Posterior Reversible Encephalopathy Syndrome

Etiology

People who are at risk for developing PRES tend to have one or more of the following risk factors, triggers, or etiologies: 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; exposure to cytotoxic medications or immunosuppressants; autoimmune disorders (such as thrombotic thrombocytopenic purpura, eosinophilic granulomatosis with polyangiitis, and systemic lupus erythematosus); or sepsis.[2][6] 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][7]

Epidemiology

PRES has been a syndrome that has been underdiagnosed, perhaps due to limited awareness; however, given the increasing availability 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 mostly middle-aged females.[1][8][1]

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.[4] Most of the individuals in the study presented 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. Per Laetitia della Faille and colleagues, having exposure to chemotherapy and having renal failure were also crucial predictors of PRES.[9]

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 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.[10] 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.[11] The amount of sympathetic nerve involvement is thought to be proportional to the effectiveness of autoregulation.[10]

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][12] 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][10]

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.[6][13][14]

History and Physical

PRES is a clinical and radiographic diagnosis. Performing a thorough history and physical examination are indispensable. 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.[15] 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. 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.[16][17]

Evaluation

Obtaining imaging is essential since the assessment of radiographs is the gold standard for the diagnosis of PRES.[18] 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.[4] 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] 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.[19]

Part of the work-up for PRES also includes evaluation of potential etiologies 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 etiologies. 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 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.[20]

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.[21] Treatment is recommended when the blood pressure exceeds 160 mmHg/110 mmHg, with a goal of 130 to 150 mmHg/80 to 100 mmHg.[17] [Level 5] 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 for more than 10 to 20 mmHg every 10 to 20 minutes.[17] 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. 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.[22] 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.[21] Some antiepileptic treatment is given during the acute phase of PRES and discontinued once PRES resolves.[23] In certain circumstances, complications such as epilepsy emerge, and treatment with antiepileptic drugs will be long-term.[1](B3)

If PRES is attributed to an immunosuppressant, reduction of the dose or substitution of the agent is recommended.[24]

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
• Vasculitis of the central nervous system
• Herpes simplex encephalitis
• Autoimmune encephalitis
• 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][8] 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.[15] 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.[10] In certain situations, if there is the involvement of the brainstem, the prognosis can also worsen.[10] Recurrence of PRES is possible and has been reported in individuals undergoing dialysis.[2]

Complications

Complications of PRES 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, as reported in children.[5]