Review

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Posterior reversible encephalopathy
syndrome (PRES): diagnosis
and management
James D Triplett,1 Mansur Amirovich Kutlubaev ‍ ‍ ,2
Allan G Kermode ‍ ‍ ,3,4 Todd Hardy1,5

excluding patients with eclampsia.2 4

1
Neurology, Concord Hospital, Abstract
Concord, New South Wales, 5
Posterior reversible encephalopathy syndrome Among adults, PRES is present in up
Australia
2
Bashkir State Medical (PRES) may present with diverse clinical to 98% of patients with eclampsia6; in
University, Ufa, Russian symptoms including visual disturbance, 2.7%–25% of patients following bone
Federation
3
headache, seizures and impaired consciousness. marrow transplantation7 8; in 0.4%–6%
Perron Institute, University
of Western Australia, Perth,
MRI shows oedema, usually involving the of patients following solid organ trans-
Western Australia, Australia posterior subcortical regions. Triggering factors plantation9; and less commonly (0.4%–
4
CMMIT, Murdoch University, include hypertension, pre-­eclampsia/eclampsia, 0.8%) in end-­ stage renal disease or
Murdoch, Western Australia,
Australia
renal failure, cytotoxic agents and autoimmune systemic lupus erythematosus.10–12
5 conditions. The mechanism underlying PRES PRES is in the differential diagnosis of
Brain and Mind Centre,
University of Sydney, Sydney, is not certain, but endothelial dysfunction is many acute neurological presentations;
New South Wales, Australia implicated. Treatment is supportive and involves the key to its diagnosis is to have a high
correcting the underlying cause and managing index of suspicion in several scenarios
Correspondence to
Dr James D Triplett, Neurology, associated complications, such as seizures. when there are consistent findings on MR
Concord Hospital, Concord, Although most patients recover, PRES is not brain scan. The following sections deal
NSW 2139, Australia; always reversible and may be associated with
J​ ames.​triplett@h​ ealth.​nsw.​ with a clinical approach to the diagnosis
considerable morbidity and even mortality. and management of PRES.
gov.​au

Accepted 23 November 2021

Published Online First Acute evaluation
19 January 2022 Introduction
Early on, what information do I need and
Posterior reversible encephalopathy
what should I look for?
syndrome (PRES) is a clinicoradiological
PRES often presents non-­specifically with
diagnosis that is based on a combination
symptoms manifesting over several hours
of typical clinical features and risk factors,
or days.1 Encephalopathy develops in
​pn.​bmj.​com and supported by magnetic resonance
28%–94% of patients and ranges from
(MR) brain scan findings. Neurological
symptoms can be multiple or occur in mild confusion and cognitive deficits to
isolation and may evolve over the course stupor and sometimes coma.1–3 Seizures
of the acute phase of the disease. Its clas- affecting up to 74%–87% of patients1 2
sical presentation is a combination of and typically occur within 24–48 hours of
visual loss, headache, altered mental func- presentation13 14; in a minority (3%–17%),
tion, seizures and nausea, but may include seizures may evolve into status epilepticus,
other focal deficits including weakness, and rarely this is the presenting symptom.
sensory disturbance or speech disturbance. Headaches develop in up to half of
The syndrome of PRES has many under- patients with PRES3 and are usually dull,
lying causes and may result from medical diffuse and gradual in onset. A thunder-
treatments (eg, antineoplastic therapy) or clap headache can occur in the context
© Author(s) (or their may develop as part of a PRES-­associated of PRES but should raise the suspicion
employer(s)) 2022. No medical condition (eg, autoimmune disor- of reversible cerebral vasoconstriction
commercial re-­use. See rights syndrome (RCVS). This condition occurs
and permissions. Published
ders or eclampsia) (box 1).1 2
by BMJ. PRES may develop at any age from in the context of similar risk factors to
infants to the elderly, but most frequently PRES but is distinguished mainly by thun-
To cite: Triplett JD,
Kutlubaev MA, Kermode AG, affects young or middle-­aged adults, with derclap headache, cerebral vasculopathy,
et al. Pract Neurol a mean age of 45 years.1 3 There appears infarction, and subarachnoid or intracra-
2022;22:183–189. to be a female predominance, even after nial haemorrhage.15–21

Triplett JD, et al. Pract Neurol 2022;22:183–189. doi:10.1136/practneurol-2021-003194 1 of 9

Review

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Box 1 Conditions associated with the development Box 1 Continued
of PRES
►► Intravenous contrast
General conditions ►► Intravenous immunoglobulin
►► Hypertension ►► Tyrosine kinase inhibitors
►► Sepsis
►► Solid organ transplantation
►► Eclampsia and pre-­eclampsia Despite PRES often affecting the occipital regions,
►► Renal failure only 39% of patients have visual symptoms.1 3 These
►► Malignancy (solid organ and haematological) include reduced visual acuity, diplopia, visual field defi-
►► Bone marrow transplantation cits, cortical blindness, colour vision abnormality and
►► Stem cell transplantation visual hallucinations. Focal neurological deficits such
►► Hypomagnesaemia as aphasia and hemiparesis occur in 19% of patients.3
►► Hypercalcaemia Because the symptoms linked to PRES commonly
►► Hypercholesterolaemia occur in other conditions, its diagnosis is challenging and
►► Late radiation-­associated encephalopathy, for requires clear communication among clinicians and with
example, SMART radiologists. It is essential to review the patient’s current
and medical history, medication charts and examination
Autoimmune disorders findings, including blood pressure and level of conscious-
►► Rheumatoid arthritis ness. Despite PRES being associated with accelerated
►► Crohn’s disease hypertension, about 20%–30% of patients are normo-
►► Systemic lupus erythematosus tensive or hypotensive during initial evaluation, especially
►► Scleroderma when PRES is due to medications or systemic conditions
►► Vasculitis other than hypertension or eclampsia.4 21
►► Neuromyelitis spectrum disorder PRES is associated with numerous conditions and
Toxins iatrogenic causes (box 1), though most frequently with
►► Scorpion poison hypertension, renal failure, eclampsia, transplant and
►► LSD intoxication immunosuppressive use, sepsis, autoimmune disorders
►► Ephedra overdose and exposure to cytotoxic medications.22–24 Rarer iatro-
►► Alcohol intoxication genic causes include linezolid,25 intravenous immuno-
►► Cocaine globulin26 and intoxication with LSD,27 cocaine,28 and
even scorpion poisoning.29
Cytotoxic and immunosuppressive medications
►► Hydroxydaunorubicin/adriamycin What baseline tests should I perform?
►► Vinblastine/vincristine MR scan of the brain assists with confirming the diag-
►► Gemcitabine nosis of PRES and in showing its extent. It is therefore
►► Platinum-­containing drugs: cisplatin, oxaliplatin and preferred to CT scanning due to its superior resolution,
carboplatin especially of posterior fossa structures. Nevertheless, CT
►► Bortezomib scanning is usually the first form of imaging acutely and
►► Cyclophosphamide PRES is often diagnosed using CT scan alone. The typical
►► Daunorubicin CT and MRI features of PRES include almost symmet-
►► Interferon therapy rical hemispheric vasogenic oedema affecting subcor-
►► Capecitabine, 5-­fluorouracil tical white matter and often extending to the overlying
►► Cytarabine cortex, best seen on MRI with fluid-­attenuation inversion
►► Etoposide recovery (FLAIR) sequences.22 MRI diffusion-­weighted
►► Corticosteroids imaging usually confirms vasogenic oedema with absence
►► Rituximab of restricted diffusion. Postcontrast enhancement occurs
►► Ciclosporin in 38%–50% of patients23 30 31 in one of three patterns: a
►► Tacrolimus leptomeningeal pattern, a cortical pattern within regions
►► Sirolimus of altered FLAIR signal or a combined pattern (figure 1).4
►► Mycophenolate mofetil 31

►► Methotrexate Brain imaging shows bilateral cortical–subcortical

►► Azathioprine vasogenic oedema that falls into three anatomical patterns
Other medications seen in about 70% of patients: a dominant parieto-­
►► Lithium
occipital pattern (22%), a holohemispheric watershed
►► Linezolid
pattern (23%); and superior frontal sulcus pattern
(27%).4 32 A central-­variant (brainstem) pattern has also
Continued been identified, affecting the brainstem, basal ganglia,

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Figure 1 Imaging findings in typical PRES. MR scan of the brain of a 39-­year-­old woman with PRES who presented with visual
disturbance, seizure and fever. (A–C) Prominent cortical and subcortical white matter signal hyperintensity on T2 FLAIR involving
bilateral occipital and left anterior parietal lobe, left frontal lobe, and the splenium of the corpus callosum with additional foci
involving both the anterior left thalamus and posterior left putamen. There are also patchy hyperintense T2 FLAIR signal foci within
the right cerebellar hemisphere. (D,E) Areas of diffusion-­weighted imaging hyperintensity and hyperintense apparent diffusion
coefficient signal involving the occipital cortex bilaterally consistent with vasogenic oedema, which corresponds to regions of
high T2 signal on the FLAIR images. (F) There is a small focus of blooming within the left occipital lobe, in keeping with petechial
haemorrhage. FLAIR, fluid-­attenuated inversion recovery; PRES, posterior reversible encephalopathy syndrome.

posterior limb of the internal capsule, cerebellum and vasoconstriction, focal vasculopathy or vessel pruning.39
periventricular regions, but has no cortical or subcortical Therefore, it is conceivable that PRES and RCVS are
involvement.33 PRES may rarely even involve the spinal divergent phenotypical manifestations of a shared
cord.34 Frontal and temporal lobe involvement can occur pathophysiology.20
in up to 75% of cases,4 but in practice, these patterns are Laboratory investigations should be guided by the clin-
commonly mixed; PRES with such combined patterns is ical context. It is reasonable to take an initial blood panel
actually more common than PRES with isolated parieto-­ of full blood count, renal function, electrolytes, liver
occipital involvement.4 35 function tests, ammonia and a urine toxicology screen.
Intracranial haemorrhages are found on imaging in Patients with significant unexplained hypertension need
10%–25% of cases, mostly intraparenchymal or subarach- specific testing for secondary causes of hypertension, such
noid.31 36 Up to 65% of patients who undergo follow-­up as a phaeochromocytoma, Conn’s syndrome or Cushing’s
MRI with susceptibility-­weighted imaging have micro- syndrome. If clinically indicated, and given the association
haemorrhages.31 PRES-­ associated intracranial haemor- of PRES with autoimmune disease, it is worth considering
rhage probably results either from reperfusion injury in a serum vasculitis screen including antinuclear antibody,
the setting of vasoconstriction or from pial vessel rupture antineutrophil cytoplasmic antibody, extractable nuclear
secondary to severe hypertension.37 antigens, rheumatoid factor, complement, lupus anticoag-
PRES and RCVS are well known to overlap, and so ulant, anticardiolipin antibodies, paraproteins, ACE, HIV
cerebral CT or MR angiography is recommended to serology, erythrocyte sedimentation rate and C reactive
help to distinguish them.15 16 In RCVS, vessel wall MR protein. Cerebrospinal fluid (CSF) examination is usually
angiography shows arterial wall thickening but without not necessary in clear cases of PRES, unless atypical MRI
arterial wall enhancement, consistent with transient patterns make it important to exclude an alternative diag-
vasoconstriction.38 However, PRES occurs in 9%–38% nosis such as encephalitis or demyelination (figure 2).
of RCVS cases,15–18 and 87% of PRES cases have angio- Obviously a lumbar puncture should not be performed if
graphic changes consistent with RCVS, such as diffuse there are signs of raised intracranial pressure.

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Figure 2 Imaging findings in atypical PRES. MR scan of the brain of a 45-­year-­old woman with PRES and a history of multiple
sclerosis who presented with reduced level of consciousness. (A,B) Axial FLAIR sequence shows extensive brainstem, cerebellar,
bilateral thalami, corpus callosum and bilateral anterior temporal lobe hyperintense signal change. (C) Sagittal FLAIR sequence shows
extensive brainstem and corpus callosum hyperintensities. (D) Coronal FLAIR showing confluent brainstem, bilateral temporal lobe
and left parietal lobe hyperintensities. (E,F) Areas of diffusion-­weighted imaging hyperintensity and hyperintense apparent diffusion
coefficient signal involving the midbrain and bilateral cerebellar hemispheres consistent with vasogenic oedema, which corresponds
to regions of high T2 signal. FLAIR, fluid-­attenuated inversion recovery; PRES, posterior reversible encephalopathy syndrome.

Do I need to request further imaging? migraine attacks after radiation therapy syndrome.
Most cases of PRES do not need formal digital Differentiating PRES from these other conditions
subtraction angiography, but it is worth consid- requires a thorough review of risk factors, additional
ering this in patients with possible RCVS or those targeted testing and follow-­up imaging.32
in whom CT or MR angiography shows a possible
intracranial arteriopathy. Digital subtraction angiog-
raphy may identify typical features of RCVS or of Management
How do I approach the acute management of PRES?
cerebral vasculitis, leading to specific therapies for
each, including calcium channel blockers for RCVS The acute management of PRES is supportive and
or immune therapy for cerebral vasculitis. includes removing or reversing any suspected cause,
for example, correcting hypertension (table 2).
Differential diagnoses of PRES There have been no randomised trials on the various
Table 1 shows the numerous conditions that clini- interventions used to treat PRES, and treatment
cians need to consider in the differential diagnosis guidelines are generally by consensus opinion. It is
of PRES. While not all of these would be mistaken essential to recognise the condition promptly and to
for classic PRES, they share clinical and/or radiolog- remove or reverse the precipitating factor, including
ical features with PRES that could lead to diagnostic chemotherapy or an immunosuppressive agent.1
confusion. The most important differentials include Patients need to be hydrated and to have any electro-
viral and autoimmune encephalitis, demyelinating lyte disturbances corrected. Patients in whom cere-
disease, toxic leucoencephalopathies, malignancy bral oedema is causing raised intracranial pressure
such as gliomatosis cerebri, CNS vasculitis, central/ may require neurosurgical measures (see What about
extrapontine myelinolysis and acute stroke, espe- cases of malignant PRES? section)
cially due to cerebral venous thrombosis.32 A history Patients with acute hypertension should have
of prior radiation exposure might suggest stroke-­like their blood pressure gradually reduced by no more

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Table 1 Imaging and other key findings distinguishing between differential diagnoses
Differential diagnosis Imaging and laboratory findings
Rhomboencephalitis Limited to the brainstem and cerebellum, ring-­enhancing abscesses associated with Listeria; inflammatory CSF
Reversible cerebral Vasoconstriction on cerebral angiography
vasoconstriction syndrome
Demyelination Postgadolinium enhancement with acute lesions; microhaemorrhages do not occur with demyelination; CSF evaluation
especially for oligoclonal bands.
Paraneoplastic encephalitis Inflammatory CSF, positive antineuronal antibodies.
CNS vasculitis Circumferential arterial wall thickening and enhancement on vessel wall MRI, inflammatory CSF; serum vasculitis
screen may be positive.
SMART syndrome Prominent gyral enhancement with mild mass effect and cortical thickening (hyperintense on T2 and FLAIR) with or
without diffusion restriction; typically, it is unilateral.
Acute hepatic encephalopathy FLAIR hyperintensity and reduced diffusion in thalami, posterior limb of the internal capsules and periventricular white
matter. Serum ammonia may be elevated.
Leucoencephalopathy Symmetrical confluent T2 and FLAIR hyperintensities limited to the white matter; follow-­up scans show persistent
abnormalities.
Central pontine myelinolysis Raised ADC and postgadolinium enhancement
Malignancy Persistent abnormalities on follow-­up scans commonly enlarging over time, asymmetrical and often focal
Gliomatosis cerebri Isointense on T1 and hyperintense on T2, elevated choline/NAA peak
Acute stroke Decreased ADC suggesting cytotoxic oedema
Cerebral venous sinus thrombosis Abnormal signal in cerebral venous sinuses
ADC, apparent diffusion coefficient; CNS, central nervous system; CSF, cerebrospinal fluid; FLAIR, fluid-­attenuated inversion recovery; NAA, n-­acetyl aspartate;
SMART, stroke-­like migraine attacks after radiation therapy.

20%–25% in the first few hours to avoid the risk of agents include nicardipine (5–15 mg/hour), labetalol
cerebral, coronary and renal ischaemia.40 Clinicians (2–3 mg/min) and nimodipine; second-­ line agents
should aim for a mean arterial pressure of between 105 include sodium nitroprusside, hydralazine and
and 125 mm Hg, and continuous intravenous infu- diazoxide.41 Nitroglycerine is not recommended
sions are often required. First-­line antihypertensive in patients with PRES as it may aggravate cerebral

Table 2 Acute therapies for PRES

Drug Mechanism of action Dose
First-­line antihypertensive agents
Labetalol Alpha-­1 blocker/non-­selectiveInitial: 20 mg slow injection over 3 min
beta blocker Titrate: additional 40 mg at 10 min intervals until achieving the desired BP reduction or until 300 mg
has been injected
Nicardipine Dihydropyridine calcium channel Initial: 5 mg/hour
blocker Titrate: Increase by 2.5 mg/hour every 5–15 min until achieving the desired BP reduction
Nimodipine Calcium channel blocker Initial: 0.5–1 mg/hour (15mcg/kg/hour)
Titrate: increase to 2 mg/hour (30 mg/kg/hour)
Second-­line antihypertensive agents
Enalapril ACE inhibitor Dose: 1.25 mg intravenously four times per day.
Notes: Use for less than 48 hours, avoid in pregnancy
Hydralazine Vasodilator by direct relaxation Dose: 1.7–3.5 mg/kg divided into four to six doses
of vascular smooth muscle
Sodium nitroprusside   Initial dose: 0.25–0.5 mcg/kg/min
Titrate: increase by 0.2 mcg/kg/min until desired clinical response
Maximum dose: 6 mcg/kg/min
Antiseizure medications
Sodium valproate   Initial loading dose: 30–40 mg/kg (maximum dose of 3500 mg)
Continuing dose: 400–1000 mg two times per day (maximum dose 2000 mg two times per day)
Phenytoin   Initial loading dose: 15–20 mg/kg (maximum dose of 1500 mg)
Continuing dose: 4–8 mg/kg initially titrating to plasma concentration of 15–20 mg/L
Initial infusion rate cannot exceed 50 mg/min.
Levetiracetam   Initial loading dose: 40–60 mg/kg (maximum dose 6000 mg)
Continuing dose: 500–1000 mg two times per day (maximum dose 2000 mg two times per day)
BP, blood pressure; PRES, posterior reversible encephalopathy syndrome.

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oedema.42 Table 1 details the antihypertensive agents hypertensive crises, renal failure and mitochondrial
recommended for managing PRES. disorders.53
Once PRES is suspected, clinicians should consider Although PRES was initially described as benign,
transfer to an intensive care setting, as up to 70% of wholly reversible and with a good prognosis, its mortality
patients ultimately require intensive care for symptom is around 19%, and about 44% of patients are left with
management,43 and 35%–40% require mechanical varying degrees of functional impairments.3 54 Follow-­up
ventilation for 3–7 days.1 44 Indications for transfer to imaging may find residual structural lesions in 40% of
an intensive care unit setting include encephalopathy, cases.5
seizures, ventilatory depression and the need for inva- Factors associated with poor outcomes include severe
sive blood pressure support.43 encephalopathy, a hypertensive cause, hyperglycaemia, a
neoplastic cause, a longer time to control the causative
Management of PRES in specific situations
factor, the presence of multiple comorbidities, elevated C
It is crucial for neurological improvement that patients reactive protein, low CSF glucose and coagulopathy.3 54–56
with intraparenchymal or subarachnoid haemorrhage Various imaging features associated with poor outcome
should have their blood pressure gradually reduced.45 include corpus callosum involvement, extensive cere-
Those with marked renal failure need prompt dialysis. bral oedema or worsening imaging severity, intracerebral
Pregnant women should be considered for early delivery46 haemorrhage, subarachnoid haemorrhage and restrictive
and should best avoid ACE inhibitors. diffusion on imaging.30 55 57 58
Patients who develop status epilepticus require emer- It is difficult to identify a single predictor of outcome in
gency management with benzodiazepines and loading PRES. Several studies have found a correlation between
doses of sodium valproate, levetiracetam or phenytoin the degree of hypertension and both the clinical outcome
(table 2). However, there are no standard guidelines for and severity of oedema on imaging, but the presence or
managing PRES-­associated seizures without status epilep- patterns of gadolinium-­based contrast enhancement does
ticus, and here treatment with antiseizure medications is not correlate with functional outcomes.30
decided on an individual basis. Epilepsy develops in only The occurrence of seizures during the acute phase is
1.0%–3.9% of patients who suffer a PRES-­ associated not associated with increased length of hospital stay,
seizure,13 47 and so most patients do not need long-­
term antiseizure medications; clinicians should consider Key points
weaning and stopping these medications once the acute
phase of PRES has resolved. ►► Posterior reversible encephalopathy syndrome (PRES)
most commonly presents with visual disturbance,
What about cases of malignant PRES? seizures and altered consciousness.
Malignant PRES is defined based on clinical criteria ►► PRES can occur in the context of hypertension, renal
consisting of a Glasgow Coma Scale (GCS) score of <8 and failure, autoimmune disease and with the use of
clinical decline despite standard medical management for immunosuppressive therapy or chemotherapy.
elevated intracranial pressure. In addition, there must be ►► MR scan of the brain confirms the oedema, which is
radiological evidence of oedema or intracerebral haem- often, but not exclusively, in posterior cortical and
orrhage exerting mass effect, such as effacement of basal subcortical structures.
cisterns, transtentorial, tonsillar or uncal herniation.48 ►► The treatment of PRES can be challenging but should
Malignant PRES requires aggressive supportive care that be implemented early to minimise the potential for
may include mechanical ventilation, transfusion of blood significant morbidity and mortality that can occur in
products for reversal of coagulopathy and corticosteroids more severe cases.
for those with autoimmune disorders. Patients with PRES
whose GCS score is ≤8 should have intracranial pressure
monitoring whenever possible.48 Various interventions Further reading
undertaken in patients with raised intracranial pressure
include osmotherapy, CSF drainage by external ventric- ►► Bartynski WS, Boardman JF. Distinct imaging patterns
ular drain, craniectomy and evacuation of haematomas; and lesion distribution in posterior reversible
these are reported to reduce mortality rates in compar- encephalopathy syndrome. AJNR Am J Neuroradiol.
ison to historic reports.49 50 Patients with acute obstruc- (2007) 28:1320–7.
tive hydrocephalus may require an external ventricular ►► Singhal AB, Hajj-­Ali RA, Topcuoglu MA, et al.
drain.51 Reversible cerebral vasoconstriction syndromes:
analysis of 139 cases. Arch Neurol 2011;68:1005–12.
►► Fugate JE, Rabinstein AA. Posterior reversible
Long-term management of PRES
encephalopathy syndrome: clinical and radiological
Retrospective studies suggest that recurrent PRES occurs
manifestations, pathophysiology, and outstanding
in 4% of patients,52 especially in those with persistent risk
questions.Lancet Neurol.(2015) 14:914–25.
factors such as sickle cell crises, autoimmune conditions,

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morbidity, mortality or nursing home placement on Allan G Kermode http://orcid.org/0000-0002-4476-4016
discharge.13 14 43 Despite a high frequency of seizures
during the acute phase, patients have only a low risk of
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Contributors JDT, AGK and TH undertook design of the seizures and epilepsy in patients with posterior reversible
article, drafting of the article and critical review of the article. encephalopathy syndrome. Epilepsia 2015;56:564–8.
MAK undertook drafting of the article and critical review of 14 Kastrup O, Gerwig M, Frings M, et al. Posterior reversible
the article.
encephalopathy syndrome (PRES): electroencephalographic
Funding The authors have not declared a specific grant for this findings and seizure patterns. J Neurol 2012;259:1383–9.
research from any funding agency in the public, commercial or
15 Ducros A, Boukobza M, Porcher R, et al. The clinical and
not-­for-­profit sectors.
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