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food allergy with low serum zinc levels. Although our patient also had food allergies, the parents claimed to be strictly compliant with dietary restrictions, and the patients lesions resolved only with zinc supplementation. The symptoms of zinc deficiency are highly variable and depend on the severity in pediatric population.1 Some of its manifestations on the integumentary system are delayed wound healing, bullous pustular dermatitis, and blepharitis; other systemic manifestations include increased allergic sensitivity and inflammatory activity on the immune system.1 Zinc deficiency should be in the differential diagnosis in cases where multiple medications for blepharitis and hordeolum prove ineffective, and there is accompanying perioral rash and slightly decreased levels of zinc. Matrix metalloproteinases (MMPs) and cytokine balance have direct effects on ocular surface homeostatic mechanisms.4 Zinc acts to prevent reactive oxygen species formation and other inflammatory mediators and also contributes to wound healing by zinc-dependent MMPs.1 Additionally, increased inflammatory statuses in the meibomian glands, tears, and serum with induced morphological alterations in the glands were revealed in copper, zinc-Superoxide Dismutase-1 (Sod1) knockout mice.5 In allergic children, significant lower hair zinc levels can be determined compared to healthy ones.6 Chronic inflammation has been shown to cause a significant decline in serum zinc levels in experimental studies. Zinc levels were found relatively decreased in children with bronchial asthma compared to a control group, so the changes in trace element status may be the effect of the chronic disease state and not the cause of the disease per se.7 For example, hospitalization for bronchial asthma attack was found as a risk factor for significant lower zinc levels in children.8 In a rat model study of asthma, higher numbers of eosinophils, neutrophils, and monocytes, higher contents of eotaxin and monocyte chemoattractant protein-1, and lower expression of lung interferon-g mRNA were detected in bronchoalveolar lavage fluid for zinc-deficient rats compared to the zinc-normal diet group.9 Zinc deficiency in humans could drive differentiation of T lymphocytes toward the Th-2 direction.10 In our case chronic inflammation caused by asthma or food allergy could have been the underlying reason for zinc deficiency. While children with excessive amounts of zinc deficiency requires higher doses and longer treatment periods, children with acquired zinc deficiency should be treated with elemental zinc supplementation of 0.5 to 1 mg/kg/ d for 4 months.1 Diagnosis and treatment of zinc definciency will prevent not only blepharitis but other more serious and life-threatening conditions.
Acknowledgments The authors thank Yusuf Sevim, MD, for his assistance in the writing of this article.
Volume 20 Number 1 / February 2016 References 1. Corbo MD, Lam J. Zinc deficiency and its management in the pediatric population: a literature review and proposed etiologic classification. J Am Acad Dermatol 2013;69:616-624.e1. 2. Wuehler SE, Peerson JM, Brown KH. Use of national food balance data to estimate the adequacy of zinc in national food supplies: methodology and regional estimates. Public Health Nutr 2005;8: 812-9. 3. Martin DP, Tangsinmankong N, Sleasman JW, Day-Good NK, Wongchantara DR. Acrodermatitis enteropathica-like eruption and food allergy. Ann Allergy Asthma Immunol 2005;94:398-401. 4. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci 2011;52:2050-64. 5. Ibrahim OM, Dogru M, Matsumoto Y, et al. Oxidative stress induced age dependent meibomian gland dysfunction in Cu, Zn-superoxide dismutase-1 (Sod1) knockout mice. PLoS One 2014;9:e99328. 6. Di Toro R, Galdo Capotorti G, Gialanella G, Miraglia del Giudice M, Moro R, Perrone L. Zinc and copper status of allergic children. Acta Paediatr Scand 1987;76:612-7. 7. Ermis B, Armutcu F, Gurel A, Kart L, Demircan N, Altin R, et al. Trace elements status in children with bronchial asthma. Eur J Gen Med 2004;1:4-8. 8. Yilmaz EA, Ozmen S, Bostanci I, Misirlioglu ED, Ertan U. Erythrocyte zinc levels in children with bronchial asthma. Pediatric Pulmonol 2011;46:1189-93. 9. Lu H, Xin Y, Tang Y, Shao G. Zinc suppressed the airway inflammation in asthmatic rats: effects of zinc on generation of eotaxin, MCP-1, IL-8, IL-4, and IFN-gamma. Biol Trace Elem Res 2012;150:314-21. 10. Prasad AS. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J Infect Dis 2000;182(Suppl 1):S62-8.
Tonic pupil after botulinum toxin-A injection for treatment of esotropia in children Pediatric Eye Disease Investigator Group* A total of 27 children with esotropia (mean age, 3.9 years; range, 9 months to 13.8 years) were enrolled in a 9-month observational study following botulinum toxin A (BTX-A) injection of one (n 5 7) or both (n 5 20) medial rectus muscles. BTX-A dosage ranged from 3.0 to 6.0 units per muscle. Three participants developed tonic
Supported by National Eye Institute of National Institutes of Health, Department of Health and Human Services EY011751, EY018810, and EY023198. The funding organization had no role in the design or conduct of this research. Presented in part at the Annual Meeting of the Association for Research in Vision and Ophthalmology, Denver, Colorado, May 3-7, 2015. * A listing of the Writing Committee appears at the end of this article; the members of the Pediatric Eye Disease Investigator Group members participating in this study appears in e-Supplement 1. Submitted August 4, 2015. Revision accepted September 30, 2015. Correspondence: Stephen P. Christiansen, MD, c/o Jaeb Center for Health Research, 15310 Amberly Drive Suite 350, Tampa, FL 33647 (email: [email protected]). J AAPOS 2016;20:78-81. Copyright Ó 2016 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.09.011
Journal of AAPOS
Volume 20 Number 1 / February 2016 pupil, noted at the first follow-up visit, occurring 12-19 days after injection. All 3 cases occurred in the left eye of participants who underwent bilateral BTX-A injection by the same surgeon. Anisocoria diminished from a maximum of 4 mm at the 2-week visit to 1–2 mm in all patients over the 9-month postinjection data collection period. No adverse visual outcomes were noted. Tonic pupil is an infrequently reported complication of BTX-A injection for strabismus. The experience of our investigator group suggests the need for careful injection technique and thorough preinjection counseling.
B
otulinum toxin A (BTX-A) has been used successfully in the management of strabismus, both as a primary therapeutic intervention1-3 and as adjunctive treatment with incisional strabismus surgery.4 Because it is administered by injection, treatment complications relate principally to trauma from the needle or unintended effects of toxin leakage outside the targeted extraocular muscle capsule. It is not surprising, then, that ptosis and vertical strabismus are commonly reported,5 presumably due to chemodenervation of the levator muscle or one or both vertical rectus muscles. The pharmacological effect of BTX-A on other intraconal and extraconal structures is less well known but may contribute to an infrequently reported complication, tonic pupil.6-10 Our investigator group undertook a 9-month observational pilot study to assess recruitment potential for a randomized controlled trial comparing BTX-A to incisional surgery for treatment of esotropia. Participants \17 years of age with esotropia were enrolled following BTX-A injection of one or both medial rectus muscles. Children who had incisional extraocular muscle surgery at the time of injection were excluded. Because the BTX-A injection was performed as part of routine patient care and was not part of the study, the injection technique was not standardized. Most injections were performed using a closed conjunctival technique without electromyography control; a single investigator used an electromyography needle for the injection for 1 participant. Participants were managed according to investigators’ routine clinical practice. Demographic, historical, and preinjection clinical data as well as details of the BTX-A injection and perioperative complications were collected at enrollment. Transient ptosis, consecutive exodeviations, and vertical deviations are common occurrences following BTX-A injection and were not considered complications for this study. Postinjection data from each visit were collected retrospectively after 9 months. Safety data are reported herein but postoperative alignment outcomes are not included because of substantial missing data, a small cohort, multiple etiologies of esotropia, and lack of a comparison group. At 13 sites (13 surgeons), 27 participants aged 9 months to 13.8 years (mean, 3.9 3.3) were enrolled; 11 (41%) were female and 19 (70%) were white. Esotropia onset occurred before 6 months of age in 13 participants (48%) and after 6 months of age in 14 (52%). Eight (30%) participants had prior strabismus surgery, and 1
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(4%) had prior BTX-A injection. Mean age at injection was 3.9 3.3 years (range, 9 months to 13.8 years). BTX-A injection was unilateral (n 5 7) or bilateral (n 5 20), and the dosage ranged from 3.0 to 6.0 units per muscle under general anesthesia. Preoperative esodeviation, measured by prism and alternate cover test, ranged from 10D to 65D (mean, 26D) at distance and from 12D to 65D (mean, 28D) at near (distance and near data reported for 20 and 22 participants, resp.). Of 27 participants, 4 (15%; 95% CI, 4%-34%) experienced a complication from the injection. One participant (4%; 95% CI, 0%-19%) had a left eye scleral perforation, which was noted at the time of injection and treated by laser retinopexy the same day with good visual and motor outcomes. Three participants (11%; 95% CI, 2%-29%) developed tonic pupil (3 of 5 participants with BTX-A injection by the same surgeon). The 3 cases of tonic pupil were noted at the first postinjection visit occurring from 12-19 days after treatment. All 3 cases occurred in the left eye of participants who underwent bilateral BTX-A injection by the same surgeon, under general anesthesia. BTX-A, 4 units, in 0.1 cc of nonpreserved normal saline was administered through a 30gauge, 16 mm needle without incising conjunctiva. Motility testing at the first postinjection visit showed minimal to no adduction weakness of the affected eye for all 3 participants. Initial pupil testing showed left eye mydriasis and minimal reactivity to light or an accommodative target. The only symptom reported in any subject was mild photosensitivity. Subsequent testing of affected eyes showed dilated pupils that were unresponsive to light but constricted to a near accommodative target. Two of the 3 participants had pharmacological testing with pilocarpine 0.125% within 4 weeks of injection; reversal of anisocoria did not occur in either participant. In all 3 cases, however, denervation hypersensitivity to pilocarpine 0.125% with reversal of the anisocoria was evident by 6-8 weeks postBTX-A injection (Figure 1). The anisocoria gradually diminished during the 9-month data collection period, from 2.5, 3.5, and 4 mm differences at 2 weeks to 2.5, 2, and 2 mm differences at 2 months, and 1, 2, and 1 mm differences at 9 months. The photosensitivity that was present initially resolved by 9 months in all 3 cases. Visual acuity remained stable in all 3 participants. Our investigator group experienced a somewhat higher-than-expected rate of complications following BTX-A treatment of children with esotropia. In a previous report of 5,587 BTX-A injections in 3,104 patients treated for horizontal strabismus, 9 patients had scleral perforations (0.28%).7 In the same series, 5 patients (0.16%) developed pupillary changes consistent with tonic pupil. This rate of tonic pupil is far lower than we report. One possible explanation for the higher incidence of tonic pupil in our series may have been inaccurate needle placement in the muscle. The tonic pupil occurred in the left eye of bilaterally treated patients. The surgeon for all cases was right-handed and reported
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FIG 1. Pre- and postinjection photographs showing pupil findings in a patient who developed a tonic left pupil after botulinum toxin-A injection of both medial rectus muscles for treatment of strabismus. A, Preinjection. B, 2 weeks after injection. C, 55 days after injection. D, 55 days after injection, post-pilocarpine. In this patient, as in all cases, affected pupils showed minimal responsiveness to light but constriction with fixation on a near accommodative target. At 55 days post injection anisocoria was reversed after treatment of both eyes with pilocarpine 0.125%, diagnostic for tonic pupil.
that the left eye injection was more technically challenging than the right eye injection. The lack of significant adduction weakness following injection suggests that the BTX-A injection occurred outside the muscle capsule, either superficial to the muscle or, less likely, through the muscle. This could give rise to pharmacological blockade of the cholinergic terminals in the iris,10 either by means of trans-scleral diffusion or by ciliary artery perfusion if the injection was superficial to the muscle or to anticholinergic toxicity6 or direct injury at the level of the ciliary ganglion if the injection was deep to the muscle. While the tonic pupil occurred acutely after injection, denervation hypersensitivity to dilute pilocarpine was a delayed response. This is characteristic of tonic pupils after acute injury11 and probably results from up-regulation of acetylcholine receptors in the iris. In older patients and adults, the risk of inaccurate needle placement may be mitigated by electromyography control. At the time of the Allergan series,7 injection with an electromyography needle was the clinical standard and may have ensured more reliable placement of the needle intramuscularly. Differences in level of investigator experience with BTX-A injections for strabismus may also have been a factor.
Writing Committee Stephen P. Christiansen, MD, Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts; Danielle L. Chandler, MSPH, Jaeb Center for Health Research, Tampa, Florida; Katherine A. Lee, MD, PhD, St. Luke’s Hospital, Boise, Idaho; Rosanne Superstein, MD, Centre Hospitalier
Universitaire Sainte-Justine, Montreal, Quebec, Canada; Alejandra de Alba Campomanes, MD, Department of Ophthalmology, University of California San Francisco, San Francisco, California; Erick D. Bothun, MD, Department of Ophthalmology & Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota; Julie Morin, MD, Centre Hospitalier Universitaire SainteJustine, Montreal, Quebec, Canada; David K. Wallace, MD, MPH, Duke Eye Center, Durham, North Carolina; Raymond T. Kraker, MSPH, Jaeb Center for Health Research, Tampa, Florida.
References 1. Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980;87:1044-9. 2. McNeer KW, Tucker MG, Guerry CH, Spencer RF. Incidence of stereopsis after treatment of infantile esotropia with botulinum toxin A. J Pediatr Ophthalmol Strabismus 2003;40:288-92. 3. de Alba Campomanes AG, Binenbaum G, Campomanes Eguiarte G. Comparison of botulinum toxin with surgery as primary treatment for infantile esotropia. J AAPOS 2010;14:111-6. 4. Ozkan SB, Topalo glu A, Aydin S. The role of botulinum toxin A in augmentation of the effect of recession and/or resection surgery. J AAPOS 2006;10:124-7. 5. Sener EC, Sanac¸ AS. Efficacy and complications of dose increments of botulinum toxin-A in the treatment of horizontal comitant strabismus. Eye (Lond) 2000;14:873-8. 6. Hemmerdinger C, Srinivasan S, Marsh IB. Reversible pupillary dilation following botulinum toxin injection to the lateral rectus. Eye (Lond) 2006;20:1478-9. 7. Botox [package insert]. Irvine, CA: Allergan Inc; 2009. 8. Speeg-Schatz C. Persistent mydriasis after botulinum toxin injection for congenital esotropia. J AAPOS 2008;12:307-8. 9. Akkaya S, K€ okcen HK, Atakan T. Unilateral transient mydriasis and ptosis after botulinum toxin injection for a cosmetic procedure. Clin Ophthalmol 2015;9:313-5.
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10. Levy Y, Kremer I, Shavit S, Korczyn AD. The pupillary effects of retrobulbar injection of botulinum toxin A (oculinum) in albino rats. Invest Ophthalmol Vis Sci 1991;32:122-5. 11. Thompson HS. Adie’s syndrome: some new observations. Trans Am Ophthalmol Soc 1977;75:587-626.
Foveal hypoplasia in autosomal recessive spastic ataxia of Charlevoix-Saguenay Christopher T. Shah, MD,a Tyson S. Ward, MD,a Julie A. Matsumoto, MD, FACR,b and Yevgeniy Shildkrot, MDa A 14-year-old boy presented with a presumed diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The neurological examination, nerve conduction study, and brain imaging results were all consistent with the diagnosis. The ophthalmologic examination was notable for a prominent myelinated nerve fiber layer extending from the disk along the major temporal arcades in both eyes. Loss of foveal depression was noted clinically and on spectral domain optical coherence tomography. This case highlights a novel finding that may aid in the diagnosis of ARSACS.
A
utosomal recessive spastic ataxia of CharlevoixSaguenay (ARSACS) was first described in 1978 as a cause of early-onset cerebellar ataxia in the eponymous region of Canada and has since been confirmed in France, Turkey, Italy, Spain, Tunisia, Holland, and Japan.1 Various mutations in the SACS gene located on chromosome 13q12 have since been found to be responsible for ARSACS.1 The clinical phenotype is characterized by early-onset cerebellar ataxia, lower limb spasticity, and peripheral neuropathy.1 Electromyography shows signs of severe denervation in the distal muscles, and nerve conduction studies demonstrate signs of axonal neuropathy with associated demyelinating features.2 Magnetic resonance imaging (MRI) findings include atrophy of the superior vermis, cerebellar hemispheres and cervical cord, and linear hypointensities on T2- and T2/FLAIR-weighted images in the pons, thinning of the corpus callosum, and a rim of T2 hyperintensity around the thalami.3 Patients with ARSACS have been noted to have abnormal thickening or myelination of the peripapillary nerve fiber layer.1,4-7
Author affiliations: aDepartment of Ophthalmology, University of Virginia, Charlottesville, Virginia; bDepartment of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia Submitted March 17, 2015. Revision accepted October 7, 2015. Correspondence: Yevgeniy Shildkrot, MD, Department of Ophthalmology, PO Box 800715, Charlottesville, VA 22908 (email: [email protected]). J AAPOS 2016;20:81-83. Copyright Ó 2016 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.10.007
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FIG 1. A, Magnetic resonance imaging demonstrating atrophy of the superior vermis (long arrow), with enlarged posterior fossa subarachnoid space and thinning of the posterior body of the corpus callosum (short arrows). B, Characteristic bilateral paramedian T2/FLAIR-hypointense stripes in the basis pontis. C, Linear T2/FLAIR-hyperintense rims along the lateral thalami are also present.
Mirza and Sevim
food allergy with low serum zinc levels. Although our patient also had food allergies, the parents claimed to be strictly compliant with dietary restrictions, and the patients lesions resolved only with zinc supplementation. The symptoms of zinc deficiency are highly variable and depend on the severity in pediatric population.1 Some of its manifestations on the integumentary system are delayed wound healing, bullous pustular dermatitis, and blepharitis; other systemic manifestations include increased allergic sensitivity and inflammatory activity on the immune system.1 Zinc deficiency should be in the differential diagnosis in cases where multiple medications for blepharitis and hordeolum prove ineffective, and there is accompanying perioral rash and slightly decreased levels of zinc. Matrix metalloproteinases (MMPs) and cytokine balance have direct effects on ocular surface homeostatic mechanisms.4 Zinc acts to prevent reactive oxygen species formation and other inflammatory mediators and also contributes to wound healing by zinc-dependent MMPs.1 Additionally, increased inflammatory statuses in the meibomian glands, tears, and serum with induced morphological alterations in the glands were revealed in copper, zinc-Superoxide Dismutase-1 (Sod1) knockout mice.5 In allergic children, significant lower hair zinc levels can be determined compared to healthy ones.6 Chronic inflammation has been shown to cause a significant decline in serum zinc levels in experimental studies. Zinc levels were found relatively decreased in children with bronchial asthma compared to a control group, so the changes in trace element status may be the effect of the chronic disease state and not the cause of the disease per se.7 For example, hospitalization for bronchial asthma attack was found as a risk factor for significant lower zinc levels in children.8 In a rat model study of asthma, higher numbers of eosinophils, neutrophils, and monocytes, higher contents of eotaxin and monocyte chemoattractant protein-1, and lower expression of lung interferon-g mRNA were detected in bronchoalveolar lavage fluid for zinc-deficient rats compared to the zinc-normal diet group.9 Zinc deficiency in humans could drive differentiation of T lymphocytes toward the Th-2 direction.10 In our case chronic inflammation caused by asthma or food allergy could have been the underlying reason for zinc deficiency. While children with excessive amounts of zinc deficiency requires higher doses and longer treatment periods, children with acquired zinc deficiency should be treated with elemental zinc supplementation of 0.5 to 1 mg/kg/ d for 4 months.1 Diagnosis and treatment of zinc definciency will prevent not only blepharitis but other more serious and life-threatening conditions.
Acknowledgments The authors thank Yusuf Sevim, MD, for his assistance in the writing of this article.
Volume 20 Number 1 / February 2016 References 1. Corbo MD, Lam J. Zinc deficiency and its management in the pediatric population: a literature review and proposed etiologic classification. J Am Acad Dermatol 2013;69:616-624.e1. 2. Wuehler SE, Peerson JM, Brown KH. Use of national food balance data to estimate the adequacy of zinc in national food supplies: methodology and regional estimates. Public Health Nutr 2005;8: 812-9. 3. Martin DP, Tangsinmankong N, Sleasman JW, Day-Good NK, Wongchantara DR. Acrodermatitis enteropathica-like eruption and food allergy. Ann Allergy Asthma Immunol 2005;94:398-401. 4. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci 2011;52:2050-64. 5. Ibrahim OM, Dogru M, Matsumoto Y, et al. Oxidative stress induced age dependent meibomian gland dysfunction in Cu, Zn-superoxide dismutase-1 (Sod1) knockout mice. PLoS One 2014;9:e99328. 6. Di Toro R, Galdo Capotorti G, Gialanella G, Miraglia del Giudice M, Moro R, Perrone L. Zinc and copper status of allergic children. Acta Paediatr Scand 1987;76:612-7. 7. Ermis B, Armutcu F, Gurel A, Kart L, Demircan N, Altin R, et al. Trace elements status in children with bronchial asthma. Eur J Gen Med 2004;1:4-8. 8. Yilmaz EA, Ozmen S, Bostanci I, Misirlioglu ED, Ertan U. Erythrocyte zinc levels in children with bronchial asthma. Pediatric Pulmonol 2011;46:1189-93. 9. Lu H, Xin Y, Tang Y, Shao G. Zinc suppressed the airway inflammation in asthmatic rats: effects of zinc on generation of eotaxin, MCP-1, IL-8, IL-4, and IFN-gamma. Biol Trace Elem Res 2012;150:314-21. 10. Prasad AS. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. J Infect Dis 2000;182(Suppl 1):S62-8.
Tonic pupil after botulinum toxin-A injection for treatment of esotropia in children Pediatric Eye Disease Investigator Group* A total of 27 children with esotropia (mean age, 3.9 years; range, 9 months to 13.8 years) were enrolled in a 9-month observational study following botulinum toxin A (BTX-A) injection of one (n 5 7) or both (n 5 20) medial rectus muscles. BTX-A dosage ranged from 3.0 to 6.0 units per muscle. Three participants developed tonic
Supported by National Eye Institute of National Institutes of Health, Department of Health and Human Services EY011751, EY018810, and EY023198. The funding organization had no role in the design or conduct of this research. Presented in part at the Annual Meeting of the Association for Research in Vision and Ophthalmology, Denver, Colorado, May 3-7, 2015. * A listing of the Writing Committee appears at the end of this article; the members of the Pediatric Eye Disease Investigator Group members participating in this study appears in e-Supplement 1. Submitted August 4, 2015. Revision accepted September 30, 2015. Correspondence: Stephen P. Christiansen, MD, c/o Jaeb Center for Health Research, 15310 Amberly Drive Suite 350, Tampa, FL 33647 (email: [email protected]). J AAPOS 2016;20:78-81. Copyright Ó 2016 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.09.011
Journal of AAPOS
Volume 20 Number 1 / February 2016 pupil, noted at the first follow-up visit, occurring 12-19 days after injection. All 3 cases occurred in the left eye of participants who underwent bilateral BTX-A injection by the same surgeon. Anisocoria diminished from a maximum of 4 mm at the 2-week visit to 1–2 mm in all patients over the 9-month postinjection data collection period. No adverse visual outcomes were noted. Tonic pupil is an infrequently reported complication of BTX-A injection for strabismus. The experience of our investigator group suggests the need for careful injection technique and thorough preinjection counseling.
B
otulinum toxin A (BTX-A) has been used successfully in the management of strabismus, both as a primary therapeutic intervention1-3 and as adjunctive treatment with incisional strabismus surgery.4 Because it is administered by injection, treatment complications relate principally to trauma from the needle or unintended effects of toxin leakage outside the targeted extraocular muscle capsule. It is not surprising, then, that ptosis and vertical strabismus are commonly reported,5 presumably due to chemodenervation of the levator muscle or one or both vertical rectus muscles. The pharmacological effect of BTX-A on other intraconal and extraconal structures is less well known but may contribute to an infrequently reported complication, tonic pupil.6-10 Our investigator group undertook a 9-month observational pilot study to assess recruitment potential for a randomized controlled trial comparing BTX-A to incisional surgery for treatment of esotropia. Participants \17 years of age with esotropia were enrolled following BTX-A injection of one or both medial rectus muscles. Children who had incisional extraocular muscle surgery at the time of injection were excluded. Because the BTX-A injection was performed as part of routine patient care and was not part of the study, the injection technique was not standardized. Most injections were performed using a closed conjunctival technique without electromyography control; a single investigator used an electromyography needle for the injection for 1 participant. Participants were managed according to investigators’ routine clinical practice. Demographic, historical, and preinjection clinical data as well as details of the BTX-A injection and perioperative complications were collected at enrollment. Transient ptosis, consecutive exodeviations, and vertical deviations are common occurrences following BTX-A injection and were not considered complications for this study. Postinjection data from each visit were collected retrospectively after 9 months. Safety data are reported herein but postoperative alignment outcomes are not included because of substantial missing data, a small cohort, multiple etiologies of esotropia, and lack of a comparison group. At 13 sites (13 surgeons), 27 participants aged 9 months to 13.8 years (mean, 3.9 3.3) were enrolled; 11 (41%) were female and 19 (70%) were white. Esotropia onset occurred before 6 months of age in 13 participants (48%) and after 6 months of age in 14 (52%). Eight (30%) participants had prior strabismus surgery, and 1
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(4%) had prior BTX-A injection. Mean age at injection was 3.9 3.3 years (range, 9 months to 13.8 years). BTX-A injection was unilateral (n 5 7) or bilateral (n 5 20), and the dosage ranged from 3.0 to 6.0 units per muscle under general anesthesia. Preoperative esodeviation, measured by prism and alternate cover test, ranged from 10D to 65D (mean, 26D) at distance and from 12D to 65D (mean, 28D) at near (distance and near data reported for 20 and 22 participants, resp.). Of 27 participants, 4 (15%; 95% CI, 4%-34%) experienced a complication from the injection. One participant (4%; 95% CI, 0%-19%) had a left eye scleral perforation, which was noted at the time of injection and treated by laser retinopexy the same day with good visual and motor outcomes. Three participants (11%; 95% CI, 2%-29%) developed tonic pupil (3 of 5 participants with BTX-A injection by the same surgeon). The 3 cases of tonic pupil were noted at the first postinjection visit occurring from 12-19 days after treatment. All 3 cases occurred in the left eye of participants who underwent bilateral BTX-A injection by the same surgeon, under general anesthesia. BTX-A, 4 units, in 0.1 cc of nonpreserved normal saline was administered through a 30gauge, 16 mm needle without incising conjunctiva. Motility testing at the first postinjection visit showed minimal to no adduction weakness of the affected eye for all 3 participants. Initial pupil testing showed left eye mydriasis and minimal reactivity to light or an accommodative target. The only symptom reported in any subject was mild photosensitivity. Subsequent testing of affected eyes showed dilated pupils that were unresponsive to light but constricted to a near accommodative target. Two of the 3 participants had pharmacological testing with pilocarpine 0.125% within 4 weeks of injection; reversal of anisocoria did not occur in either participant. In all 3 cases, however, denervation hypersensitivity to pilocarpine 0.125% with reversal of the anisocoria was evident by 6-8 weeks postBTX-A injection (Figure 1). The anisocoria gradually diminished during the 9-month data collection period, from 2.5, 3.5, and 4 mm differences at 2 weeks to 2.5, 2, and 2 mm differences at 2 months, and 1, 2, and 1 mm differences at 9 months. The photosensitivity that was present initially resolved by 9 months in all 3 cases. Visual acuity remained stable in all 3 participants. Our investigator group experienced a somewhat higher-than-expected rate of complications following BTX-A treatment of children with esotropia. In a previous report of 5,587 BTX-A injections in 3,104 patients treated for horizontal strabismus, 9 patients had scleral perforations (0.28%).7 In the same series, 5 patients (0.16%) developed pupillary changes consistent with tonic pupil. This rate of tonic pupil is far lower than we report. One possible explanation for the higher incidence of tonic pupil in our series may have been inaccurate needle placement in the muscle. The tonic pupil occurred in the left eye of bilaterally treated patients. The surgeon for all cases was right-handed and reported
80
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FIG 1. Pre- and postinjection photographs showing pupil findings in a patient who developed a tonic left pupil after botulinum toxin-A injection of both medial rectus muscles for treatment of strabismus. A, Preinjection. B, 2 weeks after injection. C, 55 days after injection. D, 55 days after injection, post-pilocarpine. In this patient, as in all cases, affected pupils showed minimal responsiveness to light but constriction with fixation on a near accommodative target. At 55 days post injection anisocoria was reversed after treatment of both eyes with pilocarpine 0.125%, diagnostic for tonic pupil.
that the left eye injection was more technically challenging than the right eye injection. The lack of significant adduction weakness following injection suggests that the BTX-A injection occurred outside the muscle capsule, either superficial to the muscle or, less likely, through the muscle. This could give rise to pharmacological blockade of the cholinergic terminals in the iris,10 either by means of trans-scleral diffusion or by ciliary artery perfusion if the injection was superficial to the muscle or to anticholinergic toxicity6 or direct injury at the level of the ciliary ganglion if the injection was deep to the muscle. While the tonic pupil occurred acutely after injection, denervation hypersensitivity to dilute pilocarpine was a delayed response. This is characteristic of tonic pupils after acute injury11 and probably results from up-regulation of acetylcholine receptors in the iris. In older patients and adults, the risk of inaccurate needle placement may be mitigated by electromyography control. At the time of the Allergan series,7 injection with an electromyography needle was the clinical standard and may have ensured more reliable placement of the needle intramuscularly. Differences in level of investigator experience with BTX-A injections for strabismus may also have been a factor.
Writing Committee Stephen P. Christiansen, MD, Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts; Danielle L. Chandler, MSPH, Jaeb Center for Health Research, Tampa, Florida; Katherine A. Lee, MD, PhD, St. Luke’s Hospital, Boise, Idaho; Rosanne Superstein, MD, Centre Hospitalier
Universitaire Sainte-Justine, Montreal, Quebec, Canada; Alejandra de Alba Campomanes, MD, Department of Ophthalmology, University of California San Francisco, San Francisco, California; Erick D. Bothun, MD, Department of Ophthalmology & Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota; Julie Morin, MD, Centre Hospitalier Universitaire SainteJustine, Montreal, Quebec, Canada; David K. Wallace, MD, MPH, Duke Eye Center, Durham, North Carolina; Raymond T. Kraker, MSPH, Jaeb Center for Health Research, Tampa, Florida.
References 1. Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology 1980;87:1044-9. 2. McNeer KW, Tucker MG, Guerry CH, Spencer RF. Incidence of stereopsis after treatment of infantile esotropia with botulinum toxin A. J Pediatr Ophthalmol Strabismus 2003;40:288-92. 3. de Alba Campomanes AG, Binenbaum G, Campomanes Eguiarte G. Comparison of botulinum toxin with surgery as primary treatment for infantile esotropia. J AAPOS 2010;14:111-6. 4. Ozkan SB, Topalo glu A, Aydin S. The role of botulinum toxin A in augmentation of the effect of recession and/or resection surgery. J AAPOS 2006;10:124-7. 5. Sener EC, Sanac¸ AS. Efficacy and complications of dose increments of botulinum toxin-A in the treatment of horizontal comitant strabismus. Eye (Lond) 2000;14:873-8. 6. Hemmerdinger C, Srinivasan S, Marsh IB. Reversible pupillary dilation following botulinum toxin injection to the lateral rectus. Eye (Lond) 2006;20:1478-9. 7. Botox [package insert]. Irvine, CA: Allergan Inc; 2009. 8. Speeg-Schatz C. Persistent mydriasis after botulinum toxin injection for congenital esotropia. J AAPOS 2008;12:307-8. 9. Akkaya S, K€ okcen HK, Atakan T. Unilateral transient mydriasis and ptosis after botulinum toxin injection for a cosmetic procedure. Clin Ophthalmol 2015;9:313-5.
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10. Levy Y, Kremer I, Shavit S, Korczyn AD. The pupillary effects of retrobulbar injection of botulinum toxin A (oculinum) in albino rats. Invest Ophthalmol Vis Sci 1991;32:122-5. 11. Thompson HS. Adie’s syndrome: some new observations. Trans Am Ophthalmol Soc 1977;75:587-626.
Foveal hypoplasia in autosomal recessive spastic ataxia of Charlevoix-Saguenay Christopher T. Shah, MD,a Tyson S. Ward, MD,a Julie A. Matsumoto, MD, FACR,b and Yevgeniy Shildkrot, MDa A 14-year-old boy presented with a presumed diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The neurological examination, nerve conduction study, and brain imaging results were all consistent with the diagnosis. The ophthalmologic examination was notable for a prominent myelinated nerve fiber layer extending from the disk along the major temporal arcades in both eyes. Loss of foveal depression was noted clinically and on spectral domain optical coherence tomography. This case highlights a novel finding that may aid in the diagnosis of ARSACS.
A
utosomal recessive spastic ataxia of CharlevoixSaguenay (ARSACS) was first described in 1978 as a cause of early-onset cerebellar ataxia in the eponymous region of Canada and has since been confirmed in France, Turkey, Italy, Spain, Tunisia, Holland, and Japan.1 Various mutations in the SACS gene located on chromosome 13q12 have since been found to be responsible for ARSACS.1 The clinical phenotype is characterized by early-onset cerebellar ataxia, lower limb spasticity, and peripheral neuropathy.1 Electromyography shows signs of severe denervation in the distal muscles, and nerve conduction studies demonstrate signs of axonal neuropathy with associated demyelinating features.2 Magnetic resonance imaging (MRI) findings include atrophy of the superior vermis, cerebellar hemispheres and cervical cord, and linear hypointensities on T2- and T2/FLAIR-weighted images in the pons, thinning of the corpus callosum, and a rim of T2 hyperintensity around the thalami.3 Patients with ARSACS have been noted to have abnormal thickening or myelination of the peripapillary nerve fiber layer.1,4-7
Author affiliations: aDepartment of Ophthalmology, University of Virginia, Charlottesville, Virginia; bDepartment of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia Submitted March 17, 2015. Revision accepted October 7, 2015. Correspondence: Yevgeniy Shildkrot, MD, Department of Ophthalmology, PO Box 800715, Charlottesville, VA 22908 (email: [email protected]). J AAPOS 2016;20:81-83. Copyright Ó 2016 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.10.007
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FIG 1. A, Magnetic resonance imaging demonstrating atrophy of the superior vermis (long arrow), with enlarged posterior fossa subarachnoid space and thinning of the posterior body of the corpus callosum (short arrows). B, Characteristic bilateral paramedian T2/FLAIR-hypointense stripes in the basis pontis. C, Linear T2/FLAIR-hyperintense rims along the lateral thalami are also present.
