Pure Red Cell Aplasia after 13 Years of Sodium Valproate, and Bone Marrow Suppression after 17 Years of Carbamazepine

A 38-y-old woman with Down syndrome was admitted to hospital for investigation of a 6-mo history of anorexia and weight loss of 40 lbs. Six months prior to admission, her weight was 175 lbs, and her body mass index was 36. On admission, her complete blood count was normal, but over a 2-wk period she developed acute pancytopenia (Figure 1). During this acute episode, her lowest hematological parameters were as follows: hemoglobin (Hb), 80 g/l (normal range 120–160 g/l); mean cell volume (MCV), 121 fl (80–95 fl); white blood cell count (WBC), 2.9 3 10/l (4.8–10.83 10/l); absolute neutrophil count, 1.1 3 10/l (1.5–6.2 3 10/l); and platelet count, 763 10/l (150–3503 10/l). She had been taking carbamazepine for 17 y and sodium valproate for 13 y for a mixed seizure disorder. At age 22 y, before starting any anticonvulsants, her baseline hematological parameters were as follows: Hb,123 g/ l; MCV, 106 fl; platelets, 296310/l; and WBC, 10.7 3 10/l. After starting carbamazepine, her WBC dropped to 4.5–5.53 10/l, and her absolute neutrophil count dropped from 93 10/l to about 2.53 10/l. When the sodium valproate was added, her MCV increased to 112 fl, her platelet count fell to 100–150 3 10/l, and her Hb dropped to 110–120 g/l. The patient’s other medications on admission were carnitine and low-dose L-thyroxine for hypothyroidism; she had been taking both for several years. She had not been recently exposed to any new medications, environmental toxins, or over-the-counter dietary supplements. There was no family history of aplastic anemia. The patient lived at home with her mother, who cares for her and has legal guardianship. A bone marrow biopsy (Figure 2) showed a hypocellular bone marrow with a normal myeloid:erythroid ratio and no malignant cells or megaloblastic changes. Cytogenetic study showed a Robertsonian (i.e., of the whole arms) translocation of Chromosome 14 and 21 involving the long arm of Chromosome 21. Except for mild adrenal insufficiency noted on an adrenocorticotropic hormone stimulation test, all her tests, including viral and immunological investigations to identify known causes of aplastic anemia, were negative. The patient’s thyroid function tests were normal. She was started on low-dose hydrocortisone for her adrenal insufficiency and megestrol acetate to increase her appetite. The patient’s carbamazepine was discontinued. Within 10 d, her WBC had risen to 6.7 3 10/l and her platelet count to 2483 10/l. Serial complete blood counts showed worsening anemia over the next 15 wk, requiring two packed red blood cell transfusions at week 6 and week 14, when her Hb was 31 and 53 g/l, respectively. Throughout this period, her reticulocyte count was low, at about 0.18% (normal range 0.5%–2%), while her WBC and platelet count were normal. We made a diagnosis of pure red cell aplasia (PRCA). A second bone marrow biopsy under minimally conscious sedation was unsuccessful, and the patient declined further attempts. After the first transfusion she was started on prednisone and erythropoietin for her PRCA. Meanwhile, because of her worsening seizures, we increased her sodium valproate dose, increasing her serum valproate level from 70 mcg/ml to 110 mcg/ml. After the second transfusion, we discontinued her sodium valproate and started her on clonazepam and oxcarbazepine as alternative anticonvulsants. The patient had a brisk reticulocyte response. Her reticulocyte count rose from 0.36% to 0.78% in the second week and to 6.61% in the fourth week after stopping the valproate. Six weeks after stopping the drug, her Hb was 125 g/l and her MCV was 106 fl,