Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome also called PRES, PRES syndrome, reversible posterior leukoencephalopathy syndrome, reversible posterior cerebral edema syndrome or reversible occipital parietal encephalopathy is a rare brain disorder (encephalopathy) that presents with sudden or constant non-localized headaches, visual disturbances  (e.g., visual hallucinations, cortical blindness, hemianopia, quadrantanopia, and diplopia), seizures (focal or general tonic-clonic) and altered mental status (disorders of consciousness, confusion, drowsiness or sometimes stupor) ¹, ², ³, ⁴, ⁵, ⁶, ⁷. PRES syndrome has been described with hypertensive encephalopathy (the effects of high blood pressure on the brain), preeclampsia (a complication of pregnancy in which affected women develop high blood pressure), and the use of chemotherapy ³. PRES has been reported to occur in cancer patients who are undergoing chemotherapy, particularly with certain classes of chemotherapeutic agents. The precise mechanisms by which chemotherapy may lead to PRES are not completely understood; however, there are some theories that suggest that it may be related to changes in blood pressure, vascular permeability, or direct toxicity to the brain ¹.

Posterior reversible encephalopathy syndrome (PRES) can unfold acutely or subacutely, with symptoms developing within hours to days. Often, the presentation occurs in the context of acute severe hypertension, with systolic blood pressures ranging between 160 to 190 mmHg, beyond the upper limits of cerebral autoregulation ⁸. The percent of elevation and the severity of blood pressure over baseline are important with approximately 75% of patients have moderate to severe hypertension at presentation ⁹. Posterior reversible encephalopathy syndrome (PRES) should not be confused with chronic hypertensive encephalopathy, also known as hypertensive microangiopathy, which results in microhemorrhages in the basal ganglia, pons, and cerebellum ¹⁰.

The name designated to posterior reversible encephalopathy syndrome or PRES is derived from ⁴:

1. Brain radiographic findings of white matter edema (i.e., hyperintense T2 signal or hypointense T1 signal on magnetic resonance imaging (MRI)), typically found in the posterior cerebrum in a symmetric fashion (although asymmetric presentations are possible); and
2. The symptoms are reversible, provided that PRES syndrome is recognized and treated promptly.

However, the name posterior reversible encephalopathy syndrome (PRES) used to describe the syndrome is misleading because the brain edema (brain swelling) is not localized necessarily to the posterior cerebrum white matter and can appear in watershed zones other than parietal-occipital regions such as the thalamus, and sometimes in the anterior circulation ⁸, ¹¹, ¹². Furthermore, although most PRES syndrome cases involve a resolution of changes with the treatment of the precipitating cause and clinical recovery, some patients can progress to develop permanent cerebral injury and be left with residual neurological defects ⁴, ¹⁰. Some people can develop life-threatening complications, such as transforaminal cerebellar herniation and focal neurologic deficits, especially if prompt treatment is not initiated ¹¹, ¹³.

Identifying, treating, and managing the underlying cause, in addition to careful treatment of hypertension, is crucial for the management of posterior reversible encephalopathy syndrome. There is no specific, established antihypertensive regimen for the treatment of acute hypertension in people with posterior reversible encephalopathy syndrome (PRES) ¹⁴. Treatment is recommended when the blood pressure exceeds 160 mmHg/110 mmHg, with a goal of 130 to 150 mmHg/80 to 100 mmHg ¹⁵. A sudden or drastic reduction of blood pressure can lead to cerebral hypoperfusion and increase the risk of developing ischemia; therefore, blood pressure should not be reduced for more than 10 to 20 mmHg every 10 to 20 minutes  ¹⁵. Such careful acute blood pressure management may warrant a need for admission to the intensive care unit (ICU) until a stable blood pressure goal is reached. Thereafter, maintaining target blood pressure on the medical floors and in the outpatient setting is recommended. The exact duration for treatment post-acutely with antihypertensives is unclear and will vary among individuals.

Sometimes individuals with PRES develop life-threatening complications, such as status epilepticus or coma, and treatment and management of such complications at an intensive care unit (ICU) should follow ¹⁶. At this time, there is no established antiepileptic treatment for seizures in people with PRES, and studies aimed to identify a specific antiseizure regimen are lacking ¹⁴. Some antiepileptic treatment is given during the acute phase of posterior reversible encephalopathy syndrome (PRES) and discontinued once PRES resolves ¹⁷. In certain circumstances, complications such as epilepsy emerge, and treatment with antiepileptic drugs will be long-term ¹.

If posterior reversible encephalopathy syndrome (PRES) is caused by using an immunosuppressant, reduction of the dose or substitution of the agent is recommended ¹⁸.

Figure 1. Posterior reversible encephalopathy syndrome

Footnote: Brain MRIs showing locations affected by vasogenic edema in PRES syndrome. Axial fluid-attenuated inversion recovery magnetic resonance images depicting examples of mild (A), moderate (b), and severe (C) vasogenic edema in posterior reversible encephalopathy syndrome.

[Source ¹² ]

Figure 2. PRES syndrome MRI

Footnote: The bilateral occipital high signal on fluid attenuated inversion recovery (FLAIR), consistent with PRES. Followup scan two weeks later, after blood pressure control and resolution of symptoms demonstrated resolution of radiological findings.

[Source ¹⁹ ]

Figure 3. Posterior reversible encephalopathy syndrome in pregnancy

Footnotes: PRES syndrome in a pregnant woman with eclampsia. (A to C) Axial fluid-attenuated inversion recovery (FLAIR) MRI images (TR/TE/TI/NEX, 11,002/140/2250/1; FOV, 20) show symmetric abnormal signal intensity, primarily in the territories of the posterior circulation. The affected area predominantly involves the white matter, but cortex is also involved. Note the involvement of the caudates, which was unusual in our series. (D to F) Isotropic diffusion-weighted MRI images (TR/TE, 10,000/91.7; FOV, 40; b = 1,000 s/mm²) show low to normal signal intensity in the areas of the FLAIR abnormality. (G to I) ADC maps show increased values in the areas of FLAIR abnormality.

[Source ²⁰ ]

Figure 4. Posterior reversible encephalopathy syndrome pathophysiology

Footnotes: Posterior reversible encephalopathy syndrome pathophysiology is not well understood, but there are two leading theories regarding the pathophysiology of PRES (Figure 4) ²¹. The first hypothesis proposes a rapid increase of arterial blood pressure up to a hypertensive crisis or emergency, which has been observed in a majority of patients at PRES onset ⁵. According to this hypothesis, elevation of blood pressure levels above the upper autoregulatory limit leads to cerebral hyperperfusion, which may cause vascular leakage and vasogenic edema ²². Increased cerebral perfusion pressure contributes to additional blood–brain barrier dysfunction causing extravasation of plasma and macromolecules through tight-junction proteins ²¹. The second theory regarding the cause of posterior reversible encephalopathy syndrome is that PRES syndrome is triggered by endothelial dysfunction caused by circulating endogenous or exogenous toxins ²¹.

[Source ¹ ]

Posterior reversible encephalopathy syndrome causes

Posterior reversible encephalopathy syndrome is most commonly thought to occur secondary to marked hypertension (high blood pressure), however, this does not appear to be a necessary or sufficient explanation, given the very large and heterogeneous clinical scenarios that precipitate the development of posterior reversible encephalopathy syndrome and the fact that hypertension is not present or does not reach the upper limits of self-regulation (140-160 mmHg) in 25% of patients ¹⁰.

People who are at risk for developing PRES tend to have one or more of the following risk factors, triggers or causes ⁴, ⁸, ²³, ²⁴, ²⁵:

• Hypertension (high blood pressure)
• Preeclampsia. Preeclampsia is a complication of pregnancy in which affected women develop high blood pressure (hypertension); they can also have abnormally high levels of protein in their urine (proteinuria). Preeclampsia usually occurs in the last few months of pregnancy and often requires early delivery of the infant. However, preeclampsia can also appear shortly after giving birth also known as postpartum preeclampsia.
• Eclampsia. Eclampsia is the new onset of seizures or coma in a pregnant woman with preeclampsia. These seizures are not related to an existing brain condition.
• Kidney disease such as nephrotic syndrome, which can lead to hypovolemia and secondary hypertension via activation of the renin-angiotensin system.
• Kenal failure.
• Liver disease.
• Exposure to certain chemotherapy drugs or immunosuppressants
  • cisplatin
  • cyclophosphamide ²⁶
  • interferon
  • erythropoietin (EPO)
  • tacrolimus
  • cyclosporine
  • azathioprine
  • L-asparaginase
  • filgrastim ²⁷
  • ustekinumab ²⁸, ²⁹
• Autoimmune diseases such as thrombotic thrombocytopenic purpura (TTP), eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and systemic lupus erythematosus (SLE).
• Infection and sepsis. Sepsis (sepsis is your body’s extreme improper reaction to an infection) especially those caused by Gram-positive bacteria
• Transplantation including bone marrow or stem cell transplantation

Of these causes or triggers, uncontrolled hypertension is the most common ¹². However, having acute hypertension does not suggest that an individual will develop PRES, and it is difficult to determine which hypertensive individuals will develop posterior reversible encephalopathy syndrome (PRES) ⁸, ³⁰.

Posterior reversible encephalopathy syndrome pathophysiology

Posterior reversible encephalopathy syndrome pathophysiology is not well understood, but there are two leading theories regarding the pathophysiology of PRES (Figure 4) ²¹. The first hypothesis proposes a rapid increase of arterial blood pressure up to a hypertensive crisis or emergency, which has been observed in a majority of patients at PRES onset ⁵, ⁸. According to this hypothesis, elevation of blood pressure levels above the upper autoregulatory limit leads to cerebral hyperperfusion, which may cause vascular leakage and vasogenic edema ²². Increased cerebral perfusion pressure contributes to additional blood–brain barrier dysfunction causing extravasation of plasma and macromolecules through tight-junction proteins ²¹.

Cerebrovascular autoregulation is supposed to preserve a continuous cerebral blood flow independently of systemic blood pressure fluctuations ³¹. This is ensured by vasodilation of the cerebral arteries during hypotensive episodes. In contrast, during periods of hypertension, this results in cerebral vasoconstriction. This adaptive mechanism is mainly regulated by pressure and carbon dioxide reactivity, as well as the release of vasoactive substances such as nitric oxide, thromboxane A2 or endothelin-1 from the vascular endothelium ⁵.

In healthy individuals a continuous cerebral blood flow can be maintained between the lower and upper autoregulatory limits, usually a cerebral perfusion pressure between 50 and 150 mmHg ³². When blood pressures are high, typically above a systolic pressure of 160 mmHg for most people, the amount of narrowing of blood vessels (vasoconstriction) to achieve constant cerebral blood flow is maximized, and blood flow begins to rise with increasing blood pressure. Increased hydrostatic pressure can contribute to the breakdown of the blood-brain barrier, causing intravascular fluid to extravasate to the surrounding brain tissue, leading to brain edema. There is the belief that the posterior circulation is mostly affected in cases of PRES because it has less adaptive mechanisms to regulate the extent of extravasation and the breakdown of the blood-brain barrier in the context of high blood pressures, compared to the anterior circulation ²⁰. Such speculation is perhaps inspired by findings of a formaldehyde histofluorescence study conducted by Edvinsson and colleagues ³³ that revealed a more significant number of adrenergic perivascular fibers innervating the anterior cerebral circulation compared to the vertebral circulation. The amount of sympathetic nerve involvement is thought to be proportional to the effectiveness of autoregulation ²⁰.

Various conditions such as arterial hypertension, acute fluctuations of blood pressure or autonomic activity may induce changes of these autoregulatory thresholds. This may lead to increased vulnerability of the cerebral circulation and predispose to cerebral ischemia during periods of hypotension on the one hand, or cerebral hyperperfusion and vascular leakage on the other, when blood pressure rises above the upper autoregulatory limit ³⁴, ³⁵. The “hyperperfusion theory” is supported by observations of elevated or fluctuating blood pressure, or hypertensive episodes in a majority of patients with PRES at disease onset ³⁶.

The posterior areas of the cerebral hemispheres seem to be particularly susceptible, which is supported by clinical as well as imaging findings. This might be caused by a reduced density of sympathetic innervation in the posterior, compared to the anterior, circulation, the latter being more densely innervated by the superior cervical ganglion ⁵. This may prevent excessive vasodilation, which could reduce the risk of cerebral hyperperfusion in these areas compared to the posterior regions.

However, arguing against hypertensive-hyperperfusion hypothesis is that about 30% of patients with PRES show normal or only slightly elevated blood pressure values that do not necessarily exceed the normal upper autoregulatory capability of the brain, as would be expected in the context of cerebral hyperperfusion ³⁷, ¹, ³⁸. Therefore, the theory of hypertensive episodes and cerebral hyperperfusion as the underlying pathological condition in PRES is still a matter of controversy ⁴. Furthermore, not all cases of PRES occur in the context of hypertension. For instance, there have been some case reports that revealed the presence of PRES in normotensive individuals who have been taking cytotoxic therapies, such as tacrolimus in the context of liver transplantation, lending credence to the idea that endothelial dysfunction plays a crucial role in the pathophysiology of the disease ¹, ¹¹. Although not yet fully understood, tacrolimus, cyclosporine, cisplatin, and other immunosuppressants can have direct toxic effects on the endothelium, compromising the blood-brain barrier ¹¹, ²⁰.

The second theory regarding the cause of posterior reversible encephalopathy syndrome is that the syndrome is triggered by endothelial dysfunction caused by circulating endogenous or exogenous toxins ²¹. Arguing for this hypothesis is that posterior reversible encephalopathy syndrome is frequently observed in patients with (pre)eclampsia, sepsis or during treatment regimens with immunosuppressive agents or cytotoxic medication ²⁵, ³⁹, ⁴⁰. The common factor in these diverse conditions is the presence of endogenic (preeclampsia, sepsis) or exogenic (chemotherapy, immunosuppressive agents) toxins causing endothelial dysfunction ⁴¹. One of the key features of the vascular endothelium is the preservation of vascular integrity by inter-endothelial adhesion molecules. Circulating toxins could trigger vascular leakage and edema formation, and additionally lead to endothelial activation resulting in the release of immunogenic and vasoactive substances ⁴¹. Vasoconstrictive agents released by vascular endothelial cells are thought to mediate cerebral vasospasm, which is frequently observed in posterior reversible encephalopathy syndrome patients ⁴². In this “toxic” theory, blood pressure elevations occur as a consequence of primary endothelial dysfunction. A variation on the “toxic/immunogenic” theory is that the trigger is the excessive release of pro-inflammatory cytokines resulting in endothelial activation, release of vasoactive agents, increased vascular permeability and edema formation. This mechanism is regarded as the key feature causing posterior reversible encephalopathy syndrome in patients with autoimmune disorders or sepsis ⁴¹.

Apart from arterial hypertension, a variety of conditions have been linked to the diagnosis of posterior reversible encephalopathy syndrome. Etiologies may be manifold; however, a clear correlation between clinical signs and symptoms, lesion site or specific trigger factors has not been observed ⁴², ⁴³. PRES has been frequently reported in patients receiving immunosuppressive medication after solid organ, bone marrow or stem cell transplantation ⁴⁴, ⁴⁵. The incidence of PRES after solid organ transplantation is reported to be between 0,4 and 6%, whereas up to 8% of patients after bone marrow transplantation may be affected ⁴⁴, ⁴⁶.

Compared to solid organ transplantation immunosuppressive medication is usually administered at a higher dose with bone marrow or stem cell transplantation, possibly explaining the higher incidence of posterior reversible encephalopathy syndrome after non-solid organ transplantation. However, it is unclear whether posterior reversible encephalopathy syndrome is linked to the dose of causative agents. Plasma levels of immunosuppressive substances do not necessarily correlate with the severity of clinical signs or imaging findings ⁴⁶, ⁴⁷. Moreover, posterior reversible encephalopathy syndrome has been observed up to several months after administration of cytotoxic agents ⁴⁶. Adding to this controversy, there are numerous reports of posterior reversible encephalopathy syndrome in patients with plasma concentrations of immunosuppressants within the therapeutic range. Nevertheless, tapering off or reducing the dosage of causative agents usually leads to clinical improvement and/or a reduction in lesion size ⁴⁶. This observation supports a positive correlation between the dose of the offending agent and the neurological/radiological manifestations.

The exact mechanism of how specific substances may cause this form of encephalopathy is unknown. Numerous authors have reported calcineurin inhibitors to be linked with PRES development ⁴⁸, ⁴⁹, ⁵⁰. These substances are well-known for their neurotoxic properties, which have been attributed to the release of vasoconstrictive substances, aggravation of hypomagnesemia, and arterial hypertension ⁵¹, ⁵². In a retrospective study, Hammerstrom and colleagues ⁴⁷ observed an average increase of 35% in the mean arterial blood pressure under a Tacrolimus regimen. Adding to the reported effects, polymorphisms in the multidrug resistance protein 1 gene may allow central nervous system dissemination of these substances ⁵³. Importantly, Tacrolimus but also antiangiogenic drugs such as Bevacizumab, Sunitinib or Sorafenib may mediate increased vascular permeability, thereby contributing to edema formation ⁵.

Not only can immunosuppressants affect the blood-brain barrier, but also neuroinflammation, such as in the context of sepsis and autoimmune disorders. Astrogliosis, microgliosis, and endothelial activation occurring in sepsis or endothelial injury in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides can enhance blood-brain barrier permeability, allowing for extravasation of intravascular fluid and potential for developing PRES syndrome ²³, ⁵⁴, ⁵⁵.

Autoimmune disorders have been frequently reported in the context of posterior reversible encephalopathy syndrome. Fugate and colleagues ⁴³ report a history of autoimmune disease in 45% of patients in a retrospective study of 120 cases. Several explanations have been provided for this linkage ⁴³, ⁴¹. As is the case in post-transplant patients, immunosuppressive medication may play an important role. Additionally, (auto)immunologic reactions may trigger endothelial activation by excessive cytokine release followed by vascular leakage of proteins and fluid into the interstitial space.

Kidney disease and preeclampsia have also been linked to posterior reversible encephalopathy syndrome. Impaired renal function has been reported in 55% of all patients with posterior reversible encephalopathy syndrome ⁵. However, it is unclear whether accompanying arterial hypertension or renal dysfunction itself is the primary causal factor.

Posterior reversible encephalopathy syndrome occurs frequently in the setting of preeclampsia or eclampsia ⁵⁶. In a retrospective study, posterior reversible encephalopathy syndrome was found in more than 90% of eclamptic and about 20% of preeclamptic patients with neurological symptoms ⁵⁷. Compared with pregnant women with eclampsia or preeclampsia without posterior reversible encephalopathy syndrome, significant elevations of hematocrit, serum creatinine, aspartate transaminase, alanine transaminase and lactate dehydrogenase values were noted ⁵⁷.

Posterior reversible encephalopathy syndrome symptoms

Posterior reversible encephalopathy syndrome symptoms include the following ⁵⁸, ⁵⁹, ⁶⁰:

• sudden or constant non-localized headaches
• seizures (focal or general tonic-clonic)
• encephalopathy (acute confusion or altered mental state or decreased level of consciousness)
• visual disturbances  (e.g., visual hallucinations, cortical blindness, hemianopia, quadrantanopia, and diplopia)

However, the presentation can be quite varied, and may include other neurological symptoms such as ataxia, focal neurological deficits, vertigo, or tinnitus ⁵⁹.

Posterior reversible encephalopathy syndrome diagnosis

Posterior reversible encephalopathy syndrome is a clinical and radiographic diagnosis, which is why CT or MRI is a critical diagnostic tool. Performing a thorough history and physical examination are important. While obtaining a history, asking about the presence of headache, visual impairment (e.g., binocular diplopia, vision loss, no light perception vision, hemianopia, or quadrantanopia), seizure and seizure history, and medications taken are crucial ⁶¹. Sometimes the affected individual may have changes in mental status and not provide a reliable history; therefore, obtaining information from relatives, friends, or acquaintances is valuable. When conducting a physical examination, attention to the following should be noted: hemianopia, quadrantanopia, visual neglect, cortical blindness, horizontal gaze palsy with intact vestibulo-ocular reflex, papilledema, oral trauma (tongue biting seen during a seizure), brisk reflexes, active convulsions, and urinary and fecal incontinence ⁶², ¹⁵.

Part of the work-up for PRES syndrome also includes evaluation of potential causes, triggers and risk factors since their identification will be crucial for management. Obtaining blood work can help evaluate electrolyte imbalances, hypoalbuminemia, protein deficiency, an underlying infection (for example, herpes simplex virus type 1 or 2, which can cause herpes simplex encephalitis), and autoimmune disorders. Blood work can also help exclude severe hypoglycemia as a potential diagnosis. A lumbar puncture is sometimes done in immunocompromised individuals to assess for encephalitis.

Obtaining imaging is essential since the assessment of radiographs is the gold standard for the diagnosis of posterior reversible encephalopathy syndrome ⁶³. A head CT is critical to assess for neurologic emergencies that can explain an acute onset of altered mentation, headache, and seizures, such as intracranial hemorrhage. An MRI of the brain without intravenous (IV) contrast is the imaging modality of choice, looking for vasogenic edema as a hyperintense signal on T2, most commonly in the parieto-occipital lobes—although other areas can be involved, such as the temporal lobe, frontal lobe, brainstem, and deep white matter ¹². The MRI will also help in the evaluation of other potential diagnoses, such as hypoxic-ischemic encephalopathy, posterior circulation infarct, and primary central nervous system vasculitis ⁸. A magnetic resonance angiography (MRA) of the brain, which is typically normal in PRES, can show focal vasoconstriction or vasodilation patterns present in CNS vasculitis; and magnetic resonance venography (MRV), which is also typically normal in PRES, can help exclude sagittal sinus thrombosis as a possible diagnosis ⁶⁴.

Posterior reversible encephalopathy syndrome differential diagnosis

The differential diagnosis of posterior reversible encephalopathy syndrome is broad and includes the following ⁸:

• Intracranial hemorrhage
• Subdural hemorrhage
• Subarachnoid hemorrhage
• Cerebral sinus venous thrombosis
• Posterior circulation ischemic or hemorrhagic stroke
• thrombosis of the basilar artery
• Vasculitis of the central nervous system
• Herpes simplex encephalitis
• Autoimmune encephalitis
• Uremic encephalopathy
• Hypoglycemia

Posterior reversible encephalopathy syndrome treatment

Identifying, treating, and managing the underlying cause, in addition to careful treatment of hypertension, is crucial for the management of posterior reversible encephalopathy syndrome. There is no specific, established antihypertensive regimen for the treatment of acute hypertension in people with posterior reversible encephalopathy syndrome (PRES) ¹⁴. Treatment is recommended when the blood pressure exceeds 160 mmHg/110 mmHg, with a goal of 130 to 150 mmHg/80 to 100 mmHg ¹⁵. A sudden or drastic reduction of blood pressure can lead to cerebral hypoperfusion and increase the risk of developing ischemia; therefore, blood pressure should not be reduced for more than 10 to 20 mmHg every 10 to 20 minutes  ¹⁵. Such careful acute blood pressure management may warrant a need for admission to the intensive care unit (ICU) until a stable blood pressure goal is reached. Thereafter, maintaining target blood pressure on the medical floors and in the outpatient setting is recommended. The exact duration for treatment post-acutely with antihypertensives is unclear and will vary among individuals.

Sometimes individuals with PRES develop life-threatening complications, such as status epilepticus or coma, and treatment and management of such complications at an intensive care unit (ICU) should follow ¹⁶. At this time, there is no established antiepileptic treatment for seizures in people with PRES, and studies aimed to identify a specific antiseizure regimen are lacking ¹⁴. Some antiepileptic treatment is given during the acute phase of posterior reversible encephalopathy syndrome (PRES) and discontinued once PRES resolves ¹⁷. In certain circumstances, complications such as epilepsy emerge, and treatment with antiepileptic drugs will be long-term ¹.

If posterior reversible encephalopathy syndrome (PRES) is caused by using an immunosuppressant, reduction of the dose or substitution of the agent is recommended ¹⁸.

Posterior reversible encephalopathy syndrome prognosis

Posterior reversible encephalopathy syndrome prognosis is typically good if recognized and treated early, with symptom improvement or resolution in a few days to several weeks ⁸, ⁶⁵. Treatment of the cause usually restores symptoms and neuroradiological findings within several weeks. If the condition is left untreated, brain edema and irreversible brain injury may occur ⁶. Visual symptoms often completely resolve, especially with early treatment of posterior reversible encephalopathy syndrome, although there are some reported cases where residual visual deficits can remain (albeit improved) at 3 to 4 months after onset ⁶¹. It is unclear which individuals are at risk of having prolonged visual deficits. PRES symptom irreversibility can ensue if treatment is delayed. If the amount of cerebral vasogenic edema is large, the prognosis can worsen, as the increased pressure to surrounding blood vessels can compromise blood flow and result in ischemia ²⁰. In certain situations, if there is the involvement of the brainstem, the prognosis can also worsen ²⁰. Zou et al ⁶³ previously found that posterior reversible encephalopathy syndrome in patients with blood cancer confers worse prognosis. All the PRES patients with blood cancer had worse prognosis than those without hematologic tumor ⁶⁶.

Recurrence of posterior reversible encephalopathy syndrome is possible and has been reported in individuals undergoing dialysis ⁸.

1. Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. J Neurol. 2017 Aug;264(8):1608-1616. doi: 10.1007/s00415-016-8377-8[↩][↩][↩][↩][↩][↩][↩]
2. Inan S, Polat O, Cetinkaya E, Inan UU. Bilateral serous retinal detachment accompanied by a rare intraretinal fluid configuration in preeclampsia and PRES Syndrome. Rom J Ophthalmol. 2019 Jan-Mar;63(1):86-90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531768[↩]
3. Alsultan M, Basha K. Resistant hypertension and PRES syndrome induced by carbamazepine in a patient with SLE: A case report and literature review. Ann Med Surg (Lond). 2022 May 11;78:103767. doi: 10.1016/j.amsu.2022.103767[↩][↩]
4. Zelaya JE, Al-Khoury L. Posterior Reversible Encephalopathy Syndrome. [Updated 2022 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554492[↩][↩][↩][↩][↩]
5. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015;14(9):914–925. doi: 10.1016/S1474-4422(15)00111-8[↩][↩][↩][↩][↩][↩][↩]
6. McKinney AM, Short J, Truwit CL, McKinney ZJ, Kozak OS, SantaCruz KS, Teksam M. Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings. AJR Am J Roentgenol. 2007 Oct;189(4):904-12. doi: 10.2214/AJR.07.2024[↩][↩]
7. Roth C, Ferbert A. The posterior reversible encephalopathy syndrome: what’s certain, what’s new? Pract Neurol. 2011 Jun;11(3):136-44. doi: 10.1136/practneurol-2011-000010[↩]
8. Hobson EV, Craven I, Blank SC. Posterior reversible encephalopathy syndrome: a truly treatable neurologic illness. Perit Dial Int. 2012 Nov-Dec;32(6):590-4. doi: 10.3747/pdi.2012.00152[↩][↩][↩][↩][↩][↩][↩][↩][↩]
9. Terry A.Neill M. 2018. Reversible Posterior Leukoencephalopathy Syndrome. Up to date.[↩]
10. Posterior reversible encephalopathy syndrome. https://radiopaedia.org/articles/posterior-reversible-encephalopathy-syndrome-1?lang=us[↩][↩][↩]
11. 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. N Engl J Med. 1996 Feb 22;334(8):494-500. doi: 10.1056/NEJM199602223340803[↩][↩][↩][↩]
12. Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc. 2010 May;85(5):427-32. doi: 10.4065/mcp.2009.0590[↩][↩][↩][↩]
13. Cordelli DM, Masetti R, Ricci E, Toni F, Zama D, Maffei M, Gentili A, Parmeggiani A, Pession A, Franzoni E. Life-threatening complications of posterior reversible encephalopathy syndrome in children. Eur J Paediatr Neurol. 2014 Sep;18(5):632-40. doi: 10.1016/j.ejpn.2014.04.014[↩]
14. Strother R, Wong H, Miller NE. Posterior Reversible Encephalopathy Syndrome Secondary to Hypertensive Encephalopathy Brought on by a MAO Inhibitor: A Case Report. J Prim Care Community Health. 2019 Jan-Dec;10:2150132719869539. doi: 10.1177/2150132719869539[↩][↩][↩][↩]
15. Vandenbossche G, Maquet J, Vroonen P, Lambert G, Nisolle M, Kridelka F, Emonts E. A reversible posterior leucoencephalopathy syndrome including blindness caused by preeclampsia. Facts Views Vis Obgyn. 2016 Sep;8(3):173-177. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172574[↩][↩][↩][↩][↩]
16. Gokhale A, Kimona A, Kantor S, Prakash S, Manhas Y. Posterior Reversible Leukoencephalopathy Syndrome (PRES) in Intensive Care Unit – Case series. Indian J Crit Care Med. 2017 Nov;21(11):772-778. doi: 10.4103/ijccm.IJCCM_235_17[↩][↩]
17. Spencer D. PRES-ing for Answers About Long-Term Seizure Risk in Patients With Posterior Reversible Encephalopathy Syndrome. Epilepsy Curr. 2015 Nov-Dec;15(6):317-8. doi: 10.5698/1535-7511-15.6.317[↩][↩]
18. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol. 1999 May;246(5):339-46. doi: 10.1007/s004150050360[↩][↩]
19. Posterior reversible encephalopathy syndrome (PRES). https://radiopaedia.org/cases/pres[↩]
20. Covarrubias DJ, Luetmer PH, Campeau NG. Posterior reversible encephalopathy syndrome: prognostic utility of quantitative diffusion-weighted MR images. AJNR Am J Neuroradiol. 2002 Jun-Jul;23(6):1038-48. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976914[↩][↩][↩][↩][↩][↩]
21. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol. 2008;29(6):1043–1049. doi: 10.3174/ajnr.A0929[↩][↩][↩][↩][↩][↩]
22. Strandgaard S, Olesen J, Skinhoj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. Br Med J. 1973;1(5852):507–510. doi: 10.1136/bmj.1.5852.507[↩][↩]
23. Garner O, Ramirez A, Iardino A. A case of posterior reversible encephalopathy syndrome associated with sepsis. BMJ Case Rep. 2018 Jul 10;2018:bcr2018225128. doi: 10.1136/bcr-2018-225128[↩][↩]
24. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 2015;14:914–25. 10.1016/S1474-4422(15)00111-8[↩]
25. Bartynski WS, Boardman JF, Zeigler ZR, Shadduck RK, Lister J. Posterior reversible encephalopathy syndrome in infection, sepsis, and shock. AJNR Am J Neuroradiol. 2006 Nov-Dec;27(10):2179-90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977225[↩][↩]
26. Jayaweera JL, Withana MR, Dalpatadu CK, Beligaswatta CD, Rajapakse T, Jayasinghe S, Chang T. Cyclophosphamide-induced posterior reversible encephalopathy syndrome (PRES): a case report. J Med Case Rep. 2014 Dec 18;8:442. doi: 10.1186/1752-1947-8-442[↩]
27. Stübgen JP. Posterior reversible encephalopathy syndrome (PRES) after granulocyte-colony stimulating factor (G-CSF) therapy: a report of 2 cases. J Neurol Sci. 2012 Oct 15;321(1-2):35-8. doi: 10.1016/j.jns.2012.07.028[↩]
28. Gratton D, Szapary P, Goyal K, Fakharzadeh S, Germain V, Saltiel P. Reversible posterior leukoencephalopathy syndrome in a patient treated with ustekinumab: case report and review of the literature. Arch Dermatol. 2011 Oct;147(10):1197-202. doi: 10.1001/archdermatol.2011.161[↩]
29. Mishra A, Seril DN. Posterior Reversible Encephalopathy Syndrome following Ustekinumab Induction for Crohn’s Disease. Case Rep Gastroenterol. 2018 Aug 29;12(2):521-527. doi: 10.1159/000492462[↩]
30. Chowdhary M, Kabbani AA, Tobey D, Hope TD. Posterior reversible encephalopathy syndrome in a woman with focal segmental glomerulosclerosis. Neuropsychiatr Dis Treat. 2015 Apr 21;11:1111-4. doi: 10.2147/NDT.S84010[↩]
31. Lassen NA. Regulation of cerebral circulation. Acta Anaesthesiol Scand Suppl. 1971;45:78–80. doi: 10.1111/j.1399-6576.1971.tb00661.x[↩]
32. Meng L, Gelb AW. Regulation of cerebral autoregulation by carbon dioxide. Anesthesiology. 2015;122(1):196–205. doi: 10.1097/ALN.0000000000000506[↩]
33. Edvinsson L, Owman C, Sjöberg NO. Autonomic nerves, mast cells, and amine receptors in human brain vessels. A histochemical and pharmacological study. Brain Res. 1976 Oct 22;115(3):377-93. doi: 10.1016/0006-8993(76)90356-5[↩]
34. Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum WI, Patterson JL., Jr Responses of cerebral arteries and arterioles to acute hypotension and hypertension. Am J Physiol. 1978;234(4):H371–H383[↩]
35. MacKenzie ET, Strandgaard S, Graham DI, Jones JV, Harper AM, Farrar JK. Effects of acutely induced hypertension in cats on pial arteriolar caliber, local cerebral blood flow, and the blood-brain barrier. Circ Res. 1976;39(1):33–41. doi: 10.1161/01.RES.39.1.33[↩]
36. Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol. 2008;65(2):205–210. doi: 10.1001/archneurol.2007.46[↩]
37. Feske SK. Posterior reversible encephalopathy syndrome: a review. Semin Neurol. 2011;31(2):202–215. doi: 10.1055/s-0031-1277990[↩]
38. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol. 2008 Jun;29(6):1036-42. doi: 10.3174/ajnr.A0928[↩]
39. Lamy C, Oppenheim C, Mas JL. Posterior reversible encephalopathy syndrome. Handb Clin Neurol. 2014;121:1687-701. doi: 10.1016/B978-0-7020-4088-7.00109-7[↩]
40. Mayama M, Uno K, Tano S, Yoshihara M, Ukai M, Kishigami Y, Ito Y, Oguchi H. Incidence of posterior reversible encephalopathy syndrome in eclamptic and patients with preeclampsia with neurologic symptoms. Am J Obstet Gynecol. 2016 Aug;215(2):239.e1-5. doi: 10.1016/j.ajog.2016.02.039[↩]
41. Marra A, Vargas M, Striano P, Del Guercio L, Buonanno P, Servillo G. Posterior reversible encephalopathy syndrome: the endothelial hypotheses. Med Hypotheses. 2014;82(5):619–622. doi: 10.1016/j.mehy.2014.02.022[↩][↩][↩][↩]
42. Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol. 2008;29(6):1036–1042. doi: 10.3174/ajnr.A0928[↩][↩]
43. Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc. 2010;85(5):427–432. doi: 10.4065/mcp.2009.0590[↩][↩][↩]
44. Bartynski WS, Tan HP, Boardman JF, Shapiro R, Marsh JW. Posterior reversible encephalopathy syndrome after solid organ transplantation. AJNR Am J Neuroradiol. 2008;29(5):924–930. doi: 10.3174/ajnr.A0960[↩][↩]
45. Masetti R, Cordelli DM, Zama D, Vendemini F, Biagi C, Franzoni E, Pession A. PRES in children undergoing hematopoietic stem cell or solid organ transplantation. Pediatrics. 2015;135(5):890–901. doi: 10.1542/peds.2014-2325[↩]
46. Wu Q, Marescaux C, Wolff V, Jeung MY, Kessler R, Lauer V, Chen Y. Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur Neurol. 2010;64(3):169–177. doi: 10.1159/000319032[↩][↩][↩][↩]
47. Hammerstrom AE, Howell J, Gulbis A, Rondon G, Champlin RE, Popat U. Tacrolimus-associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation. Am J Hematol. 2013;88(4):301–305. doi: 10.1002/ajh.23402[↩][↩]
48. Reinohs M, Straube T, Baum P, Berrouschot J, Wagner A. Recurrent reversible cerebral edema after long term immunosuppression with tacrolimus. J Neurol. 2002;249(6):780–781. doi: 10.1007/s00415-002-0703-7[↩]
49. Wong R, Beguelin GZ, de Lima M, Giralt SA, Hosing C, Ippoliti C, Forman AD, Kumar AJ, Champlin R, Couriel D. Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2003;122(1):128–134. doi: 10.1046/j.1365-2141.2003.04447.x[↩]
50. Saner F, Gu Y, Minouchehr S, Ilker K, Fruhauf NR, Paul A, Radtke A, Dammann M, Katsarava Z, Koeppen S, Malago M, Broelsch CE. Neurological complications after cadaveric and living donor liver transplantation. J Neurol. 2006;253(5):612–617. doi: 10.1007/s00415-006-0069-3[↩]
51. Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int Off J Eur Soc Organ Transplant. 2000;13(5):313–326. doi: 10.1111/j.1432-2277.2000.tb01004.x[↩]
52. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol. 1999;246(5):339–346. doi: 10.1007/s004150050360[↩]
53. Yamauchi A, Ieiri I, Kataoka Y, Tanabe M, Nishizaki T, Oishi R, Higuchi S, Otsubo K, Sugimachi K. Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation. 2002;74(4):571–572. doi: 10.1097/00007890-200208270-00024[↩]
54. Nwafor DC, Brichacek AL, Mohammad AS, Griffith J, Lucke-Wold BP, Benkovic SA, Geldenhuys WJ, Lockman PR, Brown CM. Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment. J Cent Nerv Syst Dis. 2019 Apr 9;11:1179573519840652. doi: 10.1177/1179573519840652[↩]
55. Marra AM, Barilaro G, Villella V, Granata M. Eosinophilic granulomatosis with polyangiitis (EGPA) and PRES: a case-based review of literature in ANCA-associated vasculitides. Rheumatol Int. 2015 Sep;35(9):1591-5. doi: 10.1007/s00296-015-3261-x[↩]
56. Liman TG, Bohner G, Heuschmann PU, Endres M, Siebert E. The clinical and radiological spectrum of posterior reversible encephalopathy syndrome: the retrospective Berlin PRES study. J Neurol. 2012;259(1):155–164. doi: 10.1007/s00415-011-6152-4[↩]
57. Mayama M, Uno K, Tano S, Yoshihara M, Ukai M, Kishigami Y, Ito Y, Oguchi H. Incidence of posterior reversible encephalopathy syndrome in eclamptic and patients with preeclampsia with neurologic symptoms. Am J Obstet Gynecol. 2016;215(2):239 e231–239 e235. doi: 10.1016/j.ajog.2016.02.039[↩][↩]
58. Sudulagunta SR, Sodalagunta MB, Kumbhat M, Settikere Nataraju A. Posterior reversible encephalopathy syndrome(PRES). Oxf Med Case Reports. 2017 Apr 3;2017(4):omx011. doi: 10.1093/omcr/omx011[↩]
59. Tetsuka S, Ogawa T. Posterior reversible encephalopathy syndrome: A review with emphasis on neuroimaging characteristics. J Neurol Sci. 2019 Sep 15;404:72-79. https://doi.org/10.1016/j.jns.2019.07.018[↩][↩]
60. Bandyopadhyay S, Mondal KK, Das S, Gupta A, Biswas J, Bhattacharyya SK, Biswas G. Reversible cortical blindness: posterior reversible encephalopathy syndrome. J Indian Med Assoc. 2010 Nov;108(11):778-80.[↩]
61. Lifson N, Pasquale A, Salloum G, Alpert S. Ophthalmic Manifestations of Posterior Reversible Encephalopathy Syndrome. Neuroophthalmology. 2018 Aug 17;43(3):180-184. doi: 10.1080/01658107.2018.1506938[↩][↩]
62. Hawatmeh A, Studyvin S, Al-Halawani M, Amireh S, Thawabi M. Posterior reversible encephalopathy syndrome associated with left horizontal gaze palsy. Ann Transl Med. 2017 Mar;5(5):104. doi: 10.21037/atm.2017.03.09[↩]
63. Zou LP, Liu LY, Li H, Wang YY, Liu Y, Chen J, Hu LY, Liu MJ, Zhang MN, Lu Q, Ma SF. Establishment and utility assessment of posterior reversible encephalopathy syndrome early warning scoring (PEWS) scale establishment and utility assessment of PEWS scale. BMC Neurol. 2019 Feb 21;19(1):30. doi: 10.1186/s12883-019-1247-0[↩][↩]
64. Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol. 2008 Mar;29(3):447-55. doi: 10.3174/ajnr.A0839[↩]
65. Sundin CS, Johnson ML. Posterior Reversible Encephalopathy Syndrome. MCN Am J Matern Child Nurs. 2018 Mar/Apr;43(2):77-82. doi: 10.1097/NMC.0000000000000409[↩]
66. Li H, Liu Y, Chen J, Tan X, Ye XY, Ma MS, Huang JP, Zou LP. Posterior reversible encephalopathy syndrome in patients with hematologic tumor confers worse outcome. World J Pediatr. 2015 Aug;11(3):245-9. doi: 10.1007/s12519-015-0027-1[↩]