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Introduction Cost of illness studies are essential to estimate societal costs of chronic inflammatory demyelinating polyneuropathy (CIDP) and identify cost-driving factors. Methods In total, 108 patients were recruited from 3 specialized neuroimmunological clinics. Costs were calculated for a 3-month period, including direct and indirect costs. The following outcomes were assessed: inflammatory neuropathy cause and treatment disability scale, Mini-Mental State Examination, Beck Depression Inventory, Charlson comorbidity index, EuroQol-5D, World Health Organization quality of life instrument, and socioeconomic status. Univariate and multivariate analyses were applied to identify cost-driving factors. Results Total quarterly costs were €11,333. Direct costs contributed to 83% of total costs (€9,423), whereas indirect costs accounted for 17% (€1,910) of total costs. The cost of intravenous immunoglobulin (IVIg) was the main determinant of total costs (67%). Reduced health-related quality of life and depressive symptoms were identified as independent predictors of higher total costs. Discussion CIDP is associated with high societal costs, mainly resulting from the cost of IVIg treatment. Muscle Nerve 58: 681-687, 2018.

Background It is a continuous matter of discussion whether immune activation by vaccination in general and Influenza vaccination in particular increases the risk for clinical deterioration of autoimmune diseases. This prospective study investigated the serological and clinical course of autoimmune Myasthenia gravis (MG) after a seasonal influenza vaccination. Methods This randomized, placebo-controlled, double-blind study enrolled MG patients with antibodies against acetylcholine-receptors (AChR-ab). They were allocated to receive seasonal influenza vaccine or placebo. The primary endpoint was the relative change of AChR-ab-titer over 12 weeks. A relative increase of 20% was set as non-inferiority margin. Secondary endpoints were clinical changes in the modified Quantitative Myasthenia Gravis Score (QMG), increase of anti-influenza-ELISA-antibodies, and changes of treatment. The study is registered with Clinicaltrialsregister.eu, EudraCT number 2006-004374-27. Findings 62 patients were included. Mean ± standard deviation (median) in the vaccine and placebo group were AChR-ab-titer changes of − 6.0% ± 23.3% (− 4.0%) and − 2.8% ± 22.0% (− 0.5%) and QMG score changes of − 0.08 ± 0.27 (0.17) and 0.11 ± 0.31 (0.00), respectively. The difference between groups (Hodges-Lehmann estimate with 95% CI) was - for the AChR-ab-titer change 4·0% [− 13.3%, 4.5%] (p = 0.28 for testing a difference, p, Highlights • The ProPATIent trial is the first RCT on seasonal influenza vaccination in Myasthenia gravis (MG). • Vaccination neither affects the titer of the acetylcholine receptor antibody, nor muscle strength of clinically stable MG patients. • Patients receiving standard immunosuppressive therapy can show a low vaccination response according to WHO recommendations. • In patients receiving standard immunosuppressive therapy a second dose of seasonal influenza vaccination should be considered. Evidence from randomized controlled trials about the safety of influenza vaccinations in patients with myasthenia gravis was non-existent before this study. 2 retrospective studies implied that vaccinations were safe without aggravation of clinical symptoms. With the evidence derived from the present randomized controlled trial, it can now be concluded that patients with myasthenia gravis do not experience a clinically relevant increase in AChR-antibody titers. Furthermore the slightly higher incidence of flu-like symptoms in the verum group does not change risk-benefit ratio in MG patients, Hence, the ProPATIent-trial provides class 1b evidence, that the risk-benefit ration of influenza vaccination in autoimmune MG is positive. Therefore vaccination should be recommended in this patient group. Since myasthenia gravis is an index disease for antibody-mediated autoimmunity, this finding can be postulated for other antibody-mediated autoimmune disorders. Presumably, the use of other attenuated vaccines may be similarly safe, but should be studied further. The finding of a reduced immune response, particularly in the subgroup of patients receiving immunosuppressive therapy indicates the need to investigate the effect of a second vaccine dose in these patients. The current study is the first randomized placebo-controlled trial to show that seasonal influenza vaccination of myasthenia gravis patients does not induce clinically relevant changes in the titer of antibodies against the acetylcholine receptor, independent of immunosuppressive treatment.

Introduction: In cases of exacerbation or crisis, myasthenia gravis (MG) patients can be treated with intravenous immunoglobulin (IVIg), plasmapheresis, or immunoadsorption. However, IVIg efficacy data in maintenance treatment are sparse. Methods: We prospectively observed 16 index patients with chronic and insufficiently controlled MG under standard immunosuppressant therapy and symptomatic treatment. The IVIg treatment response was measured using changes in quantitative myasthenia gravis (QMG) score and surrogates. Based on these results, a sample size calculation for a future randomized, controlled trial (RCT) was simulated. Results: There was an enduring decline in QMG score and other parameters of about 50% under IVIg maintenance treatment. RCT sample size calculation results in 73 or 33 patients per arm to detect at least a 20% vs. 30% clinical difference in QMG score. Conclusion: We recommend using the QMG score as a primary endpoint for an RCT of IVIg maintenance for chronic MG. Muscle Nerve 50: 999–1004, 2014

Stress constitutes a risk factor for diseases where the immune system plays a significant role. Stress is recognized as a possible trigger for flare ups during the course of multiple sclerosis (MS). The disclosure to the patient of the diagnosis of MS, the commencement of immunomodulatory therapy, and the unpredictability and vagaries of disease progression are all sources of stress. Biological stress systems such as the hypothalamic-pituitary-adrenal system and the sympathetic nervous system may influence the pathogenesis and the disease course of MS. The ability to cope with stress may also be impaired, mediated for example by cognitive deficits or loss of abilities and resources as disease progresses or by the high prevalence of concurrent mood disturbances such as depression and chronic fatigue. Psychiatric comorbidities of MS disease or therapy as well as impairments of coping strategies are underrecognized in clinical practice. Treatment plans for depression among MS patients, as the most common psychiatric comorbidity, should be individualized with integrated approaches. Antidepressants are effective for the treatment of depression in MS patients although further clinical research into the neurobiological and psychological bases of depressive disorders in MS patients is clearly needed. In therapy, coping strategies can be enhanced through multidisciplinary assessment of the various challenges and restrictions imposed by the disease and assisting and supporting the patient in addressing these. Exercise, as a form of positive stress (eustress), also has a role in therapy.

Background: The objective of this study was to address the differences in onset and disease progression between familial and sporadic multiple sclerosis (MS) and the association within sibling pairs. Methods: Ninety-eight siblings and their controls were included from a database of 763 sporadic MS-patients, randomly pair-matched for age, gender, clinical course, disease duration and treatment. Sixty-eight available siblings completed a prospective six-year follow-up. Outcome parameters included baseline Expanded Disability Status Scale (EDSS), age at onset, mono- or multifocal onset, disease progression and conversion to secondary progression of initially relapsing–remitting MS. For statistical analyses Wilcoxon’s signed-rank statistics for categorical differences, t-statistics for continuous variables, McNemar’s test for relative frequencies of categories, intra-class correlations for within sibling-pair associations, or Kaplan–Meier analysis for survival analyses were used; all two-sided at the 5% level. Results: Disease onset was slightly earlier (29.01 vs. 29.44 years, p = 0.0492) and multifocal onset significantly more often ( p = 0.0052) in familial than in sporadic MS. Notably, a substantial within sibling-pair correlation for disease progression (rho = 0.40; p = 0.0062) as well as a higher risk for siblings than for controls to convert into secondary progression (0.545 vs. 0.227; p = 0.018) could be observed. Conclusions: Familial MS differs from sporadic cases with respect to age at onset, multifocal involvement as first clinical event, and conversion into secondary progression. The progression rate of one out of two affected siblings may act as a predictor for the other sib.

Midregional Proenkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) are stable fragments of the precursor peptides for enkephalins and substance P, respectively. We measured MR-PENK A and NT-PTA concentrations by sensitive chemiluminescence immunoassays in cerebrospinal fluid (CSF) of 19 neurologically healthy controls (NHC), 28 patients with other neurologic disorders (OND), 70 patients with dementia disorders (38 Alzheimer's disease [AD], 8 dementia with Lewy bodies [DLB], 12 frontotemporal dementia [FTD], and 12 patients with vascular dementia [VD]), and 16 patients with acute neuroinflammation (AN). Median concentrations of NT-PTA were decreased in all patient groups compared to NHC showing significant differences between patients with NHC and AN (p0.001), OND and AN (p0.001), FTD and AN (p0.01) and pAD and AN (p0.05). Median MR-PENK A levels were lower in patients with OND, dementia disorders (including AD, FTD, DLB and VD) and AN compared to NHC subjects, although this differences did not reach statistical significance (p0.05). A maximum difference of both proneuropeptide fragments was found between NHC subjects and patients with AN, with a more than 2fold decrease in median NT-PTA and a 1.5fold decrease in median MR-PENK A levels. Concentrations of both proneuropeptide fragments were positively correlated in all patients (r=0.77, p0.001). Our results indicate alterations of the cerebral PENK A- and PTA-system in both, dementia and acute neuroinflammatory disorders. These neuropeptide systems seem to be highly correlated in healthy and pathological status.

The relationship between practised monitoring activities and performance, especially in mathematics was examined within three nested studies. The first study deals with problems of faulty term rewritings submitted to three groups of subjects—10th to 13th graders, differing in their mathematical performance—whose task was to find the mistakes. Moreover, a questionnaire on the practice and appreciation of monitoring activities was developed. The third study, first, repeats the first study with a similar population and secondly adds interviews with some of the subjects while solving additional items concerning faulty term rewritings. Studies 1 and 3 show similar success in finding mistakes and in the replies to the questionnaire within the various groups. Furthermore, the third study points up that the subject’s answers do neither predict the practised monitoring nor the success in the test. However, the success correlates significantly with the practised monitoring. For a deeper understanding concerning the role of metacognition in explaining performance, the second study examined two of the groups who had already been involved in the first study. These were assigned some problems of a matrices test as used in cognitive psychology. While trying to solve the problem, their eye movements were recorded by means of an eye-tracker. Afterwards they had to justify their solutions in an interview. The eye movements were analysed, the verbal comments classified. Again, the groups differ in their problem solving success, dependant on the quality of the monitoring practised. Altogether, the results of the three studies elucidate the importance of practised metacognitive monitoring activities not only for success in school algebra, but furthermore the ability and the willingness to do it is deeper anchored in a person than just a trained behaviour for school algebra.

Little is known about pathogenesis -- and especially about involvement of CD8(+) T-cells -- in late-onset myasthenia gravis (LOMG). Remarkably, outstanding CD8(+) TCRVbeta-subset expansions were found in 64% and 72% of recent onset LOMG or thymoma-associated MG (vs. 16% with early-onset MG (p

The inhibitory Fc-gamma receptor FcgammaRIIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and autoimmunity, and is required for the antiinflammatory activity of intravenous Ig (IVIG) in various murine disease models. However, the function of FcgammaRIIB and its regulation by IVIG in human autoimmune diseases are less well understood. Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common treatable acquired chronic polyneuropathy, and IVIG is widely used as a first-line initial and maintenance treatment. We found that untreated patients with CIDP, compared with demographically matched healthy controls, showed consistently lower FcgammaRIIB expression levels on naive B cells, and failed to up-regulate or to maintain up-regulation of FcgammaRIIB as B cells progressed from the naive to the memory compartment. Concomitantly, the rare -386C/-120A FcgammaRIIB promoter polymorphism resulting in reduced promoter activity previously associated with autoimmune phenotypes was overrepresented in CIDP. Also, FcgammaRIIB protein expression was up-regulated on monocytes and B cells after clinically effective IVIG therapy. Thus, our results suggest that the inhibitory FcgammaRIIB is impaired at a critical B cell differentiation checkpoint in CIDP, and that modulating FcgammaRIIB expression might be a promising approach to efficiently limit antibody-mediated immunopathology in CIDP.

Immunoreactive fibronectin (Fn) was quantified in paired cerebrospinal fluid (CSF) and serum samples from patients with bacterial meningitis (n = 46), tick-borne encephalitis (TBE) (n = 6), HIV infection (n = 6), Guillain-Barré syndrome (n = 5), carcinomatous meningitis (n = 11), multiple sclerosis (n = 15), disk disease (n = 11), and controls (n = 28). A highly significant elevation of CSF Fn was found in bacterial meningitis, TBE, and carcinomatous meningitis. There were no significant differences in serum Fn between any of the groups. An Fn index to estimate the rate of intrathecal Fn synthesis reached the highest value in bacterial meningitis. Our findings suggest that CSF Fn may be an indicator of adequate host reaction and tissue repair. For diagnostic purposes, the determination of CSF Fn probably does not add much to routine CSF laboratory tests.

Untersucht wird die Frage des Einflusses der Schulform als spezifischer Lernumgebung auf Ausmas und Struktur des Lernzuwachses im Fach Mathematik. Dazu werden die Daten der PISA-E-2000 Studie1 herangezogen. Es handelt sich um eine Querschnittstudie, d.h. der „Lernzuwachs” wird uber die Kompetenzunterschiede 15jahriger Schulerinnen und Schuler abgeschatzt, die unterschiedliche Schuljahrgange besuchen. Die Veranderung der Losungshaufigkeiten der PISA-E-2000 Mathematikitems fallt von Klassenstufe zu Klassenstufe fur Haupt-, Realschuler und Gymnasiasten unterschiedlich aus. Diese Zuwachse werden mit Anforderungsmerkmalen der Items in Beziehung gesetzt, die sich in Regressionsanalysen zur Vorhersagbarkeit der empirischen Schwierigkeit der PISA-Aufgaben als besonders aussagekraftig erwiesen haben.

In Darstellungen von Ergebnissen der PISA-Studie wird haufig beim Vergleich verschiedener Untersuchungsgruppen eine Beziehung zwischen Punktdifferenz und Schulzeit hergestellt, die dieser Punktdifferenz als Aquivalent entsprechen wurde. Diese Zuordnung mag als erhellende Metapher gemeint sein, die auf die Relevanz derartiger Differenzen aufmerksam machen mochte. In Analysen der Autoren des deutschen PISA-Konsortiums, wie auch in Stellungnahmen in Sekundarliteratur und Presse, scheint diese Ubertragung aber haufig wortlich gemeint bzw. verstanden zu werden. Eine genauere Untersuchung dieser Zuordnung Punktdifferenz — Schulzeit zeigt die Bandbreite auf, die in Studien zu beobachten ist, und benennt Rahmenbedingungen, die bei der Betrachtung dieser Zuordnung zu beachten sind.

Ein Aspekt der Diskussion um die internationalen Vergleichsuntersuchungen zur Schulerleistung betrifft die Folgerungen, die eine Einzelschule aus der Anlage einschlieslich der Instrumente dieser Untersuchungen und den gewonnenen Erkenntnissen fur ihre schulinterne Qualitatsentwicklung ziehen kann. Dabei wird haufig beklagt, dass uber die Wirkung der wissenschaftlichen und offentlichen Diskussion in und auf Schule wenig bekannt ist, und vermutet, dass dieser Effekt wohl eher klein sei. Der Artikel stellt dar, wie eine einzelne Schule durch Vergleichsarbeiten unter Bezug auf Aufgaben aus groseren Vergleichsuntersuchungen Schulleistung evaluieren und eine Grundlage fur die Entwicklung der Unterrichtsqualitat legen kann und welche Probleme dabei auftreten.

The accumulation of beta-amyloid (A beta) in neuritic plaques is thought to be causative for the progression of Alzheimer's disease (AD). Recently, both active immunization and passive administration of A beta antibodies dramatically attenuated amyloid plaque deposition, neuritic dystrophy, astrogliosis and behaviour deficits in transgenic animals. In addition, we and others have found that titres of naturally occurring anti-A beta antibodies in the CSF of AD patients are significantly lower than those in age-matched controls. Treatment with intravenous immunoglobulins (a preparation that contained anti-A beta antibodies) significantly lowered CSF levels of A beta in non-demented patients. In this study, anti-A beta antibodies were isolated from immunoglobulin preparations and these anti-A beta antibodies strongly block fibril formation or disrupt formation of fibrilar structures. Furthermore, these antibodies almost completely prevented neurotoxicity of A beta. In contrast, immunoglobulins depleted of anti-A beta antibodies had little effect on A beta fibril formation or protection of neuronal cells. This study supports the findings that human anti-A beta antibodies may interfere with the pathogenesis of AD by more than one mechanism, and administration of polyclonal human anti-A beta antibodies isolated from plasma is a potential therapeutic agent to prevent or slow down disease progression.

Borrelia burgdorferi may cause an acute infection of the central nervous system (CNS) that rarely leads to chronic disease. To characterize host immunity to B. burgdorferi in humans, we performed serial T cell receptor (TCR) variable beta (TCRBV) chain analyses in blood and cerebrospinal fluid (CSF) samples from 10 patients with acute neuroborreliosis. In most patients, we found significant differences in TCRBV expression between CSF and peripheral blood T cells, predominantly involving CD8(+) T cells. T cells that accumulated in the CSF had a memory phenotype and expressed high levels of C-C chemokine receptor 5 and CD69. Serial studies demonstrated that CD8(+) T cell accumulation decreased continuously after resolution of the infection. In 2 patients, serial analysis of the TCR-alpha and -beta chain sequences revealed that overexpression of TCRBV in CSF was caused by extensive clonal expansion of CD8(+) T cells. Our findings support the role of CD8(+) T cells during the early host defense against spirochete infection of the CNS.

Naturally occurring antibodies directed against beta-amyloid (Abeta) were detected in intravenous immunoglobulin preparations. After intravenous immunoglobulin treatment in patients with different neurological diseases, total Abeta and Abeta(1-42) in the cerebrospinal fluid was reduced significantly compared with baseline values. In the serum, total Abeta levels increased after intravenous immunoglobulin treatment, whereas no significant change was observed in Abeta(1-42) levels. Antibodies against Abeta were found to be increased in the serum and cerebrospinal fluid after intravenous immunoglobulin treatment. This study provides evidence that intravenous immunoglobulin or purified Abeta antibodies may modify Abeta and Abeta(1-42) levels, suggesting potential utility as a therapy for Alzheimer disease.

Multiple sclerosis is a chronic inflammatory demyelinating disease of the CNS. Although the aetiology of multiple sclerosis is still unknown, it is widely believed that T cells play a central role in its pathogenesis. To identify and characterize disease-relevant T cells, we analysed CD4+ and CD8+ T cells freshly isolated from the CSF and peripheral blood of 36 multiple sclerosis patients for their T-cell receptor variable beta (TCRBV) chain repertoire. In most patients, we found significant overexpression of individual TCRBV chains on CD8+ T cells from CSF compared with peripheral blood. In contrast, only a few multiple sclerosis patients showed differences between the two compartments in TCRBV expression on CD4+ T cells. The overexpression of specific TCRBV chains on CD8+ T cells was found to be stable over several months in selected patients and involved mainly T cells with a memory phenotype. In two patients studied, individual TCRBV chain overexpression was found to be caused by the expansion of T cell populations with identical or highly similar rearranged T-cell receptor beta- and alpha-chain sequences, which were not found among peripheral blood CD8+ T cells. Our findings demonstrate selective enrichment of memory CD8+ T cells in the CSF of multiple sclerosis patients, suggesting a role for these CD8+ T cells in the pathogenesis of multiple sclerosis. Our study provides a basis for future trials to identify disease-associated antigens and disease pathogenesis in multiple sclerosis.

In cases of exacerbation or crisis, myasthenia gravis (MG) patients can be treated with intravenous immunoglobulin (IVIg), plasmapheresis, or immunoadsorption. However, IVIg efficacy data in maintenance treatment are sparse.We prospectively observed 16 index patients with chronic and insufficiently controlled MG under standard immunosuppressant therapy and symptomatic treatment. The IVIg treatment response was measured using changes in quantitative myasthenia gravis (QMG) score and surrogates. Based on these results, a sample size calculation for a future randomized, controlled trial (RCT) was simulated.There was an enduring decline in QMG score and other parameters of about 50% under IVIg maintenance treatment. RCT sample size calculation results in 73 or 33 patients per arm to detect at least a 20% vs. 30% clinical difference in QMG score.We recommend using the QMG score as a primary endpoint for an RCT of IVIg maintenance for chronic MG.

Multiple sclerosis is a chronic inflammatory and demyelinating disease of the CNS with, as yet, an unknown aetiology. Temporal profile, intensity and treatment responses are highly variable in multiple sclerosis suggesting pathogenetic heterogeneity. This hypothesis has been supported by histopathological studies disclosing at least four different subtypes of acute demyelinating lesions. Although stratification of multiple sclerosis patients into these categories would be extremely helpful for clinical studies, this approach is impractical as it requires brain biopsy. In this study we investigated CSF cytology from 60 multiple sclerosis patients by flow cytometry. We identified different patterns of CSF cytology, which were independent of immunological parameters in the peripheral blood. The most variable CSF parameter was the B cell to monocyte ratio, which remained stable during different phases of disease in selected patients. The ratio correlated with disease progression but not with disability or disease duration in a retrospective, consecutive analysis. A high ratio (predominance of B cells) was associated with more rapid disease progression, whereas a low ratio (predominance of monocytes) was found in patients with slower progression. Our study demonstrates the existence and potential clinical relevance of different CSF cytology patterns. We hypothesize that CSF cytology patterns may reflect the heterogeneity in the pathogenesis of multiple sclerosis.

Alpha-2-macroglobulin (A2M) is a proteinase inhibitor involved in deactivation of cytokines and modulation of antigen-mediated immune responses. Based on its role in inflammatory and neurodegenerative disorders, we investigated the role of A2M and its receptor low-density lipoprotein receptor-related protein (LRP) for the development of multiple sclerosis (MS). We analyzed the frequency of two polymorphisms in the A2M (Val 1000 Ile, Exon 18 del), and one polymorphism in the LRP (A216V) gene in a case control study involving 326 MS patients, and 290 controls, all defined for the expression of HLA-DR15. No association was found for any of the three polymorphism with MS. Furthermore, no differences in serum A2M levels were detected between MS patients and controls. The results do not suggest a contribution of A2M and LRP to the development of MS.

The MHC class II molecule H2-A(s), expressed in the SJL mouse strain, is the principle restriction element of autoreactive CD4(+) T cells mediating experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. We deduced the H2-A(s) ligand motif from the analysis of naturally processed self peptides and from peptide binding studies. Major anchor residues were identified using various sets of substituted and truncated peptides, derived from natural peptide ligands and known H2-A(s) binders like myelin basic protein 81 - 99. The nine-residue H2-A(s) core binding motif comprises an arrangement of anchors in relative positions P1, P4, P6, P7, and P9. The P1 pocket is relatively unspecific and the P6 pocket favors hydrophobic-aliphatic side chains. The P1 pocket contributes little to peptide binding. Primary anchors were identified in P4, P7, and in particular in P9. The preferred anchor residues are Lys (P4), His/Arg (P7), and Pro (P9), respectively. Ala-polysubstituted peptides containing only one of these dominant anchor residues still retain the capacity to bind to H2-A(s). Thus, the presence of only one suitable anchor side chain in P4, P7, or P9 is sufficient for high-affinity peptide binding, at least in the absence of negatively charged side chains nearby. The identified ligand motif facilitates the analysis of immunogenic peptides interacting with H2-A(s) and will allow a better prediction of pathogenetically relevant peptide antigens in the autoimmune mouse model.

Myasthenia gravis (MG) is caused by autoantibodies against proteins at the neuromuscular junction. This autoimmune process leads to abnormal fatiguability and weakness of striated muscle. Ptosis and diplopia are among the most common manifestations of MG. The term "ocular MG" (OMG) as opposed to "generalised MG" (GMG) is used to define the clinical subtype of MG with isolated eye muscle weakness. Although OMG may appear to cause only moderate disability, it can significantly impair the patient's activities of daily living and progress to generalised myasthenia. Therefore, a clear management plan should be installed early in these patients. Since prospective treatment trials have not been performed, basic management strategies for OMG have to be deduced from retrospective studies, trials in GMG, and generally accepted clinical experience. Cholinesterase inhibitors are used in all types of MG, but are often less helpful in OMG. In the absence of thymoma, thymectomy is usually not considered in OMG, although a few studies have described histological abnormalities in thymuses from patients with OMG. Corticosteroids are of great short term benefit in most patients with OMG but potential adverse effects limit their long term use. Azathioprine is needed to reduce long term corticosteroid adverse effects, but this agent requires about 6 months to be effective. In summary, OMG has a good prognosis in most patients, with corticosteroids and azathioprine being the major treatment options. The challenges for the clinician are to recognise the condition despite the large number of differential diagnoses, to minimise the patient's symptoms using the therapies available and to carefully limit potentially hazardous therapeutic efforts, especially in mild or even uncertain cases.

Oligoclonal expansion of antigen-specific T cells occurs frequently during inflammatory diseases. These cells may persist for a long time at high frequency in the body and be enriched in the affected tissues. As a screening test for expanded cell T cell populations at sites of inflammation, we developed an optimized methodology for flow-cytometry-based quantification of T cell receptor Vbeta (TCRBV) expression. We first validated the specificity of a TCRBV-specific monoclonal antibody set by direct comparison with PCR-based analysis of mono- and polyclonal T cell samples. This monoclonal antibody (mAb) panel recognized approximately two thirds of the T cell receptor alpha/beta repertoire in a group of 64 healthy donors and allowed defining TCR usage in the CD4+ and CD8+ subsets. The reliable detection of expanded Vbeta gene families in T cell populations was confirmed in experiments on superantigen-stimulated T cells. Through differential TCR analysis on T cell subpopulations in cerebrospinal fluid and blood in patients with acute encephalitis, we were able to identify locally expanded CD8+ T cells. The power of this approach affords not only high-throughput comparative TCR analysis for immunological studies in vitro, but also rapid ex vivo identification of cell populations enriched in organ compartments during inflammatory diseases.

CD95-mediated apoptosis is a potent endogenous pathway of T cell elimination that has been suggested to be altered in multiple sclerosis (MS). MS is associated with the HLA-DR2, Dw2, DQ6 HLA class II haplotype. We have previously reported that T cell lines from HLA-DR2-positive individuals show enhanced production of tumor necrosis factor (TNF), a cytokine homologous to CD95 ligand, in response to specific antigen. Here we have studied CD95 expression and susceptibility to CD95-mediated apoptosis in peripheral blood mononuclear cells (PBMC) and activated T cells of 20 healthy individuals and 20 MS patients, half of whom were HLA-DR2-positive. MS patients did not differ from healthy individuals in either parameter. There was also no difference in CD95 expression or CD95-mediated apoptosis when MS patients and healthy individuals were grouped and compared according to HLA-DR status. These data reveal no differential regulation of PBMC/T cell apoptosis induced by CD95 receptor ligation in MS and show no impact of HLA-DR2 status on PBMC/T cell susceptibility to the same apoptotic stimulus. However, to assess the contribution of T cell apoptosis to the pathogenesis of MS further studies on other details of the complex system leading to T cell apoptosis are required.

Extensive research in the field of multiple sclerosis (MS) has lead to a preliminary pathogenetic concept without solving the etiopathogenesis. According to animal experiments and human in vitro studies MS is a T cell-mediated autoimmune disease. Experimental therapeutical strategies are aiming at the inhibition of T cell activation, transmigration through the blood brain barrier and local inflammation and demyelination. Several substances are already being tested in clinical studies with magnetic resonance imaging as a tool to quantify inflammatory lesions and to shorten the study course. This review will give a summary about actual experimental therapies resulting from the current pathogenetic concept.

OBJECTIVE: Ocular myasthenia gravis is a subtype of myasthenia gravis that causes relatively mild disability, but may convert into severe generalised muscle weakness. A universal management plan for ocular myasthenia gravis has not been established. This study was performed to determine the outcome of ocular myasthenia gravis with the currently available therapeutic options. METHODS: Retrospective analysis of 78 patients with ocular myasthenia gravis with a mean disease duration of 8.3 (range 0.5-58.3) years. RESULTS: In 54 patients (69%) symptoms and signs remained confined to the extraocular muscles during the observation period. The remaining 24 patients (31%) developed symptoms of generalised myasthenia gravis; 50% of them within two years, 75% within four years after onset. A somewhat reduced risk of generalisation was found in those with mild symptoms, normal repetitive nerve stimulation test, and low or absent antiacetylcholine receptor (AChR) antibodies at the time of diagnosis. Patients receiving immunosuppressive treatment (corticosteroids and/or azathioprine) rarely developed generalised myasthenia gravis (six of 50, 12%). Those without such treatment, usually due to uncertain diagnosis and late referral, converted into generalised myasthenia gravis significantly more often (18 of 28, 64%). CONCLUSIONS: The prognosis of ocular myasthenia gravis is good. A conventional scheme with short-term corticosteroids and long-term azathioprine seems adequate to achieve remission in most patients. The proportion of patients developing generalised myasthenia gravis was smaller in this population compared with previously published groups (usually 50%-70%). Early immunosuppressive treatment is at least partially responsible for this finding. Thymectomy (performed here in 12 patients with an abnormal chest CT) also correlated with a good outcome, but had no apparent advantage over medical treatment alone.

Objective: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer’s disease (AD). Recently, it has been shown that antibodies against b-amyloid (Ab) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of Ab. This study reports the results from a pilot study using IVIgG in patients with AD. Methods: Five patients with AD were enrolled and received monthly IVIgG over a 6 month period. Efficacy assessment included total Ab/Ab1–42 measured in the CSF/serum as well as effects on cognition (ADAS-cog; CERAD) at baseline and at 6 months following IVIgG. Results: Following IVIgG, total Ab levels in the CSF decreased by 30.1% (17.3–43.5%) compared to baseline (p,0.05). Total Ab increased in the serum by 233% (p,0.05). No significant change was found in Ab1–42 levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7i2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline. Conclusion: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.

Aims: To estimate costs of multiple sclerosis (MS) in a German cohort according to severity of the disease and clinical symptoms. Methods: 144 patients were recruited from an MS outpatient clinic. Costs were calculated according to current German health-economic guidelines from the perspective of the social health insurance system. Patients were either interviewed or completed a questionnaire. Cost assessment covered a 3-month period. Health outcomes were: Expanded Disability Status Scale, MS Functional Composite, Functional Assessment of MS, fatigue, depression (Beck Depression Inventory II) and patients’ socioeconomic status. Multivariate linear regression identified independent cost predictors. Results: Total quarterly costs per patient were EUR 10,329 (95% CI 9,357–11,390). Direct costs were EUR 5,344 for the social health insurance system and EUR 140 for the patient. Drugs represented the major share of direct costs (and 35% of total costs); indirect costs accounted for 47% of total costs. Univariate and multivariate analyses identified age, disability, fatigue and depression as independent predictors for total, indirect or drug costs. Conclusion: MS represents a high economic burden, with direct costs exceeding indirect costs. To reduce costs, research should focus on prevention that slows down progression of MS. Rehabilitation and symptomatic treatment may have merits in decreasing indirect costs.

Myasthenia gravis (MG) is probably the best studied autoimmune disease caused by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction, subsequently leading to abnormal fatigability and weakness of skeletal muscle. Extraocular muscle weakness with droopy eyelids and double vision is present in about 90% of MG patients, being the initial complaint in about 50%. In approximately 20% of the patients the disease will always be confined to the extraocular muscles. The single most important diagnostic test is the detection of serum antibodies against AChR which is positive in 90% of patients with generalized MG, but only in 65% with purely ocular MG. Electromyographic studies and the Tensilon test are of diagnostic value in clear-cut cases, but may be equivocal in purely ocular myasthenia, especially the latter not rarely producing false-positive results. Treatment response to corticosteroids and anti-cholinesterase agents is satisfactory in many patients with ocular MG, however other immunosuppressive drugs may also be needed. Pathogenetically relevant steps of the underlying autoimmune process have been elucidated during the last few years; nevertheless a number of questions remain open, especially what starts off the autoimmune process, and why are eye muscles so frequently involved in MG?

Neurological complications are a major cause of morbidity and mortality in patients with disseminated malignant melanoma. We have studied and correlated clinical and cerebrospinal fluid (CSF) findings in 20 patients with central nervous system metastases from malignant melanoma including 8 patients with metastatic meningeal melanomatosis (MMM) and 12 patients with solid cerebral metastases (SCM). The putative CSF tumor markers, fibronectin and beta 2-microglobulin, were elevated significantly in MMM but not in SCM patients. A prominent increase in the IgM index, which reflects intrathecal B-cell stimulation, and a rise of IgG index, interleukin-6, and tumor necrosis factor-alpha in MMM patients provide preliminary evidence for a local intrathecal immune response triggered by melanoma cell invasion of the subarachnoid space.

Cerebrospinal fluid (CSF) and serum samples of 20 patients with central nervous system manifestations of hematological malignancies including primary cerebral lymphoma (n = 5) and disseminated non-Hodgkin lymphoma (n = 7) were examined for albumin, IgG, IgM, fibronectin, beta 2-microglobulin, interleukin-6, soluble interleukin-2 receptor, tumor necrosis factor alpha, and oligoclonal immunoglobulin bands. Although a broad range of abnormalities were detected, no reliable CSF parameter for the diagnosis of leptomeningeal spread from hematological neoplasias could be identified. An analysis of 61 repeat lumbar punctures added little to the findings of the first CSF examinations. Currently, immunochemical studies of CSF cell surface markers and early biopsy have probably more clinical value than the determination of the humoral CSF parameters included in this study. However, analysis of cytokine synthesis by single CSF cells using molecular biology techniques may improve the differential diagnosis of hematological neoplasia of the brain and spinal cord in the future.

The intrathecal immune response in neoplastic meningitis (NM) was studied by quantitation of immune parameters such as immunoglobulin G (IgG); IgM; interleukins (IL) 1, 2, 4, and 6; soluble IL-2 receptors (sIL-2R); interferon gamma (IFNy); tumor necrosis factor-alpha (TNF alpha); and three tumor markers, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and fibronectin (FN), in 47 paired cerebrospinal fluid (CSF) and serum samples from patients with NM from different carcinomas, malignant melanoma, and lymphoma. Elevated IgG and IgM indices, CSF oligoclonal Ig bands, and CSF IL-6 indicated an intrathecal immune activation in most patients with NM. Results for IL-1, IL-2, and IL-4 were always negative. sIL-2R and IFNy were detected occasionally but not associated with specific malignant neoplasms. CSF TNF alpha was detected only in NM from cases of malignant melanoma. None of the immune parameters proved useful for the differentiation of NM from autoimmune or inflammatory conditions. Immune parameters were not correlated with tumor markers CEA, AFP, or FN. Results for AFP were positive only in a case of glioblastoma. CEA was a useful and specific diagnostic parameter in carcinomatous NM. CSF FN levels frequently were elevated but are not specific for NM.

Cerebrospinal fluid (CSF) and serum IgG and IgM antibodies to seven gangliosides were determined in patients with neuroborreliosis (NB) (n = 20), Guillain-Barré syndrome (GBS) (n = 13), and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (n = 10). The incidence of elevated antibodies was highest in NB and lowest in CIDP. Correlation between CSF and serum antibodies was only observed for IgG antibodies to GM1, GD1b and GT1b in GBS. The strong IgM antibody reactivity to gangliosides in the CSF of NB patients may be involved in the variety of neurological disorders attributed to Borrelia burgdorferi infection. Since one CIDP and three GBS patients had serologic evidence of prior or concurrent borrelia infection, this infection may belong to the infections that can trigger GBS or CIDP. The lack of specific ganglioside antibody patterns in these four patients suggests that ganglioside antibodies are not the link between Borrelia burgdorferi infection and the demyelination of peripheral nerves in GBS and CIDP.

Serum IgG and IgM antibodies to gangliosides GM1, GM2, GM3, AGM1, GD1a, GD1b and GT1b were determined in 210 patients with different degenerative and inflammatory disorders including motor neuron diseases, peripheral radiculopathies and neuropathies, multiple sclerosis and neuroborreliosis. No single disorder was associated specifically with ganglioside antibodies. No characteristic patterns of ganglioside antibodies were observed in any disease category. However, 32% of all patients had pathological antibody titres to at least one ganglioside. Four patients had pathological IgG and IgM titres for all gangliosides evaluated. They suffered from systemic lupus erythematosus [2], neuroborreliosis and schizophrenia, respectively. The results of this study indicate that the introduction of ganglioside antibody determination as a differential diagnostic test in clinical neurology is only helpful in a few patients with typical lower motor neuron syndromes.

Ubiquitous viruses have frequently been proposed as a cause or trigger of chronic immune-mediated diseases. Infections are reported to be temporally associated with clinical exacerbations in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We examined immunological parameters of herpesvirus infections in untreated patients with CIDP compared to demographically matched controls. Patients with CIDP were uniformly seropositive for EBV-specific IgG and the disease was associated with a moderately enhanced IgG reactivity to EBV-encoded antigens expressed during both B cell transformation and productive viral replication. Moreover, cellular EBV copy numbers were 3-fold increased in patients with CIDP. In contrast, humoral immune responses to other herpesviruses (HCMV, HSV) as well as virus-specific IgM responses were unchanged in CIDP. These data indicate that host-pathogen interactions during chronic EBV infection are dysregulated in treatment-naive patients with CIDP.

Objective: To address the differences in disease progression between familial and sporadic multiple scleroris (MS) and the association within sib-pairs. Methods: 48 sibling pairs and 98 controls from a databank of 445 sporadic MS-patients, randomly pair-matched for age, gender, clinical course and disease duration were included. In 33 available sibling-pairs follow-up data were collected prospectively Outcome parameters included baseline expanded disability status scale (EDSS), age at onset, mono- or multifocal onset and disease progression. For analyses within-group distributions were described and compared, using Wilcoxon's signed-rank statistics for categorical differences, and t-statistics for continous variables. Relative frequencies of categories were tested by McNemar's test, and within sibling-pair associations using an intraclass correlation coefficient. Statistical tests were performed 2-sided at the 5% level using UNIVARIATE and FREQ SAS software 9.1. Results: Disease onset was slightly earlier (29.01 vs. 29.44 years, p=0.492) and multifocal onset significantly more often (p=0.0052) in familial than sporadic MS. Notably, a substantial within-pair correlation for disease progression could be observed (rho=0.40; r2=0.16, p=0.0062). However, there was neither a difference in baseline EDSS, nor in EDSS progression between the groups. Conclusions: Familial MS differs from sporadic cases with respect to age at onset and multifocal involvement as first clinical event. The progression rate of one out of two affected siblings may provide as a predictor for the other sib. However, prognosis over a six-year follow-up concerning the EDSS was similar in both groups. Larger longitudinal studies are required to find clinical, genetic, immunological or therapeutic implications.

Interleukins (IL) 1, 2, 4, 6 and soluble IL-2 receptor (sIL-2R), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were measured in CSF and serum from patients with relapsing-remitting and chronic multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, HIV infection, bacterial meningitis, viral encephalitis, meningeal carcinomatosis, hematologic meningeal malignancies, and disseminated melanoma. Our findings suggest that monitoring of disease activity in neuroimmunologic disorders by means of IL-1 beta, IL-2, sIL-2R, or IL-4 determination will not prove useful. IL-6, on the other hand, indicates relapse in multiple sclerosis and active disease in Guillain-Barré syndrome and meningeal carcinomatosis. High CSF TNF-alpha in metastatic melanoma and frequent detection in CSF of the multifunctional B-cell growth factor, IL-6 (27/30) and oligoclonal immunoglobulin bands (33%) in meningeal carcinomatosis confirm an intrathecal immune response in disseminated leptomeningeal neoplasia which might be amenable to therapeutic immunomodulation.

Publisher Summary Myasthenia gravis (MG) is a human autoimmune disease. Autoantibodies against neuromuscular antigens play a key role in the pathogenesis of MG, and the detection and monitoring of these antibodies is essential for the clinical management of myasthenic patients. This chapter reviews the immunopathogenesis of MG. The chapter provides an overview of some fundamental principles of immunology, and then addresses the role of antibodies, T cells, immunogenetic aspects, and thymus. The relevant animal models of MG, the risk factors of MG and associations with other immunological diseases are discussed. Complement system mediates destruction of the postsynaptic membrane of the neuromuscular junction. The detection of autoantibodies against acetylcholine receptor (AChR) is a key element for making the diagnosis of autoimmune MG. CD4+ helper T cells are crucially involved in the immunopathogenesis of MG. MG is associated with other autoimmune diseases (e.g., rheumatoid arthritis, thyroid disease) pointing to a general autoimmune predisposition of MG patients conferred by unknown genes. The thymus is thought to play an important role in MG pathogenesis. Patients with thymic tumors carry a markedly increased risk of developing myasthenia gravis. The features of experimental autoimmune myasthenia gravis (EAMG) vary with the species and strain, source of AChR, use of adjuvants, and immunization schedules. Epidemiological data indicates that the prevalence of late onset MG is increasing. If aging is an independent risk factor for the development of MG is yet to be determined.