Abstract
Background/Aim: There is increasing evidence that patients infected with SARS-CoV-2 develop neurological manifestations such as encephalitis. The purpose of this article was to present a case of viral encephalitis associated with SARS-CoV-2 in a 14-year-old child with Chiari malformation type I. Case Report: The patient manifested frontal headache, nausea, vomiting, skin pallor, right side Babinski sign and was diagnosed with Chiari malformation type I. He was admitted with generalized seizures and suspected encephalitis. Brain inflammation and viral RNA in the cerebrospinal fluid suggested SARS-CoV-2 encephalitis. These findings indicate that the SARS-CoV-2 test in CSF of patients with neurological manifestations, confusion, and fever during the COVID-19 pandemic should be carried out even when there is no evidence of respiratory infection. To our knowledge, this presentation of encephalitis associated with COVID-19 has not yet been reported in a patient with a congenital syndrome such as Chiari malformation type I. Conclusion: Further clinical data are needed to determine the complications of encephalitis due to SARS-CoV-2 in patients with Chiari malformation type I to standardize diagnosis and treatment.
Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), frequently is associated with symptoms such as fever, severe respiratory complications, and neurological manifestations (1). Encephalitis is a central nervous system (CNS) complication that has been reported in patients with SARS-CoV-2 infection (1-5). Nevertheless, little evidence exists about COVID-19 in children with congenital diseases such as Chiari malformation type I. This malformation is defined as a cerebellar tonsil position ≥5 mm below the foramen magnum by imaging (6, 7). Chiari malformation type I symptoms are suboccipital headache, neck pain, vertigo, tinnitus, and photophobia (6, 7).
As COVID-19 is a new emerging disease, research continues to reveal different aspects of the disease in children. Previous studies have reported cases of encephalitis in patients with SARS-CoV-2 (1-4, 8). Still, these results cannot be compared with this study because this patient had a different condition due to Chiari malformation type I. Little evidence exists about SARS-CoV-2 infection in children with congenital disease. Severe types of congenital heart disease were reported in a case series of children with COVID-19 (9). However, only one report described the co-existence of Chiari malformation type I and viral meningoencephalitis associated with Epstein-Barr virus in a 3-year-old child (10).
Herein, we present a case of a child with Chiari Malformation Type I who developed SARS-CoV-2-related encephalitis. To the best of our knowledge, this report is the first case confirming viral encephalitis linked to SARS-CoV-2 infection in a patient with congenital cerebellar malformation.
Written informed consent was obtained from the patient to publish this case report and any accompanying images.
Case Report
On February 23rd 2021, a 14-year-old child was admitted with fever (>38°C), frontal headache, odynophagia, and vomiting. His family history was unremarkable. Fever, nausea, and photophobia were present for two weeks. Physical examination showed skin pallor, altered state of consciousness, weakness, disorientation, isochoric pupils, neck stiffness, and oral ulcerations. Upper and lower limb strength was 5/5 with hyperreflexia and positive right-side Babinski’s sign. The patient received supplementary oxygen during hospital stay (SpO2 <85%) as needed. No acute respiratory distress or cyanosis was documented. No inotropic support was installed. The patient developed generalized seizures.
Laboratory exams (Table I), including a complete blood count, showed neutrophilia, lymphopenia, decreased red blood cells, low serum proteins (albumin and globulins), hyperglycemia, hyperbilirubinemia and high phosphorous. Magnetic resonance imaging (MRI) detected cerebral edema (Figure 1A), brain inflammation (Figure 1B), hyperintensity and atrophy (Figure 1C), and diffuse leptomeningeal enhancement (Figure 1D), suggesting encephalitis on hospital stay day 6. The patient was treated with vancomycin (45 mg/Kg/day) and acyclovir (10 mg/Kg/day). Cerebrospinal fluid (CSF) analysis showed lactate dehydrogenase (LDH) of 20 U/l, white blood cell (WBC) count of 30 cells/μl, microalbumin 42 mg/dl (normal range=<6.5), and glucose 71 mg/dl (normal range=40-70 mg/dl). CSF gram stain and culture were negative (hospital day 7). Blood culture was negative as well. “TORCH” pathogens (Toxoplasma gondii, other, rubella virus, cytomegalovirus, and herpes simplex virus) screening (all from Diatron, Budapest, Hungary) was positive for serum anti-toxoplasma IgG, anti-cytomegalovirus (CMV) IgG, anti-herpes simplex virus 1 (HSV-1) IgG, anti-herpes simplex virus 2 (HSV-2) IgG, anti-hepatitis B (HBV) IgG, and anti-rubella (RV) IgG antibodies. Toxoplasma tachyzoites or cysts were not detected by histopathological analysis. Real-Time Reverse Transcriptase-Polymerase Chain Reaction (real-time RT-PCR) test for CMV, HSV-1, HSV-2, HBV, and RV in the CSF was negative (Thermo Fisher, Waltham, MA, USA). CSF was negative for HSV-6 and HSV-8 using real-time RT-PCR (Thermo Fisher). Droplet digital PCR (ddPCR) analysis of CSF was positive for SARS-CoV-2 RNA (hospital day 7). Antibiotics were discontinued following SARS-CoV-2 positivity, and only antiviral therapy with acyclovir (10 mg/Kg/day) continued for two weeks. Phenytoin [diphenylhydantoin (PHE); 5 mg/Kg/day], piracetam (800 mg/Kg/day), and levetiracetam (20 mg/Kg/day) were added on hospital stay day 7. Patient’s neurological symptoms improved, and seizures stopped. MRI scanning (hospital day 6) revealed that the child had low-lying cerebellar tonsils more than 5 mm below the level of the foramen magnum (Figure 2), confirming Chiari malformation type I diagnosis.
Laboratory results of a patient with viral encephalitis, Chiari malformation type I, and SARS-CoV-2 infection.
Brain magnetic resonance imaging findings in a child with SARS-CoV-2 infection. (A) T1-weighted magnetic resonance image showing small foci of reduced diffusion on axial diffusion trace imaging (white arrow) and diffuse brain edema of the left hemisphere with mass effect effacing the sulci and cortical (black arrow). (B) Inflammatory changes are restricted to the left temporal lobe (white arrow) with edema without mass effect (hyperintensity in the white matter). (C) Axial T1-weighted image showing a hyperintensity in the left hippocampus (white arrow) and atrophy of the right hippocampus (black arrow). (D) A coronal T1-weighted image representing enhancement consistent with leptomeningitis over the right and left frontal, temporal region (white arrows).
Chiari I malformation in a 14-year-old child with encephalitis related to SARS-CoV-2 infection. T1-weighted sagittal image showing cerebellar tonsils (white arrow), which were elongated and extended approximately 5.6 mm below the plane of the foramen magnum (dotted line), the anterior border of which is the basion (a). The posterior wall is the opisthion (b). There is a small vertically oriented fourth ventricle (white arrowhead). The degree of tonsillar herniation measured as the length perpendicular from c to a-b.
Urine analysis (U/A) showed light yellow colored urine with leukocytes (49.50 cells/μl, hospital day 14; and 15.84 cells/μl, hospital day 17) and red blood cells (20.24 cells/μl, hospital day 14; and 9.68 cells/μl, hospital day 17). Urine culture was negative, but ceftriaxone (50 mg/Kg/day) was administered. U/A (hospital day 15) had a creatinine clearance of 128.3 ml/min (normal range=80-120 ml/min), and total protein of 168.74 mg/24 h (normal range=50-80 mg/24 h). The patient was discharged from the hospital 21 days after admission without neurological deficit.
SARS-CoV-2 detection in the CSF using ddPCR. The SARS-CoV-2 detection assay targeted the N1 gene using the IDT 2019-Novel Coronavirus (2019-nCoV) CDC Real-time PCR panel primers and probes (Integrated DNA Technologies, Inc., Coralville, IA, USA). We used the 2019-nCoV_N1 Forward Primer (2019-nCoV_N1-F 5′-GAC CCC AAA ATC AGC GAA AT-3′), the 2019-nCoV_N1 Reverse Primer [2019-nCoV_N1-R (5′-TCT GGT TAC TGC CAG TTG AAT CTG-3′)], and the 2019-nCoV_N1 probe [2019-nCoV_N1-P (5′-FAM-ACC CCG CAT TAC GTT TGG TGG ACC-BHQ1-3′)]. Droplet digital PCR was performed with the QX ONE Droplet Digital PCR (ddPCR) System (BIO-RAD, Hercules, CA, USA). The reaction mixtures (20 μl) contained 5 μl of One-Step RT-ddPCR Advanced Kit for Probes (Cat. 1864021; BIO-RAD), 2 μl reverse transcriptase, 1 μl 300 mM DTT, 300 nM of target primers and probe, and 3 μl of extracted RNA. The detection and quantitative enumeration of SARS-CoV-2 was performed by transferring the mixture into the DG8 cartridge GCR96 (Cat. 12006858; BIO-RAD), which was sealed using the PX1 PCR Plate Sealer (Cat. 1814000; BIO-RAD). Finally, the RT-ddPCR reaction was performed using the following cycling protocol: 50°C/20 min for reverse transcription, 95°C/5 min for enzyme activation, 45 cycles of 95°C/30 s for denaturation, 60°C/1 min for annealing and extension, and 98°C/10 min for enzyme deactivation. Data analysis was performed using Quanta Soft TM analysis software. The negative and positive control determined the detection threshold and positive samples.
Discussion
Chiari malformation type I is usually associated with recurrent neck pain, headache, tinnitus, vertigo, and nystagmus frequently encountered during adolescence or adulthood (6, 7). Although children generally have mild COVID-19 symptoms (4), our patient did not have any of these symptoms except for marked lymphopenia and increased neutrophils within the first five days (Table I). The patient did not demonstrate any of the symptoms of Chiari malformation type I. Instead, the only presenting clinical features were altered state of consciousness, disorientation, and focal neurological signs such as seizures. MRI scanning revealed the diagnosis of viral encephalitis and Chiari malformation type I. Brain MRI findings were consistent with encephalitis caused by SARS-CoV-2 (1-5) and other viruses (10, 11). The incidence of encephalitis related to SARS-CoV-2 infection is relatively low (∼6.7%) (12). Symptoms of encephalitis include decreased level of consciousness, altered mental state, weakness, and seizures (4, 6) that were present in the patient.
Moreover, encephalitis was evidenced in the patient by the inflammation in the CNS (WBC count in the CSF analysis and MRI scan) as previously reported (8). Numerous other CNS infections were excluded by culture and real-time RT-PCR. The patient was positive for serum anti-toxoplasma IgG, anti-CMV IgG, anti-HSV-1 IgG, anti-HSV-2 IgG, anti-HBV IgG, and anti-RV IgG antibodies; however, these antibodies are markers of past exposure and not an indicator of latent infection in the human (13-15). TORCH screening is crucial for early infection diagnosis where the anti-IgM antibody positivity is a strong indicator of acute and present infection. In contrast, anti-IgG antibody detection reflects past exposure or vaccination (16).
The sensitivity of traditional CSF tests for virus identification is demanding due to the short viremia period and difficulty in obtaining brain tissue through biopsy (17). Since the ddPCR test is an ultrasensitive method to detect low levels of SARS-CoV-2 RNA (18), this diagnostic tool was included to investigate the presence of SARS-CoV-2 in CSF. Because the ddPCR test in CSF was positive for SARS-CoV-2, the association between viral infection and encephalitis was suggested. Some patients may develop encephalitis weeks after initial SARS-CoV-2 infection and others during the same period (12). Neurological manifestations and brain MRI findings related to SARS-CoV-2 and viral RNA detection in the CSF suggested that the child with Chiari malformation type I had also viral encephalitis due to SARS-CoV-2 infection. These findings are similar to studies performed by Moriguchi et al., Varatharaj et al., and Huang et al., who reported the detection of SARS-CoV-2 RNA in the CSF (3, 8, 19).
Lymphopenia, as an indicator of the COVID-19 severity (20), was observed in the patient during the first five days of hospitalization (Table I). During the first 11 days of hospitalization, the patient had low globulin and higher albumin/globulin ratio, associated with brain structure, function, and perfusion (21). The liver function tests could have suggested neurological damage by SARS-CoV-2, including higher levels of bilirubin (direct and indirect) (22) determined during the first six days of hospitalization. The possible routes of SARS-CoV-2 entry to the CNS are 1) via the ACE-2 on endothelial cells of the blood-cerebrospinal fluid barrier or 2) via retrograde axonal transport of peripheral neural pathways such as via the olfactory mucosa through TLR4 and neuropilin 1 (4, 5, 12, 23).
Conclusion
Encephalitis may be associated with SARS-CoV-2 infection in patients with Chiari malformation type I. Hence, clinical case management such as this case report could help to stablish better treatment.
Acknowledgements
The Authors would like to thank the patient for cooperating with this case report.
Footnotes
Authors’ Contributions
All Authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. JMR-R, GM-M, FB-G, GM-G, and RM-Á: supervision. JMR-R: conceptualization. JMR-R, GM-M, FB-G, GM-G, and RM-Á: investigation and writing-original draft. JMR-R and RM-Á: formal analysis. JMR-R, GM-M, GM-G, C-MC, AS-M, FML-M, EV-Á, PZ-S, FB-G, and RM-Á: writing-review and editing. All Authors contributed to the article and approved the submitted version.
Conflicts of Interest
The Authors declare no conflicts of interest regarding this study.
Funding
This research was supported by CONACYT (Mexico), grants: Pronaii 302979 and A1-S-9005 from RA.
- Received January 28, 2023.
- Revision received February 8, 2023.
- Accepted February 9, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
