\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[greek,ngerman,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{Multisystem inflammatory syndrome in children (MIS-C) caused a rare
presentation of ataxia and papilledema; A case report}



\author[1]{hesam nabavizadeh}%
\author[1]{Rafat Noeiaghdam}%
\author[1]{Leila Johari}%
\author[2]{Hamidreza Ghasemirad}%
\author[1]{Reza Moshfeghinia}%
\affil[1]{Shiraz University of Medical Sciences}%
\affil[2]{Shahid Sadoughi  University of Medical Sciences and Health Services}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup








\sloppy


\textbf{Multisystem inflammatory syndrome in children (MIS-C) caused a
rare presentation of ataxia and papilledema; A case report}

Running title: a multi-system inflammatory syndrome in children (MIS-C)
with ataxia and papilledema

\textbf{Abstract:}

Background: Multisystem inflammatory syndrome in children (MIS-C) is
observed with severe signs of COVID-19. Some reports indicated the
effect of MIS-C on the neurological manifestations of the children.

Case presentation: A 13-year-old Iranian boy was transferred to the
emergency department of Shiraz, Iran in May 2022 from a deprived area
with fever, generalized skin rashes, palmar erythema, vomiting, vomit,
and diarrhea. Severe conjunctivitis, photophobia, headache, and ataxia
were also observed on the day of admission. His neurological
manifestations were improved by the treatments including high-dose
methylprednisolone and intravenous immunoglobulin (IVIG). He was
discharged nine days after the admission\textbf{.}

Conclusions: Because of the low presence of ataxia and papilledema in
MIS-C after COVID-19, as far as we know, we presented the first study of
this presentation.

\textbf{Keywords:} Multisystem inflammatory syndrome; COVID-19; Ataxia;
Papilledema

\textbf{Background:}

Multisystem inflammatory syndrome in children (MIS-C) is observed in
children with severe signs of COVID-19. MIS-C is known as a multisystem
inflammation in individuals below 21 years with the presentation of
organ involvement (at least two organs out of 4 including heart, skin,
eye, and gastrointestinal organs), laboratory signs of inflammation,
fever, and being in contact with a COVID-19 patient or SARS-COV2
confirmed by laboratory tests (1). The incidence of neurologic symptoms
like headache, meningitis, encephalopathy, photophobia, fever, and
rarely papilledema and ataxia was 13--21\% in MIS-C patients (2). Ataxia
contains an absence of coordination of muscle movements including eye
movements abnormality, gait abnormality, and speech changes. Some types
of ataxia like acute post-infectious cerebellar ataxia can take place
among children after bacterial or viral infections (3). Papilledema is
known as swelling of optic nerves as a result of high intracranial
pressure, which leads to nerve damage and vision loss. It may be a
hallmark of pseudotumor cerebri. Pseudotumor cerebri is known for the
elevation of lumbar puncture (LP) opening pressure, normal Magnetic
Resonance Imaging (MRI) findings, and abducens palsy but other normal
neurological exams. High intracranial pressure may be induced by
inflammatory disorders like Kawasaki disease and systemic lupus
erythematosus (4). As far as we know, we reported the first case of
MIS-C presented by papilledema and ataxia, simultaneously.

\textbf{Case presentation:}

A 13-year-old Iranian boy without any underling disease was transferred
to the emergency department of Shiraz, Iran in May 2022 from a deprived
area with the symptoms of fever since 5 days ago, generalized skin
rashes, palmar erythema, nausea, vomiting, and diarrhea. Severe
conjunctivitis, photophobia, headache, and ataxia were also observed on
the day of admission. He was moved to the pediatric intensive care unit
(PICU) for additional management. His vital signs were blood pressure of
114/57 mmHg, pulse rate of 111 PR/min, respiratory rate of 20 RR/min,
the body temperature of 37.8 centigrade, and oxygen saturation of 96\%
without oxygen supplements at rest in the room. Polymerase Chain
Reaction (PCR) was negative for COVID-19 but the serology IgG and IgM
test was positive. No signs of respiratory disorder were observed. In
the physical examination, conjunctivitis, loss of vision, and strawberry
tongue were seen. The sounds of the heart and lungs were bilaterally
clear.

Inflammatory markers were elevated in the first days of admission. Full
laboratory results were summarized in Table 1.

Table 1-The detailed laboratory tests by day of admission\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Test & Admission day & Discharge day\tabularnewline
Hemoglobin, g/dL & 11.2 & 12.3\tabularnewline
Hematocrit, \% & 33.1 & 37.3\tabularnewline
White blood cell, cells per mm & 8.4 & 12.9\tabularnewline
Neutrophil, \% & 89.3 & 76\tabularnewline
Lymphocyte, \% & 7.5 & 14\tabularnewline
Platelet, cells per mm & 123 & 346\tabularnewline
CRP, \textless{}6 mg/L & \textgreater{}150 & 14\tabularnewline
ESR, mm/h & 76 & 48\tabularnewline
Albumin & 20.3 & 3.6\tabularnewline
CPK, mcg/L & 31 &\tabularnewline
D-dimer, \selectlanguage{greek}μ\selectlanguage{english}g/mL & 2850 &\tabularnewline
Procalcitonin & & 1.15\tabularnewline
Troponin I & Negative &\tabularnewline
Fibrinogen level, mg/dL & 506.2 &\tabularnewline
Blood culture & No growth & No growth\tabularnewline
Urine culture & No growth & No growth\tabularnewline
Sodium, mEq/L & 139 &\tabularnewline
Potassium, mEq/L & 4 &\tabularnewline
Albumin & 20.3 & 3.6\tabularnewline
Creatinine, mg/dL & 0.95 & 1.15\tabularnewline
BUN, mg/dL & 14 & 22\tabularnewline
AST, U/L & 145 & 43\tabularnewline
ALT, U/L & 294 & 51\tabularnewline
CRP indicates C-reactive protein; ESR, Erythrocyte sedimentation rate;
CPK, Creatine phosphokinase; LDH, Lactate dehydrogenase; BUN, Blood Urea
Nitrogen; AST, Aspartate transaminase; ALT, Alanine transaminase & CRP
indicates C-reactive protein; ESR, Erythrocyte sedimentation rate; CPK,
Creatine phosphokinase; LDH, Lactate dehydrogenase; BUN, Blood Urea
Nitrogen; AST, Aspartate transaminase; ALT, Alanine transaminase & CRP
indicates C-reactive protein; ESR, Erythrocyte sedimentation rate; CPK,
Creatine phosphokinase; LDH, Lactate dehydrogenase; BUN, Blood Urea
Nitrogen; AST, Aspartate transaminase; ALT, Alanine
transaminase\tabularnewline
\bottomrule
\end{longtable}

Because of the involvement of three main organs (brain, skin, and
gastrointestinal organs), the diagnosis of Multisystem inflammatory
syndrome in children (MIS-C) was suspected. brain MRI and retinal nerve
fiber layer (RNFL) thickness and optic nerve head (ONH) analysis were
reported with the signs of papilledema and flattening of the posterior
globe (Figure 1 and 2), and the sonography of kidneys showed marked
parenchymal thinning and cortical damage. The echography showed minimal
pericardial effusion and trivial tricuspid and pulmonary valve
regurgitation. Lumbar Puncture (LP) was performed on the patient. The
result showed opening pressure of 40 cmH2O. The pressure of CSF was 30
cmH2O. Protein of 28, sugar of 65, and 0 cell count were also observed.

\textbf{Figure 1- Magnetic Resonance Imaging (MRI). The signs of
papilledema and flattening of the posterior globe}

\textbf{Figure 2- Optic nerve head (ONH) and retinal nerve fiber layer
(RNFL) - signs of papilledema}

As the result, high dose methylprednisolone for 3 days and acetazolamide
were started for the patient. Due to loss of vision, high opening
pressure in LP, eye problems, papilledema, and ataxia treatment with
high-dose methylprednisolone 30 mg/kg three times a day and Intravenous
Immunoglobulin (IVIG) IV stat in 10-12 hours (2gr/kg), ciprofloxacin eye
drop, ceftriaxone 1gr Intravenous (IV) per 12 hours, intravenous
acetaminophen (Apotel) 650 mg IV stat, were started for the patient.
After these chain of therapies 10 days after the admission, the headache
and ataxia of the patient were disappeared, the vision became better
than before and the ophthalmology reports were shown no signs of
papilledema. He was discharged with the treatment of prednisolone 15mg
four times a day for three days, acetazolamide 250mg, and betamethasone,
and ciprofloxacin. At the day of discharge ESR and CRP were reduced but
the count of WBC was elevated.

\textbf{Discussion and Conclusions:}

The prevalence of neurologic symptoms in MIS-C is not completely clear
in the past articles, but it may be about 20\% in complicated cases (5,
6). MIS-C has some neurological manifestations like encephalopathy,
reduced reflexes, muscle weakness, and headaches; (7). In a study
showing neuroimaging presentations in children, encephalopathy with
SARS-CoV-2, acute encephalomyelitis-like changes of the brain, and
myelitis were also the common presentations. Corpus callosum reversible
changes was observed in MIS-C patients in some cases, but
cerebrovascular disorders in children were less than adults (8). Ataxia
is not common in the presentation of MIS-C. Even though acute ataxia is
commonly presented in children, it is rare in SARS-COV2 patients. This
rare happening can be related to children's relative resistance to the
severe types of COVID-19. Cerebellar ataxia is common in children 2-5. 9
years old as an uncommon age range for COVID-19 infection. It might take
place because of immunosuppression or chronic diseases conditions (9).
Further investigations are needed to investigate the presence of ataxia
in MIS-C children after COVID-19.

As far as we know, we reported the first case of ataxia in a MIS-C
patient with the presentation of other rare manifestations like
papilledema. Ak\selectlanguage{ngerman}çay et al. reported a rare case of cerebellitis in a
MIS-C patient. The signs of nystagmus, ataxia, and dysarthria were
observed in the child. But the patient wasn't complicated with the signs
of eye problems (10).

Due to ataxia and headache in our case, the patient underwent brain MRI
and CSF assessment by LP. Papilledema were observed in MRI of our
patient as a rare presentation of MIS-C. LP was abnormal in about one
fourth of the past studies' investigations (11). CSF assessment revealed
high opening pressure (40 cmH2O) and elevation of the pressure of CSF
(30 cmH2O). The etiology of this high pressure in MIS-C patients is not
still completely clear (12). Additionally, high opening pressure caused
by immunomodulatory treatment earlier than LP could be mistaken as a
result of MIS-C instead of aseptic meningitis (13). But because of
starting pulse therapy with methylprednisolone after LP, one of the
reasons for high pressure could be because of the presence of MIS-C. In
our patient, abnormal circulation of CSF might lead to papilledema and
ataxia, simultaneously.

The results of kidney sonography revealed marked parenchymal thinning
and cortical damage. The level of ferritin was 506.2 at the fourth day
of admission. High level of ferritin is significantly associated with
acute kidney injury. As an inflammatory marker it is also observed in
hepatitis. The levels of ALT and AST were significantly high at the
fifth day of admission. Due to statistical analysis, the prevalence of
hepatitis and acute kidney injury were 49\% and 25\%, respectively (14).

In spite of reduction of neutrophil, ESR and CRP after the treatment,
the WBC count increased significantly. It might be because of the role
of methylprednisolone as a glucocorticoid in the elevation of WBC count
after the treatment (15).

Due to rare presence of ataxia and papilledema in MIS-C after COVID-19,
as far as we know, we presented the first study of this presentation.
Neurologic symptoms, especially Pseudotumor cerebri, should be kept in
mind in MIS-C patients, and for prevention of vision loss even in mild
cases of MIS-C treatment also should be started immediately.

\textbf{Declarations}

\textbf{Ethics approval and consent to participate}

The authors confirm that they have obtained all proper patient consent
forms. The patient has consented for his images and other clinical
information to be reported in the journal. The patient understands that
his name and initials will not be published and due efforts will be made
to conceal his identity, but anonymity cannot be guaranteed. Also, a
signed and consent form was received from the patient in Persian. All
methods were performed in accordance with the ethical standards in the
Declaration of Helsinki.

\textbf{Consent for publication}

Written informed consent was obtained from the patient for publication
of this case report and accompanying images

\textbf{Availability of data and materials}

All data an materials of the study are available by corresponding author

\textbf{Competing interests}

The authors declare that they have no competing interests

\textbf{Funding:}

No funding was received for this work

\textbf{Authors' contributions}

ShN and RN saw the case for the first time and realized its specialness
and completed its information with the cooperation of LJ. RM and HG did
the work of writing and reviewing the literature and collecting
information, also ShN managed all the steps as the professor and
supervisor of team. All authors read and approved the final manuscript.

\textbf{Acknowledgment:}

The authors would like to thank all the persons and staff help us with
this report.

\textbf{References:}

1. CDC Health Alert Network. Multisystem Inflammatory Syndrome in
Children

(MIS-C) Associated With Coronavirus Disease 2019 (COVID-19). Available

online at: https://emergency.cdc.gov/han/2020/han00432.asp (accessed
April

27, 2022)

2. Radia T, Williams N, Agrawal P, Harman K, Weale J, Cook J, et al.
Multi-system inflammatory syndrome in children \& adolescents (MIS-C): A
systematic review of clinical features and presentation. Paediatric
respiratory reviews. 2021;38:51-7.

3. Tomar LR, Shah DJ, Agarwal U, Batra A, Anand I. Acute Post-Infectious
Cerebellar Ataxia Due to COVID-19. Mov Disord Clin Pract.
2021;8(4):610-2.

4. Becker AE, Chiotos K, McGuire JL, Bruins BB, Alcamo AM. Intracranial
Hypertension in Multisystem Inflammatory Syndrome in Children. J
Pediatr. 2021;233:263-7.

5. LaRovere KL, Riggs BJ, Poussaint TY, Young CC, Newhams MM, Maamari M,
et al. Neurologic involvement in children and adolescents hospitalized
in the United States for COVID-19 or multisystem inflammatory syndrome.
JAMA neurology. 2021;78(5):536-47.

6. Son MBF, Friedman K. COVID-19: Multisystem inflammatory syndrome in
children (MIS-C) clinical features, evaluation, and diagnosis. upToDate.
Waltham.(Accessed on August 19, 2021); 2021.

7. Olivotto S, Basso E, Lavatelli R, Previtali R, Parenti L, Fiori L, et
al. Acute encephalitis in pediatric multisystem inflammatory syndrome
associated with COVID-19. Eur J Paediatr Neurol. 2021;34:84-90.

8. Lindan CE, Mankad K, Ram D, Kociolek LK, Silvera VM, Boddaert N, et
al. Neuroimaging manifestations in children with SARS-CoV-2 infection: a
multinational, multicentre collaborative study. The Lancet Child \&
Adolescent Health. 2021;5(3):167-77.

9. O'Neill KA, Polavarapu A. Acute Cerebellar Ataxia Associated with
COVID-19 Infection in a 5-Year-Old Boy. Child Neurology Open.
2021;8:2329048X211066755.

10. Akçay N, O\selectlanguage{polish}ğ\selectlanguage{english}ur M, Emin Menento\selectlanguage{polish}ğ\selectlanguage{english}lu M, \selectlanguage{polish}İ\selectlanguage{english}rem Sofuo\selectlanguage{polish}ğ\selectlanguage{english}lu A, Boyda\selectlanguage{polish}ğ \selectlanguage{english}G\selectlanguage{ngerman}üvenç
K, Bakirta\selectlanguage{polish}ş \selectlanguage{english}Palabiyik F, et al. Acute Cerebellitis in MIS-C: A Case
Report. Pediatr Infect Dis J. 2022;41(1):e16-e8.

11. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M,
et al. An outbreak of severe Kawasaki-like disease at the Italian
epicentre of the SARS-CoV-2 epidemic: an observational cohort study. The
Lancet. 2020;395(10239):1771-8.

12. Becker AE, Chiotos K, McGuire JL, Bruins BB, Alcamo AM. Intracranial
hypertension in multisystem inflammatory syndrome in children. The
Journal of pediatrics. 2021;233:263-7.

13. Kemmotsu Y, Nakayama T, Matsuura H, Saji T. Clinical characteristics
of aseptic meningitis induced by intravenous immunoglobulin in patients
with Kawasaki disease. Pediatric Rheumatology. 2011;9(1):1-5.

14. Guimar\selectlanguage{ngerman}ães D, Pissarra R, Reis\selectlanguage{english}-Melo A, Guimaraes H. Multisystem
inflammatory syndrome in children (MISC): a systematic review.
International Journal of Clinical Practice. 2021;75(11):e14450.

15. Shoenfeld Y, Gurewich Y, Gallant LA, Pinkhas J. Prednisone-induced
leukocytosis. Influence of dosage, method and duration of administration
on the degree of leukocytosis. Am J Med. 1981;71(5):773-8.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1- Magnetic Resonance Imaging (MRI). The signs of papilledema and
flattening of the posterior globe. flattening of the posterior sclera
(red arrows) and distention of the perioptic nerve (green arrows)\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2 . Optic nerve head (ONH). The signs of papilledema.
cross-section of the optic nerve head shows swelling of the nerve fibre
layer (right, up; left, down)

\selectlanguage{english}
\FloatBarrier
\end{document}

