- Email: [email protected]
Glaucoma Treatment with Once-Daily Levobunolol
544
October, 1986
AMERICAN JOURNAL OF OPHTHALMOLOGY
A 72-year-old woman sustained a closedhead injury with concussion in a motor vehicle accident. Initial examination showed evidence of a right oculomotor palsy. Skull radiographs showed a linear right temporal skull fracture, and computed tomographic head scan showed no additional abnormalities. Eleven days after the injury, she had a complete third-nerve palsy on the right, with sparing of the fourth, fifth, and sixth nerves. The right pupil measured 4.7 mm in diameter, and no segment of the pupil reacted to light. Spontaneous contractions of portions of the pupillary sphincter were apparent with slit-lamp examination. A IS-degree segment centered at the 2:30 o'clock meridian contracted intermittently; each contraction was rapid, with immediate relaxation. The interval between successive contractions ranged from one to 15 seconds, and the amplitude of contractions was variable. With larger contractions of the 2:30 segment, adjacent portions of the sphincter moved. No sphincter activity was apparent from the 3:30 to 4:30 meridian, but a segment between 4:30 and 5:30 0' clock also contracted with larger contractions at the 2:30 segment. Contractions of these upper and lower nasal segments were not synchronous, giving a vermiform appearance to the pupillary movements. Most of the temporal portion of the pupil did not move; however, there were occasional feeble movements at the 10 o'clock position with larger contractions of the 2:30 o'clock segment. The movements of the two pupils were observed with the infrared video system of a binocular television pupillometer for simultaneous visualization under different conditions of illumination. Spontaneous contractions of the right pupil occurred in the dark as well as in room light and were not correlated with ocular movements or activity of the opposite pupil. The sphincter contractions of this patient's pupil are analogous to the intermittent contractions of segments of the pupillary dilator muscle in some patients with Horner's syndrome." Both types of movement probably have the same electrophysiologic mechanism. Spontaneous activity of portions of the pupillary sphincter may have arisen from abnormal impulses generated in damaged axons at the site of oculomotor nerve injury. Although Adrian" described the persistent discharge of impulses in resected nerves of cats and rabbits, he found that the fibers that reacted in this way were sensory fibers. Whether autonomic fibers behave similarly is speculative. Another possible source of abnormal action potentials might be spontaneous activity within the ciliary gangli-
on. Czarnecki and Thompson" described a patient with the tonic pupil of Adie's syndrome who had spontaneous contractions of a small segment of the pupillary sphincter; damaged ganglion cells in the ciliary ganglion may have generated these abnormal action potentials. Previous series of patients with "vermiform movements" of the iris included cases similar to mine. For example, in one of McGregor's cases! the patient had traumatic ophthalmoplegia and segmental contractions of the iris; it is not clear from his report whether these movements were spontaneous or induced by light."
References 1. Thompson, H. 5., Zackon, D. H., and Czarnecki, J. S. c.: Tadpole-shaped pupils caused by segmental spasm of the iris dilator muscle. Am. J. Ophthalmol. 96:467, 1983. 2. Adrian, E. D.: The effects of injury on mammalian nerve fibres. Proc. R. Soc. Lond. (BioI.) 106:596, 1930. 3. Czarnecki, J. S. c.. and Thompson, H. 5.: Spontaneous cyclic sphincter spasms in an Adies tonic pupil. Am. J. Ophthalmol. 82:636, 1976. 4. McGregor, I. 5.: Segmental movement of the pupil. Br. Med. J. 1:629, 1945. 5. Thompson, H. 5.: Segmental palsy of the iris sphincter in Adies syndrome. Arch. Ophthalmol. 96:1615, 1978.
Correspondence Correspondence concerning recent articles or other material published in THE JOURNAL should be submitted within six weeks of publication. Correspondence must be typed double-spaced, on 8'12 x ll-inch bond paper with 1'/2-inch margins on all four sides and should be no more than two typewritten pages in length. Every effort will be made to resolve controversies between the correspondents and the authors of the article before formal publication.
Glaucoma Treatment with Once-Daily Levobunolol EDITOR:
In the article, "Glaucoma treatment with once-daily levobunolol" by T. Wandel, A. D. Charap, R. A. Lewis, L. Partamian, S. Cobb, J. C. Lue, G. D. Novack, R. Gaster, J. Smith,
Vol. 102, No. 4
and E. Duzman (Am. J. Ophthalmol. 101:298, March 1986), the authors recommend that "Judging from the study, patients may be treated with once-daily instillation of levobunolol." This simple statement may be easily misinterpreted. The initial clinical trial included 92 patients with open-angle glaucoma or ocular hypertension. Of these, only 78 were entered into three groups (limited by their protocol) to determine efficacy. This leaves a small data base per group for analysis. Control of intraocular pressure was loosely defined as follows: 1. In patients without previous glaucoma medications, a decrease less than 20% from baseline intraocular pressure was considered inadequate. (Thus, in a patient with an intraocular pressure of 30 mm Hg, reduction to 24 mm Hg would be considered adequate.) 2. In patients with prior glaucoma medications, an intraocular pressure increase of greater than or equal to 5 mm Hg from prewashout values was considered as inadequate control. (Therefore, in a patient with a prewashout intraocular pressure of 23.5 mm Hg an increase to 28 mm Hg would be considered adequately controlled.) This definition of successful control can be misleading. Patients are not identified within the designated groups as to previous medications. This raises the possibility that the groups are not adequately matched. Based on life-table estimates, the probability of controlled intraocular pressure on oncedaily levobunolol was not significantly different from that of once-daily timolol. The only statistically significant finding was that overall mean reduction of intraocular pressure was greater for the levobunolol groups. Mean reduction of intraocular pressure was determined on a single measurement at 9:00 A.M., 24 hours after drop instillation, rechecked on seven occasions over three months. The problem is that significant spikes in intraocular pressure may be missed by a single measurement. In a previous study, diurnal recordings showed peak intraocular pressure at 7:00 A.M. Treatment with twice-daily levobunolol at 9:00 A.M. and 9:00 P.M. significantly reduced intraocular pressure; however, peak intraocular pressure still occurred at 7:00 A.M. six and 12 months into therapy." Additionally, sustained reduction in intraocular pressure on levobunolol or timolol may not prevent progressive glaucomatous damage. In the present study intraocular pressure was lowered to 21.2 and 20.4 mm Hg in the levobunolol
Correspondence
545
group and to 21.9 mm Hg in the timolol group. These data suggest that although levobunolol may statistically show a greater mean reduction in intraocular pressure, clinically it is not significant. If once-daily dosage is inadequate, Wandel and associates recommend going to twicedaily treatment using levobunolol, yet their discussion section opens with a reference statement that the mean decrease in intraocular pressure is not significantly different on this increased dosage schedule. Therefore, increasing levobunolol to twice daily may not result in a further reduction in intraocular pressure because of its already long-acting properties. Side effects such as a decrease in heart rate, may actually be increased when compared to timolol. We agree with the authors that once-daily dosage each morning is appropriate. If twicedaily therapy is needed it may be better to consider other drugs. Increasing timolol 0.25% from once- to twice-daily further reduced intraocular pressure from 18% to 25%.3 Betaxolol in twice-daily dosage results in significant intraocular pressure reduction with markedly less side effects." We commend the authors on this preliminary but innovative study suggesting oncedaily levobunolol for the treatment of glaucoma. A new beta-blocker that may improve patient compliance while providing greater safety at reduced cost would be a welcome addition to glaucoma sufferers. Whether this will be adequate in stabilizing visual function in these patients remains speculative. If twice-daily dosage is required, other alternatives should be considered.
RICHARD J. STARITA, M.D. RONALD 1. FELLMAN, M.D.
Dallas, Texas
References 1. Silverstone, D. E., Arkfeld, D., Cowan, G., Lue, J. C.; and Novack, G. D.: Long-term diurnal control of intraocular pressure with levobunolol and with timolol. Glaucoma 7:138, 1985. 2. Cinotti, A., Cinotti, D., Grant, W., Jacobs, 1., Galin, M., Silverstone, D., Shin, D., Esters, J., Lee, J., Bouchey, R., Novack, G., Duzrnan, E., and Lue, J.: Levobunolol vs timolol for open-angle glaucoma in ocular hypertension. Am. J. Ophthalmol. 99:11, 1985. 3. Soll, D. B.: Evaluation of timolol in chronic open-angle glaucoma; once a day vs twice a day. Arch. Ophthalmol. 98:2178, 1980.
546
4. Schoene, R. B., Abuan, T., Ward, R. 1., and Beasley, C. H.: Effect of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am. J. Ophthalmol. 97:86, 1984.
_ _ _ _ _ _ _ Reply EDITOR:
October, 1986
AMERICAN JOURNAL OF OPHTHALMOLOGY
_
We agree with Drs. Starita and Fellman concerning the benefits of "a new beta-blocker that may improve patient compliance while providing greater safety at reduced cost" and wish to. respond to some of the questions they have raised about our once-daily levobunolol study. Statistics-Because we were able to detect a statistical difference between the levobunolol and timolol groups, a priori, the sample size was large enough. Drs. Starita and Fellman calculated intraocular pressure values by subtracting the overall means from the baseline values, which we believe is incorrect. Rather than suggesting, as they indicate, that the effect of levobunolol though statistically significant is not clinically significant, the opposite appears to be the case when the data from individual visits are evaluated. In the intraocular pressure graph there was a clinically significant difference between the levobunolol and timolol groups of 2 to 4 mm Hg at each time period, which finally became statistically significant when the differences between the overall means were tested. Protocol-Drs. Starita and Fellman suggest that the study protocol definition of controlled intraocular pressure was misleading. During our study, definition (b) was never invoked. Also, regarding prestudy medications, we found no differences between the groups in either the types of prestudy medications taken or the numbers of medications used. Cited literature-There were several inconsistencies in the literature cited by Drs. Starita and Fellman, who suggested that there were significant pressure spikes at 7:00 A.M. in a study of long-term diurnal intraocular pressure control by levobunolol and timolol.' In the quoted paper, Silverstone and associates stated that, "diurnal variations were minimal in subjects treated with either drug: large fluctuations in intraocular pressure were not observed."? From their citation, Drs. Starita and Fellman infer that twice-a-day levobunolol might be less safe than twice-a-day timolol. The results
of several long-term, large, multicenter studies indicate that twice-a-day levobunolol and twice-a-day timolol have similar safety and efficacy profiles." The 5011 study, 3 comparing once-daily treatment with timolol and twice-daily treatment, was a parallel group study, not a titration study as indicated by Drs. Starita and Fellman. Dr. 5011 found no statistical differences between the groups in efficacy. We would like to reaffirm our suggestion that if once-daily treatment with levobunolol is inadequate, twice-daily treatment should be tried. Drug studies give guidelines in terms of average behavior of the study populaion. However, individual patients may gain additional intraocular pressure control when the amount of beta-blocker delivered is increased.v' It makes sense to increase the dosage rather than change to a new pharmaceutical agent that may possess a different efficacy and comfort profile." When choosing a therapeutic agent, many factors must be considered and balanced, including efficacy, safety, comfort, and compli~nce. B~sed on the data presented in our origmal article, once-daily levobunolol appears to optimize many of these factors. We look forward to the results of future studies and clinical usage of levobunolol at this dosage regimen. THADDEUS WANDEL, M.D.
Houston, Texas
ARTHUR CHARAP, PH.D., M.D.
Irvine, California
RICHARD A. LEWIS, M.D.
Davis, California
LEON PARTAMIAN, M.D.
Los Angeles, California STEPHEN COBB, M.D.
Boston, Massachusetts JOHN LUE, M.S.
Irvine, California
GARY D. NOVACK, Ph.D.
Irvine, Calfornia
RONALD GASTER, M.D.
Irvine, California
JESS SMITH, M.D.
Houston, Texas
EFRAIM DUZMAN, M.D.
Irvine, California
References 1. Silverstone, D. E., Arkfeld, D., Cowan G., Lue,
J. c.,
and Novack, G. D.: Long-term diurnal control
October, 1986
AMERICAN JOURNAL OF OPHTHALMOLOGY
A 72-year-old woman sustained a closedhead injury with concussion in a motor vehicle accident. Initial examination showed evidence of a right oculomotor palsy. Skull radiographs showed a linear right temporal skull fracture, and computed tomographic head scan showed no additional abnormalities. Eleven days after the injury, she had a complete third-nerve palsy on the right, with sparing of the fourth, fifth, and sixth nerves. The right pupil measured 4.7 mm in diameter, and no segment of the pupil reacted to light. Spontaneous contractions of portions of the pupillary sphincter were apparent with slit-lamp examination. A IS-degree segment centered at the 2:30 o'clock meridian contracted intermittently; each contraction was rapid, with immediate relaxation. The interval between successive contractions ranged from one to 15 seconds, and the amplitude of contractions was variable. With larger contractions of the 2:30 segment, adjacent portions of the sphincter moved. No sphincter activity was apparent from the 3:30 to 4:30 meridian, but a segment between 4:30 and 5:30 0' clock also contracted with larger contractions at the 2:30 segment. Contractions of these upper and lower nasal segments were not synchronous, giving a vermiform appearance to the pupillary movements. Most of the temporal portion of the pupil did not move; however, there were occasional feeble movements at the 10 o'clock position with larger contractions of the 2:30 o'clock segment. The movements of the two pupils were observed with the infrared video system of a binocular television pupillometer for simultaneous visualization under different conditions of illumination. Spontaneous contractions of the right pupil occurred in the dark as well as in room light and were not correlated with ocular movements or activity of the opposite pupil. The sphincter contractions of this patient's pupil are analogous to the intermittent contractions of segments of the pupillary dilator muscle in some patients with Horner's syndrome." Both types of movement probably have the same electrophysiologic mechanism. Spontaneous activity of portions of the pupillary sphincter may have arisen from abnormal impulses generated in damaged axons at the site of oculomotor nerve injury. Although Adrian" described the persistent discharge of impulses in resected nerves of cats and rabbits, he found that the fibers that reacted in this way were sensory fibers. Whether autonomic fibers behave similarly is speculative. Another possible source of abnormal action potentials might be spontaneous activity within the ciliary gangli-
on. Czarnecki and Thompson" described a patient with the tonic pupil of Adie's syndrome who had spontaneous contractions of a small segment of the pupillary sphincter; damaged ganglion cells in the ciliary ganglion may have generated these abnormal action potentials. Previous series of patients with "vermiform movements" of the iris included cases similar to mine. For example, in one of McGregor's cases! the patient had traumatic ophthalmoplegia and segmental contractions of the iris; it is not clear from his report whether these movements were spontaneous or induced by light."
References 1. Thompson, H. 5., Zackon, D. H., and Czarnecki, J. S. c.: Tadpole-shaped pupils caused by segmental spasm of the iris dilator muscle. Am. J. Ophthalmol. 96:467, 1983. 2. Adrian, E. D.: The effects of injury on mammalian nerve fibres. Proc. R. Soc. Lond. (BioI.) 106:596, 1930. 3. Czarnecki, J. S. c.. and Thompson, H. 5.: Spontaneous cyclic sphincter spasms in an Adies tonic pupil. Am. J. Ophthalmol. 82:636, 1976. 4. McGregor, I. 5.: Segmental movement of the pupil. Br. Med. J. 1:629, 1945. 5. Thompson, H. 5.: Segmental palsy of the iris sphincter in Adies syndrome. Arch. Ophthalmol. 96:1615, 1978.
Correspondence Correspondence concerning recent articles or other material published in THE JOURNAL should be submitted within six weeks of publication. Correspondence must be typed double-spaced, on 8'12 x ll-inch bond paper with 1'/2-inch margins on all four sides and should be no more than two typewritten pages in length. Every effort will be made to resolve controversies between the correspondents and the authors of the article before formal publication.
Glaucoma Treatment with Once-Daily Levobunolol EDITOR:
In the article, "Glaucoma treatment with once-daily levobunolol" by T. Wandel, A. D. Charap, R. A. Lewis, L. Partamian, S. Cobb, J. C. Lue, G. D. Novack, R. Gaster, J. Smith,
Vol. 102, No. 4
and E. Duzman (Am. J. Ophthalmol. 101:298, March 1986), the authors recommend that "Judging from the study, patients may be treated with once-daily instillation of levobunolol." This simple statement may be easily misinterpreted. The initial clinical trial included 92 patients with open-angle glaucoma or ocular hypertension. Of these, only 78 were entered into three groups (limited by their protocol) to determine efficacy. This leaves a small data base per group for analysis. Control of intraocular pressure was loosely defined as follows: 1. In patients without previous glaucoma medications, a decrease less than 20% from baseline intraocular pressure was considered inadequate. (Thus, in a patient with an intraocular pressure of 30 mm Hg, reduction to 24 mm Hg would be considered adequate.) 2. In patients with prior glaucoma medications, an intraocular pressure increase of greater than or equal to 5 mm Hg from prewashout values was considered as inadequate control. (Therefore, in a patient with a prewashout intraocular pressure of 23.5 mm Hg an increase to 28 mm Hg would be considered adequately controlled.) This definition of successful control can be misleading. Patients are not identified within the designated groups as to previous medications. This raises the possibility that the groups are not adequately matched. Based on life-table estimates, the probability of controlled intraocular pressure on oncedaily levobunolol was not significantly different from that of once-daily timolol. The only statistically significant finding was that overall mean reduction of intraocular pressure was greater for the levobunolol groups. Mean reduction of intraocular pressure was determined on a single measurement at 9:00 A.M., 24 hours after drop instillation, rechecked on seven occasions over three months. The problem is that significant spikes in intraocular pressure may be missed by a single measurement. In a previous study, diurnal recordings showed peak intraocular pressure at 7:00 A.M. Treatment with twice-daily levobunolol at 9:00 A.M. and 9:00 P.M. significantly reduced intraocular pressure; however, peak intraocular pressure still occurred at 7:00 A.M. six and 12 months into therapy." Additionally, sustained reduction in intraocular pressure on levobunolol or timolol may not prevent progressive glaucomatous damage. In the present study intraocular pressure was lowered to 21.2 and 20.4 mm Hg in the levobunolol
Correspondence
545
group and to 21.9 mm Hg in the timolol group. These data suggest that although levobunolol may statistically show a greater mean reduction in intraocular pressure, clinically it is not significant. If once-daily dosage is inadequate, Wandel and associates recommend going to twicedaily treatment using levobunolol, yet their discussion section opens with a reference statement that the mean decrease in intraocular pressure is not significantly different on this increased dosage schedule. Therefore, increasing levobunolol to twice daily may not result in a further reduction in intraocular pressure because of its already long-acting properties. Side effects such as a decrease in heart rate, may actually be increased when compared to timolol. We agree with the authors that once-daily dosage each morning is appropriate. If twicedaily therapy is needed it may be better to consider other drugs. Increasing timolol 0.25% from once- to twice-daily further reduced intraocular pressure from 18% to 25%.3 Betaxolol in twice-daily dosage results in significant intraocular pressure reduction with markedly less side effects." We commend the authors on this preliminary but innovative study suggesting oncedaily levobunolol for the treatment of glaucoma. A new beta-blocker that may improve patient compliance while providing greater safety at reduced cost would be a welcome addition to glaucoma sufferers. Whether this will be adequate in stabilizing visual function in these patients remains speculative. If twice-daily dosage is required, other alternatives should be considered.
RICHARD J. STARITA, M.D. RONALD 1. FELLMAN, M.D.
Dallas, Texas
References 1. Silverstone, D. E., Arkfeld, D., Cowan, G., Lue, J. C.; and Novack, G. D.: Long-term diurnal control of intraocular pressure with levobunolol and with timolol. Glaucoma 7:138, 1985. 2. Cinotti, A., Cinotti, D., Grant, W., Jacobs, 1., Galin, M., Silverstone, D., Shin, D., Esters, J., Lee, J., Bouchey, R., Novack, G., Duzrnan, E., and Lue, J.: Levobunolol vs timolol for open-angle glaucoma in ocular hypertension. Am. J. Ophthalmol. 99:11, 1985. 3. Soll, D. B.: Evaluation of timolol in chronic open-angle glaucoma; once a day vs twice a day. Arch. Ophthalmol. 98:2178, 1980.
546
4. Schoene, R. B., Abuan, T., Ward, R. 1., and Beasley, C. H.: Effect of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am. J. Ophthalmol. 97:86, 1984.
_ _ _ _ _ _ _ Reply EDITOR:
October, 1986
AMERICAN JOURNAL OF OPHTHALMOLOGY
_
We agree with Drs. Starita and Fellman concerning the benefits of "a new beta-blocker that may improve patient compliance while providing greater safety at reduced cost" and wish to. respond to some of the questions they have raised about our once-daily levobunolol study. Statistics-Because we were able to detect a statistical difference between the levobunolol and timolol groups, a priori, the sample size was large enough. Drs. Starita and Fellman calculated intraocular pressure values by subtracting the overall means from the baseline values, which we believe is incorrect. Rather than suggesting, as they indicate, that the effect of levobunolol though statistically significant is not clinically significant, the opposite appears to be the case when the data from individual visits are evaluated. In the intraocular pressure graph there was a clinically significant difference between the levobunolol and timolol groups of 2 to 4 mm Hg at each time period, which finally became statistically significant when the differences between the overall means were tested. Protocol-Drs. Starita and Fellman suggest that the study protocol definition of controlled intraocular pressure was misleading. During our study, definition (b) was never invoked. Also, regarding prestudy medications, we found no differences between the groups in either the types of prestudy medications taken or the numbers of medications used. Cited literature-There were several inconsistencies in the literature cited by Drs. Starita and Fellman, who suggested that there were significant pressure spikes at 7:00 A.M. in a study of long-term diurnal intraocular pressure control by levobunolol and timolol.' In the quoted paper, Silverstone and associates stated that, "diurnal variations were minimal in subjects treated with either drug: large fluctuations in intraocular pressure were not observed."? From their citation, Drs. Starita and Fellman infer that twice-a-day levobunolol might be less safe than twice-a-day timolol. The results
of several long-term, large, multicenter studies indicate that twice-a-day levobunolol and twice-a-day timolol have similar safety and efficacy profiles." The 5011 study, 3 comparing once-daily treatment with timolol and twice-daily treatment, was a parallel group study, not a titration study as indicated by Drs. Starita and Fellman. Dr. 5011 found no statistical differences between the groups in efficacy. We would like to reaffirm our suggestion that if once-daily treatment with levobunolol is inadequate, twice-daily treatment should be tried. Drug studies give guidelines in terms of average behavior of the study populaion. However, individual patients may gain additional intraocular pressure control when the amount of beta-blocker delivered is increased.v' It makes sense to increase the dosage rather than change to a new pharmaceutical agent that may possess a different efficacy and comfort profile." When choosing a therapeutic agent, many factors must be considered and balanced, including efficacy, safety, comfort, and compli~nce. B~sed on the data presented in our origmal article, once-daily levobunolol appears to optimize many of these factors. We look forward to the results of future studies and clinical usage of levobunolol at this dosage regimen. THADDEUS WANDEL, M.D.
Houston, Texas
ARTHUR CHARAP, PH.D., M.D.
Irvine, California
RICHARD A. LEWIS, M.D.
Davis, California
LEON PARTAMIAN, M.D.
Los Angeles, California STEPHEN COBB, M.D.
Boston, Massachusetts JOHN LUE, M.S.
Irvine, California
GARY D. NOVACK, Ph.D.
Irvine, Calfornia
RONALD GASTER, M.D.
Irvine, California
JESS SMITH, M.D.
Houston, Texas
EFRAIM DUZMAN, M.D.
Irvine, California
References 1. Silverstone, D. E., Arkfeld, D., Cowan G., Lue,
J. c.,
and Novack, G. D.: Long-term diurnal control