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ORIGINAL ARTICLE
Year : 2021 | Volume
: 46
| Issue : 3 | Page : 160-165
Posterior reversible encephalopathy syndrome during management of hematological disorders: experience from a tertiary care center in India
Gopila Gupta MBBS, MD (Paediatrics) 1, Tulika Seth1, Vikas Garg2, Pawan Kumar3, Priyanka Naranje3, Arpit Agrawal4, Manoranjan Mahapatra5, Mukul Aggarwal1
1 Department of Haematology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
4 Neurology, All India Institute of Medical Sciences, New Delhi, India
5 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
Correspondence Address:
Gopila Gupta
DM Clinical Hematology, Department of Hematology, AIIMS, New Delhi; Department of Hematology, AIIMS, A-4/56, Alok Kunj, Sector-15, Rohini, Delhi 110089
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ejh.ejh_6_21
Background Posterior reversible encephalopathy syndrome (PRES) is a disorder of reversible subcortical vasogenic brain edema with acute neurological symptoms. Diagnosis of PRES is based on exclusion, and treatment consists of symptomatic management.
Aims To study the clinical features, radiological findings, and outcomes of PRES in patients with hematological disorders.
Patients and methods Case files of patients diagnosed with PRES from January 2016 to November 2019 were reviewed. PRES was diagnosed based on clinical features and MRI findings. Primary diagnosis, clinical history, vital signs, laboratory parameters, treatment summary, and neuroimaging findings were recorded.
Results A total of 16 patients were diagnosed with PRES. Their median age was 7 years (range, 2–25 years). A total of 12 patients had acute lymphoblastic leukemia, who were on induction phase, two patients had aplastic anemia, and one each had acute myeloid leukemia and beta-thalassemia major. All patients had hypertension and 15 had seizures as initial presentation of PRES. Overall, 12 patients had bilateral subcortical white matter hyperintensity on T2 in occipital and parietal lobes on MRI. All patient recovered, except one, who had residual neurological deficit. All patients were restarted on the disease therapy once the patients were stabilized. No recurrences were observed.
Conclusion Early recognition of PRES may help initiate timely treatment and reduce morbidity and mortality. Implicating agents may be withheld during the symptomatic period. Its management is symptomatic, and therapy may be restarted once patient is clinically stable. Its prognosis is favorable, but some patients may have residual neurological deficit.
Keywords: acute lymphoblastic leukemia, chemotherapy, immunosuppressive therapy, posterior reversible encephalopathy syndrome, steroids
Posterior reversible encephalopathy syndrome (PRES) is a neurological condition, which was first described by Hinchey et al. [1]. It is also termed as reversible posterior leukoencephalopathy syndrome. It is a reversible disorder of white matter of brain with rapid-onset symptoms like headache, seizures, altered mental status, and visual blurring. It is commonly associated with hypertension, renal failure, immunosuppressive agents, and autoimmune disorders [2],[3]. It may also occur in patients with hematological disorders receiving cytotoxic drugs and immunosuppressive agents and in patients undergoing hematopoietic stem cell transplant (HSCT) [4],[5],[6]. Clinical features usually mimic stroke, metabolic causes viz. hyponatremia, leukostasis, and involvement of nervous system by disease or infection. Workup includes complete blood count, blood chemistry to rule out metabolic causes, cerebrospinal fluid (CSF) analysis to rule out disease involvement and infection, and brain neuroimaging to rule out stroke [7]. MRI usually shows symmetric parieto-occipital subcortical white matter hyperintensity [8]. Atypical findings like cortical involvement or lesions in other areas of brain (frontal lobe, cerebellum, brain stem, basal ganglia, or spinal cord) may also occur [9],[10],[11]. There are no standard diagnostic criteria so far, and diagnosis is made by excluding other differentials. Clinical symptoms as well as imaging features are reversible in most patients. Management is usually supportive, and the outcome is mostly favorable [12]. Literature on PRES in hematological disorders is limited. The aim of our study is to study the clinical features, radiologic findings, and outcomes of patients with hematological disorders who developed PRES.
Patients and methodsThe records of all patients admitted in the hematology wards of a tertiary care center in India between January 2016 and November 2019 were analyzed. Informed and signed consent was obtained from each patient/ guardian for the given study. The study was conducted after taking approval from the Institute’s ethical committee. The study was conducted after taking approval from the Institute’s ethical committee. Patients who were diagnosed with PRES were included in the study. Diagnosis was made on the basis of clinical features, blood chemistry, CSF studies, and MRI [13]. The clinical profiles of patients including demographic data, any comorbidities (including hypertension and previous neurological disease), clinical feature and vital signs at the time of diagnosis of PRES, underlying hematological disorder, treatment protocol and phase of treatment (viz. induction, consolidation, and maintenance), drugs administered, blood chemistry, CSF analysis, and MRI findings at time of diagnosis were recorded. Duration of antihypertensives and antiepileptics drugs, follow-up of patients, and any residual neurological deficit were also recorded.
ResultsA total of 16 patients were diagnosed with PRES, and the majority were males (n=9, 56%). Their median age was 7 years (2–25 years), and 14 (87.5%) patients were younger than 18 years. Most common underlying hematological disorder was acute lymphoblastic leukemia (ALL) in 12 (75%) patients, followed by aplastic anemia, acute myeloid leukemia (AML), and thalassemia.
Details on clinical profile and implicating agents are presented in [Table 1]. All patients with ALL were on induction phase of Berlin-Frankfurt-Münster 90 protocol, which included prednisolone, vincristine, daunorubicin, L-asparaginase, and intrathecal methotrexate. Median time of onset of symptoms after start of therapy was 13 days (3–33 days). Two patients had aplastic anemia: one was receiving cyclosporine and prednisolone for management of acute graft versus host disease on day 47 after matched sibling donor allogenic HSCT, and other was on immunosuppressive therapy (cyclosporine and stanozolol). One patient with thalassemia was also receiving cyclosporine and prednisolone for management of acute graft versus host disease on day 30 after matched sibling donor allogenic HSCT. One patient with AML developed PRES on day 22 of first consolidation high-dose cytarabine (HiDAC). No patients had prior history of seizures, hypertension, or any central nervous system disease.
Table 1 Clinical profile of patients diagnosed with posterior reversible encephalopathy syndromeA total of 15 (94%) patients had generalized tonic-clonic seizures at onset, with three of these having status epilepticus. Four patients also complained of headache, two had associated vomiting, and one patient had visual disturbances. On examination, all patients had acute elevation of blood pressure (>95th centile for age, sex, and height) [14]. Blood pressure remained elevated during the symptomatic period. Only one patient had focal neurological deficit in the form of right-sided hemiparesis.
Blood chemistry, including glucose, electrolytes, and renal and liver functions, was tested in all patients at the time of onset. No abnormality was detected in any of the patient. Lumbar puncture for CSF was done in all cases, and samples were tested for glucose, proteins, cytology, and cultures. CSF proteins were mildly raised in two patients, and there was no pleocytosis or abnormal cells in any patient, and all the CSF cultures were sterile. MRI was done in all the patients within a median of 2 days of onset of symptoms. The most common finding (75%, n=12) was bilateral symmetrical subcortical white matter involvement of the occipital and parietal lobes without diffusion restriction or hemorrhage. [Figure 1] shows MRI of a 2-year-old male child with ALL, who had status epilepticus at onset. Five patients also had frontal lobe involvement also in the form of T2 hyperintensity in subcortical white matter. Two patients had involvement of temporal lobe, and one patient each had involvement of thalamus and cerebellum. Localization of brain lesions on MRI is depicted in [Table 2]. A few cases showed some atypical features such as hemorrhages ([Figure 1]d) or diffusion restriction ([Figure 2]).
Figure 1 (a–d) A 2-year-old male child known case of B-cell ALL on day 4 of induction chemotherapy presented with status epilepticus and altered sensorium with elevated blood pressure 150/110 mmHg. (a, b). T2-weighted and FLAIR axial MRI images showing areas of T2 and FLAIR hyperintensity in the subcortical white matter of the bilateral frontal, parietal, and occipital lobes (black arrows). (c) Axial DWI: these areas did not show any significant diffusion restriction. (d) Axial SWI showing multiple hypointense ‘blooming foci’ in the subcortical white matter of left frontal lobe (thick arrow), suggestive of microhemorrhages. ALL, acute lymphoblastic leukemia; DWI, diffusion weighted image; FLAIR, fluid-attenuated inversion recovery sequence; SWI, susceptibility weighted image.
Figure 2 (a–d) A 7-year-old female child with B-cell acute lymphoblastic leukemia on day 12 of induction chemotherapy presented with generalized tonic-clonic seizures and hypertension (a, b) T2WI and FLAIR axial MRI showing hyperintensity in the cortex and subcortical white matter of the bilateral parieto-occipital regions (white arrows). (c, d) Axial DWI and ADC map – these areas are hyperintense on DWI and hypointense on ADC map (thick arrow), suggestive of restricted diffusion. This patient improved clinically with no neurological deficit. ADC, apparent diffusion coefficient; DWI, diffusion weighted image; FLAIR, fluid-attenuated inversion recovery sequence.Antiepileptics were started in all patients at the onset of seizures. Injection levetiracetam was started in most patients (66.6%, n=10), and rest received injection phenytoin. Patients were continued on antiepileptics for 6–12 months after last seizure episode. All patients were administered oral antihypertensive (amlodipine and labetalol), and three patients also required labetalol infusion for control of blood pressure. Most patients experienced normalization of blood pressure on an average of 8.6 days (range, 4–15 days), following which antihypertensive medication was tapered and stopped [14]. As a management of PRES, chemotherapeutic regimens were withheld while patients were investigated for diagnosis. In patients with ALL, chemotherapy was restarted once diagnosis of PRES was confirmed and patients were stable. In post-HSCT patients, cyclosporine was continued throughout. All patients recovered without any neurological sequela except one patient with thalassemia after matched sibling donor allogenic HSCT who had persistence of neurological deficit in the form of right-sided hemiparesis. Two patients died later: one case of acute leukemia because of probable fungal pneumonia and another aplastic anemia secondary to acute intracerebral hemorrhage (owing to thrombocytopenia).
DiscussionHematology-oncology patients are at increased risk of PRES because of a number of predisposing factors like cytotoxic chemotherapy, immunosuppressive drugs, and HSCT [5],[6]. Among the malignancies, PRES is most commonly associated with ALL, where corticosteroids form the backbone of induction chemotherapy [4]. Steroids cause hypertension, which may lead to development of encephalopathy in these patients [15],[16]. Other chemotherapeutic agents incriminated in PRES include methotrexate, L-asparaginase, anthracyclines, vincristine, and cyclophosphamide. These agents may contribute in causation of PRES by exacerbating hypertension owing to steroids or by causing renal dysfunction [17]. In a series of 19 patients from South Korea, almost half of the patients (47.4%) with PRES had ALL [18]. In a review on PRES in pediatric cancer, 31 (55%) of 56 patients had ALL [4]. In our study, three-fourths of the patients were ALL on Berlin-Frankfurt-Münster induction chemotherapy. Other malignant disorders, such as AML, lymphoma, and other solid tumors, can also be complicated by PRES [4],[19]. One proposed mechanism for PRES in malignancies can be disruption of blood–brain barrier caused by direct endothelial injury secondary to repetitive and prolonged chemotherapy (systemic and intrathecal), further leading to vasogenic edema [9],[20]. Immunosuppressive therapy (calcineurin inhibitors and steroids) in aplastic anemia and transplant patients has also been implicated as a cause of PRES in a number of studies similar to that seen in our patients. Proposed mechanisms are marked fluctuations in blood pressure, release of vasoactive substance endothelin, and hypomagnesemia secondary to renal wasting [12],[21],[22].
Hypertension is believed to be one of the key risk factors for PRES, and this may be a reason why some authors use acute hypertensive encephalopathy as its synonym [17]. In concordance with other authors, most patients in our series had hypertension and generalized tonic-clonic seizures at the onset of PRES, but conversely, headache as a presentation was seen in only a few patients [5],[11]. MRI has been the imaging modality of choice classically involving bilateral parietal and occipital regions, but atypical sites like frontal lobe, thalamus, and cerebellum may also be affected, as reported in this as well as some other studies [23]. Early imaging plays a key role in initiating prompt treatment, thus leading to speedy symptom recovery and prevention of long-term neurological sequelae. There is no standard treatment approach for management of PRES. Close blood pressure monitoring in settings of induction chemotherapy and immunosuppressive drugs like calcineurin inhibitors should always be advised [24],[25]. Studies have described that early initiation of symptom-directed therapy (antiepileptics, antihypertensive, and anti-edema medications) and withholding potential triggering agents is the key to successful management. Maximum patients have reversibility of symptoms within few days without any neurological sequela after PRES. There are no strict guidelines for class and duration of anti-epileptic therapy, but most authors continued anti-convulsant (levetiracetam, phenytoin or both) for 6 months and longer [19],[26].
None of our patients with ALL had recurrence of PRES on re-introduction of chemotherapy. All patients were strictly monitored for vital signs and metabolic abnormalities after therapy was restarted. Like other patients in various studies, none of the patients in our study had long-term clinical sequelae except one patient with thalassemia major after allogenic HSCT on steroid prophylaxis for graft vs host disease who had persistence of neurological deficit in the form of right-sided hemiparesis [5].
ConclusionHigh index of suspicion for PRES should be considered in patients with hematological disorders on chemotherapy, immunosuppressive therapy, or undergoing HSCT who develop sudden neurological symptoms, as early diagnosis and prompt institution of therapy may result in complete recovery of these patients. Symptomatic management with close monitoring of vitals should be done once the diagnosis of PRES is made. As most patients are on multiple drugs at time of diagnosis, so it is difficult to find the implicating agent. Therapy may be restarted once the patient is stabilized, as recurrence of symptoms is uncommon. Most patients have complete recovery, and only some may have residual deficit.
Author contributions: G.G.: conceptualization, literature search, data collection, drafting of the article, and final revision of the article. V.G., P.K., and A.A.: literature search, drafting of the article, and final revision of article. T.S., M.M., M.A., and P.N.: supervision, final drafting, and final revision of article.
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