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1.  Gaze palsy, hypogeusia and a probable association with miscarriage of pregnancy - the expanding clinical spectrum of non-opticospinal neuromyelitis optica spectrum disorders: a case report 
BMC Research Notes  2015;8:36.
Background
Neuromyelitis optica is characterised by optic neuritis, longitudinally-extensive transverse myelitis and presence of anti-aquaporin-4 antibodies in the serum. However, non-opticospinal central nervous system manifestations have been increasingly recognised. Awareness of the widening clinical spectrum of neuromyelitis optica (unified within the nosology of ‘neuromyelitis optica spectrum disorders’) is key to earlier diagnosis and appropriate therapy. We report 2 patients to illustrate the varied clinical manifestations of neuromyelitis optica spectrum disorders while postulating an effect of anti-aquaporin-4 antibodies on the miscarriage of pregnancy. This is the first report of horizontal gaze palsy as a presenting symptom of neuromyelitis optica spectrum disorders.
Case presentation
Patient 1
A 17-year-old Sri Lankan female presented with hypersomnolence, lateral gaze palsy and loss of taste of 1 week duration. Two years previously she had presented with intractable hiccups and vomiting followed by a brainstem syndrome. Magnetic resonance imaging showed a lesion in the left cerebellum extending into the pons while lesions in bilateral hypothalami and medulla noted 2 years ago had resolved. Autoimmune, vasculitis and infection screens were negative. Anti-aquaporin-4 antibodies were detected in serum. All her symptoms resolved with immunosuppressive therapy.
Patient 2
A 47-Year-old Sri Lankan female presented with persistent vomiting lasting over 3 weeks. Three years previously, at 25-weeks of her 4th pregnancy, she had presented with quadriparesis and was found to have a longitudinally extensive transverse myelitis from C2 to T2 vertebral levels, which gradually improved following intravenous steroid therapy. Magnetic resonance imaging showed a hyper-intense lesion in the area postrema and longitudinally extensive atrophy of the cord corresponding to her previous myelitis. Autoimmune, vasculitis and infection screens were negative. Anti-aquaporin-4 antibodies were detected in serum. Her vomiting subsided with immunosuppressive therapy. Her second pregnancy had resulted in a first-trimester miscarriage.
Conclusion
The clinical spectrum of neuromyelitis optica spectrum disorders has expanded beyond optic neuritis and myelitis to include non-opticospinal syndromes involving the diencephalon, brainstem and cerebrum. Our report highlights the varied central nervous system manifestations of neuromyelitis optica spectrum disorders and miscarriage of pregnancy possibly related to anti-aquaporin-4 antibodies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13104-015-0991-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13104-015-0991-5
PMCID: PMC4328076
NMOSD; Gaze palsy; Hypogeusia; Area postrema; Miscarriage
2.  Severe optic neuritis in a patient with combined neuromyelitis optica spectrum disease and primary Sjögren’s syndrome: a case report 
Introduction
Optic neuritis, although uncommon, can be the initial presentation of Sjögren’s syndrome. Coexisting Sjögren’s syndrome has also been reported with neuromyelitis optica spectrum disorder. This case report highlights the association between the two diseases and the importance of rheumatological and neurological evaluations in patients with such diagnoses. Distinction of neuromyelitis optica with coexisting connective tissue disease has both prognostic and therapeutic significance for the patient.
Case presentation
We report a case of a 56-year-old Chinese woman who presented with bilateral asymmetric visual loss secondary to optic neuritis. She was subsequently found to be seropositive for neuromyelitis optica immunoglobulin G (NMO-IgG) (anti-aquaporin-4 antibody) and was diagnosed with neuromyelitis optica spectrum disorder. She also fulfilled the international criteria for Sjögren’s syndrome. Despite initial high dose immunosuppressive therapy, she failed to regain vision in one eye.
Conclusion
Patients presenting with optic neuritis and severe visual loss should be screened for neuromyelitis optica and treated appropriately. Neuromyelitis optica has been associated with systemic autoimmune diseases, in particular Sjögren’s syndrome, and current evidence indicates that they are two distinct entities. We recommend that both diagnoses be considered in cases of optic neuritis with severe visual loss.
doi:10.1186/1752-1947-6-401
PMCID: PMC3533877  PMID: 23176203
3.  Neuromyelitis optica presenting with relapses under treatment with natalizumab: a case report 
Introduction
Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system. To date, optimal therapeutic approaches for neuromyelitis optica have yet to be defined. Natalizumab is highly effective in relapsing-remitting multiple sclerosis and might be considered as an option.
Case presentation
Here, we describe a 67-year-old Caucasian man with definite neuromyelitis optica with detection of anti-aquaporin-4 antibodies over the course of the disease. After initially discussing the diagnosis of multiple sclerosis at an outside hospital, our patient received interferon beta 1a as well as repeated corticosteroid pulses without success. Under subsequent therapy with natalizumab, he continued to present relapses. It was not until discontinuation of natalizumab, repeated cycles of plasma exchanges and initiation of therapy with rituxan that the disease course started to stabilize. Although B cells were completely depleted, our patient experienced another severe myelitis relapse during further follow-up and an additional immunosuppressive therapy with cyclophosphamide was started. Under this regimen, no further relapses occurred over the next 24 months.
Conclusions
This case adds further evidence to the previously discussed notion that natalizumab, while highly effective in multiple sclerosis, may not work sufficiently in neuromyelitis optica. It further advocates for repetitive testing of anti-aquaporin-4 antibodies before and after treatment initiation.
doi:10.1186/1752-1947-8-155
PMCID: PMC4046517  PMID: 24886528
Neuromyelitis optica; Natalizumab; Multiple sclerosis; Rituxan; Anti-AQP-4 antibodies; Seroconversion
4.  Detection of anti-aquaporin-4 autoantibodies in the sera of Chinese neuromyelitis optica patients★ 
Neural Regeneration Research  2013;8(8):708-713.
In this study, we recruited 10 neuromyelitis optica patients, two multiple sclerosis patients and two myelitis patients. Chinese hamster lung fibroblast (V79) cells transfected with a human aquaporin-4-mCherry fusion protein gene were used to detect anti-aquaporin-4 antibody in neuromyelitis optica patient sera by immunofluorescence. Anti-aquaporin-4 autoantibody was stably detected by immunofluorescence in neuromyelitis optica patient sera exclusively. The sensitivity of the assay for neuromyelitis optica was 90% and the specificity for neuromyelitis optica was 100%. The anti-aquaporin-4 antibody titers in sera were tested with serial dilutions until the signal disappeared. A positive correlation was detected between Expanded Disability Status Scale scores and serum anti-aquaporin-4 antibody titers. The anti-aquaporin-4 antibody assay is highly sensitive and specific in the sera of Chinese neuromyelitis optica patients. Detection of aquaporin-4 autoantibody is important for the diagnosis and treatment of neuromyelitis optica.
doi:10.3969/j.issn.1673-5374.2013.08.005
PMCID: PMC4146080  PMID: 25206717
neural regeneration; neurodegenerative diseases; neuromyelitis optica; multiple sclerosis; aquaporin-4; autoimmune disease; autoantibody; immunofluorescence; Expanded Disability Status Scale; grants-supported paper; photographs-containing paper; neuroregeneration
5.  Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice 
Brain  2010;133(2):349-361.
Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system associated with autoantibodies against the glial water channel protein aquaporin-4. It has recently been reported that immunoglobulin from neuromyelitis optica patients injected peripherally does not cause lesions in naive rats, but only when pre-existing central nervous system inflammation is present. Here, we investigated whether immunoglobulin G from aquaporin-4-autoantibody-positive neuromyelitis optica patients has the potential to damage the central nervous system either alone or in the presence of human complement. Immunoglobulin G from neuromyelitis optica patients did not activate mouse complement and was not pathogenic when injected into mouse brain. However, co-injection of immunoglobulin G from neuromyelitis optica patients with human complement produced neuromyelitis optica-like lesions in mice. Within 12 h of co-injecting immunoglobulin G from neuromyelitis optica patients and human complement, there was a striking loss of aquaporin-4 expression, glial cell oedema, myelin breakdown and axonal injury, but little intra-parenchymal inflammation. At 7 days, there was extensive inflammatory cell infiltration, perivascular deposition of activated complement components, extensive demyelination, loss of aquaporin-4 expression, loss of reactive astrocytes and neuronal cell death. In behavioural studies, mice injected with immunoglobulin G from neuromyelitis optica patients and human complement into the right hemisphere preferentially turned to the right at 7 days. No brain inflammation, demyelination or right-turning behaviour was seen in wild-type mice that received immunoglobulin G from non-neuromyelitis optica patients with human complement, or in aquaporin-4-null mice that received immunoglobulin G from neuromyelitis optica patients with human complement. We conclude that co-injection of immunoglobulin G from neuromyelitis optica patients with human complement reproduces the key histological features of neuromyelitis optica and that aquaporin-4 is necessary and sufficient for immunoglobulin G from neuromyelitis optica patients to exert its effect. In our mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions.
doi:10.1093/brain/awp309
PMCID: PMC2822632  PMID: 20047900
autoantibody; immunoglobulin; Devic’s syndrome; mouse model; water channel
6.  Paucity of natural killer and cytotoxic T cells in human neuromyelitis optica lesions 
Neuroreport  2012;23(18):1044-1047.
Neuromyelitis optica is a severe inflammatory demyelinating disease of the central nervous system. Most patients with neuromyelitis optica have circulating immunoglobulin G (IgG) antibodies against the astrocytic water channel protein aquaporin-4 (AQP4), which are pathogenic. Anti-AQP4 IgG-mediated complement-dependent astrocyte toxicity is a key mechanism of central nervous system damage in neuromyelitis optica, but the role of natural killer and cytotoxic T cells is unknown. Our objective was to determine whether natural killer and cytotoxic T cells play a role in human neuromyelitis optica lesions. We immunostained four actively demyelinating lesions, obtained from patients with anti-AQP4 IgG positive neuromyelitis optica, for Granzyme B and Perforin. The inflammatory cells were perivascular neutrophils, eosinophils and macrophages, with only occasional Granzyme B+ or Perforin + cells. Greater than 95% of inflamed vessels in each lesion had no surrounding Granzyme B+ or Perforin + cells. Granzyme B+ or Perforin+ cells were abundant in human spleen (positive control). Although natural killer cells produce central nervous system damage in mice injected with anti-AQP4 IgG, our findings here indicate that natural killer-mediated and T cell-mediated cytotoxicity are probably not involved in central nervous system damage in human neuromyelitis optica.
doi:10.1097/WNR.0b013e32835ab480
PMCID: PMC3590012  PMID: 23108041
antibody-dependent cellular cytotoxicity; complement-dependent cytotoxicity; Devic’s disease; mouse model; NMO-IgG
7.  Antibody to Aquaporin 4 in the Diagnosis of Neuromyelitis Optica 
PLoS Medicine  2007;4(4):e133.
Background
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).
Conclusions
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
Background.
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 http://dx.doi.org/10.1371/journal.pmed.0040133.
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
doi:10.1371/journal.pmed.0040133
PMCID: PMC1852124  PMID: 17439296
8.  C1q-targeted monoclonal antibody prevents complement-dependent cytotoxicity and neuropathology in in vitro and mouse models of neuromyelitis optica 
Acta neuropathologica  2013;125(6):829-840.
Neuromyelitis optica (NMO) is an autoimmune disorder with inflammatory demyelinating lesions in the central nervous system, particularly in the spinal cord and optic nerve. NMO pathogenesis is thought to involve binding of anti-aquaporin-4 (AQP4) autoantibodies to astrocytes, which causes complement-dependent cytotoxicity (CDC) and downstream inflammation leading to oligo-dendrocyte and neuronal injury. Vasculocentric deposition of activated complement is a prominent feature of NMO pathology. Here, we show that a neutralizing monoclonal antibody against the C1q protein in the classical complement pathway prevents AQP4 autoantibody-dependent CDC in cell cultures and NMO lesions in ex vivo spinal cord slice cultures and in mice. A monoclonal antibody against human C1q with 11 nM binding affinity prevented CDC caused by NMO patient serum in AQP4-transfected cells and primary astrocyte cultures, and prevented complement-dependent cell-mediated cytotoxicity (CDCC) produced by natural killer cells. The anti-C1q antibody prevented astrocyte damage and demyelination in mouse spinal cord slice cultures exposed to AQP4 autoantibody and human complement. In a mouse model of NMO produced by intracerebral injection of AQP4 autoantibody and human complement, the inflammatory demyelinating lesions were greatly reduced by intracerebral administration of the anti-C1q antibody. These results provide proof-of-concept for C1q-targeted monoclonal antibody therapy in NMO. Targeting of C1q inhibits the classical complement pathway directly and causes secondary inhibition of CDCC and the alternative complement pathway. As C1q-targeted therapy leaves the lectin complement activation pathway largely intact, its side-effect profile is predicted to differ from that of therapies targeting downstream complement proteins.
doi:10.1007/s00401-013-1128-3
PMCID: PMC3941651  PMID: 23677375
NMO; Aquaporin-4; Complement; Neuroinflammation; Autoimmunity
9.  Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis 
Objective:
We examined a cohort of adults with aquaporin-4 (AQP4) antibody–negative neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD) for antibodies to myelin oligodendrocyte glycoprotein (MOG).
Methods:
We performed a flow cytometry cell-based assay using live human lentivirus–transduced cells expressing full-length surface MOG. Serum was tested in 23 AQP4 antibody–negative NMO/NMOSD patients with bilateral and/or recurrent optic neuritis (BON, n = 11), longitudinally extensive transverse myelitis (LETM, n = 10), and sequential BON and LETM (n = 2), as well as in patients with multiple sclerosis (MS, n = 76) and controls (n = 52).
Results:
MOG antibodies were detected in 9/23 AQP4 antibody–negative patients with NMO/NMOSD, compared to 1/76 patients with MS and 0/52 controls (p < 0.001). MOG antibodies were detected in 8/11 patients with BON, 0/10 patients with LETM, and 1/2 patients with sequential BON and LETM. Six of 9 MOG antibody–positive patients had a relapsing course. MOG antibody–positive patients had prominent optic disc swelling and were more likely to have a rapid response to steroid therapy and relapse on steroid cessation than MOG antibody–negative patients (p = 0.034 and p = 0.029, respectively). While 8/9 MOG antibody–positive patients had good follow-up visual acuity, one experienced sustained visual impairment, 3 had retinal nerve fiber layer thinning, and one had residual spinal disability.
Conclusions:
MOG antibodies have a strong association with BON and may be a useful clinical biomarker. MOG antibody–associated BON is a relapsing disorder that is frequently steroid responsive and often steroid dependent. Failure to recognize the disorder early and institute immunotherapy promptly may be associated with sustained impairment.
Classification of evidence:
This study provides Class II evidence that MOG antibodies are associated with AQP4 antibody–negative BON (sensitivity 69%, 95% confidence interval [CI] 42%–87%; specificity 99%, 95% CI 93.7%–99.8%).
doi:10.1212/NXI.0000000000000040
PMCID: PMC4215392  PMID: 25364774
10.  ANTI-AQUAPORIN-4 MONOCLONAL ANTIBODY BLOCKER THERAPY FOR NEUROMYELITIS OPTICA 
Annals of Neurology  2012;71(3):314-322.
Objective
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system. Circulating autoantibodies (NMO-IgG) against astrocyte water channel aquaporin-4 (AQP4) cause complement- and cell-mediated astrocyte damage with consequent neuroinflammation and demyelination. Current NMO therapies, which have limited efficacy, include immunosuppression and plasma exchange. The objective of this study was to develop a potential new NMO therapy based on blocking of pathogenic NMO-IgG to its target, AQP4.
Methods
We generated non-pathogenic recombinant monoclonal anti-AQP4 antibodies that selectively block NMO-IgG binding to AQP4. These antibodies comprise a tight-binding anti-AQP4 Fab and a mutated Fc that lacks functionality for complement- and cell-mediated cytotoxicity. The efficacy of the blocking antibodies was studied using cell culture, spinal cord slice and in vivo mouse models of NMO.
Results
In AQP4-expressing cell cultures, the non-pathogenic competing antibodies blocked binding of NMO-IgG in human sera, reducing to near zero complement- and cell-mediated cytotoxicity. The antibodies prevented the development of NMO lesions in an ex vivo spinal cord slice model of NMO and in an in vivo mouse model, without causing cytotoxicity.
Interpretation
Our results provide proof-of-concept for therapy of NMO with blocking antibodies. The broad efficacy of antibody inhibition is likely due to steric competition because of its large physical size compared to AQP4. Blocker therapy to prevent binding of pathogenic autoantibodies to their targets may be useful for treatment of other autoimmune diseases as well.
doi:10.1002/ana.22657
PMCID: PMC3314396  PMID: 22271321
11.  Idiopathic Transverse Myelitis and Neuromyelitis Optica: Clinical Profiles, Pathophysiology and Therapeutic Choices 
Current Neuropharmacology  2011;9(3):417-428.
Transverse myelitis is a focal inflammatory disorder of the spinal cord which may arise due to different etiologies. Transverse myelitis may be idiopathic or related/secondary to other diseases including infections, connective tissue disorders and other autoimmune diseases. It may be also associated with optic neuritis (neuromyelitis optica), which may precede transverse myelitis. In this manuscript we review the pathophysiology of different types of transverse myelitis and neuromyelitis optica and discuss diagnostic criteria for idiopathic transverse myelitis and risk of development of multiple sclerosis after an episode of transverse myelitis. We also discuss treatment options including corticosteroids, immunosuppressives and monoclonal antibodies, plasma exchange and intravenous immunoglobulins.
doi:10.2174/157015911796557948
PMCID: PMC3151596  PMID: 22379456
Transverse myelitis; neuromyelitis optica; epidemiology; pathology; pathogenesis; treatment.
12.  Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain 
Introduction
Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) are present in some neuromyelitis optica patients who lack antibodies against aquaporin-4 (AQP4-IgG). The effects of neuromyelitis optica MOG-IgG in the central nervous system have not been investigated in vivo. We microinjected MOG-IgG, obtained from patients with neuromyelitis optica, into mouse brains and compared the results with AQP4-IgG.
Results
MOG-IgG caused myelin changes and altered the expression of axonal proteins that are essential for action potential firing, but did not produce inflammation, axonal loss, neuronal or astrocyte death. These changes were independent of complement and recovered within two weeks. By contrast, AQP4-IgG produced complement-mediated myelin loss, neuronal and astrocyte death with limited recovery at two weeks.
Conclusions
These differences mirror the better outcomes for MOG-IgG compared with AQP4-IgG patients and raise the possibility that MOG-IgG contributes to pathology in some neuromyelitis optica patients.
doi:10.1186/2051-5960-2-35
PMCID: PMC3977893  PMID: 24685353
Antibody; Demyelination; Myelin oligodendrocyte glycoprotein; Neuromyelitis optica
13.  Sjögren’s syndrome and Neuromyelitis Optica spectrum disorders (NMOSD) – a case report and review of literature 
BMC Neurology  2014;14(1):200.
Background
Neuromyelitis optica (NMO) is a rare relapsing auto-immune disease of the central nervous system which is sometimes found in association with other autoimmune disorders including Sjogren’s syndrome. We present the case of a middle aged female with Sjogren’s syndrome (SS) and Neuromyelitis optica spectrum disorders (NMOSD) who had a rapidly declining neurological illness that responded to immunosuppressive therapy.
Case presentation
A 51-year-old female with Sjogren’s syndrome and recent history of varicella zoster infection presented with right upper and lower extremity weakness of one week duration. She was noted to have contrast enhancement at C2-C4 cord levels on cervico-thoracic MRI. Comprehensive work up was negative except for presence of a mild lymphocytic pleocytosis and oligoclonal bands in the CSF. She was diagnosed with transverse myelitis secondary to varicella zoster infection and was treated with high dose steroids in addition to acyclovir with improvement in her symptoms. Two months later she developed left upper and lower extremity weakness, bilateral dysesthesias and urinary incontinence. Repeat MRI of the cervico-thoracic spine revealed worsening enhancement at lower cervical cord levels (C5-7) with extension to T1. CSF analysis was unchanged; however immunological work up was abnormal for elevated NMO-IgG/AQP4 antibody. She was diagnosed with NMOSD and was treated with immunosuppressive therapy. Initially with IV methylprednisone and Cyclophosphamide therapy followed by Mycophenolate mofetil (MMF) maintenance therapy with good response. Repeat MRI 6 months later showed near complete resolution of previous abnormal cord signal changes.
Conclusion
One needs to recognize the relationship between autoimmune diseases especially SS and NMOSD. The presence of NMO antibody has been associated with a relapsing disease course and a careful follow-up, besides use of remission maintenance agents such as MMF and Azathioprine are important to consider.
doi:10.1186/s12883-014-0200-5
PMCID: PMC4193162  PMID: 25291981
Neuromyelitis optica; Neuromyelitis optica spectrum disorders; Sjogren’s syndrome; Aquaporin 4 antibody
14.  Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS) 
Journal of Neurology  2013;261(1):1-16.
Neuromyelitis optica (NMO, Devic’s syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.
doi:10.1007/s00415-013-7169-7
PMCID: PMC3895189  PMID: 24272588
Neuromyelitis optica; Differential diagnosis; Diagnostic tests; Therapy
15.  Aquaporin-4: orthogonal array assembly, CNS functions, and role in neuromyelitis optica 
Acta pharmacologica Sinica  2011;32(6):702-710.
Aquaporin-4 (AQP4) is a water-selective transporter expressed in astrocytes throughout the central nervous system, as well as in kidney, lung, stomach and skeletal muscle. The two AQP4 isoforms produced by alternative spicing, M1 and M23 AQP4, form heterotetramers that assemble in cell plasma membranes in supramolecular structures called orthogonal arrays of particles (OAPs). Phenotype analysis of AQP4-null mice indicates the involvement of AQP4 in brain and spinal cord water balance, astrocyte migration, neural signal transduction and neuroinflammation. AQP4-null mice manifest reduced brain swelling in cytotoxic cerebral edema, but increased brain swelling in vasogenic edema and hydrocephalus. AQP4 deficiency also increases seizure duration, impairs glial scarring, and reduces the severity of autoimmune neuroinflammation. Each of these phenotypes is likely explicable on the basis of reduced astrocyte water permeability in AQP4 deficiency. AQP4 is also involved in the neuroinflammatory demyelinating disease neuromyelitis optica (NMO), where autoantibodies (NMO-IgG) targeting AQP4 produce astrocyte damage and inflammation. Mice administered NMO-IgG and human complement by intracerebral injection develop characteristic NMO lesions with neuroinflammation, demyelination, perivascular complement deposition and loss of glial fibrillary acidic protein and AQP4 immunoreactivity. Our findings suggest the potential utility of AQP4-based therapeutics, including small-molecule modulators of AQP4 water transport function for therapy of brain swelling, injury and epilepsy, as well as small-molecule or monoclonal antibody blockers of NMO-IgG binding to AQP4 for therapy of NMO.
doi:10.1038/aps.2011.27
PMCID: PMC3601948  PMID: 21552296
AQP4; water transport; transgenic mice; brain edema; astrocyte migration; neuroexcitation; neuroinflammation; epilepsy; neuromyelitis optica
16.  Aquaporin-4: orthogonal array assembly, CNS functions, and role in neuromyelitis optica 
Acta Pharmacologica Sinica  2011;32(6):702-710.
Aquaporin-4 (AQP4) is a water-selective transporter expressed in astrocytes throughout the central nervous system, as well as in kidney, lung, stomach and skeletal muscle. The two AQP4 isoforms produced by alternative spicing, M1 and M23 AQP4, form heterotetramers that assemble in cell plasma membranes in supramolecular structures called orthogonal arrays of particles (OAPs). Phenotype analysis of AQP4-null mice indicates the involvement of AQP4 in brain and spinal cord water balance, astrocyte migration, neural signal transduction and neuroinflammation. AQP4-null mice manifest reduced brain swelling in cytotoxic cerebral edema, but increased brain swelling in vasogenic edema and hydrocephalus. AQP4 deficiency also increases seizure duration, impairs glial scarring, and reduces the severity of autoimmune neuroinflammation. Each of these phenotypes is likely explicable on the basis of reduced astrocyte water permeability in AQP4 deficiency. AQP4 is also involved in the neuroinflammatory demyelinating disease neuromyelitis optica (NMO), where autoantibodies (NMO-IgG) targeting AQP4 produce astrocyte damage and inflammation. Mice administered NMO-IgG and human complement by intracerebral injection develop characteristic NMO lesions with neuroinflammation, demyelination, perivascular complement deposition and loss of glial fibrillary acidic protein and AQP4 immunoreactivity. Our findings suggest the potential utility of AQP4-based therapeutics, including small-molecule modulators of AQP4 water transport function for therapy of brain swelling, injury and epilepsy, as well as small-molecule or monoclonal antibody blockers of NMO-IgG binding to AQP4 for therapy of NMO.
doi:10.1038/aps.2011.27
PMCID: PMC3601948  PMID: 21552296
AQP4; water transport; transgenic mice; brain edema; astrocyte migration; neuroexcitation; neuroinflammation; epilepsy; neuromyelitis optica
17.  Neuromyelitis optica: Aquaporin-4 based pathogenesis mechanisms and new therapies 
Neuromyelitis optica (NMO) is an autoimmune ‘aquaporinopathy’ of the central nervous system that causes inflammatory demyelinating lesions primarily in spinal cord and optic nerve, leading to paralysis and blindness. NMO lesions show loss of aquaporin-4 (AQP4), GFAP and myelin, infiltration of granulocytes and macrophages, and perivascular deposition of activated complement. Most patients with NMO are seropositive for immunoglobulin autoantibodies (AQP4-IgG) against AQP4, the principal water channel of astrocytes. There is strong evidence that AQP4-IgG is pathogenic in NMO, probably by a mechanism involving complement-dependent astrocyte cytotoxicity, causing leukocyte infiltration, cytokine release and blood-brain barrier disruption, which leads to oligodendrocyte death, myelin loss and neuron death. Here, we review the evidence for this and alternative proposed NMO pathogenesis mechanisms, such as AQP4-IgG-induced internalization of AQP4 and glutamate transporters, complement-independent cell-mediated cytotoxicity, and AQP4-IgG inhibition of AQP4 water transport function. Based on the initiating pathogenic role of AQP4-IgG binding to astrocyte AQP4 in NMO, selective blocker therapies are under development in which AQP4-targeted monoclonal antibodies or small molecules block binding of AQP4-IgG to astrocytes and consequent downstream pathology.
doi:10.1016/j.biocel.2012.06.013
PMCID: PMC3676174  PMID: 22713791
NMO; Devic’s disease; Aquaporin-4; Astrocyte; Complement; Autoimmunity
18.  Aquaporin 4 and neuromyelitis optica 
Lancet neurology  2012;11(6):535-544.
Neuromyelitis optica is an inflammatory demyelinating disorder of the CNS. The discovery of circulating IgG1 antibodies against the astrocyte water channel protein aquaporin 4 (AQP4) and the evidence that AQP4-IgG is involved in the development of neuromyelitis optica revolutionised our understanding of the disease. However, important unanswered questions remain—for example, we do not know the cause of AQP4-IgG-negative disease, how astrocyte damage causes demyelination, the role of T cells, why peripheral AQP4-expressing organs are undamaged, and how circulating AQP4-IgG enters neuromyelitis optica lesions. New drug candidates have emerged, such as aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor). Despite rapid progress, randomised clinical trials to test new drugs will be challenging because of the small number of individuals with the disorder.
doi:10.1016/S1474-4422(12)70133-3
PMCID: PMC3678971  PMID: 22608667
19.  Neuromyelitis Optica with NMO-IgG/Anti-AQP4 Antibody Positive: First Case Reported from Uttarakhand India 
Neuromyelitis optica (also known as Devic’s disease) is an idiopathic, severe, demyelinating disease of the central nervous system that preferentially affects the optic nerve and spinal cord. The presence of a highly specific serum autoantibody marker (NMO-IgG) further differentiates neuromyelitis optica from multiple sclerosis and has helped to define a neuromyelitis optica spectrum of disorders. We present a case of 37-year-old man who has initially presented with transverse myelitis from which he recovered partially after treatment but later presented with bilateral optic neuritis. MRI brain revealed hyperintensity in bilateral optic nerves, periventricular area and also in the thalamic region. Diagnosis was confirmed by positive NMO – IgG/anti-AQP4 antibody.
doi:10.7860/JCDR/2014/8577.4625
PMCID: PMC4149100  PMID: 25177594
Multiple sclerosis; Neuromyelitis optica
20.  A Rare Case of Neuromyelitis Optica Spectrum Disorder in Patient with Sjogren's Syndrome 
Case Reports in Rheumatology  2014;2014:158165.
We report a 48-year-old female with the history of Sjogren's syndrome who presented with 3-week history of tingling, numbness, and shooting back, waist, and bilateral leg pain and numbness in the pelvic region with urinary and bowel incontinence. Physical examination was remarkable for reduced motor power in both lower extremities with spasticity. Sensory deficit was noted at the T6 level. Laboratory investigation revealed elevated ESR and CRP and positive serum antiaquaporin-4 IgG. Thoracic and lumbar magnetic resonance imaging revealed abnormal patchy areas, leptomeningeal enhancement through the thoracic cord extending from T3 through T6 levels, without evidence of cord compression. Impression of neuromyelitis optica spectrum disorder was made and patient was treated with methylprednisolone intravenously followed by tapering oral prednisone. Neurological symptoms gradually improved with resolution of bowel and urinary incontinence. In a patient with Sjogren's syndrome who presents with neurological complaints, the possibility of neuromyelitis optica or neuromyelitis optica spectrum disorder should be considered. Awareness of the possibility of CNS disease is important due to the serious nature of CNS complications, some of which are treatable with immunosuppressants. Our patient with Sjogren's syndrome who presented with myelopathy benefited from early recognition and institution of appropriate therapy.
doi:10.1155/2014/158165
PMCID: PMC4253696  PMID: 25506022
21.  Neuromyelitis optica in a young child with positive serum autoantibody 
Pediatric neurology  2008;39(3):209-212.
Relapsing neuromyelitis optica is rare in children. The identification of highly specific serum autoantibody marker (neuromyelitis optica –immunoglobulin G) differentiates neuromyelitis optica from other demyelinating disorders particularly in clinically challenging cases. We present a child with multiple episodes of transverse myelitis and optic neuritis with positive neuromyelitis optica-immunoglobulin G titers consistent with a diagnosis of relapsing neuromyelitis optica. Serial titers of neuromyelitis optica–immunoglobulin G then normalized during remission.
doi:10.1016/j.pediatrneurol.2008.05.016
PMCID: PMC2696460  PMID: 18725070
NMO; immunoglobulin G; myelitis; optic neuritis
22.  INVOLVEMENT OF ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY IN INFLAMMATORY DEMYELINATION IN A MOUSE MODEL OF NEUROMYELITIS OPTICA 
Acta neuropathologica  2013;126(5):699-709.
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that can cause paralysis and blindness. The pathogenesis of NMO involves binding of immunoglobulin G autoantibodies to aquaporin-4 (AQP4) on astrocytes, which is thought to cause complement-dependent cytotoxicity (CDC) and a secondary inflammatory response leading to oligodendrocyte and neuronal damage. Here we investigate in vivo the role of antibody-dependent cell-mediated cytotoxicity (ADCC) triggered by AQP4 autoantibodies (AQP4-IgG) in the development of NMO pathology. A high-affinity, human recombinant monoclonal AQP4-IgG was mutated in its Fc region to produce 'NMO superantibodies' with enhanced CDC and/or ADCC effector functions, without altered AQP4 binding. Pathological effects of these antibodies were studied in a mouse model of NMO produced by intracerebral injection of AQP4-IgG and human complement. The original (non-mutated) antibody produced large NMO lesions in this model, with loss of AQP4 and GFAP immunoreactivity, inflammation and demyelination, as did a mutated antibody with enhanced CDC and ADCC effector functions. As anticipated, a mutated AQP4-IgG lacking CDC but having 10-fold enhanced ADCC produced little pathology, though, unexpectedly, a mutated antibody with 9-fold enhanced CDC but lacking ADCC produced less pathology than the original AQP4-IgG. Also, pathology was greatly reduced following administration of AQP4-IgG and complement to mice lacking the Fc III receptor involved in effector cell activation during ADCC, and to normal mice injected with a Fcγ receptor blocking antibody. Our results provide evidence for the central involvement of ADCC in NMO pathology, and suggest ADCC as a new therapeutic target in NMO.
doi:10.1007/s00401-013-1172-z
PMCID: PMC3890328  PMID: 23995423
NMO; aquaporin; CDC; ADCC; Fcγ receptor; astrocyte
23.  AQP4 antibody–positive Thai cases 
Neurology  2011;77(9):827-834.
Objective:
To evaluate the prevalence of aquaporin-4 (AQP4) antibody in Thai patients with idiopathic inflammatory demyelinating CNS diseases (IIDCDs) and to analyze the significance of the autoantibody to distinguish neuromyelitis optica (NMO) and other NMO spectrum disorders (ONMOSDs) from other IIDCDs, especially multiple sclerosis (MS).
Methods:
We retrospectively evaluated 135 consecutive patients with IIDCDs seen at the MS clinic at Siriraj Hospital, Bangkok, Thailand, and classified them into NMO, ONMOSDs, optic-spinal MS (OSMS), classic MS (CMS), and clinically isolated syndrome (CIS) groups in this order with accepted diagnostic criteria. The patients' coded sera were tested separately for AQP4 antibody. Then the relations between the clinical diagnosis and the AQP4 antibody serologic status were analyzed.
Results:
Among the 135 patients, 53 (39.3%) were AQP4 antibody–positive. Although the AQP4 antibody–positive group had features of NMO, such as female predominance, long cord lesions (>3 vertebral bodies), and CSF pleocytosis, only 18 patients (33% of 54) fully met Wingerchuk 2006 criteria except for AQP4 antibody–seropositive status. We also detected some AQP4 antibody–positive patients in the OSMS (4 of 7), CMS (11 of 46), and CIS (1 of 16) groups. These patients had been misdiagnosed with MS because they often had brain lesions and never underwent spinal cord MRI examination or lacked long cord lesions.
Conclusions:
AQP4 antibody was highly prevalent (almost 40%) in Thai patients with IIDCDs. Moreover, only one-third of AQP4 antibody–positive patients fully met Wingerchuk 2006 criteria, and many were misdiagnosed with MS. A sensitive AQP4 antibody assay is required in this region because the therapy for NMO is different from that for MS.
doi:10.1212/WNL.0b013e31822c61b1
PMCID: PMC3463102  PMID: 21813785
24.  Intrathecal Pathogenic Anti-Aquaporin-4 Antibodies in Early Neuromyelitis Optica 
Annals of neurology  2009;66(5):617-629.
Objective
The serum of most neuromyelitis optica (NMO) patients contains autoantibodies (NMO-IgGs) directed against the aquaporin-4 (AQP4) water channel located on astrocyte foot processes in the perivessel and subpial areas of the brain. Our objectives were to determine the source of central nervous system (CNS) NMO-IgGs and their role in disease pathogenesis.
Methods
Fluorescence activated cell sorting and single-cell reverse transcriptase PCR were used to identify overrepresented plasma cell immunoglobulin (Ig) sequences in the cerebrospinal fluid (CSF) of an NMO patient after a first clinical attack. Monoclonal recombinant antibodies (rAbs) were generated from the paired heavy and light chain sequences and tested for target specificity and Fc effector function. The effect of CSF rAbs on CNS immunopathology was investigated by delivering single rAbs to rats with experimental autoimmune encephalomyelitis (EAE).
Results
Repertoire analysis revealed a dynamic, clonally expanded plasma cell population with features of an antigen-targeted response. Using multiple independent assays, 6 of 11 rAbs generated from CSF plasma cell clones specifically bound to AQP4. AQP4-specific rAbs recognized conformational epitopes and mediated both AQP4-directed antibody-dependent cellular cytotoxicity and complement-mediated lysis. When administered to rats with EAE, an AQP4-specific NMO CSF rAb induced NMO immunopathology: perivascular astrocyte depletion, myelinolysis and complement and Ig deposition.
Interpretation
Molecular characterization of the CSF plasma cell repertoire in an early NMO patient demonstrates that AQP4-specfic Ig is synthesized intrathecally at disease onset and directly contributes to CNS pathology. AQP4 is now the first confirmed antigenic target in human demyelinating disease.
doi:10.1002/ana.21802
PMCID: PMC3180961  PMID: 19938104
25.  Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss 
Acta neuropathologica  2012;123(6):861-872.
The pathogenesis of neuromyelitis optica (NMO) involves targeting of NMO-immunoglobulin G (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system. Prior work provided evidence for complement-dependent cytotoxicity (CDC) in NMO lesion development. Here, we show that antibody-dependent cellular cytotoxicity (ADCC), in the absence of complement, can also produce NMO-like lesions. Antibody-dependent cellular cytotoxicity was produced in vitro by incubation of mouse astrocyte cultures with human recombinant monoclonal NMO-IgG and human natural killer cells (NK-cells). Injection of NMO-IgG and NK-cells in mouse brain caused loss of AQP4 and GFAP, two characteristic features of NMO lesions, but little myelin loss. Lesions were minimal or absent following injection of: (1) control (non-NMO) IgG with NK-cells; (2) NMO-IgG and NK-cells in AQP4-deficient mice; or (3) NMO-IgG and NK-cells in wild-type mice together with an excess of mutated NMO-IgG lacking ADCC effector function. NK-cells greatly exacerbated NMO lesions produced by NMO-IgG and complement in an ex vivo spinal cord slice model of NMO, causing marked myelin loss. NMO-IgG can thus produce astrocyte injury by ADCC in a complement-independent and dependent manner, suggesting the potential involvement of ADCC in NMO pathogenesis.
doi:10.1007/s00401-012-0986-4
PMCID: PMC3581313  PMID: 22526022
NMO; Aquaporin; Natural killer cell; Astrocyte; Demyelination

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