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, 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.