Journal of Ophthalmic and Vision Research

Published date: Jun 24 2025

Journal Title: Journal of Ophthalmic and Vision Research

Issue title: ‎Volume 20 - 2025

Pages: 1 - 13

DOI: 10.18502/jovr.v20.14666

Mohammad Reza Talebnejadtalebmor@sums.ac.irPoostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz

Roghayyeh Baghbanbaghbanroghayyeh@gmail.comPoostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz

Alireza Attaralireza.attar8374@gmail.comPoostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz

Aidin Meshksarmeshksarai@gmail.comPoostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz

Mansoureh BagheriMansooreh_bagheri@yahoo.comPoostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz

Mohammad Reza Khalilipsorc@yahoo.comPoostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Shiraz

This review article explores the etiology of oculomotor palsies—including third, fourth, and sixth cranial nerve palsies—and addresses the application of botulinum toxin type A (BoNT-A) in the management of these conditions, along with its associated complications and side effects. The objective is to assess BoNT-A’s potential efficacy and its role across various types of nerve palsies. A comprehensive analysis of relevant studies reveals that BoNT-A holds promise as a therapeutic option in managing these conditions. BoNT-A injection into the lateral rectus muscle proves to be an effective treatment for addressing post-traumatic third nerve palsy. This is achieved by providing symptom relief and diminishing the necessity for subsequent surgical interventions. In the context of fourth nerve palsy, BoNT-A injection into the inferior oblique or inferior rectus muscles presents potential benefits but is accompanied by certain limitations. Additionally, previous studies have shown that BoNT-A injection into the antagonist medial rectus muscle for treatment of sixth nerve palsy results in favorable outcomes, such as contributing to functional improvement. The literature highlights the importance of timing, dosage, and grade of muscle dysfunction when administering BoNT-A injections. BoNT-A injection is an effective option to manage different types of cranial nerve palsies and improve binocular function. Furthermore, it plays an integral role in preventing antagonist muscle contracture and, hence, the need for future surgical intervention.

Keywords: Botulinum Toxin Type A, Cranial Nerve, Motor Nerve Palsy

1. Çolpak Aİ, Çağlayan HB. Isolated third, fourth, and sixth cranial nerve palsies in the Turkish population: Etiologic factors and clinical course. Turk Noroloji Dergisi 2019;25:32–35.

2. Berlit P. Isolated and combined pareses of cranial nerves III, IV and VI. A retrospective study of 412 patients. J Neurol Sci 1991;103:10–15.

3. Singh A, Bahuguna C, Nagpal R, Kumar B. Surgical management of third nerve palsy. Oman J Ophthalmol 2016;9:80–86.

4. Kim P, Henderson AD. Fourth nerve palsy. Controversies in neuro-ophthalmic management: An evidence and casebased appraisal. Springer; 2021. p. 139–146.

5. Srimanan W, Panyakorn S. Retrospective analysis of factors related to the long-term recovery of third, fourth, and sixth cranial nerve palsy with etiologies and clinical course in a tertiary hospital. Clin Ophthalmol 2024;18:441– 450.

6. Tamhankar MA, Biousse V, Ying GS, Prasad S, Subramanian PS, Lee MS, et al. Isolated third, fourth, and sixth cranial nerve palsies from presumed microvascular versus other causes: A prospective study. Ophthalmology 2013;120:2264–2269.

7. Ílhan O, Şener EC, Özyar E. Outcome of abducens nerve paralysis in patients with nasopharyngeal carcinoma. Eur J Ophthalmol 2002;12:55–59.

8. Saranya V. The efficacy of botulinum toxin injection in acute sixth nerve palsy: A prospective observational study. Aravind Eye Hospital and Post Graduate Institute of Ophthalmology; 2020.

9. Kowal L, Wong E, Yahalom C. Botulinum toxin in the treatment of strabismus. A review of its use and effects. Disabil Rehabil 2007;29:1823–1831.

10. Adler CH. Perioperative use of botulinum toxins. Toxicon 2009;54:654–657.

11. Kopera D. Botulinum toxin historical aspects: From food poisoning to pharmaceutical. Int J Dermatol 2011;50:976– 980.

12. Dutton JJ, Fowler AM. Botulinum toxin in ophthalmology. Surv Ophthalmol 2007;52:13–31.

13. Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol 2000;43:249–259.

14. Humeau Y, Doussau F, Grant NJ, Poulain B. How botulinum and tetanus neurotoxins block neurotransmitter release. Biochimie 2000;82:427–446.

15. Park MY, Ahn KY. Scientific review of the aesthetic uses of botulinum toxin type A. Arch Craniofac Surg 2021;22:1–10.

16. Brooks VB. The action of botulinum toxin on motor-nerve filaments. J Physiol 1954;123:501–515.

17. Broniarczyk-Loba A, Czupryniak L, Nowakowska O, Loba J. Botulinum toxin A in the early treatment of sixth nerve palsy-induced diplopia in type 2 diabetes. Diabetes Care 2004;27:846–847.

18. Metz HS, Mazow M. Botulinum toxin treatment of acute sixth and third nerve palsy. Graefes Arch Clin Exp Ophthalmol 1988;226:141–144.

19. Fang C, Leavitt JA, Hodge DO, Holmes JM, Mohney BG, Chen JJ. Incidence and etiologies of acquired third nerve palsy using a population-based method. JAMA Ophthalmol 2017;135:23–28.

20. Canady FJ, Ricca AM, Stiff H, Shriver E, Ko A. Self-resolving ischemic third nerve palsy. EyeRounds.org; 2018.

21. Miller NR. Solitary oculomotor nerve palsy in childhood. Am J Ophthalmol 1977;83:106–111.

22. Choi KD, Choi SY, Kim JS, Choi JH, Yang TH, Oh SY, et al. Acquired ocular motor nerve palsy in neurology clinics: A prospective multicenter study. J Clin Neurol 2019;15:221– 227.

23. Bagheri A, Fallahi MR, Abrishami M, Salour H, Aletaha M. Clinical features and outcomes of treatment for fourth nerve palsy. J Ophthalmic Vis Res 2010;5:27–31.

24. Hörner R, Kassubek J, Dreyhaupt J, Ludolph AC. The spectrum and differential diagnosis of acquired ocular motor nerve palsies: A clinical study of 502 patients. J Neurol 2022;269:2140–2148.

25. Dotan G, Rosenfeld E, Stolovitch C, Kesler A. The role of neuroimaging in the evaluation process of children with isolated sixth nerve palsy. Childs Nerv Syst 2013;29:89– 92.

26. Lee MS, Galetta SL, Volpe NJ, Liu GT. Sixth nerve palsies in children. Pediatr Neurol 1999;20:49–52.

27. Merino P, Gómez de Liaño P, Villalobo JM, Franco G, Gómez de Liaño R. Etiology and treatment of pediatric sixth nerve palsy. J AAPOS 2010;14:502–505.

28. Kalita IR, Veena K, Mouttappa F, Sundaralakshmi P, Singh HV. Clinical profile and management of sixth nerve palsy in pediatric patients (0-15 years) in Southern India - A hospital-based study. Indian J Ophthalmol 2022;70:952– 957.

29. Aroichane M, Repka MX. Outcome of sixth nerve palsy or paresis in young children. Slack Incorporated Thorofare; 1995. p. 152–156.

30. Kowal L, Wong E, Yahalom C. Botulinum toxin in the treatment of strabismus. A review of its use and effects. Disabil Rehabil 2007;29:1823–1831.

31. Gómez de Liaño R. The use of botulinum toxin in strabismus treatment. J Binocul Vis Ocul Motil 2019;69:51– 60.

32. Escuder AG, Hunter DG. The role of botulinum toxin in the treatment of strabismus. Semin Ophthalmol 2019;34:198– 204.

33. Ganesh S, Anilkumar SE, Narendran K. Botulinum toxin A in the early treatment of sixth nerve palsy in type 2 diabetes. Indian J Ophthalmol 2019;67:1133–1136.

34. Scott AB. Botulinum treatment of strabismus following retinal detachment surgery. Arch Ophthalmol 1990;108:509–510.

35. Sanjari MS, Falavarjani KG, Kashkouli MB, Aghai GH, Nojomi M, Rostami H. Botulinum toxin injection with and without electromyographic assistance for treatment of abducens nerve palsy: A pilot study. J AAPOS 2008;12:259–262.

36. Yang HK, Kim DH, Hwang JM. Botulinum toxin injection without electromyographic guidance in consecutive esotropia. PLoS One 2020;15:e0241588.

37. Xu H, Sun W, Dai S, Cheng Y, Zhao J, Liu Y, et al. Botulinum toxin injection with conjunctival microincision for the treatment of acute acquired comitant esotropia and its effectiveness. J Ophthalmol 2020;2020:1702695.

38. Kao LY, Chao AN. Subtenon injection of botulinum toxin for treatment of traumatic sixth nerve palsy. Slack Incorporated Thorofare; 2003. p. 27–30.

39. Han SH, Kwon HS, Chang YH, Kim SS, Lee MS, Choi YC. Morphological changes after subtenon botulinum toxin A injection into rabbit extraocular muscles. Invest Ophthalmol Vis Sci 2005;46:2959.

40. Razmju H, Shaygannejad V, Dehghan A, Akhlaghi M, Saberi A. Subtenon Injection of botulinum toxin a in acute sixth nerve palsy; a randomized clinical trial. Bina J Ophthalmol. 2008;13:222–6.

41. Talebnejad MR, Sharifi M, Nowroozzadeh MH. The role of botulinum toxin in management of acute traumatic thirdnerve palsy. J AAPOS 2008;12:510–513.

42. Saad N, Lee J. The role of botulinum toxin in third nerve palsy. Aust N Z J Ophthalmol 1992;20:121–127.

43. Garnham L, Lawson JM, O’Neill D, Lee JP. Botulinum toxin in fourth nerve palsies. Aust N Z J Ophthalmol 1997;25:31– 35.

44. Talebnejad MR, Tahamtan M, Nowroozzadeh MH. Botulinum toxin injection for treatment of acute traumatic superior oblique muscle palsy. J Ophthalmic Vis Res 2015;10:263–267.

45. Fitzsimons R, Lee J, Elston J. The role of botulinum toxin in the management of sixth nerve palsy. Eye 1989;3:391– 400.

46. Holmes JM, Leske DA. Botulinum toxin in chronic sixth nerve palsy. International Strabismological Association ISA 2002. CRC Press; 2021. p. 233–236.

47. Murray AD. Early and late botulinum toxin treatment of acute sixth nerve palsy. Aust N Z J Ophthalmol 1989;17:239–245.

48. Holmes JM, Leske DA, Christiansen SP. Initial treatment outcomes in chronic sixth nerve palsy. J AAPOS 2001;5:370–376.

49. Kerr NC, Hoehn MB. Botulinum toxin for sixth nerve palsies in children with brain tumors. J AAPOS 2001;5:21–25.

50. Ganesh S, Anilkumar SE, Narendran K. Botulinum toxin A in the early treatment of sixth nerve palsy in type 2 diabetes. Indian J Ophthalmol 2019;67:1133–1136.

51. Wagner RS, Frohman LP. Long-term results: Botulinum for sixth nerve palsy. SLACK Incorporated Thorofare; 1989. p. 106–108.

52. Díaz-Maroto V, Ferrán V, Gómez De Liaño Sánchez P, Villarejo Díaz-Maroto I, Gómez De Liaño Sánchez R, Bonales Domínguez A, et al. [Treatment of sixth nerve palsy of traumatic or tumor etiology using botulinum toxin]. Arch Soc Esp Oftalmol 2000;75:471–476.

53. Sugano DM, Fernandez CL. Rehder JRCdL. Botulinum toxin for strabismus correction. Rev Bras Oftalmol 2013;72:321–325.

54. Talebnejad M, Alavi A, Attarzadeh A. Botulinum toxin- A injection in acute complete sixth nerve palsy. In: Jan- Tjeerd De Faber, editor. 29th European Strabismological Association Meeting. Routledge; 2003. 4 p.

55. Chuenkongkaew W, Dulayajinda D, Deetae R. Botulinum toxin treatment of the sixth nerve palsy: An experience of 5-year duration in Thailand. J Med Assoc Thai 2001;84:171–176.

56. Murray AD. Early botulinum toxin treatment of acute sixth nerve palsy. Eye 1991;5:45–47.

57. Metz HS, Dickey CF. Treatment of unilateral acute sixthnerve palsy with botulinum toxin. Am J Ophthalmol 1991;112:381–384.

58. Holmes JM, Beck RW, Kip KE, Droste PJ, Leske DA. Botulinum toxin treatment versus conservative management in acute traumatic sixth nerve palsy or paresis. J AAPOS 2000;4:145–149.

59. Hung HL, Kao LY, Sun MH. Botulinum toxin treatment for acute traumatic complete sixth nerve palsy. Eye 2005;19:337–341.

60. Lee J, Harris S, Cohen J, Cooper K, MacEwen C, Jones S. Results of a prospective randomized trial of botulinum toxin therapy in acute unilateral sixth nerve palsy. SLACK Incorporated Thorofare; 1994. p. 283–286.

61. Kao LY, Chao AN. Subtenon injection of botulinum toxin for treatment of traumatic sixth nerve palsy. J Pediatr Ophthalmol Strabismus 2003;40:27–30.

62. Chen YH, Sun MH, Hsueh PY, Kao LY. Botulinum injection for the treatment of acute esotropia resulting from complete acute abducens nerve palsy. Taiwan J Ophthalmol 2012;2:140–143.

63. Ganesh S, Anilkumar SE, Narendran K. Botulinum toxin A in the early treatment of sixth nerve palsy in type 2 diabetes. Indian J Ophthalmol 2019;67:1133–1136.

64. Kerr NC, Hoehn MB. Botulinum toxin for sixth nerve palsies in children with brain tumors. J AAPOS 2001;5:21–25.

65. Lee J, Harris S, Cohen J, Cooper K, MacEwen C, Jones S. Results of a prospective randomized trial of botulinum toxin therapy in acute unilateral sixth nerve palsy. J Pediatr Ophthalmol Strabismus 1994;31:283–286.

66. Metz HS, Dickey CF. Treatment of unilateral acute sixthnerve palsy with botulinum toxin. Am J Ophthalmol 1991;112:381–384.

67. Murray AD. Early botulinum toxin treatment of acute sixth nerve palsy. Eye 1991;5:45–47.

68. Wagner RS, Frohman LP. Long-term results: Botulinum for sixth nerve palsy. J Pediatr Ophthalmol Strabismus 1989;26:106–108.

69. Chuenkongkaew W, Dulayajinda D, Deetae R. Botulinum toxin treatment of the sixth nerve palsy: An experience of 5-year duration in Thailand. J Med Assoc Thai 2001;84:171–176.

70. De Liano Sanchez P Gomez, Diaz-Maroto I Villarejo, De Liano Sanchez R Gomez, Dominguez A Bonales, Ferran I Valls, Rodriguez A Alzamora. Treatment of sixth nerve palsy of traumatic or tumor etiology using botulinum toxin. Arch Soc Esp Oftalmol 2000;75:471–476.

71. Merino P, de Liaño P Gómez, Villalobo JM, Franco G, de Liaño R Gómez. Etiology and treatment of pediatric sixth nerve palsy. J AAPOS 2010;14:502–505.

72. Wong ES, Lam CP, Lau FH, Lau WW, Yam JC. Botulinum toxin as an initial therapy for management of sixth nerve palsies caused by nasopharyngeal carcinomas. Eye 2018;32:768–774.

73. Azarmina M, Azarmina H. The six syndromes of the sixth cranial nerve. J Ophthalmic Vis Res 2013;8:160–171.

74. Harley RD. Paralytic strabismus in children. Etiologic incidence and management of the third, fourth, and sixth nerve palsies. Ophthalmology 1980;87:24–43.

75. Fitzsimons R, Lee J, Elston J. The role of botulinum toxin in the management of sixth nerve palsy. Eye 1989;3:391–400.

76. Marais W, Barrett S. An overview of the third, fourth and sixth cranial nerve palsies. CME 2013;31:147–151.

77. Lam CP, Chan J, Lau WW, Yam JC. Botulinum toxin in strabismus. In: Agrawal S, editor. Strabismus: For every Ophthalmologist. Springer; 2019. p. 147–157.

78. Elston JS, Lee JP. Paralytic strabismus: The role of botulinum toxin. Br J Ophthalmol 1985;69:891–896.

79. Khalili MR, Roshanshad A, Vardanjani HM. Botulinum toxin injection for the treatment of third, fourth, and sixth nerve palsy: A meta-analysis. J Pediatr Ophthalmol Strabismus 2024;61:160–171.

80. Naumann M, Albanese A, Heinen F, Molenaers G, Relja M. Safety and efficacy of botulinum toxin type A following long-term use. Eur J Neurol 2006;13:35–40.

81. Patel SV, Mutyala S, Leske DA, Hodge DO, Holmes JM. Incidence, associations, and evaluation of sixth nerve palsy using a population-based method. Ophthalmology 2004;111:369–375.

82. Sugano DM, Fernandez CL, Rehder JRCdL. Botulinum toxin for strabismus correction. Rev Bras Oftalmol 2013;72:321–325.

83. Levy N, Beylerian M, Dambricourt L, Esposito F, Denis D. [Persistent mydriasis after botulinum toxin injection for infantile early onset esotropia]. J Fr Ophtalmol 2019;42:e473–e474.

84. Bagheri A, Eshaghi M. Botulinum toxin injection of the inferior oblique muscle for the treatment of superior oblique muscle palsy. J AAPOS 2006;10:385–388.

85. Talebnejad MR, Tahamtan M, Nowroozzadeh MH. Botulinum toxin injection for treatment of acute traumatic superior oblique muscle palsy. J Ophthalmic Vis Res 2015;10:263–267.