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CORRESPONDENCE
Year : 2014  |  Volume : 10  |  Issue : 2  |  Page : 393-396

Recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy-posterior reversible encephalopathy syndrome can strike twice!!!


1 Department of Radiation Oncology, Institute Rotary Cancer Hospital, AIIMS, New Delhi, India
2 Department of Radio Diagnosis, Institute Rotary Cancer Hospital, AIIMS, New Delhi, India

Date of Web Publication14-Jul-2014

Correspondence Address:
Soumyajit Roy
Department of Radiation Oncology, Institute Rotary Cancer Hospital, AIIMS, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.136668

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 > Abstract 

Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiological syndrome characterized by seizures, altered level of consciousness, visual disturbance, and hyperintense lesions on magnetic resonance imaging most commonly in the posterior regions. PRES is typically associated with a number of complex clinical conditions including: Preeclampsia/eclampsia, allogeneic bone marrow transplantation, solid organ transplantation, autoimmune diseases, and high-dose anti-neoplastic therapy. We herein describe a case of recurrent PRES in a 29-year-old lady of refractory anaplastic large-cell lymphoma who was on second-line chemotherapy with Ifosfamide-Carboplatin-etoposide regimen. We have also tried to illustrate the pathogenesis, radiological features, and management of PRES. Although reversible in most cases, PRES may be recurrent even in chemotherapy - induced cases and result in fatal outcomes despite appropriate intervention. This is the first - reported case of recurrent PRES with such a fatal outcome, as a complication of anti-neoplastic systemic therapy.

 > Abstract in Chinese 

恶性血液病中的可逆性后部脑病综合征化疗后复发:可逆性脑病综合征两次打击!!!
摘要
可逆性后部脑病综合征(PRES)是一种神经影像学综合征,临床表现为癫痫发作,意识水平的改变,视力障碍,磁共振成像常见脑中后部区域的高信号病灶。PRES通常是与一些复杂的临床条件相关,包括:先兆子痫/子痫,异基因骨髓移植,器官移植,自身免疫性疾病,高剂量抗肿瘤治疗。本文报道一位29岁的女性患者,有复发的难治性间变性大细胞淋巴瘤,予卡铂-足叶乙甙-异环磷酰胺二线化疗方案。本文分析PRES的病理学发生机制,影像学特征,以及PRES的治疗方案。虽然在大多数情况下可恢复,PRES甚至可能在化疗后的病例中复发并导致致命的结果。本文既是第一次报告复发性PRES伴致命的结果,作为抗肿瘤的全身治疗的并发症。
关键词:卡铂,足叶乙甙,异环磷酰胺,后部可逆性脑病综合征,复发


Keywords: Carboplatin, etoposide, ifosfamide, posterior reversible encephalopathy syndrome, recurrent


How to cite this article:
Roy S, Gandhi AK, Jana M, Julka PK. Recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy-posterior reversible encephalopathy syndrome can strike twice!!!. J Can Res Ther 2014;10:393-6

How to cite this URL:
Roy S, Gandhi AK, Jana M, Julka PK. Recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy-posterior reversible encephalopathy syndrome can strike twice!!!. J Can Res Ther [serial online] 2014 [cited 2019 Nov 17];10:393-6. Available from: http://www.cancerjournal.net/text.asp?2014/10/2/393/136668


 > Introduction Top


Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic state accompanied by a unique brain imaging pattern typically associated with a number of complex clinical conditions like: Preeclampsia or eclampsia, allogeneic bone marrow transplantation, solid organ transplantation, autoimmune diseases, and high-dose anti-neoplastic therapy. Clinically, this entity is characterized by subacute onset of headache, seizures, altered level of consciousness state, and visual disturbances ranging from blurred vision to total cortical blindness.

Two opposing hypotheses are commonly cited for the mechanism of PRES. The current theory suggests that severe hypertension exceeds the limits of auto regulation, leading to breakthrough brain edema. The original theory suggests that hypertension leads to cerebral auto regulatory vasoconstriction, ischemia, and subsequent brain edema. [1] However, the exact mechanism remains unknown. We have described here a case of recurrent PRES in a 29-year-old woman having anaplastic large-cell lymphoma (ALCL), after receiving salvage chemotherapy with ICE.


 > Case report Top


A 29-year-old lady, a known case of ALCL, who had received four cycles of chemotherapy with Cyclophosphamide-doxorubicin-Oncovin- Prednisolone followed by palliative radiation to right axilla, presented with complaint of gradually progressive non-healing painful ulcer over chest wall, which on biopsy proved to be ALCL. She had no history of hypertension, diabetes, or any long-term renal dysfunction. She was planned for salvage chemotherapy with ICE regimen. She received 9 g of Ifosfamide, 600 mg of Etoposide, divided over 3 days with Carboplatin 450 mg on 1 st day of the first cycle. On 2 nd day after completion of the first cycle, she developed an episode of partial seizure in the form of repeated jerky movements of her left leg along with frothing of saliva, lasted less than a minute. Her blood pressure (BP), (systolic blood pressure (SBP): 106 mm of Mercury and diastolic blood pressure (DBP): 77 mm of Mercury), body temperature (98.2°F) and other vitals (Pulse: 107/min, regular with normal volume; rate of respiration: 26/min, SpO 2 : 98%) were stable. She was managed using intravenous anti-epileptics (intravenous lorazepam 4 mg followed by a loading dose of intravenous phenytoin 1 g over 1 h) and shifted to intensive care unit (ICU). There were no further episodes of overt seizures, but she remained obtunded with a Glasgow coma scale score of 10. Cerebrospinal fluid (total protein: 36 mg/dl; gamma-globulin: 1.8 mg/dl; total sugar: 45 mg/dl; cellularity: Acellular; gram staining and Acid Fast B acilli staining: No growth as confirmed by culture-sensitivity) and serum chemistry parameters (random blood sugar: 136 mg/dl; Urea: 32 mg/dl; Creatinine: 0.7 mg/dl; Sodium: 132 meq/L; Potassium: 4.2 meq/L; Calcium: 9.4 mg/dl; Bilirubin: 0.6 mg/dl; Alanine aminotransferase/Aspartate aminotransferase: 34 U/L/32 U/L. AlkalinePhophatase: 279 U/L) were also within normal limits. Electroencephalogram (EEG) showed generalized slowing indicative of a diffuse encephalopathy without any evident seizure activity. From the next day, she started complaining of blurring of vision, but Fundoscopic evaluation was normal. Contrast - enhanced magnetic resonance imaging (MRI) of brain was done which showed T2-hyperintense cortical edema, symmetrically involving the bilateral parieto-occipital region and cerebellar hemispheres. fluid attenuation inversion recovery images showed no restriction of diffusion [Figure 1] and [Figure 2]. In such clinical context and recent chemotherapy, the radiological findings were believed to be consistent with PRES. She recovered within 2 weeks. After 3 months, she again presented with repeated episodes of partial seizures in the form of short-lasting episodes of repeated jerky movements of her legs, progressively worsening ataxia, and visual blurring. Vitals (SBP: 114 mm of Mercury; DBP: 84 mm of Mercury; temperature: 98.6°F; Pulse: 92/min, regular with normal volume; rate of respiration: 26/min, Spo 2 : 85%) were again within normal limits. Contrast-enhanced computed tomography scan of brain, fundoscopy, and cerebro-spinal fluid parameters showed no abnormality. Random blood sugar, liver function test parameters (Bilirubin: 0.8 mg/dl; ALT/AST: 45/34 U/L; ALP: 200 U/L), kidney function test parameters especially, serum creatinine level (value: 0.9 mg/dl). And serum electrolytes (Sodium: 134 meq/L; Potassium: 3.9 meq/L; Calcium: 10 mg/dl) were within normal limits. EEG was again indicative of a diffuse encephalopathy. She was given an intravenous (iv) injection lorazepam (4 mg) immediately with immediate endotracheal intubation to protect airway followed by loading dose of intravenous phenytoin (1 g over 1 h), during which she was shifted to the ICU. She was managed with IV phenytoin (100 mg thrice-a-day), broad-spectrum empirical IV antibiotics (Injection: Cefoperazone-sulbactum combination 2 g IV twice daily along with IV metronidazole 500 mg IV thrice daily and amikacin 500 mg IV twice daily). The patient was kept in synchronized intermittent-mandatory ventilation mode of ventilation with appropriate sedation. Continuous monitoring of the vitals was done. The blood investigations (complete blood count, kidney, and liver function tests) were repeated every day. Both blood and urine were sent for culture and sensitivity testing and revealed no growth. Chest skiagram was repeated every alternate day but did not show any feature of consolidation or infection. No confounding factors like hypertension, sepsis, immunosuppression, or renal dysfunction for this recurrence was identified. Despite appropriate management, her clinical condition went on deteriorating; she expired after 4 days. The recurrence of symptoms was attributed to PRES though diagnosis could not be established.
Figure 1: Magnetic resonance imaging of brain showing axial fluid attenuation inversion recovery fluid attenuation inversion recovery sequences. They are showing bilateral hyperintense foci of signal change in occipital and parietal lobes (arrows)

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Figure 2: Magnetic resonance imaging of brain showing axial fluid attenuation inversion recovery fluid attenuation inversion recovery sequences. Arrows are indicating bilateral cerebellar involvement in this image

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 > Discussion Top


PRES is almost exclusively seen in the setting of a significant systemic process/condition, including transplantation, infection/sepsis/shock, toxemia of pregnancy, autoimmune disease, and cancer chemotherapy. The mechanism of PRES is unknown. Two opposing hypotheses are commonly cited. The current theory suggests that severe hypertension exceeds the limits of auto regulation, leading to breakthrough brain edema. The original theory suggests that hypertension leads to cerebral auto-regulatory vasoconstriction, ischemia, and subsequent brain edema. [1]

The mechanism by which anti-neoplastic agents cause PRES is not clear. Toxicity secondary to chemotherapeutic agents can be facilitated by a leak in the blood-brain barrier, or by increased intravascular pressure (usually as a result of hypertensive emergency), both of which processes result in vasogenic edema. Potential triggers include: (1) CD8 + T-cell recognition of unique tumor antigens expressed on tumor cell major histocompatibility complex type-I (MHC-I) molecules or (2) CD4 + T-cell recognition of unique tumor antigens expressed on antigen presenting cells (APC); i.e., dendritic cells or macrophages) MHC-II molecules. PRES typically occurs several weeks after cancer chemotherapy and tumor cell lysis, APC tumor antigen expression, CD4 + T-cell activation and monocyte/macrophage activation, likely develops with subsequent cytokine expression. In our case, it was on 2 nd day after completion of chemotherapy. The direct effect of chemotherapy on the endothelial cells cannot be ruled out. [1]

Fugate et al. found that in the 115 cases (109 patients) for which MRI findings were available, the parieto-occipital regions were the most commonly involved (n = 108 [94%]), followed by the frontal lobe (n = 88 [77%]), temporal lobe (n = 74 [64%]), and cerebellum (n = 61 [53%]). Some patients had more than one site of involvement as evident on imaging. [2]

On T2-weighted sequences, vasogenic edema is usually marked by hyperintensity, mostly involving white matter, and cytotoxic edema is marked by T2-hyperintensity that involves grey matter, white matter, or both. Diffusion-weighted imaging, however, clearly distinguishes between the two. Regions with cytotoxic edema show diffusion coefficients that are restricted compared with those of white matter, whereas vasogenic edema demonstrates diffusion coefficients that are increased compared with those of normal white matter. In PRES, however, focal areas of restricted diffusion are infrequent (11-26%). [3]

No single chemotherapeutic agent or therapeutic regimen has been identified to date as being consistently associated with PRES. Implicated drugs have included single-agent cisplatin or cytarabine as well as combinations of adriamycin, cyclophosphamide, vincristine, ifosfamide, and cytarabine. Most published reports of PRES complicating combination chemotherapy for adult hematological malignancies involved the use of intrathecal chemotherapy, with methotrexate, cytarabine, or both. One constant feature in all the reported cases of PRES complicating cytotoxic chemotherapy is the presence of systemic hypertension. Our patient had normal BP.

There has been single case report of PRES after carboplatin infusion in a carcinoma lung patient who previously had received five cycles of cisplatin. The question whether PRES was specifically related to carboplatin or to the cumulative dose of platinum could not be solved. [4]

The acute treatment of PRES involves the cessation of cytotoxic agents, treatment of elevated BP with anti-hypertensive drugs, and the correction of any electrolyte abnormality. Anti-epileptics should be initiated in the acute setting upon commencement of seizures. Long-term therapy may not be necessary as the recurrence of seizures following the resolution of encephalopathy is uncommon. [5]

Recurrence has been reported in 6% and death has been reported in up to 15% of the patients. However, the relative contributions of PRES and of associated factors to the fatal outcome are unclear. [6]

Our observation was unique because:

  • Our patient had normal BP in both the instances while hypertension has been a constant feature in chemotherapy induced PRES
  • We could not attribute the development of PRES at the time of first presentation to a particular drug among ifosfamide, etoposide, or carboplatin - any or all of these in combination might have been responsible. The role of sepsis, which might have resulted from the super-added infection of the chest wall ulcer, could not be ignored
  • We also do not know the possible cause of recurrence of PRES
  • This is the first-reported case of recurrent PRES with such a fatal outcome, as a complication of anti-neoplastic systemic therapy.



 > Conclusion Top


PRES is not a well-known entity. Due to poor knowledge of this syndrome, it is often missed as a diagnosis. Although reversible, especially in chemotherapy-induced cases, PRES can be recurrent very rarely and in few cases may result in fatal outcomes despite appropriate intervention. This is the first-reported case of recurrent PRES with such a fatal outcome, as a complication of anti-neoplastic systemic therapy.

 
 > References Top

1.Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: Controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol 2008;29:1043-9.  Back to cited text no. 1
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2.Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA. Posterior reversible encephalopathy syndrome: Associated clinical and radiologic findings. Mayo Clin Proc 2010;85:427-32.  Back to cited text no. 2
    
3.Schaefer PW, Buonanno FS, Gonzalez RG, Schwamm LH. Diffusion-weighted imaging discriminates between cytotoxic and vasogenic edema in a patient with eclampsia. Stroke 1997;28:1082-5.  Back to cited text no. 3
    
4.Vieillot S, Pouessel D, de Champfleur NM, Becht C, Culine S. Reversible posterior leukoencephalopathy syndrome after carboplatin therapy. Ann Oncol 2007;18:608-9.  Back to cited text no. 4
[PUBMED]    
5.Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996;334:494-500.  Back to cited text no. 5
    
6.Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol 2008;65:205-10.  Back to cited text no. 6
    


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