Posterior Reversible Encephalopathy Syndrome in Chronic Kidney Disease: Meta-summary of Case Reports

INTRODUCTION

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome presenting with neurological and ophthalmological symptoms and characteristic temporary changes in the posterior cerebral perfusion on imaging. ¹ Several clinical conditions are said to be related to the development of PRES, including severe hypertension, collagen vascular diseases, organ transplantation, use of cytotoxic/immunosuppressive agents, eclampsia, thrombotic thrombocytopenic purpura, acute intermittent porphyria, and infection with human immunodeficiency virus. ² Rarely, PRES has been reported secondary to chronic kidney disease (CKD). ^{3 - 30}

Chronic kidney disease patients are particularly vulnerable to developing neurological complications, which may present as acute or chronic manifestations ranging from cognitive dysfunction, encephalopathy, and acute stroke to involvement of the peripheral nervous system exhibiting autonomic and peripheral neuropathies. Uremia may lead to uremic encephalopathy with cerebral and cerebellar atrophy. CKD patients are frequently hypertensive, which may increase the chances of developing hypertensive encephalopathy. Further, these patients are at higher risk of developing dyselectrolytemia and secondary infections, increasing the chances of developing metabolic and septic encephalopathy. Hemodialysis itself may cause sudden electrolyte and volume changes leading to fluctuations in intracranial pressure and resultant brain injury. Certain dialysate solutions containing aluminum hydroxide have also been reported to lead to the development of cerebral atrophy in patients requiring hemodialysis. ³¹ These acute presentations may make the diagnosis of PRES more challenging in CKD patients and hence many patients may be misdiagnosed, leading to underdiagnosis and underreporting of PRES.

Chronic kidney disease patients have several risk factors that may predispose them to developing PRES. Hypertension, uremia, and immunosuppressive drugs may all lead to disruption of the cerebrovascular endothelium, increasing the risk of developing edema and consequently, PRES. ³² Rarely, PRES has been reported as the first manifestation of CKD. ¹⁰ Through this meta-summary, we aimed to identify the patient profile, symptomology, risk factors, and outcomes of CKD patients with PRES by analyzing the data published in various case reports and series.

METHODOLOGY

For this meta-summary, we performed a methodical search of PubMed, Google Scholar, and Reference Citation Analysis databases. We used the following search terms: “chronic kidney failure,” “chronic renal insufficiency,” AND “hypertensive encephalopathy,” “PRES,” “reversible posterior leukoencephalopathy syndrome,” OR “posterior leukoencephalopathy syndrome” in combination. The obtained results were then filtered for case reports published in English and on adults (above 18 years). The relevant literature pertaining to CKD and PRES was manually screened, and duplicate articles from different databases were removed.

RESULTS

This meta-summary was performed as per the PRISMA 2020 checklist ( Fig. 1 ). It included 19 case reports and 9 case series, having 41 different patients meeting the set inclusion criteria. ^{3 - 30} Most of the cases belonged to Japan (11, 26.8%), followed by India and Ireland, with five patients (12.2%) each ( Fig. 2 ).

Fig. 1:

Fig. 2:

The symptoms most commonly reported were seizures (65.9%) and headache (58.5%). Visual defects, which ranged from blurred vision to cortical blindness, were present in 36.6% of cases. In two patients, PRES was the first manifestation of CKD. Underlying hypertension was reported in 51.2% of cases ( Table 1 ). Severe hypertension, defined as systolic blood pressure (BP) >180 mm Hg or diastolic BP >110 mm Hg, was present in 70.7% of patients at the time of presentation or development of PRES. Only 14.6% of patients were posttransplant on immunosuppressive therapy.

Along with supportive therapy, modification of antihypertensive therapy was reported in 78.1% of cases. Osmotic therapy, including 3% saline, mannitol, and glycerol to reduce cerebral edema, was reportedly used in 9.8% of cases. The need for intensive care unit (ICU) admission was reported in 43.9% of cases, with 17.1% of patients requiring invasive mechanical ventilation (IMV).

The majority of patients reported complete recovery by the time of discharge, with only 19.5% of cases reporting residual neurological deficit. The median time for reversal was 10.5 days. Only 3 (7.3%) deaths were reported.

DISCUSSION

Patients with CKD are at heightened risk for developing PRES. However, this diagnosis may be challenging given the nonspecific symptomatology; hence, PRES remains mainly underdiagnosed and underreported. For this meta-summary, data from 41 CKD cases with PRES were collated. Underlying hypertension was reported in only 51.2% of cases, but severe hypertension was present in 70.7% of cases at the time of presentation. Most of the cases required modification of antihypertensive therapy (78.1%), with 43.9 and 17.1% reported to require ICU and IMV, respectively. Only 19.5% had residual neurological deficit at the time of discharge, with reported mortality being 7.3%.

The underlying pathophysiological mechanisms associated with PRES are yet to be completely elucidated. However, multiple theories have been suggested to describe the underlying pathophysiology of PRES. The extensively accepted theory suggests disruption of the blood-brain barrier due to raised intracranial pressure or endothelial injury and cerebral ischemia because of cerebral vasoconstriction due to elevated BP and/or circulating cytokines/toxins. The cerebral vasospasm secondary to acute hypertension may further lead to ischemia and cytotoxic edema. Another recent theory suggests that abrupt and severe elevation of BP may damage cerebral autoregulation, leading to arteriolar vasodilation, endothelial dysfunction, and irregular blood flow. The resultant endothelial damage causes extravasation of plasma and blood cells, causing vasogenic edema. ^{1 , 2 , 33} The sympathetic innervation is of lower level in the posterior cerebral arterial circulation, making the parieto-occipital regions more prone to developing PRES. However, other regions of the brain may also be rarely affected. ^{4 , 34}

Classically, PRES has been shown to develop in the presence of severe hypertension. In our analysis, 70.7% of cases reported severe hypertension at the time of presentation. Because PRES has been reported even with mild or no elevation of BP, which may make suspicion of PRES even more challenging, it may be postulated that certain unknown risk factors, which may cause cerebral vasospasm or loss of auto-regulation, may also lead to PRES. ³⁵ Further, no relationship has been shown between the severity of hypertension and prognosis in PRES. ³⁶

The suggested diagnostic criteria for PRES include the development of neurological clinical symptoms in the presence of risk factors and no other possible cause of encephalopathy, with a documented reversible course (resolution of clinical symptoms or disappearance of signal changes in follow-up imaging). ³⁴

Posterior reversible encephalopathy syndrome may clinically manifest with neurological and visual manifestations. Patients can present with headache, altered sensorium, confusion, seizures, loss of consciousness, visual disturbances, or blindness. ¹ Neurological symptoms (seizures in 65.9% and headache in 58.5%) were more commonly reported in the present meta-summary. Ophthalmological symptoms, ranging from mild visual disturbances to complete blindness, were reported in 36.6% of cases.

Computed tomography of the brain may show areas of low attenuation involving the posterior white matter. However, MRI brain is the imaging modality of choice, which typically shows bilateral symmetrical edema involving the parieto-occipital area, hypointense on T1-weighted sequences and hyperintensities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. The calcarine fissure and paramedian lobe are usually spared. Apparent diffusion coefficient (ADC) maps may show high signal intensity, whereas diffusion-weighted MR images may show normal or reduced signal intensity. This may help differentiate PRES lesions (vasogenic edema) from acute cerebral infarction (cytotoxic edema), which shows reduced intensity on ADC and high signal intensity on diffusion-weighted imaging (DWI) images. ³⁴ Rarely, PRES may present with atypical manifestations on MRI, making diagnosis difficult. In such cases, more advanced imaging modalities like MR spectroscopy or positron emission tomography (PET) scan may aid in achieving the diagnosis. ³⁷ Typically, the lesions are reversible with appropriate treatment. However, factors including the coexisting disorders and site of the lesions affect the reversibility. ³⁸

The primary management of PRES includes management of BP. Any sudden drop of BP may lead to hypoperfusion, resulting in cerebral ischemia or infarction; therefore, a gradual reduction in BP is warranted. The mean arterial pressure must be lowered only by 20–25% with a target diastolic BP of <100 mm Hg in the first 1–2 hours. Antiseizure medications may be essential to control seizures. Hyperosmolar therapy using intravenous mannitol or 3% saline may be tried to reduce cerebral edema and intracranial hypertension. Other therapeutic interventions include symptomatic therapy, management of complications, and organ support. Rarely, these patients may require endotracheal intubation and IMV for airway protection.

Early diagnosis and appropriate management may lead to complete recovery. However, delay in treatment may cause increased morbidity with permanent brain damage and chronic epilepsy. It is reported that most of the cases show complete clinical recovery within 1–2 weeks. ³⁶ The median time for recovery reported in our cohort was 10.5 days, with only 19.5% having residual neurological deficits at the time of discharge. Rarely, the symptoms, along with the radiological lesions, may recur, even after complete resolution. ^{8 , 20 , 39} Patients with renal dysfunction have been shown to have more severe lesion volume and are more likely to have involvement of atypical regions. ⁴⁰ However, reversibility of PRES lesions has been found to be comparable to those without renal dysfunction, suggesting similar underlying pathophysiology. ⁴⁰ Nonetheless, some patients of recurrent PRES in CKD patients have also been reported. ^{8 , 20} .

CONCLUSION

Chronic kidney disease patients may be particularly vulnerable to developing PRES. However, due to nonspecific symptomatology overlapping with several other more common causes of neurological dysfunction in these patients, PRES may largely be missed and underdiagnosed. PRES may also present without any associated severe hypertension or a background of immunosuppressive treatment, making the diagnosis more difficult. However, a combination of neurological and ophthalmological symptoms should raise suspicion of PRES in these patients. BP management, anti-edema measures, and supportive care are generally effective interventions, leading to complete recovery.

ORCID

Deven Juneja https://orcid.org/0000-0002-8841-5678

Ravi Jain https://orcid.org/0000-0001-9260-479X

Prashant Nasa https://orcid.org/0000-0003-1948-4060