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Inicio Neurología (English Edition) Cerebellar toxicity due to cytarabine: a series of 4 cases
Información de la revista
Vol. 31. Núm. 7.
Páginas 491-492 (septiembre 2016)
Vol. 31. Núm. 7.
Páginas 491-492 (septiembre 2016)
Letter to the Editor
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Cerebellar toxicity due to cytarabine: a series of 4 cases
Toxicidad cerebelosa por citarabina: serie de 4 casos
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S. Sainz de la Maza Canteroa,
Autor para correspondencia
susana.sainzdelamaza@gmail.com

Corresponding author.
, A. Jiménez Martínb, A. de Felipe Mimbreraa, Í. Corral Corrala
a Servicio de Neurología, Hospital Universitario Ramón y Cajal, Madrid, Spain
b Servicio de Hematología, Hospital Universitario Ramón y Cajal, Madrid, Spain
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Tablas (2)
Table 1. Patient characteristics at baseline.
Table 2. Clinical manifestations.
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Dear Editor,

Cytarabine is an antimetabolite antineoplastic agent indicated mainly as a first-line treatment for acute myeloid leukaemia and as a second- or third-line treatment for lymphomas. At high doses (>48g/m2), it may cause a pancerebellar syndrome characterised by ataxia, dysarthria, and oculomotor alterations.1 However, at a total dose <15g/m2, cytarabine-induced neurotoxicity is extremely rare, with very few published cases in the literature.2,3 We present the first case series of cerebellar toxicity in patients receiving low doses of cytarabine.

Between 2008 and 2013, 4 patients in our hospital developed cerebellar syndrome secondary to treatment with cytarabine. Tables 1 and 2 summarise patients’ baseline characteristics and clinical symptoms, respectively. All patients had lymphoma; they were receiving cytarabine as part of rescue chemotherapy after relapse due to first-line treatment failure. They had all completed at least one cycle of chemotherapy, that meaning that all patients had been in contact with cytarabine but had never manifested any neurotoxic effects. The dose of cytarabine was adjusted to each patient's age: the 2 patients older than 60 (patients 1 and 4) received half doses, whereas the 2 youngest (patients 2 and 3) received the standard dose. None of them had a history of kidney disease but 3 of them had pre-existing liver disease.

Table 1.

Patient characteristics at baseline.

Patient  Age (years)  History of liver disease  Tumour  Chemotherapy regimen  Cycle  Dose per cycle  Total cumulative dose 
77  HCV chronic hepatitis  DLBCL  R-DHAP  3rd  2g/m2  6g/m2 
57  HBV infection in the past  HD  DHAP  2nd  4g/m2  8g/m2 
49  None  Follicular lymphoma (NHL)  Hyper-CVAD  2nd  12g/m2  24g/m2 
71  Heterozygous for H63D, hepatic steatosis secondary to alcohol use, HBV infection in the past  Mantle cell lymphoma (NHL)  Hyper-CVAD  2nd  4g/m2  8g/m2 

HD, Hodgkin disease; DLBCL, diffuse large B-cell lymphoma; NHL, non-Hodgkin lymphoma; HBV, hepatitis B virus; HCV, hepatitis C virus. R-DHAP: chemotherapy regimen including cisplatin, cytarabine (2g/m2/12h during day 2 of the cycle), dexamethasone, and rituximab. Hyper-CVAD: chemotherapy regimen consisting of 2 cycles; the first one with cyclophosphamide, doxorubicin, vincristine, and dexamethasone, and the second with methotrexate and cytarabine (3g/m2/12h during days 2 and 3 of the cycle).

Table 2.

Clinical manifestations.

Patient  Creatinine (mg/dL)  SymptomsSeverity  Recovery 
    Ataxia  Dysmetria  Dysarthria  Other     
2.68  ++  ++  −  Moderate  Full 
3.56  ++  ++  ++    Severe  Partial 
3.61  +++  +++  +++  Confusion, somnolence, nystagmus, dysphagia, vomiting  Very severe  Death 
1.84  ++  −  Mild to moderate  Full 

Symptoms: –, absent; +, mild; ++, moderate; +++, severe/disabling.

Cerebellar symptoms appeared 3 to 5 days after the first dose of cytarabine was administered, and symptoms were always associated with acute renal failure. This loss of renal function had occurred 48 to 72hours previously and was attributed to either the toxic effects of another chemotherapeutic agent or to tumour lysis syndrome. Symptoms appeared suddenly in all cases and consisted of a pancerebellar syndrome characterised by ataxic gait, bilateral dysmetria, and dysarthria. The most severe of the cases (patient 3) also presented multidirectional nystagmus and a decreased level of consciousness. Symptom severity was directly associated with the degree of renal dysfunction (expressed as the serum creatinine level). Patient 3 was the only one to also present liver dysfunction secondary to drug toxicity.

All patients underwent a thorough aetiological study, including a CSF analysis and a brain MRI scan, which ruled out other possible causes of cerebellar dysfunction (vertebrobasilar stroke, CNS infection, tumour infiltration, or space-occupying lesion). Patients 1 and 4, who had received lower doses of cytarabine due to their advanced age but who at the same time were the ones with milder signs of kidney failure, showed more favourable outcomes, with symptoms resolving in the following 3 to 4 days. Patient 2, who was severely affected, was left with ataxic gait and mild bilateral dysmetria as sequelae. Patient 3, who presented the most severe neurological symptoms of all in addition to liver failure, died in the hospital.

Cerebellar toxicity is a dose-dependent secondary effect of cytarabine; high doses of this drug are therefore linked to the greatest risk of developing this syndrome. Given that cytarabine is mainly eliminated through urinary excretion of its inactive metabolite, age and kidney failure may decrease cytarabine excretion, leading to drug accumulation and neurotoxicity,4 even at standard doses as in our case series. Liver dysfunction has also been described as a risk factor for cerebellar syndrome secondary to cytarabine1; 3 of our 4 patients had a history of liver disease. In addition, some genotypes have been found to increase the likelihood of developing this syndrome, which may explain the considerable inter-individual variability in the toxic response to cytarabine.5 Although symptoms are normally mild and transient, they can also be severe and irreversible,6 as occurred in 2 of our patients. Prevention and early diagnosis are essential for avoiding long-term sequelae or even death. We recommend adjusting the dose to the patient's age, closely monitoring renal function, preventing volume depletion with adequate oral hydration, and treating kidney disease with fluid therapy.

Funding

This study received no funding of any kind.

Conflicts of interest

The authors have no conflicts of interest to declare.

References
[1]
W.J. Baker, G.L. Royer, R.B. Weiss.
Cytarabine and neurologic toxicity.
J Clin Oncol, 9 (1991), pp. 679-693
[2]
M. Yeshurun, K.M. Dupuch.
Acute cerebellar syndrome following intermediate-dose cytarabine.
Br J Haematol, 113 (2001), pp. 846
[3]
R.J. Cersosimo, R.T. Carter, S.J. Mathews, M. Coderre, D.D. Karp.
Acute cerebellar syndrome, conjunctivitis, and hearing loss associated with low-dose cytarabine administration.
Drug Intell Clin Pharm, 21 (1987), pp. 798-803
[4]
H. Hasle.
Cerebellar toxicity during cytarabine therapy associated with renal insufficiency.
Cancer Chemother Pharmacol, 27 (1990), pp. 76-78
[5]
D. Braunagel, M. Schaich, M. Kramer, C.L. Dransfeld, G. Ehninger, U. Mahlknecht.
The T_T genotype within the NME1 promoter single nucleotide polymorphism -835 C/T is associated with an increased risk of cytarabine induced neurotoxicity in patients with acute myeloid leukemia.
Leuk Lymphoma, 53 (2012), pp. 952-957
[6]
T. Zawacki, J.H. Friedman, J. Grace, N. Shetty.
Cerebellar toxicity of cytosine arabinoside: clinical and neuropsychological signs.
Neurology, 55 (2000), pp. 1234

Please cite this article as: Sainz de la Maza Cantero S, Jiménez Martín A, de Felipe Mimbrera A, Corral Corral Í. Toxicidad cerebelosa por citarabina: serie de 4 casos. Neurología. 2016;31:491–492.

This study was presented as an oral communication at the 66th Annual Meeting of the Spanish Society of Neurology.

Copyright © 2014. Sociedad Española de Neurología
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