Journal of Clinical Neuroscience xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients Ryan T. Fitzgerald ⇑, Steven M. Wright, Rohan S. Samant, Manoj Kumar, Raghu H. Ramakrishnaiah, Rudy Van Hemert, Aliza T. Brown, Edgardo J. Angtuaco Department of Radiology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, #556, Little Rock, AR 72205-7199, USA
a r t i c l e
i n f o
Article history: Received 27 January 2014 Accepted 2 March 2014 Available online xxxx Keywords: Chemotherapy Hypertensive encephalopathy LDH Posterior reversible encephalopathy syndrome PRES
a b s t r a c t The pathophysiology of posterior reversible encephalopathy syndrome (PRES) is incompletely understood; however, an underlying state of immune dysregulation and endothelial dysfunction has been proposed. We examined alterations of serum lactate dehydrogenase (LDH), a marker of endothelial dysfunction, relative to the development of PRES in patients receiving chemotherapy. A retrospective Institutional Review Board approved database of 88 PRES patients was examined. PRES diagnosis was confirmed by congruent clinical diagnosis and MRI. Clinical features at presentation were recorded. Serum LDH values were collected at three time points: prior to, at the time of, and following PRES diagnosis. Student’s t-test was employed. LDH values were available during the course of treatment in 12 patients (nine women; mean age 57.8 years [range 33–75 years]). Chemotherapy-associated PRES patients were more likely to be normotensive (25%) versus the non-chemotherapy group (9%). LDH levels at the time of PRES diagnosis were higher than those before and after (p = 0.0263), with a mean difference of 114.8 international units/L. Mean time intervals between LDH measurement prior to and following PRES diagnosis were 44.8 days and 51.4 days, respectively. Mean elapsed time between last chemotherapy administration and PRES onset was 11.1 days. In conclusion, serum LDH, a marker of endothelial dysfunction, shows statistically significant elevation at the onset of PRES toxicity in cancer patients receiving chemotherapy. Our findings support a systemic process characterized by endothelial injury/dysfunction as a factor, if not the prime event, in the pathophysiology of PRES. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic process that occurs in the setting of systemic infection, transplantation, pregnancy, autoimmune disease, and malignancy, processes that involve activation of the immune system, with or without concurrent hypertension. Examination of the milieu in which PRES typically occurs, coupled with the significant minority of cases that occur in the absence of hypertension, has challenged the traditional notion of PRES as a direct result of hypertension exceeding auto-regulatory control. Instead, PRES is now thought to occur as a result of systemic endothelial dysfunction leading to altered vasoregulatory control, blood pressure lability, and cerebral hypoperfusion [1]. Various pharmaceuticals have been implicated as factors in the development of PRES including immune suppressant agents, such ⇑ Corresponding author. Tel.: +1 501 526 7501; fax: +1 501 526 6436. E-mail address: fi[email protected] (R.T. Fitzgerald).
as cyclosporine and tacrolimus, and anti-cancer chemotherapeutics. In the case of tacrolimus, a direct toxic affect on the endothelium has been proposed [2]. The mechanism by which other pharmaceuticals initiate or propagate a physiologic cascade leading to PRES is less well known, however an increasing number of agents, including many anti-cancer chemotherapeutic agents, have been implicated in PRES development. In order to better understand the pathophysiologic basis of PRES, we examined serum levels of lactate dehydrogenase (LDH) relative to the onset of PRES during anti-neoplastic chemotherapy treatment in a retrospective series of PRES patients. We hypothesized that elevation of serum LDH, a marker of endothelial dysfunction, would coincide with the development of PRES. 2. Materials and methods A database of PRES patients was compiled through an Institutional Review Board approved search of our electronic medical database from 2007 through 2012 using International Classification
http://dx.doi.org/10.1016/j.jocn.2014.03.004 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fitzgerald RT et al. Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.03.004
2
R.T. Fitzgerald et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
of Diseases version 9 codes encompassing a diagnosis of PRES. Included subjects had MRI of the brain consistent with PRES as verified by consensus of two subspecialty certified neuroradiologists and a clinical diagnosis of PRES within the electronic medical record. Retrospectively collected data included pertinent medical history (predisposing factors for the development of PRES), current drugs/therapies, and serum LDH. Serum LDH values were obtained at three time points: prior to PRES development, at toxicity, and following resolution of symptoms. Clinical features at presentation including first reported blood pressure and symptomatology were obtained from the electronic record. Hypertension was classified according to criteria of the American Heart Association as systolic pressure P140 and/or diastolic pressure P90 mmHg [3]. Extreme hypertension was defined as systolic pressure P180 and/or diastolic pressure P110 mmHg. Student’s t-test using SAS (SAS Institute Inc., Cary, NC, USA) was used to analyze the normal distribution of serum LDH measurement at the three recorded time points (prior to, at the time of, and following PRES diagnosis).
3. Results
normotensive, 32 (49%) were hypertensive, and 28 (42%) had extreme hypertension at presentation. Two of the non-chemotherapy patients did not have recorded blood pressure at presentation. Seizure was the most common presentation, documented in 14 (70%) of the chemotherapy group. Additional or alternative presentations included altered mental status (six patients; 30%), headache (four patients; 20%), and vision changes (seven patients; 35%). For 12 of the 20 patients, serum LDH values were available at all three time points. Of this subset, nine were female, with mean age of 57.8 years (range 33–75 years). Mean serum LDH (normal range 100–248 international units [IU]/L) at the time of PRES diagnosis was 319 IU/L (standard error 47) versus 210 IU/L (standard error 31) before PRES and 199 IU/L (standard error 25) following PRES resolution. Comparison of LDH at PRES toxicity with PRES at the other time points (Fig. 1) revealed a statistically significant mean difference of 114.8 IU/L (p = 0.0263, t = 2.565). Mean time intervals between LDH measurement prior to and following PRES diagnosis were 44.8 days and 51.4 days, respectively. Mean elapsed time between last chemotherapy administration and PRES diagnosis was 11.1 days. 4. Discussion
Twenty (23%) of the 88 patients in our PRES database developed PRES while undergoing chemotherapeutic treatment for neoplastic disease (mean age 59.7 years; range 33–75; 17 women, three men). Malignancy type, demographic information, and chemotherapy treatment at the time of PRES diagnosis are included in Table 1. Of the 20 cancer patients, 12 (60%) were undergoing treatment for multiple myeloma. Five of the chemotherapy patients (25%) were normotensive at the time of PRES diagnosis and eight (40%) exhibited extreme hypertension as classified by the American Heart Association criteria. In the remainder of the cohort, six patients (9%) were
Table 1 Malignancy type, demographic information, and chemotherapy treatment at the time of posterior reversible encephalopathy syndrome diagnosis Malignancy
Age/ Sex
Drug(s)
Melanoma/NSCLC Ovarian carcinoma MM (BMT) MM MM MM (BMT) MM (BMT) Melanoma Sarcoma MM Gastrointestinal stromal tumor MM (BMT);TTP MM
67/F 70/F 68/F 53/M 51/F 54/F 54/M 56/F 33/F 64/F 67/F
Cisplatin, etoposide Bevacizumab, cyclophosphamide VDT, BEAM, cisplatin, sirolimus VDT, sirolimus VDT Carfilizomib, thalidomide, dexamethasone BEAM Ipilimumab Isosfamide VDT Imatinib
61/F 72/M
Melanoma MM MM MM (BMT) MM Pancreatic adenocarcinoma Rectal carcinoma
48/F 75/F 60/F 54/F 67/F 67/F
Melphalan, rituximab Adriamycin, bortezomib, cisplatin, thalidomide, temsirolimus Paclitaxel, paxopanib Thalidomide, dexamethasone Carfilzomib, thalidomide MVDTPACE VDTPACE gemcitabine
53/F
Bevacizumab, FOLFOX
NSCLC: non-small cell lung cancer; MM: multiple myeloma; BMT: allogeneic bone marrow transplant; VDT: bortezomib, doxorubicin, thalidomide; BEAM: carmustine, etoposide, cytarabine, melphalan; TTP: thrombotic thrombocytopenia purpura; MVDTPACE: melphalan, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide; VDTPACE: bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide; FOLFOX: folinic acid, fluorouracil, oxaliplatin.
Investigation of the proposed immune basis of PRES pathophysiology is challenging given the lack of routine clinical sampling of biomarkers indicative of endothelial activation/dysfunction in this population. As such, hypotheses regarding PRES pathophysiology have been drawn in part from prior work in the realm of conditions such as preeclampsia/eclampsia that closely parallel PRES. Recent literature suggesting that the imaging manifestations of PRES are ubiquitous in eclamptic patients [4] supports such an approach, and we posit that the pathophysiologic phenomena leading to PRES likely parallel those that occur in eclampsia. Established evidence has linked the endothelial activation/injury that characterizes preeclampsia with a pro-inflammatory cytokine cascade, serum markers of endothelial injury, and elucidation of endothelial-derived vasoconstrictors such as endothelin-1 [5,6]. In these patients, endothelial activation is further exemplified by increased serum levels of fibronectin and von Willebrand factor, decreased production of nitric oxide and prostacyclin, increased production of thromboxane, and heightened reactivity to angiotensin II [6]. In sum, these factors contribute to an environment of vasoconstriction, as has
Fig. 1. Mean serum lactate dehydrogenase (y axis) at the three sampled time points (x axis): prior to posterior reversible encephalopathy syndrome (PRES) (1), at PRES diagnosis (2), and following PRES (3). IU = international units, LDH = lactate dehydrogenase.
Please cite this article in press as: Fitzgerald RT et al. Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.03.004
R.T. Fitzgerald et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
been recognized in PRES [7]. Given the lack of such data points in a retrospective series of PRES patient such as ours, we were reliant on LDH as a surrogate marker for endothelial dysfunction. Among our entire database of 88 patients, LDH values were only reliably available in those with a concurrent diagnosis of cancer. LDH is a ubiquitous enzyme within the glycolytic pathway facilitating the conversion of pyruvate to lactate. In general, elevation of LDH can be thought of as a generic marker of tissue damage or cell death [8,9]. The utility of serum LDH assessment has been recognized in various fields including hematology, oncology, and cardiology [10]. In relation to the PRES population reported herein, we consider LDH primarily as a marker of endothelial dysfunction and secondarily as a potential measure of neoplastic disease activity [11,12]. In regard to the former, elevation of LDH has been equated with a generalized state of endothelial activation in patients with sickle cell disease and is frequently encountered in preeclampsia [11,13]. Among various soluble markers of endothelial dysfunction, increased levels of plasma adhesion molecules such as vascular cell adhesion molecule may accompany serum increases in LDH in these patients [11]. Further, LDH elevation in the setting of sickle cell disease has been linked with impaired bioavailability of nitric oxide, a potent vasodilatory molecule that also serves to repress endothelial-derived soluble adhesion molecules [11]. Based on the similarities between such a pro-vasoconstrictive milieu and our current understanding of the underlying physiology of PRES [7], we posit that LDH may serve as a marker of endothelial dysfunction in PRES patients in whom more specific markers are not retrospectively available. In regard to the relationship between LDH and neoplastic disease, LDH has been shown to correlate with disease activity and elevation of LDH has been recognized as a negative prognostic indicator in several hematologic and non-hematologic malignancies including non-Hodgkin’s lymphoma, germ cell neoplasms, multiple myeloma, nasopharyngeal carcinoma, and melanoma [10,12,14,15]. In multiple myeloma, which constituted 60% of our cohort, LDH has been shown to effectively distinguish subsets of patients with poor overall survival, even within International Staging System groups [12]. In order to minimize potential confounding tumor-related fluctuations of LDH levels, all LDH measurements were collected during the course of chemotherapy treatment. Those at the two non-PRES time points were temporally distant from PRES diagnosis by 6–8 weeks. Thus, our observation of a statistically significant LDH elevation at PRES toxicity relative to non-PRES time points is supportive of a systemic endothelial-mediated process concurrent with the development of PRES above and beyond any tumor-related changes in LDH. Prior investigation into the relationship between LDH and PRES, primarily from case reports or small series, has shown elevation of serum LDH at the time of PRES development in patients with a variety of underlying conditions [16]. Elevation of LDH has also been reported to precede the development of brain edema in preeclampsia/eclampsia by several days [9,17]. Bo et al. have proposed that serum LDH correlates with the extent of vasogenic edema in PRES [18,19]. Although well known to occur in the setting of high-dose chemotherapy, our series is the largest collection of cancer-related PRES patients to our knowledge. We report onset of disease concurrent with treatment with 22 different drugs or regimens (Table 1). PRES associated with cytotoxic cancer therapy is increasingly reported to occur during treatment of a growing number of therapies, alone or combination drug regimens, and can occur in the setting of intrathecal or intravenous administration [20–24]. Although predominantly reported in the setting of hematologic malignancies, PRES also occurs during treatment of solid neoplasms. In the literature, a wide variety of timeframes have been reported between drug administration and onset of PRES ranging
3
from 2 days after first dosing of cisplatin [24] to the development of PRES 11 months into a twice daily regimen of thalidomide [25]. Our finding of 11.1 days (mean) between last dosing and PRES onset (range 1–28 days) suggests that initiation and propagation of a cascade of events leading to PRES more typically falls along the short end of this spectrum. Given that alterations in vascular endothelial growth factor (VEGF) are thought to play a role in the development of PRES [26,27], it is not surprising that bevacizumab has been increasingly cited as a contributing factor in PRES [23,28,29]. Several additional anti-VEGF agents have been reported to contribute to PRES including aflibercept, and tyrosine kinase inhibitors targeting the VEGF pathway such as sunitinib and sorafenib [30–33]. In the setting of multiple myeloma, PRES has been previously reported to occur in patients receiving dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, and etoposide (DT-PACE) [21]. Other drugs and classes that have been implicated include gemcitabine, cytarabine, cisplatin, thalidomide, etoposide, tiazofurin, and dexamethasone [22,23,32,34,35]. Often, as seen in our cohort and the literature, multi-drug regimens complicate determination of the offending agent in cases of chemotherapy-associated PRES. Further, the relative contributions of cancer-related immune activation versus drug-related endothelial injury in PRES development are unclear. It seems likely that both factors may act synergistically to initiate a cascade leading to PRES. 5. Conclusion A wide variety of chemotherapeutic agents are now recognized to play a role in the development of PRES in cancer patients. Serum LDH, a marker of endothelial dysfunction, is elevated at the onset of PRES toxicity relative to other treatment time points prior to and after PRES. Our findings support a systemic process characterized by endothelial injury/dysfunction as a factor, if not a principle event, in the pathophysiology of PRES; however, the etiology of such endothelial dysfunction (drug-related, tumor-related immune activation, or both) remains incompletely understood. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol 2008;29:1043–9. [2] Kochi S, Takanaga H, Matsuo H, et al. Induction of apoptosis in mouse brain capillary endothelial cells by cyclosporin A and tacrolimus. Life Sci 2000;66:2255–60. [3] Pickering TG, Hall JE, Appel L, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the subcommittee of professional and public education of the American heart association council on high blood pressure research. Circulation 2005;111:697–716. [4] Brewer J, Owens MY, Wallace K, et al. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol 2013;208:468.e1–6. [5] Friedman SA, Taylor RN, Roberts JM. Pathophysiology of preeclampsia. Clin Perinatol 1991;18:661–82. [6] Myatt L, Webster RP. Vascular biology of preeclampsia. J Thromb Haemost 2009;7:375–84. [7] Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2008;29:447–55. [8] Ballas SK. Lactate dehydrogenase and hemolysis in sickle cell disease. Blood 2013;121:243–4. [9] Vargas M, Servillo G, Striano P. Serum lactate dehydrogenase as early marker of posterior reversible encephalopathy syndrome: keep your eyes open. Anaesth Intensive Care 2012;40:570–1.
Please cite this article in press as: Fitzgerald RT et al. Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.03.004
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[10] Huijgen HJ, Sanders GT, Koster RW, et al. The clinical value of lactate dehydrogenase in serum: a quantitative review. Eur J Clin Chem Clin Biochem 1997;35:569–79. [11] Kato GJ, McGowan V, Machado RF, et al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 2006;107:2279–85. [12] Terpos E, Katodritou E, Roussou M, et al. High serum lactate dehydrogenase adds prognostic value to the international myeloma staging system even in the era of novel agents. Eur J Haematol 2010;85:114–9. [13] Catanzarite VA, Steinberg SM, Mosley CA, et al. Severe preeclampsia with fulminant and extreme elevation of aspartate aminotransferase and lactate dehydrogenase levels: high risk for maternal death. Am J Perinatol 1995;12:310–3. [14] Eigentler TK, Figl A, Krex D, et al. Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma. Cancer 2011;117:1697–703. [15] Zhou GQ, Tang LL, Mao YP, et al. Baseline serum lactate dehydrogenase levels for patients treated with intensity-modulated radiotherapy for nasopharyngeal carcinoma: a predictor of poor prognosis and subsequent liver metastasis. Int J Radiat Oncol Biol Phys 2012;82:e359–65. [16] Sweany JM, Bartynski WS, Boardman JF. ‘‘Recurrent’’ posterior reversible encephalopathy syndrome: report of 3 cases–PRES can strike twice! J Comput Assist Tomogr 2007;31:148–56. [17] Schwartz RB, Bravo SM, Klufas RA, et al. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 1995;165:627–31. [18] Goa B, Lui FL, Zhao B. Association of degree and type of edema in posterior reversible encephalopathy syndrome with serum lactate dehydrogenase level: initial experience. Eur J Radiol 2012;81:2844–7. [19] Bo G, Hui L, Feng-li L, et al. Relationships between edema degree and clinical and biochemical parameters in posterior reversible encephalopathy syndrome: a preliminary study. Acta Neurol Belg 2012;112:281–5. [20] Henderson RD, Rajah T, Nicol AJ, et al. Posterior leukoencephalopathy following intrathecal chemotherapy with MRA-documented vasospasm. Neurology 2003;60:326–8. [21] Tam CS, Galanos J, Seymour JF, et al. Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J Hematol 2004;77:72–6. [22] Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol 2008;29:1036–42.
[23] Dersch R, Stich O, Goller K, et al. Atypical posterior reversible encephalopathy syndrome associated with chemotherapy with bevacizumab, gemcitabine and cisplatin. J Neurol 2013;260:1406–7. [24] Zahir MN, Masood N, Shabbir-Moosajee M. Cisplatin-induced posterior reversible encephalopathy syndrome and successful re-treatment in a patient with non-seminomatous germ cell tumor: a case report. J Med Case Rep 2012;6:409. [25] Chow S, Cheung CS, Lee DH, et al. Posterior reversible encephalopathy syndrome in a patient with multiple myeloma treated with thalidomide. Leuk Lymphoma 2012;53:1003–5. [26] Kofler J, Bartynski WS, Reynolds TQ, et al. Posterior reversible encephalopathy syndrome (PRES) with immune system activation, VEGF up-regulation, and cerebral amyloid angiopathy. J Comput Assist Tomogr 2011;35:39–42. [27] Horbinski C, Bartynski WS, Carson-Walter E, et al. Reversible encephalopathy after cardiac transplantation: histologic evidence of endothelial activation, Tcell specific trafficking, and vascular endothelial growth factor expression. AJNR Am J Neuroradiol 2009;30:588–90. [28] Seet RCS, Rabinstein AA. Clinical features and outcomes of posterior reversible encephalopathy syndrome following bevacizumab treatment. QJM 2012;105:69–75. [29] Chang Y, Mbeo G, Littman SJ. Reversible posterior leukoencephalopathy syndrome associated with concurrent bevacizumab, gemcitabine, and oxaliplatin for cholangiocarcinoma. J Gastrointest Cancer 2012;43:505–7. [30] Tlemsani C, Mir O, Boudou-Rouquette P, et al. Posterior reversible encephalopathy syndrome induced by anti-VEGF agents. Target Oncol 2011;6:253–8. [31] Govindarajan R, Adusumilli J, Baxter DL, et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43– 9006. J Clin Oncol 2006;24:e48. [32] Kapiteijn E, Brand A, Kroep J, et al. Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome. Ann Oncol 2007;18:1745–7. [33] Leighl NB, Raez LE, Besse B, et al. A multicenter, phase 2 study of vascular endothelial growth factor trap (Aflibercept) in platinum- and erlotinibresistant adenocarcinoma of the lung. J Thorac Oncol 2010;5:1054–9. [34] Marrone LC, Marrone BF, de la Puerta Raya J, et al. Gemcitabine monotherapy associated with posterior reversible encephalopathy syndrome. Case Rep Oncol 2011;4:82–7. [35] Pandey R, Patel A, Shah S, et al. A rare complication in a case of multiple myeloma on therapy with thalidomide and dexamethasone—reversible posterior lobe leukoencephalopathy. Leuk Lymphoma 2006;47:1431–4.
Please cite this article in press as: Fitzgerald RT et al. Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.03.004
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients Ryan T. Fitzgerald ⇑, Steven M. Wright, Rohan S. Samant, Manoj Kumar, Raghu H. Ramakrishnaiah, Rudy Van Hemert, Aliza T. Brown, Edgardo J. Angtuaco Department of Radiology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, #556, Little Rock, AR 72205-7199, USA
a r t i c l e
i n f o
Article history: Received 27 January 2014 Accepted 2 March 2014 Available online xxxx Keywords: Chemotherapy Hypertensive encephalopathy LDH Posterior reversible encephalopathy syndrome PRES
a b s t r a c t The pathophysiology of posterior reversible encephalopathy syndrome (PRES) is incompletely understood; however, an underlying state of immune dysregulation and endothelial dysfunction has been proposed. We examined alterations of serum lactate dehydrogenase (LDH), a marker of endothelial dysfunction, relative to the development of PRES in patients receiving chemotherapy. A retrospective Institutional Review Board approved database of 88 PRES patients was examined. PRES diagnosis was confirmed by congruent clinical diagnosis and MRI. Clinical features at presentation were recorded. Serum LDH values were collected at three time points: prior to, at the time of, and following PRES diagnosis. Student’s t-test was employed. LDH values were available during the course of treatment in 12 patients (nine women; mean age 57.8 years [range 33–75 years]). Chemotherapy-associated PRES patients were more likely to be normotensive (25%) versus the non-chemotherapy group (9%). LDH levels at the time of PRES diagnosis were higher than those before and after (p = 0.0263), with a mean difference of 114.8 international units/L. Mean time intervals between LDH measurement prior to and following PRES diagnosis were 44.8 days and 51.4 days, respectively. Mean elapsed time between last chemotherapy administration and PRES onset was 11.1 days. In conclusion, serum LDH, a marker of endothelial dysfunction, shows statistically significant elevation at the onset of PRES toxicity in cancer patients receiving chemotherapy. Our findings support a systemic process characterized by endothelial injury/dysfunction as a factor, if not the prime event, in the pathophysiology of PRES. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic process that occurs in the setting of systemic infection, transplantation, pregnancy, autoimmune disease, and malignancy, processes that involve activation of the immune system, with or without concurrent hypertension. Examination of the milieu in which PRES typically occurs, coupled with the significant minority of cases that occur in the absence of hypertension, has challenged the traditional notion of PRES as a direct result of hypertension exceeding auto-regulatory control. Instead, PRES is now thought to occur as a result of systemic endothelial dysfunction leading to altered vasoregulatory control, blood pressure lability, and cerebral hypoperfusion [1]. Various pharmaceuticals have been implicated as factors in the development of PRES including immune suppressant agents, such ⇑ Corresponding author. Tel.: +1 501 526 7501; fax: +1 501 526 6436. E-mail address: fi[email protected] (R.T. Fitzgerald).
as cyclosporine and tacrolimus, and anti-cancer chemotherapeutics. In the case of tacrolimus, a direct toxic affect on the endothelium has been proposed [2]. The mechanism by which other pharmaceuticals initiate or propagate a physiologic cascade leading to PRES is less well known, however an increasing number of agents, including many anti-cancer chemotherapeutic agents, have been implicated in PRES development. In order to better understand the pathophysiologic basis of PRES, we examined serum levels of lactate dehydrogenase (LDH) relative to the onset of PRES during anti-neoplastic chemotherapy treatment in a retrospective series of PRES patients. We hypothesized that elevation of serum LDH, a marker of endothelial dysfunction, would coincide with the development of PRES. 2. Materials and methods A database of PRES patients was compiled through an Institutional Review Board approved search of our electronic medical database from 2007 through 2012 using International Classification
http://dx.doi.org/10.1016/j.jocn.2014.03.004 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fitzgerald RT et al. Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.03.004
2
R.T. Fitzgerald et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
of Diseases version 9 codes encompassing a diagnosis of PRES. Included subjects had MRI of the brain consistent with PRES as verified by consensus of two subspecialty certified neuroradiologists and a clinical diagnosis of PRES within the electronic medical record. Retrospectively collected data included pertinent medical history (predisposing factors for the development of PRES), current drugs/therapies, and serum LDH. Serum LDH values were obtained at three time points: prior to PRES development, at toxicity, and following resolution of symptoms. Clinical features at presentation including first reported blood pressure and symptomatology were obtained from the electronic record. Hypertension was classified according to criteria of the American Heart Association as systolic pressure P140 and/or diastolic pressure P90 mmHg [3]. Extreme hypertension was defined as systolic pressure P180 and/or diastolic pressure P110 mmHg. Student’s t-test using SAS (SAS Institute Inc., Cary, NC, USA) was used to analyze the normal distribution of serum LDH measurement at the three recorded time points (prior to, at the time of, and following PRES diagnosis).
3. Results
normotensive, 32 (49%) were hypertensive, and 28 (42%) had extreme hypertension at presentation. Two of the non-chemotherapy patients did not have recorded blood pressure at presentation. Seizure was the most common presentation, documented in 14 (70%) of the chemotherapy group. Additional or alternative presentations included altered mental status (six patients; 30%), headache (four patients; 20%), and vision changes (seven patients; 35%). For 12 of the 20 patients, serum LDH values were available at all three time points. Of this subset, nine were female, with mean age of 57.8 years (range 33–75 years). Mean serum LDH (normal range 100–248 international units [IU]/L) at the time of PRES diagnosis was 319 IU/L (standard error 47) versus 210 IU/L (standard error 31) before PRES and 199 IU/L (standard error 25) following PRES resolution. Comparison of LDH at PRES toxicity with PRES at the other time points (Fig. 1) revealed a statistically significant mean difference of 114.8 IU/L (p = 0.0263, t = 2.565). Mean time intervals between LDH measurement prior to and following PRES diagnosis were 44.8 days and 51.4 days, respectively. Mean elapsed time between last chemotherapy administration and PRES diagnosis was 11.1 days. 4. Discussion
Twenty (23%) of the 88 patients in our PRES database developed PRES while undergoing chemotherapeutic treatment for neoplastic disease (mean age 59.7 years; range 33–75; 17 women, three men). Malignancy type, demographic information, and chemotherapy treatment at the time of PRES diagnosis are included in Table 1. Of the 20 cancer patients, 12 (60%) were undergoing treatment for multiple myeloma. Five of the chemotherapy patients (25%) were normotensive at the time of PRES diagnosis and eight (40%) exhibited extreme hypertension as classified by the American Heart Association criteria. In the remainder of the cohort, six patients (9%) were
Table 1 Malignancy type, demographic information, and chemotherapy treatment at the time of posterior reversible encephalopathy syndrome diagnosis Malignancy
Age/ Sex
Drug(s)
Melanoma/NSCLC Ovarian carcinoma MM (BMT) MM MM MM (BMT) MM (BMT) Melanoma Sarcoma MM Gastrointestinal stromal tumor MM (BMT);TTP MM
67/F 70/F 68/F 53/M 51/F 54/F 54/M 56/F 33/F 64/F 67/F
Cisplatin, etoposide Bevacizumab, cyclophosphamide VDT, BEAM, cisplatin, sirolimus VDT, sirolimus VDT Carfilizomib, thalidomide, dexamethasone BEAM Ipilimumab Isosfamide VDT Imatinib
61/F 72/M
Melanoma MM MM MM (BMT) MM Pancreatic adenocarcinoma Rectal carcinoma
48/F 75/F 60/F 54/F 67/F 67/F
Melphalan, rituximab Adriamycin, bortezomib, cisplatin, thalidomide, temsirolimus Paclitaxel, paxopanib Thalidomide, dexamethasone Carfilzomib, thalidomide MVDTPACE VDTPACE gemcitabine
53/F
Bevacizumab, FOLFOX
NSCLC: non-small cell lung cancer; MM: multiple myeloma; BMT: allogeneic bone marrow transplant; VDT: bortezomib, doxorubicin, thalidomide; BEAM: carmustine, etoposide, cytarabine, melphalan; TTP: thrombotic thrombocytopenia purpura; MVDTPACE: melphalan, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide; VDTPACE: bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide; FOLFOX: folinic acid, fluorouracil, oxaliplatin.
Investigation of the proposed immune basis of PRES pathophysiology is challenging given the lack of routine clinical sampling of biomarkers indicative of endothelial activation/dysfunction in this population. As such, hypotheses regarding PRES pathophysiology have been drawn in part from prior work in the realm of conditions such as preeclampsia/eclampsia that closely parallel PRES. Recent literature suggesting that the imaging manifestations of PRES are ubiquitous in eclamptic patients [4] supports such an approach, and we posit that the pathophysiologic phenomena leading to PRES likely parallel those that occur in eclampsia. Established evidence has linked the endothelial activation/injury that characterizes preeclampsia with a pro-inflammatory cytokine cascade, serum markers of endothelial injury, and elucidation of endothelial-derived vasoconstrictors such as endothelin-1 [5,6]. In these patients, endothelial activation is further exemplified by increased serum levels of fibronectin and von Willebrand factor, decreased production of nitric oxide and prostacyclin, increased production of thromboxane, and heightened reactivity to angiotensin II [6]. In sum, these factors contribute to an environment of vasoconstriction, as has
Fig. 1. Mean serum lactate dehydrogenase (y axis) at the three sampled time points (x axis): prior to posterior reversible encephalopathy syndrome (PRES) (1), at PRES diagnosis (2), and following PRES (3). IU = international units, LDH = lactate dehydrogenase.
Please cite this article in press as: Fitzgerald RT et al. Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.03.004
R.T. Fitzgerald et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
been recognized in PRES [7]. Given the lack of such data points in a retrospective series of PRES patient such as ours, we were reliant on LDH as a surrogate marker for endothelial dysfunction. Among our entire database of 88 patients, LDH values were only reliably available in those with a concurrent diagnosis of cancer. LDH is a ubiquitous enzyme within the glycolytic pathway facilitating the conversion of pyruvate to lactate. In general, elevation of LDH can be thought of as a generic marker of tissue damage or cell death [8,9]. The utility of serum LDH assessment has been recognized in various fields including hematology, oncology, and cardiology [10]. In relation to the PRES population reported herein, we consider LDH primarily as a marker of endothelial dysfunction and secondarily as a potential measure of neoplastic disease activity [11,12]. In regard to the former, elevation of LDH has been equated with a generalized state of endothelial activation in patients with sickle cell disease and is frequently encountered in preeclampsia [11,13]. Among various soluble markers of endothelial dysfunction, increased levels of plasma adhesion molecules such as vascular cell adhesion molecule may accompany serum increases in LDH in these patients [11]. Further, LDH elevation in the setting of sickle cell disease has been linked with impaired bioavailability of nitric oxide, a potent vasodilatory molecule that also serves to repress endothelial-derived soluble adhesion molecules [11]. Based on the similarities between such a pro-vasoconstrictive milieu and our current understanding of the underlying physiology of PRES [7], we posit that LDH may serve as a marker of endothelial dysfunction in PRES patients in whom more specific markers are not retrospectively available. In regard to the relationship between LDH and neoplastic disease, LDH has been shown to correlate with disease activity and elevation of LDH has been recognized as a negative prognostic indicator in several hematologic and non-hematologic malignancies including non-Hodgkin’s lymphoma, germ cell neoplasms, multiple myeloma, nasopharyngeal carcinoma, and melanoma [10,12,14,15]. In multiple myeloma, which constituted 60% of our cohort, LDH has been shown to effectively distinguish subsets of patients with poor overall survival, even within International Staging System groups [12]. In order to minimize potential confounding tumor-related fluctuations of LDH levels, all LDH measurements were collected during the course of chemotherapy treatment. Those at the two non-PRES time points were temporally distant from PRES diagnosis by 6–8 weeks. Thus, our observation of a statistically significant LDH elevation at PRES toxicity relative to non-PRES time points is supportive of a systemic endothelial-mediated process concurrent with the development of PRES above and beyond any tumor-related changes in LDH. Prior investigation into the relationship between LDH and PRES, primarily from case reports or small series, has shown elevation of serum LDH at the time of PRES development in patients with a variety of underlying conditions [16]. Elevation of LDH has also been reported to precede the development of brain edema in preeclampsia/eclampsia by several days [9,17]. Bo et al. have proposed that serum LDH correlates with the extent of vasogenic edema in PRES [18,19]. Although well known to occur in the setting of high-dose chemotherapy, our series is the largest collection of cancer-related PRES patients to our knowledge. We report onset of disease concurrent with treatment with 22 different drugs or regimens (Table 1). PRES associated with cytotoxic cancer therapy is increasingly reported to occur during treatment of a growing number of therapies, alone or combination drug regimens, and can occur in the setting of intrathecal or intravenous administration [20–24]. Although predominantly reported in the setting of hematologic malignancies, PRES also occurs during treatment of solid neoplasms. In the literature, a wide variety of timeframes have been reported between drug administration and onset of PRES ranging
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from 2 days after first dosing of cisplatin [24] to the development of PRES 11 months into a twice daily regimen of thalidomide [25]. Our finding of 11.1 days (mean) between last dosing and PRES onset (range 1–28 days) suggests that initiation and propagation of a cascade of events leading to PRES more typically falls along the short end of this spectrum. Given that alterations in vascular endothelial growth factor (VEGF) are thought to play a role in the development of PRES [26,27], it is not surprising that bevacizumab has been increasingly cited as a contributing factor in PRES [23,28,29]. Several additional anti-VEGF agents have been reported to contribute to PRES including aflibercept, and tyrosine kinase inhibitors targeting the VEGF pathway such as sunitinib and sorafenib [30–33]. In the setting of multiple myeloma, PRES has been previously reported to occur in patients receiving dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, and etoposide (DT-PACE) [21]. Other drugs and classes that have been implicated include gemcitabine, cytarabine, cisplatin, thalidomide, etoposide, tiazofurin, and dexamethasone [22,23,32,34,35]. Often, as seen in our cohort and the literature, multi-drug regimens complicate determination of the offending agent in cases of chemotherapy-associated PRES. Further, the relative contributions of cancer-related immune activation versus drug-related endothelial injury in PRES development are unclear. It seems likely that both factors may act synergistically to initiate a cascade leading to PRES. 5. Conclusion A wide variety of chemotherapeutic agents are now recognized to play a role in the development of PRES in cancer patients. Serum LDH, a marker of endothelial dysfunction, is elevated at the onset of PRES toxicity relative to other treatment time points prior to and after PRES. Our findings support a systemic process characterized by endothelial injury/dysfunction as a factor, if not a principle event, in the pathophysiology of PRES; however, the etiology of such endothelial dysfunction (drug-related, tumor-related immune activation, or both) remains incompletely understood. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol 2008;29:1043–9. [2] Kochi S, Takanaga H, Matsuo H, et al. Induction of apoptosis in mouse brain capillary endothelial cells by cyclosporin A and tacrolimus. Life Sci 2000;66:2255–60. [3] Pickering TG, Hall JE, Appel L, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the subcommittee of professional and public education of the American heart association council on high blood pressure research. Circulation 2005;111:697–716. [4] Brewer J, Owens MY, Wallace K, et al. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol 2013;208:468.e1–6. [5] Friedman SA, Taylor RN, Roberts JM. Pathophysiology of preeclampsia. Clin Perinatol 1991;18:661–82. [6] Myatt L, Webster RP. Vascular biology of preeclampsia. J Thromb Haemost 2009;7:375–84. [7] Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2008;29:447–55. [8] Ballas SK. Lactate dehydrogenase and hemolysis in sickle cell disease. Blood 2013;121:243–4. [9] Vargas M, Servillo G, Striano P. Serum lactate dehydrogenase as early marker of posterior reversible encephalopathy syndrome: keep your eyes open. Anaesth Intensive Care 2012;40:570–1.
Please cite this article in press as: Fitzgerald RT et al. Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.03.004
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Please cite this article in press as: Fitzgerald RT et al. Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.03.004
