Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-016-3281-6

OCULOPLASTICS AND ORBIT

Chemodenervation of extraocular muscles with botulinum toxin in thyroid eye disease David B. Granet 1 & Nickisa Hodgson 1 & Kyle J. Godfrey 1 & Ricardo Ventura 1 & Don O. Kikkawa 1 & Leah Levi 2 & Michael Kinori 1

Received: 5 November 2015 / Revised: 9 December 2015 / Accepted: 25 January 2016 # Springer-Verlag Berlin Heidelberg 2016

Abstract Background Thyroid eye disease (TED) presents a management dilemma for strabismologists due to the variability of its clinical course. Prisms may be prescribed to relieve diplopia in small deviations. Surgical intervention, on the other hand, should not be done until the active phase of the disease has subsided. We report our experience with chemodenervation utilizing botulinum toxin (BT) injection in the management of TED-related strabismus. Methods A retrospective chart review was done on twentytwo (22) consecutive patients receiving BT injections at the University of California, San Diego (UCSD) Thyroid Eye Center. All BT injections were administered by a single physician under electromyographic guidance. Results The clinical records of 22 patients (18 females) were reviewed. Seven patients (32 %) had a reduction of their deviation to a point where surgery was not required. In six patients (27 %), surgery was required but an improvement in ocular deviation was found, altering the original surgical plan. In four patients (18 %), the deviation continued to progress after BT injection. Success rates were higher if pre-treatment deviation was less than 20 prism diopters (Δ). Conclusion One third of the chemodenervation-treated patients avoided surgical intervention, with an additional 27 % (total of 40 % of those who needed surgery) having a reduced

* David B. Granet [email protected]

1

Department of Ophthalmology and The Thyroid Eye Center, University of California, San Diego, CA, USA

2

Division of Ophthalmology, Scripps Clinic, La Jolla, CA, USA

deviation prior to surgery. Using BT injection to extraocular muscles to treat diplopia in TED patients is most effective in preventing surgery in those patients with 20Δ or less of deviation. Keywords Thyroid eye disease . Restrictive strabismus . Botulinum toxin . Strabismus surgery

Introduction Diplopia in patients with thyroid eye disease (TED) presents a management dilemma for strabismologists due to the variability of its clinical course. Prisms may be prescribed to relieve diplopia in small deviations. Large deviations, on the other hand, are usually managed surgically; however, surgical intervention is generally delayed until the active phase of the disease has subsided. This period of waiting is extraordinarily frustrating to the patient [1]. In an acute mild TED, establishing an euthyroid state, smoking cessation, a course of selenium and ocular lubrication are recommended [2, 3]. In moderate to severe cases, immunosuppression with systemic corticosteroids is the main treatment modality [4]. Where steroids are not tolerated, or are ineffective (in about third of the cases [5]) steroid sparing agents (such as azathioprine) or biological agents (such as anti-TNFα [6] and anti-CD20 antibodies [7]) can be used. Other treatment options include low-dose external beam radiation and early orbital decompression in cases of sightthreatening compressive optic neuropathy or severe corneal exposure [3]. The use of botulinum toxin (BT) for treating eye misalignments, first described by Alan Scott, [8, 9], has gained popularity in some forms of strabismus. Limited previous investigations on patients with strabismus due to TED have shown

Graefes Arch Clin Exp Ophthalmol

that chemodenervation with BT injection might be useful in the alleviation of symptoms, in decreasing the amount of surgery required, and even in obviating the need for strabismus surgery in TED. It seems than BT Injection would be of greater value in earlier stages of the disease when the inflammatory process is active, as opposed to later stages when muscle fibrosis occurs [10]. Favorable outcomes have been reported in small series [10–12]. However, the efficacy of BT in a larger series of TED patients at Moorfields Eye Hospital, London, was estimated by Kowel et al. to be not encouraging [13], with only one out of eight patients even with relatively mild disease having a reasonable chance of long-term benefit [14]. We report our experience at the University of California, San Diego (UCSD) Thyroid Eye Center with the use of BT injection in the management of strabismus in TED patients.

Outcomes of the BT injection were divided into three categories: 1. Success, which included those patients who had a reduction of their deviation and diplopia to a point where surgery was not needed. In general, those were patients who were diplopia free, fusing or within a prism correction range (8Δ or less). 2. Partial success, which included patients who still needed strabismus surgery due to persistent diplopia but with decreased amount of correction needed in comparison to the pre-injection deviation. 3. Neutral, which included patients with persistent diplopia who needed the same or greater amount of surgery after BT injections.

Results Methods University of California, San Diego (UCSD) Institutional Review Board approval with HIPAA compliance was obtained for this study. A retrospective chart review was done on 22 consecutive patients who had diplopia in primary position or downgaze related to TED and received BT (BOTOX; Allergan, Irvine, CA, USA) injections at the University of California Ratner Children’s Eye Center. All patients were under the care of a primary care physician and/or endocrinologist, with no significant uncontrolled medical issues other than thyroid-related. None of the patients underwent orbital irradiation. All Injections were performed by one of the authors (DBG) during the active phase of the disease, as an attempt to prevent bothersome diplopia and subsequent surgery. As all deviations were either hypotropia or esotropia, the inferior or medial rectus muscles were injected as needed. The injections were done under topical anesthesia using electromyographic (EMG) guidance to confirm correct placement of the injection into the muscle (Fig. 1). All solutions were prepared immediately prior to injection using standard procedures and diluent. A final concentration of 50 U/cc (5 U/0.1 cc) was used. Toxin dosage ranged from 5–10 U per extraocular muscle (EOM) if the muscle was not enlarged in computerized tomogarphy, and up to 15 U per muscle if muscle enlargement was seen. All deviations were measured by the injecting physician immediately prior to the procedure. Post-injection results were characterized after the measured effect of the toxin reversed and then stabilized for three visits over an additional 6 months to a year. Patients were examined at 1 month, 3 months, and 6 months after the injection. When stabilization was documented post injection, it was confirmed by three visits over an additional 6 months to a year.

The clinical records of 22 patients (18 females) were reviewed. The mean age was 60.4 years (range 39–90 years). Overall, 13 patients (59 %) benefited from BT injection. Seven patients (32 %) did not need surgery at all, and six additional patients (27 %) needed less surgery than originally planned. All injections were well tolerated. No local or systemic adverse events were noted. Seven of the 22 patients had a reduction of their deviation to a point where surgery was not needed. In this group, one patient noted only occasional diplopia, and another had only slight diplopia on extreme right gaze. Six of seven patients (86 %) required only one BT injection. One patient needed repeated injections to maintain fusion. Six of these seven patients were orthophoric or had 6Δ or less of heterophoria after the injection while one patient had 12Δ of esophoria. Although the use of prism glasses to prevent residual diplopia was still considered as success, none of these patients required them. There was a trend toward the need of surgical intervention in patients with a pre-treatment deviation of greater than 20Δ (Odds ratio 4.5, p = 0.11). In 15 patients (68 %), diplopia was still present once the deviation stabilized after the BT injection, necessitating surgery. Among these, six patients (27 %) had sufficient improvement in the deviation from the BT injection that the amount of surgery needed was less than had been planned based on the pre-injection measurements; five (23 %) had no improvement from the pre-injection deviation, and four patients (18 %) had progression of the deviation (Fig. 2 Top). A total of 27 EOMs were injected with BT. Of those, ten (37 %) did not require surgical correction after BT injection. When divided into two groups by degree of deviation (above or below 20Δ), there was an obvious trend toward better results after BT injection in the latter group (Fig. 2 Bottom).

Graefes Arch Clin Exp Ophthalmol

Fig. 1 An example of electromyographic (EMG)-guided botulinum toxin (BT) injection to the left medial rectus (LMR) under topical anesthesia. a After applying topical anesthesia, a lid speculum is placed. A special 26G needle with electrically sensitive tip and an electrode on the patient’s forehead is attached to the electomyogram. b Patient is asked to look in the opposite direction to the action of the muscle being injected (in this case left lateral gaze. A forceps can be used). The needle is inserted through the conjunctiva, superficial to the sclera and into the target

muscle. c When the needle is believed to be in the muscle, the patient is asked to look in the direction of action of the extraocular muscle being injected (in this case right lateral gaze; note a restriction in the right eye). If the needle is correctly positioned, there will be an audible increase in signal output from the EMG. Then the toxin is slowly injected to the muscle. d The needle is carefully ejected with the help of an applicator. The patient is immediately seated to avoid penetration of the toxin to the levator palpebrae muscle and cause lid ptosis

Discussion

inactive quiescent phase (typically occuring 18 months to 3 years after onset of the disorder [19]), EOMs undergo contracture and fibrosis, with a motility deficit [20]. Bothersome diplopia in the active phase of TED, prior to the establishment of fibrosis, could be considered an appropriate clinical situation for the use of BT, since the antagonist muscle is not paretic. BT works properly when a functioning antagonist is present in order to contract and stretch the chemodenervated muscle, change its length, its length–tension curve and histology [13]. In TED, EOMs are pathologic, but not paretic (especially the typical Bantagonists^ muscles — the superior and lateral rectii). This is true mainly for the early stages of the disease when muscles are not fibrotic and inelastic. For comparison, in the case of complete sixth nerve palsy (as opposed to paresis), BT injection to the medial rectus will have less effect, since the completely paralyzed lateral rectus will not overcome the chemodenervated medial rectus. Other options to treat diplopia in TED, such as surgical interventions, should be delayed until the disease reaches stability, since the active phase is typically temporary and unstable. In addition, surgical correction is not always technically straightforward due to pathological muscles. Since the early studies on the use of BT in strabismus by Dr. Alan B. Scott [8, 9], this modality has found

Graves’ disease is a progressive and debilitating disorder. About 3.3 % of patients suffering from Graves’ disease develop diplopia [15]. Surgery is a definitive procedure for correcting double vision. However, this should generally not be done until the disease process has stabilized. Treatment options during the active phase include prisms or, in more severe cases, patching. The latter option may leave the patient anxious, frustrated, and in some cases dependent on others to perform tasks that they used to be able to do themselves. However, surgical intervention can be difficult, especially where the muscle restriction has become so severe that the procedure is complex or where even multiple surgeries are needed. Thyroid eye disease has two phases. In the first phase, there is a lymphocytic infiltrate in the affected extraocular muscles [16]. In this Binflammatory^ phase, an amorphous granular material consisting primarily of collagen fibrils and glycosaminoglycans accumulates in the EOMs. The highly hydrophilic nature of these glycosaminoglycans leads to significant enlargement of the muscles [17, 18], with resultant diplopia. This most commonly involves the inferior rectus muscle [17]. Later, in the

Graefes Arch Clin Exp Ophthalmol

Fig. 2 Results of botulinum toxin (BT) injections to extraocular muscles (EOM) in patients with thyroid eye disease (TED). (a) Results by patients. Surgery was no longer needed after BT injections in 32 % of patients. Of the remaining 68 % needing surgery, 27 % had improved eye alignment, requiring less surgical correction than previously planned. b Results by EOMs and deviation. In total, 37 % of EOMs did not need surgical correction after BT injection. When deviation was greater than 20Δ, only 18 % of EOMs avoided additional surgical correction. When deviation was smaller than 20Δ, 50 % of EOMs avoided additional surgical correction

various applications in ophthalmology. However, only a few studies have specifically evaluated the application of BT in strabismus secondary to TED. In one report by Gair et al. [14] involving 65 patients, only one out of eight patients achieved comfortable single binocular vision after injection with BT. Dunn [11] reported a series of eight patients with good results. Lyons et al. [21] reported a 75 % decrease in mean deviation for three-quarters of their patients, and obviating the need for surgery in one out of six patients. In the present report, about a third of the treated patients were able to avoid surgical intervention, with an additional 27 % (or 40 % of those needing an operation) having a reduced deviation compared to their pre-

injection deviation. This reduction from the pre-injection deviation made the ensuing surgery more manageable and straightforward. Even in those patients in whom the deviation increased (18 %), we can speculate the intervention with BT may well have reduced the magnitude of the eventual deviation, as injections were performed during the active phase of the disease, which is expected to progress. It is apparent that BT can be an important and beneficial adjunct to the management of patients with restrictive dysthyroid myopathy. Side-effects of BT injections are uncommon. Lid ptosis is the most well-known side-effect, but Dawson reported an incidence of only 4 % out of 503 patients who underwent BT injection for strabismus correction [22]. Moreover, it is rarely seen in inferior rectus injections (<1 %), compared to 38 % after superior rectus injections [23]. The incidence of eyelid ptosis could be even lower if patient is asked to immediately sit up after the injection. It should be noted that ptosis induced by BT can be a desirable result – for example, as a temporary treatment of corneal exposure [24] or even treating lid retraction associated with TED [25]. Optic neuropathy has also been described after BT injection to EOMs [26]. However, although attention should be given to this sight-threatening complication, it is extremely rare. Recently, ocular surface parameters were found to alter after BT injection to EOM, but these were mild and temporary [27]. Another reported Bside-effect^ is lowering of intraocular pressure (IOP) in primary and upgaze, probably due to decreased tension on the globe as muscle relaxes and restriction is relieved [28]. This might actually serve as a secondary benefit of BT injection to EOMs, since a significant percentage of patients with elevated IOP secondary to TED do develop glaucoma [29]. The main limitations of our study are its retrospective nature, small group population, and the lack of control group. Therefore, we cannot be sure whether the beneficial effect of the toxin is superior to the natural course of the disease. In summary, chemodenervation with BT injection is another therapeutic modality in the management of restrictive myopathy of TED. This treatment may obviate the need for strabismus surgery, or significantly decrease the amount of surgery needed to correct the strabismus and/or relieve the frustration felt by patients while waiting for their disease to stabilize. We therefore recommend that this option be considered in patients for whom the disease is still active or for those whose deviation is less than 20Δ but is too great for satisfactory prismatic solution. Although we did not reach statistical significance (probably due to the small groups of patients) it is our impression that when the deviations are greater than 20Δ, BT injection may have a less dramatic effect.

Graefes Arch Clin Exp Ophthalmol Acknowledgments This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Compliance with ethical standards

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Funding No funding was received for this research. Conflict of interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript. Ethical approval All procedures performed in this study were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent For this type of study formal consent is not required. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

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References 1.

2.

3.

4.

5.

6.

7.

8.

9. 10.

Granet DB (2011) Strabismus: aligning the doctor’s vision with the patient’s need. Br J Ophthalmol 95:443–444. doi:10.1136/bjo. 2010.188326 Phillips ME, Marzban MM, Kathuria SS (2010) Treatment of thyroid eye disease. Curr Treat Options Neurol 12:64–69. doi:10.1007/ s11940-009-0054-0 Verity DH, Rose GE (2013) Acute thyroid eye disease (TED): principles of medical and surgical management. Eye (Lond) 27:308– 319. doi:10.1038/eye.2012.284 Marcocci C, Marino M (2012) Treatment of mild, moderate-tosevere and very severe Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab 26:325–337. doi:10.1016/j.beem.2011.11.005 Pillar AJ, Richa DC (2014) Treatment options for thyroid eye disease. Curr Treat Options Neurol 16:303. doi:10.1007/s11940-0140303-8 Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM (2005) The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye (Lond) 19:1286–1289. doi:10. 1038/sj.eye.6701768 Salvi M, Vannucchi G, Campi I, Curro N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P (2007) Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 156:33–40. doi:10.1530/eje.1.02325 Scott AB (1980) Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 87:1044– 1049 Scott AB (1981) Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc 79:734–770 Scott AB (1984) Injection treatment of endocrine orbital myopathy. Doc Ophthalmol 58:141–145

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

Dunn WJ, Arnold AC, O’Connor PS (1986) Botulinum toxin for the treatment of dysthyroid ocular myopathy. Ophthalmology 93: 470–475 Wu X, Lin N, Ai LK, Wang JH, Yan LJ (2006) The application of botulinum toxin A in the treatment of restrictive strabismus in thyroid associated ophthalmopathy]. [Zhonghua yan ke za zhi] Chin J Pphthalmol 42:1063–1067 Kowal L, Wong E, Yahalom C (2007) Botulinum toxin in the treatment of strabismus. A review of its use and effects. Disabil Rehabil 29:1823–1831. doi:10.1080/09638280701568189 Gair EJ, Lee JP, Khoo BK, Maurino V (1999) What is the role of botulinum toxin in the treatment of dysthyroid strabismus? J AAPOS 3:272–274 Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA (1996) Clinical features of Graves’ ophthalmopathy in an incidence cohort. Am J Ophthalmol 121: 284–290 Heufelder AE (2000) Pathogenesis of ophthalmopathy in autoimmune thyroid disease. Rev Endocr Metab Disord 1:87–95 Bahn RS (2010) Graves’ ophthalmopathy. N Engl J Med 362:726– 738. doi:10.1056/NEJMra0905750 Smith TJ, Bahn RS, Gorman CA (1989) Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocr Rev 10:366– 391. doi:10.1210/edrv-10-3-366 Dagi LR, Elliott AT, Roper-Hall G, Cruz OA (2010) Thyroid eye disease: honing your skills to improve outcomes. J AAPOS 14: 425–431. doi:10.1016/j.jaapos.2010.07.005 Mourits MP, Koornneef L, Wiersinga WM, Prummel MF, Berghout A, van der Gaag R (1989) Clinical criteria for the assessment of disease activity in Graves’ ophthalmopathy: a novel approach. Br J Ophthalmol 73:639–644 Lyons CJ, Vickers SF, Lee JP (1990) Botulinum toxin therapy in dysthyroid strabismus. Eye (Lond) 4(Pt 4):538–542. doi:10.1038/ eye.1990.74 Dawson EL, Sainani A, Lee JP (2005) Does botulinum toxin have a role in the treatment of secondary strabismus?*. Strabismus 13:71– 73. doi:10.1080/09273970590935048 McNeer KW (1989) Botulinum toxin injection into the superior rectus muscle of the non-dominant eye for dissociated vertical deviation. J Pediatr Ophthalmol Strabismus 26:162–164 Bittencourt MK, de Vasconcellos JP, Bittencourt MD, Malago R, Bacellar M (2013) Evaluation of the efficacy and safety of botulinum toxin type A to induce temporary ptosis in dogs. J Ocul Pharmacol Ther 29:431–436. doi:10.1089/jop.2012.0119 Dintelmann T, Sold J, Grehn F (2005) Botulinum toxin injectiontreatment of upper lid retraction in thyroid eye disease. Ophthalmologe 102:247–250. doi:10.1007/s00347-004-1091-4 Korn BS, Seo SW, Levi L, Granet DB, Kikkawa DO (2007) Optic neuropathy associated with botulinum A toxin in thyroid-related orbitopathy. Ophthal Plast Reconstr Surg 23:109–114. doi:10. 1097/IOP.0b013e318032eb12 Taylan Sekeroglu H, Kocabeyoglu S, Mocan MC, Muz E, Karakaya J, Irkec M, Sanac AS (2014) Ocular surface changes following botulinum toxin injection for strabismus. Cutan Ocul Toxicol 1–4 Doi: 10.3109/15569527.2014.941996 Kikkawa DO, Cruz RC Jr, Christian WK, Rikkers S, Weinreb RN, Levi L, Granet DB (2003) Botulinum A toxin injection for restrictive myopathy of thyroid-related orbitopathy: effects on intraocular pressure. Am J Ophthalmol 135:427–431 Ohtsuka K, Nakamura Y (2000) Open-angle glaucoma associated with Graves disease. Am J Ophthalmol 129:613–617