- Email: [email protected]
The Value and Caveats of Interpreting Small Case Series: Implications for Patient Care
Journal Pre-proof The value and caveats of interpreting small case series – implications for patient care Richard K. Parrish, II, Ta Chen Chang, Sarah L. Duncan Powers PII:
S0002-9394(19)30530-6
DOI:
https://doi.org/10.1016/j.ajo.2019.10.027
Reference:
AJOPHT 11119
To appear in:
American Journal of Ophthalmology
Received Date: 30 October 2019 Accepted Date: 30 October 2019
Please cite this article as: Parrish II RK, Chang TC, Duncan Powers SL, The value and caveats of interpreting small case series – implications for patient care, American Journal of Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.10.027. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
The value and caveats of interpreting small case series – implications for patient care
Richard K. Parrish II1 Ta Chen Chang1 Sarah L. Duncan Powers2
1
University of Miami Miller School of Medicine, Department of Ophthalmology, Bascom Palmer
Eye Institute, Miami, Florida 2
American Journal of Ophthalmology, Saint Augustine, Florida
[email protected]
Purpose: To discuss the value and limitations of interpreting small case series for the purpose of understanding the pathophysiology of conditions affecting the visual system and how they may influence patient care decision making
Design: Selective review of English language ophthalmic articles published in peer review journals since 1950.
Methods: Author initiated PubMed Central query of small case series in glaucoma, pediatric neuro-ophthalmology, and diabetic retinopathy
Results: A review of well-known ophthalmic case studies by Gass, Irvine, Brockhurst and others show that small samples can provide suggestions to the skilled clinician for adding steps to the examination process when uncovering rare or previously unknown associated complications, as is the case for this perspective’s initiating studies by Groth and Brodsky. However, as shown by the now-retracted small case series in Lancet connecting MMR vaccinations with autism, small case series do not replace the value of clinical trials, with rare exception, when considering impacts to widespread, common clinical practice.
Conclusion: Small case series may contribute to an improved understanding of pathophysiology of rare ophthalmic conditions, but alone are insufficient to provide evidence for changing clinical practice of common eye diseases.
Groth and coworkers report the association of optic nerve cupping with visual field defects in two young patients with a history of premature birth and periventricular leukomalacia (PVL).1 Magnetic resonance imaging demonstrated cerebral atrophy of the visual pathway which offers a biologically plausible explanation for previously-reported optic disc abnormalities2,3 The authors observed peripapillary retinal nerve fiber layer thinning that remained stable in one patient after 4 years. A second patient demonstrated similar optic nerve changes and corresponding visual field defects.
Although the authors describe these finding in only two patients, the implications for assessing the optic nerves of young patients with a history of very premature births are apparent. Physicians might wrongly diagnose “normal tension glaucoma” and initiate lifelong therapy to lower intraocular pressure (IOP), in the absence of the usual risk factors for primary open angle glaucoma. Knowing this association could inform physicians of a static condition that could be monitored with regular serial perimetric evaluations and optical coherence tomographic measurements of the peripapillary retinal nerve fiber layer and ganglion cell/inner plexiform layer before initiating IOP lowering treatment.
Additionally, Brodsky and coworkers describe cortical visual impairment associated with hypoxic-ischemic encephalopathy in seven children.4 They recommend neuro-imaging in patients with a clinical history of perinatal hypoxia-ischemia to identify antecedent brain malformation and timing of injury to guide patient management.
Other previously reported small case series have contributed to our understanding the pathophysiology of rare conditions in pediatric neuro-ophthalmology.5-7 Brodsky and coworkers described the fatal consequences of adrenal crisis in five children with septo-optic dysplasia (SOD), corticotropin deficiencies, fever, and dehydration associated with a presumed viral illness.5 Recognition of SOD in three infants with infection, jaundice, and hyponatremia was prompted by a high index of suspicion based on a complete ophthalmic examination.6 Donahue and associates recommended adding a fourth step to the Parks-Bielschowsky head tilt test to assess the ocular tilt reaction (OTR) based on 5 patients with suspected superior oblique palsies (SOP) 7 but without the excyclotorison of the hypertropic eye as would be expected in SOP. The authors noted tonic OTR consisting of vertical divergence of the eye (skew deviation), bilateral conjugate ocular torsion, and paradoxical head tilt. Widespread brainstem disease was the basis for OTR in all patients.
The clinical value of these reports is not based on principles of biostatistical inference. Astute clinicians have made novel observations and hypothesized links between findings and disease pathogenesis in ophthalmology. Gass described cystoid macular edema in three patients who had ingested large doses of vitamin B6 to reduce serum lipids.8 He proposed the pathogenesis of tears of the retinal pigment epithelium as a result of “subpigment epithelial choroidal neovascularization and not irregular separation of the basement membrane from its pigment epithelium ” in four patients.9 Irvine described the “prolapse of the vitreous into the anterior chamber with late rupture of the hyaloid face following intracapsular cataract extraction… [with] ultimate reduction of vision as a result of vitreous opacities or of macular degeneration.”
He observed these findings in 73 patients with vitreous adhesions.10 Gass later demonstrated fluorescein angiographic changes of cystoid macular edema in 44 patients after “uncomplicated cataract surgery” that was associated with pupillary peaking or distortion and adherence of vitreous to the wound.11
Brockhurst described the association of exudative choroidal effusions and non rhegmatogenous retinal detachments after glaucoma filtering surgery in 5 patients with nanophthalmos.12 His novel recognition of unusually thick sclera was the basis for facilitating drainage of the suprachoroidal fluid by dissecting the sclera around vortex veins.13 Dellporta described chorioretinal folds and papilledema in association with very low IOP after cataract surgery and cyclodialysis surgery in four aphakic eyes of three patients.14 With this understanding, Nuyt and coworkers developed surgical procedures to improve vision by increasing aqueous outflow resistance and raising IOP, thereby flattening the folds.15 Neither the hypothesis of the pathogenesis nor the meaning of the results of these therapeutic interventions were based on the results of clinical trials.
Intuition that hypothesizes a mechanism of injury and predicts a possible therapeutic option should not be construed as an excuse not to perform a valid clinical trial to establish the safety and efficacy of a new treatment. Rarely are novel medical or surgical therapeutic interventions curative or definitive. An exception was the acceptance of penicillin for the treatment pneumococcal pneumonia, a condition with an unusually high mortality, based on the survival of 43 of 46 patients.16 The vision saving results of pan retinal photocoagulation for the
treatment of proliferative retinopathy, suggested by several small case series,17,18 were the impetus for the first National Eye Institute sponsored randomized clinical trial, the Diabetic Retinopathy Study, that conclusively defined the benefit of this treatment.19 Small pilot studies described the possible benefit of anti-scarring drugs after trabeculectomy,20,21 but general acceptance awaited the results of the Fluorouracil Filtering Surgery Study clinical trial.22 It was not until 2017, 29 years after Brockhurst described that complications of cataract surgery in nanophthalmic eyes, that a randomized clinical trial demonstrated the value of prophylactic sclerostomy at the time of cataract surgery in reducing the rate of postoperative uveal effusions.23,24
The danger of misinterpreting the meaning of small case series by wrongly implying causality has been the subject of recent public attention.25 (A hedge fund manager and his wife are bankrolling the anti-vax movement – and having enormous impact. The Washington Post June 19, 2019 Accessed on June 21, 2019 https://s2.washingtonpost.com/camprw/?e=cmtwYXJyaXNoaWlAZ21haWwuY29t&s=5d0a6081fe1ff6190279d602&linknum=4&linkto t=69) The unsubstantiated effects of mumps-measles-rubella (MMR) vaccination on the development of autism continue to plague public health policy. A single report of 10 children with ileal-jejunal inflammation led to well intentioned, but misinformed parents boycotting vaccination of their children.26 Although ten of the 12 authors denounced the erroneous interpretation of the article in 2004,27 the editors of the Lancet did not print a retraction until 2010.28 “From June 1 to June 13, 2019, 1044 individual cases of measles were confirmed across 28 states. This was an increase of 22 cases from the previous week. This is the greatest
number of cases reported in the U.S. since 1992 and since measles was declared eliminated in 2000.” (https://www.cdc.gov/measles/cases-outbreaks.html Accessed June 20, 2019) The long-term effects of this emerging epidemic are unknown.
Recommending that ophthalmologists ask relevant questions to obtain accurate medical data, including prenatal histories, and perform thorough ophthalmic examinations for the purpose of defining baseline risks in a specific group of patients is different than advocating for an unproven new therapy or changing the standard of clinical care. As the authors point out, although the incidence of blindness related to ROP continues to decrease, the number of babies with PVL will likely increase. Children and young adults with similar histories and physical findings should have baseline examinations of the optic nerve and imaging studies to inform future diagnostic and therapeutic decisions.
1. Groth SL, Donohue SP, Reddy A, Sarma A, Wushensky C. Pseudo-glaucomatous cupping in patients with periventricular leukomalacia. Am J Ophthalmol 2019; (forthcoming). 2. Ho M-L, Mansukhani S, Brodsky. Prenatal or preinatal injury? Diagnosing the cortically blind infant. Am J Ophthalmol 2019; (forthcoming). 3. Brodsky MC, Conte FA, Taylor D, Hoyt CS, Mrak RE. Sudden death in septo-optic dysplasia. Report of 5 cases. Arch Ophthalmol 1997;115(1):66-70. 4. Donahue SP, Lavina A, Najjar J. Infantine infection and diabetes insipidus in children with optic nerve hypoplasia. Brit J Ophthalmol 2005;89(10):1275-1277. 5. Donahue SP, Lavin PJ, Hamed LM. Tonic ocular tilt reaction simulating a superior oblique palsy. Diagnostic confusion with the 3-stip test. Arch Ophthalmol 1999;117(3):347-352. 6. Olsen P, Paakko E, Vainionpaa L, Pyhtinen J, Jarvelin M-R. Magnetic resonance imaging of periventricular leukomalacia and its clinical correlation in children. Ann Neurol 1997;41(6):754-761. 7. Brodsky MC. Periventricular leukomalacia an intracranial cause of pseudoglaucomatous cupping. Arch Ophthalmol 2001:119(4):626-627. 8. Gass JDM. Nicotinic acid maculopathy. Am J Ophthalmol 1973;76(4):500-510. 9. Gass JDM. Pathogenesis of tears of the retinal pigment epithelium. Brit J Ophthalmol 1984;68(8):513-519. 10. Irvine ST. A newly defined vitreous syndrome following cataract surgery. Interpreted according to recent concept of the structure of the vitreous. The seventh Francis I. Proctor Lecture. Am J Ophthalmol 1953;36(5):599-619.
11. Gass JDM, Norton EWD. Cystoid macular edema and papilledema following cataract extraction. A fluorescein fundoscopy and angiographic study. Arch Ophthalmol 1966;76(5):646-661. 12. Brockhurst RJ. Nanophthalmos with uveal effusion: a new clinical entity. Trans Am Ophthalmol Soc 1974;72:371-403. 13. Brockhurst RJ. Vortex vein decompression for nanophthalmic uveal effusion. Arch Ophthalmol 1980;98(11):1987-1990. 14. Dellaporta A. Fundus changes in postoperative hypotony. Am J Ophthalmol 1955; 40(6):781-785. 15. Nuyts RMMA, Greve EL, Geijssen HC, Langerhost CT. Treatmetn of hypotonous maculopathy after trabeculectomy with mitomycin C. Am J Ophthalmol 1994;118(3):322-331. 16. Tillett WS, Cambrier MJ, McCormack JE. The treatment of lobar pneumonia and pneumococcal empyema with penicillin. Bull N Y Acad Med 1944;20(3)142-178. 17. Wetzig PC, Worlton JT. Treatment of diabetic retinopathy by light-coagulation. A preliminary study. Brit J Ophthalmol 1963;47(9):539-541. 18. Okun E, Cibis PA. The role of photocoagulation in the therapy of proliferative diabetic retinopathy. Arch Ophthalmol 1966;75(3):337-352. 19. Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976;81(4):383-396. 20. Chen C-W. Enhanced intraocular pressure controlling effectiveness of trabeculectomy by local application of mitomycin-C. Trans Asia-Pacific Acad Ophthalmol 1983;9:172-177.
21. Heuer DK, Parrish RK II, Gressel MG, Hodapp E, Palmberg PF, Anderson DR: 5-fluorouracil and glaucoma filtering surgery II. A Pilot Study. Ophthalmology 91(4):384-394,1984. 22. Fluorouracil Filtering Surgery Study Group. Five-year follow-up of the Fluorouracil Filtering Surgery Study. Am J Ophthalmol 1996;121(4):349-366. 23. Brockhurst RJ. Cataract surgery in nanophthalmic eyes. Arch Ophthalmol 1990;108(7):965-967. 24. Rajendrababu S, Babu N, Sinha S, Balakrishnan V, et al. A randomized controlled trial comparing outcomes of cataract surgery in nanophthalmos with and without prophylactic sclerostomy. Am J Ophthalmol 2017:183:125-133. 25. DeStefano F, Price CS, Weintraub ES. Increasing exposure to antibody-stimulating proteins and polysacchrarides in vaccines is not associated with risk of autism. J Pediatr 2013;163(2):561-567. 26. Wakefield AJ, Murch SH, Anthony A, Linnell j, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637-641. 27. Murch SH, Anthony A, Casson DH, Malik M, Berelowitz M, Dhillon AP et al. Retraction of an interpretation. Lancet 2004;363:750. 28. Editors of the Lancet. Retraction- Ileal-lymphoid -nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 2010;375:445.
S0002-9394(19)30530-6
DOI:
https://doi.org/10.1016/j.ajo.2019.10.027
Reference:
AJOPHT 11119
To appear in:
American Journal of Ophthalmology
Received Date: 30 October 2019 Accepted Date: 30 October 2019
Please cite this article as: Parrish II RK, Chang TC, Duncan Powers SL, The value and caveats of interpreting small case series – implications for patient care, American Journal of Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.10.027. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
The value and caveats of interpreting small case series – implications for patient care
Richard K. Parrish II1 Ta Chen Chang1 Sarah L. Duncan Powers2
1
University of Miami Miller School of Medicine, Department of Ophthalmology, Bascom Palmer
Eye Institute, Miami, Florida 2
American Journal of Ophthalmology, Saint Augustine, Florida
[email protected]
Purpose: To discuss the value and limitations of interpreting small case series for the purpose of understanding the pathophysiology of conditions affecting the visual system and how they may influence patient care decision making
Design: Selective review of English language ophthalmic articles published in peer review journals since 1950.
Methods: Author initiated PubMed Central query of small case series in glaucoma, pediatric neuro-ophthalmology, and diabetic retinopathy
Results: A review of well-known ophthalmic case studies by Gass, Irvine, Brockhurst and others show that small samples can provide suggestions to the skilled clinician for adding steps to the examination process when uncovering rare or previously unknown associated complications, as is the case for this perspective’s initiating studies by Groth and Brodsky. However, as shown by the now-retracted small case series in Lancet connecting MMR vaccinations with autism, small case series do not replace the value of clinical trials, with rare exception, when considering impacts to widespread, common clinical practice.
Conclusion: Small case series may contribute to an improved understanding of pathophysiology of rare ophthalmic conditions, but alone are insufficient to provide evidence for changing clinical practice of common eye diseases.
Groth and coworkers report the association of optic nerve cupping with visual field defects in two young patients with a history of premature birth and periventricular leukomalacia (PVL).1 Magnetic resonance imaging demonstrated cerebral atrophy of the visual pathway which offers a biologically plausible explanation for previously-reported optic disc abnormalities2,3 The authors observed peripapillary retinal nerve fiber layer thinning that remained stable in one patient after 4 years. A second patient demonstrated similar optic nerve changes and corresponding visual field defects.
Although the authors describe these finding in only two patients, the implications for assessing the optic nerves of young patients with a history of very premature births are apparent. Physicians might wrongly diagnose “normal tension glaucoma” and initiate lifelong therapy to lower intraocular pressure (IOP), in the absence of the usual risk factors for primary open angle glaucoma. Knowing this association could inform physicians of a static condition that could be monitored with regular serial perimetric evaluations and optical coherence tomographic measurements of the peripapillary retinal nerve fiber layer and ganglion cell/inner plexiform layer before initiating IOP lowering treatment.
Additionally, Brodsky and coworkers describe cortical visual impairment associated with hypoxic-ischemic encephalopathy in seven children.4 They recommend neuro-imaging in patients with a clinical history of perinatal hypoxia-ischemia to identify antecedent brain malformation and timing of injury to guide patient management.
Other previously reported small case series have contributed to our understanding the pathophysiology of rare conditions in pediatric neuro-ophthalmology.5-7 Brodsky and coworkers described the fatal consequences of adrenal crisis in five children with septo-optic dysplasia (SOD), corticotropin deficiencies, fever, and dehydration associated with a presumed viral illness.5 Recognition of SOD in three infants with infection, jaundice, and hyponatremia was prompted by a high index of suspicion based on a complete ophthalmic examination.6 Donahue and associates recommended adding a fourth step to the Parks-Bielschowsky head tilt test to assess the ocular tilt reaction (OTR) based on 5 patients with suspected superior oblique palsies (SOP) 7 but without the excyclotorison of the hypertropic eye as would be expected in SOP. The authors noted tonic OTR consisting of vertical divergence of the eye (skew deviation), bilateral conjugate ocular torsion, and paradoxical head tilt. Widespread brainstem disease was the basis for OTR in all patients.
The clinical value of these reports is not based on principles of biostatistical inference. Astute clinicians have made novel observations and hypothesized links between findings and disease pathogenesis in ophthalmology. Gass described cystoid macular edema in three patients who had ingested large doses of vitamin B6 to reduce serum lipids.8 He proposed the pathogenesis of tears of the retinal pigment epithelium as a result of “subpigment epithelial choroidal neovascularization and not irregular separation of the basement membrane from its pigment epithelium ” in four patients.9 Irvine described the “prolapse of the vitreous into the anterior chamber with late rupture of the hyaloid face following intracapsular cataract extraction… [with] ultimate reduction of vision as a result of vitreous opacities or of macular degeneration.”
He observed these findings in 73 patients with vitreous adhesions.10 Gass later demonstrated fluorescein angiographic changes of cystoid macular edema in 44 patients after “uncomplicated cataract surgery” that was associated with pupillary peaking or distortion and adherence of vitreous to the wound.11
Brockhurst described the association of exudative choroidal effusions and non rhegmatogenous retinal detachments after glaucoma filtering surgery in 5 patients with nanophthalmos.12 His novel recognition of unusually thick sclera was the basis for facilitating drainage of the suprachoroidal fluid by dissecting the sclera around vortex veins.13 Dellporta described chorioretinal folds and papilledema in association with very low IOP after cataract surgery and cyclodialysis surgery in four aphakic eyes of three patients.14 With this understanding, Nuyt and coworkers developed surgical procedures to improve vision by increasing aqueous outflow resistance and raising IOP, thereby flattening the folds.15 Neither the hypothesis of the pathogenesis nor the meaning of the results of these therapeutic interventions were based on the results of clinical trials.
Intuition that hypothesizes a mechanism of injury and predicts a possible therapeutic option should not be construed as an excuse not to perform a valid clinical trial to establish the safety and efficacy of a new treatment. Rarely are novel medical or surgical therapeutic interventions curative or definitive. An exception was the acceptance of penicillin for the treatment pneumococcal pneumonia, a condition with an unusually high mortality, based on the survival of 43 of 46 patients.16 The vision saving results of pan retinal photocoagulation for the
treatment of proliferative retinopathy, suggested by several small case series,17,18 were the impetus for the first National Eye Institute sponsored randomized clinical trial, the Diabetic Retinopathy Study, that conclusively defined the benefit of this treatment.19 Small pilot studies described the possible benefit of anti-scarring drugs after trabeculectomy,20,21 but general acceptance awaited the results of the Fluorouracil Filtering Surgery Study clinical trial.22 It was not until 2017, 29 years after Brockhurst described that complications of cataract surgery in nanophthalmic eyes, that a randomized clinical trial demonstrated the value of prophylactic sclerostomy at the time of cataract surgery in reducing the rate of postoperative uveal effusions.23,24
The danger of misinterpreting the meaning of small case series by wrongly implying causality has been the subject of recent public attention.25 (A hedge fund manager and his wife are bankrolling the anti-vax movement – and having enormous impact. The Washington Post June 19, 2019 Accessed on June 21, 2019 https://s2.washingtonpost.com/camprw/?e=cmtwYXJyaXNoaWlAZ21haWwuY29t&s=5d0a6081fe1ff6190279d602&linknum=4&linkto t=69) The unsubstantiated effects of mumps-measles-rubella (MMR) vaccination on the development of autism continue to plague public health policy. A single report of 10 children with ileal-jejunal inflammation led to well intentioned, but misinformed parents boycotting vaccination of their children.26 Although ten of the 12 authors denounced the erroneous interpretation of the article in 2004,27 the editors of the Lancet did not print a retraction until 2010.28 “From June 1 to June 13, 2019, 1044 individual cases of measles were confirmed across 28 states. This was an increase of 22 cases from the previous week. This is the greatest
number of cases reported in the U.S. since 1992 and since measles was declared eliminated in 2000.” (https://www.cdc.gov/measles/cases-outbreaks.html Accessed June 20, 2019) The long-term effects of this emerging epidemic are unknown.
Recommending that ophthalmologists ask relevant questions to obtain accurate medical data, including prenatal histories, and perform thorough ophthalmic examinations for the purpose of defining baseline risks in a specific group of patients is different than advocating for an unproven new therapy or changing the standard of clinical care. As the authors point out, although the incidence of blindness related to ROP continues to decrease, the number of babies with PVL will likely increase. Children and young adults with similar histories and physical findings should have baseline examinations of the optic nerve and imaging studies to inform future diagnostic and therapeutic decisions.
1. Groth SL, Donohue SP, Reddy A, Sarma A, Wushensky C. Pseudo-glaucomatous cupping in patients with periventricular leukomalacia. Am J Ophthalmol 2019; (forthcoming). 2. Ho M-L, Mansukhani S, Brodsky. Prenatal or preinatal injury? Diagnosing the cortically blind infant. Am J Ophthalmol 2019; (forthcoming). 3. Brodsky MC, Conte FA, Taylor D, Hoyt CS, Mrak RE. Sudden death in septo-optic dysplasia. Report of 5 cases. Arch Ophthalmol 1997;115(1):66-70. 4. Donahue SP, Lavina A, Najjar J. Infantine infection and diabetes insipidus in children with optic nerve hypoplasia. Brit J Ophthalmol 2005;89(10):1275-1277. 5. Donahue SP, Lavin PJ, Hamed LM. Tonic ocular tilt reaction simulating a superior oblique palsy. Diagnostic confusion with the 3-stip test. Arch Ophthalmol 1999;117(3):347-352. 6. Olsen P, Paakko E, Vainionpaa L, Pyhtinen J, Jarvelin M-R. Magnetic resonance imaging of periventricular leukomalacia and its clinical correlation in children. Ann Neurol 1997;41(6):754-761. 7. Brodsky MC. Periventricular leukomalacia an intracranial cause of pseudoglaucomatous cupping. Arch Ophthalmol 2001:119(4):626-627. 8. Gass JDM. Nicotinic acid maculopathy. Am J Ophthalmol 1973;76(4):500-510. 9. Gass JDM. Pathogenesis of tears of the retinal pigment epithelium. Brit J Ophthalmol 1984;68(8):513-519. 10. Irvine ST. A newly defined vitreous syndrome following cataract surgery. Interpreted according to recent concept of the structure of the vitreous. The seventh Francis I. Proctor Lecture. Am J Ophthalmol 1953;36(5):599-619.
11. Gass JDM, Norton EWD. Cystoid macular edema and papilledema following cataract extraction. A fluorescein fundoscopy and angiographic study. Arch Ophthalmol 1966;76(5):646-661. 12. Brockhurst RJ. Nanophthalmos with uveal effusion: a new clinical entity. Trans Am Ophthalmol Soc 1974;72:371-403. 13. Brockhurst RJ. Vortex vein decompression for nanophthalmic uveal effusion. Arch Ophthalmol 1980;98(11):1987-1990. 14. Dellaporta A. Fundus changes in postoperative hypotony. Am J Ophthalmol 1955; 40(6):781-785. 15. Nuyts RMMA, Greve EL, Geijssen HC, Langerhost CT. Treatmetn of hypotonous maculopathy after trabeculectomy with mitomycin C. Am J Ophthalmol 1994;118(3):322-331. 16. Tillett WS, Cambrier MJ, McCormack JE. The treatment of lobar pneumonia and pneumococcal empyema with penicillin. Bull N Y Acad Med 1944;20(3)142-178. 17. Wetzig PC, Worlton JT. Treatment of diabetic retinopathy by light-coagulation. A preliminary study. Brit J Ophthalmol 1963;47(9):539-541. 18. Okun E, Cibis PA. The role of photocoagulation in the therapy of proliferative diabetic retinopathy. Arch Ophthalmol 1966;75(3):337-352. 19. Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976;81(4):383-396. 20. Chen C-W. Enhanced intraocular pressure controlling effectiveness of trabeculectomy by local application of mitomycin-C. Trans Asia-Pacific Acad Ophthalmol 1983;9:172-177.
21. Heuer DK, Parrish RK II, Gressel MG, Hodapp E, Palmberg PF, Anderson DR: 5-fluorouracil and glaucoma filtering surgery II. A Pilot Study. Ophthalmology 91(4):384-394,1984. 22. Fluorouracil Filtering Surgery Study Group. Five-year follow-up of the Fluorouracil Filtering Surgery Study. Am J Ophthalmol 1996;121(4):349-366. 23. Brockhurst RJ. Cataract surgery in nanophthalmic eyes. Arch Ophthalmol 1990;108(7):965-967. 24. Rajendrababu S, Babu N, Sinha S, Balakrishnan V, et al. A randomized controlled trial comparing outcomes of cataract surgery in nanophthalmos with and without prophylactic sclerostomy. Am J Ophthalmol 2017:183:125-133. 25. DeStefano F, Price CS, Weintraub ES. Increasing exposure to antibody-stimulating proteins and polysacchrarides in vaccines is not associated with risk of autism. J Pediatr 2013;163(2):561-567. 26. Wakefield AJ, Murch SH, Anthony A, Linnell j, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637-641. 27. Murch SH, Anthony A, Casson DH, Malik M, Berelowitz M, Dhillon AP et al. Retraction of an interpretation. Lancet 2004;363:750. 28. Editors of the Lancet. Retraction- Ileal-lymphoid -nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 2010;375:445.