A 7-year-old girl presents with bilateral nystagmus. Her medical history is significant for the development of acute quadriplegia accompanied by dysesthesias and recurrent myelitis requiring positive airway pressure support. She subsequently developed right-sided ptosis, unilateral nystagmus, followed by bilateral nystagmus. The initial magnetic resonance imaging (MRI) performed during a myelitis episode in 2002 showed an extensive longitudinal lesion of the spinal cord. A subsequent MRI performed in 2003 showed an acute brainstem lesion. The absence of optic neuritis in the presence of brainstem lesions led her physicians at the time to favor a diagnosis of multiple sclerosis (MS).
On examination, the patient had bilateral, moderate to severe optic atrophy and upgoing plantar responses (Babinski reflex).
This patient presents with optic neuritis and a history of MRI-confirmed brain lesions. She has a history of discrete attacks that remain undiagnosed, including an episode of unexplained and prolonged vomiting at onset and 2 episodes of myelitis. A disseminated encephalomyelitis phenotype is suspected.
Order serologic testing for aquaporin-4 (AQP4)-immunoglobulin G (IgG) to confirm or rule out a diagnosis of neuromyelitis optica spectrum disorder (NMOSD) as an alternate diagnosis to MS.
We present a case illustrating the differential diagnosis of a child presenting with optic neuritis.
NMO was considered a variant of MS from the late 19th century until 2004, when circulating AQP4 antibodies were found in patients who did not have MS but shared key elements of presentation, symptoms, and spinal cord MRI findings.1 AQP4-IgG is a serum autoantibody expressed mainly by astrocytes in the central nervous system that is present in approximately 60% of patients with NMOSD.2
In the case above, we evaluated a 7-year-old girl with optic neuritis who developed brain lesions and confusion, an acute disseminated encephalomyelitis phenotype that can be seen in NMO. Several of her physicians had suspected fulminant MS until positive test results for AQP4 antibodies enabled us to confidently diagnose the patient with NMO.
This young patient’s case was one of the early cases that convinced me that we need to conceive of NMO as a “spectrum disorder,” a broader condition than we had previously recognized. Such patients led the NMO community to propose the expanded designation of this condition to NMOSD in 2007.3
The concept was formally adopted in the recommendations of the 2015 International Panel for NMO Diagnosis,4 which presented internationally accepted criteria that allowed for the diagnosis of NMOSD in patients with any syndrome typical of NMO — even those affecting the brain — who are seropositive for AQP4-IgG. Importantly, patients who are seronegative for AQP4-IgG but who have symptoms of optic neuritis, myelitis, or area postrema syndrome also satisfy the criteria for NMOSD.
In October 2000, Julia, a 7-year-old girl, was brought to a neurology clinic for evaluation of troubling symptoms. Julia presented with protracted, unexplained vomiting and was found to have nystagmus on physical examination. MRI showed a lesion of the cervicomedullary junction (Figure 1). The patient’s family history revealed 2 cousins who had been diagnosed with MS, but it was otherwise unremarkable for autoimmune disease.
In March 2001, Julia, now 8 years of age, developed myelitis. She became quadriplegic and had dysesthesias, but she recovered over a period of several months.
In February 2002, the patient developed recurrent myelitis accompanied by respiratory failure that required bilevel positive airway pressure treatment.
In March 2003, Julia developed ptosis of the right eye and new nystagmus. Repeat MRI disclosed a new lesion in the right midbrain (Figure 2a). She had upbeat nystagmus and end-gaze horizontal nystagmus, which was worse when she looked to her left. An AQP4-IgG test at that time was positive.
Julia’s reduced visual acuity went unnoticed until we performed a vision examination. Her visual acuity was 20/100 in her right eye and 20/200 in her left eye. Her optic discs were very pale. Based on these findings, it is likely that she had prior optic neuritis. However, children of her age do not often report vision loss. Neurologic examination showed that she had normal strength and tone but brisk deep tendon reflexes, and the plantar response was upgoing bilaterally (Figure 2b).
In the early 2000s, a diagnosis of NMO in this patient would have been thought to be unusual based on her presenting symptoms, lack of clinical history of optic neuritis, and brainstem syndrome. Other diagnoses we considered were:
- Acute disseminated encephalomyelitis
Confirming a Diagnosis of NMO
Symptoms and clinical findings in this young patient that were typical of NMO included:
- Severe attacks of myelitis accompanied by a longitudinally extensive spinal cord lesion on T2-weighted MRI sequences;
- History of unexplained vomiting at disease onset;
- Evidence of optic neuritis on examination; and
- Absence of MRI evidence of periventricular lesions, which are typically present in MS.
The positive result for AQP4-IgG was extremely helpful in making a conclusive diagnosis, although at the time this patient was evaluated, the medical community was just beginning to appreciate the concept of NMO as a spectrum of diseases rather than a single entity. Rituximab would have been the treatment of choice at the time.
Both the diagnostic process and the treatment for NMOSD have changed dramatically since we managed this patient’s case in the early 2000s. We now recognize that NMOSD can occur in any age group. There is a bimodal distribution and although the largest affected group is late middle-aged women, children — even those younger than the age of 12 — may also be affected. Therefore, pediatric neurologists should be aware of this condition and must consider it in the differential diagnosis of a relapsing CNS inflammatory disease. Julia never described symptoms consistent with optic neuritis and might not have satisfied the criteria being used to diagnose NMO in 2005.5
The new diagnostic criteria for NMOSD published in 2015 enabled clinicians to make an earlier diagnosis of NMOSD when AQP4-IgG is detected, even in the presence of a single characteristic.4 It is now estimated that more than two-thirds of patients with NMOSD have AQP4-IgG antibodies.6 Importantly, certain therapies to prevent attacks in MS appear to aggravate NMO, making an early and accurate diagnosis of NMOSD imperative.4
Treatment Options for NMOSD
The FDA has approved 3 new agents for AQP4-positive NMOSD: eculizumab, a complement C5 inhibitor; inebilizumab, an anti-CD19 antibody; and satralizumab, an interleukin-6 inhibitor. Many patients with long-standing NMOSD are treated with rituximab, which, like inebilizumab, is a B-cell-depleting drug. In general, however, FDA-approved drugs are considered preferable for patients with newly diagnosed NMOSD because of the greater rigor of evidence supporting their use.6-9 Furthermore, although immunosuppressive therapies such as rituximab have been used without regulatory approval for relapse prevention in NMOSD, up to 60% of patients receiving these agents continue to experience recurrent attacks.6,7
It is difficult to choose between eculizumab, inebilizumab, and satralizumab when selecting therapy for NMOSD given that the approval of these drugs was based on prevention of a first on-treatment attack. Long-term follow-up efficacy data are limited and just emerging. The available data are insufficient to show a significant difference in efficacy between the 3 drugs, especially when taking into account differences between the pivotal trials in terms of enrollment criteria and methods for evaluating relapses.
The only reported experience with one of these agents in a pediatric population was with satralizumab. Yamamura et al published a study that included some adolescent patients and found that satralizumab was associated with a longer time to relapse compared with placebo,6 but experience with these monoclonal antibodies in NMOSD is limited. Clinicians must evaluate the potential risks and benefits of new vs historically used agents (such as rituximab) in deciding how to treat their patients with NMOSD.
The FDA-approved drugs for NMOSD have been reported to decrease the relapse rate by 74% to 94%.10
Serious side effects associated with satralizumab have been rare, with no major increase observed in the risk of serious infections.10,11 Eculizumab is associated with an established risk of meningococcal meningitis and septicemia. Patients who are prescribed eculizumab should be immunized against all strains of meningococcus prior to initiation of treatment.7 There has been some evidence that use of B-cell-depleting drugs may increase the risk of COVID-19 or worsen its severity12; this may also be a concern with inebilizumab, which is also likely to reduce antibody levels.
Patients must stay on treatment indefinitely to prevent NMOSD attacks. Tolerance for breakthrough attacks is very low. If a patient with NMOSD experiences a severe attack during treatment with a specific drug, switching agents would be warranted. However, guidelines to inform decisions about switching therapy are lacking.
The experience with NMOSD in children has been limited. In general, brain lesions tend to be more common among children than adults. Children also may be more likely than adults to have optic neuritis as the first symptom rather than spinal cord lesions.
Differentiating Features in Children
Although brain lesions can occur in both adults and children, a higher proportion of children may first present with brain lesions or seem to develop brain lesions early in the course of their disease. The following features help differentiate NMOSD from MS in a patient presenting with optic neuritis and myelitis.
- Attacks are more severe in NMOSD;
- MRI lesions are longer in the optic nerve and spinal cord in patients with NMOSD;
- There are no oligoclonal bands or other indicators of intrathecal IgG synthesis, the presence of which is characteristic of MS; and
- Approximately 60% of patients with NMO test positive for AQP4-IgG, which has a sensitivity of 76% and a specificity of 100% when cell-based arrays are used.13
Updated NMOSD Treatment
Today, the diagnosis and treatment of NMOSD is much more rapid and effective. For example, one of our patients has a history and presentation similar to Julia. She was diagnosed with NMOSD by positive AQP4-IgG in 2019 and prescribed satralizumab at a dosage of 120 mg subcutaneously every 2 weeks at weeks 0, 2, and 4, and then every 4 weeks thereafter. Over the past 2 years, she has responded well to therapy. This patient did experience a minor breakthrough event of right eye pain associated with a 2-line change in visual acuity in the right eye, but she was monitored while remaining on treatment with the drug and the episode subsided.
Unlike patients with MS, patients with NMOSD rarely experience disease progression outside of acute attacks. Most of the disability resulting from acute attacks is residual. Acute treatments for NMOSD attacks are the same as those for MS, specifically intravenous corticosteroids and rescue plasma exchange if necessary. However, most of the disease-modifying treatments that we use for MS are ineffective and (with the exception of B-cell-depleting agents) may even be harmful to patients with NMOSD.
Owing to the advent of effective treatments for managing NMOSD and suppressing attacks, NMOSD prognosis has improved considerably compared with the extremely poor outcomes that patients had to face in the past.
Brian G. Weinshenker, MD, was a consulting neurologist for the development of this program. Dr Weinshenker, a professor emeritus at Mayo Clinic in Rochester, Minnesota, codeveloped the diagnostic criteria and characterized the natural history of NMO (also known as Devic disease), including the recent International Panel for NMO Diagnosis. The panel’s recommendations were published in 2015 and serve as the standard for diagnosis of this condition. Additionally, Dr Weinshenker was a member of the team whose research led to the discovery of NMO-IgG (AQP4-IgG), a highly specific and moderately sensitive new antibody biomarker for NMO and other restricted types of inflammatory demyelination.
Brian G. Weinshenker, MD, reported affiliations with RSR Ltd, MVZ Labor PD Dr Volkmann und Kollegen GbR, AstraZeneca, Horizon Therapeutics PLC, Alexion Pharmaceuticals Inc, UCB Biosciences, Mitsubishi Tanabe Pharma Corporation, and Genentech, Inc.
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Reviewed January 2022