The high incidence and risk factors of levetiracetam and lacosamide-related skin rashes in glioma patients

doi:10.21203/rs.3.rs-1731972/v1

Antiseizure drug (ASD)-induced skin rash remains the main side effect of seizure management in patients with glioma. New generations of ASDs, such as levetiracetam (LEV) and lacosamide (LCM) are associated with less frequent skin rashes than conventional ASDs. However, there are few reports regarding the incidence of skin rashes by LEV and LCM in patients with glioma. Therefore, the aim of this study was to investigate the incidence and risk factors of LEV- and LCM-associated skin rashes in patients with glioma. We compared the incidence of ASD-associated skin rash between 353 patients with glioma and 125 patients with meningioma, who received LEV or LCM and underwent surgery between 2017 and 2019 at our institution. Furthermore, to evaluate the association between potential risk factors and ASD-associated skin rashes, univariate and multivariate analyses were performed. The incidence of ASD-associated skin rash in patients with glioma was higher (11%) than in those with meningiomas (1.6%). The multivariate regression analysis showed that adjuvant treatment with radiotherapy (p = 0.023) and a history of drug allergy (p = 0.023) were significant risk factors for ASD-associated skin rash. The rate of ASD-related skin rashes in patients with glioma was also higher than the previously reported rates of 1-3% in patients with epilepsy. Our results indicate that adjuvant treatment with radiotherapy and a history of drug allergy correlated with a high incidence of ASD-related skin rashes in patients with patients who receive LEV and LCM. Patients with these two factors should be carefully checked for skin rashes.

levetiracetam

lacosamide

skin rash

drug allergy

glioma

Brain tumor-related epilepsy (BTRE) is common in patients with gliomas. The risk of seizure varies between 40–60%, and patients with low grade gliomas have approximately 20–40% more frequent attacks than those with high grade gliomas. [23] Although there is no strong evidence for the use of prophylactic antiseizure drugs (ASD), seizure control in patients with gliomas is essential for maintaining quality of life (QOL), [13] because perioperative seizures extend hospital stays and increase readmission and mortality. [8] In fact, many neurosurgeons use ASD in the perioperative period. [27] A new generation of ASDs, such as levetiracetam (LEV) and lacosamide (LCM) have been reported to have the same seizure control rate as conventional ASDs, and are suitable for seizure control in patients with glioma, owing to their low side effects and drug interactions. [5] ASD-associated skin rash is the leading cause of withdrawal from ASD, [1] and can develop into life-threatening Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). [11] The fatality rates of each adverse event have been reported to be 3% and 20–40%, respectively. LEV and LCM have been associated with less frequent skin rash than conventional ASD; [18] therefore, our institution has mainly used these ASDs for patients with brain tumors since 2017.

However, in patients with diffuse glioma, we have observed that the incidence of skin rashes while on LEV and LCM has been higher than reported previously. [2, 4, 6, 10, 18]. Notably, previous studies have reported that the incidence of skin rash of new ASDs, including LEV and LCM, is 1–3%, although very few studies have investigated the incidence in patients with glioma. [2, 4, 6, 10, 18].

Therefore, in this study, we retrospectively analyzed the incidence and associated factors of skin rashes caused by LEV and LCM in patients with gliomas who received these ASDs, to evaluate the safety of new ASDs in patients with glioma. Further, we evaluated patients with meningiomas as the control group.

Patient selection

This study included 374 patients with glioma who underwent biopsy or tumor resection at our institution between January 2017 and December 2019 and received LEV or LCM. Of the 374 patients, 21 who did not undergo LEV or LCM, and were excluded from this study. The control group included 183 patients with meningioma who underwent surgery and received LEV or LCM during the same period. Of the 183 patients, 58 who did not receive LEV or LCM were excluded from this study. Therefore, we compared the incidence of ASD-associated skin rashes between 353 patients with glioma and 125 patients with meningioma who received LEV or LCM. (Fig. 1) The doses of LEV and LCM started from the standard amounts of LEV 1000 mg/day and LCM 100 mg/day with an increasing maintenance dose of 200 mg/day in Japan, and no treatment deviated from the standard dose.

The study protocol was approved by the Ethics Committee of Tokyo Women’s Medical University (No. 3540). The requirement for informed consent was waived because of the retrospective design of the study.

Data Collection

We collected data on age at surgery, sex, pathological diagnosis based on the World Health Organization (WHO) 2016 classification, postoperative adjuvant therapy, administration of ASD, drug allergy history, new diagnosis or recurrence, and the presence of ASD-associated skin rash from electronic medical records. An ASD-associated skin rash was defined as a systemic rash that led to discontinuation of the drug. Local rashes on the scalp that were apparently due to irradiation were excluded.

Statistical Analysis

The data were analyzed using JMP Pro 15.0 (SAS Institute, Cary, North Carolina). Categorical data were examined using the chi-squared test. Continuous data were examined using a t-test or Wilcoxon test. To evaluate associations between potential risk factors and skin rash with ASD administration in patients with glioma, each variable of interest, including age at surgery, sex, pathology based on the WHO 2016 classification, postoperative adjuvant therapy, administration of ASD, drug allergy history, and new diagnosis or recurrence were examined using univariate analyses. The multivariate analysis included risk factors that showed significant differences in the univariate analysis. A multivariate logistic regression analysis was used to explore the relationship between the presence of skin rash and candidate factors. P-values < 0.05 were considered statistically significant.

Incidence of ASD-associated skin rash

The overall incidence of skin rash due to LEV or LCM in patients with glioma was 39/353 (11.1%) (Table 1). The incidences of rash due to LEV and LCM were 21/216 (9.7%) and 20/154 (13.0%), respectively. The incidence of rashes due to LEV or LCM in patients with meningiomas was only 1.6%. Notably, the incidence in patients with glioma was significantly higher than that in patients with meningioma in the control group (p = 0.006).

Table 1

Clinical characteristics and ASD-associated skin rash in patients with glioma and meningioma.
	Glioma	Meningioma	P value
No.	353	125
Sex: Male / Female	203 / 150	53 / 72	0.004*
Age (mean ± SD)	44 ± 14.78	58 ± 13.19	< 0.001*
ASD administration
LEV administration	216	76	0.94
LCM administration	154	49	0.48
ASD-associated skin rash (%)	39 (11.1)	2 (1.6)	0.006*
LEV-associated skin rash (%)	21 / 216 (9.7)	1 / 76 (1.3)	0.005*
LCM-associated skin rash (%)	20 / 154 (13.0)	1 / 49 (2.0)	0.01*
ASD, antiseizure drugs; SD, standard deviation; LEV, levetiracetam; LCM, lacosamide.
*This P value indicates a statistically significant difference.

Clinical Characteristics Of Patients With Glioma

The clinical characteristics of the 353 patients with gliomas are shown in Table 2. Eighty-six and 267 patients had low and high grade gliomas, respectively. A total of 205 patients underwent chemotherapy and radiotherapy. Among these 205 patients, TMZ and ACNU were used in 129 and 76 patients, respectively. Sixty-three patients received chemotherapy alone, and six patients underwent radiotherapy alone. Seventy-seven patients (22%) with gliomas had a history of drug allergies.

Table 2

Clinical characteristics of 353 patients with glioma.
	Number
No. of total cases	353
Age (mean ± SD)	44 ± 14.78
Male / Female	203 /150
Newly-diagnosed / Recurrence	229 /124
WHO grade
WHO grade Ⅳ (%)	158 (45)
WHO grade Ⅲ (%)	109 (31)
WHO grade Ⅱ (%)	79 (22)
WHO grade Ⅰ (%)	7 (2)
G I, II / G III, IV	86 / 267
Adjuvant therapy
Radiotherapy + chemotherapy	205
RT + TMZ (%)	129 (63)
RT + ACNU (%)	76 (37)
Chemotherapy alone	63
TMZ (%)	42 (67)
ACNU (%)	21 (33)
Radiotherapy only	6
No additional postoperative treatment	76
History of drug allergy (%)	77 (22)
SD, standard deviation; WHO, world health organization; TMZ, temozolomide; ACNU, nimustine.

Administration Of Antiseizure Drugs

The administration of ASD is detailed in Table 3. Of the 353 patients, 268 (75%) were treated with monotherapy of LEV or LCM, while 85 underwent polytherapy for ASDs with various combinations, including LEV or LCM.

Table 3

Administration of antiseizure drugs.
	Number
No. of total cases	353
Monotherapy
LEV (%)	157 (44.5)
LCM (%)	111 (31.4)
Polytherapy
LEV་others (%)	42 (11.9)
LCM་others (%)	26 (7.4)
LEV་LCM (%)	16 (4.5)
LEV་LCM་others (%)	1 (0.2)
LEV, levetiracetam; LCM, lacosamide.

Analysis Of Risk Factors For Asd-associated Skin Rash In Patients With Glioma

Newly diagnosed vs. recurrence, adjuvant treatment with radiotherapy vs. no radiotherapy, adjuvant chemotherapy alone vs. any other treatment, and drug allergy history vs. no history showed significant differences in the univariate analysis of risk factors for skin rash (Table 4). The WHO grade was not a significant factor (p = 0.08). The incidence of ASD-related skin rashes did not significantly differ between the LEV and LCM groups. In addition, monotherapy with LEV or LCM was not associated with a significantly lower incidence than polytherapy, including LEV or LCM.

Table 4

Univariate and multivariate analyses of the risk factors for skin rash in patients with glioma.
Variable	Rash	No rash	Univariate		Multivariate
	39 (11.0%)	314 (89.0%)	OR (95% CI)	P value	OR (95% CI)	P value
Sex
Male vs female	27 / 12	176 / 138	1.76 (0.86–3.61)	0.12
Mean Age ± SD	43 ± 14.93	45 ± 14.78	0.71 (0.14–3.56)	0.68
Newly-diagnosed vs recurrence	32 / 7	197 / 117	2.72 (1.16–6.35)	0.021*	0.54 (0.21–1.37)	0.193
High grade (GIII / IV) vs low grade (GI / II)	34 / 5	233 / 81	2.36 (0.89–6.25)	0.08
Adjuvant treatment
Radiotherapy vs no radiotherapy	35 / 4	178 / 136	6.69 (2.32–19.26)	< 0.001*	4.13 (1.22-14.00)	0.023*
Chemotherapy alone vs any other treatment	1 / 38	64 / 250	0.10 (0.01–0.76)	0.026*	0.47 (0.04–5.10)	0.536
ASD
LEV vs LCM	16 / 14	141 / 97	1.13 (0.24–5.38)	0.87
Monotherapy of LEV vs polytherapy including LEV	16 / 5	140 / 55	1.32 (0.65–2.71)	0.44
Monotherapy of LCM vs polytherapy including LCM	14 / 6	97 / 37	0.73 (0.35–1.52)	0.40
History of drug allergy vs no history	14 / 25	63 / 251	2.23 (1.10–4.54)	0.027*	2.40 (1.13–5.10)	0.023*
OR, odds ratio; CI, confidence interval; SD, standard deviation; LEV, levetiracetam; LCM, lacosamide.
*This P value indicates a statistically significant difference.

The multivariate analysis included four factors that showed significant differences in the univariate analysis. Adjuvant treatment with radiotherapy vs. no radiotherapy (odds ratio [OR], 4.13; 95% confidence interval [CI], 1.22-14.00, p = 0.023) and drug allergy history (OR: 2.40, 95% CI; 1.13–5.10, p = 0.023) showed significant differences.

In this study, the frequencies of ASD-related skin rashes in patients with glioma (9.7% in the LEV group and 13.0% in the LCM group) were significantly higher than in those with meningioma in the control group (1.3% in the LEV group and 2.0% in the LCM group) (Table 1). The frequency of ASD-related skin rashes in patients with glioma was also higher than the previously reported rate of 1–3% in patients with epilepsy using LEV or LCM. [2, 4, 6, 10, 18] In the multivariate analysis, a history of drug allergy and adjuvant treatment with radiotherapy were identified as significant risk factors for ASD-associated skin rashes in patients with glioma. The incidence of ASD-related skin rashes did not significantly differ between the LEV and LCM groups (Table 4). Furthermore, monotherapy with LEV or LCM was not associated with a significantly lower incidence, as compared to combination therapies with LEV or LCM. These results suggest that patients with glioma are at a high risk of ASD-associated skin rashes when using LEV and LCM. In addition, the multivariate analyses indicated that adjuvant treatment with radiotherapy was associated with ASD-associated skin rashes.

Levetiracetam- And Lacosamide-associated Skin Rash

Previous reports have shown that LEV and LCM have fewer side effects than conventional ASDs. [5, 6, 13, 14] A previous systematic review that investigated the efficacy of LEV for BTRE, including 21 articles (3 randomized controlled trials, 7 prospective observational studies, and 11 retrospective observational studies), did not examine the incidence of ASD-related eruptions. [16] In prior reports regarding the influence of LCM on BTRE, three of nine studies examined the incidence of eruptions and reported rates of 1-1.9%. [12–14, 18–22, 24] One report included more than 100 patients and reported a 1.9% risk of eruption. [24] However, these reports did not examine the incidence of ASD-related eruptions in patients with glioma. Therefore, the incidence of ASD-related skin rashes in patients with gliomas has not been thoroughly reported. Therefore, in this study, we first identified a high incidence of ASD-related skin rashes that were associated with LEV and LCM in patients with glioma. We suspect that certain factors related to glioma are involved in the high incidence of skin rash.

Risk Factors Of Asd-associated Skin Rash For Patients With Glioma

In the multivariate analysis, adjuvant treatment with radiotherapy and a drug allergy history were identified as risk factors (Table 4). Patients with a drug allergy history were more likely to have skin rashes, which was a predictable result. Drug allergy to ASD can cause cross-reactivity despite the different chemical structures of previously administered drugs, which leads to an increased incidence of skin rash. [9]

Adjuvant treatment with radiotherapy was also shown to be a risk factor for ASD-associated skin rash. However, chemotherapy alone was not associated with a significant risk of skin rash in the multivariate analysis (Table 4). In this study, radiotherapy alone could not be analyzed because of the small number of patients (six patients). A previous study reported a correlation between drug eruption and radiation therapy in ASD, especially with phenytoin. [3] The investigators reported that erythema multiforme associated with phenytoin and cranial radiation therapy (EMPACT) syndrome is a disease in which the appearance of a rash occurs with a high probability upon the use of radiation therapy while taking phenytoin. [3] The eruption was systemic and not limited to the irradiation site. Furthermore, Woo et al. examined the risk of drug eruption in patients with high-grade glioma treated with phenytoin and valproic acid, and reported that the diagnosis of GBM and radiation therapy were the associated risk factors. [26]

Certain mechanisms have been proposed for the involvement of radiotherapy in eruption. One possible hypothesis is that cytochrome P450 is involved in the conversion of medications, such as phenytoin, phenobarbital, carbamazepine, and sulfonamides, into toxic reactive arene oxide metabolites. [15] These metabolites are normally detoxified by epoxide hydrolase. [25] The addition of radiotherapy may cause enzyme deficiency, which in turn could prevent biotransformation of reactive metabolites. As these metabolites accumulate, they may act as haptens and initiate a secondary immunological response. [17] Therefore, we hypothesize that patients with glioma who receive adjuvant treatment with radiotherapy may experience these mechanisms, and have a high risk of ASD-associated skin rashes when treated with LEV and LCM.

Limitations

First, drug allergy-related skin rash is defined as an immunological mechanism (either drug-specified antibody or T-cell) [7]. Furthermore, biomedical allergy-related eruptions were not observed in this study. However, the fact that all eruptions in this study disappeared due to ASD interruption supports the possibility of drug allergy-related skin rash. Second, we could not examine the direct correlation between radiotherapy and the occurrence of skin rash. Third, this study was retrospective; therefore, additional prospective studies are required to validate the high incidence of ASD-related eruptions with LEV or LCM in patients with gliomas observed in this study.

In this study, we demonstrated that the frequencies of ASD-related skin rashes in patients with glioma, who were treated with LEV and LCM, were higher than those in patients with meningioma as well as previously reported rates in patients with epilepsy. Furthermore, our results suggest that adjuvant treatment with radiotherapy and a drug allergy history were associated with a high incidence of ASD-related skin rashes in patients with glioma treated with LEV and LCM. Patients with a history of drug allergies or those who received adjuvant treatment with radiotherapy need to be carefully checked for skin rashes to prevent deterioration of SJS/TEN.

Ethical Approval and Consent to participate

Ethical approval was obtained from the ethics committee of Tokyo Women’s Medical University (No. 3540).　Given the retrospective design of the study, the institutional review board waived the requirement for informed consent. To protect patient privacy, we removed all identifiers from our records upon completion of our analyses.

Human and Animal Ethics

This study complied with the Declaration of Helsinki.

Consent for publication

Not applicable.

Availability of supporting data

The datasets that were collected and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Funding

This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant No. 18K09006.

Authors' contributions

Conceptualization: [Mikoto Onodera], [Taiichi Saito], [Yoshihiro Muragaki]; formal analysis and investigation: [Ken Masamune], [Shunichi Koriyama], [Shunsuke Tsuzuki]; writing and original draft preparation: [Mikoto Onodera]; writing-review and editing: [Taiichi Saito], [Yoshihiro Muragaki]; funding acquisition: [Taiichi Saito]; resources: [Atsushi Fukui], [Masayuki Nitta]; visualization: [Shunsuke Tsuzuki], [Atsushi Fukui]; supervision: [Ken Masamune], [Takakazu Kawamata].

Acknowledgements

We thank Takashi Sakayori and Asuka Komori, Department of Pathology, Tokyo Women’s Medical University, Tokyo, Japan, for the immunohistochemical staining and the molecular genetic analyses.

Authors' information

Not applicable.

Arif H, Buchsbaum R, Weintraub D, Koyfman S, Salas-Humara C, Bazil CW, Resor SR, Jr., Hirsch LJ (2007) Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology 68:1701–1709. doi:10.1212/01.wnl.0000261917.83337.db
Bhoi SK, Kalita J, Misra UK (2016) Skin rash following levetiracetam. Seizure 37:45–47. doi:10.1016/j.seizure.2016.02.014
Bishop AJ, Chang M, Lacouture ME, Barker CA (2014) EMPACT syndrome: limited evidence despite a high-risk cohort. J Neurooncol 119:129–134. doi:10.1007/s11060-014-1457-7
Biton V, Gil-Nagel A, Isojarvi J, Doty P, Hebert D, Fountain NB (2015) Safety and tolerability of lacosamide as adjunctive therapy for adults with partial-onset seizures: Analysis of data pooled from three randomized, double-blind, placebo-controlled clinical trials. Epilepsy Behav 52:119–127. doi:10.1016/j.yebeh.2015.09.006
Blaszczyk B, Lason W, Czuczwar SJ (2015) Antiepileptic drugs and adverse skin reactions: An update. Pharmacol Rep 67:426–434. doi:10.1016/j.pharep.2014.11.009
Cardona AF, Rojas L, Wills B, Bernal L, Ruiz-Patiño A, Arrieta O, Hakim EJ, Hakim F, Mejía JA, Useche N, Bermúdez S, Carranza H, Vargas C, Otero J, Mayor LC, Ortíz LD, Franco S, Ortíz C, Gil-Gil M, Balaña C, Zatarain-Barrón ZL (2018) Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma. J Neurooncol 136:363–371. doi:10.1007/s11060-017-2660-0
Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, Khan DA, Lang DM, Park HS, Pichler W, Sanchez-Borges M, Shiohara T, Thong BYH (2014) International Consensus on drug allergy. Allergy 69:420–437. doi:10.1111/all.12350
Dewan MC, White-Dzuro GA, Brinson PR, Thompson RC, Chambless LB (2016) Perioperative seizure in patients with glioma is associated with longer hospitalization, higher readmission, and decreased overall survival. J Neurosurg 125:1033–1041. doi:10.3171/2015.10.Jns151956
Fowler T, Bansal AS, Lozsadi D (2019) Risks and management of antiepileptic drug induced skin reactions in the adult out-patient setting. Seizure 72:61–70. doi:10.1016/j.seizure.2019.07.003
Hong Z, Inoue Y, Liao W, Meng H, Wang X, Wang W, Zhou L, Zhang L, Du X, Tennigkeit F, Group EPS (2016) Efficacy and safety of adjunctive lacosamide for the treatment of partial-onset seizures in Chinese and Japanese adults: A randomized, double-blind, placebo-controlled study. Epilepsy Res 127:267–275. doi:10.1016/j.eplepsyres.2016.08.032
Kim HK, Kim DY, Bae EK, Kim DW (2020) Adverse Skin Reactions with Antiepileptic Drugs Using Korea Adverse Event Reporting System Database, 2008–2017. J Korean Med Sci 35:e17. doi:10.3346/jkms.2020.35.e17
Maschio M, Dinapoli L, Mingoia M, Sperati F, Pace A, Pompili A, Carapella CM, Vidiri A, Muti P (2011) Lacosamide as add-on in brain tumor-related epilepsy: preliminary report on efficacy and tolerability. J Neurol 258:2100–2104. doi:10.1007/s00415-011-6132-8
Maschio M, Zarabla A, Maialetti A, Fabi A, Vidiri A, Villani V, Giannarelli D (2017) Quality of life, mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group. Epilepsy Behav 73:83–89. doi:10.1016/j.yebeh.2017.05.031
Maschio M, Zarabla A, Maialetti A, Sperati F, Dinapoli L, Dispenza S, Petreri G, Cantelmi T (2018) Lacosamide on background eeg activity in brain tumor-related epilepsy patients: A case series study. Brain Behav 8:e01067. doi:10.1002/brb3.1067
Micali G, Linthicum K, Han N, West DP (1999) Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies. Pharmacotherapy 19:223–227. doi:10.1592/phco.19.3.223.30917
Nasr ZG, Paravattil B, Wilby KJ (2016) Levetiracetam for seizure prevention in brain tumor patients: a systematic review. J Neurooncol 129:1–13. doi:10.1007/s11060-016-2146-5
Oner Dincbas F, Yoruk S, Demirkesen C, Uzel O, Koca S (2004) Toxic epidermal necrolysis after cranial radiotherapy and phenytoin treatment. Onkologie 27:389–392. doi:10.1159/000079094
Rudà R, Houillier C, Maschio M, Reijneveld JC, Hellot S, De Backer M, Chan J, Joeres L, Leunikava I, Glas M, Grant R (2020) Effectiveness and tolerability of lacosamide as add-on therapy in patients with brain tumor-related epilepsy: Results from a prospective, noninterventional study in European clinical practice (VIBES). Epilepsia 61:647–656. doi:10.1111/epi.16486
Rudà R, Pellerino A, Franchino F, Bertolotti C, Bruno F, Mo F, Migliore E, Ciccone G, Soffietti R (2018) Lacosamide in patients with gliomas and uncontrolled seizures: results from an observational study. J Neurooncol 136:105–114. doi:10.1007/s11060-017-2628-0
Saria MG, Corle C, Hu J, Rudnick JD, Phuphanich S, Mrugala MM, Crew LK, Bota DA, Dan Fu B, Kim RY, Brown T, Feely H, Brechlin J, Brown BD, Drappatz J, Wen PY, Chen CC, Carter B, Lee JW, Kesari S (2013) Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors: clinical article. J Neurosurg 118:1183–1187. doi:10.3171/2013.1.Jns12397
Sepulveda-Sanchez JM, Conde-Moreno A, Baron M, Pardo J, Reynes G, Belenguer A (2017) Efficacy and tolerability of lacosamide for secondary epileptic seizures in patients with brain tumor: A multicenter, observational retrospective study. Oncol Lett 13:4093–4100. doi:10.3892/ol.2017.5988
Toledo M, Molins A, Quintana M, Santamarina E, Martinez-Ricarte F, Martinez-Saez E, Salas-Puig J (2018) Outcome of cancer-related seizures in patients treated with lacosamide. Acta Neurol Scand 137:67–75. doi:10.1111/ane.12809
Vecht CJ, Kerkhof M, Duran-Pena A (2014) Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist 19:751–759. doi:10.1634/theoncologist.2014-0060
Villanueva V, Saiz-Diaz R, Toledo M, Piera A, Mauri JA, Rodriguez-Uranga JJ, Lopez-Gonzalez FJ, Gomez-Ibanez A, Garces M, Gonzalez de la Aleja J, Rodriguez-Osorio X, Palao-Duarte S, Castillo A, Bonet M, Ruiz-Gimenez J, Palau J, Arcediano A, Toledo M, Gago A (2016) NEOPLASM study: Real-life use of lacosamide in patients with brain tumor-related epilepsy. Epilepsy Behav 65:25–32. doi:10.1016/j.yebeh.2016.09.033
Wolkenstein P, Charue D, Laurent P, Revuz J, Roujeau JC, Bagot M (1995) Metabolic predisposition to cutaneous adverse drug reactions. Role in toxic epidermal necrolysis caused by sulfonamides and anticonvulsants. Arch Dermatol 131:544–551
Woo PY, Chan DT, Chan KY, Wong WK, Po YC, Kwok JC, Poon WS (2015) Risk factors for seizures and antiepileptic drug-associated adverse effects in high-grade glioma patients: A multicentre, retrospective study in Hong Kong. Surg Pract 19:2–8. doi:10.1111/1744-1633.12102
Youngerman BE, Joiner EF, Wang X, Yang J, Welch MR, McKhann GM, 2nd, Wright JD, Hershman DL, Neugut AI, Bruce JN (2020) Patterns of seizure prophylaxis after oncologic neurosurgery. J Neurooncol 146:171–180. doi:10.1007/s11060-019-03362-1

No competing interests reported.

The high incidence and risk factors of levetiracetam and lacosamide-related skin rashes in glioma patients

Status:

Version 1

Abstract

Figures

Introduction

Patients And Methods

Patient selection

Data Collection

Statistical Analysis

Results

Incidence of ASD-associated skin rash

Clinical Characteristics Of Patients With Glioma

Administration Of Antiseizure Drugs

Analysis Of Risk Factors For Asd-associated Skin Rash In Patients With Glioma

Discussion

Levetiracetam- And Lacosamide-associated Skin Rash

Risk Factors Of Asd-associated Skin Rash For Patients With Glioma

Limitations

Conclusions

Declarations

References

Additional Declarations

Status:

Version 1