A 13-month-old girl presented with an asymmetric weakness and hypertonia in the four limbs (both arms and legs), which appeared more severe on the right side than on the left side, with right head deviation. She could only perform some abnormal dystonic movements with the right limbs because her left limbs were almost plegic. She also presented with an altered state of consciousness, alternating periods of sleepiness with severe psychomotor agitation. Notably, 4 days before her neurological symptoms occurred, she presented with fever and cough, and 1 month prior to this, the patient had received vaccination against diphtheria, tetanus, pertussis, poliomyelitis, haemophilus B, hepatitis B, and pneumococcus. A cerebrospinal fluid (CSF) analysis revealed that the level was within the normal range, and a broad screening for infectious agents showed a negative result. The patient was also tested for the presence of oligoclonal bands, anti-AQP4, and anti-MOG antibodies. Brain magnetic resonance imaging (MRI) showed symmetrical thalamic lesions, with extension to the hemispheric white matter and to the right optic tract, without contrast enhancement (Figure 1A). A diagnosis of acute disseminated encephalomyelitis (ADEM) was made, and endovenous high-dose methylprednisolone therapy was started for 7 days, which involved a cycle of high-dose intravenous immunoglobulins (IVIg), leading to rapid clinical recovery and radiological response at the 3-month control brain MRI, without any radiological progression (Figure 1B). Due to the unusual coexistence of extrapyramidal dystonic manifestations at onset, thiamine-responsive basal ganglia disease (BTBGD) was excluded by sequencing the SLC19A3 gene; likewise, inherited inborn errors of metabolism, including mitochondrial diseases, were excluded.
Oral prednisone was tapered in 2 months. Four months later, the child reached the gait milestone, and a limping on the right leg was noticed, with an attitude in extra rotation of the right lower limb. One month later, and 17 days after the vaccination against measles, parotitis, and rubella, the patient presented with a second neurological episode characterized by the acute onset of gaze paralysis, left eye esophoria, vertical nystagmus, and inability to walk due to severe gait ataxia. The patient again underwent a brain and spinal cord MRI, which showed new lesions in the supra- and infratentorial white matter, optic nerves, some of which with gadolinium enhancement, and longitudinally extensive transverse myelitis (LTEM) lesion at the C2-C4 level, suggestive of neuromyelitis optica spectrum disorder (NMOSD) (Figure 2). Visual evoked potentials (EPs) showed an increase in P100 latency in both eyes, while brainstem auditory and somatosensory EP demonstrated an increased central conduction velocity. CSF analysis again showed that the level was within normal range, and no oligoclonal bands nor anti-AQP4 or anti-MOG antibodies were detected. However, a CSF cytokine panel assay showed multiple increases in proinflammatory cytokines, such as IL-6, IL-1Ra, MCP-1, and IP-10/CXCL10 (Supplementary Table S1). Blood tests showed antinuclear antibody (ANA) positivity (>1:640 titer) and the presence of HLA-B51. The patient was re-treated with high-dose steroids and monthly high-dose IVIg, which resulted in good neurological recovery, despite the persistence of a fluctuating limp in the right leg with a limited range of motion.
An MRI performed at 29 months of age did not show any new brain or spinal cord lesion but highlighted the presence of active arthritis of the right temporomandibular joint (Supplementary Figure S1). A complete joint assessment performed at that time by pediatric rheumatologists revealed swelling, pain, and limitation in the motion of the right knee and ankle. The presence of active arthritis was confirmed by an ultrasound assessment.
The very early onset of neurological manifestations and the subsequent development of polyarthritis led us to consider the wide spectrum of inherited diseases characterized by neuroinflammation. Type I interferon signature was negative. Whole-exome sequencing was then performed, with a particular focus on the genes involved in neuroinflammatory pathways without any evidence of pathogenic variants.
Given the broad differential diagnosis performed, the presence of CNS parenchymal lesions located in the brain and spinal cord with a relapsing-remitting course, the good clinical recovery with immunomodulating treatment, and the evidence of polyarthritis associated with HLA-B51 positivity suggested a possible diagnosis of Bechet's disease with neurological involvement.
Intra-articular steroid injections were administered on the right knee and ankle, and therapy with colchicine (0.5 mg/daily) and methotrexate (7.5 mg/weekly) was started, with a stabilization of the neurological picture both clinically and radiologically. Due to the occurrence of tibiotarsal arthritis relapses, two more intraarticular steroid injections with the addition of biologic therapy with anti-IL6 (tocilizumab) were required for the girl at the age of 3 years and 3 months, which resulted in a very good clinical response and complete articular remission.
However, 3 years and 6 months from the disease onset, the patient developed bilateral uveitis despite ongoing treatment with tocilizumab and was, therefore, switched to adalimumab as part of anti-TNFalpha treatment, following which she showed a positive clinical and ophthalmological response. At the last follow-up, performed at the age of 5 years, 6 months after the start of adalimumab, the patient appeared fine with the disease and uveitis in remission.