Changes in preoperative serum immunoglobulin concentrations in dental patients receiving long-term anticonvulsant therapy

Dear Editor:

Dental treatment (DT) in patients with epilepsy often requires general anesthesia (GA), and these patients may have received long-term (> 6 months) anticonvulsant therapy (LTACT). Various antiepileptic drugs (AEDs) are associated with immunological alterations, such as low immunoglobulin (Ig) concentrations [1,2,3], and Igs are essential for mucosal defense and pathogen clearance in dental patients. Since we encountered post-discharge sepsis in an IgA-deficient patient who received DT under GA [4], preoperative serum Ig (IgG, IgA, and IgM) concentrations have typically been measured in our institution to prevent perioperative infections in suspected Ig-deficient cases, such as patients receiving LTACT. In these patients, some individuals undergo DT under GA again several years after their previous treatment, and Ig concentrations are measured as part of the preoperative evaluation. In this report, we present the changes in preoperative Ig concentrations in such patients and discuss the perioperative implications for dental patients receiving LTACT. Institutional review board approval for this retrospective small case series was waived at our institution. Written informed consent to use individual patient data was obtained from the parents of all patients.

This study included patients aged ≥ 18 years who had received LTACT, had previously undergone elective DT under GA at our institution, and were scheduled to undergo DT again between January 1, 2023, and December 31, 2025. Blood samples for serum IgG, IgA, and IgM concentrations and other preoperative laboratory parameters were obtained simultaneously. The attending physician confirmed that the serum AED concentrations were within the therapeutic range. Patients without previous Ig testing, those with poor nutritional status, routine administration of antibiotics, congenital immunological abnormalities, or any inflammatory or infectious disease within 1 month of preoperative testing were excluded. Five patients were eligible for this study. Their characteristics and preoperative Ig concentrations are shown in Table 1.

Table 1. Changes in preoperative serum immunoglobulin concentrations in patients receiving long-term anticonvulsant therapy.

Patient	Age (y)/sex	Primary disorder	Comorbidity	AED	Previous Ig Cs	Latest Ig Cs	Interval (PT-LT)
1	25/F	MR	-	VPA	IgG: 1459	IgG: 1790↑	8 y, 9 mo
					IgA: 159	IgA: 265
					IgM: 296↑	IgM: 432↑
2	22/M	CP	DLD	LTG	IgG: 1698	IgG: 1332	2 y, 4 mo
					IgA: 550↑	IgA: 451↑
					IgM: 203↑	IgM: 110
3	35/M	MR	-	VPA, CZP	IgG: 2221↑	IgG: 2807↑	2 y, 11 mo
					IgA: 553↑	IgA: 490↑
					IgM: 108	IgM: 70
4	20/F	MR	Mild PS	CBZ	IgG: 1063	IgG: 1137	5 y, 6 mo
					IgA: 84↓	IgA: 98↓
					IgM: 68	IgM: 71
5	18/M	CP	-	VPA, DZP, LTG	IgG: 1819↑	IgG: 1849↑	4 y, 6 mo
					IgA: 145	IgA: 252
					IgM: 181	IgM: 192↑

Abbreviations: AED, antiepileptic drug; Ig, immunoglobulin; Cs, concentrations; PT, previous testing; LT, latest testing; F, female; M, male; MR, mental retardation; CP, cerebral palsy; DLD, developmental language disorder; PS, pulmonary stenosis; VPA, valproate; LTG, lamotrigine; CZP, clonazepam; CBZ, carbamazepine; DZP, diazepam. Reference values for Japanese adults: IgG (870–1,700 mg/dL); IgA (110–410 mg/dL); IgM (men: 33–190 mg/dL, women: 46–260 mg/dL).

Compared with previous testing, IgA concentrations remained low in Patient 4, who was taking carbamazepine. However, IgA concentrations were elevated in Patient 2, who was taking lamotrigine, despite an increase in IgA and IgM concentrations in previous testing. Patients 1, 3, and 5 were taking valproate, and elevated concentrations of two Ig classes were observed in each patient. Patients 1 and 5 showed new increases in IgG and IgM concentrations, respectively.

The use of any AED is associated with an increased risk of hypogammaglobulinemia (HGG) [1], and decreas ed serum IgA concentrations are frequent immunological abnormalities in patients receiving LTACT. Various AEDs reduce Ig concentrations, and carbamazepine and lamotrigine are associated with low IgA concentrations [1]. Perrott et al. [1] found that carbamazepine and lamotrigine have an exposure–response relation with HGG. They showed an association between exposure to AEDs and HGG over time and calculated the odds ratios with adjustments for age, sex, and Charlson Comorbidity Index compared with Ig control groups. The adjusted odds ratios for carbamazepine and lamotrigine exposure of 4 to 6 years were 3.54 and 1.96, respectively, and those for carbamazepine and lamotrigine exposure of more than 6 years were 6.73 and 3.55, respectively. These findings suggest a trend toward an increased risk of HGG with increasing duration of carbamazepine and lamotrigine exposure [1]. Among our cases, Patient 4 had been taking carbamazepine for at least 6 years (5 years and 6 months+ the period before the previous treatment) and showed decreased IgA concentrations in the latest testing, consistent with previous testing. Given the duration of exposure, IgA concentrations may have decreased, and pan-HGG may have occurred in this patient. By contrast, Patient 2, who was taking lamotrigine, showed increased IgA concentrations, similar to previous testing; however, the reason for this finding remains unclear. Liimatainen et al. [5] suggested that alterations in Ig concentration are associated with epilepsy. IgA concentrations before initiating lamotrigine were not measured in Patient 2, but epilepsy might be one of the causes of increased IgA concentrations in this patient. Although the test results of these patients differed, we strongly recommend that patients taking carbamazepine and/or lamotrigine have their Ig concentrations evaluated during preoperative testing, regardless of the duration of administration.

Carbamazepine has been used not only as an anticonvulsant but also as a first-line treatment for trigeminal neuralgia (TN) [6]. This drug can be administered for months or years to treat TN, and decreased Ig concentrations can occur, leading to unusual or recurrent infections. To prevent these infections, measuring baseline Ig concentrations in patients before initiating carbamazepine might be crucial. Godhwani et al. [2] recommended that the complete blood count and chemistry profile be normal before initiating AEDs. Furthermore, they proposed that periodic follow-up may occur approximately every 3 months but could be extended to every 6 to 12 months, as determined by the clinician and the patient’s response [2]. In addition to their proposal, including serum Ig measurement in laboratory testing is advisable. Therefore, in patients with TN scheduled for carbamazepine therapy, regular measurement of serum Ig concentrations before and after treatment initiation may be advisable to prevent infectious diseases.

In the latest preoperative test, Patients 1, 3, and 5 showed increased IgG concentrations above the upper reference range, and the previous IgG concentrations in Patients 3 and 5 were much higher than this range. All these patients were taking valproate, which can cause not only decreased IgA concentrations and pan-HGG but also increased IgG concentrations [2]. The reason for the increase in IgG levels remains unclear. In a Dutch study on Ig concentrations in children with epilepsy receiving LTACT [3], valproate, as a monotherapy or as part of combination therapy, was associated with an increase in the IgG1 subclass. The authors speculated that this finding might be associated with the effects of valproate on B cell maturation or on regulatory T lymphocytes [3]. Although this study focused on children and we did not measure the IgG1 subclass, changes in the humoral immune system could occur even in adults receiving LTACT, and predicting how immunity will change after valproate administration is difficult. Therefore, patients taking valproate, with or without other AEDs, should be considered to have a potential immune disorder and should be treated with maximum infection control measures, even in dental practice.

If preoperative Ig alterations are found in dental patients receiving LTACT, pre- and postoperative antibiotic use, the administration of propofol for GA to maintain airway ciliary motility, use of povidone-iodine mouth rinses, and close medical observation are strongly recommended to prevent perioperative infections [4].

In conclusion, dental anesthesiologists should consider immunological alterations, measure serum Ig concentrations as required, and treat dental patients receiving LTACT with maximum infection control measures.