Neuro-Oncology Practice Neuro-Oncology Practice 1(4), 184 – 190, 2014 doi:10.1093/nop/npu024 Advance Access date 14 September 2014
Primary brain tumors and posterior reversible encephalopathy syndrome Carlos Kamiya-Matsuoka†, David Cachia†, Adriana Olar, Terri S. Armstrong, and Mark R. Gilbert Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.K.-M., D.C., T.S.A., M.R.G.); Department of Family Health, The University of Texas Health Science Center School of Nursing, Houston, Texas (T.S.A.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.O.) Corresponding Author: Carlos Kamiya-Matsuoka, MD, 1400 Holcombe Blvd, Room FC7.3000, Unit 431, Houston, TX 77030 ([email protected]). †
These authors contributed equally to this manuscript.
Methods. We identified 4 cases with PBT who developed PRES at MD Anderson Cancer Center (MDACC) between 2012 and 2014. Clinical and radiological data were abstracted from their records. In addition, we also solicited 8 cases from the literature. Results. The median age at PRES onset was 19 years, male-to-female ratio was 1:1, and the syndrome occurred in patients with ependymoma (n ¼ 4), glioblastoma (n ¼ 3), diffuse intrinsic pontine glioma (DIPG; n ¼ 3), juvenile pilocytic astrocytoma (n ¼ 1), and atypical meningioma (n ¼ 1). Two glioblastomas and 2 DIPG cases received bevacizumab and vandetanib before the onset of symptoms, respectively. The most common clinical presentation was seizures (n ¼ 7). Three MDACC patients recovered completely in 3– 4 weeks after the onset of symptoms. One patient died due to active cancer and several comorbidities including PRES. Conclusions. Hypertension seems to be the most important coexisting risk factor for development of PRES; however, the potential effects of chemotherapeutic agents in the pathogenesis of PRES should also be examined. The clinicoradiological course of PRES in PBT patients did not vary from the classical descriptions of PRES found in other causes. PRES must be considered as part of the differential diagnosis in patients with PBTs presenting with seizures or acute encephalopathy. Keywords: bevacizumab, glioblastoma, glioma, posterior reversible encephalopathy syndrome, primary brain tumor.
Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic encephalopathic state associated with reversible cerebral vasogenic edema that was first described in 1996.1 The clinical presentation ranges from headaches to confusion or frank encephalopathy. Additionally, patients commonly have visual disturbances and seizures.2 Brain imaging usually demonstrates abnormalities, preferentially in the bilateral parietooccipital lobes, which might be related to lower concentrations of sympathetic innervation of the posterior intracranial arteries in comparison with other cerebral regions.3,4 There is still controversy about the pathophysiological trigger; however, the mechanism that produces vasogenic edema seems to be associated with loss of integrity of the blood-brain barrier. Recognized risk factors that are commonly found at the onset of PRES include hypertension, preeclampsia/eclampsia, autoimmune disease, renal disease, infections, and multiple drugs (Table 1). Moderate-to-severe hypertension is seen in 75% of patients with PRES.5 However, the potential causes of PRES in the oncology population are diverse
because these patients often receive multiple chemotherapy regimens, monoclonal antibody therapies, immunosuppressants, and stem cell transplantation.6 – 8 However, in contradistinction to other cancer patients, PRES is very uncommon in patients with primary brain tumors (PBTs). Only 3 adult and 5 pediatric cases have been reported in the literature9 – 14, which indicates the challenge of diagnosing PRES. The diagnosis of PRES is particularly challenging in the PBT patient population because PERS can mimic the clinical and radiological features of brain tumor progression as well as central nervous system infections. The aim of this study was to analyze the clinical manifestations and radiological features and to report the clinical outcomes of PRES in PBT patients.
Methods We conducted a retrospective data and tissue analysis of all adult and pediatric primary brain tumor cases in the MD
Received 4 June 2014, Advance Access publication 14 September 2014 # The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
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Background. Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic encephalopathic state associated with reversible cerebral vasogenic edema. It is an increasingly recognized occurrence in the oncology population. However, it is very uncommon in patients with primary brain tumors (PBTs). The aim of this study was to analyze the clinicoradiological features and report the clinical outcomes of PRES in PBT patients.
Kamiya-Matsuoka et al.: PRES and primary brain tumors
Table 1. Medical conditions and drugs associated with posterior reversible encephalopathy syndrome Hypertension Hypertensive encephalopathy Preeclampsia/eclampsia Renal Disease Acute or chronic renal disease Hemolytic uremic syndrome Hepatorenal syndrome Glomerulonephritis Nephrotic syndrome
Abbreviations: mTOR, mammalian target of rapamycin (Table reproduced with kind permission from,7 Springer Science + Business Media: Curr Oncol Rep, Posterior reversible encephalopathy syndrome: a neurologic phenomenon in cancer patients, volume 5, 2014, 383, Le EM, Loghin ME, Table 2).
Anderson Cancer Center institutional database from 2012 – 2014 under a protocol with waiver of consent having been approved by the institutional review board. All patients had undergone tumor biopsy or surgical resection with confirmed pathological diagnosis of a PBT and developed PRES during the course of disease. In addition, we also solicited cases from the literature. The diagnosis of PRES in all cases was confirmed by brain MRI using standard MRI sequences including axial T2 and FLAIR sequences, T1 axial pre- and postcontrast, T1 postcontrast in the coronal and sagittal planes, T2-gradient-echo axial, diffusionweighted imaging, and apparent diffusion coefficient (ADC) map. Pre- and postcontrast MRIs were performed on machines with either 1.5 tesla or 3 tesla units using a 22 mm field of view and 5 mm slice thickness with 1.5 mm gap. The radiological
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patterns were classified into typical and atypical according to the lesion distribution after Bartynski and Boardman.8 The typical pattern includes involvement of the occipital, parietal, frontal, and temporal lobes as well as the cerebellum. Atypical cases include distinct involvement of basal ganglia, thalamus, corpus callosum, and the periventricular white matter in addition to partial expression of the typical pattern with lack of involvement in the parietal or occipital lobes. We collected demographic, treatment, and survival data from the database. Resolution of PRES was defined as radiological resolution of vasogenic edema. Death was confirmed by review of medical records, death certificate, and/or the Social Security Death Index. Additional clinical, neuropathological, and neuroimaging data were obtained from institutional electronic medical records.
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Autoimmune disease Systemic lupus erythematosus Systemic scleroderma Wegener’s polyarteritis nodosa Rheumatoid arthritis Antiphospholipid syndrome Infection/sepsis/shock Systemic inflammatory syndrome Multiorgan dysfunction syndrome Vascular disorders Microangiopathy Vasculitis Takayasu’s arteritis Metabolic disorders Hypomagnesemia Hypercalcemia Hypocholesterolemia Aluminum overload Endocrine disorders Pheochromocytoma Primary aldosteronism Other conditions Guillain-Barre´ syndrome Following organ transplantation Tumor lysis syndrome Contrast media exposure Hepatic encephalopathy Posterior fossa surgery
Medications Chemotherapy Anthracyclines: Adriamycin Antimetabolites: Gemcitabinecytarabine Alkalating agent: Cyclophosphamide Folate antagonists: 5-fluorouracil, methotrexate Platinum analogues: Cisplatin, carboplatin, oxaliplatin Proteasome inhibitor: Bortezomib Vinca alkaloids: Vincristine, vinblastine, vinorelbine Multidrug regimens for acute lymphocytic leukemia (L-asparaginase, intrathecal methotrexate) Targeted therapy Monoclonal antibody: Bevacizumab, rituximab Tyrosine kinase inhibitors: Sorafenib, sunitinib, erlotinib, vandetanib mTOR kinase inhibitor: Temsirolimus Immunosuppressant drugs Cyclosporin A Tacrolimus Sirolimus Azathioprine Miscellaneous drugs Corticosteroids Interferon alfa Intravenous immunoglobulin Linezolid Midodrine Oxybutynin Growth factor support: Erythropoetin, granulocyte colony stimulating factor Over-the-counter stimulants Phenylpropanolamine Ephedrine Pseudoephedrine Caffeine
Kamiya-Matsuoka et al.: PRES and primary brain tumors
Results
Discussion PRES is being increasingly recognized in cancer patients.15 – 20 This recognition has led to an apparent increase in the incidence of PRES and earlier detection, although newer and more intensive treatments may also be contributing to the rise. PRES has been reported in patients who received platinum analogues (eg, cisplatin and carboplatin),17,19 – 21 antimetabolites (eg, gemcitabine),17,19,22 folate antagonists,23 – 25 anthracyclines,24 and the vinca alkaloids,16 growth factors,26,27 immunosuppresants,28,29 monocloncal antibodies,16,18,25,30 or small molecule inhibitors13,15,30,31 (Table 1). The ready availability of sophisticated brain imaging has also contributed to early diagnosis. The pathophysiology of PRES is still controversial, and there are 2 main hypotheses. One hypothesis involves impaired cerebral autoregulation responsible for an increase in cerebral blood flow (hyperperfusion), which may explain the changes that occur in hypertension. A second hypothesis involves endothelial dysfunction, which is thought to represent those cases with normal or minimally elevated blood pressure that do not fit within the
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We searched our medical record database and identified 72 cases of PRES in cancer patients. Only 4 cases were PBT patients out of a total population of 1980. We also identified 3 more adult and 5 pediatric cases with a literature review.9 – 14 The median age at diagnosis of PRES was 19 years (range 4 – 62y), and the male-to-female ratio was 1:1. PRES occurred in 4 patients with ependymoma, 3 patients with glioblastoma, 3 patients with diffuse intrinsic pontine glioma (DIPG), 1 patient with juvenile pilocytic astrocytoma, and 1 patient with atypical meningioma. Patient demographics and clinical characteristics are listed in Table 2. Five patients received cancer treatment within 2 months of onset of PRES. The 4 cases from literature review had received antiangiogenic agents, either bevacizumab or vandetanib, and only one received intensive chemotherapy consisting of cisplatin, etoposide, vincristine, and temozolomide before the onset of symptoms. Four cases developed PRES in the perioperative period for posterior fossa tumors; 2 of those cases occurred intraoperatively. Clinical presentation included seizures (n ¼ 7), altered mental status (n ¼ 6), headache (n ¼ 3), focal neurological deficits (n ¼ 3; aphasia, dysphagia, vocal cord dysfunction), and visual changes (n ¼ 2). PRES was associated with elevated blood pressure in all patients. Three patients had a history of hypertension, but only one of them had good blood-pressure control. The median systolic, diastolic, and median arterial pressures at onset were 167 mmHg, 100 mmHg, and 122 mmHg, respectively. Two patients developed PRES within the context of acute kidney injury (case 2 with serum creatinine ¼ 3.9 mg/dL and case 4 with serum creatinine ¼ 1.9 md/dL). Mean platelet count and serum magnesium level were 152 K/uL and 2.2 mg/dL, respectively. Five patients had typical parietooccipital imaging findings, while 5 other patients had atypical imaging findings (Fig. 1). One patient with a watershed distribution of PRES also developed infarctions in those areas with corresponding DWI restriction and ADC map changes that were confirmed by autopsy (Fig. 2). Three of our MDACC patients recovered completely in 3 to 4 weeks after the onset of symptoms. One patient died due to active cancer and several comorbidities including PRES (case 2).
paradigm of overwhelmed cerebral autoregulation. This eventually results in cerebral hypoperfusion and might be more relevant to cases of PRES associated with cytotoxic therapy and possibly uremia. The resultant pathway of both hypotheses is blood-brain barrier dysfunction and consequent cerebral vasogenic edema.32 There are only 8 cases in the literature reporting an association between PBTs and PRES. Two cases had glioblastoma and received bevacizumab,9,10 a monoclonal antibody that produces angiogenesis inhibition by blocking the vascular endothelial growth factor A (VEGF-A). Bevacizumab is known to cause hypertension as one of its most common adverse events, provoking cerebral vascular autoregulation breakthrough, but it can also cause endothelial dysfunction resultant in PRES. The association between bevacizumab and PRES has also been described in patients with cancer other than brain/spinal cord and includes gastrointestinal cancer, renal cell carcinoma, and breast cancer.9 Two other cases had DIPG and received vandetanib,13 an oral vascular endothelial growth factor receptor 2 and epidermal growth factor receptor inhibitor. Vandetanib also causes hypertension and may share the same pathophysiological pathway as bevacizumab in provoking PRES. Four cases had posterior fossa tumors consisting of ependymoma (3 cases) and juvenile pilocytic astrocytoma (1 case), with involvement of the fourth ventricle, medulla, brainstem, and cerebellum, respectively. Those 4 cases underwent excessive manipulation of the brainstem or cerebellum during surgery, leading to severe hypertension and development of PRES. None of the MDACC cases received bevacizumab as a tumor treatment, nor did they develop thrombocytopenia or hypomagnesemia as is commonly reported in PRES, but 3 of them were exposed to chronic steroid use. The identified etiologies in these cases were sudden onset of hypertension and acute kidney injury, both of which are well-described causes of PRES. PRES distribution did not correlate with the brain tumor location, or specific tumor histology. The recognition of PRES in patients with PBTs can be challenging because PRES can mimic various conditions such as tumor progression/recurrence, strokes, and infections that can lead to misdiagnosis and delay in treatment. Although the clinical presentation might be helpful in certain cases, diagnosis might still be difficult, especially in patients who present with focal neurological deficits and radiological findings atypical for PRES. A thorough workup in a timely manner, is necessary to assist with an early diagnosis in order to avoid complications.33 Bartynski and Boardman have described typical or atypical radiological patterns of PRES in 136 patients, and atypical distribution of vasogenic edema was the most common pattern seen in their study. In contrast, the most common pattern in our cases was typical. One patient had a watershed distribution of T2 hyperintensity changes, which unfortunately progressed to ischemia with corresponding diffusion-weighted imaging restriction and ADC map changes (Fig. 1C and D). Although PRES is typically reversible, permanent neurological deficits due to ischemic infarction occur in about 10% –23% of cases, and this is why prompt correction of the underlying factors leading to PRES should be instituted as soon as possible.8,34 Three of our patients had clinical and radiological resolution of PRES after 3– 4 weeks from onset, while the cases reported in the literature recovered after 8 – 12 weeks from onset.9,11,12,14 The occurrence of PRS in children with cancer has also been increasing. Morris et al reported 11 pediatric cases with cancer
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Table 2. Demographics, clinical presentation, radiological features, and treatments of primary brain tumors and posterior reversible encephalopathy syndrome cases reported Authors
Sex/Age (years)
Type of Cancer
Location of Tumor PRES Onset Clinical after Cancer Presentation Diagnosis of PRES or Recurrence
History of HTN
BP at Onset (mmHg)
PRES Pattern
Sz, aphasia, paresthesia HA, Sz
Uncontrolled 201/117
Atypical
NR
160/100
Atypical
Treatment Concomitant Drugs
Tumor
Lisinopril, nifedipine, clonidine NR
Bev and TMZ
PRES
Lou et al (9) F/46
Glioblastoma
Armstrong F/47 et al (10) Moriarity M/19 et al (11)
Glioblastoma
Left temporal lobe 6 months and insula Corpus callosum 18 months
Ependymoma
Fourth ventricle
Same day
AMS, HA, Sz, visual loss
No
200/130
Typical stroke
NR
Patel et al M/6 (12) Broniscer et al (13) Case 1 NR/2– 20 Case 2 NR/2– 20 Gephart et al (14) Case 1 M/4
JPA
Cerebellum
Same day
AMS, Sz, dysphagia
No
220/NR
Atypical stroke
NR
DIPG DIPG
Pons Pons
NR NR
NR NR
No No
HTN HTN
NR NR
Dexamethasone Dexamethasone
Vandetanib Vandetanib
Hold Vandetanib Hold Vandetanib
8 days 3 days
NR NR
Recurrent Medulla anaplastic ependymoma
1 week
AMS, Sz
No
HTN
Typical
NR
Levetiracetam, antihypertensives
1 week
Yes, 12 weeks
Recurrent Brainstem diffuse ependymoma
NR
Sz, visual changes
No
HTN
Atypical
NR
Surgery Previously Bev and lapatinib Surgery Previously etoposide and celecoxib
Levetiracetam, antihypertensives
5 days
NR
Start on levetiracetam, enalaprilat, amlodipine Hold chemo
4 months
Yes, 4 weeks
5 days
No, died 1 week after PRES onset
Case 2
M/7
Glioblastoma
Right 11 months temporoparietal lobe
AMS, HA
Uncontrolled 153/95
Typical
Dexamethasone 8 mg /day
Pons
No
142/97
Atypical stroke
Dexamethasone 16 mg/day
No
148/90
Typical
Dexamethasone 1 mg/day
Controlled
173/100
Typical
Lisinopril, hydrochlorothiazide
Case 2
F/5
DIPG
Case 3
M/18
Recurrent Left frontal lobe anaplastic ependymoma
6 months
Respiratory failure, vocal cord dysfunction AMS
Case 4
F/61
Atypical meningioma
37 months
AMS, Sz
Bilateral frontoparietal region
11 months
Bev and lomustine Previously TMZ Cisplatin, etoposide, vincristine and TMZ Surgery Previously 5-FU and oxaliplatin Surgery
3 weeks
Yes, 12 weeks
3 weeks
NR
Intraoperative Yes, 8 weeks
Intraoperative Yes, 12 weeks
Start on enalapril, 4 months clonidine, labetalol
Yes, 3 weeks
Nicardipine drip, levetiracetam, valproate
Yes, 3 weeks
37 months
Abbreviations: AED,antiepileptic drug; AMS, altered mental status; Bev, bevacizumab; BP, blood pressure; chemo, chemotherapy; DIPG, diffuse intrinsic pontine gliomas; F, female; FOLFOX, folinic acid, fluorouracil, oxaliplatin; FU,¼ fluorouracil; HA, headaches; HTN, hypertension; JPA, juvenile pilocytic astrocytoma; M, male; NR, non-reported; PRES, posterior reversible encephalopathy syndrome; Sx, surgery; Sz, seizures; TMZ, temozolomide.
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Present study Case 1 F/62
Hold Bev and TMZ temporarily Bev Hold Bev permanently Posterior fossa Phenylephrine, surgery esmolol, labetalol, AED Posterior fossa Nicardipine drip, AED surgery
Resolution of Interval PRES and between Chemo/Sx and Timing PRES Onset
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Kamiya-Matsuoka et al.: PRES and primary brain tumors
other than brain/spinal cord; the most frequent risk factors for developing PRES were intensive systemic chemotherapy and elevated blood pressure (apparently secondary to chronic steroid use or renal failure). All of the patients survived, but 6 of them had presented with recurrent seizures.35 Case 2 in our study received intense chemotherapy and presented with elevated blood pressure as well as acute kidney injury. Unfortunately, the patient died after 1 week from active cancer and multiple comorbidities including PRES. Siebert et al reported radiological patterns of PRES in a series of 18 pediatric cases, most of them with autoimmune diseases and cancer but no PBTs. The holohemispheric watershed pattern was frequently seen (22%) and was associated with residual laminar necrosis in 23% of cases.36 Interestingly, the same pattern was confirmed at autopsy in case 2. In the majority of children with cancer, PRES seems to leave radiological or clinical sequelae that may indicate a more aggressive clinical course than that seen in adults.35 The current study describes a series of cases in which a diagnosis of PRES was made despite complicating issues associated with the concurrent existence of a primary brain tumor. These cases demonstrate that PRES remains a potential cause for neurological decline and is particularly relevant because it often reverses if recognized and treated appropriately. The relatively small number of patients, the retrospective nature of the data collection, and the patient accrual from a tertiary care center limit formal conclusions regarding the cause(s) of PRES from
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this series. Furthermore, the potential effects of chemotherapeutic agents predisposing PRES cannot be excluded nor accurately determined. Despite these limitations, this study underscores the importance of having a high index of suspicion to enable early diagnosis and subsequent discontinuation of potential causes. Although no conclusions can be made, we suspect that the cause of PRES in these cases was either acute kidney injury or hypertension rather than the underlying tumor. This theory is further reinforced by the fact that the clinical and radiological course of PRES in brain tumor patients did not vary from the classical descriptions of PRES found in other causes. The presence of new, bilateral, and somewhat symmetrical edema, without correlation with the tumor/surgical cavity location, is the radiological hallmark and key for diagnosing PRES in the context of brain tumors and differentiating it from brain-tumor progression or worsening peritumoral edema. Resolution of PRES was an independent process even after evidence of tumor progression. Moreover, Lou et al suggested that bevacizumab may be reinitiated gradually using reduced dosing9 after controlling risk factors such as hypertension and acute kidney injury, although we do not have information to either support or refute this claim. In cases associated with hypertension, we would suggest that the blood pressure be lowered gradually because a rapid reduction in blood pressure can cause or increase the size of the involved ischemic area.37
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Fig. 1. Brain MRI findings in MDACC cases. Case 1: Axial T2/FLAIR sequence shows extensive and symmetrical confluent hyperintensity involving both parietooccipital lobes at PRES onset (A) and resolution of vasogenic edema after 4 weeks. The surgical cavity is unchanged (B). Case 2: DWI restriction (C) correlates with extensive areas of cortical and subcortical T2/FLAIR hyperintensities (D). The distribution corresponds to watershed areas between each major vascular territory (C and D). Case 3: Bilateral T2/FLAIR hyperintensity predominantly affecting the parietooccipital lobes as well as the temporal lobes (E) and resolution of vasogenic edema after 3 weeks (F). Case 4: T2/FLAIR hyperintensity within bilateral parietooccipital lobes (G) and resolution of vasogenic edema after 3 weeks (H).
Kamiya-Matsuoka et al.: PRES and primary brain tumors
Conflict of Interest Statement: C. Kamiya-Matsuoka and D. Cachia report no disclosure. T.S. Armstrong serves as a consultant for Tocagen and Immunocyte and receives research support from Merck and Genentech. M.R. Gilbert reports personal fees and nonfinancial support from Genentech; personal fees from Merck, EMD Serono, Abbott, Bristol-Meyers Squibb, Novartis, Hoffman-La Roche; and nonfinancial support from GlaxoSmithKline outside the submitted work.
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Funding This study did not involve use of any grant funds. A. Olar was supported by the National Institutes of Health/National Cancer Institute (Training Grant No. 5T32CA163185).
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Fig. 2. Case 2: Postmortem histopathological findings. Diffuse infiltrative pontine glioma (A). The tumor is moderately hypercellular, composed of pleomorphic atypical astrocytes in a myxoid background (H&E stain, x100; scale bar, 200 mm). Very rare mitotic figures are observed (H&E stain, x400; scale bar, 50 mm; inset) (A). Acute hypoxic-ischemic encephalopathy (B – D). Diffuse neuropil vacuolation (edema), more pronounced in the cortex (H&E stain, x40; scale bar, 500 mm) (B) accompanied by various degrees of acute neuronal damage (H&E stain, x400; scale bar, 50 mm; inset) (B). These changes are accentuated in the frontal, parietal, and occipital lobes bilaterally, where multiple small foci of reactive vascular proliferation and microhemorrhages are identified (H&E stain, x40; scale bar, 500 mm) (C). An inflammatory component is inconspicuous (H&E stain, x100; scale bar. 200 mm) (D); 2 hypereosinophilic, pyknotic neurons (arrows) in comparison with an unaffected neuron situated above (H&E stain, x400; scale bar, 50 mm; inset) (D).
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Primary brain tumors and posterior reversible encephalopathy syndrome Carlos Kamiya-Matsuoka†, David Cachia†, Adriana Olar, Terri S. Armstrong, and Mark R. Gilbert Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (C.K.-M., D.C., T.S.A., M.R.G.); Department of Family Health, The University of Texas Health Science Center School of Nursing, Houston, Texas (T.S.A.); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.O.) Corresponding Author: Carlos Kamiya-Matsuoka, MD, 1400 Holcombe Blvd, Room FC7.3000, Unit 431, Houston, TX 77030 ([email protected]). †
These authors contributed equally to this manuscript.
Methods. We identified 4 cases with PBT who developed PRES at MD Anderson Cancer Center (MDACC) between 2012 and 2014. Clinical and radiological data were abstracted from their records. In addition, we also solicited 8 cases from the literature. Results. The median age at PRES onset was 19 years, male-to-female ratio was 1:1, and the syndrome occurred in patients with ependymoma (n ¼ 4), glioblastoma (n ¼ 3), diffuse intrinsic pontine glioma (DIPG; n ¼ 3), juvenile pilocytic astrocytoma (n ¼ 1), and atypical meningioma (n ¼ 1). Two glioblastomas and 2 DIPG cases received bevacizumab and vandetanib before the onset of symptoms, respectively. The most common clinical presentation was seizures (n ¼ 7). Three MDACC patients recovered completely in 3– 4 weeks after the onset of symptoms. One patient died due to active cancer and several comorbidities including PRES. Conclusions. Hypertension seems to be the most important coexisting risk factor for development of PRES; however, the potential effects of chemotherapeutic agents in the pathogenesis of PRES should also be examined. The clinicoradiological course of PRES in PBT patients did not vary from the classical descriptions of PRES found in other causes. PRES must be considered as part of the differential diagnosis in patients with PBTs presenting with seizures or acute encephalopathy. Keywords: bevacizumab, glioblastoma, glioma, posterior reversible encephalopathy syndrome, primary brain tumor.
Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic encephalopathic state associated with reversible cerebral vasogenic edema that was first described in 1996.1 The clinical presentation ranges from headaches to confusion or frank encephalopathy. Additionally, patients commonly have visual disturbances and seizures.2 Brain imaging usually demonstrates abnormalities, preferentially in the bilateral parietooccipital lobes, which might be related to lower concentrations of sympathetic innervation of the posterior intracranial arteries in comparison with other cerebral regions.3,4 There is still controversy about the pathophysiological trigger; however, the mechanism that produces vasogenic edema seems to be associated with loss of integrity of the blood-brain barrier. Recognized risk factors that are commonly found at the onset of PRES include hypertension, preeclampsia/eclampsia, autoimmune disease, renal disease, infections, and multiple drugs (Table 1). Moderate-to-severe hypertension is seen in 75% of patients with PRES.5 However, the potential causes of PRES in the oncology population are diverse
because these patients often receive multiple chemotherapy regimens, monoclonal antibody therapies, immunosuppressants, and stem cell transplantation.6 – 8 However, in contradistinction to other cancer patients, PRES is very uncommon in patients with primary brain tumors (PBTs). Only 3 adult and 5 pediatric cases have been reported in the literature9 – 14, which indicates the challenge of diagnosing PRES. The diagnosis of PRES is particularly challenging in the PBT patient population because PERS can mimic the clinical and radiological features of brain tumor progression as well as central nervous system infections. The aim of this study was to analyze the clinical manifestations and radiological features and to report the clinical outcomes of PRES in PBT patients.
Methods We conducted a retrospective data and tissue analysis of all adult and pediatric primary brain tumor cases in the MD
Received 4 June 2014, Advance Access publication 14 September 2014 # The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
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Background. Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic encephalopathic state associated with reversible cerebral vasogenic edema. It is an increasingly recognized occurrence in the oncology population. However, it is very uncommon in patients with primary brain tumors (PBTs). The aim of this study was to analyze the clinicoradiological features and report the clinical outcomes of PRES in PBT patients.
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Table 1. Medical conditions and drugs associated with posterior reversible encephalopathy syndrome Hypertension Hypertensive encephalopathy Preeclampsia/eclampsia Renal Disease Acute or chronic renal disease Hemolytic uremic syndrome Hepatorenal syndrome Glomerulonephritis Nephrotic syndrome
Abbreviations: mTOR, mammalian target of rapamycin (Table reproduced with kind permission from,7 Springer Science + Business Media: Curr Oncol Rep, Posterior reversible encephalopathy syndrome: a neurologic phenomenon in cancer patients, volume 5, 2014, 383, Le EM, Loghin ME, Table 2).
Anderson Cancer Center institutional database from 2012 – 2014 under a protocol with waiver of consent having been approved by the institutional review board. All patients had undergone tumor biopsy or surgical resection with confirmed pathological diagnosis of a PBT and developed PRES during the course of disease. In addition, we also solicited cases from the literature. The diagnosis of PRES in all cases was confirmed by brain MRI using standard MRI sequences including axial T2 and FLAIR sequences, T1 axial pre- and postcontrast, T1 postcontrast in the coronal and sagittal planes, T2-gradient-echo axial, diffusionweighted imaging, and apparent diffusion coefficient (ADC) map. Pre- and postcontrast MRIs were performed on machines with either 1.5 tesla or 3 tesla units using a 22 mm field of view and 5 mm slice thickness with 1.5 mm gap. The radiological
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patterns were classified into typical and atypical according to the lesion distribution after Bartynski and Boardman.8 The typical pattern includes involvement of the occipital, parietal, frontal, and temporal lobes as well as the cerebellum. Atypical cases include distinct involvement of basal ganglia, thalamus, corpus callosum, and the periventricular white matter in addition to partial expression of the typical pattern with lack of involvement in the parietal or occipital lobes. We collected demographic, treatment, and survival data from the database. Resolution of PRES was defined as radiological resolution of vasogenic edema. Death was confirmed by review of medical records, death certificate, and/or the Social Security Death Index. Additional clinical, neuropathological, and neuroimaging data were obtained from institutional electronic medical records.
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Autoimmune disease Systemic lupus erythematosus Systemic scleroderma Wegener’s polyarteritis nodosa Rheumatoid arthritis Antiphospholipid syndrome Infection/sepsis/shock Systemic inflammatory syndrome Multiorgan dysfunction syndrome Vascular disorders Microangiopathy Vasculitis Takayasu’s arteritis Metabolic disorders Hypomagnesemia Hypercalcemia Hypocholesterolemia Aluminum overload Endocrine disorders Pheochromocytoma Primary aldosteronism Other conditions Guillain-Barre´ syndrome Following organ transplantation Tumor lysis syndrome Contrast media exposure Hepatic encephalopathy Posterior fossa surgery
Medications Chemotherapy Anthracyclines: Adriamycin Antimetabolites: Gemcitabinecytarabine Alkalating agent: Cyclophosphamide Folate antagonists: 5-fluorouracil, methotrexate Platinum analogues: Cisplatin, carboplatin, oxaliplatin Proteasome inhibitor: Bortezomib Vinca alkaloids: Vincristine, vinblastine, vinorelbine Multidrug regimens for acute lymphocytic leukemia (L-asparaginase, intrathecal methotrexate) Targeted therapy Monoclonal antibody: Bevacizumab, rituximab Tyrosine kinase inhibitors: Sorafenib, sunitinib, erlotinib, vandetanib mTOR kinase inhibitor: Temsirolimus Immunosuppressant drugs Cyclosporin A Tacrolimus Sirolimus Azathioprine Miscellaneous drugs Corticosteroids Interferon alfa Intravenous immunoglobulin Linezolid Midodrine Oxybutynin Growth factor support: Erythropoetin, granulocyte colony stimulating factor Over-the-counter stimulants Phenylpropanolamine Ephedrine Pseudoephedrine Caffeine
Kamiya-Matsuoka et al.: PRES and primary brain tumors
Results
Discussion PRES is being increasingly recognized in cancer patients.15 – 20 This recognition has led to an apparent increase in the incidence of PRES and earlier detection, although newer and more intensive treatments may also be contributing to the rise. PRES has been reported in patients who received platinum analogues (eg, cisplatin and carboplatin),17,19 – 21 antimetabolites (eg, gemcitabine),17,19,22 folate antagonists,23 – 25 anthracyclines,24 and the vinca alkaloids,16 growth factors,26,27 immunosuppresants,28,29 monocloncal antibodies,16,18,25,30 or small molecule inhibitors13,15,30,31 (Table 1). The ready availability of sophisticated brain imaging has also contributed to early diagnosis. The pathophysiology of PRES is still controversial, and there are 2 main hypotheses. One hypothesis involves impaired cerebral autoregulation responsible for an increase in cerebral blood flow (hyperperfusion), which may explain the changes that occur in hypertension. A second hypothesis involves endothelial dysfunction, which is thought to represent those cases with normal or minimally elevated blood pressure that do not fit within the
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We searched our medical record database and identified 72 cases of PRES in cancer patients. Only 4 cases were PBT patients out of a total population of 1980. We also identified 3 more adult and 5 pediatric cases with a literature review.9 – 14 The median age at diagnosis of PRES was 19 years (range 4 – 62y), and the male-to-female ratio was 1:1. PRES occurred in 4 patients with ependymoma, 3 patients with glioblastoma, 3 patients with diffuse intrinsic pontine glioma (DIPG), 1 patient with juvenile pilocytic astrocytoma, and 1 patient with atypical meningioma. Patient demographics and clinical characteristics are listed in Table 2. Five patients received cancer treatment within 2 months of onset of PRES. The 4 cases from literature review had received antiangiogenic agents, either bevacizumab or vandetanib, and only one received intensive chemotherapy consisting of cisplatin, etoposide, vincristine, and temozolomide before the onset of symptoms. Four cases developed PRES in the perioperative period for posterior fossa tumors; 2 of those cases occurred intraoperatively. Clinical presentation included seizures (n ¼ 7), altered mental status (n ¼ 6), headache (n ¼ 3), focal neurological deficits (n ¼ 3; aphasia, dysphagia, vocal cord dysfunction), and visual changes (n ¼ 2). PRES was associated with elevated blood pressure in all patients. Three patients had a history of hypertension, but only one of them had good blood-pressure control. The median systolic, diastolic, and median arterial pressures at onset were 167 mmHg, 100 mmHg, and 122 mmHg, respectively. Two patients developed PRES within the context of acute kidney injury (case 2 with serum creatinine ¼ 3.9 mg/dL and case 4 with serum creatinine ¼ 1.9 md/dL). Mean platelet count and serum magnesium level were 152 K/uL and 2.2 mg/dL, respectively. Five patients had typical parietooccipital imaging findings, while 5 other patients had atypical imaging findings (Fig. 1). One patient with a watershed distribution of PRES also developed infarctions in those areas with corresponding DWI restriction and ADC map changes that were confirmed by autopsy (Fig. 2). Three of our MDACC patients recovered completely in 3 to 4 weeks after the onset of symptoms. One patient died due to active cancer and several comorbidities including PRES (case 2).
paradigm of overwhelmed cerebral autoregulation. This eventually results in cerebral hypoperfusion and might be more relevant to cases of PRES associated with cytotoxic therapy and possibly uremia. The resultant pathway of both hypotheses is blood-brain barrier dysfunction and consequent cerebral vasogenic edema.32 There are only 8 cases in the literature reporting an association between PBTs and PRES. Two cases had glioblastoma and received bevacizumab,9,10 a monoclonal antibody that produces angiogenesis inhibition by blocking the vascular endothelial growth factor A (VEGF-A). Bevacizumab is known to cause hypertension as one of its most common adverse events, provoking cerebral vascular autoregulation breakthrough, but it can also cause endothelial dysfunction resultant in PRES. The association between bevacizumab and PRES has also been described in patients with cancer other than brain/spinal cord and includes gastrointestinal cancer, renal cell carcinoma, and breast cancer.9 Two other cases had DIPG and received vandetanib,13 an oral vascular endothelial growth factor receptor 2 and epidermal growth factor receptor inhibitor. Vandetanib also causes hypertension and may share the same pathophysiological pathway as bevacizumab in provoking PRES. Four cases had posterior fossa tumors consisting of ependymoma (3 cases) and juvenile pilocytic astrocytoma (1 case), with involvement of the fourth ventricle, medulla, brainstem, and cerebellum, respectively. Those 4 cases underwent excessive manipulation of the brainstem or cerebellum during surgery, leading to severe hypertension and development of PRES. None of the MDACC cases received bevacizumab as a tumor treatment, nor did they develop thrombocytopenia or hypomagnesemia as is commonly reported in PRES, but 3 of them were exposed to chronic steroid use. The identified etiologies in these cases were sudden onset of hypertension and acute kidney injury, both of which are well-described causes of PRES. PRES distribution did not correlate with the brain tumor location, or specific tumor histology. The recognition of PRES in patients with PBTs can be challenging because PRES can mimic various conditions such as tumor progression/recurrence, strokes, and infections that can lead to misdiagnosis and delay in treatment. Although the clinical presentation might be helpful in certain cases, diagnosis might still be difficult, especially in patients who present with focal neurological deficits and radiological findings atypical for PRES. A thorough workup in a timely manner, is necessary to assist with an early diagnosis in order to avoid complications.33 Bartynski and Boardman have described typical or atypical radiological patterns of PRES in 136 patients, and atypical distribution of vasogenic edema was the most common pattern seen in their study. In contrast, the most common pattern in our cases was typical. One patient had a watershed distribution of T2 hyperintensity changes, which unfortunately progressed to ischemia with corresponding diffusion-weighted imaging restriction and ADC map changes (Fig. 1C and D). Although PRES is typically reversible, permanent neurological deficits due to ischemic infarction occur in about 10% –23% of cases, and this is why prompt correction of the underlying factors leading to PRES should be instituted as soon as possible.8,34 Three of our patients had clinical and radiological resolution of PRES after 3– 4 weeks from onset, while the cases reported in the literature recovered after 8 – 12 weeks from onset.9,11,12,14 The occurrence of PRS in children with cancer has also been increasing. Morris et al reported 11 pediatric cases with cancer
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Table 2. Demographics, clinical presentation, radiological features, and treatments of primary brain tumors and posterior reversible encephalopathy syndrome cases reported Authors
Sex/Age (years)
Type of Cancer
Location of Tumor PRES Onset Clinical after Cancer Presentation Diagnosis of PRES or Recurrence
History of HTN
BP at Onset (mmHg)
PRES Pattern
Sz, aphasia, paresthesia HA, Sz
Uncontrolled 201/117
Atypical
NR
160/100
Atypical
Treatment Concomitant Drugs
Tumor
Lisinopril, nifedipine, clonidine NR
Bev and TMZ
PRES
Lou et al (9) F/46
Glioblastoma
Armstrong F/47 et al (10) Moriarity M/19 et al (11)
Glioblastoma
Left temporal lobe 6 months and insula Corpus callosum 18 months
Ependymoma
Fourth ventricle
Same day
AMS, HA, Sz, visual loss
No
200/130
Typical stroke
NR
Patel et al M/6 (12) Broniscer et al (13) Case 1 NR/2– 20 Case 2 NR/2– 20 Gephart et al (14) Case 1 M/4
JPA
Cerebellum
Same day
AMS, Sz, dysphagia
No
220/NR
Atypical stroke
NR
DIPG DIPG
Pons Pons
NR NR
NR NR
No No
HTN HTN
NR NR
Dexamethasone Dexamethasone
Vandetanib Vandetanib
Hold Vandetanib Hold Vandetanib
8 days 3 days
NR NR
Recurrent Medulla anaplastic ependymoma
1 week
AMS, Sz
No
HTN
Typical
NR
Levetiracetam, antihypertensives
1 week
Yes, 12 weeks
Recurrent Brainstem diffuse ependymoma
NR
Sz, visual changes
No
HTN
Atypical
NR
Surgery Previously Bev and lapatinib Surgery Previously etoposide and celecoxib
Levetiracetam, antihypertensives
5 days
NR
Start on levetiracetam, enalaprilat, amlodipine Hold chemo
4 months
Yes, 4 weeks
5 days
No, died 1 week after PRES onset
Case 2
M/7
Glioblastoma
Right 11 months temporoparietal lobe
AMS, HA
Uncontrolled 153/95
Typical
Dexamethasone 8 mg /day
Pons
No
142/97
Atypical stroke
Dexamethasone 16 mg/day
No
148/90
Typical
Dexamethasone 1 mg/day
Controlled
173/100
Typical
Lisinopril, hydrochlorothiazide
Case 2
F/5
DIPG
Case 3
M/18
Recurrent Left frontal lobe anaplastic ependymoma
6 months
Respiratory failure, vocal cord dysfunction AMS
Case 4
F/61
Atypical meningioma
37 months
AMS, Sz
Bilateral frontoparietal region
11 months
Bev and lomustine Previously TMZ Cisplatin, etoposide, vincristine and TMZ Surgery Previously 5-FU and oxaliplatin Surgery
3 weeks
Yes, 12 weeks
3 weeks
NR
Intraoperative Yes, 8 weeks
Intraoperative Yes, 12 weeks
Start on enalapril, 4 months clonidine, labetalol
Yes, 3 weeks
Nicardipine drip, levetiracetam, valproate
Yes, 3 weeks
37 months
Abbreviations: AED,antiepileptic drug; AMS, altered mental status; Bev, bevacizumab; BP, blood pressure; chemo, chemotherapy; DIPG, diffuse intrinsic pontine gliomas; F, female; FOLFOX, folinic acid, fluorouracil, oxaliplatin; FU,¼ fluorouracil; HA, headaches; HTN, hypertension; JPA, juvenile pilocytic astrocytoma; M, male; NR, non-reported; PRES, posterior reversible encephalopathy syndrome; Sx, surgery; Sz, seizures; TMZ, temozolomide.
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Present study Case 1 F/62
Hold Bev and TMZ temporarily Bev Hold Bev permanently Posterior fossa Phenylephrine, surgery esmolol, labetalol, AED Posterior fossa Nicardipine drip, AED surgery
Resolution of Interval PRES and between Chemo/Sx and Timing PRES Onset
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Kamiya-Matsuoka et al.: PRES and primary brain tumors
other than brain/spinal cord; the most frequent risk factors for developing PRES were intensive systemic chemotherapy and elevated blood pressure (apparently secondary to chronic steroid use or renal failure). All of the patients survived, but 6 of them had presented with recurrent seizures.35 Case 2 in our study received intense chemotherapy and presented with elevated blood pressure as well as acute kidney injury. Unfortunately, the patient died after 1 week from active cancer and multiple comorbidities including PRES. Siebert et al reported radiological patterns of PRES in a series of 18 pediatric cases, most of them with autoimmune diseases and cancer but no PBTs. The holohemispheric watershed pattern was frequently seen (22%) and was associated with residual laminar necrosis in 23% of cases.36 Interestingly, the same pattern was confirmed at autopsy in case 2. In the majority of children with cancer, PRES seems to leave radiological or clinical sequelae that may indicate a more aggressive clinical course than that seen in adults.35 The current study describes a series of cases in which a diagnosis of PRES was made despite complicating issues associated with the concurrent existence of a primary brain tumor. These cases demonstrate that PRES remains a potential cause for neurological decline and is particularly relevant because it often reverses if recognized and treated appropriately. The relatively small number of patients, the retrospective nature of the data collection, and the patient accrual from a tertiary care center limit formal conclusions regarding the cause(s) of PRES from
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this series. Furthermore, the potential effects of chemotherapeutic agents predisposing PRES cannot be excluded nor accurately determined. Despite these limitations, this study underscores the importance of having a high index of suspicion to enable early diagnosis and subsequent discontinuation of potential causes. Although no conclusions can be made, we suspect that the cause of PRES in these cases was either acute kidney injury or hypertension rather than the underlying tumor. This theory is further reinforced by the fact that the clinical and radiological course of PRES in brain tumor patients did not vary from the classical descriptions of PRES found in other causes. The presence of new, bilateral, and somewhat symmetrical edema, without correlation with the tumor/surgical cavity location, is the radiological hallmark and key for diagnosing PRES in the context of brain tumors and differentiating it from brain-tumor progression or worsening peritumoral edema. Resolution of PRES was an independent process even after evidence of tumor progression. Moreover, Lou et al suggested that bevacizumab may be reinitiated gradually using reduced dosing9 after controlling risk factors such as hypertension and acute kidney injury, although we do not have information to either support or refute this claim. In cases associated with hypertension, we would suggest that the blood pressure be lowered gradually because a rapid reduction in blood pressure can cause or increase the size of the involved ischemic area.37
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Fig. 1. Brain MRI findings in MDACC cases. Case 1: Axial T2/FLAIR sequence shows extensive and symmetrical confluent hyperintensity involving both parietooccipital lobes at PRES onset (A) and resolution of vasogenic edema after 4 weeks. The surgical cavity is unchanged (B). Case 2: DWI restriction (C) correlates with extensive areas of cortical and subcortical T2/FLAIR hyperintensities (D). The distribution corresponds to watershed areas between each major vascular territory (C and D). Case 3: Bilateral T2/FLAIR hyperintensity predominantly affecting the parietooccipital lobes as well as the temporal lobes (E) and resolution of vasogenic edema after 3 weeks (F). Case 4: T2/FLAIR hyperintensity within bilateral parietooccipital lobes (G) and resolution of vasogenic edema after 3 weeks (H).
Kamiya-Matsuoka et al.: PRES and primary brain tumors
Conflict of Interest Statement: C. Kamiya-Matsuoka and D. Cachia report no disclosure. T.S. Armstrong serves as a consultant for Tocagen and Immunocyte and receives research support from Merck and Genentech. M.R. Gilbert reports personal fees and nonfinancial support from Genentech; personal fees from Merck, EMD Serono, Abbott, Bristol-Meyers Squibb, Novartis, Hoffman-La Roche; and nonfinancial support from GlaxoSmithKline outside the submitted work.
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Funding This study did not involve use of any grant funds. A. Olar was supported by the National Institutes of Health/National Cancer Institute (Training Grant No. 5T32CA163185).
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Fig. 2. Case 2: Postmortem histopathological findings. Diffuse infiltrative pontine glioma (A). The tumor is moderately hypercellular, composed of pleomorphic atypical astrocytes in a myxoid background (H&E stain, x100; scale bar, 200 mm). Very rare mitotic figures are observed (H&E stain, x400; scale bar, 50 mm; inset) (A). Acute hypoxic-ischemic encephalopathy (B – D). Diffuse neuropil vacuolation (edema), more pronounced in the cortex (H&E stain, x40; scale bar, 500 mm) (B) accompanied by various degrees of acute neuronal damage (H&E stain, x400; scale bar, 50 mm; inset) (B). These changes are accentuated in the frontal, parietal, and occipital lobes bilaterally, where multiple small foci of reactive vascular proliferation and microhemorrhages are identified (H&E stain, x40; scale bar, 500 mm) (C). An inflammatory component is inconspicuous (H&E stain, x100; scale bar. 200 mm) (D); 2 hypereosinophilic, pyknotic neurons (arrows) in comparison with an unaffected neuron situated above (H&E stain, x400; scale bar, 50 mm; inset) (D).
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