Posterior Reversible Encephalopathy Syndrome

Etiology

Those at risk for developing PRES tend to have one or more of the following risk factors, triggers, or etiologies such as hypertension; preeclampsia; kidney disease (such as nephrotic syndrome, which can lead to hypovolemia and secondary hypertension via activation of the renin-angiotensin system; renal failure; liver disease; various chemotherapy agents like platinum-containing medications, gemcitabine, CHOP/R-CHOP, exposure to cytotoxic medications or immunosuppressants such as tacrolimus, sirolimus, interferon therapies as well as various immunotherapies and monoclonal antibodies like bevacizumab, pazopanib, sorafenib, and sunitinib.[3][6][7][8] In addition, autoimmune disorders (such as hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, eosinophilic granulomatosis with polyangiitis, and systemic lupus erythematosus); or sepsis.[2][9][10][11][12] Of these etiologies or triggers, uncontrolled hypertension is the most common.[4] However, having acute hypertension does not suggest that an individual will develop PRES, and it is difficult to determine which hypertensive individuals will develop PRES.[2][13]

Epidemiology

PRES is a syndrome that has been historically underdiagnosed, perhaps due to limited awareness; however, given the increasing availability of imaging, and improvement in the quality of imaging, awareness of PRES has improved, and an understanding of the epidemiology of PRES has been emerging. Based on several reports and studies, PRES affects people of all ages but is more common in middle-aged females.[1][14]

In a retrospective study involving the review of demographics, risk factors, and clinical presentation of 113 patients with PRES, Fugate, and colleagues found that 51 individuals (45%) had an autoimmune disease with most of the individuals presenting with seizures (74%), followed by encephalopathy (28%), headache (26%), and visual disturbance (20%).[4] Having an epileptic seizure at presentation was found to be the best predictor for PRES, and encephalopathy was the second-best predictor. The same study found that having a recent exposure to chemotherapy and those with underlying renal failure were also crucial predictors of PRES.[15]

Pathophysiology

The pathophysiology of PRES remains unclear, but some proposed mechanisms center around the dysregulation of cerebral autoregulation, the brain’s ability to maintain constant cerebral blood flow over a range of blood pressures via the constriction or dilation of the cerebral blood vessels.[2] When blood pressures are high, typically above a systolic pressure of 160 mmHg for most people, the amount of 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 edema. There is the belief that posterior circulation is mostly affected in cases of PRES because it has fewer adaptive mechanisms to regulate the extent of extravasation and the breakdown of the blood-brain barrier in the context of high blood pressure compared to anterior circulation.[16] Such speculation is perhaps inspired by findings of a formaldehyde histofluorescence study conducted by Edvinsson and colleagues that revealed a more significant number of adrenergic perivascular fibers innervating the anterior cerebral circulation compared to the vertebral circulation.[17] The amount of sympathetic nerve involvement is thought to be proportional to the effectiveness of autoregulation.[16] 

One critique of the hypertensive-hyperperfusion hypothesis above is that there have been cases where individuals exhibited PRES. Still, their blood pressures were not high enough to surpass the autoregulative capability of the brain.[1][18] 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][3] Although not yet fully understood, tacrolimus, cyclosporine, cisplatin, and other immunosuppressants can have direct toxic effects on the endothelium, compromising the blood-brain barrier.[3][16]

The theory of ischemia as a proposed mechanism from dysregulated cerebral autoregulation leading to vasoconstriction and then resultant cytotoxic edema has been considered based on some patients showing vasoconstriction in radionuclide studies.[19][20][21][22] These results reflect a minority of patients, and further pathology studies have failed to show evidence of ischemia or infarction. [23]

Immunosuppressants can affect not only the blood-brain barrier but also neuroinflammation, such as in the context of sepsis and metabolic disorders like uremia, hypomagnesemia, 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.[12][24][25][26]

History and Physical

PRES is a clinical and radiographic diagnosis and performing a thorough history and physical examination is indispensable. There are multiple different clinical presentations that can vary in severity and acuity. The most common presenting symptoms include headache (50%), encephalopathy (28%), visual disturbances like binocular diplopia, vision loss, no light perception vision, hemianopia, or quadrantanopia(39%), seizures (80%), and focal neurological deficits (10-15%).[27] Sometimes the affected individual may have changes in mental status and not provide a reliable history; therefore, obtaining collateral information from relatives, friends, or acquaintances is valuable. While only a few patients will be normotensive, up to 75% will have moderately to severely elevated blood pressure on initial presentation.[18] Some theorize that it is not the height of the blood pressure but the rapidity of the elevation, similar to the theory with febrile seizures in children, not the height of the fever, but the rapidity of its elevation. 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.[28][29]

Evaluation

Imaging remains essential and the gold standard in the diagnosis of PRES as it cannot be made based on clinical symptoms alone.[30] 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 the presence of vasogenic edema that will appear as a hyperintense signal on T2 with the fluid-attenuated inversion recovery (FLAIR) sequences helping to improve sensitivity. This is most commonly seen in the parieto-occipital lobes—although other areas can be involved, such as the temporal lobe, frontal lobe (superior frontal gyrus), cerebellum, brainstem, and deep white matter.[4] The cortex is theorized to be more involved than white matter and is more densely packed and able to resist the accumulation of edema. 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.[2] When the classic posterior cerebral hemispheres are involved, what differentiates it from an infarction of the posterior cerebral artery infarction, is the sparing of the calcarine and paramedian parts of the occipital lobe. Similarly, the use of diffusion-weighted imaging (DWI) can aid in the differentiation of PRES from stroke and be either hypo- or isointense.

Vascular imaging with either a CTA or magnetic resonance angiography (MRA) of the brain, which is typically normal in PRES, can sometimes 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.[31] 

Part of the workup for PRES also includes the evaluation of potential etiologies since their identification will be crucial for management. Obtaining blood work can help evaluate electrolyte imbalances like uremia and hypomagnesemia, hypoalbuminemia, protein deficiency, and CSF studies for underlying infection (for example, herpes simplex virus type 1 or 2, which can cause herpes simplex encephalitis), and autoimmune etiologies. Blood work can also help exclude severe hypoglycemia as a potential diagnosis. A lumbar puncture is sometimes done in immunocompromised individuals or others with clinical suspicion of infection in order to assess for the presence of encephalitis.

Obtaining an electroencephalogram (EEG) in people with PRES can be helpful. For instance, if there is persistently altered mentation in the absence of tonic, clonic, or tonic-clonic movements, an individual may have subclinical seizure activity that can be captured on EEG. EEG patterns, however, are generally non-specific.[32]

Treatment / Management

Identifying, treating, and managing the underlying etiology, in addition to careful treatment of hypertension, is crucial for the management of PRES. There is no specific, established antihypertensive regimen for the treatment of acute hypertension in people with PRES.[33] Treatment is recommended when the blood pressure exceeds 160 mmHg/110 mmHg, with a goal of 130 to 150 mmHg/80 to 100 mmHg.[29] A sudden or drastic reduction of blood pressure can lead to cerebral hypoperfusion and increase the risk of developing ischemia; thus, blood pressure should not be reduced by more than 25% of the initial presenting blood pressure in the first six hours.[29] Such careful acute blood pressure management may warrant a need for admission to the intensive care unit until a stable blood pressure goal is reached with the use of titratable IV antihypertensives like nicardipine, clevidipine, and labetalol. 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. (B3)

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.[34] 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 but common medications such as levetiracetam and phenytoin are often used.[33] Some antiepileptic treatment is given during the acute phase of PRES and discontinued once PRES resolves.[35] In certain circumstances, complications such as epilepsy emerge, and treatment with antiepileptic drugs will be long-term.[1](B3)

Corticosteroids have been theorized to improve the symptoms of PRES through their role in reducing vasogenic edema, however, this has not been shown to be the case clinically as there are no reports of their success in clinical practice and they have even been shown to be a trigger for causing PRES in some patients taking it for asthma.[36]  If PRES is attributed to an immunosuppressant like bevacizumab, pazopanib, sorafenib, and sunitinib, a reduction of the dose or substitution of the agent is recommended.[37]

Differential Diagnosis

The differential diagnosis of PRES is broad and includes the following:[2]

• Intracranial hemorrhage
• Subdural hemorrhage
• Subarachnoid hemorrhage
• Cerebral sinus venous thrombosis
• Posterior circulation ischemic or hemorrhagic stroke
• Thrombosis of the basilar artery
• Encephalitis (autoimmune or infectious etiologies like HSV)
• Uremic encephalopathy
• Hypoglycemia

Prognosis

The prognosis of PRES is typically favorable if recognized and treated early, with symptom improvement or resolution in a few days to several weeks.[2][14] Visual symptoms often completely resolve, especially with early treatment of PRES, although there are some reported cases where residual visual deficits can remain (albeit improved) at 3 to 4 months after onset.[27] Although rare, it is unclear which individuals are at risk of having prolonged visual deficits and/or persistent seizures. 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 the surrounding blood vessels can compromise blood flow and result in ischemia.[16] In certain situations, if there is the involvement of the brainstem, the prognosis can also worsen.[16] Recurrence of PRES is possible and has been reported in individuals undergoing dialysis.[2]

Complications

Complications of PRES can develop if the disease is not treated promptly. Complications include focal neurologic deficits from ischemic injury, epilepsy, and life-threatening conditions, such as transforaminal cerebellar herniation, which is reported as one of the most common neurological complications that occur in children following hematopoietic stem cell transplantation.[5][38][5]