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Bilateral Sixth Nerve Palsy
Letters to the Editor The State of Being Noninferior Dear Editor: We appreciate this opportunity to provide additional information to address 2 concerns about our study1 raised by Drs Musch and Gillespie in their recent editorial.2 The first issue pertained to whether our trial adhered closely to the original efficacy trials for the active control— here, the unfixed combination of latanoprost and timolol. Support for the efficacy of the unfixed combination developed largely through clinical experience rather than through registration trials. Of the potential combinations of ocular hypotensive therapies available for use in patients with intraocular pressure (IOP) levels insufficiently responsive to monotherapy, clinical practice demonstrated that the unfixed combination of latanoprost and timolol was effective and safe. These empirical observations were bolstered by findings of studies of latanoprost plus timolol versus timolol alone3; however, the designs of these studies were not identical either to each other or to our research. The efficacy and safety of the fixed combination of latanoprost and timolol were compared with the individual components in trials conducted by Higginbotham et al4 and Pfeiffer et al.5 These studies and ours were similar with regard to inclusion diagnoses and primary end points. However, the Higginbotham and Pfeiffer studies included morning dosing of the fixed combination and latanoprost, whereas our trial was based on evening dosing of these agents; this difference may have resulted in an additional IOP-lowering effect of both latanoprost and the fixed combination in our study. The authors also pointed out that bias can be introduced by between-group differences in compliance or instances of data imputation as well as by the exclusion of patients from intention-to-treat analyses. We agree that compliance is a problem for many glaucoma patients. New compliancemonitoring devices are under development6 and could be used in future clinical trials of topical ocular treatment to monitor compliance as a possible cause of bias. In our research, few patients randomized to either the fixed or the unfixed combinations of latanoprost and timolol had major protocol deviations (23/263 [9%] and 17/254 [7%], respectively). Mean durations of therapy were similar in the fixed and unfixed combination groups for those completing treatment (by investigator judgment; 85.9⫾4.2 days and 86.6⫾5.7 days, respectively) and for patients terminating therapy early (40.6⫾31.0 days vs. 36.7⫾28.7 days, respectively). Of the 1506 data points in the intention-to-treat analysis (3 for each of the 502 patients included in the analysis), 17 were imputed using the “last observation carried forward” method (12 for 4 patients in the fixed combination group and 5 for 2 patients in the unfixed combination group); this small number of imputations did not bias our overall findings because the per protocol analysis reached the same conclusion using completed subjects without major protocol deviations or any data imputation. Finally, 15 randomized patients were excluded from our original intention-to-treat analysis. A post hoc assessment that
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included all randomized patients (n ⫽ 517) yielded results identical to those reported in our original publication because these 15 patients did not have any posttreatment IOP measurements at weeks 6 or 12; thus, the last observation carried forward approach could not be applied to these patients. As Drs Musch and Gillespie noted, “showing that a treatment has an effect that is no worse than average is not necessarily bad, when ‘average’ is based on a known, efficacious treatment.” Our trial demonstrated that once-daily evening administration of the fixed combination of latanoprost and timolol is no worse than the known efficacious regimen of latanoprost instilled in the evening and timolol instilled both morning and evening. The easier delivery and instillation of less of the drug associated with use of the fixed combination may confer additional advantages over the unfixed combination. MICHAEL DIESTELHORST FOR THE EUROPEAN–CANADIAN LATANOPROST FIXED COMBINATION STUDY GROUP Cologne, Germany References 1. Diestelhorst M, Larsson LI, European-Canadian Latanoprost Fixed Combination Study Group. A 12-week, randomized, double-masked, multicenter study of the fixed combination of latanoprost and timolol in the evening versus the individual components. Ophthalmology 2006;113:70 – 6. 2. Musch DC, Gillespie BW. The state of being noninferior. Ophthalmology 2006;113:1–2. 3. Diestelhorst M, Nordmann JP, Toris CB. Combined therapy of pilocarpine or latanoprost with timolol versus latanoprost monotherapy. Surv Ophthalmol 2002;47(suppl):S155– 61. 4. Higginbotham EJ, Feldman R, Stiles M, et al. Latanoprost and timolol combination therapy vs monotherapy: one-year randomized trial. Arch Ophthalmol 2002;120:915–22. 5. Pfeiffer N, European Latanoprost Fixed Combination Study Group. A comparison of the fixed combination of latanoprost and timolol with its individual components. Graefes Arch Clin Exp Ophthalmol 2002;240:893–9. 6. Hermann MM, Diestelhorst M. Microprocessor-controlled compliance monitor for eyedrop medication. Br J Ophthalmol 2006;90:830 –2.
Bilateral Sixth Nerve Palsy Dear Editor: The etiology and outcomes of bilateral sixth nerve palsy have not been reported for many years,1–3 and more recently published data focus on trauma.4,5 This letter reports the results of a multicenter retrospective review based on all patients seen by one neuro-ophthalmologist (JLC) over the last 30 years. Sixty-nine patients were identified, and their case notes were accessed to gather the required information. Data collected included date of birth, age at onset, visual acuity, gender, etiology of the sixth nerve palsy, degree of monocular abduction deficit, time to recovery, whether surgery was required, involvement of other cranial nerves, coexistence of cardiovascular risk factors, and follow-up period.
The mean age at diagnosis was 34.9 years (range, 1–79). Sixteen (23%) of the patients were children (under 18), and 43 (62%) were male. The median follow-up period was 12 months, with the lower quartile being 4 months and the upper quartile 42 months. Imaging techniques were used to define the precise location of the sixth nerve involvement. In only 21 cases (36.2%) was there direct involvement of the sixth nerve nucleus or its intracranial pathway; in the remainder, the palsy was mediated indirectly by processes such as raised intracranial pressure. Many patients exhibited other neurologic signs (particularly altered conscious state), and 36 (52.2%) had involvement of other cranial nerves. The most common etiology was trauma, with 29 (42%) patients represented. Of these, 24 (82.8%) were involved in a motor vehicle accident, 3 were injured in assaults, and 2 were injured in falls. The next most common pathology involved vascular lesions (n ⫽ 16 [23.2%]). These were defined broadly to include aneurysms and subsequent subarachnoid hemorrhage, cardiovascular-related cerebrovascular accident, and arteriovenous malformations. Almost universally, these resulted in abducens palsy through indirect effects such as raised intracranial pressure. There was, however, one case of coincident bilateral ischemic abducens neuropathy in a patient with type 2 diabetes mellitus and hypertension. The third most common etiologic agent was tumor, which accounted for 14 (20.3%) of the affected patients. Four of the tumors were in a position to involve directly the nerves or their nuclei. However, the majority of tumors resulted in bilateral sixth nerve palsy through an increase in intracranial pressure or distortion of intracranial contents. There was no one tumor type that predominated, but they were more frequently primary central nervous system tumors (n ⫽ 8) than distant metastases from elsewhere in the body (n ⫽ 5). The final category (involving 10 patients) included a range of etiologic agents such as nonspecific encephalitis, vasculitis, meningitis, and congenital lesions. The causes of bilateral sixth nerve palsy in children were spread equally across each of the 3 main etiologies. There were 5 (31%) who sustained traumatic injuries, 5 (31%) who had a vascular lesion, and 4 (25%) who had a brain tumor. The remaining 2 (13%) children had other conditions—namely, congenital hydrocephalus and otitis media leading to meningoencephalitis and hydrocephalus. Children (5/16 [31%]) were less likely to experience a traumatic lesion than adults (24/53 [45%]) but were more likely to suffer from tumor (25% for children, 19% for adults) or a vascular event (31% for children, 21% for adults). The severity of monocular abduction deficit was recorded in 58 patients. Twenty of these patients (34.5%) had complete bilateral sixth nerve palsy, and the remainder had at least one eye that was incompletely affected. A full spontaneous bilateral recovery was achieved in 22 patients (37.9%). There were 6 patients in whom a unilateral recovery was achieved; however, surgery was required to correct the abducens palsy that continued to affect the other eye. Surgery was performed on a total of 14 patients (24%; including the 6 above) at a mean of 15 months after the onset of the bilateral sixth nerve palsy. There were 2 patients who required subsequent surgery to achieve binocularity in primary gaze.
Associations could be drawn among several variables. Trauma was more likely to be associated with complete abducens palsy than tumors (P ⫽ 0.001). There was, however, no association between etiologic agent and the likelihood of full spontaneous recovery (P ⫽ 0.99). Trauma was significantly more likely to be associated with the involvement of other cranial nerve lesions (47% of the time; P ⫽ 0.03) than other forms of etiology. Trauma was also the most common etiology responsible for the need to undertake strabismus surgery. Of the 14 patients who required surgery, 8 (57%) were involved in trauma. Complete lesions were more likely to require surgery and accounted for 80% of those who had squint operations. This series demonstrates the wide variety of etiology responsible for bilateral sixth nerve palsy. The most common cause was trauma, followed by vascular lesions including aneurysms and subsequent subarachnoid hemorrhage, cardiovascular-related cerebrovascular accident, and arteriovenous malformations. Tumor was the third most likely etiology and was predominantly secondary to primary intracranial malignancy. Children were less likely to sustain traumatic bilateral sixth nerve palsy than adults; however, it was more common for them to have this condition in association with tumor or vascular anomalies. Trauma and complete sixth nerve lesions were most predictive of an eventual need to proceed to strabismus surgery. SHANE R. DURKIN, MBBS (HONS) SARATH TENNEKOON, MD ANDREW KLEINSCHMIDT, MBBS (HONS) ROBERT J. CASSON, DPHIL DINESH SELVA, FRANZCO JOHN L. CROMPTON, FRANZCO Adelaide, Australia References 1. Keane J. Bilateral sixth nerve palsy: analysis of 125 cases. Arch Neurol 1976;33:681–3. 2. Rucker CW. The causes of paralysis of the third, fourth, and sixth cranial nerves. Am J Ophthalmol 1966;61:1293– 8. 3. Johnston AC. Etiology and treatment of abducens paralysis. Trans Pac Coast Otoophthalmol Soc Annu Meet 1968;49:259 – 77. 4. Holmes JM, Droste PJ, Beck RW. The natural history of acute traumatic sixth nerve palsy or paresis. J AAPOS 1998;2:265– 8. 5. Holmes JM, Beck RW, Kip KE, et al. Predictors of nonrecovery in acute traumatic sixth nerve palsy and paresis. Ophthalmology 2001;108:1457– 60.
Intravitreal Triamcinolone and PDT Dear Editor: We read with great interest Augustin et al’s article1 stating that verteporfin photodynamic therapy combined with intravitreal triamcinolone may improve the outcome of standard verteporfin photodynamic therapy in the treatment of choroidal neovascularization secondary to age-related macular degeneration (AMD). In their study, they administered intravitreal triamcinolone within a mean of 16 hours after photodynamic therapy. We offer our opinions about and experience with this treatment. Intravitreal triamcinolone has been used widely in combination with photodynamic therapy for treatment of neovascular
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included all randomized patients (n ⫽ 517) yielded results identical to those reported in our original publication because these 15 patients did not have any posttreatment IOP measurements at weeks 6 or 12; thus, the last observation carried forward approach could not be applied to these patients. As Drs Musch and Gillespie noted, “showing that a treatment has an effect that is no worse than average is not necessarily bad, when ‘average’ is based on a known, efficacious treatment.” Our trial demonstrated that once-daily evening administration of the fixed combination of latanoprost and timolol is no worse than the known efficacious regimen of latanoprost instilled in the evening and timolol instilled both morning and evening. The easier delivery and instillation of less of the drug associated with use of the fixed combination may confer additional advantages over the unfixed combination. MICHAEL DIESTELHORST FOR THE EUROPEAN–CANADIAN LATANOPROST FIXED COMBINATION STUDY GROUP Cologne, Germany References 1. Diestelhorst M, Larsson LI, European-Canadian Latanoprost Fixed Combination Study Group. A 12-week, randomized, double-masked, multicenter study of the fixed combination of latanoprost and timolol in the evening versus the individual components. Ophthalmology 2006;113:70 – 6. 2. Musch DC, Gillespie BW. The state of being noninferior. Ophthalmology 2006;113:1–2. 3. Diestelhorst M, Nordmann JP, Toris CB. Combined therapy of pilocarpine or latanoprost with timolol versus latanoprost monotherapy. Surv Ophthalmol 2002;47(suppl):S155– 61. 4. Higginbotham EJ, Feldman R, Stiles M, et al. Latanoprost and timolol combination therapy vs monotherapy: one-year randomized trial. Arch Ophthalmol 2002;120:915–22. 5. Pfeiffer N, European Latanoprost Fixed Combination Study Group. A comparison of the fixed combination of latanoprost and timolol with its individual components. Graefes Arch Clin Exp Ophthalmol 2002;240:893–9. 6. Hermann MM, Diestelhorst M. Microprocessor-controlled compliance monitor for eyedrop medication. Br J Ophthalmol 2006;90:830 –2.
Bilateral Sixth Nerve Palsy Dear Editor: The etiology and outcomes of bilateral sixth nerve palsy have not been reported for many years,1–3 and more recently published data focus on trauma.4,5 This letter reports the results of a multicenter retrospective review based on all patients seen by one neuro-ophthalmologist (JLC) over the last 30 years. Sixty-nine patients were identified, and their case notes were accessed to gather the required information. Data collected included date of birth, age at onset, visual acuity, gender, etiology of the sixth nerve palsy, degree of monocular abduction deficit, time to recovery, whether surgery was required, involvement of other cranial nerves, coexistence of cardiovascular risk factors, and follow-up period.
The mean age at diagnosis was 34.9 years (range, 1–79). Sixteen (23%) of the patients were children (under 18), and 43 (62%) were male. The median follow-up period was 12 months, with the lower quartile being 4 months and the upper quartile 42 months. Imaging techniques were used to define the precise location of the sixth nerve involvement. In only 21 cases (36.2%) was there direct involvement of the sixth nerve nucleus or its intracranial pathway; in the remainder, the palsy was mediated indirectly by processes such as raised intracranial pressure. Many patients exhibited other neurologic signs (particularly altered conscious state), and 36 (52.2%) had involvement of other cranial nerves. The most common etiology was trauma, with 29 (42%) patients represented. Of these, 24 (82.8%) were involved in a motor vehicle accident, 3 were injured in assaults, and 2 were injured in falls. The next most common pathology involved vascular lesions (n ⫽ 16 [23.2%]). These were defined broadly to include aneurysms and subsequent subarachnoid hemorrhage, cardiovascular-related cerebrovascular accident, and arteriovenous malformations. Almost universally, these resulted in abducens palsy through indirect effects such as raised intracranial pressure. There was, however, one case of coincident bilateral ischemic abducens neuropathy in a patient with type 2 diabetes mellitus and hypertension. The third most common etiologic agent was tumor, which accounted for 14 (20.3%) of the affected patients. Four of the tumors were in a position to involve directly the nerves or their nuclei. However, the majority of tumors resulted in bilateral sixth nerve palsy through an increase in intracranial pressure or distortion of intracranial contents. There was no one tumor type that predominated, but they were more frequently primary central nervous system tumors (n ⫽ 8) than distant metastases from elsewhere in the body (n ⫽ 5). The final category (involving 10 patients) included a range of etiologic agents such as nonspecific encephalitis, vasculitis, meningitis, and congenital lesions. The causes of bilateral sixth nerve palsy in children were spread equally across each of the 3 main etiologies. There were 5 (31%) who sustained traumatic injuries, 5 (31%) who had a vascular lesion, and 4 (25%) who had a brain tumor. The remaining 2 (13%) children had other conditions—namely, congenital hydrocephalus and otitis media leading to meningoencephalitis and hydrocephalus. Children (5/16 [31%]) were less likely to experience a traumatic lesion than adults (24/53 [45%]) but were more likely to suffer from tumor (25% for children, 19% for adults) or a vascular event (31% for children, 21% for adults). The severity of monocular abduction deficit was recorded in 58 patients. Twenty of these patients (34.5%) had complete bilateral sixth nerve palsy, and the remainder had at least one eye that was incompletely affected. A full spontaneous bilateral recovery was achieved in 22 patients (37.9%). There were 6 patients in whom a unilateral recovery was achieved; however, surgery was required to correct the abducens palsy that continued to affect the other eye. Surgery was performed on a total of 14 patients (24%; including the 6 above) at a mean of 15 months after the onset of the bilateral sixth nerve palsy. There were 2 patients who required subsequent surgery to achieve binocularity in primary gaze.
Associations could be drawn among several variables. Trauma was more likely to be associated with complete abducens palsy than tumors (P ⫽ 0.001). There was, however, no association between etiologic agent and the likelihood of full spontaneous recovery (P ⫽ 0.99). Trauma was significantly more likely to be associated with the involvement of other cranial nerve lesions (47% of the time; P ⫽ 0.03) than other forms of etiology. Trauma was also the most common etiology responsible for the need to undertake strabismus surgery. Of the 14 patients who required surgery, 8 (57%) were involved in trauma. Complete lesions were more likely to require surgery and accounted for 80% of those who had squint operations. This series demonstrates the wide variety of etiology responsible for bilateral sixth nerve palsy. The most common cause was trauma, followed by vascular lesions including aneurysms and subsequent subarachnoid hemorrhage, cardiovascular-related cerebrovascular accident, and arteriovenous malformations. Tumor was the third most likely etiology and was predominantly secondary to primary intracranial malignancy. Children were less likely to sustain traumatic bilateral sixth nerve palsy than adults; however, it was more common for them to have this condition in association with tumor or vascular anomalies. Trauma and complete sixth nerve lesions were most predictive of an eventual need to proceed to strabismus surgery. SHANE R. DURKIN, MBBS (HONS) SARATH TENNEKOON, MD ANDREW KLEINSCHMIDT, MBBS (HONS) ROBERT J. CASSON, DPHIL DINESH SELVA, FRANZCO JOHN L. CROMPTON, FRANZCO Adelaide, Australia References 1. Keane J. Bilateral sixth nerve palsy: analysis of 125 cases. Arch Neurol 1976;33:681–3. 2. Rucker CW. The causes of paralysis of the third, fourth, and sixth cranial nerves. Am J Ophthalmol 1966;61:1293– 8. 3. Johnston AC. Etiology and treatment of abducens paralysis. Trans Pac Coast Otoophthalmol Soc Annu Meet 1968;49:259 – 77. 4. Holmes JM, Droste PJ, Beck RW. The natural history of acute traumatic sixth nerve palsy or paresis. J AAPOS 1998;2:265– 8. 5. Holmes JM, Beck RW, Kip KE, et al. Predictors of nonrecovery in acute traumatic sixth nerve palsy and paresis. Ophthalmology 2001;108:1457– 60.
Intravitreal Triamcinolone and PDT Dear Editor: We read with great interest Augustin et al’s article1 stating that verteporfin photodynamic therapy combined with intravitreal triamcinolone may improve the outcome of standard verteporfin photodynamic therapy in the treatment of choroidal neovascularization secondary to age-related macular degeneration (AMD). In their study, they administered intravitreal triamcinolone within a mean of 16 hours after photodynamic therapy. We offer our opinions about and experience with this treatment. Intravitreal triamcinolone has been used widely in combination with photodynamic therapy for treatment of neovascular
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