Characteristic retinal atrophy pattern allows differentiation between pediatric MOGAD and MS after a single optic neuritis episode.

BACKGROUND: Optic neuritis (ON) is the most prevalent manifestation of pediatric multiple sclerosis (MSped) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGADped) in children > 6 years. In this study, we investigated retinal atrophy patterns and diagnostic accuracy of optical coherence tomography (OCT) in differentiating between both diseases after the first ON episode. METHODS: Patients were retrospectively identified in eight tertial referral centers. OCT, VEP and high/low-contrast visual acuity (HCVA/LCVA) have been investigated > 6 months after the first ON. Prevalence of pathological OCT findings was identified based on data of 144 age-matched healthy controls. RESULTS: Thirteen MOGADped (10.7 ± 4.2 years, F:M 8:5, 21 ON eyes) and 21 MSped (14.3 ± 2.4 years, F:M 19:2, 24 ON eyes) patients were recruited. We observed a significantly more profound atrophy of both peripapillary and macular retinal nerve fiber layer in MOGADped compared to MSped (pRNFL global: 68.2 ± 16.9 vs. 89.4 ± 12.3 µm, p < 0.001; mRNFL: 0.12 ± 0.01 vs. 0.14 ± 0.01 mm3, p < 0.001). Neither other macular layers nor P100 latency differed. MOGADped developed global atrophy affecting all peripapillary segments, while MSped displayed predominantly temporal thinning. Nasal pRNFL allowed differentiation between both diseases with the highest diagnostic accuracy (AUC = 0.902, cutoff < 62.5 µm, 90.5% sensitivity and 70.8% specificity for MOGADped). OCT was also substantially more sensitive compared to VEP in identification of ON eyes in MOGAD (pathological findings in 90% vs. 14%, p = 0.016). CONCLUSION: First MOGAD-ON results in a more severe global peripapillary atrophy compared to predominantly temporal thinning in MS-ON. Nasal pRNFL allows differentiation between both diseases with the highest accuracy, supporting the additional diagnostic value of OCT in children with ON.

[Neuromyelitis optica spectrum disorder and pregnancy]. / Neuromyelitis-optica-Spektrum-Erkrankung und Schwangerschaft.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory diseases of the central nervous system that mainly affect women. In some of these patients NMOSD occurs during fertile age. For this reason, treating physicians may be confronted with questions concerning family planning, pregnancy and birth. OBJECTIVE: This study provides an overview on the influence of NMOSD on fertility, pregnancy complications and pregnancy outcome. The effect of pregnancy on NMOSD course and therapy options during pregnancy are discussed. MATERIAL AND METHODS: A search of the current literature was carried out using the PubMed database. RESULTS AND CONCLUSION: Animal studies have shown lower fertility rates in NMOSD; however, studies investigating fertility in NMOSD patients are lacking. Pregnancy in NMOSD patients are associated with an increase in postpartum disease activity and a higher grade of disability after pregnancy. Some studies showed higher risks of pregnancy complications e. g. spontaneous abortions and preeclampsia. With a few limitations, acute relapses during pregnancy can be treated with methylprednisolone and/or plasma exchange/immunoadsorption. Stopping or continuing immunosuppressive therapy with azathioprine or rituximab during pregnancy should be critically weighed considering previous and current disease activity. Therefore, a joint supervision by a specialized center is recommended, particularly in specific situations such as pregnancy.

[Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action]. / Monitoring von Blutparametern unter verlaufsmodifizierender MS-Therapie : Substanzspezifische Relevanz und aktuelle Handlungsempfehlungen.

With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.

Moxifloxacin is not anti-inflammatory in experimental pneumococcal pneumonia.

OBJECTIVES: Anti-inflammatory functions of antibiotics may counteract deleterious hyperinflammation in pneumonia. Moxifloxacin reportedly exhibits immunomodulatory properties, but experimental evidence in pneumonia is lacking. Therefore, we investigated moxifloxacin in comparison with ampicillin regarding pneumonia-associated pulmonary and systemic inflammation and lung injury. METHODS: Ex vivo infected human lung tissue and mice with pneumococcal pneumonia were examined regarding local inflammatory response and bacterial growth. In vivo, clinical course of the disease, leucocyte dynamics, pulmonary vascular permeability, lung pathology and systemic inflammation were investigated. In addition, transcellular electrical resistance of thrombin-stimulated endothelial cell monolayers was quantified. RESULTS: Moxifloxacin reduced cytokine production in TNF-α-stimulated, but not in pneumococci-infected, human lung tissue. In vivo, moxifloxacin treatment resulted in reduced bacterial load as compared with ampicillin, whereas inflammatory parameters and lung pathology were not different. Moxifloxacin-treated mice developed less pulmonary vascular permeability during pneumonia, but neither combination therapy with moxifloxacin and ampicillin in vivo nor examination of endothelial monolayer integrity in vitro supported direct barrier-stabilizing effects of moxifloxacin. CONCLUSIONS: The current experimental data do not support the hypothesis that moxifloxacin exhibits potent anti-inflammatory properties in pneumococcal pneumonia.

Neuromyelitis optica and pregnancy during therapeutic B cell depletion: infant exposure to anti-AQP4 antibody and prevention of rebound relapses with low-dose rituximab postpartum.

Neuromyelitis optica (NMO) predominantly affects women, some in childbearing age, and requires early therapeutic intervention to prevent disabling relapses. We report an anti-AQP4 antibody-seropositive patient who became pregnant seven months after low-dose (100 mg) rituximab application. Pregnancy showed no complications, and low-dose rituximab restarted two days after delivery resulted in neurological stability for 24 months. Remarkably, her otherwise healthy newborn presented with anti-AQP4 antibody and reduced B lymphocyte counts in umbilical cord blood, which normalized three months later. Confirming and extending previous reports, our case suggests that low-dose rituximab might be compatible with pregnancy and prevent rebound NMO disease activity postpartum.

Natalizumab treatment during pregnancy - effects on the neonatal immune system.

BACKGROUND: Pregnancies in women with severe relapsing-remitting multiple sclerosis treated with natalizumab constitute a major challenge, because withdrawal of the drug may cause relapses but continuation might have unknown effects on the infantile immune system. AIMS OF THE STUDY: To identify the impact of maternal natalizumab treatment during pregnancy on basic immune functions of the newborn. METHODS: Basic immunological testing and assessment of the chemotaxis rate of freshly isolated T lymphocytes in the presence and absence of CXCL12 was performed in two neonates, whose mothers were treated with natalizumab until the 34th week of pregnancy (pw). RESULTS: Both children had an uneventful birth. However, a reduction in the CXCL12-induced T-cell chemotaxis was found in both children. In contrast, the chemotaxis rate of unstimulated T lymphocytes was not altered. The distribution of the lymphocyte subpopulations was investigated only in case 1 and was normal. CONCLUSIONS: Here, we present to our knowledge the first assessment of T lymphocytes chemotaxis rate in two natalizumab-exposed newborns. A significant reduction in the CXCL12-induced chemotaxis rate of T lymphocytes has been observed and may compromise host defence function in early life. More clinical and immunological data on natalizumab-exposed neonates are warranted.

Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort.

OBJECTIVE: To investigate the rate of seropositivity of anti-JC virus (JCV) antibodies in a German multiple sclerosis (MS) cohort treated with natalizumab in the postmarketing setting and to assess anti-JCV serostatus in samples obtained before diagnosis of progressive multifocal leukoencephalopathy (PML). METHODS: This was a blinded, retrospective cross-sectional and longitudinal analysis for anti-JCV antibodies using a confirmatory 2-step ELISA on 2,782 blood samples obtained from 2,253 patients nationwide for routine testing for anti-natalizumab antibodies during open-label treatment between 2007 and 2010. RESULTS: Of the natalizumab-treated patients with MS, 58.8% tested positive for anti-JCV antibodies. The rate of seropositivity was higher in males and increased with age, with a plateau between age intervals 20-29 and 30-39 years. In longitudinal analyses, 19 of 194 (9.8%) patients converted from anti-JCV antibody-negative to seropositive status over 7.7 months; 4.7% reverted from antibody-positive to seronegative status over 7.9 months. Antibody levels, especially in the latter group, were low, indicating fluctuations around the lower cut point of the assay. Neither anti-JCV serostatus nor antibody levels were associated with immunosuppressive pretreatment, duration of natalizumab treatment, or anti-natalizumab antibodies. All samples obtained from 10 patients who developed PML were seropositive (13 samples before PML diagnosis [2.0-37.6 months]; 2 samples at diagnosis). Antibody levels in these samples were higher than those in samples from seropositive patients who did not develop PML. CONCLUSIONS: These data argue for the potential clinical utility of JCV serology for PML risk stratification. However, further investigations of fluctuations in serostatus and of antibody levels for a more precise understanding of the predictive value are warranted.

Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis.

BACKGROUND: Natalizumab is neither licensed for the use in adolescents nor during pregnancy. There are no reports of accidental natalizumab exposure during pregnancy continued as long as to the third trimester of pregnancy. AIMS: We report the outcome of pregnancy in a 17-year-old adolescent patient with multiple sclerosis (MS) treated with natalizumab from the age of 16, who was diagnosed to be pregnant in the 31st gestational week (gw) of pregnancy. To our knowledge, this report describes the first patient receiving natalizumab to the third trimester of pregnancy. CASE REPORT: Because of high relapse activity, natalizumab treatment was administered in an adolescent patient with MS. Pregnancy was diagnosed in the 31st gw after 17 natalizumab infusions, seven of them accidentally during pregnancy. RESULTS: Pre- and postnatal development of the child was normal. CONCLUSIONS: The case reported indicates that accidentally continued natalizumab treatment until few weeks before delivery may have no negative impact on the developing foetus.

The feasibility of a less invasive method to assess endometrial maturation--comparison of simultaneously obtained uterine secretion and tissue biopsy.

OBJECTIVE: To compare the assessment of endometrial maturation parameters in endometrial secretion samples obtained by a novel minimally invasive technique with those assessed in tissue biopsies. DESIGN: Prospective study. SETTING: University Hospital. POPULATION: Healthy female volunteers attending a gynaecological outpatient clinic. METHODS: Endometrial secretion fluid and tissue sampling 5 days after a spontaneous ovulation assessed with ultrasound. MAIN OUTCOME MEASURES: Progesterone (P) receptor, Ki-67 expression and the Noyes criteria were used to date endometrial biopsies. In the endometrial fluid samples, glycodelin A (GdA), leukaemia inhibitory factor (LIF) and P levels were analysed, and protein content and electrophoresis patterns were determined. RESULTS: All data were correlated to estradiol (E2) and P serum concentrations. The dating according to histology and immunohistochemical staining patterns correlated significantly with GdA levels (r=0.376, P=0.048) in endometrial fluid samples as well with serum levels of E2 (r=0.568, P=0.001) and P (r=0.408, P=0.023). No correlation was observed between tissue dating and LIF levels and protein content in endometrial fluid samples. CONCLUSIONS: The measurement of GdA in endometrial secretion samples may provide a less invasive method for assessing endometrial maturation in potential conception cycles without disrupting implantation.

Impact of ovarian stimulation on mid-luteal endometrial tissue and secretion markers of receptivity.

The objective of this study was to investigate the effect of ovarian stimulation for IVF on endometrial secretion and tissue markers of receptivity in the mid-luteal phase. In 10 oocyte donors, endometrial secretions and biopsies were sampled 5 days after spontaneous ovulation and oocyte retrieval in consecutive cycles. Four subjects received progesterone in the luteal phase of the stimulated cycles. Mid-luteal endometrial maturation in the stimulated cycle was compared with the spontaneous cycle, by histological dating, Ki-67, oestrogen receptor (ER) and progesterone receptor (PR) expression, secretion levels of leukaemia inhibitory factor (LIF), glycodelin A (GdA) and progesterone, and protein profile. No significant differences in histological markers, expression of Ki-67, PR, ER, secretion protein profiles or concentrations of LIF, GdA, or progesterone were observed when comparing natural with stimulated cycles. Progesterone supplementation of stimulated cycles was associated with significantly lower Ki-67 (P = 0.03) and ER (P = 0.04) expression compared with the non-supplemented stimulated cycle. In this pilot study, ovarian stimulation was not demonstrated to alter the studied markers of endometrial maturation in the mid-luteal phase.

[Open use of natalizumab. Neutralising antibodies and clinical data]. / Natalizumab im klinischen Alltag. Neutralisierende Antikörper und klinische Daten.

BACKGROUND: Since June 2006 natalizumab has been available for use as monotherapy in relapsing-remitting MS with high disease activity. The AFFIRM study showed the occurrence of persisting and neutralising antinatalizumab antibodies (nAb) in 6% of the patients. We present data revealing the number of nAb-positive patients assessed in our independent laboratory. Additionally we provide retrospective clinical data on the efficacy of natalizumab as escalating immunotherapy. PATIENTS AND METHODS: Blood samples of patients treated with natalizumab in Germany were tested for nAb using an enzyme-linked immunosorbent assay. If nAb were detectable at a single time point, the according patients were categorised as transiently positive. They were diagnosed as persistently positive if they had nAb at two or more time points which were at least 6 weeks apart. The treating neurologists sending the serum samples were asked to provide clinical data of their patients. RESULTS: Forty-seven of 593 samples (9.1%) were nAb-positive, 19 of them (3.7%) persistently positive and two (0.3%) transiently. Twenty-six patients (5%) were not retested for nAb, as we did not receive material for confirmatory analysis. Infusion-related adverse events were reported for 53 patients (10.3%). Averages of 2.6 relapses per year were reported previous to natalizumab therapy and 0.3 per year during natalizumab therapy. CONCLUSION: During natalizumab therapy, testing for nAb should be strongly considered for further therapy decisions and in cases of suspected allergic reaction. Basically the obtained data compare with those of the AFFIRM study. Natalizumab is applied as escalating therapy in MS according to the recommendations of the MSTKG, and it seems to match the expectations in open-label use.

Reproductive counselling, treatment and course of pregnancy in 73 German MS patients.

Multiple sclerosis (MS) often affects women during the reproductive years of their life. During this period, issues such as choice of immunomodulatory treatment, seeking advice from specialists, relapse-induced steroid application before, during or after pregnancy in combination with breastfeeding gain importance. The objective was to investigate these issues retrospectively using a questionnaire among 73 MS patients with a total of 88 pregnancies. Eighty per cent of the participants consulted their neurologists before and 60% during pregnancy. The annual relapse rate decreased during pregnancy and significantly increased during the first 3 months after delivery. Immunomodulatory treatment was stopped due to desired pregnancy for a mean of 4 years. Fourteen of the MS patients received intravenous immunoglobulin treatment post-natal. Ninety per cent of the study subjects started breastfeeding. However, nearly 30% ablactated, as they received steroids due to a relapse. Weight and height of the full-term children of singleton pregnancies from MS patients were significantly lower compared with the ones of age-matched healthy controls. Our results confirm the known reduced relapse rate during pregnancy, which is followed by an increased relapse rate after delivery. They shed light on the epidemiology of childbirth in patients with MS.

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm(R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Repeat intrathecal triamcinolone acetonide application is beneficial in progressive MS patients.

Available immunomodulatory and conventional steroid treatment regimens provide a limited symptomatic benefit for patients with progressive multiple sclerosis (MS). We performed an open trial on the short-term efficacy of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 27 progressive MS patients. Six TCA administrations, performed every third day, reduced the Expanded Disability Status Scale (EDSS) score [initial: 5.4+/-1.3, 3-7.5 (mean+/-SD, range); end: 4.9+/-1.1; 2.5-6.5; P<0.001] and significantly increased the walking distance and speed in particular after the fourth TCA injection. Concomitantly serially determined cerebrospinal fluid (CSF) markers of cell injury, neuron-specific enolase, total tau-protein, S-100, and beta-amyloid did not significantly change within the interval of TCA treatment. No serious side effects appeared. We conclude that repeat intrathecal injection of 40 mg TCA provides a substantial benefit in progressive MS patients with predominant spinal symptoms and does not alter CSF markers of neuronal cell injury.

Endometrial secretion aspiration prior to embryo transfer does not reduce implantation rates.

Analysis of protein patterns in endometrial secretion fluid may offer a relatively non-invasive means of assessing endometrial receptivity during fertility treatment cycles. In order to study the impact of the removal of endometrial secretions on embryo implantation, a prospective matched controlled study was performed. In 66 women undergoing IVF, endometrial fluid was obtained transcervically by aspiration just prior to embryo transfer (study group). Biochemical and ongoing pregnancy rates were compared with 66 control patients matched for stimulation treatment protocol, age, number of collected oocytes and number of high quality embryos. The protein content and uterine fluid protein profile in each sample was determined. Respective biochemical and ongoing pregnancy rates per embryo transfer were 36 and 33% in patients who underwent aspiration of endometrial secretion, compared with 33 and 30% respectively in matched control patients (P = 0.84 and P = 0.85). The protein content in endometrial fluid was sufficient for protein pattern analysis. Uterine fluid aspiration prior to IVF embryo transfer is a safe method for obtaining sufficient material for uterine secretion electrophoresis, thus allowing analysis of protein patterns serving as receptivity markers during treatment cycles. This technique may offer a novel tool for assessing endometrial receptivity during treatment cycles without affecting implantation rates.

Ovarian stimulation for IVF and endometrial receptivity--the missing link.

The contemporary approach to ovarian stimulation for IVF treatment results in supraphysiological concentrations of steroids during the follicular and luteal phases of the menstrual cycle. These sex steroids act directly and indirectly to mature the endometrium, influencing receptivity for implantation. Corpus luteum function is distinctly abnormal in IVF cycles, and therefore luteal support is widely used. Various reasons may underlie the defective luteal phase, including (i) ovarian hyperstimulation per se, (ii) gonadotrophin-releasing hormone (GnRH) analogue co-treatment and (iii) the use of human chorionic gonadotrophin (HCG) to induce final oocyte maturation. The recent introduction of GnRH antagonist co-treatment for the prevention of a premature LH rise during the late follicular phase allows for different approaches to ovarian stimulation for IVF. However, a recent meta-analysis showed that implantation rates may be compromised by using GnRH antagonists in currently employed regimens. The development of endometrium receptive to embryo implantation is a complex process and may be altered by inappropriate exposure to sex steroids in terms of timing, duration and magnitude. New approaches to the assessment of endometrial receptivity are now required. Novel approaches to ovarian stimulation aimed at adjusted GnRH antagonist regimens and achieving a more physiological luteal phase endocrinology are now appearing in the literature and may represent an important step in the improvement of the overall health economics of IVF.