Valgancyclovir‐induced encephalopathy in a child after hematopoietic stem cell transplant

Abstract

To the Editor: A 4-year-old female child, with transfusion-dependant β-thalassemia underwent 10/10-matched unrelated donor-hematopoietic stem cell transplant (HSCT). Conditioning regimen included intravenous thiotepa (8mg/kg/dayonday–7), intravenous treosulphan (14g/m2/dayondays –6 to–4), intravenous fludarabine (40mg/m2/day on days –6 to –3), and intravenous rabbit anti-thymocyte globulin (2.5 mg/kg total dose from day –3 to –1). Peripheral blood stem cells were used as the source of stem cells. Graft versus host disease prophylaxis consisted of short-course intravenous methotrexate and cyclosporine. She had bacterial sepsis prior to neutrophil engraftment, which was treated with antibacterial agents. She had white cell engraftment on day +13 and platelet engraftment on day +20. Whole blood cytomegalovirus (CMV) viral load was monitored twice a week after white cell engraftment. On day +27 and +31, the whole blood CMV viral load was 69 and 169 copies/mL, respectively. On day +35, viral load increased to 1998 copies/mL. She remained asymptomatic without signs of CMV disease. In view of a progressive increase in the CMV viral load, she was pre-emptively started on intravenous gancyclovir (5 mg/kg/dose q12 hourly). She was monitored for cytopenias and renal dysfunction. On day +46, the CMV viral load was 979 copies/mL. As per our institution policy, intravenous gancyclovir was changed to oral valgancyclovir at a dose of 450 mg/day (dose calculated using creatinine clearance as suggested by the United States Food and Drug Administration recommendation for pediatric organ transplant patients).1 She was discharged from the hospital on day +47. On day +49, she presented with one episode of right focal seizures with secondary generalized seizures. Clinically, cyclosporine-induced posterior reversible encephalopathy syndrome (PRES) was suspected. However, her blood pressure was normal for age. Her trough serum cyclosporine level was 190 ng/mL. She also developed one episode of high grade fever on day +49. Her sepsis screen was negative. Whole blood CMV viral load was 531 copies/mL and Epstein-Barr virus (EBV) PCR was negative. Magnetic resonance imaging of the brain was normal. She was empirically started on intravenous meropenem pending results of investigations. Cerebrospinal fluid (CSF) study demonstrated three white cells (all polymorphonuclear cells); CSF sugar was 67 mg/dL (corresponding blood sugar was 80 mg/dL), and CSF protein was 30 mg/dL. CSF PCR (Film Array – BIOFIREMeningitis/encephalitis panel) for seven viruses, six bacteria, and crytococcus was negative. Her medications included cyclosporine, valgancyclovir, twiceweekly liposomal amphotericin-B, cotrimoxazole, and urseodeoxycholic acid. She did not have any further episode of fever or seizures. On day +52, she developed somnolence and aphasia. Electroencephalogram showed generalized slowing of waves suggestive of diffuse encephalopathy. Her complete blood count, blood gas analysis, and liver and renal function tests were within normal limits. Her CMV viral load in whole blood was below the detection limit of <57 copies/mL at this time and the trough serum cyclosporine level was 200ng/mL. Since therewas no obvious cause for the encephalopathy, after thorough investigations, her drug list was scrutinized. On careful evaluation, valgancyclovir-induced encephalopathy was consideredas theetiological agent.Hence, valgancyclovirwas stoppedand replaced by acyclovir. Gradually, her sensorium improved. She started interactingwith her parents like beforewithin 24 h of stopping valgancyclovir and within the next 48–72 h, she did not have somnolence or aphasia and her sensorium completely normalized without any residual neurodeficit. Acyclovir, gancyclovir, and their pro-drugs such as valacyclovir and valgancyclovir are commonly used for treatment of CMV reactivation and disease. These drugs are generally well tolerated. However, they can cause central nervous system adverse events mostly reported in patients with renal failure.2 However, this child had normal renal functions throughout. Her creatinine clearance was 128 mL/min/1.73 m2 when she developed encephalopathy. The mechanism of action of gancyclovir-induced encephalopathy remains largely unknown.3 Neuropsychiatric symptoms after initiating gancyclovir can sometimes occur within 24 h after starting the antiviral treatment.4,5 Hussein et al6 reported symptoms occurring within 1–2 days of exposure to gancyclovir. Our patient had a similar occurrence. She developed features of encephalopathy on day 3 of initiating valgancyclovir. Interestingly, our patient tolerated gancyclovir for 11 dayswithout any neurological adverse events. A plausible explanation for this could be the per kilogram body weight dosing of gancyclovir as against a fixed dosing of valgancyclovir based on creatinine clearance, especially because children undergoing HSCT generally have normal renal function.7 In conclusion, the cause of encephalopathy in the post-HSCT setting can be multifactorial and difficult to ascertain. A drug-induced etiology must be suspected when all other causes are ruled out. Withdrawal of the drug and reversal of the symptoms can help in proving the diagnosis of a drug-induced adverse event. The dose for valgancyclovir in children is calculated as per creatinine clearance and as most children undergoing HSCT usually have normal creatinine clearance, they tend to be administered a higher dose of valgancyclovir. This may potentially be the cause of the toxicity observed due to valgancyclovir in this child who otherwise tolerated gancyclovir and acyclovir well.