Time matters: Early-phase multiple sclerosis is accompanied by considerable impairments across multiple domains.

Impairments across multiple domains are a disabling consequence of multiple sclerosis (MS). Originating from preventive medical strategies, the "time matters"-perspective has become a focal point when treating MS. In particular, early detection of physical and cognitive deficits, along with deficits in patient-reported outcomes seems crucial to further optimize both pharmacological and non-pharmacological MS treatment strategies. Therefore, this topical review investigates the level of impairments across multiple domains (physical function, cognitive function, and patient-reported outcomes) in the early stage of MS (⩽5 years since diagnosis, including clinically isolated syndrome (CIS)), when compared to matched healthy controls. Even at early disease stages, studies show impairments corresponding to 8%-34% and small-to-large numerical effect sizes (0.35-2.85) in MS/CIS patients across domains. This evidence call for early screening programs along with early interventions targeting the multiple impaired domains. This further highlights the importance of preventive initiatives preserving and/or restoring physical and cognitive reserve capacity if possible.

The association between heart diseases and suicide: a nationwide cohort study.

OBJECTIVE: To assess the association between specific heart diseases and suicide. DESIGN: Nationwide retrospective cohort study. PARTICIPANTS: A total of 7 298 002 individuals (3 640 632 males and 3 657 370 females) aged ≥15 years and living in Denmark during 1980-2016. MAIN OUTCOME MEASURES: Incidence rate ratios (IRR) with 95% confidence intervals. In multivariate analysis, we adjust for sex, period, age group, living status, income level, Charlson Comorbidity Index, psychiatric disorders prior to heart disease and self-harm prior to heart disease. RESULTS: Excess suicide rate ratios were found for following disorders: heart failure (IRR: 1.48; 95% CI: 1.38-1.58); cardiomyopathy (IRR: 1.41; 95% CI: 1.16-1.70); acute myocardial infarction (IRR: 1.28; 95% CI: 1.21-1.36); cardiac arrest with successful resuscitation (IRR: 4.75; 95% CI: 3.57-6.33); atrial fibrillation and flutter (IRR: 1.42; 95% CI: 1.32-1.52); angina pectoris (IRR: 1.19; 95% CI: 1.12-1.26); and ventricular tachycardia (IRR: 1.53; 95% CI: 1.20-1.94). A higher rate of suicide was noted during the first 6 months after the diagnosis of heart failure (IRR: 2.38; 95% CI: 2.04-2.79); acute myocardial infarction (IRR: 2.24; 95% CI: 1.89-2.66); atrial fibrillation and flutter (IRR: 2.70; 95% CI: 2.30-3.18); and angina pectoris (IRR: 1.83; 95% CI: 1.53-2.19) when compared to later. CONCLUSION: Several specific disorders were found to be associated with elevated rates of suicide. Additionally, we found temporal associations with higher suicide rates in the first time after diagnosis. Our results underscore the importance of being attentive towards psychological distress in individuals with heart disease.

Hospital ethics reflection groups: a learning and development resource for clinical practice.

BACKGROUND: An ethics reflection group (ERG) is one of a number of ethics support services developed to better handle ethical challenges in healthcare. The aim of this article is to evaluate the significance of ERGs in psychiatric and general hospital departments in Denmark. METHODS: This is a qualitative action research study, including systematic text condensation of 28 individual interviews and 4 focus groups with clinicians, ethics facilitators and ward managers. Short written descriptions of the ethical challenges presented in the ERGs also informed the analysis of significance. RESULTS: A recurring ethical challenge for clinicians, in a total of 63 cases described and assessed in 3 ethical reflection groups, is to strike a balance between respect for patient autonomy, paternalistic responsibility, professional responsibilities and institutional values. Both in psychiatric and general hospital departments, the study participants report a positive impact of ERG, which can be divided into three categories: 1) Significance for patients, 2) Significance for clinicians, and 3) Significance for ward managers. In wards characterized by short-time patient admissions, the cases assessed were retrospective and the beneficiaries of improved dialogue mainly future patients rather than the patients discussed in the specific ethical challenge presented. In wards with longer admissions, the patients concerned also benefitted from the dialogue in the ERG. CONCLUSION: This study indicates a positive significance and impact of ERGs; constituting an interdisciplinary learning resource for clinicians, creating significance for themselves, the ward managers and the organization. By introducing specific examples, this study indicates that ERGs have significance for the patients discussed in the specific ethical challenge, but mostly indirectly through learning among clinicians and development of clinical practice. More research is needed to further investigate the impact of ERGs seen from the perspectives of patients and relatives.

Ethical challenges assessed in the clinical ethics Committee of Psychiatry in the region of Southern Denmark in 2010-2015: a qualitative content analyses.

BACKGROUND: The aim of this article is to give more insight into what ethical challenges clinicians in mental healthcare experience and discuss with a Clinical Ethics Committee in psychiatry in the Region of Southern Denmark. Ethical considerations are an important part of the daily decision-making processes and thereby for the quality of care in mental healthcare. However, such ethical challenges have been given little systematic attention - both in research and in practices. METHODS: A qualitative content analysis of 55 written case-reports from the Clinical Ethics Committee. The Committee offers clinicians in mental healthcare structured ethical analyses of ethical challenges and makes a thorough written case-report. RESULTS: The ethical challenges are grouped into three overarching topics: 1. Clinicians and their relation to patients and relatives. 2. Clinicians and institutional aspects of mental healthcare 3. Clinicians and mental healthcare in a wider social context. Through presentation of illustrative examples the complexity of daily clinical life in mental healthcare becomes evident, as well as typical interests, values and arguments. CONCLUSIONS: This qualitative study indicates that difficult ethical challenges are an inherent part of mental healthcare that requires time, space and competence to be dealt with adequately.

Cerebrospinal fluid biomarkers for Parkinson's disease - a systematic review.

Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease modifying treatments. Developments in analytical chemistry allow the detection of large numbers of molecules in plasma or cerebrospinal fluid, associated with the pathophysiology or pathogenesis of PD. This systematic review includes cerebrospinal fluid biomarker studies focusing on different disease pathways: oxidative stress, neuroinflammation, lysosomal dysfunction and proteins involved in PD and other neurodegenerative disorders, focusing on four clinical domains: their ability to (1) distinguish PD from healthy subjects and other neurodegenerative disorders as well as their relation to (2) disease duration after initial diagnosis, (3) severity of disease (motor symptoms) and (4) cognitive dysfunction. Oligomeric alpha-synuclein might be helpful in the separation of PD from controls. Through metabolomics, changes in purine and tryptophan metabolism have been discovered in patients with PD. Neurofilament light chain (NfL) has a significant role in distinguishing PD from other neurodegenerative diseases. Several oxidative stress markers are related to disease severity, with the antioxidant urate also having a prognostic value in terms of disease severity. Increased levels of amyloid and tau-proteins correlate with cognitive decline and may have prognostic value for cognitive deficits in PD. In the future, larger longitudinal studies, corroborating previous research on viable biomarker candidates or using metabolomics identifying a vast amount of potential biomarkers, could be a good approach.

Psychosocial therapy and causes of death after deliberate self-harm: a register-based, nationwide multicentre study using propensity score matching.

BACKGROUND: Psychosocial therapy after deliberate self-harm might be associated with reduced risk of specific causes of death. METHOD: In this matched cohort study, we included patients, who after an episode of deliberate self-harm received psychosocial therapy at a Suicide Prevention Clinic in Denmark between 1992 and 2010. We used propensity score matching in a 1:3 ratio to select a comparison group from 59 046 individuals who received standard care. National Danish registers supplied data on specific causes of death over a 20-year follow-up period. RESULTS: At the end of follow-up, 391 (6.9%) of 5678 patients in the psychosocial therapy group had died, compared with 1736 (10.2%) of 17 034 patients in the matched comparison group. Lower odds ratios of dying by mental or behavioural disorders [0.54, 95% confidence interval (CI) 0.37-0.79], alcohol-related causes (0.63, 95% CI 0.50-0.80) and other diseases and medical conditions (0.61, 95% CI 0.49-0.77) were noted in the psychosocial therapy group. Also, we found a reduced risk of dying by suicide as well as other external causes, however, not by neoplasms and circulatory system diseases. Numbers needed to treat were 212.9 (95% CI 139.5-448.4) for mental or behavioural disorders as a cause of death, 111.1 (95% CI 79.2-210.5) for alcohol-related causes and 96.8 (95% CI 69.1-161.8) for other diseases and medical conditions. CONCLUSIONS: Our findings indicate that psychosocial therapy after deliberate self-harm might reduce long-term risk of death from select medical conditions and external causes. These promising results should be tested in a randomized design.

Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene.

BACKGROUND: In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted. OBJECTIVE: The objective of this research paper is to search for rare genetic MS risk variants in the genetically homogenous population of the isolated Faroe Islands. METHODS: Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome-chip. The individuals make up 1596 pair-combinations in which we searched for identical-by-descent shared segments using the PLINK-program. RESULTS: A segment spanning 63 SNPs with excess case-case-pair sharing was identified (0.00173 < p > 0.00212). A haplotype consisting of 42 of the 63 identified SNPs which spanned the entire the Sortilin-related vacuolar protein sorting 10 domain containing receptor 3 (SORCS3) gene had a carrier frequency of 0.34 in cases but was not present in any controls (p = 0.0008). CONCLUSION: This study revealed an oversharing in case-case-pairs of a segment spanning 63 SNPs and the entire SORCS3. While not previously associated with MS, SORCS3 appears to be important in neuronal plasticity through its binding of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis.

Minocycline added to subcutaneous interferon ß-1a in multiple sclerosis: randomized RECYCLINE study.

BACKGROUND AND PURPOSE: Combining different therapies may improve disease control in patients with relapsing-remitting multiple sclerosis (RRMS). This study assessed the efficacy and safety of minocycline added to subcutaneous (sc) interferon (IFN) ß-1a therapy. METHODS: This was a double-blind, randomized, placebo-controlled multicentre study. Within 3 months (±1 month) of starting sc IFN ß-1a 44 µg three times weekly, patients with RRMS were randomized to minocycline 100 mg twice daily or placebo, added to sc IFN ß-1a, for 96 weeks. The primary efficacy endpoint was the time to first qualifying relapse. Secondary efficacy endpoints were the annualized relapse rate for qualifying relapses, the number of new/enlarging T2-weighted lesions and change in brain volume [magnetic resonance imaging (MRI) was performed only in a few selected centres]. In addition, a number of tertiary efficacy endpoints were assessed. RESULTS: One hundred and forty-nine patients received minocycline and 155 received placebo; MRI data were available for 23 and 27 patients, respectively. The time to first qualifying relapse did not differ significantly for minocycline versus placebo (hazard ratio 0.85; 95% confidence interval 0.53, 1.35; log-rank = 0.50; P = 0.48). There were no statistically significant differences between the two groups on other efficacy endpoints, although some numerical trends in favour of minocycline were observed. No unexpected adverse events were reported, but more patients discontinued because of adverse events with minocycline versus placebo. CONCLUSION: Minocycline showed no statistically significant beneficial effect when added to sc IFN ß-1a therapy.

Acute and chronic cytokine responses to resistance exercise and training in people with multiple sclerosis.

Exercise is a well-established part of rehabilitation for people with multiple sclerosis (PwMS), and it has been hypothesized to stimulate an anti-inflammatory environment that might be disease modifying. Yet, investigations on exercise-induced immune responses are scarce and generally not paying attention to the medical treatments of the patient. At present, PwMS are routinely enrolled in immunosuppressive medication, but exercise-induced immunomodulatory effects have not been investigated under these circumstances. The objective of this study was to investigate the acute and chronic cytokines responses to resistance exercise training in medicated PwMS. Thirty-five people with relapsing-remitting multiple sclerosis (MS) treated with interferon (IFN)-ß, were randomized to a 24-week progressive resistance training (PRT) or control group. Plasma interleukin (IL)-1ß, IL-4, IL-10, IL-17F, IL-23, tumor necrosis factor-α and IFN-γ were measured before and after 24 weeks of PRT. The acute effect was evaluated following standardized single-bout resistance exercise in the untrained and the trained state. No changes were observed in resting cytokine levels after PRT. However, an indication of reduced IL-17F secretion following resistance exercise was observed in the trained compared with the untrained state. This study suggests little acute and chronic effect of PRT on cytokine levels in IFN-treated PwMS.

High inbreeding in the Faroe Islands does not appear to constitute a risk factor for multiple sclerosis.

BACKGROUND: Large population-based genome-wide association studies have identified several multiple sclerosis (MS) genetic risk variants, but the existing missing heritability warrants different strategies. Isolated populations offer an alternative way of searching for rare genetic variants and evaluating the possible role of consanguinity in the development of MS. Studies of consanguinity and MS risk have yielded conflicting results. OBJECTIVES: In this study we investigated the role of consanguinity on MS risk in the relatively isolated Faroe Islands, which have a presumed high level of inbreeding. METHODS: A total of 29 cases and 28 matched controls were genotyped and assessed for inbreeding coefficients, number of runs of homozygosity (ROH) at different lengths and observed number of homozygotes as measures of relatedness. Parametric and non-parametric statistical models were applied. RESULTS: Both cases and controls exhibited considerable relatedness demonstrated by very high inbreeding coefficients, large number of observed homozygotes and many long ROH. However, apart from the number of ROH ≥ 2.5 mega base pairs, no significant differences between the two groups were observed. CONCLUSIONS: Overall, no significant difference between cases and controls were found, indicating that consanguinity in itself does not appear to be an important risk factor for MS in the population of the Faroe Islands.

The effect of exercise on depressive symptoms in multiple sclerosis based on a meta-analysis and critical review of the literature.

BACKGROUND AND PURPOSE: The purpose of this study was to perform a systematic review of the literature on the effects of exercise on depressive symptoms in patients with multiple sclerosis (MS), as well as to apply meta-analytical procedures to the results. METHODS: A systematic search covering eight databases was conducted. The included studies were randomized controlled trials applied to people with definite MS who completed a structured exercise intervention which were compared to any comparator, including other forms of exercise. The outcomes included a primary measure of depression/depressive symptoms or an instrument with a clearly defined depression subscale. RESULTS: Fifteen randomized controlled trial studies were identified including a total of 331 exercising subjects and 260 controls. The average Physiotherapy Evidence Database (PEDro) score was 5.6 ± 1.3 points. Only one study applied depressive symptoms as the primary outcome. Four studies showed positive effects of exercise on depressive symptoms. An in-depth analysis of the studies revealed that the baseline level of depressive symptoms, patient disability level, choice of depression instrument and exercise intensity may influence the results. The meta-analysis included 12 studies reflecting a total of 476 subjects. The standardized mean difference across studies was g = -0.37, 95% confidence interval (-0.56; -0.17), and the null hypothesis of homogeneity within the sample could not be rejected (Q = 12.05, df = 11, P = 0.36). DISCUSSION: Exercise may be a potential treatment to prevent or reduce depressive symptoms in individuals with MS, but existing studies do not allow solid conclusions. Future well-designed studies evaluating the effects of exercise on depressive symptoms and major depression disorder in MS are highly warranted.

Changes in cognition, arm function and lower body function after slow-release Fampridine treatment.

OBJECTIVE: We aimed to evaluate the effect of slow-release (SR) Fampridine on multiple outcome measures reflecting different domains, and to compare the responsiveness of the Six Spot Step Test (SSST) and the Timed 25 Foot Walk (T25FW). METHODS: For this study 108 participants were included. On day 0 they were tested with the T25FW, the SSST, the 9-Hole Peg Test (9-HPT), the 5 Times Sit-To-Stand test (5-STS) and the Symbol Digit Modalities Test (SDMT). Four weeks of treatment with SR Fampridine 10 mg BID was commenced. Participants were tested again after 26-28 days of treatment. RESULTS: Mean changes observed were: SSST -3.4±6.4 s (p<0.001), T25FW -1.2±3.7 s (p<0.001), 9-HPT -1.2±6.0 s (p<0.001), 5- STS -3.4±7.2 s (p<0.001) and SDMT 1.4±4.8 a.u. (p=0.003). Change on the SSST differed significantly from T25FW (SSST 17.0±19.6% vs. T25FW 11.2±17.1%, p=0.0013). Some 48.6% were found to have a meaningful change on the SSST compared with 25.7% on the T25FW. The response to treatment with SR Fampridine did not correlate with age, sex, Expanded Disability Status Scale and disease duration. CONCLUSION: SR Fampridine treatment has significant effects on different domains including upper and lower body and cognition. Furthermore, the SSST is more responsive to the effect of SR Fampridine than is the T25FW. ClinicalTrials.gov identifier: NCT01656148.

Endurance training is feasible in severely disabled patients with progressive multiple sclerosis.

This study tested whether upper-body endurance training (ET) is feasible and can be performed at sufficient intensity to induce cardiovascular adaptations in severely disabled patients with progressive multiple sclerosis (MS). Eleven progressive MS patients (6.5 ≤ EDSS ≤ 8.0) scheduled for a four-week inpatient rehabilitation program were randomized to a control group (CON, n = 5) that received standard individualized MS rehabilitation or an intervention group (EXE, n = 6) that in addition received 10 sessions of predominantly upper-body ET. One patient dropped out of the EXE group (drop-out rate: 1/6~17%) and no adverse events were recorded. The EXE group completed on average 9.3±0.8 sessions (~96.0±5%). During the ET sessions an average heart rate of 93.9±9.3beats*min(-1) were sustained corresponding to 91.6±6.8% of the maximal pre-intervention heart rate. In the EXE group a trend toward a time*group interaction was seen for VO2peak (p = 0.06). ET is feasible in severely disabled patients with progressive MS and it can probably be performed at sufficient intensity to induce cardiovascular adaptations.

Multiple sclerosis and risk of Parkinson's disease: a Danish nationwide cohort study.

BACKGROUND AND PURPOSE: Case reports have observed a co-occurrence of multiple sclerosis (MS) and Parkinson's disease (PD) and it has been hypothesized that MS lesions could affect dopaminergic pathways causing parkinsonism. Our aim was to examine the association between MS and PD in a historically prospective cohort study using Danish nationwide register data. METHODS: Multiple sclerosis patients identified in the Multiple Sclerosis Registry were followed for PD from 1977 to 2011 in the National Patient Register. As measures of relative risk, ratios of observed to expected incidence rates of first hospitalization for PD amongst persons with MS were used, i.e. standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). RESULTS: Amongst 15,557 MS patients 26 cases of PD were observed versus 26.51 expected, reflecting no overall increased risk of PD (SIR 0.98, 95% CI 0.67-1.44). Similar estimates were seen for female (SIR 0.99, 95% CI 0.58-1.67) and male MS patients (SIR 0.97, 95% CI 0.55-1.72). Likewise, no increased risk of PD amongst MS patients was observed in a robustness analysis backdating the date of diagnosis of PD by 5 years to account for the time lag between disease onset and first hospital contact with PD (SIR 0.57, 95% CI 0.32-1.00). CONCLUSION: Our data do not suggest an increased risk of PD amongst patients with MS.

HLA, PTPN22 and PD-1 associations as markers of autoimmunity in neuromyelitis optica.

BACKGROUND: Neuromyelitis optica (NMO) is a disease with autoimmune characteristics. A genetic autoimmune dependency for NMO has not been clarified in detail. OBJECTIVE: To investigate immunogenetic aspects of NMO. METHODS: Forty-one patients with NMO and 42 patients with multiple sclerosis (MS) were diagnosed in a population-based Caucasian cohort. HLA DQA1, DQB1, and DRB1 alleles were determined. Polymorphisms in programmed death 1 (PD-1) PD-1.3 G/A and protein tyrosine phosphatase non-receptor 22 (PTPN22) 1858 C/T were genotyped. RESULTS: In the NMO group 15% had other autoimmune disorders and 39% had family occurrence of autoimmunity, comparable to MS. A higher frequency of a family history (17%) of NMO and MS was found in the NMO group (p < 0.026). The frequency of HLA-DQB1*0402 allele was increased in NMO (p after Bonferroni correction, cp < 0.035) and the HLA-DRB1*15 and DQB1*06 alleles were increased in MS (cp < 0.0027, cp < 0.01), compared to controls. No associations of the PTPN22 1858 T were detected. The PD-1.3A allele was increased both in NMO (p < 0.0023) and in MS patients (p < 0.028) compared to controls. CONCLUSION: Patients with NMO had frequent co-existence of autoimmunity and family occurrence of NMO and MS. The PD-1.3A allele was associated with NMO. The data suggest genetic autoimmune dependency of NMO.

Evaluating the use and limitations of the Danish National Patient Register in register-based research using an example of multiple sclerosis.

BACKGROUND: The Danish National Patient Register, Landspatientregistret (LPR), is a register of all hospital discharges and outpatient treatments in Denmark. AIMS: It is increasingly used in research so it is important to understand to what extent this can be used as an accurate source of information. Virtually all patients in Denmark with multiple sclerosis (MS) are reported to the Combined MS Registry (DMSR), so this was used as the standard which the LPR was compared against. METHODS: All residents of Denmark are assigned a unique Civil Register (CPR) number; this was used to compare data between registers. The LPR completeness was estimated by the proportion of cases from the DMSR that could be retrieved from the LPR. The LPR validity was estimated by the proportion of cases, listed in the LPR and DMSR, in whom the MS diagnosis could be confirmed as definite/probable/possible by the DMSR. RESULTS: We found that 86.9% of those who were DMSR listed with an approved MS diagnosis were also listed in the LPR with a MS diagnosis. The diagnosis was valid in 96.3% of patients listed in the LPR when compared against the DMSR. CONCLUSIONS: The low completeness reduces the usefulness of the LPR in epidemiological MS research, in particular incidence studies. The study also found that the completeness of the LPR could be increased to 92.8% by including LPR records from other departments in addition, but this reduced the validity of the LPR to 95.1%. However, these results cannot uncritically be applied to registration of other diseases in the LPR.

The effect of exercise therapy on fatigue in multiple sclerosis.

BACKGROUND: Fatigue occurs in the majority of patients with multiple sclerosis (MS) and therapeutic possibilities are few. Exercise therapy is a therapeutic option but no studies have systematically reviewed the existing literature evaluating the effect of exercise therapy on MS fatigue. OBJECTIVE: To determine the effect of exercise therapy on MS fatigue by systematically reviewing the literature. METHODS: A comprehensive literature search (PubMed, SweMed +, Embase, Cochrane, CINAHL, PEDro, Sport Discuss and Bibliotek.dk) was conducted. RESULTS: Studies evaluating the effect of exercise therapy on MS fatigue show heterogeneous results and only few studies have evaluated MS fatigue as the primary outcome. The heterogeneous findings seem to be related to the selected study population, which in many studies are non-fatigued. Most studies that have included fatigued patients with MS show positive effects, although it is not clear whether any exercise modalities are superior to others because there are no comparative studies regarding different exercise interventions. CONCLUSION: Exercise therapy has the potential to induce a positive effect on MS fatigue, but findings are heterogeneous probably because many studies have applied non-fatigued study populations. Furthermore, only few studies have evaluated MS fatigue as the primary outcome measure, emphasizing the need for future studies within this field.

Neuromyelitis optica (NMO)--an autoimmune disease of the central nervous system (CNS).

In the past 10 years, neuromyelitis optica (NMO) has evolved from Devic's categorical clinical description into a broader disease spectrum. Serum IgG antibodies have been identified in NMO patients with the water channel aquaporin-4 (AQP4) as their main target antigen. AQP4 antibodies/NMO-IgG have been shown to be a highly specific and moderately sensitive serum biomarker for NMO. The immunopathology of NMO lesions supports that anti-AQP4 antibodies/NMO-IgG are involved in the pathogenesis of NMO. In vitro studies have demonstrated that human NMO-IgG induce necrosis and impair glutamate transport in astrocytes. Certain ethnic groups, notably of Asian and African origin, seem to be more susceptible to NMO than others. The genetic background for these putative differences is not known, a weak human leucocyte antigen association has been identified. AQP4 gene variants could represent a genetic susceptibility factor for different clinical phenotypes within the NMO spectrum. Experimental models have been described including a double-transgenic myelin-specific B- and T-cell mouse. NMO-like disease has been induced with passive transfer of human anti-AQP4 antibodies to the plasma of mice with pre-established experimental autoimmune encephalomyelitis or by intrathecal administration to naive mice. NMO may be characterized as a channelopathy of the central nervous system with autoimmune characteristics.