Posterior Reversible Encephalopathy Syndrome (PRES)

Acute cerebral vasogenic edema most often in the posterior parietal-occipital region
Unknown pathophysiology. Endothelial injury, immune activation and cytokine release, failure of cerebral autoregulation and breakdown of blood-brain-barrier are hypothesized
Lack of sympathetic innervation in the posterior circulation might explain its preferencial involvement
May be neither posterior nor reversible
Moderate to severe hypertension is seen in about 70% of patients with PRES, but the upper limits of autoregulation (MAP 150–160 mmHg) are typically not reached
The extent of brain edema in PRES does not appear to increase with the severity of hypertension.
PRES is seen in the absence of hypertension in 20%–40% of patients
Has been reported in all age groups from infants to elderly but most common in young and middle-aged adults
Slight female predominance even when correcting for eclampsia
General incidence is unknown but incidence in specific cohorts is estimated as:
- Pediatric patients: 0.04%
- Pediatric ICU: 0.4%
- Adults with bone marrow transplantation: 2.7-25%
- Adults with solid organ transplantation: 0.4%
- Adults with systemic SLE: 0.69%
- Adults with end stage renal failure: 0.84%
Mortality approaches 19% and functional impairments of varying degree are seen in 44% of patients

Risk factors for PRES

Blood pressure dysregulation
- Toxemia of pregnancy (preeclampsia/eclampsia)
- Dysautonomia
  - Guillain-Barré syndrome
  - Post carotid endarterectomy with cerebral reperfusion syndrome
  - Induced hypertension
    - Prevention of vasospasm following SAH (“Triple-H therapy”)
    - Drug withdrawal (clonidine, triamterene. prazosin, ephedrine, etc)
- Infection (sepsis)
- Renal disease
  - Acute and chronic renal failure
  - Renal artery stenosis
  - Acute glomerulonephritis
  - Hemolytic uremic syndrome
- Immunosuppressive, chemotherapeutic and other drugs
  - Cyclosporin A
  - Methotrexate (especially intrathecal)
  - Tacrolimus
  - Sirolimus
  - Interferon A
  - Intravenous immunoglobulin
  - Cytostatics (cisplatin, vincristine, cytarabine, gemcitabine, many others)
  - Erythropoetin
  - Rituximab
  - GM-CSF
  - Tyrosine kinase inhibitors
  - Antiretrovirals
  - High dose glucocorticoids
  - Lithium
  - Dimethyl sulfoxide in stem cell suspension
- Post solid organ or bone marrow transplantation
- Tumor lysis syndrome
- Autoimmune disorders
  - SLE
  - Sjögren’s disease
  - GPA and other systemic vasculitides
  - Cryoglobulinemia
  - Primary sclerosing cholangitis
  - Hashimoto thyreoiditis
- Pheochromocytoma
- Electrolyte disorders
  - Hypercalcemia
  - Hypomagnesemia
- Blood transfusion
- Acute porphyria
- Hypocholesterolemia

Clinical presentation

Encephalopathy of varying grades (28–94%)
Seizures, commonly occur early in the course (74–87%)
- generalized tonic clonic (54–64%)
- partial seizures (3–28%)
- status epilepticus (3–17%, may be the presenting symptom of PRES)
Headache (50%)
- usually dull, diffuse, and gradual in onset
Visual symptoms (39%)
- decreased visual acuity
- diplopia
- visual field deficits
- cortical blindness
- color vision abnormality
- visual hallucinations
- Fundoscopic examination is often unremarkable but papilledema, retinal exudates and flame shaped hemorrhages may exist in the setting of severe hypertension
Focal neurologic deficits (19%)
Myelopathy in rare cases of spinal cord involvement

Imaging

Vasogenic edema manifests as patchy, confluent regions in subcortical white matter with variable involvement of the adjacent grey matter
- MRI:
  - hyperintense on T2/FLAIR
  - hypointense on T1
  - Variable enhancement patterns from none to focal/patchy parenchymal or cortico-pial may be seen. Leptomeningeal enhancement may be best appreciated on delayed post-contrast FLAIR sequences
  - Normal to low signal on DWI, high ADC values
  - DWI signal and ADC value approaching that of normal appearing white matter may result from intravoxel averaging in areas with both vasogenic and cytotoxic edema and may represent the earliest marker of nonreversible lesions
  - Low ADC in the cortex, thalamic pulvinar, and splenium of the corpus callosum can also be caused by seizure activity which may also complicate PRES
  - Up to 60% of cases will have hemorrhagic foci (microbleeds, sulcal SAH, or focal parenchymal hematomas) best appreciated on T2* or SWI imaging
  - Patients with hemorrhage or cytotoxic edema are more likely to have poor outcomes
- Unenhanced CT:
  - Hypoattenuating lesions that may be indistinguishable from acute infarcts
- Perfusion (CT/DSC/ASL/SPECT)
  - Different patterns have been described, both hypo- and hyperperfusion may exist, sometimes alternating in serial imaging of the same patient
  - Increased brain perfusion in areas proximal to parenchymal signal abnormality
  - Decreased rCBV, rCBF, and heterogeneous MTT in affected cortical areas may be seen
- CTA/MRA:
  - Approximately 85% of patients have angiographic pattern indistinguishable from RCVS
  - Multifocal vasoconstriction, focal vasodilatation, or string-of-bead appearance of second- and third- order branches of cerebral arteries close to areas of vasogenic edema
  - These changes appear reversible, like in RCVS
Posterior parieto-occipital regions are typically but not invariably affected
Frontal and temporal regions are often involved
Basal ganglia, brainstem, and cerebellum are the least affected areas
Bilateral involvement, fairly symmetric but may also be asymmetric
Three distinct patterns have been described:
1. “classical posterior distribution” (most common)
2. “superior frontal sulcus pattern”
3. “holo-hemispheric watershed pattern”
Spinal cord involvement in PRES is rare and often associated with severe hypertension
- Central spinal cord edema originates at the cervico-medullary junction and spans at least four segments
- Usually accompanied by brainstem involvement

Other investigations

CSF
- Elevated protein (70%)
- Pleocytosis is rare and may be a marker of hemorrhage or infarction
Blood and serologic tests
- May reveal specific pathology (eg. electrolyte disturbance, sepsis, renal failure).
- Elevated LDH has been reported in patients with malignancy and preeclampsia
- Elevated CRP has been associated with increased mortality
- Low serum albumin levels have been observed in 70% of patients

Management

There is no specific treatment for PRES, management is supportive

Removal or reduction of the triggering factor
Prompt delivery in pregnant women
Supportive care (hydration, correction of electrolyte disturbances)
Intubation and ventilation support may be required in patients with altered mental status
In hypertensive patients, gradual reduction of blood pressure
- not more than 20-25% in the first few hours
- maintain mean arterial pressure at 105-125 mmHg
- continuous infusion is preferred to avoid fluctuations
- first line agents include nicardipine, labetalol, nimodipine, second line agents include sodium nitroprusside, hydralazine, and diazoxide
Treat seizures/status epilepticus
- Continuous EEG monitoring may be considered
- In pregnant women, magnesium sulfate is indicated to prevent seizures

References

Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions Lancet Neurol. 2015 Sep;14(9):914-925. doi: 10.1016/S1474-4422(15)00111-8
Posterior Reversible Encephalopathy Syndrome, Part 1: Fundamental Imaging and Clinical Features. American Journal of Neuroradiology 29, no. 6 (June 2008): 1036–42. doi: 10.3174/ajnr.A0928
Posterior Reversible Encephalopathy Syndrome, Part 2: Controversies Surrounding Pathophysiology of Vasogenic Edema. American Journal of Neuroradiology 29, no. 6 (June 2008): 1043–49. doi: 10.3174/ajnr.A0929
Posterior Reversible Encephalopathy Syndrome: Clinical Features and Outcome Front. Neurol., 14 February 2020 doi: 10.3389/fneur.2020.00071
Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome AJNR Am J Neuroradiol. 2007 Aug;28(7):1320-7. doi: 10.3174/ajnr.A0549
Posterior reversible encephalopathy syndrome with spinal cord involvement. Neurology. 2014 Nov 25;83(22):2002-6. doi: 10.1212/WNL.0000000000001026
PRES with asymptomatic spinal cord involvement. Is this scenario more common than we know? Spinal Cord Ser Cases 2, 15001 (2016). doi: 10.1038/scsandc.2015.1