Evaluation of Anticonvulsant-Induced Leukocytosis: A Review of Evidence for Carbamazepine, Lamotrigine, and Phenobarbital

Abstract

Objective: The objective was to determine the incidence of leukocytosis associated with carbamazepine, lamotrigine, and phenobarbital. Data sources: A comprehensive literature review was conducted with the assistance of a medical reference librarian on PubMed, MEDLINE, Embase, and Google Scholar through June 2023 using the following search terminology: “leukocytosis/chemically induced”[MeSH Terms] AND (“Anticonvulsants”[MeSH Terms] OR (“Anticonvulsants”[Pharmacological Action] OR “Anticonvulsants”[MeSH Terms] OR “Anticonvulsants”[All Fields] OR “anticonvulsant”[All Fields] OR “anticonvulsion”[All Fields] OR “anticonvulsive”[All Fields] OR “anticonvulsives”[All Fields]) OR (“Anticonvulsants”[Pharmacological Action] OR “Anticonvulsants”[MeSH Terms] OR “Anticonvulsants”[All Fields] OR “antiepileptic”[All Fields] OR “antiepileptics”[All Fields])). Study selection and data extraction: Thirteen reports were included from 64 potential results of our literature review following the application of inclusion and exclusion criteria: 7 of the reports involved carbamazepine, 4 of the reports involved lamotrigine, and 2 of the reports involved phenobarbital. Data synthesis: Drug-induced leukocytosis is commonly a diagnosis of exclusion and is a phenomenon that has numerous ramifications to patients and clinicians at the bedside, including mandating a full infectious evaluation, the identification of confounding variables, and the eventual discontinuation of the offending agent. Despite several medications and medication classes possessing this adverse drug effect, an evaluation of the specific clinical presentation and management strategies for drug-induced leukocytosis associated with anticonvulsant medications has not been elucidated in the literature. Conclusions: Clinicians should be judicious when evaluating leukocytosis in patients on potentially precipitating medications, including carbamazepine, lamotrigine, and phenobarbital.

Background

Drug-induced leukocytosis is a potential adverse effect associated with the use of anticonvulsant medications, which are commonly prescribed to manage seizure disorders. Although drug-induced leukocytosis is generally benign and transient, it is crucial to differentiate it from other potential causes, such as infections or other underlying medical conditions. ¹ Health care professionals should exercise caution when prescribing anticonvulsant medications, particularly in individuals with a history of blood disorders or compromised immune systems, as they may be more susceptible to developing leukocytosis as an adverse effect. ¹

The exact mechanism underlying drug-induced leukocytosis with anticonvulsant medications is not fully understood and may vary depending on the specific medication; however, there are several proposed mechanisms that could contribute to this finding.^2-5 Hypersensitivity reactions may lead to an immune-mediated hypersensitivity reaction, resulting in an increase in the white blood cell (WBC) count. This type of leukocytosis is typically associated with other symptoms such as fever, rash, and organ involvement and may include diagnoses such as drug reaction with eosinophilia and systemic symptoms (DRESS), drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome, or toxic epidermal necrolysis.^2-5 It is important to differentiate hypersensitivity-induced leukocytosis from other causes and promptly manage the underlying reaction. It has also been noted that anticonvulsants may exert immunomodulatory effects on the immune system, leading to alterations in WBC counts. The specific mechanisms involved in these immunomodulatory effects are not well elucidated, but could include interactions with neurotransmitter receptors or modulation of cytokine levels. Finally, literature elucidating leukocytosis associated with anticonvulsant medications as an idiosyncratic reaction was evaluated.^2-5

Each of the medications in this review is classified as anticonvulsants; however, their use for the treatment of other conditions is common as their underlying mechanisms of action allow for the broader use of these medications. Carbamazepine is a first-generation anticonvulsant that enhances the inactivation of voltage-gated ion channels. Carbamazepine is used for the treatment of focal onset seizures, generalized onset seizures, neuropathic pain, and psychiatric disorders.^6,7 Lamotrigine is a second-generation anticonvulsant that enhances the fast inactivation of voltage-gated sodium ion channels.^7,8 Lamotrigine is used for the treatment of focal onset seizures, generalized onset seizures, and bipolar disorder. ⁷ Phenobarbital is a first-generation anticonvulsant that binds to gamma-aminobutyric acid (GABA)-A receptors and potentiates the GABA receptor via modulation of chloride efflux.^7,9 Phenobarbital is commonly utilized for sedation and seizure disorders. ⁹

While each of the 3 medications discussed has their unique set of uses in therapy, they all share commonality in their structure. Carbamazepine, lamotrigine, and phenobarbital each have a lipophilic structure, which undergoes metabolism in the body to form highly polar molecules that can more readily be eliminated. ⁷ Water-soluble or lipid-soluble metabolites formed from a lipophilic parent drug are more likely to be reabsorbed from the kidney, causing accumulation of the metabolites, some of which may be toxic. ⁷ Carbamazepine, lamotrigine, and phenobarbital each form their own reactive intermediate, which contains an epoxide structure. They rely on the epoxide hydrolase enzyme to break down the reactive intermediate, detoxifying the intermediate into further metabolites of the parent drug. The reactive metabolites are thought to play a role in the common adverse effects, including hypersensitivity reactions, seen by carbamazepine, lamotrigine, and phenobarbital. ⁷ It is possible that leukocytosis and other adverse drug reactions could be traced back to this commonality among the 3 structures and their reactive metabolites.

The purpose of this review article was to describe reports of drug-induced leukocytosis associated with carbamazepine, lamotrigine, and phenobarbital.

Methods

A comprehensive review of the literature was conducted on PubMed, Embase, and Google Scholar through June 2023 using the following search terminology: “leukocytosis/chemically induced”[MeSH Terms] AND (“Anticonvulsants”[MeSH Terms] OR (“Anticonvulsants”[Pharmacological Action] OR “Anticonvulsants”[MeSH Terms] OR “Anticonvulsants”[All Fields] OR “anticon-vulsant”[All Fields] OR “anticonvulsion”[All Fields] OR “anticonvulsive”[All Fields] OR “anticonvulsives”[All Fields]) OR (“Anticonvulsants”[Pharmacological Action] OR “Anticonvulsants”[MeSH Terms] OR “Anticon-vulsants”[All Fields] OR “antiepileptic”[All Fields] OR “antiepileptics”[All Fields])). Reports that detailed a case of drug-induced leukocytosis in adult patients associated with an anticonvulsant with the absence or accounting for confounding medications or pathologies were included. Nonhuman studies, studies in pregnant patients, and those with active malignancy, and reports not readily translatable to English were excluded.

Results

The initial search resulted in 450 pieces of literature combined from PubMed, Google Scholar, and Embase. After review of the literature results from these 3 sources, 64 potentially relevant pieces of literature were selected to be examined for further relevance to the topic. The inclusion and exclusion criteria were applied to the full-text articles, yielding 13 included articles. Seven of the reports involved carbamazepine, 4 of the reports involved lamotrigine, and 2 of the reports involved phenobarbital. Twenty-six patient encounters are described in the “Results” section and Table 1.

Table 1.

Results.

Author, year	Study design	Patients (age/sex)	Anticonvulsant indication	Offending anticonvulsant	Duration of anticonvulsant therapy	Duration of leukocytosis	WBC count (×109/L, range)	Intervention	Outcome
Miyasaka et al, 2021 10	Case report	1 (51/F)	Epilepsy	Carbamazepine	63 days	56 days	12.11-13.94	Initiation of methylprednisolone steroid pulse treatment. Discontinuation of carbamazepine on day 42.	Resolved a
Hoshina et al, 2015 11	Case report	1 (38/F)	Schizophrenia	Carbamazepine	3 months	26 days	12.3	Initiation of prednisolone. Discontinuation of carbamazepine.	Resolved b
Uhara et al, 2013 12	Observational study	3 (55-76/1M, 2F)	Syncope, postherpetic neuralgia, neuralgia	Carbamazepine	15-40 days	Not specified	12.1-16.9	Initiation of hydration with or without topical steroid. Discontinuation of carbamazepine.	Resolved a
Morimoto et al, 2011 13	Case report	1 (51/M)	Right third branch trigeminal neuralgia	Carbamazepine	1 month	28 days	13.1-22.9	Initiation of prednisolone. Discontinuation of carbamazepine.	Resolved a
Ganeva et al, 2008 14	Case series	3 (23-34/1M, 2F)	Post-traumatic epilepsy, bipolar affective disorder, postoperative seizure prophylaxis	Carbamazepine	3-4 weeks	Not specified	11-21	Initiation of valproic acid. Discontinuation of carbamazepine.	Resolved b
Laad and Miranda, 2005 15	Case report	1 (50/M)	Idiopathic epilepsy	Carbamazepine	10 weeks	1 week	20	Initiation of prednisolone, sodium valproate, emollients, antihistamines, acetaminophen, and high-protein diet. Discontinuation of carbamazepine.	Resolved a
Choi et al, 2003 16	Observational study	4 (49-65/M)	Not specified	Carbamazepine	3-24 weeks	3-9 weeks	9.7-15.21	Initiation of prednisolone, systemic antihistamines, and topical steroids. Discontinuation of carbamazepine	Resolved
Abdelnabi et al, 2022 17	Case report	1 (20/F)	Bipolar affective disorder	Lamotrigine	72 hours after doubling dose	Not specified	14.03	Initiation of pulse steroids. Discontinuation of lamotrigine.	Improvement of symptoms b
Salah et al, 2021 18	Case report	1 (49/M)	Epilepsy	Lamotrigine	15 days	3 weeks	12.16	Initiation of topical steroids and systemic steroids. Increase in valproic acid dose. Discontinuation of lamotrigine.	Resolved b
Bozca et al, 2020 19	Case report	1 (31/F)	Epileptic seizures	Lamotrigine	3 weeks	2 weeks	11.6	Initiation of topical methylprednisolone aceponate and systemic methylprednisolone. Discontinuation of lamotrigine.	Resolved b
Mylonakis et al, 1999 20	Case report	1 (49/M)	Bipolar disorder	Lamotrigine	5 days	4 days	19.1	Initiation of prednisolone. Discontinuation of lamotrigine, methylphenidate, gabapentin, allopurinol.	Resolved
Romanelli et al, 2016 21	Case report	1 (74/M)	Alcohol withdrawal syndrome	Phenobarbital	1 month	Not specified	11.1-13.3	Initiation of IV corticosteroids and levetiracetam. Discontinuation of phenobarbital.	Resolved b
Zeng et al, 2013 22	Case report	1 (27/F)	Epilepsy	Phenobarbital	3 weeks	18 days	18-128	Initiation of methylprednisolone, anti-anaphylactic treatment, liver protection, supporting therapy, and IV immunoglobulin shock therapy. Discontinuation of phenobarbital.	Resolved a

Abbreviation: WBC, white blood cell.

^aDrug-induced hypersensitivity syndrome.

^bDrug reaction with eosinophilia and systemic symptoms.

Carbamazepine

Miyasaka et al ¹⁰ reported a case of a 51-year-old female patient who presents to the hospital with an episode of epilepsy, although epilepsy was not seen upon general admission examination. Three weeks prior to admission, the patient began oral carbamazepine treatment for epilepsy. The patient presented with a fever, liver dysfunction, leukocytosis (WBC 13.94 × 109/L), eosinophilia, and skin rash. They suspected drug-induced liver dysfunction, so they began a steroid pulse treatment with methylprednisolone injections with a stop date of day 18. The skin rash and fever disappeared after initial treatment; however, eosinophil count and fever began to increase, once again, when the steroid was discontinued. Prednisolone was initiated on day 21 with discontinuation on day 25. As a result of prednisolone treatment, fever, eosinophilia, and leukocytosis gradually improved. Based on skin eruption, fever, increased eosinophil count, and leukocytosis, it was concluded she was experiencing DIHS caused by carbamazepine that is consistent with DRESS. Therefore, carbamazepine was discontinued on day 42 and leukocytosis with elevated eosinophils continued for another 2 weeks. The patient was discharged from the hospital on day 67 once symptoms were resolved. ¹⁰

Hoshina et al ¹¹ reported a case of a 28-year-old female with schizophrenia who presented to the hospital with a 1-week history of fever, malaise, and skin eruptions. Skin biopsy revealed a perivascular infiltration with lymphocytes and eosinophilia. Laboratory findings revealed leukocytosis (WBC 12.3 × 109/L) with eosinophilia and liver dysfunction. Prior to skin eruptions, the patient had received carbamazepine for approximately 3 months. Carbamazepine was discontinued 1 week prior to admission, but all other antipsychotic medications were continued. Based on the presenting symptoms and laboratory findings, she was diagnosed with DRESS. The patient was treated with prednisolone 1 mg/kg/day which led to improvement of her symptoms. The patient was discharged from the hospital on day 26. ¹¹

Uhara et al ¹² conducted an observational study of 12 patients who were suspected to have DIHS at their initial hospital visit. Within this study, the offending agents included carbamazepine, salazosulfapyridine, mexiletine, and zonisamide. Of these 12 patients, 3 patients met our inclusion and exclusion criteria. These patients were patient 1, patient 5, and patient 11. Patient 1 was a 66-year-old female who presented with a rash, fever, live abnormalities, leukocytosis (WBC 12.5 × 10⁹/L), and human herpesvirus 6 (HHV-6) reactivation. Patient 1 had taken carbamazepine routinely for 35 days prior to appearance of symptoms. Treatment included discontinuation of carbamazepine and initiation of hydration only, no corticosteroids. Patient 5 was a 76-year-old male who presented with a rash, leukocytosis (WBC 16.9 × 109/L), lymphadenopathy, and HHV-6 reactivation. Patient 5 had received carbamazepine routinely for 15 days prior to appearance of symptoms. Carbamazepine was discontinued, and hydration treatment was initiated. Patient 11 was a 55-year-old female who presented with a rash, fever, liver abnormalities, leukocytosis (WBC 12.1 × 109/L), lymphadenopathy, and HHV-6 reactivation. Patient 11 had received carbamazepine routinely for 40 days prior to appearance of symptoms. Treatment included initiation of hydration with topical steroids and discontinuation of carbamazepine. All patients included in the study recovered without complications within 7-37 days (median of 18 days) after withdrawal of the offending agent. ¹²

Morimoto et al ¹³ reported a case of a 51-year-old male who presented to the hospital with right mandibular gingival swelling and pain. The patient had received carbamazepine 200 mg by mouth daily for 5 weeks for trigeminal neuralgia. Once this resolved, the carbamazepine was discontinued. However, the trigeminal neuralgia recurred 10 months later, and carbamazepine 400 mg by mouth daily was initiated. One month after initiation, the patient was admitted to the hospital with suspected DIHS, following which the carbamazepine was discontinued. Laboratory findings revealed a WBC count of 15.6 × 109/L with 7% eosinophils, indicating leukocytosis. Oral prednisolone was initiated at 30 mg/day and increased to 60 mg/day on day 3 when symptoms of rash continued to worsen. On day 5, symptoms started improving and prednisolone was reduced to 5 mg. Then, prednisolone was reduced to 5 mg/day on day 15, and the patient was discharged. One week after discharge, erythema recurred, and the patient’s prednisolone was increased to 10 mg/day for 4 days. The patient’s symptoms had resolved, and prednisolone was discontinued on day 28 after hospital admission. ¹³

Ganeva et al ¹⁴ reported a series of 4 patients with a diagnosis of DRESS caused by carbamazepine. Three patients met our inclusion and exclusion criteria which were included in cases 1, 2, and 4. Case 1 is a 23-year-old male who presented to the hospital with a fever and skin eruption. Past medical history included the initiation of carbamazepine 1 month prior to post-traumatic epilepsy. One week prior to admission, the patient had taken cephalexin, dipyrone, and acetaminophen for pharyngitis and fever. Laboratory findings revealed a WBC count of 6 × 109/L with 9% eosinophil that soon elevated to a WBC count of 11 × 109/L with 20% eosinophils, indicating leukocytosis. The treatment plan included reduction of the carbamazepine dose over 1 week while gradually introducing valproic acid. Systemic corticosteroids and antihistamines were administered to resolve clinical and laboratory symptoms. Case 2 is a 28-year-old female who presents with a skin rash, cold chills, and fever. Prior to admission, she had been treated for bipolar affective disorder with carbamazepine, clonazepam, and chlorprothixene for 3 weeks. Laboratory findings revealed a WBC count of 21 × 109/L with 24% eosinophils. Blood cultures, serology for syphilis and viral hepatitis, stool cultures, and antinuclear antibodies were negative. Drug reaction with eosinophilia and systemic symptoms was suspected, with carbamazepine being the offending agent. All psychotropic drugs were discontinued until the skin rash was resolved. Systemic corticosteroids and antihistamines were initiated to resolve clinical and laboratory symptoms. She was discharged 1 week later with quetiapine and valproic acid for bipolar affective disorder. Case 4 is a 34-year-old female who presented to this hospital with a pruritic eruption that had spread over her entire body, afebrile, periorbital edema, and lymphadenopathy. Four weeks priorly, she began carbamazepine for postoperative seizure prophylaxis following neurosurgery. Two weeks prior to skin eruptions, the patient experienced cold chills and fever, and she was treated with acetaminophen and sulfamethoxazole/trimethoprim for 5 days. Upon admission, laboratory findings revealed a WBC count of 11 × 109/L with 14% eosinophils. The serology of syphilis, streptococcal infection, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) was negative. The treatment plan included discontinuation of carbamazepine and initiation of systemic corticosteroids and antihistamines. In each case, the corticosteroid dose was tapered and discontinued once the clinical and laboratory symptoms had resolved. ¹⁴

Laad and Miranda described a case of a 50-year-old male who presented to the hospital with erythema and 8-day scaling and edema of the face and extremities. ¹⁵ Prior to admission, the patient had been taking carbamazepine 200 mg daily for 10 weeks for idiopathic epilepsy. After the first 4 days of skin eruption, he stopped carbamazepine upon orders of a private practitioner. Four days later, he presented to the dermatology department at the hospital with continued erythroderma, edema, and fever. Laboratory findings revealed leukocytosis (WBC 20 × 109/L with 52% eosinophils). Based on the patient’s symptoms, treatment included oral prednisolone 40 mg daily and sodium valproate 500 mg daily. One week after oral corticosteroid treatment, scaling reduced and WBC count reduced to 9 × 109/L. Two weeks after initiation of oral corticosteroid treatment, WBC count reduced to 6.2 × 109/L. The oral prednisolone was tapered over 3 weeks with complete resolution of symptoms. In addition to the corticosteroid, the patient was treated with emollients, antihistamines, acetaminophen, and a high-protein diet. ¹⁵

Choi et al ¹⁶ conducted an observational study of 8 patients who presented to the authors’ clinic with a diagnosis of pseudolymphoma syndrome (PLS) between February 1993 and March 2001. Of these 8 patients, 4 patients met our inclusion and exclusion criteria. Cases 1, 3, 4, and 5 are the patients. Case 1 is a 49-year-old male who experienced skin lesions, fever, facial edema, lymphadenopathy, and leukocytosis (WBC 10.7 × 109/L) 3 weeks after initiation of carbamazepine treatment. Resolution of symptoms occurred within 3 weeks of discontinuation of the offending agent and initiation of treatment. Case 3 is a 59-year-old male who experienced skin lesions, fever, facial edema, lymphadenopathy, splenomegaly, and leukocytosis 24 weeks after initiation of carbamazepine treatment. Resolution of symptoms occurred within 6 weeks of discontinuation of the offending agent and initiation of treatment. Case 4 is a 65-year-old male who experienced skin lesions, facial edema, lymphadenopathy, and leukocytosis (WBC 10 × 109/L) 5 weeks after initiation of carbamazepine treatment. Resolution of symptoms occurred within 6 weeks of discontinuation of the offending agent and initiation of treatment. Case 5 is a 61-year-old male who experienced skin lesions, fever, facial edema, lymphadenopathy, and leukocytosis (WBC 9.7 × 109/L) 4 weeks after initiation of carbamazepine treatment. Resolution of symptoms occurred within 9 weeks of discontinuation of the offending agent and initiation of treatment. In each case, treatment consisted of oral prednisolone 0.5-1 mg/kg/day, systemic antihistamines, and topical steroids. Alternative anticonvulsants were allowed and administered when necessary. ¹⁶

Lamotrigine

Abdelnabi et al reported a case of a 20-year-old female with bipolar affective disorder who presented to the hospital with a generalized erythematous maculopapular rash, fever, myalgia, nausea, reduced urine output, peripheral edema, and dyspnea on exertion. Prior to presenting to the hospital, the patient doubled her dose of lamotrigine 72 hours earlier, which coincided with rash development increasing in size. Upon further examination, laboratory tests revealed leukocytosis (WBC 14.03 × 109/L), elevated aspartate aminotransferase at 42 units/L, elevated alanine aminotransferase 79 units/L, blood urea nitrogen 50 mg/dL, and creatinine 5.6 mg/dL. A positive monospot test indicated active EBV infection and a positive IgG test indicated previous CMV infection. A formal diagnosis of DRESS induced by lamotrigine complicated by concomitant infection was made. Lamotrigine was discontinued and pulse steroids were initiated, leading to a gradual improvement in signs and symptoms. ¹⁷

Salah et al described a case of a 49-year-old male with epilepsy treated previously with valproic acid since the age of 34 years, who presented to the hospital with febrile itchy maculopapular skin rash, facial edema, and cervical lymphadenopathy. Upon further examination, laboratory tests revealed leukocytosis (WBC 12.16 × 109/L) with an elevated eosinophil count of 800 cells/m³. Symptoms began 15 days after initiation of lamotrigine. Lamotrigine was withdrawn and valproic acid dose was increased to 1500 mg/day. Topical steroids were prescribed, but after only partial improvement of symptoms achieved, he was given systemic steroids 1 mg/kg daily. Resolution of skin lesions and biologic abnormalities resolved in 3 weeks. ¹⁸

Bozca et al ¹⁹ reported a case of a 31-year-old female with epileptic seizures presented to the hospital with widespread rash, fever, and fatigue following initiation of lamotrigine 3 weeks before. Lamotrigine was initiated at a dose of 12.5 mg for the first 2 weeks, and then, a dose escalation in week 3 to 25 mg/day. Laboratory tests revealed leukocytosis (WBC 11.6 × 109/L), neutrophilia (10.17 × 109/L), and lymphopenia (720/mm³), elevation in liver function tests, and deteriorating thyroid function tests. Lamotrigine-induced DRESS was diagnosed based on clinical and laboratory findings. Lamotrigine was discontinued and IV methylprednisolone 1 mg/kg/day was initiated. Following initiation of treatment, the patient’s signs and symptoms improved rapidly in 2 weeks and she was discharged. ¹⁹

Mylonakis et al ²⁰ reported a case of a 49-year-old male with bipolar affective disorder who presented to the hospital with a 2-day history of low-grade fever, erythema, and edema involving the periorbital area. Five days prior to hospital admission, lamotrigine was initiated. He inadvertently received 4 daily doses of lamotrigine 2700 mg. Upon further examination, laboratory tests revealed leukocytosis (WBC 19.1 × 109/L). They suspected a drug-induced reaction following lamotrigine overdose. The patient was treated with prednisone 1 mg/kg/day, and all medications, excluding levothyroxine and lithium, were discontinued. Symptoms improved over the course of the next 4 days and he was discharged on day 6. ²⁰

Phenobarbital

Of the literature describing phenobarbital, 1 patient was female, age 27 years, and 1 patient was male, age 74 years.^21,22 The reason for phenobarbital use for the female patient was epilepsy and the reason for phenobarbital use for the male patient was alcohol withdrawal syndrome. The duration of phenobarbital therapy averaged 3.5 weeks. The treatment initiated following symptoms was discontinuation of phenobarbital for both patients, along with initiation of IV corticosteroids. The leukocytosis and symptoms resolved following treatment.^21,22

Discussion

Drug-induced hypersensitivity syndrome can be described as the triad of fever, rash, and multiorgan failure that occurs 1-8 weeks after initiation of the offending drug. ²³ The most common offending agents are anticonvulsants, antimicrobials, allopurinol, and dapsone. The most common anticonvulsants that may cause DIHS include carbamazepine, lamotrigine, and phenobarbital. ²³ Drug-induced hypersensitivity syndrome may be classified as typical or atypical. A diagnosis of typical DIHS requires all 7 criteria to be met; however, a diagnosis of atypical DIHS requires 5 of the 7 criteria to be met. The DIHS diagnostic criteria can be found in Table 2.

Table 2.

Drug-Induced Hypersensitivity Syndrome (DIHS) Diagnostic Criteria. ¹³

1. Maculopapular rash developed >3 weeks after starting with a limited number of drugs. 2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug. 3. Fever (>38°C). 4. Liver abnormalities (alanine aminotransferase >100 IU/L) a . 5. Leukocyte abnormalities (at least 1 present). a. Leukocyte abnormalities (>11 × 109/L). b. Atypical lymphocytosis (>5%). c. Eosinophilia (>1.5 × 109/L). 6. Lymphadenopathy. 7. Human herpesvirus 6 (HHV-6) reactivation. Typical DIHS: presence of all 7 criteria described below. Atypical DIHS: presence of 5 of the criteria described below.

^aMay be replaced by other organ involvement.

Drug reaction with eosinophilia and systemic symptom syndrome is a severe type of DIHS. Anticonvulsants including carbamazepine, lamotrigine, and phenobarbital may cause this severe cutaneous adverse reaction as well. A definite diagnosis of DRESS syndrome requires 6 or more of the diagnostic criteria to be met.^24,25 A probable diagnosis of DRESS syndrome requires 4 or 5 of the diagnostic criteria to be met. The Registry of Severe Cutaneous Adverse Reactions DRESS syndrome diagnostic criteria can be found in Table 3.^24,25

Table 3.

Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) DRESS Syndrome Diagnostic Criteria.^24,25

1. Hospitalization. 2. Reaction suspected to be drug related. 3. Acute rash. 4. Fever >38°C*. 5. Enlarged lymph nodes at a minimum of 2 sites*. 6. Involvement of at least 1 internal organ*. 7. Blood count abnormalities*. 8. Lymphocytes above or below normal limits. 9. Eosinophils above the laboratory limits. 10. Platelets below the laboratory limits. Definite: Presence of 6 or more criteria described below. Probable: Presence of 4 or 5 criteria described below. Possible: Presence of 2 or 3 criteria described below. No DRESS: Presence of <2 criteria described below.

Abbreviation: DRESS, drug reaction with eosinophilia and systemic symptoms.

^*Three of the 4 asterisked (*) must be present for diagnosis.

Patients presenting with drug-induced leukocytosis will present with various other symptoms that meet the criteria for DIHS or DRESS syndrome, unless the reaction is dose related. Five of our studies presented patients with DIHS, 6 of our studies presented patients with, 6 of our studies presented patients with DRESS syndrome, 1 study presented patients with PLS, and 1 study presented a patient with lamotrigine overdose.^10-22 The most common presenting diagnosis was DIHS or DRESS. The presentation of DIHS and DRESS is most commonly seen within 5-6 weeks of initiation of the offending agent, with a range from 1 to 24 weeks.^10-22 Eleven of the 13 studies had patients who presented with drug-induced leukocytosis and eosinophilia.^10-18 It can be concluded those presenting with DIHS or DRESS syndrome will present with leukocytosis and eosinophilia. Once the patient’s DIHS and DRESS began to improve, the leukocytosis and eosinophilia will begin to improve as well. Although improvement of symptoms occurs in each study analyzed, rechallenge of the offending agent was not attempted in any study analyzed due to the associated risk. If an anticonvulsant is needed, an alternative medication must be initiated.

Dosing may play a vital role in the development of DIHS, DRESS syndrome, and anticonvulsant-induced leukocytosis. Many of our studies did not specify the dosing of the offending anticonvulsant or if an increase in dosage was made before onset of symptoms; however, Abdelnabi et al ¹⁷ expressed a case of lamotrigine-induced DRESS syndrome that occurred after doubling of the patient’s lamotrigine. Similarly, Salah et al ¹⁸ described a case of lamotrigine-induced DRESS that occurred after an unspecified dose increase. Myolanakais et al ²⁰ described a case with a presentation that closely aligns with anticonvulsant-induced hypersensitivity syndrome that occurred due to a lamotrigine overdose of 2700 mg daily for 4 days. It is possible that increased doses of anticonvulsants may increase chances of DIHS, DRESS, and drug-induced leukocytosis. Additional research needs to be conducted to determine the dose of anticonvulsants that increases the risk of developing a severe cutaneous adverse reaction and leukocytosis.

There are limitations to the findings of this review that require discussion. The heterogeneity of the articles included in this review make it difficult to determine the dose at which leukocytosis is likely to occur when taking carbamazepine, lamotrigine, or phenobarbital. However, it is most likely that an adverse reaction accompanied with leukocytosis will occur within 5-6 weeks upon initiation or dose titration of therapy with 1 of the 3 agents. The search strategy and inclusion criteria used may have affected the results of the study as some reviews may have been inadvertently overlooked, though efforts were made to minimize the risk. Although we have found similarities between the structures of carbamazepine, lamotrigine, and phenobarbital that may play a role in their adverse reactions, other medications including oxcarbazepine, mephobarbital, and primidone with similar structures did not appear in our literature review.

Conclusions

This review discusses the incidence and characterization of drug-induced leukocytosis associated with carbamazepine, lamotrigine, and phenobarbital. These drugs share a common structure and form reactive metabolites that can lead to adverse effects, including hypersensitivity reactions such as DIHS, DRESS, and PLS that account for a majority of cases describing drug-induced leukocytosis with these agents. It appears that the dosing and frequency of administration of these medications may be implicated in the presentation of drug-induced leukocytosis, though further clinical evaluation is needed to fully appreciate this dose-response relationship.