Abstract
Background/Objectives
The most frequently reported ocular finding in the acute phase of the multisystem inflammatory syndrome in children (MIS-C), is conjunctivitis. More rarely, punctuate epitheliopathy, anterior uveitis and optic disc oedema can be seen. We aimed to investigate the acute and long-term ocular effects of MIS-C.
Subjects/Methods
Cases aged 1 month to 18 years who were diagnosed with MIS-C between January 2022 and June 2022 in the Department of Pediatric Infectious Diseases in our hospital were included in the study. Ophthalmological examinations were performed immediately after diagnosis, at one month, three months, and six months.
Results
Males consisted of 64.7% of the 34 cases included in the study and the mean age was 8.68 ± 4.32 years (min-max:2–17). In the first examination, conjunctivitis was observed in 6 (17.6%), punctuate epitheliopathy in 4 (11.7%), and subconjunctival haemorrhage in 3 (8.8%) patients. Two patients (5.8%) had optic disc oedema. No pathological anterior or posterior segment findings were observed in the sixth-month examination. The relationship between subconjunctival haemorrhage and intensive care hospitalisation was statistically significant (p = 0.014). Also, all patients with subconjunctival haemorrhage were clinically classified as severe MIS-C (p = 0.002).
Conclusion
Although pathological ocular findings were observed in the acute phase of the disease, all of them were found to be improved at the sixth-month follow-up. The most striking finding of our study is that cases with subconjunctival haemorrhage were clinically more severe, and all patients needed intensive care. This study may be informative in establishing ocular follow-up protocols that are expected to be carried out in the acute period and in the follow-up of these patients.
Similar content being viewed by others
Introduction
The multisystem inflammatory syndrome in children (MIS-C) was first described in the second half of April 2020 as a new syndrome possibly associated with SARS-CoV-2 infection in children and adolescents [1, 2]. Features of this syndrome are similar to those of Kawasaki Disease, toxic shock syndrome, and hyperinflammatory conditions such as secondary hemophagocytic lymphohistiocytosis and macrophage activation syndrome [3]. The exact pathogenesis of MIS-C is unclear. Given that many patients with MIS-C are found to be positive for SARS-CoV-2 antibodies, it has been suggested that an abnormal immune response to SARS-CoV-2 plays a key role [4]. The fact that MIS-C usually occurs one month after SARS CoV-2 infection also supports that the underlying mechanism may be post-infectious inflammation [5]. Clinically, fever (96.4%), gastrointestinal symptoms (76.7%), shock (61.5%), rash (57.1%), and neurological findings (36.8%) are observed most frequently [6].
In the literature, the most frequently reported ocular finding in the acute phase in patients undergoing MIS-C is conjunctivitis, similar to Kawasaki disease, and less commonly punctuate epitheliopathy, anterior uveitis and papilledema [7,8,9,10,11,12]. Studies in the literature generally include the findings of MIS-C in the acute period. Our study is the first prospective observational study as far as we know in which the ocular findings in MIS-C were evaluated both in the acute period and in which the patients were followed up for six months.
Since MIS-C is a newly defined clinical condition and causes an exaggerated immune response, the damage it causes to the organs is not yet known. Therefore, our study aimed to investigate the acute and long-term ocular effects of MIS-C.
Material and methods
Cases aged 1 month to 18 years who were diagnosed with MIS-C according to the diagnostic criteria of the Center for Disease Control and Prevention (CDC) between January 2022 and June 2022 in the Pediatric Infectious Diseases Clinic in our hospital were included in the study. Cases with a history of serious eye problems (such as cataract, active uveitis, glaucoma, and previous intraocular surgery) and cases who refused to participate in the study were excluded.
Detailed ophthalmological examinations of the cases were performed immediately after diagnosis, at one month, three months, and six months. The best corrected visual acuities, anterior and posterior segment examinations, and Schirmer 2 tests were performed, and the findings were recorded. Since patients were examined immediately after diagnosis, some patients were examined in the ward at the bedside or in the intensive care unit. In some cases, the Schirmer 2 test could not be applied healthily because they were very young and agitated. Since the follow-up of the patients was planned as a six-month follow-up, the same applicable methods were preferred for standardisation. At each examination, the ocular surface was examined by staining with fluorescein papers. All examinations were performed by the same ophthalmologist. Bedside examination was performed with an indirect ophthalmoscope and 20/28 D lenses. In the age group who cannot express their vision reliably, amblyopia and all risk factors that may reduce vision were screened in detail, and refraction examinations with cycloplegia were performed. In addition, the medical records of the cases were examined and their demographic data, MIS-C clinical classification, and previous treatments were noted. The severity of cardiac findings, echocardiogram findings, and laboratory results were evaluated together for the MIS-C clinical classification [13].
Ethics committee approval was obtained from the Health Sciences University Izmir Tepecik Training and Research Hospital Ethics Committee for this prospective observational study (Decision no: 2021/12-18). Informed consent was obtained from the parents of all patients participating in the study.
Statistical analysis was performed using SPSS version 24.0 using the obtained data (IBM Corp., Armonk, New York, USA). Descriptive analyses are given as mean ± standard deviation [minimum-maximum (min-max)] or median [Interquartile range (IQR)] values according to the normal distribution for numerical variables. Normally distributed numerical variables were compared with the t-test, while non-normally distributed variables were compared with the Mann–Whitney U test. Categorical data are given numerically and as a percentage. Pearson and chi-square tests were used to compare categorical data. A p value below 0.05 was considered statistically significant.
Results
During the study period, a total of 38 patients were diagnosed with MIS-C. A total of four patients were excluded from the study because one of them died and three patients did not accept to participate in the study. Schirmer 2 test could not be applied to seven cases out of 34 cases.
A total of 34 cases, 12 (35.3%) females and 22 (64.7%) males, diagnosed with MIS-C were included in the study and their ophthalmological examinations were performed. The mean age of the cases was 8.68 ± 4.32 years (min-max:2–17). According to the clinical classification, 17 (50%) of the cases were followed up with a diagnosis of mild, 10 (29.4%) with moderate, and 7 (20.6%) with severe MIS-C. Nine of the patients (26.4%) were admitted to the intensive care unit.
No loss of vision was observed in any of the cases during their follow-up. In the first examination of the patients, follicular conjunctivitis was observed in 6 (17.6%), subconjunctival haemorrhage in 3 (8.8%), and punctuate epitheliopathy in 4 (11.7%) patients. Almost all patients with follicular conjunctivitis had a superficial hyperaemia with preservation of the limbus, but no discharge was observed in any of them. Conjunctivitis symptoms regressed in all cases the day after systemic treatment started. Therefore, none of the cases needed topical treatment. The median Schirmer values were 18 mm (IQR:15–22) in the right eye and 20 mm (IQR:15–25) in the left eye. The anterior segment findings of the other 21 patients (61.7%) were normal. Optic disc oedema was observed in two patients (5.8%). There was no neurological defect in 2 of our cases, but when optic disc oedema was detected during our examination, detailed neurological examination and imaging were performed. Oral carbonic anhydrase treatment was given in one of our cases with high cerebrospinal pressure, while no additional treatment was given in the other case.
In the first month’s examination, punctuate epitheliopathy was observed in only two (5.8%) patients, while anterior segment examinations of all the others were normal. Fundus examination was normal in all cases. The findings completely regressed in two cases with optic disc oedema. Systemic therapy was also discontinued of the patient who received oral carbonic anhydrase treatment. The median Schirmer values were 24.5 mm (IQR:17.7–30) in the right eye and 25.5 mm (IQR: 18–30) in the left eye.
In the three-month examination, punctuate epitheliopathy was observed in only one (2.9%) of the patients, while the anterior segment examinations of the others were normal. Fundus examination was normal in all cases. The median Schirmer values were 25 mm (IQR:22–30) in the right eye and 25 mm (IQR:20–30) in the left eye.
In the sixth-month examination of the patients, pathological anterior or posterior segment findings were not observed in any of the cases. The median Schirmer values were 25 mm (IQR:24–30) in the right eye and 26.5 mm (IQR:25–30) in the left eye. Topical artificial tear treatment was given to patients with punctuate epitheliopathy and low schirmer until the symptoms improve. No corneal involvement was observed during the entire follow-up. In cases with optic disc oedema, the findings did not recur in the 6-month follow-up.
There was no statistically significant relationship between pathological ocular examination findings and age and gender (p = 0.180, p = 0.089, respectively). Also, there was no statistically significant relationship between pathological ocular examination findings and the treatment administered (IVIG, steroid, anakinra, or plasmapheresis) (p = 0.374, p = 0.115, p = 0.054, p = 0.392, respectively). However, there was a statistically significant correlation between hospitalisation in the intensive care and the development of pathological ocular findings (p = 0.034). While no statistically significant relationship was found between other pathological findings and hospitalisation in the intensive care, the relationship between subconjunctival haemorrhage and hospitalisation in the intensive care was statistically significant (p = 0.014) (Table 1). Both patients with optic disc oedema had a history of intensive care admission, but no statistically significant relationship was found (p = 0.056).
While no statistically significant relationship was observed between other pathological ocular examination findings and MIS-C clinical classification (p = 0.314), a statistically significant correlation was observed between subconjunctival haemorrhage (p = 0.002) (Table 1). All patients with subconjunctival haemorrhage were followed up with a diagnosis of severe MIS-C. No statistically significant correlation was found between the presence of conjunctivitis at the first examination and the development of pathological ocular examination findings (p = 0.416). When the change in Schirmer 2 tests was analysed in the sixth-month follow-up, a statistically significant increase was observed in both eyes between the first and the sixth months (p = 0.019 for the right eye, p = 0.009 for the left eye). In the sixth-month examination of the patients, no pathological findings were observed in the anterior and posterior segments, and improvement was found in all patients with pathological ocular findings.
Discussion
The most common ocular finding in children in the acute period of MIS-C is conjunctivitis [7, 14, 15]. In a study that included 1458 cases in which systemic and ocular findings were evaluated by a meta-analysis, conjunctivitis was reported with a rate of 48.4% [6]. Although the rate was lower in our study, the most common finding in the first examination was conjunctivitis (17.6%). Conjunctivitis is the swelling and inflammation of the conjunctival tissue with the occlusion of the vessels [16]. It can cause epiphora, chemosis, pain, a reaction in tarsal follicles, and regional lymphadenopathy. Conjunctivitis in MIS-C may be induced due to a systemic immunological reaction rather than a local virus attack [17, 18].
Angurama et al. reported haemorrhagic nonpurulent conjunctivitis in three cases with MIS-C [19]. This finding has been described for the first time. It took two to three weeks for the haemorrhage to recede. The authors thought that haemorrhagic nonpurulent conjunctivitis may have been due to SARS CoV-2-induced endothelial cell damage and necrosis or vasculitis in conjunctival vessels. The described setting was stated as subconjunctival haemorrhage in our study. In our study, subconjunctival haemorrhage was observed during the initial examination of the patients with a rate of 8.8% and similarly, it was not observed in any case in the first month examinations. In our study, there was a relationship between intensive care admission and MIS-C clinical classification and subconjunctival haemorrhage. The correlation between the severity of the disease and subconjunctival haemorrhage in our study is an important finding. Subconjunctival haemorrhage can be an important examination finding that can inform us about the course of the disease. However, there is not enough information on this subject in the literature yet.
In our study, punctuate epitheliopathy was observed in the first examination of the patients with a rate of 11.7%, while it was observed only with a rate of 5.8% in the first-month examinations and 2.9% in the third-month examinations. At the sixth-month examination, this finding was not observed in any of the cases. Ozturk et al. reported non-granulomatous anterior uveitis and three severe corneal punctuate epitheliopathies in five acute MIS-C patients [8]. In our study, anterior uveitis was not observed in any of our patients in the acute period or during follow-up. However, there was a case in which we still observed punctuate epitheliopathy in the third month. The dry eye may be the cause of corneal punctuate epitheliopathy. Although there is no information in the literature regarding dry eye in MIS-C cases, in a study involving 535 COVID-19 patients in China, the rate of the dry eye without conjunctival congestion was found to be 20.1% [20]. Since the first examination of our patients was usually done at the bedside in our study, we could only use the Schirmer 2 test to objectively evaluate the dry eye. While values below 10 mm were observed in only two (7.4%) of 27 patients for whom the Schirmer 2 test was performed, values below 5 mm were not observed in any of the cases. No Schirmer value below 10 mm was observed in any of the patients in the examinations from the first month. However, when the change in Schirmer 2 tests was analysed in the sixth-month follow up, a statistically significant increase was observed in both eyes between the first and the sixth months. Dry eye is a common finding in autoimmune diseases [21]. For this reason, it is expected that MIS-C, whose underlying pathogenesis is thought to be an abnormal immune response, also causes dry eye [4]. In our study, although there was no finding other than punctuate epitheliopathy to support severe dry eye at the time of the first examination, the increase in Schirmer values in the sixth-month follow-up supports this.
In our study, bilateral optic disc oedema was observed in the first examination of two patients. There was no complaint of low vision in either of these two cases, and it was thought that it was detected incidentally within the study. There are case reports of papilledema in MIS-C patients in the literature, albeit in a small number. Similar to the cases in our study, in the case report published by Divya et al, in the examination of an 11-year-old patient, the visual acuity was 20/20, and colour vision was complete in both eyes [9]. Similar to the one patient in our study, this patient was diagnosed with pseudotumor cerebri and received systemic acetazolamide therapy. After treatment, optic disc oedema resolved. Bilen et al. also reported a case of bilateral papilledema with low vision [10]. Baccarella et al. reported two cases with increased intracranial pressure and papilledema [11]. Becker et al. also reported four cases with increased intracranial pressure, but only one of these cases had papilledema [12]. Papilledema is swelling of the optic nerve due to increased intracranial pressure, and if left untreated, it can cause optic nerve damage and vision loss [22]. Since it can be seen without causing any complaints as in our study, although there are still a small number of cases, it shows us the importance of fundus examination in these cases in terms of rapid diagnosis and treatment.
MIS-C is a rare complication of SARS-CoV-2 infection [23]. For this reason, the fact that our study was conducted with a small number of cases is a limitation. In addition, the necessity of performing the first examination of the patients in the intensive care unit or the ward and the poor cooperation in the paediatric age group constitute other limitations. However, the study provided valuable data in terms of monitoring the patients for six months and monitoring the improvement of the findings in cases with pathological findings.
Conclusion
In our study, a relationship was found between subconjunctival haemorrhage and hospitalisation in the intensive care and the severity of the disease. Subconjunctival haemorrhage may be an examination finding that can give us information about the course of the disease. However, there is not enough information on this subject in the literature yet.
Moreover, a significant increase was observed in Schirmer 2 tests between the first and the sixth months in our study. Additionally, no pathological findings were observed in the anterior and posterior segments at the sixth-month examination of the patients, and improvement was found in all patients with pathological ocular findings. It was seen that two cases with optic disc oedema also returned to normal in the first-month examination.
MIS-C is a newly defined disease and information about the disease is very limited. It is not known what changes occur in the eye in patients who have undergone MIS-C. This study is important in terms of establishing ocular follow-up protocols that are foreseen to be carried out both in the acute period and in the follow-up of the patients. More publications are needed to elucidate the MIS-C ophthalmologic examination findings in the acute and chronic stages.
Summary
What was known before
-
The most frequently reported ocular finding in the acute phase of the multisystem inflammatory syndrome in children is conjunctivitis.
What this study adds
-
The most striking finding of our study is that cases with subconjunctival haemorrhage were clinically more severe, and all patients needed intensive care.
Data availability
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock inchildren during COVID-19 pandemic. Lancet. 2020;395: P1607–8.
Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe awasaki-like disease at the Italian epicentre of the SARS CoV-2 epidemic: an observational cohort study. Lancet. 2020;95:1771–8.
Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: review of clinical 247 presentation, hypothetical pathogenesis, and proposed management. Children. 2020;7:69.
Rowley AH. Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat Rev Immunol. 2020;20:453–4.
Belot A, Antona D, Renolleau S, Javouhey E, Hentgen V, Angoulvant F, et al. SARS CoV-2-related paediatric inflammatory multisystem syndrome, an epidemiological study, France, 1 March to 17 May 2020. Euro Surveill. 2020;25:2001010.
Lo TC, Chen YY. Ocular and systemic manifestations in paediatric multisystem inflammatory syndrome associated with COVID-19. J Clin Med. 2021;10:2953.
Rafferty MS, Burrows H, Joseph JP, Leveille J, Nihtianova S, Amirian ES. Multisystem inflammatory syndrome in children (MIS-C) and the coronavirus pandemic: current knowledge and implications for public health. J Infect Public Health. 2021;14:484–94.
Öztürk C, Yüce Sezen A, Savaş Şen Z, Özdem S. Bilateral acute anterior uveitis and corneal punctate epitheliopathy in children diagnosed with multisystem inflammatory syndrome secondary to COVID-19. Ocul Immunol Inflamm. 2021;15:1–5.
Divya K, Indumathi C, Vikrant K, Padmanaban S. Pseudotumor cerebri complicating multisystem inflammatory syndrome in a child. J Curr Ophthalmol. 2021;33:358–62.
Bilen NM, Bal ZS, Arslan SY, Kanmaz S, Kurugol Z, Ozkinay F. Multisystem inflammatory syndrome in children presenting with pseudotumor cerebri and a review of the literature. Pediatr Infect Dis J. 2021;40:497–500.
Baccarella A, Linder A, Spencer R, Jonokuchi AJ, King PB, Maldonado-Soto A, et al. Increased intracranial pressure in the setting of multisystem inflammatory syndrome in children, associated with COVID-19. Pediatr Neurol. 2021;115:48–9.
Becker AE, Chiotos K, McGuire JL, Bruins BB, Alcamo AM. Intracranial hypertension in multisystem inflammatory syndrome in children (MIS-C). J Pediatr. 2021;233:263–274.
Cetin BS, Kısaarslan AP, Baykan A, Akyıldız BN, Poyrazoglu H. Erciyes Clinical Guideline For Multisystem Inflammatory Syndrome In Children (MIS-C) Associated With COVİD-19: Erciyes MIS-C Guideline. J Pediatr Acad. 2022;3:87–94.
Hoste L, Van Paemel R, Haerynck F. Multisystem inflammatory syndrome in children related to COVID-19: a systematic review. Eur J Pediatr. 2021;180:2019–34.
Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet. Infect. Dis. 2020;20:276–88.
Alnahdi MA, Alkharashi M. Ocular manifestations of COVID-19 in the pediatric age group. Eur J Ophthalmol. 2022;3:21–8.
Fernández Alcalde C, Granados Fernández M, Nieves Moreno M, Calvo Rey C, Falces Romero I, Noval Martin S. COVID-19 ocular findings in children: a case series. World J Pediatrics WJP. 2021;17:329–34.
Kabeerdoss J, Pilania RK, Karkhele R, Kumar TS, Danda D, Singh S. Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: Immunological mechanisms, clinical manifestations and management. Rheumatol Int. 2021;41:19–32.
Angurana SK, Kumar A, Malav T. Hemorrhagic nonpurulent conjunctivitis in MIS-C. Indian J Pediatr. 2022;89:195–6.
Chen L, Deng C, Chen X, Zhang X, Chen B, Yu H, et al. Ocular manifestations and clinical characteristics of 535 cases of COVID-19 in Wuhan, China: a cross-sectional study. Acta Ophthalmol. 2020;98:951–9.
Kemeny-Beke A, Szodoray P. Ocular manifestations of rheumatic diseases. Int Ophthalmol. 2020;40:503–10.
Heidary G. Pediatric papilledema: review and a clinical care algorithm. Int Ophthalmol Clin. 2018;58:1–9.
Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med. 2020;383:347–58.
Author information
Authors and Affiliations
Contributions
EKG and EKO designed the study and the computational framework and analysed the data. EKG and AS carried out the implementation. AKA performed the calculations. EKG wrote the manuscript with input from all authors. DY and YEK conceived the study and were in charge of overall direction and planning.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kaya-Guner, E., Sahin, A., Ekemen-Keles, Y. et al. A prospective long-term evaluation of the ocular findings of children followed with the diagnosis of multisystem inflammatory syndrome (long-term evaluation of ocular findings following MIS-C). Eye 37, 3442–3445 (2023). https://doi.org/10.1038/s41433-023-02530-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41433-023-02530-y