Discussion

NMOSD cases are a rare complication following SARS-CoV-2 infection, and this report contributes to the global knowledge of this pathology by detailing an atypical pediatric presentation. While the clinical course, radiological findings, and laboratory results of pediatric NMOSD generally mirror those of adults - typically featuring LETM - pediatric patients experience a lower frequency of optic neuritis, APS, and brainstem syndrome [1]. In the presented case, however, the extensive infratentorial involvement (LETM, APS, and brainstem syndrome) was a prominent feature, requiring careful differentiation from pediatric MS and MOGAD (Table 2) [5,9,16,17]. Accurate differentiation dictated the treatment strategy; while traditional MS therapies can exacerbate NMOSD, confirming AQP4+ NMOSD justified the initiation of lifelong immunosuppressive biologic therapy to prevent severe relapses.

Aspect | Pediatric MS | Pediatric MOGAD | Pediatric AQP4+ NMOSD
Incidence (per 100k/yr) | 0.5-1 (adults 3-5) | 0.3-0.4 (adults 3-4) | 0.05-0.2 (adults 2)
Sex ratio (F:M) | 2-3:1 | 1:1 | 1.5-3:1 (adults 9:1)
Other antibodies | ANA± (5-10%) | None | ANA+ 30-50%
Optic neuritis | Unilateral/short retrobulbar (~67%) | Bilateral/large anterior (25-50% retrobulbar) | Bilateral/longitudinal retrobulbar (~60-70%)
ON fundoscopy | Normal (2/3 cases) | Papilledema (50-75%); normal retrobulbar | Normal acute (60-70%)
Myelitis | Short peripheral (<2VSS) | Symmetric LETM (>3VSS) | Severe LETM (>3VSS), central grey
Area postrema | Rare (<5%) | Rare/None | 20-40%
Brainstem syndrome | Common (20-30%), pontine | 20-35%; multifocal, MCP/pons/medulla | 12-57%; isolated + nausea/hiccups (56% BSIFE)
Brain MRI lesions | Periventricular, Dawson's, persistent | Fluffy/cortical/talamic, 60% resolution | Periventricular/postrema, 25% resolution
CSF OCB | 70-90% | 5-11% | 20-40%
Rituximab response | Excellent (>90%) | Partial (50-70%) | Excellent (80-95%)
Acute treatment | Methylprednisolone ± IVIG/plasmapheresis | Methylprednisolone ± IVIG or plasmapheresis | Methylprednisolone + early plasmapheresis
Maintenance therapy | High-efficacy DMTs; relapse ↓>70% | AZA/mycophenolate/RTX; relapse ↓50-70% | RTX > AZA/mycophenolate
Recovery post-relapse | Good progressive | Good (monophasic 50%) | Poor
Disease course | Progressive, >100 lesions | Monophasic/good recovery | Relapsing, poor recovery

This case is highly atypical due to the patient's male sex (NMOSD F:M ratio is 1.5-9:1) and the specific presentation of retrobulbar optic neuritis (featuring mild MRI enhancement with a completely normal fundoscopy, a pattern seen in 60-70% of NMOSD cases). The AQP4-IgG-positive result is highly reliable, as it was processed using a CBA. While anti-MOG antibodies are statistically more frequent in pediatric demyelinating cohorts (11:1 compared with AQP4), the patient was confirmed to be MOG-negative via CBA. The clinical, radiological, laboratory, and therapeutic response data unequivocally support the isolated AQP4+ NMOSD diagnosis, aligning with the literature indicating that dual AQP4/MOG positivity is exceedingly rare (<0.1%). A monophasic course is unusual for NMOSD and is a hallmark of this report [3-5].

Considering the subgroup of NMOSD associated with SARS-CoV-2 infection, the review by Harel et al. [14] of 15 studies provides a valuable benchmark, although the presented case diverges in several demographic and clinical aspects. Harel et al.'s cohort demonstrated a strong female predominance (73%) and a mean age of 38 years (range, 7.5-71 years), with Latin American reports originating exclusively from Brazil; the current report, therefore, adds a rare pediatric male presentation from Colombia. In their review, the median interval between viral infection and NMOSD symptoms was 14 days, with 67% of the total cohort testing AQP4+ and 53% presenting with LETM. Focusing specifically on the four pediatric cases in that review (all girls aged 7.5 to 16 years, one with comorbid juvenile idiopathic arthritis), their SARS-CoV-2 serology and testing varied: two were asymptomatic (one PCR+ and one IgG+), one had typical COVID-19 symptoms (PCR+), and one lacked symptom data (IgG+/IgM+). The presented case directly mirrors the asymptomatic, isolated SARS-CoV-2 IgG+ serological profile seen in one of these girls. Regarding NMOSD serology, three of the four pediatric girls in Harel et al.'s review were AQP4-positive (aligning with the presented case), while the youngest (7.5 years old) was double-negative (AQP4-/MOG-). Notably, treatment responses in the literature diverged based on these serological profiles: the three AQP4+ girls improved with methylprednisolone alone, whereas the double-negative patient required triple therapy (methylprednisolone, plasmapheresis, and immunoglobulin). Strikingly, despite sharing the isolated AQP4+ serology of the steroid-responsive pediatric cases, the presented patient was highly resistant to initial high-dose steroids and required rapid escalation to plasmapheresis to achieve clinical improvement.

A review by Mirmosayyeb et al. [10] included a 15-year-old male who developed optic neuritis four weeks post-COVID-19 (PCR+). While demographically similar to the presented case, that patient was dual-positive for AQP4 and MOG antibodies, and diagnostic evaluation was limited solely to a brain MRI. Their patient responded well to methylprednisolone - a favorable steroid response and monophasic course typical of MOG positivity. This contrasts sharply with the isolated AQP4-positive disease documented here, which demonstrated severe steroid resistance. Furthermore, unlike MOG positivity, isolated AQP4+ NMOSD is notoriously relapsing (non-monophasic), necessitating the aggressive long-term biologic maintenance therapy utilized in this case.

Regarding vaccine-associated AQP4+ NMOSD, a systematic review by Harahsheh et al. [11] of 16 cases found that symptom onset occurred within a maximum of six weeks post-vaccination (mean of one week). Their cohort consisted entirely of adults (23-80 years) and predominantly women (69%), with 62% presenting with LETM and 20% featuring optic neuritis and/or APS. Furthermore, 31% had a history of immune-mediated conditions. While the extensive spinal cord and area postrema involvement in the presented case clinically mirrors these vaccine-triggered profiles (which share pathophysiological similarities with the non-vaccinated, post-infectious cases described by Harel et al. [14]), a vaccine etiology was confidently excluded here. The extensive two-year interval elapsed since this patient's COVID-19 vaccination far exceeds the established six-week window, ruling out causality.

A special consideration in this report is the patient's concurrent active dengue infection. Because dengue symptoms appeared only on the last day of the acute illness, the timeline indicates the virus did not act as the primary trigger for LETM-NMOSD. However, it is hypothesized that this concurrent viral infection contributed to the patient's inadequate steroid response. Previous literature describes NMOSD triggered by dengue in two adults and two adolescents, all of whom were AQP4+ and presented with optic neuritis and/or LETM [18]. In those pediatric reports, an 11-year-old improved with initial steroids, and a 17-year-old experienced a recurrence that successfully resolved with just a second course of methylprednisolone. Conversely, the concurrent dengue infection in the presented case was associated with severe steroid refractoriness.

Consequently, management aligned with standard escalation protocols [1,5]. Because the patient exhibited an inadequate response to high-dose IV methylprednisolone within the first five days, treatment was promptly escalated to plasmapheresis (five cycles), which successfully halted the inflammatory cascade. Preventive maintenance therapy was subsequently established using azathioprine and rituximab, resulting in complete clinical and radiological resolution at follow-up and underscoring the efficacy of this stepwise approach in severe pediatric NMOSD.