PRES (Posterior Reversible Encephalopathy Syndrome) J. Ryan Altman, MD AM Report 15 July 2008 PRES A clinical radiologic syndrome of heterogenic etiologies Many Names Posterior Reversible Encephalopathy Syndrome (PRES) Reversible Posterior Cerebral Edema Syndrome Posterior Leukoencephalopathy Syndrome Hyperperfusion Encephalopathy Brain Capillary Leak Syndrome PRES Epidemiology All age groups susceptible (ages 2-90) More common in women, even when eclampsia excluded Risk Factors Hypertensive disorders Renal disease Immunosuppressive therapies PRES Pathogenesis—unclear Autoregulatory Failure Normal autoregulation maintains constant cerebral blood flow over range of systemic BP by arteriolar constriction and dilatation. As upper limits of cerebral autoregulation exceeded, arterioles dilate and cerebral blood flow increases. Results in brain hyperperfusion, and may lead to breakdown of BBB Chronic HTN Vascular changes “reset” range of autoregulation As a result, pts with PRES in setting of longstanding HTN may have markedly elevated BP, while less severe elevations, even nl BP, are associated with PRES in other settings. PRES Pathogenesis—unclear Endothelial dysfunction Cytotoxic therapies may have direct toxicity on vascular endothelium, leading to capillary leakage, and BBB with axonal swelling, triggering vasogenic edema. may occur in normotensive individuals with nontoxic levels of these drugs Preeclampsia PRES best dx by elevated markers Elevated endothelial cell markers: fibronectin, tPA, thrombomodulin, endothelin-1, von Willebrand factor Markers also elevated in PRES associated with chronic renal failure, lupus nephritis, HUS Other possible causes: uremia, sepsis, hypomagnesemia, fluid overload PRES Anatomy Combination of acute HTN and endothelial damage results in hydrostatic edema (type of vasogenic edema characterized by forced leakage of serum through capillary walls and into the brain interstitium) The cortex, structurally more tightly packed than the white matter, resists accumulation of edema, hence predilection of abnormalities in white matter Primary involvement of posterior brain regions not well understood. (One thought is regional heterogeneity of sympathetic nerve innervation of intracranial arterioles, which protects the brain from marked increases in BP, have greater concentration around pial and intracerebral vessels in anterior cirulation.) PRES Associated Conditions Comorbidities that exacerbate neurologic deterioration: ischemic bowel disease, sepsis, hyponatremia, fever, proteinuria Hypertensive Encephalopathy PRES likely caused by vasogenic edema from breakthrough of autoregulation Risk for HE: rapidly developing, fluctuating, or intermittent hypertension May be seen in pts with chronic HTN, renal failure, or preeclampsia-eclampsia Percent elevation of BP above baseline as well as severity of HTN are associated with development of PRES. Therefore, it may occur in normotensive pts. PRES Associated Conditions Immunosuppresive Therapy Toxic levels of meds NOT required for development of PRES and prior Rx exposure does NOT appear to be protective. Cyclosporine Exacerbates HTN by inhibiting nitric oxide production and thought to mediate cellular injury through mitochondrial dysfunction Systemic HTN was only major factor associated with neurotoxic effects (MAHA, thrombocytopenia, and hypoalbuminemia were common thought) Elevated levels NOT related to onset of neurologic sx Other Rx: Tacrolimus, Sirolimus, Cisplatin, Interferon therapies, Bevacizumab PRES CLINICAL MANIFESTATIONS Headache Typically constant, nonlocalized, mod to sev, unresponsive to analgesia Altered Consciousness Ranged from mild somnolence to confusion and agitation, progressing to stupor or coma Seizures Usually generalized tonic clonic. May begin focally and often recur. Status epilepticus has been reported. Preceding visual loss/hallucinations suggest occipital lobe origin. Minority of pts may be seizure free. Visual Distubances Hemianopia, visual neglect, auras, visual hallucinations, cortical blindness Cortical blindness may be associated with denial of blindness (Anton’s syndrome) Fundoscopic exam often normal. May find papilledema with accompanying flame- shaped retinal hemorrhages or exudates Other findings DTR may be brisk with Babinski signs present HTN is frequent but not invariable. The hypertensive crisis may precede the neurologic syndrome by 24h or longer. PRES DDx Stroke Venous thrombosis Toxic or metabolic encephalopathy Demyelinating disorders Vasculitis Bilateral posterior cerebral a. infarctions (“top of the Basilar syndrome”) Encephalitis PRES Neuroimaging Symmetrical white matter edema in posterior cerebral hemispheres, particularly in parieto-occipital regions With tx, resolution of findings expected within days to weeks. Important localizations Calcarine and paramedian parts of occipital lobe are usually spared: this distinguishes PRES from bilat post cerebral a. infarcts Involvement of cerebellum and brainstem is common Lesions are usually in anterior cortex occur in more severe cases Although abnormalities primarily affect subcortical white matter, cortex and basal ganglia may be involved. Distribution is NOT usually confined to a single vascular territory. PRES Neuroimaging 2 FLAIR sequences improve sensitivity and detect subtle peripheral lesions Gyriform signal enhancement, reflecting disruption of BBB, can be present following administration of gadolinium. Petechial and large parenchymal hemorrhages have been described DWI aids to distinguish PRES from a top of the basilar stroke The anatomical extent of MRI findings have been shown to correlate with patient outcome. PRES Resolution after 2 weeks Gyriform enhancement PRES Treatment HTN Lower diastolic BP to 100-105 mmHg within 2-6 hrs. Max initial fall of BP should not exceed 25% of presenting value. More aggressive tx may reduce beyond autoregulatory range and possibly lead to ischemic event Use of IV Labetalol or Nicardipine to attain desired BP. If neither agent effective, may consider nitroprusside, with caveat of theoretical concern of paradoxically increasing intracranial pressure through vasodilatation. PRES Treatment Seizures Phenytoin Can probably be safely tapered as sx and neuroimaging findings resolve, usually after 1-2 wks. In setting of eclampsia: Delivery of baby and placenta are usually sufficient, but if not tx with Mg as opposed to Phenytoin or Diazepam No indication pts at long-term risk for sz recurrence or epilepsy (although long term studies are lacking) PRES Treatment Cytotoxic Immunosuppressive Therapy Reduce dose or remove agent Not recommended that agents known to induce PRES be reintroduced In setting of cytotoxic agent, pt with one or more are at risk for PRES (based on 2 case studies and lit review) Significant fluid overload (>10% baseline weight) Mean BP >25% baseline Cr >1.8 mg/dL Note: Decadron NOT recommended given associated risk of HTN, fluid overload, and electrolyte disturbance. PRES Prognosis Death may result from progressive cerebral edema, intracerebral hemorrhage or as complication of underlying condition. In one series, elev Cr levels were a risk factor for death, but neither BP levels or percent elevation from baseline values appeared to correlate with prognosis More extensive brain involvement, particularly in brainstem correlates with worse prognosis. Bibliography Reversible Posterior Leukoencephalopathy Syndrome. www.uptodate.com. 14 July 2008.