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\begin{document}

\title{COVID-19 encephalitis as a differential diagnosis of a Cyclosporine
related Posterior Leukoencephalopathy Syndrome (PRES)}



\author[1]{sanda mrabet}%
\author[1]{Achraf Jaziri}%
\author[1]{maha araoud}%
\author[2]{Wissal Sahtout}%
\author[1]{Dorsaf Zellama}%
\author[1]{Abdellatif Achour}%
\author[3]{Nihed Abdessayed}%
\author[3]{Moncef Mokni}%
\author[1]{Salma Naija}%
\author[2]{Sana Ben Amor}%
\author[1]{Alaa Souissi}%
\author[1]{Hela Jemni}%
\affil[1]{Sahloul University Hospital}%
\affil[2]{Affiliation not available}%
\affil[3]{Farhat Hached University Hospital of Sousse}%


\vspace{-1em}



  
  \date{May 14, 2024}


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\selectlanguage{english}
\begin{abstract}
PRES is a rare neurological disease possibly associated with the use of
calcineurin inhibitors like cyclosporine A. Severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, is responsible
for the outbreak of coronavirus disease 19 (COVID-19) and can cause
neurological manifestations. We describe a case of CSA-related PRES
whose diagnosis was difficult due to concurrent infection with
SARS-CoV-2. The 16-year-old patient was known to have
corticosteroid-resistant nephrotic syndrome secondary to minimal change
disease. CSA was therefore introduced and on the fifth day of treatment,
he presented with seizures followed by fever. Biological and MRI data
were in favor of SARS-CoV-2 encephalitis. Relief of immunosuppression by
discontinuation of CSA was decided and the patient was put on
anticonvulsants. After being declared cured of COVID-19, which was
without other clinical signs, the CSA was reintroduced but the patient
presented with seizures the next day. This allowed us to rectify the
diagnosis and relate the seizures to a CSA-related PRES. We concluded
that infection with SARS-CoV-2 could be a differential diagnosis of a
PRES related to anticalcineurins.%
\end{abstract}%



\sloppy


\textbf{Introduction}

PRES is a serious neurological disorder of (sub) acute onset
characterized by abnormalities in cerebral white matter. Clinical
symptoms may include headaches, visual disturbances, disorders of
consciousness, seizures, or focal neurological deficits {[}1{]}. PRES
develops frequently in the context of cytotoxic medication, (pre)
eclampsia, sepsis, renal disease, or autoimmune disorders~{[}1{]}.

Among drugs,~PRES~may complicate calcineurin inhibitors such as
cyclosporine A (CSA). Organ-transplanted patients and those with
nephrotic syndrome on this drug have reportedly experienced this
complication {[}2, 3, and 4{]}.

This article reports a unique and challenging case of a 16-year-old boy
admitted to our department with steroid-resistant nephrotic syndrome
(NS) and COVID-19 in February 2022. SARS-CoV-2 infection misled the
diagnosis of CSA-induced PRES.

\textbf{Case Report}

The patient is a 16-years-old Tunisian boy known for nephrotic syndrome
related to a minimal change disease diagnosed based on a renal biopsy in
October 2021. In February 2022, he was admitted to the Nephrology
department for a corticosteroid-resistant NS with severe adverse events
of glucocorticoids (Cushing syndrome, glaucoma, and dyslipidemia).On
clinical examination, the boy's weight was 75 kg, his height was 1.68m,
and he was afebrile and had no respiratory symptoms. His blood pressure
was 130/70 mmHg with a heart rate of 80 beats per minute. He also had
lower limb edema related to his nephrotic syndrome. Regarding his
corticosteroid nephrotic syndrome, we decided to start CSA treatment at
a dose of 3mg/kg/day with progressive tapering of corticosteroids.

On the fifth day of CSA start, the patient presented two short left
clonic focal seizures with a duration inferior to two minutes. After one
minute, he had a third motor focal onset seizure with secondary
generalization and conscious alteration. The recovery of consciousness
was after 30 minutes. Apart from a high CRP, biological tests were in
the normal range and could not explain these symptoms (Table 1).
Intravenous sodium valproate was initiated quickly and we have not
objectified a new seizure. The cranial magnetic resonance imaging (MRI)
showed leptomeningeal enhancement with a predilection in the cerebellar
hemispheres (Figure 1). The cerebrospinal fluid (CSF) analysis
shoIntravenouswed normal cellularity with hyperproteinorachia (0.71g/l)
(Table 2) and the CSF bacterial culture was negative. In the meantime,
the patient experienced sinus tachycardia, with one episode of fever.
Therefore, we decided to perform nasopharyngeal RT-PCR for
SARS-CoV-2since the patient was in contact with a COVID-19 subject. The
test returned positive.

Although the RT-PCR for SARS-CoV-2in the CSF was negative, the data from
the MRI and the CSF analysis, along with the positivity of the
nasopharyngeal RT-PCR for SARS-CoV-2, led to the diagnosis of secondary
encephalitis to SARS-CoV-2infection. As a result, we decided to
discontinue CSA, being immunosuppressive, during the infectious period.

For the next ten days, the patient showed no recurrence of the seizure,
did not require oxygen therapy, and did not present any new symptoms.
After a second nasopharyngeal swab for SARS-CoV-2 that was negative, the
patient was declared cured. The analysis of the CSF of a second lumbar
punction analysis showed normal cellularity with normal glycorrhachia
and proteinorachia. The patient was discharged with a maintenance oral
dose of sodium valproate. Two weeks later, the patient had not
experienced any recurrence of neurological symptoms and he had a
persistent severe nephrotic syndrome. Therefore, we decided to restart
CSA treatment. Despite being under an anti-epileptic drug, the patient
experienced generalized tonic-clonic seizure one day after the
immunosuppressant resumed treatment. This allowed us to rectify the
diagnosis and relate the seizures to the CSA. A second cranial MRI
(Figure 2) showed a progression of the previous lesions and the
appearance of new cortical and subcortical hyperintensities in axial
FLAIR- weighted and diffusion in the biparietal and right frontal lobe
with an exaggerated meningeal gadolinium enhancement in front of these
lesions. Imaging, as well as clinical data and the causal link with the
taking of the treatment, the diagnosis of CSA-induced PRES, was
retained. As an alternative to CSA, we opted for Rituximab at a dose of
1g per dose (two doses spaced two weeks apart) with good clinical and
biological tolerance.

\textbf{Discussion}

Herein we reported the case of a 16-year-old boy whose treatment by CSA
for a corticoresistant nephrotic syndrome was complicated by a PRES. The
diagnosis of CSA-related PRES was challenging since it was initially
mistaken for COVID-19 encephalitis.

The primary pathophysiological process of PRES, first described by
Hinchey et al. in 1996 {[}5{]}, was identified as vasogenic edema that
denotes fluid extravasation from intracerebral capillaries {[}3{]}. It
is believed that the underlying cause of PRES may create a breakdown in
cerebral autoregulation, leading to the leakage of fluid into the brain
parenchyma. In these patients, either passive over distension of the
vessels due to elevations in blood pressure or direct toxic effects on
the endothelium {[}6{]} blunt the myogenic response.

The consequent symptoms are variable ranging from confusion headache,
nausea vomiting, and visual disturbance, to encephalopathy, and seizures
associated with transient lesions on neuroimaging {[}7{]}.

CSA was found to be efficient in decreasing proteinuria in both
steroid-dependent and steroid-resistant nephrotic patients and is now
largely used in nephrology {[}8{]}. The association of PRES with CSA use
has been previously described in NS patients, with successful recovery
after drug withdrawal {[}3, 9, and 10{]}. Although the exact prevalence
has not yet been determined\textbf{,} 5.7\% of pediatric patients with
nephrotic syndrome who received cyclosporine developed PRES during the
previous series of observations {[}3{]}. Cyclosporine is responsible for
a direct endothelial dysfunction resulting in a release of endothelin,
prostacyclin, and thromboxane. These factors may cause microthrombi and
damage the blood-brain barrier {[}5{]}. In the presence of altered
permeability, CSA may overcome the blood-brain barrier and enter the
brain. In one study, the entrance of CSA into the brain inhibited
gamma-aminobutyric acid neurotransmission in rats, resulting in
convulsions {[}11{]}.

It is worth mentioning that NS itself may be a predisposing factor for
developing PRES in both adults and children {[}3{]}. In addition to CSA,
Other factors seen in the nephrotic state could induce vasogenic edema
due to decreased intravascular oncotic pressure, increased permeability
of intracerebral capillaries, and fluid overload. Furthermore, children
with hypertension, high-dose steroid treatments, hypercholesterolemia,
high proteinuria levels, and low serum albumin levels are at a higher
risk of PRES {[}13{]}. Our case had all these risk factors mentioned
above. On the other hand, he also presented another possible explanation
for seizures and PRES: SARS-CoV-2 infection. Indeed, SARS-CoV-2has
recently been admitted to be a potential cause of PRES {[}14, 15{]}.
There are two possible explanations in this context. Firstly, SARS-CoV-2
is known to cause endothelial dysfunction. Furthermore, the virus binds
directly to the angiotensin-converting enzyme 2 (ACE2) receptors causing
an increase in blood pressure along with the weakening of the
endothelial layer. Consequently, this leads to a weakened blood-brain
barrier, which may result in dysfunction of the brain's autoregulation
of cerebral circulation {[}15{]}. The prevalence of PRES in COVID-19
patients is estimated to be between 1--4\% {[}16{]}.

However, the resumption of seizures directly after reinitiating of
treatment made it possible to incriminate CSA as the cause of PRES in
the reported case.

Considering all of this, we believe that CSA and SARS-CoV-2 infection
may have synergistic neurologic toxic effects in our case. Therefore,
this may explain the short period between the treatment initiation and
the symptom installation. As reported in the literature, this period can
range from one week to as long as 26 months {[}5, 17{]}. Our patient
experienced neurological manifestations four days after CSA initiation
and was diagnosed with COVID-19 on the same day of symptoms onset.

On another hand, we wonder if CSA had a protective effect against
SARS-CoV-2 in the reported case. Indeed, although he was
immunosuppressed, he did not present with a severe form of infection.
That may be explained by the capacity of CSA to inhibit the replication
of several different coronaviruses in vitro, as demonstrated by several
independent studies {[}18{]}.

The MRI is the gold standard exam to confirm PRES. It shows high-density
signals in the white matter, especially in the occipital or temporal
area {[}7{]}. This preference distribution may be due to the paucity of
sympathetic innervation in this vascular territory {[}10{]}. In addition
to parieto-occipital involvement, high signal intensity areas may be
seen in the frontal lobe in up to 82\% of patients {[}11{]}. Involvement
of the anterior circulations and regions other than the
parieto-occipital lobes like the cerebellum (34.2\%) is, therefore,
common {[}19{]}. In this case, occasionally called atypical PRES.

\textbf{Conclusion}

Through this observation, we come to two conclusions. Firstly, infection
with SARS-CoV-2 could be a differential diagnosis of a PRES related to
anticalcineurins. Nevertheless, it is essential to establish the correct
diagnosis because management depends on it. Secondly, CSA would be a
protective factor against infection by SARS-CoV-2 and its cessation
would not be justified during infection by this virus.

\textbf{References:}

1. Fischer M, Schmutzhard E. Posterior reversible encephalopathy
syndrome. J Neurol. 2017;264(8):1608-1616. doi:10.1007/s00415-016-8377-8

2. Huenges K, Kolat P, Panholzer B, Haneya A. CSA-Induced PRES after
Heart Transplantation-Report of Two Cases and Review. Thorac Cardiovasc
Surg Rep. 2021;10(1):e59-e60. doi:10.1055/s-0041-1732344

3. Ishikura K, Ikeda M, Hamasaki Y, et al. Nephrotic state as a risk
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4. de Oliveira RA, Fechine LM, Neto FC, Nicodemus JM, Silva GB, Silva
LSV. Posterior reversible encephalopathy syndrome (PRES) induced by
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5. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior
leukoencephalopathy syndrome. N Engl J Med. 1996;334(8):494-500.
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6. Roy S, Gandhi AK, Jana M, Julka PK. Recurrent posterior reversible
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7. Lee VH, Wijdicks EFM, Manno EM, Rabinstein AA. Clinical spectrum of
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9. Zhang Y, Zhou J, Chen Y. Posterior reversible encephalopathy syndrome
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14. Harapan BN, Yoo HJ. Neurological symptoms, manifestations, and
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doi:10.2214/AJR.07.2024

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