An infant with high-dose Cytarabine induced cerebellar

involution:
a case report and review of the literature.
Guido Alarcón, Mary Lou Schmidt, Saba Ahmad, Micaela Della Torre, Edward Michals, John G. Quigley,

Hernán Sierra-Fernández.
University of Illinois Chicago College of Medicine,

840 S Wood St, Chicago IL, 60612

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Introduction:

We report the case of a 10-month-old infant with a history of prenatal exposure to high dose Cytarabine
for maternal Acute Myeloid Leukemia (AML), who presented to the pediatric hematology oncology clinic
with abnormal head movements. An MRI showed involution of a previously normal cerebellum.

The patient’s mother was treated at 14 weeks gestation with a standard AML induction chemotherapy
course (7+3, 7 days of Cytarabine 100mg/m2 CIV and 3 days of Daunorubicin 90mg/m2 IVP). Eight weeks
later, due to the continued rapid growth of her persistent AML, she was re-induced with a high dose
Cytarabine/Mitoxantrone regimen (Cytarabine 2g/m2 iv q12 h and Mitoxantrone 30mg/m2 on days 1 and
5 (1)). Ten days after the last dose of Mitoxantrone a 440 gram, 25 weeks gestational age infant was
delivered with severe pancytopenia that resolved within a week after multiple transfusions and G-CSF. No
other significant complications occurred in the infant. We discharged her after three months, with the
diagnoses of extreme prematurity and low-grade intraventricular hemorrhage, with hypotonia noted on
exam. No cardiac issues were noted at discharge or at the two-month follow up. The mother recovered
her counts within 4 weeks, as expected with her re-induction chemotherapy; there was no evidence of
hepatic, renal or neurological toxicity during this re-induction period.

At four months corrected age, the infant presented with “head bobbing”. Neurologic assessment
confirmed head titubations. An MRI showed near absence of the cerebellum and atrophy of the frontal
lobes (Image 1). Review of a fetal ultrasound before chemotherapy (Image 2A), and a postnatal head
ultrasound on day one of life showed presence of the cerebellum on both occasions. (Image 2B).
Radiological evaluation was performed, looking for acute changes suggestive of a vascular event. However
serial ultrasounds demonstrated a progressive cerebellar process, making a vascular event less likely.

Discussion:

High dose Cytarabine (at doses of 3g/m2) for AML was introduced into clinical practice in the early 1980s
due to its improved efficacy in consolidating remission when compared to conventional or intermediate
dosing. Cytarabine is an anti-metabolite, which disrupts DNA synthesis in dividing cells. High dose
Cytarabine has been noted to be toxic to the cerebellum for reasons that are incompletely understood.

There are 103 cases reported in the literature of the use of Cytarabine in AML during pregnancy. The most
common adverse effect observed is blood disorders, seen in 12% of the patients. No cardiac, neurologic
or development disorders were observed in follow up visits (2–5). However, there have been few long-
term studies of cardiac abnormalities, leukemia or neurologic disorders, which may present even decades
after exposure (6). The literature on high dose Cytarabine during pregnancy is also scant. Only 5 cases
have reported on the effects of high dose Cytarabine (1-3 g/m2). The outcomes in these reports were
mainly blood disorders during the newborn period, with normal development, neurologic and cardiac
status reported at follow-up visits (3,7,8).

Preclinical studies have demonstrated cerebellar cytotoxicity in rats and in in vitro studies of neurons
(9,10). Adult patients have reported ataxia before demonstrable imaging changes. There is one report of
cerebellar involution on MRI Images 10 years after exposure to high dose Cytarabine (11). The incidence
of cerebellar toxicity 5 to 7 days after exposure to high dose Cytarabine was found to be 16.7 % in a case
series (12) , with post-mortem analysis of cerebellar tissue indicating selective Purkinje cell loss in the
cerebellar cortex (11,12). Purkinje cells are post-mitotic cells and are the primary output for motor
coordination. They have an elaborate dendritic arbor and their function requires expression of a large

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number of unique genes. It remains unclear why an anti-metabolite would be selectively toxic to a post-
mitotic cell, however it is postulated that the complexity of these cells (with likely increased rates of DNA
synthesis for gene amplification, synaptogenesis, and pruning) may increase their susceptibility to toxicity
from anti-metabolites (13,14).

Additionally, it is believed that the Purkinje cells and those of the granular layer are particularly sensitive
to oxidative stress, resulting in DNA breakages, poor DNA repair capacity and, ultimately, programmed
cell death (9,15). Lastly, cytarabine also exerts cytoskeletal effects on cerebellar cells, decreasing
neurofilaments. It is postulated that this may also result in neuronal calcium (10).

We hypothesize that in this patient's rare clinical presentation, high dose Cytarabine affected the Purkinje
cells during the proliferative phase of neuronal development (which occurs throughout brain maturation
but has two peaks: 2-4 months of gestation and then 5-12 months post-natal), causing apoptosis of
Purkinje cells and abnormal or absent dendritic connections in those that survived. The loss of Purkinje
cells plus the lack of synapses in surviving cells, led to a significant underdevelopment of synaptic
connections (normally 200,000 per Purkinje cell) and a consequent involution of neighboring cerebellar
neurons by a process called “organization and pruning". This is a neuronal growth process, by which
neurons that fail to make necessary synaptic connections involute, and those that make appropriate
synaptic connections strengthen. This process of "toxicity followed by involution" could explain the clinical
picture observed in our patient in which the cerebellum was observed in pre- and postnatal ultrasounds
but was absent at nine months of age.

We conclude that this patient’s neurological findings are likely secondary to in-utero exposure to high
dose Cytarabine causing cerebellar toxicity in the fetus during the second trimester—previously
unreported in the scientific literature. We recommend caution with use of high dose Cytarabine during
pregnancy, as well as discussion of the risk of infant cerebellar dysfunction during prenatal counseling of
mothers undergoing chemotherapy with high dose Cytarabine as part of their AML treatment. Lastly, we
recommend that physicians providing long term care for these patients consider some form of
neuroimaging as part of their follow up care.

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Acknowledgments: Danilo Noboa M.D. Research Assistant University of Illinois at Chicago College of
Medicine

Authorship Contributions:

Alarcon, Guido; University of Illinois at Chicago College of Medicine

Schmidt, Mary Lou; University of Illinois at Chicago College of Medicine, Department of Pediatrics, Division
of Hematology/Oncology.

Ahmad, Saba; University of Illinois at Chicago College of Medicine, Division of Pediatric Neurology

Della Torre, Micaela; University of Illinois at Chicago College of Medicine, Division of Maternal Fetal
Medicine

Michals, Edward; University of Illinois at Chicago, Department of Radiology

Quigley, John; University of Illinois at Chicago. Department of Medicine, Division of

Hematology/Oncology.

Sierra-Fernandez, Hernan; University of Illinois at Chicago College of Medicine, Division of Neonatology

Disclosure of Conflicts of Interest:

The authors do not have a financial relationship with the company or companies that develop the
products described in this case report.

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