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.