determined by ELISA. The mean CSF TNF-alpha concentration in 12 specimens obtained during the first week of therapy was 17 pg/mL, and the mean was 11 pg/mL during each of the subsequent weeks (14 specimens were evaluated in the second week and 15 specimens in the third and fourth weeks of therapy). Mean IL-1beta concentrations in these same groups of specimens were 52 pg/mL, 43 pg/mL, 42 pg/mL, and 18 pg/mL. No correlation could be shown between cytokine concentration and stage of disease, and no differences existed between those who did and those who did not receive prednisone. A significant decline in IL-1beta concentrations was shown during the 4-week period, but none in TNF-alpha or IFN-gamma concentrations was noted. Persistently high CSF INF-gamma concentrations in cases of TBM (as in cases of aseptic meningitis but not bacterial meningitis) at the time of diagnosis suggest an immune response fundamentally different from that in bacterial meningitis.

The polymerase chain reaction (PCR) was used to detect DNA of herpes simplex virus (HSV) in 38 samples of cerebrospinal fluid (CSF) obtained from 22 patients (7 children and 15 adults) 1-20 days after the onset of encephalitis. The results were best with amplification on the pellet of the CSF-extracted DNA and with analysis of the amplified products by dot-blotting (sensitivity, 100%). A highly significant difference was evident in the chi 2 test when PCR was compared with specific antigen detection or antibody evaluation (n = 19; chi 2 = 7; sensitivity = 100% vs. 63%) or with interferon alpha determination (n = 20; chi 2 = 11; sensitivity = 95% vs. 42%). PCR was positive as early as 1 day after onset of disease and was often the first test to become positive. The detection of HSV DNA by PCR is the most specific, rapid, and sensitive tool for early diagnosis and therapeutic management of acute HSV encephalitis.

Sixty-five cerebrospinal fluid (CSF) samples from 54 infants and children with bacterial meningitis were analyzed for the presence of interferon (IFN)-alpha with a biologic assay. Of the 65 samples, 3 were positive (2-4 IU/mL) and only 1 of 56 collected early was at 4 IU/mL. These results suggest that some subtypes of IFN-alpha already reported as present in viral infections of the central nervous system are not detected in bacterial meningitis by our IFN assay. This difference may be helpful in differentiating bacterial from viral infections and also in evaluating the quality of the virologic investigation; moreover, the rarity of IFN-gamma in CSF in bacterial meningitis needs further investigation to understand its role in the pathogenesis of the disease.

Objective: Since the level of interferon-alpha (IFN alpha) is increased in the sera of patients with active systemic lupus erythematosus (SLE) and is detectable in the cerebrospinal fluid (CSF) of some SLE patients with neuropsychiatric manifestations, we investigated the contribution of IFN alpha to the pathogenesis of the neuropsychiatric manifestations of SLE., Methods: IFN alpha levels were quantitated by radio-immunoassay in CSF and serum samples from 17 SLE patients with neuropsychiatric manifestations and 28 patients with SLE alone or SLE and other neurologic disorders., Results: Levels of IFN alpha were increased in the CSF of 5 of 6 patients with lupus psychosis, and in 4 of these 5 patients, the levels in CSF were higher than those in serum. IFN alpha levels decreased when the manifestation of lupus psychosis subsided. In contrast, IFN alpha levels in CSF samples from patients with seizures alone were not increased. One patient with lupus psychosis died of complications of generalized seizures resulting from the SLE. At autopsy, we investigated whether IFN alpha protein or messenger RNA was detectable in the subject's brain. IFN alpha protein was immunohistochemically demonstrated in the neurons and in the microglia (focal accumulation), features not present in the brain tissues of subjects who died of other diseases., Conclusion: These findings support the hypothesis that IFN alpha, possibly synthesized in the brain, is the cause of the manifestation of psychosis in patients with SLE.

Serum and/or cerebrospinal fluid (CSF) alpha interferon (aIFN) levels were determined in 31 neonates hospitalized for suspected sepsis. Final diagnosis was bacterial sepsis in 15, viral infection in 13 and no infection in 3. Among the 13 neonates with viral infection, enterovirus was isolated 5 times and coxsackievirus 4 times. No aIFN was found in cerebro-spinal fluid and/or serum among the neonates with bacterial sepsis or without infection. By contrast, in neonates with viral infection, CSF and/or serum aIFN levels were always elevated except in one case in which serum aIFN determination was not available. We conclude that in neonates, elevated levels of CSF and serum aIFN appear to be specific of viral infection, and that this might be helpful in the differential diagnosis of suspected sepsis.