Acute eculizumab treatment in a pediatric patient with AQP4-IgG+ NMOSD

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory immune-mediated disorder associated with the aquaporin-4 antibody immunoglobulin G antibody (AQP4). Diagnostic criteria include a positive AQP4 test and at least one core clinical characteristic (optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome, or symptomatic cerebral syndrome). Alternatively, the diagnosis can be established with at least two core clinical characteristics and a negative AQP4-IgG test. ¹ Onset in childhood occurs in <5% of cases and presentations below age 12 are rare. ² Children commonly present with vision changes, vomiting, hiccups, and arm or leg weakness consistent with optic nerve, brainstem, and spinal cord involvement. ³ Acute management includes 3–5 days of intravenous steroids and/or plasma exchange (PLEX). Long-term immunosuppression is usually necessary to prevent relapse. No therapies for pediatric NMOSD have received Food and Drug Administration (FDA) approval, but rituximab is often used followed by azathioprine or mycophenolate. ⁴ To date, there are only four FDA-approved medications for adult NMOSD (eculizumab, inebilizumab, satralizumab, and ravulizumab). Eculizumab efficacy is established for NMOSD through the trial where patients receiving eculizumab had significantly lower risk of relapse compared to placebo. ⁵ Here, we describe a case of a 10-year-old girl with longitudinally extensive transverse myelitis (LETM) due to AQP4+ NMOSD with notable improvement after steroids, PLEX, and eculizumab infusion.

Case description

A 10-year-old female with no significant medical history presented with ascending left leg numbness and weakness. She had no recent illness.

Four days prior to arrival to the emergency department (ED), the patient experienced ascending numbness in the left lower extremity and progressive bilateral leg weakness limiting her ability to walk. She had no constitutional symptoms except for 1 week of constipation. Family history was non-contributory.

On initial neurologic examination, the patient was alert and oriented with intact cranial nerve examination. Her visual acuity was 20/20 bilaterally with full visual fields on confrontation and no red desaturation. She had no pallor on fundoscopic examination. She had full strength in both arms. She had diminished sensation in lower limbs up to the T4 dermatome bilaterally with 0/5 and 3/5 strength in the left and right leg, respectively. Post-void bladder scan revealed 110 mL of urine, a sign of urinary retention. Serum testing was positive for antinuclear antibodies (ANA) (titer of 1:160), otherwise her rheumatologic and infectious workup was unremarkable. Cerebrospinal fluid studies including cultures, flow cytometry, and meningitis–encephalitis panel were negative. Oligoclonal bands eventually resulted negative.

Magnetic resonance imaging (MRI) total spine with and without contrast showed a T2 hyperintense cord signal abnormality involving the entire spinal cord, from C2 level to conus medullaris, consistent with holocord LETM (Figure 1(a)–(c)). The central cord and gray matter was predominantly involved, with no definite enhancement and no evidence of spinal cord expansion or swelling. MRI brain with and without contrast showed multiple tiny non-enhancing cerebral white matter hyperintensities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Figure 1(d)).

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Figure 1.

MRI total spine in sagittal (a, b) and axial (c) views shows a T2-hyperintense cord signal consistent with longitudinally extensive transverse myelitis. MRI axial brain (d) reveals area of white matter hyperintensity in the right posterior occipital lobe on FLAIR imaging.

Given the severity of her presentation and extent of spinal involvement, a 5-day course of IV methylprednisolone and PLEX was initiated on hospital day 2. On hospital day 8, serum testing for AQP4 via Mayo Clinic fluorescence-activated cell sorting assay resulted positive (titer of >1:10,000), confirming the diagnosis of AQP4+ NMOSD. Myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. After completion of IV steroids and seven sessions of PLEX, she had 4/5 and 5/5 strength in her left and right leg, respectively. She exhibited improvement in sensation, although it was still diminished up to the T4 sensory level bilaterally.

Due to persistent sensorimotor deficits including inability to walk without support, the initial severity of LETM, and to improve chance of recovery, the decision was made to initiate eculizumab for acute attack treatment. On hospital day 10, she received the meningococcal vaccine and penicillin prophylaxis to decrease risk of meningococcal disease. On hospital day 12, she received eculizumab 600 mg without complications. Within 30 minutes of infusion completion, she reported subjective improvement in sensation. Neurologic exam revealed improved strength of 4+/5 in the left leg and she appeared to more easily ambulate with a walker.

She was discharged home the next day with outpatient physical therapy and follow-up in pediatric neuroimmunology clinic. She completed an oral prednisolone taper over 15 days (40 mg for 3 days, then 20 mg for 3 days, 10 mg for 3 days, and 5 mg for 3 days). One week following discharge, she was able to ambulate around the house and upstairs without a walker, but continued to use a walker outside of the house. To increase the chance of an acute benefit, she continued eculizumab treatment 900 mg every 2 weeks as an outpatient (dosing regimen according to the pediatric hemolytic uremic syndrome (HUS) prescribing information). After 8 weeks on eculizumab, the patient was switched to rituximab for easier infusion scheduling as she returned full-time to school. Her course was complicated by painful NMOSD-related paroxysmal spasms that resolved with daily oxcarbazepine. Five months after initial presentation, her exam revealed full strength and she was able to ambulate without support. She subjectively reported her strength and sensation were back to baseline.

Unfortunately, 10 weeks after starting rituximab she developed a myelitis relapse which required admission for IV steroids and PLEX for seven sessions. She was restarted on eculizumab with plans to transition to ravalizumab, which had been approved for NMOSD in the interim. She was discharged to an acute rehab facility.

Discussion

We report a case of a 10-year-old girl who presented with holocord LETM from AQP4+ NMOSD treated with steroids, PLEX, and eculizumab. Early initiation of eculizumab could be a treatment option for the acute attacks of NMOSD in pediatric and adult patients, but its true effect should be further evaluated.

Eculizumab, a C5 complement inhibitor monoclonal antibody, has been suggested for acute relapse in adult NMOSD due to its rapid onset of action. ⁶ One unpublished abstract for eculizumab use in an acute NMOSD attack revealed significant improvement in symptoms hours after infusion. ⁷ Eculizumab is widely accepted as a safe medication for the pediatric population among the HUS literature.^8,9 Since NMOSD prescribing information is only available for adults with NMOSD, we referred to the pediatric dosing regimen provided in HUS prescribing information. The most serious complication associated with eculizumab is meningococcal disease; therefore, vaccination and/or antibiotic prophylaxis are recommended. Other complications include headache and infusion reaction. ¹⁰ Little is known about how to transition patients from these highly effective therapies. A 2023 case series of six Turkish patients who participated in the PREVENT trial but could not continue on eculizumab due to reimbursement issues found four of six patients relapsed within 3 months of stopping eculizumab, despite some being treated with rituximab. ¹¹

Conclusion

NMOSD in children is rare. Despite a severe holocord presentation, this patient with AQP4+ NMOSD had near complete recovery after acute treatment with IV steroids, PLEX, and early eculizumab initiation. It is difficult to assess the degree to which eculizumab specifically contributed to her recovery; therefore, further research is needed on safe and effective treatment options for children with NMOSD. More data are needed to understand the risk of relapse if transitioning off of these medications.