Improving the Diagnosis of Neuromyelitis Optica Spectrum Disorder
Editor’s Note: This article was originally posted on Neurology Advisor on 07/01/2021.
Neuromyelitis optica (NMO) is an uncommon inflammatory autoimmune disease of the central nervous system that has a clinical and radiologic presentation similar to multiple sclerosis (MS).1-3 Unlike MS, however, NMO is mediated by an antibody response to aquaporin-4 (AQP4), a water channel located in brain regions in contact with cerebrospinal fluid (with specific localization to astrocytes at the blood-brain barrier). In addition to wide expression in the brain, spinal cord, and optic nerve, AQP4 is present in other organ systems throughout the body including the kidneys, stomach, skeletal muscle, lungs, tear and salivary glands, inner ear, olfactory epithelia, and placenta.1,2,4
The lack of firm criteria for the diagnosis of NMO led to expansion of the definition in 2015 to encompass a spectrum of disorders (NMOSD), including central clinical signs of optic neuritis, area postrema syndrome, acute myelitis, acute brainstem and diencephalic syndromes, and cerebral syndrome with typical brain lesions.2,4
Clinical Manifestations and Disease Course
Attacks of NMOSD tend to be severe and escalate quickly, peaking within a week of onset.1 Common presenting symptoms include severe optic neuritis and bouts of severe intractable vomiting and hiccupping, along with clinical findings of extensive spinal cord inflammation.1
The usual course of NMOSD is not considered progressive; however, disability mounts with each successive attack.1 Epidemiologic evidence shows that without treatment, about half of those with NMOSD will either become wheelchair-bound or blind and up to one-third will die within 5 years of the first episode.1 Relapses must be treated aggressively over the long term with immunosuppressive therapies to prevent severe disability.1
Epidemiology
NMOSD is a rare disease that occurs worldwide, but similar to MS, it disproportionately affects women, with 5 to 10 times as many women than men having NMOSD.2 Onset has been reported between the ages of 3 years and 80 years, and at an average age of 40 years.2,4
Reviews of studies conducted globally have identified patterns that suggest higher incidence and prevalence of NMOSD among Black and Asian populations compared with White populations.5 Specifically, higher rates of NMOSD cluster closer to the equator, and people of African ethnicity appear to be at highest risk.5,6 It is difficult to draw firm conclusions in this regard because all of the evaluated studies were conducted in isolated populations, no direct comparisons were made between the study groups, and there were differences in the design of the various investigations.
Core Clinical Manifestations
Several constellations of symptoms or multisymptomatic syndromes seen in NMOSD can be mimicked by other disorders but may be used to distinguish NMOSD from MS. These are readily identified as 6 distinct syndromes.
Longitudinally extensive transverse myelitis (LETM): Patterns of inflammation of the central gray matter covering 3 or more contiguous vertebrae characterize this syndrome.1,7 Depending on the spinal cord region involved, LETM can produce paraplegia, tetraplegia, loss of bladder and sphincter control, pruritus and intense itching sensations, neuropathic pain, and paroxysmal tonic spasms.1,2 Short spinal cord lesions (<3 vertebral segments) may also be evident on magnetic resonance imaging (MRI) in up to 14% of cases.8 Although this finding mimics MS, the absence of brain lesions typical of MS provides strong evidence favoring the diagnosis of NMOSD.1
Optic neuritis: A primary symptom of both MS and NMOSD, optic neuritis causes vision loss and pain with eye movements.2 Specific patterns of optic neuritis may help clinicians to distinguish among the 2 diseases. In patients with NMOSD, for example, optic neuritis is often longitudinally extensive, affecting more than half of the optic nerve.7 In MS, optic neuritis is unilateral and anterior. A diagnosis of NMOSD is suggested by severe or bilateral optic neuritis with poor recovery.8 Optical coherence tomography studies have demonstrated that patients with NMO have a thinner retinal nerve fiber layer, suggesting a greater degree of axonal damage than that seen in MS.9,10
Area postrema syndrome (APS): Symptoms of intractable nausea, vomiting, and hiccups in APS are the presenting signs in approximately 12% of cases of NMOSD. Although these symptoms may suggest gastroenteritis, they are actually caused by activation of the emetic reflex due to inflammation of the area postrema in the medulla oblongata.1,11
Symptomatic brainstem syndrome: Brainstem lesions — which may be evident on MRI — are associated with a wide range of symptoms including hemiparesis, dysphagia, respiratory difficulties, oculomotor abnormalities, hearing loss, vertigo, and vestibular ataxia, as well as facial palsy, cranial nerve abnormalities, trigeminal neuralgia, and excessive yawning.1,2
Diencephalic syndrome: This syndrome, which suggests a hypothalamic pathology, is also a sign of NMOSD. Primary signs include narcolepsy or hypersomnia but may also include disturbances of temperature regulation and the endocrine system, obesity, anorexia, and hormonal overproduction (eg, hyperprolactinemia, dysmenorrhea). Thalamic lesions may cause severe anhidrosis or altered consciousness.2,12
Cerebral syndrome: Approximately 60% of patients with NMOSD may have brain involvement, which may be asymptomatic or cause seizures, encephalopathy, and hemiparesis.1
Cognitive Impairment
Demyelinating diseases may result in cognitive impairment. Several studies have reported the frequency of specific signs of cognitive impairment in patients with NMOSD, indicating that at least one-third will experience some type of cognitive deficit.2 The 2 highest reported rates of deficits in recent studies were 57% and 67%, but some studies reported rates ranging between 29% and 36%.2,13,14 Impairment was reported in the domains of attention, memory, processing speed, verbal fluency, verbal learning, and executive function.2 It is not clear what variables may influence the risk of cognitive impairment in individuals with NMOSD.13 Associations between advancing age and the duration of NMOSD have been suggested, but no studies to date have found a connection between degree of disability and diminished cognitive function.2
Making the Diagnosis
Despite its identification as a separate entity by Eugene Devic and Fernand Gault in 1894, NMO, also known as Devic disease, was widely regarded as a subtype of MS.2-4 The discovery in 2004 of serum antibodies to AQP4 was the first clear characteristic to differentiate NMOSD from clinical MS.2,3
As originally described, a diagnosis of NMO was based on the presence of bilateral optic neuritis and myelitis occurring simultaneously, with NMO generally considered a variant of MS. By the mid-20th century, relapses were often noted, and the advent of MRI technology revealed that patients had normal brain scans with 3 or more extensive transverse myelitis lesions occurring across multiple vertebral segments.3
The discovery of the AQP4 connection to NMO created the opportunity for an expanded definition of the disorder.4 The new criteria for NMOSD were updated in 2015; a person who tests AQP4 seropositive and has any of the 6 described core clinical syndromes is considered to be diagnosed with NMOSD.1,3
Laboratory Distinctions
AQP4 Expression
Comorbidities are common and related to AQP4 status; an estimated 1 in 4 patients with NMOSD who test positive for AQP4 antibodies have concomitant autoimmune disorders such as myasthenia gravis, systemic lupus erythematosus (SLE), Sjögren syndrome, or celiac disease.1 Although AQP4 antibodies are highly specific for NMO, not all patients testing positive for AQP4 antibodies meet all of the criteria for NMO. Conversely, some studies have identified AQP4 positivity associated with other autoimmune disorders, such as Sjögren syndrome and SLE.3
MOG Antibody Disease
Serum autoantibodies specific to myelin oligodendrocyte glycoprotein (MOG) found on myelin sheath surfaces present a new potential marker in support of a diagnosis of AQP4-seronegative NMOSD.2 The antibodies have been identified in the serum of 25% to 42% of AQP4-seronegative patients, suggesting an alternate pathophysiology that might lead to NMOSD.15,16
MRI Evidence
Early evidence suggested that brain lesions were atypical for NMO and more likely pointed to a diagnosis of MS.3 This was contradicted by data from Jarius and others in the early 2000s, who demonstrated the presence of brain lesions in approximately 60% of patients with NMO, which may in some cases meet the MRI diagnostic criteria for MS.3,17
MRI is an invaluable tool for distinguishing NMOSD lesions from those of MS and other demyelinating diseases.7 Although imaging results may be unremarkable in many patients with NMOSD, selected patients have MRI studies showing a range of findings.7
- Lesions that correlate with NMOSD are frequently periependymal lesions located around the cerebral aqueduct and third and fourth ventricles, including regions of the thalamus, hypothalamus, and brainstem, where AQP4 is highly expressed. These types of periaqueductal lesions are common to NMOSD, but they are rarely seen in the brains of MS patients.
- Lesions forming in the APS, the emesis-inducing area of the brain, are associated with common early symptoms of NMOSD including nausea, vomiting, and intractable hiccups.7 Like the attacks they cause, lesions in NMOSD tend to be transient; therefore, MRI should be performed promptly at the time patients present with symptoms so that the lesions can be visualized.7
- Additional brain abnormalities include large subcortical white matter lesions greater than 3 centimeters in size; these are most commonly observed in patients with AQP4-seropositive NMOSD.7
- Vision loss is an early sign of NMOSD, and the associated optic nerve lesions are readily distinguishable from those of patients with MS. In MS the optic lesions are shorter, unilateral, and more anterior. Optic nerve lesions in NMOSD extend over more than half of the posterior optic nerve, often into the optic chiasm.7
Summary
The feature of NMOSD that most clearly defines it as separate from other demyelinating diseases is seropositivity to AQP4, although not all patients with NMOSD are AQP4 seropositive. In patients who are AQP4 seronegative or those in whom AQP4 status is unknown, MRI studies are essential to support the diagnosis of NMOSD, along with a more stringent requirement that at least 2 core characteristics be present.
References
1. Huda S, Whittam D, Bhojak M, et al. Neuromyelitis optica spectrum disorders. Clin Med (Lond). 2019;19:169-176. doi:10.7861/clinmedicine.19-2-169
2. Czarnecka D, Oset M, Karlińska I, Stasiołek M. Cognitive impairment in NMOSD – More questions than answers. Brain Behav. 2020;10(11):e01842. doi:10.1002/brb3.1842
3. Jarius S, Wildemann B. The history of neuromyelitis optica. J Neuroinflammation. 2013;10:8. doi:10.1186/1742-2094-10-8
4. Wingerchuk DM, Banwell B, Bennett JL, et al; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729
5. Papp V, Magyari M, Aktas O, et al. Worldwide incidence and prevalence of neuromyelitis optica: a systematic review. Neurology. 2021;96:59-77. doi:10.1212/WNL.0000000000011153
6. Hor JY, Asgari N, Nakashima I, et al; on behalf of the Guthy-Jackson Charitable Foundation International Clinical Consortium for NMOSD. Epidemiology of neuromyelitis optica spectrum disorder and its prevalence and incidence worldwide. Front Neurol. 2020;11:501. doi:10.3389/fneur.2020.00501
7. Solomon JM, Paul F, Chien C, Oh J, Rotstein DL. A window into the future? MRI for evaluation of neuromyelitis optica spectrum disorder throughout the disease course. Ther Adv Neurol Disord. 2021;14:1-18. doi:10.1177/17562864211014389
8. Flanagan EP, Weinshenker BG, Krecke KN, et al. Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders. JAMA Neurol. 2015;72(1):81-87. doi:10.1001/jamaneurol.2014.2137
9. Ratchford JN, Quigg ME, Conger A, et al. Optical coherence tomography helps differentiate neuromyelitis optica and MS optic neuropathies. Neurology. 2009;73(4):302-308. doi:10.1212/WNL.0b013e3181af78b8
10. Naismith RT, Tutlam NT, Xu J, et al. Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis. Neurology. 2009;72:1077-1082. doi:10.1212/01.wnl.0000345042.53843.d5
11. Pittock SJ, Lucchinetti CF. Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later. Ann NY Acad Sci. 2016;1366:20-39. doi:10.1111/nyas.12794
12. Akaishi T, Nakashima I, Sato DK, Takahashi T, Fujihara K. Neuromyelitis optica spectrum disorders. Neuroimaging Clin N Am. 2017;27:251-265. doi:10.1016/j.nic.2016.12.010
13. Blanc F, Zéphir H, Lebrun C, et al. Cognitive functions in neuromyelitis optica. Arch Neurol. 2008;65(1):84-88. doi:10.1001/archneurol.2007.16
14. Moore P, Methley A, Pollard C, et al. Cognitive and psychiatric comorbidities in neuromyelitis optica. J Neurol Sci. 2016;360:4-9. doi:10.1016/j.jns.2015.11.031
15. Narayan R, Simpson A, Fritsche K, et al. MOG antibody disease: a review of MOG antibody seropositive neuromyelitis optica spectrum disorder. Mult Scler Relat Disord. 2018;25:66-72. doi:10.1016/j.msard.2018.07.025
16. Weinshenker BG, Wingerchuk DM. Neuromyelitis spectrum disorders. Mayo Clin Proc. 2017;92(4):663-679. doi:10.1016/j.mayocp.2016.12.014
17. Jarius S, Ruprecht K, Wildemann B, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation. 2012;9:14. doi:10.1186/1742-2094-9-14
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Reviewed June 2021
