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October 2022; 12 (5) Cases

Pediatric SARS-CoV-2–Related Diplopia and Mesencephalic Abnormalities

Sara Signa, Noemi Brolatti, Chiara Trincianti, View ORCID ProfileDomenico Tortora, Carolina Saffioti, Eddi Di Marco, Maura Acquila, Elisabetta Amadori, Chiara Fiorillo, Erica Ricci, View ORCID ProfilePasquale Striano, Elio Castagnola, Maria Stella Vari
First published August 31, 2022, DOI: https://doi.org/10.1212/CPJ.0000000000200076
Sara Signa
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Noemi Brolatti
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Chiara Trincianti
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Domenico Tortora
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Carolina Saffioti
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Eddi Di Marco
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Maura Acquila
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Elisabetta Amadori
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Chiara Fiorillo
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Erica Ricci
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Pasquale Striano
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Elio Castagnola
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Maria Stella Vari
UOC Malattie Infettive (S.S., C.S., E.R., E.C.), IRCCS Istituto Giannina Gaslini; COVID Hospital (S.S., E.R.), IRCCS Istituto Giannina Gaslini; UOC Neurologia Pediatrica e Malattie Muscolari (N.B., E.A., C.F., P.S., M.S.V.), IRCCS Istituto Giannina Gaslini; Dipartimento di Neuroscienze (C.T., C.F., P.S.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Università di Genova; UOC Neuroradiologia (D.T.), IRCCS Istituto Giannina Gaslini; and UOC Laboratorio Analisi (E.D.M., M.A.), IRCCS Istituto Giannina Gaslini, Genoa, Italy.
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Citation
Pediatric SARS-CoV-2–Related Diplopia and Mesencephalic Abnormalities
Sara Signa, Noemi Brolatti, Chiara Trincianti, Domenico Tortora, Carolina Saffioti, Eddi Di Marco, Maura Acquila, Elisabetta Amadori, Chiara Fiorillo, Erica Ricci, Pasquale Striano, Elio Castagnola, Maria Stella Vari
Neurol Clin Pract Oct 2022, 12 (5) e124-e128; DOI: 10.1212/CPJ.0000000000200076

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Abstract

Objective This case report describes a patient with mesencephalic MRI signal abnormality and diplopia, possibly associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods We describe a boy with binocular diplopia and nystagmus. The pattern of serology positivity and negative direct research of SARS-CoV-2 RNA in our patient allowed us to consider novel coronavirus as the trigger of possible immune-mediated phenomena against the central nervous system.

Results During hospitalization, blood tests revealed a recent SARS-CoV-2 infection. MRI revealed hyperintensity of the mesencephalic tegmentum and periaqueductal region, consistent with an inflammatory lesion of the midbrain tegmentum. Viral and bacterial molecular screening on cerebrospinal fluid and isoelectrofocusing analysis, anti–myelin oligodendrocyte glycoprotein, anti–aquaporine-4, and anti–N-methyl-d-aspartate antibodies were negative. The patient was treated with steroids and immunoglobulin therapy with complete remission of neurologic symptoms.

Discussion This report expands the spectrum of pediatric COVID-19–associated neurologic symptoms and highlights a possible isolated neurologic COVID-19–related symptom.

PRACTICAL IMPLICATIONS

Consider idiopathic intracranial hypertension in the differential diagnosis for patients undergoing hormonal therapy presenting with headaches and transient visual obscurations.

Case

A previously healthy, not vaccinated against SARS-CoV-2, 14-year-old adolescent boy presented with a 2-day history of binocular diplopia, particularly evident for distant vision, without any other neurologic symptom. At admission, a nasopharyngeal swab real-time PCR (RT-PCR) for detection of SARS-CoV-2 was negative. The boy reported persisting binocular diplopia at a distance primary position and lateral gaze bilaterally. Spontaneous nystagmus more right beating than left beating was present, whereas no ocular movement abnormality or ocular alignment defect was noticed. Pupils were isocyclic, isochoric, and normally reactive to light; no photophobia was recorded. Physical examination was otherwise normal. The boy was alert and oriented, denying weakness, headache, vomiting, or dizziness. Fundus examination was normal. Brain MRI revealed hyperintensity of the mesencephalic tegmentum and periaqueductal region on fluid attenuated inversion recovery and T2-weighted images, with no diffusion restriction or contrast enhancement (Figure, A.a. and A.b.).

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Figure Brain MRI Findings at the Onset and Follow-up

Sagittal (A.a) and axial (A.b) fluid attenuated inversion recovery (FLAIR) images at admission showing hyperintensity of the midbrain tegmentum (arrows) consistent with an inflammatory lesion. Sagittal (B.a) and axial (B.b) FLAIR images after 1 month showed a reduction of midbrain lesions. Sagittal (C.a) and axial (C.b) FLAIR images acquired after 4 months showed complete resolution of signal changes.

Spinal MRI was normal. Routine blood tests were normal, including inflammatory markers (erythrocyte sedimentation rate, c-reactive protein), thyroid function, and autoantibodies (antinuclear antibodies—ANA, anti-cardiolipin and anti–B2-glycoprotein antibodies). The results of infectious diseases detection tests are reported in Table 1.

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Table 1

Infectious Diseases' Detection Tests

CSF analysis showed increased glycorrhachia and pleocytosis; 9 cells were present, mostly mononucleated. No malignant cell was detected (Table 2).

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Table 2

Cerebrospinal Fluid Investigations

CSF viral and bacterial molecular screening, as well as isoelectric focusing assay, anti–myelin oligodendrocyte glycoprotein, anti–aquaporine-4 and anti–N-methyl-d-aspartate antibodies, were negative. SARS-CoV-2 PCR experimentally tested on CSF was not detected (Table 1).

SARS-CoV-2 serology, using Snibe 2019-Novel Coronavirus (nCoV) Kit Ab, on MAGLUMI 800 (Snibe Co), a fully automated chemiluminescence immunoassay analyzer, showed immunoglobulin M 1.834 AU/mL (positive if ≥1) and immunoglobulin G 31.9 AU/mL (positive if ≥1,1).

Then, methylprednisolone pulses (30 mg/kg/d) were started and administered for 3 days, with a subsequent shift to oral prednisone (1 mg/kg/d) on the fourth day together with a course of intravenous immunoglobulin (400 mg/kg/d) for 5 days. Gradual improvement of nystagmus and diplopia with complete resolution in a few days was observed. MRI follow-up after 1 month showed a significant reduction of signal changes in the midbrain (Figure, B.a. and B.b.). Steroid therapy was progressively tapered and finally stopped after further 2 months. At the 4-month follow-up, neurologic examination and neuroimaging were normal (Figure, C.a. and C.b.).

Discussion

Neurologic manifestations of SARS-CoV-2 may arise because of the direct invasion, parainfectious, or postinfectious immune mechanisms1,2 with central nervous system (CNS) inflammatory disorders, which include encephalitis, myelitis, and meningitis, more frequently reported among patients younger than 19 years.3 In children, neurologic symptoms have been observed in 22% of cases in an American cohort,4 most of them being transient and with a good outcome. In a UK study,5 the incidence of these manifestations reached 3.8 cases per 100 hospitalized pediatric patients. In another study, almost half of the pediatric patients were diagnosed with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2.6 Among neuroimaging observations, the most common were postinfectious immune-mediated acute disseminated encephalomyelitis-like changes, myelitis, and neural enhancement that could occur in the absence of corresponding neurologic symptoms,7 whereas splenial lesion and myositis seemed to be more common in patients with MIS-C.

This boy presented with nystagmus and diplopia consistent with a fascicular lesion involving the medial and anterior portions of the midbrain tegmentum and temporally related to SARS-CoV-2 infection. Despite striking imaging findings, neurologic symptoms were mild and promptly resolved with immunosuppressive therapy. The pattern of positive SARS-CoV-2 serology and the negative direct research of SARS-CoV-2 RNA suggested that coronavirus was the trigger of possible immune-mediated phenomena against CNS, as reported for SARS-CoV-2 and other coronaviruses.1 This hypothesis was further supported by the exclusion of other common etiologies and the favorable response to immunomodulation. This report expands the spectrum of pediatric COVID-19–associated neurologic manifestations and suggests a COVID-19–related inflammatory lesion of the midbrain tegmentum.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been found to be related to neurologic manifestations, possibly because of a direct invasion, parainfectious, or postinfectious immune mechanisms.1,2 Although less frequently compared with adults, neurologic manifestations have been reported3 in children also, ranging from cerebrovascular disease to peripheral nervous system involvement. Neurologic symptoms may also occur in patients with multisystem inflammatory syndrome (MIS-C).

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.

Appendix Authors

Table

Footnotes

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.

  • ↵* These authors contributed equally to this work as first authors.

  • Submitted and externally peer reviewed. The handling editor was Editor Luca Bartolini, MD.

  • COVID-19 Resources: NPub.org/COVID19

  • Received April 14, 2022.
  • Accepted July 28, 2022.
  • © 2022 American Academy of Neurology

References

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