Time is retina: Focus on the ocular aspects of neuromyelitis optica
Symptoms of acute optic neuritis resulting from the disease can resolve in treated rapidly.
Optic neuritis (inflammation of the optic nerve) arises from numerous causes including infections (e.g. herpes zoster and Lyme disease), vaccines’ adverse events and autoimmune diseases.1,2 Optic neuritis is, for example, the presenting symptom in about 20% of multiple sclerosis (MS) cases.1,3 Acute optic neuritis also characterises neuromyelitis optica spectrum disorder (NMOSD), a rare but severe autoimmune disease.4
In at least 70–80% of NMOSD cases, immunoglobulin G (IgG) autoantibodies to the water channel protein aquaporin-4 (AQP4) are detectable in the serum and play a relevant role in disease pathogenesis.4,5
Many of the remaining cases arise from autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG). As the name suggests, oligodendrocytes as well as myelin sheaths express MOG.4 These cases should now be diagnosed as a separate disease entity, MOGAD (myelin oligodendrocyte glycoprotein antibody associated diseases).6
Although NMOSD is rare, ophthalmologists and optometrists need to remain aware of it as a potential differential diagnosis. Early diagnosis and rapid treatment maximise the chances that patients will fully recover their vision.4,7 As “time is retina,” this article aims to reduce the delay to diagnosis by reminding ophthalmologists and optometrists about NMOSD’s ocular hallmarks.8
Epidemiology
NMOSD is rare: the incidence is between 0.4 and 2 per 1,000,000 person-years and the prevalence 0.5 to 4 per 100,000.9 Ethnicity largely accounts for the variation.10,11 AQP4-NMOSD is more common in people of Afro-Caribbean descent than in other ethnic groups.12
Several human leukocyte antigen (HLA) alleles and other polymorphisms seem to be associated with the risk of developing NMO. The particular HLA alleles depend on the population studied.4 So, as with other autoimmune diseases, genetic predisposition seems to be influential in determining NMOSD risk.
Age at presentation can help differentiate NMOSD from MS. The peak age of diagnosis for MS is between 25 and 35 years of age whereas, in European studies, the median age at onset for AQP4-NMOSD and MOGAD was 40 and 31 years, respectively.4 As a rule of thumb, the age of onset is about a decade later in NMOSD than in MS.13
Moreover, MOGAD is the most common neuroinflammatory disease in children.12 Paediatric AQP4-NMOSD is uncommon.12
Most autoimmune diseases are more common in females than males. Indeed, females account for between 70% and 90% of relapsing AQP4-NMOSD cases.10,14 MOGAD, in contrast, shows little sex-related epidemiological difference.11 The incidence and prevalence of NMOSD will probably increase over the next few years, reflecting greater awareness, improved differential diagnosis, earlier diagnosis and better treatments.4
Pathogenesis
NMOSD is characterised by attacks of acute optic neuritis and transverse myelitis (inflammation of the spinal cord).4 The spinal cord involvement offers another point of differentiation from MS. Long spinal cord lesions that extend over three or four vertebral segments, which are very rare in MS, often show on magnetic resonance imaging (MRI) of people with AQP4-NMOSD.15
In some cases, the autoimmune attack involves the brain stem, and spinal cord lesions can extend into the medulla oblongata.4 The optic nerve often shows longitudinally extensive lesions on MRI, occasionally involving the chiasm.16 In contrast, MS tends to cause short lesions.4
AQP4 is expressed predominately by astrocytes, which have numerous roles including regulating the development and permeability of the blood–brain barrier. Increased permeability of the blood–brain barrier may allow IgG to access the central nervous system (CNS).
Astrocytes also contribute to information processing, dispose of old and damaged organelles and modulate neurotransmitter levels in the CNS.4,5,17,18 AQP4 regulates changes in the extracellular volume that modulate the concentration of solutes and, in turn, neuronal electrical activity. As such, AQP4 modulates neuronal transmission and excitability.18
In people with NMOSD, the autoimmune attack on AQP4 produces dysfunctional astrocytes and can cause astrocyte death. The autoimmune attack also triggers bystander inflammation, whichexposes other, usually hidden, autoantigens and can damage oligodendrocytes and neurons.4
So, testing for IgG targeting AQP4 offers a highly specific serum test for AQP4-NMOSD. Indeed, the antibody assay allows the diagnosis of AQP4-NMOSD at the first event.19 Again, this differs from MS, in which neurologists typically wait for MRI-confirmed dissemination in time and space following optic neuritis or another element of the clinically isolated syndrome before diagnosis.20
Ophthalmologists should bear in mind that the sensitivity and specificity of cell-based assays for IgG targeting AQP4 are much better than for other techniques such as enzyme-linked immunosorbent assay.21
Oligodendrocytes, which produce myelin, and neurons do not express AQP4.4,17 Between 10% and 40% of NMOSD patients who are negative for IgG targeting AQP4 in the best cell-based assay have IgG autoantibodies to MOG, which is expressed on the surface of oligodendrocytes and the outside of myelin sheaths.4
MOG accounts for only 0.05% of CNS myelin proteins.6 Nevertheless, the autoimmune attack can still cause clinically significant demyelination.4 It is important to bear in mind that the clinical phenotype of MOGAD only partly overlaps with that of AQP4-IgG-NMOSD.
There is some evidence of remyelination and other repair mechanisms, predominantly in animal and ex-vivo models of NMOSD.22 Although it is an area of active research, drawing conclusions about the clinical relevance to humans would be premature. Moreover, compensatory mechanisms seem to be more common in MS than NMOSD.
Less commonly, other conditions, including sarcoidosis, infections, connective tissue disorders and paraneoplastic neurological disorders, can be associated with or trigger NMOSD.
An increasing number of risk factors are associated with the likelihood of developing NMOSD. Smoking may adversely affect NMOSD progression and severity, for example. Low vitamin D levels are common in people with NMOSD, although whether this predisposes to NMOSD or is secondary to neurological disability is unclear.4
Acute infections (usually respiratory) precede about one-third of NMOSD attacks. Moreover, the gastrointestinal microbiota in NMOSD seems to differ from that in healthy controls and MS patients.23,24
Clostridium perfringen seems particularly enriched in people with NMOSD compared with healthy controls. Whereas MS patients also showed higher C. perfringens populations, the increase was of marginal statistical significance and, unlike in NMOSD, no longer remained significant after multiple comparisons.24
These observations raise the prospect that molecular mimicry (environmental and other proteins expressing epitopes similar to those on AQP4) may contribute to NMOSD.18 For instance, the epitope for AQP4 in NMOSD is homologous with a sequence expressed by C. perfringens.24The altered gastrointestinal microbiota may also regulate cellular and humoral immunity, such as the relative abundance of T cell subpopulations.23,24
Ocular manifestations
NMOSD is a multi-system disorder: 52% of patients with AQP4-NMOSD and 34% of those with MOGAD show transverse myelitis on presentation, which can cause symptoms that range from mild sensory abnormalities to bladder, bowel and erectile dysfunction and to very severe quadraparesis (weakness in all four limbs).4
Cerebral involvement can result in headache, intractable vomiting or persistent hiccups.4 In addition, MOGAD can trigger impaired consciousness, altered behaviour, psychiatric symptoms (e.g. depression), neuropsychological deficits (e.g. poor attention and memory) and epileptic seizures.4
Optic neuritis is also common in people with NMOSD: 50% of patients with AQP4-NMOSD and 74% with MOGAD show optic neuritis alone or with other symptoms at presentation.
The ocular changes associated with NMOSD vary widely. Acute optic neuritis can be mild, causing, for example, hazy vision and poor high-contrast visual acuity as assessed by a Snellen chart. Some people find that the optic neuritis affects only low-contrast visual acuity or colour vision. Many people with NMOSD report scotomas.4
In most people, optic neuritis can progress to complete, uni- or bilateral functional blindness.
Even after treatment for the attack, recovery from optic neuritis is usually poorer in AQP4-NMOSD than in MOGAD or MS.3 Bilateral optic neuritis is more common in MOGAD than AQP4-NMOSD and MS. Over time, however, optic neuritis will affect both eyes in AQP4-NMOSD.4
The ocular phenotypes of AQP4-NMOSD and MOGAD differ. For example, optic neuritis in people with AQP4-NMOSD predominantly affects the posterior optic nerve and often encompasses the chiasma.16 Optic neuritis associated with MOGAD more frequently involves the anterior optic nerve and can present as papillitis or papilloedema.
However, optic neuritis in people with MOGAD can cause posterior lesions, retinal haemorrhages or macular stars. In such cases, ophthalmologists and optometrists should consider the possible differential diagnoses.4
Pain is among the most common and debilitating NMOSD symptoms.4 Between 62% and 91% of NMOSD patients experience central neuropathic pain.4,25
Ocular pain, pain on eye movement or both often precedes or accompanies optic neuritis. Indeed, 86% of patients with optic neuritis due to MOGAD reported pain when they move their eyes.4
Early diagnosis helps minimise the impact on visual acuity. Optical coherence tomography (OCT) can detect optic nerve damage, sometimes even before symptoms become clinically apparent.4,8
OCT reveals that optic neuritis caused by autoantibodies to AQP4 can markedly thin the retinal nerve fibre and ganglion cell/inner plexiform layers. The thinning of these layers is, on average, more pronounced in AQP4-NMOSD than MS.4 People with AQP4-NMOSD may also show a thickened inner nuclear layer compared with healthy controls.26
Moreover, in contrast to MS, most clinically unaffected eyes of people with AQP4-NMOSD are normal on OCT.4 Ongoing studies at my centre and elsewhere are using the pattern of retinal damage on OCT to train diagnostic artificial intelligence algorithms.27,28 We hope that these will be ready for clinical use in the next few years.
Treatment
Intravenous methylprednisolone for at least 3–5 consecutive days, plasma exchange or immunoadsorption are the usual treatment for acute attacks.4,29 In addition, patients may need treatments to alleviate symptoms such as pain and depression.30
Symptoms can completely resolve after acute attacks, especially if treated rapidly.4 For example, starting intravenous methylprednisolone within 4 days of the onset of optic neuritis due to AQP4-NMOSD and MOGAD can increase the chance of full visual recovery, whereas treatment 7 days or more after onset is associated with a higher risk of poor visual recovery.4,7
Nevertheless, the visual loss arising from NMOSD is not always fully responsive to high-dose corticosteroids. European studies, for example, reported no or incomplete recovery after 66% and 48% of optic neuritis attacks in patients with AQP4-NMOSD and MOGAD, respectively.4
About one-quarter of patients who experienced optic neuritis due to MOGAD had uni- or bi-lateral functional blindness. Another 10% of patients showed severe visual deficiency. About half had some visual loss.4 In many patients, visual quality of life is severly impaired.31
Maintenance treatment with agents (e.g. rituximab, azathioprine, mycophenolate mofetil) that deplete B-cells (which develop into antibody producing plasma cells) may be needed to prevent relapse. Several monoclonal antibodies (eculizumab, satralizumab and inebilizumab) that target the complement system , interleukin-6 or CD19 positive B cells have been approved for AQP4-NMOSD.4,5,32
In people with AQP4-NMOSD, interleukin-6 may increase survival of plasmablasts (which are plasma cell precursors), stimulate the production of antibodies against AQP4, disrupt the integrity and functionality of the blood–brain barrier and enhance proinflammatory T cell populations.33
Future drugs targeting specific abnormalities in NMOSD and therapies that induce immune tolerance could transform prospects for people with NMOSD.34 These may become available in the next 5–10 years. So, although NMOSD is rare, ophthalmologists and optometristsneed to remain aware of it as a potential differential diagnosis.
After all, in people with NMO, time is retina.
References
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