Child Neurology: Neuromyelitis optica spectrum disorders

Clinical features of NMOSD in children.

In one analysis of children with NMOSD, the most common presenting features included visual, motor, and constitutional syndromes.³ In the largest report of children with NMO, 83% and 78% of children with AQP4-IgG had at least one episode of ON or transverse myelitis, respectively, while 45% had other symptoms such as encephalopathy, seizures, ophthalmoparesis, ataxia, or area postrema syndrome.⁴ Children with NMOSD were older than those with acute disseminated encephalomyelitis (ADEM) (mean 10–12 vs 5 years), but approximately the same age as those with MS (13 years).^3,4 Female patients and non-Caucasians are overrepresented in NMOSD. NMOSD is associated with additional autoimmunity, with 42% and 76% of patients with other autoimmune diagnoses or autoantibodies, respectively.⁴ Sixty-four percent have a positive ANA, as in our case. There is one other case of autoimmune hepatitis associated with NMO reported in the literature.⁵

Imaging features of NMOSD in children.

MRI with gadolinium is the imaging modality of choice for evaluating possible demyelinating disease, although there are no definitive radiologic criteria for NMO in children. MRI brain, orbits, and cervical ± thoracic spinal cord should be imaged as clinically indicated. Among 56 patients with MRI data included in one study, 56% had brain parenchymal abnormalities and 34% had optic nerve contrast enhancement; 5 had involvement of the chiasm and 1 had bilateral ON.⁴ ON caused by NMOSD is more likely to be clinically severe, bilateral, and longitudinally extensive, and to involve the optic chiasm, compared to other causes of ON.⁶ Features that help distinguish NMOSD myelitis from MS include longitudinally extensive (≥3 spinal segments) myelitis involving the central cord with >50% of the cross-sectional area, compared to the shorter, smaller, and more dorsolateral lesions seen in MS.⁶

Brain lesions are common in pediatric NMOSD and may overlap with MS or ADEM. NMOSD lesions tend to be periependymal T2 hyperintense lesions predominantly. Periventricular NMOSD lesions tend to be longer than the Dawson fingers seen in MS, which are usually shorter and confined to the pericallosum. Lesions in the corpus callosum occur in NMOSD, where they are often large and follow the ependymal lining, while those seen in MS tend to be smaller, ovoid, or flame-shaped and oriented radially to the ventricles.⁶ Extensive and confluent predominantly white matter hemispheric lesions, which may be associated with encephalopathy, can make it difficult to distinguish NMOSD from ADEM.⁴ In that setting, laboratory features, particularly the presence of AQP4-IgG, can be critical to the diagnosis.

Laboratory features of NMOSD in children.

Roughly 65% of children with NMOSD tested positive for AQP4-IgG, rates similar to those observed in adults with NMOSD, but seropositivity may occur up to 4–5 years after onset.³ Testing for AQP4-IgG is the most sensitive and cost-effective when performed on serum, which is the source recommended by the Mayo Clinic laboratory.⁷ In ON from NMOSD, the CSF may appear bland, while during an episode of myelitis, CSF may be highly inflamed, with pleocytosis >100 cells/μL, commonly with neutrophils or eosinophils. Oligoclonal bands are observed in roughly 25% of patients with NMOSD. This is contrasted with CSF in MS, which commonly contains oligoclonal bands (90%) and only rarely is pleocytosis >50, typically lymphocytic.⁶ CSF studies in children with ADEM are variable and often nondiagnostic; however, oligoclonal bands are only rarely present.³ Children with features of NMOSD but with negative serum AQP4-IgG should have CSF AQP4-IgG testing and may also be tested for myelin-oligodendrocyte glycoprotein antibodies (in the United States, only available through research laboratories). AQP4-IgG may appear up to 4 years after disease onset, and sequential testing should be employed for initially seronegative patients.

Diagnostic criteria in children.

The Wingerchuk 2006 criteria were 49% sensitive for a diagnosis of pediatric NMO, while the 2015 updated international panel for NMO diagnosis criteria, which allowed for diagnosis after one attack and the presence of AQP4-IgG, were 97% sensitive and can be applied to children.³ This is in part due to the lower lesion accrual in pediatric NMO.

Treatment of NMOSD in children.

In contrast to MS, in which disability is driven primarily by progressive disease and there is relatively good recovery after acute exacerbations, in NMOSD, acute exacerbations can be severe with little recovery and drive virtually all of the disability. In addition, 93%–95% of children with NMOSD have relapsing disease,^3,4 and there is some evidence that acute exacerbations respond more favorably when the patient is on preventative medicaiton.⁸ Therefore, prompt recognition and initiation of acute abortive therapy and preventative medication is critical. Some disease-modifying therapies used in MS (including interferons, fingolimod, and natalizumab) are ineffective and may worsen NMOSD.⁶ No randomized controlled trials have been conducted in adult or pediatric NMOSD; therefore, all treatments are considered off-label and based on available literature and expert recommendations.

Acute treatment.

Acute exacerbations are commonly treated with IVMP (in children 20 mg/kg/d for 5 days), an approach extrapolated from data on treating other immune-mediated neurologic conditions. We advocate for urgent PLEX as a first-line therapy for NMOSD exacerbations based on evidence demonstrating improved outcomes in patients treated with PLEX and IVMP compared to IVMP alone.^8,9 At Vanderbilt Children's Hospital, we exchange 1.5 volumes of plasma 5 times over 5–8 days. Complications are uncommon in experienced centers, but include those related to the central line, electrolyte abnormalities, and coagulopathy associated with the exchange process and transfusion-related complications. IV immunoglobulin may be beneficial and can be considered when there is a poor response to steroids and contraindication to PLEX exists. Children with NMOSD should be given a prednisone taper over several months.

Preventative therapy.

The most common preventative agents include azathioprine, prednisone, mycophenolate mofetil, and rituximab. There is evidence to support the use of rituximab or mycophenolate over azathioprine.⁶ The same strategies used to treat adults with NMOSD have been applied to children, and results appear comparable.³ Studies intended to assist with the dosing and monitoring of rituximab for pediatric NMOSD have begun to emerge in the literature.¹⁰

As recently demonstrated,³ the updated international panel for NMO diagnosis criteria are sensitive for the diagnosis of NMOSD in children. Prompt recognition and treatment of exacerbations followed by initiation of preventative agents are critical for minimizing disability. Strong consideration should be given to treating acute exacerbations with urgent PLEX in addition to IVMP, which appears to be more effective than IVMP alone.