Neuromyelitis optica

Synonyms

3

Overview

Neuromyelitis optica (NMO, also known as Devic's disease or Devic's syndrome), is a heterogeneous condition consisting of the simultaneous inflammation and demyelination of the optic nerve (optic neuritis) and the spinal cord (myelitis). It can be monophasic or recurrent.

Currently at least two different causes are proposed based on the presence of autoantibodies against AQP4. AQP4+ NMO is currently considered an autoimmune disease (autoimmune astrocytopathy, or autoimmune astrocytic channelopathy) in which a person's own immune system attacks the astrocytes of the optic nerves and spinal cord. The cause of the AQP4- variants is unknown.

Although inflammation may also affect the brain, the lesions are different from those observed in the related condition, multiple sclerosis. Spinal cord lesions lead to varying degrees of weakness or paralysis in the legs or arms, loss of sensation (including blindness), and/or bladder and bowel dysfunction.

Devic's disease is now studied along a collection of similar diseases called "Neuromyelitis optica spectrum diseases". Some cases of this spectrum resemble multiple sclerosis (MS) in several ways, but require a different course of treatment for optimal results.

In 2004, NMO-IgG (currently known as Anti-AQP IgG) was first described leading to the distinction between positive and negative cases.

In Anti-AQP positive variants, CNS astrocytes, which are the basis for the glymphatic system are the target of the autoimmune attack. NMO-IgG-negative cases are less understood. It seems currently that astrocytes are spared in these IgG negative cases.

Symptoms

The main symptoms of Devic's disease are loss of vision and spinal cord function. Optic neuritis may manifest as visual impairment with decreased visual acuity, although visual field defects, or loss of color vision may occur in isolation or prior to formal loss of acuity. Spinal cord dysfunction can lead to muscle weakness, reduced sensation, or loss of bladder and bowel control. The typical patient has an acute and severe spastic weakness of the legs (paraparesis) or all four limbs (quadriparesis) with sensory signs, often accompanied by loss of bladder control.

Causes

NMO has been associated with many systemic diseases, based on anecdotal evidence of some Devic's disease patients with a comorbid condition. Such conditions include: collagen vascular diseases, autoantibody syndromes, infections with varicella-zoster virus, Epstein-Barr virus, and HIV, and exposure to clioquinol and antituberculosis drugs.

The discovery of NMO-IgG has opened a new way into the research for the causes. Currently two principal causes are accepted:

  • In NMO-IgG positive patients, the cause of the neuromyelitis optica (understood as the syndrome) is an autoimmune aquaporin-4 channelopathy, due to these specific autoantibodies. In these cases, astrocytes are the victims of the autoimmune attack.
  • In NMO-IgG negative patients, or at least a subset of them, the cause is an antiMOG associated encephalomyelitis,

About the presence of NMO-IgG, some researchers have pointed out that some other cases could be paraneoplastic. It seems also clear that lupus can produce NMO-IgG autoantibodies sometimes, leading to some cases of lupus-derived NMO.

In any case, the IgG generation is produced mainly intrathecally

Diagnosis

The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic's disease in 2006. Those new guidelines require two absolute criteria plus at least two of three supportive criteria.[10] In 2015 a new review was published by an international panel[5] refining the previous clinical case definition but leaving the main criteria unmodified:

Absolute criteria:

  1. Optic neuritis
  2. Acute myelitis

Supportive criteria:

  1. BrainMRI not meeting criteria for MS at disease onset
  2. Spinal cord MRI with contiguous T2-weighted signal abnormality extending over three or more vertebral segments, indicating a relatively large lesion in the spinal cord
  3. NMO-IgG seropositive status (The NMO-IgG test checks the existence of antibodies against the aquaporin 4antigen.)

Variants

After the development of the NMO-IgG test, the spectrum of disorders comprising Devic's disease was expanded. The spectrum is now believed to consist of:

  • Standard Devic's disease, according to the diagnostic criteria described above
  • Limited forms of Devic's disease, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis
  • Asian optic-spinal MS - this variant can present brain lesions like MS.
  • Longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease
  • Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem
  • NMO-IgG negative NMO: AQP4 antibody-seronegative NMO poses a diagnostic challenge. Some cases could be related to anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies.

Whether Devic's disease is a distinct disease or part of the wide spectrum of multiple sclerosis is debated. Devic's disease differs in that it usually has more severe sequelae after an acute episode than standard MS, MS infrequently presents as transverse myelitis, and oligoclonal bands in the CSF, as well as white matter lesions on brain MRI, are uncommon in Devic's disease, but occur in over 90% of MS patients.

Recently, AQP4 has been found to distinguish standard multiple sclerosis from neuromyelitis optica, but as MS is a heterogeneous condition, and some MS cases are reported to be Kir4.1channelopathies (autoimmunity against the potassium channels) it is still possible to consider NMO as part of the MS spectrum. Besides, some NMO-AQP(-) variants are not astrocytopathic, but demyelinating.

Tumefactive lesions

Tumefactive demyelinating lesions in NMO are not usual, but they have been reported to appear in several cases mistakenly treated with interferon beta.

Prognosis

Normally, some measure of improvement appears in a few weeks, but residual signs and disability may persist, sometimes severely.

The disease can be monophasic, i.e. a single episode with permanent remission. However, at least 85% of patients have a relapsing form of the disease with repeated attacks of transverse myelitis and/or optic neuritis. In patients with the monophasic form, the transverse myelitis and optic neuritis occur simultaneously or within days of each other. On the other hand, patients with the relapsing form are more likely to have weeks or months between the initial attacks, and to have better motor recovery after the initial transverse myelitis event. Relapses usually occur early, with about 55% of patients having a relapse in the first year and 90% in the first five years.

It is possible that the relapsing form is related to the antiAQP4+ seropositive status and the monophasic form related to its absence Unlike multiple sclerosis, Devic's disease rarely has a secondary progressive phase in which patients have increasing neurologic decline between attacks without remission. Instead, disabilities arise from the acute attacks.

Approximately 20% of patients with monophasic Devic's disease have permanent visual loss, and 30% have permanent paralysis in one or both legs. Among patients with relapsing Devic's disease, 50% have paralysis or blindness within five years. In some patients (33% in one study), transverse myelitis in the cervical spinal cord resulted in respiratory failure and subsequent death. However, the spectrum of Devic's disease has widened due to improved diagnostic criteria, and the options for treatment have improved; as a result, researchers believe these estimates will be lowered.

Treatment

Currently, there is no cure for Devic's disease, but symptoms can be treated. Some patients recover, but many are left with impairment of vision and limbs, which can be severe.

Attacks

Attacks are treated with short courses of high dosage intravenous corticosteroids such as methylprednisolone IV.

Plasmapheresis can be an effective Treatment when attacks progress or do not respond to corticosteroid treatment. Clinical trials for these treatments contain very small numbers, and most are uncontrolled, though some report high success percentage.

Secondary prevention

No controlled trials have established the effectiveness of treatments for the prevention of attacks. Many clinicians agree that long term immunosuppression is required to reduce the frequency and severity of attacks, while others argue the exact opposite. Commonly used immunosuppressant treatments include azathioprine (Imuran) plus prednisone, mycophenolate mofetil plus prednisone, rituximab, mitoxantrone, intravenous immunoglobulin (IVIG), and cyclophosphamide. The monoclonal antibody rituximab is under study. In 2007, Devic's disease was reported to be responsive to glatiramer Acetate and to low-dose corticosteroids.