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Reversible posterior leukoencephalopathy syndrome

Reversible posterior leukoencephalopathy syndrome
Author:
Terry A Neill, MD
Section Editors:
Michael J Aminoff, MD, DSc
Alejandro A Rabinstein, MD
Deputy Editor:
Janet L Wilterdink, MD
Literature review current through: Oct 2022. | This topic last updated: Jun 20, 2022.

INTRODUCTION AND TERMINOLOGY — Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical radiographic syndrome of heterogeneous etiologies that are grouped together because of similar findings on neuroimaging studies. It is also often referred to as:

Posterior reversible encephalopathy syndrome (PRES)

Reversible posterior cerebral edema syndrome

Posterior leukoencephalopathy syndrome

Hyperperfusion encephalopathy

Brain capillary leak syndrome

None of these names are completely satisfactory; the syndrome is not always reversible, and it is often not confined to either the white matter or the posterior regions of the brain.

Although described in various specific case reports for some time, it was first codified as a single named syndrome in a 1996 case series, which described a clinical syndrome of headache, confusion or decreased level of consciousness, visual changes, and seizures, and which was associated with characteristic neuroimaging findings of posterior cerebral white matter edema [1].

RPLS has been described in a number of medical conditions, with hypertensive encephalopathy, eclampsia, and the use of cytotoxic and immunosuppressant drugs being the most common. Prompt recognition and treatment is important in preventing the permanent damage that can occur in this otherwise typically reversible condition. Related syndromes are discussed separately:

(See "Eclampsia".)

(See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults".)

(See "Evaluation and treatment of hypertensive emergencies in adults".)

EPIDEMIOLOGY — RPLS is increasingly recognized and reported in case reports and case series; however, the incidence of RPLS is not known.

Patients in all age groups appear susceptible; reported cases exist in patients as young as 2 years and as old as 90 years [2-7]. Case series suggest that RPLS is more common in women, even when patients with eclampsia are excluded [1,8-11].

PATHOGENESIS — The pathogenesis of RPLS remains unclear, but it appears to be related to disordered cerebral autoregulation and endothelial dysfunction [1,12]. Because of the heterogeneous nature of this disorder, it may be that different mechanisms are etiologically important in different clinical situations.

Proposed mechanisms

Autoregulatory failure and hypertension – Normal autoregulation maintains constant cerebral blood flow over a range of systemic blood pressure by means of arteriolar constriction and dilatation (figure 1 and figure 2) [13,14]. As the upper limit of cerebral autoregulation is exceeded, arterioles dilate and cerebral blood flow increases in a pressure-passive manner with rises in systemic blood pressure. The resulting brain hyperperfusion, particularly in arterial border zones, may lead to breakdown of the blood-brain barrier allowing extravasation of fluid and blood products into the brain parenchyma [13].

The rate of blood pressure elevation is likely to be important. In chronic hypertension, adaptive vascular changes "reset" the range of autoregulation to higher systemic blood pressures (figure 2). As a result, patients with RPLS in the setting of longstanding hypertension may have markedly elevated blood pressures, while less severe elevations or even normal blood pressures are associated with RPLS in other settings. Children appear particularly vulnerable to RPLS at lower blood pressures than adults [2,15].

Cerebral ischemia – Alternatively, in severe cases, it has been postulated that disordered cerebral autoregulation leads to reactive focal vasoconstriction, thereby resulting in local hypoperfusion, cytotoxic edema, and cerebral infarction [8,16,17]. It is also possible that the cerebral infarctions, which uncommonly occur in RPLS, could result from compression of the microcirculation from the mass effect of vasogenic edema. Some patients, but not all, have demonstrable vasoconstriction on radiologic imaging [10,18]. Also, radionuclide studies have demonstrated perfusion deficits in some patients with RPLS [19,20]. (See 'Neuroimaging' below.)

However, ischemia is not believed to play the major pathophysiologic role in most patients with RPLS. Pathologic studies, while quite limited, have not revealed ischemia or infarction [21]; increased rather than decreased perfusion can also be seen on radionuclide imaging studies [22], and many patients with RPLS do not have demonstrable vascular narrowing. Most persuasive in this regard is that clinical and neuroradiographic findings are completely reversible in most patients.

Endothelial dysfunction – Endothelial dysfunction has also been implicated in the pathophysiology of RPLS, especially in cases associated with preeclampsia or cytotoxic therapies [1,2]. The latter may have direct toxicity on vascular endothelium, leading to capillary leakage and to blood-brain barrier disruption and axonal swelling, which may then trigger vasogenic edema [1,23]. RPLS associated with these therapies may occur in normotensive individuals and with nontoxic levels of these drugs [2].

In preeclampsia, markers of endothelial cell dysfunction (lactate dehydrogenase, abnormal red blood cell morphology) typically arise prior to the clinical syndrome and correlate better with the extent of cerebral edema than do blood pressure changes [24-26]. More specific markers of endothelial dysfunction that also are released in patients with preeclampsia include fibronectin, tissue plasminogen activator, thrombomodulin, endothelin-1, and, in particular, von Willebrand factor [27-29]. Secretion of trophoblastic cytotoxic factors originating from a poorly perfused fetal unit may provide the initial stimulus [30]. (See "Preeclampsia: Pathogenesis".)

Markers of endothelial cell dysfunction have been reported in patients with RPLS in other clinical settings including chronic renal failure, lupus nephritis, and hemolytic uremic syndrome [2]. While cases of RPLS associated with thrombotic thrombocytopenic purpura usually occur with coexistent hypertension and renal failure [31], one reported case in the absence of these complications suggests a primary role for endothelial injury in this setting as well [32].

Other mechanisms – In some clinical settings, uremia, sepsis, hypomagnesemia, and other metabolic disturbances have been implicated [8,23]. These factors affect the function of the vascular endothelium. Fluid overload may also contribute to cerebral edema in some patients.

Anatomic distribution — RPLS characteristically involves the subcortical white matter in the posterior cerebral hemispheres. However, other brain regions may be affected. (See 'Neuroimaging' below.)

The combination of acute hypertension and endothelial damage results in hydrostatic edema, a specific form of vasogenic edema characterized by the forced leakage of serum through capillary walls and into the brain interstitium. If this is severe enough, it will be evident radiographically. Endothelial injury or dysfunction in the blood-brain barrier endothelium leads to edema, protein extravasation, and fibrinoid necrosis [33]. The cortex, structurally more tightly packed than the white matter, resists accumulation of edema, hence the predilection of abnormalities to be seen in the white matter [34].

The preferential involvement of posterior brain regions is not well understood. One possibility involves the regional heterogeneity of the sympathetic innervation of the intracranial arterioles, which has been shown to protect the brain from marked increases in blood pressure [35]. A histochemical study revealed a greater concentration of adrenergic nerves around pial and intracerebral vessels in the anterior circulation than posteriorly [36]. This observation may explain why the hyperperfusion and edema is mainly seen in the posterior circulation in RPLS.

RISK FACTORS AND CLINICAL SETTING — A wide variety of medical conditions have been implicated as causes of RPLS (table 1) [37-39]. Some conditions (eg, autoimmune disease) may be associated with RPLS either because of their secondary effects on blood pressure or because of medications used to treat them [37,40]. The more common causes of RPLS are reviewed here.

Hypertension — Hypertension with autoregulatory failure is believed to play a role in most patients with RPLS. However, in some series, as many as half of patients do not have severe hypertension, and it is hypothesized that a rapid rise or fluctuations in blood pressure may be more important than the absolute blood pressure [41,42]. The percent elevation of blood pressure over baseline, as well as the severity of the hypertension, is important [13,14]. While some patients are normotensive at presentation, the blood pressure in many of these patients is elevated over baseline [1,43]. However, a minority of patients with RPLS are truly normo- or even hypotensive at presentation.

Therefore, while approximately 75 percent of patients have moderate to severe hypertension at presentation, RPLS may occur in normotensive patients [44]. Although RPLS is described in malignant hypertension alone, it appears to be more common in patients with comorbid conditions, such as systemic lupus erythematosus [22,45-47], cryoglobulinemia [48], thrombotic thrombocytopenic purpura [31], or hemolytic uremic syndrome [45,49,50], and in patients treated with cyclosporine [51] or cisplatin [23]. The fact that renal failure appears to be particularly prevalent among hypertensive patients with RPLS suggests a role for either fluid overload, electrolyte disturbances, or uremia [52].

Immunosuppressive therapy — RPLS occurs in patients prescribed immunosuppressive and immunomodulatory therapies for malignancy, transplantation, rheumatologic conditions, and other indications. A partial list of these implicated drugs is provided in the table (table 1). In one large series, approximately half of patients were being treated with one or more of these medications [38].

The neurotoxic effects of these therapies are well known but still poorly understood. Toxic or even elevated levels of medications are not required for the development of RPLS, and prior exposure to the drug does not appear to be protective [2]. Even after several months of exposure to the drug, patients with therapeutic levels can develop RPLS [2].

Cyclosporine is one of the more common cytotoxic therapies associated with the neurologic deficits of RPLS. After renal toxicity, neurotoxicity is the most serious side effect with cyclosporine, affecting 25 to 59 percent of transplant patients [53]. Hypomagnesemia, hypocholesterolemia, the vasoactive agent endothelin, and hypertension have all been implicated in facilitating cyclosporine neurotoxicity [53]. Elevated serum cyclosporine levels are not related to the onset of neurologic symptoms [51]. Cyclosporine may in turn exacerbate hypertension by inhibiting nitric oxide production [54]. (See "Pharmacology of cyclosporine and tacrolimus".)

Among patients with cancer, platinum-containing drugs, CHOP/R-CHOP regimens, and gemcitabine are the most commonly implicated chemotherapeutics according to one review, but most agents have been cited in at least one case review [11]. RPLS has been associated with other agents, including tacrolimus, sirolimus, and interferon therapies; agents that target angiogenesis such as bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor (VEGF); and small molecule tyrosine kinase inhibitors that target the VEGF receptor (pazopanib, sorafenib, sunitinib) (table 1) [1,23,55-61]. The mechanisms are thought to be similar. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Reversible posterior leukoencephalopathy and brain capillary leak syndrome'.)

Renal disease — In the initial case series of RPLS, a variety of renal diseases were prevalent including lupus nephritis and glomerulonephritis [1]. In subsequent reports, renal disease has been more variably associated with the disorder, ranging from no association in one series of 69 cancer patients with RPLS [62] to an approximate 30 percent prevalence in other large series [38,63]. In patients with systemic lupus erythematosus, renal dysfunction appears to be a particularly important risk factor [63-65]. Both acute and chronic kidney disease appear to be associated with RPLS.

Others — A number of other, possibly related conditions have been described in case reports of patients with RPLS. A partial list is provided in the table (table 1).

Autoimmune disorders are prevalent in approximately one-third to one-half of patients with RPLS; these include thrombotic thrombocytopenic purpura, systemic lupus erythematosus, polyarteritis nodosa, cryoglobulinemia, granulomatosis with polyangiitis, inflammatory bowel disease, rheumatoid arthritis, Sjögren syndrome, and neuromyelitis spectrum disorder [38,63,66]. However, it is not clear whether it is the presence of these conditions or the medications used to treat them that is the primary association.

RPLS has been associated with treatment of many kinds of cancer, as discussed above, as well as solid organ, bone marrow, or stem cell transplantation [67,68].

Sickle cell disease [69] and sepsis [38,68] are also settings in which RPLS has been described.

CLINICAL MANIFESTATIONS — The symptoms of RPLS evolve rapidly over hours to days. Hypertension is frequent but not invariable. The hypertensive crisis may precede the neurologic syndrome by 24 hours or longer [2,10].

The clinical syndrome of RPLS is characterized by [38]:

Headaches – The headache is typically constant, nonlocalized, moderate to severe, and unresponsive to analgesia [10].

Altered consciousness – Altered consciousness ranges from mild somnolence to confusion and agitation, progressing to stupor or coma in extreme cases [1,10,59,70].

Visual disturbances – Visual perception abnormalities are often detectable. Hemianopia, visual neglect, auras, visual hallucinations, and cortical blindness may occur [1,71]. Cortical blindness may be accompanied by denial of blindness (Anton syndrome).

Seizures – Seizures are often the presenting manifestation [1,7,52,72]. Seizures are usually generalized tonic-clonic; they may begin focally and often recur. Status epilepticus has been reported [60,73]. Preceding visual loss or visual hallucinations suggest occipital lobe origin in some patients. Only a minority of patients, usually those with milder disease, are seizure free [2].

The funduscopic examination is often normal, particularly in eclamptic and chronically hypertensive patients, but papilledema may be present with accompanying flame-shaped retinal hemorrhages and exudates. The deep tendon reflexes may be brisk, and Babinski signs may be present [10]. A few patients may have weakness and incoordination of the limbs [1,8,74]. Other focal neurologic deficits are rare.

Relatively unusual patients with symptoms referable to the upper cervical spinal cord (limb weakness, bladder dysfunction), along with one or more of the symptoms above have also been described [75].

EVALUATION

Neuroimaging — Neuroimaging is essential to the diagnosis of RPLS. While a noncontrast brain magnetic resonance imaging (MRI) should be performed in all cases, a noncontrast head computed tomography (CT) is often the first study performed in the emergency department. Neuroradiographic abnormalities of RPLS are often apparent on CT scans (image 1) [76] but are best depicted by MRI (image 2) [22].

Typical findings are bilateral areas of white matter edema in the posterior cerebral hemispheres, particularly the parieto-occipital regions, but variations do occur [37,38,77]. Extensive vasogenic edema has been associated with worse clinical outcomes in some series [2,78], but not with the severity of clinical presentation [38,66]. (See 'Prognosis' below.)

Features common to CT or MRI include:

The white matter edema is typically most prominent in both posterior cerebral hemispheres (image 1); however, the calcarine and paramedian parts of the occipital lobe are usually spared, helping to distinguish RPLS from bilateral posterior cerebral infarctions [1,38]. Relative sparing of the cortical gray matter in RPLS also distinguishes this from posterior cerebral artery infarction.

Involvement of the cerebellum and brainstem is common. Isolated or predominant posterior fossa lesions, while uncommon, are increasingly described (sometimes called hypertensive brainstem encephalopathy or central-variant RPLS) [2,38,52,77,79-84].

In rare cases, changes are seen also in the cervical spinal cord [75,85,86].

Lesions of the frontal lobes do occur, but usually with edema being present also in the posterior circulation territories [2,38,52]. The superior frontal gyrus is preferentially affected [87]. Temporal lobe edema is seen in a minority of patients [87].

Although abnormalities primarily affect the subcortical white matter, the cortex and basal ganglia are often involved [52,77,88,89]. In some milder cases, abnormalities have been seen more conspicuously in the gray matter, suggesting that edema sometimes begins in the cortex [2,38,79].

The distribution of abnormalities is usually not confined to a single vascular territory [37].

Characteristic MRI findings include:

The most commonly observed abnormalities on MRI are focal or confluent areas of increased signal on T2-weighted images [37].

Fluid-attenuated inversion recovery (FLAIR) sequences improve sensitivity and detect subtle peripheral lesions, showing cortical lesions to be more common than once thought by T2 imaging (image 2) [2,79].

Gyriform signal enhancement, reflecting disruption of the blood-brain barrier, can be present following the administration of gadolinium; some cases demonstrate nodular subcortical enhancement (image 3) [22].

Diffusion-weighted imaging (DWI) aids in the distinction of RPLS from top-of-the-basilar stroke. The vasogenic edema that is characteristic of RPLS is usually visualized as a hypo- or isointense signal on DWI (sometimes slightly hyperintense due to T2 shine-through) and increased signal on apparent diffusion coefficient (ADC) maps (image 2) [2,9,79,88].

By contrast, acute cerebral infarction produces marked hyperintensity on DWI and hypointensity on ADC maps (image 4).

Complications of RPLS may also be demonstrable on MRI:

Ischemia – While patients with RPLS may have areas of signal abnormality consistent with ischemia, these are usually superimposed on areas of increased ADC values. Patients with areas of decreased ADC values usually, but not always, progress to true infarction [2,8,16,79,90,91]. A pseudonormalization of ADC values in areas of high DWI signal may be the earliest sign of permanent brain injury in patients with RPLS [2]. Ischemic areas are usually small, but larger infarctions can occur [92], likely in association with acute vasoconstriction.

Intracranial hemorrhage – Petechial and large parenchymal hemorrhages have been described, as well as convexal subarachnoid hemorrhage [22,52,76]. These complications, which occur in as many as 20 percent of patients with RPLS, are more common in patients with a coagulopathy or thrombocytopenia [62,64,65,68,93,94].

Follow-up imaging – Because the neuroradiographic findings are not specific to RPLS, repeat neuroimaging may be necessary. With treatment, resolution of findings on neuroimaging within days to weeks is expected. In most follow-up studies, the abnormalities have partially or completely resolved, suggesting edema rather than infarction (image 5) [1,37,52].

Other modalities Vascular imaging is not always required in the evaluation of a patient with RPLS but should be performed when reversible cerebral vasoconstriction syndrome (RCVS) is suspected because of focal neurologic deficits or infarction on MRI.

Conventional angiography and magnetic resonance angiography (MRA) studies have documented vascular narrowing in some patients with RPLS in a variety of clinical settings [95-102]. The severity ranges from irregular in medium- to large-sized vessels in some groups to diffuse and multisegmental in other groups [96]. A finding of prominent vasoconstriction suggests co-occurrence of reversible vasoconstriction syndrome. (See 'Reversible cerebral vasoconstriction syndrome' below.)

Other testing — The clinical and radiologic features of RPLS are not specific; other conditions such as toxic-metabolic encephalopathy should be evaluated thoroughly. Thus, laboratory studies should include a blood count, electrolytes, creatinine, blood urea nitrogen (BUN), and liver function tests. Comorbid medical conditions (eg, sepsis, hyponatremia, renal failure, ischemic bowel disease) can exacerbate neurologic deterioration and are important to identify for that reason as well [8]. (See "Acute toxic-metabolic encephalopathy in adults" and "Acute toxic-metabolic encephalopathy in children".)

A lumbar puncture is not required for the evaluation of most patients with suspected RPLS but may be obtained if there is a specific concern for meningitis, encephalitis, or malignancy. In RPLS, cerebrospinal fluid (CSF) typically shows a modestly elevated protein level (mean 58 mg/dL in one study) but no pleocytosis [103]. An elevated white blood cell count in the CSF should prompt consideration of other diagnoses. (See 'Differential diagnosis' below.)

Due to the significant prevalence of seizures with RPLS, there should be a low threshold to perform electroencephalographic (EEG) monitoring in a patient with persistent altered level of consciousness to exclude nonconvulsive status epilepticus. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis".)

DIAGNOSIS — While there are no specific diagnostic criteria for RPLS, it is becoming an increasingly recognized disorder. In the appropriate clinical setting (in particular hypertension, immunosuppressive or cytotoxic therapy, kidney disease), clinicians should recognize the neurologic syndrome of headache, visual symptoms, confusion, and seizures, and order brain MRI, which typically supports the diagnosis. Diffusion-weighted imaging (DWI), if available, adds considerable diagnostic and prognostic information. (See 'Neuroimaging' above.)

Because the neuroradiographic findings are not specific, repeat neuroimaging may be necessary. With treatment, resolution of findings on neuroimaging within days to weeks is expected. Atypical MRI findings and clinical treatment failure should prompt consideration of other diagnoses. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS

Related conditions — It is not clear that hypertensive encephalopathy and eclampsia are distinct from RPLS. The syndrome of reversible cerebral vasoconstriction shares many but not all pathogenic and clinical features with RPLS.

Hypertensive encephalopathy — In acute, severe hypertension, acute elevation of blood pressure beyond the upper limits of cerebral autoregulation (typically ≥180/120 mmHg) leads to cerebral edema and neurologic symptoms [22,45,104,105]. Rapidly developing, fluctuating, or intermittent hypertension carries a particular risk for hypertensive encephalopathy [106]. Patients with untreated or undertreated chronic hypertension or renal failure are especially at risk for RPLS. Typical patients have insidious onset of headache, nausea and vomiting, and nonlocalizing neurologic symptoms, which can progress to seizures and coma. Hypertensive retinopathy characterized by retinal hemorrhages and/or exudates and papilledema is often identified on funduscopic examination.

There is substantial overlap between the clinical syndrome of hypertensive encephalopathy and RPLS, and some may argue whether these are distinct entities. Treatment of hypertension is an essential aspect of treatment in both.

Hypertensive encephalopathy is discussed separately. (See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults".)

Eclampsia — Most investigators believe hypertensive encephalopathy and preeclampsia share similar mechanisms [19,107-109]. In many patients, the syndrome occurs during the puerperium rather than during pregnancy [110]. Some suggest that RPLS (typical clinical syndrome and neuroimaging findings) could be considered an indicator of eclampsia, even when the other features of eclampsia (proteinuria, hypertension) are not present. Blood pressures in patients with preeclampsia and eclampsia who develop RPLS are generally lower than in patients who develop RPLS in other settings [24]. (See "Eclampsia".)

Reversible cerebral vasoconstriction syndrome — Reversible cerebral vasoconstriction syndrome (RCVS) and RPLS are thought to share a common pathophysiology of dysregulation of cerebral arterial tone. Vasoactive drugs are often implicated as a trigger in RCVS [111].

The clinical syndrome of RCVS also shares clinical features with RPLS, especially headache, although the headache in RCVS is more classically sudden rather than insidious in onset (table 2). While visual symptoms, seizures, and MRI abnormalities can occur with RCVS, these are less commonly a feature than with RPLS. Evidence of arterial constriction is documented by vascular imaging (conventional, magnetic resonance, or CT angiography, or transcranial Doppler). Such studies should be performed when clinical features suggest possible RCVS such as focal neurologic deficits on examination or MRI findings such as ischemia or sulcal subarachnoid hemorrhage. RCVS and RPLS can co-occur [112].

RCVS is discussed in detail separately. (See "Reversible cerebral vasoconstriction syndrome".)

Other differential diagnoses — The clinical findings are not specific for RPLS, which can resemble other neurologic conditions, such as stroke, venous thrombosis, toxic or metabolic encephalopathy, demyelinating disorders, vasculitis, or encephalitis among others [90,110,113]. While findings on MRI typically distinguish RPLS from infarction and other conditions, serial studies may be required in some cases.

Chronic subcortical white matter ischemic changes, when confluent, may mimic the radiologic appearance of RPLS, particularly on CT scan. As a consequence, hypertensive patients with these findings who present with acute toxic metabolic encephalopathy may sometimes be suspected of having RPLS. This alternative diagnosis should be suspected when there are concomitant periventricular white matter changes, and other causes of acute encephalopathy should be investigated. (See "Acute toxic-metabolic encephalopathy in adults", section on 'Diagnosis'.)

The differential diagnosis of RPLS is extensive. Some diagnoses that produce similar clinical features and MRI changes include:

Cerebrovascular syndromes – Specific cerebrovascular syndromes that may be confused radiographically with RPLS include the "top-of-the-basilar" syndrome with bilateral posterior cerebral artery infarctions. Features that help distinguish this syndrome from RPLS include that oculomotor and pupillary abnormalities typically, but not always, accompany the mental status and visual changes in this syndrome, while headache and seizures are relatively uncommon.

Central nervous system (CNS) vasculitis or multifocal embolic infarctions such as might occur with infective or nonbacterial thrombotic endocarditis can also produce a clinical syndrome similar to RPLS that includes headache, confusion, and seizures.

It is important to distinguish between RPLS and ischemic stroke, as the treatment of hypertension may be very different in these conditions. Diffusion-weighted imaging (DWI) and the distribution of abnormal signal on fluid-attenuated inversion recovery (FLAIR)/T2-weighted sequences (predominantly subcortical white matter versus cortex) on MRI help distinguish ischemia and infarction from RPLS on initial presentation as described above (see 'Neuroimaging' above). Clinical and radiologic follow-up is usually definitive.

When there is concern that the process is primarily cerebrovascular, cardiac evaluation (echocardiography, rhythm monitoring, blood cultures) and/or angiographic studies may be required for further evaluation.

These stroke syndromes are discussed in detail separately.

(See "Posterior circulation cerebrovascular syndromes", section on 'Rostral brainstem ischemia and "top of the basilar" syndrome'.)

(See "Nonbacterial thrombotic endocarditis".)

(See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

(See "Primary angiitis of the central nervous system in adults" and "Childhood primary angiitis of the central nervous system".)

Infectious, paraneoplastic, or autoimmune encephalitis – These entities also produce confusion and mental status changes with seizures. Patients with infections typically have fever in addition to neurologic impairments.

MRI is often, but not always, abnormal; prominent involvement of the posterior regions is not typical, and usually the cortex is more often affected than the subcortical white matter.

Cerebrospinal fluid (CSF) evaluation is essential when these conditions are suspected and usually reveals pleocytosis. Specific testing (culture, antibody testing, polymerase chain reaction) is used to identify the specific cause.

These conditions are discussed in detail separately. (See "Viral encephalitis in adults" and "Acute viral encephalitis in children: Clinical manifestations and diagnosis" and "Paraneoplastic and autoimmune encephalitis".)

Cerebral venous thrombosis – The clinical syndrome of cerebral venous thrombosis (CVT) is highly variable but often includes headache, encephalopathy, and seizures. CVT usually occurs in the setting of genetic or acquired thrombophilia; however, this condition may not be known at the time of presentation. In addition, cancer and certain inflammatory conditions are associated with CVT, as they are with RPLS.

In such cases, brain MRI reveals focal or multifocal areas of edema and venous infarction that are usually distinguishable from RPLS. Brain MRI typically reveals thrombus on routine sequences; however, magnetic resonance venography may be required.

The clinical and neuroimaging features and diagnosis of CVT are described in detail separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".)

Acute demyelinating encephalomyelitis – Acute demyelinating encephalomyelitis (ADEM) typically presents with a rapid onset of headache and altered mental status along with multifocal neurologic signs and symptoms; seizures are uncommon but can occur. The clinical setting for ADEM is usually postinfectious or postvaccinial; however, in a significant minority of patients no preceding illness is identified.

As with RPLS, MRI findings are prominent and affect the white matter prominently; however, a predilection for posterior regions is not typical.

ADEM is discussed in detail separately. (See "Acute disseminated encephalomyelitis (ADEM) in adults" and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)

Malignancy, in particular CNS lymphoma, carcinomatous meningitis, or gliomatosis cerebri – Typically such conditions evolve less abruptly than RPLS. MRI findings are heterogenous, but bilateral involvement of posterior white matter is atypical. The diagnosis is typically made by pathologic examination of the CSF or brain tissue. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors" and "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas".)

Acute toxic leukoencephalopathy – The term "toxic leukoencephalopathy" appears to refer to a category of conditions that include RPLS as well as a slowly progressive white matter disease that occurs with exposures to brain toxins including radiation (see "Delayed complications of cranial irradiation") and heroin (see "Leukoencephalopathy due to heroin use") [114-116].

However, there are examples of toxins that appear to produce a distinctive encephalopathic syndrome associated with white matter changes on MRI. These entities should be considered in the differential diagnosis of RPLS, particularly when risk factors are absent. Examples include:

Carbon monoxide – Acute severe carbon monoxide poisoning presents with headache, encephalopathy, and seizures. MRI typically shows prominent abnormalities in the globus pallidus in addition to diffuse white matter changes. (See "Carbon monoxide poisoning".)

Inhaled hydrocarbons (eg, toluene). (See "Inhalant misuse in children and adolescents".)

Other drugs of abuse – Overdoses of amphetamines, opiates, and/or benzodiazepines have been reported to produce a clinical and radiographic syndrome that overlaps with RPLS. MRI in these settings is reported to more often show restricted diffusion indicating a cytotoxic rather than a vasogenic edema [114,117].

Lead – Acute severe lead poisoning is rare but can produce similar clinical and neuroimaging features. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure, toxicity, and poisoning in adults".)

Cranial irradiation – In rare cases an acute encephalopathy with MRI changes occurs when high-dose radiation fractions are administered to a large brain volume. (See "Acute complications of cranial irradiation", section on 'Acute encephalopathy'.)

MANAGEMENT — RPLS should be promptly recognized since it is usually reversible with appropriate management. Treating clinicians should have a high clinical suspicion in the appropriate settings (hypertension, pregnancy, cytotoxic therapy), recognize the neurologic syndrome, and evaluate for RPLS with brain MRI.

Treatment recommendations are based on observational data and vary depending on the associated medical conditions present on each case.

Blood pressure management — Hypertension is a feature in the majority of RPLS patients, regardless of etiology [1,23,99,100,118,119]. With gradual blood pressure lowering, patients will often improve dramatically. Except in cases of malignant hypertension, patients with RPLS often present with only moderate levels of hypertension; in the majority of cases, however, this still represents a significant increase above baseline levels.

Goal blood pressures are not well defined and depend in part on presenting levels. The goal blood pressure should be reassessed in conjunction with the patient's clinical recovery:

In malignant hypertension, the initial aim of treatment is to lower the diastolic pressure to approximately 100 to 105 mmHg; this goal should be achieved within two to six hours, with the maximum initial fall in blood pressure not exceeding 25 percent of the presenting value [120,121] (see "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults"). More aggressive blood pressure lowering is generally unnecessary and may reduce the blood pressure below the autoregulatory range, possibly leading to cerebral ischemia, as well as increasing the risk of coronary and renal ischemia [122].

For patients with lower levels of hypertension, lowering blood pressure is also recommended to treat RPLS, but no specific guidelines are suggested as discussed for malignant hypertension above. Using clinical symptoms and any prior knowledge of baseline blood pressure as a guide, careful, incremental downward titration in 10 to 25 percent increments of the mean arterial blood pressure seems a reasonable approach. Overaggressive blood pressure lowering can lead to complications; comorbid medical conditions should be considered in management.

The use of easily titratable parenteral agents such as clevidipine, nicardipine, and labetalol is effective and safe in reducing the blood pressure to a desirable range [123]. The pharmacology and side effects of these agents are reviewed in detail elsewhere. (See "Drugs used for the treatment of hypertensive emergencies".)

Oral antihypertensive agents have a slower onset of action and are not usually effective in consistently lowering the blood pressure to an appropriate range in hypertensive crises to prevent and treat RPLS.

Seizure management — Except in the setting of eclampsia, most patients with RPLS and seizures are treated with antiseizure medications [8,10,73]. When seizures are documented or strongly suspected, an antiseizure medication that can be given as intravenous bolus or at least does not require titration should be started. Agent selection should take into account renal function (doses of levetiracetam and lacosamide must be adjusted in patients with renal function impairment), sedation potential (a particular concern with phenytoin), and other side effects of the drugs and comorbidities of the patient [8,10,73]. (See "Initial treatment of epilepsy in adults".)

The threshold to obtain an EEG should be low in patients with altered consciousness, even in the absence of motor manifestations indicative of seizures. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis", section on 'Diagnosis'.)

Although some case series report continuation of therapy for one to three months, the antiseizure medication can probably be safely tapered as symptoms and neuroimaging findings resolve, usually after one to two weeks [73]. While long-term follow-up studies are limited, seizure recurrence or epilepsy appear to be rare. In one case series of 127 patients who had recovered from an episode of RPLS, unprovoked seizures occurred in eight patients over a median 3.2 years of follow-up [124]. When recurrent, unprovoked seizures have occurred after recovery from an RPLS episode, it is reasonable to resume or initiate antiseizure medication therapy [123-125].

Discontinuation of immunosuppressive therapy — Reduction in drug dose or prompt removal of the cytotoxic or immunosuppressive drug is usually recommended in cases of RPLS and is often associated with clinical improvement [126-128]. However, cases are reported in which symptoms resolve while the medication is maintained [51]. We have observed that sirolimus appears to be associated with a lower risk of RPLS than tacrolimus.

When another immunosuppressive agent is substituted, patients must be followed closely for recurrence of RPLS. Routine surveillance neuroimaging is not recommended, but there should be a low threshold to pursue neuroimaging if symptoms arise suddenly or persist. It is not recommended that agents known to induce RPLS be reintroduced, as recurrence has been reported in this setting [2,43,129,130], although cases are reported in which the original agent was restarted without re-inciting RPLS.

Based on two cases and a literature review of RPLS in the setting of cytotoxic chemotherapy administration, one group of investigators found that patients with one or more of the following are at risk of RPLS [131]:

Significant fluid overload (>10 percent of baseline weight)

Mean blood pressure >25 percent of baseline

Creatinine >1.8 mg/dL (160 micromol/L)

They further suggested that in these patients, weight changes and blood pressure should be followed closely during aggressive fluid resuscitation (>3 L of daily intravenous fluid). Although the number of cases was small and this approach has not been independently validated, this marks one of the few attempts to focus on specific guidelines for treatment and may prove useful as a general means of preventing RPLS.

Pregnancy — In the setting of pregnancy, eclampsia rather than RPLS is diagnosed. Recommendations for the treatment of eclampsia differ from RPLS in other clinical settings. Delivery of the baby and placenta is often sufficient. Magnesium is used to treat seizures and is superior to phenytoin and diazepam in this setting. The choice of antihypertensive drug is also influenced by concerns for placental function and fetal health. (See "Eclampsia" and "Treatment of hypertension in pregnant and postpartum patients" and "Preeclampsia: Antepartum management and timing of delivery".)

Other — Because comorbid conditions including electrolyte disturbances, fluid overload, uremia, and sepsis are suggested to contribute to the development and prognosis in patients with RPLS, aggressive screening for and treatment of these conditions is recommended.

Treatment of thrombotic thrombocytopenic purpura with plasmapheresis or immunoglobulin has resulted in resolution of RPLS [38].

Patients with RPLS have been treated with dexamethasone [8,132], but because of its associated risk of hypertension, fluid overload, and electrolyte disturbance as well as the fact that high-dose steroid therapy has been associated with the development of RPLS, this is not a recommended therapy.

PROGNOSIS — Most case series and case reports suggest that RPLS is usually benign. In many cases, RPLS seems to be fully reversible within a period of days to weeks, after removal of the inciting factor and control of the blood pressure [1,7,46,47,70,133]. Radiologic improvement lags behind clinical recovery.

However, death and permanent serious neurologic disability have been reported as consequences of RPLS [12]. Death may result from progressive cerebral edema, from intracerebral hemorrhage, or as a complication of the underlying condition [2,8,10]. Brain imaging, in particular MRI with diffusion-weighted imaging (DWI), is essential to identify cerebrovascular complications. Extensive vasogenic edema, brain ischemia, and intracerebral hemorrhage have been associated with worse functional outcome [78].

Recurrence of RPLS appears to be infrequent (<10 percent) despite the fact that inciting factors commonly recur in these patients [133].

Some patients develop unprovoked seizures and epilepsy after recovering from RPLS, but this appears to be rare. (See 'Seizure management' above.)

SUMMARY AND RECOMMENDATIONS

Clinical and imaging features – Reversible posterior leukoencephalopathy syndrome (RPLS) is a neurologic syndrome defined by clinical and radiologic features.

The typical clinical syndrome includes headache, confusion, visual symptoms, and seizures. (See 'Clinical manifestations' above.)

Typical MRI findings are consistent with vasogenic edema in the subcortical white matter and are predominantly localized to the posterior cerebral hemispheres. The differentiation of vasogenic versus cytotoxic edema with diffusion-weighted imaging (DWI) is helpful in distinguishing RPLS from stroke. (See 'Neuroimaging' above.)

Clinical setting and risk factors – RPLS most often occurs in the setting of hypertensive crisis, preeclampsia, or with cytotoxic immunosuppressive therapy; however, it can also occur in many other clinical settings (table 1). (See 'Risk factors and clinical setting' above.)

Management

Blood pressure – Treatment of hypertension is the mainstay of treatment in patients with RPLS.

In addition, we suggest cautious blood pressure lowering in patients with blood pressure that is only borderline hypertensive (eg, 120 to 140 mmHg systolic), particularly if such measurements exceed the patient's baseline values (Grade 2C).

We target an approximate 10 to 25 percent reduction of blood pressure initially and use an easily titratable parenteral agent such as clevidipine, nicardipine, or labetalol. Overaggressive blood pressure lowering can lead to complications; comorbid medical conditions should be considered in management. (See 'Blood pressure management' above.)

Discontinuation of causative agent – We suggest stopping or lowering the dose of the offending immunosuppressant or cytotoxic agent, permanently if possible (Grade 2C). When another agent is substituted, or if the original agent is restarted, patients should be followed closely for recurrence of RPLS. (See 'Discontinuation of immunosuppressive therapy' above.)

Treatment of other acute medical conditions (eg, sepsis, renal failure) may also hasten patient's recovery. (See 'Other' above.)

Seizure management – Antiseizure medications are administered to patients with seizures. Agent selection should take into consideration renal clearance, potential for sedation, and other side effects of the drug and comorbidities of the patient.

We suggest that antiseizure medications be discontinued after symptoms and neuroimaging findings resolve (Grade 2C). The risk of late recurrence or epilepsy after uncomplicated RPLS appears to be low. (See 'Seizure management' above.)

Pregnancy – In the partum or postpartum setting, patients with RPLS should be treated as for preeclampsia or eclampsia. (See "Eclampsia".)

Clinical course and prognosis – Most patients recover within two weeks. A small number have residual neurologic deficits resulting from secondary cerebral infarction or hemorrhage; some patients die as a result of increased intracranial pressure or as a complication of the underlying condition. MRI findings can be helpful in identifying patients with potentially worse prognosis. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges J Claude Hemphill, III, MD, MAS, who contributed to an earlier version of this topic review.

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Topic 4835 Version 18.0

References