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Delirium Likely Caused by Interaction Between Phenytoin and Temozolomide

TO THE EDITOR: Delirium is a frequent complication of treatment in hospitalized medical patients; it has known risks for morbidity, mortality, and increased length of hospital stay. We present a case of an individual undergoing treatment for metastatic brain tumor with subsequent delirium likely related to possible interaction between temozolomide, an agent used in cancer chemotherapy, and the widely-used antiepileptic drug, phenytoin (Dilantin). The patient was seen on an urgent outpatient assessment basis by our psychiatric consultation service.

Case Report
"Mr. X" is a 68-year-old gentleman who was in good health before the onset of personality change and word-finding and memory difficulty. He was diagnosed with a high-grade glioma. He underwent subsequent surgical left-temporal lobectomy and had pathology confirmation of a Grade III oligoastrocytoma. Postsurgically, he was placed on dexamethasone taper and Dilantin and was discharged. At no point were seizures noted. He participated in rehabilitation services and was discharged home with notable expressive aphasia, whereas abilities in walking, balance, coordination, and vision were maintained. He then underwent two treatment cycles: in mid-April, with both external-beam radiotherapy and temozolomide, and then again in June 2005, at a substantially increased temozolomide dosage of 400 mg daily. Medications at that time included Dilantin 250 mg bid, Protonix 40 mg per day, terazosin 10 mg at night, Colace, multivitamins, Zofran prn, and Lovonox bid. The clinic was contacted by the patient’s family on July 11th with the complaint that he was: "constantly picking at things that are not there, is easily agitated, and gets confused at times." Haloperidol 0.5 mg bid was begun. When seen by the psychiatric consultation service in the clinic in July 2005, the patient manifested continued difficulty, characterized by increased confusion, visual hallucinations involving insects and mice, poor sleep and restlessness at night, and inability to walk unaided. Dilantin level checked at that time had increased abruptly to 34.1. Dilantin had been adjusted to 250 mg bid mg daily by about April of that year, and levels checked at that dosage ranged between 12.3 mcg/ml and 22.9 mcg/ml through June 24, 2005 (reference range: 10.0–20.0). Serum chemistries and liver enzymes were noted as within normal limits; he demonstrated a low (stable) serum protein of 5.2 g/dl (range: 6.0–8.2), and albumin was 3.5 g/dl (range: 3.5–5.2). MRI at that time demonstrated a small subdural hematoma felt to be unchanged from his previous recent study. He also demonstrated (again stably) low white blood-count indices of 2.78,000/µl (range: 4.3–10.0) and had a platelet count of 126,000/µl (range: 150–400). Urinalysis was within normal limits, as well.

As compared with his previous neurologic evaluation, he was profoundly confused, averbal, and unresponsive to most questions. No new focal neurologic findings were evident. Given the rapid onset and marked changes in behavior, cognition, hallucinations, and sleep-wake cycle, the etiology for mental-status change was felt to be most consistent with delirium. Without any alteration in the patient’s medical regimen or condition, it was felt that the cause for his delirium was likely closely related to an increase in Dilantin levels induced by interaction with temozolomide. The patient was subsequently lost to follow-up.

Discussion
Review of the literature suggests that although cases of delirium or encephalopathy have been noted with Dilantin,¹ a substantial majority occur in the setting of either hepatic compromise^2,3 or drug–drug interaction.^4–6 Cases outside of accidental overdose or significant CNS compromise appear to be relatively uncommon and usually respond to medication withdrawal and supportive care.⁷ A recent review by Beenen et al.⁸ suggests that in postcraniotomy patients similar to ours, Dilantin prescribed for seizure prophylaxis is generally fairly well-tolerated. Given the evidence for stable dosing based on previously-drawn levels and intact hepatic functioning, it seems most likely that the increased Dilantin levels and delirium resulted from a drug–drug interaction. Unlike Shores et al.,⁹ we were not aware of the characteristic visual side effects, such as diplopia or changes of color vision in our patient.

Metabolism of Dilantin occurs in large part via the liver cytochrome P450 system. This creates the potential for adverse drug–drug interactions via other compounds that are also substrates via specific inhibition of the CYP2CP enzyme pathway.¹⁰ Patients after treatment for either primary or secondary brain metastases frequently become candidates for both chemotherapy and treatment for seizure prophylaxis. Reviews have highlighted the concerns with antiepileptics’ potential for interaction with chemotherapeutic agents often used postsurgically and the resultant adverse effects.¹¹ These would seem to be significant concerns for potential patients. Given the timing in our patient and the significant adverse outcome, we would suggest the possibility that this was the first note of an interaction via the cytochrome P450 CYP2C9 system between temozolomide and Dilantin. Oberndorfer et al.,¹² in their case series, did not note adverse outcomes in those patients jointly treated with temozolomide and Dilantin with regard to hemotoxicity or survival; they do not comment on delirium or confusion resulting from the combination. Dilantin serum levels were not reviewed.¹² We would suggest the possibility of such interactions, but we do agree with their recommendation for caution and consideration of alternative antiepileptic agents in patients after cancer surgery and treatment.

REFERENCES

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