Cosmetic Side Effects of Antiepileptic Drugs in Dults With Epilepsy

8/10/2019 Cosmetic Side Effects of Antiepileptic Drugs in Dults With Epilepsy

1/9


2/9


3/9


4/9

VPA-related CSEs (30.6% vs. 11.9%; p b 0.05) and ICSEs (18.1% vs. 7.9%;

p b0.05) compared with male patients. In females, more CSEs and

ICSEs were also attributed to PGB (CSE: 10.8%; ICSE: 6.5%) than to the

average of other AEDs (Table 2b). In males, more CSEs were attributed

to PGB (8.0%) and PHT (4.9%) (Table 2c).

In patients newly started on one of the AEDsin monotherapy, signif-icantly more CSEs (30.2%) and ICSEs (17.1%) were observed in patients

takingVPA compared with the average (Supplementary Table 5).Only 9

patients were newly started on PGBin monotherapy,and the rate of CSE

and ICSE was not signicantly different from the average.

3.4. Specic CSE and ICSE analysis

3.4.1. Weight gain

Weight gain was reported in 3.6% (68/1903) of the patients and was

themost commonCSE (68/110, 61.8%). Intolerability to weightgain was

reported in 3.3% (63/1903) of the patients. Specically, higher inci-

dences of weight gain (attributed: 4.3% vs. 2.6%, p b 0.05; intolerable:

4.2%vs. 2.1%, p b0.05) werereported inwomen than inmen (Fig. 1).Pa-

tients who reported weight gain as a CSE had, on average, 7.68 kg or

10.4% increase from their weight before starting an AED blamed for

weight gain. Of these patients, the men, on average, had an absolute

gain of 8.51 kg and a relative gain of 10.0%, while the women, on aver-

age, had an absolute gain of 7.19 kg and a relative gain of 10.8%.

Signicantly more patients taking PGB (12/143, 8.4%) and patients

taking VPA (35/270, 13.0%) experienced weight gain compared withthe average rate of patients taking all other AEDs (p b0.001). Some

cases of weight gain were seen in patients taking gabapentin (7/251;

2.8%; NS) (Table 2d). All of the patients who experienced PGB-

attributed weightgain either decreased or discontinuedthe medication,

while all but one of the patients who experienced VPA-attributed

weight gain either decreased or discontinued the drug. In patients

who developed weight gain attributed to an AED, the average time

from introduction of the drug to dosage change or discontinuation

was127 days (range = 8722; IQR = 81; SD = 248). Time to intolera-

bility in PGB-attributed weight gain was 107 days (range =5465;

IQR = 61; SD = 204), and time to intolerability in VPA-attributed

weight gain was 133 days (range = 7903; IQR = 92; SD = 280).

Time to intolerability appeared to be similar for all AEDs (p N0.05)

(Supplementary Table 6).

Table 2a

Comparison of AED-attributed cosmetic side effects in adults with epilepsy newly started on an AED.

AED nCSE% (n) pValue OR

ICSE% (n) pValue OR

CBZ 326 1.5 (5) 0.031* 0.40 (0.18, 0.92) 0.6 (2) 0.045* 0.31 (0.10, 0.97)

CLB 80 0.0 (0) NS 0.0 (0) NS

FBM 53 1.9 (1) NS 0.89 (0.21, 3.64) 1.9 (1) NS 1.37 (0.33, (5.72)

GBP 251 2.8 (7) NS 0.74 (0.36, 1.52) 1.2 (3) NS 0.55 (0.20, 1.52)

LCM 86 0.0 (0) NS 0.0 (0) NS

LEV 524 1.3 (7) 0.002** 0.32 (0.15, 0.65) 1.0 (5) 0.019* 0.37 (0.16, 0.85)

LTG 521 1.9 (10) 0.012* 0.45 (0.24, 0.84) 1.0 (5) 0.020* 0.37 (0.16, 0.86)

OXC 160 0.6 (1) NS 0.28 (0.07, 1.13) 0.6 (1) NS 0.43 (0.11, 1.78)

PB 98 0.0 (0) NS 0.0 (0) NS

PGB 143 9.8 (14) < 0.001** 2.85 (1.63, 5.01) 5.6 (8) 0.011* 2.51 (1.24, 5.09)

PHT 404 4.2 (17) NS 1.07(0.65, 1.78) 3.2 (13) NS 1.32 (0.74, 2.34)

PRM 14 0.0 (0) NS 0.0 (0) NS

TGB 25 0.0 (0) NS 0.0 (0) NS

TPM 230 1.7 (4) NS 0.49 (0.20, 1.20) 1.7 (4) NS 0.77 (0.31, 1.92)

VGB 32 3.1 (1) NS 1.48 (0.35, 6.26) 0.0(0) NS

VPA 270 21.9 (59) < 0.001** 10.40 (7.26, 14.88) 13.3 (36) < 0.001** 8.55 (5.54, 13.18)

ZNS 230 0.9 (2) 0.033* 0.29 (0.09, 0.91) 0.0 (0) NS

Average 3.7 2.3

Abbreviations: AED: antiepileptic drug; CSE: cosmetic side effect; CBZ: carbamazepine; CI: condence interval; CLB: clobazam; FBM: felbamate; GBP: gabapentin; ICSE: intolerable

cosmeticside effect; LCM: lacosamide; LEV: levetiracetam; LTG: lamotrigine; OR: odds ratio;O XC: oxcarbazepine; PB: phenobarbital; PGB: pregabalin; PHT: phenytoin; PRM: primidone;TGB: tiagabine; TPM: topiramate; VGB: vigabatrin; VPA: valproate; ZNS: zonisamide.

p b 0.003 (0.05/17 = 0.003).Controlled for gender.Signicant: p b 0.003.Trend: 0.003 b p b 0.05.

132 B. Chen et al. / Epilepsy & Behavior 42 (2015) 129137


5/9


6/9

4. Discussion

This study provides a real-world comparison of rates of cosmetic

side effects among a large cohort of patients newly started on either

old or newer antiepileptic drugs. Overall, over 5% of the patients report-

ed CSEs and, in almost 4% of the patients, the CSE necessitated a changein dosage or discontinuation of the drug.

We identied gender as theonlynon-AED predictor of both CSE and

ICSE. Our results showed that women were over twice as likelyto report

CSEs as men, ultimately requiring dose reduction or discontinuation of

the AED. This might suggest that female patients were either more sus-

ceptible to the occurrence of CSEs or more sensitive to noticing CSEs

whentheyoccurred or both. The fact that the risk of developingCSEsin-

creased when a patient already experienced CSE(s) may suggest that

there is potential individual susceptibility to developing CSE regardless

of the AED.

In our study, we did not nd a signicant difference in CSE occur-

rence between monotherapy and polytherapy, and there was a lack of

correlation between AED dose and CSE as well as between AED drug

load and CSE. Similarly, an earlier study published by Canevini et al.

[12]found that adverse effects of AEDs did not differ between mono-

therapy and polytherapy and were not correlated with AED load.

Our study conrms prior evidence that VPA is one of the major con-

tributors to cosmetic side effects in people with epilepsy. Cosmetic side

effects related to VPA in monotherapy and polytherapy have been doc-

umented in a number of previous studies [1315]. Weight gainis one ofthe most common side effects with VPA and has been found to occur in

up to 57% of adults[1618], and women appeared to be more suscepti-

ble to VPA-related weight gain compared with men[14,19,20]. There

are major implications associated with VPA-related weight gain in

women beyond its cosmetic effects. Aside from the elevated risk of

insulin-related metabolic changes that have been shown to be linked

with VPA treatment [21], female-specic reproductive endocrine disor-

ders such as hyperandrogenism, irregular menses, and polycystic

changes in the ovaries have been reported in women who take VPA

and are especially common among women who have gained weight

as a result of taking VPA for epilepsy[22]. Still, the exact mechanism

by which VPA increases body weight is not well understood. There is

some evidence that VPA-related weight gain is associated with the di-

rect stimulation of pancreatic beta cells, the indirect enhancement of

Table 2c

Comparison of AED-attributed cosmetic side effects inmaleadults with epilepsy newly started on an AED.

AED nCSE% (n) pValue OR

ICSE% (n) pValue OR

CBZ 135 0.0 (0) NS 0.0 (0) NS

CLB 41 0.0 (0) NS 0.0 (0) NS

FBM 22 0.0 (0) NS 0.0 (0) NS

GBP 116 0.9 (1) NS 0.31 (0.04, 2.26) 0.0 (0) NS

LCM 44 0.0 (0) NS 0.0 (0) NS

LEV 253 1.2 (3) NS 0.40 (0.12, 1.32) 0.8 (2) NS 0.46 (0.11, 2.00)

LTG 238 2.1 (5) NS 0.77 (0.30, 2.00) 1.3 (3) NS 0.79 (0.23, 2.69)

OXC 63 1.6 (1) NS 0.59 (0.08, 4.39) 1.6 (1) NS 1.04 (0.14, 7.82)

PB 37 0.0 (0) NS 0.0 (0) NS

PGB 50 8.0 (4) 0.022* 3.51 (1.20, 10.30) 4.0 (2) NS 2.83 (0.65, 12.43)

PHT 184 4.9 (9) 0.042* 2.20 (1.03, 4.72) 2.7 (5) NS 2.01 (0.74, 5.49)

PRM 6 0.0 (0) NS 0.0 (0) NS

TGB 9 0.0 (0) NS 0.0 (0) NS

TPM 82 0.0 (0) NS 0.0 (0) NS

VGB 18 5.6 (1) NS 2.24 (0.29, 17.22) 0.0 (0) NS

VPA 126 11.9 (15) < 0.001** 7.60 (3.87, 14.90) 7.9 (10) < 0.001** 9.02 (3.87, 21.01)

ZNS 75 0.0 (0) NS 0.0 (0) NS

Average 2.6 1.5

Abbreviations: AED: antiepileptic drug; CSE: cosmetic Side Effect; CBZ: carbamazepine; CI: condence interval; CLB: clobazam; FBM: felbamate; GBP: gabapentin; ICSE: intolerable

cosmeticside effect; LCM: lacosamide; LEV: levetiracetam; LTG: lamotrigine; OR: odds ratio;O XC: oxcarbazepine; PB: phenobarbital; PGB: pregabalin; PHT: phenytoin; PRM: primidone;

TGB: tiagabine; TPM: topiramate; VGB: vigabatrin; VPA: valproate; ZNS: zonisamide.p b 0.003 (0.05/17 = 0.003).Signicant: p b 0.003.Trend: 0.003 b p b 0.05.



7/9

insulin resistance by suppressing insulin-mediated peripheral glucose

uptake, and the elevation in both fasting as well as postprandial insulin

levels[20,23,24]. Valproic acid has also been shown to increase binge

eating and motivation to eat compared with placebo which, in turn,

may cause weight gain[25].

Valproic acid-attributed hair loss led to more intolerability than allother AEDs in our study. This is consistent with previous studies that

have reported VPA-induced hair loss to be between 2% and 12% in pa-

tients on monotherapy. Hair loss is more frequent in patients taking

high doses of VPA in long-term therapy [2628]and in patients who

are female[29]. The mechanisms through which VPA may cause alope-

cia are still uncertain. While some studies have shown that VPA intake

reduces serum and hair zinc levels that may lead to hair loss[3032],

others did not nd sufcient evidence to support that claim[3336].

Serum biotinidase enzyme activity may play a role in VPA-induced alo-

pecia. Some studies have found lower biotinidase activity with VPA

treatment, and VPA-induced alopecia disappeared after the administra-

tion of biotin supplement[37,38].

We found PHTto have thehighest rate of gingival hyperplasia leading

to intolerability (2.5%), signicantlyhigher than anyotherAEDs included

in our study. This nding is consistent with the large number of studies

that have also shown gingival overgrowth as a prominent adverse effect

of PHT, occurring in as many as 50% of patients and as early as 3 months

after the initiation of therapy with PHT[3941]. Prevalence of gingival

hyperplasia appears to be higher in children than in adults and is similar

among men and women[42,43]. Though not found in our study, acneand hirsutism have been linked to the chronic use of PHT, particularly

in women[44]. The pathogenesis of PHT-induced gingival hyperplasia

is likely to be multifactorial and centers around its primary effect on so-

dium channel inux[45,46]. Other studies also suggest adding folic acid

as an adjuvant for patients with epilepsy on PHT therapy as a possible

preventive measure against gingival hyperplasia[47,48]. In our study,

out of the 10 patients who developed PHT-attributed gingival hyperpla-

sia, 1 patient took a folate supplement but stopped the supplement prior

to starting PHT, and another patient took folate while on PHT treatment,

while the other 8 patients never took folate supplements. Furthermore,

there is evidence in literature showing that poor oral hygiene is correlat-

ed with higher incidences of gingival hyperplasia[49]; however, patient

dental hygiene was rarely discussed in neurology clinic visits; therefore,

we were unable to take it into account in our study.

Table 2d

Comparison of individual AED-attributed cosmetic side effects in adults with epilepsy newly started on an AED.

AED n

Gingivalhyperplasia(att % /int %)

Hirsutism(att % /int %)

Hair Loss(att % /int %)

Weight Gain(att % /int %)

Acne(att % /int %)

Overall(att % /int %)

CBZ 326 0.3/0.3 1.2/1.2 1.5*/0.6

CLB 80

FBM 53 1.9*/1.9* 1.9/1.9

GBP 251 2.8/2.0 2.8/1.2

LCM 86

LEV 524 0.4/0.4 1.0/0.8 1.3*/1.0*

LTG 521 0.2/0.2 0.8/0.6 0.4/0.4 0.6*/0.6* 1.9*/1.0*

OXC 160 0.6/0.6 0.6/0.6

PB 98

PGB 143 0.7/0.7 8.4*/8.4* 0.7/0.7 9.8**/5.6*

PHT 404 2.5**/2.5** 1.0/1.0 0.3/0.3 0.3/0.0 0.3/0.3 4.2/3.2

PRM 14

TGB 25

TPM 230 1.7/1.7 1.7/1.7

VGB 32 3.1/3.1 3.1/0.0

VPA 270 8.9**/8.2** 13.0**/12.6** 21.9**/13.3**

ZNS 230 0.9/0.9 0.9*/0.0

Average 0.7/0.7 0.4/0.4 1.8/1.7 2.9/2.6 0.2/0.2 3.7/2.3

Abbreviations: AED: antiepileptic drug; att: attributed; CSE: cosmetic side effect; CBZ: carbamazepine; CI: con

dence interval; CLB: clobazam; FBM: felbamate; GBP: gabapentin; ICSE:intolerable cosmetic side effect; int: intolerable; LCM: lacosamide; LEV: levetiracetam; LTG: lamotrigine; OR: odds ratio; OXC: oxcarbazepine; PB: phenobarbital; PGB: pregabalin; PHT:

phenytoin; PRM: primidone; TGB: tiagabine; TPM: topiramate; VGB: vigabatrin; VPA: valproate; ZNS: zonisamide.

p b 0.003 (0.05/17 = 0.003), controlled for gender.Signicant: p b 0.003.Trend: 0.003 b p b 0.05.

135B. Chen et al. / Epilepsy & Behavior 42 (2015) 129137


8/9

Coarsening of facial features has also been reported in patients on

chronic phenytoin therapy[50,51], but no case was reported in our co-

hort. This might have been underreported because of the prolonged pe-

riod of time it would take for coarsening to become noticeable.

Among thenewer AEDs, PGBwas found to be more likely associated

with weight gain compared with other newer AEDs. Several double-

blind clinical trials have reported on PGB's effect on weight gain com-

pared with placebo[5255]. While French et al. found in their random-

ized double-blind placebo-controlled study that weight gain associatedwith PGB was dose-related[52], a similar study by Elger et al. did not

nd a signicant correlation between PGB dose and weight gain [55].

In prior studies, the effect of PGB on weight gain was considered mild

and rarely led to withdrawal of the drug [5255]. In contrast, our

study found that weight gain due to PGB was intolerable in all cases,

leading to either dosage adjustment or medication discontinuation in

every patient. Similar to VPA, the mechanismthrough which PGBcauses

weight gain in patients is not well understood, with some theories relat-

ing to PGB's potential appetite-regulating effects in the central nervous

system[56], sedating effects that may alter energy consumption, and

antidiuretic effects[57].

Oneof the biggest limitations of this study is its retrospective design.

In order to minimize potential bias associated with CSE reporting, attri-

bution of CSE(s) to a given AED was determined by the treating

epileptologists at Columbia. Another limitation is that non-AED

comedications were not taken into account. It is possible that

comedications may aggravate or mitigate AED-related CSEs and, there-

fore, exaggerate or understate CSE and ICSE rates. In addition, prior

knowledge of potential AED side effect proles may change AED pre-

scription behaviors such that physicians may avoid prescribing specic

AEDs to certain high-risk populations. This, in turn, may falsely lower

CSE rates of certain AEDs. To minimize the effects these potential biases

may have on our results, we applied several additional analytical and

statistical methods such as controlling for signicant non-AED predic-

tors of CSEs and examining the CSE rate in patients while being treated

with (but not necessarily attributed to) a given AED and the CSE rate of

the rst newly started AED for a given patient (results not shown).

Adverse cosmetic effects are common comorbid conditions in pa-

tients with epilepsy taking AEDs and can inuence one's quality of life[58]. Of all the CSEs we examined, weight gain was the most common.

Not only can excessive weight gain affect a patient cosmetically, but it

can also impact overall health such as increasing the risk of diabetes

mellitus, heart diseases, the metabolic syndrome, and other health con-

ditions[59,60]. Our study is unique as it includes a large cohort of pa-

tients using newer AEDs and may provide valuable information for

clinicians to better assess the risk/benet ratios of older and newer

AEDs in adult patients with epilepsy. We found that female patients

with epilepsy and patients who have a history of AED-attributed CSEs

may be more susceptible to developing CSEs. For patients who are at a

higher risk of developing CSEs or those who are mainly concerned

about CSEs when taking an AED, physicians should consider prescribing

AEDs associated with a lower risk of CSE, such as LEV, and be cautious

about prescribing VPA and PGB.Supplementary data to this article can be found online athttp://dx.

doi.org/10.1016/j.yebeh.2014.10.021.

Role of the funding source

The funding sources had no inuence over the study design, data

collection, data analysis, data interpretation, and writing of the

manuscript.

Disclosure

The Columbia and Yale AED Database has been supported by Elan,

GlaxoSmithKline, Ortho-McNeil, Pzer, Lundbeck (IN002264), Esai,

and UCB Pharma (PG002141). Dr. Hirsch has received honoraria,

consultation fees and/or speaker fees from all the supporting compa-

nies. Dr. Detyniecki and Dr. Choi have both received research support

for investigator-initiated studies from UCB Pharma and Lundbeck.

Other coauthors have no relevant disclosures.

References

[1] Bootsma HP, Ricker L, Hekster YA,Hulsman J, Lambrechts D, Majoie M, et al. The im-pact of side effects on long-term retention in three new antiepileptic drugs. Seizure2009;18(5):32731.

[2] Chung S, Wang N, Hank N. Comparative retention rates and long-term tolerability ofnew antiepileptic drugs. Seizure 2007;16(4):296304.

[3] de Kinderen RJ, Evers SM, Rinkens R, Postulart D, Vader CI, Majoie MH, et al. Side-effects of antiepileptic drugs: the economic burden. Seizure 2013;23(3):18490.

[4] Ness-Abramof R, Apovian CM. Drug-induced weight gain. Drugs Today (Barc) 2005;41(8):54755.

[5] Bauer J1, Isojrvi JI, Herzog AG, Reuber M, Polson D, Taubll E, et al. Reproductivedysfunctionin women with epilepsy: recommendations forevaluation andmanage-ment. J Neurol Neurosurg Psychiatry 2002;73(2):1215.

[6] Greenwood R, FenwickPB, CunliffeWJ. Acneand anticonvulsants. Br Med J(Clin ResEd) 1983;287(6406):166970.

[7] Tengstrand M, Star K, van Puijenbroek EP, Hill R. Alopecia in association withlamotrigine use: an analysis of individual case safety reports in a global database.Drug Saf 2010;33(8):6538.

[8] Cornacchio AL, Burneo JG, Aragon CE. The effects of antiepileptic drugs on oralhealth. J Can Dent Assoc 2011;77:b140.

[9] Talati R, et al. Effectiveness and safety of antiepileptic medications in patients withepilepsy; 2011 [Rockville (MD)].[10] Yerby MS. Special considerations for women with epilepsy. Pharmacotherapy 2000;

20(8 Pt 2):159S70S.[11] ATC/DDD classication (nal); 2011.[12] Canevini MP, De Sarro G, Galimberti CA, Gatti G, Licchetta L, Malerba A, et al. Rela-

tionship between adverse effects of antiepileptic drugs, number of coprescribeddrugs, and drug load in a large cohort of consecutive patients with drug-refractoryepilepsy. Epilepsia 2010;51(5):797804.

[13] Corman CL,Leung NM, Guberman AH.Weightgain in epileptic patients during treat-ment with valproic acid: a retrospective study. Can J Neurol Sci 1997;24(3):2404.

[14] Belcastro V, D'Egidio C, Striano P, Verrotti A. Metabolic and endocrine effects ofvalproic acid chronic treatment. Epilepsy Res 2013;107(12):18.

[15] Ramakrishnappa SK, Belhekar MN. Serum drug level-related sodium valproate-induced hair loss. Indian J Pharmacol 2013;45(2):1878.

[16] Dinesen H, Gram L, Andersen T, Dam M. Weight gain during treatment withvalproate. Acta Neurol Scand 1984;70(2):659.

[17] Morrell MJ, Isojrvi J, Taylor AE, Dam M, Ayala R, Gomez G, et al. Higher androgensand weight gain with valproate compared with lamotrigine for epilepsy. Epilepsy

Res 2003;54(23):18999.[18] Jallon P, Picard F. Bodyweight gain and anticonvulsants: a comparative review. Drug

Saf 2001;24(13):96978.[19] El-Khatib F, Rauchenzauner M, Lechleitner M, Hoppichler F, Naser A, Waldmann M,

et al. Valproate, weight gain and carbohydrate craving: a gender study. Seizure2007;16(3):22632.

[20] Stephen LJ, Kwan P, Shapiro D, DominiczakM, Brodie MJ. Hormone proles in youngadults with epilepsy treated with sodium valproate or lamotrigine monotherapy.Epilepsia 2001;42(8):10026.

[21] Pylvnen V, Pakarinen A, KnipM, IsojrviJ. Insulin-relatedmetabolic changesduringtreatment with valproate in patients with epilepsy. Epilepsy Behav 2006;8(3):6438.

[22] Isojarvi JI, Tauboll E, Herzog AG. Effect of antiepileptic drugs on reproductive endo-crine function in individuals with epilepsy. CNS Drugs 2005;19(3):20723.

[23] Verrotti A, la Torre R, Trotta D, Mohn A, Chiarelli F. Valproate-induced insulin resis-tance and obesity in children. Horm Res 2009;71(3):12531.

[24] Luef G, Abraham I, Hoppichler F, Trinka E, Unterberger I, Bauer G, et al. Increase inpostprandial serum insulin levels in epileptic patients with valproic acid therapy.Metabolism 2002;51(10):12748.

[25] Martin CK, Han H, Anton SD, Greenway FL, Smith SR. Effect of valproic acid on bodyweight, food intake, physical activity and hormones: results of a randomized con-trolled trial. J Psychopharmacol 2009;23(7):81425.

[26] Jeavons PM, Clark JE. Sodium valproate in treatment of epilepsy. Br Med J 1974;2(5919):5846.

[27] Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepinefor the treatment of complex partial seizures and secondarily generalized tonicclonic seizures in adults. The Department of Veterans Affairs Epilepsy CooperativeStudy No. 264 Group. N Engl J Med 1992;327(11):76571.

[28] Mercke Y, Sheng H, Khan T, Lippmann S. Hair loss in psychopharmacology. Ann ClinPsychiatry 2000;12(1):3542.

[29] McKinney PA, Finkenbine RD, DeVane CL. Alopecia and mood stabilizer therapy.AnnClin Psychiatry 1996;8(3):1835.

[30] Yilmaz Y, Tasdemir HA, Paksu MS. The inuence of valproic acid treatment on hairand serum zinc levels and serum biotinidase activity. Eur J Paediatr Neurol 2009;13(5):43943.

[31] Armutcu F, Ozerol E, Gurel A, Kanter M, Vural H, Yakinci C, et al. Effect of long-termtherapy with sodium valproate on nail and serum trace element status in epileptic

children. Biol Trace Elem Res 2004;102(1

3):1

10.



9/9

[32] Graf WD, Oleinik OE, Glauser TA, Maertens P, Eder DN, Pippenger CE. Altered antiox-idant enzyme activities in children with a serious adverse experience related tovalproic acid therapy. Neuropediatrics 1998;29(4):195201.

[33] Altunbaak S, Biatmakoui F, Baytok V, Hergner O, Burgut HR, Kayrin L. Serum andhair zinc levels in epileptic children taking valproic acid. Biol Trace Elem Res 1997;58(12):11725.

[34] Verrotti A, Basciani F, Trotta D, Pomilio MP, Morgese G, Chiarelli F. Serum copper,zinc, selenium, glutathione peroxidase and superoxide dismutase levels in epilepticchildren before and after 1 year of sodium valproate and carbamazepine therapy.Epilepsy Res 2002;48(12):715.

[35] KajiM, Ito M,Okuno T, Momoi T, Sasaki H, Yamanaka C, etal. Serumcopperand zinc

levels in epileptic children with v alproate treatment. Epilepsia 1992;33(3):555

7.[36] Ponka-Ptorak E, Zagrodzki P, Chopicka J, BartoH, Westermarck T, Kaipainen P,et al. Valproic acid modulates superoxide dismutase, uric acid-independent FRAPand zinc in blood of adult epileptic patients. Biol Trace Elem Res 2011;143(3):142434.

[37] Schulpis KH,KarikasGA, TjamouranisJ, Regoutas S, TsakirisS. Lowserumbiotinidaseactivity in children with valproic acid monotherapy. Epilepsia 2001;42(10):135962.

[38] Castro-Gago M, Prez-Gay L, Gmez-Lado C, Castieiras-Ramos DE, Otero-MartnezS, Rodrguez-Segade S. The inuence of valproic acid and carbamazepine treatmenton serum biotin and zinc levels and on biotinidase activity. J Child Neurol 2011;26(12):15224.

[39] Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia.Oral Surg Oral Med Oral Pathol 1972;34(6):898906.

[40] Seymour RA. Drug-induced gingival overgrowth. Adverse Drug React Toxicol Rev1993;12(4):21532.

[41] Prasad VN, Chawla HS, Goyal A, Gauba K, Singhi P. Incidence of phenytoin inducedgingival overgrowth in epileptic children: a six month evaluation. J Indian SocPedod Prev Dent 2002;20(2):7380.

[42] Klar LA. Gingival hyperplasia during Dilantin-therapy; a survey of 312 patients. JPublic Health Dent 1973;33(3):1805.

[43] Brunet L, et al. Gingival enlargement induced by drugs. Drug Saf 1996;15(3):21931.

[44] Trevisol-Bittencourt PC, da Silva VR, Molinari MA, Troiano AR. Phenytoin as the rstoption in female epileptic patients? Arq Neuropsiquiatr 1999;57(3B):7846.

[45] Seymour RA, Ellis JS, Thomason JM. Risk factors for drug-induced gingival over-growth. J Clin Periodontol 2000;27(4):21723.

[46] Dongari-Bagtzoglou A. Drug-associated gingival enlargement. J Periodontol 2004;75(10):142431.

[47] Singh Nayyar A, Khan M, Vijayalakshmi KR, Subhas GT,Nataraju B, Anitha M. A studyon gingivalenlargement andfolic acidlevelsin phenytoin-treatedepileptic patients:testing hypotheses. Surg Neurol Int 2013;4:133.

[48] Sener U, Zorlu Y, Karaguzel O, Ozdamar O, Coker I, Topbas M. Effects of commonanti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12,folic acid and vitamin B6. Seizure 2006;15(2):7985.

[49] Reali L, Zuliani E, Gabutti L, Schnholzer C, Marone C. Poor oral hygiene enhancesgingival overgrowth caused by calcineurin inhibitors. J Clin Pharm Ther 2009;34(3):25560.

[50] Sasaki H, Ikedo D, Kataoka M, Kido J, Kitamura S, Nagata T. Pronounced palatal andmandibular toriobserved in a patientwith chronic phenytoin therapy: a case report.

J Periodontol 1999;70(4):445

8.[51] Ikedo D, Ohishi K, Yamauchi N, Kataoka M, Kido J, Nagata T. Stimulatory effects ofphenytoin on osteoblastic differentiation of fetal rat calvaria cells in culture. Bone1999;25(6):65360.

[52] French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA. Doseresponse trial ofpregabalin adjunctive therapy in patients with partial seizures. Neurology 2003;60(10):16317.

[53] Arroyo S, Anhut H, Kugler AR, Lee CM, K napp LE, Garofalo EA, et al. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, doseresponse studyin adults with partial seizures. Epilepsia 2004;45(1):207.

[54] Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA, et al. Safetyand efcacy of two pregabalin regimens for add-on treatment of partial epilepsy.Neurology 2005;64(3):47580.

[55] Elger CE, Brodie MJ, Anhut H, Lee CM, Barrett JA. Pregabalin add-on treatment in pa-tients with partial seizures: a novel evaluation ofexible-dose and xed-dose treat-ment in a double-blind, placebo-controlled study. Epilepsia 2005;46(12):192636.

[56] Singh RK, Sinha VP, Pal US, Yadav SC, Singh MK. Pregabalin in post traumatic neuro-pathic pain: case studies. Natl J Maxillofac Surg 2012;3(1):915.

[57] Freynhagen R, Strojek K, GriesingT, Whalen E, Balkenohl M. Efcacy of pregabalin in

neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre,placebo-controlled trial ofexible- and xed-dose regimens. Pain 2005;115(3):25463.

[58] St. Louis EK. Minimizing AED adverse effects: improving quality of life in theinterictal state in epilepsy care. Curr Neuropharmacol 2009;7(2):10614.

[59] Kannel WB, Cupples LA, Ramaswami R, Stokes 3rd J, Kreger BE, Higgins M. Regionalobesity and risk of cardiovascular disease; the Framingham Study. J Clin Epidemiol1991;44(2):18390.

[60] Kannel WB, Gordon T, Castelli WP. Obesity, lipids, and glucose intolerance. The Fra-mingham Study. Am J Clin Nutr 1979;32(6):123845.

137B. Chen et al. / Epilepsy & Behavior 42 (2015) 129137

Cosmetic Side Effects of Antiepileptic Drugs in Dults With Epilepsy

Documents

Transcript of Cosmetic Side Effects of Antiepileptic Drugs in Dults With Epilepsy