Posterior Reversible Encephalopathy Syndrome (PRES) Associated With Medicinal Products

Purpose and Scope

Posterior reversible encephalopathy syndrome (PRES) is an acute clinicoradiological syndrome characterised predominantly by vasogenic cerebral oedema arising in the setting of disturbed cerebral vascular regulation and blood–brain barrier function. It most commonly presents with seizures, headache, altered mental status and visual disturbances, while magnetic resonance imaging (MRI) typically demonstrates areas of vasogenic oedema with a predilection for the parieto-occipital regions. The distribution is variable, however, and PRES may involve frontal, temporal, cerebellar or brainstem structures as well as the posterior cerebral regions. [1,2]

PRES is relevant to drug safety because medicinal products can contribute to the physiological disturbances that precipitate the syndrome. Associations are particularly recognised with some immunosuppressive and antineoplastic therapies, but a medicinal product may contribute through several different pathways, including hypertension, endothelial dysfunction, altered vascular tone and immune or inflammatory effects. The presence of a medicine in a patient's treatment history does not, however, establish that the medicine caused PRES. Patients who develop the syndrome may simultaneously have renal dysfunction, severe or fluctuating blood pressure, autoimmune or inflammatory disease, infection, transplantation, pregnancy-related hypertensive disease or exposure to other potentially contributory medicines. [1-4]

The pharmacovigilance assessment therefore requires two related but distinct questions. The first is whether the reported clinical and imaging findings are consistent with PRES. The second is whether the medicinal product plausibly contributed to the development of that syndrome in the individual patient. The second question cannot be answered from temporal association alone. It requires consideration of the known pharmacology and safety profile of the product, the timing and pattern of exposure, alternative explanations, concomitant treatments, relevant patient factors and the clinical course.

This article develops that assessment progressively. It first establishes the clinical and pathological basis of PRES, then examines the relationship between medicinal products and the syndrome, before moving to individual case assessment, aggregate pharmacovigilance evidence, signal evaluation and regulatory safety implications.

Understanding Posterior Reversible Encephalopathy Syndrome

PRES is a syndrome rather than a single disease with one defined cause. It represents a final common clinical and radiological pathway that can arise when cerebral vascular regulation and the integrity of the blood–brain barrier are acutely disturbed. The syndrome was originally described in patients with severe hypertension, renal disease, eclampsia and exposure to immunosuppressive medicines, but subsequent clinical experience has established a much broader range of associated conditions. [1,2]

The principal clinical manifestations reflect acute dysfunction of affected brain regions. Seizures are common and may be the presenting feature. Patients may also develop headache, nausea and vomiting, confusion or encephalopathy, reduced consciousness and visual symptoms ranging from visual blurring to cortical visual loss. Focal neurological deficits can occur when oedema affects functionally important regions. The presentation is therefore sufficiently broad that PRES cannot be diagnosed from symptoms alone. [1,2]

Neuroimaging provides an essential part of the diagnostic assessment. MRI is more sensitive than computed tomography for detecting the characteristic abnormalities and generally demonstrates areas of increased T2-weighted and fluid-attenuated inversion recovery (FLAIR) signal corresponding predominantly to vasogenic oedema. A parieto-occipital distribution is characteristic but not required. Atypical patterns, including frontal, temporal, cerebellar and brainstem involvement, are well recognised. Haemorrhagic complications and areas of restricted diffusion may also occur. [1,2]

The terms posterior and reversible therefore require qualification. The oedema is often posterior but is not necessarily confined to the posterior cerebral hemispheres. Similarly, many patients recover clinically and radiologically after correction of the precipitating factors, but PRES can result in cerebral infarction, intracranial haemorrhage, persistent neurological impairment or death when severe vascular dysfunction or complications occur. Reversibility is consequently a frequent outcome rather than an absolute property of every episode. [1,2]

For drug safety purposes, this distinction is particularly important. A report may contain the adverse-event term PRES before the diagnostic evidence is complete, or the diagnosis may be inferred from the clinical course and imaging rather than explicitly documented. Medical assessment must therefore consider the evidence supporting the diagnosis as well as the evidence supporting a medicinal-product relationship. Treating the coded event term as a conclusion about causality would collapse two separate clinical and pharmacovigilance questions into one.

Pathophysiology of PRES

The pathophysiology of PRES is not completely established. Current models converge on disruption of cerebral vascular homeostasis, endothelial dysfunction and breakdown of the blood–brain barrier, with acute changes in cerebral perfusion and vascular tone contributing to the development of predominantly vasogenic oedema. The relative importance of these mechanisms varies according to the clinical setting. [1-3]

Cerebral autoregulation and blood pressure

Cerebral autoregulation normally maintains relatively stable cerebral blood flow despite changes in systemic blood pressure. Cerebral arterioles alter their vascular tone to prevent excessive increases or decreases in cerebral perfusion. When blood pressure rises rapidly or substantially beyond the capacity of this regulatory system, autoregulatory failure may occur. Increased cerebral perfusion and capillary hydrostatic stress can then promote disruption of the blood–brain barrier and movement of fluid into the extracellular space, producing vasogenic oedema. [1,3]

This mechanism provides a clear explanation for the frequent association between PRES and severe or rapidly changing hypertension. It does not, however, explain every case. A substantial proportion of patients do not have extreme hypertension at presentation, and some develop PRES with blood pressures that would not ordinarily be expected to exceed the upper limit of cerebral autoregulation. [1,3]

Consequently, blood pressure should be regarded as an important precipitating factor rather than an obligatory diagnostic feature. In a medicinal-product-associated case, a product may contribute to PRES by inducing hypertension or substantial blood-pressure variability, but the absence of severe hypertension does not by itself exclude a drug-related mechanism.

Endothelial dysfunction and blood–brain barrier disruption

The vascular endothelium and blood–brain barrier maintain the separation between the circulating blood and the neural environment. Disruption of endothelial integrity increases vascular permeability and can interfere with normal regulation of cerebral vascular tone. Leakage of fluid into the cerebral interstitium produces the vasogenic oedema that characterises PRES on MRI. [1-3]

Endothelial dysfunction provides a mechanistic link between otherwise diverse causes of PRES. Systemic inflammation, autoimmune disease, sepsis, pregnancy-related endothelial disturbance and exposure to certain medicinal products can all affect endothelial function. In drug-associated PRES, the medicine may therefore contribute without producing a conventional direct neurotoxic effect. A pharmacological or toxicological effect on the vascular endothelium can be sufficient to create susceptibility to cerebral oedema. [2,3]

This model also explains why PRES can occur without marked hypertension. If endothelial integrity and vascular reactivity are sufficiently impaired, disruption of the blood–brain barrier may occur without a major increase in systemic blood pressure. The haemodynamic and endothelial mechanisms should therefore be viewed as overlapping pathways rather than competing explanations in every individual patient.

Vascular tone, vasoconstriction and hypoperfusion

A second component of the pathophysiological model involves abnormal cerebral vascular tone. Disturbance of autoregulation may produce regional vasoconstriction and impaired perfusion, potentially causing endothelial stress and contributing to blood–brain barrier dysfunction. Historical models of PRES therefore proposed both hyperperfusion following autoregulatory failure and hypoperfusion associated with excessive vasoconstriction. Current understanding does not require a single mechanism to account for all cases. [2,3]

The coexistence of these mechanisms is relevant when evaluating medicinal products because some medicines can affect vascular tone while also influencing systemic blood pressure or endothelial function. A product may consequently contribute to PRES through several interacting physiological effects rather than through one isolated pharmacological action.

Immune and inflammatory mechanisms

Systemic immune activation and inflammation can further compromise endothelial function. Cytokines and other inflammatory mediators may activate endothelial cells, alter vascular permeability and modify cerebral vascular reactivity. This provides a plausible mechanistic pathway in autoimmune disease, severe infection and some treatment-related immune states. [1,2]

The same principle is relevant to patients receiving immunomodulatory medicines. In such cases, the causal assessment may need to distinguish effects of the medicinal product from effects of the underlying disease and from changes in the patient's immune state. A medicine may be one component of a multifactorial pathway rather than the sole cause of the neurological event.

How medicinal products can contribute to PRES

The preceding mechanisms explain why medicinal products associated with PRES are not necessarily linked to the syndrome through a single common pharmacological action. Some medicines may increase blood pressure or alter vascular tone; others may produce endothelial injury or interfere with endothelial signalling; still others may alter immune or inflammatory pathways. Immunosuppressive and antineoplastic therapies provide important examples of treatment contexts in which these mechanisms may operate. [2,4]

Calcineurin inhibitors such as ciclosporin and tacrolimus have long been recognised in association with PRES. Proposed mechanisms include hypertension, vasoconstrictive effects and endothelial dysfunction. PRES has also been reported with several antineoplastic and antiangiogenic therapies, for which endothelial effects and blood-pressure changes provide plausible biological pathways. Importantly, reported cases have occurred even when drug concentrations were within therapeutic ranges, indicating that a simple dose-toxicity relationship cannot be assumed for every medicinal product. [4]

The resulting clinical pathway can therefore be conceptualised as:

medicinal product exposure → disturbance of blood pressure, vascular tone, endothelial function or immune signalling → blood–brain barrier dysfunction → vasogenic cerebral oedema → clinical and radiological PRES

This pathway establishes biological plausibility, but biological plausibility alone does not establish causality in an individual case. The patient's underlying disease, renal function, blood pressure, concomitant medicines and other precipitating factors must be considered alongside the medicinal product. The subsequent pharmacovigilance assessment therefore needs to determine whether the product provides a coherent explanation for the event and how strongly that explanation is supported by the complete evidence.

Medicinal Products Associated With PRES

The association between PRES and medicinal products is best understood through the biological effects that can disturb cerebral vascular homeostasis. The evidence is not equally strong for every medicine or medicine class, and the presence of a report in a particular therapeutic class should not be interpreted as proof that all members of that class carry the same risk. A clinically useful classification therefore considers both the strength of the reported association and the mechanism by which exposure could plausibly contribute to PRES.

Calcineurin inhibitors

Ciclosporin and tacrolimus are among the medicinal products most consistently associated with PRES. Both are widely used as immunosuppressants, particularly in transplantation and selected immune-mediated diseases. Their association with PRES has been recognised for many years, and proposed mechanisms include hypertension, vasoconstriction, endothelial dysfunction and altered cerebral vascular reactivity. [4,5]

The association is nevertheless not adequately described by serum drug concentration alone. PRES has been reported at therapeutic concentrations, and patients receiving calcineurin inhibitors often have several concurrent risk factors, including renal dysfunction, hypertension, infection, transplantation-related endothelial stress and other immunosuppressive treatments. The medicinal product may therefore be an important contributor without being the sole determinant of risk.

Antiangiogenic and vascular endothelial pathway therapies

Medicinal products that interfere with vascular endothelial growth factor (VEGF) signalling and angiogenesis have also been associated with PRES. Bevacizumab and other antiangiogenic therapies can affect vascular endothelial biology and may also increase blood pressure. These effects provide biologically plausible pathways through which treatment may increase susceptibility to cerebral endothelial dysfunction and vasogenic oedema. [4,6]

The same reasoning applies to other targeted therapies for which vascular endothelial effects, hypertension or endothelial injury are established or plausible. The existence of a class association should, however, be interpreted according to the evidence for the individual medicinal product rather than assumed automatically from pharmacological class membership.

Antineoplastic therapies

PRES has been reported during treatment with several cytotoxic and targeted antineoplastic medicines. The oncology setting is particularly challenging because patients may simultaneously have malignancy-related inflammation, renal impairment, infection, hypertension, thrombocytopenia, endothelial injury and multiple concomitant therapies. These factors can independently contribute to PRES or modify the effect of a suspected medicine. [4,6]

For this reason, the safety assessment of a PRES case occurring during anticancer treatment should reconstruct the complete treatment history rather than focus on the most recently administered medicine. The temporal relationship between each potentially contributory treatment and the onset of neurological symptoms, together with dose changes and the sequence of concomitant interventions, can materially change the interpretation.

Immunomodulatory and immune-based therapies

PRES has also been described in association with therapies that modify immune activity. The biological interpretation may be particularly complex in these cases because the medicinal product, the underlying inflammatory disease and treatment-related immune activation may all influence endothelial function. [2,4]

The presence of an immune-mediated mechanism should therefore not be inferred simply from the therapeutic class. A robust assessment asks what changed around the time of the event and whether the proposed mechanism is consistent with the patient's clinical circumstances.

Other medicinal products

Reports of PRES have occurred with a range of additional medicinal products. Some associations are supported by multiple case reports, case series and mechanistic evidence, whereas others may rest on limited individual observations. The evidentiary status of a medicine–PRES association should therefore be stated explicitly.

A useful distinction is between a medicinal product for which PRES is a recognised or well-characterised adverse reaction, a product for which a safety signal or repeated reports provide a plausible association that remains under evaluation, and an isolated report in which the evidence for a product contribution is weak or substantially confounded. These categories should not be conflated in pharmacovigilance communication.

Assessing the Association in an Individual Case

Once PRES has been clinically recognised, the next question is whether a medicinal product contributed to the event. This is a causality problem rather than a diagnostic one. The assessment should reconstruct the patient's course and determine whether the medicinal product provides a more coherent explanation than competing causes.

Establishing the temporal relationship

Temporal relationship is the first component of the assessment because exposure must precede the event for a causal relationship to be possible. The relevant chronology includes treatment initiation, dose escalation, dose reduction, interruption and restart, as well as the onset of hypertension, renal dysfunction, infection, neurological symptoms and radiological abnormalities.

The appropriate interval depends on the medicinal product and proposed mechanism. A latency that is compatible with the known pharmacology supports plausibility, whereas an exposure that began only after the neurological syndrome developed cannot explain its initiation. Temporal compatibility alone, however, provides only a necessary condition for causality and is not sufficient evidence that the product caused the event.

Characterising the clinical event

The strength of the attribution depends partly on the quality of the PRES diagnosis. The reviewer should determine whether the report contains a coherent clinical syndrome and supporting imaging findings, whether alternative neurological diagnoses were investigated and whether the reported radiological abnormalities are compatible with vasogenic oedema.

Important information includes the nature and timing of seizures, headache, altered mental status and visual symptoms; blood-pressure measurements; neurological examination; MRI or other imaging; renal function; relevant laboratory findings; and the subsequent clinical course. Where available, the original radiology report and follow-up imaging may be substantially more informative than a coded diagnosis alone.

The distinction between an adverse-event term and a medically substantiated diagnosis is especially important in spontaneous reporting. A case coded as PRES may ultimately prove to have another explanation, while a report without the exact diagnostic term may contain sufficient clinical and imaging information to support PRES after medical review.

Assessing competing causes

PRES frequently occurs in patients with several simultaneous risk factors. The reviewer should therefore identify competing causes rather than treating them as background information.

Relevant factors may include severe or rapidly changing hypertension, renal impairment, autoimmune or inflammatory disease, infection or sepsis, transplantation, pregnancy-related hypertensive disease, malignancy and exposure to other medicinal products associated with PRES. The relative contribution of each factor depends on its timing, severity and biological plausibility.

A patient receiving tacrolimus who develops PRES during a period of severe hypertension and acute renal failure represents a different causal problem from a patient receiving the same medicine who develops PRES without major blood-pressure elevation, renal deterioration or other obvious precipitant. In the first situation, tacrolimus may still contribute, but the event is more plausibly multifactorial. In the second, the medicinal product may assume greater causal importance if the chronology and biological evidence are supportive.

Considering concomitant medicinal products

Concomitant treatment is one of the most important potential sources of confounding. Patients at risk of PRES are often receiving several medicines, and more than one may plausibly affect blood pressure, vascular endothelium or immune function.

The assessment should therefore identify all relevant medicines rather than considering only the suspected product selected in the original report. Where several products are plausible contributors, the case should be evaluated as a multiple-exposure problem. The analysis should consider which products were started or changed recently, which have established associations with PRES, whether their mechanisms overlap and whether the sequence of exposure provides evidence favouring one product over another.

Dose and exposure considerations

For some medicinal products, dose, exposure or blood concentration may provide useful supporting information. An exposure-related pattern can strengthen a causal hypothesis when it is consistent with the known pharmacology. Conversely, a therapeutic concentration does not exclude an adverse reaction where the mechanism is not dependent on supratherapeutic exposure.

Dose should therefore be interpreted mechanistically rather than as an automatic causality test. The absence of an overdose or high concentration does not make a medicinal-product association implausible, particularly when endothelial susceptibility or idiosyncratic mechanisms are involved.

Dechallenge and rechallenge

Clinical improvement following withdrawal or interruption of a suspected medicine can provide supportive evidence, particularly when the timing of recovery is biologically plausible and other precipitating factors have also been controlled. It does not, however, prove causality because PRES may improve after treatment of hypertension, renal dysfunction, infection or other underlying triggers even when the suspected medicine is continued or stopped for unrelated reasons.

Rechallenge is potentially informative but should be interpreted cautiously. Deliberate rechallenge may be inappropriate when recurrence could expose the patient to serious neurological harm. Where an unintentional or clinically necessary rechallenge occurs, recurrence after re-exposure may substantially strengthen the causal hypothesis, particularly when alternative explanations are unchanged or absent.

From Individual Case to Pharmacovigilance Assessment

An individual case report is one piece of safety evidence. The pharmacovigilance significance of PRES emerges when the individual case is considered together with the established safety profile of the medicinal product, other reports, literature, clinical-trial evidence, epidemiological information and biological plausibility.

Individual case safety reports

A report of suspected PRES should contain enough clinical information to permit meaningful medical assessment. Under the EU pharmacovigilance framework, valid individual case safety reports are collected and managed according to GVP requirements, and the available medical and administrative information should be represented appropriately in the safety report. [7]

For PRES, clinically important information includes the suspected medicinal product and exposure dates, indication, relevant concomitant medicines, underlying diseases, blood pressure, renal function, symptoms, neurological findings, imaging, treatment of the episode, outcome and follow-up information. Where a case lacks essential information, targeted follow-up may materially improve the assessment.

The objective of follow-up is not simply to obtain more narrative detail. It is to resolve specific uncertainties that affect the medical and regulatory interpretation of the case. Examples include confirmation of MRI findings, clarification of the onset date, documentation of blood-pressure changes, identification of alternative causes and clarification of whether the suspected product was withdrawn and what happened subsequently.

Seriousness and clinical outcome

PRES is potentially serious because it can result in hospitalisation, prolonged neurological impairment, intensive care, cerebral haemorrhage, infarction or death. The seriousness assessment of an individual case should nevertheless follow the applicable pharmacovigilance criteria and the facts of that particular case rather than assuming that every report has the same seriousness outcome.

Outcome information also contributes to the clinical interpretation. Complete or near-complete neurological and radiological recovery supports the common reversible phenotype, while persistent deficits, infarction or haemorrhage may indicate a more severe form of the syndrome. The outcome does not by itself determine causality.

Expectedness and product information

Whether PRES is an expected adverse reaction is a separate question from whether the event is serious or causally related to a medicinal product. The assessment should therefore compare the medically reviewed event with the applicable reference safety information and current product information rather than infer expectedness from the clinical severity of the event.

Changes to product information are regulatory decisions that require appropriate evidence and assessment. An individual PRES case should not automatically be interpreted as establishing a new identified risk. Conversely, repeated credible cases may justify broader evaluation even when the individual reports are not independently conclusive.

Signal Detection and Evaluation

At aggregate level, PRES can become relevant as a potential safety signal when reporting patterns suggest a new or changing association between a medicinal product and the event. EU signal management is governed by the pharmacovigilance framework established in EU legislation and GVP Module IX. EMA describes signal management as a process involving scientific evaluation and quality aspects, with roles for marketing authorisation holders, national competent authorities and the Agency. [8,9]

Signal detection is not equivalent to signal confirmation. A statistical or clinical signal is an observation that warrants assessment; it is not a conclusion that the medicinal product causes PRES. The subsequent evaluation should examine the cases, alternative explanations, reporting patterns, biological plausibility, existing knowledge and relevant external evidence.

Case-series review

A PRES signal is particularly dependent on case quality because the syndrome occurs in populations with substantial background risk. A case-series review should therefore move beyond case counting and examine the clinical phenotype and causal context of each report.

Useful questions include whether the cases contain compatible clinical and imaging findings, whether the latency is plausible, whether common alternative precipitants are present, whether the suspected product was the only plausible medicinal exposure, whether dechallenge or rechallenge information is available and whether similar cases have been described independently in the literature.

The series should also be examined for consistency. A heterogeneous collection of reports labelled as PRES may contain different clinical entities, different diagnostic standards or different levels of evidence. Conversely, apparently heterogeneous cases may become coherent when viewed through a common biological mechanism.

Disproportionality and quantitative evidence

Spontaneous-reporting databases can be screened quantitatively for disproportionate reporting of PRES in association with a medicinal product. Such analyses can help identify patterns that warrant clinical review, but they cannot establish incidence or causality because spontaneous reporting is affected by under-reporting, stimulated reporting, reporting competition, differences in patient populations, indication effects and other forms of reporting bias.

For PRES, quantitative findings are particularly dependent on case definition and coding. Different terms may be used for the same clinical syndrome, while a broad neurological term may obscure the underlying diagnosis. Quantitative findings should therefore be interpreted alongside medically reviewed cases and other evidence rather than treated as self-sufficient proof of an association.

Biological plausibility and external evidence

Biological plausibility becomes more informative when it connects the reported cases with known pharmacological effects. A cluster of PRES reports associated with a medicine that is also known to cause hypertension or endothelial dysfunction provides a coherent hypothesis, although it remains necessary to assess alternative explanations.

External evidence can strengthen or weaken the signal. Relevant sources may include clinical trials, observational studies, published case reports and case series, mechanistic research, regulatory assessments and evidence concerning pharmacologically related medicines. The objective is to determine whether the spontaneous reports represent an isolated reporting phenomenon or fit into a broader body of evidence.

Signal validation and prioritisation

Not every report or statistical association requires the same level of investigation. Signal management involves determining whether the available information supports a credible new association or a meaningful change in an existing risk that warrants further evaluation. The level of concern should reflect the seriousness of PRES, the strength and consistency of the evidence, the magnitude of uncertainty, the plausibility of alternative explanations and the potential consequences for patients.

A well-characterised signal can then be considered in the appropriate pharmacovigilance and regulatory processes. Depending on the evidence, possible outcomes range from continued monitoring and targeted follow-up to additional analyses, regulatory assessment, changes to product information or risk-management action. The appropriate response depends on the evidence rather than on the existence of a signal term alone.

Relationship Between Clinical Causality and Signal Assessment

Individual-case causality and aggregate signal assessment answer related but different questions. In an individual case, the reviewer asks whether the medicinal product plausibly contributed to this patient's PRES. At aggregate level, the question is whether the available body of evidence supports an association between the medicinal product and PRES across patients.

The two levels of assessment should inform one another without being confused. A single highly informative case may identify a plausible new mechanism, while a large series of poorly documented cases may provide little causal information. Conversely, a consistent aggregate pattern can increase the plausibility of an individual report even when that individual case contains important confounding factors.

The most robust assessment therefore integrates the two levels:

individual case evidence → case-series understanding → aggregate signal evaluation → regulatory interpretation → updated individual-case context

This iterative relationship is central to effective pharmacovigilance. As the evidence base develops, the interpretation of subsequent cases can become more precise, while newly identified cases can also challenge or refine an existing safety hypothesis.

Differential Diagnosis and Confounding

PRES should be distinguished from other causes of acute neurological deterioration, particularly when the clinical presentation is dominated by seizures, encephalopathy, headache or visual symptoms. Differential diagnosis may include acute ischaemic stroke, intracranial haemorrhage, cerebral venous thrombosis, infectious or autoimmune encephalitis, toxic or metabolic encephalopathy and other causes of reversible cerebral oedema. The interpretation depends on the clinical setting and imaging rather than on a single symptom.

The distinction is especially important in pharmacovigilance because the same patient factors that predispose to PRES may also produce alternative neurological diagnoses. For example, severe hypertension can contribute to several forms of acute neurological injury, while malignancy, transplantation, infection and autoimmune disease can each generate neurological complications independently of treatment.

MRI findings should therefore be interpreted in clinical context. Typical vasogenic oedema supports PRES, but atypical imaging, restricted diffusion, haemorrhage or an unexpected clinical course may require reconsideration of the diagnosis. Follow-up imaging can be useful when the initial diagnosis is uncertain or when the distinction between reversible vasogenic oedema and permanent tissue injury affects the clinical interpretation.

Confounding should be addressed explicitly rather than treated as a reason to dismiss a case. A patient may have several plausible contributors operating simultaneously. In such circumstances, the appropriate conclusion may be that the medicinal product is a possible contributor to a multifactorial event rather than that the product is either completely causal or completely unrelated.

Practical Assessment of a PRES Case

A structured review can help ensure that the medically important information is considered consistently. The following sequence is useful for both individual case assessment and preparation of an aggregate case series.

Confirm the clinical phenotype

First establish whether the reported event is compatible with PRES. Determine the neurological manifestations, timing of onset, neurological examination findings and imaging evidence. Where the diagnosis was made clinically without MRI confirmation, the limitations of the available evidence should be recorded rather than silently treating the diagnosis as certain.

Reconstruct the exposure history

Next reconstruct exposure to the suspected medicinal product and all potentially relevant concomitant products. Dates of initiation, discontinuation, dose changes and re-exposure should be established wherever possible. The exposure history should be aligned with the onset of hypertension, renal dysfunction, infection and neurological symptoms because these events may form part of the causal sequence.

Identify precipitating conditions

The reviewer should then determine which recognised precipitants were present and how closely they coincided with the event. Blood pressure should be considered as a trajectory rather than only as a value measured at the time of presentation. Acute renal deterioration, systemic inflammation, infection, transplantation, autoimmune activity and pregnancy-related hypertensive disease may materially alter the causal interpretation.

Compare competing explanations

Each plausible explanation should be assessed against the chronology and the biological mechanism. The question is not whether an alternative cause exists in the abstract, but whether it explains the observed event better than the suspected medicinal product. When several explanations remain credible, the uncertainty should be retained in the final assessment.

Evaluate the course after intervention

The subsequent course provides additional evidence. Improvement after blood-pressure control, treatment of infection or recovery of renal function may explain clinical recovery independently of medicine withdrawal. Conversely, improvement following withdrawal of a suspected product can provide supportive evidence when the timing is compatible and other interventions do not adequately explain the change.

Integrate external evidence

Finally, the individual case should be considered against the known safety profile of the product, published evidence and the wider pharmacovigilance database. The strength of the resulting conclusion should reflect the combined evidence rather than any single feature of the report.

Illustrative Clinical Scenarios

The following scenarios are illustrative and are intended to demonstrate analytical principles rather than represent specific published cases.

PRES during calcineurin-inhibitor treatment with renal deterioration and hypertension

A transplant recipient receiving tacrolimus develops acute hypertension, renal deterioration, seizures and MRI findings compatible with PRES. Tacrolimus is interrupted and the patient improves after blood-pressure control and supportive treatment.

The case provides a biologically plausible temporal association with tacrolimus, but the concurrent renal deterioration and hypertension are also recognised precipitants. The most defensible assessment may therefore be that tacrolimus is a plausible contributor to a multifactorial event rather than assuming that tacrolimus alone caused the syndrome. The distinction matters because the evidence supports a different interpretation from a case in which the same medicine is used without major competing precipitants.

PRES during antiangiogenic therapy with acute hypertension

A patient receiving an antiangiogenic anticancer medicine develops marked blood-pressure elevation followed by headache, seizures and characteristic MRI abnormalities. No alternative neurological disease is identified, and the medicine is withdrawn with subsequent improvement.

Here the exposure, pharmacological mechanism, temporal sequence and clinical course form a coherent causal hypothesis. The assessment should nevertheless document the contribution of hypertension rather than treating it as irrelevant. The medicine may have contributed through its known vascular effects and associated hypertension, making the causal pathway indirect but biologically plausible.

PRES in a patient with substantial alternative explanations

A patient receiving several medicines develops seizures and altered consciousness during severe sepsis, acute renal failure and rapidly fluctuating blood pressure. MRI findings are initially interpreted as compatible with PRES, but the report contains limited information about the timing of each medicine and no clear evidence concerning withdrawal or subsequent imaging.

The event may still be clinically important, but the evidence for attributing it to any particular medicine is weak. The appropriate pharmacovigilance response is not to select the most recently administered medicine by default. Instead, the case should be followed up where feasible and assessed as a highly confounded event unless additional information changes the balance of evidence.

Special Situations

PRES without severe hypertension

The absence of marked hypertension does not exclude PRES or a medicinal-product contribution. Endothelial dysfunction, altered vascular reactivity and inflammatory mechanisms can impair the blood–brain barrier without a major systemic blood-pressure increase. Such cases require careful attention to the medicinal product's pharmacology and to other factors capable of producing endothelial disturbance.

Multiple suspected medicinal products

Multiple exposure is common in populations at risk of PRES. Where several medicines are plausible contributors, the assessment should compare their mechanisms, timing and prior evidence rather than assigning causality to all products automatically. The resulting case may support more than one suspect medicine, or it may remain insufficiently specific to identify the principal contributor.

Recurrent PRES

A recurrent episode warrants assessment of whether the same precipitating factor was present previously and whether the suspected medicine was continued, withdrawn or restarted. Recurrence may indicate persistent susceptibility rather than repeated direct toxicity from a medicine. If recurrence follows re-exposure to the same product under otherwise comparable circumstances, the evidence for a product contribution becomes stronger, but deliberate rechallenge should not be undertaken merely to establish causality when the event is potentially life-threatening.

Pregnancy and hypertensive disease

Pregnancy and the postpartum period introduce important alternative and interacting mechanisms, particularly pre-eclampsia and eclampsia. When PRES occurs in this setting, the pregnancy-related condition must be assessed alongside any medicinal exposure. A medicine administered during pregnancy should not automatically be regarded as the cause of PRES merely because the event followed exposure.

Risk Management and Regulatory Implications

The regulatory significance of a PRES association depends on the strength and nature of the evidence and on the existing understanding of the medicinal product's benefit–risk profile. A credible association may lead to continued surveillance, further analysis or consideration of whether existing product information adequately communicates the risk. Where evidence supports a confirmed or important risk, regulatory authorities may consider appropriate changes to product information or other risk-management measures.

Risk management should be proportionate to the evidence. A single poorly documented and heavily confounded case does not have the same regulatory significance as a consistent series of well-characterised cases supported by biological plausibility and external evidence. Conversely, a rare but potentially severe neurological event may warrant careful evaluation even when the number of cases is small because numerical frequency alone does not determine safety importance.

For the marketing authorisation holder, the relevant evidence should be integrated across the pharmacovigilance system. Individual case reports, literature findings, signal-detection outputs, periodic safety evaluation, risk-management activities and emerging regulatory information should not operate as isolated processes. The interpretation of PRES should remain consistent across these interfaces, while recognising that each process has its own purpose and evidentiary requirements.

EU signal management provides the framework for evaluating whether new evidence suggests a new potentially causal association or a meaningful change in a known association. EMA also emphasises that the presence of a safety signal does not itself mean that the medicine caused the reported event; the purpose of signal assessment is to determine whether a causal relationship is supported by the available evidence. [8,9]

Inspection Considerations

An inspection of the pharmacovigilance management of PRES would be concerned primarily with whether the system can identify, assess, document and act on relevant safety information effectively. The existence of an SOP or a database search is not sufficient evidence that the process is effective. Inspectors would reasonably expect the organisation to be able to demonstrate how relevant cases are identified, medically reviewed, followed up where appropriate, assessed for causality and incorporated into aggregate safety evaluation.

For an individual case, useful evidence would include the source report, follow-up attempts and responses, medical assessment, relevant clinical and imaging information, assessment of alternative causes and the rationale for the final pharmacovigilance interpretation. The evidence chain should allow a reviewer to understand how the conclusion was reached and whether important uncertainties were recognised.

At aggregate level, inspection-relevant evidence may include signal-detection outputs, search strategies where applicable, validation and assessment records, case-series analyses, literature evaluation, documented decisions and the rationale for actions or decisions not to take action. Where a PRES signal is not pursued, the basis for that decision should be sufficiently clear to demonstrate that the available evidence was considered rather than overlooked.

These are inspection considerations, not statements that a particular inspection finding necessarily occurs. The underlying principle is traceability: the organisation should be able to demonstrate that potentially important neurological safety information moves through the pharmacovigilance system in a controlled, medically meaningful and reproducible manner.

Common Analytical Errors

Several errors can weaken the assessment of medicinal-product-associated PRES.

The first is equating temporal association with causality. Exposure preceding an event is necessary for a causal hypothesis but is not sufficient to establish one. PRES often occurs in patients with multiple simultaneous risk factors, making temporal reasoning particularly vulnerable to confounding.

The second is treating the diagnosis and the causal assessment as the same question. A well-established diagnosis of PRES does not establish that the medicinal product caused it, just as uncertainty about the diagnostic label does not automatically exclude a medicine-related neurological event.

The third is ignoring the patient's physiological context. Blood-pressure trajectory, renal function, infection, autoimmune activity, transplantation and pregnancy-related conditions can all substantially alter the interpretation.

The fourth is attributing the event to the most recently administered medicine. In patients receiving multiple therapies, recency is not a substitute for pharmacological reasoning.

The fifth is overinterpreting therapeutic drug concentrations. A therapeutic concentration may be entirely compatible with an adverse reaction when susceptibility depends on endothelial effects, vascular regulation or other mechanisms rather than simple overdose.

The sixth is relying on disproportionality without reviewing the underlying cases. Quantitative signals can identify patterns for investigation, but they do not establish incidence or causality and may be affected by substantial reporting biases.

The seventh is assuming that reversibility proves drug causality. Recovery is compatible with PRES, but recovery may result from correction of hypertension, renal dysfunction, infection or another precipitating condition even when the suspected medicine was not responsible.

An Experienced Safety Physician's Approach

An experienced safety physician approaches PRES as a reconstruction of a biological and clinical sequence rather than as a search for a single decisive fact. The first task is to establish what happened: whether the clinical syndrome and imaging are consistent with PRES and how severe the episode was. The second is to reconstruct exposure and identify all relevant physiological and treatment changes around the event.

The physician then asks which mechanism could connect the suspected medicine to the event. If the medicine can plausibly produce hypertension, endothelial dysfunction, vascular dysregulation or immune-mediated endothelial effects, that mechanism strengthens the hypothesis. If the patient simultaneously developed renal failure, sepsis or another major precipitant, the contribution of the medicine must be weighed against those factors rather than ignored.

The next step is to examine what happened after the event. Withdrawal, blood-pressure control, treatment of infection and correction of renal dysfunction may all occur simultaneously, so recovery should be attributed cautiously. Rechallenge information, when it occurs naturally, can be informative but must never be pursued merely to obtain stronger pharmacovigilance evidence when the potential recurrence is serious.

Finally, the individual case is placed within the wider evidence base. The physician considers previous cases, the known product profile, literature, clinical-trial evidence, pharmacological class effects and signal-detection findings. The conclusion should express the strength of the evidence and its uncertainty rather than force a binary answer when the event is intrinsically multifactorial.

This approach can be summarised as:

diagnosis → chronology → mechanism → competing causes → clinical course → external evidence → integrated causal assessment

The same sequence provides a durable framework for aggregate assessment. A strong pharmacovigilance system does not merely count PRES reports; it progressively improves the quality of the evidence used to understand them.

Key Takeaways

PRES is an acute clinicoradiological syndrome characterised predominantly by vasogenic cerebral oedema resulting from disturbed cerebral vascular regulation and blood–brain barrier function. Although posterior cerebral involvement is characteristic, the syndrome can have a broader distribution, and severe or irreversible neurological injury can occur.

Medicinal products can contribute to PRES through several mechanisms, including hypertension, altered vascular tone, endothelial dysfunction and immune or inflammatory effects. Calcineurin inhibitors and several antineoplastic and antiangiogenic therapies are important examples, but the strength of evidence must be assessed for the individual medicinal product rather than inferred automatically from therapeutic class.

The presence of a medicinal product in a PRES case does not establish causality. Individual assessment requires reconstruction of exposure, clinical phenotype, blood-pressure and renal status, concomitant medicines, underlying disease, alternative causes, dechallenge or rechallenge information and the subsequent clinical course.

At aggregate level, case quality is particularly important because many patients who develop PRES have substantial background risk. Disproportionality and other quantitative methods can support signal detection but cannot independently establish causality. Signal assessment requires integration of individual cases, biological plausibility and external evidence.

From a regulatory and inspection perspective, the central requirement is effective evidence management. The pharmacovigilance system should be able to demonstrate that potentially important PRES cases are identified, medically assessed, followed up when useful, evaluated in aggregate and translated into proportionate safety action when the evidence warrants it.

References

1. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurology. 2015;14(9):914-925. doi:10.1016/S1474-4422(15)00111-8.

2. Granata G, Greco A, Iannella G, et al. Posterior reversible encephalopathy syndrome—Insight into pathogenesis, clinical manifestations and treatment. Journal of Neurology. 2015;262:1440-1450. doi:10.1007/s00415-015-7807-7.

3. Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. Journal of Neurology. 2017;264:1608-1616. doi:10.1007/s00415-016-8377-8.

4. Chen X, Xu X, Wang Y, et al. Posterior reversible encephalopathy syndrome associated with chemotherapy and immunosuppressive therapy: clinical and imaging considerations. The published literature provides evidence for associations across several immunosuppressive, antineoplastic and vascular-targeted treatment settings.

5. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR American Journal of Neuroradiology. 2008;29(6):1036-1042. doi:10.3174/ajnr.A0928.

6. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR American Journal of Neuroradiology. 2008;29(6):1043-1049. doi:10.3174/ajnr.A0929.

7. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP), Module VI: Collection, management and submission of reports of suspected adverse reactions to medicinal products. Current EU pharmacovigilance framework and applicable revisions should be consulted when applying the requirements.

8. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP), Module IX: Signal management (Rev. 1). EMA/827661/2011. Legal effective date 22 November 2017.

9. European Medicines Agency. Signal management. Current regulatory and procedural information on EU safety-signal detection and assessment, including the implementation of Commission Implementing Regulation (EU) 2025/1466 and related guidance.

Regulatory Note

This article distinguishes clinical and scientific interpretation from EU pharmacovigilance requirements. The GVP framework and applicable EU legislation establish regulatory obligations for pharmacovigilance activities; scientific literature and clinical reasoning provide the evidence used to interpret PRES and its possible relationship with a medicinal product. Examples of case assessment and inspection considerations in this article are illustrative and are not presented as actual regulatory findings.

The EU pharmacovigilance framework is subject to revision. Current legislation, EMA GVP guidance, applicable product-specific guidance, product information and PRAC or competent-authority decisions should therefore be consulted when making an actual regulatory or pharmacovigilance decision. In particular, changes to Commission Implementing Regulation (EU) 2025/1466 are being incorporated into the GVP framework, and current EMA implementation guidance should be considered alongside existing modules. [9]