Introduction

Neuromyelitis optica (NMO), also known as Devic’s disease, describes a spectrum of rare autoimmune demyelinating CNS conditions.

It is often a differential diagnosis for multiple sclerosis, as it shares many similarities with the neurological condition, including features such as optic neuritis.

NMO predominately affects the optic nerve and spinal cord and most cases follow a relapsing pattern (80-90%) compared to a monophasic pattern. It can occur at any age and occurs more frequently in women.

Primarily managed in secondary care, treatment focuses on controlling attacks and reducing their frequency. Prognosis is mainly affected by the severity and frequency of attacks, with longterm neurological deficits a potential consequence.

Aetiology

Most cases (>90%) are thought to occur sporadically
  • 25% have an other autoimmune comorbidity.
  • Incidence of NMO is higher in females (10:1).
  • Incidence of NMO is higher in Asian and African populations
    • These populations have a worse prognosis.
  • The median age of onset ranges between 30-40 years but cases are reported in children and older adults.

Familial history of NMO among families is relatively rare.
  • 3% of patients have relatives with NMO.
  • 50% have a personal or family history of autoimmunity.

Pathophysiology

It is believed that most cases of NMO occur due to IgG Antibodies to Aquaporin-4 (AQP4-Abs)
  • Aquaporin 4 is a water channel protein highly expressed in the body and can be located in the brain, spinal cord, and optic nerves.
    • The areas where Aquaporin-4 is located in the body but is unaffected by NMO (e.g. stomach, airways, secretory glands) have local inhibitory effects that prevent the actions of the antibodies.

Peripheral production of AQP4-Abs (by an unestablished process)→antibodies travel to the Central Nervous System (CNS) →activation of T-helper 17 cells and complement pathway (including IL-6 production)→ triggers cell-mediated astrocyte, oligodendrocyte and neurone damage→ leads to demyelination, axonal loss and perivascular lymphocytic infiltration→presents as optic neuritis and/or transverse myelitis

Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG), are also seen in NMO, particularly in the non-relapsing variant. They are thought to have a similar physiological effect as AQP4-ABs to induce demyelination.

Clinical features

In general, the hallmark presentation of NMO is of attacks of optic neuritis and/or transverse myelitis.

Most cases of NMO have a relapsing pattern, with attack of symptoms occurring all at once (e.g. optic neuritis and transverse myelitis) or separated over a time interval (e.g. optic neuritis followed a week later by transverse myelitis).

The remaining cases of NMO mostly have a monophasic pattern occurring with concurrent optic neuritis and transverse myelitis.

Common features
  • Optic neuritis
    • May be bilateral, unilateral or sequential
    • Eye pain, typically worse with movement
    • Visual loss (more severe than in multiple sclerosis)
  • Transverse myelitis
    • Limb weakness- symmetric paraparesis or quadriparesis
    • Bladder dysfunction
    • Sensory loss-below the level of the spinal cord lesion
    • Paroxysmal tonic spasms-affects the trunk or limbs
    • Radicular pain
  • Brainstem syndromes
    • Area postrema (located on the floor of the 4th ventricle) lesions-intractable hiccups, nausea, or vomiting
  • Pruritus
    • Caused by inflammation of fibres in the spinothalamic tract
  • Pain
    • Very common symptom (80% of attacks)
    • Involving the eye in cases with optic neuritis
    • Involving the trunk or legs in cases transverse myelitis

Rarer features
  • Myalgia-few cases reported
  • Encephalopathy-may cause seizures
  • Hypothalamic dysfunction -may cause narcolepsy, obesity, and autonomic dysfunction (hypotension, bradycardia, and hypothermia)

Investigations

A 2015 neurology international consensus agreed that diagnosis should be made on the following criteria:
  • At least 1 core clinical characteristic
  • Positive Aquaporin 4-Antibodies
  • Alternative diagnosis exclusion

Therefore, investigations focus on excluding differentials and confirming antibodies pathognomonic for NMO are present.

Investigations done usually for NMO and to exclude other diagnoses include:
  • Lumbar puncture
  • Aquaporin 4-antibodies
  • Anti-MOG (myelin oligodendrocyte glycoprotein) antibodies
  • MRI of the head and spine
  • Visually evoked potentials

What to expect with investigation findings?
  • Bloods
    • Presence of Aquaporin 4-IgG antibodies in serum
    • Presence of Anti-MOG (myelin oligodendrocyte glycoprotein) antibodies in serum
  • Lumbar puncture
    • CSF oligoclonal bodies-absent
  • MRI Head
    • Most often normal
    • Demyelinating lesions may be found
    • Peri-aqueductal lesions or lesions involving the thalamic and hypothalamic region may be found
    • Often done to differentiate from Multiple sclerosis
    • For Area postrema syndrome, an MRI brain would reveal a dorsal medulla/area postrema lesion on MRI brain
  • MRI of the spinal cord-longitudinal and central cord lesions
    • >/= 3 contiguous vertebral segment lesions
  • MRI of the optic nerve
    • Longitudinal Lesion
  • Visually evoked potentials
    • Differentiates neuromyelitis optica from other causes of optic neuropathy
    • Reduced amplitudes or prolonged latencies

For diagnosis, if aquaporin 4-antibodies are negative,
  • At least 2 core clinical characteristics from >/=1 acute attacks
  • At least 1 of either optic neuritis, transverse myelitis or area postrema syndrome
  • MRI evidence of NMO
    • MRI spine
    • MRI brain
    • MRI optic nerve

Core clinical characteristics include
  • Optic neuritis
  • Area postrema syndrome
  • Myelitis
  • Brainstem syndrome
  • Narcolepsy or acute diencephalic syndrome
    • Present with diencephalic MRI lesions
  • Cerebral syndrome
    • Present with diencephalic MRI lesions


Differential diagnosis

Many of the differentials are conditions that also present with optic neuritis and/or transverse myelitis. NMO is associated with other systemic autoimmune conditions (e.g. Systemic lupus erythematosus (SLE) , Sarcoidosis, Behcet disease and Sjögren’s syndrome) and it may be challenging to differentiate whether symptoms are caused by NMO or another condition. Investigations should be based in secondary care (e.g. neurology, rheumatology) and should focus on identifying specific antibodies due to these autoimmune conditions.

Possible differentials include:
  • Multiple sclerosis
    • The most likely alternative diagnosis. MS is more common than NMO and must be ruled through investigations and a consultation with neurologist.
    • Similarities: Both have relapsing courses, both can feature optic neuritis and/or transverse myelitis, both respond to similar treatment including corticosteroids
    • Differences: Multiple sclerosis can affect regions outside of the optic nerves and spinal cord where as NMO rarely does, Lumbar puncture is normal usually in NMO, MRI of the head is often normal

  • Vascular and degenerative disorders of the spinal cord (e.g. Anterior spinal artery occlusion, degenerative disc disease)
    • Similarities: Both can feature pain and paraesthesiae from spinal cord lesions, If vascular may present as acutely as NMO
    • Differences: Presentation of symptoms-usually gradual in degenerative pathology, Absence of optic neuritis, Different MRI of the spine findings (longitudinal lesions in NMO)

  • Guillian Barre Syndrome (GBS)
    • Similarities: Both can feature pain and paraesthesiae from spinal cord lesions
    • Differences: clinical pattern of symptoms ( GBS has symmetrical ascending progressive weakness and paraesthesia of all four limbs, NMO affects areas relative to transverse myelitis lesion), Antibody investigations ( GBS has anti-ganglioside antibodies in serum)


Management

Management is through secondary care, with diagnosis and treatment initiated through neurology. The process of diagnosis, investigations and management is broadly similar to MS management.

The main aims of treatment are;
  • To reduce the frequency of attacks
  • To reduce the severity of attacks when they do occur

Acute attacks
  • Corticosteroids
    • 1st Intravenous Methylprednisolone for 5 days
    • 2nd Oral prednisolone tapered over weeks to months
  • Plasma exchange therapy (PLEX)
    • If unresponsive to corticosteroids
    • Usually for 5 cycles

Most guidelines advocate the use of corticosteroids, including European Federation of Neurological Societies (EFNS). This is similar to treatment for acute exacerbations of multiple sclerosis and other causes of optic neuritis, as outlined by NICE guidelines. The same guidelines advocate the use of plasma exchange as a rescue treatment if steroids are contraindicated or fail.There is some evidence supporting the use of PLEX as first line, especially when presentations are attacks of transverse myelitis. In comparison to the evidence supporting corticosteroids, this is less substantive.

Prophylaxis and remission treatment

Long-term immunotherapy is recommended to incept as soon as a diagnosis is made. There is a lack of guidelines on a set regimen but a host of drugs have been shown to be effective in sustaining remission.
Immunosuppressive drugs
  • Corticosteroids; Oral prednisolone should be given alongside other immunosuppressives drugs
  • Azathioprine; Around 70% reduction in relapses
  • Mycophenolate mofetil; Around 80% reduction in relapses
  • Monoclonal antibodies
    • Options include Eculizumab, Rituximab and Satralizumab.
    • In the UK used as second line treatment; they are not used first line mainly owing to cost.
    • Can reduce relapse rates by up to 90%

There is a lack of strong evidence for a particular immunotherapy regime. More evidence is emerging supporting monoclonal antibodies but their expense is a prime concern.

Symptomatic treatment

This is similar as for multiple sclerosis. The effects of NMO that need MDT management include neuropathic pain, muscular spasms fatigue and depression. A referral to a local pain management team is vital.

Complications

Attacks of NMO may progress in severe or untreated episodes to neurogenic respiratory failure, particularly if lesions affect the brainstem.

Other complications may be related to optic neuritis, transverse myelitis and the other features of an NMO acute attack. Examples include
  • Vision loss from optic neuritis
  • Erectile dysfunction from transverse myelitis
  • Paralysis or paraplegia from transverse myelitis

Complications may occur as a result of treatment, including;
  • Osteoporosis from steroid use
  • Agranulocytosis from monoclonal antibody, azathioprine or mycophenolate use

NMO is associated with as significant mental health burden, with cases of anxiety and depression noted among patient.

In pregnancy, NMO is associated with an increased risk of miscarriage and increased frequency of attacks.

Prognosis

If left untreated, patients have a stepwise deterioration in neurological function in conjunction with their acute attacks. Each attack often takes weeks to months to recover from.

Generally, 50% of patients will have long-term paraparesis, paraplegia and visual difficulties. 1/3 of patients die within 5 years of their first attack, usually from respiratory failure

Worse prognosis is indicated in relation to the following correlations:
  • Number of attacks within the first two years of diagnosis
  • Severity of the 1st attack
  • Increasing age
  • Co-morbid with other autoimmune conditions or the presence of other autoimmune antibodies (e.g. Rheumatoid factor)
  • Presence of aquaporin-4 IgG antibodies