1Clinical Pharmacist, Sharp Grossmont Hospital, San Diego, California
2Medical Toxicology Fellow, California Poison Control System – San Francisco,Division, University of California, San Francisco
3Managing Director, Professor of Clinical Pharmacy, California Poison Control System – San Francisco Division, Department of Clinical Pharmacy, University of California, San Francisco, School of Pharmacy
Received: 10 June 2014 Accepted: 22 July 2015 Published: 29 July 2015
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Lamotrigine, Pancytopenia, Agranulocytosis, Sepsis
Drug induced pancytopenia is a serious adverse reaction that can be fatal due to the lack of early detection and treatment. A number of case-reports suggest that lamotrigine (LTG), a second-generation anticonvulsant, is associated with blood dyscrasias. [1-25] Despite multiple serious case reports, one reported fatality, and manufacturer recognition of LTG- induced haematological abnormalities upon drug initiation, current guidelines for monitoring still do not exist. Here, we report a life-threatening case of LTG- induced pancytopenia leading to sepsis and provide a literature review of case reports.
A 25- year- old hypotensive and febrile female reported to the emergency department following a 3 week course of LTG. On admission, the patient was found to be septic with pancytopenia. The patient was transferred to the ICU and was successfully treated with fluid resuscitation, vasopressor therapy, broad-spectrum antibiotics, and granulocyte colony stimulating factor. The patient was discharged home on hospital day 6 with an alternative anticonvulsant regimen of topiramate and levetiracetam.
We provide evidence of a temporal relationship with the initiation and discontinuation of LTG therapy that suggests LTG was a probable cause of pancytopenia that led to sepsis in this patient. Clinicians need to be aware of this serious adverse event and should be informed on the importance of performing routine haematological monitoring during the induction of LTG therapy.
LTG is in a class of second-generation anticonvulsants which was developed for its improved side-effect record and reduced need for monitoring [1,26]. LTG has been favoured for its claimed benefit of an improved adverse reaction profile over older anticonvulsants [27,28]. Although thought to be a safe treatment option for patients with epilepsy, there have been a number of case reports in post-marketing use of LTG and manufacturer acknowledgment suggesting that there is a risk for development of haematological abnormalities during LTG initiation [29]. We report a life-threatening case report of LTG-induced pancytopenia that led to an ICU admission and sepsis.
A 25-year-old white woman presented to the emergency department (ED) of a local hospital with a two-week history of persistent fever, productive cough, vomiting, malaise, and headache. The patient reported having a small wound on her right finger that led to swelling and pain upon contact with a piece of rotten fruit. On presentation, her vital signs included temperature 38.3oC, blood pressure 81/46 mmHg, heart rate 105 beats/min, respiratory rate 24 breaths/min, and O2 saturation 100%. On physical exam, she was lethargic, dehydrated with dry mucus membranes, but awake and oriented. Her skin examination showed right finger cellulitis with bloody discharge, and the rest of exam was normal.
Her past medical history was significant for a 13-year history of absence and juvenile myoclonic seizures with no prior history of infection. Three weeks before her presentation, she episodes of myoclonus. At that time, the patient was on levetiracetam (LEV) 1000 mg orally twice daily and no other concurrent medications. On this visit, the patient’s LEV was increased (2,500 mg daily) and was also started on lamotrigine (LTG) with the following titration schedule: 25 mg orally twice daily on week 1, 50 mg twice daily on week 2, 75 mg twice daily on week 3, and 100 mg twice daily on week 4. At the time of admission she was on week 3 of was seen by her neurologist for daily the titration regimen and taking LTG 75 mg twice daily and LEV 2,500 mg daily. She admitted to smoking marijuana daily but denied drug or alcohol use.
In the ED, she was immediately started on intravenous (IV) fluid resuscitation and received a total of 6 litters of normal saline with improvement in her blood pressure, but became oedematous and was given 20 mg of IV furosemide to manage her fluid overload. Vasopressor therapy was initiated with norepinephrine and titrated to a mean arterial pressure of 65 mmHg. Additionally, LTG and LEV were discontinued. Blood cultures were sent and she was started on empiric antibiotic therapy with ceftriaxone and vancomycin for a presumptive diagnosis of pneumonia versus cellulitis. The patient was admitted to the intensive care unit (ICU) and remained hypoxic and tachycardia.
Initial laboratory tests revealed pancytopenia as evidenced by a haemoglobin of 8.9 g/dl [reference range 12-16 g/dL], hematocrit 25.3 % [36-47%], white blood cell count (WBC) 0.8 x103/uL [4.8-10.8 103/uL], absolute neutrophil count (ANC) 0.0 x 103 cells/uL [1.9-8.0 103/uL], and platelets 82 x 103/uL [130-400 103/uL]. The progression of her WBC, ANC, and platelet counts are illustrated in Figure 1. Blood counts prior to LTG therapy never revealed a past history of blood dyscrasias. Her chemistry panel also showed multiple electrolyte imbalances: sodium 129 mmol/l , potassium 2.9 mmol/l, chloride 95 mmol/L, bicarbonate 23 mmol/l , BUN 8 mg/dl , creatinine 1.1 mg/dl , glucose 152 mg/dl, calcium 7 mg/dl, magnesium 1.4 mg/dl, and phosphorus 1.2 mg/dl. Her lactate was 2.2 mmol/l [0.5-2.2 mmol/L], and C-reactive protein (CRP) was 29.23 mg/dl [0.0-0.7 mg/dL]. Liver function tests were normal with aspartate aminotransferase (AST) 21 U/L [10-38 u/L] and slightly elevated alanine aminotransferase (ALT) 74 U/L [0-34 u/L]. Urine toxicology screen was negative for amphetamine, benzodiazepine, cocaine and opiates, but was positive for cannabinoid.
In the ICU, the patient remained hypotensive and febrile. She had central line placed and required norepinephrine for two days and was weaned off gradually as her BP improved. Her electrolytes were repleted and laboratory results during the ICU course showed negative blood/urine cultures and negative serologies for HIV, Hep B, Hep C, and TB. The pathologist’s review of the blood smear was reported as “pancytopenia with severe leukopenia, neutropenia and normocytic anemia which could be consistent with drug induced agranulocytosis”.
The patient was treated with granulocyte colony stimulating factor (G-CSF) 300 micrograms subcutaneously daily for four doses from hospital day 1 to 4. The patient was also initiated on topiramate 25 mg orally twice daily in the ED, but had a seizure on hospital day 3. The decision was made to increase the topiramate to 100 mg orally twice daily and re-start LEV 1000 mg orally twice daily. The patient remained seizure free for the remainder of the hospital stay.
On day four of the patient’s hospital course, the patient’s WBC, ANC and platelets peaked at 42.4 x103/uL, 37.6 x103/uL and 249 x103/uL respectively. By day six, the patient’s WBC, ANC and platelets trended down to 22.4 x103/uL and 19.1 x103/uL and 182 x103/uL respectively (see Figure 1). The patient was discharged to home on topiramate 100 mg orally twice daily and LEV 1000 mg orally twice daily. Ten days after discharge, the patient had a follow-up visit with an outpatient physician and laboratory results revealed a WBC 3.4 x103/uL.
Figure 1: White blood cell (WBC), absolute neutrophil count (ANC), and platelet count at 19 months pre-admission until 10 days postadmission. Lamotrigine (LTG) initiated 3 weeks prior to admission on an escalating dose regimen, week 1 = 50 mg/day, week 2 = 100 mg/ day, week 3 = 150 mg/day. LEV= levetiracetam; G-CSF = granulocyte colony stimulating factor
The mechanism by which LTG-induced blood dyscrasias occur is unknown [25]. After conducting a thorough literature search for English articles using PubMed from January 1940 to December 2012 and the Cochrane Library from January 1960 to December 2012, we identified 30 cases with a spectrum of blood dyscrasias associated with LTG that varied, and included neutropenia, thrombocytopenia, leukopenia, anemia, pancytopenia, and agranulocytosis. Table 1 provides a summary of case reports of LTGinduced blood dyscrasias from our literature review [1-25] . Table 2 provides the occurrence of adverse reactions reported by the manufacturer in the prescribing information for the drug, Lamictal. It is noteworthy that the incidence of pancytopenia was not listed by the manufacturer, although leukopenia was described as “infrequent” and other hematologic and lymphatic system adverse reactions described as “rare” [30].
Table 1:
Table 2: Adverse Events and Side Effects Reported by the Manufacturers of the Drug Lamotrigine
Most of the hematologic reactions associated with LTG occur during the initial stage of treatment, between one and four months [1,25]. In all reported cases, discontinuation of LTG or dose reduction, with or without supportive care, lead to complete recovery [1,19,20,29,31]. Failure to discontinue the drug during development of haematological abnormalities can be fatal. There is one fatal case report of a 40 year old woman who developed agranulocytosis after starting therapy that included LTG in combination with other psychotropic medications [25]. It was suspected that the fatality of that case was a direct result of a delayed response to discontinue the patient’s LTG and other psychotropic medications upon recognition of agranulocytosis.
Our patient had features of pancytopenia with anemia, leucopenia and thrombocytopenia which have been previously reported as possibly associated with LTG use [4,31]. However, some of these cases were associated with a hypersensitivity reaction and generalized rash [4,32]. There are other reports of an atypical LTG- induced drug reaction and purpura observed 2 months after initiation of therapy [33]. Our patient did not have any skin manifestations suggestive of a hypersensitivity reaction apart from the cellulitis in her arm.
An objective causality assessment using the Naranjo scale yielded a score of 7, indicating a probable adverse drug reaction in our case. We suspected LTG-induced haematological abnormalities in our patient because of the close temporal relationship between the initiation of LTG and the onset of symptoms, improvement with LTG discontinuation, pathologist’s review of blood smear, results of appropriate laboratory tests ruling out other pathologies, re-challenge with levetiracetam without LTG not resulting in pancytopenia, and the normalization of blood counts after discharge. Some case reports demonstrated that LTG induced leukopenia persisted even after stopping other anti-epileptic drugs and increasing the dose of LTG [15]. Others have re-challenged their patients with LTG after a potential episode of LTG-induced neutropenia which resulted in the recurrence of neutropenia demonstrating a strong causality association [8]. A re- challenge with LTG was not performed in our patient.
The possibility of other aetiologies or contributing factors for this patient’s pancytopenia cannot be definitively ruled out. Improvement of blood counts coincidental with a de-challenge of LTG is not definitive proof of causation. Our patient was ill for approximately two weeks with a possible viral illness or bacterial infection, which could have been a potential etiology for her neutropenia [34]. However, our patient improved after stopping LTG and she had significant bone marrow suppression and pancytopenia within two weeks of LTG therapy. Additionally, we are unaware of any published cases of an association between marijuana use and pancytopenia. Furthermore, our patient admitted to chronic daily use of marijuana suggesting this to be an unlikely cause of this patient’s presentation.
This report provides further evidence of a causal link between LTG and pancytopenia. We have not found similar reports of patients developing severe sepsis following lamotrigine initiation. There are no current recommendations in the manufacturer’s package insert for complete blood count monitoring during LTG therapy. Clinicians need to be aware of this serious adverse event and should be informed on the importance of performing routine haematological monitoring during the induction of LTG therapy.
Authors reported no conflicts of interest.
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