We welcome the letter by Finsterer (1) in response to our article: Encephalitis Associated With SARS-CoV-2 Infection in a Child With Chiari Malformation Type I (2). Finsterer raised 10 points to be clarified or discussed. Hence, we appreciate the opportunity to provide additional insights into our case report.
The first point concerns the triad of SARS-CoV-2 infection, oral ulcerations and odynophagia. Although rare, oral ulcerations and odynophagia have been described in patients with COVID-19 (3-5). There is a broad discussion about the etiology of oral manifestations of COVID-19, which might be attributed to (i) the direct or indirect action of SARS-CoV-2 on oral mucosal cells; (ii) other pathogens such as viruses; and (iii) immunodepression (6-8). SARS-CoV-2 has tropism to the tongue (keratinized and non-keratinized mucosa) and salivary gland epithelium due to the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors in oral mucosa epithelia (7-10). In this regard, studies suggest that the interaction between SARS-CoV-2 and their receptors could potentially disrupt the function of oral keratinocytes resulting in odynophagia and oral mucosal ulcerations (3-5).
Furthermore, Brandão et al. observed that the evolution of oral ulcerations and the healing process occurred in parallel with the resolution of COVID-19 (4). Nevertheless, one limitation of our study was the lack of robust validation, such as by including an incisional biopsy, followed by reverse-transcription polymerase chain reaction testing for SARS-CoV-2 and immunohistochemistry to evaluate ACE2 and TMPRSS2 expression. For sure, a differential diagnosis would also have been helpful to rule out other pathogens, diseases, or drugs associated with the oral ulcerations. We were not able to eliminate other possibilities due to the family’s economic limitations and the financing aspects of the institution.
The second point is regarding Chiari-I malformation and how SARS-CoV-2 entered the central nervous system. In our article, the presentation of encephalitis associated with COVID-19 in a patient with Chiari malformation type I was reported (2). Although this remark seems trivial, it is necessary to emphasize that we are not talking about the causal relationship between Chiari malformation type I and the development of SARS-CoV-2-related encephalitis, but only about possible implications for the health of the patient with this congenital syndrome and coronavirus-related encephalitis. Recently, Brugliera et al. reported a novel case involving therapy for pain management in a patient with Chiari malformation type I during concomitant SARS-COV-2 infection (11). Thus, our findings also expanded the understanding of clinicians’ different challenges.
Regarding the entry of SARS-CoV-2 into the central nervous system (CNS), these mechanisms were discussed in our case study (2). Jakhmola et al. summarized the mode of action and brain or cerebrospinal fluid (CSF)/plasma ratio of antivirals with properties of high bioavailability in the brain, such as lopinavir/ritonavir, darunavir, remdesivir, and favipiravir (12), which have shown promising outcomes in COVID-19 treatment (13). Moreover, efficient blood–brain barrier penetrating drugs such as clomipramine (tricyclic antidepressant) and melatonin (natural hormone) might be helpful to prevent psychiatric consequences or the onset of neurological manifestations (14) and SARS-CoV-2 entry into the brain (15), respectively.
As far as the third point is concerned, upon admission to the hospital, the patient’s parents did not comment on the reasons for bringing him to the hospital until 2 weeks after the development of fever, nausea and photophobia. The patient developed frontal headache, odynophagia, and vomiting 24 hours before hospital admission.
The fourth point focuses on the consciousness of the patient. The child had a mild disorder of consciousness, which was defined by Romero-Sánchez et al. as disorientation, confusion, or somnolence in patients hospitalized with COVID-19 (16).
Regarding the fifth point, the patient had cerebral atrophy of unclear etiology; consequently, it is essential to mention that he did not have a history or signs of pre-existing cerebral disease associated with atrophy. However, we cannot exclude subclinical cerebral atrophy of another, as yet unidentified, etiology or cognitive impairment manifesting before encephalitis and independently from SARS-CoV-2 infection. In this sense, cerebral atrophy has been observed in children with COVID-19 (17-19).
The sixth point relates to the fact the patient received piracetam to treat CNS disorders. Piracetam (2-oxo-1-pyrrolindine acetamide) is a nootropic drug with neuroprotective and anticonvulsant properties, improving neuronal function (20). There are evidence-based clinical investigations about using piracetam in patients with CNS disorders such as cognition/memory, epilepsy, and seizure (21-23). Moreover, piracetam has been used as neurological therapy in patients with COVID-19 (24, 25). We emphasize that we are not suggesting using piracetam to treat neurological complications of SARS-CoV-2 infection.
Regarding the seventh point, the child received supplementary oxygen, and his chest computed tomography showed no abnormality, and the patient had no acute respiratory distress (2). Fricchione et al. reported the case of a patient with COVID-19-associated neuroinflammation which was treated with supplemental oxygen even though she had normal chest radiography (26). It is possible that neuronal damage during SARS-COV-2 infection may influence the control of respiration by interacting in neuromodulation, as a silent mechanism of CNS hypoxia in COVID-19 (27). Hence, neuromuscular dysfunction might be an alternative cause of respiratory insufficiency in patients with SARS-CoV-2 infection, especially those with minimal chest imaging findings (27).
As for as the eighth point is concerned, leptomeningeal enhancement can be seen in Figure 1D of our report (2), similar to the observations made by Brun et al. (28), Klironomos et al. (29), Pilotto et al. (30) and Kremer et al. (31). Nevertheless, according to the radiological imaging score proposed by Sommer et al., the image quality of our study was “poor, and diagnosis strongly impaired” (32). Leptomeningeal enhancement is easily detectable on standard T1-weighted images through the subtraction technique, where the magnetic resonance signal is removed from the final image, obtaining an improved detection of meningeal inflammation (33). In this sense, further work is required by our team to elucidate the ideal magnetic resonance imaging protocol to image leptomeningeal enhancement.
Regarding the ninth point, we agree with Finsterer: (i) We were referring to the fact that the patient had not presented any of the symptoms of Chiari malformation type I or COVID-19 in children, such as recurrent neck pain, neck stiffness, tinnitus, vertigo and nystagmus except headache and seizure; (ii) Lymphopenia and increased neutrophil count are not symptoms. These hematological parameters were used in the sentence to highlight a difference between the clinical and laboratory findings of the patient, but we do not assume that they were symptoms.
Finally, for the tenth point, we did not explore the levels of biomarkers of inflammation in the CSF due to the economic limitations of our Institution. Nevertheless, we agree with Finsterer that these biomarkers might have provided information on the inflammatory state of the brain of our patient during SARS-CoV-2 infection.
Footnotes
Conflicts of Interest
The Authors have nothing to disclose.
- Received July 10, 2023.
- Revision received August 26, 2023.
- Accepted August 30, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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).
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