Differential gene expression in B cells and T helper cells following high-dose glucocorticoid therapy for multiple sclerosis relapse.

BACKGROUND: Despite remarkable advances in the therapy of multiple sclerosis (MS), patients with MS may still experience relapses. High-dose short-term methylprednisolone (MP) remains the standard treatment in the acute management of MS relapses due to its potent anti-inflammatory and immunosuppressive properties. However, there is a lack of studies on the cell type-specific transcriptome changes that are induced by this synthetic glucocorticoid (GC). Moreover, it is not well understood why some patients do not benefit adequately from MP therapy. METHODS: We collected peripheral blood from MS patients in relapse immediately before and after ∼3-5 days of therapy with MP at 4 study centers. CD19+ B cells and CD4+ T cells were then isolated for profiling the transcriptome with high-density arrays. The patients' improvement of neurological symptoms was evaluated after ∼2 weeks by the treating physicians. We finally analyzed the data to identify genes that were differentially expressed in response to the therapy and whose expression differed between clinical responders and non-responders. RESULTS: After MP treatment, a total of 33 genes in B cells and 55 genes in T helper cells were significantly up- or downregulated. The gene lists overlap in 10 genes and contain genes that have already been described as GC-responsive genes in the literature on other cell types and diseases. Their differential expression points to a rapid and coordinated modulation of multiple signaling pathways that influence transcription. Genes that were previously suggested as potential prognostic biomarkers of the clinical response to MP therapy could not be confirmed in our data. However, a greater increase in the expression of genes encoding proteins with antimicrobial activity was detected in CD4+ T cells from non-responders compared to responders. CONCLUSION: Our study delved into the cell type-specific effects of MP at the transcriptional level. The data suggest a therapy-induced ectopic expression of some genes (e.g., AZU1, ELANE and MPO), especially in non-responders. The biological consequences of this remain to be explored in greater depth. A better understanding of the molecular mechanisms underlying clinical recovery from relapses in patients with MS will help to optimize future treatment decisions.

Pregnancy outcomes in female multiple sclerosis patients exposed to intramuscular interferon beta-1a or peginterferon beta-1a reported in a German Patient Support Programme - results from the non-interventional post-authorization safety study PRIMA.

Background: Based on data from two large cohort studies, a label update became applicable for the class of interferon beta therapies in 9/2019, allowing interferons during pregnancy and breastfeeding. Objective: To assess pregnancy outcomes of women with multiple sclerosis (MS) exposed to peginterferon beta-1a or intramuscular interferon beta-1a therapy (IFN). Design: Non-interventional post-authorization safety study. Methods: PRIMA was conducted from April to October 2021 in Germany. Retrospective pregnancy data were retrieved from adult female patients diagnosed with relapsing-remitting MS or clinically isolated syndrome, exposed to IFN before or during pregnancy and registered in the patient support programme (PSP) of the marketing authorization holder's MS Service Centre. The primary endpoint was the outcome of pregnancy. Prospective postpartum data were collected from mothers reporting live births. Results: In total, 426 women reporting 542 pregnancies between December 2001 and July 2020 (14 pregnancies after the label update) were enrolled. Among patients with confirmed exposure during pregnancy (N = 362), 306 pregnancies (84.5%) resulted in live births (77.6% without defects, 1.9% with defects and 4.4% preterm). Spontaneous abortion, elective termination and stillbirth were reported in 10.9%, 2.8% and 0.2% of the cases, respectively. Higher rates of spontaneous abortions were reported in women with continuous IFN use. A total of 162 women completed the questionnaire for 192 live births within the prospective study part. Mothers restarted IFN therapy or switched to another disease-modifying therapy postpartum in 51.0% and 14.1% of cases, respectively. 158/192 infants (82.3%) were breastfed [34/158 (21.5%)] during IFN therapy. Postpartum relapse activity was low (mothers of 87.3% of breastfed infants remained relapse-free during lactation). Conclusion: Overall, the prevalence of spontaneous abortions and congenital anomalies of females exposed to IFN exposure before or during pregnancy was within the range reported for the general population. Most mothers paused IFN during pregnancy and breastfeeding. Relapse activity during pregnancy and lactation was observed to be low. These real-world data from a PSP corroborate European and Scandinavian registry data. Trial registration: NCT04655222, EUPAS38347.

Impact of interferon beta exposure on birth outcome and child development - Results from the post-authorisation safety study PRIMA.

BACKGROUND: Interferon beta therapies are well-established disease-modifying treatments for patients with relapsing multiple sclerosis (MS). Based on clinical evidence from two large cohort studies, both, the EMA and FDA updated the labels of the interferon beta class in terms of pregnancy and breastfeeding in 2019 and 2020, respectively. To complement pregnancy label updates with patient-reported real-world data, this study examined German pregnancy and outcome reports including available data on child development from women with MS treated with peginterferon beta-1a or intramuscular (IM) interferon beta-1a. METHODS: The post-authorisation safety study PRIMA included adult women diagnosed with relapsing-remitting MS or clinically isolated syndrome, who were treated with peginterferon beta-1a or IM interferon beta-1a before or during pregnancy and registered in the marketing authorisation holder's MS Service center patient support program. In the prospective part of the study, conducted from April to October 2021, data on developmental milestones of the newborns were collected via telephone interview from mothers reporting live births. RESULTS: In total, 426 women were enrolled, reporting 542 pregnancies that resulted in 466 live births. A total of 162 women completed the questionnaire for 192 live births (53.1% male). Newborns had Apgar scores indicative of healthy infants. Weight, length and head circumference at birth and physical growth curves up to 48 months lay within the expected range of the German general population. Most newborn screenings and examinations during check-ups were inconspicuous over the study period of 48 months. Out of 158 breastfed infants, 112 (70.9%) were breastfed exclusively until month 5. CONCLUSION: Study results confirmed former reports indicating that exposure to interferon beta therapies during pregnancy or lactation had no adverse effects on intrauterine growth and child development over the study period, which covered the first 4 years of life. These real-world data obtained within the scope of a patient support program for peginterferon beta-1a or IM interferon beta-1a corroborate German and Scandinavian registry data and support the label update of all interferon beta therapies. REGISTRATION: NCT04655222, EUPAS38347.

Fatigue, depression, and product tolerability during long-term treatment with intravenous immunoglobulin (Gamunex® 10%) in patients with chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIMS: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patient's ability to walk and perform activities of daily living independently. Furthermore, patients often report fatigue and depression which can affect their quality of life. These symptoms were assessed in CIDP patients receiving long-term intravenous immunoglobulin (IVIG) treatment. METHODS: GAMEDIS was a multi-center, prospective, non-interventional study in adult CIDP patients treated with IVIG (10%) and followed for two years. Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, Hughes Disability Scale (HDS), Fatigue Severity Scale (FSS), Beck Depression Inventory II (BDI), Short Form-36 health survey (SF-36) and Work Productivity and Activity Impairment Score Attributable to General Health (WPAI-GH) were assessed at baseline and quarterly. Dosing and treatment intervals, changes in outcome parameters, and adverse events (AEs) were analyzed. RESULTS: 148 evaluable patients were followed for a mean of 83.3 weeks. The mean maintenance IVIG dose was 0.9 g/kg/cycle (mean cycle interval 38 days). Disability and fatigue remained stable throughout the study. Mean INCAT score: 2.4 ± 1.8 at baseline and 2.5 ± 1.9 at study end. HDS: 74.3% healthy/minor symptoms at baseline and 71.6% at study end. Mean FSS: 4.2 ± 1.6 at baseline and 4.1 ± 1.7 at study end. All patients reported minimal/no depression at baseline and throughout. SF-36 and WPAI-GH scores remained stable. Fifteen patients (9.5%) experienced potentially treatment-related AEs. There were no AEs in 99.3% of infusions. DISCUSSION: Long-term treatment of CIDP patients with IVIG 10% in real-world conditions maintained clinical stability on fatigue and depression over 96 weeks. This treatment was well-tolerated and safe.

Disease-modifying therapies for relapsing/active secondary progressive multiple sclerosis - a review of population-specific evidence from randomized clinical trials.

Although the understanding of secondary progressive multiple sclerosis (SPMS) is evolving, early detection of relapse-independent progression remains difficult. This is further complicated by superimposed relapses and compensatory mechanisms that allow for silent progression. The term relapsing multiple sclerosis (RMS) subsumes relapsing-remitting multiple sclerosis (RRMS) and SPMS with relapses. The latter is termed 'active' SPMS, for which disease-modifying therapies (DMTs) approved for either RMS or active SPMS can be used. However, the level of evidence supporting efficacy and safety in SPMS differs between drugs approved for RMS and SPMS. Our review aims to identify current evidence from published clinical trials and European public assessment reports from the marketing authorization procedure on the efficacy, especially on progression, of DMTs approved for RMS and SPMS. To identify relevant evidence, a literature search has been conducted and European public assessment reports of DMTs approved for RMS have been screened for unpublished data specific to SPMS. Only two clinical trials demonstrated a significant reduction in disability progression in SPMS study populations: the EXPAND study for siponimod, which included a typical SPMS population, and the European study for interferon (IFN)-beta 1b s.c., which included patients with very early and active SPMS. Both DMTs also achieved significant reductions in relapse rates. Ocrelizumab, cladribine, ofatumumab, and ponesimod are all approved for RMS - ocrelizumab, ofatumumab, and ponesimod based on an RMS study, cladribine based on an RRMS study. Data on efficacy in SPMS are only available from post hoc analyses of very small subgroups, representing only up to 15% of the total study population. For these DMTs, approval for RMS, including active SPMS, was mainly based on the assumption that the reduction in relapse rate observed in patients with RRMS can also be applied to SPMS. Based on that, the potential of these drugs to reduce relapse-independent progression remains unclear.

[Public health situation of CIDP patients in nine German centers-neuritis network Germany]. / Versorgungssituation von CIDP-Patienten in neun deutschen Zentren des Neuritis Netzes.

BACKGROUND: Diagnosis and treatment of patients with immune-mediated neuropathies is challenging due to the heterogeneity of the diseases. OBJECTIVES: To assess similarities and differences in the current care of patients with immune-mediated polyneuropathies in specialized centers in Germany within the German neuritis network "Neuritis Netz". MATERIAL AND METHODS: We conducted a cross-sectional survey of nine neurological departments in Germany that specialize in the care of patients with immune-mediated neuropathies. We assessed the diagnosis, the approach to diagnostic work-up and follow-up, typical symptoms at manifestation and progression of the disease, and treatment data. RESULTS: This report includes data from 1529 patients per year treated for immune-mediated neuropathies, of whom 1320 suffered from chronic inflammatory demyelinating polyneuropathy (CIDP). Diagnostic work-up almost always included nerve conduction studies, electromyography, and lumbar puncture in accordance with current guidelines. The use of ultrasound, biopsy, and MRI varied. The most important clinical parameter for therapy monitoring in all centers was motor function in the clinical follow-up examinations. A wide range of different immunosuppressants was used for maintenance therapy in about 15% of patients. CONCLUSIONS: These data provide important epidemiological insights into the care of patients with immune-mediated neuropathies in Germany. The further development of specific recommendations for treatment and follow-up examinations is necessary to ensure a uniform standard of patient care. This effort is greatly facilitated by a structured collaboration between expert centers such as Neuritis Netz.

Calprotectin in Chronic Inflammatory Demyelinating Polyneuropathy and Variants-A Potential Novel Biomarker of Disease Activity.

Background: In chronic inflammatory demyelinating polyneuropathy (CIDP), there is an urgent need for biomarkers to monitor ongoing disease activity. Serum calprotectin (CLP) induces signaling pathways involved in inflammatory processes and has been shown to correlate with markers of disease activity in other autoimmune disorders. Thus, we wanted to study the potential value of CLP in comparison to serum neurofilament light chain (sNfl) to monitor disease activity. Materials and Methods: Sera from 63 typical and atypical CIDP and 6 MMN patients with varying degrees of disease activity were analyzed in comparison with 40 healthy controls (HC) in a cross-sectional design. Association of CLP and sNfl levels with socio-demographics, disease duration, CIDP disease activity scale (CDAS), and impairment status [medical research council-sum score (MRC-SS), the inflammatory neuropathy cause and treatment disability score (INCAT-DS), grip strength, and maximum walking distance], patient-reported outcome (PRO) parameters [SF-36 questionnaire, Beck's depression index (BDI), and fatigue severity scale (FSS)], as well as treatment regime were investigated using uni- and multivariate analysis. Results: CLP and sNfl levels were significantly higher in all CIDP patients compared to HC (p = 0.0009). Multivariate analysis adjusted for age and gender revealed that CLP acts as an independent predictor for CIDP and MMN. CLP was significantly associated with active disease course according to CDAS and correlated with MRC-SS, whereas sNfl correlated with parameters of disease impairment. There was no correlation with PRO, except for sNfl and the mental health composite score. Subgroup analysis revealed no differences between typical CIDP and atypical variants. Conclusions: CLP was elevated in CIDP and variants and was associated with active disease course, whereas sNfl shows further potential as biomarker of axonal degeneration. Thus, CLP might be a suitable additive biomarker for measurement of ongoing inflammation, which is greatly needed to guide better patient care in CIDP.

Quantitative grip force assessment of muscular weakness in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: In patients suffering from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) disease severity is assessed by Medical Research Counsil (MRC) Scale or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. However, none of these methods is appropriate to objectively assess muscle weakness or to detect very small subclinical changes. More objective and quantitative measures are needed in order to evaluate treatment efficiency or to detect subclinical affection of upper limps for early diagnosis. The goal of our study was to objectively quantify muscular weakness in CIDP patients with the non-invasive Quantitative Motor (Q-Motor) test of Grip Force Assessment (QGFA) as well as the Involuntary Movement Assessment (QIMA) and to search for differences between typical and atypical CIDP variants. In addition, we hypothesized that Q-Motor findings correlate with disease severity scales such as MRC or INCAT score. METHODS: In this cross-sectional exploratory proof-of-concept study subjects with confirmed diagnosis of typical or atypical CIDP were examined and compared to healthy controls (HC). For Q-Motor tests all subjects had to lift a device (250 g and 500 g) equipped with an electromagnetic sensor that measured grip force (GF) and three-dimensional changes in position and orientation. The measures "grip force variability" (GFV), "position index" (PI) and "orientation index" (OI) were provided to assess involuntary movements due to muscular weakness. RESULTS: 33 patients with CIDP and 28 HC were included. All measures were significantly elevated in CIDP patients for both devices in the right and left hand compared to healthy controls. Subgroup analysis revealed no differences between typical and atypical CIDP variants. INCAT score only weakly correlated with OI and PI. However, there was a stronger correlation between MRC and QIMA parameters in both hands. CONCLUSION: Q-Motor assessments were capable to objectively assess muscular weakness in CIDP. In particular, QIMA measures detected subclinical generalized muscle weakness even in patients with milder disability. Sensitivity and rater-independence of Q-Motor assessments support a further exploration of QIMA measures as potential endpoints for future clinical trials in CIDP.

Neurofascin and Compact Myelin Antigen-Specific T Cell Response Pattern in Chronic Inflammatory Demyelinating Polyneuropathy Subtypes.

OBJECTIVE: The objective of this study is to investigate whether chronic inflammatory demyelinating polyneuropathy (CIDP) and its subtypes differ in their type 1 T-helper (TH1) cell response against nodal/paranodal neurofascin (NF186, NF155) as well as myelin protein zero (P0 180-199) and myelin basic protein (MBP 82-100). METHODS: Interferon-gamma (IFN-γ) enzyme-linked immunospot assay was used to detect antigen-specific T cell responses in 48 patients suffering typical CIDP (n = 18), distal acquired demyelinating polyneuropathy (n = 8), multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM; n = 9), and sensory CIDP (n = 13) compared to other non-immune polyneuropathy (ON; n = 19) and healthy controls (n = 9). RESULTS: Compared to controls, MADSAM and sensory CIDP patients showed broadest IFN-γ T cell responses to all four antigens. Positive IFN-γ responses against two or more antigens were highly predictive for CIDP (positive predictive value = 0.95) and were found in 77% of CIDP patients. Patients with limited antigen-specific response were females, more severely affected with neuropathic pain and proximal paresis. The area under the receiver operating characteristics curve (AUC) of NF186 in MADSAM was 0.94 [95% confidential interval (CI) 0.82-1.00] compared to ON. For sensory CIDP, AUC of P0 180-199 was 0.94 (95% CI 0.86-1.00) and for MBP 82-100 0.95 (95% CI 0.88-1.00) compared to ON. CONCLUSION: Cell-mediated immune responses to (para)nodal and myelin-derived antigens are common in CIDP. TH1 response against NF186 may be used as a biomarker for MADSAM and TH1 responses against P0 180-199 and MBP 82-100 as biomarkers for sensory CIDP. Larger multicenter studies study are warranted in order to establish these immunological markers as a diagnostic tools.

Analysis of anti-ganglioside antibodies by a line immunoassay in patients with chronic-inflammatory demyelinating polyneuropathies (CIDP).

BACKGROUND: Unlike for acute immune-mediated neuropathies (IN), anti-ganglioside autoantibody (aGAAb) testing has been recommended for only a minority of chronic IN yet. Thus, we used a multiplex semi-quantitative line immunoassay (LIA) to search for aGAAb in chronic-inflammatory demyelinating polyneuropathy (CIDP) and its clinical variants. METHODS: Anti-GAAb to 11 gangliosides and sulfatide (SF) were investigated by LIA in 61 patients with IN (27 typical CIDP, 12 distal-acquired demyelinating polyneuropathy, 6 multifocal-acquired demyelinating sensory/motor polyneuropathy, 10 sensory CIDP, 1 focal CIDP and 5 multifocal-motoric neuropathy), 40 with other neuromuscular disorders (OND) (15 non-immune polyneuropathies, 25 myasthenia gravis), 29 with multiple sclerosis (MS) and 54 healthy controls (HC). RESULTS: In contrast to IgG, positive anti-GAAB IgM against at least one ganglioside/SF was found in 17/61 (27.9%) IN compared to 2/40 (5%) in OND, 2/29 MS (6.9%) and 4/54 (7.4%) in HC (p=0.001). There was a statistically higher prevalence of anti-sulfatide (aSF) IgM in IN compared to OND (p=0.008). Further, aGM1 IgM was more prevalent in IN compared to OND and HC (p=0.009) as well as GD1b in IN compared to HC (p<0.04). The prevalence of aGM1 IgM in CIDP was lower compared to in multifocal motor neuropathy (MMN) (12% vs. 60%, p=0.027). Patients showing aSF, aGM1 and aGM2 IgM were younger compared to aGAAb negatives (p<0.05). Patients with aSF IgM positivity presented more frequently typical CIDP and MMN phenotypes (p<0.05, respectively). CONCLUSIONS: The aGAAb LIA revealed an elevated frequency of at least one aGAAb IgM in CIDP/MMN patients. Anti-SF, aGM1 and aGM2 IgM were associated with younger age and anti-SF with IN phenotypes.

A prospective study comparing tryptophan immunoadsorption with therapeutic plasma exchange for the treatment of chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare paralyzing inflammatory neuropathy with probably autoimmune origin. While plasma exchange (PE) constitutes a first-line treatment option for CIDP, there is only little known about the efficacy and safety of immunoadsorption (IA), a more selective apheresis procedure with assumed better tolerability. METHODS: In this prospective-randomized pilot trial, patients were randomly assigned to receive 6 sessions of PE (n = 10) or IA (n = 10) treating equal plasma volumes. To evaluate efficacy, we calculated the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score and the Medical Research Council (MRC) sum score at baseline (V1), after completion of 6 sessions (V2) as well as 4 weeks after completion (V3) in 9 patients per group (1 patient in each group did not complete follow-up). We additionally assessed safety and tolerability of treatments by monitoring adverse event and blood parameters. RESULTS: With IA, 6 out of 9 (66.7%) patients improved clinically, whereas with PE, 4 out of 9 (44.4%) patients improved, most of them immediately with completion of the apheresis treatment series. There was one adverse event (AE) out of 52 treatment sessions for the 9 patients in the IA group. In the PE group of 9 patients, there was 1 AE out of 51 sessions and a trend of greater fibrinogen reduction. No severe AE occurred in either group. CONCLUSION: The results of this pilot study suggest that IA is at least equally effective and safe compared to PE in CIDP patients.

Neurofascin (NF)155- and NF186-Specific T Cell Response in a Patient Developing a Central Pontocerebellar Demyelination after 10 Years of CIDP.

BACKGROUND: Information and pathobiological understanding about central demyelinating manifestation in patients, who primarily suffer from chronic inflammatory demyelinating polyneuropathy (CIDP), are scarce. METHODS: IFN-γ-response as well as antibodies against the (para)nodal antigens neurofascin (NF)155 and NF 186 had been tested by Elispot assay and ELISA before clinical manifestation and at follow-up. CASE DESCRIPTION AND RESULTS: The patient described here developed a subacute brainstem syndrome more than 10 years after diagnosis of CIDP under low-dose maintenance treatment of intravenous immunoglobulins (IVIG). MRI revealed enhancing right-sided pontocerebellar lesion. CSF examination showed mild pleocytosis and elevated protein, and negative oligoclonal bands. Further diagnostics exclude differential diagnoses such as tuberculoma, sarcoidosis, or metastasis. Specific IFN-γ response against NF155 and NF186 as measured by Elispot assay was elevated before clinical manifestation. NF155 and NF186 antibodies were negative. Escalation of IVIG treatment at 2 g/kg BW followed by 1.4 g/kg BW led to clinical remission albeit to a new asymptomatic central lesion. Follow-up NF155 and NF186-Elispot turned negative. CONCLUSION: The case reported here with a delayed central manifestation after an initially typical CIDP and NF155 and NF186 T cell responses does not resemble described cases of combined central and peripheral demyelination but may reflect a novel subtype within the great clinical heterogeneity of CIDP.

Stroke induces specific alteration of T memory compartment controlling auto-reactive CNS antigen-specific T cell responses.

Whether and when auto-reactivity after stroke occurs is still a matter of debate. By using overlapping 15mer peptide pools consisting of myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) we show increased frequencies of immunodominant MOG- and MBP T cell responses in acute ischemic stroke which were associated with reduced frequencies of naïve T cells as well as CD8+ TEMRA cells. Auto-reactive CNS antigen-specific T cells responses as well as alterations of T cell subpopulations normalized in long-term follow up after stroke. Our findings suggest that stroke-induced immunodepression might function as an adaptive mechanism in order to inhibit harmful and long-lasting CNS antigen-specific immune responses.

Blocking stroke-induced immunodeficiency increases CNS antigen-specific autoreactivity but does not worsen functional outcome after experimental stroke.

Stroke-induced immunodepression (SIDS) is an essential cause of poststroke infections. Pharmacological inhibition of SIDS appears promising in preventing life-threatening infections in stroke patients. However, SIDS might represent an adaptive mechanism preventing autoreactive immune responses after stroke. To address this, we used myelin oligodendrocyte glycoprotein (MOG) T-cell receptor transgenic (2D2) mice where >80% of peripheral CD4(+) T cells express a functional receptor for MOG. We investigated in a murine model of middle cerebral artery occlusion the effect of blocking SIDS by inhibiting body's main stress axes, the sympathetic nervous system (SNS) with propranolol and the hypothalamic-pituitary-adrenal axis (HPA) with mifepristone. Blockade of both stress axes robustly reduced infarct volumes, decreased infection rate, and increased long-term survival of 2D2 and C57BL/6J wild-type mice. Despite these protective effects, blockade of SIDS increased CNS antigen-specific Type1 T helper cell (Th1) responses in the brains of 2D2 mice 14 d after middle cerebral artery occlusion. One month after experimental stroke, 2D2 mice developed signs of polyradiculitis, which were diminished by SIDS blockade. Adoptive transfer of CD4(+) T cells, isolated from 2D2 mice, into lymphocyte-deficient Rag-1KO mice did not reveal differences between SIDS blockade and vehicle treatment in functional long-term outcome after stroke. In conclusion, inhibiting SIDS by pharmacological blockade of body's stress axes increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen functional long-term outcome after experimental stroke, even in a mouse model where CNS antigen-specific autoreactive T-cell responses are boosted.

Circulating lymphocyte and T memory subsets in glucocorticosteroid versus IVIG treated patients with CIDP.

The present study compared lymphocyte and T memory subsets in currently untreated patients with chronic inflammatory demyelinating polyneuropathy (CIDP) to glucocorticosteroid (GS) and intravenous immunoglobulin (IVIG) treated patients. Peripheral blood from 48 CIDP patients (21 untreated who were either treatment naïve or without treatment during the last 3 months, 17 IVIG and 10 GS treatment) and from 12 age-matched controls was evaluated using flow cytometric analysis. Our data demonstrate that long-term GS treatment is associated with reduced frequencies of total CD4+ T cells, CD4+ memory subsets and NK cells while long-term IVIG treatment is associated with alterations of the CD8+ memory compartment. Reduction of CD4+ naïve T cell counts may explain the observation that GS treatment induces prolonged clinical remission compared to IVIG treatment.

Impact of myasthenia gravis on family planning: How do women with myasthenia gravis decide and why?

INTRODUCTION: We analyzed the impact of myasthenia gravis (MG) on decision-making in family planning by women with the disease. METHODS: In a cross-sectional, anonymous survey, a standardized questionnaire was sent or handed out to 1,637 women with MG. RESULTS: In total, 801 questionnaires were eligible for analysis. Over fifty percent of the patients had abstained from having children due to MG. The concern mentioned most often was the possible influence of MG medication on the unborn child (87.1%). Spouses/partners (91.8%) and MG treating physicians (82.9%) were the most important persons involved in the decision-making process. Higher age and personal experience of intensive-care treatment for MG were independently associated with the decision to abstain from having children. Lower level of knowledge was independently associated with the probability of discouraging other MG patients from having children. CONCLUSIONS: Women with MG need specific guidance about family planning issues, which may lead to lower rates of voluntary childlessness. On the basis of our data, more specific hypotheses can be generated that require prospective investigation.

Effective treatment with intravenous immunoglobulins reduces autoreactive T-cell response in patients with CIDP.

OBJECTIVE: To investigate changes in autoreactive T-cell responses against PMP-22 and P2 antigen as well as a T-cell memory repertoire in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) induced by repeated intravenous immunoglobulin (IVIg) treatment. METHODS: In an observational trial, we prepared cryopreserved human peripheral blood monocytes from blood from 34 patients with CIDP (18 treatment naïve and 16 maintenance IVIg treatment) and from 14 healthy controls (non-immune neuropathy and healthy control). Treatment response was defined by clinical evaluation. The autoantigen-specific T-cell response was analysed by enzyme linked immunosorbent spot (ELISPOT) assay before IVIg start (baseline) and at follow-up. The T-cell memory subsets were analysed by using flow cytometric analysis. RESULTS: Myelin-derived P2-specific and PMP-22-specific IFN-γ producers were increased in IVIg responders compared with non-responders before treatment, which decreased by repeated IVIg infusion cycles. Treatment responders but not non-responders showed higher frequencies of CD4 T effector memory (TEM) and T central memory frequencies at baseline compared with maintenance IVIg treatment patients and controls. In addition, IVIg treatment was associated with a significant reduction in CD8 TEM at follow-up. CONCLUSIONS: Our data demonstrate that immunomodulatory treatment with IVIgs on a long-term basis reduces the autoreactive T-cell response against PMP-22 and P2-antigens, which may be influenced by the altered maintenance of CD8 and CD4 effector/memory T-cell subsets towards a more anti-inflammatory immune status. Elevated PMP-22 and P2-specific T-cell responses may serve as predictors for treatment responsiveness to IVIgs warranting validation in larger studies.

A circle-monitor for computerised assessment of visual neglect in peripersonal space.

UNLABELLED: Current assessment of visual neglect involves paper-and-pencil tests or computer-based tasks. Both have been criticised because of their lack of ecological validity as target stimuli can only be presented in a restricted visual range. This study examined the user-friendliness and diagnostic strength of a new "Circle-Monitor" (CM), which enlarges the range of the peripersonal space, in comparison to a standard paper-and-pencil test (Neglect-Test, NET). METHODS: Ten stroke patients with neglect and ten age-matched healthy controls were examined by the NET and the CM test comprising of four subtests (Star Cancellation, Line Bisection, Dice Task, and Puzzle Test). RESULTS: The acceptance of the CM in elderly controls and neglect patients was high. Participants rated the examination by CM as clear, safe and more enjoyable than NET. Healthy controls performed at ceiling on all subtests, without any systematic differences between the visual fields. Both NET and CM revealed significant differences between controls and patients in Line Bisection, Star Cancellation and visuo-constructive tasks (NET: Figure Copying, CM: Puzzle Test). Discriminant analyses revealed cross-validated assignment of patients and controls to groups was more precise when based on the CM (hit rate 90%) as compared to the NET (hit rate 70%). CONCLUSION: The CM proved to be a sensitive novel tool to diagnose visual neglect symptoms quickly and accurately with superior diagnostic validity compared to a standard neglect test while being well accepted by patients. Due to its upgradable functions the system may also be a valuable tool not only to test for non-visual neglect symptoms, but also to provide treatment and assess its outcome.

Regulatory T cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO.

Local and peripheral immune responses are activated after ischemic stroke. In our present study, we investigated the temporal distribution, location, induction, and function of regulatory T cells (Tregs) and the possible involvement of microglia, macrophages, and dendritic cells after middle cerebral artery occlusion (MCAO). C57BL/6J and Foxp3(EGFP) transgenic mice were subjected to 30 minutes MCAO. On days 7, 14, and 30 after MCAO, Tregs and antigen presenting cells were analyzed using fluorescence activated cell sorting multicolor staining and immunohistochemistry. A strong accumulation of Tregs was observed on days 14 and 30 in the ischemic hemisphere accompanied by the elevated presence and activation of microglia. Dendritic cells and macrophages were found on each analyzed day. About 60% of Foxp3(+) Tregs in ischemic hemispheres were positive for the proliferation marker Ki-67 on days 7 and 14 after MCAO. The transfer of naive CD4(+) cells depleted of Foxp3(+) Tregs into RAG1(-/-) mice 1 day before MCAO did not lead to a de novo generation of Tregs 14 days after surgery. After depletion of CD25(+) Tregs, no changes regarding neurologic outcome were detected. The sustained presence of Tregs in the brain after MCAO indicates a long-lasting immunological alteration and involvement of brain cells in immunoregulatory mechanisms.

STRoke Adverse outcome is associated WIth NoSocomial Infections (STRAWINSKI): procalcitonin ultrasensitive-guided antibacterial therapy in severe ischaemic stroke patients - rationale and protocol for a randomized controlled trial.

RATIONALE: Stroke-associated pneumonia is one of the most common causes of poor outcome in stroke patients. Clinical signs and laboratory parameters of stroke-associated infections are often inconclusive. Biomarkers may help to identify stroke patients at high risk for pneumonia and to guide physicians in an early antibiotic treatment, thereby improving stroke outcome. AIM: The aim of the present study is to investigate whether procalcitonin ultrasensitive-guided antibiotic treatment improves functional outcome after severe ischaemic stroke by early treatment of pneumonia. DESIGN: STRAWINSKI is an investigator-initiated, multicentre, randomized, controlled trial with blinded assessment of outcome comparing procalcitonin ultrasensitive-guided antibiotic treatment with standard care. STUDY: 200 patients with ischaemic stroke in the middle cerebral artery territory and a score >9 on the National Institutes of Health Stroke Scale will be included and randomly assigned to two groups. One group will receive procalcitonin-based antibiotic therapy guidance; the other group will receive standard stroke unit care. OUTCOMES: The primary endpoint is functional outcome at day 90 after stroke on the modified Rankin Scale, dichotomized as favourable (0-4) or unfavourable outcome (5-6). Secondary endpoints are time to first event of death, rehospitalization, or recurrent stroke; death rate, infection rate, and days with fever up to day 7; length of hospital stay and hospital discharge disposition; shift analysis of the modified Rankin Scale; Barthel Index and days alive and out of hospital at day 90; use of antibiotics until day 90; and modified Rankin Scale, Barthel Index, and infarct volume at day 180.