Children with COVID-19 may present with new neurological symptoms involving the central and peripheral nervous systems, and splenial changes on imaging, according to a study published online July 1 in JAMA Neurology.
Omar Abdel-Mannan, M.D., from Great Ormond Street Hospital for Children in London, and colleagues reported neurological manifestations of children with COVID-19 in a case series involving patients younger than 18 years. Data were included for 27 patients with COVID-19 pediatric multisystem inflammatory syndrome.
The researchers found that four of the patients (14.8 percent) who were previously healthy had new-onset neurological symptoms, including encephalopathy, headaches, brainstem and cerebellar signs, muscle weakness, and reduced reflexes.
All four required intensive care unit admission for treatment. In all four patients, splenium signal changes were seen on magnetic resonance imaging of the brain.
Samples were acellular in the two patients whose cerebrospinal fluid was tested, with no evidence of infection on polymerase chain reaction or culture and negative oligoclonal band test results.
A mild excess of slow activity was found in all three patients who underwent electroencephalography. Mild myopathic and neuropathic changes were seen in all three patients who underwent nerve conduction studies and electromyography. In all patients, there was neurological improvement, with two patients making a complete recovery by the end of the study.
“Clinicians should be adding SARS-CoV-2 to their differential diagnosis for children presenting with new neurologic symptoms,” the authors write.
Two authors disclosed financial ties to the pharmaceutical industry.
Importance Neurological manifestations have been reported in adults with coronavirus disease 2019 (COVID-19), which is caused by the highly pathogenic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Objective To report the neurological manifestations of children with COVID-19.
Design, Setting, and Participants In this case-series study, patients younger than 18 years who presented with SARS-CoV-2 infection and neurological symptoms to Great Ormond Street Hospital for Children (London, UK) between March 1, 2020, and May 8, 2020, were included after infection was confirmed by either a quantitative reverse transcription–polymerase chain reaction assay by nasopharyngeal swab or a positive test result for IgG antibodies against SARS-CoV-2 in serum.
Main Outcomes and Measures Clinical and paraclinical features were retrieved from electronic patient records.
Results Of the 27 children with COVID-19 pediatric multisystem inflammatory syndrome, 4 patients (14.8%) who were previously healthy had new-onset neurological symptoms. Symptoms included encephalopathy, headaches, brainstem and cerebellar signs, muscle weakness, and reduced reflexes.
All 4 patients required intensive care unit admission for the treatment of COVID-19 pediatric multisystem inflammatory syndrome. Splenium signal changes were seen in all 4 patients on magnetic resonance imaging of the brain.
In the 2 patients whose cerebrospinal fluid was tested, samples were acellular, with no evidence of infection on polymerase chain reaction or culture (including negative SARS-CoV-2 polymerase chain reaction results) and negative oligoclonal band test results.
In all 3 patients who underwent electroencephalography, a mild excess of slow activity was found. Tests for N-methyl-d-aspartate receptor, myelin oligodendrocyte glycoprotein, and aquaporin-4 autoantibodies had negative results in all patients.
In all 3 patients who underwent nerve conduction studies and electromyography, mild myopathic and neuropathic changes were seen. Neurological improvement was seen in all patients, with 2 making a complete recovery by the end of the study.
Conclusions and Relevance In this case-series study, children with COVID-19 presented with new neurological symptoms involving both the central and peripheral nervous systems and splenial changes on imaging, in the absence of respiratory symptoms. Additional research is needed to assess the association of neurological symptoms with immune-mediated changes among children with COVID-19.
Fifty children presented with SARS-CoV-2 infection during the study time frame. Of these, 27 had features consistent with COVID-19 pediatric multisystem inflammatory syndrome. A total of 4 patients (14.8%) with multisystem inflammatory syndrome had neurological involvement.
The median age at onset of symptoms was 12 (range, 8-15) years. A summary of the clinical and paraclinical features is provided in Table 1, Table 2, and the Figure. Neurological symptoms included encephalopathy (n = 4), headache (n = 3), brainstem signs with dysarthria or dysphagia (n = 2), meningism (n = 1), and cerebellar ataxia (n = 1). Peripheral nervous system involvement was seen in all patients, with global proximal muscle weakness (n = 4) and reduced reflexes (n = 2). Neurological symptoms were part of the initial presentation in 2 patients.
Systemic manifestations included fever (n = 4), cardiovascular shock (n = 4), rash (n = 4), and dyspnea (n = 2). All patients required mechanical ventilation and intensive care admission for cardiovascular shock (n = 4) and/or respiratory decompensation (n = 1). The intensive care unit stay was for a median 6.5 (range, 2-14) days, and mechanical ventilation duration was for a median of 5 (range, 1-7) days.
A comprehensive screening of all 4 patients for other infective causative mechanisms had negative results. In the 2 patients who had lumbar punctures, cerebrospinal fluid samples were acellular with normal protein and glucose levels, negative results for oligoclonal bands, and negative results for bacterial cultures and viral and bacterial PCR (including negative SARS-CoV-2 PCR). Tests for N-methyl-d-aspartate receptor, myelin oligodendrocyte glycoprotein, and aquaporin-4 autoantibodies had negative results in all patients.
Signal changes in the splenium of the corpus callosum (SCC) were seen in all 4 patients; T2-hyperintense lesions associated with restricted diffusion were seen in 3 children. The fourth patient presented with a splenial lesion on computed tomography, but on subsequent magnetic resonance imaging, no restricted diffusion was evident, although the signal change remained.
The genu was involved in 2 patients and the bilateral centrum semiovale in 2 patients (Figure). No spinal cord involvement or pathological enhancement was observed. Patient 2 had a repeated magnetic resonance image on day 5 that showed resolution of diffusion restriction in the SCC and centrum semiovale.
Electroencephalography showed a mild excess of slow activity in the 3 patients tested. Nerve conduction studies and electromyography showed mild myopathic and neuropathic changes in all 3 patients tested.
Three patients received immunomodulatory therapies as part of COVID-19 pediatric multisystem inflammatory syndrome management (Table 1); these were intravenous methylprednisolone (n = 2), dexamethasone (n = 2), intravenous immunoglobulin (n = 2), anakinra (n = 2), and rituximab (n = 1).
No patients required antiviral treatment. After a median follow-up of 18 (range, 11-32) days, patients 2 and 4 fully recovered and were discharged from hospital after 11 and 18 days respectively, fully ambulating. The remaining 2 patients have been discharged from the intensive care unit and remain inpatients. Both are improving clinically but currently wheelchair bound (as a result of proximal lower-limb muscle weakness).
In this case series, we describe 4 children with confirmed COVID-19 who presented with a distinct neurological syndrome associated with lesions of the SCC on neuroimaging. In an adult cohort7 in Wuhan, China, 78 of 214 patients (36.4%) had neurological manifestations, which included dizziness (n = 36), headache (n = 28), impaired consciousness (n = 16), acute cerebrovascular disease (n = 6), ataxia (n = 1), and seizures (n = 1).
In comparison with patients with nonsevere infection, those with severe infection had more neurological presentations, including acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]) and impaired consciousness (13 [14.8%] vs 3 [2.4%]). Neuroimaging, cerebrospinal fluid, or neurophysiology tests were not performed in this cohort7 to reduce the risk of cross-infection.
A key observation in this cohort was the acute splenial lesions seen on neuroimaging in all 4 patients. Reversible lesions of the SCC are rare but have been previously reported in patients with encephalopathies and are thought to represent focal intramyelin edema secondary to inflammation.
In a multicenter study from Japan of 15 adult patients, a variety of viral prodromes were reported in 5 patients; these were influenza A (n = 1), mumps (n = 2), adenovirus (n = 1), and varicella-zoster virus (n = 1).8
Other differential diagnoses of splenial lesions include ischemia, posterior reversible encephalopathy syndrome, severe electrolyte disturbances, and lymphoma.9 Interestingly, a typical, transient, oval-shaped lesion in the median aspect of the SCC, either in isolation or with more extensive brain involvement, has also been reported10 in children with Kawasaki disease.
Similar to the previous 2009 influenza A (H1N1) virus pandemic, the neurological symptom findings have not demonstrated neurotropism, and the pathobiology has been considered secondary to an immune-mediated causative mechanisms.11
A number of neuroimmune disorders are known to occur in close timing to viral infection; examples are in children who develop anti–N-methyl-d-aspartate receptor encephalitis after recovery from herpes simplex virus encephalitis and those who develop a primary CNS vasculitis after varicella-zoster virus infection.12
The phenotype of our cohort raises the possibility of a virus-specific immunological syndrome. A plausible mechanism would be exposure of the immune system to new CNS antigens as a result of blood-brain barrier damage from SARS-CoV-2, which causes endotheliopathy13 and leads to an immune-directed attack on the CNS.
Alternatively, the neurological symptoms may be part of the systemic autoinflammatory disease in keeping with the raised systemic inflammatory markers seen in our cohort (Table 1).
The combinations of both CNS and peripheral nervous system symptom profiles are rare in pediatrics but can be seen in children with hemophagocytic lymphohistiocytosis.14 This condition, which can be either genetic or acquired, is traditionally characterized by a cytokine storm with multiorgan dysfunction.
More recently, isolated CNS presentations have also been reported.15 Similarly, neurological symptoms secondary to cytokines storms were reported in 23 of 51 pediatric and young adult patients (45.1%) receiving chimeric antigen receptor–modified T-cell therapy.16
1.Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(6):1088-1095. doi:10.1111/apa.15270PubMedGoogle ScholarCrossref
2.Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1PubMedGoogle ScholarCrossref
3.Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778. doi:10.1016/S0140-6736(20)31103-XPubMedGoogle ScholarCrossref
4.Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. 2020;11(7):995-998. doi:10.1021/acschemneuro.0c00122PubMedGoogle ScholarCrossref
5.Gutiérrez-Ortiz C, Méndez A, Rodrigo-Rey S, et al. Miller Fisher syndrome and polyneuritis cranialis in COVID-19. Neurology. 2020;10.1212/WNL.0000000000009619. doi:10.1212/WNL.0000000000009619PubMedGoogle Scholar
6.Pilotto A, Odolini S, Stefano Masciocchi S, et al Steroid-responsive encephalitis in COVID-19 disease. Ann Neurol. Published online May 17, 2020. doi:10.1002/ana.25783Google Scholar
7.Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020. doi:10.1001/jamaneurol.2020.1127
8.Tada H, Takanashi J, Barkovich AJ, et al. Clinically mild encephalitis/encephalopathy with a reversible splenial lesion. Neurology. 2004;63(10):1854-1858. doi:10.1212/01.WNL.0000144274.12174.CBPubMedGoogle ScholarCrossref
9.Doherty MJ, Jayadev S, Watson NF, Konchada RS, Hallam DK. Clinical implications of splenium magnetic resonance imaging signal changes. Arch Neurol. 2005;62(3):433-437. doi:10.1001/archneur.62.3.433
10.Kontzialis M, Soares BP, Huisman TAGM. Lesions in the splenium of the corpus callosum on MRI in children: a review. J Neuroimaging. 2017;27(6):549-561. doi:10.1111/jon.12455PubMedGoogle ScholarCrossref
11.Sejvar JJ, Uyeki TM. Neurologic complications of 2009 influenza A (H1N1): heightened attention on an ongoing question. Neurology. 2010;74(13):1020-1021. doi:10.1212/WNL.0b013e3181d6b869PubMedGoogle ScholarCrossref
12.Wells E, Hacohen Y, Waldman A, et al; attendees of the International Neuroimmune Meeting. Neuroimmune disorders of the central nervous system in children in the molecular era. Nat Rev Neurol. 2018;14(7):433-445. doi:10.1038/s41582-018-0024-9PubMedGoogle ScholarCrossref
13.Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-1418. doi:10.1016/S0140-6736(20)30937-5PubMedGoogle ScholarCrossref
14.Horne A, Trottestam H, Aricò M, et al; Histiocyte Society. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2008;140(3):327-335. doi:10.1111/j.1365-2141.2007.06922.xPubMedGoogle ScholarCrossref
15.Benson LA, Li H, Henderson LA, et al. Pediatric CNS-isolated hemophagocytic lymphohistiocytosis. Neurol Neuroimmunol Neuroinflamm. 2019;6(3):e560. doi:10.1212/NXI.0000000000000560PubMedGoogle Scholar
16.Gofshteyn JS, Shaw PA, Teachey DT, et al. Neurotoxicity after CTL019 in a pediatric and young adult cohort. Ann Neurol. 2018;84(4):537-546. doi:10.1002/ana.25315PubMedGoogle ScholarCrossref
Journal information:Archives of Neurology