Introduction
Devic's Optic NeuroMyelitis is a clinical syndrome described over 100 years ago and characterized by episodes of severe Transverse Myelitis, affecting several Spinal Segments, and simultaneously or otherwise, Neuritis of the Optic Nerve.

Both types of disorder may be acute or subacute. In spite of many reviews in recent years, it is still not clear whether it is a distinct clinical entity or whether it is really a form of Multiple Sclerosis.

In recent years several authors have drawn up a list of diagnostic criteria to distinguish between Devic's Disease and Multiple Sclerosis.

Several Etiologies have been implicated in causing this syndrome, from Infectious Diseases to DeMyelinating Disorders.

However, there is a group of patients who have no associated pathology, in whom it is correct to speak of Devic's Disease.

Clinical Case
We studied a patient with a clinical condition compatible with Devic's Disease, with an inflammatory Tumor in the Cervical region, a Radiological finding not previously reported.

Conclusion
When making the diagnosis in patients with Inflammatory Spinal Tumors and no symptoms of DeMyelination in the rest of the Central Nervous System, Devic's Disease should be borne in mind.

Acute Transverse Myelitis (ATM) with moderate symptomatology and smaller multiple MRI lesions is often caused by Multiple Sclerosis.

Severe ATM with extensive MRI lesions with or without associated Meningitis often has a Viral cause, particularly in the younger age groups.

Whereas, Vascular Disorders may prevail among older patients.

Previously, one had to rely on indirect evidence such as Viral serology or Viral identification in throat washings to confirm a diagnosis of Myelitis.

Thus, Mycoplasma Myelitis may occur coincident with a Mycoplasma Pneumonia.

Viral Myelitis is now often diagnosed by specific polymerase chain reaction of the CerebroSpinal Fluid, for EchoVirus, Coxsackie Virus, Mumps Virus, Herpes Simplex Virus or Varicella-Zoster Virus.

But an AutoImmune component may still be important. An Anterior Horn Syndrome may be produced by the tick-borne EncephaloMyelitis Virus.

Severe ATM may also be a PostInfectious or PostVaccinal Disorder [i.e. a partial Acute Disseminated EncephaloMyelitis (ADEM)].

NeuroMyelitis Optica, a combination of severe Myelitis and Optic Neuritis, is often a manifestation of ADEM or Systemic Lupus Erythematosus.

Many of these disorders are potentially treatable with specific AntiViral agents or ImmunoSuppression. 'Idiopathic' ATM is probably a consequence of inadequate examination and follow up.

The differential diagnoses - Viral Myelitis, Multiple Sclerosis, ADEM, NeuroMyelitis Optica, Spinal Arteriovenous Malformation and Arteritis - should be considered and are usually identified by a rapid diagnostic work-up, leaving few ATM cases undiagnosed.

Objective
To review the Clinical, laboratory, and Radiological findings of 9 patients who had Progressive Idiopathic Myelopathy with evidence of Spinal Cord Necrosis.

Design And Methods
We reviewed personally examined cases of Myelopathy that fulfilled the following criteria:

1. Regional Loss of Reflexes, Flaccidity, and Muscle Atrophy

2. Magnetic Resonance Imaging showing a Shrunken or Cavitated Cord, Without Evidence of AterioVenous Malformation

3. ElectroMyogram showing denervation over several contiguous Spinal Cord Segments with preservation of Sensory Potentials in some cases

4. Absence of Evidence of Systemic Disease or Neoplasm

Results
The illness began in these patients after the age of 40 years, with Prominent Burning or Tingling Limb Pain, occasionally with Radicular features or with Less well-defined Back, Neck, or Abdominal Pain.

Leg or infrequently Arm Weakness appeared concurrently or soon after the onset of Pain.

The most distinctive feature was a Saltatory Progression of symptoms, punctuated by both acute and subacute worsenings approximately every 3 to 9 months, culminating in Paraplegia or Tetraplegia.

The distinguishing clinical findings, together indicative of destruction of Gray Matter elements of the Cord, were Limb Atrophy, Persistent Areflexia, and Flaccidity.

The concentration of CerebroSpinal Fluid protein was typically elevated between 500 g/L and 1000 g/L, without OligoClonal Bands, accompanied infrequently by Pleocytosis.

Magnetic Resonance Imaging showed features suggesting Cord Necrosis, specifically Swelling, T₂-weighted HyperIntensity, and Gadolinium enhancement over several Spinal Cord Segments, succeeded months later by Atrophy in the same regions.

Necrosis of the Cord was found in biopsy material from one patient and postmortem pathology in another case, but inflammation and blood vessel abnormalities were absent.

Only 2 patients had prolonged Visual Evoked Responses. The disease progressed despite ImmuneModulating treatments although several patients had brief epochs of limited improvement.

Conclusions
The Saltatory Course, prolonged Visual Evoked Responses in 2 patients, and a Cranial abnormality on Magnetic Resonance Imaging in another, raised the possibility of a link to Multiple Sclerosis.

However, the normal Cranial Magnetic Resonance Imaging scans in 6 other patients, uniformly absent OligoClonal Bands, and poor response to treatment were atypical for Multiple Sclerosis.

On the basis of shared clinical and laboratory features, idiopathic Progressive Necrotic Myelopathy is indistinguishable from a limited form of Devic's Disease.

Devic's Disease [NeuroMyelitis Optica (NMO)] is an Idiopathic Inflammatory DeMyelinating Disease of the CNS, characterized by attacks of optic Neuritis and Myelitis.

The mechanisms that result in selective localization of inflammatory DeMyelinating lesions to the Optic Nerves and Spinal Cord are unknown. Serological and clinical evidence of B-Cell AutoImmunity has been observed in a high proportion of patients with NMO.

The purpose of this study was to investigate the importance of Humoral mechanisms, including Complement activation, in producing the Necrotizing DeMyelination seen in the Spinal Cord and Optic Nerves.

Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's Disease.

DeMyelinating activity in the lesions was ImmunoCytoChemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or ReMyelinating (eight lesions) by examining the antigenic profile of Myelin degradation products within Macrophages.

The pathology of the lesions was analyzed using a broad spectrum of Immunological and NeuroBiological markers.

Lesions were defined on the basis of Myelin protein loss, the geography and extension of plaques, the patterns of Oligodendrocyte destruction and the ImmunoPathological evidence of Complement activation. The pathology was identical in all nine patients.

Extensive DeMyelination was present across multiple Spinal Cord levels, associated with Cavitation, Necrosis and acute Axonal pathology (spheroids), in both Gray and White Matter. There was a pronounced loss of Oligodendrocytes within the lesions.

The inflammatory infiltrates in active lesions were characterized by extensive Macrophage infiltration associated with large numbers of PeriVascular Granulocytes and Eosinophils and rare CD3⁺ and CD8⁺ T-Cells.

There was a pronounced PeriVascular deposition of ImmunoGlobulins (mainly IgM) and Complement C9neo Antigen in active lesions associated with prominent Vascular Fibrosis and hyalinization in both active and inactive lesions.

The extent of Complement activation, Eosinophilic infiltration and Vascular Fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic Multiple Sclerosis, and supports a role for Humoral Immunity in the pathoGenesis of NMO.

Based on this study, future therapeutic strategies designed to limit the deleterious effects of Complement activation, Eosinophil DeGranulation and Neutrophil/Macrophage/Microglial activation are worthy of further investigation.

Objectives
To evaluate the clinical characteristics, course and prognosis of Devic's NeuroMyelitis Optica (DNO), to evaluate the prognostic role of demographic and clinical features, to evaluate the current DNO diagnostic criteria.

Methods
Demographic, clinical, CSF and MRI data of patients affected by DNO were collected from fifteen Italian MS Centers.

Inclusion criteria were:
1) Two or more acute episodes of Neurological dysfunction indicating involvement of the Optic Nerve and Spinal Cord, in a simultaneous or subsequent temporal relationship;

2) No evidence of lesions beyond the Optic Nerve or the Spinal Cord;

3) Brain MRI at onset negative or non-specific for Multiple Sclerosis (MS) (White Matter lesions < or = 2).

Disability was scored by means of Kurtzke's Expanded Disability Status Scale (EDSS).

Results
46 patients with Relapsing DNO were included, 37 females and 9 males, with mean age at onset of 40.1 +/- 16.3 years (range 12-77 years).

The follow up duration was 8.8 +/- 3.5 years, the mean annualized relapse rate was 1.3 +/- 1.2.

After 5, 10 and 15 years EDSS 3.0 was reached respectively by 65%, 82 % and 86% of cases. EDSS 6.0 respectively by 42%, 53 % and 69% of cases, EDSS 10 respectively by 8%, 12% and 23% of cases.

The probability of reaching EDSS 3 was statistically correlated with age at onset, interval between the first and 2(nd) attack, and relapse rate.

The probability of reaching EDSS 6.0 was correlated with the residual EDSS at onset and to relapse rate. During the follow up, Brain White Matter lesions appeared in 8 subjects.

Spinal Cord MRI showed lesions extending across 3 or more segments in 39 subjects, only 1 lesion involving 1 segment in 4 subjects, and was normal in 3 subjects.

One or more CSF abnormalities were found at least once in 29/44 patients (65.9 %), the most frequent findings being PleoCytosis (38.6 %), OligoClonal Bands (34.1 %), high protein level (25 %), and high Albumin ratio (20.5 %).

Conclusions
DNO has a poor prognosis in most cases. Compared with MS, DNO patients have a higher age at onset, females are more frequently affected, the course is more severe.

Brain and Spinal Cord MRI permit the differentiation of DNO from MS. CSF supports the probability of DNO if it shows increased cells and proteins.

Background
NeuroMyelitis Optica is an Inflammatory DeMyelinating Disease with generally poor prognosis that selectively targets Optic Nerves and Spinal Cord.

It is commonly misdiagnosed as Multiple Sclerosis. Neither disease has a distinguishing biomarker, but optimum treatments differ. The relation of NeuroMyelitis Optica to Optic-Spinal Multiple Sclerosis in Asia is uncertain.

We assessed the capacity of a putative marker for NeuroMyelitis Optica (NMO-IgG) to distinguish NeuroMyelitis Optica and related disorders from Multiple Sclerosis.

Methods
Indirect immunofluorescence with a composite substrate of mouse tissues identified a distinctive NMO-IgG staining pattern, which we characterised further by dual immunostaining.

We tested masked serum samples from 102 North American patients with NeuroMyelitis Optica or with syndromes that suggest high risk of the disorder, and 12 Japanese patients with Optic-Spinal Multiple Sclerosis.

Control patients had Multiple Sclerosis, Other Myelopathies, Optic Neuropathies, and miscellaneous disorders.

We also established clinical diagnoses for 14 patients incidentally shown to have NMO-IgG among 85000 tested for suspected Paraneoplastic Autoimmunity.

Findings
NMO-IgG outlines CNS MicroVessels, Pia, Subpia, and Virchow-Robin Space. It partly colocalises with Laminin.

Sensitivity and specificity were 73% (95% CI 60-86) and 91% (79-100) for NeuroMyelitis Optica and 58% (30-86) and 100% (66-100) for Optic-Spinal Multiple Sclerosis.

NMO-IgG was detected in half of patients with high-risk syndromes. Of 14 SeroPositive cases identified incidentally, 12 had NeuroMyelitis Optica or a high-risk syndrome for the disease.

Interpretation
NMO-IgG is a specific marker AutoAntiBody of NeuroMyelitis Optica and binds at or near the Blood-Brain Barrier.

It distinguishes NeuroMyelitis Optica from Multiple Sclerosis. Asian Optic-Spinal Multiple Sclerosis seems to be the same as NeuroMyelitis Optica.

NeuroMyelitis Optica (NMO) is an Inflammatory DeMyelinating Disease that selectively affects Optic Nerves and Spinal Cord.

It is considered a severe variant of Multiple Sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ.

A Serum ImmunoGlobulin G AutoAntiBody (NMO-IgG) serves as a specific marker for NMO.

Here we show that NMO-IgG binds selectively to the Aquaporin-4 water channel, a component of the Dystroglycan protein complex located in Astrocytic foot processes at the Blood-Brain Barrier. NMO may represent the first example of a novel class of Autoimmune Channelopathy.

Objective
To study Immunologic alterations in patients with NeuroMyelitis Optica (NMO).

Methods
The authors studied 8 patients with NMO together with 16 healthy subjects, 16 patients with Relapsing/Remitting Multiple Sclerosis (RRMS), and 16 patients with Secondary/Progressive MS (SPMS), matched for age and sex, as controls.

Because recent histopathologic studies have demonstrated that active NMO lesions consist of PeriVascular ImmunoGlobulin (Ig) deposition and Eosinophil infiltration.

IL-5, IL-6, IL-12, IgG, and IgM production by Anti-Myelin Oligodendrocyte Glycoprotein (MOG) MonoNuclear Cells in peripheral blood and CSF were selected for study using ELISPOT.

Eotaxin-2 (Eo-2) and Eotaxin-3 (Eo-3) levels were also assessed using ELISA and Eosinophil Cationic Protein (ECP) levels by radioimmunoassay.

Results
MOG-specific responses in CSF showed significant increase in IL-5, IL-6, IgG, and IgM secreting cells in NMO patients.

Compared with patients with RRMS, SPMS and healthy subjects. Interestingly, numbers of IgM secreting cells were significantly higher than identical specificity IgG secreting ones.

Moreover, CSF Eo-2, Eo-3, and ECP levels were also significantly higher in NMO patients compared to all three control populations. Anti-MOG IL-12 secreting cells were increased in CSF and peripheral blood from NMO, RRMS, and SPMS patients when compared to healthy subjects.

Conclusions
These observations suggest that NeuroMyelitis Optica is associated with a major Humoral Immune Response (particularly Anti-MOG IgM production) and Eosinophil activation present exclusively in CSF.

Objective
To determine the long-term risk of developing Clinically Definite Multiple Sclerosis (CDMS) in patients with Acute Partial Transverse Myelitis (APTM) and normal Cerebral Magnetic Resonance Imaging (MRI) scans.

Methods
We retrospectively studied 30 consecutive patients with clinical evidence of APTM. Patients with symmetric severe Acute Transverse Myelitis were considered to have complete Transverse Myelitis and were excluded.

All patients underwent Spinal and Cerebral MRIs, 13 underwent CerebroSpinal Fluid analysis and 11 patients underwent Evoked Potential studies.

Various other studies were performed to assess for connective tissue disease and causes of APTM other than DeMyelinating Disease.

Results
After an average follow-up of 61 months, all laboratory and clinical evidence, including relapse history, indicated that three patients developed lesions on Cerebral MRI and could be classified as CDMS by either Poser criteria (two patients) or McDonald criteria (one patient).

Relapses limited to the Spinal Cord seen clinically were seen in 14/30 (46.6%) patients. OligoClonal Bands were seen in 8/13 (62%) patients; one patient transitioned to CDMS.

Unifocal lesions of the Cord were seen in 19/30 (63%) patients, multifocal lesions were seen in 8/30 (27%) and 3/30 (10%) had negative MRIs. The three patients who converted to CDMS did so within five years of the onset of Myelitis.

Conclusion
APTM with normal Cerebral MRI had a low rate of conversion to CDMS in this long-term study. To date, there have been only a few follow-up studies that have addressed this issue.

Background
Anti-AquaPorin 4 (AQP4) AntiBodies were found in patients with NeuroMyelitis Optica (NMO) and Japanese Optic-Spinal Multiple Sclerosis (OSMS).

Objective
To review the clinical features and investigate Anti-AQP4 AntiBodies of Japanese patients with Multiple Sclerosis (MS), with or without long Spinal Cord lesions (LCL).

Methods
Anti-AQP4 AntiBodies were examined in the Sera of 128 consecutive Japanese patients by the immunofluorescence method using AQP4 transfected cells.

Results
The 45 LCL-MS patients included 28 with a long Spinal Cord lesion extending contiguously over three Vertebral segments on sagittal T₂ weighted images (long T₂ lesion).

And 17 with Segmental Cord Atrophy extending more than Three Vertebral Segments. We identified 25 patients with Anti-AQP4 AntiBody with LCL and Anti-AQP4 AntiBody.

Anti-AQP4 AntiBody was found in 12/17 (70.6%) LCL-MS patients with Segmental Cord Atrophy, and in 13/28 (46.4%) LCL-MS patients without segmental long Cord Atrophy (p = 0.135, Fisher's exact test).

SeroPositive MS patients with LCL had more relapses than SeroNegative patients (p = 0.0004, Mann-Whitney U test).

9 patients with OSMS were negative for Anti-AQP4 AntiBody who did not show LCL.

Conclusion
These results suggest that an Anti-AQP4 AntiBody is found not only in MS patients with long T₂ lesions but also in patients with Segmental Cord Atrophy extending more than three Vertebral segments.

It is a marker of LCL-MS showing frequent exacerbations. Japanese OSMS cases comprised those that were identical to NMO cases and those that were more closely related to classic MS.

Purpose Of Review
We review recent advances in NeuroMyelitis Optica, an idiopathic Inflammatory DeMyelinating Disease of the Central Nervous System predominantly affecting Optic Nerves and Spinal Cord.

We concentrate on a recently identified Serum antibody biomarker, NeuroMyelitis Optica ImmunoGlobulin G (NMO-IgG), which distinguishes NeuroMyelitis Optica from Multiple Sclerosis.

Recent Findings
NMO-IgG is detected by indirect immunofluorescence. Its presence and specificity for NeuroMyelitis Optica was confirmed in diverse populations.

SeroPositivity is now incorporated into new diagnostic criteria for NeuroMyelitis Optica.

Testing for this biomarker has suggested that the Neuromyelitis Optica spectrum is broader than previously recognized. Recently, the molecular target of NMO-IgG was identified as Aquaporin-4.

Immunopathologic studies suggest that loss of Aquaporin-4 immunostaining is detectable in early lesions of NeuroMyelitis Optica. A B-Cell-specific MonoClonal AntiBody, Rituximab, may be an effective treatment even in patients not responding to other treatments.

Summary
Clinical, radiologic, and Immunologic features distinguish NeuroMyelitis Optica from other severe cases of Multiple Sclerosis.

NMO-IgG is the first specific marker for a Central Nervous System DeMyelinating Disease.

The discovery of Aquaporin-4 as the putative target of NMO-IgG, and recent data suggesting that Aquaporin-4-specific AntiBodies are pathogenic may enhance our understanding of idiopathic Inflammatory DeMyelinating Diseases and their treatment.

NeuroMyelitis Optica (NMO) is a severe DeMyelinating Disease of the CNS that preferentially affects the Optic Nerves and Spinal Cord, tends to relapse, and results in early permanent disability for most affected patients.

A new AutoAntiBody marker called NeuroMyelitis Optica ImmunoGlobulin G (NMO-IgG), which targets the water channel protein Aquaporin-4, is highly specific for NMO.

The marker has demonstrated that the NMO spectrum of disorders is wider than previously known.

And, includes some patients with single-episode or recurrent longitudinally extensive Myelitis, recurrent isolated Optic Neuritis, Asian Optic-Spinal Multiple Sclerosis, and patients with co-existing Systemic Autoimmune Diseases such as Lupus Erythematosus or Sjögren's Syndrome.

We review the place of NMO within the nosology of CNS DeMyelinating diseases, the discovery of NMO-IgG and its impact on the definition of NMO and its spectrum, implications for understanding NMO pathogenesis, and informing treatment decisions.