key: cord-0854971-wc8ludpz authors: Verrotti, Alberto; Mazzocchetti, Chiara; Iannetti, Paola title: Definitive pathognomonic signs and symptoms of paediatric neurological COVID‐19 are still emerging date: 2021-03-21 journal: Acta Paediatr DOI: 10.1111/apa.15827 sha: ed5d5f90e687b10f9297b0639fd94456ad9678cc doc_id: 854971 cord_uid: wc8ludpz Children with COVID‐19 tend to show milder symptoms than adults during the pandemic, but growing evidence of neurological involvement has emerged. Some studies have reported neurological symptoms in children with COVID‐19, which include multisystem inflammatory syndrome, a disease that shares some, but not all, of the characteristics of Kawasaki disease. This review presents, and discusses, the evidence to date. Our initial findings suggest that neurological manifestations can be considered to be the direct result of central nervous system viral invasion or post‐infection immuno‐mediated disease. Syndrome', 'MIS-C', neurological involvement. We included original studies, reviews, viewpoints, commentaries, case series and case reports which were relevant to our objectives. Most of the infections came out as asymptomatic. One study found that the majority of the asymptomatic patients had a mild infection, very few of them required intensive care and their prognosis was good. 9 Another study was conducted on 100 children under 18 years of age, who showed up at an emergency department with COVID-19. Most of them had mild diseases, while severe and critical cases were found in patients with co-existing conditions, and no deaths were reported. 10 A review of 72,314 Chinese patients showed that less than 1% were children under 10 years of age. Most of the children had a mild clinical course and were asymptomatic. Determining the transmission potential of these asymptomatic patients is important when developing measures to control the ongoing pandemic. 11 The neurological effects of COVID-19 in children have only been discussed in random reports, with little information on possible relationships between COVID-19 and impairment of the central nervous system. Reports of neurological manifestations have increased as the pandemic has grown and these can be considered as a direct effect of the virus on the nervous system or para-infectious or postinfectious immune-mediated disease. In contrast with adults, children and adolescents with COVID-19 appear to have a milder clinical course. They are often asymptomatic, but anosmia and ageusia have been reported. 12 Ouhala et al 13 conducted a retrospective, single-centre, observational study in a paediatric intensive and high dependency care unit. They analysed data from 27 confirmed or highly suspected virus cases aged from 1 month to 18 years. The median age at the disease onset was six and 19 of the patients (70%) had comorbidities, including seven of them with neurological comorbidities. The authors reported that five children died, including three with no previous medical problems. They included a previously healthy 16-year-old boy, who was positive to the virus, with no past medical history or respiratory symptoms. He showed up with aseptic meningitis associated with stupor. Magnetic resonance imaging of his brain showed a sphenoidal sinusitis with cavernous sinus thrombosis. In the following days, right hemiparesis related to a left middle cerebral artery stroke appeared, along with loss of consciousness. The patient died from intracranial hypertension and brain ischaemia 17 days after admission. The authors also reported a 6-year-old girl with no past medical history, who presented COVID-19, fever, respiratory distress, stupor and hypotensive shock. The patient developed septic shock due to Staphylococcus aureus involvement, followed by acute neurological deterioration related to a massive brain haemorrhage. She died 15 days after admission. Neurological symptoms, especially meningeal signs, have also been reported in children with COVID-19 and Kawasaki-like disease. 14 Verdoni There are many reasons why the virus can invade the brain. First, axonal transport is a common route of infection and this happens when the virus enters the eyes, nose, mouth and infects nearby olfactory or trigeminal nerves. 21 Secondly, the virus enters the cells via the angiotensin converting enzyme receptors, expressed in the lungs and the brain. 22 Thirdly, the latest virus damages the brainstem and could lead to respiratory failure. 23 Fourthly, common symptoms, like loss of smell and taste, could be caused by damage to brain's olfactory system. 24 Laboratory studies have demonstrated the possible mechanisms for neurological manifestations of COVID-19. These show that the main host-cell receptor of the virus is the angiotensin converting enzyme 2, which is expressed in both neurons and glial cells, causing direct viral invasion of the central nervous system. 25 The potential role of microvascular pathology in the neurological involvement of the virus has been reported. Once the airway epithelia and lung cells have been invaded, the viral infection can spread via olfactory, trigeminal and vagus nerves, via meningeal vasculature, via the blood brain barrier and via the lymphatic system. 26 In conclusion, the fact that specific antibodies suggesting acute infection or viral isolation have been found in cerebral spinal fluid could indicate that we are dealing with a neurotropic virus that may lead to multiple neurological involvement. 4 Both Kawasaki disease and MIS-C have been associated with a common trigger that provokes a significant cytokine storm that results in systemic inflammation and multi-organ dysfunction, including neurological symptoms. The number of paediatric viral infections leading to neurological disease will probably remain small, but as COVID-19 spreads, reports of children developing systemic inflammatory responses that require intensive care may increase. Even children with mild acute infections may face a high risk of secondary inflammation. The combination of central and peripheral nervous system profiles are rare in paediatrics, but can be seen in MIS-C. Neurological manifestations can be considered to be the direct result of central nervous system viral invasion, parainfection or post-infection immuno-mediated disease. The different severity level of neuroinvasion, neurotropism and neurovirulence in neuro COVID-19 patients may result from an interaction between viral and host factors. 27, 28 Close fetal observation is also required to monitor even minor abnormalities in psychomotor development. Paediatric neurological COVID-19 still needs to be clarified as the knowledge of definitive pathognomonic signs and symptoms is still emerging. 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