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Carbamazepine induced leukopenia: A case series

This is a case series of 4 patients who developed leukopenia on, controlled-release carbamazepine (CBZCR) monotherapy for focal seizure prophylaxis. All 4 cases (2 males and 2 females), presented to the neurology department with history of episodes of sudden onset, abnormal body movements. Patients were diagnosed as cases of focal seizures and were prescribed tablet CBZ-CR 300 mg twice a day for seizure prophylaxis. One month later patients presented for follow-up and were continuing with the treatment. Blood biochemistry parameters indicated leukopenia with total leukocyte count less than 4000 per mm3. According to World Health Organization Uppsala monitoring Centre (WHO-UMC) causality assessment, all 4 cases were classified as ‘probable/likely’ for carbamazepine-induced leukopenia. Carbamazepine was continued and total leukocyte count gradually recovered on 3-months follow-up. Conclusion: Total leukocyte count should be documented before initiating carbamazepine therapy. Patients with pre-existing leukopenia should not receive carbamazepine. All patients receiving carbamazepine should be monitored for leukocyte count in addition to other blood biochemistry parameters. © This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction
'Seizure' refers to transient alteration of behavior due to abnormal, synchronous and rhythmic firing of brain neurons.Antiepileptic drugs are administered orally for seizure prophylaxis. 1 Carbamazepine is used widely for focal seizure and focal with secondary generalization seizures. 2 It blocks voltage-gated sodium channels, responsible for the rising phase of neuronal action potentials. 2 Hematological adverse effects include aplastic anemia, agranulocytosis and thrombocytopenia in 1 to 2%. 1,3 Decrease in total leukocyte count due to CBZ use is due to inhibition of colony stimulating factor in the bone marrow. 3 Incidence of leukopenia is 12% in children and 7% in adults. The leukopenia and neutropenia are more common in patients with low-normal pretreatment WBC or neutrophil counts and need frequent monitoring. Classically, WBC count may decrease by as much as 25% and this usually occurs within first three months of treatment. Leukopenia may persist in some cases without clinical significance. 4 Abnormality in CBZ metabolism and resultant toxic CBZ metabolites has been hypothesized as the cause of hematologic dyscrasias. The lymphocytes of CBZ hypersensitive individuals are susceptible to toxic arene oxide metabolites of CBZ in vitro. CBZ did not suppress cell proliferation or function in an in vitro study.It has been postulated that hematologic effects reported in early 1960s were due to impurities in original manufactured tablet. Refined manufacturing techniques, have decreased the impurities since then. 4 CBZ dose needs to be decreased or discontinued if WBC count falls below 3000/mm 3 or neutrophil count is below 1000/mm 3 or platelet count is less than 100,000/mm 3 . 5 Leukopenia usually reverses, even if CBZ treatment is continued. A risk of severe infections is there when the neutrophil count falls below 500/mm 3 . 6

Case
We are reporting case series of 4 patients (2 men & 2 women), from post-graduate academic thesis, who developed leukopenia within 4 weeks of CBZ-CR intake.
The patients visited neurology OPD with complaints of abnormal body movements. Each episode lasted for 3 to 5 minutes. No family history of seizures was there in any of the 4 cases. All 4 cases were having CT scan/MRI confirmed neurocysticercosis as the cause of seizures. The patients were diagnosed as cases of focal seizures. Mean age was 39.5 years for men and 23.5 years for women.
The baseline TLC was; 4400 (42 years male), 5200 (37 years male), 4600 (27 years female) and 6400 (20 years female) per mm 3 . Patients had no history of drug or food allergy. They were randomly allocated to CBZ-CR 300 mg orally twice daily arm. Adverse effects like somnolence and dizziness were reported by all 4 patients. They were advised to continue the treatment.
At 1 st month follow-up all 4 cases were seizure free, without any complaints. Blood biochemistry revealed normal results except for leukopenia. The TLC was 3900, 3790, 3600 and 3800 per mm 3 respectively. Treatment was continued.
At 3 rd month follow-up 3 patients were seizure free, while the 20 years old woman had breakthrough seizure for which her evening dose of CBZ-CR was raised to 400 mg. All blood biochemistry parameters were within normal limits. The TLC rose above 4000/mm 3 for all the 4 patients. The TLC was reported as 5800, 6000, 5400 and 4800 mm 3 respectively. The patients were diagnosed as cases of carbamazepine induced transient leukopenia. Treatment was continued.
At 6 th month follow-up all the patients were seizure free. Also, all biochemistry parameters were within normal limits. The TLC was 5700, 6100, 5600 and 5100 per mm 3 respectively. According to the World Health Organization Uppsala monitoring Centre (WHO-UMC) causality assessment system, the cases were classified as 'probable/likely' for carbamazepine-induced transient leukopenia.

Discussion
There is evidence of leukopenia due to carbamazepine use. In our study 4 patients developed transient leukopenia, 1-month after CBZ intake. They were classified as drug induced leukopenia.
Owens CW. et al. 7 (1980)reported a case of 61 years patient in which TLC was reduced to 1300/mm 3 from the baseline 9600/mm 3 after 48 days of treatment with CBZ. This reduction was evident on blood biochemical profile because patient was suffering from malaise, sore throat and fever. Patient was suffering from oral candidiasis secondary to drug induced leukopenia. CBZ was discontinued and TLC raised to 2700/mm 3 after 8 days.
Sabotka JL. et al. 4 (1990) recommended that all patients receiving CBZ, should have CBC prior to initiation of treatment. Patients should be advised to report immediately if signs and symptoms such as infections, fever, fatigue, ecchymosis and bleeding through mucous membranes appears.
Hughes JR. et al. 8 (1995) reported 28 (21.4%) cases of leukopenia at some point during treatment out of total 131 patients receiving CBZ and 18 (13.7%) cases out of 131 in control arm (p=0.072). They also reported that decrease in TLC was associated with increase in CBZ dose.
Daughton JM. et al. 9 (2006) concluded that prompt reduction or withdrawal of CBZ is warranted based on laboratory investigations. Anti-infectious therapy may also be necessary in symptomatic cases of infection due to underlying leukopenia.

Conclusion
Cautious monitoring and patient education regarding adverse events are of paramount importance, after starting therapy with any drug. Keeping in mind the possibility of drug induced leukopenia, it is imperative to investigate complete blood counts before initiating CBZ therapy and follow-up regularly. Patients with pre-existing leukopenia should not be treated with CBZ.

Source of Funding
No financial support was received for the work within this manuscript.

Conflict of Interest
The authors declare they have no conflict of interest.