Neuromyelitis Optica

PART VI. RELATED DISEASES

Amanda L. Piquet and John R. Corboy

KEY POINTS FOR THE CLINICIAN

• Neuromyelitis optica (NMO) is a distinct clinical–pathological disease that is different from multiple sclerosis (MS).

• NMO occurs as acute attacks, and only rarely may evolve into a slow progressive phase of disability accumulation.

• NMO typically targets the optic nerves and spinal cord; however, it may also involve the hypothalamus, area postrema (intractable nausea and vomiting, or hiccoughs), or cerebral locations, hence the terminology neuromyelitis optica spectrum disorder (NMOSD) to include those individuals who do not have a classic presentation.

• NMOSD is defined by a pathogenic antibody, aquaporin-4 immunoglobulin G (AQP4-IgG).

• Treatment for acute attacks of NMOSD consists of high-dose methylprednisolone, +/− plasma exchange.

• Prophylactic treatment for NMOSD includes aggressive, early intervention given the high disability that is directly related to clinical relapses, with rituximab or azathioprine as first-line therapies for relapse prevention. Duration of prophylactic therapy remains unclear.

NMO, also known as Devic’s disease, is an autoimmune demyelinating disease of the central nervous system (CNS). Once thought to be a form of MS, NMO has now been defined as a distinct clinical–pathological disorder, although the initial clinical presentation often mimics MS. Clinically, NMO preferentially targets the optic nerves and spinal cord; however, over time, the clinical spectrum has expanded and NMO is now known to affect the brain in a substantial minority of patients. The diagnosis and pathogenesis of NMO have been greatly advanced by the discovery of the NMO-immunoglobulin G (IgG), an antibody directed against, and with high affinity to, the water channel aquaporin-4 (AQP4) in the CNS. The NMO-IgG, also known as the AQP4-IgG, appears to be pathogenic. The term NMOSD was established to describe those individuals who are seropositive for the AQP4-IgG, but who do not have the classical presentation of isolated longitudinally extensive myelitis or optic neuritis. Given the clinical aggressiveness of NMO with the associated disability, rapid recognition and diagnosis is important to appropriately tailor both acute and long-term therapies, which are often different than therapies for MS and other related disorders.

NMO is a distinct disease, different than MS.

EPIDEMIOLOGY

Large studies defining the prevalence and incidence rate of NMO in populations are lacking; furthermore, incidence and prevalence varies between geographical regions and various ethnic populations. Data from systematic review of published peer-reviewed studies suggest a prevalence rate between 0.52 and 4.4 per 100,000 people per year and incidence rate of 0.053 to 0.40 per 100,000 people in various locations around the world (1–3). NMO prevalence is approximately 1% to 2% that of MS in the United States (4) 352and there is a higher representation of NMO among nonwhite populations (5). Given this observation, in a patient with a non-Caucasian background with severe optic neuritis or myelitis, NMO should be high on the differential diagnosis.

The median age of onset is 39 years old, which is later than MS (Table 38.1), although NMO has been described in both children and the elderly. The prevalence of NMO is three to nine times higher in women than men (1,8,9).

CLINICAL FEATURES

NMO most frequently presents as severe optic neuritis, transverse myelitis, or a combination of both. The diagnosis of NMO should be considered in patients with those presenting syndromes, especially if an MRI of the brain is normal or atypical for MS.

NMO most often presents as severe optic neuritis, myelitis, or both.

NMO-associated optic neuritis is similar in clinical presentation to other causes of inflammatory optic neuritis. Vision loss typically occurs over hours to days and peaks within 1 to 2 weeks. Mild ocular pain, often associated with eye movement, is common. Dyschromatopsia (particularly red desaturation), central or paracentral scotoma, and photopsias may also occur. The vision loss in NMO is commonly more severe than in MS (10). Bilateral simultaneous or rapidly sequential optic neuritis may also be more indicative of NMO.

Transverse myelitis is often severe and complete and can present with a symmetric para, or tetra, paresis, spinal sensory level, and significant sphincter dysfunction early in the course. Myelitis is often heralded by severe spinal pain. In comparison, MS-related myelitis typically has a more mild, unilateral, and asymmetrical clinical presentation (Table 38.1). Approximately one third of NMO patients have associated Lhermitte’s phenomenon, paroxysmal tonic spasms, or radicular pain associated with the myelitis (11).

Beyond the involvement of optic nerves and spinal cord, NMO may also present with brainstem symptoms such as intractable nausea and hiccupping (from area postrema involvement) (12), vertigo, trigeminal neuralgia, diplopia, and nystagmus. Cases have also been described with acute encephalopathy, cognitive changes, and hypothalamic dysfunction such as syndrome of inappropriate antidiuretic hormone secretion (SIADH) (13).

NMO may also be associated with organ-specific autoimmunity (e.g., myasthenia gravis, type 1 diabetes, pernicious anemia, and ulcerative colitis) and non-organ-specific autoimmune disease (e.g., systemic lupus erythematosus (SLE) and Sjögren’s syndrome). Evidence suggests that systemic autoimmune diseases coexist with NMO rather than act as a direct cause. Autoantibodies to antinuclear antigen (ANA; 44%) and Sjögren’s syndrome A autoantibody (SSA; 16%) are found more frequently in NMO patients than in seronegative individuals, while no patients with SLE or Sjögren’s without manifestations consistent with NMO are AQP4-IgG seropositive (14). There is a high rate of coexisting neural-specific autoantibodies in NMOSD (35%), such as muscle acetylcholine receptor antibody (AChR), voltage-gated potassium channel complex antibodies (VGKC; LGI-1 and Caspr2), and collapsing response-mediator protein (CRMP-5) (10,15). NMO may present as a paraneoplastic syndrome, especially in the elderly. Neoplasms reported in NMO AQP4-IgG positive patients include breast, lung, thymic, uterine, ovarian teratoma, B-cell lymphoma, stomach carcinoid, and leiomyosarcoma (16–21).

TABLE 38.1 NMO and MS Comparison

CLINICAL FACTORS	NMO	MS
Average age of onset	Late fourth to early fifth decade	Third to early fourth decade
Gender (Female: Male)	3:1 to 9:1	2:1
Population prevalence	Higher prevalence in nonwhite populations	Varies geographically, white populations more affected
Clinical features	Primarily severe optic neuritis and myelitis; greater than 90% with relapsing course, rarely monophasic course; slowly progressive symptoms are rare	Dissemination in time and space affecting multiple CNS sites, typically of milder severity; 85% relapsing–remitting, 15% progressive at onset; many relapsing patients later have a progressive course
Coexisting autoimmune disease MRI	Common (SLE, Sjögren’s, myasthenia gravis)	Rare
Brain	Often normal, may have nonspecific T2 hyperintensities and hypothalamic, periventricular (third/fourth ventricle), or medullary lesions	Lesions are ovoid and periventricular, juxtacortical, callosal, and infratentorial locations
Spine	Lesions typically longitudinally extensive (three or more vertebral segments), centrally located with cord expansion	one to two vertebral segments, asymmetric, peripheral location
CSF profile	Pleocytosis in about 50%(up to 50–1,000 × 10⁶ WBC/L) (6) with increased neutrophils and eosinophils; increased protein; elevated IL-6 (7) and GFAP	Mild pleocytosis or normal
CSF oligoclonal bands	Uncommon (15–30%) (6)	Common (90%)
Serum AQP4-IgG	Present in majority	Absent

AQP4-IgG, aquaporin4-immunoglobulin G; CNS, central nervous system; CSF, cerebrospinal fluid; GFAP, glial fibrillary acidic protein; IL, interleukin; MS, multiple sclerosis; NMO, neuromyelitis optica; SLE, systemic lupus erythematosus; WBC, white blood cell.

353Pediatric NMO

Children as young as 2 years old have been reported with NMO; however, pediatric NMO most commonly has onset between the ages of 10 to 14 years old (6). In pediatric cases, the brain tends to be more commonly involved than adults. Children may present with symptoms of encephalopathy, ataxia, seizure, and/or intractable nausea and vomiting. In seropositive NMO cases, 68% of children have brain abnormalities on MRI (22).

NMO and Pregnancy

Unlike MS, which tends to be quiescent during pregnancy with a decreased relapse rate, studies have shown an increase in relapse rate in NMO patients during pregnancy (23). Both NMO and MS have an increased risk of relapse rate within the immediate postpartum period. Additionally, patients with NMO have an increased rate of pregnancy complications with risks to both fetal and maternal health. Obstetric complications include spontaneous abortion, stillbirth, preterm delivery, low birth weight, and preeclampsia or pregnancy-induced hypertension (23).

IMAGING

MRI Spine

Spinal cord MRI is helpful in patients with signs and symptoms suggestive of a myelopathy. Lesions are typically longitudinally extensive (usually greater than three vertebral segments in length), centrally located, often occupy more than one-half of the cord area, and are associated with cord expansion and edema (Figure 38.1). T2 hyperintensities are best seen on short tau inversion recovery (STIR) or proton density sequences and may have associated T1 hypointensity. Gadolinium enhancement, often seen during the acute attack, is frequently homogenous and involves the central portion of the lesion (Figure 38.1). The pattern of T2 hyperintensity and gadolinium enhancement may help differentiate NMO from other etiologies of longitudinally extensive myelitis, such as neurosarcoidosis, which is demonstrated in Figure 38.1. NMO will typically have central spinal cord involvement, often with relative sparing of the peripheral cord. In contrast, neurosarcoidosis often will have both central and peripheral involvement, classically sparing the small region between the central and peripheral cord. A small subset of patients may present with short MRI lesions, which should not exclude the diagnosis of NMO (25,26). On the contrary, rarely MS may actually mimic NMO with longitudinally extensive transverse myelitis (LETM) and this should be considered in the setting of AQP4 seronegativity (27). NMO patients with a history of a prior acute myelitis often can have extensive cord atrophy as chronic sequela (Figure 38.2).

Spinal cord lesions are typically greater than three vertebral segments in length.

MRI Brain

Over time, it has been recognized that NMO is not limited to only the optic nerves and spinal cord, and there are reports of both symptomatic and asymptomatic brain lesions on neuroimaging. The lesions are often located within the areas of high AQP4 concentrations such as the hypothalamus, around the third and fourth ventricles, and in the brainstem, particularly the medulla near the area postrema, and are typically distinct from MS lesion appearance. Brain MRI early in the disease course is often normal, but up to 60% of NMO patients may develop brain MRI abnormalities over time, albeit many changes are often nonspecific (28). Optic nerve imaging may also help distinguish NMO from MS as MRI abnormalities often show extensive optic nerve involvement in NMO as well as enhancement of the optic chiasm; chiasmal involvement is not typical of MS (29).

DIAGNOSIS

The diagnosis of NMO is based on clinical features with paraclinical support from neuroimaging and serological testing. NMO should be considered in all patients with severe optic neuritis, longitudinally extensive transverse myelitis (> three vertebral segments long), recurrent episodes of isolated optic neuritis, or bilateral simultaneous or sequential optic neuritis. The current 2015 International Consensus Diagnostic Criteria offer guidance in the diagnosis of NMOSD (Table 38.2) (30). In 2006, as part of the revised Mayo Clinic criteria for NMO, the term NMOSD was introduced to describe individuals seropositive for AQP4-IgG, but with a form of CNS involvement beyond just longitudinally extensive transverse myelitis and/or bilateral simultaneous or recurrent optic neuritis (31). In 2015, the International Panel for NMO Diagnosis changed the nomenclature to unify the term NMO and NMOSD and further stratify the disorder by serological testing (30). With a positive AQP4 antibody, one must have at least one of the six core clinical characteristics (Table 38.3). With a negative AQP4 antibody or unknown antibody status, a patient must meet more stringent clinical criteria (Table 38.2).

354

FIGURE 38.1 MRI for Patient 1 demonstrates a longitudinally extensive transverse myelitis in the setting of a positive AQP4-IgG. (A) T2-weighted sagittal image of the thoracic spine shows a longitudinally extensive T2 hyperintense lesion with the (B) T1-postcontrast sagittal image and (C) axial image demonstrating associated central cord enhancement. As seen in the axial image, it is common for spinal cord lesions to occupy more than half of the spinal cord in cross section. Patient 2 was diagnosed with neurosarcoidosis with biopsy-proven noncaseating granulomas of the lymph node, as well as a negative AQP4-IgG antibody. (D) T2-weighted sagittal image of cervical spine with longitudinally extensive myelitis and associated edema. (E and F) T1-postcontrast sagittal and axial images, respectfully, demonstrate posterior subpial enhancement. This pattern of dorsal subpial enhancement with central cord involvement (described as the “trident sign”) in spinal neurosarcoidosis is distinctly different from NMO, which tends to have primarily central cord involvement, often with relative sparing of the peripheral and subpial regions.

Source: Images are original but source supports the terminology of the trident sign. Zalewski NL, Krecke KN, Weinshenker BG, et al. Central canal enhancement and the trident sign in spinal cord sarcoidosis. Neurology. 2016;87(7):743–744. (24)

FIGURE 38.2 T2-weighted MRI of thoracic cord demonstrating thoracic cord atrophy extending greater than three vertebral segments in a patient with NMO.

NMO, neuromyelitis optica.

Other etiologies of optic neuritis and/or transverse myelitis must be considered and include MS, acute disseminated encephalomyelitis (ADEM), a systemic vasculitis such as SLE or Sjögren’s syndrome (in the absence of an overlap syndrome with NMO supported by a negative AQP4 antibody), neurosarcoidosis, nutritional deficiency such as vitamin B₁₂, and infectious etiologies including neurosyphilis. Additionally, patients once thought to have seronegative NMOSD are now identified as having alternative autoantibodies such as myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Optic neuritis is the most common presentation with seropositive myelin oligodendrocyte glycoprotein (MOG)-IgG patients, followed by myelitis, and brainstem encephalitis (32). Unlike NMO, MOG-IgG seropositive disease is more likely to have a monophasic course (80%) and clinical or radiographic involvement of the brain, brainstem, or cerebellum (50%). Male-to-female ratio is 1:2 (32). Glial fibrillary acidic protein (GFAP)-IgG has also been recognized as a biomarker of autoimmune astrocytopathy with or without coexisting AQP4-IgG (33). Patients typically present with features of a subacute relapsing meningoencephalomyelitis. Unlike NMO, there is not a strong female predominance; in a study of 102 patients, only 54% were female (33).

355TABLE 38.2 NMOSD Diagnostic Criteria

DIAGNOSTIC CRITERIA FOR NMOSD WITH POSITIVE AQP4-IGG

1) At least one core clinical characteristic (Table 38.3)

2) Positive test for AQP4-IgG using best available detection method

3) Exclusion of alternative diagnosis

DIAGNOSTIC CRITERIA FOR NMOSD WITHOUT AQP4-IgG (ANTIBODY NEGATIVE OR UNKNOWN STATUS DUE TO UNAVAILABLE TESTING)

1) At least two core clinical characteristics as one or more clinical attacks as well as:

a) At least one core clinical characteristic must be optic neuritis, acute myelitis with LETM, or area postrema syndrome

b) Dissemination in space (two or more different core clinical characteristics)

c) Additional MRI requirements as applicable:

1) Optic neuritis: requires brain MRI to show either normal findings OR T2-hyperintense lesion or T1-weighted gadolinium-enhanced lesion extending over half the optic nerve length or involving the optic chiasm

2) Acute myelitis: requires associated intramedullary MRI lesions extending over ≥ three continuous segments (LETM) OR ≥ contiguous segments of focal spinal cord atrophy in patients with a history of acute myelitis (Figure 38.1 and 38.2)

3) Area postrema syndrome: requires lesions in the dorsal medulla/area postrema

4) Acute brainstem syndrome: requires periependymal brainstem lesions

2) Exclusion of alternative diagnosis

AQP4-IgG, aquaporin-4 immunoglobulin G; LETM, longitudinally extensive transverse myelitis; NMOSD, neuromyelitis optica spectrum disorder.

Source: Wingerchuk DM, Banwell B, Bennett JL, et al., International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177–189, p.179 and http://n.neurology.org/content/85/2/177.long

TABLE 38.3 Core Clinical Characteristics in NMOSD

• Optic neuritis

• Acute myelitis

• Area postrema syndrome (unexplained hiccups or nausea and vomiting)

• Acute brainstem syndrome

• Symptomatic narcolepsy or acute diencephalic clinical syndrome with associated radiographic lesions on MRI

• Symptomatic brain lesions typical of NMO such as hypothalamic, brainstem, and periventricular

NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder.

LABORATORY STUDIES

The discovery of the autoantibody directed against AQP4 has aided in the distinction of NMO from other inflammatory demyelinating disorders. AQP4 is an osmosis-driven, water-selective transporter expressed on the astrocytic foot processes throughout the CNS and is involved in water homeostasis, astrocyte migration, neuronal signal transduction, and neuroinflammation. There are high concentrations of AQP4 in subpial, subependymal areas, and the hypothalamus, in addition to the optic nerve and spinal cord. The precise role of AQP4-IgG has not been fully elucidated; however, there is substantial evidence that this antibody has a pathogenic role in NMO (14,34). The original indirect immunofluorescence assay for AQP4-IgG, used with a composite substrate of mouse tissues, identified NMO patients with a sensitivity of 73% and specificity of 91% (35). Subsequently, the development of transfected cell-based assays (CBA) has increased the sensitivity of the test significantly, to almost 90% (6). The CBAs use either observer-based immunofluorescence or automated-flow cytometry for the detection of AQP4 antibodies. Currently, the AQP4-transfected CBA with fluorescence-activated cell sorting assay (FACS) is considered the best method for antibody detection. The CBA also has a lower rate of false positivity (specificity >99%) 356(6) compared with the enzyme-linked immunosorbent assay (ELISA; sensitivity of 60%–65% and specificity of 99%) (36). AQP4-IgG testing should be performed on serum as the sensitivity is much better when compared to the cerebrospinal fluid (CSF) (6,14).