Neuromyelitis optica spectrum disorder

Neuromyelis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) are closely related severe demyelinating diseases caused by an autoantibody to the aquaporin-4 water channel. The classic presentation of NMO is with the triad of optic neuritis, longitudinally extensive myelitis, and positive anti-AQP4 antibody, although a far wider range of manifestations are now recognised as part of NMOSD ^8-13.

Terminology

Neuromyelitis optica (NMO) was previously referred to as Devic disease, and traditionally NMO was thought to have limited if any intracranial manifestations. Over the past decade, however, a far wider range of manifestations have been recognised as belonging together and thus the term NMOSD has been proposed to encompass them all. 

Epidemiology

Neuromyelitis optica is typically found in patients somewhat older than those with multiple sclerosis (MS), with an average of presentation of 41 years, and there is an even stronger female predilection (F:M  6.5:1) ^6,8. It is found more frequently in patients of Asian, Indian, and African descent ⁸. 

Clinical presentation

NMO is characterized by bilateral optic neuritis and myelitis resulting in blindness and paraplegia. Although the two usually present concurrently, it is not uncommon for one to precede the other by up to several weeks ³. Additionally, it is now recognized that some patients present with unilateral optic nerve involvement. 

Although NMO was initially thought of as a monophasic illness, it is now evident that, as with MS, it is usually a relapsing-remitting disease with symptomatic events separated by many years ⁵. 

Furthermore, NMOSD also encompasses non-neurological manifestations in anti-AQP4 antibody seropositive patients including systemic lupus erythematosus (SLE) and Sjögren syndrome ¹³.

The current diagnostic criteria are defined by the International Panel for NMO Diagnosis.

Pathology

In approximately 70% (sensitivity of 70-90%; specificity of 90%) of patients with established NMO, a specific immunoglobulin can be isolated (AQP4-IgG which targets a transmembrane water channel (aquaporin 4) present on astrocyte foot processes abutting the limiting membrane ^5,8. This accounts for some of the predilection for the circumventricular organs (e.g. periaqueductal grey matter) which are particularly rich in aquaporin 4 ⁸. 

Early in the disease, demyelinating regions will demonstrate similar findings to MS, such as macrophage/microglia activation and axonal damage. Additionally, however, and relatively specific for NMO, these regions will also demonstrate extensive eosinophilic infiltration, perivascular deposition of immunoglobulins (especially IgM) and local activation of the complement cascade ³. Another differentiating feature is that axonal damage precedes demyelination in NMO ⁵. 

Generally, the condition is sporadic, although some overlap in immunogenic features between certain viruses and aquaporin-4 water channel have been identified ⁸. 

Radiographic features

MRI

MRI is the modality of choice for NMOSD and the orbits, brain and spinal cord should be imaged in suspected cases. 

Orbits

Targeted imaging of the orbits (including fat saturated T1 C+ and T2 weighted sequences (see MRI protocol: orbit) may demonstrate typical features of optic neuritis: 

• optic nerves appearing hyperintense and swollen on T2 weighted sequences and enhancing on T1 C+
• bilateral optic nerve involvement and extension of the abnormal signal posteriorly as far as the chiasm is particularly suggestive of NMO ⁵
• atrophy of the optic nerves with associated hyperintensities on T2 weighted sequences may be seen in chronic stages of the disease ¹¹

Brain

Although traditionally NMO was thought to have normal intracranial appearance it is increasingly evident that asymptomatic abnormalities are present in the majority of seropositive NMOSD patients. These can be divided into four categories ^5,8,13:

1. lesions which mirror the distribution of aquaporin 4 in the brain, which is particularly found in the periependymal regions abutting the ventricles:
   • periventricular (hemispheric) confluent smooth sessile white matter involvement (unlike MS, there are usually no Dawson's fingers)
   • periaqueductal grey matter
   • hypothalamus/medial thalamus
   • dorsal pons/medulla 
   • corpus callosum
     • multiple callosal lesions with heterogeneous signal leading to a marbled pattern ⁷ 
     • the splenium may be diffusely involved and expanded
2. deep (or less frequently subcortical) punctate white matter lesions (which may appear similar to those seen in MS)
3. corticospinal tract involvement by extensive longitudinal lesions; has been reported more frequently in Korean patients ⁵
4. larger >3cm diameter hemispheric white matter lesions
   • radially oriented (spilt-ink appearances) or spindle-shaped
   • limited if any mass effect although tumefactive lesions do occur ¹³
   • may involve overlying cortex ¹⁴
   • facilitated diffusion
   • may be more common in children and in patients from the Far East and Africa
   • often vanish but cystic change is seen in a minority of cases ¹³

Spinal cord

Spinal cord involvement is extensive, with high T2 signal spanning at least three vertebral segments, often many more (known as a longitudinally extensive spinal cord lesion) ^4,5,8,11. Cord swelling is usually present in the acute phase. Although less common, short transverse myelitis is seen in 14.5% of cases ¹¹.

Bright spotty lesions are a specific feature of NMO. It consists of marked T2 hyperintense (higher than CSF) and T1 hypointense foci in the central grey matter.

Imaging features include ^5,8: 

• T1
  • hypointense
  • follow-up scans may demonstrate cord atrophy and low T1 signal ⁵
• T2
  • hyperintense (often >3 vertebral body lengths) 
  • central grey matter involvement
  • bright spotty lesions (see above)
• T1 C+ (Gd)
  • patchy "cloud-like" enhancement of the aforementioned T2 bright lesions may be present
  • thin ependymal enhancement similar to ependymitis
  • enhancement in a lens-shaped appearance on the sagittal images can be distinctive for NMO ¹¹
    • due to enhancement surrounding the bright spotty lesion
  • NB: open ring enhancement is not a feature of NMO

Treatment and prognosis

Treatment of NMO is evolving, with immunosuppression (e.g. anti-CD20 monoclonal antibody rituximab) appearing effective ⁵.

It is important to distinguish NMO from MS as the treatment not only is different but treating a patient with NMO with MS-specific therapies (e.g. beta-interferon or natalizumab) can actually lead to its exacerbation ⁵. 

Patients with a relapsing course have a poorer prognosis ⁴:

• blind in one or both eyes: monophasic  22% vs. relapsing 60%
• monoplegia or paraplegia: monophasic 31% vs. relapsing 52%

History and etymology

The disease was first described in 1870 by Sir Thomas Clifford Allbutt ¹². The French term "neuromyélite optique aiguë" (literally acute optic neuromyelitis) was later coined by Dr Eugène Devic and Fernand Gault in 1894 in a case series of 16 patients ¹². At the time, the disorder was thought to be acute and monophasic.

Differential diagnosis

The differential diagnosis depends on the presentation, and when classic, the diagnosis can be made with a fair degree of certainty. The most important clinical and imaging differential is MS as both can present with optic neuritis, cerebral and spinal demyelination including involvement of the corpus callosum (see Practical points).

For patients with cerebral involvement, the differential is broad and includes:

• multiple sclerosis
• Susac syndrome: involves the central portion of the corpus callosum
• neuro-Behçet: mesodiencephalic involvement is typical
• primary angiitis of the CNS (PACNS)
• acute disseminated encephalomyelitis (ADEM): grey-white matter involvement with a more tumefactive appearance
• amyotrophic lateral sclerosis (ALS): bilateral corticospinal tract involvement is more symmetrical

For patients with optic nerve involvement, the differential is that of optic neuritis.

For patients with spinal cord involvement, the differential is that of a longitudinally extensive spinal cord lesion. For the typical bright spotty lesion, an important differential is acute spinal cord ischaemia.

Practical points

Features helpful in favouring NMO over MS include ^5,7: 

• periventricular/aqueductal distribution (see above)
• corticospinal tract and diencephalic involvement (see above)
• absent perivenular orientation of periventricular lesions (no Dawson's fingers)
• more extensive involvement of the corpus callosum
  • especially its ependymal surface
• larger, more confluent lesions
• lack of open ring enhancement
• more longitudinally extensive spinal cord lesion
  • preferential involvement of the central cord rather than the peripheral cord
• more longitudinally extensive optic neuritis
  • with preferential involvement of the posterior optic pathway