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1.  Neuroplasticity and functional recovery in multiple sclerosis 
Nature reviews. Neurology  2012;10.1038/nrneurol.2012.179.
The development of therapeutic strategies that promote functional recovery is a major goal of multiple sclerosis (MS) research. Neuroscientific and methodological advances have improved our understanding of the brain’s recovery from damage, generating novel hypotheses for potential targets or modes of intervention and laying the foundation for the development of scientifically informed strategies promoting recovery in interventional studies. This Review aims to encourage the transition from characterization of recovery mechanisms to the development of strategies that promote recovery in MS. We discuss current evidence for functional reorganization that underlies recovery and its implications for development of new recovery-oriented strategies in MS. Promotion of functional recovery requires an improved understanding of recovery mechanisms modulated by interventions and the development of reliable measures of therapeutic effects. As imaging methods can be used to measure functional and structural alterations associated with recovery, this Review discusses their use as reliable markers to measure the effects of interventions.
PMCID: PMC3770511  PMID: 22986429
2.  Treatment of Neuromyelitis Optica: Review and Recommendations 
Neuromyelitis optica (NMO) is an autoimmune demyelinating disease preferentially targeting the optic nerves and spinal cord. Once regarded as a variant of multiple sclerosis (MS), NMO is now recognized to be a different disease with unique pathology and immunopathogenesis that does not respond to traditional MS immunomodulators such as interferons. Preventive therapy in NMO has focused on a range of immunosuppressive medications, none of which have been validated in a rigorous randomized trial. However, multiple retrospective and a few recent prospective studies have provided evidence for the use of six medications for the prevention of NMO exacerbations: azathioprine, rituximab, mycophenolate mofetil, prednisone, methotrexate and mitoxantrone. This review provides a comprehensive analysis of each of these medications in NMO and concludes with a set of recommended consensus practices.
PMCID: PMC3926208  PMID: 24555176
Neuromyelitis optica; aquaporin 4; drug therapy; immunosuppression
3.  UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model 
BMJ Open  2014;4(1):e004073.
In 2002, the UK's National Institute for Health and Care Excellence concluded that the multiple sclerosis (MS) disease modifying therapies; interferon-β and glatiramer acetate, were not cost effective over the short term but recognised that reducing disability over the longer term might dramatically improve the cost effectiveness. The UK Risk-sharing Scheme (RSS) was established to ensure cost-effective provision by prospectively collecting disability-related data from UK-treated patients with MS and comparing findings to a natural history (untreated) cohort. However, deficiencies were found in the originally selected untreated cohort and the resulting analytical approach. This study aims to identify a more suitable natural history cohort and to develop a robust analytical approach using the new cohort.
The Scientific Advisory Group, recommended the British Columbia Multiple Sclerosis (BCMS) database, Canada, as providing a more suitable natural history comparator cohort. Transition probabilities were derived and different Markov models (discrete and continuous) with and without baseline covariates were applied.
MS clinics in Canada and the UK.
From the BCMS database, 898 ‘untreated’ patients with MS considered eligible for drug treatment based on the UK's Association of British Neurologists criteria.
Outcome measure
The predicted Expanded Disability Status Scale (EDSS) score was collected and assessed for goodness of fit when compared with actual outcome.
The BCMS untreated cohort contributed 7335 EDSS scores over a median 6.4 years (6357 EDSS ‘transitions’ recorded at consecutive visits) during the period 1980–1995. A continuous Markov model with ‘onset age’ as a binary covariate was deemed the most suitable model for future RSS analysis.
A new untreated MS cohort from British Columbia has been selected and will be modelled using a continuous Markov model with onset age as a baseline covariate. This approach will now be applied to the treated UK RSS MS cohort for future price adjustment calculations.
PMCID: PMC3902459  PMID: 24441054
quality of life; risk sharing scheme; interferon-beta; glatiramer acetate; Markov model
4.  Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study 
Journal of Neurology  2013;261:267-276.
The aim of this study was to evaluate short-term safety and tolerability of fingolimod in a real-world population with relapsing multiple sclerosis, focusing on cardiac safety during treatment initiation. Patients received fingolimod 0.5 mg once daily for four months. Patients excluded from the pivotal studies with certain pre-existing cardiac conditions or baseline cardiac findings (PCCs), and those receiving beta blockers (BBs) and/or calcium channel blockers (CCBs), were eligible. Heart rate (HR) and electrical conduction events were monitored using ambulatory electrocardiography for at least 6 h after the first dose. Of 2,417 enrolled patients, 2,282 (94.4 %) completed the study. Fingolimod initiation was associated with a transient, mostly asymptomatic decrease in HR. Bradycardia adverse events occurred in 0.6 % of patients and were more frequent in individuals receiving BBs/CCBs (3.3 %) than in other patient subgroups (0.5–1.4 %); most events were asymptomatic, and all patients recovered without pharmacological intervention. In the 6 h post-dose, the incidences of Mobitz type I second-degree atrioventricular block (AVB) and 2:1 AVB were higher in patients with PCCs (4.1 and 2.0 %, respectively) than in those without (0.9 and 0.3 %, respectively); at pre-dose screening, patients with PCCs had the same incidence of Mobitz type I second-degree AVB (4.1 %) and a slightly lower incidence of 2:1 AVB (0.7 %) than 6 h post-dose. All recorded conduction abnormalities were asymptomatic. This study adds to the evidence showing that cardiac effects during fingolimod initiation remain consistent with those known from previous, controlled studies, even if patients with PCCs are included.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-013-7115-8) contains supplementary material, which is available to authorized users.
PMCID: PMC3915082  PMID: 24221641
Fingolimod; Multiple sclerosis; Safety; Tolerability
5.  Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution 
Neurology  2013;80(14):1330-1337.
Neuromyelitis optica and its spectrum disorder (NMOSD) can present similarly to relapsing-remitting multiple sclerosis (RRMS). Using a quantitative lesion mapping approach, this research aimed to identify differences in MRI brain lesion distribution between aquaporin-4 antibody–positive NMOSD and RRMS, and to test their diagnostic potential.
Clinical brain MRI sequences for 44 patients with aquaporin-4 antibody–positive NMOSD and 50 patients with RRMS were examined for the distribution and morphology of brain lesions. T2 lesion maps were created for each subject allowing the quantitative comparison of the 2 conditions with lesion probability and voxel-wise analysis.
Sixty-three percent of patients with NMOSD had brain lesions and of these 27% were diagnostic of multiple sclerosis. Patients with RRMS were significantly more likely to have lesions adjacent to the body of the lateral ventricle than patients with NMOSD. Direct comparison of the probability distributions and the morphologic attributes of the lesions in each group identified criteria of “at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or the presence of a subcortical U-fiber lesion; or a Dawson's finger-type lesion,” which could distinguish patients with multiple sclerosis from those with NMOSD with 92% sensitivity, 96% specificity, 98% positive predictive value, and 86% negative predictive value.
Careful inspection of the distribution and morphology of MRI brain lesions can distinguish RRMS and NMOSD.
PMCID: PMC3656462  PMID: 23486868
6.  Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS – Neurofilament as a Surrogate of Disease Progression 
PLoS ONE  2013;8(8):e70019.
Lamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.
SPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12–24 and 0–24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.
Treatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12–24 months p = 0.043, Nfh 0–24 months p = 0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.
The relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.
PMCID: PMC3731296  PMID: 23936370
7.  Relating Brain Damage to Brain Plasticity in Patients With Multiple Sclerosis 
Failure of adaptive plasticity with increasing pathology is suggested to contribute to progression of disability in multiple sclerosis (MS). However, functional impairments can be reduced with practice, suggesting that brain plasticity is preserved even in patients with substantial damage.
Here, functional magnetic resonance imaging (fMRI) was used to probe systems-level mechanisms of brain plasticity associated with improvements in visuomotor performance in MS patients and related to measures of microstructural damage.
23 MS patients and 12 healthy controls underwent brain fMRI during the first practice session of a visuomotor task (short-term practice) and after 2 weeks of daily practice with the same task (longer-term practice). Participants also underwent a structural brain MRI scan.
Patients performed more poorly than controls at baseline. Nonetheless, with practice, patients showed performance improvements similar to controls and independent of the extent of MRI measures of brain pathology. Different relationships between performance improvements and activations were found between groups: greater short-term improvements were associated with lower activation in the sensorimotor, posterior cingulate, and parahippocampal cortices for patients, whereas greater long-term improvements correlated with smaller activation reductions in the visual cortex of controls.
Brain plasticity for visuomotor practice is preserved in MS patients despite a high burden of cerebral pathology. Cognitive systems different from those acting in controls contribute to this plasticity in patients. These findings challenge the notion that increasing pathology is accompanied by an outright failure of adaptive plasticity, supporting a neuroscientific rationale for recovery-oriented strategies even in chronically disabled patients.
PMCID: PMC3674542  PMID: 22328685
8.  Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease 
Neurology  2012;79(11):1145-1154.
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).
A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function.
Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme.
We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.
PMCID: PMC3525307  PMID: 22933740
9.  Congenital myasthenic syndromes due to mutations in ALG2 and ALG14 
Brain  2013;136(3):944-956.
Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed linkage analysis, whole-exome and whole-genome sequencing to determine the underlying defect in patients with an inherited limb-girdle pattern of myasthenic weakness. We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome. Through analogy with yeast, ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation. We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells. ALG2 is an alpha-1,3-mannosyltransferase that also catalyses early steps in the asparagine-linked glycosylation pathway. Mutations were identified in two kinships, with mutation ALG2p.Val68Gly found to severely reduce ALG2 expression both in patient muscle, and in cell cultures. Identification of DPAGT1, ALG14 and ALG2 mutations as a cause of congenital myasthenic syndrome underscores the importance of asparagine-linked protein glycosylation for proper functioning of the neuromuscular junction. These syndromes form part of the wider spectrum of congenital disorders of glycosylation caused by impaired asparagine-linked glycosylation. It is likely that further genes encoding components of this pathway will be associated with congenital myasthenic syndromes or impaired neuromuscular transmission as part of a more severe multisystem disorder. Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation.
PMCID: PMC3580273  PMID: 23404334
congenital myasthenic syndrome; ALG2; ALG14; mutation; N-linked glycosylation
10.  A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology 
Brain  2012;135(10):2938-2951.
Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a ‘tract-specific’ pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.
PMCID: PMC3470716  PMID: 23065787
multiple sclerosis; post-mortem imaging; diffusion imaging; white matter tracts; neurodegeneration
11.  Antibody to Aquaporin 4 in the Diagnosis of Neuromyelitis Optica 
PLoS Medicine  2007;4(4):e133.
Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) of putative autoimmune aetiology. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. Recently, using indirect immunofluorescence analysis, a new serum autoantibody (NMO-IgG) has been detected in NMO patients. The binding sites of this autoantibody were reported to colocalize with aquaporin 4 (AQP4) water channels. Thus we hypothesized that AQP4 antibodies in fact characterize NMO patients.
Methods and Findings
Based on these observations we cloned human water channel AQP4, expressed the protein in a eukaryotic transcription/translation system, and employed the recombinant AQP4 to establish a new radioimmunoprecipitation assay (RIPA). Indeed, application of this RIPA showed that antibodies against AQP4 exist in the majority of patients with NMO (n = 37; 21 positive) as well as in patients with isolated longitudinally extensive transverse myelitis (n = 6; six positive), corresponding to a sensitivity of 62.8% and a specificity of 98.3%. By contrast, AQP4 antibodies were virtually absent in 291 other participants, which included patients with MS (n = 144; four positive), patients with other inflammatory and noninflammatory neurological diseases (n = 73; one positive), patients with systemic autoimmune diseases (n = 45; 0 positive), and healthy participants (n = 29; 0 positive).
In the largest series reported so far to our knowledge, we quantified AQP4 antibodies in patients with NMO versus various other diseases, and showed that the aquaporin 4 water channel is a target antigen in a majority of patients with NMO. The newly developed assay represents a highly specific, observer-independent, and easily reproducible detection method facilitating clinically relevant discrimination between NMO, MS, and other inflammatory diseases.
A newly developed method to detect antibodies to the aquaporin 4 water channel can help discriminate between neuromyelitis optica, multiple sclerosis, and other inflammatory diseases.
Editors' Summary
Neuromyelitis optica (NMO or Devic syndrome) is a rare disease in which the immune system destroys the myelin (fatty material that insulates nerve fibers so that the body and the brain can communicate using electrical messages) in the optic nerve and spinal cord. Myelin destruction (demyelination) in these parts of the central nervous system (CNS) causes pain and swelling (inflammation) of the optic nerve (optic neuritis) and spinal cord (myelitis). The resultant disruption of communication along these nerves means that patients with NMO experience temporary or permanent blindness in one or both eyes that is preceded or followed by limb weakness or paralysis and loss of bladder and bowel control. These two sets of symptoms can occur many months apart and may happen once during a person's lifetime or recur at intervals. There is no cure for NMO, but corticosteroids or plasmapheresis reduce inflammation during acute attacks and, because NMO is an autoimmune disease (one in which the immune system attacks the body's own tissues instead of foreign organisms), long-term immunosuppression may prevent further attacks.
Why Was This Study Done?
There are many inflammatory/demyelinating diseases of the CNS with clinical symptoms similar to those of NMO. It is particularly hard to distinguish between NMO and multiple sclerosis, an autoimmune disease that involves widespread demyelination. Neurologists need to make a correct diagnosis before starting any treatment and usually use clinical examination and magnetic resonance imaging (to detect sites of inflammation) to help them in this task. Recently, however, a biomarker for NMO was identified. Many patients with NMO make autoantibodies (proteins that recognize a component of a person's own tissues) called NMO-IgGs. These recognize aquaporin 4 (AQP4), a protein that allows water to move through cell membranes. It is not known how often patients with NMO or other demyelinating diseases make antibodies to AQP4, so it is unclear whether testing for these antibodies would help in the diagnosis of NMO. In this study, the researchers have developed a new assay for antibodies to AQP4 and then quantified the antibodies in patients with NMO and other demyelinating diseases.
What Did the Researchers Do and Find?
The researchers made radioactively labeled AQP4 in a test tube, then incubated samples of this with serum (the liquid portion of blood), added small beads coated with protein A (a bacterial protein that binds to antibodies) and allowed the beads to settle. The amount of radioactivity attached to the beads indicates the amount of antibody to AQP4 in the original serum. The researchers used this radioimmunoprecipitation assay to measure antibodies to AQP4 in sera from 37 patients with NMO and from six with another neurological condition, longitudinally extensive transverse myelitis (LETM), which is characterized by large demyelinated lesions across the width of the spinal cord but no optic neuritis; these patients often develop NMO. They also measured antibodies to AQP4 in the sera of nearly 300 other people including patients with multiple sclerosis, other neurological conditions, various autoimmune diseases, and healthy individuals. Nearly two-thirds of the patients with NMO and all those with LETM made antibodies against AQP4; very few of the other study participants made these antibodies. In particular, only four of the 144 patients with multiple sclerosis made AQP4 antibodies.
What Do These Findings Mean?
These findings indicate that testing for antibodies to AQP4 could help neurologists distinguish between NMO and multiple sclerosis and between NMO and other demyelinating diseases of the CNS. In addition, the new radioimmunoprecipitation assay provides a standardized, high-throughput way to quantitatively test for these antibodies, whereas the indirect immune fluorescence assay for measurement of unspecific NMO-IgG is observer-dependent and nonquantitative. Although these findings need to be confirmed in more patients and the assay's reliability demonstrated in different settings, the measurement of antibodies to AQP4 by radioimmunoprecipitation may become a standard part of the differential diagnosis of NMO. Additional research will determine whether AQP4 is the only protein targeted by autoantibodies in NMO and whether this targeting is a critical part of the disease process.
Additional Information.
Please access these Web sites via the online version of this summary at
US National Institute of Neurological Disorders and Stroke has information for patients who have neuromyelitis optica, transverse myelitis, and multiple sclerosis
The Transverse Myelitis Association offers information and useful links for patients and their carers about transverse myelitis and neuromyelitis optica (in several languages, including English and Spanish)
Mayo Clinic information for patients on Devic's syndrome
Medline Plus encyclopedia pages discuss autoimmune disorders (in English and Spanish)
A brief overview of aquaporins is available from the University of Miami
The American MS Society has information on MS
PMCID: PMC1852124  PMID: 17439296

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