Original Article Neurologic Features Associated With SARS-CoV-2 Infection in Children: A Case Series Report Journal of Child Neurology 1-14 ª The Author(s) 2021 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0883073821989164 journals.sagepub.com/home/jcn Francisca Sandoval, MD1 , Katherine Julio, MD1, Gastón Méndez, MD1 , Carolina Valderas, MD1, Alejandra C. Echeverrı́a, MD1, Marı́a José Perinetti, MD1, N. Mario Suarez, MD1, Gonzalo Barraza, MD2,3, Cecilia Piñera, MD4,5, Macarena Alarcón, MD1,2, Fernando Samaniego, MD1, Pı́a Quesada-Rios, MD1, Carlos Robles, MD6, and Giannina Izquierdo, MD4,5 Abstract Introduction: Although multiple neurologic manifestations associated with SARS-CoV-2 infection have been described in adults, there is little information about those presented in children. Here, we described neurologic manifestations associated with COVID-19 in the pediatric population. Methods: Retrospective case series report. We included patients younger than 18 years, admitted with confirmed SARS-CoV-2 infection and neurologic manifestations at our hospital in Santiago, Chile. Demographics, clinical presentations, laboratory results, radiologic and neurophysiological studies, treatment, and outcome features were described. Cases were described based on whether they presented with predominantly central or peripheral neurologic involvement. Results: Thirteen of 90 (14.4%) patients admitted with confirmed infection presented with new-onset neurologic symptoms and 4 patients showed epilepsy exacerbation. Neurologic manifestations ranged from mild (headache, muscle weakness, anosmia, ageusia), to severe (status epilepticus, Guillain-Barré syndrome, encephalopathy, demyelinating events). Conclusions: We found a wide range of neurologic manifestations in children with confirmed SARS-CoV-2 infection. In general, neurologic symptoms were resolved as the systemic presentation subsided. It is essential to recognize and report the main neurologic manifestations related to this new infectious disease in the pediatric population. More evidence is needed to establish the specific causality of nervous system involvement. Keywords neurologic, children, MIS-C, SARS-CoV-2, COVID-19, Guillain-Barré syndrome, multiple sclerosis, encephalopathy Received September 24, 2020. Received revised November 10, 2020. Accepted for publication December 27, 2020. In December 2019, a pneumonia outbreak caused by the novel severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) emerged in China. Later, the disease caused by this virus was called coronavirus disease 2019 (COVID-19).1,2 It rapidly spread worldwide and, by the beginning of March 2020 the first confirmed case was identified in Chile. By mid-July 2020, 356 695 cases were reported in this country, of which 27 390 (8.1%) were pediatric patients and 1096 (4%) of them required hospitalization.3 COVID-19 can manifest with various symptoms, the most frequent life-threatening condition being severe respiratory distress, usually seen in adults. This infection is less frequent and shows milder symptoms in the pediatric population. 4 Nonetheless, some patients can develop multisystem inflammatory syndrome in children (MIS-C), a potentially fatal condition that often requires intensive care.5-7 1 Department of Neurology, Hospital Dr. Exequiel González Cortés, Santiago, Región Metropolitana, Chile 2 Faculty of Medicine, Universidad de Santiago de Chile, Santiago, Chile 3 Electromyography and Evoked Potentials Unit, Hospital Dr. Exequiel González Cortés, Región Metropolitana, Chile 4 Infectious Diseases Unit, Hospital Dr. Exequiel González Cortés, Región Metropolitana, Chile 5 Faculty of Medicine, Universidad de Chile, Santiago, Chile 6 Department of Radiology, Hospital Dr. Exequiel González Cortés, Región Metropolitana, Chile Corresponding Author: Francisca Sandoval, Department of Neurology, Hospital Dr. Exequiel González Cortés, Gran Avenida José Miguel Carrera 3300, Santiago, Región Metropolitana 8900085, Región Metropolitana, Chile. Email: [email protected] 2 Journal of Child Neurology XX(X) Figure 1. Patient selection flow chart. CNS, central nervous system; HEGC, Hospital Dr. Exequiel González Cortés; PNS, peripheral nervous system. Multiple neurologic manifestations associated with SARS-CoV-2 have been described in adults. The most common are nonspecific symptoms such as headache, dizziness, and myalgia.8,9 Hyposmia and hypogeusia have also been described as key COVID-19 symptoms.8-10 However, more severe neurologic manifestations, such as Guillain-Barré syndrome, encephalopathy, encephalitis, acute disseminated encephalomyelitis, and stroke have also been reported.8,9,11-14 To date, there is a limited number of publications on neurologic manifestations associated with COVID-19 in children. In this case series, we report 17 pediatric patients who presented with neurologic symptoms related to the infection. Among them, we highlight 3 clinical vignettes including a Guillain-Barré syndrome case, encephalopathic symptoms in a critically ill patient, and a clinical isolated syndrome. The importance of this publication lies in its contribution to our current knowledge about this new disease, expanding the spectrum of possible symptoms. We reinforce previous reports showing that manifestations of COVID-19 are not restricted to the respiratory system, and that children can also develop various severe presentations. To our knowledge, this is the largest cohort of pediatric patients with neurologic manifestations published. Methods We included patients younger than 18 years of age with confirmed SARS-CoV-2 infection and neurologic manifestations admitted at the tertiary referral pediatric hospital Dr. Exequiel González Cortés (HEGC) between April 1 and July 14, 2020. Infection was confirmed either by real-time polymerase chain reaction (qPCR) assay from a nasopharyngeal swab or by positive serology. As per hospital protocol, all hospitalized patients had qPCR assay performed at admission regardless of their diagnosis. Serology testing was performed in all MIS-C cases and in patients with negative qPCR, but with highly suggestive clinical settings and history of close contact with a COVID-19 confirmed case. If possible, a qPCR test on cerebrospinal fluid was also performed. We excluded patients without clear neurologic symptoms, as well as cases with etiology probably unrelated to COVID-19. We also omitted patients who could be misleading on the real impact that the infection had on the manifestation of their symptoms, mainly those with severe neurologic baseline conditions (Figure 1). Data were retrieved from an electronic clinical deidentified database and all electronic medical records that matched the search terms COVID-19 and SARS-CoV-2 were reviewed. Records that reported neurologic manifestations were selected. Child neurologists in close consultation with pediatric infectologists analyzed demographics, epidemiologic variables, comorbidities, systemic and neurologic manifestations, laboratory results, neuroimaging and neurophysiological studies, treatments, and outcomes. Cases were separated and described based on whether they presented with predominantly central or peripheral neurologic involvement. Frequency, percentages, and central tendency measures were calculated when possible. Internationally validated diagnostic criteria were used for Guillain-Barré syndrome,15 multiple sclerosis,16 status epilepticus,17 Sandoval et al 3 Figure 2. Key clinical features in 13 patients with new-onset neurologic manifestations associated with SARS-CoV-2 infection. (As in Tables 1 and 2). *Other than anosmia and hypo/ageusia. COVID-19,18 MIS-C,5 and Kawasaki-like syndrome.19 COVID-19 severity was determined based on the World Health Organization (WHO) classification.18 When needed, muscle strength was quantified using the Medical Research Council (MRC) scale.20 This study is included in a larger multicentric Chilean COVID-19 study, approved by the director of our establishment and complying with the protocols and regulations required by the hospital’s Teaching, Research, and Innovation Unit and the Ethics Committee for Clinical Investigation in Humans, from the Faculty of Medicine, Universidad de Chile. Written consent was obtained from all patients’ guardians. Results Ninety children with confirmed SARS-CoV-2 infection were admitted within the stipulated time frame. Twenty-one presented with neurologic manifestations associated with the infection. Four of them were excluded: a child with many sequelae due to prematurity and limitation of therapeutic effort, an adolescent under radiotherapy treatment for an advanced diffuse glioma, a toddler who suffered acute hypoxicischemic encephalopathy after an accidental loss of ventilatory support, and a newborn who presented with nonepileptic paroxysmal events who had normal EEG results and non-neurologic etiology was suspected (Figure 1). New-Onset Neurologic Manifestations New-onset neurologic manifestations were found in 14.4% (13/ 90) of the patients (Figures 2 and 3). Of these, 61.5% (8/13) were female (15 months to 17 years old), with a median age of 6.5 years. Comorbidities or medical history were found in 6 patients, 3 of them neurologic. Five patients presented with predominant central nervous system involvement (Table 1), whereas 8 presented with predominant peripheral nervous system (PNS) involvement (Table 2). More than half of the patients (7/13) presented with central and peripheral nervous system symptoms. New neurologic symptoms were present on admission on 7.8% (7/90) of hospitalized patients. Neurologic symptoms appeared at different times in relation to the infection: it was concomitant in 30.8% (4/13) of the cases, whereas in 69.2% (9/13) of cases, the onset was a few weeks after the infection was no longer active. Interestingly, 23% (3/13) of patients had neurologic symptoms as the only manifestation of the disease. Of the patients who presented with MIS-C (17/90), 8 had new-onset neurologic manifestations, with 3 types of MIS-C phenotypes: 12.5% Kawasaki-like syndrome, 25% distributive shock, and 62.5% had both. All of these patients presented with fever, 75% with exanthema, 75% with gastrointestinal symptoms (abdominal pain, vomiting, or diarrhea) and 62.5% with conjunctivitis. Echocardiographic tests were performed in all MIS-C patients, 75% showed significant signs of coronary compromise or myocardial failure. Laboratory results showed that inflammatory markers were elevated (shown as average with minimum and maximum values): white blood cell count: 17.46 K/uL (13.39-30.30); C-reactive protein: 334 mg/L (126-457); brain natriuretic peptide: 5672 pg/mL (1210-17 500) and D-dimer: 7721 ug/mL (2375-19989). 4 Journal of Child Neurology XX(X) Figure 3. New-onset neurologic signs and symptoms. *Other than anosmia and hypo/ageusia. Central Nervous System Involvement Two critically ill patients presented with signs of encephalopathy described as mixed delirium, fluctuating psychomotor agitation, sleep-wake cycle disturbances, and visual hallucinations. In both patients, cerebrospinal fluid analysis was normal and neurologic symptoms reverted as the clinical condition improved. Seizures occurred in 3 toddlers; all had normal cerebrospinal fluid findings and 2 of them presented with status epilepticus. The third patient presented with fever, MIS-C, seizures, and encephalopathy with abnormal electroencephalogram (EEG) (case 3, clinical vignette A). Antiseizure treatment was initiated in all 3 cases and maintained for at least 2 months. At the time of this publication, none of the patients presented with new seizures. A single patient (case no. 5) presented with headache, blurry vision and pyramidal tract signs that resulted in the discovery of a multifocal demyelinating event (clinical vignette B). Seven cerebrospinal fluid analyses were performed. Only 1 case (no. 5) had abnormal findings with pleocytosis, elevated proteins, and positive oligoclonal bands. Cerebrospinal fluid SARS-CoV-2 qPCR was performed in 4 cases, all of them yield negative results. Neuroimaging was performed in 5 patients: 3 had normal brain computed tomography (CT) scans. The CT scan from case 2 showed a frontal hypodensity that was later confirmed to be an unenhanced subcortical lesion by magnetic resonance imaging (MRI) (Figure 4). Case 5 had a brain and total-spine MRI that showed multifocal demyelinating lesions (Figure 5). 381.5 U/L). Electromyography/nerve conduction studies were performed in a single patient from this group (case 7), with normal findings. These tests were waived in all remaining cases due to rapid and complete clinical recovery. At the time of discharge, all MIS-C patients had normal muscle strength and preserved reflexes. Case 6 presented with a progressive ascendant acute flaccid tetraparesis, areflexia, and multiple cranial nerve palsies, with an electromyography and nerve conduction study compatible with acute motor axonal neuropathy (AMAN) Guillain-Barré syndrome variant (clinical vignette C). Hypo/ageusia and anosmia were present in 2/13 patients. Other cranial nerves impairments (2/13) as well as autonomic symptoms, such as orthostatic intolerance and hypotension (2/13), were also found. Clinical Stay, Treatments, and Outcomes On average, patients with new-onset neurologic symptoms were hospitalized for 13 days (range 4-23), 69.2% (9/13) required 9 days (range 2-11) in the ICU and 53.8% (7/13) needed ventilatory support for 3.2 days (range 0.5-5). Seven patients received immunomodulatory therapy (intravenous immunoglobulin and corticosteroids) as part of MIS-C treatment. In every case, corticosteroid treatment was maintained for less than a week (range 3-6 days). Other therapies included antiseizure medications (3/13), antibiotics (7/13), and antithrombotics (8/13). At discharge, 77.7% (10/13) of patients showed substantial or complete recovery from neurologic symptoms, 1 had moderate motor strength improvement, and 2 showed persistent dysgeusia. Peripheral Nervous System Involvement. Eight of 13 children (61.5%) presented with muscle weakness. Seven of them had MIS-C. On average, paresis was established 6 days after admission (range 5-10 days), with a median MRC total score of 37.6/60. Three of the patients had hyporeflexia and 3 had elevated creatine kinase (CK) serum levels (average Patients With Epilepsy and COVID-19 Out of the total number of patients admitted with COVID-19, 4.4% (4/90) had a previous epilepsy diagnosis, which was exacerbated by the infection (Table 3). 5 No comorbidity 14 y, M Atopic dermatitis 5 y, M N/p EEG: severely abnormal with slow continuous background activity. EEG: normal EEG: normal Neurophysiology N/p Prot: 80 mg/dL, Glu: 61 mg/dL, leucocytes 3 50/mm (10% PMN- 90% MN), erythrocytes 0/mm3 ADA 12 U/L, OCBs (þ) Prot: 19.1 mg/dL, Glu: 68.1 mg/dL, leucocytes 0/mm3, erythrocytes 100/mm3 Prot: 13 mg/dL, Glu: 58 mg/dL, leucocytes 1/mm3 (100% MN), erythrocytes 4/mm3 Prot: 15.8 mg/dL, Glu: 84.7 mg/dL, Leucocytes 2/mm3 (100% MN), erythrocytes 0 Prot: 14.6 mg/dL Glu: 51.3 mg/dL, leucocytes 0/mm3, erythrocytes 0/mm3 CSF Neurologic tests Brain and spine MRI: multifocal demyelinating lesions with signs of activity Brain CT: normal Contrast-enhanced brain MRI: unenhanced right frontal nodular white matter hypointensity. N/p Brain CT: normal Neuroimaging CK-T 70 U/L, anti-AQP4 (–), anti-MOG (–), Vit D 23 ng/mL Normal autoimmune and rheumatology comprehensive study.b Normal Routine laba CK-T: 469 U/L CK-MB: 33 U/L. CK-T: 377 U/L CK-MB: 34.7 U/L Normal routine lab a Normal routine laba Other relevant lab results Others CSF culture (–), BC (–), UC (–) PCR swab (þ) Discharged after 4 d; LEV was initiated, no new seizures. Multifocal demyelinating event. Concomitant MIS-C Multifactorial encephalopathy, acute flaccid tetraparesis One-month follow-up: complete strength recovery, persistent hyperreflexia in the left lower limb, right eye papilledema, and increased blind spot. Oral prednisone is maintained. Under clinical and radiologic follow-up. Discharged after 13 d; complete strength recovery, fully ambulant, encephalopathy resolved. Discharged after 4 d; LEV was initiated, Active asymptomatic no new seizures. SARS-CoV-2 Under clinical and infection radiologic follow-up. Multifactorial Discharged after encephalopathy, 18 d; Symptomatic encephalopathy seizures resolved, PB was initiated. Concomitant MIS-C Concomitant mild COVID-19 Status epilepticus Febrile status epilepticus Final neurologic/ infectologic diagnosis Outcome EB serology: IgM (–) Concomitant mild IgG (þ), HIV (NR), COVID-19 VDRL (NR) CSF culture (–), VDRL (NR), Encephalitis viral panelc (–) PCR CSF culture (–), swab (þ), BC (–), UC (–) IgG (þ) PCR swab (þ), CSF (–) IgM (–), IgG (þ) CSF: PCR: HSV-1 (–), HSV-2 (–), Enterovirus (–), Culture (–), BC (–), UC (–) PCR CSF: PCR: HSV-1 swab (þ), (–), HSV-2 (–), CSF (–) enterovirus (–), culture (–), PCR swab (þ) SARS-CoV-2 Microbiology Abbreviations: ADA, adenosine deaminase; anti-AQP4, anti-aquaporin 4 antibodies; BC, blood culture; CK-MB, creatine kinase MB isoenzyme; CK-T, total creatine kinase; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; F, female; Glu, glucose; HIV, human immunodeficiency virus; HSV, herpes simplex virus; LEV, levetiracetam; M, male; MIS-C, multisystem inflammatory syndrome in children; MN, mononuclears; MOG, myelin oligodendrocyte glycoprotein; MRC-T, Medical Research Council–Total; MRI, magnetic resonance imaging; N/p, not performed; NR, nonreactive; OCBs, oligoclonal bands; PB, phenobarbital; PCR, polymerase chain reaction; PMN, polymorphonuclears; Prot, proteins; UC, urine culture; VDRL, Venereal Disease Research Laboratory. a Including hemogram, glycemia, creatinine, liver panel, venous blood gases, plasma electrolytes, lactic acid, ammonia b Including rheumatoid factor (–), ANA (–), ANCA (–), anti-DNA (–), C3-C4, thyroid profile c Encephalitis viral panel: Enterovirus, Herpes Simplex Virus 1 and 2, Human Parechovirus, Varicella zoster virus and Mumps virus. 5 4 No comorbidity 15 mo, F At admission: 11-min-long seizure At admission: 32-min-long febrile seizure Neurologic symptoms Shock, At admission: 3 febrile Kawasaki-like seizures On day 9: syndrome, mixed delirium fever (fluctuating psychomotor agitation and hyporesponsiveness) Shock, On day 4: psychomotor Kawasaki-like agitation, insomnia, syndrome, visual hallucinations, fever headache. On day 7: mainly proximal generalized weakness (MRC-T: 32/60), hyporeflexia, orthostatic intolerance None At admission: headache, blurry vision, papilledema VI right cranial nerve palsy, asymmetric mild paraparesis. Bilateral ankle clonus, left Babinski sign 2 3 None A previous single febrile seizure 2 y, F 1 No comorbidity Fever, cough 2 y, F Case No. Systemic symptoms Age, sex, comorbidity/ medical history Clinical progression Table 1. Patients With Predominantly Central Nervous System Involvement. 6 11 10 9 8 7 8 y, M 6 Obesity, insulin resistance 12 y, F No comorbidity 5 y, F No comorbidity 16 mo, M Allergic rhinitis 10 y, F No comorbidity 3 y, M TBI with a previous skull fracture Age, sex. Comorbidity/ medical history Case No. Shock, fever, GI symptoms Kawasaki-like syndrome, fever Kawasaki-like syndrome, fever, hypertension Shock, fever, GI symptoms Shock, Kawasaki-like syndrome, fever. None Systemic symptoms N/p Prot:19 mg/dL, Glu: 70 mg/dL, leucocytes 1/mm3 (100% MN), erythrocytes 0/mm3 CSF At admission: headache, ageusia (started 14 days before admission) On day 7: generalized muscle weakness. (MRC-T: 46/60), hyporeflexia N/p N/p On day 10: predominantly N/p proximal generalized weakness (MRC-T: 44/60) normal reflexes, orthostatic intolerance, headache On day 5: generalized Prot: 15.8 mg/dL, muscle weakness (MRCGlu: T: 48/60) normal 84.7 mg/dL, reflexes leucocytes 2/mm3 (100% MN), erythrocytes 0/mm3 On day 7: generalized muscle weakness. (MRC-T: 16/60), hyporeflexia. At admission: ophthalmoparesis, facial diparesis, acute progressive ascending flaccid tetraparesis, areflexia, headache. Neurologic symptoms Clinical progression Neuroimaging N/p N/p N/p N/p EMG/NCS: normal N/p N/p N/p N/p N/p EMG/NCS: moderate Brain CT: acute motor normal axonal neuropathy (AMAN) with incipient signs of reinnervation Neurophysiology Neurologic tests Table 2. Patients With Predominantly Peripheral Nervous System Involvement. PCR swab (þ), serum antibodies: IgM (–), IgG (þ) PCR swab (–), Serum antibodies: IgM (indeterminate), IgG (þ). PCR swab (–), CSF (–) SARS-CoV-2 CK-T 52 U/L, CK-MB 45 U/L CK-T 88 U/L, CK-MB 23.4 U/L Serum antibodies: IgM (–), IgG (þ) PCR swab (–), Serum antibodies: IgM (–), IgG (þ) PCR swab (–), Serum antibodies: IgM (indeterminate), IgG (þ) CK-T 49 U/L CK-MB PCR swab (–), 37.3 U/L Serum antibodies: IgM (–), IgG (þ) CK-T 382 U/L, CK-MB 38.8 U/L CK-T 89 U/L, CK-MB 21.5 U/L CK-T 97 U/L, Normal autoimmune and rheumatology comprehensive study.a Normal routine labb Other lab results Others Previous asymptomatic SARS-CoV-2 infection Acute flaccid tetraparesis Guillain-Barré syndrome AMAN variant with multiple cranial nerve impairment Concomitant MIS-C Acute flaccid tetraparesis BC (–), UC (–) Acute flaccid Respiratory tetraparesis viruses IIFc: (–), Concomitant BC (–), UC (–) MIS-C Ageusia Respiratory c IIF virus (–) Concomitant BC (–), UC (–) MIS-C Respiratory viruses IIFc: (–), Rotavirus (–), Salmonella (–), Shigella (–), Concomitant MIS-C (continued) Discharged after 15 d; persistent dysgeusia Discharged after 23 d; complete strength recovery, walking independently Discharged after 10 d; complete strength recovery, fully ambulant Discharged after 12 d; complete strength recovery, fully ambulant Discharged after 18 d; complete strength recovery, fully ambulant Discharged after 18 d; moderate improvement in facial diparesis, ophthalmoparesis, and strength; walking with aids Final Neurologic/ Infectologic diagnosis Outcome Concomitant BC (–), UC (–) MIS-C BC (–), UC (–) Acute flaccid tetraparesis Respiratory viruses IIFc: (–) HIV (NR), HBV (NR) Microbiology 7 17 y, F Epilepsy, juvenile idiopathic arthritis 5 y, F 12 13 Shock, Kawasaki-like syndrome, fever Fever, GI symptoms N/p At admission: headache. On N/p day 3: generalized muscle weakness (MRCT: 16/60), normal reflexes At admission: headache, ageusia, anosmia. Neurologic symptoms Clinical progression Systemic symptoms CSF N/p N/p Neurophysiology Neurologic tests N/p N/p Neuroimaging CK-T 294 U/L, CK-MB 27.2 U/L Normal routine labb Other lab results Serum antibodies: IgM (–), IgG (þ) PCR swab (þ), Serum antibodies: IgM (þ), IgG (þ) PCR swab (þ), Others Concomitant mild COVID-19 Ageusia, anosmia Concomitant MIS-C Discharged after 10 d; complete strength recovery, fully ambulant Discharged after 8 d; persistent dysgeusia Final Neurologic/ Infectologic diagnosis Outcome BC (–), UC (–) Acute flaccid tetraparesis UC (–) Microbiology SARS-CoV-2 Abbreviations: AMAN, acute motor axonal neuropathy; BC, blood culture; CK-MB, creatine kinase MB isoenzyme; CK-T, total creatine kinase; CSF, cerebrospinal fluid; CT, computed tomography; EMG, electromyography; F, female; GI, gastrointestinal; Glu, glucose; IFI, indirect immunofluorescence; HIV, human immunodeficiency virus; M, male; MIS-C, multisystem inflammatory syndrome in children; MN, mononuclears; MRC-T, Medical Research Council–Total; NCS, nerve conduction study; N/p, not performed; NR, nonreactive; PCR, polymerase chain reaction; PMN, polymorphonuclears; Prot, proteins; TBI, traumatic brain injury; UC, urine culture; VDRL, Venereal Disease Research Laboratory. a Including rheumatoid factor (–), ANA (–), ANCA (–), anti-DNA (–), C3-C4, thyroid profile. b Including: hemogram, glycemia, creatinine, liver panel, venous blood gases, plasma electrolytes, lactic acid, ammonia. c Indirect immunofluorescence (IIF) of respiratory viruses: Influenza A, Influenza AH1, Influenza AH3, Influenza B, Respiratory Syncytial Virus (RSV) A, RSV B, Parainfluenza 1, Parainfluenza 2, Parainfluenza 3, Parainfluenza 4, Coronavirus 220E, Coronavirus NL63, Coronavirus OC43, Coronavirus HKU1, Metapneumovirus, Rhinovirus/Enterovirus, Adenovirus, Bocavirus, Chlamydophila pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae. No comorbidity Age, sex. Comorbidity/ medical history Case No. Table 2. (continued) 8 Journal of Child Neurology XX(X) Figure 4. Case 2 brain computed tomographic (CT) scan and gadolinium-enhanced (Gdþ) magnetic resonance imaging (MRI) study. (A and B) Brain CT scan. Subtle nodular hypodensity is present in the right frontal subcortical white matter (white arrows). (C, D, and E) Enhanced-MRI study. (C) T2-weighted fluid-attenuated inversion recovery. (D) T2-weighted fluid-attenuated inversion recovery coronal. (E) T1-weighted Gdþ. The right frontal subcortical lesion is better depicted (C and D). No enhancement is seen (E, white arrow). Discussion America is one of the most critical epicenters of the current COVID-19 pandemic. Chile had the sixth highest number of infections up to the time these data were collected in mid-July 2020,21 with a cumulative national incidence rate of 1833 per 100 000 inhabitants.3 It also had one of the highest testing rates in Latin America (73.8 tests per 100 000 inhabitants).22 HEGC is one of the major referral tertiary pediatric hospitals in Santiago (Chile’s most populated city) and was designated by the Ministry of Health to be one of the 3 hospitals to admit pediatric COVID-19 patients during the ongoing pandemic. In this study, we reported multiple central and peripheral nervous system symptoms of varying severity, associated with concurrent or previous SARS-CoV-2 infection. These conditions are consistent with other previously reported series.8,9,11,13 Paterson et al published a series of 43 adult patients with confirmed or suspected infection and neurologic manifestations, establishing 5 main groups: encephalopathic symptoms (10/43), inflammatory central nervous system syndromes (12/43), ischemic strokes (8/43), peripheral neurologic disorders (8/43), and other miscellaneous disorders (5/43).11 Similarly, Abdel-Mannan et al reported a series of 4 children with MIS-C and new-onset neurologic manifestations. They found encephalopathy, headache, brainstem and cerebellum signs, muscle weakness, and hyporeflexia. It is noteworthy that the brain MRI of these 4 patients showed transient signal alterations at the corpus callosum splenium that reversed in control images.13 These findings have been reported in patients with diverse illnesses, such as Kawasaki disease and influenza, being the probable underlying mechanism of a focal intramyelin edema secondary to inflammation.13,23 Diverse pathophysiological mechanisms behind neurologic manifestations associated with SARS-CoV-2 infection have been Sandoval et al 9 Figure 5. Case 5 gadolinium-enhanced (Gdþ) brain and spine magnetic resonance imaging (MRI). (A) T2-weighted fluid-attenuated inversion recovery. (B) T1-weighted Gdþ. Multiple demyelinated plaques with perivenular distribution are present (A, white arrow). Subtle nodular enhancement is evident with gadolinium (B, white arrow). (C) T2-weighted fluid-attenuated inversion recovery. (D) T1-weighted Gdþ. Demyelinated plaques are present in the left temporal lobe and in the left cerebral peduncle with intense enhancement (D, white arrows). (E) T2-weighted fluid-attenuated inversion recovery. (F) T1-weighted Gdþ. Demyelinated plaques in both cerebellar peduncles, with contrast enhancement (white arrows). (G) T2-weighted STIR. (H) T2-weighted SE. (I) T1-weighted Gdþ. Small demyelinated plaque can be seen in the anterior medulla (G and H, yellow arrows) with lineal enhancement (I, yellow arrow). SE, spin echo; STIR, short-tau inversion recovery. proposed, and yet they remain unproven. The foremost reported neurologic features are secondary to systemic alterations usually found in COVID-19 hospitalized patients, such as severe inflammation, metabolic or electrolyte disturbances, and multiorgan failure.8,11,12 Other manifestations are immune-mediated conditions that affect the nervous system, of which the best described so far are Guillain-Barré syndrome9,24-29 and acute disseminated encephalomyelitis.30-32 Based on the proven neurotropism of other coronavirus strains (SARS-CoV, MERS-CoV),33,34 and the fact that different central nervous system cell types express angiotensin-converting enzyme 2 (ACE2), which functions as SARS-CoV-2 receptor,35,36 it is probable that SARS-CoV-2 could also invade the nervous system.33,34,37 However, it still needs to be determined why most of the published cases with central nervous system involvement had negative cerebrospinal fluid qPCR results, as was the case in all our tested patients. Nonetheless, there are a few encephalitis cases with confirmed SARS-CoV-2 in cerebrospinal fluid samples38,39 or brain tissue.40 Some authors have proposed that the virus might be transmitted in a cell-to-cell fashion, that viral RNA titers could be below the detection level of currently available testing methods, or that RNA titers could depend on illness severity or time of cerebrospinal fluid sample collection.40,41 In other case series reports, encephalopathy was relatively frequent in severe patients.8,13 In our study, 2 patients presented with encephalopathy and MIS-C. Both had shock progression, respiratory failure, and previous short-term use of central nervous system depressant drugs. Cerebrospinal fluid analyses yielded normal results, including negative cerebrospinal fluid SARS-CoV-2 qPCR. Multifactorial encephalopathy was suspected in both patients. Seizures have rarely been reported in adult case series.8,9 In a Chinese study of 304 COVID-19 admitted patients, no new-onset seizures occurred, despite their critical condition, confirmed brain insults, or metabolic imbalances.42 In our study, only 1 patient had seizures as part of her critical condition symptomatology. Others had a predisposition to seizure since they have had a prior epilepsy diagnosis or febrile seizure history. SARS-CoV-2 infection probably acted as a seizure trigger, as can occur in predisposed patients during any infection.43,44 Similarly, 1 case presented with a nonfebrile status epilepticus without other symptoms. Neuroimaging revealed an unenhanced right frontal subcortical lesion, 10 Journal of Child Neurology XX(X) Table 3. Patients With Epilepsy and COVID-19. Neurologic background Case No. Age, Sex Diagnostics Seizure-free period 14 14 y, M Juvenile myoclonic epilepsy 4 mo 15 11 y, F Severe PH, secondary epilepsy. 2 mo 16 3 mo 13 y, F Awakening myoclonic seizures 12 mo 9 y, F Genetic generalized epilepsy, chronic ataxia, microcephaly, mild ID 17 Antiseizure drugs Clinical setting COVID-19 Seizure features Treatment and Outcome VPA 200 mg/12 h was added GTC seizure to treatment Discharged (10 min) after 5 d, no new seizures Subsided spontaneously VPA 350 mg/12 h LEV VPA 350 mg/12 h Mild COVID-19 GTC seizure 350 mg/12 h was added to (1 min) Subsided treatment Discharged spontaneously after 5 d, no new seizures LEV 1500 mg /12 h was No. Mild COVID-19 GTC seizure (4 initiated Discharged after min) Subsided 4 d, no new seizures spontaneously VPA dosage was raised to VPA 200 mg/12 h Mild COVID-19 Tonic seizure (10 200 mg/8 h. LEV LEV 500 mg/12 h min) PHT is 500 mg/12 h Discharged administered after 3 d, no new seizures LTG 5 mg/d Asymptomatic SARS-CoV-2 infection Abbreviations: F, female; GTC, generalized tonic-clonic seizure; ID, intellectual disability; LEV, levetiracetam; LTG, lamotrigine; M, male; PH, pulmonary hypertension; VPA, valproic acid. suggesting either a demyelinating event or low-grade neoplasia (Figure 4). Central nervous system tumors, especially in cortical regions, can cause seizures. Alternatively, a demyelinating lesion could have resulted from the infection. Demyelinating disorders may be related to infectious processes. Multiple sclerosis has been associated with Epstein-Barr virus and cytomegalovirus infections.45 The presence of other coronaviruses has been detected in the brain of patients with multiple sclerosis. Furthermore, upper respiratory tract infections can trigger multiple sclerosis attacks.46 Our patient (case5), had a first demyelinating event with multiple lesions associated with positive cerebrospinal fluid oligoclonal bands, meeting McDonald’s dissemination criteria in time and space.16 These results plus the complete workup study performed allowed for a multiple sclerosis diagnosis to be made. However, because of the COVID-19 diagnosis, multiple sclerosis could not be confirmed. In addition, a SARS-CoV-2 central nervous system infection could not be ruled out because a cerebrospinal fluid qPCR assay method was not available in Chile at the time. Consequently, the patient was kept under close clinical and radiologic follow-up. Another classic demyelinating immune-mediated neurologic disease is acute disseminated encephalomyelitis. In most acute disseminated encephalomyelitis cases, there is a previous viral infection and the pathophysiology is related to molecular mimicry.47 The association between infections by other coronaviruses and acute disseminated encephalomyelitis has been proven.48 Although this condition mainly affects the pediatric population, notably, it has been reported only on adult patients.30-32 No acute disseminated encephalomyelitis cases were found in this study. It is possible to suggest that the exaggerated inflammatory state present in patients with severe COVID-19, more frequently seen in adults, would favor the development of an acute disseminated encephalomyelitis event. Furthermore, the lower prevalence of COVID-19 in children could hinder the diagnosis of acute disseminated encephalomyelitis. Guillain-Barré syndrome is one of the most reported neurologic syndromes associated with COVID-19. Two Italian series reported 10 adult cases.24,25 Miller-Fisher and polyneuritis cranialis variant patients have also been identified.49,50 Only 3 pediatric reports have been made at the time this paper was written.26,27,29 Paybast et al51 described a case of a 14-year-old girl and her father, both diagnosed with Guillain-Barré syndrome in relation to a family outbreak. The patient with Guillain-Barré syndrome of our series is one of the first reported pediatric Guillain-Barré syndrome after an asymptomatic SARS-CoV-2 infection and the first AMAN variant in this population, although it has been reported in adults. In this study, patients who developed MIS-C presented mainly with nonspecific neurologic manifestations, such as generalized muscle weakness 29% (5/17), and less frequently, encephalopathy 11% (2/17). These symptoms began in the context of multisystemic dysfunction and other associated factors (mechanical ventilation, polypharmacy, a hyperinflammation state among others), with rapid improvement once the systemic disease subsided. Other series on patients with MIS-C only reported some signs of encephalopathy. Whittaker et al described confusion in 5 of 58 (9%) cases.52 Verdoni et al reported drowsiness in 1 of 10 (10%), and they also found meningeal signs in 4 of 10 cases (40%).53 It is not clear if muscular weakness was not described in either report because it was Sandoval et al absent or because it was not assessed. Extensive series of hospitalized adult patients reported a prevalence of 44% to 70% myalgia or fatigue, with no more in-depth characterization, except for CK elevation in up to 33% of patients.1,8,12 These data suggest that this novel coronavirus could also cause muscle destruction, viral myositis, or rhabdomyolysis.54 Anosmia and ageusia are the most common peripheral nervous system symptoms of SARS-COV-2. However, the exact pathologic mechanisms are not yet clear. Several hypotheses have been proposed: according to a study in animal models, coronaviruses can disseminate throughout the brain transneuronally using olfactory pathways. The invasion of the olfactory neuroepithelium occurs through ACE2 in sustentacular cells. Consequently, disruption of the olfactory neuroepithelium leads to anosmia.33,55 In our cohort, only 2 of all admitted patients presented with these symptoms. We speculate that this low incidence could be because the selection of cases was restricted only to hospitalized patients, most of them with severe onset of the disease that might have caused milder symptoms like anosmia and ageusia to be overlooked especially in younger patients that cannot verbalize these symptoms adequately. Finally, it is hard to establish a direct causality between SARS-CoV-2 infection and neurologic manifestations. One of the variables that guide us to this correlation is the temporality of the initial neurologic picture and infection onset. A direct infection of the nervous system could explain concurrent neurologic symptomatology and COVID-19, while immune-mediated processes would manifest several days later.56 Limitations This study is not a population-based analysis. Our selection of cases was restricted to hospitalized patients. Therefore, there is possible underreporting of neurologic manifestations of minor severity or of those that appear in patients who do not need hospitalization. Moreover, the current in-hospital prevention measures to reduce cross-contamination risk and the national quarantine caused difficulties in obtaining full workup studies for some patients, such as neurophysiological (EEG, electro- 11 myography, and nerve conduction study) and MRI studies, the latter being particularly difficult because the available MRI scanner is out of the hospital premises. Therefore, patients in need of the exam must be transported to another location, and as MRI in children is usually performed under anesthesia, the risk of contamination was even higher. Thus, if the clinical conditions allowed it, exams and procedures were waived or deferred until the cessation of the infective phase. Finally, our observations are limited by the study’s retrospective design. Consequently, further prospective studies are required to confirm our observations and to evaluate the patients’ neurocognitive and functional impact. Conclusions In this Chilean case report series, we presented 17 pediatric patients with neurologic symptoms associated with confirmed SARS-CoV-2 infection, a rate of almost 20% among pediatric patients with COVID-19 sever enough to be admitted. We described a wide range of new-onset neurologic manifestations. The most relevant were encephalopathy, seizures, and muscle weakness, as had been reported in previous published series mainly on adult COVID-19 patients. In contrast to adult case reports, our cohort showed fewer cases of hypogeusia and hyposmia and no acute disseminated encephalomyelitis or vascular events. We highlighted a few unique cases, such as Guillain-Barré syndrome and demyelinating disorders. And we also showed that neurologic symptoms in patients with MIS-C were common and often resolved as the systemic symptoms subsided. We are in a new world-wide medical scenario where we are faced with many unknowns, especially concerning children. Our study presents the main neurologic manifestations related to COVID-19 in pediatric patients and a detailed description of their clinical features. From our analyses, we can only infer the pathophysiological mechanisms for how SARS-CoV-2 causes these neurologic manifestations. Currently, there is no substantial evidence to establish causality patterns. Clinical Vignettes Clinical Vignette A: Case 3 Fifteen-month-old girl, with no previous clinical record, started with vomiting, malaise, and added fever 2 days later. She was brought to the emergency department after presenting with 2 generalized tonic-clonic febrile seizures lasting about 6 minutes each. At admission, basic infectious screening and cerebrospinal fluid analysis were normal. SARS-CoV-2 PCR was positive in nasopharyngeal swab and negative in cerebrospinal fluid; serology confirmed a previous SARS-CoV-2 infection. On the second day after admission, she persisted febrile, irritable, and developed a generalized rash, palmoplantar edema, conjunctival infection, and hemodynamic failure requiring vasoactive drugs (MIS-C and Kawasaki-like syndrome). She received intravenous immunoglobulin (IVIG), intravenous methylprednisolone, enoxaparin, and acetylsalicylic acid. While being in critical condition, she presented with a third febrile seizure, and phenobarbital (PB) was initiated. Then, she exhibited fluctuating consciousness for a few days. EEG was severely altered with continuous slow-wave background activity. Plasma PB levels were not obtained. After a favorable evolution, she was discharged after 18 days of supportive treatment, with maintenance PB and no neurologic symptoms. 12 Journal of Child Neurology XX(X) Clinical Vignette B: Case 5 A 14-year-old boy, without previous history, presented with 3 weeks of severe intermittent headache and progressive unilateral blurred right vision. An outpatient ophthalmologic evaluation confirmed ipsilateral papilledema. On examination by a child neurologist, he had fully preserved consciousness, right blurred vision, sixth cranial nerve palsy, asymmetric paraparesis MRC M4/M5 score, bilateral ankle clonus, left Babinski sign, a right upper limb tremor, and walking difficulty. Contrast-enhanced brain and total-spine MRI showed multifocal demyelinating lesions with signs of activity (Figure 5). He was hospitalized, with a positive SARS-CoV-2 PCR swab. Etiologic study highlights: cerebrospinal fluid analysis with elevated proteins (80 mg/dL) and leukocytes (50 /mm3, mononuclear predominance), positive oligoclonal bands, SARS-CoV-2 cerebrospinal fluid PCR assay could not be performed; serologic study for Epstein-Barr virus IgG(þ) and a vitamin D deficiency (23 ng/mL); the rest of the study with basic general laboratory, infectious study for HIV, syphilis and encephalitis viral panel, basic immunologic study, anti-AQP4, and anti-MOG antibodies were negative. Treatment with high-dose intravenous methylprednisolone was administered with significant clinical improvement, continuing at discharge with oral corticosteroids and vitamin D supplementation. At 1-month follow-up, no new symptoms or worsening of previous symptomatology had developed. Follow-up MRI is still pending. Clinical Vignette C: Case 6 A healthy 8-year-old boy, with no respiratory or gastrointestinal infections in the last 3 months, who had direct physical contact with a confirmed COVID-19 case 4 weeks before, presented with difficulty walking and frequent falls, headache, and pain in shoulders and thighs. After 2 days, he was admitted to the emergency department with a predominantly distal and symmetrical flaccid tetraparesis, generalized areflexia, and preserved sensitivity. Brain CT and early cerebrospinal fluid analysis were normal. On the fourth day, he added ophthalmoparesis (third and sixth cranial nerve bilateral palsies). Intravenous immunoglobulin 2 g/kg was administered for 2 days. Five days after admission, he had increased muscle weakness ascending from the lower limbs to the trunk and arms, adding facial diparesis, without respiratory involvement. An electromyogram / nerve conduction velocity study on the fourth day of symptoms was normal. On the 18th day, findings were compatible with AMAN with exclusive motor involvement of moderate degree and incipient reinnervation signs. SARS-CoV-2 PCR was negative in swab and cerebrospinal fluid, IgM(inconclusive), and IgG(þ). HIV and hepatitis B virus (HBV) infection were ruled out. After 18 days, he was discharged with a moderate improvement of muscle strength, facial diparesis, and ophthalmoparesis, still not achieving independent walk. Acknowledgments Ethical Approval We thank the following people for their contributions to this case series: Aldo Gaggero, Alicia N. Minniti, team members of the Neurology Department, Infectious Diseases Unit, and Electrophysiology and Procedures Units of our hospital. We also thank the referring teams from other regional hospitals. This study is included in a larger multicentric Chilean COVID-19 study, approved by the director of our establishment and the Ethics Committee for Clinical Investigation in Humans, from the Faculty of Medicine, Universidad de Chile. Project Number: 021-2020; Record Number: 005 CEISH. Author Contributions FSan was the guarantor; designed and conceptualized the study. FSan, KJ, GM, CV, MJP, FSam, and PQR drafted the manuscript. and, FSan, KJ, ACE, MJP, NMS, CP, FSam, PQR, and GI took part in acquisition of data; GM and CV played a significant role in the acquisition of data. FSan, KJ, GM, ACE, GB, CP, MA, CR, and GI revised the manuscript for intellectual content. KJ, GM, CV, MJP, NMS, CP, FSam, PQR, and GI performed the literature research. KJ and ACE performed the needed translation. NMS performed data analysis, and together with CR carried out the figure and graphic design. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The authors received no financial support for the research, authorship, and/or publication of this article. ORCID iDs Francisca Sandoval https://orcid.org/0000-0003-3919-9240 Gastón Méndez https://orcid.org/0000-0002-4421-4428 References 1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 2. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. https://www.who.int/ emergencies/diseases/novel-coronavirus-2019/technical-gui dance/naming-the-coronavirus-disease-(covid-2019)-and-thevirus-that-causes-it. Published 2020. Accessed July 18, 2020. 3. Departamento de Epidemiologı́a MINSAL. 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