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Neuromyelitis optica (NMO, Devic's disease) is an autoimmune disorder of the CNS that mainly affects the optic nerves and spinal cord and, if not treated, can leave patients blind and wheelchair-bound. NMO was long considered a clinical variant of multiple sclerosis (MS). While the history of MS has been studied extensively, relatively little is known about the early history of NMO. A dissertation written by Fernand Gault (1873–1936), a doctoral student to Eugène Devic (1858–1930), a Lyon-based neurologist after whom the disease would later be named, is considered by many the first review of NMO. We would like to draw attention to a forgotten earlier review by the German oculist Friedrich Albin Schanz (1863–1923)—still known to ophthalmologists as one of the inventors of the corneal microscope (“slit lamp”)—on which Devic and Gault's work was based and which points to most of the clinical and pathological features nowadays considered characteristic for NMO. The discovery of aquaporin-4 antibodies (NMO-IgG) has revived the interest in NMO, which is now extensively studied as a prototypic autoimmune condition. We believe it is now time to do justice to those who were seminal in describing this rare yet intriguing disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Neuromyelitis optica (NMO, Devic’s syndrome) is a severely disabling disorder of the central nervous system characterized by optic neuritis and longitudinally extensive myelitis. In around 80% of cases, NMO is caused by autoantibodies to astrocytic aquaporin-4 (AQP4), the most abundant water channel in the CNS. Acute NMO attacks are frequently accompanied by elevated levels of lactate in the cerebrospinal fluid (CSF). As a strongly dissociated anion (pK′=3.7) directly changing the strong ion difference, lactate causes a reduction in the dependent anion [ ] and a rise in [H+], resulting in “metabolic” acidosis in the CSF. CSF acidosis also develops during respiratory failure due to brainstem or high cervical spinal cord lesions, the most common cause of death in NMO. However, lactic acid and more generally, a decrease in pH, has been shown to increase the membrane expression of AQP4 in astrocytes. An increase in AQP4 membrane expression during acute NMO attacks could potentially enhance the complement-mediated humoral immune reaction against AQP4-expressing astrocytes characteristic for NMO and, thus, result in more severe astrocytic damage. Moreover, lactate and acidosis have been shown to cause astrocytic swelling and to affect astrocytic viability, potentially rendering astrocytes more susceptible to AQP4-Ab-mediated damage. Finally, increased AQP4 expression could be an independent risk factor in NMO and other forms of CNS inflammation, as indicated by the finding of grossly attenuated experimental autoimmune encephalomyelitis in AQP4-null mice. Therefore, we hypothesize that CSF acidosis might play a role in the pathophysiology of AQP4-Ab-positive NMO and that alterations in CSF pH might possibly influence the outcome of acute attacks in this condition. In addition, we discuss potential clinical implications and make proposals on how to test the hypothesis. Finally, other factors that influence astrocytic AQP4 membrane expression and might play a role in NMO are discussed. [Copyright &y& Elsevier]

Abstract: Background: Several assays have been developed to detect antibodies to aquaporin-4 (NMO-IgG/AQP4-Ab). However, many of these assays require sophisticated techniques and are thus only available at specialized laboratories. This is problematic since NMO-IgG/AQP4-Ab testing has important prognostic and therapeutic implications. Objective: To evaluate a newly developed, commercial, enzyme-linked immunosorbent assay (ELISA) for detecting NMO-IgG/AQP4-Ab. Methods: Serum samples from 261 patients with NMO spectrum disorders (NMOSD; n=108) and controls (n=153) were tested for AQP4-Ab by using ELISA. Of these patients, 207 were tested in parallel using a standard immunohistochemical (IHC) assay. Results: Fifty of 66 (75.8%) patients with NMO, 17/25 (68%) with LETM, 3/14 (21.4%) with ON, 2/3 (66.7%) with ON and non-extensive transverse myelitis, and 2/153 (1.3%) controls tested positive in the ELISA. Of those NMOSD patients tested by both ELISA and IHC, 10 were positive only in the ELISA and 3 exclusively in the IHC assay, suggesting that the overall sensitivity of the ELISA was higher than that of the standard IHC assay. The ELISA yielded very good intra- and inter-run reproducibility with regard to AQP4-Ab detection and good intrarun, but only moderate inter-run reproducibility with regard to AQP4-Ab quantification. Anti-AQP4 serum concentrations correlated with disease activity (p<0.00001), but did not differ between patients with NMO and patients with isolated LETM or ON. Conclusion: The ELISA evaluated here provides a relatively sensitive and easy-to-use diagnostic tool for detecting antibodies to AQP4 and could make AQP4-Ab testing, which is of high clinical relevance, more widely available. [Copyright &y& Elsevier]

Abstract: Neuromyelitis optica (NMO) is associated with antibodies to aquaporin-4 (termed NMO-IgG or AQP4-Ab) in 60–90% of cases. Little is known about the aetiology of NMO in NMO-IgG/AQP4-Ab negative patients. Here we report on CV2/CRMP5 antibodies in a 69-year-old male patient with NMO-IgG/AQP4-Ab negative NMO. The association of CV2/CRMP5-Ab with prostate cancer suggests a paraneoplastic aetiology of NMO in our patient. Our report strengthens the case of antibodies other than AQP4-Ab being involved in the immunopathogenesis in a subset of patients with NMO. We conclude that CV2/CRMP5-Ab should be included in the differential diagnosis of NMO, in particular if AQP4-Ab are negative and irrespective of whether a tumour is known or not. We recommend that recombinant tests, which are increasingly used because of their higher sensitivity and specificity, should always be accompanied by standard indirect immunofluorescence employing brain tissue sections in order to avoid CV2/CRMP5-Ab or other paraneoplastic antibodies being overlooked. In addition, we provide a comprehensive review of all patients with CV2/CRMP5-Ab and NMO-like disease published in the English literature so far. [Copyright &y& Elsevier]

Neuromyelitis optica (NMO, Devic's disease) is an often severely disabling disorder of the central nervous system (CNS) which mainly affects the optic nerves and spinal cord. NMO was long considered a clinical subform of multiple sclerosis (MS). In 2004, however, Lennon and colleagues described a novel autoantibody in NMO which targets aquaporin-4, the most abundant water channel in the CNS, and which was later shown to be directly pathogenic. This has led to the recognition of NMO as a distinct disease entity in its own right. While the history of ‘classical’ MS has been extensively studied, only little is known about the early history of NMO. The term neuromyelitis optica was coined in 1894 by Eugène Devic (1858–1930) and Fernand Gault (1873–1936), who were the first to provide a systematic description of that disorder. Here we re-present a very early description of a case of NMO by a Polish physician, Adolf Wurst, which appeared in 1876 in Przegląd Lekarski, one of the oldest Polish medical journals. This report predates Devic and Gault's seminal work on NMO by more than two decades. The patient, a 30-year-old woman, subacutely developed simultaneous bilateral optic neuritis with papilloedema and bilateral blindness and transverse myelitis with severe paraparesis, anaesthesia, and bladder and bowel dysfunction. At last follow-up, one year after onset, she had recovered except for a residual spastic gait and some visual deficit on the right side. Of note, this is the first known case of NMO in a Caucasian patient ever reported outside Western Europe. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO; also termed Devic's disease) is a severely disabling autoimmune disorder of the central nervous system (CNS), which predominantly affects the optic nerves and spinal cord. In up to 80% of cases, NMO is associated with antibodies to aquaporin-4 (AQP4-IgG), the most abundant water channel in the CNS. AQP4-IgG have been demonstrated to be directly pathogenic. Gamma-aminobutyric acid A receptor (GABAAR) agonists are frequently used in patients with NMO, e.g., for symptomatic treatment of spasticity or epilepsy or for non-NMO-related indications such as treatment of insomnia. However, GABAAR signaling has recently been shown to strongly promote AQP4 expression. This is of potential clinical importance since any increase in AQP4 membrane expression during acute NMO attacks may enhance the complement-mediated humoral immune reaction against AQP4-expressing cells characteristic for NMO and, thus, result in more severe CNS damage. We therefore hypothesize that GABAAR agonist-induced AQP4 upregulation may be a potential risk factor in NMO. This would also include a potential role for (GABAAR-enhanced) damage to the subependymal zone neural stem cells, the major source of both glial cells and neuroblasts in the adult brain, in NMO. We also make proposals on how to test that hypothesis and underline the general need for evaluating possible detrimental effects of commonly used drugs affecting AQP4 expression in NMO. [ABSTRACT FROM AUTHOR]

Abstract: So far, only very little is known about the early history of neuromyelitis optica (Devic''s syndrome). Here, we discuss a then widely recognized but now forgotten 1844 report by the Genoese physician Giovanni Battista Pescetto (1806–1884) on a 42-year-old man, who simultaneously developed acute amaurosis and cervical myelitis. Pescetto''s report represents the earliest account of a case of neuromyelitis optica in the Western literature known so far. [Copyright &y& Elsevier]

Introduction Antibodies against neurofascin, an axo-glial protein located around the node of Ranvier, have been shown to contribute to axonal pathology both in vitro and in experimental autoimmune encephalomyelitis models. Moreover, small case studies have reported anti-NF antibodies in samples from patients with progressive multiple sclerosis (MS). Patients and methods Building up on this observation, we compared the anti-NF reactivity in serum samples from 83 chronic progressive MS (PMS) patients to those with relapsing remitting MS (RRMS, n = 159) and 50 healthy controls. Anti-NF seroreactivity was quantified by enzyme-linked immunosorbent assay using recombinant rat neurofascin. In addition, to identify a potential intrathecal anti-NF antibody synthesis, we calculated the specific antibody index in paired cerebrospinal fluid and serum samples from MS patients with positive anti-NF seroreactivity. Results Prevalence of anti-NF seroreactivity in PMS patients (4.8%; all with primary progressive MS) was significantly higher than that detected in RRMS (0.6%; p = 0.030). However, we found no significant difference between PMS patients and healthy controls (2.0%; p = 0.408). MS patients with positive anti-NF reactivity experienced an above-average progression of disability compared to MS natural-history controls. Anti-NF-specific intrathecal antibody synthesis was not detected in MS patients with positive anti-NF seroreactivity. Conclusions Although present only in a minor subgroup, seroprevalence of anti-NF reactivity was significantly more frequent in patients with PMS than in those with RRMS, but was also occasionally found in healthy controls. Further prospective studies are warranted to investigate whether anti-NF antibodies anticipate disease progression. [ABSTRACT FROM AUTHOR]