Intracranial hypertension following intrathecal administration of liposomal cytarabine

Abstract

We report a case of cytarabine-induced intracranial hypertension. Liposomal cytarabine, a standard intrathecal chemotherapeutic, is a slow-release formulation of cytarabine produced by encapsulating the aqueous drug solution in spherical 20 lm diameter multivesicular lipid foam particles. With the 50 mg standard adult dose, sustained cytotoxic drug levels can be reached in the CSF over a 14 day period [1–5]. Neurological complications are arachnoiditis, myelitis, epilepsy, cauda equina syndrome, and toxic leukoencephalopathy [4–9]. A 27-year-old man was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL). After a low dose of intravenous (IV) cyclophosphamide and corticosteroids during 5 days, treatment was initiated consisting of cyclophosphamide 1,200 mg/m IV on the first day of chemotherapy (indexed as day 1), vincristin 2 mg IV on days 3-10-17, daunorubicin 45 mg/m IV on days 3–4, asparaginase 10,000 U/m IV on days 3-5-7-9-11-13-15, and oral methylprednisolone 80 mg from day 3 until day 24. Corticosteroids were tapered from day 24 onwards and stopped on day 39. Cerebrospinal fluid (CSF) analysis on day 2 revealed the presence of blast-like cells (in the absence of peripheral blood blasts) (Table 1). A gadolinium-enhanced brain magnetic resonance imaging (MRI) scan did not reveal any abnormalities. On days 2, 13 and 27 liposomal cytarabine was administered intrathecally. CSF analysis on day 27 was strictly normal (Table 1). An ophthalmological evaluation prior to each of these lumbar punctures was negative. On day 28, the patient developed an intense headache and lumbosacral pain associated with nausea, photophobia and sonophobia, and neck flexion rigidity. Mental status examination was normal. On day 28, he was on methylprednisolone 16 mg/d. Computerized tomography (CT) of the brain and CSF analysis (including cultures for bacteria and fungi and Cryptococcus antigen detection) were normal (Table 1). On day 33, the patient complained of diplopia and worsening headache. Clinical examination revealed a left abducens paresis and bilateral papilledema, with an elevated and hyperemic disc, more severe to the right with presence of numerous peripapillary retinal hemorrhages. Contrast-enhanced MRI of the brain and MRI venography were negative. A repeat lumbar puncture on day 34 revealed an elevated opening pressure of 46 mmHg, without other abnormalities (Table 1), leading to a diagnosis of liposomal cytarabine-induced intracranial hypertension. Intrathecal chemotherapy was discontinued, a single evacuating lumbar puncture was performed and acetazolamide was started (3 9 500 mg IV daily for 2 weeks, followed by 3 9 250 mg orally for 5 weeks). The abducens palsy recovered fully. A mild form of papilledema persisted, without visual loss. Six months later the patient was still symptom-free neurologically. Four similar cases of intracranial hypertension following intrathecal administration of liposomal cytarabine, most often after the third or fourth administration, have been reported before, three with acute myeloid leukemia and one with ALL [7–9]. The temporal sequence of events, with onset shortly after the third administration of liposomal cytarabine, and the nearly complete and prolonged recovery following discontinuation of cytarabine and initiation of acetazolamide, strongly argue against a neoplastic origin in S. Lunskens B. Bergmans R. Vandenberghe (&) Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium e-mail: rik.vandenberghe@uz.kuleuven.ac.be