Hemat case report

1. Atal Bihari Vajpayee Institute of Medical Sciences
and DR. Ram Manohar Lohia Hospital
Lamotrigine Induced Febrile Neutropenia and
Agranulocytosis-A Rare Case Report
Dr. Divya Tiwari, Dr. Manish, Dr. Gurmeet, Dr. Kavita, Dr. Garima Baweja, Dr. Vijay Kumar

2. Introduction
● Lamotrigine is a phenyltriazine based antiepileptic drug that blocks voltage-
gated sodium and calcium channels. It's FDA-approved for various types of
seizures and type-1 bipolar disorder [1].
● Lamotrigine often triggers skin problems but infrequently leads to severe
thrombocytopenia, neutropenia etc. These blood disorders may result from
complex metabolic reactions, including interference with dihydrofolate
reductase and hypersensitivity syndrome,presumed to be induced by
lamotrigine‐arene‐oxide intermediate [2].

3. ● A significant number of patients with bipolar disorder may be
prescribed three or more psychotropic drugs simultaneously which
increases the risk of agranulocytosis. Hence, vigilance for
agranulocytosis is crucial when treating bipolar disorder with
lamotrigine, especially in complex medication regimens [3],[4].

4. Case Report
A 24-year-old female, known case of seizure disorder, presented to the
emergency department with fever (high grade) and generalized body ache.
She had been on Tab. Lamotrigine and Tab. Clonazepam for two weeks.
Physical examination revealed mild splenomegaly, pallor, and blanching
erythema. Complete blood count and peripheral smear showed dimorphic
anemia and neutropenia.
Hb-7.1g/dl, TLC-1000/ul, DLC: N-26%, L- 72%, M-02%, Platelets-1.8 lakhs/ul,
HCT- 23.0%, MCV-77.4fl, MCH-23.9pg, MCHC-30.9g/dl, Reticulocyte count-2.4%

5. Peripheral Smear
RBCs showed mild to moderate
anisocytosis with normocytic
normochromic to microcytic
hypochromic cells along with few
tear drop cells and target cells.
WBCs revealed leucopenia with
relative lymphocytic prominence.
Platelets were adequate on smear.

6. ● To determine the cause of neutropenic high grade fever, blood and urine cultures, viral
PCR, and autoimmune workup were conducted. Despite antibiotic treatment, high-
grade fever persisted. A bone marrow aspiration and biopsy indicated marked myeloid
suppression, suggestive of agranulocytosis.
Bone marrow aspirate and Imprint smears were markedly hemodiluted comprising
mainly of normoblastic erythroid series cells with few megaloblasts and features of mild
dyserythropoiesis.Occasional megakaryocyte and very few scattered myeloid series
cells were seen.

7. Bone marrow biopsy mainly comprised
erythroid series cells, showing
predominantly normoblastic maturation.
Megakaryocytes appeared to be
increased, with a few showing features
of dysmegakaryopoiesis. Myeloid series
cells revealed marked suppression. A
fair number of lymphocytes, along with
procedural hemorrhage, were also
noted.

8. Predominantly lymphocytes
and erythroid series cells

9. Bone marrow biopsy findings in conjunction with peripheral smear and bone
marrow aspiration findings were suggestive of agranulocytosis, possibly drug
(lamotrigine) induced.
Lamotrigine was discontinued on 8th day of admission and Filgrastim injection
initiated. With Lamotrigine cessation, the patients counts started to improve
day 3 onwards, reversing myeloid suppression and neutropenia. WBC count
and ANC were normalised within a week, by day 7.The patient remained
afebrile for over a week under supervision, deemed fit for discharge (10 days after
stopping lamotrigine), provided close hematological follow-up would continue.

10. Discussion
● Idiosyncratic drug-induced agranulocytosis (IDIA) is a relatively rare
disorder, with an annual incidence of 2–15 cases per million [5].
● IDIA is a life-threatening disorder at any age, as well as in elderly subjects
presenting with several comorbidities, accounting for a mortality rate of 5–
20% [5].
● Classical causative drugs include antibiotics (49.3%), especially β-lactams
and cotrimoxazole; antithyroid drugs (16.7%); neuroleptic drugs, anti-
epileptic agents (11.8%) and platelet aggregation inhibitors (6.9%),
especially ticlopidine [6].

11. ● Poly-medication is a predisposing factor for IDIA [6].
● Lamotrigine-induced agranulocytosis has a tendency to occur at the early
phase of treatment, which is unlike clozapine that rarely induces
agranulocytosis within the first 6 weeks [3].

12. Conclusion
● Drug induced agranulocytosis can be reversed by cessation of causative
drug.
● This case underscores the rarity of drug-induced severe agranulocytosis and
the imperative need for early diagnosis and monitoring to prevent life-
threatening conditions like sepsis.

13. References
1.Mitra‐Ghosh T, Callisto SP, Lamba JK, et al. PharmGKB summary: lamotrigine pathway, pharmacokinetics and
pharmacodynamics. Pharmacogenet Genomics. 2020;30(4):81‐90.
2.Maggs JL, Naisbitt DJ, Tettey JN, Pirmohamed M, Park BK. Metabolism of lamotrigine to a reactive arene oxide
intermediate. Chem Res Toxicol. 2000;13(11):1075‐1081.
3.Solvason HB. Agranulocytosis associated with lamotrigine [letter] Am J Psychiatry. 2000;157:1704.
4.Cocito L, Maffini M, Loeb C. Long-term observations on the clinical use of lamotrigine as add-on drug in patients
with epilepsy. Epilepsy Res. 1994;19:123–127.
5.Andrès E, Zimmer J, Mecili M, Weitten T, Alt M. Clinical presentation and management of drug-induced
agranulocytosis. Expert Rev Hematol 2011; 4:143–51.
6. Andrès, R. Mourot-Cottet, F. Maloisel, F. Séverac, O. Keller, T. Vogel, M. Tebacher, J.-C. Weber, G. Kaltenbach,
J.-E. Gottenberg, B. Goichot, J. Sibilia, A.-S. Korganow, R. Herbrecht, Idiosyncratic drug-induced neutropenia and
agranulocytosis, QJM: An International Journal of Medicine, Volume 110, Issue 5, May 2017, Pages 299–305