Teaching Case

55-year-old woman with stage IVA ovarian adenocarcinoma (peritoneal carcinomatosis), treated with chemotherapy, surgery and, during last week, immunotherapy with Niraparib.

She presented persistent vomiting, neurological deterioration and elevated blood pressure (BP) at home, and a generalized tonic-clonic seizure, 170/110 of BP, 10 points in GCS and 20000 platelets/µL in hospital.

Urgent cranial CT scan was normal.  Brain MRI was requested, showing diffuse and symmetrical signal hyperintensity on T2-weighted sequences (TSE, figure 1 and FLAIR, figure 2) of both putamen nuclei (black arrows in figure 1-2), caudate (arrowhead in figure 1-2) and anteromedial nuclei of thalami (black arrows in figure 1-2), which did not show diffusion restriction (figure 3). Millimetric enhancement with nodular morphology in both thalami and putamen nuclei (black and white arrows, respectively, in figure 4).

Background

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity that manifests in more than 90% of cases with symmetrical cortical and subcortical oedema in the parieto-occipital and posterior frontal areas [1]. The most accepted theory is the posterior circulation susceptibility to BP elevations with vasogenic oedema development [1,2]. In the central variant of PRES or "central reversible encephalopathy syndrome" [1] lesions are limited to the brainstem and/or basal ganglia, thalami and periventricular white matter while sparing cerebral cortex and subcortical white matter, constituting the 4-22% [1,2] of PRES cases. Pathophysiological mechanisms suggested are hypoperfusion due to endothelial dysfunction [1], drug cytotoxicity, inflammatory and autoimmune mechanism.

Immunotherapy is increasingly applied as cancer therapy. Due to immune system stimulation, severe forms of PRES have been described as immune-related adverse events related (ir-AEs) [1,3], as with the drug Niraparib, a poly [ADP-ribose] polymerase inhibitor used for ovarian cancer [4]. Moreover, high BP can be triggered or uncontrolled with immunotherapy, which may facilitate PRES [4].

Clinical perspective

Common symptoms in PRES are headache (51%), altered mental status (44%), seizures (42%), visual disturbances (35%), nausea or vomiting (23%) and focal neurological deficits (18%) [5]. The central variant of PRES associate arterial hypertension in more than 70% of cases [5] and predisposing factors, such as chemotherapy, immunotherapy, autoimmune disorders, or infection/sepsis/shock [5].

Imaging perspective

MRI is the gold standard diagnostic test in PRES [2] showing hyperintense lesions on T2-weighted imaging (WI). In the central variant of PRES, the central location (basal ganglia, thalami, periventricular or deep white matter, brainstem and spinal cord, li frontiers) is noteworthy, but posterior located lesions can also concur. The lesions do not show restriction on diffusion-enhanced sequences [1,5] and 23-47% show intravenous gadolinium enhancement [6–8]. Microhaemorrhages in the pons and basal ganglia are visible on susceptibility-WI in more than 50% of the central variant of PRES [1].

Outcome

The prognosis of the central variant of PRES is favourable, characteristically reversible within 2-3 weeks after early antihypertensive therapy, sedation, when necessary, triggers correction  [2,5] and biopsy avoidance. However, 50% of ICU-admitted patients may complicate with infarction [1], haemorrhage, brain herniation and fatal outcome [2]. Recurrences have been reported in 7%. The safety of restarting Niraparib after PRES as ir-AE is unknown [4]. Our patient completely recovers after antihypertensive (solinitrine and urapidil) and immunoglobulin therapy for 5 days. Niraparib was definitively discontinued.

Teaching points

- Reversible posterior encephalopathy syndrome (PRES) is an adverse effect described in patients treated with immune checkpoint inhibitors for cancer treatment.

- Clinicians should pay special attention to the development of newly diagnosed or uncontrolled hypertension during immunotherapy for early detection or prevention of this rare but serious adverse event.

- Magnetic resonance imaging is the gold standard for the diagnosis of PRES.

- In the central variant of PRES, the basal ganglia and brainstem are predominantly affected.