Case
A 45 year old Afro-Caribbean female presents with acute bilateral simultaneous loss of vision to 20/200 in both eyes (OU). Both optic discs are edematous. Three weeks prior to presentation, the patient reported a bout of unexplained nausea and vomiting as well as hiccups. Cranial magnetic resonance imaging (MRI) shows chiasmal and optic nerve enhancement OU but no demyelinating periventricular white matter lesions.
Introduction
Since its description in 1894 by Eugene Devic, many had considered neuromyelitis optica (NMO) to be a “variant” of multiple sclerosis (MS). Clinical and MRI differences between MS and NMO along with the landmark discovery of highly specific anti-aquaporin 4 (AQP4) antibodies in 2004 indicated that NMO is a distinct disease marked by severe demyelination of the central nervous system (CNS) with particular predilection for the optic nerves, spinal cord, and area postrema in the medulla. Over the last 13 years, there has been a plethora of research and clinical interest in NMO facilitating improved awareness among physicians. Despite this, controversies on how to best diagnosis and treat NMO persist. This chapter will discuss the current evidence-based understanding of optic neuritis as the presenting feature of NMO while highlighting a few actively debated differences in its clinical care throughout the world.
Epidemiology
NMO is ubiquitous, occurring among virtually all ethnicities , geographic locations, and age groups [1, 2]. In two separate geographic locations (Olmstead County, Minnesota and Martinique) the ethnicity-specific prevalence of NMO was nearly identical between the two locations but was significantly higher for those of African descent compared to Caucasians [3]. The age of onset may vary considerably from 3 to 80, but the average age of onset found by epidemiological studies throughout the world varies little (30–39.5) [1]. Worldwide opinion based upon clinical evidence has concluded that the opticospinal variant of MS historically diagnosed in Asia actually represented NMO, a notion now widely accepted by Asian clinicians and researchers [4]. Five epidemiological NMO studies all found a female predominance with a female to male ratio ranging from 2.27:1 in Iran to 9.8:1 in the French West Indies [1].
Symptoms and Exam
The clinical features of idiopathic and MS associated optic neuritis (MS-ON) were defined by the Optic Neuritis Treatment Trial (ONTT) and include evidence of acute vision loss with associated eye pain (92%) often worse with eye movements, ipsilateral color vision loss (88%), visual field defect on automated static perimetry, and an ipsilateral relative afferent pupillary defect (if vision loss unilateral) [5]. The prognosis for vision recovery in idiopathic and MS-ON is excellent regardless of whether the patient is treated with corticosteroids. Long-term data showed that 87% recovered to 20/25 or better visual acuity (VA) and 93% recovered to 20/40 or better [6]. In almost all patients, visual recovery began within the first month [7].
This is in contrast to NMO associated optic neuritis (NMO-ON) which manifests with more severe vision loss at onset and less visual recovery. In one longitudinal study of 30 Afro-Caribbean patients with NMO over a mean follow-up of 9.5 years, 50% developed severe vision loss in both eyes (≤20/200) and another 20% had severe unilateral vision loss [8]. Indeed, severe vision loss and/or lack of expected visual recovery beginning within 1 month should prompt further consideration for NMO. Additional clinical features that suggest NMO-ON include bilateral simultaneous optic neuritis, recurrent optic neuritis, and associated neurologic symptoms suggesting concurrent or historical transverse myelitis (bowel/bladder dysfunction, extremity weakness or numbness, and lower back or extremity pain) or area postrema syndrome (intractable nausea or vomiting) due to medullary demyelination [2].
Ancillary Testing
Axial T1 fat-saturated, post contrast MRI demonstrating expansion and enhancement of the entire intraorbital right optic nerve and ventral pons. Not visualized here, the enhancement extended into the chiasm
Axial T2 flair MRI demonstrating longitudinally extensive hyperintensities along the corticospinal tract including the anterior limb of the internal capsule bilaterally
Axial T2 flair MRI demonstrating an extensive, expanded, T2-hyperintense tumefactive demyelinating lesion of the right hemisphere
Sagittal T2 cervical spine MRI demonstrating hyperintense signal and expansion involving the central more than peripheral cord extending from the cervicomedullary junction to C7
As expected, considering the poor visual recovery in NMO-ON, mean retinal nerve fiber layer (RNFL) on OCT is consistently lower following NMO-ON as compared to MS-ON. Across studies there is no agreement on a characteristic pattern of RNFL loss (e.g. temporal, nasal, etc.) that is specific for NMO. However an average RNFL less than 70 microns on OCT in an eye maximally recovered from acute optic neuritis should raise concern for NMO [13, 14].
Testing for highly specific (95–100%) anti-AQP4 antibodies to astrocytic foot processes has revolutionized the diagnosis of NMO [2]. The quality of AQP4 antibody testing has evolved over time. Currently the most sensitive (≈70%) commercially available tests are serum cell-based AQP4-IgG assays which are significantly more sensitive than enzyme-linked immunosorbent assays (ELISA) [15]. Considering the bulk of AQP4 antibody production arises from the blood, cerebrospinal fluid testing is considerably less sensitive than serum and therefore not routinely recommended [2, 16]. Seroconversion from negative to positive serum AQP4 status may occur. Thus, clinicians should consider repeating antibody testing 3–6 months following an initial negative result and/or with future disease recurrences [16]. The current 2015 criteria for NMO (see below) emphasize the role of AQP4 antibody testing allowing for a diagnosis of NMO spectrum disorder (NMOSD) after only one characteristic clinical event in the presence of the antibody [4].
Serum myelin oligodendrocyte autoantibody (MOG) testing is an area of active research. MOG positivity has been associated with a variety of demyelinating phenotypes including acute disseminated encephalomyelitis (ADEM), recurrent optic neuritis, isolated transverse myelitis, and AQP4 negative NMO [17–20].
MOG positive NMO constitutes about 25% of AQP4 negative NMO and it remains unclear whether these antibodies are pathogenic or simply surrogate markers of CNS demyelination. Early evidence suggests that MOG associated NMOSD results in less severe disease compared to AQP4 but otherwise their phenotype overlaps considerably. Anti MOG antibody testing is now commercially available and should be considered in AQP4 antibody negative patients.
Clinical Controversy: Should All Patients with Optic Neuritis Have Serum AQP4 Testing?
Pro stance: Clinicians who order universal AQP4 testing for all patients with optic neuritis emphasize the tremendous importance of antibody status on both acute and long-term treatment. Plasmapheresis is rarely considered in the acute management of isolated, idiopathic demyelinating optic neuritis or MS-ON due to expense, risk, and lack of evidence demonstrating a benefit over conventional therapy. As we will discuss later, however, early plasmapheresis in steroid refractory NMO-ON has become an accepted mainstay of treatment. The long-term management of NMO (immune suppression) also differs greatly from that of MS-ON or isolated optic neuritis with high risk features for development of MS (immunomodulatory therapy). AQP4 antibodies have high specificity and thus false positives are relatively rare.
- 1.
Profound vision loss at presentation (threshold varies from 20/200 to light perception)
- 2.
Poor visual recovery (threshold varies from 20/50 to 20/200)
- 3.
Bilateral simultaneous optic neuritis
- 4.
Recurrent optic neuritis (including ipsilateral recurrence or contralateral recurrence)
- 5.
History or current symptoms of other common NMO sequelae (nausea, vomiting, transverse myelitis symptoms)
- 6.
MRI brain showing features suggestive of NMO or normal (and not suggestive of MS)
- 7.
History of other autoimmune disease including prior myasthenia gravis
- 8.
Mean OCT RNFL thickness less than 70 microns
The Differential Diagnosis of NMO-ON
While both MS-ON and NMO-ON are inflammatory diseases of the central nervous system (CNS), there are clear differences in their presentation and clinical course. The refractory nature of the loss of visual acuity in NMO is a leading telltale sign that the patient involved likely does not have MS-ON. The diagnostic criteria below will allow for the distinction between the two disorders.
Other mimickers of NMO include neurological disease that present with both optic neuritis and myelitis. Kim et al. presented a detailed differential diagnosis of NMOSD [21]. Their list, along with features distinguishing them from NMOSD, includes acute disseminated encephalomyelitis (more common in the pediatric population, is preceded by an infection or vaccination and typically manifests with an alteration in consciousness or behavior), idiopathic acute transverse myelitis (may be difficult to distinguish from either MS or NMOSD), neuro-sarcoidosis (can be distinguished from NMOSD due to the presence of systemic granulomatous involvement and serum that is positive for elevated angiotensin converting enzyme), Sjogren syndrome (can be difficult to distinguish from NMOSD), systemic lupus erythematous (usually manifest with a headache, seizure, hemiparesis or memory impairment; only a small number of these patients present with optic neuritis), CNS lymphoma (can be distinguished from NMOSD via CSF analysis, persistent gadolinium enhancement after 3 months of onset, and a positive lymph node biopsy), Neuro-Behcet disease (can be distinguished from NMOSD due to the presence of a headache with or without meningoencephalitis, a progressive course, and severe brainstem/cerebral atrophy and/or leukoencephalopathy in brain MRI), and rarely CNS infections (neuro-syphillis, herpes simplex, Epstein-Barr virus, cytomegalovirus, etc.). Rarely, Leber hereditary optic neuropathy can also mimic NMO [22].
Diagnostic Criteria for NMO
The diagnostic criteria of NMO has evolved several times since it was first described by Eugene Devic in the late 1800s [23]. Until relatively recently, the identification of these patients rested predominantly on clinical grounds. Despite the use of neuroimaging to support its diagnosis, conclusive evidence proved to be problematic due to the variable presentations of NMO.
As noted above, the discovery of the strong link between NMO and the serological presence of an immunoglobulin G antibody targeting the aquaporin-4 water channels on astrocytes (AQP4-IgG) has allowed for more rapid and precise diagnosis of NMO [24]. This antibody was found to be 73% sensitive and 91% specific and this lead to a revision of the diagnostic criteria for NMO in 2006 [25]. The revised criteria incorporated the presence of AQP4-IgG, modified the required clinical signs but maintained the requirement for myelitis and optic neuritis [4]. The nomenclature of NMO’s description was changed in 2007 to the NMO spectrum disorder (NMOSD) in order to take into account the variety of clinical presentations of this disease [26].
The most recent iteration of the diagnostic criteria was articulated in an article entitled, “International consensus diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD),” prepared by the International Panel for NMO diagnosis (IPND) [4]. With the use of literature reviews, the IPND reached a consensus by taking into account the clinical spectrum of NMO’s presentation, serological markers (cell-based assays for AQP4-IgG were recommended), typical neuro-imaging characteristics and, in the absence of serological AQP4-IgG, the stringent clinical criteria required to fulfill this diagnosis.
Table 2.1 IPND Diagnostic Criteria for NMOSD Diagnosis (2015)
Diagnostic criteria for NMOSD with AQP4-IgG |
• At least one core clinical characteristic • Positive serological AQP4-IgG • Exclusion of alternative diagnoses |
Diagnostic criteria for NMOSD without AQP4-IgG (or with an unknown AQP4-IgG status) |
• At least two core clinic characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements: – At least one core clinical characteristic must be optic neuritis, acute myelitis with longitudinal extensive transverse myelitis (LETM) or area postrema syndrome – Dissemination in space (two or more core clinical characteristics) – Fulfillment of additional magnetic resonance imaging (MRI) requirements, as applicable • Negative serological AQP4-IgG (or testing is not available) • Exclusion of alternative diagnoses |
Core clinical characteristics |
• Optic neuritis • Acute myelitis • Acute postrema syndrome (unexplained episodes of hiccups, nausea and vomiting) • Acute brainstem syndrome • Symptomatic narcolepsy or acute diencephalic syndrome with NMOSD-typical MRI lesions • Symptomatic NMOSD-typical cerebral brain lesions |
Additional MRI requirements for serum negative or unknown AQP4-IgG status |
• Acute optic neuritis requires brain MRI demonstrating one of the following: – A normal brain or only non-specific white matter changes OR – An optic nerve MRI demonstrating a T2 hyperintense or a T1 weighted gadolinium enhancing lesion that extends over half of the optic nerve length or one that involves the optic chiasm • Acute myelitis, the diagnosis of which requires: – Associated intramedullary lesions extending more than or equal to three contiguous segments (LETM) OR – More than or equal to three contiguous areas of spinal cord atrophy in patients with a history of acute myelitis • Area postremal syndrome requiring dorsal medullary area/postrema lesions • Acute brainstem syndrome requiring associated peri-ependymal brainstem lesions |
In the past few years several patients with NMOSD have been found to be serologically negative for AQP4-IgG but positive for the IgG antibody targeting myelin oligodendrocyte glycoprotein (MOG) [27]. It is very likely that the next iteration of the NMOSD diagnostic criteria will include the presence of the MOG antibody. Both serologic tests are now commercially available.
The Treatment of NMO
NMO is an autoimmune disorder that targets the optic nerves and spinal cord. Given the potential for significant long-term irreversible disability, prompt diagnosis and early intervention are imperative for NMOSD patients whether presenting initially or as a relapse. The underlying inflammatory etiology of NMO has directed therapeutic regimens towards immunomodulation particularly those that target B-cells and complement-mediated activation of AQP4 [2]. It has been demonstrated that the principal mode of cellular injury is via complement mediated chemoattractant generation as well as neutrophil and eosinophil toxicity [28].
In the early stages of developing treatment protocols for NMOSD, steroids were commonly used as the first line therapy. Although high doses of intravenous steroids (IVS) can provide a moderate degree of neurologic recovery in NMO, the addition of plasma exchange (PLEX) does improve the outcome in steroid unresponsive cases [29]. The underlying principle of PLEX is to rid the patient of offending immune agents in this neuro-inflammatory disease. In the event of a relapse, the chances of a patient’s return to a neurological baseline when treated with both steroids and plasma exchange was noted to be enhanced when they were on a concurrent immunosuppressive regimen at the time of a relapse [29].
When considering treatment modalities beyond IVS, the questions facing a clinician with a refractory ON patient include the following: (1) What clinical “features” define poor response to steroids? (2) What duration of time must pass before making a diagnosis of “lack of response to steroids”? (3) When is the most effective time to administer PLEX or other immune-modulating agents once a patient is considered refractory to steroids? [30].
Initially, it was thought that immunomodulation regimens related to multiple sclerosis (MS) may serve equally well against NMOSD. Unfortunately, several clinicians have noted that some of the medications formulated for use in MS have proven to be ineffective or injurious for NMOSD patients. These medications include beta interferons, natalizumab, fingolimod, alemtuzumab and glatimer acetate [31–36].
Although there is no definitive study that directs us to a precise therapeutic regimen, there are recent articles that allow us to formulate a clinical opinion on an ad hoc basis as to how to treat individual NMOSD patients [2, 37–39].
The 2017 Mayo Clinic Proceedings review of NMO, conveniently divides the treatment options into first-line and second-line medications [2]. The first-line drugs include azathioprine, mycophenolate mofetil, prednisone, and rituximab (the anti-CD20 monoclonal antibody). The second-line drugs include methotrexate, tocilizumab, and mitoxantrone (as a “later-line” therapy). Each of these medications is associated with its own profile that includes pretreatment tests and monitoring, adverse effects and latency to expected immunosuppressive activity. However, due to the lack of an accepted trial on NMOSD treatment, the choice of a therapeutic regimen is left to the clinician on a case by case basis. Fortunately several studies are underway which are targeting key mediators in NMO immunopathogenesis [16, 40].
Global Perspective: Should All Refractory Optic Neuritis Be Treated with a Combination of Intravenous Steroids and Plasmapheresis?
Pro stance
Although the presence of serum anti-AQP4-Ig has vastly changed the landscape in the diagnosis of NMOSD , it is not present in all patients with this disorder. The lack of this IgG component in a particular patient’s serum does not rule out NMOSD but only underscores the need to look for other markers in this neuro-inflammatory disorder such as anti-MOG antibodies. In addition, given the complexity of the immunopathogenesis of NMOSD, a clinician must include other treatment modalities in its treatment besides IVS if there is no treatment effect. Thus, when presented with an optic neuritis patient who is seronegative for anti-AQP4 antibodies and/or with a refractory optic neuritis, the clinician is faced with distinguishing between refractory MS-ON and NMOSD. In the former, PLEX has no known proven effect and in the latter there is some documented effect. Given its reasonable tolerance profile, once a trial of IVS has been administered without success, PLEX should be considered as the next therapeutic choice in medically stable patients [29].
Con stance
As scientist/clinicians we should be cautious about embracing unproven therapeutic regimens. Although there are indications that PLEX may be used as an adjunct to immune modulating agents, its precise mechanism of action is not entirely known for NMOSD. In addition, due to the logistics involved in arranging PLEX, its administration may delay the use of other more effective oral or intravenous medications.
Patients who are prone to bleeding disorders or are hemodynamically unstable, should be considered for PLEX with extreme caution. However, to minimize fluid shifts and risk of bleeding, newer methods of plasma exchange allow for a more focused removal of IgG components while leaving clotting agents such as fibrinogen in the serum [41].
Acknowledgments
The authors would like to thank Dr. Claire Sheldon for contributing materials helpful to the creation of this chapter.