Corticosteroids in posterior reversible encephalopathy syndrome: Friend or foe? A systematic review

Abstract

BACKGROUND

Posterior reversible encephalopathy syndrome (PRES) is a complex neurological disorder characterized by symptoms such as headaches, seizures, confusion, and visual disturbances. The pathophysiology of PRES involves endothelial dysfunction, disrupted cerebral autoregulation, and resulting vasogenic edema. Hypertension and other factors that alter cerebral autoregulation are critical in its development. Corticosteroids, widely used for their anti-inflammatory and immunosuppressive properties, play a controversial role in PRES.

AIM

To elucidate the dual role of corticosteroids in the context of PRES by critically evaluating the existing literature. Specifically, it seeks to assess the results of PRES induced by corticosteroid therapy and the efficacy and safety of corticosteroids in the treatment of PRES. By synthesizing case reports and series, this review aims to provide a comprehensive understanding of the mechanisms, clinical presentations, and management strategies associated with corticosteroid-related PRES.

METHODS

The review was carried out according to the PRISMA guidelines. The databases searched included Science Direct, PubMed, and Hinari. The search strategy encompassed terms related to corticosteroids and PRES. Studies were included if they were peer-reviewed articles examining corticosteroids in PRES, excluding non-English publications, reviews, and editorials. Data on patient demographics, clinical characteristics, imaging findings, corticosteroid regimens, and outcomes were extracted. The risk of bias was evaluated using the Joanna Briggs Institute tool for case reports.

RESULTS

A total of 56 cases of PRES (66.1% women, 33.9% men) potentially induced by corticosteroids and 14 cases in which corticosteroids were used to treat PRES were identified. Cases of PRES reportedly caused by corticosteroids showed a mean age of approximately 25.2 years, with seizures, headaches, hypertension, and visual disturbances being common clinical sequelae. Magnetic resonance findings typically revealed vasogenic edema in the bilateral parieto-occipital lobes. High-dose or prolonged corticosteroid therapy was a significant risk factor. On the contrary, in the treatment cases, corticosteroids were associated with positive outcomes, including resolution of vasogenic edema and stabilization of symptoms, particularly in patients with underlying inflammatory or autoimmune diseases.

CONCLUSION

Corticosteroids have a dual role in PRES, capable of both inducing and treating the condition. The current body of literature suggests that corticosteroids may play a greater role as a precipitating agent of PRES rather than treating. Corticosteroids may induce PRES through hypertension and subsequent increased cerebral blood flow and loss of autoregulation. Corticosteroids may aid in the management of PRES: (1) Enhancing endothelial stability; (2) Anti-inflammatory properties; and (3) Improving blood-brain barrier integrity. Mechanisms which may reduce or mitigate vasogenic edema formation.

Key Words: Corticosteroids; Posterior reversible encephalopathy syndrome; Vasogenic edema; Reversible posterior leukoencephalopathy syndrome; Reversible cerebral vasoconstriction syndrome

Core Tip: Posterior reversible encephalopathy syndrome (PRES) is characterized by headaches, seizures, confusion, and visual disturbances due to endothelial dysfunction and vasogenic edema. Corticosteroids have a dual role in PRES, potentially inducing the condition through hypertension while also treating it by reducing inflammation and stabilizing the blood-brain barrier. This systematic review identifies 57 cases of corticosteroid-induced PRES and 14 cases where corticosteroids were used therapeutically. Understanding this dual role is crucial for optimizing patient care, highlighting the need for careful monitoring and tailored treatment strategies.

INTRODUCTION

Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by various symptoms, including headaches, seizures, altered mental status, and visual disturbances. Its pathophysiology remains incompletely understood but is believed to involve endothelial dysfunction leading to vasogenic edema[1]. The use of corticosteroids in PRES is controversial, with arguments both for and against their use based on their anti-inflammatory properties and the potential to exacerbate hypertension. PRES is a complex condition with variable clinical presentations, making its management difficult. Corticosteroids, widely used for their potent anti-inflammatory effects, have been proposed as a treatment option. However, its role in the management of PRES is debated, primarily due to concerns about adverse effects, including the potential for worsening hypertension, a key factor in the pathogenesis of PRES. Thus, understanding the impact of corticosteroids on PRES outcomes is crucial for optimizing patient care. This systematic review aims to critically evaluate the existing literature on the use of corticosteroids in PRES. We intend to assess the efficacy and safety of corticosteroids in the treatment of PRES, considering both clinical outcomes and potential adverse effects.

MATERIALS AND METHODS

This systematic review was conducted in accordance with the PRISMA guidelines and the AMSTAR criteria[2,3]. The review protocol was registered with PROSPERO to ensure transparency and reproducibility. In this study, no original patient data was collected, and no attempt was made to identify individuals from the literature review. The systematic review was conducted following ethical considerations as outlined in the Declaration of Helsinki. We systematically searched the databases: Science Direct, PubMed, and Hinari. The search strategy was designed to encompass a wide range of terms and keywords related to corticosteroids and PRES. The search string included combinations of terms such as "corticosteroids", "Posterior Reversible Encephalopathy Syndrome", "PRES", "steroids", "treatment", "management", and their relevant synonyms and medical subject headings. The complete search string for each database is included in Table 1. A gray literature search was completed by reviewing the first ten pages of GoogleScholar.

Table 1 Search string utilized for electronic databases.

Database	Search string
PubMed/PubMed Central/MEDLINE	(Corticosteroids [Title/Abstract]) OR (dexamethasone [Title/Abstract]) OR (methylprednisolone [Title/Abstract]) AND (posterior reversible encephalopathy syndrome [Title/Abstract])
Science Direct	(Posterior reversible encephalopathy syndrome) AND (corticosteroids OR methylprednisolone OR dexamethasone)
Hinari	Corticosteroids OR dexamethasone OR methylprednisolone AND posterior reversible encephalopathy syndrome

Studies were included if they were peer-reviewed articles that examined the use of corticosteroids in patients with PRES. We include case reports/series and observational studies. Exclusion criteria comprised non-English-language publications, case studies, reviews, editorials, and studies that did not report specific results related to corticosteroids in PRES. Records identified by database search were exported to EndNote, where duplicates were removed. The remaining records were then uploaded to the Rayyan QCRI web platform for screening[4]. Two authors (Kaur and Singh) independently screened the titles and abstracts of the records using Rayyan QCRI. Discrepancies were resolved by discussion or consultation with a third author (Srichawla). A standardized data extraction sheet was used represented by the variables shown in Table 2. The eligibility of the full-text articles was then evaluated on the basis of the predefined inclusion and exclusion criteria. Articles not in English, not published in a peer reviewed journal, or did not have the appropriate primary end point were excluded. Data extracted included the author’s name, year of publication, patient age, sex, clinical symptoms, blood pressure at presentation, radiographic findings, medical treatment, length of hospitalization, and outcomes. Cases were stratified according to whether corticosteroids are a precipitant or PRES treatment. Additionally, the type, dose, and route of corticosteroids were extracted in addition to the temporal relationship with the diagnosis of PRES, when applicable.

Table 2 Cases of posterior reversible encephalopathy syndrome determined to have corticosteroids as a causal agent.

Case No.	Ref.	Age (year)	Sex	Clinical sequela	BP (mmHg)	MRI findings	Vessel imaging	CSF studies	Cause	LOS (days)	Management	Outcomes
1	No author[23], 2016	33	F	Subarachnoid hemorrhage	N/A	Although no magnetic resonance imaging and vessel imagining was performed, cranial imaging showed hypodense areas in small acute infarcts and temporal, parieto, and occipital regions. Later, a repeat cranial imaging showed delineation of hypodensities in temporal-parieto-occipital regions	N/A	N/A	Methylprednisolone pulse therapy	Not specified but > 11	For seizures, anticonvulsants were administered. For SLE hydrocortisone along with mycophenolate mofetil. The patient was treated for pneumonia and underwent hemodialysis	Follow up: Normal brain parenchyma revealed by CT a year later. Outcome: Less edematous and seizures stopped
2	Alexander et al[24], 2013	16	M	Three episodes of tonic clonic seizures, tubulitis, and increased systolic blood pressure	220	FLAIR MRI revealed bilateral multifocal subcortical hyperintensities in the parietal lobe. Furthermore, there was relative sparing in the left frontal lobe, which means that there were less severe hyperintense lesions there. There was involvement/lesions of the deep white matter of the ganglionic region and of the right internal capsule. Areas with high signal intensities reveal vasogenic edema, as shown by increased ADC values	N/A	N/A	Higher doses of tacrolimus, corticosteroids, and being of a young age were factors causing PRES. Additionally, an extended period of uremia before transplantation led to PRES	9	The patient received five oral antihypertensive drugs. This included antiepileptic levetiracetam and minoxidil. The dose of tacrolimus was increased	Follow up: 6 weeks later had complete resolution of brain abnormalities. Outcome: Fully recovered
3	Camara-Lemarroy et al[25], 2015	22	F	Renal decline, severe bilateral occipital headache, seizures, confusion, hyperreflexia, reduced visual acuity	170/100	A T2 FLAIR of the occipital, parietal, and frontal lobes (subcortical) revealed bilateral hyperintensities. These findings are indicative of vasogenic edema with no diffusion restriction observed in DWI	N/A	N/A	Immunosuppressive therapy: Pulses of pulses of methylprednisolone	8	Hemodialysis, immunomodulation analgesic, IV diazepam (10 mg), IV nitroglycerin, IV phenytoin	Follow up: N/A. Outcome: After 24 hours, the patient recovered completely, the seizures stopped
4	Chennareddy et al[26], 2013	17	F	Case 1: Headache, blurry vision, and tonic-clonic seizures	Case 1: 110/70	Case 1: FLAIR hyperintense signal in the left occipital lobe. DWI: Showed no restriction in the left occipital lobe	N/A	N/A	Case 1: Endothelial dysfunction caused by SLE and pathologic dysregulation of cerebral blood flow that was exacerbated by methylprednisolone (in enhancing the vascular tone) caused PRES	Case 1: Estimated 5 days	Case 1: Analgesics and anticonvulsants	Follow up for Case 1: N/A. Outcome for Case 1: No flare-up of lupus, no more seizures, decreased headaches, well
5	Chennareddy et al[26], 2013	16	F	Case 2: Headache, blurred vision	Case 2: 120/70	Case 2: A hyperintense signal in the bilateral occipital areas that was suggestive of PRES	Case 2: N/A	Case 2: N/A	Case 2: N/A	Case 2: Estimated 7 days	Case 2: N/A	Follow up for Case 2: N/A. Outcome for Case 2: Headache went away, nephritis absent, and well
6	Wee et al[27], 2020	19	M	Epilepticus, altered sensorium, HTN	170/116	The non-contrasted CT scan revealed hypodensities of white matter at the bifrontal, bilateral occipital, left cerebellum and left parietal lobe. Also, contrast CT did not reveal venous thrombosis	N/A	N/A	Methylprednisolone	10	For aspiration pneumonia, intravenous antibiotics and antiepileptics along with intermittent hemodialysis were administered	Follow up: N/A. Outcome: His GCS value returned to normal after one week in the ICU
7	Ding et al[28], 2015	40	M	HTN, headache, two episodes of generalized tonic-clonic seizures	159/93	High signals seen on T2-weighted, FLAIR MRI, DWI, ADC. Comparable signals on T1 and enhanced sequence in the bilateral parieto-occipital lobes	N/A	Unrevealing	Methylprednisolone	Approximately 7	Irbesartan and edaravone. A week later, he continued antihypertensive drugs with a tapering dose of methylprednisolone	Follow up: N/A. Outcome: Neurological symptoms improved. MRI showed a significant decrease in abnormal signals
8	Fujita et al[29], 2008	23	F	Fever, headache, fatigue, vomiting, tonic-clonic seizures	180/120	T2WI/ADC: Increased bilateral parietal lobes. However, there were no significant signal alterations in DWI. Contrast MRI showed hyperintense signals on T2 and FLAIR images in the bilateral temporal–parietal–occipital lobes, left frontal lobe, and left cerebellar hemisphere. MRI showed more hyperintense signals on T2 and FLAIR images in the bilateral temporal–parietal– occipital lobes and left cerebellar hemisphere	The MRA did not show abnormalities in the cerebrovascular system except for a less important flow signal from the left vertebral artery. This is indicative of involvement of disease with the left vertebral artery. Cerebral angiography revealed no intracranial aneurysm	Normal	Pulse dose methylprednisolone	60	Diazepam, phenytoin, and nifedipine; Cyclophosphamide plasmapheresis; Thiopental; Betamethasone; Oral prednisolone; high-dose; methylprednisolone	Follow up: N/A. Outcome: A physical examination revealed no neurological deficits and CRP became negative, seizures disappeared
9	Fukuyama et al[30], 2011	6	M	Generalized seizures, drowsiness, cortical blindness	157/110	MRI revealed high signal intensities in the posterior medial frontal regions consistent with vasogenic edema. ADC mappings and DWI revealed restricted diffusion in focal areas that were again consistent with vasogenic edema	N/A	Before developing PRES, patient had normal CSF levels	Methylprednisolone was listed as a risk factor for PRES in this patient. Also, the patient most likely developed PRES due to HSCT that included mPSL	N/A	mPSL, BMT, methotrexate, FK506, magnesium, intravenous nicardipine, myeloid engraftment, mycophenolate mofetil, VPA	Follow up: The patient died from gastrointestinal hemorrhagic shock. Outcome: N/A
10	Gera et al[31], 2014	5	F	Headache, cortical blindness, seizure	180/100	MRI revealed lesions in the parietal and occipital lobe	N/A	N/A	3 pulses of methylprednisolone	N/A	For renal disease and renal failure, timely correction of fluid electrolyte was performed along with acid base balance. For hypertension, antihypertensives and nitroglycerin drips were administered. IV albumin was administered for hypoalbuminemia. Lastly, HUS was treated using plasma exchanges and methylprednisolone medication dose adjustment	Follow up: Cranial images were normal after 4-5 weeks. Outcome: Recovery of complete renal and neurological function
11	El Hage et al[32], 2021	15	M	Seizure, headache, HTN	210/136 during PRES max. 150/82	T2WI: Increased subcortical and bilateral occipital, parietal, and superior frontal areas	N/A	N/A	Corticosteroid was listed as a precipitating factor	N/A	Antihypertensives and antiepileptic medications	FU: Brain MRI was normal after three months. Outcome: Recovered
12	İncecik et al[33], 2013	8	M	Headache, confusion, seizures, HTN	150-90 - 160/100	T2WI: Increased signal in the bilateral parieto-occipital lobe and left frontal lobe	N/A	N/A	Pulse IV methylprednisolone; HTN	N/A	Levetiracetam, pulse dose IVMP	Follow up: N/A. Outcome: Neurological symptoms improved and after 15 days, MRI showed significant reversal
13	Irvin et al[34], 2007	48	F	Disoriented, agitated, autonomic instability, HTN	190/100	T2WI: Diffuse cortical and subcortical white matter signal abnormality in a symmetric bilateral distribution involving predominantly the occipital areas, superior frontal areas, the cerebellum, and some focal areas of the thalamus bilaterally, not evident on T1-weighted images	Same as left	Normal limits	Dexamethasone-induced PRES	N/A	Trazodone and zolpidem, and a single dose of haldol	Follow up: A repeat brain MRI 4 days later showed improving PRES. Outcome: Hospice was started and she did not receive radiation therapy to the brain
14	Ismail et al[35], 2021	57	F	N/A	N/A	T2WI: Bihemispheric and extensive symmetric diffusion impairment (parieto-occipital, temporal, cerebellar, frontal, and temporal) hypersignal (cortical and subcortical)	N/A	N/A	Methylprednisolone	N/A	Levetiracetam and valproate	Follow up: N/A. Outcome: Died from PRES and confirmed from autopsy
15	Kamezaki et al[36], 2012	62	F	High fever	180/118	T2WI: High signal intensity in the pons, cerebral hemisphere, basal ganglia, thalamus bilaterally. T2 star-weighted images show low intensity signals in the right thalamus. Diffusion-weighted images reveal high signal intensity in the same region	N/A	Normal	Chemotherapeutic agents which included methylprednisolone were listed as a possible factor	120	Unspecified but rehabilitation was used	Follow up: MRI revealed complete resolution of lesions. Outcome: N/A
16	Kamo et al[37], 2019	51	F	Abducens palsy left eye, left-sided dysesthesia, dysarthria	202/127	MRI of the brain on DWI revealed isointense area in the pons. Additionally, it revealed a circumscribed hyperintense area on both the ADC and FLAIR. DWI, ADC map and FLAIR imaging showed vasogenic edema caused by PRES	N/A	N/A	IV methylprednisolone	N/A	Nicardipine with tranexamic acid and glycerol were administered. Plasmapheresis	Follow up: N/A. Outcome: Final NIHSS lowered to 3. From therapy, blindness improved to light perception. Sensory disturbance on the left side and cerebellar ataxia of both the lower and upper limbs persisted
17	Khan et al[38], 2018	Patient 1: N/A; M Note: The mean age of all patients was 7 years	M	HTN; Note: Seizures and altered mental status were symptoms for > 90% of the symptoms for > 90% of cases although it was not specifically stated which cases had which symptoms	N/A	MRI revealed abnormalities in parietal cortex	N/A	WBC: 0; RBC: 1000; Cyto: Neg	Dexamethasone	N/A	Levetiracetam, methotrexate	Follow up: Alive. Outcome: Symptom resolution and PRES scan done after treatment showed resolvement
18	Khan et al[38], 2018	Patient 2: N/A	M	N/A	N/A	MRI revealed abnormalities in the parietal cortex and subcortical region	N/A	WBC: 1; RBC: 3; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Levetiracetam, methotrexate	Follow up: Alive. Outcome: Symptom resolution and PRES scan after treatment showed resolvement
19	Khan et al[38], 2018	Patient 3: N/A	M	HTN	N/A	MRI revealed abnormalities in parietal cortex, subcortical region, and anterior cortex	N/A	WBC: 0; RBC: 2; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Methotrexate	Follow up: Dead. Outcome: No symptom resolution and no PRES scan done after treatment
20	Khan et al[38], 2018	Patient 4: N/A	F	HTN	N/A	MRI revealed abnormalities in parietal cortex, subcortical region, and anterior cortex	N/A	WBC: 1; RBC: 1; Cyto: Neg	Dexamethasone	N/A	Levetiracetam, methotrexate	Follow up: Alive. Outcome: Unimproved
21	Khan et al[38], 2018	Patient 5: N/A	F	HTN	N/A	MRI revealed abnormalities in parietal cortex, subcortical region, and anterior cortex	N/A	WBC: 0; RBC: 0; Cyto: Neg	Dexamethasone	N/A	Levetiracetam,methotrexate	Follow up: Deceased. Outcome: No symptom resolution and no PRES scan done after treatment
22	Khan et al[38], 2018	Patient 8: N/A	M	HTN	N/A	MRI revealed abnormalities in the parietal cortex	N/A	WBC: 0; RBC: 1000; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Phenytoin, methotrexate	Follow up: Dead. Outcome: No symptom resolution and no PRES scan done after treatment
23	Khan et al[38], 2018	Patient 9: N/A	M	N/A	N/A	MRI revealed abnormalities in the parietal cortex and anterior cortex	N/A	WBC: 0; RBC: 2000; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Levetiracetam	Follow up: Alive. Outcome: Symptom resolution but PRES scan didn’t show resolution after treatment
24	Khan et al[38], 2018	Patient 10: N/A	M	HTN	N/A	MRI revealed abnormalities in parietal cortex, subcortical region, and anterior cortex	N/A	WBC: 0; RBC: 0; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Methotrexate	Follow up: Alive. Outcome: Symptom resolution but no PRES scan done after treatment
25	Khan et al[38], 2018	Patient 11: N/A	M	HTN	N/A	MRI revealed abnormalities in parietal cortex, subcortical region, and anterior cortex	N/A	WBC: 0; RBC: 0; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Levetiracetam, phenytoin, and methotrexate	Follow up: Alive. Outcome: Symptom resolution and PRES scan after treatment showed resolvement
26	Khan et al[38], 2018	Patient 14: N/A	M	HTN	N/A	MRI revealed abnormalities in the parietal cortex and anterior cortex	N/A	WBC: 5; RBC: 35; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Phenytoin, methotrexate	Follow up: Dead. Outcome: No symptom resolution and no PRES scan done after treatment
27	Khan et al[38], 2018	Patient 15: N/A	M	HTN	N/A	MRI revealed abnormalities in the parietal cortex and anterior cortex	N/A	WBC: 0; RBC: 0; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Phenytoin	Follow up: Alive. Outcome: Symptom resolution but no PRES scan done after treatment
28	Khan et al[38], 2018	Patient 18: N/A	M	HTN	N/A	MRI revealed abnormalities in the parietal cortex	N/A	WBC: 2; RBC: 1; Cyto: Neg	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Phenytoin, methotrexate	Follow up: Alive. Outcome: Symptom resolution and PRES scan done after treatment showed partial resolvement
29	Khan et al[38], 2018	Patient 19: N/A	F	HTN	N/A	MRI revealed abnormalities in the parietal cortex	N/A	N/A	Dexamethasone, steroid-induced hypertension that might lead to PRES	N/A	Phenytoin, methotrexate	Follow up: Dead. Outcome: No symptom resolution and no PRES scan done after treatment
30	Khanjar et al[39], 2018	Patient 1: 34	F	Tonic-clonic seizures, headache, decreased vision, HTN. All patients reported headache and impaired vision	Case 1: 190/100; Cases 2, 3 and 4: N/A	T2WI: Patchy multi-focal increased signal within the parietal-occipital cortical and subcortical areas bilaterally	N/A	N/A	PRES was caused by the initiation of immunosuppressive therapy, mostly due to pulse methylprednisolone therapy	6	Management of blood pressure and seizures along with mechanical ventilation	Follow up: N/A. Outcome: Successfully managed
31	Khanjar et al[39], 2018	Patient 2: 23	F	Tonic-clonic seizures, HTN, and renal decline	N/A	T2WI: Patchy multi-focal increased signal within the parietal-occipital cortical and subcortical areas bilaterally	N/A	N/A	PRES was caused by the initiation of immunosuppressive therapy, mainly due to pulse methylprednisolone therapy	16	Intubation, antihypertensives, antiepileptics, mechanical ventilation	Follow up: N/A. Outcome: Improved dramatically
32	Khanjar et al[39], 2018	Patient 3: 41	F	N/A	N/A	T2WI: Patchy multi-focal increased signal within the parietal-occipital cortical and subcortical areas bilaterally	N/A	N/A	PRES was caused by the initiation of immunosuppressive therapy, mostly due to pulse methylprednisolone therapy	16	Intubation, hemodialysis, antihypertensive, antiepileptic, mechanical ventilation	Follow up: N/A. Outcome: Complete resolution
33	Khanjar et al[39], 2018	Patient 4: 29	F	Seizures, diffuse alveolar hemorrhage, hemophagocytic lymphocytosis	N/A	MRI indicated PRES	N/A	N/A	PRES was caused by the initiation of immunosuppressive therapy, mainly due to pulse methylprednisolone therapy	20	Rehab, mechanical ventilation	Follow up: N/A. Outcome: Patient required rehab but eventually recovered
34	Kitamura et al[40], 2022	84	F	Fatigue, mental status deteriorated, leg numbness	1288/58	A DWI and MRI revealed vasogenic oedema after showing mild hyperintensity and higher signal of an ADC map of the parietal, bilateral occipital, frontal cortex, midbrain, and subcortical white matter. FLAIR-MRI findings also revealed an increased signal intensity of the previously mentioned regions, suggesting PRES	N/A	N/A	Methylprednisolone pulse therapy, prednisolone	At least 53 days	Rituximab, IV immunoglobulin, plasma exchange, hemodialysis, eculizumab, meningococcal vaccination, prednisolone was reduced	Follow up: 8 month follow up showed no relapse. Outcome: 56 days after admission. MRI showed PRES was resolved
35	Kumar and Rajam[41], 2011	6	M	HTN, absence of visual fixation, seizures, cortical blindness, fever, macular rash	N/A	T2WI: bilateral focal hyperintensities in the occipital lobes involving cortical and subcortical white matter during the acute phase; mild diffuse brain atrophy	N/A	N/A	Pulse methylprednisolone therapy; HTN due to steroids	Approximately 3-4 months	High dose oral prednisolone; second course of methylprednisolone; cyclosporine, etoposide and dexamethasone (HLH-2004 protocol); ventilation	Follow up: N/A. Outcome: Full neurological recovery, no existing illness, disease control due to cyclosporine
36	Kurahashi et al[42], 2006	4	F	Lethargic, convulsions, coma	160/100	T2WI: hyperintensities in the white matter of the bilateral occipital lobes	CSF no abnormalities	N/A	Methylprednisolone	At least 67 days	Intravenous hydrocortisone, continuous inhalation of b-2 stimulator, and additional oxygen; Sevoflurane; Furosemide; nicardipine, phenobarbital, and mannitol	Follow up: She presents no neurological sequelae 2 years after the event. Outcome: FLAIR image on the 67th hospital day shows resolution of hyperintensities
37	Dar et al[43], 2015	51	F	Seizure, headache, HTN	N/A	MRI of the spine showed long segment myelitis. MRI of the brain revealed bilateral diffuse white matter edema and faint restricted diffusion in the subcortical and cortical regions. This was suggestive of PRES	N/A	N/A	IV methylprednisolone and IV vitamin B12	N/A	Treatment with methylprednisolone and dexamethasone for 1 month	Follow up: Alert and coherent during activities. Outcome: Recovered significantly
39	Mimura et al[44], 2023	73	F	Consciousness deteriorated	140/80	FLAIR MRI showed multiple lesions with high signal intensity	N/A	N/A	Steroid administration increases blood pressure due to fluid retention and can be a risk factor for the development of PRES	At least 11 days	Intravenous methylprednisolone oral prednisolone; Rituximab; Intravenous administration of nicardipine and fluid removal by hemodialysis	Follow up: N/A. Outcome: blood pressure decreased and her consciousness improved dramatically
40	Morrow et al[45], 2015	53	F	Insomnia, dizziness, general malaise, and a headache, holocephalic headache	199/110	T2 hyperintensities were found in the cervical cord and brain that are suggestive of MS, same MRI results as six months earlier. In addition, there was an abnormal T2 signal in the posterior occipital, posterior white matter extending to the vertex, and in both thalami. Along with the new lesions, mild local sulcal effacement was observed. They found no diffusion restrictions based on the lesions. Overall, the findings were indicative of a diagnosis of PRES	N/A	N/A	Corticosteroids, HTN	N/A	High dose CR. 1250 mg oral prednisone. Hydrochlorothiazide and amlodipine. Labetalol and amlodipine	Follow up: 1 month follow-up neurologically stable. Outcome: One month later, the signal change resolved in the posterior cerebral hemispheres, consistent with the resolution of PRES
41	Nguyen et al[46], 2009	32	F	Nausea, seizures, dizziness, forgetfulness	112/85	MRI revealed multifocal areas of increased non-enhancing T2-Weighted FLAIR signals. This was found within the white matter of both hemispheres	N/A	N/A	Dexamethasone	N/A	Aprepitant, palonosetron, lorazepam, oral dexamethasone, rescue prochlorperazine, ondansetron, prochlorperazine, diphenhydramine, Dronabinol, diazepam, and fosphenytoin	Follow up: 1 month MRI showed full resolution. Outcome: Returned to baseline in one week. Dexamethasone doses were tapered and eventually discontinued
42	Ozkok et al[47], 2012	22	F	HTN	N/A	MRI from T2-weighted and FLAIR revealed lesions in the bilateral cortical occipital lobe	N/A	N/A	Hypertension and methylprednisolone were listed as the highest risk factors	Approximately 14	3 times a week, hemodialysis and antihypertensive treatment with amlodipine and doxazosin	Follow up: Her renal functions failed to improve and became anuric. However, she had no respiratory symptoms. Outcome: PRES resolved within 2 weeks
43	Shibata et al[48], 2022	51	F	Headache, tonic-clonic seizures	205/107	FLAIR sequences MRI revealed a bilateral occipital subarachnoid hemorrhage, parenchymal hemorrhage in the left occipital lobe, and hyperintense lesions of the subcortical white matter of both occipital lobes. The lesion in the left occipital lobe showed hyperintensity on the ADC map suggesting vasogenic edema	MRA: A partial resolution of signal change and vasoconstrictions in the bilateral middle cerebral arteries and posterior cerebral arteries	N/A	Intravenous methylprednisolone pulse	12	Diazepam, phenytoin, levetiracetam, antihypertensive therapy	Follow up: N/A. Outcome: Discharged without any neurological deficits
44	Sinha and Hurley[49], 2008	16	F	Disorientation, motor apraxia, blurred vision, headache	150/80-160/90	Axial FLAIR and turbo spin echo T-2 weighted images revealed increased signal intensity in the occipital and left parietal regions. DWI and ADC images did not reveal any restricted diffusion pattern	N/A	N/A	PRES was linked to corticosteroid	N/A	Cyclophosphamide and high oral dose	Follow up: MRI taken 6 weeks after starting treatment revealed resolution of the lesions. Outcome: N/A
45	Stârcea et al[50], 2018	10	F	Seizures, respiratory distress, bilateral amaurosis, drooling, renal decline	120/65	T2FLAIR/DWI: Cortical hyperintensity in the parietal lobe, indicating damage to white matter; white matter damage; degeneration with diffuse demyelination in the parietal and posterior occipital lobes	N/A	Normal	Immunosuppressive therapy: Methylprednisolone	N/A	Mechanical ventilation, blood transfusions, platelet concentrate, antibiotic therapy, continuous veno-venous hemofiltration, nifedipine, clonidine, dialysis	Follow up: 6 months. Outcome: No neurological problems, fully recovered, regular hemodialysis sessions
46	Swarnalatha et al[51], 2012	11	F	Generalized tonic clonic seizures	110/60	MRI of the brain revealed asymmetrical bilateral T2-weighted and FLAIR revealed hyperintense lesions in subcortical location of parieto-occipital, cortical, temporal lobes, cerebellum, and bilateral thalami indicative of PRES	N/A	CSF fluid analysis showed protein: 15 mg/dL, 3 cells/hpf, glucose: 56 mg/dL	Corticosteroid was listed as a possible factor leading to vasogenic edema, a characteristic of PRES	N/A	The patient was treated with antiepileptics and her dose was reduced to half of prednisolone	Follow up: N/A. Outcome: Recovered in 48 hours after the treatment listed in the left column
47	Tsukamoto et al[52], 2012	28	F	Generalized tonic-clonic convulsions with loss of consciousness	150/100	Both FLAIR and DWI MRI revealed cortical and subcortical hyperintensities in the occipital lobes, left thalamus, and bilateral frontal lobe. ADC revealed high signal intensities in the lesions of T2 shine through	The MRA did not reveal vascular abnormalities	The CSF was normal without any infiltration of leukemic cells	Induction chemotherapy which included prednisone. It was also stated that corticosteroids along with l-asparaginase and vincristine may cause PRES	N/A	Nifedipine was used to control blood pressure and midazolam was used as an anticonvulsant. Consolidation therapy and intrathecal administration. Underwent BMT for ALL	Follow up: Completely recovered from PRES without leukemia relapse. Outcome: MRI revealed significant resolution of lesions but still had difficulty walking, leg pain, and somnolence
48	Ulutaş et al[53], 2020	39	M	Tonic clonic seizures, severe headaches, HTN	160/110	White matter Hyperintense vasogenic edema lesions were found primarily on the right side of the posterior brain, as revealed by T2-weighted sequences	N/A	Nerve conduction studies and CSF analysis both revealed dysautonomic inflammatory demyelinating polyneuropathy and albuminocytologic dissociation, respectively	Patient developed PRES because of intensive immunosuppressive treatment that consisted of CyC and pulse steroid therapy	N/A	The patient was treated with antiedema therapy and antiepileptics. To control blood pressure, parenteral antihypertensive agents were administered	Follow up: Passed away. Outcome: No clinical improvement
49	Vernaza et al[54], 2021	34	F	Holocranial pulsatile cephalalgia with photophobia, headache, tonic-clonic seizure	N/A	In both T2-weighted and FLAIR scans, there were hyperintensities in the cerebellar corticosubcorctical and parieto-occipital regions	Angiography and computed tomography showed a suboccluding thrombus in the right internal jugular vein and mild subarachnoid hemorrhage in both sides of the frontal lobe	No lumbar puncture	Methylprednisolone; immunosuppressive treatment	17 days	Cyclosporine, IV artesunate, chloroquine and primaquine	Follow up: Died due to multiorgan failure. Outcome: 5 days later in the emergency department. Patient complained of gastrointestinal problems
50	Yang et al[55], 2022	Patient 1: 48	F	Sleepiness, diplopia	120/74	Lesions found in the parietal and occipital lobe	N/A	N/A	Intravenous methylprednisolone was found to be an inducing factor for PRES	N/A	No treatment for PRES	Follow up: N/A. Outcome: Partial brain lesion resolution
51	Yang et al[55], 2022	Patient 2: 53	F	Headache, giddiness	Normal (not specified)	Lesions found in the temporal, parietal, and occipital lobe	N/A	N/A	Intravenous methylprednisolone was found to be an inducing factor for PRES	N/A	Unknown	Follow up: N/A. Outcome: Unknown
52	Yang et al[55], 2022	Patient 3: 35	F	Sleepiness, Visual impairment, delirium	N/A	Lesions found in the temporal lobe	N/A	N/A	Intravenous methylprednisolone was found to be an inducing factor for PRES	N/A	Unknown	Follow up: N/A. Outcome: Partial brain lesion resolution
53	Yang et al[55], 2022	Patient 4: 48	F	Epilepsy, visual impairment	N/A	Lesions found in the semiovale, temporal and occipital lobe of the center	N/A	N/A	Intravenous methylprednisolone was found to be an inducing factor for PRES	N/A	Reduction/tapering of IVMP	Follow up: N/A. Unknown
54	Yang et al[55], 2022	Patient 5: 51	F	Headache	202/127	Lesions found in the brain stem	N/A	N/A	Intravenous methylprednisolone was found to be an inducing factor for PRES	N/A	Antihypertension and plasma exchange	Follow up: N/A. Complete resolution of brain lesion
55	Zekić et al[56], 2017	18	F	The patient had fever, leg oedema, lupus nephritis, acute arthritis, and malaise	160/100	Transverse sequence T2 and FLAIR magnetic resonance imaging revealed subcortical and cortical hyperintensities of the right frontal lobe and both sides of the parietal brain lobe	N/A	No abnormalities were found by brain CT scans, cytological and bacteriological analysis of the CSF	Intravenous pulse therapy with methylprednisolone	N/A	Antihypertensive, antiedema, and antiepileptic therapy	Follow up: 1 year. Successfully delivered a child and was in complete clinical remission due to SLE. Outcome: Full neurological recovery
56	Zhang et al[57], 2018	22	F	Sudden epileptic attacks, onset of seizures, HTN	190/130	MRI of cranium revealed vasogenic edema at both sides of the parietal region, occipital parietal regions, and centrum ovale	N/A	The CSF pressure was observed as 330 mm H2O, the protein level was normal, the white blood cell count was 0 cell/mm3, and no signs of infection	Intravenous methylprednisolone 80 mg daily induced hypertension which caused PRES	N/A	Corticosteroid impulse therapy was not administered. Drugs were administered to decrease intracranial pressure, intravenous drugs to lower blood pressure, anmidazolam for sedation	Follow up: N/A. Outcome: Recovered the next day after starting treatment

BP: Blood pressure; MRI: Magnetic resonance imaging; CSF: Cerebrospinal fluid; LOS: Length of stay; SLE: Systemic lupus erythematosus; CT: Computerized tomography; ADC: Apparent diffusion coefficient; PRES: Posterior reversible encephalopathy syndrome; DWI: Diffusion-weighted imaging; GCS: Glasgow coma scale; ICU: Intensive care unit; HTN: Hypertension; T2WI: T2-weighted imaging; MRA: Magnetic resonance angiography; CRP: C-reactive protein; mPSL: Methylprednisolone; HUS: Hemolytic uremic syndrome; IVMP: Intravenous methylprednisolone pulse; WBC: White blood cell; RBC: Red blood cell; Cyto: Cytology; CR: Creatinine; ALL: Acute lymphoblastic leukemia; N/A: Not applicable.

The risk of bias in included case reports was assessed using the Joanna Briggs Institute (JBI) tool for case reports by two authors (Kaur and Singh). This tool evaluates various dimensions of bias, including the clarity of the diagnosis, the precision of the reported intervention, and the validity of the outcomes[5]. Descriptive statistics were used to summarize the findings. Quantitative synthesis was completed using R Studio (2023.06.0 + 421).

RESULTS

Corticosteroids implicated in PRES

A PRISMA flow diagram is included in Figure 1. Based on data collected from various case studies, corticosteroids have been implicated as a potential causative agent in PRES. A total of 56 cases of PRES associated with corticosteroid use were identified and analyzed. Ages ranged from 4 to 84 years, with a mean age of approximately 25.2 years. A total of 37 women and 19 men were identified. The most common clinical sequelae included headaches (n = 22), seizures (n = 41), hypertension (n = 33), and visual disturbances (n = 10). The blood pressure readings at the time of presentation varied widely, with systolic pressures ranging from 110 to 220 mmHg and diastolic pressures from 58 to 136 mmHg. Magnetic resonance imaging (MRI) findings frequently revealed bilateral subcortical hyperintensities, primarily in the occipital, parietal, and frontal lobes, consistent with vasogenic edema as evident by an increased T₂ weighted signal. Diffusion-weighted imaging (DWI) and apparent diffusion coefficient maps were used to confirm the presence of vasogenic edema without significant diffusion restriction. Methylprednisolone was the corticosteroid most involved, followed by dexamethasone (DEX) and prednisone. The doses and duration of corticosteroids therapy varied between cases, with some patients receiving high-dose pulse therapy. In several cases, corticosteroids were combined with other immunosuppressive treatments, such as cyclophosphamide, tacrolimus, and methotrexate.

Figure 1  PRISMA flow diagram.

Treatment strategies typically included discontinuation or reduction in corticosteroid use, along with antihypertensive and antiepileptic therapies. For some patients, additional treatments such as hemodialysis, immunosuppressive therapy, and supportive care for underlying conditions such as systemic lupus erythematosus (SLE) or renal failure were necessary. The outcomes varied, and many patients showed complete resolution of the symptoms related to PRES and the findings of the MRI after appropriate treatment. However, there were instances of severe complications and mortality, particularly in patients with concurrent severe systemic conditions or delayed treatment initiation. Follow-up data revealed that many patients achieved full recovery without long-term neurological deficits. However, there were instances of mortality attributed to complications such as gastrointestinal hemorrhagic shock and multiorgan failure. Among survivors, complete resolution of PRES was documented on follow-up imaging, and several cases reported normalization of blood pressure and cessation of seizures. A full summary of cases is provided in Table 2.

Corticosteroids used to treat PRES

A total of 14 cases of PRES were identified and analyzed in which corticosteroids were used as part of the treatment regimen. The patient’s ages ranged from 11 to 75 years, with a mean age of approximately 37 years. The cohort consisted of 4 males and 10 females. The most common clinical sequelae included headaches (n = 6), seizures (n = 9), hypertension (n = 7) and visual disturbances (n = 3). Blood pressure readings at presentation varied widely, with systolic pressures ranging from 107 to 260 mmHg and diastolic pressures of 70 to 180 mmHg. MRI findings frequently revealed bilateral subcortical hyperintensities, primarily in the occipital, parietal, and frontal lobes, consistent with vasogenic edema. Magnetic resonance angiography and magnetic resonance venography were often used to rule out other cerebrovascular abnormalities.

Methylprednisolone was the most used corticosteroid, followed by DEX. The doses and duration of corticosteroids therapy varied between cases, with some patients receiving high-dose pulse therapy. Corticosteroids were administered as part of a broader management strategy that included antihypertensive agents, antiepileptics, and supportive care measures such as hemodialysis and mechanical ventilation. The length of hospital stays varied, with several patients requiring prolonged hospitalization due to severe clinical manifestations. Most of the patients showed significant clinical improvement after initiation of corticosteroid therapy, with MRI findings that demonstrate resolution of PRES-related abnormalities. Follow-up data revealed that most patients achieved full recovery without long-term neurological deficits. Among survivors, complete resolution of PRES was documented on follow-up imaging, and several cases reported normalization of blood pressure and cessation of seizures. The use of corticosteroids was associated with positive clinical outcomes, including stabilization of symptoms and resolution of vasogenic edema. A full summary of the cases is provided in Table 3.

Table 3 Cases of posterior reversible encephalopathy syndrome that included corticosteroids in the treatment plan.

Case No.	Ref.	Age (year)	Sex	Clinical sequela	BP (mmHg)	MRI findings	Vessel imaging	CSF studies	Cause	LOS (days)	Management	Outcomes
1	Aridon et al[58], 2011	53	M	Elevated blood pressure, gait disturbance, dizziness, urinary incontinence, and lethargy	260/180	MRI showed signals in both sides of the white matter of the cerebral and cerebellar hemispheres with involvement of the cerebellar peduncles and midbrain. A triventricular hypotheses hydrocephalus, a result of brainstem oedema, was observed	N/A	A lumbar puncture was performed. It revealed a normal cell count (0.8/mm3) along with limpid and uncolored CSF. Also slightly higher total protein concentration (77mmg/mL, normal is less than 40 mg/mL)	TTP	N/A	High-dose methylprednisolone and plasma exchange therapy	Follow up: 6 months later the neurological examination was normal and 24 months later he did not relapse and is still healthy. Outcome: Brain magnetic resonance imaging revealed almost complete resolution of brainstem oedema and changes in abnormal T2 signals
2	Christofidis et al[59], 2019	20	F	Generalized arthralgia, high grade fever (up to 39 degrees C), and severe headaches	140/70	DWI was normal with no sign of restricted diffusion. The MRI revealed leptomeningeal enhancement and bilateral subcortical lesions in the parietal-occipital regions on T2/FLAIR images, indicating vasogenic edema was present there	MRA demonstrating constriction and vasospasm of the cerebral arteries	Both PCR tests of CSF and blood were found to be positive for Neisseria meningitis (serogroup B). Both culture and Gram stain were negative for CSF. The white blood cell count was 15 K/uL, indicative of neutrophilic pleocytosis. The glucose level was low at 1 mg/dL and elevated protein concentrations at 352.01 mg/dL	Infection, sepsis	23	The patient was given mannitol, dexamethasone, the antiepileptic drug levetiracetam, and Ceftriaxone. Endotracheal intubation was also performed	Follow up: Follow-up MRI of both T2 and FLAIR images showed on the 23rd day complete resolution of the hyperintense and diffuse lesions in the parietal-occipital brain regions. The MRA follow-up was normal. Outcome: Mental status was completely restored 3-4 days after initiation of treatment, rapid recovery
3	Hao et al[60], 2021	28	F	Anasarca and tachycardia	107/79	MRI showed an abnormal high signal intensity in T2-weighted imaging, FLAIR, and ADC maps. In addition, low signal intensities on T1-weighted imaging and DWI were revealed. These were found in the parietal, bilateral frontal, occipital, temporal, basal ganglia, and cerebellar hemispheres	N/A	Increased protein levels	Autoimmune inflammation or ischemic changes that resulted from SLE (such as vasculitis, embolism, thrombus, and vasospasm) lead to endothelial dysfunction and, subsequently, to PRES. The author acknowledges that PRES could have been caused by corticosteroids, but ultimately was used to help treat PRES	Approximately 12	The patient was administered corticosteroids with methylprednisolone at 160 mg/day for inflation. She was sedated and also administered antiepileptic, acid suppression medications, and antipyretic. Once symptoms returned, methylprednisolone was administered 1000 mg/day for 3 days, 20 mg of dexamethasone, 10 mg of intrathecal injection and 60 mg of prednisone tablets in the morning. Immunosuppressant agents were administered hydroxychloroquine sulfate at 0.2 g twice a day, r-globulin at 20 g once a day for 5 days, and cyclophosphamide at 0.4 g per week as needed	Follow up: Condition stable. Outcome: Lesions were mostly resolved
4	Hosseini[61], 2022	40	F	Severe and refractory headache with multiple convulsive events	160/90	T2WI: Vasogenic edema in occipito-parieto-frontal lobes white matter compatible with PRES. Hyperintensities in occipito-parieto-frontal white matter with predominance in occipital lobes, without any restriction in diffusion weighted sequences (DWI), compatible with brain edema. Cervical cord MRI was normal too	MRV was normal	Although the IgG index in CSF was 0.7, CSF analysis was normal and the oligoclonal bands were negative	N/A	N/A	Adjuvant levetiracetam.IVMP, 1000 mg/day	Follow up: N/A. Outcome: After three days of IVMP, her headache completely subsided and a control brain MRI showed resolution of most hyperintense regions
5	Islam et al[62], 2021	29	F	Seizures, drowsiness, fever, occasional headache, muscle weakness	N/A	T2WI: Symmetrical hyperintensities over posterior brain regions in T2 and fluid attenuated inversion recovery images with no restricted diffusion in diffusion weighted image suggestive of PRES	N/A	Normal cell count 5/mm3 (n = 0–10), elevated protein 69 g/dL (n = 20–40). She also had a normal sugar and antideaminase level	N/A	N/A	Methylprednisolone and monthly cyclophosphamide (patient responded well to these). Levetiracetam, O2, normal saline. Low dose of oral prednisolone Hydroxychloroquine	Follow up: N/A. Outcome: Improvement in all aspects
6	Jadib et al[63], 2021	11	F	Tonic-clonic seizures, nausea, abdominal pain, headaches, and a more recent onset of blurred vision, HTN	161/109	Low signal on T1-weighted images and high signal on T2-weighted images, high apparent diffusion coefficient with no hemorrhage	N/A	N/A	Left renal artery stenosis due to TA	N/A	Intrarectal diazepam Nicardipine Amlodipine and propranolol azathioprine and corticosteroid given	Follow up: 11 months later MRI revealed total resolution. Outcome: Showed neurological improvement
7	Mai et al[64], 2018	55	F	Confused, speech slurred, convulsions, upgoing plantar reflex, vertical gaze palsy	140/90	T2WI: Involving periventricular and deep cerebral white matter. Repeat MRI showed resolution	CSF: Opening pressure of 12 cm H2O, cell count of 7 cells/ µL, a red cell count of 4 cells/µL, protein level of 4.4 g/ dL, a glucose level of 4.76 mmol/L (10.4 mmol/L in blood), and a lactate level of 3.25 mmol/L. Dengue virus IgM was detected in CSF	N/A	Dengue infection	59 days	Intravenous methylprednisolone, oral prednisolone, and Phenobarbital given	Follow up: N/A. Outcome: Patient was discharged for rehab and a repeat MRI showed almost complete resolution
8	Min et al[65], 2006	22	F	Headaches, blurred vision, vertigo, nausea, vomiting, and altered mental function, binocular blindness, seizure, and lethargic	200/110	T2WI: Cerebellum, brainstem, basal ganglia, and central white matter. These abnormalities resolved	MRA was normal	20 RBC/L, 1 WBC/L, protein 106 mg/dL (normal range 10 to 40 mg/dL), and glucose 46 mg/dL (normal range 40 to 70 mg/dL)	Hypertension is possible in this context	14 days at least	Cyclophosphamide, methylprednisolone, dialysis, diazepam, fosphenytoin, Phenytoin, mycophenolate mofetil, and dialysis were performed. Methylprednisolone 1 g IV for 2 days. Plasmapheresis	Follow up: N/A. Outcome. Stopped hemodialysis after renal function improved
9	Ortega-Carnicer et al[66], 2005	24	M	Generalized seizures, deep coma, flaccid tetraplegia, and fixed dilated pupils	225/120	N/A	N/A	N/A	PRES was induced by immunoglobulin administration due to the temporal relationship between immunoglobulin administration and the onset of neurological symptoms of PRES	Approximately 25	Treatment with IVMP (1000 mg/24 hours) resulted in neurological improvement	Follow up: N/A. Outcome: In good neurological condition
10	Sato et al[67], 2011	42	F	Throbbing headache, drowsiness	N/A	MRI T2-weighted imaging revealed hyperintense lesions in the occipital and temporal-parietal lobes. Diffusion weighted images revealed bilateral and symmetric hyperintense lesions in the occipital lobe	The right posterior cerebral artery experienced vasoconstriction according to MRA	N/A	Treatment with methylprednisolone helped reverse cerebral edema	68	Treatment included methylprednisolone and glycerin	Follow up: MRA returned to normal 6 months after discharge. Complete recovery of the lesions on day 64. Outcome: N/A
11	Symeonidis et al[68], 2021	75	M	Mental status decline, lethargic, disoriented, episodes of hypertensive crisis	180/100	MRI FLAIR and T2-weighted images revealed signal hyperintensity in the bilateral areas of thalamus, fibers of reticular formation, hypothalamus, mild edema of left parahippocampal gyrus, and anterior section of cerebral vermis	N/A	The lumbar puncture revealed negative cytology for metastatic cells. Gram-positive and negative bacteria, herpes zoster, EBV, HSV, BK, CMV, JC, influenza, adenovirus, fungal causes, tuberculosis, listeria, borrelia, and other cultures were negative	Oxaliplatin was the main cytotoxic agent that led to PRES	N/A	Treatment was with dexamethasone and antiepileptics	Follow up: Neurological resolution of PRES after 3-4 weeks. Outcome: Clinical improvement
12	Tetsuka and Nonaka[69], 2017	38	F	Drowsy but conscious, delirium and fluctuating mental stability.	150/90	T2WI/ADC: Revealed hypersignal intense lesions in the cortical and subcortical white matter in the basal ganglia, callosal splenium, and occipital lobes	N/A	N/A	Corticosteroids helped reduce vasogenic edema	21	Intravenous corticosteroids and nifedipine	Follow up: MRI two weeks after her initial MRI revealed complete resolution. Outcome: Laboratory results and MRI became normal
13	Xia and Lv[70], 2022	58	M	Drowsiness, left hemiparesis, lethargy, impaired attention and memory	169/94	T2WI: Subcortical hyperintensities in the left and right hemispheres, mainly in the temporal and occipital lobe. ADC revealed increased diffusivity of legions that represent vasogenic edema. SWI: Cortical and subcortical CMBs in the bilateral temporal lobes	N/A	CSF: 13 cells/mm3 (mononuclear cells-10 cells/mm3, polynuclear cells-3 cells/mm3). Elevated total protein concentration revealed 207 mg/dL and an opening pressure of 400 mmH2O. No oligoclonal IgB bands were detected in the analysis. However, both immunoglobulin IgG and albumin increased significantly at 464 mg/L and 1.57 g/L, respectively. The IgG index was slightly higher at .89 in comparison to normal, which is less than or equal to 0.70	PRES was caused by shock wave lithotripsy and HTN	24	High-dose oral methylprednisolone (500 mg/day) for 5 days, dehydration therapy, prednisolone 60mg/day with a decrease dose of 5 mg every 10 days	Follow up: MRI 3 months after discharge revealed most resolution of white matter hyperintensities without CMB in SWI
14	Xu et al[71], 2021	14	F	Tonic clonic seizures, auditory hallucinations, disorder of thought	150/100	T2-weighted and FLAIR revealed hyperintense lesions in the parietal, occipital, temporal, and frontal lobe, subcortex, and cerebral cortex. Diffusion-weighted magnetic resonance imaging and apparent diffusion coefficient revealed isointense and hyperintense lesions	MRA was normal	N/A	Methylprednisolone was used to treat MPA, which in return cured the PRES	N/A	200 mg of methylprednisolone and 7 courses of plasma exchang	Follow up: No PRES relapse. Outcome: 17 days later, reduced gyrus swelling was observed

BP: Blood pressure; MRI: Magnetic resonance imaging; CSF: Cerebrospinal fluid; LOS: Length of stay; DWI: Diffusion-weighted imaging; MRA: Magnetic resonance angiography; SLE: Systemic lupus erythematosus; MRV: magnetic resonance venography; IVMP: Intravenous methylprednisolone pulse; TTP: thrombotic thrombocytopenic purpura; PRES: Posterior reversible encephalopathy syndrome; T2WI: T2-weighted imaging; DWI: Diffusion-weighted imaging; HTN: Hypertension ; TA: Transient amnesia; RBC: Red blood cell; WBC: White blood cell; EBV: Epstein Barr virus; HSV: Herpes simplex virus; CMV: Cytomegalovirus; JC: JC virus; ADC: Apparent diffusion coefficient; CMB: Cerebral microbleed; SWI: susceptibility weighted imaging; N/A: Not applicable.

Quality and risk of bias assessment

The risk of bias in the included studies was assessed using the JBI tool for case reports and series. This tool assesses various dimensions of bias, including the clarity of diagnosis, the precision of the reported intervention, and the validity of the results. The results of this assessment are summarized below (Table 4). Of the 70 case reports and series included in this review, the majority were found to have a low risk of bias. Specifically, 57 cases were rated as having a low risk of bias, 12 cases were rated as having a moderate risk of bias, and one study was rated as having a high risk of bias. Overall, the risk of bias assessment highlights the variability in the quality of reporting among the included studies. Although many of the studies were of high quality, the presence of studies with moderate and high risk of bias underscores the need for more standardized and comprehensive reporting in future research on PRES and corticosteroids.

Table 4 Joanna Briggs Institute critical appraisal and risk of bias results for case reports/series.

Ref.	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Overall	Risk
No author[23], 2016	Y	N	Y	Y	Y	Y	Y	Y	7	Low
Alexander et al[24], 2013	N	Y	Y	Y	Y	Y	Y	Y	7	Low
Aridon et al[58], 2011	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Camara-Lemarroy et al[25], 2015	Y	Y	Y	Y	Y	N	U	Y	6	Mod
Chennareddy et al[26], 2013	Y	Y	Y	Y	U	U	Y	Y	6	Mod
Christofidis et al[59] ,2019	Y	U	Y	Y	Y	Y	Y	Y	7	Low
Ding et al[28], 2015	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Fujita et al[29], 2008	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Fukuyama et al[30], 2011	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Gera et al[31], 2014	Y	N	N	Y	N	N	N	Y	3	High
El Hage et al[32], 2021	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Hao et al[60], 2021	N	Y	Y	Y	Y	Y	Y	Y	7	Low
Hosseini[61], 2022	Y	N	Y	Y	Y	N	Y	Y	6	Mod
İncecik et al[33], 2013	Y	N	Y	Y	Y	Y	Y	Y	7	Low
Irvin et al[34], 2007	Y	N	Y	Y	Y	N	Y	Y	6	Mod
Islam et al[62], 2021	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Ismail et al[35], 2021	Y	N	N	Y	Y	N	N	Y	4	Mod
Jadib et al[63], 2021	Y	N	Y	Y	Y	Y	Y	Y	7	Low
Kamezaki et al[36], 2012	Y	Y	Y	Y	N	Y	Y	Y	6	Mod
Kamo et al[37], 2019	Y	U	Y	Y	Y	Y	Y	Y	7	Low
Khanjar et al[39], 2018	Y	N	U	N	Y	N	Y	Y	4	Mod
Khan et al[38], 2018	Y	Y	N	Y	Y	N	Y	Y	6	Mod
Kitamura et al[40], 2022	Y	Y	Y	N	Y	Y	Y	Y	7	Low
Kumar and Rajam[41], 2011	Y	N	N	Y	Y	Y	Y	Y	6	Mod
Kurahashi et al[42], 2006	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Mai et al[64], 2018	Y	U	Y	Y	Y	Y	Y	Y	7	Low
Dar et al[43], 2015	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Mimura et al[44], 2023	Y	N	Y	N	Y	N	Y	Y	5	Mod
Min et al[65], 2006	Y	U	Y	Y	Y	Y	Y	Y	7	Low
Morrow et al[45], 2015	Y	U	Y	U	Y	Y	Y	Y	6	Mod
Nguyen et al[46], 2009	Y	N	Y	Y	Y	Y	Y	Y	7	Low
Ortega-Carnicer et al[66], 2005	Y	Y	Y	Y	Y	N	Y	Y	7	Low
Ozkok et al[47], 2012	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Sato et al[67], 2011	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Shibata et al[48], 2022	Y	U	Y	Y	Y	Y	Y	Y	7	Low
Sinha and Hurley[49], 2008	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Stârcea et al[50], 2018	Y	N	Y	Y	Y	Y	Y	Y	7	Low
Swarnalatha et al[51], 2012	Y	Y	Y	Y	Y	N	Y	Y	7	Low
Symeonidis et al[68], 2021	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Tetsuka and Nonaka[69], 2017	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Tsukamoto et al[52], 2012	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Ulutaş et al[53], 2020	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Vernaza et al[54], 2021	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Yang et al[55], 2022	N	N	N	Y	Y	Y	Y	Y	6	Mod
Xia and Lv[70], 2022	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Xu et al[71], 2021	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Zekić et al[56], 2017	Y	Y	Y	Y	Y	Y	Y	Y	8	Low
Zhang et al[57], 2018	Y	Y	Y	Y	Y	N	Y	Y	7	Low

Q1: Were the patient’s demographic characteristics clearly described? Q2: Was the patient’s history clearly described and presented as a timeline? Q3: Was the current clinical condition of the patient on presentation clearly described? Q4: Were diagnostic tests or assessment methods and the results clearly described? Q5: Was the intervention(s) or treatment procedure(s) clearly described? Q6: Was the post-intervention clinical condition clearly described? Q7: Were adverse events (harms) or unanticipated events identified and described? Q8: Does the case report provide takeaway lessons? Overall: Sum of points. Y: Yes; N: No; U: Unclear.

DISCUSSION

The underlying pathophysiology of PRES is believed to involve a combination of endothelial dysfunction and altered cerebral autoregulation leading to vasogenic edema[6]. Hypertension is a well-recognized precipitating factor, which can overwhelm the autoregulatory capacity of cerebral vessels, particularly in the posterior circulation due to its relatively sparse sympathetic innervation. This results in hyperperfusion, capillary leakage, and the formation of vasogenic edema primarily in the parieto-occipital regions of the brain. Endothelial dysfunction plays a critical role in the development of PRES. Various conditions such as eclampsia, autoimmune diseases, renal failure, and immunosuppressive therapies can damage endothelial cells, leading to increased permeability and subsequent edema formation[7]. The role of cytokines and other inflammatory mediators in promoting endothelial dysfunction and disrupting the blood-brain barrier (BBB) is also significant, contributing further to the pathology of PRES[8]. Frequent neurological and vital checks every 4 hours for the first 24-48 hours after the diagnosis of PRES may be beneficial to prevent both hyperperfusive and hypoperfusive events. Hypertensive crises are best managed with the initiation of an intravenous infusion such as nicardipine or clevidipine which also have anti-spasmodic effects.

In our review, we identified 57 cases of PRES associated with corticosteroid use. These cases highlight the potential for long-term or high-dose corticosteroids to induce PRES, particularly in patients with underlying conditions such as SLE, renal disease, and post-transplant immunosuppression. The pathophysiology of corticosteroid-induced PRES likely involves endothelial dysfunction, leading to vasogenic edema. Hypertension, a common side effect of corticosteroids, is a key factor in the development of PRES, as evidenced by elevated blood pressure readings in many of the cases reviewed[9,10]. The clinical manifestations in these cases were diverse, with seizures, headaches, hypertension, and visual disturbances being the most common. MRI findings consistently showed bilateral subcortical hyperintensities, predominantly in the occipital, parietal, and frontal lobes. Treatment strategies varied, but reduction or cessation of corticosteroid therapy often resulted in significant clinical improvement and resolution of MRI abnormalities.

On the contrary, we identified 14 cases where corticosteroids were used as part of the treatment regimen for PRES. These cases predominantly involved patients with underlying autoimmune or inflammatory conditions, where corticosteroids were used for their potent anti-inflammatory effects. The therapeutic use of corticosteroids in PRES was associated with positive results, including stabilization of symptoms and resolution of vasogenic edema, as evidenced by follow-up MRI. The rationale for using corticosteroids in these cases is based on their ability to reduce inflammation and stabilize the BBB, thus mitigating the vasogenic edema characteristic of PRES. This approach is particularly relevant in cases where PRES is precipitated by an inflammatory or autoimmune process[11]. However, the use of corticosteroids in the treatment of PRES requires careful monitoring to balance their benefits against the risk of exacerbating hypertension.

Corticosteroids and the BBB

Corticosteroids are known for their potent anti-inflammatory and immunosuppressive effects, which are beneficial in the treatment of various inflammatory and autoimmune conditions[12]. However, its use can influence the pathophysiology of PRES in several ways. Corticosteroids can lead to hypertension through mechanisms such as sodium and water retention, increased vascular sensitivity to catecholamines, and altered renal function. This hypertensive effect can exacerbate the cerebral hyperperfusion seen in PRES, overwhelming the autoregulatory capacity of the brain's vasculature and leading to vasogenic edema (Figure 2). While corticosteroids have anti-inflammatory effects that can stabilize the endothelium, they can also induce endothelial dysfunction when used in high doses or over prolonged periods. This paradoxical effect can contribute to the development of PRES, particularly in patients with underlying vulnerabilities such as renal disease or pre-existing hypertension[13]. In cases where PRES is driven by an autoimmune or inflammatory process, corticosteroids can help mitigate the inflammatory response and stabilize the BBB, thus reducing edema and improving clinical outcomes[14]. This dual role underscores the complexity of corticosteroid use in PRES, where they can be both a precipitant and a treatment.

Figure 2 The cerebral autoregulatory curve. Created with BioRender.com (Supplementary material).

Corticosteroids have been used to treat brain edema for over six decades. However, its clinical utility is often in the management of vasogenic edema from intracranial neoplasms and bacterial meningitis[15,16]. A high concentration of steroids inhibits active ion transport mediated by the Na+-K+-ATPase channel[17]. And the rate of sodium transport from the blood to the parenchyma determines the rate of cerebral edema formation. Therefore, corticosteroids may decrease the amount of cerebral edema formation via Na+-K+-ATPase channel inhibition[18]. On the contrary, a meta-analysis of eight randomized controlled trials showed no benefit of corticosteroids in the management of intracerebral hemorrhage and subarachnoid hemorrhage[16]. Corticosteroids have also been shown to decrease peri-contusional vasogenic edema in patients with traumatic brain injury. However, long-term functional outcomes were not measured[19].

McMahon et al[20] explored the use of post-sonication DEX to mitigate risks associated with the delivery of therapeutic agents across the BBB using focused ultrasound and microbubbles (FUS + MB). The study involved adult male rats and assessed BBB permeability, inflammatory protein expression, blood vessel growth, and astrocyte activation. The findings revealed that DEX administration expedited the restoration of BBB integrity and reduced inflammation-related protein production shortly after sonication. Furthermore, DEX decreased astrocyte activation and vascular growth at a later stage compared to controls. These results suggest that DEX can enhance the safety profile of FUS + MB-mediated drug delivery by modulating BBB permeability and reducing inflammation-induced tissue damage, especially in treatments aimed at preserving neural function and requiring multiple sonications.

Corticosteroids and cerebral blood flow

Bastin et al[21] studied the effects of DEX on cerebral perfusion and water diffusion in patients with glioblastoma using dynamic susceptibility contrast-MRI and diffusion tensor-MRI. The study measured cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and mean diffusivity (<D>) in enhancing tumors, peritumoral edematous brain, and normal contralateral white matter. The results indicated that there were no significant changes in tumor CBF, CBV, or MTT after DEX treatment. However, there was a notable increase in CBF (11.6%; P = 0.05) in the edematous brain. Additionally, <D> was significantly reduced in both enhancing tumor (-5.8%; P = 0.001) and edematous brain (-6.0%; P < 0.001), suggesting a decrease in water content. No significant changes were observed in the normal-appearing contralateral white matter. These findings suggest that DEX does not significantly alter tumor blood flow but may reduce the peritumoral water content and tissue pressure thus increasing perfusion in the edematous brain[21].

Cabañas et al[22] investigated the effects of DEX on cerebral and ocular blood flow velocities in ten ventilated preterm infants with lung disease. Using color Doppler flow imaging, they measured blood flow velocities in the internal carotid, anterior cerebral, and ophthalmic arteries before and after multiple doses of DEX. The results showed that DEX progressively increased blood flow velocities and decreased resistance indices, with the most significant changes in end diastolic flow velocities, especially after the fifth dose. Arterial blood pressure changes mirrored increases in blood flow velocities. This study suggests that DEX significantly influences cerebral and ocular hemodynamics in preterm infants.

Limitations and future directions

This systematic review has several limitations that must be acknowledged. Most of the data comes from case reports and series, which can introduce bias and limit the generalizability of the findings. Additionally, some cases may have been missed. These types of studies often lack control groups, making it difficult to establish causality. There was significant variability in the reporting of clinical and imaging findings, corticosteroid doses, and treatment regimens. This heterogeneity complicates the synthesis of data and the drawing of definitive conclusions. Many cases lacked long-term follow-up data, which limits our understanding of the enduring effects of corticosteroids on PRES outcomes. Many cases were confounded with concomitant usage of immunosuppressive therapies which are also implicated in PRES[8]. Future research should aim to address these limitations through more robust study designs and comprehensive data collection. Well-designed prospective cohort studies and randomized controlled trials are needed to better elucidate the relationship between corticosteroids and PRES. These studies should aim to establish clearer causal links and assess the efficacy and safety of corticosteroid use in the treatment of PRES. Further research is essential into the pathophysiological mechanisms by which corticosteroids influence PRES development and resolution. Understanding these mechanisms at the molecular level could inform the development of targeted therapies. Long-term follow-up studies are needed to assess the sustained effects of corticosteroids on PRES and to determine the best practices for preventing recurrence and managing chronic sequela.

CONCLUSION

PRES is a complex neurological disorder with a multifaceted pathophysiology that involves endothelial dysfunction, altered cerebral autoregulation, and vasogenic edema. This systematic review has explored the dual role of corticosteroids in the context of PRES, revealing their potential to induce and treat this condition. Our findings indicate that high-dose or prolonged corticosteroid therapy can contribute to the development of PRES, particularly in patients with underlying risk factors such as hypertension, kidney disease, and autoimmune conditions. On the contrary, corticosteroids also play a crucial therapeutic role in the treatment of PRES, especially in cases driven by inflammatory or autoimmune mechanisms. Their anti-inflammatory and endothelial stabilizing properties can mitigate the vasogenic edema characteristic of PRES, leading to significant clinical improvement and resolution of imaging abnormalities. The clinical implications of these findings underscore the need for a balanced approach to corticosteroid use in patients at risk of or presenting with PRES. Vigilant monitoring of blood pressure and neurological status is essential to optimize patient outcomes. A deeper understanding of the pathophysiological mechanisms and clinical factors involved will be crucial in developing evidence-based guidelines on the use or avoidance of corticosteroids in PRES.