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Disease

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is a syndrome with clinical and radiographical signs with heterogeneous etiologies that are assembled together and referred to as:

Posterior reversible encephalopathy syndrome (PRES)
Reversible posterior cerebral edema syndrome
Hyperperfusion encephalopathy
Brain capillary leak syndrome
Posterior leukoencephalopathy syndrome

The presumed pathogenesis related to neurotoxicity in the setting of posterior cerebral edema visualized on neuroimaging in the setting of an inciting or predisposing incident.

None of these names are fully satisfactory; the syndrome is not always reversible, and it is frequently not limited to the white matter or the posterior pole of the brain.

(RPLS) is a relevant condition to the Ophthalmologist as the neurotoxicity is often manifest as visual disturbances such as loss of vision, blurry vision, scotoma, and visual hallucination. Other neurotoxic manifestations include headache, aphasia, facial numbness, seizure, and ataxia.

Etiology

The neurotoxic manifestations are thought to result from cerebral edema. The edema is typically in the parieto-occipital lobes and occurs in a watershed pattern. Edema can also be present in the frontal lobes, brainstem, cerebellum, and spinal cord.

Risk Factors

A variety of conditions can predispose to RPLS . The most common conditions include toxemia of pregnancy (eclampsia and preeclampsia), posttransplantation after allogenic bone marrow transplant or solid organ transplant, immunosuppresion with cyclosporine or tacrolimus, systemic inflammatory response syndrome, mulitorgan dysfunction syndrome, and autoimmune conditions such as systemic lupus erythematosis, scleroderma, granulomatosis with polyangiitis (formerly known as Wegener's), and polyarteritis nodosa. RPLS can also occur after chemotherapy, usually in high doses, with cytarabine, cisplatin, gemcitabine, tiazofurin, bevacizumab, and kinase inhibitor BAY 34-9006. Additionally, case reports exist of RPLS occurring in the setting of hypomagnesemia, uremia, sepsis, hypercalcemia, hypocholesterolemia, intravenous immunoglobulin treatment for Guillen-Barre syndrome, ephedra overdose, and tumor lysis syndrome.

Pathophysiology

The pathogenesis of RPLS remains unclear with heterogeneous nature; however the proposed mechanism appears to be related to dysfunction of cerebral autoregulation and endothelialuim which may lead to breakdown of the blood-brain barrier, and impaired cerebral autoregulation.

The proposed mechanisms for the pathogenesis of RPLS are" hypertension leading to failure of cerebral autoregulation causing an injury to the capillary network and thus hyperperfusion causing a vasogenic cerebral edema. The other theory suggests endothelial dysfunction especially implicated in cases associated with preeclampsia or cytotoxic therapies which may have direct toxicity on vascular endothelium, leading to capillary leakage and to blood-brain barrier disruption and axonal swelling causing vasoconstriction and then hypoperfusion causing ischemia and then vasogenic cerebral edema. Alternatively, Cerebral ischemia postulated to lead to cerebral autoregulation and reactive focal vasoconstriction, resulting in local hypoperfusion, cytotoxic edema, and cerebral infarction.

all proposed theories acknowledge a role in the breakdown of the blood-brain barrier causing vasogenic cerebral edema, which is evident on neuroimaging.

Diagnosis

Neuroimaging such as CT and MRI are utilized to discern cerebral edema. MRI findings commonly consist of T2-hyperintense vasogenic edema typically involving the cortical or subcortical white matter or both of the affected region. Although these findings are usually in the parieto-occipital region, the frontal and temporal lobes can also be affected. Advanced neuroimaging such as catheter angiogram, MRA with 3D time of flight, Tc99m SPECT, and rCBV can be utilized. Clinical suspicion, with attention to predisposing factors, along with neuroimaging evidence of cerebral edema are sufficient for diagnosis. The characteristic MRI findings of RPLS include:

focal or confluent areas of increased signal on T2-weighted images
cortical lesions to be more common than once thought by T2 imaging on Fluid-attenuated inversion recovery (FLAIR) sequences
Gyriform signal enhancement, reflecting disruption of the BBB
Vasogenic edema is characteristic of RPLS and it is usually seen as a hypo- or isointense signal on DWI and increased signal on apparent diffusion coefficient (ADC) maps

Physical examination

A general examination, with attention to vital signs, and full neurologic examination should be performed. A full ophthalmic exam should be performed to evaluate for any potential other causes of visual complaints. Funduscopic examination often normal, but papilledema may be present with retinal hemorrhages and exudates. Formal Goldmann visual field testing should be strongly considered to evaluate for any scotoma.

Symptoms

RPLS symptoms may progress rapidly over hours to days. Hypertension although frequent but not invariable. Hypertensive crisis may precede other symptoms by 24 hours or more.

RPLS is characterized by headache, altered consciousness ranges from mild somnolence to coma. Seizure is often the presenting manifestation.

Visual symptoms can range from loss of vision as severe as NLP. Hemianopic visual field defects, visual neglect, auras, visual hallucinations, cortical blindness or denial of blindness (Anton syndrome).

Laboratory test

Laboratory tests can help as needed to identify any predisposing or inciting factors such as toxic-metabolic encephalopathy and comorbid medical conditions (sepsis, hyponatremia, renal failure). A lumbar puncture is not required but may be considered in specific situations such as meningitis, encephalitis, or malignancy.

Management

RPLS should be promptly recognized and clinicians should have a high clinical suspicion in the appropriate settings. The management of RPLS requires a multidisciplinary role and

reatment recommendations vary depending on the associated medical conditions.

The ophthalmologist should continue to follow the patient to ensure resolution of visual manifestations. A neurologist is vital in both initial evaluation and management, especially with seizure prophylaxis. Additional specialists, such as obstetricians, rheumatologists, oncologists, are needed to assist with individualized management of the inciting factors. An internist is vital to management of blood pressure, as many patients will require intravenous medications for appropriate control. Definitive treatment and follow up is aimed at treatment of the inciting factors. Neuroradiology can assist in the monitoring of neuroimages with interpretation of advanced imaging as needed.

Prognosis

RPLS itself carries a relatively good prognosis with partial to complete resolution of neuroimaging abnormalities and partial to complete resolution of visual manifestations. The overall prognosis of the patient is individualized and based upon the inciting factor.

References

Bartynski WS. Posterior Reversible Encephalopathy Syndrome, Part 1: Fundamental Imaging and Clinical Features. AJNR 29. Jun-Jul 2009. 1036-1042.
Bartynski WS. Posterior Reversible Encephalopathy Syndrome, Part 2: Controversies Surrounding Pathophysiology of Vasogenic Edema. AJNR 29. Jun-Jul 2009. 1043-1049.
Moratalla MB. Posterior reversible encephalopathy syndrome. Emerg Med J 2010 27: 547.
Pula J, Eggenberger E. Posterior Reversible Encephalopathic Syndrome. Current Opinion in Ophthalmology 2008, 19:479–484
Roth C, Ferbert A. Posterior Reversible Encephalopathy Syndrome: Is there a difference between Pregnant and Non-Pregnant Patients? European Neurology, 2009; 62: 142-149.
Zhang H, Mao X, Zheng X, Wu J. Posterior Reversible Encephalopathy Syndrome: Imperative to Define. Arch Neurol. Dec 2010. 67 (12): 1535.
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