Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.

Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.

Incidence and predictors of delirium on the intensive care unit after acute myocardial infarction, insight from a retrospective registry.

OBJECTIVES: This study aimed to identify the incidence and potential risk factors for delirium after myocardial infarction (MI). BACKGROUND: Delirium is a common complication on intensive care units. Data on incidence and especially on predictors of delirium in patients after acute MI are rare. METHODS: In this retrospective study, all patients hospitalized for MI treated with coronary angiography in an university hospital in 2018 were included and analyzed. Onset of delirium within the first 5 days after MI was attributed to the MI and was defined by a Nursing Delirium screening scale (NuDesc) ≥2. This score is taken as part of daily care in every patient on intensive care unit three times a day by especially trained nurses. RESULTS: A total of 624 patients with MI (age 68.5 ± 13.2 years, ST-elevation MI 41.6%, hospital mortality 3.2%) were included in the study. Delirium was detected in 10.9% of all patients. In the subgroup of patients with a stay on the intensive care unit (ICU) for more than 24 hr (n = 229), delirium was detected in 29.7%. Hospital and ICU stay were significantly longer in patients with delirium (p < .001). Delirium was an independent predictor of prolonged ICU-stay. Independent predictors of delirium were age, dementia, alcohol abuse, cardiac arrest, hypotension, and leucocytosis. Infarct size or presentation with ST-elevation were not associated with incidence of delirium. CONCLUSION: Development of delirium is frequent after acute MI and prolongs hospitalization. Incidence of delirium is associated with clinical instability, preexisting comorbidity, and age rather than MI type or size.

Neurologists, neurosurgeons, and psychiatrists' personality traits: a comparison.

BACKGROUND: Clinicians in neuroscientific disciplines may present distinct personality profiles. Despite of potential relevance to clinical practice, this has not yet been studied. We therefore aimed to compare personality profiles of physicians working in the three main disciplines of clinical neuroscience, i.e., neurologists, neurosurgeons, and psychiatrists, between each other, across levels of training and to other specialties. METHODS: An online survey using the Ten-Item Personality Inventory (TIPI), an internationally validated measure of the five-factor model of personality dimensions, was distributed to board-certified physicians, residents, and medical students in several European countries and Canada. Differences in personality profiles were analyzed using multivariate analysis of variance and canonical linear discriminant analysis on age- and sex-standardized z-scores of personality traits. Single personality traits were analyzed using robust t tests. RESULTS: Of the 5148 respondents who completed the survey, 723 indicated the specialties neurology, neurosurgery, or psychiatry. Compared to all other specialties, personality profiles of training and trained physicians in these three main clinical neuroscience disciplines ("NN&P") significantly differed, with significantly higher scores in openness to experience. Within NN&P, there were significant differences in personality profiles, driven by lower neuroticism in neurosurgeons, higher conscientiousness in neurosurgeons and neurologists, and higher agreeableness in psychiatrists. Across levels of training, NN&P personality profiles did not differ significantly. CONCLUSION: The distinct clinical neuroscience personality profile is characterized by higher levels of openness to experience compared to non-neuroscience specialties. Despite high variability within each discipline, moderate, but solid differences in the personality profiles of neurologists, neurosurgeons and psychiatrists exist.

Restless legs syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon.

Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.

Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.

Chronic Inflammation Mediates the Association between Cortisol and Hyperglycemia: Findings from the Cross-Sectional Population-Based KORA Age Study.

(1) Background: The study aimed to investigate the role of subclinical inflammation on the association between diurnal cortisol patterns and glycaemia in an aged population. (2) Methods: Salivary cortisol, interleukin-6 (IL-6) and glycated haemoglobin (HbA1c) were analysed in a sample of 394 men and 364 women (mean age = 5 ± 6.3, 65-90 years). The ratio of morning after awakening and late-night cortisol was calculated as an indication of diurnal cortisol slope (DCS). Multivariable regression models were run to examine whether IL-6 mediates the relationship between the DCS and glycaemia. The Sobel test and bootstrapping methods were used to quantify the mediation analyses. (3) Results: In comparison to normoglycaemic counterparts (n = 676, 89.2%), an increase in IL-6 concentrations, in individuals with hyperglycaemia (HbA1c ≥ 6.5%) (n = 82, 10.8%) (p = 0.04), was significantly associated with a flatter DCS. The link between flatter DCS and elevated HbA1c level was significant mediated by a heightened IL-6 level. Our results do not suggest reverse-directionality, whereby cortisol did not mediate the association of IL-6 with HbA1c. (4) Conclusions: In our sample, the relation between flatter DCS and hyperglycaemia was partly explained by IL-6 levels. The paradigm of subclinical inflammation-mediated cortisol response on glucose metabolism could have widespread implications for improving our understanding of the pathophysiology of type 2 diabetes mellitus.

Donepezil, a cholinesterase inhibitor used in Alzheimer's disease therapy, is actively exported out of the brain by abcb1ab p-glycoproteins in mice.

Polymorphisms in the drug transporter gene ABCB1 predict the treatment response of selected antidepressants and limit anticonvulsive medication's effectiveness. The ABCB1 locus encodes the energy-dependent transporter P-glycoprotein (P-gp) of the blood brain barrier (BBB), which serves as an efflux pump of its substrates in the expressing tissues of vertebrates. One experimental setup to determine a posteriori the P-gp substrate status is the use of the double abcb1ab knock-out (KO) mice model. Since so far, P-gp substrate status of donepezil, a cholinesterase inhibitor wildly used in Alzheimer's disease therapy was inconclusive, we performed subcutanous (s.c.), continuous injections over 11 days in double abcb1ab KO and P-gp competent wildtype (WT) mice. Both in brain and in testis concentrations of donepezil were significantly higher in P-gp deficient mice compared to WT controls (2.39 and 2.24 times respectively). In conclusion, in mice donepezil's brain bioavailability depends on P-gp.

Identification of two compound heterozygous VPS13A large deletions in chorea-acanthocytosis only by protein and quantitative DNA analysis.

BACKGROUND: Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. METHODS: Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. RESULTS: We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. CONCLUSION: Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.

Sex difference in cerebrospinal fluid/blood albumin quotients in patients with schizophreniform and affective psychosis.

BACKGROUND: The importance of cerebrospinal fluid (CSF) diagnostics for psychiatry is growing. The CSF/blood albumin quotient (QAlb) is considered to be a measure of the blood-CSF barrier function. Recently, systematically higher QAlb in males than in females was described in neurological patients. The aim of this study was to investigate whether a sex difference could also be detected in a well-characterized psychiatric cohort. METHODS: The patient cohort comprised 989 patients, including 545 females and 444 males with schizophreniform and affective syndromes who underwent CSF diagnostics, including QAlb measurement. The basic CSF findings and antineuronal autoantibody data of this cohort have already been published. This re-analysis employed analysis of covariance with age correction for QAlb mean values and chi2-testing for the number of increased age-corrected QAlb levels to investigate sex differences in QAlb. RESULTS: The QAlb levels were elevated above reference levels by 18% across all patients, and a comparison between male and female patients revealed a statistically significant sex difference, with increased values in 26% of male patients and a corresponding rate of only 10% in female patients (chi2 = 42.625, p < 0.001). The mean QAlb values were also significantly higher in males (6.52 ± 3.69 × 10-3) than in females (5.23 ± 2.56 × 10-3; F = 52.837, p < 0.001). DISCUSSION: The main finding of this study was a significantly higher QAlb level in male compared to female patients with psychiatric disorders, complementing previously described sex differences in neurological patient cohorts. This result indicates bias from some general factors associated with sex and could be partly explained by sex differences in body height, which is associated with spine length and thus a longer distance for CSF flow within the subarachnoid space down the spine from the occipital area to the lumbar puncture site in males compared to females. Hormonal influences caused by different estrogen levels and other sex-specific factors could also play a relevant role. The significance of the study is limited by its retrospective design, absence of a healthy control group, and unavailability of exact measures of spine length.

Insular Cell Integrity Markers Linked to Weight Concern in Anorexia Nervosa-An MR-Spectroscopy Study.

OBJECTIVE: An insular involvement in the pathogenesis of anorexia nervosa (AN) has been suggested in many structural and functional neuroimaging studies. This magnetic resonance spectroscopy (MRS) study is the first to investigate metabolic signals in the anterior insular cortex in patients with AN and recovered individuals (REC). METHOD: The MR spectra of 32 adult women with AN, 21 REC subjects and 33 healthy controls (HC) were quantified for absolute N-acetylaspartate (NAA), glutamate + glutamine (Glx), total choline, myo-inositol, creatine concentrations (mM/L). After adjusting the metabolite concentrations for age and partial gray/white matter volume, group differences were tested using one-way multivariate analyses of variance (MANOVA). Post-hoc analyses of variance were applied to identify those metabolites that showed significant group effects. Correlations were tested for associations with psychometric measures (eating disorder examination), duration of illness, and body mass index. RESULTS: The MANOVA exhibited a significant group effect. The NAA signal was reduced in the AN group compared to the HC group. The REC and the HC groups did not differ in metabolite concentrations. In the AN group, lower NAA and Glx signals were related to increased weight concern. DISCUSSION: We interpret the decreased NAA availability in the anterior insula as a signal of impaired neuronal integrity or density. The association of weight concern, which is a core feature of AN, with decreased NAA and Glx indicates that disturbances of glutamatergic neurotransmission might be related to core psychopathology in AN. The absence of significant metabolic differences between the REC and HC subjects suggests that metabolic alterations in AN represent a state rather than a trait phenomenon.

Suppressive effect of mirtazapine on the HPA system in acutely depressed women seems to be transient and not related to antidepressant action.

Impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system is a consistent finding among patients with depression, which can be most sensitively detected with the combined dexamethasone (dex)/corticotrophin releasing hormone (CRH) test. The majority of patients with acute depression shows an exaggerated plasma corticotrophin (ACTH) and cortisol response to this test that normalizes gradually during successful antidepressant therapy. In contrast, persistently high HPA-responses to this challenge are prognostically less favorable. It has been recently questioned, whether this observation applies also to treatment with the atypical antidepressant mirtazapine, as patients treated with this drug showed a distinct attenuation of the endocrine response to the dex/CRH test already after 1 week of treatment. In the present study, we investigated whether the attenuating effect of mirtazapine on the HPA system is an acute pharmacological reaction disappearing after physiological adaptation or whether this effect is related to the antidepressant action of the drug. We examined plasma ACTH and cortisol responses to the dex/CRH test in acutely depressed inpatients treated either with mirtazapine (n=55) or a monoamine reuptake inhibitor (n=105) according to doctor's choice and compared the test results with healthy controls (n=40). Patients treated with monoamine reuptake inhibitors received either selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) or the combined serotonin and noradrenalin reuptake inhibitor venlafaxine. We found increased plasma ACTH and cortisol responses to the dex/CRH test in depressed patients compared with healthy controls, but also significantly (p=.017) attenuated plasma cortisol secretion in the mirtazapine group compared to the group of monoamine reuptake inhibitor treated patients. This effect was not significant in male patients. Furthermore this effect was independent of the psychopathological state, but depended on treatment duration. Patient treatment with mirtazapine for up to 7 days resulted in dex/CRH test outcome that was indistinguishable from controls. This effect, however waned as it was not observable in patients treated for a longer period. These results suggest that short-term administration of mirtazapine has immediate but only transient suppressive effects on the HPA system predominantly in women. Our results confirm that dex/CRH tests can be used as predictors of clinical course also under mirtazapine treatment.

Clinical characteristics and treatment outcome in a representative sample of depressed inpatients - findings from the Munich Antidepressant Response Signature (MARS) project.

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.

abcb1ab p-glycoprotein is involved in the uptake of the novel antidepressant vortioxetine into the brain of mice.

A clinically important and well-studied transporter of the blood-brain barrier (BBB) is P-glycoprotein (P-gp), the gene product of ABCB1. Animal studies have shown that brain concentrations of many antidepressants depend on P-gp. However, biochemical properties, which might allow the prediction of pharmacodynamical involvement of P-gp have not yet been identified, hence thorough experimental testing of each novel drug is needed to determine its P-gp substrate status. In the current study, we tested the P-gp substrate status for the antidepressant vortioxetine using double abcb1ab knock-out (KO) mice. Cerebral concentrations of vortioxetine were 2.3 times higher in P-gp deficient mice compared to wildtype (WT) controls. No significant difference was found regarding the concentration of the drug in the plasma and other organs (liver, kidney, spleen) between KO and WT mice. The results of our study provide conclusive in-vivo evidence that in mice vortioxetine's brain bioavailability is P-gp dependent, expanding previous findings on this topic.

Conscious Experience and Psychological Consequences of Awake Craniotomy.

BACKGROUND: Experiencing cranial surgery under awake conditions may expose patients to considerable psychological strain. METHODS: This study aimed to investigate the occurrence and course of psychological sequelae following awake craniotomy (AC) for brain tumors in a series of 20 patients using a broad, validated psychological assessment preoperatively, intraoperatively, postoperatively and a standardized follow-up of 3 months. In addition, the association of the preoperative psychological condition (including, but not limited to, anxiety and fear) with perioperative pain perception and interference was assessed. RESULTS: AC did not induce any shift in the median levels of anxiety, depression, and stress symptoms already present prior to the procedure. Furthermore, anxiety and depression were all moderately to strongly associated over time (all P < 0.05). Stress symptoms also correlated positively over all times of measurement. Stress 3 days after surgery was strongly associated with stress 3 months after surgery (P < 0.001), whereas the correlation between preoperative and immediate postoperative stress showed a statistical trend (P = 0.07). Preoperative fear was not related to intraoperative pain, but to pain and its interference with daily activity on the third postoperative day (P < 0.001 and P < 0.01, respectively). CONCLUSIONS: Postoperative psychological symptoms clearly correlated with their corresponding preoperative symptoms. Thus, mental health was not negatively affected by the AC experience in our series. Intraoperative fear and pain were not related to the preoperative psychological condition. However, preoperative fear and anxiety were positively related with pain and its interference with daily activity in the immediate postoperative period.

DNA Methylation Signatures of Depressive Symptoms in Middle-aged and Elderly Persons: Meta-analysis of Multiethnic Epigenome-wide Studies.

Importance: Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers. Objective: To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood. Design, Setting, and Participants: To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts. Main Outcomes and Measures: Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire. Results: The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression. Conclusions and Relevance: This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.

Comparison of Delay Times Between Symptom Onset of an Acute ST-elevation Myocardial Infarction and Hospital Arrival in Men and Women <65 Years Versus ≥65 Years of Age.: Findings From the Multicenter Munich Examination of Delay in Patients Experiencing Acute Myocardial Infarction (MEDEA) Study.

Early administration of reperfusion therapy in acute ST-elevation myocardial infarctions (STEMI) is crucial to reduce mortality. Although female sex and old age are key factors contributing to an inadequate long prehospital delay time, little is known whether women ≥65 years are a particular risk population. Hence, we studied the interaction of sex and age (<65 years or ≥65 years) and the contribution of chest pain to delay time during STEMI. Bedside interview data were collected in 619 STEMI patients from the Munich Examination of Delay in Patients Experiencing Acute Myocardial Infarction (MEDEA) study. Sex and age group stratification disclosed an excess delay risk for women ≥65 years, accounting for a 2.39 (95% confidence interval (CI) 1.39 to 4.10)-fold higher odds to delay longer than 2 hours compared with all other patient groups including younger women (p ≤0.002). Median delay time was 266 minutes in women ≥65 years and 148 minutes in younger women (p <0.001). Chest pain during STEMI had the lowest frequency both in women (81%) and men ≥65 years (83%) and the highest frequency (95%) in younger women. Experiencing non-chest pain was 2.32-fold (95% CI, 1.20 to 4.46, p <0.05) higher in women ≥65 years than in all other patients. Mediation analysis disclosed that the effect accounted for only 9% of the variance. Age specific educational strategies targeting women ≥65 years at risk are urgently needed. To tailor adequate strategies, more research is required to understand age- and sex driven barriers to timely identification of ischemic symptoms.

Acute transverse myelitis and psoriasiform dermatitis associated with Sjoegren's syndrome: a case report.

BACKGROUND: Clinical complications of Sjoegren's syndrome include myelitis and skin manifestations. There is scarce observational data and a lack of randomised controlled studies regarding the treatment of Sjoegren's syndrome in the presence of such complications. CASE PRESENTATION: Here we report the case of a 41-year-old Caucasian female patient with biopsy-proven Sjoegren's syndrome who initially presented with generalized exanthema and subsequently developed acute extensive transverse myelitis. In view of the rapid deterioration we opted for an intensive treatment using a combination of corticosteroid pulse therapy, plasmapheresis and cyclophosphamide, which we later changed to rituximab. Under that treatment the skin manifestations resolved entirely whereas transverse myelitis showed incomplete remission. CONCLUSION: Severe neurological and dermatological complications may occur in Sjoegren's syndrome. This suggests a close yet currently unclear pathogenetic relationship. Intensive immunosuppressant treatment resulted in significant improvement of both symptom clusters. Skin manifestations may precede other severe complications in Sjoegren's syndrome and therefore require particular attention.