This case illustrates the diagnostic and management challenges of infratentorial-predominant posterior reversible encephalopathy syndrome (IPPRES), an uncommon PRES variant with life-threatening potential due to involvement of brainstem respiratory centers.
Diagnostic Challenge
IPPRES represents a distinct clinical entity that is frequently misdiagnosed. While cerebellar involvement occurs in approximately 30–34% of PRES cases, it typically accompanies supratentorial findings (1, 2). Isolated or predominant infratentorial involvement is considerably rarer, representing only 7.5% of PRES cases in one institutional series (3). In this patient, the initial CT hypodensity in the left cerebellum appropriately raised concern for acute ischemic stroke. However, the subsequent MRI findings of bilateral T2/FLAIR hyperintensity with minimal diffusion restriction confirmed vasogenic rather than cytotoxic edema, establishing the diagnosis of PRES. This case reinforces that IPPRES should be considered in the differential diagnosis of acute posterior fossa syndromes, particularly when hypertension accompanies atypical stroke presentations.
Differential Diagnosis
Two primary diagnoses warranted consideration. Acute ischemic stroke was initially suspected given the unilateral CT hypodensity; however, MRI demonstrated predominantly vasogenic edema inconsistent with infarction. Reversible cerebral vasoconstriction syndrome (RCVS) merits discussion given the patient's thunderclap headache, the hallmark feature of RCVS. Although CTA did not reveal the characteristic "string-of-beads" appearance, PRES and RCVS exist on a pathophysiological spectrum, with up to 38% of RCVS patients demonstrating concurrent PRES findings (4). The absence of serial angiography precludes definitive exclusion of RCVS.
Proposed Pathophysiology
The temporal association between vaccination and symptom onset of approximately 2 hours raises the possibility of an immune-mediated contribution to PRES development in this case, though causation cannot be established. A recent systematic review of the VAERS database identified 20 cases of PRES following vaccination, predominantly COVID-19 mRNA vaccines, with a mean time to symptom onset of 10.5 days (9). Our patient's presentation within 2 hours is notably shorter than this reported interval.
The pathophysiology of PRES involves either hyperperfusion from hypertension exceeding cerebral autoregulatory capacity (typically MAP > 150 mmHg), or primary endothelial dysfunction from circulating toxins or cytokines (1, 6). In this case, the patient's MAP of approximately 137 mmHg was below the traditional autoregulatory threshold but may have been sufficient to precipitate PRES in the setting of pre-existing endothelial vulnerability. We speculate that vaccine-induced immune activation with associated release of pro-inflammatory cytokines including TNF-α and IL-6 may have primed the cerebrovascular endothelium, effectively lowering the hypertensive threshold required for blood-brain barrier disruption (7, 8). This "two-hit" hypothesis remains speculative, as cytokine levels were not measured.
The predominant infratentorial distribution may reflect the posterior circulation's relative paucity of sympathetic innervation compared to the anterior circulation, rendering it more vulnerable to autoregulatory failure during hypertensive surges (5).
Mechanism of Respiratory Arrest
A critical teaching point of this case is the pathogenesis of respiratory arrest, which was likely multifactorial. "Malignant PRES," while lacking a standardized definition, has been described as PRES complicated by brainstem herniation, status epilepticus, or respiratory failure (1). In our patient, three mechanisms may have contributed: (1) direct ponto-medullary compromise from vasogenic edema affecting respiratory centers, (2) postictal suppression of brainstem cardiorespiratory function, and (3) opioid-induced respiratory depression via mu-receptor-mediated suppression of medullary respiratory drive. Notably, the patient's brainstem involvement likely diminished her respiratory reserve, such that a standard dose of hydromorphone acted as the final precipitant on an already compromised system. This underscores that respiratory deterioration in IPPRES may reflect brainstem dysfunction rather than simple medication effect, requiring heightened vigilance and consideration of airway protection.
Limitations
Several limitations warrant acknowledgment. First, as a single case report, causation between vaccination and PRES cannot be established; temporal association alone is insufficient given that millions of individuals receive vaccinations daily without adverse events. Second, no rechallenge occurred to confirm association, nor was a cytokine panel obtained to support the proposed immune-mediated mechanism. Third, the patient was lost to neurologic follow-up without repeat imaging, preventing confirmation of radiographic reversibility, a defining feature of PRES. Finally, alternative explanations for respiratory arrest, such as primary seizure-related apnea, could not be definitively excluded.