Positive Aquaporin-4 Antibody Research Articles

Postinfectious Aquaporin-4-positive Neuromyelitis Optica Syndrome Disorder and Nephrotic Syndrome

Neuromyelitis optica (NMO), or Devic's disease, is one of the demyelinating disorders of the central nervous system, with autoimmune inflammatory etiology. The optic nerves and spinal cord are the major organs involved in the disease; however, the involvement of the brain can also be seen in rare instances. Here, we report a case of a 34-year-old female, diagnosed with NMO and concurrent nephrotic syndrome (NS). NMO was diagnosed by positive Aquaporin-4 antibodies in the serum, radio imaging such as magnetic resonance imaging of the brain and spinal cord showing the demyelinating lesions, as well as the presence of optic neuritis on visually evoked potential. Biochemical investigations revealed heavy proteinuria, hypoalbuminemia, and hypertriglyceridemia, meeting the diagnostic criteria of NS. Therefore, considering the diagnosis of NMO with NS, the patient was treated with plasmapheresis and methylprednisolone pulse therapy. This concurrence is very uncommon in clinical practice, as previously only two such cases are reported to date.

Assessment of intelligence quotient in patients with neuromyelitis optica spectrum disease and multiple sclerosis.

Cognitive impairment is common in people living with neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS). However, there is little published data on intelligence quotient (IQ) in NMOSD patients. Therefore, we performed the present study to compare IQ scores across NMOSD, MS, and control groups. In this cross-sectional study, 49 NMOSD (30 with positive aquaporin4 antibody), 41 MS, and 20 control individuals were recruited. The IQ score for each person was measured using Wechsler Adult Intelligence Scale-Revised (WAIS-R). Participants were reported on eleven scores of subsets, verbal IQ (VIQ), performance IQ (PIQ), and full score IQ (FSIQ). The scores of FSIQ, VIQ, PIQ, vocabulary, similarities, and digit-symbol in NMOSD and MS individuals were lower than the control group. Relative to control, NMOSD patients reported a lower score of information. We found no difference between NMOSD and MS groups, except in vocabulary and similarities. No significant difference between seropositive and seronegative NMOSD groups was observed except for the information and block design. In NMOSD group, a greater EDSS score was associated with decreased scores of FSIQ, VIQ, and PIQ. Being employed and being married were associated with greater scores of VIQ and PIQ, respectively. In both NMOSD and MS groups, advanced education was associated with increased scores of FSIQ and VIQ. Our study showed decreased IQ scores in NMOSD and MS. Further studies are required to examine intellectual quotient in people with NMOSD and MS.

Reduced quality of life in a pediatric-onset Neuromyelitis optica spectrum disorders cohort

BackgroundNeuromyelitis optica spectrum disorders (NMOSD) is a severe condition associated with high disability and low quality of life (QoL) in adults. Since this evaluation had been rarely perfomed in children, this study aimed to describe QoL in pediatric-onset NMOSD with positive aquaporin4 antibody (AQP4-IgG) patients. MethodsThis was a cross-section evaluation of patients and parents’ proxy QoL from individuals enrolled in a longitudinal cohort of AQP4-IgG positive NMOSD with onset ≤ 18 years of age. ResultsEighteen patients were included, sixteen girls. The mean (SD) age at disease onset was 11.5 (3.6) years. Eleven of patients experienced disability during a mean (SD) of 8.3 (5.3) years of follow-up. NMOSD had impact in QoL in 10 patients, being associated with higher EDSS and poor academic performance at last follow-up. Results from the PedsQL inventory for 13 patients and 10 parents disclosed low QoL specially in emotional functioning. ConclusionThis study indicates impaired quality of life, high disability and high impact of the disease in daily life of adolescents and young adults with pediatric onset NMOSD.

Central Sleep Apnea Syndrome Can Complicate Neuromyelitis Optica Spectrum Disorder: A Case Report

Neuromyelitis optica spectrum disorder is a rare, relapsing autoimmune disease of the central nervous system. Various initial presentations can delay diagnosis and treatment. A 14-year-old girl was admitted to the emergency department owing to respiratory insufficiency. Repeated history-taking and neuroimaging revealed an area postrema syndrome. A diagnosis of neuromyelitis optica spectrum disorder with positive aquaporin-4 antibodies has finally been established. The patient improved significantly with immunosuppressive therapy. However, her 3-year follow-up still showed sleep-disordered breathing requiring nocturnal bilevel positive airway pressure therapy. We report an original case of NMOSD leading to persistent central sleep apnea syndrome.

Comparison of the low frequency fluctuation between AQP4 antibody positive and MOG antibody positive patients with optic neuritis

Objective To compare the changes of spontaneous brain activity in myelin oligodendrocyte glycoprotein antibody (MOG-Ab) positive and Aquaporin 4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorder (NMOSD) by using resting-state functional magnetic resonance imaging (fMRI). Methods A case control study was designed.A total of 11 NMOSD patients with positive MOG-Ab and 21 NMOSD patients with positive AQP4-Ab were enrolled from October 2006 to May 2017 in PLA General Hospital.Thirty-four healthy controls closely matched in age, sex and education were recruited and underwent resting-state fMRI scans.The amplitude of low-frequency fluctuation (ALFF) was extracted to investigate the spontaneous brain activity.This study was approved by Ethics Committee of PLA General Hospital (S2019-111-01). All subjects enrolled signed informed consent. Results Two patients in the MOG-Ab positive group had seizure history, and no seizure history was observed in AQP4-Ab positive group and healthy control group.Compared with healthy control group, all patients in MOG-Ab positive group and AQP4-Ab positive group had significantly increased ALFF values of prefrontal gyrus.The ALFF values of bilateral anterior central gyrus and bilateral posterior central gyrus in AQP4-Ab positive group were 1.89±0.56 and 2.10±0.69, respectively, which were lower than 3.32±1.15 and 3.61±1.23 in MOG-Ab positive group, the differences were statistically significant (both at P<0.001, AlphaSim correction). Conclusions Resting-state fMRI could provide new evidence of possibly multi-focal disease mechanisms.Hyperactivity in prefrontal cortex, motor cortex and somatosensory cortex might reflect differences in pathological processes between MOG-Ab positive and AQP4-Ab positive NMOSD patients. Key words: Optic neuritis; Resting-state functional magnetic resonance imaging; Amplitude of low frequency fluctuation; Neuromyelitis optica spectrum disorder; Aquaporin 4 antibody; Myelin oligodendrocyte glycoprotein antibody

Aquaporin-4 Serostatus and Visual Outcomes in Clinically Isolated Acute Optic Neuritis.

Aquaporin-4 antibodies (AQP4-Ab) are associated with neuromyelitis optica spectrum disorder (NMOSD) and typically this disorder has a poor visual prognosis as a result of optic neuritis (ON). Our aim was to report the clinical features at onset and final visual outcomes at 6 months of patients with ON who were positive for AQP4-Ab vs. those who were negative for AQP4-Ab. Retrospective cohort study. AQP4-Ab were tested by indirect immunofluorescence in 57 patients with a first episode of ON. All patients initially were referred for consideration of multiple sclerosis ON (MSON), NMOSD, or any other inflammatory central nervous system disorder during follow-up (41.31 ± 24.32 months). Our patients were diagnosed as having NMOSD, MSON, chronic relapsing inflammatory ON, and single isolated ON. Risk factors associated with visual outcomes of ON patients were assessed through an ordinal regression model. Positive AQP4-Ab were associated with male sex (P = 0.02), earlier age of onset (P = 0.01), and myelitis relapses (P = 0.04). Seronegative group had fewer recurrences of ON than the seropositive group (35% vs 58%, P = 0.14). Patients that were positive for AQP4-Ab did not have worse visual acuity at baseline and after 6 months. However, poor visual acuity during first attack was associated with a worse visual acuity at 6 months (odds ratio = 2.28, 95% CI [1.58-3.28], P = 0.03). At 6 months, positive AQP4-Ab vs negative AQP4-Ab patients no evidence of poorer visual acuity. Lower visual acuity at baseline was associated with poor visual recovery at 6 months.

Paraneoplastic Neuromyelitis Optica Spectrum Disorder: A single center cohort description with two cases of histological validation

BackgroundParaneoplastic syndromes are remote effects of cancer caused by an autoimmune response triggered by tumor cells. Paraneoplastic Neuromyelitis Optica Spectrum Disorders (NMOSD) has been previously described, but the underlying mechanism for these rare cases is not well characterized. This paper presents a newly described case series of paraneoplastic NMOSD, including 2 new histological types of cancer and histological validation. MethodsThe UBC NMO clinic database was surveyed and identified 6 patients with paraneoplastic NMOSD. In 2 cases, aquaporin-4 (AQP4) immunoreactivity was assessed on patients’ tumor specimens. ResultsThe mean age at NMOSD diagnosis was 56 years old and 5/6 patients were older than 50 years old. 4/6 patients with paraneoplastic NMOSD have positive AQP4 antibodies. The median time between NMOSD and cancer was 12 months. Two new cancer types- serous ovarian carcinoma and adrenocortical carcinoma - were found in paraneoplastic NMOSD cases. A serous ovarian carcinoma and a thymoma, found in patients with AQP4 serological evidence, showed a positive reactivity to AQP4 immunostaining. ConclusionsOur findings will increase the recognition of NMOSD as a paraneoplastic syndrome. Cancer cells can express AQP4, increasing the likelihood of a direct mechanism between cancer cells and the development of NMOSD in paraneoplastic cases.

An update on the evidence for the efficacy and safety of rituximab in the management of neuromyelitis optica.

Neuromyelitis optica spectrum disorders (NMOSDs) is a new concept which includes classical neuromyelitis optica (NMO) and partial forms of NMO such as recurrent optic neuritis with positive aquaporin-4 antibodies (AQP4) or brainstem symptoms (intractable hiccups or vomiting). This disease is clearly distinguished from multiple sclerosis (MS) and the therapeutic approach is clearly different. Rituximab is actually considered to be one of the most efficient treatments of NMOSD, even if class I studies are clearly lacking. In the present review, we describe the state of the art about rituximab treatment in NMOSD, including adults and children, plus its efficacy and tolerance and we also underline the questions that should be addressed in the near future.

The thickness of retinal nerve fiber layer and structural changes of inner macular segmented layers in optic neuritis patients with positive aquaporin-4 antibody

Objective To observe the thickness of per-papillary retinal fiber layer (pRNFL) and structural changes of inner macular segmented layers in optic neuritis (ON) patients with positive aquaporin-4 antibody [AQP4-Ab(+ )]. Methods 60 ON patients (84 eyes) including 30 of AQP4-Ab(+ ) ON patients (42 eyes) and AQP4-Ab(-) ON patients (42 eyes), and 40 age-gender matched health controls(80 eyes) were recruited in present study. There was no statistical significance in gender (χ2=0.568) and age (χ2=1.472) between the three groups (P>0.05). There was no statistical significance in the percentage of different course (χ2=0.000) and logMAR best corrected visual acuity (Z=-1.492) between AQP4-Ab(+ )ON and AQP4-Ab(-)ON group (P=1.000, 0.136). All subjects were examined by Spectralis-OCT. The thickness of per-papillary, nasal, nasal lower, temporal lower, temporal, temporal upper, nasal upper and papillomacular bundle (PMB) were analyzed as well as nasal pRNFL/temporal pRNFL (N/T). The macular area was divided into three concentric circles which including central region with 1 mm diameter, inner area with >1 mm but ≤3 mm diameter, and outer ring area with >3 mm but ≤6 mm diameter. The macular volume in each partition and volume in macular RNFL (mRNFL), macular ganglion cell layer (mRGCL), macular inner plexiform layer (mIPL) and macular inner nuclear layer (mINL) were analyzed. Results Compared to HC group, the thickness of pRNFL, every quadrants and PMB were decreased significantly in ON group (P=0.000); the macular volume and the volume of mRNFL, mRGCL, mIPL were also decreased significantly in ON group (P=0.000); but there was no statistical difference in mINL volume between two groups (P=0.700). Compared to AQP4-Ab(-)ON group, the thickness of nasal and nasal lower were decreased significantly in AQP4-Ab(+ )ON group (P=0.010, 0.000); the macular and mIPL volume were also decreased significantly in AQP4-Ab(+ )ON group (P=0.038, 0.033); the thickness of inferior, superior and inferior mIPL in outer ring area and nasal mRNFL in inner area were decreased significantly in AQP4-Ab(+ )ON group (P<0.05). Conclusions Compared to AQP4-Ab(-)ON patients, the pRNFL thickness and mIPL volume decreased in AQP4-Ab(+ )ON patients. The thinner pRNFL area is mainly located in nasal, nasal lower quadrants, and inferior, superior mIPL. Key words: Optic neuritis/physiopathology; Optic neuritis/diagnosis; Macula lutea/physiopathology; Aquaporin 4; Tomography, optical coherence

Neuromyelitis optica spectrum disorders may be misdiagnosed as Wernicke's encephalopathy

Purpose: To raise doctors’ attention to the differential diagnosis of neuromyelitis optica spectrum disorders (NMOSD) and Wernicke's encephalopathy (WE).Patients and methods: We extensively reviewed the medical records of 136 patients who had visited our hospital since 2008 and were suspected of having central nervous system demyelinating diseases. Four of those patients had somnolence, electrolyte imbalance and brain lesions around the third ventricle and were included in the study. We tested the serum of the four patients for the presence of aquaporin-4 (AQP4) M23 antibody.Results: All the four patients had positive AQP4 antibody in their serum. Two of the patients were misdiagnosed as WE before AQP4 antibody detection occurred.Conclusions: NMOSD and WE have similar brain lesion locations, histopathological changes and clinical manifestations. It is important to distinguish NMOSD from WE by detecting AQP4 antibody in serum or cerebral spinal fluid. Vitamin B1 should also be administered to the patients who have a history of thiamine deficiency.

Analysis of clinical features of five multiple sclerosis patients with positive serum aquaporin 4 antibody

Objective To investigate the clinical features of multiple sclerosis (MS) patients with positive serum aquaporin 4 (AQP4) antibody. Methods A total of 18 MS patients who had been diagnosed in accord with McDonald Criteria (2010) were enrolled and were divided into AQP4 positive group (N = 5) and AQP4 negative group (N = 13). In combination with accessory examination, clinical features and laboratory data of MS patients were correlatively studied between 2 groups in association with follow-up study in Outpatient Clinic. Results Five seropositive patients, including 2 men and 3 women, were collected. The median age of onset was 43 years and the median clinical course was 4 months. Compared with patients with negative AQP4 antibody, MS patients with positive AQP4 antibody demonstrated increased spinal cord lesions and optic nerve involvement. MRI revealed multiple abnormal long T 1 and long T 2 signals in brain and cervicothoracic spinal cord (3/5), and multiple abnormal long T 1 and long T 2 signals in cervicothoracic spinal cord (2/5) in seropositive group. Relatively more patients in seropositive group had increased cerebral spinal fluid (CSF) IgG index (4/4) and 24 h intrathecal IgG synthesis rate (3/4), and positive oligoclonal bands (OBs, 3/4). Two patients presented with positive anti-nuclear antibody (ANA) and one Sjogren's syndrome (SS) in seropositive group. Conclusions There were some differences in clinical features between AQP4 antibody positive MS and classical MS, suggesting distinctive pathogenesis may exist between these two entities, which need to be emphasized and treated accordingly from the diagnostic and therapeutic points of view. HE Yang and YANG Ting-ting contributed equally to this study DOI: 10.3969/j.issn.1672-6731.2015.03.012

Neuromyelitis optica and aquaporin-associated syndromes

Identification of aquaporin-4 antibodies in neuromyelitis optica (NMO) is highly important to provide early diagnosis for starting pathogenetic treatment, and for differential diagnosis in neuromyelitis optica spectrum disorders (NMO-SD). In this paper, we review current pathogenetic and clinical aspects of NMO and NMO NMO-SD. We present our data on the identification of aquaporin-4 antibodies in CNS disorders. Aquaporin-4 antibodies were detected in 86.36% of patients with neuromyelitis optica, in 12.5% of patients with partial syndromes and in 100% of patients with systemic lupus erythematosus with longitudinally extensive transverse myelitis or optic neuritis. There was the correlation between the extent of lesion in the spinal cord and positive aquaporin-4 antibodies.

Neuromyelitis Optica Spectrum Disorder and Neurosyphilis Coexist in A Chinese Woman

Background: Neuromyelitisoptica spectrum disorder (NMOSD) is a series of central nervous system diseases with positive aquaporin-4 antibody. And neurosyphilis is a manifestation of the late syphilis. Although Neuromyelitisoptica (NMO) following syphilis has been previously reported, transverse myelitis and neurosyphilis in the same patient with positive aquaporin-4 antibody has never been mentioned. Method: We presented the coexistence of NMOSD and syphilis in a 72-year-oldChinese woman and analyzed the relationship of these two diseases. The pertinent literatures were also reviewed. Result: Previous studies showed that syphilitic myelitis might be more frequent in male than in female and it tended to be asymptomatic. However our case was a woman who experienced acute attack, with positive AQP4 antibody. Therefore, her myelitis occurrence mainly associated with AQP4 antibodies autoimmunity, and neurosyphilis might be an asymptomatic episode in our case. Although there was no evidence that treponema pallidum subspecies pallidum involved in the pathogenesis of NMO, it seemed that anti-syphilitic treatment was helpful to attenuate disability in our present case. Conclusion: Anti-NMO and anti-syphilitic treatment should be used together to treat the patient with both NMOSD and neurosyphilis.

A recurrent longitudinally extensive transverse myelitis with Aquaporin-4(AQP4) antibody after herpes zoster

Longitudinally extensive transverse myelitis (LETM) is a syndrome that involves three or more vertebral segments in the spinal cord lesion, and it is one of the characteristic features of neuromyelitis optica (NMO) differentiating it from multiple sclerosis. Many studies proved the importance of aquaporin-4 (AQP4) antibody, which plays a vital role in the pathogenesis of NMO. Recent reports suggest that recurrent LETM patients with positive anti-AQP4 antibody titers have a higher chance of converting to NMO, and they are now termed as NMO spectrum disorders (NMOSD). The specific role of AQP4 antibody in NMO is yet to be elucidated but there are reports to bring up the pathogenesis in relation with infectious events. Interestingly, parainfectious NMOSD tends to spare the optic nerve unlike classic NMOSD. Here we report a young woman who was once diagnosed as herpes zoster-related LETM, but later developed as recurrent LETM with positive AQP4 antibody titers, which renders the diagnosis of parainfectious LETM without optic neuritis.

Neuromyelitis optica and aquaporin‐4 (AQP4) autoantibodies in consecutive optic neuritis patients in Southern Finland

To analyse the frequency of neuromyelitis optica (NMO) among consecutive optic neuritis (ON) patients in Southern Finland and the feasibility of Aquaporin-4 (AQP4) autoantibody assay in the diagnosis of NMO. Consecutive patients with symptoms suggestive of acute ON and managed in the Helsinki University Central Hospital were evaluated critically screened for AQP4 autoantibody during a 47.5-month period. The antibodies were determined using radioimmunoprecipitation method. AQP4 index >15 was considered positive, 10-15 borderline and <10 normal. Brain magnetic resonance imaging (MRI) was performed for all patients. Of the 300 patients with suspected ON, 191 were eventually diagnosed as ON, and 66 (35%) of them had a previous diagnosis or were diagnosed with multiple sclerosis (MS). Of the 125 patients without MS diagnosis, 62 (50%) had demyelinative lesions in MRI, which is a risk factor for developing MS. Two patients (1.1%; 95% CI 0.3-4.5) fulfilled the criteria of NMO. Positive AQP4 antibodies were found in three patients (1.6% 95% CI 0.3-4.5), one of them had NMO, one had MS and one became diagnosed with MS a month later. Borderline autoantibody levels were found in 10 patients, 7 of whom had MS. NMO is rare among ON patients in the population of Southern Finland. In this small cohort, the sensitivity and positive predictive values of the AQP4 autoantibody index for NMO were low, 1/2 and 1/3 respectively, and do not support initiating routine screening.

Utility of aquaporin-4 antibody assay in patients with neuromyelitis optica spectrum disorders

Objective: Our aim was to evaluate the utility of aquaporin-4 antibodies (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD). Methods: The clinical and radiological characteristics of 78 patients with NMOSD and 22 with multiple sclerosis (MS), who were tested for AQP4-Ab by a cell-based assay, were assessed. Results: The mean time interval between symptom onset and development of optic neuritis and myelitis was 39.9 months in neuromyelitis optica (NMO). About 40% of patients with limited NMO would have fulfilled the diagnostic criteria for MS in the absence of the antibody assay results. In patients with longitudinally extensive transverse myelitis, positive AQP4-Ab assay results were associated with the poor response to acute steroid treatment and asymptomatic visual evoked potential abnormality. Presence of either painful tonic spasm associated with myelitis or severe disability at onset had high specificity and relatively high sensitivity in differentiating NMOSD with AQP4-Ab from MS. Conclusions: The AQP4-Ab assay can facilitate the early diagnosis of NMO and prevent limited NMO from being misdiagnosed as MS. It can predict the poor response to first-line acute-phase treatment and probably detect the subclinical optic nerve involvement in subgroups of NMOSD. Lastly, it will contribute to the upcoming revision of the current diagnostic criteria for NMO.

Aquaporin-4 seropositivity in a patient with coeliac disease but normal neurological examination and imaging

A 32-year-old woman presented in 2002 with a headache associated with numbness of her right arm, right side of her face and left leg. Examination was normal. Investigations revealed prolonged visual evoked responses (VER) on the right and a low vitamin B12 level. Cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) of her brain and spine were normal. She was given a diagnosis of multiple sclerosis (MS) and commenced on vitamin B12 replacement. Three years later, her case was reviewed by the neurology service. She had experienced ongoing sensory disturbances, urinary dysfunction and episodic visual disturbances, consisting of blurred vision, particularly in her right eye, which would last for hours. She also experienced episodes of loss of strength of her right arm and a sensation of dragging her legs. Relevant past medical history included coeliac disease. Examination was normal. Investigations showed prolonged VERs, initially only on the right then bilateral. Somatosensory evoked potentials showed defective conduction in both lower limbs. MRI brain and spine were repeated and were normal. Oligoclonal bands in the CSF were normal. Autoimmune screen was negative. B12 and folate levels, thyroid function tests and syphilis serology were all negative. Tests for aquaporin-4 antibodies were performed twice using a cell based assay with aquaporin-4 M23 isoform and were positive. The titre was three out of four. Given her worsening VERs, with both being greater than 150 ms, her ongoing symptoms and positive aquaporin-4 antibodies, she was commenced on azathioprine. We believe that this patient’s symptoms are due to neuromyelitis optica (NMO). Therapy was initiated due to her prolonged VERs and our concerns regarding future functional visual deterioration. The patient was counseled with regard to the side effects of azathioprine but was very keen herself to commence therapy. Subjectively she feels better on treatment but there has been no change electrophysiologically. We believe that this patient is part of the evolving spectrum of NMO due to her clinical history, prolonged VERs, co-existent autoimmune disease and strongly positive aquaporin-4 antibodies. NMO is an inflammatory, demyelinating syndrome of the central nervous system with predominance of optic nerve and spinal cord involvement [1]. Aquaporin-4 antibodies were first described in 2004 [2]. The sensitivity of the aquaporin-4 antibody cell based assay ranges from 85 to 91% and the specificity is 100% [3, 4]. This patient’s symptoms were mild and her neurological examination was normal. Her symptoms were suggestive of mild transient optic neuritis and myelitis. Although her imaging has been normal thus far, it is possible that her disease may represent a milder phenotype of NMO and any radiological abnormalities present at the time of symptoms could reverse quickly leaving no appreciable abnormalities. The neurophysiological testing and the aquaporin-4 antibodies aided greatly in reaching a diagnosis in this patient and facilitating therapeutic decisions. Given the sensitivity P. H. McNamara (&) 32 Albert College Avenue, Glasnevin, Dublin 9, Ireland e-mail: pmcnamara2004@hotmail.com

PAW33 Aquaporin-4 M 23 isoform provides a more sensitive assay for aquaporin-4 antibodies

Neuromyelitis optica (NMO) is a serious inflammatory, demyelinating disease affecting the spinal cord and optic nerves. IgG antibodies to aquaporin-4 (AQP4) in patients' sera are now taken as evidence for...