Devic's disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Synonyms and keywords:

Overview

Devic's disease, also known as Devic's syndrome or neuromyelitis optica (NMO), is an autoimmune, inflammatory disorder in which a person's own immune system attacks the optic nerves and spinal cord. This produces an inflammation of the optic nerve (optic neuritis) and the spinal cord (myelitis). Although inflammation may also affect the brain, the lesions are different to 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, and/or bladder and bowel dysfunction.

Devic's disease is a rare disorder which resembles multiple sclerosis (MS) in several ways, but requires a different course of treatment for optimal results.. The likely target of the autoimmune attack at least in some patients with NMO has been identified. The target is a protein of the nervous system cells called aquaporin 4.

Historical Perspective

In 1870, Sir Thomas Clifford Allbutt first reported an association between myelitis and an optic nerve disorder. In 1894, Eugène Devic and his PhD. student Fernand Gault described 16 patients who had lost vision in one or both eyes and within weeks developed severe spastic weakness of the limbs, loss of sensation and often bladder control. They recognized that these symptoms were the result of inflammation of the optic nerve and spinal cord, respectively.

Similar instances of optic neuritis and myelitis were reported, and many believed it constituted a distinct clinical entity. However, some patients had pathology in other parts of the brain, a feature which was more suggestive of acute disseminated encephalomyelitis (ADEM) or MS.

In 2004 the Mayo Clinic identified the aquaporin 4 protein as the target of the disease and developed a test to aid in the diagnosis of Devic's disease by detection of an antibody, NMO-IgG, in the blood. Some patients with NMO may be seronegative for NMO Ig-G whilst some patients with NMO-IgG may still not fulfill clinical criteria for NMO thus serological testing is now an important part of the diagnostic procedure and seropositive and seronegative cases are described in a manner similar to myasthenia gravis. According to the Mayo Clinic report, this was the first time that a molecular target had been identified for a type of demyelinating inflammatory disease.

Classification

After the development of the NMO-IgG test, the spectrum of disorders that comprise Devic's disease was expanded. The Devic's disease 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
• Longitudinally extensive myelitis or optic neuritis associated with systemic auto-immune disease
• Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem

Pathophysiology

Devic's disease is similar to MS in that the body's immune system attacks the myelin surrounding nerve cells. Unlike standard MS, the attacks are not believed to be mediated by the immune system's T cells but rather by antibodies called NMO-IgG. These antibodies target a protein called aquaporin 4 in the cell membranes of astrocytes which acts as a channel for the transport of water across the cell membrane. Aquaporin 4 is found in the processes of the astrocytes that surround the blood-brain barrier, a system responsible for preventing substances in the blood from crossing into the brain. The blood-brain barrier is weakened in Devic's disease, but it is currently unknown how the NMO-IgG immune response leads to demyelination.

Most research into the pathology of Devic's disease has focused on the spinal cord. The damage in the spinal cord can range from inflammatory demyelination to necrotic damage of the white and grey matter. The inflammatory lesions in Devic's disease have been classified as type II lesions (complement mediated demyelinization), but they differ from MS pattern II lesions in their prominent perivascular distribution. Therefore, the pattern of inflammation is often quite distinct from that seen in MS.

Differentiating Devic's Disease from other Diseases

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 in 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.

Devic's disease has been associated with many systemic diseases, based on anecdoctal 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.

Epidemiology and Demographics

The prevalence and incidence of Devic's disease has not been established partly because the disease is underrecognized and often confused with MS. Devic's disease is more common in women than men, with women comprising over 2/3 of patients and more than 80% of those with the relapsing form of the disease. NMO is more common in women than men.

Devic's disease is more common in Asiatic people than Caucasians. In fact, Asian optic-spinal MS (which constitutes 30% of the cases of MS in Japan) has been suggested to be identical to Devic's disease(Differences between optic-spinal and classic MS in Japanese patients). In the indigenous populations of tropical and subtropical regions, MS is rare, but when it appears it often takes the form of optic-spinal MS.

The majority of Devic's disease patients have no affected relatives, and it is generally regarded as a non-familial condition.

Natural History, Complications and Prognosis

Normally, there is some measure of improvement 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 5 years. Unlike MS, 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 more legs. Among patients with relapsing Devic's disease, 50% have paralysis or blindness within 5 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 that these estimates will be lowered.

Diagnosis

Diagnostic Criteria

The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic's disease in 2006. The new guidelines for diagnosis require two absolute criteria plus at least two of three supportive criteria being:

Absolute criteria:

1. Optic neuritis
2. Acute myelitis

Supportive criteria:

1. Brain MRI not meeting criteria for MS at disease onset
2. Spinal cord MRI with contiguous T2-weighted signal abnormality extending over 3 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 4 antigen.

Symptoms

The main symptoms of Devic's disease are loss of vision and spinal cord function. As for other etiologies of optic neuritis,the visual impairment usually manifests as 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 (tetraparesis) with sensory signs, often accompanied by loss of bladder] control.

Treatment

Medical Therapy

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 are treated with short courses of high dosage intravenous corticosteroids such as methylprednisolone IV. When attacks progress or do not respond to corticosteroid treatment, plasmapheresis can be an effective treatment. Clinical trials for these treatments contain very small numbers, and most are uncontrolled.

Prevention

No controlled trials have established the effectiveness of treatments for the prevention of attacks. Most clinicians agree that long term immunosuppression is required to reduce the frequency and severity of attacks. Commonly used immunosuppresant 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.

See also

• Multiple sclerosis
• Multiple sclerosis borderline

External links

• Devic's Disease (Neuromyelitis Optica) at myelitis.org
• Devics Disease - Information and treatment options at Mayo Clinic
• The Walton centre for Neurology and Neurosurgery, Liverpool, United Kingdom, information for patients and physicians - at NHS
• EDMUS, European Database for Multiple Sclerosis at edmus.org