Posterior Reversible Encephalopathy Syndrome (PRES)

Alternative Nomenclature

  • Brain Capillary Leak Syndrome
  • Hyperperfusion Encephalopathy
  • Posterior Leukoencephalopathy Syndrome
  • Reversible Posterior Cerebral Edema Syndrome
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Epidemiology

History

  • First Reported in 1996 as “Reversible Posterior Leukoencephalopathy Syndrome” by Hinchey (NEJM, 1996) [MEDLINE]
    • Nearly Half of the 15 Patients Reported were Receiving Immunosuppressive Therapy
    • Most of the Patients Had Impaired Renal Function

Etiology

Renal Disease

Autoimmune Disease

  • Antiphospholipid Antibody Syndrome (see xxxx, [[xxxx]])
  • Autoimmune Hepatitis (see xxxx, [[xxxx]])
  • Cryoglobulinemia (see Cryoglobulinemia, [[Cryoglobulinemia]])
  • Goodpasture’s Syndrome (see xxxx, [[xxxx]])
  • Granulomatous Interstitial Nephritis
  • Grave’s Disease (see xxxx, [[xxxx]])
  • Hashimoto Thyroiditis (see xxxx, [[xxxx]])
  • Inflammatory Bowel DIsease
    • Crohn’s Disease (see xxxx, [[xxxx]])
    • Ulcerative Colitis (see xxxx, [[xxxx]])
  • Insulin-Dependent Diabetes Mellitus (IDDM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
  • Neuromyelitis Optica
  • Polyarteritis Nodosa (PAN) (see Polyarteritis Nodosa, [[Polyarteritis Nodosa]])
  • Polyglandular Autoimmune Syndromes (see xxxx, [[xxxx]])
  • Rheumatoid Arthritis (RA) (see xxxx, [[xxxx]])
  • Scleroderma (see Scleroderma, [[Scleroderma]])
  • Sjogren’s Syndrome (see xxxx, [[xxxx]])
  • Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus, [[Systemic Lupus Erythematosus]])
  • Thromboangiitis Obliterans (see xxxx, [[xxxx]])
  • Thrombotic Thrombocytopenic Purpura (TTP) (see Thrombotic Thrombocytopenic Purpura-Acquired, [[Thrombotic Thrombocytopenic Purpura-Acquired]])
  • Wegener’s Granulomatosis (see Wegener’s Granulomatosis, [[Wegeners Granulomatosis]])

Drugs

  • Bevacizumab (Avastin) (see Bevacizumab, [[Bevacizumab]])
  • Calcineurin Inhibitors
    • General Comments
      • Multiple Case Series Have Been Reported (Medicine, 2016) [MEDLINE] and (Transplant Proc, 2014) [MEDLINE]
      • May Be Associated with Calcineurin Levels Above or at the High End of Therapeutic Ranges, Although Cases Have Been Reported with Therapeutic Calcineurin Levels
    • Cyclosporine A (see Cyclosporine A, [[Cyclosporine A]]): commonly-reported etiology
    • Tacrolimus (FK-506, Fujimycin, Prograf, Advagraf, Protopic) (see Tacrolimus, [[Tacrolimus]]): commonly-reported etiology
  • Interferon Alfa
  • Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin, [[Intravenous Immunoglobulin]])
  • Ipilimumab (MDX-101, MDX-010, Yervoy) (see Ipilimumab, [[Ipilimumab]])
  • Methotrexate (see Methotrexate, [[Methotrexate]])
  • Platinum-Based Agents
    • Carboplatin (see Carboplatin, [[Carboplatin]])
    • Cisplatin (see Cisplatin, [[Cisplatin]])
    • Oxaliplatin (Eloxatin, Oxaliplatin Medac) (see Oxaliplatin, [[Oxaliplatin]])
  • Pyrimidine Analogs
    • Cytarabine (Arabinofuranosyl Cytidine, ARA-C, Cytosine Arabinoside, Cytosar-U) (see Cytarabine, [[Cytarabine]])
    • Gemcitabine (Gemzar) (see Gemcitabine, [[Gemcitabine]])
  • Radiographic Contrast (see Radiographic Contrast, [[Radiographic Contrast]]): used for cerebral/coronary angiography
  • Rituximab (Rituxan) (see Anti-CD20 Therapy, [[Anti-CD20 Therapy]])
  • Sirolimus (Rapamune, Rapamycin) (see Sirolimus, [[Sirolimus]])
  • Tyrosine Kinase Inhibitors
    • Pazopanib (Votrient) (see Pazopanib, [[Pazopanib]])
    • Sorafenib (Nexavar) (see Sorafenib, [[Sorafenib]])
    • Sunitinib (Sutent) (see Sunitinib, [[Sunitinib]])
  • Vincristine (see Vincristine, [[Vincristine]])

Other


Physiology

Probable Mechanisms

  • General Comments
    • Exact Mechanism is Unclear (Although the Following are Probably the Predominant Mechanisms)
  • Disordered Cerebral Autoregulation
    • As Upper Level of Cerebral Autoregulation is Exceeded, Cerebral Blood Flow Increases Proportional to Systemic Blood Pressure with Resulting Brain Hyperperfusion (Especially in Arterial Border Zones) with Breakdown of the Blood-Brain Barrier and Extravasation of Fluid/Blood into the Brain Parenchyma (i.e. Cerebral Edema)
    • Although Less Likely, Disordered Cerebral Autoregulation May Alternatively Result in Focal Vasoconstriction: resulting in local hypoperfusion, cytotoxic edema, and cerebral infarction
  • Endothelial Dysfunction: probably plays a role (especially in cases associated with eclampsia or cytotoxic therapies)
    • Damage to Vascular Endothelium with Capillary Leak, Blood-Brain Barrier Disruption, and Axonal Swelling Resulting in Vasogenic Edema
    • PRES May Occur with Normal Blood Pressure and with Normal Levels of the Cytotoxic Drugs

Anatomic Distribution

  • Predilection for Edema of the White Matter: cortex is structurally more tightly packed than the white matter and is therefore more resistant to the accumulation of cerebral edema
  • Predilection for Edema in Posterior Brain Regions: not clearly understood, but may involve a lesser concentration of adrenergic nerves around pial and intracerebral vessels in the posterior regions of the brain (this results in less protection of posterior region of the brain from marked increases in systemic blood pressure)

Diagnosis

Head CT (see Head Computed Tomography, [[Head Computed Tomography]])

  • Insensitive

Brain MRI (see Brain Magnetic Resonance Imaging, [[Brain Magnetic Resonance Imaging]])

  • Diagnostic Procedure of Choice
  • Findings
    • T2-Weighted Images: typically localized subcortical edema in bilateral posterior hemisphere and occipital areas
      • Note: In general, T1 and T2-weighted images can be easily differentiated by looking at the CSF -> CSF is dark on T1-weighted images and bright on T2-weighted images
    • Fluid-Attenuated Inversion Recovery (FLAIR) Images: typically localized subcortical edema in bilateral posterior hemisphere and occipital areas
      • Note: the Flair sequence is similar to a T2-weighted image except that the time to echo (TE) and repetition time (TR) times are very long
    • Diffusion-Weighted Images: usually normal
  • Localization (Am J Roentgenol, 2007) [MEDLINE] and (Mayo Clin Proc, 2010) [MEDLINE]: based on the extent of localization by brain MRI, the term “posterior” is probably a misnomer
    • Parieto-Occipital Lobe Involvement: 94%-98% of cases
    • Frontal Lobe Involvement: 77%-79% of cases
    • Temporal Lobe Involvement: 64%- 68% of cases

Clinical Manifestations

Cardiovascular Manifestations

  • Hypertension (see Hypertension, [[Hypertension]]): frequent, but not universally present
    • Importantly, the Hypertensive Crisis May Precede the Neurologic Syndrome by ≥24 hrs

Neurologic Manifestations

  • Altered Level of Consciousness (see Altered Mental Status, [[Altered Mental Status]]): wide range of presentations
  • Headache (see Headache, [[Headache]]): usually constant, non-localized, moderate-severe, and unresponsive to analgesics
    • Funduscopic Exam: often normal (especially in patients with chronic hypertension or eclampsia), but may demonstrate papilledema/retinal flame hemorrhages or exudates
  • Hyperreflexia (see Hyperreflexia, [[Hyperreflexia]]): often
  • Neurologic Symptoms Suggestive of Upper Cervical Spinal Cord Involvment: has been described in some cases
    • Bladder Dysfunction
    • Limb Weakness
    • Limb Discoordination
  • Positive Babinski Sign: often
  • Seizures (see Seizures, [[Seizures]])
    • Epidemiology
      • Seizures are a Common Presenting Symptom
      • Only a Minority of Cases (Particularly Those with Mild Disease) Present without Seizures
    • Clinical
      • Seizures are Generally Tonic-Clonic
      • Seizures May Begin Focally
      • Seizures May Be Preceded by Visual Loss or Hallucinations (Suggesting an Occipital Origin) in Some Cases
      • Seizures Often Recur
      • Status Epilepticus Has Been Reported
  • Visual Disturbances: often present
    • Aura
    • Cortical Blindness: may be accompanied by denial of blindness (Anton’s syndrome)
    • Hemianopsia
    • Visual Hallucinations
    • Visual Neglect

Malignant Posterior Reversible Encephalopathy Syndrome

  • Definition: clinical variant with refractory intracranial hypertension and/or hemorrhagic features
  • Clinical
    • Clinical Features
      • GCS <8
      • Clinical Decline Despite Standard Medical Management for Increased Intracranial Pressure
    • Radiographic Features
      • Cerebral Edema with Mass Effect
      • Brain Hemorrhage with Mass Effect
      • Effacement of Basal Cisterns
      • Transtentorial/Tonsillar/Uncal Herniation
  • Prognosis
    • No Fatalities were Reported in a Recent Case Series of 5 Patients (Clin Neurol Neurosurg, 2014) [MEDLINE]

Treatment

Treatment of Hypertension (see Hypertension, [[Hypertension]])

  • Agents
    • Nicardipine (Cardene) (see Nicardipine, [[Nicardipine]])

Treatment of Seizures (see Seizures, [[Seizures]])

  • Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]])

Treatment of Eclampsia (see Pre-Eclampsia, Eclampsia, [[Pre-Eclampsia, Eclampsia]])

  • xxx

Management of Cytotoxic Thrapies

  • Dose Reduction/Cessation: usually required

Other


References

  • A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334(8):494-500, 1996 [MEDLINE]
  • Posterior reversible encephalopathy syndrome: Incidence of atypical regions of involvement and imaging findings. Am J Roentgenol 189(4):904-912, 2007 [MEDLINE]
  • Posterior reversibleencephalopathy syndrome: Associated clinical and radiologic findings. Mayo Clin Proc 85(5):427-432, 2010 [MEDLINE]
  • Management and outcomes of malignant posterior reversible encephalopathy syndrome.  Clin Neurol Neurosurg. 2014 Oct;125:52-7. doi: 10.1016/j.clineuro.2014.06.034. Epub 2014 Jul 1 [MEDLINE]
  • Posterior reversible encephalopathy syndrome.  Semin Ultrasound CT MR.  2014;35:118–135 [MEDLINE]
  • Posterior reversible encephalopathy syndrome in lung transplantation: 5 case reports. Transplant Proc. 2014 Jul-Aug;46(6):1845-8. doi: 10.1016/j.transproceed.2014.05.032 [MEDLINE]
  • Calcineurin inhibitors associated posterior reversible encephalopathy syndrome in solid organ transplantation.  Medicine.  2016;95:1–8 [MEDLINE]