Letter to the Editor in response to Dr. Josef Finsterer et al. “Intense work-up is required for pediatric COVID-related acute necrotizing encephalopathy with RANBP2 variants”

Dear Editor, We thank Dr. Josef Finsterer et al. for their interest in our study “Pediatric recurrent acute necrotizing encephalomyelitis, RANBP2 genotype and Sars-CoV-2 infection: diagnosis, pathogenesis and targeted treatments from a case study” [1]. They suggest the need of extensive work up for the diagnosis of acute necrotizing encephalopathy and ask for in depth details on clinical onset, differential diagnosis, treatment and follow-up. At admission we described the patient as already comatose with generalized hypotonia, she could not collaborate to tests of visual function (possibly impaired due to visual pathways involvement at MRI), tendon reflexes were reduced as it occurs in the hyperacute phase of brain damage when cortical disinhibition and hyperreflexia had probably not yet occurred. Quite later in the course of her hospitalization she developed critical illness myopathy, that resolved after few months. Regarding the diagnosis of ANE1 in our patient, we would like to point out that the manuscript already includes the requested information. Our previous study [1] report a figure showing the brain MRI with SWI sequences performed after few hours from the clinical onset, with evidence of bilateral thalamic micro hemorrhages. The CT scan performed few hours before MRI did not show signs of bleeding therefore we thought that was not worth to show it in the figure. Moreover, magnetic resonance spectroscopy (MRS) showed elevation of choline, an inverted peak of lactate indicative of hypoxia and a lipid peak, within the capsular-thalamic lesions, suggesting necrosis, as reported in the manuscript. The brain MRI performed at 2 years of life during the first episode are reported in the manuscript (Figure 3). Follow up images at 3 years of age (not shown) demonstrated partial recovery with residual gliosis located in the site of previous lesions. The same gliosis was seen as old residual lesions in the MRI done at the onset of recurrence at 10 years of age, distinguishable from the new lesions characterized by cytotoxic edema of recent onset. The diagnostic work up described in the manuscript included CSF and serum antibodies associated with autoimmune encephalitis (GAD, LG1, NMDAR, MOG and AQP4) that were all negative as well as the oligoclonal IgG bands, as reported in the manuscript. Concerning the terminology ANE and AHNE, they are two entities of the same spectrum of disorder, often with blurred boundaries not fully defined in the literature. The genetically determined recurrent form of this spectrum of disease is referred as ANE1 [2]. A recent manuscript published after we submitted our paper reported a single case of acute necrotizing encephalopathy associated to Covid-19 with RANBP2 pathogenic variants in whom micro hemorrhagic foci were also detected by SWI sequences on MRI. The authors called it AHNE but we argue the appropriateness of this term since there were only microhemorrhages and the patient was carrier of RANBP2 pathogenic variant confirming the diagnosis of ANE1 [3]. Finsterer et al. argue that the expansion of the cerebral lesion in the acute phase could be due to steroids. However, we are not aware of the possibility that steroids can acutely cause bilateral symmetrical cytotoxic edema and microhemorrhagic foci. Moreover, they ask for more data about CSF levels of cytokines, chemokines, glial factors, 14-3-3. These tests are not routinely performed in the clinical practice, however we tested IL-6 and Il-17 both in serum and CSF because of the possible therapeutic implications (both of them resulted normal). Considering treatment, steroids, cycles of plasmapheresis and then immunoglobulins were administered within the first few days, unfortunately hampering the possibility of disentangling the therapeutic role of the different treatments. This therapeutic decision was determined by the severity of the clinical presentation and the rapid deterioration within hours/days. The manuscript was written soon after the acute phase and the postacute follow up was not available yet, anyway at the time of this letter the patient has partially recovered consciousness, she is bedridden with axial hypotonia and arms and legs asymmetric hypertonia with exaggerated tendon reflexes, Babinski sign and the Rankin Scale is 5.