Young Je Sung; Jong Seo Park; Helen Lew

doi:10.3341/jkos.2016.57.5.691

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Sung, Park, and Lew: Effect of Mixed Injection of Botulinum Neurotoxin, Triamcinolone and 5-Fluorouracil in Graves’ Upper Eyelid Retraction

Original Article

J Korean Ophthalmol Soc 2016;57(5):691-699.

Published online: 7 September 2016

DOI: https://doi.org/10.3341/jkos.2016.57.5.691

Effect of Mixed Injection of Botulinum Neurotoxin, Triamcinolone and 5-Fluorouracil in Graves’ Upper Eyelid Retraction

Young Je Sung, MD, Jong Seo Park, MD, Helen Lew, MD, PhD

Department of Ophthalmology, CHA Bundang Medical Center, CHA University, Seongnam, Korea

Address reprint requests to Helen Lew, MD, PhD Department of Ophthalmology, CHA Bundang Medical Center, #59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea Tel: 82-31-780-5330, Fax: 82-31-780-5333 E-mail: eye@cha.ac.kr

Received 14 January 201627 January 2016 Accepted 29 March 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/ which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

The aim of this study is to evaluate the effects and complications of mixed injections of botulinum neurotoxin A (BoNT-A), triamcinolone acetonide, 5-fluorouracil (5-FU) in patients with Graves upper eyelid retraction.

Methods

Twenty-four eyes of 17 patients with a mean age of 43.9 years showed symptoms of Grave’s upper eyelid retraction (GUER). They received mixed injections of BoNT-A 4 IU/0.1 mL, triamcinolone acetonide 4 mg/0.1 mL and 5-FU 5 mg/0.1 mL via subconjunctival injection. The response to treatment and the presence of adverse effects were followed up for 9.0 ± 6.0 months and evaluated retrospectively.

Results

Margin reflex distance 1 decreased significantly from 5.6 ± 1.2 mm to 4.7 ± 1.1 mm at 1 month after injection. Tarsal platform show increased significantly from 1.4 ± 1.3 mm to 1.8 ± 1.3 mm, and tear break up time increased significantly from 5.2 ± 3.1 seconds to 10.3 ± 7.8 seconds. When success was defined as the correction amount of GUER being larger than 1 mm, the success rate was 66.7%. Kaplan-Meier survival analysis showed that GUER correction effects last longer in patients with a duration of disease longer than 6 months. There were no severe adverse effects such as diplopia, blepharoptosis and intraocular pressure elevation.

Conclusions

Mixed injections of BoNT-A, triamcinolone acetonide and 5-FU, which compensate the side effects of solitary injection and enhances the anti-fibrotic effect, improves the eyelid position and tear film stability in the patients with GUER. It is an effective and safe method for treating GUER with long maintenance with less adverse effects.

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Keywords: Botulinum neurotoxin A, 5-Fluorouracil, Graves upper eyelid retraction, Periocular injection, Triamcinolone

References

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Figure 1.

Morphologic outcome measurement. MRD1 = margin reflex distance; IPF = interpalpebral fissure; TPS = tarsal platform show; MLD = margin limbal distance.

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Figure 2.

Clinical outcomes after mixed injection of botulinum neurotoxin A (BoNT-A), triamcinolone and 5-fluorouracil (5-FU) in Graves’ upper eyelid retraction. MRD = margin reflex distance; IPF = interpalpebral fissure; TPS = tarsal platform show; MLD = margin-limbal distance; BUT = break-up time; TAO-QoL = thyroid associated ophthalmopathy quality of life questionnaire; LTMH = lower eyelid tear meniscus height. ∗p< 0.05, Wilcoxon signed-rank test.

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Figure 3.

Tear film stability before and after mixed injection of botulinum neurotoxin A (BoNT-A), triamcinolone and 5-fluorouracil (5-FU) in Graves’ upper eyelid retraction. 35 year-old female patient with Graves’ upper eyelid retraction (Case #9). Mixed injection of BoNT-A, triamcinolone and 5-FU was performed in the both upper eyelid. Margin reflex distance 1 (MRD1) decreased from 6.4 mm and 5.2 mm (A) to 3.8 mm and 3.9 mm (B) after 3 month. Spectralis optical coherence tomography shows lower eyelid tear meniscus height decrease after mixed injection (C, D). Keratogragh shows almost broken tear film of the left eye (E, red color) and recovered status after mixed injection (F, green color). OD = oculus dexter; OS = oculus sinister.

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Figure 4.

Kaplan-Meier Survival Analysis for Graves’ upper eyelid retraction Correction following mixed Injection of botulinum neurotoxin A (BoNT-A), Triamcinolone and 5-fluorouracil (5-FU).

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Figure 5.

Case series before and after mixed injection of botulinum neurotoxin A (BoNT-A), triamcinolone and 5-fluorouracil (5-FU) in Graves’ upper eyelid retraction. 43 year-old female patient with Graves’ upper eyelid retraction (Case #2, A, B). Mixed injection of BoNT-A, triamcinolone and 5-FU was performed in the both upper eyelid. Margin reflex distance 1 (MRD1) decreased from 6.2 mm and 6.8 mm (A) to 5.0 mm and 5.1 mm (B). 28 year-old female patient with Graves upper eyelid retraction of her right eye (Case #12, C, D). MRD1 decreased from 4.6 mm (C) to 3.4 mm (D). 40 year-old female patient with Graves upper eyelid retraction of her right eye (Case #17, E, F). MRD1 decreased from 5.2 mm (E) to 4.1 mm (F).

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Table 1.

Demographic characteristics of the patients

Variables	Patients
Numbers (eyes)	17 (24)
Sex (male:female)	1:16
Age (years)	43.9 ± 10.4
Thyroid status (hyperthyroid:euthyroid:hypothyroid)	13:3:1
Smoker (n, %)	3 (17.6)
Visual acuity (Snellen)	0.9 ± 0.1
QoL sum of scores	12.4 ± 6.6
CAS	2.6 ± 1.4
Duration of illness (months)	17.4 ± 28.3
Follow up periods (months)	9.0 ± 6.0
Thyroid stimulating anti body positive rate (%)	94.1
TSH receptor antibody positive rate (%)	100

Values are presented as mean ± SD unless otherwise indicated. QoL = quality of life questionnaire; CAS = clinical activity score; TSH = thyroid stimulating hormone.

Table 2.

Characteristics of the Graves upper eyelid retraction patients treated with mixed injections of botulinum neurotoxin A (BoNT-A), triamcinolone and 5-fluorouracil (5-FU)

Patient number	Sex	Age (years)	Side	Duration of Graves’ disease (months)	Follow-up (months)	CAS^∗	Thyroid status	TSHR^† Ab (IU/L)	TS Ab^‡ (%)	Smoking	Previous treatment	Before injection			One month after injection			Three months after injection
Patient number	Sex	Age (years)	Side	Duration of Graves’ disease (months)	Follow-up (months)	CAS^∗	Thyroid status	TSHR^† Ab (IU/L)	TS Ab^‡ (%)	Smoking	Previous treatment	MRD₁ (mm)	TPS (mm)	LTMH (μm)	MRD₁ (mm)	TPS (mm)	LTMH (μm)	MRD₁ (mm)	TPS (mm)	LTMH (μm)
1	F	34	OD	2	9	3	Hypothyroid	24.33	416.6	Nonsmoker	None	6.2	0.0	396	5.0	1.1	294	4.1	1.5	261
2	F	43	OD	2	4	6	Hyperthyroid	16.18	520.6	Smoker	IV methylprednisolone	6.8	1.5	141	5.1	2.2	374	4.2	2.0	152
			OS									7.1	2.6	199	5.6	3.4	411	4.0	3.2	187
3	M	57	OD	2	7	2	Hyperthyroid	3.3	145.7	Smoker	None	6.8	0.5	239	5.4	0.9	166	5.5	0.0	224
			OS									7.0	1.1	210	4.7	2.2	177	4.8	1.4	163
4	F	60	OD	3	17	1	Hyperthyroid	>40.0	343.3	Nonsmoker	None	5.2	0.9	354	5.4	0.0	517	5.2	0.0	443
			OS									5.1	0.0	355	5.1	0.0	690	4.9	0.0	470
5	F	52	OD	4 4	3	3	Hyperthyroid	4.02	462.6	Nonsmoker	Oral prednisolone	3.8	0.0	245	3.8	0.0	130	3.6	0.0	305
6	F	48	OD	4	3	4	Hyperthyroid	21.6	588.3	Nonsmoker	None	3.8	2.1	383	2.8	2.6	419	2.9	1.8	353
			OS									4.5	1.0	285	3.8	1.2	321	3.6	0.7	293
7	F	48	OD	6	20	2	Euthyroid	3.68	240.1	Nonsmoker	Oral prednisolone	6.9	1.0	228	6.9	1.1	268	6.6	1.9	268
			OS									3.5	3.3	116	4.0	2.9	232	3.3	3.0	232
8	F	27	OS	7	10	3	Euthyroid	25.65	809.3	Nonsmoker	Oral prednisolone	7.1	0.7	247	5.6	1.0	369	5.1	0.6	264
9	F	35	OD	7	19	2	Hyperthyroid	<0.30	517.6	Nonsmoker	Oral prednisolone	6.4	1.5	524	3.6	2.2	239	3.8	2.3	222
			OS									5.2	1.4	311	4.0	2.0	222	3.9	2.2	237
10	F	40	OS	9	4	1	Hyperthyroid	2.68	246.9	Nonsmoker	Topical fluorometholone	5.8	1.5	408	4.9	1.9	228	5.0	0.5	201
11	F	41	OS	9	9	2	Hyperthyroid	5.89	492.5	Nonsmoker	Topical fluorometholone	4.4	1.7	141	2.5	1.7	180	4.5	1.9	147
12	F	28	OD	12	3	2	Euthyroid	2.67	506.7	Nonsmoker	Oral prednisolone Orbital decompression	4.6	2.7	192	3.6	3.3	246	3.4	3.4	181
13	F	58	OS	18	6	2	Hyperthyroid	2.49	162.5	Nonsmoker	None	3.7	0.0	207	6.0	0.0	233	5.3	0.0	222
14	F	52	OS	30	11	2	Hyperthyroid	>40.0	633.9	Nonsmoker	Oral prednisolone	5.7	3.3	387	5.1	3.2	217	4.9	4.3	264
15	F	51	OS	24	18	3	Hyperthyroid	>40.0	488.1	Nonsmoker	None	5.6	4.3	607	5.4	3.9	387	4.7	4.4	356
16	F	32	OD	36	7	2	Hyperthyroid	6.48	493.2	Nonsmoker	None	6.7	0.0	117	6.1	0.7	152	6.6	0.0	130
			OS									7.3	0.0	90	5.4	0.7	130	6.1	0.0	115
17	F	40	OD	120	3	4	Hyperthyroid	>40.0	517.1	Smoker	Oral prednisolone	5.2	3.6	278	4.1	4.5	470	4.1	4.0	275
Mean		43.9		17.4	9.0	2.6			446.2			5.6	1.4	277.5	4.7	1.8	294.7	4.6	1.6	248.5
SD		10.4		28.3	6.0	1.2			172.7			1.2	1.3	130.2	1.1	1.3	137.4	1.0	1.5	90.4

Ab = antibody; MRD1 = margin reflex distance 1; TPS = tarsal platform show; LTMH = lower tear meniscus height; F = female; M = male.

^∗ Clinical activity score (CAS) (by Mourits);

^† Thyroid stimulating hormone receptor antibody (TSHR Ab) (reference: 0-1.75 IU/L);

^‡ Thyroid stimulating (TS) antibody (reference: 0-140%).

Table 3.

Clinical outcomes after mixed injections of botulinum neurotoxin A (BoNT-A), triamcinolone and 5-fluorouracil (5-FU)

	Parameters	Before injection	1 month after injection	3 months after injection	Last follow-up
Eyelid position	MRD₁	5.6 ± 1.2	4.7 ± 1.1^∗	4.6 ± 1.0^∗	5.2 ± 0.9
	MRD₂	5.1 ± 0.9	5.2 ± 0.9	5.0 ± 1.0	5.1 ± 0.9
	IPF	10.6 ± 1.4	10.0 ± 1.4	9.8 ± 1.4^∗	10.3 ± 1.2
	TPS	1.4 ± 1.3	1.8 ± 1.3^∗	1.6 ± 1.5	1.7 ± 1.4
	MLD	10.3 ± 0.9	9.8 ± 0.9	10.0 ± 1.1	10.0 ± 0.7
Tear film stability	LTMH	277.5 ± 130.2	294.7.1 ± 137.4	248.5.0 ± 90.4^†	297.0 ± 138.1
Tear film stability	BUT	5.2 ± 3.1	10.3 ± 7.8^∗	-	-
TAO-QoL	Sum of scores	12.4 ± 6.6	-	-	10.1 ± 8.6^∗

Values are presented as mean ± SD unless otherwise indicated.

MRD = margin reflex distance; IPF = interpalpebral fissure; TPS = tarsal platform show; MLD = margin-limbal distance; LTMH = lower eyelid tear meniscus height; BUT = break-up time; TAO-QoL = thyroid associated ophthalmopathy quality of life questionnaire.

^∗ p < 0.05, Wilcoxon signed-rank test to status before injection;

^† p < 0.05, Wilcoxon signed-rank test to status of 1 month.

Table 4.

Kaplan-Meier survival analysis and success rate for upper eyelid retraction correction following mixed injections of botulinum neurotoxin A (BoNT-A), triamcinolone and 5-fluorouracil (5-FU)

	≤6 months (n = 12)	> 6 months (n = 12)	Overall (n = 24)
Mean period of maintenance (months, 95 % CI)	5.7 (3.9-7.6)	7.5 (5.6-9.5)	6.8 (5.2-8.3)
50% survival period (months, 95% CI)	6.0 (1.0-12.7)	9.0 (1.0-17.6)	9.0 (3.6-14.4)
Success rate (%)	58.3	75.0	66.7

CI = confidence interval.

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