Carbamazepine-induced delayed-onset agranulocytosis in a case of bipolar disorder with Kikuchi’s disease

Background

A 48-year-old married man with no significant family history was being treated for bipolar disorder from our centre from 2015. He had comorbidities of nicotine dependence, systemic hypertension and anaemia. There is history of vitamin B₁₂ deficiency, which was corrected. The patient was maintaining well on carbamazepine (600 mg/day) and quetiapine (600 mg/day) until June 2018, when he developed fever, persistent vomiting, leucopenia, lymphadenopathy, and a significant loss of weight and appetite. With regard to the leucopenia, it was a combination of both neutropaenia and lymphopaenia, with predominant neutropaenia and one documented agranulocytosis in June 2018.

Investigations

Over the next 2 weeks, the treating medical team investigated thoroughly. Blood cultures done showed no growth. Bone marrow showed no granulomas/atypical cells or dyserythropoiesis/megakaryocytosis. Fungal, mycobacterial and bacterial cultures from bone marrow were all sterile. No major abnormality was found on cross-sectional imaging of his thorax and abdomen while looking for intra-abdominal lymphadenopathy which could be biopsied or any abdominal masses. Upper and lower gastrointestinal scopies ruled out any occult malignancies that may not have been seen through CT scan.

Lymph node biopsy (figure 1) showed reactive lymphoid follicles and patchy paracortical and interfollicular foci of necrosis, with surrounding paracortical regions showing a few transformed large mononuclear cells, resembling immunoblasts. The areas of necrosis are surrounded by lymphoid cells, a few plasma cells and occasional plasmacytoid-appearing mononuclear cells. There were no obvious eosinophils or neutrophils in the levels examined and no definite granulomas or any morphological evidence of atypical abnormal lymphoid cells, and the stains for acid fast bacilli and fungi were negative. In view of these features, Kikuchi’s disease was considered the likely histological diagnosis. A possibility of drug-induced myelosuppression was also considered.

Differential diagnoses

The various differential diagnoses considered for investigations were lymphoproliferative malignancies such as lymphoma and leukaemia, macrophage-activating syndromes such as haemophagocytic lymphohistiocytosis, disseminated tuberculosis, chronic malaria, HIV infection, chronic parasitic infection with bowel obstruction and malabsorption, hypocortisolaemia secondary to steroid abuse and superadded infections, drug-induced myelosuppression (secondary to carbamazepine/quetiapine), megaloblastic anaemia secondary to vitamin B₁₂ or folic acid deficiency, infiltrative disorders such as sarcoidosis, and disseminated solid organ malignancies.

Treatment

The consulting psychiatrist noted that there were fluctuations in leucocyte counts despite the psychiatric medications being continued, as depicted in figure 2. It was decided to stop carbamazepine since it is known to cause myelosuppression. The caregiver revealed that the patient had been having few depressive symptoms for a few weeks prior to admission. Hence, the dose of quetiapine was increased to prevent any crisis situation given its mood-stabilising properties. There was gradual improvement in counts after carbamazepine was stopped, as depicted in figure 2. After around 10 days, the medical team reported that evaluations for other causes of agranulocytosis had not yielded results and that that the total counts were gradually improving. Given that he has been off carbamazepine, there is a possibility that the quetiapine could also be contributing to the low counts. Therefore, we considered other options including stopping quetiapine and starting lithium as a mood stabiliser. However, 20 days after stopping carbamazepine, total and differential counts returned to normal and the patient was planned for discharge.

Outcome and follow-up

The patient’s counts improved and he was discharged on maintenance dose of quetiapine. The diagnosis of drug-induced myelosuppression was retained. The patient was maintaining well on follow-up after a year.