Incidence of paediatric multiple sclerosis and other acquired demyelinating syndromes: 10-year follow-up surveillance study

Abstract

Aim: To describe a 10-year follow-up of children (<16y) with acquired demyelinating syndromes (ADS) from a UK-wide prospective surveillance study.

Method: Diagnoses were retrieved from the patients' records via the patients' paediatric or adult neurologist using a questionnaire. Demyelinating phenotypes at follow-up were classified by an expert review panel.

Results: Twenty-four out of 125 (19.2%) children (64 males, 61 females; median age 10y, range 1y 4mo-15y 11mo), identified in the original study, were diagnosed with multiple sclerosis (incidence of 2.04/million children/year); 23 of 24 fulfilled 2017 McDonald criteria at onset. Aquaporin-4-antibody neuromyelitis optica spectrum disorders were diagnosed in three (2.4%, 0.26/million children/year), and relapsing myelin oligodendrocyte glycoprotein antibody-associated disease in five (4%, 0.43/million children/year). Three out of 125 seronegative patients relapsed and 85 of 125 (68%) remained monophasic over 10 years. Five of 125 patients (4%) originally diagnosed with ADS were reclassified during follow-up: three children diagnosed initially with acute disseminated encephalomyelitis were subsequently diagnosed with acute necrotising encephalopathy (RAN-binding protein 2 mutation), primary haemophagocytic lymphohistiocytosis (Munc 13-4 gene inversion), and anti-N-methyl-d-aspartate receptor encephalitis. One child initially diagnosed with optic neuritis was later diagnosed with vitamin B12 deficiency, and one presenting with transverse myelitis was subsequently diagnosed with Sjögren syndrome.

Interpretation: The majority of ADS presentations in children are monophasic, even at 10-year follow-up. Given the implications for treatment strategies, multiple sclerosis and central nervous system autoantibody mimics warrant extensive investigation.

Figure 1. A total of 125 children were included in the original cohort.

Initial presentations were acute disseminated encephalomyelitis (ADEM) in 43 (34.4%), optic neuritis (ON) in 31 (24.8%), transverse myelitis (TM) in 25 (20%), and other clinically isolated syndrome (CIS) presentations in 26 patients (20.1%). At 10-year follow-up, 85 (68%) of the 125 children included had a monophasic acquired demyelinating syndrome. Thirty-five children (28%) had a relapsing demyelinating syndrome (RDS); 24 had a final diagnosis of multiple sclerosis (MS), four had relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOG-AD), three had aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorder (NMOSD), and three had seronegative RDS. Incidence was calculated for MS, relapsing MOG-AD, and AQP4-Ab NMOSD and is shown below the relevant diagnoses. ANEC, acute necrotising encephalopathy; HLH, haemophagocytic lymphohistiocytosis; MDEM, multiphasic disseminated encephalomyelitis; RRMS, relapsing remitting multiple sclerosis; PPMS, primary progressive multiple sclerosis; NMDA-R, N-methyl-D-aspartate receptor.

Figure 2. Five cases with alternative diagnoses at 10-year follow-up.

(a) A female patient presented at age 16 months with encephalopathy, generalized seizures, abnormal eye movements, and hypotonia. The sister also presented previously with acute disseminated encephalomyelitis at a similar age. Axial T2-weighted fluid attenuated inversion recover (FLAIR) brain magnetic resonance imaging (MRI) showed abnormal hyperintensity of the left cerebellar grey matter and fairly symmetrical hyperintensity of the cerebral white matter, including the external capsules. Genetic screening confirmed RANBP2 mutation in both siblings. (b) A female patient presented at age 2 years with severe encephalopathy, seizures, and a complex movement disorder. The patient was noted to have a right-sided hemiparesis on clinical examination. The patient was positive for serum anti-N-methyl-D-aspartate receptor (NMDA-R) antibodies, and negative for myelin oligodendrocyte glycoprotein-antibodies. Axial T2-weighted FLAIR brain MRI showed an asymmetric distribution of multiple hyperintense grey and white matter lesions, with a notable grey matter predominance. (c) A female patient presented at 14 years of age with encephalopathy, bilateral weakness, sensory loss with cerebrospinal fluid protein elevation (2.6g/L), and positive oligoclonal bands. Axial T2-weighted brain MRI showed an extensive bilateral, asymmetrical, patchy parenchymal signal abnormality involving the deep white matter, brainstem, internal capsules, and cerebellar peduncles. The patient also had longitudinally extensive transverse myelitis (LETM) from C1 to T4 (not shown here). The patient went on to have two further relapses with a similar presentation within the first year. (d) A female patient presented at 12 years of age with bilateral weakness of upper and lower limbs in addition to sphincter dysfunction. Sagittal T2-weighted MRI of the spinal cord showed a lesion in the conus medullaris. (e) A male patient presented at 8 years of age with left convergent squint, ataxia, seizures in addition to lung infiltrates, cycling cytopenia, and hepatosplenomegaly. Coronal T2-weighted FLAIR and contrast enhanced T1-weighted brain MRI at presentation showed a heterogeneously enhancing lesion in the right cerebellar hemisphere bearing some localized oedema and leptomeningeal enhancement. Follow-up imaging on relapse showed symmetrical hyperintense lesions on T2-weighted images in the cerebellum and dorsal pons, symmetrical lesions in the cerebral hemispheres as well as an LETM. The patient underwent a bone marrow transplant with an unsuccessful central nervous system response with clinical and neurological evidence of progression that led to death.