Multiple sclerosis in the elderly: a retrospective cohort study.

BACKGROUND: There is a lack of knowledge of disease course, prognosis, comorbidities and potential treatments of elderly MS patients. OBJECTIVE: To characterize the disease course including disability progression and relapses, to quantify the use of DMTs and to identify comorbidities and risk factors for progression in elderly multiple sclerosis (MS) patients. METHODS: This is a retrospective study of 1200 Austrian MS patients older than 55 years as of May 1st, 2017 representing roughly one-third of all the MS patients of this age in Austria. Data were collected from 15 MS centers including demographics, first symptom at onset, number of relapses, evolvement of disability, medication, and comorbidities. RESULTS: Median observation time was 17.1 years with 957 (80%) relapsing and 243 (20%) progressive onsets. Average age at diagnosis was 45 years with a female predominance of 71%. Three-hundred and twenty-six (27%) patients were never treated with a DMT, while most treated patients received interferons (496; 41%) at some point. At last follow-up, 420 (35%) patients were still treated with a DMT. No difference was found between treated and never-treated patients in terms of clinical outcome; however, patients with worse disability progression had significantly more DMT switches. Pyramidal onset, number of comorbidities, dementia, epilepsy, and psychiatric conditions as well as a higher number of relapses were associated with worse outcome. The risk of reaching EDSS 6 rose with every additional comorbidity by 22%. In late and very-late-onset MS (LOMS, VLOMS) time to diagnosis took nearly twice the time compared to adult and early onset (AEOMS). The overall annualized relapse rate (ARR) decreased over time and patients with AEOMS had significantly higher ARR compared to LOMS and VLOMS. Four percent of MS patients had five medications or more fulfilling criteria of polypharmacy and 20% of psychiatric drugs were administered without a matching diagnosis. CONCLUSIONS: In this study, we identified number of comorbidities, pyramidal and cerebellar signs, and a higher number of relapses as unfavorable prognostic factors in elderly MS patients filling gaps of knowledge in patients usually underrepresented in clinical trials and may guide future therapeutic studies.

Screening for osteoporosis in people with MS: A new risk score.

BACKGROUND: Due to the demographic development and improved treatment options, the role of comorbidities is of increasing importance in the medical care of people with MS (pwMS). A higher risk of osteoporosis is well known in chronic autoimmune diseases, and is also described in MS. While there are several screening guidelines in the elderly or in patients with rheumatoid arthritis, there are no generally accepted recommendations when to perform bone mineral testing in pwMS under the age of 65 years. We aimed to determine risk factors of osteoporosis in pwMS and to develop a risk score which can be applied in daily clinical routine. METHODS: Densitometry (hip and lumbar spine) was performed in 159 pwMS aged ≤65 years and in 81 age- and sex-matched healthy controls (HC). Osteoporosis was defined according to WHO criteria as a bone density 2.5 standard deviation or more below the mean of young adults. Risk factors were identified by logistic regression analysis. RESULTS: Osteoporosis occurred more frequently in postmenopausal pwMS and male pwMS as compared to HC. Besides age, sex, menopausal status in females, body-mass-index and smoking, a higher degree of disability - as assessed by the Expanded Disability Status Scale - was identified as MS specific risk factor for osteoporosis, whereas the cumulative glucocorticoid dose was not associated with osteoporosis risk. Based on these risk factors, we developed an MS-specific risk score which allows to estimate the individual probability of osteoporosis. CONCLUSION: This risk score enables individual screening recommendation for pwMS and, subsequently, early prevention of osteoporosis which probably should result in reduction of fractures and morbidity.

Immunization status in patients with multiple sclerosis: A cross-sectional, monocenter study in Austria.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) under certain disease-modifying therapies (DMT) show a higher risk of infection and a lower immune response to vaccination. Hence, assessing immunization status prior to DMT start and, where necessary, performing vaccinations is  recommended. We aimed to determine the immunization status in MS patients and to identify factors associated with low vaccination rates. METHODS: Patients with MS who were seen at the MS clinic of the Medical University of Innsbruck throughout a period of 14 months in 2020 and 2021 were eligible for inclusion into this prospective, single-center study. Immunization status against 17 different pathogens was obtained from vaccination certificate and by patient questionnaire. Antibody detection against seven antigens was performed in peripheral blood. RESULTS: Of 424 patients with MS at a mean age of 43 ± 12 years, the vast majority had vaccinations against tetanus (94%), diphtheria (92%), and poliomyelitis (90%), whereas a lower proportion had vaccinations against tick-borne encephalitis (70%), pertussis (69%), hepatitis B (65%), rubella (55%), hepatitis A (50%), measles (49%), mumps (47%), and only a minority against influenza (10%), pneumococcal (6%) and meningococcal disease (4%), human papillomavirus (4%), yellow fever (2%), and varicella zoster virus (1%). A total of 87% received vaccination against SARS-CoV-2. Overall, higher vaccination rates were associated with younger age, relapsing disease course, and education level. Misinformation on infectious diseases and vaccines was associated with lower vaccination rates. CONCLUSIONS: The majority of MS patients did not fulfil vaccination recommendations. Efforts to increase vaccination rates, preferentially before DMT start, should be promoted.

Sexual dysfunction in female and male people with multiple sclerosis: disability, depression and hormonal status matter.

BACKGROUND AND PURPOSE: Sexual dysfunction (SD) in people with multiple sclerosis (pwMS) is common and an often underestimated issue in the care of pwMS. The objective of the study was to evaluate risk factors for SD in pwMS, correlate its prevalence with patient-reported measures (quality of life and physical activity) and analyse its association with hormonal status. METHODS: Sexual dysfunction was determined in 152 pwMS using the Multiple Sclerosis Intimacy and Sexuality Questionnaire 19. A logistical regression model was used to identify independent risk factors for SD. RESULTS: The prevalence of SD in pwMS was 47%. Independent risk factors for the development of SD were ever-smoking (odds ratio [OR] 3.4, p = 0.023), disability as measured by the Expanded Disability Status Scale (OR 2.0, p < 0.001), depression (OR 4.3, p = 0.047) and bladder and bowel dysfunction (OR 8.8, p < 0.001); the use of disease-modifying treatment was associated with a lower risk for SD (OR 0.32, p = 0.043). SD was associated with worse quality of life (Multiple Sclerosis Impact Scale 29: physical score 6.3 vs. 40.0; psychological score 8.3 vs. 33.3; both p < 0.001) and lower physical activity (Baecke questionnaire, p < 0.001). Laboratory analysis revealed significantly higher luteinizing hormone and follicle-stimulating hormone levels and lower 17-beta oestradiol, androstenedione, dehydroepiandrosterone sulfate, oestrone and anti-Mullerian hormone levels in female pwMS with SD. In male pwMS and SD, there was a significant decrease in inhibin B levels. CONCLUSIONS: Our findings highlight the requirement of a holistic approach to SD in MS including physical, neurourological and psychosocial factors. Active screening for SD, especially in patients with disability, depression or bladder and bowel dysfunction, is recommended.

Anti-NMDA receptor encephalitis and MOG-associated demyelination - a case report with long-term follow-up and a systematic review.

BACKGROUND: Overlap syndromes of anti-NMDA receptor encephalitis and MOG-mediated demyelination have been reported. In this case we provide a long-term longitudinal follow-up of clinical and imaging characteristics as well as of antibody dynamics. CASE PRESENTATION: We report a 32-year-old male patient who presented with psychosis, decreased consciousness and movement disorders and was tested positive for anti-NMDA receptor antibodies. Forty-four months after symptom onset and diagnosis of autoimmune encephalitis, he suffered from relapse. At this time, the patient developed anti-MOG and anti-Caspr2 antibodies. Treatment with plasmapheresis, steroids and rituximab eventually led to substantial clinical and radiological improvement. Anti-Caspr2 antibodies persisted, anti-NMDA receptor antibodies decreased, while anti-MOG antibodies turned negative again. CONCLUSION: We provide long-term longitudinal follow-up of a patient with anti-NMDA receptor encephalitis who developed triple antibody positivity at the time of relapse. Antibody dynamics were associated with clinical disease course.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

BACKGROUND: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. OBJECTIVE: To analyze systematically the CSF profile in COVID-19. METHODS: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. CONCLUSIONS: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease and Varicella Zoster Virus Infection - Frequency of an Association.

To determine whether there is a correlation between myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases and varicella zoster virus (VZV) infection. We provide a case report and performed a study to determine the frequency of MOG antibodies (MOG-IgG) in neurological VZV infections. Patients admitted to the Medical University of Innsbruck from 2008-2020 with a diagnosis of a neurological manifestation of VZV infection (n=59) were included in this study; patients with neuroborreliosis (n=34) served as control group. MOG-IgG was detected using live cell-based assays. In addition, we performed a literature review focusing on MOG and aquaporin-4 (AQP4) antibodies and their association with VZV infection. Our case presented with VZV-associated longitudinally extensive transverse myelitis and had MOG-IgG at a titer of 1:1280. In the study, we did not detect MOG-IgG in any other patient neither in the VZV group (including 15 with VZV encephalitis/myelitis) nor in the neuroborreliosis group. In the review of the literature, 3 cases with MOG-IgG and additional 9 cases with AQP4 IgG associated disorders in association with a VZV infection were identified. MOG-IgG are rarely detected in patients with VZV infections associated with neurological diseases.

Functional Recovery in Autoimmune Encephalitis: A Prospective Observational Study.

Background: Prospective observations of functional recovery are lacking in patients with autoimmune encephalitis defined by antibodies against synaptic proteins and neuronal cell surface receptors. Methods: Adult patients with a diagnosis of autoimmune encephalitis were included into a prospective registry. At 3, 6 and 12 months of follow-up, the patients' modified Rankin Scale (mRS) was obtained. Results: Patients were stratified into three groups according to their antibody (Ab) status: anti-NMDAR-Ab (n=12; group I), anti-LGI1/CASPR2-Ab (n=35; group II), and other antibodies (n=24; group III). A comparably higher proportion of patients in group I received plasma exchange/immunoadsorption and second line immunosuppressive treatments at baseline. A higher proportion of patients in group II presented with seizures. Group III mainly included patients with anti-GABABR-, anti-GAD65- and anti-GlyR-Ab. At baseline, one third of them had cancer. Patients in groups I and III had much higher median mRS scores at 3 months compared to patients in group II. A median mRS of 1 was found at all follow-up time points in group II. Conclusions: The different dynamics in the recovery of patients with certain autoimmune encephalitides have important implications for clinical trials. The high proportion of patients with significant disability at 3 months after diagnosis in groups I and III points to the need for improving treatment options. More distinct scores rather than the mRS are necessary to differentiate potential neurological improvements in patients with anti-LGI1-/CASPR2-encephalitis.

Transverse myelitis as a rare presentation of antiphospholipid-antibody-associated disorders.

We report the case of a 35-year-old male patient suffering from a clinical and radiological manifestation of a transverse myelitis associated with antiphospholipid antibodies. After a challenging diagnosis the patient improved substantially due to immunosuppressive treatment. The demyelinating spinal cord lesion and the impressive therapeutic outcome may support the possibility of a direct binding of antiphospholipid antibodies to CNS antigens and consequently leading to a neuroimmunological pathomechanism distinct from the well-known pro-thrombotic effect of antiphospholipid antibodies. In terms of clinical routine diagnostic this case report highlights a rare but notable differential diagnosis of Multiple Sclerosis-like syndromes.

Smelling multiple sclerosis: Different qualities of olfactory function reflect either inflammatory activity or neurodegeneration.

BACKGROUND: Peripapillary retinal nerve fiber layer (pRNFL) thickness and olfactory function are both emerging biomarkers in multiple sclerosis (MS). Impairment of odor identification and discrimination is an irreversible feature of more advanced MS suggested to be associated with neurodegeneration, while olfactory threshold is a transient feature of early, active MS possibly associated with short-term inflammatory disease activity. OBJECTIVE: The aim of this study was to validate the association of olfactory (dys)function and parameters of MS disease course in a large cohort of MS patients and to correlate olfactory function with pRNFL thickness as a surrogate biomarker of neurodegeneration. METHODS: In a cross-sectional design, olfactory function was assessed using the Sniffin' Sticks test, which quantifies three different qualities of olfactory function (threshold, discrimination, and identification). pRNFL thickness was measured by spectral-domain optical coherence tomography (OCT). Results were correlated with age, sex, disease duration, relapses, Expanded Disability Status Scale (EDSS), cognitive function, depression, smoking, and pRNFL thickness by multivariable linear regression models. RESULTS: We included 260 MS patients (mean age of 35.9 years, 68.7% female). Olfactory threshold correlated significantly with number of relapses in the year prior to assessment and shorter disease duration. Odor discrimination, identification, and their sum score were significantly correlated with longer disease duration, higher EDSS, and reduced cognitive function. pRNFL thickness was associated with identification and discrimination, but not with threshold. CONCLUSION: Olfactory threshold is a marker of short-term inflammatory relapse activity unrelated to parameters of neurodegeneration, while odor identification and discrimination are markers of neurodegeneration mostly independent of relapse activity. Assessment of olfactory function provides an opportunity to stratify MS patients with regard to inflammation and neurodegeneration.

Conversion and reversion of anti-John Cunningham virus antibody serostatus: A prospective study.

INTRODUCTION: Determination of antibodies against the John Cunningham virus (JCV) is an important tool for risk stratification in Natalizumab-treated multiple sclerosis (MS) patients. Six-monthly testing has been suggested for anti-JCV antibody negative patients and patients with low antibody index in order to detect changes of serostatus. We conducted a prospective study with predefined testing intervals in order to investigate the predictability of anti-JCV antibody status and the intervals for repetitive testing. METHODS: Our study included 109 patients at the MS Clinic of the Departments of Neurology, Medical Universities of Innsbruck and Salzburg. Blood withdrawals were performed at five time points: baseline, month 1, 3, 6, and 12. Patients' sera were sent to Unilabs, Copenhagen, Denmark, where anti-JCV antibodies were tested by a two-step enzyme-linked immunosorbent assay. Qualitative (negative/positive) and quantitative results (anti-JCV antibody index) were used for statistical analyses. RESULTS: In our cohort, 52.3% of the patients were positive for anti-JCV antibodies at baseline, with a significant correlation with age, but no association with sex or prior disease-modifying therapy. Seven patients converted and reverted from negative to positive status and vice versa around the cut-off index of 0.4, but no patient showed a permanent seroconversion from negative to highly positive anti-JCV antibody status. CONCLUSION: Long-term anti-JCV antibody status, including seroconverters/-reverters around the cut-off index, is highly predictable by testing three times within short intervals, however, we cannot suggest clearly defined intervals for repetitive testing. The rate of real seroconverters, i.e., new infections with JCV, per year seems lower than previously described.

Impact of Disease-Modifying Treatments on the Longitudinal Evolution of Anti-JCV Antibody Index in Multiple Sclerosis.

Background: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. Objective: To investigate the impact of disease-modifying treatments (DMT) on the longitudinal evolution of anti-JCV antibody index. Methods: Patients with multiple sclerosis who had serum sampling at intervals of 6 ± 3 months over up to 6 years and who either started DMT (interferon-ß, glatiramer acetate or natalizumab) during the observation period with at least one serum sample available before and after treatment initiation or received no DMT during the observation period were included. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. Results: A total of 89 patients were followed for a median time of 55.2 months. Of those, 62 (69.7%) started DMT and 27 (30.3%) were without therapy during the observation period. Variation of longitudinal anti-JCV antibody index ranged from 9 to 15% and was similar in patients with and without DMT. Applying a mixed model considering the combined effects of treatment and time as well as individual heterogeneity did not show a significant change of anti-JCV antibody index by the start of treatment with interferon-ß, glatiramer acetate, or natalizumab. Conclusion: Evaluated DMTs do not impact longitudinal anti-JCV antibody index evolution.

Smoking is not associated with higher prevalence of JC virus in MS patients.

John Cunningham virus (JCV) causes rare, but potentially life-threatening progressive multifocal leukoencephalopathy (PML) in natalizumab-treated multiple sclerosis (MS) patients. Beside JCV index, there is currently no other factor for further risk stratification. Because smoking was reported as potential risk factor for several viral and bacterial infections, we aimed to investigate whether smoking could increase the risk for JCV infection in MS patients. We screened our database of the MS Clinic of the Department of Neurology, Medical University of Innsbruck, Austria, for patients with known smoking status and test result for anti-JCV antibody index as determined by two-step ELISA at Unilabs, Copenhagen, Denmark. In a representative cohort of 200 MS patients with a rate of 36% current smokers plus 6% former smokers, we were not able to detect any association between smoking and JCV status. Furthermore, there was no association between smoking status and anti-JCV antibody index. Smoking does not seem to be a risk factor for JCV infection in MS patients and, therefore, does not represent a suitable marker for PML-risk stratification under treatment with natalizumab.

Stability and predictive value of anti-JCV antibody index in multiple sclerosis: A 6-year longitudinal study.

BACKGROUND: Risk of natalizumab-related progressive multifocal leukoencephalopathy is associated with the presence of anti-JC-virus (JCV) antibodies. OBJECTIVE: To investigate the longitudinal evolution of anti-JCV antibody index and to determine the predictive value of baseline anti-JCV antibody index for long-term stability of anti-JCV antibody status. METHODS: MS patients from the MS centre of Medical University of Innsbruck, who had serum sampling for a time period of 4-6 years at intervals of 6±3 months, were included in this retrospective, longitudinal study. Anti-JCV antibody serological status and index were determined by 2-step second-generation anti-JCV antibody assay. RESULTS: 154 patients were included in this study. Median follow-up time was 63.7 months, with median 11 samples available per patient. At baseline, 111 (72.1%) patients were anti-JCV antibody positive. Baseline anti-JCV antibody index significantly correlated with age (R = 0.22, p = 0.005); there was no difference with respect to sex, disease duration or previously used disease-modifying treatment. During follow-up anti-JCV antibody status changed from negative to positive or vice versa in 17% of patients. In seronegative patients at baseline, baseline anti-JCV antibody index was significantly lower in those remaining seronegative at follow-up compared to those converting to seropositivity (median 0.16 vs. 0.24, p = 0.002). In seropositive patients at baseline, index was higher in those remaining seropositive compared to those reverting to seronegativity (2.6 vs. 0.45, p<10-7). Baseline anti-JCV antibody index >0.90 predicted stable positive serostatus (sensitivity 88.7%, specificity 96.5%) and <0.20 stable negative serostatus (sensitivity 61.3%, specificity 97.6%). CONCLUSIONS: Anti-JCV antibody index remained relatively stable over 6-year follow-up with annual serostatus change of ~3%. Baseline anti-JCV antibody index predicted stable negative and stable positive JCV serostatus.

Serum Cotinine Does Not Predict Neutralizing Antibodies Against Interferon Beta in an Austrian MS Cohort.

Previous epidemiologic studies showed an increased risk of neutralizing antibody (NAb) development against Interferon beta in multiple sclerosis patients who smoke. Cotinine is an easily detectable metabolite of nicotine and, therefore, can be used as an objective surrogate marker for smoking status. We measured cotinine levels in NAb-positive and NAb-negative patients to find a potential association of nicotine consumption and NAb development. Cotinine was measured in 37 patients with known smoking status and in 123 patients with unknown smoking status, all of whom were routinely tested for NAb. Cotinine was detected by an enzyme-linked immunosorbent assay, inhibition assay. We compared cotinine levels by NAb status and tested for the strength of association between cotinine and NAb status. We found a discrepancy between smoking status stated by patients and status defined by cotinine levels in 7 of 37 patients. In both cohorts, together with and without previously known smoking status (n = 160), we found 34% and 39% smokers, respectively, as defined by cotinine levels in NAb-negative and NAb-positive patients (P = 0.511). In our analysis, smoking was not associated with higher risk of NAb development. Moreover, smoking habits stated by patients do not always correlate with cotinine levels.

Bi-insular cortical involvement in anti-NMDA-receptor encephalitis - a case report.

BACKGROUND: Anti-NMDA-receptor encephalitis is an immune-mediated inflammatory disorder of the central nervous system. Brain MRI is unremarkable in at least 50% of patients and highly variable in the remaining patients with signal abnormalities in different brain regions. Only scarce reports exist on other imaging modalities. CASE PRESENTATION: A 31-year-old woman sub-acutely developed psychosis, behavioural changes, amnesia, alternating states of agitation and mutism, fever and epileptic seizures. Clinically suspected diagnosis of anti-NMDA-receptor encephalitis was confirmed by the detection of anti-NMDA receptor antibodies in CSF and serum. During the acute phase, brain MRI abnormalities were found in both insular cortices and hippocampi, whereas F(18)-FDG-PET showed hypermetabolism bilaterally in insular and prefrontal cortex. After resection of the underlying ovarian teratoma and with multimodal immunotherapy the patient substantially improved reaching a modified Rankin Scale score of 2 after 3 months. At follow-up, both hippocampi were still affected on MRI, whereas insular cortex appeared normal; however, both regions showed prominent glucose hypometabolism. CONCLUSIONS: Here, we report bi-insular cortical abnormalities on MRI and F(18)-FDG-PET in a patient with anti-NMDA-receptor encephalitis during the acute phase and after clinical improvement.

Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort.

JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study. Overall, anti-JCV antibody prevalence was 57.6%. Anti-JCV antibody prevalence in MS patients ranged from approximately 47% to 68% across these countries: Norway, 47.4%; Denmark, 52.6%; Israel, 56.6%; France, 57.6%; Italy, 58.3%; Sweden, 59.0%; Germany, 59.1%; Austria, 66.7% and Turkey, 67.7%. Prevalence increased with age (from 49.5% in patients < 30 years of age to 66.5% in patients ≥ 60 years of age; p < 0.0001 comparing all age categories), was lower in females than in males (55.8% versus 61.9%; p < 0.0001) and was not affected by prior immunosuppressant or natalizumab use.

Clinical and immunological follow-up of B-cell depleting therapy in CNS demyelinating diseases.

The aim of this observational study was to analyze clinical and immunological effects of rituximab treatment in neuromyelitis optica (NMO) and longitudinally extensive transverse myelitis (LETM) patients. We report on four NMO and two recurrent LETM patients who were treated with rituximab. Overall, B-cell depletion resulted in profound clinical stabilization in all patients. Rituximab did not affect titers of antibodies to aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein, immunoglobulin (Ig) isotypes and IgG subtype distribution, even after long-term B-cell depletion. Relapses were not associated with re-emerging B-cells, serum levels of B-cell activating factor (BAFF) or AQP4-IgG titers. BAFF serum levels increased following rituximab treatment.

Proteomic biomarker discovery in cerebrospinal fluid for cerebral vasospasm following subarachnoid hemorrhage.

Currently, there are no established biomarkers for diagnosing preclinical vasospasm or monitoring its progression. Two areas of extensive biomarker research are neuroimaging and biochemical markers in body fluids, such as cerebrospinal fluid (CSF). We performed a review of studies conducted over the past 2 decades summarizing the science to date and the evolution of CSF biomarkers in subarachnoid hemorrhage (SAH). A Medline search performed using the search terms "subarachnoid hemorrhage marker AND cerebrospinal fluid," limited to the period January 1, 1990 to June 1, 2009, returned 62 references. Abstracts that did not deal primarily with SAH and potential markers in the CSF of humans were excluded, resulting in 27 abstracts. Only articles providing sufficient information for a substantiated analysis were selected. In addition, articles identified in reference lists of individual articles were selected if considered appropriate. Evidence was classified as class I-IV and recommendations were classified as category A-C according to European Federation of Neurological Societies guidelines. We evaluated CSF markers in SAH patients and divided them into 3 categories: A, markers with auspicious value; B, candidate markers; and C, noncandidate markers. Category A markers included tumor necrosis factor (TNF)-α, soluble tumor necrosis factor receptor I (sTNFR-I), and interleukin (IL)-1 receptor antagonist (IL-1ra), as well as the neurofilament proteins NFL and NfH. Category B markers included apolipoprotein E (ApoE), F2-isoprostane (F2-IsoP), NOx, and the indicators for thrombin activity membrane-bound tissue factor (mTF) and thrombin-antithrombin III complex (TAT) for neurologic outcome prediction, as well as E-selectin, lactate, alpha-II spectrin breakdown products (SBDPs), asymmetric dimethyl-L-arginine (ADMA), and monocyte chemoattractant protein-1 (MCP-1) for vasospasm prognostication. Category C markers included S100B, platelet-derived growth factor (PDGF), YKL-40, chitotriosidase, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL-8. Cytokines and their receptors, as well as neuronal intracellular proteins, seem to be potential markers for outcome determination in patients after SAH.

Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders.

BACKGROUND: Serum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved. RESULTS: We analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels. CONCLUSIONS: We could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.