Posterior Reversible Encephalopathy Syndrome

by Peter Tepler, MD

A 40-year-old woman comes to the hospital by taxi. After reporting severe headache, the triage nurse notices that she is garbling her words and immediately takes her to the stroke assessment area and grabs you.

Her ABCs are all intact.

Patients triage vitals are:

HR: 84/min
RR: 16/min
BP: 247/164 mm Hg
Temp: 99.3 F (37.4 C)
SaO2: 100% on room air
Fingerstick glucose: 107 mg/dl.

You do a quick neurological screen and agree that patient has new-onset dysarthria. You call a stroke code. While waiting for neurology to come down, you get IV access and send a β-hCG. You get more history: She has a past medical history of hypertension and pre-eclampsia with all 3 of her pregnancies. She is not currently on any medications and is allergic to ace-inhibitors. She does not drink, smoke, or use illicit drugs, and her family history is only significant for paternal hypertension. She is here today because of a headache that started about 3 hours ago described as throbbing over occipital region. She does not know when her speech problems started. Neurology comes down and rapidly does their stroke exam. Aside from dysarthria, there is a right visual field deficit. She is rushed to CT which is negative for a bleed. The patient is placed on a nicardipine drip and her systolic blood pressure (SBP) is lowered to 170. She is given tissue plasminogen activator (tPA). Her speech starts to improve, when low and behold, the patients headache suddenly becomes worse. She screams and develops severe right arm weakness. You shut off the tPA and rush her back to CT. Woe is you, she has developed an intracranial hemorrhage.

After managing the bleed and appropriately sending her to the MICU, you record the case information to follow-up and see how the patient does. When you look through her chart one week later, she seems to be doing fine, but her MR shows that she never had a stroke at all!

Turns out that her symptoms were all from Posterior Reversible Encephalopathy Syndrome (PRES) ! What the heck is this thing, and how did you miss it?

What is PRES?

Although described in various case reports, PRES was not defined as a syndrome until a 1996 New England Journal of Medicine case series defined it as “a reversible syndrome of headache, altered mental functioning, seizures, and loss of vision associated with findings indicating predominantly posterior leukoencephalopathy on imaging studies”.¹ This is not really all that helpful, especially because the syndrome is not always reversible, and because it is often not confined to either the white matter or the posterior regions of the brain. It is essentially a vasogenic edema that causes neurological problems.

Pathophysiology?

Endothelial injury-> Breakdown of blood-brain barrier-> Reversible vasogenic edema

High blood pressure, when high enough, overwhelms the autoregulation mechanisms in the cerebral circulation, leads to hyperperfusion, and causes direct microvascular endothelial injury. The blood–brain barrier breaks down, allowing for interstitial extravasation of plasma and macromolecules to cause edema. The posterior brain regions can be particularly susceptible to hyperperfusion because there is minimal sympathetic innervation in the posterior fossa and therefore that area will be “hit” by a failure of autoregulation first.

There doesn’t even need to be persistent high blood pressure. Fluctuating blood pressure can also lead to PRES (think shearing forces as a cause of endothelial injury) as 15-20% of patients present normotensive or hypotensive.²

It makes sense that more than just high blood pressure can cause localized endothelial injury and the cascade leading to vasogenic edema; hence, PRES is also found among patients who take certain medications or have autoimmune conditions like vasculitis or thrombotic thrombocytopenic purpura.³

How does PRES present?

Most patients present with encephalopathy (50-80%) ranging from mild confusion to deep stupor. There are seizures in 60-75%% of patients, headaches in 50% and visual disturbances in 33%. These can range from decreased visual acuity, visual field deficits, cortical blindness, or hallucinations. Of particular concern for us is that 10-15% of patients present with focal neurological deficits.⁴

Who gets PRES?

There is a strong female predominance, even excluding those with pre-eclampsia. Hypertension is the most common associated co-morbid condition (53%–91.7%), followed by kidney disease (20.8%–45%), autoimmune disease (45%), malignancy (32%), organ transplant (24%), cytotoxic medications (19%), renal artery stenosis (12.5%), sepsis (7%), and pre-eclampsia (6%).

So, how am I going to diagnose PRES?

PRES is ultimately diagnosed radiologically. Vasogenic edema can be visualized using non-contrast CT in SOME patients. Brain MRI (particularly T2-weighted sequences such as fluid-attenuated inversion recovery [FLAIR]) is much more sensitive. Recently, there have been some studies and case reports suggesting that CT perfusion study may also be utilized, though no formal prospective study has assessed its diagnostic accuracy for predicting PRES.^5,6,7

Complications

Intracranial hemorrhage occurs in 10-25% of patients and death in 3-6%, with minute hemorrhage, sulcal subarachnoid hemorrhage, and hematoma occurring with equal frequency.^8,9

Treatment

The key is to reduce the blood pressure. There are no RCTs, and recommendations are based on expert opinion. The goal is for a 25% reduction in SBP. Of note, nitroglycerin should be specifically avoided as there are reports of the agent worsening cerebral edema by enhancing cerebral vasodilation. As with all things neurological, controlling glucose (though there is no great data for specific cutoffs) is thought to be associated with positive outcome.

It’s important to note that recovery can lag a few hours behind hitting target blood pressure, and that radiographic improvement lags behind clinical recovery by a few weeks. The good new is that about 75–90% of patients have complete recovery in 2–8 days.

Why is this topic important?

PRES is a known stroke mimic and is often missed.^10,11 Controlling blood pressure prior to giving tPA doesn’t resolve the pathophysiological process right away, and besides that, we don’t want to give thrombolytics to someone who doesn’t need it. Therefore, it’s important to maintain a broad differential diagnosis in all patients being worked up for stroke and to be involved with the neurologists for the clinical exam. Additional features of visual impairment, encephalopathy, headache, or a nontraditional stroke syndrome should raise the index of suspicion for PRES. The next step would be to talk to radiology about possibly doing a more advanced imaging study. It is not necessarily feasible to MRI every patient in the ED being worked up for stroke, but there may be an expanded role for CT perfusion imaging. Ultimately, some cases of PRES perfectly mimic stroke syndromes, and unnecessary tPA administration may be unavoidable.

TL:DR

For anyone with weird neurological symptoms that don’t fit a specific infarct pattern or involve vision changes, encephalopathy, or headache, consider the possibility of PRES.

References

1 Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, Pessin MS, Lamy C, Mas JL, Caplan LR. “A reversible posterior leukoencephalopathy syndrome.” New England Journal of Medicine 334.8 (1996): 494-500.

2 Rabinstein AA, Mandrekar J, Merrell R, Kozak OS, Durosaro O, Fugate JE. “Blood pressure fluctuations in posterior reversible encephalopathy syndrome.” Journal of Stroke and Cerebrovascular Disease (2012): 254-258.

3 How J, Blattner M, Fowler S, Wang-Gilliam A, Shindler SE. “Chemotherapy-associated Posterior Reversible Encephalopathy Syndrome: A Case Report and Review of the Literature.” Neurologist (2016): 112-117.

4 Fugate JE, Rabinstein AA. “Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions.” The Lancet Neurology (2015): 914-915.

5 Hedna, Vishnumurthy Shushrutha et al. “Posterior Reversible Encephalopathy Syndrome (PRES) and CT Perfusion Changes.” International Journal of Emergency Medicine 5 (2012): 12. PMC.

6 Vanacker P, Matias G, Hagmann P, Michel P. “Cerebral Hypoperfusion in Posterior Reversible Encephalopathy Syndrome is Different from Transient Ischemic Attack on CT Perfusion.” Journal of Neuroimaging (2015): 643-646.

7 Sarbu N, Lopez-Rueda A, CHirife O, Capurro S. “CT-perfusion time-maps likely disclose the earliest imaging signs of posterior reversible encephalopathy syndrome (PRES).” Journal of Neuroradiology (2014): 147-149.

8 Fugate JE, Rabinstein AA. “Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions.” The Lancet Neurology (2015): 914-915.

9 Hefzy HM, Bartynski WS, Boardman JF and D. Lacomis. “Hemorrhage in Posterior Reversible Encephalopathy Syndrome: Imaging and Clinical Features.” American Journal of Neuroradiology August 2009, 30 (7) 1371-1379.

10 Terranova S, Kumar JD, Libman R. “Posterior Reversible Encephalopathy Syndrome Mimicking a Left Middle Cerebral Artery Stroke.” The Open Neuroimaging Journal 6 (2012): 10–12.

11 Frick D, Huecker M, Shoff H. “Posterior Reversible Encephalopathy Syndrome Presenting as Stroke Mimic.” Western Journal of Emergency Medicine: CPC-EM (May 2017).