CONTENTS

• Basics
• Pathogenesis
• Causes
• Clinical presentation
• PRES-RCVS (Reversible Cerebral Vasoconstriction Syndrome) overlap
• Imaging
• Lumbar puncture
• EEG & seizure semiology
• Diagnosis
  • Differential diagnosis
• Treatment
• Prognosis
• Podcast
• Questions & discussion
• Pitfalls

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basics

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• PRES refers to reversible, vasogenic edema which occurs predominantly in the posterior brain. PRES is less commonly known as “reversible posterior leukoencephalopathy syndrome” (RPLS). However, both terms may be misleading, because:
  • Brain injury is not always reversible.
  • Involvement is not always localized to the posterior regions of the brain, nor to the white matter.
• PRES is a clinicoradiologic diagnosis that was not discovered until the widespread application of brain imaging modalities such as CT and MRI.
• PRES often occurs in the context of a hypertensive emergency, in which case PRES is equivalent to “hypertensive encephalopathy.”
• The exact incidence of PRES is unclear, but this is commonly encountered within the ICU.

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pathogenesis

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three dimensions of pathogenesis

• Note: High-quality evidence on the pathogenesis of PRES is lacking. Consequently, the following is largely hypothetical in nature.
• (#1) Failure of autoregulation:
  • Normally, the cerebral arterioles will vasoconstrict in the context of hypertension, thereby shielding the brain tissue from experiencing hypertension.
  • At extremely high blood pressures, autoregulation may fail, causing the brain tissue to experience very high blood pressures. Hypertension may lead to fluid exudation and tissue edema.
  • Both the absolute blood pressure and the rate of blood pressure rise are important. Patients with chronic hypertension can tolerate extremely high blood pressures without developing PRES. Alternatively, patients with baseline hypotension or highly labile blood pressures may be more likely to develop PRES.
  • Posterior regions of the brain may be more susceptible to failed autoregulation, because the vasculature has less sympathetic innervation.(33630183)
• (#2) Endothelial dysfunction:
  • Dysfunction of the vascular endothelium may promote exudation of fluid from the vasculature and tissue edema.
  • Endothelial dysfunction may be especially relevant in the context of cytotoxic chemotherapies or preeclampsia.
• (#3) Focal vasoconstriction:
  • In occasional patients, dysfunctional attempts at autoregulation may result in reactive focal vasoconstriction. This may lead to focal hypoperfusion and infarction.
  • When focal vasoconstriction occurs, this may represent a combined syndrome involving both PRES and reversible cerebral vasoconstriction syndrome (RCVS) – more on this below.

varying pathogenesis in different patients

• In some patients, the primary mechanism of PRES may be failure of autoregulation (#1 above). For example, this may be the case in patients with hypertensive emergency.
• In other patients, endothelial dysfunction alone could be the cause of PRES. This may explain how PRES can occur in patients who are not hypertensive.

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causes

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hypertension is the most common contributing factor

• General principles:
  • The key contributing factor is a rapid increase in blood pressure above the patient's baseline that overwhelms cerebral autoregulation.
  • ⚠️ ~25% of patients lack any documented hypertension. Thus, a normal or low blood pressure does not exclude PRES.(35046115)
• Causes of hypertension that are commonly associated with PRES:
  • (1) Hypertensive emergency due to uncontrolled chronic hypertension. “Hypertensive encephalopathy” is one subgroup of PRES patients.
  • (2) Preeclampsia/eclampsia. 98% of patients with eclampsia in one series had PRES on MRI scan.(33630183) Eclampsia thus represents a subgroup of patients with PRES.
  • (3) Renal failure (e.g., glomerulonephritis). Renal failure may cause both hypertension and endothelial dysfunction.
  • (4) Guillain-Barre syndrome with autonomic instability. 📖
  • (5) Paroxysmal sympathetic hyperactivity (PSH). 📖

medications that cause hypertension and/or endothelial dysfunction

• Chemotherapeutics:(32596758, 33273175)
  • Anthracyclines: adriamycin, daunorubicin.
  • Antimetabolites: azathioprine, capecitabine, cytarabine, gemcitabine, nelarabine.
  • Alkylating agent: ifosfamide, cyclophosphamide.
  • Etoposide.
  • Folate antagonists: 5-fluorouracil, methotrexate.
  • Platinum analogues: cisplatin, carboplatin, oxaliplatin.
  • Proteasome inhibitor: bortezomib.
  • Taxenes (paclitaxel).
  • Vinca alkaloids: vincristine, vinblastine, vinorelbine.
  • Multidrug regimens for acute leukemia: L-asparaginase and intrathecal methotrexate.
• Anti-inflammatory:
  • Intravenous immunoglobulin (IVIG).
  • Calcineurin inhibitors (tacrolimus, sirolimus, cyclosporine).
  • Mycophenolate mofetil.
  • Rituximab.
  • Steroids, especially high-dose.
• Pro-inflammatory:
  • Checkpoint inhibitor ipilimumab and CAR T-cell therapy.(32487905)
  • Granulocyte colony stimulating factor (G-CSF).
  • Interferon therapy.(35046115)
• Targeted therapy:
  • VEGF inhibitors (e.g., bevacizumab).
  • Tyrosine kinase inhibitors: sorafenib, sunitinib, erlotinib, vandetanib, pazopanib, lenvatinib.
  • mTOR kinase inhibitor: temsirolimus.
• Sympathomimetics (therapeutic or illicit).
• Other:(35046115)
  • Carbamazepine.
  • Lithium.
  • Linezolid.
  • LSD intoxication.(35046115)

systemic inflammation & endothelial dysfunction

• Sepsis (septic patients with encephalopathy may have a prevalence of 9%).(35133605)
• Autoimmune diseases, (e.g., lupus, scleroderma, Sjogren's disease, rheumatoid arthritis, ANCA vasculitides, neuromyelitis optica spectrum disorder).(35046115)
• Thrombotic microangiopathies 📖 (e.g., hemolytic uremic syndrome, thrombotic thrombocytopenic purpura).

other risk factors

• Renal failure, both acute and chronic (promotes endothelial dysfunction & volume overload).
• Hypomagnesemia, hypercalcemia.(24476076)
• Fluid overload.
• Sickle cell disease.
• Nephrotic syndrome.(35419136)

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clinical presentation

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Course: clinical deterioration is acute or subacute (may evolve over 1-2 days).

clinical features

• Hypertension (75%)
  • ⚠️ Absence of hypertension does not exclude PRES.(34618761)
• Seizure (~70%) is very common (especially among ICU PRES cohorts).(35046115) More on seizure semiology below 📖.
• Encephalopathy (~70%): Ranges from somnolence to coma.
• Headache (~50%):
  • Usually described as constant, dull, diffuse, gradual onset, and difficult to treat.
  • If a thunderclap headache occurs, this should suggest reversible cerebral vasoconstriction syndrome (RCVS) as either an alternative or superimposed diagnosis. 📖
• Visual disturbances (~35%):
  • Auras, blurred vision, color vision abnormality, diplopia.
  • Visual field deficits.
  • Cortical blindness, visual hallucinations (Anton syndrome).
• Focal neurological abnormalities (~10%):
  • Vary depending on the site of involvement.
  • May include hemiparesis, aphasia, or ataxia.(33630183)

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PRES-RCVS overlap

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basics of PRES-RCVS (Reversible Cerebral Vasoconstriction Syndrome) overlap

• PRES and RCVS both involve dysregulation of the cerebral vasculature.
  • PRES involves failure of autoregulation, with excess blood flow through the arterioles.
  • RCVS involves excessive vasospasm, causing inadequate blood flow through the arterioles.
• Although these might seem like polar opposites, the two disorders commonly coexist.
  • (1) The most common form of PRES-RCVS overlap appears to occur in patients who initially present with PRES. Over time, cerebral vasculature responds to hypertension and endothelial damage with vasospasm, thereby causing RCVS to be superimposed on top of PRES. RCVS might complicate the majority of patients with PRES.(29274685)
  • (2) Less commonly, ~20% of RCVS may be complicated by the subsequent occurrence of PRES.(29274685) In these patients, the primary insult is RCVS – which leads to subsequent hypertension and sympathetic activation. This hypertension may overwhelm autoregulation in posterior areas of the brain which aren't experiencing vasoconstriction – leading to PRES. Essentially, the body is trying to overcome the cerebral vasoconstriction of RCVS, but this leads to an excessive blood pressure.

clinical features of PRES-RCVS overlap

• Teasing apart the features of PRES vs. RCVS is often impossible. Case series of “PRES” or “RCVS” in the literature are often contaminated with PRES-RCVS overlap syndrome. For example:
  • Papers on “RCVS” often note that some patients have cerebral edema.
  • Papers on “PRES” often note that some patients have convexity subarachnoid hemorrhage.
• The table above shows more classic features of PRES and RCVS. Patients with substantial symptomatology and imaging features of both syndromes may have PRES-RCVS overlap.

treatment implications

• Patients with PRES-RCVS overlap may theoretically benefit from consideration of treating both disease processes.

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imaging

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the hallmark finding is vasogenic edema

• Vasogenic edema is invariably seen on MRI (where it appears as hyperintensity on T2/FLAIR).
  • CT scan may be normal, but in more severe cases the edema will also be visible on CT scanning as hypodense areas within the white matter.
  • Vasogenic should be seen in 100% of cases on MRI, as this is part of the definition of PRES.
• Contrast enhancement (~40%) may occur in a leptomeningeal pattern, a cortical pattern within regions of altered FLAIR signal, or a combination.(35046115)

various patterns of edema distribution

• The four patterns most commonly seen are listed below. Edema tends to occur in a bilateral pattern within the white matter, centered at the watershed areas between vascular territories: (30531559) However, other areas can be involved as well (e.g., the cerebellum and rarely even the spinal cord).
  • Neither the pattern nor severity of vasogenic edema are related to the severity of clinical symptoms.(Busl 2022)
• Parieto-occipital pattern (~50%) – Edema is predominantly along the MCA-PCA watershed, located within the parietal and occipital lobes. This edema usually spares the paramedian parts of the occipital lobe (which may help differentiate it from ischemic stroke)(figure a, below). Even when edema is present in unusual areas such as the brainstem, a parieto-occipital pattern is generally present as well.
• Superior frontal sulcus pattern (~25%) – Edema is predominantly along the ACA-MCA watershed, located in the depth of the superior frontal sulcus (figure b, below).
• Holohemispheric watershed pattern (~25%) – Edema is located along anterior, posterior, medial, and lateral watershed zones (figure c, below).
• Central pattern (~10%) – Edema is in the deep white matter, basal ganglia, thalami, brainstem, pons, and cerebellum (figure d, below).

MRI findings of superimposed infarction

• PRES typically causes vasogenic edema, with a characteristic appearance on different MRI sequences as shown in the top row below.
• In ~20% of patients with PRES, small areas of brain tissue may become ischemic. This causes cytotoxic edema, which is marked on MRI by hyperintensity on DWI and hypointensity on ADC (the red circle in the figure below).(31582040) Areas of hypointensity on ADC have greater specificity for ischemia that will progress to tissue infarction. This is a poor prognostic sign.(33630183)

intracranial hemorrhage

• Intracranial hemorrhage is found in ~10-25% of patients.(35046115)
• Parenchymal hemorrhage may occur (either lobar hematoma or punctate microhemorrhages). GRE/SWI sequences may reveal microhemorrhages in up to 65% of patients.(35046115)
• Convexity subarachnoid hemorrhage may occur. This may suggest the coexistence of RCVS.

CT angiography (CTA) or MR angiography (MRA)

• These may be performed if there is concern for superimposed RCVS (e.g., based on MRI findings suggesting large areas of infarction, convexity subarachnoid hemorrhage, or focal neurologic deficits).

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lumbar puncture

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• Lumbar puncture is generally not required for the diagnosis of PRES. However, this may be necessary in some scenarios to exclude alternative diagnoses.
• Common findings in PRES include mildly elevated protein (~50-100 mg/dL) with a normal cell count, technically qualifying as albuminocytological dissociation. 📖 (26349950)
  • Protein elevation may correlate with edema, as a marker of blood-brain barrier dysfunction.
• Opening pressure may be elevated.

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EEG & seizure semiology

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clinical findings

• Seizures occur in ~70% of patients (and perhaps higher rates among patients sick enough to be in the ICU).
• A variety of clinical seizure types may occur (including simple seizures, epilepsia partialis continua, complex partial seizures, generalized tonic-clonic seizures, convulsive status epilepticus, and nonconvulsive status epilepticus).(LaRoche 2018)
  • Complex partial seizure may be the presenting symptom of PRES.(33630183)
  • Status epilepticus occurs in ~10%. This may be the presenting symptom.(35046115)

EEG

• ⚠️ There should be a very low threshold to obtain continuous EEG monitoring for any patients with PRES who have altered mental status (especially if mental status abnormality is fluctuating, or seems disproportionate to the MRI abnormalities).(More on the indications for EEG here: 📖)
• EEG findings in PRES may include:(LaRoche 2018)
  • Focal sharp-wave discharges.
  • Lateralized Periodic Discharges (LPDs 📖), often with a posterior distribution.
  • Bilateral Independent Posterior Discharges (BIPDs 📖).
  • Diffuse theta slowing is the most common finding.(Busl 2022)

management – see below 📖

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diagnosis

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diagnosis

• No single diagnostic test proves PRES (although MRI may be strongly suggestive).
• The above figure shows how this diagnosis is often approached, using a combination of clinical features, supportive evidence, and exclusion of other possibilities (section below).(28190431)

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differential diagnosis

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The differential diagnosis will vary depending on any specific patient's imaging and clinical findings. However, the following list may include some reasonable considerations:(35046115; 34618761)

• Reversible cerebral vasoconstriction syndrome (RCVS) – PRES and RCVS may coexist, so this differentiation may be impossible.📖
• Demyelination (e.g., acute disseminated encephalomyelitis) – gadolinium enhancement in a ring-configuration may favor demyelination; microhemorrhages don't occur with demyelination; CSF with oligoclonal bands may favor demyelination.(35046115)
• Progressive multifocal leukoencephalopathy (PML) 📖 – may be favored by immunosuppression, lesion asymmetry.
• Autoimmune or paraneoplastic encephalitis – may be favored by CSF pleocytosis, detection of autoantibodies.
• Viral encephalitis.
• SMART syndrome 📖 – favored by unilateral involvement, prominent gyral enhancement, history of radiation exposure.
• Toxic leukoencephalopathy (e.g., heroin).
• Acute hepatic encephalopathy – may cause FLAIR hyperintensity with reduced diffusion in the thalami, posterior limb of the internal capsule, and periventricular white matter.(35046115)
• Osmotic demyelination syndrome 📖 – may be suggested by epidemiological risk factors, changes in osmolarity, prominent hyperintensity on diffusion weighted imaging (DWI).
• Cerebral venous thrombosis 📖 – may be suggested by edema, epidemiological factors, abnormal vascular imaging.

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treatment

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Treatment obviously focuses on management of blood pressure and seizures. However, the full treatment package may include five items:

(#1/5) Bp control

• Among patients with hypertension, blood pressure should be promptly but carefully controlled. The management of blood pressure is similar to hypertensive emergencies in general. 📖
  • MAP should be lowered by ~20-25% within 1-2 hours.(35046115)
  • A MAP target of 105-125 mm is often reasonable, although this may need to be personalized.(35046115)
• Calcium channel blocking agents might be theoretically preferable, to reduce the risk of vasospasm:
  • Intravenous agents are initially preferred: Nicardipine infusion 💉 or clevidipine infusion 💉.
  • Oral calcium channel blockers may subsequently be utilized: Isradipine or nifedipine ER 💉.
• ⚠️ Nitroglycerine should be avoided, as this may aggravate PRES.(30531559)

(#2/5) seizure management

• Consider EEG monitoring in patients with altered consciousness (discussed above: 📖)
• Any overt seizures or status epilepticus should be treated aggressively.
  • For most patients with PRES, a general antiseizure medication may be utilized (e.g., levetiracetam).
  • Antiseizure medication may be tapered off as patients improve, often within a 1-2 week timeframe.(Busl 2022) However, 1-4% of patients may develop epilepsy and require longer term antiseizure medication.(35046115)
• The management of patients with frequent Lateralized Periodic Discharges (LPDs 📖) and/or Bilateral Independent Posterior Discharges (BIPDs 📖) is unclear.
  • In some cases, these patterns combined with clinical features might reflect an electroclinical diagnosis of nonconvulsive status epilepticus (NCSE), which would warrant therapy. 📖

(#3/5) medication review & treatment of underlying cause(s)

• Review the causes of PRES, and whether there is an underlying etiology of PRES that requires specific management.
  • 💡PRES may result from a combination of several synergistic causes.
• This predominantly involves a medication review, to ensure that the patient isn't on any medications which may be causing PRES (listed above: 📖).

(#4/5) treat hypomagnesemia if present

• Reasons to treat hypomagnesemia:
  • (a) Hypomagnesemia may contribute to PRES.(28054130)
  • (b) Magnesium is the only medication supported by RCT-level data for patients with PRES (noting that eclampsia is a subset of PRES).
  • (c) Many patients may have an overlap of both PRES and RCVS; these patients may benefit from magnesium for treatment of RCVS.
• It's unknown whether intravenous magnesium could benefit most patients with PRES, but aggressive management of any hypomagnesemia seems sensible. More on the management of hypomagnesemia here: 📖.

(#5/5) treat volume overload if present

• Reasons to treat volume overload:
  • Among patients with hypertension and volume overload, the most effective “antihypertensive” agent is often furosemide. Blood pressure can be extremely difficult to manage in the face of uncontrolled volume overload.
  • PRES involves tissue edema formation in the brain. Theoretically, edema resolution might be hastened if volume overload is managed.
• More on the management of volume overload & diuresis here: 📖.

malignant PRES

• Malignant PRES is defined based on the presence of coma, deterioration despite standard management for elevated intracranial pressure, and radiological evidence of edema.(35046115) This isn't the usual trajectory for PRES, so alternative diagnoses should be considered (e.g., cerebral venous thrombosis, acute disseminated encephalomyelitis).📖
• Management may include:(35046115)
  • Management of intracranial pressure elevation. 📖 Rarely, severe swelling in the posterior fossa may cause obstructive hydrocephalus requiring temporary placement of an external ventricular drain.
  • Aggressive treatment of any underlying condition (e.g., steroid for patients with underlying autoimmune disease).

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prognosis

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• As a general rule, patients with PRES can look awful initially (e.g., due to brainstem involvement), yet subsequently make excellent recoveries. Recovery can take several days, so patience is required. Unfortunately, PRES can occasionally cause irreversible brain injury.
• Predictors of incomplete recovery:
  • Secondary intracranial hemorrhage in addition to PRES.
  • Restricted diffusion on MRI, suggestive of cerebral infarction.
  • Extensive cerebral edema.(35046115)
• Patients may have recurrent episodes of PRES, especially if they have a persistent risk factor (e.g., sickle cell anemia, renal failure, or hypertension).(35046115)

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• 20% of patients with PRES do not have hypertension – so don't assume that simply because a patient is normotensive that they do not have PRES.
• The management of PRES is more than simply reduction in blood pressure. For example, it is important to carefully consider why the patient has PRES and whether any contributory factors can be reversed.

Acknowledgement: Thanks to Dr. Richard Choi (@rkchoi) for thoughtful comments on this chapter.

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