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Notice Medical knowledge is constantly changing. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the authors assume any liability for any injury and/or damage to persons or property arising from this publication. The Publisher
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Foreword When I first joined Robert Shaffer, MD and John Hetherington, MD in practice over 30 years ago, Dr Shaffer asked me if I would be interested in focusing on children with glaucoma. He had worked with Dr Barkan and had already developed a large practice in childhood glaucoma, especially the developmental form. That started a long-term interest in this fascinating, rewarding and sometimes discouraging disease. At one point we were seeing as many as one new case a week, which kept us all quite busy. I still see occasional patients on whom I operated 30 years ago who are seeing well and doing fine. That is very gratifying. As most young physicians, I started out focused on managing the disease but it soon became obvious that managing the family was equally important. Parents of children with developmental glaucoma are often filled with guilt, believing that something they did or did not do caused this terrible affliction that could blind their child. Solving the problem is, of course, the best solution, but helping the parents understand that they are blameless and that the most important thing they can do for their child is to give them lots of love is critical. Some of these patients will inevitably end up blind and they will function much better in the world if they grow up in a loving environment. Occasionally, after multiple surgeries and continued visual deterioration, the doctor and the parents are faced with the
difficult decision of whether to keep trying. Is the pain and risk of another operation worth it? A psychologist told me many years ago that a child who retains vision till the age of six or beyond will have visual memories that improve his later functioning. These points are nicely made in the conclusion to Chapter 10. Fortunately, these decisions are less common with the advent of antifibrosis agents and drainage implants. At some point however, it may be best to quit. The parents will have to be led to this most difficult decision by the physician. Finally, experience counts. It is often the first operation that determines the outcome in these children and whenever possible it should be done by an experienced surgeon or team. Since these tend to be rare cases and patients cannot always travel, that will not always be possible. This book will help physicians manage the process of doing the right thing for the right diagnosis at the right time. I offer my congratulations and thanks to Drs Mandal and Netland for providing all this information in a wonderfully organized and illustrated text that clarifies the diagnosis and treatment of the many forms of childhood glaucoma. I wish it had been available 35 years ago.
H. Dunbar Hoskins, Jr MD
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Preface The idea for this book originated from patient care. The effort to manage the clinical problems in children with glaucoma revealed the need for up-to-date and organized information about the topic. Over the years, we have met and discussed these problems at length. Our previous writings provided the backbone for this work. We organized our material for an Instruction Course at the American Academy of Ophthalmology, which crystallized our thoughts about the topic. We have attempted to present evidence-based information about the topic, while providing perspectives from clinical experiences. Other excellent textbooks have appeared in the
past, but are sufficiently outdated to create a need for this book. Significant advances have occurred in genetics, medical therapy, surgical management, and other topics included here. This book is intended for clinicians who care for pediatric glaucoma patients, including, in particular, glaucoma and pediatric subspecialists. We hope that other practitioners who have contact with pediatric glaucoma patients will find value in it, and that ophthalmology residents and subspecialty trainees will benefit from this information. Anil K. Mandal, MD Peter A. Netland, MD, PhD
Drs Mandal and Netland perform Koeppe gonioscopy during an examination under sedation.
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Acknowledgments We are deeply indebted to our patients, as well as our patients’ parents and families. Caring for these patients has been a group effort, and we appreciate all of the individuals on the ‘team.’ We are also grateful to our families, friends, mentors, and colleagues who provided support and guidance. Medical Publisher Karen Oberheim provided critical early support for the project, as did Senior Editor Natasha Andjelkovic and Assistant Editor Andrea P. Sherman. Joseph Mastellone and Stephen Moser assisted with photography. Jerry Harris at St. Jude Children’s Research Hospital provided assistance with graphic arts. We are especially thankful for the expert assistance of Mary E. Smith, Vijaya K. Gothwal, Anita Fernandez and Joyce Solomon. We thank Richard D. and Gail S. Siegal for their support. We would like to thank the copyeditor, Alison Woodhouse, the proofreader, J. Ian Ross, the indexer, Liza Furnival, and the illustrator Richard Tibbitts. Elsevier provided excellent publishing support through the efforts of Senior Editor Paul Fam, Project Development Manager Amy Head, Project Manager Kathryn Mason, Designer Andy Chapman, Illustration Manager Mick Ruddy and Product Managers Lisa Damico and Gaynor Jones.
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To my loving parents, Jayalaxmi and Manik, who instilled in me the desire to learn and the enjoyment of teaching and my wife, Vijaya, for her constant help and encouragement in this endeavour. Anil K. Mandal
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To my patients and their families, my colleagues and trainees, and my supportive family and friends. Peter A. Netland
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Light, my light, the world-filling light, the eye-kissing light, heart-sweetening light! Ah, the light dances at the center of my life... The butterflies spread their sails on the sea of light. Lilies and jasmines surge up on the crest of the waves of light. The light is shattered into gold on every cloud and it scatters gems in profusion. Mirth spreads from leaf to leaf and gladness without measure. The heaven’s river has drowned its banks and the flood of joy is abroad. From Gitanjali, Number 57 Rabindranath Tagore, Nobel Laureate 1913
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Chapter 1 Historical perspective of developmental glaucomas Introduction Goniotomy Description of the clinical entity Microsurgery and trabeculotomy
Introduction Congenital enlargement of the eye has been recognized since the time of Hippocrates (460–377 BC), Celsus (1st century AD), and Galen (130–201 AD), although buphthalmos or hydrophthalmos were not related to elevated intraocular pressure until the middle of the 18th century. Increased intraocular pressure was mentioned by Berger (1744), but was grouped together with a variety of heterogenous conditions varying from high myopia to anterior staphyloma and anterior megaophthalmos. In 1869, Von Muralt (1869) established the classical type of buphthalmos within the family of glaucoma. Both he and Von Graefe (1869) considered that the enlargement of the cornea was the primary phenomenon, but believed that the clinical picture with its rise of tension was due to a primary intraocular inflammation. Pathological studies of the late 1800s and early 1900s had detected congenital anomalies in the anterior chamber angle or the absence of Schlemm’s canal. These anomalies were confirmed by Von Hippel (1897), Parsons (1904), and Siegrist (1905). Exhaustive anatomical descriptions appeared in the early to middle 1900s by Gros (1897), Reis (1905–11), Seefelder (1906–1920), and others who demonstrated a number of different malformations of the angle structures as the primary abnormality, with inflammation playing a secondary role.
The poor prognosis of infantile glaucoma changed dramatically in 19382 with the introduction of goniotomy (Greek: gonio = angle + tomein = to cut) by Otto Barkan (Fig. 1.1) who revived the Italian surgeon de Vincentis’ operation (1892), which ‘incised the angle of the iris in glaucoma.’ Otto Barkan modified de Vincentis’ operation by using a specially designed glass contact lens to visualize angle structures while using a knife to create an internal cleft in the trabecular tissue.3 He called the operation goniotomy and reported several successfully treated cases in congenital glaucoma.4,5 Although instrumentation has since been refined and the operating microscope now permits more precise visualization of the angle structures, the operation has remained essentially unchanged. In 1949, Barkan described a persisting fetal membrane overlying the trabecular meshwork.5 This was confirmed by Worst (1966) who termed it ‘Barkan’s membrane.’6 Recent pathological studies by Anderson,7–9 Hansson,10 Maul and co-workers,11 and Maumenee12 could find no evidence of a membrane in any of the specimens they examined by light or electron microscopy. Despite this evidence, Worst stated that ‘though histopathological proof of this structure is almost completely lacking . . . this has little influence on the probability that this concept is valid.’13
Goniotomy As late as 1939, Anderson1 saw little hope for preservation of useful vision in these patients. Despite a detailed evaluation of all known treatment modalities available at that time, he stated that ‘one seeks in vain for a best operation in the treatment of hydrophthalmia.’ He further wrote: The future of patients with hydrophthalmia is dark. Little hope of preserving sufficient sight to permit the earning of a livelihood can be held out to them. It progresses, as a rule, in a relentless fashion until the best setting for the patient is some institution that caters for the blind.
Figure 1.1 Otto Barkan (1887–1958). Reprinted with permission from Cordes FC, Otto Barkan, MD. Trans Am Ophthalmol Soc 1958; 56:3–4.
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Historical perspective of developmental glaucomas
Description of the clinical entity A few classic textbooks that have been written on the subject include Hydrophthalmia or Congenital Glaucoma (Anderson, 1939),1 Congenital and Pediatric Glaucomas (Shaffer and Weiss, 1970),14 and Glaucoma in Infants and Children (Kwitko, 1973).15 Sir Stewart Duke-Elder (1963) wrote: Buphthalmos (hydrophthalmos) is the condition wherein developmental abnormalities offer an obstruction to the drainage of the intra-ocular fluids so that the pressure of the eye is raised and a condition of congenital glaucoma results. The essential clinical feature of the anomaly is that the coats of the eye are of sufficient plasticity to stretch under this increment of pressure with the results that the whole globe enlarges, producing an appearance which is said to resemble the eye of an ox.16 Primary congenital glaucoma was described by Shaffer and Weiss (1970) as a specific syndrome as follows: The most common hereditary glaucoma of childhood, inherited as an autosomal recessive pattern, with a specific angle anomaly consisting of absence of angle recess with iris insertion directly into the trabecular surface. There are no other major abnormalities of development. Corneal enlargement, clouding, and tears in Descemet’s membrane result from elevated intraocular pressure.14 Now it is firmly established that developmental glaucoma has as its hallmark fetal maldevelopment of the iridocorneal angle or goniodysgenesis.17 The anomalies of the angle include trabeculodysgenesis, iridodysgenesis, and corneodysgenesis, either singly or in some combination. The classic defect found in primary congenital glaucoma is isolated trabeculodysgenesis without any evidence of other iris or corneal malformation. Initial efforts at classification were directed toward eponyms and syndrome names, and many of these terms are now widely employed and recognized. The Shaffer–Weiss (1970) disease classification divides the developmental glaucomas into primary congenital glaucoma, glaucomas associated with developmental anomalies of the eye or the body, and acquired glaucomas.14,18 Recently, an excellent classification system has been described by Hoskins, Shaffer, and Hetherington (1984), which uses clinically identifiable anatomical defects of the eye as the basis of classification.19,20
Microsurgery and trabeculotomy The classic operation for the treatment of primary congenital glaucoma was Barkan’s goniotomy,2 although there has been increasing use of a newer approach, trabeculotomy ab externo. This procedure was simultaneously and independently described by Burian21,22 and Smith23 in 1960. In March, 1960, without the aid of an operating microscope, the first external trabeculotomy was performed by Burian on a young girl with Marfan’s syndrome and glaucoma.21 After 2 years, Allen and Burian published another paper on 2
trabeculotomy ab externo.22 At about the same time (1960) in London, Redmond Smith, an early microsurgeon, developed an operation that he called ‘nylon filament trabeculotomy.’23 This involved cannulating Schlemm’s canal with a nylon suture at one site, threading the suture circumferentially, withdrawing it at another site, and pulling it tight like a bowstring. The surgical technique of trabeculotomy ab externo is basically a combination of that originally evoked by Burian and Smith and modified by Harms (1969),24,25 Dannheim (1971)26,27 and McPherson (1973).28–30 Following World War II, the Zeiss Optical Instrument Company relocated to southern Germany near the ancient university town of Tubingen. Seeking to develop new markets and products, Zeiss approached Harms, who told him ideas for an ophthalmic operating microscope. A prototype was produced, and the era of ophthalmic microsurgery began. In 1966 Harms organized the First International Symposium of the Microsurgery Study Group in Tubingen. Among the ophthalmologists in attendance was Samuel D. McPherson, Jr., of Durham, NC. Impressed by the excellent results being claimed for external trabeculotomy, McPherson remained after the symposium to observe Harms in surgery and learn the procedure. McPherson then became the ophthalmologist most associated with the procedure in the United States and its most prolific proponent in the American ophthalmic literature.28–31 Throughout the 1960s, the popularity of external trabeculotomy grew in Europe. By the Second International Symposium of the Microsurgery Study Group in Burgenstock in 1968, the procedure was widely used throughout Europe. When Harms and Allen eventually met, Allen was the first to tell Harms of the Iowa City work. Although astonished, Harms thereafter gave Burian and Allen credit for the first description of the procedure. The introduction of the microsurgical techniques as exemplified by trabeculotomy revolutionized the prognosis for patients with primary congenital glaucoma, with most studies citing an initial success rate of 80–90%.24,28–37 Trabeculotomy ab externo38–39 and goniotomy40 remain as the preferred initial procedure in the surgical management of primary infantile glaucoma. The need for ‘glaucoma enucleations’ has markedly decreased over the last 50 years, with enucleation for open-angle glaucoma (including congenital glaucoma) now almost fallen into oblivion.41 During the last 50 years, ophthalmological care has improved, various pressure-lowering and antiinflammatory drugs have been developed, new surgical techniques have been introduced, and, probably most importantly, the operating microscope has been incorporated into clinical practice. These advances have enhanced the efficacy of treatment while minimizing complications, which has improved greatly the prognosis for congenital glaucoma.
References 1. Anderson JR. Hydrophthalmia or congenital glaucoma: its causes, treatment, and outlook. Cambridge University Press: London; 1939. 2. Barkan O. Technique of goniotomy. Arch Ophthalmol 1938; 19:217–221.
References 3. Barkan O. Goniotomy knife and surgical contact glasses. Arch Ophthalmol 1950; 44:431–433. 4. Barkan O. Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol 1948; 32:701. 5. Barkan O. Technic of goniotomy for congenital glaucoma. Arch Ophthalmol 1949; 41:65. 6. Worst JGF. The pathogenesis of congenital glaucoma. Royal Van Gorcum: Assen, Netherlands; 1966. 7. Anderson DR. Pathology of the glaucomas. Br J Opthalmol 1972; 56:146–157. 8. Anderson DR. The pathogenesis of primary congenital glaucoma, presented at Third Meeting of Pan-American Glaucoma Society, Miami, Florida, Feb 29, 1979. 9. Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–485. 10. Hansson HA, Jerndal T. Scanning electron microscopic studies of the development of the iridocorneal angle in human eyes. Invest Ophthalmol 1971; 10:252–265. 11. Maul E, Strozzi L, Munoz C, Reys C. The outflow pathway in congenital glaucoma. Am J Ophthalmol 1980; 89:667–673. 12. Maumenee AE. The pathogenesis of congenital glaucoma: a new theory. Trans Am Acad Ophthalmol 1958; 56:507–570. 13. Worst JGF. Congenital glaucoma. Remarks on the aspect of chamber angle, ontogenic and pathogenic background and mode of action of goniotomy. Invest Ophthalmol 1968; 7:127–134. 14. Shaffer RN, Weiss DI. Congenital and paediatric glaucomas. CV Mosby: St. Louis; 1970. 15. Kwitko ML. Glaucoma in infants and children. Appleton-Century, Crofts: Philadelphia; 1973. 16. Duke-Elder S. System of ophthalmology, Vol III, pt 2, Congenital deformities. CV Mosby: St. Louis; 1963:548–565. 17. Jerndal T, Hansson HA, Bill A. Goniodygenesis – a new perspective on glaucoma. Scriptor: Copenhagen; 1978. 18. Hoskins HD Jr, Kass M. Becker-Scheffer’s diagnosis and therapy of the glaucomas, 6th edn. CV Mosby: St, Louis; 1989:356. 19. Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classification of the developmental glaucomas. Arch Ophthalmol 1984; 102:1331–1336. 20. Hoskins HD Jr, Hetherington J Jr, Shaffer RN, Welling AM. Developmental glaucomas: diagnosis and classification. Symposium on glaucoma: transactions of the New Orleans Academy of Ophthalmology. CV Mosby: St Louis; 1981:172–190. 21. Burian HM. A case of Marfan’s syndrome with bilateral glaucoma. With a description of a new type of operation for developmental glaucoma (trabeculotomy ab externo). Am J Ophthalmol 1960; 50:1187–1192. 22. Allen L, Burian HM. Trabeculotomy ab externo. A new glaucoma operation. Technique and results of experimental surgery. Am J Ophthalmol 1962; 53:19–26.
23. Smith R. A new technique for opening the canal of Schlemm. Preliminary report. Br J Ophthalmol 1960; 44:370–373. 24. Harms H, Dannehim R. Epicritical consideration of 300 cases of trabeculotomy ab externo. Trans Ophthalmol Soc UK 1969; 89:491–499. 25. Harms H, Dannheim R. Trabeculotomy results and problems. In: Machensen G, ed. Microsurgery in Glaucoma. Second International Symposium of the Ophthalmic Micro-Surgery Study Group. Burgenstock, 1968. Adv Ophthalmol 1970; 22:121–130. 26. Dannheim R. Symposium: microsurgery of the outflow channels. Trabeculotomy. Trans Am Acad Ophthalmol Otolaryngol 1972; 76:375–383. 27. Dannheim R. Synposium: microsyrgery of the outflow channels. Trabeculotomy. Techniques and results. Arch Chili Oftal 1971; 28:149–157. 28. McPherson SD Jr. Results of external trabeculotomy. Am J Ophthalmol 1973; 76:918–920. 29. McPherson SD Jr, McFarland D. External trabeculotomy for developmental glaucoma. Ophthalmology 1980; 87:302–305. 30. McPherson SD Jr, Berry DP. Goniotomy vs external trabeculotomy for developmental glaucoma. Am J Ophthalmol 1983; 95:427–431. 31. McPherson SD, Cline JW, McCurdy D. Recent advances in glaucoma surgery, trabeculotomy, and trabeculectomy. Am Ophthalmol 1977; 9:91–96. 32. Luntz MH. Primary buphthalmos (infantile glaucoma) treated by trabeculotomy ab externo. S Afr Arch Ophthalmol 1974; 2:319–334. 33. Luntz MH, Livingston DG. Trabeculotomy ab externo and trabeculectomy in congenital and adult-onset glaucoma. Am J Ophthalmol 1977; 83:174–179. 34. Quigley HA. Childhood glaucoma: results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–225. 35. Anderson DR. In discussion of Quigley HA: Childhood glaucoma. Ophthalmology 1982; 89:225–226. 36. Hoskins HD Jr, Hetherington J Jr, Shaffer RN, Welling AM. Developmental glaucoma: therapy. Proceedings of the New Orleans Academy of Ophthalmology Glaucoma Symposium. CV Mosby: St. Louis; 1981:191–202. 37. Gregersen E, Kessing SVV. Congenital glaucoma before and after the introduction of microsurgery. Results of ‘macrosurgery’ 1943–1963 and of ‘microsurgery’ (trabeculotomy/ectomy) 1970–1974. Acta Ophthalmol 1977; 55:422–430. 38. Luntz MH. The advantages of trabeculotomy over goniotomy. J Pediatr Ophthalmol Strabismus 1984; 21:150–153. 39. Hoskins HD Jr, Shaffer RN, Hetherington J. Goniotomy vs trabeculotomy. J Pediatr Ophthalmol Strabismus 1984; 21:153–158. 40. Walton DS. Goniotomy. In: Thomas JV, Belcher CD III, Simmons RJ, eds. Glaucoma surgery, Chapter 11. Mosby Year Book: St. Louis; 1992:107–121. 41. Rohrbach JM, Schlote T, Thiel HJ. Wolfgang Stock, his ophthalmopathologic collection and progress in glaucoma treatment in the 2nd half of the 20th century. Klin Monatsbl Augenheilkd 1998; 213:87–92.
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Chapter 2 Terminology and classification of developmental glaucomas Introduction Terminology Classification Neurocristopathies Conclusion
Introduction The glaucomas that occur at birth or as a result of improper ocular development have been called by many names indicating a variety of structural changes, etiologic factors, inheritance patterns, prognoses and preferred treatments. The terminology used in the literature to describe these rare diseases is confusing and inconsistent. In infancy, elevated intraocular pressure alters the anterior segment in a way that obscures the structural defects responsible for the glaucoma. Also, terms that have general meanings have been employed to describe specific syndromes. Familiarity with terminology and classification systems used to describe the developmental glaucomas is important for clinicians who encounter these patients.
Terminology Different terms have been used to describe glaucoma in infants and children. These are either general terms, terminology related to the age of onset, or terms related to the presumed cause of the glaucoma.
General terms Buphthalmos (Greek: bous = ox + ophthalmos = eye) is derived from the Greek term for ‘ox-eye’, and refers to the marked enlargement that can occur as a result of any type of glaucoma present in infancy. Hydrophthalmia (Greek: hydor = water + ophthalmos = eye) refers to the high fluid content present with marked enlargement of an eye, which can occur in any type of glaucoma presenting in infancy. Buphthalmos and hydrophthalmia are both descriptive terms that do not imply etiology or appropriate therapy, and these terms should not be used diagnostically.
Terminology relating to age of onset In congenital glaucoma, the glaucoma exists at birth, and usually before birth. Infantile glaucoma occurs from birth
until 3 years of life. Juvenile glaucoma occurs after the age of 3 to teenage years. These terms relate to the age at onset of signs and symptoms of glaucoma and do not imply etiologic factor or inheritance pattern of the glaucoma.
Developmental glaucoma Developmental glaucoma refers to glaucoma associated with developmental anomalies of the eye present at birth. This is a broad term that encompasses most of the glaucomas in infants and children. Primary developmental glaucoma refers to glaucoma resulting from maldevelopment of the aqueous outflow system. Secondary developmental glaucoma indicates glaucoma resulting from damage to the aqueous outflow system due to maldevelopment of some other portion of the eye. Secondary developmental glaucoma may, for example, present as angle closure due to pupillary block in a small eye, an eye with micropherophakia, or an eye with a dislocated lens; or it may present as a forward shift of the lens-iris diaphragm as occurs in persistent hyperplastic primary vitreous or retinopathy of prematurity.
Terminology relating to structural maldevelopment Goniodysgenesis indicates fetal maldevelopment of the iridocorneal angle.1 Trabeculodysgenesis is maldevelopment of the trabecular meshwork, iridodysgenesis is maldevelopment of the iris, and corneodysgenesis is maldevelopment of the cornea. These may present either singly or in some combination. Isolated trabeculodysgenesis is the hallmark of primary developmental glaucoma.
Primary congenital glaucoma Primary congenital glaucoma was described by Shaffer and Weiss2 as follows: The most common hereditary glaucoma of childhood, inherited as an autosomal recessive pattern, with a specific angle anomaly consisting of absence of angle recess with iris insertion directly into the trabecular surface. There are no other major abnormalities of development. Corneal enlargement, clouding and tears in Descemet’s membrane result from elevated intraocular pressure. In many areas of the world this term is used synonymously with infantile glaucoma to designate this particular syndrome 5
Terminology and classification defined by Shaffer and Weiss. In other areas, however, the term infantile retains its intended meaning, indicating glaucoma occurring at birth.3
Table 2.2 DeLuise–Anderson (1983) classification of congenital and infantile glaucoma
Classification
2. Secondary infantile glaucoma
Various classifications of the developmental glaucomas have been employed. Initial efforts at classification were directed toward eponyms and syndrome names, and many of these terms are now widely employed and recognized. The Shaffer– Weiss (1970) disease classification divides the developmental glaucomas into primary congenital glaucoma, glaucomas associated with congenital anomalies of the eye or the body, and acquired glaucomas (Table 2.1).2,4 This system uses commonly known syndrome or eponym names for the developmental glaucomas, which can be used for most glaucomas in the pediatric age group. Some patients with developmental glaucomas may be difficult to categorize due to unusual or overlapping features. One type of glaucoma not mentioned in the Shaffer–Weiss classification is glaucoma associated with aphakia. DeLuise and Anderson (1983)5 classified the congenital and infantile glaucomas as primary or secondary infantile glaucomas. The secondary infantile glaucomas were associated with different variables (Table 2.2). This system circumvented the need to differentiate between potentially confusing syndromes that had been grouped on the basis of superficial characteristics.
1. Primary infantile glaucoma (congenital glaucoma, trabeculodysgenesis) A. Associated with mesodermal neural crest dysgenesis 1. Iridocorneotrabeculodysgenesis a. Axenfeld’s anomaly b. Rieger’s anomaly c. Peters anomaly d. Systemic hypoplastic mesodermal dysgenesis (Marfan’s syndrome) e. Systemic hyperplastic mesodermal dysgenesis (Weill– marchesani syndrome) 2. Iridotrabeculodysgenesis (aniridia) B. Associated with phakomatoses and hamartomas 1. Neurofibromatosis (Von Recklinghausen’s disease) 2. Encephalotrigeminal angiomatosis (Sturge–Weber syndrome) 3. Angiomatosis retinae (von Hippel-Lindau syndrome) 4. Oculodermal melanocytosis (Nevus of Ota) C. Associated with metabolic disease 1. Oculocerbrorenal syndrome (Lowe’s syndrome) 2. Homocystinurea D. Associated with inflammatory disease 1. Maternal rubella syndrome (congenital rubella) 2. Herpes simplex iridocyclitis E. Associated with mitotic disease 1. Juvenile xanthogranuloma (nevoxanthoendothelioma)
Table 2.1 Shaffer–Weiss (1970) classification of congenital glaucoma I. Primary congenital glaucoma (primary infantile glaucoma) II. Glaucoma associated with congenital anomalies A. Late developing primary infantile glaucoma (late developing primary congenital glaucoma)
2. Retinoblastoma F. Associated with other congenital disease 1. Trisomy 13-15 syndrome (Patau’s syndrome) 2. Rubinstein–Taybi syndrome 3. Persistent hyperplastic primary vitreous
C. Sturge–Weber syndrome D. Neurofibromatosis E. Marfan’s syndrome F. Pierre Robin syndrome G. Homocystinuria H. Goniodysgenesis (iridocorneal neural crest cell dysgenesis: Axenfeld–Reiger syndrome, Peters anomaly) I. Lowe’s syndrome J. Microcornea K. Microspherophakia L. Rubella M. Chromosomal abnormalities N. Broad thumb syndrome O. Persistent hyperplastic primary vitreous III. Secondary glaucomas in infants A. Retinopathy of prematurity B. Tumors 1. Retinoblastoma 2. Juvenile xanthogranuloma C. Inflammation D. Trauma
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An anatomic classification of the developmental glaucomas has been proposed by Hoskins, Shaffer, and Hetherington (1984).6 Clinically identifiable anatomical defects of the eye were chosen as the basis for this classification because they were readily apparent on examination of the patient (Table 2.3). This system categorizes developmental glaucoma more precisely, but does not apply to glaucomas that occur in the absence of a developmental anomaly of the eye. Certain cases, however, can only be described by anatomical defects. In addition, this classification does have prognostic implications. Isolated trabeculodysgenesis, for example, responds more favorably to surgical intervention compared with trabeculodysgenesis associated with iris or corneal anomalies. In the Hoskins–Shaffer–Hetherington system, defects are classified anatomically according to the three major anterior chamber structures affected: the trabecular meshwork, the iris, and the cornea. Trabeculodysgenesis is defined as maldevelopment of the trabecular meshwork, including the iridotrabecular junction, since the trabecular meshwork is
Classification
Table 2.3 Hoskins–Shaffer–Hetherington (1984) classification of the developmental glaucomas I.
Isolated trabeculodysgenesis (malformation of trabecular meshwork in the absence of iris or corneal anomalies) A. Flat iris insertion 1. Anterior insertion 2. Posterior insertion 3. Mixed insertion B. Concave (wrap-around) iris insertion C. Unclassified
II. Iridotrabeculodysgenesis (trabeculodysgenesis with iris anomalies) A. Anterior stromal defects 1. Hypoplasia 2. Hyperplasia B. Anomalous iris vessels 1. Persistence of tunica vasculosa lentis
the trabecular surface, and the surface of the trabecular meshwork may have a stippled, orange peel appearance. The peripheral anterior iris stroma may be thinned, but the corneal stroma and the iris collarette appear normal. In the concave (‘wrap-around’) iris insertion, the plane of iris is well posterior to the normal position of the scleral spur. However, the anterior iris stroma continues upward and over the trabecular meshwork, obscuring the scleral spur and ending just short of Schwalbe’s line. Thus, the iris sweeps around the angle, forming a concave or ‘wrap-around’ insertion. This is most easily recognized in brown irides, and is much less common than flat iris insertion. The trabeculodysgenesis in some eyes cannot be classified because of corneal clouding or previous surgery. There is no evidence of other iris or corneal malformation in isolated trabeculodysgenesis. The elevated intraocular pressure, however, may cause secondary stretching of these structures.
2. Anomalous superficial vessels C. Structural anomalies
Iridotrabeculodysgenesis
1. Holes 2. Colobomata 3. Aniridia III. Corneoiridotrabeculodysgenesis (malformation meshwork with iris and corneal anomalies)
of
trabecular
A. Peripheral B. Midperipheral C. Central D. Corneal size
formed during separation of the iris from the cornea. Isolated trabeculodysgenesis7 occurs in the absence of developmental anomalies of the iris or cornea. This is the hallmark of primary developmental glaucoma (primary congenital glaucoma) and is the only detectable ocular anomaly in approximately 50% of the infants and juvenile patients with glaucoma.
Trabeculodysgenesis Trabeculodysgenesis occurs in two major forms, distinguished primarily by the appearance of the iridotrabecular junction: flat iris insertion and concave (‘wrap-around’) iris insertion. In the flat iris insertion, patients have an iridotrabecular junction in which the iris appears to insert flatly and abruptly into a thickened trabecular meshwork. The plane of the iris is flat, and the iris tissue stops abruptly where the iris joins the trabeculum. The level of iris insertion may vary along the angle circumference, even posterior to the scleral spur. An anterior insertion, into the trabecular meshwork or anterior to the scleral spur, is the most common type of developmental glaucoma. An anterior insertion usually obscures the view of the ciliary body, although it is possible to see pigmented portion of the anterior ciliary body through a thickened trabecular meshwork when the angle is viewed obliquely from above. Small iris processes may extend onto
In iridotrabeculodysgenesis, malformation of the trabecular meshwork is accompanied by maldevelopment of the iris. Iridodysgenesis or maldevelopment of the iris is subdivided into anterior stromal defects, anomalous iris vessels, and structural anomalies. The anterior stromal defect category includes hypoplasia of the anterior iris stroma, which is the most common iris defect associated with developmental glaucoma. Because the normal infant eye has some peripheral thinning of the iris and because stretching of the iris from pressure can further thin the anterior stroma, diagnosis of true hypoplasia of the anterior stroma should be made only when there is clearly a malformation of the collarette with absence or marked reduction of the crypt layer. The defect, when present, is easily recognized. The sphincter muscle is quite obvious, whereas the iris collarette is either absent or is formed only in the far periphery. Twigs of iris stroma may be seen scattered over the surface of the iris. The iris may insert anteriorly at the level of the scleral spur, and the trabecular meshwork may appear to be thickened. An absent or poorly developed anterior iris stroma has been described as a common finding in Axenfeld’s anomaly and Rieger’s anomaly.2,8 This defect, when occurring by itself, is typical of familial hypoplasia of the iris with glaucoma.1,9,10 It should not be confused with primary congenital glaucoma since the hypoplastic iris syndrome is dominantly inherited. In hyperplasia of the anterior iris stroma, excessive anterior iris stroma appears as a diffuse thickening of the brown iris covered with abundant small nodules, giving the iris surface a cobblestone appearance. In the series reported by Hoskins et al,6 there were only two cases, both of which were associated with Sturge–Weber syndrome and developmental glaucoma. Vascular anomalies of the iris are divided into those with some form of persistence of the tunica vasculosa lentis, and those with irregularly wandering anomalous superficial vessels. Persistence of tunica vasculosa lentis is characterized by the regular arrangement of the vessels looping into the 7
Terminology and classification pupillary axis either in front of or behind the lens. The normal radial vessels of the iris surface are also prominent because this condition is usually accompanied by hypoplasia of the anterior iris stroma. In anomalous superficial vessels, the vessels wander irregularly over the iris surface, and the pupil is usually distorted. The iris surface has a whorled appearance because of the curving of the radial fibers of the iris. The anterior iris stroma is often hypoplastic. These vascular patterns must be differentiated from exposure of the radial iris vessels that may exist in normal blue-eyed infants or in eyes with hypoplasia of the anterior iris stroma. In such eyes, there is no vascular anomaly even though the vessels are easily seen. Also, the term rubeosis does not apply, because the vessels exist at birth and do not represent neovascularization. Anomalous vessels of the iris are seen most frequently in eyes presenting with glaucoma and cloudy corneas at birth and represent a more severe malformation of the anterior segment. These eyes behave quite differently from eyes whose only structural defect is trabeculodysgenesis. These patients have a poor prognosis for initial surgical treatment and usually require multiple surgeries. The type of iridodysgenesis characterized by structural anomalies or structural iris defects is easily identified by clinical examination. The anatomic defect may present in several different ways. Holes present as a full thickness opening in the iris without sphincter involvement, as seen in Rieger’s anomaly. Colobomata cause full-thickness defects of the sphincter. In aniridia, most of the iris and all of the sphincter is missing.
Corneoiridotrabeculodysgenesis Although the cornea certainly changes under the influence of elevated intraocular pressure, it may also be the site of a primary malformation. Usually a combination of iris, corneal, and trabecular dysgeneses results in glaucoma. Most commonly there are iridocorneal adhesions, hypoplasia of the anterior iris stroma, and some form of corneal opacity or structural change. For classification purposes, corneal defects are grouped according to their location as peripheral lesions, midperipheral lesions, and central lesions. Glaucoma may also be associated with abnormalities of corneal size, including microcornea and macrocornea. Peripheral corneal lesions occur adjacent to and concentric with the limbus and extend no more than 2 mm into clear cornea. Generally, these changes involve the entire circumference of the cornea and are often seen as posterior embryotoxon with adherent iris tissue (e.g., Axenfeld’s anomaly). Midperipheral lesions usually involve a sector of the cornea and are almost always opacities with iris adhesions. The iris is quite dysgenetic, manifested by hypoplasia of the stroma, hole formation, and pupillary abnormalities (e.g., Rieger’s anomaly). Central corneal anomalies are usually opacities, often with central stromal thinning. Hoskins et al (1984)6 reported two cases with a hole through the cornea, draining aqueous. Most central lesions are round, with associated iris adhesions between the collarette and the margin of the opacity, and have a clear zone separating the lesion from 8
the limbus (e.g., Peters anomaly). Occasionally, maldevelopment of the central portion of the cornea causes adhesions between the lens, iris, and cornea with no anterior chamber formation (e.g., anterior chamber cleavage syndrome, anterior staphyloma). This is an extreme form of central iridocorneodysgenesis. Patients with developmental glaucoma may have microcornea or macrocornea. Microcornea may occur as an isolated defect or may be associated with rubella syndrome, persistent hyperplastic primary vitreous (PHPV), Rieger’s anomaly, and nanophthalmos. Because increased intraocular pressure may stretch these glaucomatous eyes, corneal enlargement is not always a developmental defect. It is important to distinguish megalocornea from the corneal stretching that occurs as a part of the glaucomatous process. Megalocornea may occur as a primary defect or in association with other defects such as Axenfeld syndrome. X-linked recessive megalocornea may be associated with glaucoma, which may occur later in life. The prognosis for control of glaucoma in eyes with corneodysgenesis is not as good as in eyes with isolated trabeculodysgenesis.
Advantages of anatomical classification Classification by syndromes and eponyms is important because it allows a few words to describe a constellation of characteristics that are frequently found together. However, an anatomical classification has certain advantages over eponym or syndrome nomenclature when dealing with developmental anomalies. Often the anomalies are varied and do not fit particular syndrome or eponym patterns. Occasionally, a form not previously seen needs to be categorized and treated. Correct classification according to eponym or syndrome may require knowledge of factors not yet known about a particular patient, such as future inheritance pattern, response to therapy, or histopathologic examination. The anatomical classification is helpful because it does not require knowledge of the histopathologic findings, time of onset, response to treatment, inheritance pattern, or any other factor. Patients may be classified according to more than one classification system, and the anatomical classification has been useful as a supplement to the more traditional nomenclature. The anatomical classification improves communication among researchers in this field, because it allows greater precision in describing patients and predicting surgical outcome. At the present time, we recognize the excellent surgical prognosis in patients with isolated trabeculodysgenesis. In patients who have additional developmental defects of the anterior segment, the prognosis is worse compared with isolated trabeculodysgenesis. Patients with associated iris anomalies, especially those with anomalous iris vessels, respond poorly to primary surgical intervention and represent either a more severe form of primary congenital glaucoma or perhaps a different development defect altogether. Those with corneal dysgenesis associated with anomalous superficial iris vessels or other iris abnormalities appear to benefit least from primary surgery.
References
Neurocristopathies It has been recognized that neural crest-derived mesenchymal cells make a major contribution to the development of the tissues of the anterior segment. Therefore, one would expect that a group of ocular diseases exists that involves the cornea, iris, and trabecular meshwork, either singly or in combination and often in association with glaucoma. In some patients, these disorders would also be accompanied by abnormalities of non-ocular tissues that are also derived from neural crest cells, including craniofacial abnormalities, dental malformation, middle ear deafness, and malformation of the base of the skull. Clinical syndromes such as Axenfeld– Rieger syndrome, Peters anomaly, Sturge–Weber syndrome, and other phakomatoses can be interpreted based on their neural crest cell derivation. All of these disorders are believed to provide possible clinical evidence either of abnormalities in the migration of neural crest cells or of terminal interference with cellular interactions.11 These diseases and malformations of cells derived from the neural crest have been grouped together under the term neurocristopathies.12
Conclusion Different classification systems with varying terminology have been used to lump and split the large number of disorders associated with glaucoma affecting infants and children. Many patients with classical clinical presentation may be described according to traditional eponyms and syndromes. Hoskins and associates have advocated a shift away from eponyms and syndrome names towards an emphasis on descriptive terminology. Noting that the trabecular meshwork, iris, and cornea are the three major structures involved in these conditions, they suggested the terms
‘trabeculodysgenesis,’ ‘iridodysgenesis,’ and ‘corneodysgenesis’ or a combination thereof, as a system of classifying the developmental glaucomas. While there is value in categorizing disorders on the basis of anatomical descriptions and mechanisms, the wide range of manifestations and the limited understanding of disease mechanisms may make it difficult to apply such a system in all cases of developmental glaucomas. However, more precise terminology should be used whenever possible.
References 1. Jerndal T. Dominant goniodysgenesis with late congenital glaucoma. Am J Ophthalmol 1972; 74:28–33. 2. Shaffer RN, Weiss DI. Congenital and paediatric glaucomas. CV Mosby: St. Louis; 1970. 3. Worst JG. Congenital glaucoma: remarks on the aspect of chamber angle, ontogenetic and pathogenetic background and mode of action goniotomy. Invest Ophthalmol 1968; 7:127–134. 4. Hoskins HD Jr, Kass MA. Becker-Shaffer’s diagnosis and therapy of the glaucomas, 6th edn. CV Mosby: St. Louis; 1989:356. 5. DeLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28:1–19. 6. Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classification of the developmental glaucomas. Arch Ophthalmol 1984; 102:1331–1336. 7. Hoskins HD Jr, Hetherington J, Shaffer RN, Welling AM. Developmental glaucoma: diagnosis and classification. In: Proceedings of the New Orleans Academy of Ophthalmology Glaucoma Symposium. CV Mosby: St. Louis; 1981:172–190. 8. Hoskins HD, Shaffer RN. Rieger’s syndrome. A form of irido-corneal mesodermal dysgenesis. Pediatr J Ophthalmol 1972; 9:26. 9. Martin JP, Hart CT. Familial glaucoma. Br J Ophthalmol 1974; 58:536–542. 10. Weatherill JR, Hart CT. Familial hypoplasia of the iris stoma associated with glaucoma. Br J Ophthalmol 1969; 53:433–438. 11. Kupfer C, Datilies MB, Kaiser-Kupfer M. Development of the anterior chamber of the eye: embryology and clinical implications. In: Lutjen-Drecoll E, ed. Basic aspects of glaucoma research: international symposium held at the Department of Anatomy, University ErlangenNürnberg, September 17 and 18, 1981. Schattauer: Stuttgart; 1982. 12. Bolande RP. The neurocristopathies: a unifying concept of disease arising in neural crest maldevelopment. Hum Pathol 1974; 5:409.
9
Chapter 3 Embryologic basis of developmental glaucomas Introduction Concepts of anterior ocular segment development Normal development of the anterior segment Theories of abnormal development in primary congenital glaucoma Embryologic basis of other angular neurocristopathies Embryologic basis of different iris anomalies Developmental genetics Conclusion
Introduction During embryonic development, the human eye is derived from both ectoderm (surface and neural ectoderm, including neural crest) and paraxial mesoderm. Many structures that were originally believed to have been derived from mesoderm are now considered to be of neural crest origin. A basic understanding of normal development, particularly related to structures of the anterior ocular segment and theories of abnormal development, is helpful preparation for an understanding of developmental glaucomas.
Concepts of anterior ocular segment development In the classic germ-layer theory of development of the human body, there are three layers in the developing embryo: ectoderm, endoderm, and mesoderm. According to this theory, the ectoderm gives rise to surface epithelia and to the nervous system, the endoderm forms the gut, and the mesoderm gives rise to all other structures that are not derived from either the ectoderm or endoderm. Early studies on the development of the eye1–4 depicted the epithelium of the cornea, the retina, and the neural components of the uveal tract as derived from ectoderm, and the remainder of the ocular structures as developed from the mesoderm. Mesenchymal cells are described as a dispersed population of undifferentiated embryonic cells that are stellateshaped and loosely arranged. Although it still may be true that the non-ectodermal portions of the eye stem from the mesenchymal cells, it is now apparent that these cells differ in their embryonic origin. The importance of this realization lies in the fact that a number of congenital anomalies and other pathologic entities, especially disorders of the anterior
ocular segment, can be more thoroughly understood with consideration of the embryonic lineage of the cells involved.5,6 Recent experimental studies, most using animal models, have shown that a major portion, if not all, of the ocular mesenchyme is derived from neural crest cells.7–13 Neural crest cells may be defined as those neuroectodermal cells that proliferate from the crest of the neural folds at about the time the folds fuse to form the neural tube (Fig. 3.1). The neural crest cells that remain attached to the neural tube eventually differentiate into the cerebral and spinal ganglia and the roots of the dorsal nerves. However, many of the neural crest cells migrate away from the neural tube and form secondary mesenchyme, which differentiates into various body structures (Table 3.1).
Normal development of the anterior segment General development The earliest development of the optic vesicle in humans appears as paired outpouchings, one on each side of the developing neural tube in the region that ultimately will form the diencephalon or forebrain.1,3,14,15 As the optic vesicles extend toward the surface ectoderm, the superior and the inferior walls of the neural tube constrict, so that each optic vesicle is connected to the wall of the forebrain by the so-called optic stalk.
E
NT NC
Figure 3.1 Embryonic formation of neural crest cells (NC). These cells are derived from neuroectoderm located at the crest of the neural folds when the folds fuse to form the neural tube (NT). The cells migrate under the ectoderm (E). 11
Embryologic basis of developmental glaucomas
Table 3.1 Contributions of neural crest-derived mesenchyme and mesodermal mesenchyme to human ocular structures A Neural crest cell derivatives 1 Sclera (except caudal portion) 2 Cornea a Endothelium b Keratocytes 3 Uveal tract a b c d
Fibroblasts of choroid Ciliary body muscles Stromal cells of iris Melanocytes
4 Iridocorneal angle a Trabecular meshwork endothelium 5 Vascular system a ? Pericytes B Mesodermal cell derivatives 1 Caudal region of sclera 2 Vascular endothelium, including Schlemm’s canal 3 Extraocular muscles
Induction of the lens is first seen as a thickening of the surface ectodermal cells (the lens placode) at about the 3rd week of gestation. As the lens vesicle forms, the optic vesicle is developing into the optic cup (Fig. 3.2). By the 4th week, differential growth and movement of the cells of the optic vesicle cause the temporal and lower walls of the vesicle to
Retina
Optic cup
move inward against the upper and posterior walls. The two laterally growing edges of the cup eventually meet and fuse. This process also involves the optic stalk and results in the formation of embryonic or optic fissure. The lens vesicle separates from the surface ectoderm by the 6th week.3 At this time, the optic cup, which arises from neural ectoderm, has reached the periphery of the lens. A triangular mass of undifferentiated cells overrides the rim of the cup and surrounds the anterior periphery of the lens. From this tissue mass will arise portions of the cornea, iris, and the anterior chamber angle. The undifferentiated cells are derived from cranial neural crest cells origin.7–13 The anterior chamber is formed by three waves of tissue derived from the mass of undifferentiated (neural crest) cells, which grow in between the surface ectoderm and lens (Fig. 3.3). The first wave (avascular) differentiates into the primordial corneal endothelium by the 6th to 7th week and subsequently produces Descemet’s membrane. The second wave (vascular) insinuates between the primordia of the cornea and the lens and gives rise to the pupillary membrane and the stroma of the iris (7th week). In the later months, the pigment epithelial layer of the iris develops from neural ectoderm. The third (avascular) wave grows between the corneal endothelium and epithelium to produce keratocytes, which form the stroma of the cornea. 16,17
Development of anterior chamber angle The aqueous outflow structures in the anterior chamber angle appear to arise from the mesenchymal cells of neural crest cell origin. The precise details of this development, however, are not fully understood. At the 22 to 24 mm stage (7th to 8th week), the anterior chamber angle is undifferentiated and is occupied by loosely arranged mesenchymal cells, and the anterior chamber itself is a slit-like opening. Several hypotheses have been advanced in the attempt to explain the formation of anterior chamber angle, including atrophy3 or resorption18 (progressive disappearance of portion of fetal tissue), cleavage19 (separation of two pre-existing
Optic stalk I Epithelium
III II
Lens vesicle Embryonic fissure
Figure 3.2 Formation of the optic cup. After the optic vesicle extends to the lens placode, the lens pit develops and the optic cup is formed at the end of the optic stalk. The lens pit develops into the lens vesicle within the optic cup. The retina is developed from the inner layers of the optic cup. The embryonic fissure of the optic cup and optic stalk is located inferiorly in this sagittal view. (Modified with permission from reference 7.) 12
Lens
Retina Figure 3.3 Ingrowth of neural crest cells. Three successive waves of ingrowth of neural crest cells are associated with differentiation of the anterior chamber. The first wave (I) forms the corneal endothelium. The second wave (II) forms the iris and pupillary membrane. The third wave (III) develops into keratocytes, which form the corneal stroma.
Normal development of the anterior segment tissue layers due to differential growth rate), and rarefaction20 (mechanical distention due to growth of the anterior ocular segment). More recent work, however, suggests that none of these concepts are completely correct. Anderson21 studied 40 normal fetal and infant eyes by light and electron microscopy and found that the anterior surface of the iris at 5 months gestation inserts at the edge of the corneal endothelium, covering the cells that are destined to become trabecular meshwork. This appears to be what Worst22 called the fetal pectinate ligament, separating the corneoscleral meshwork primordium from the anterior chamber angle. The developmental process does not consist of simple cleavage or atrophy, for with either process the uveal tract would simply split away from the corneoscleral shell and the trabecular tissue. The result would be that the ciliary muscle would extend into the perpheral iris and the ciliary processes would be on the posterior surface of the peripheral iris. The trabecular meshwork later becomes exposed to the anterior chamber as the angle recess deepens and moves posteriorly (Fig. 3.4). Anderson noted a posterior repositioning of the anterior uveal structures in progressively older tissue specimens, presumably due to differential growth rates. The repositioning process is not just the sliding of the uveal tract along the inner side of the sclera but there is also repositioning of the various layers within the uveal tract in relation to one another. At birth, the insertion of the iris and ciliary body is near the level of the scleral spur, and usually posterior to it. On gonioscopy of a normal newborn eye, the insertion of the iris into the angle wall will be seen posterior to the scleral spur in most cases, with the anterior extension of the ciliary body seen as a band anterior to the iris insertion. The iris insertion into the angle wall is rather flat, as the angle recess has not yet formed. Continued posterior sliding of the uveal tissue occurs during the first 6 to 12 months of life, which is apparent gonioscopically as formation of the angle recess. Thus, the adult angle configuration in which the iris turns slightly posteriorly before inserting into the ciliary body is not normally present at birth but develops in the first year of life.
SC
SS
There is some difference of interpretation regarding the innermost layer of the trabecular meshwork primordium as it is uncovered by the posteriorly receding iris. Anderson21 felt that the smooth surface represents the multilayered mesenchymal tissue, which begins to cavitate by the 7th fetal month. Others have suggested, however, that a true endothelial layer covers the meshwork during gestation. Hansson and Jerndal23 studied human fetal eyes by scanning electron microscopy and described a single layer of endothelium, continuous with that of the cornea, extending over the primitive anterior chamber angle and iridopupillary structures, creating a closed cavity at the beginning of the 5th fetal month. Worst22 observed a similar sheet of flat endothelial cells on the pupillary membrane and felt that the disappearance of this layer progresses centrifugally toward the anterior chamber angle. Hansson and Jerndal23 noted that the anterior chamber angle portion of the endothelial layer begins to flatten, with loss of clear-cut borders, by the 7th fetal month. During the final weeks of gestation and the first weeks after birth, the endothelial layer undergoes fenestration with migration of cells into the underlying uveal meshwork. Van Buskirk24 also observed intact endothelium completely lining the anterior chamber angle by the second gestational trimester in macaque monkey eyes studied by scanning electron microscopy. He noted that fenestration and gradual retraction of this tissue occurs in the 3rd trimester and progresses in a posterior-toanterior direction. As the endothelium of the cornea and anterior chamber angle begins to differentiate, a distinct demarcation line develops at the primordium of Schwalbe’s line.23 It has also been suggested, based on transmission electron microscopy of eyes from premature infants with gestational ages of 24 to 42 weeks, that formation of the trabecular meshwork begins on the anterior chamber side and progresses toward Schlemm’s canal.25 This is thought to be consistent with some cases of primary congenital glaucoma in which the site of obstruction to aqueous outflow appears to be a thickened tissue adjacent to the inner wall of Schlemm’s canal.25,26 Shields combined various observations into a unified concept of anterior chamber angle development.27 At 5 months
CE
AR I
AR
MS
L
A
3 Months
B
Figure 3.4 Progressive deepening of the anterior chamber angle. A. At 3 months, the angle recess (AR) is anterior to a rudimentary Schlemm’s canal (SC) and scleral spur (SS) have formed. The corneal endothelium (CE) extends into the angle recess. The pigment epithelium and the marginal sinus (MS) of the ectodermal optic cup is posterior to the angle recess. B. At 4 months, the angle recess has deepened and the marginal sinus has moved anteriorly. The angle recess has extended slightly further from the corneal endothelium. Condensed tissue just posterior to Schlemm’s canal is developing scleral spur. The dilator muscle of the iris (I) has reached its root and the lens (L) has continued to develop. (Modified with permission from reference 7.)
4 Months
13
Embryologic basis of developmental glaucomas gestation, a continuous layer of endothelium creates a closed cavity, and the anterior surface of the iris inserts in front of the primordial trabecular meshwork. In the third trimester, the endothelial membrane progressively disappears from the pupillary membrane, iris, and anterior chamber angle, possibly incorporated into the trabecular meshwork. The peripheral uveal tissue begins to slide posteriorly in relation to the anterior chamber angle structures. Development of the trabecular meshwork begins in the inner, posterior aspect of the primordial tissue and progresses toward Schlemm’s canal and Schwalbe’s line. The normal anterior chamber angle is not fully developed until approximately one year of life.
Theories of abnormal development in primary congenital glaucoma Although it is generally agreed that the intraocular pressure elevation in primary congenital glaucoma is due to an abnormal development of the anterior chamber angle that leads to reduced facility of aqueous outflow, there is no universal agreement as to the nature of the developmental alteration. Theories of mechanism parallel the basic concepts regarding the normal development of the anterior chamber angle, most of which are no longer accepted as being entirely correct. The major theories that have been proposed in the past will be reviewed and the current understanding of the developmental abormality of primary congenital glaucoma will be described. Mann (1928)2 proposed that the anterior chamber angle is formed by atrophy of the mesenchyme and arrest of this process results in retention of abnormal tissue that blocks aqueous outflow in primary congenital glaucoma. Allen, Burian, and Braley (1955)19 postulated that incomplete cleavage of mesoderm results in absent angle recess in primary congenital glaucoma, although the cleavage theory for normal development has not been proved. Barkan (1955)18 suggested that incomplete resorption of the mesodermal cells by adjacent tissue led to the formation of a membrane across the anterior chamber angle. This membrane became known as ‘Barkan’s membrane,’ although its existence has not been proved histologically using light as well as electron microscopy.21,23,26,28–31 Maumenee (1958)28 demonstrated abnormal anterior insertion of the ciliary muscle over scleral spur in infantile glaucoma eyes. He noted that the longitudinal and circular fibers of the ciliary muscle inserted into the trabecular meshwork rather than into the scleral spur, and that the root of the iris can insert directly into the trabecular meshwork. He postulated that these changes might compress the scleral spur forward and externally, thus narrowing Schlemm’s canal. Maumenee (1963)31 also noted the absence of Schlemm’s canal in some histopathologic specimens and suggested that this might be a cause of aqueous outflow obstruction in congenital glaucoma, although others feel this may be a secondary change.32 Worst (1966)22 proposed a combined theory, which included elements of the atrophy and resorption concepts, but rejected the cleavage theory. He suggested that incomplete 14
development of the scleral spur leads to a high insertion of the longitudinal portion of the ciliary muscle on the trabeculum. In addition, he felt that a single layer of endothelial cells cover the anterior chamber angle during gestation, and that its abnormal retention in primary congenital glaucoma constitutes ‘Barkan’s membrane.’ Worst claimed that ‘though histopathological proof of this structure is almost completely lacking... this has little influence on the probability that this concept is valid.’33 Smelser and Ozanics (1971)20 explained primary congenital glaucoma as a failure of anterior chamber angle mesoderm to become properly rearranged into the normal trabecular meshwork. Subsequent light and electron microscopic studies favor this theory.25,26,32,34–36 Kupfer and associates (1978)5 suggested that abnormal neural crest cell migration and a defect of terminal induction by embryonic inducers is the cause of several forms of congenital glaucoma.37,38 Anderson (1981)21,39 provided histopathological support for the high insertion of the anterior uvea into the trabecular meshwork, suggesting that this is due to a developmental arrest in the normal migration of the uvea across the meshwork in the third trimester of gestation. He stated that, in eyes with primary congenital glaucoma, the iris and the ciliary body have the appearance of an eye in the seventh or eighth month of gestation rather than one at full term development. The iris and ciliary body have failed to recede posteriorly, and thus the iris insertion and anterior ciliary body overlap the posterior portion of the trabecular meshwork. Anderson believed that, in infantile glaucoma, the thickened trabecular beams have prevented the normal posterior migrations of ciliary body and iris root. Beauchamp and co-workers (1985)40 have postulated that abnormal extracellular matrix and glycoproteins lead to abnormal anterior segment development by interfering with adductors, inductors, receptors and specific time sequencing. They state that, in primary congenital glaucoma, the defects in morphogenesis and differentiation (capacitation) can be seen as mild, requiring only a minor ‘remodeling’ by, for example, goniotomy to become functional. McMenamin (1991) observed a marked increase in the volume of extracellular matrix during development.41 Tawara and Inomata (1994) found extensive accumulations of basal lamina-like material containing heparan sulfate-type proteoglycans in the thick subcanalicular tissue in trabeculectomy specimens from patients with developmental glaucoma.42 In summary, primary congenital glaucoma appears to result from a developmental abnormality of anterior chamber angle tissue derived from neural crest cells, leading to aqueous outflow obstruction by one or more of several mechanisms. Developmental arrest may lead to an anterior insertion of iris, insertion of the ciliary muscle directly into trabecular meshwork, and only rudimentary development of the scleral spur (Fig. 3.5). The high insertion of the ciliary body and iris into the posterior portion of the trabecular meshwork may compress the trabecular beams, and the extracellular matrix may be abnormal. In addition, there may be primary developmental defects at various levels of the meshwork and, in some cases, of Schlemm’s canal. However, a true
Embryologic basis of different iris anomalies
SC
II
IV
I
III
Figure 3.5 Meridional representation of the anterior chamber angle showing the embryonic configuration. The features include an anterior insertion of the iris (I), a rudimentary scleral spur (II), insertion of the ciliary muscle directly into the trabecular meshwork (III), and undifferentiated trabecular meshwork (IV). These features also may be observed in eyes with primary congenital glaucoma. SC = Schlemm’s canal. (Adapted with permission from reference 7.)
membrane over the meshwork does not appear to be a feature of this disorder.
Embryologic basis of other angular neurocristopathies It has been recognized that neural crest derived mesenchymal cells make a major contribution to the tissues of the anterior ocular segment. Although major developmental events leading to iridocorneal angle formation occur during the third trimester, embryonic insult much earlier in human gestation can induce an abnormal sequence of events leading to anterior segment dysgenesis.43 The neurocristopathies are a group of ocular diseases that involve the cornea, iris and trabecular meshwork (either singly or in combination), often are associated with glaucoma, and are frequently accompanied by abnormalities of nonocular tissue that are also derived from neural crest cells (e.g., craniofacial and dental malformation, middle ear deafness, malformation of the base of the skull).5 These diseases include Axenfeld–Rieger syndrome, Peters anomaly, and Sturge–Weber syndrome or other phakomatoses. Based on clinical and histopathologic observations and the current concepts of normal anterior segment development, a developmental arrest, late in gestation, of certain anterior segment structures derived from neural crest cells, has been postulated as the mechanism of Axenfeld–Rieger syndrome.27,44 This leads to abnormal retention of the primordial endothelial layer on portions of the iris and anterior chamber angle, and alterations in the aqueous outflow structures. The retained endothelium with associated basement membrane is believed to create the iridocorneal strands, while contraction of the tissue layer on the iris leads to the iris changes, which sometimes continue to progress after birth. The developmental arrest also may account for the high insertion of the
anterior uvea into the posterior trabecular meshwork, similar to the alterations seen in primary congenital glaucoma, and result in incomplete maturation of the trabecular meshwork and Schlemm’s canal. Neural crest cells also give rise to most of the mesenchyme related to the forebrain and pituitary gland, bones and cartilages of the upper face, and dental papillae.7,38,45 This could explain the developmental anomalies involving the pituitary gland, the facial bones, and teeth. Other defects, however, such as those of the umbilicus and genitourinary system, are more difficult to associate with a primary defect of cranial neural crest cells. Peters anomaly is characterized by a spectrum of changes in anterior segment structures, including the lens, the cornea, and the anterior chamber angle.46–48 These changes include defects in the posterior stroma of the cornea, Descemet’s membrane, and endothelium, with or without extension of iris tissue strands from the iris collarette to the edge of the corneal leukoma. They may also include a central keratolenticular stalk and cataract. The corneal abnormalities may result from incomplete migration of the neural crestderived mesenchymal cells during early embryogenesis. Incomplete migration of the first wave may leave a central defect in endothelium and Descemet’s membrane, which may couple with a stromal defect because of incomplete migration of the second wave. An anterior staphyloma represents a more severe degree of failure of mesenchyme to differentiate properly so that a thin, ectatic, leukoma lined by uveal tissue replaces the cornea. Numerous theories have been devised to account for the raised intraocular pressure in patients with phakomatoses,49–51 including Sturge–Weber syndrome and neurofibromatosis. Several investigators have reported primary defects in the structures of the aqueous outflow pathways in patients with these syndromes. The abnormalities include malformation or absence of Schlemm’s canal, persistence of embryonic tissue in the trabecular meshwork, or incomplete ‘cleavage’ of the iridocorneal angle.52–56 Abnormalities of neural crest cells could explain the pathogenesis of the associated glaucoma in these patients who have no secondary obstruction to aqueous outflow.
Embryologic basis of different iris anomalies At about the 7th week of gestation a vascular wave insinuates between the primordia of the cornea and the lens to form the anterior portion of the vascular tunic of the lens (pupillary membrane), which later becomes the superficial layer of iris stroma. At the same time, the hyaloid artery has grown through the embryonic fissure of the optic stalk and across the vitreous cavity to the posterior aspect of the lens, where it ramifies as the posterior portion of the vascular tunic of the lens. The annular vessel which forms circumferentially around the mouth of the optic cup sends branches posteriorly (between the rim of the optic cup and the equator of the lens) to anastomose with branches of the hyaloid vessel. These 15
Embryologic basis of developmental glaucomas capsulopupillary vessels are the lateral portion of the vascular tunic of the lens. Each of these portions of the vascular tunic of the lens (anterior pupillary membrane, lateral capsulopupillary vessels and the posterior hyaloid system) atrophies in later embryonic development, leaving the lens avascular in postnatal life. Failure of the anterior portion to atrophy produces a persistent pupillary membrane. If the posterior hyaloid system does not involute, persistent hyperplastic primary vitreous may result.57 In aniridia, although other abnormalities of neural crest cells are possible, several mechanisms involving the capsulopupillary vessels have been suggested,57 including absence of the superficial stromal directional membrane, primary failure of optic cup growth, and persistence of capsulopupillary vessels. If the pupillary membrane fails to form primarily, the optic cup will lack a directional membrane, and only a rudimentary iris will develop. Also, as the optic cup grows axially, it carries with it a layer of mesoderm that will become the deep stromal layer of the iris. A primary failure of the optic cup to grow in may result in a rudimentary iris. In addition, persistence of the capsulopupillary vessels extending from the iris to the lens may block the optic cup as it grows axially between the iris stroma and the lens.
Developmental genetics Experimental models for the anterior chamber angle have been developed that demonstrate organization of cellular and extracellular matrix components with a developmental sequence comparable to humans.58 Analysis of human fetal eyes has shown that uveal trabecular endothelial cells can be identified in early (12 to 22 weeks) development, and increases of extracellular matrix and intertrabecular spaces can be quantitated.41,59 At the same time, understanding of the molecular genetics of primary congenital glaucoma has improved, suggesting several genes that may play a role in the development of the anterior chamber. The majority of patients with primary congenital glaucoma demonstrate mutations in the cytochrome P4501B1 gene (CYP1B1). This gene is expressed in tissues in the anterior chamber angle of the eye, suggesting a role in anterior chamber angle development.60,61 Anterior segment dysgenesis may occur in patients with mutations of chromosome 6 (6p25), implicating the forkhead transcription-factor gene (FOXC1) in development of the anterior chamber angle.62–66 The specific morphogens involved in the development of the human anterior chamber angle are not known at this time. In an experimental glaucoma model, anterior segment anomalies resembling those in human developmental glaucoma may be modified by tyrosinase, suggesting a role for this pathway in the development of the anterior chamber angle.67
Conclusion The current knowledge about the development of the structures of the anterior segment has provided a theoretical basis for the developmental abnormality in congenital glaucoma 16
and other anterior segment anomalies. Evidence is mounting that neural crest cells make a prominent contribution to the embryonic derivation of these structures, and this realization may help provide a better explanation for the pathogenesis of the developmental glaucomas. Relatively little is known at present about the factors that induce the embryonic neural crest cells to differentiate into the structures of the anterior segment in the normal eye, and even less is understood about the causes of abnormalities that result in ocular neurocristopathies.
References 1. Duke-Elder S. System of ophthalmology, Vol III. CV Mosby: St. Louis; 1964. 2. Mann I. The development of the human eye. Cambridge University Press: Cambridge; 1928. 3. Mann I. The development of the human eye, 3rd edn. Cambridge University Press: Cambridge; 1964. 4. Streeter GL. Developmental horizons in human embryos. Contrib Embryol 1951; 34:165–196. 5. Kupfer C, Kaiser-Kupfer MI. New hypothesis of developmental anomalies of the anterior chamber associated with glaucoma. Trans Ophthalmol Soc UK 1978; 98: 213–215. 6. Bahn CF, Falls HF, Varley GA et al. Classification of corneal endothelial disorders based on neural crest origin. Ophthalmology 1984; 91:558–563. 7. Tripathi BJ, Tripathi RC. Embryology of the anterior segment of the human eye. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:3–38. 8. Johnston MC, Noden DM, Hazelton RD, et al. Origins of avian ocular and periocular tissues. Exp Eye Res 1979; 29:27–43. 9. Le Douarin N. Migration and differentiation of neural crest cells. In: Moscona AA, Monroy A, eds. Current topics in developmental biology, Vol 16. Hunt RK, ed. Neural development, Part II. Academic Press: New York; 1980. 10. Le Lievre C, Le Douarin N. Mesenchymal derivatives in the neural crest: analysis of chimaeric quail and chick embryos. J Embryol Exp Morphol 1975; 34:125–154. 11. Noden DM. An analysis of migratory behavior of avian cephalic neural crest cells. Dev Biol 1975; 42:106–130. 12. Noden DM. The control of avian cephalic neural crest cytodifferentiation. I. Skeletal and connective tissues. Dev Biol 1978; 67:296–312. 13. Noden DM. Periocular mesenchyme: neural crest and mesodermal interactions. In: Jakobiec FA, ed. Ocular anatomy, embryology, and teratology. Harper & Row: Hagerstown, MD; 1982. 14. O’Rahilly R. The prenatal development of the human eye. Exp Eye Res 1975; 21:93–112. 15. Ozanics V, Jakobiec FA. Prenatal development of the eye and its adnexa. In: Jakobiec FA, ed. Ocular anatomy, embryology, and teratology. Harper & Row: Hagerstown, MD; 1982. 16. Wulle KG. Electron microscopy of the fetal development of the corneal endothelium and Descemet’s membrane of the human eye. Invest Ophthalmol 1972; 11:897–904. 17. Hay ED. Development of the vertebrate cornea. Int Rev Cytol 1980; 63:263–322. 18. Barkan O. Pathogenesis of congenital glaucoma. Gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. Am J Ophthalmol 1955; 40:1–11. 19. Allen L, Burian HM, Braley AE. A new concept of the development of the anterior chamber angle. Its relationship to developmental glaucoma and other structural anomalies. AMA Arch Ophthalmol 1955; 53:783–798. 20. Smelser GK, Ozanics V. The development of the trabecular meshwork in primate eyes. Am J Ophthalmol 1971; 71:366–385. 21. Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–485. 22. Worst JGF. The pathogenesis of congenital glaucoma. An embryological and goniosurgical study. Charles C. Thomas: Springfield; 1966. 23 Hansson HA, Jerndal T. Scanning electron microscopic studies on the development of the iridocorneal angle in human eyes. Invest Ophthalmol 1971; 10:252–265. 24. Van Buskirk EM. Clinical implication of iridocorneal angle development. Ophthalmology 1981; 88:361–367. 25. Tawara A, Inomata H. Developmental immaturity of the trabecular meshwork in congenital glaucoma. Am J Ophthalmol 1981; 92:508–525.
References 26. Maul E, Strozzi L, Munoz C, et al. The outflow pathway in congenital glaucoma. Am J Ophthalmol 1980; 89:667–673. 27. Shields MB. Axenfeld–Rieger syndrome. A theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc 1983; 81:736–784. 28. Maumenee AE. The pathogenesis of congenital glaucoma. A new theory. Trans Am Ophthalmol Soc 1958; 56:507–570. 29. Maumenee AE. The pathogenesis of congenital glaucoma; a new theory. Am J Ophthalmol 1959; 47:827–858. 30. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Trans Am Ophthalmol Soc 1962; 60:140–146. 31. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176. 32. Anderson DR. Pathology of the glaucomas. Br J Ophthalmol 1972; 56:146–157. 33. Worst JGF. Congenital glaucoma. Remarks on the aspect of chamber angle, ontogenic and pathogenic background, and mode of action of goniotomy. Invest Ophthalmol 1968; 7:127–134. 34. Sampaolesi R, Argento C. Scanning electron microscopy of the trabecular meshwork in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 1977; 16:302–314. 35. Rodrigues MM, Spaeth GL, Weinreb S. Juvenile glaucoma associated with goniodysgenesis. Am J Ophthalmol 1976; 81:786–796. 36. Tawara A, Inomata H. Developmental immaturity of the trabcular meshwork in juvenile glaucoma. Am J Ophthalmol 1984; 98:82–97. 37. Kupfer C, Ross K. The development of outflow facility in human eyes. Invest Ophthalmol 1971; 10:513–517. 38. Kupfer C, Kaiser-Kupfer MI. Observations on the development of the anterior chamber angle with reference of the pathogenesis of congenital glaucomas. Am J Ophthalmol 1979; 88:424–426. 39. DeLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28:1–19. 40. Beauchamp GR, Lubeck D, Knepper PA. Glycoconjugates, cellular differentiation, and congenital glaucoma. J Pediatr Ophthalmol Strabismus 1985; 22:149–155. 41. McMenamin PG. A quantitative study of the prenatal development of the aqueous outflow system in the human eye. Exp Eye Res 1991; 53:507–517. 42. Tawara A, Inomata H. Distribution and characterization of sulfated proteoglycans in the trabecular tissue of goniodysgenetic glaucoma. Am J Ophthalmol 1994; 117:741–755. 43. Cook CS. Experimental models of anterior segment dysgenesis. Ophthalmic Paediatr Genet 1989; 10:33–46. 44. Shields MB. A common pathway for developmental glaucomas. Trans Am Ophthalmol Soc 1987; 85:222–237. 45. Edward WC, Torczynski E. Neural crest cell behaviour and facial anomalies. Pers Ophthalmol 1981; 5:47. 46. Kenyon KR. Mesenchymal dysgenesis in Peter’s anomaly, sclerocornea and congenital endothelial dystrophy. Exp Eye Res 1975; 21:125–142. 47. Schottenstein EM. Peters anomaly. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:887–897.
48. Waring GO, Rodrigues MM, Leibson PR. Anterior chamber cleavage syndrome: a stepladder classification. Surv Ophthalmol 1975; 20:3. 49. Cibis GW, Tripathi RC, Tripathi BJ. Glaucoma in Sturge-Weber syndrome. Ophthalmology 1984; 91:1061. 50. Tripathi RC, Tripathi BJ, Cibis GW. Sturge-Weber syndrome. In: Gold DH, Weinglist TA, eds. The eye in systemic disease. Lippincott: Philadelphia; 1987. 51. Weiss JS, Ritch R. Glaucoma in the phakomatoses. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, 2nd edn. Mosby: St. Louis; 1996:899–924. 52. Collins ET, Batten RD. Neurofibroma of the eyeball and its appendages. Trans Ophthalmol Soc UK 1905; 25:248. 53. Hoyt CM, Billson F. Buphthalmos in neurofibromatosis: is it an expression of giantism? J Ped Ophthalmol 1977; 14:228–234. 54. Leib WA, Wirth WA, Geeraets WJ. Hydrophthalmos and neurofibromatosis. Confin Neurol 1958; 19:239. 55. Wheeler JM. Plexiform neurofibromatosis involving the choroid, ciliary body and other structures. Am J Ophthalmol 1937; 20:368. 56. Wiener A. A case of neurofibromatosis with buphthalmos. Arch Ophthalmol 1925; 54:481. 57. Laibson PR, Waring GO. Disease of the cornea. In: Harely RD, ed. Paediatric ophthalmology. WB Saunders: Philadelphia; 1975. 58. Smith RS, Zabaleta A, Savinova OV, John SW. The mouse anterior chamber angle and trabecular meshwork develop without cell death. BMC Dev Biol 2001; 1:3. 59. McMenamin PG. Human fetal iridocorneal angle: a light and scanning electron microscopic study. Br J Ophthalmol 1989; 73:871–879. 60. Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye 2000; 14(Pt 3B):422–428. 61. Stoilov I, Jansson I, Sarfarazi M, Schenkman JB. Roles of cytochrome p450 in development. Drug Metabol Drug Interact 2001; 18:33–55. 62. Jordan T, Ebenezer N, Manners R, McGill J, Bhattacharya S. Familial glaucoma iridogoniodysplasia maps to a 6p25 region implicated in primary congenital glaucoma and iridogoniodysgenesis anomaly. Am J Hum Genet 1997; 61:882–888. 63. Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/wingedhelix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 1998; 63:1316–1328. 64. Smith RS, Zabaleta A, Kume T, et al. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet 2000; 9:1021–1032. 65. Nishimura DY, Searby CC, Alward WL, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 2001; 68:364–372. 66. Lehmann OJ, Ebenezer ND, Ekong R, et al. Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions. Invest Ophthalmol Vis Sci 2002; 43:1843–1849. 67. Libby RT, Smith RS, Savinova OV, et al. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 2003; 299:1578–1581.
17
Chapter 4 Epidemiology and genetics of developmental glaucomas Introduction Incidence Heredity Genetic studies Genetic counseling
The majority of patients (about 60%) are diagnosed by age 6 months, and 80% are diagnosed within the first year of life. A slight predominance of males is common (about 65%), and involvement is usually bilateral (about 70%). Figure 4.1 shows the demographic data for a group of Indian patients with primary congenital glaucoma. Except for the high rate of consanguinity, the demographic data is typical of primary congenital glaucoma.
Introduction In the pediatric age group, glaucoma is a heterogeneous group of disorders. Primary congenital glaucoma is rare, with an incidence of approximately 1 in 10 000 births in Europe and the United States. Nonetheless, although it is less common compared with primary open-angle glaucoma in adults, primary congenital glaucoma is the most common form of glaucoma in children. The majority of cases of primary congenital glaucoma occur sporadically. Most of these patients demonstrate a recessive pattern with incomplete or variable penetrance and possibly multifactorial inheritance, while some pedigrees suggest an autosomal dominant inheritance. Several genetic loci have been identified that may play a role in primary congenital glaucoma. Genetics of disorders associated with glaucoma in children have also been evaluated, including Axenfeld–Rieger anomaly and aniridia.
Incidence Primary congenital glaucoma is a rare inherited eye disorder which accounts for 0.01–0.04% of total blindness. The disease is usually manifested at birth or early childhood (before 3 years of age). The incidence of primary congenital glaucoma varies from one population to another. In western developed countries, the incidence is approximately 1 in 10 000 births.1 The incidence of primary congenital glaucoma is increased when founder effect or a high rate of consanguinity is found in a population. The ‘founder effect’ is a gene mutation observed in high frequency in a specific population due to the presence of that gene mutation in a single ancestor or a small number of ancestors. The incidence is 1 in 1250 in the Slovakian Roms (Gypsies),2 1 in 2500 in the Middle East,3 and 1 in 3300 in Andhra Pradesh, India.4 In the Indian state of Andhra Pradesh, the disease accounts for 4.2% of all childhood blindness.4 The high incidence of the disease observed among the Roms may be due to a founder effect, whereas consanguinity may play an important role in the high incidence observed in the Middle East and India.5–8
Heredity Most cases of primary congenital glaucoma occur sporadically. Patients with a familial pattern usually show a recessive inheritance with incomplete or variable penetrance and possibly multifactorial inheritance. Transmission of disease in successive generations was also reported in several pedigrees, suggesting an autosomal dominant inheritance pattern.9,10 Pseudodominant mode of inheritance may also occur in a few patients with primary congenital glaucoma. These families show parent–child transmission of the disease.5,6,8,11 The disease is familial in 10–40% of cases with variable penetrance (40–100%).1,6,12,13
Genetic studies Loci of recessively inherited primary congenital glaucoma (gene symbol GLC3) have been identified by genetic linkage analysis (Table 4.1). To date, GLC3A has been mapped to
Sex
Male
Involvement
Bilateral
Heredity
Sporadic
Consanguinity 0%
Female
Yes 20%
No 40% 60% Percentage
80%
100%
Figure 4.1 Demographic data for 129 patients with primary congenital glaucoma from L.V. Prasad Eye Institute in Hyderabad, India. There is a high incidence of consanguinity (47%) in this population. The majority of cases are bilateral (86%) with 14% unilateral, there is a slight majority of males (57%), and most (87%) are sporadic with 13% familial, all of which are typical of primary congenital glaucoma. 19
Epidemiology and genetics
Table 4.1 Known genetic loci for primary congenital glaucoma Locus
Location
Inheritance
Mutated gene (MIM)
Reference
GLC3A
2p21
AR
CYP1B1 (601771)
14
GLC3B
1p36
AR
Unknown
15
AR, autosomal recessive; MIM, Mendelian Inheritance in Man number.
chromosome 2 (2p21)14 and GLC3B to chromosome 1 (1p36).15 The majority of patients with congenital glaucoma map to GLC3A on chromosome 2 (2p21). Families linked to these loci display severe phenotypes with autosomal recessive inheritance pattern. Some types of juvenile onset glaucoma that have an autosomal dominant inheritance pattern have been mapped to chromosome 1q23–q25 (TIGR/MYOC gene). The positional candidate gene approach has shown that mutations in CYP1B1 gene (encoding the cytochrome P450 enzyme) in the GLC3A locus are associated with the primary congenital glaucoma phenotype.5 Mutated gene in GLC3B is yet to be identified. The predominant genetic cause of this disorder in the Middle East (Turkey and Saudi Arabia) is mutation in CYP1B1 gene. Several mutations from various ethnic backgrounds have been implicated in the pathogenesis of this disorder. To date more than 50 mutations in the coding region of CYP1B1 gene have been identified.6–8,16–30 It has been reported that 87% of familial and 27% of sporadic cases are due to mutations in this gene.10 Extensive allelic heterogeneity has been noticed in several populations except the Slovakian Roms. Molecular genetic studies in Slovakian Roms revealed that there is locus, allelic, and clinical homogeneity of primary congenital glaucoma in this population. This homogeneity observed was due to the founder effect of a single ancestral mutation E387K, which is found segregating with the disease phenotype in this community.7 Analysis of families from Turkey and Slovakia showed complete penetrance, whereas Saudi Arabian families showed reduced penetrance.10,31 Reduced penetrance was attributed to the possible existence of a dominant modifier locus that is not genetically linked to CYP1B1.18 Only a small proportion of Japanese families (20%) showed mutations in CYP1B1, whereas majority of the families (85%) in Middle East showed mutations in this gene.21 In several families, no mutations were found in the CYP1B1 coding regions or a single heterozygous mutation was found. This could be due to mutations in the promoter or regulatory sequences of the gene, or could be linked to another locus for primary congenital glaucoma.10,32 Digenic inheritance is an inheritance mechanism resulting from the interaction of two non-homologous genes. Digenic inheritance in glaucoma has been shown recently in two instances: in early-onset glaucoma in humans and also in the mouse. CYP1B1 and MYOC mutations were identified in early-onset glaucoma in humans,33 whereas mutations in CYP1B1 and FOXC1 were detected in the mouse with earlyonset glaucoma.34 This suggests that mutations in genes other than CYP1B1 could cause primary congenital glaucoma. 20
Primary congenital glaucoma is caused by unknown developmental defects in the trabecular meshwork and anterior chamber angle of the eye.10 Because angle structures are mainly derived from the neural crest cells, it is possible that defects in genes expressed in neural crest cells could also contribute to primary congenital glaucoma. Primary congenital glaucoma phenotypes have been associated with CYP1B1 mutations in Indian patients.8 Reddy and coworkers screened 146 primary congenital glaucoma patients from 138 pedigrees and reported six distinct CYP1B1 mutations from 45 primary congenital glaucoma patients from India.25 These include four novel mutations (ins 376 A or Ter@223{frameshift}, P193L, E229K, and R390C) and two known mutations (G61E and R368H). Of the mutations identified, R368H was the predominant mutation causing primary congenital glaucoma in India. This allele was found in a very low proportion of patients from the Middle East and Brazil, but in India 16.2% of the patients screened had this mutation.25 This indicates that the mutation frequency varies depending on the geographical location as well as ethnic background. Though a spectrum of CYP1B1 mutations from various ethnic backgrounds have been implicated in the pathogenesis of primary congenital glaucoma, very few studies have reported genotype–phenotype correlations. A severity index was developed for primary congenital glaucoma, and the severity of disease was correlated with the genotype.32 All patients with severe phenotypes showed poor prognoses (r = 0.976; P < 0.0001). Of the mutations studied, frameshift and R390C homozygous mutations were associated with very severe phenotypes and very poor prognoses. This approach may help guide therapy and counsel the afflicted family regarding the likelihood of progression of the disorder.
Genetic studies of Axenfeld–Rieger anomaly Axenfeld–Rieger anomaly is a congenital maldevelopment of the anterior segment of the eye that may be associated with glaucoma.35 It is inherited as an autosomal dominant trait, and 50–75% of the patients develop glaucoma.36 The anomaly is actually a spectrum of developmental defects of the anterior chamber of the eye, with wide variability in expression. Ocular features of Axenfeld–Rieger anomaly include prominent anterior Schwalbe’s line, abnormal angle tissue, hypoplastic iris, polycoria, corectopia, and glaucoma.37 The gene for this disorder has been mapped to the chromosome 6p25 region.36 A few mutations in a forkhead/wingedhelix transcription factor gene FOXC1 (formerly known as FREAC3 and FKHL7) have been implicated in the pathogenesis of this disorder.38–41
Genetic studies of aniridia Aniridia is a hereditary anomaly associated with varying degrees of absence of iris tissue, occurring in approximately 1.8 per 100,000 live births. The incidence of glaucoma in aniridia ranges from 6 to 75% in clinical studies.42 In the
References majority (approximately 85%) of patients, aniridia is inherited as an isolated, autosomal dominant trait, with variable expressivity. In the isolated form, aniridia is not associated with other systemic manfestations. In isolated aniridia, two-thirds of the patients have an affected parent (familial), while the remaining one-third of cases are the result of new mutations (sporadic). Wilms’ tumor occurs more frequently in sporadic cases. Approximately 13% of patients have an autosomal dominant form of aniridia that is associated with Wilms’ tumor, genitourinary abnormalities, and mental retardation (WAGR syndrome). Two percent of patients affected with aniridia have an autosomal recessive form that is associated with cerebellar ataxia and mental retardation (Gillespie’s syndrome). Aniridia is frequently the result of a deletion on chromosome 11. The genetic locus for aniridia has been established as the PAX6 gene, which is located on the eleventh chromosome, specifically on the 11p13 segment.43 Various PAX6 gene mutations have been described to account for aniridia.44–51 Molecular genetic techniques have been used to screen the PAX6 gene for mutations for prenatal diagnosis of aniridia.52 Fluorescence in situ hybridization (FISH) testing has been helpful in identifying patients at risk for Wilms’ tumor.53–55
Genetic counseling Genetic counseling for glaucoma patients usually includes providing information about the risks of glaucoma in children and other close relatives.42 It is the physician’s responsibility to inform patients and their relatives of the risk of developing the disease and the implications of the disease for their health. Also, patients must be informed of the need for early, regular monitoring in potentially affected offspring. Rarely, glaucoma patients in their reproductive years may make reproductive decisions based on information from the physician. As the understanding of the genetic basis of childhood glaucomas improves, and DNA-based diagnostic tests become more widely available, genetic counseling for childhood glaucomas will become more effective. Identification of genes and the spectrum of mutations causing primary congenital glaucoma will have both basic and clinical relevance. It may help in early treatment and diagnosis, in carrier detection and genetic counseling, in population screening and prenatal diagnosis, in establishing genotype–phenotype correlations and prognosis, in understanding pathogenesis, and in the development of better treatment strategies. Because of the potentially high life-long morbidity of childhood glaucomas,56 improved understanding of the genetics of these disorders would be expected to have an impact on the quality of life in patients with pediatric glaucomas.
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3. Jaffar MS. Care of the infantile glaucoma patient. In: Reineck RD, ed. Ophthalmol Annual. Raven Press: New York; 1988:15. 4. Dandona L, Williams JD, Williams BC, Rao GN. Population-based assessment of childhood blindness in Southern India. Arch Ophthalmol 1998; 116:545–546. 5. Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet 1997; 6:641–647. 6. Bejjani BA, Lewis RA, Tomey KF, et al. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am J Hum Genet 1998; 62:325–333. 7. Plasilova M, Stoilov I, Sarfarazi M, et al. Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma. J Med Genet 1999; 36:290–294. 8. Panicker SG, Reddy ABM, Mandal AK, et al. Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees. Invest Ophthalmol Vis Sci 2002; 43:1358–1366. 9. Duke-Elder S. Congenital deformities. In: Duke-Elder S, ed. System of Ophthalmology. Mosby: St. Louis; 1969:548–565. 10. Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye 2000; 14:422–428. 11. Stoilov I, Akarsu AN, Alozie I, et al. Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1. Am J Hum Genet 1998; 62:573–584. 12. Westerlund E. Clinical and genetic studies on the primary glaucoma diseases. NYT Norsdic Forlag, Arnold Busck: Copenhagen; 1947. 13. Gencik A. Epidemiology and genetics or primary congenital glaucoma in Slovakia: description of a form of primary congenital glaucoma in gypsies with autosomal recessive inheritance and complete penetrance. Dev Ophthalmol 1989; 16:75–115. 14. Sarfarazi M, Akarsu AN, Hossain A. Assignment of a locus (GLC3A) for primary congenital glaucoma (buphthalmos) to 2p21 and evidence for genetic heterogeneity. Genomics 1995; 30:171–177. 15. Akarsu AN, Turacli ME, Aktan SG, et al. A second locus (GLC3B) for primary congenital glaucoma (buphthalmos) maps to the 1p36 region. Hum Mol Genet 1996; 5:1199–1203. 16. Plasilova M, Ferakova E, Kadasi L, et al. Linkage of autosomal recessive primary congenital glaucoma to the GLC3A locus in Roms (Gypsies) from Slovakia. Hum Hered 1998; 48:30–33. 17. Kakiuchi-Matsumoto T, Isashiki Y, et al. A novel truncating mutation of cytochrome P4501B1 (CYP1B1) gene in primary infantile glaucoma. Am J Ophthalmol 1999; 128:370–372. 18. Bejjani BA, Stockton DW, Lewis RA, et al. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet 2000; 9:367–374. 19. Martin SN, Sutherland J, Levin AV, et al. Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness. J Med Genet 2000; 37:422–427. 20. Ohtake Y, Kubota R, Tanino T, Miyata H, Mashima Y. Novel compound heterozygous mutations in the cytochrome P450 1B1 (CYP1B1) in a Japanese patient with primary congenital glaucoma. Ophthal Genet 2000; 21:191–193. 21. Mashima Y, Susuki Y, Sergeev Y, et al. Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci 2001; 42:2211–2216. 22. Kakiuchi-Matsumoto T, Isashiki Y, Ohba N, et al. Cytochrome P4501B1 gene mutations in Japanese patients with primary congenital glaucoma. Am J Ophthalmol 2001; 131:345–350. 23. Michels-Rautenstrauss KG, Mardin CY, Zenker M, et al. Primary congenital glaucoma: three case reports on novel mutations and combinations of mutations in the GLC3A (CYP1B1) gene. J Glaucoma 2001; 10:354–357. 24. Stoilov IR, Costa VP, Vasconcellos JPC, et al. Molecular genetics of primary congenital glaucoma in Brazil. Invest Ophthalmol Vis Sci 2002; 43:1820–1827. 25. Reddy ABM, Panicker SG, Mandal AK, et al. Identification of R368H as a predominant CYP1B1 allele causing primary congenital glaucoma in Indian patients. Invest Ophthalmol Vis Sci 2003; 44:4200–4203. 26. Belmouden A, Melki R, Hamdani M, et al. A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco. Clin Genet 2002; 62:334–339. 27. Ohtake Y, Tanino T, Suzuki Y, et al. Phenotype of cytochrome P4501B1 gene (CYP1B1) mutations in Japanese patients with primary congenital glaucoma. Br J Ophthalmol 2003; 87:302–304. 28. Soley GC, Bosse KA, Flikier D, et al. Primary congenital glaucoma. A novel
21
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single-nucleotide deletion and varying phenotypic expression for the 1546–1555dup mutation in the GLC3A (CYP1B1) gene in 2 families of different ethnic origin. J Glaucoma 2003; 12:27–30. Sitorus R, Ardjo SM, Lorenz B, Preising M. CYP1B1 gene analysis in primary congenital glaucoma in Indonesian and European patients. J Med Genet 2003; 40:e9. Colomb E, Kaplan J, Garchon HJ. Novel cytochrome P450 1B1 (CYP1B1) mutations in patients with primary congenital glaucoma in France. Hum Mutat 2003; 22:496. Sarfarazi M, Stoilov I, Schenkman JB. Genetics and biochemistry of primary congenital glaucoma. Ophthalmic Clin North Am 2003; 16:543–554. Panicker SG, Mandal AK, Reddy ABM, et al. Correlations of genotype with phenotype in Indian patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci 2004; 45:1149–1156. Vincent LA, Billingsley G, Buys Y, et al. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 2002; 70:448–460. Libby RT, Smith RS, Savinova OV, et al. Modification of ocular defects in mouse developmental glaucoma models by tyrosinase. Science 2003; 299:578–581. Shields MB, Buckely E, Klintworth GK, Thresher R. Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol 1985; 29:387–409. Gould DB, Mears AJ, Pearce WG, Walter MA. Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25. Am J Hum Genet 1997; 61:765–768. Alward WLM. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 2000; 130:107–115. Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/wingedhelix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 1998; 63:1316–1328. Nishimura YD, Searby CC, Alward WL, et al. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Am J Hum Genet 2001; 68:364–372. Panicker SG, Sampath S, Mandal AK, et al. Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly. Invest Ophthalmolol Vis Sci 2002; 43:1358–1366. Komatireddy S, Chakrabarti S, Mandal AK, et al. Mutation spectrum of FOXC1 and clinical genetic heterogeneity of Axenfeld-Rieger anomaly in India. Mol Vis 2003; 9: 43–48.
42. Netland PA, Wiggs JL, Dreyer EB. Inheritance of glaucoma and genetic counseling of glaucoma patients. Int Ophthalmol Clin 1993; 33:101–120. 43. Mintz-Hittner HA. Aniridia. In: Ritch R, Shields MB, Krupin T, eds. The Glaucomas. Mosby: St. Louis; 1996:859–874. 44. Jordan T, Hanson I, Zaletayev D, et al. The human PAX6 gene is mutated in two patients with aniridia. Nat Genet 1992; 1:328–332. 45. Glaser T, Walton DS, Maas RL. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet 1992; 2:232–239. 46. Davis A, Cowell JK. Mutations in the PAX6 gene in patients with hereditary aniridia. Hum Mol Genet 1993; 2:2093–2097. 47. Axton R, Hanson I, Danes S, et al. The incidence of PAX6 mutation in patients with simple aniridia: an evaluation of mutation detection in 12 cases. J Med Genet 1997; 34:279–286. 48. Azuma N, Hotta Y, Tanaka H, Yamada M. Missense mutations in the PAX6 gene in aniridia. Invest Ophthalmol Vis Sci 1998; 39:2524–2528. 49. Lauderdale JD, Wilensky JS, Oliver ER, Walton DS, Glaser T. 3′ deletions cause aniridia by preventing PAX6 gene expression. Proc Natl Acad Sci USA 2000; 97:13755–13759. 50. Zumkeller W, Orth U, Gal A. Three novel PAX6 mutations in patients with aniridia. Mol Pathol 2003; 56:180–183. 51. Dharmaraj N, Reddy A, Kiran V, et al. PAX6 gene mutations and genotypephenotype correlations in sporadic cases of aniridia from India. Ophthalmic Genet 2003; 24:161–165. 52. Churchill AJ, Hanson IM, Markham AF. Prenatal diagnosis of aniridia. Ophthalmology 2000; 107:1153–1156. 53. Muto R, Yamamori S, Ohashi H, Osawa M. Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients. Am J Med Genet 2002; 108:285–289. 54. Gronskov K, Olsen JH, Sand A, et al. Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet 2001; 109:11–18. 55. Crolla JA, Cawdery JE, Oley CA, et al. A FISH approach to defining the extent and possible significance of deletions at the WAGR locus. J Med Genet 1997; 34:207–212. 56. Craig JE, Mackey DA. Glaucoma genetics: where are we? Where will we go? Curr Opn Ophthalmol 1999; 10:126–134.
Chapter 5 Pathology and pathogenesis of developmental glaucomas Introduction Barkan’s membrane theory Histopathological observations in primary congenital glaucoma Histopathological observations in secondary glaucoma Causes of elevated intraocular pressure Effects of elevated intraocular pressure in the infant eye Conclusion
Introduction The initial theory for the pathogenesis of primary congenital glaucoma was Barkan’s membrane theory, which attributed resistance to aqueous flow to an imperforate membrane covering the angle structures. This membrane, however, has not been confirmed histopathologically. Known histopathological changes in primary congenital glaucoma include an anterior iris insertion, thickened trabecular beams, compressed trabecular sheets with loss of intertrabecular spaces, iris processes, and insertion of the fibers of the ciliary muscle into the trabecular meshwork. The main theory that accounts for these changes is a developmental arrest of the anterior chamber angle structures derived from neural crest cells during gestation. The degree of angle immaturity has been correlated with the age of presentation of glaucoma, with more severe angle immaturity or dysgenesis presenting in the perinatal period. Other mechanisms have been proposed for other congenital and secondary glaucomas.
Barkan’s membrane theory The initial observations of Barkan1–7 suggested that in primary infantile glaucoma a thin, imperforate membrane covering the anterior chamber angle of the eyes prevents aqueous humor outflow, and leads to increased intraocular pressure. At the time of goniotomy, the theory asserts, this surface tissue is severed, the peripheral iris ‘falls’ posteriorly, and aqueous humor flow is established.8 This surface membrane, given the eponymic name Barkan’s membrane, was proposed as an endothelial surface that normally breaks apart, but which persists in congenital glaucoma. Indeed, Hansson and Jerndal9 demonstrated in scanning electron micrographs a continuous endothelial surface layer of trabecular meshwork that normally cavitates during the last weeks of fetal
development, but could conceivably remain imperforate in primary infantile glaucoma. Several reasons have been proposed for the lack of histopathological confirmation of a persistent membrane in primary congenital glaucoma, including: inadequacy of the specimens examined,10,11 surgical manipulation of the infant eye before specimens are obtained for histopathological examination, the late stage of the disease (with secondary changes) that is typically available for microscopic study, and artifacts induced by the fixation process itself.9–11 However, even in suitable specimens, Anderson,10,12 Hansson,9 Maul and co-workers,11 and Maumenee13 could find no evidence of a membrane in any of the specimens they examined by light and electron microscopy. The most likely explanation for no histopathological confirmation of a persistent membrane is that a membrane has little or no role in the pathogenesis of primary congenital glaucoma.
Histopathological observations in primary congenital glaucoma Based on the numerous examinations of the anterior chamber angle of eyes with primary congenital glaucoma, certain microscopic and ultrastructural observations have been confirmed in this disease (Table 5.1).8,10,11–22 These studies have shown an anterior iris insertion with thickened and compact trabecular beams and excessive extracellular matrix material. Proliferation of fibrous tissue has been described at the inner wall of Schlemm’s canal, with accumulation of collagen fibers and agglomerations of microfibrillar material.23 The microfibrillar material was found to form basement membrane-like structures and fingerprint-like patterns.23 Figure 5.1 shows the common microscopic findings in primary congenital glaucoma. An anterior insertion of the iris is a characteristic finding. The general appearance has been described as nondifferentiation of the trabecular meshwork and persistence of embryonic characteristics. The thickening of the uveal cords may prevent the posterior migration of the ciliary body and iris that normally occurs during the last weeks of gestation, thus causing incomplete differentiation of the angle.10,24,25 Observations strongly suggest developmental immaturity26 of the trabecular meshwork and Schlemm’s canal system, rendering it functionally incompetent. Corneal findings by in vivo confocal microscopy have been described in patients with primary congenital glaucoma.27 There was a reduction of keratocyte density in the stroma, 23
Pathology and pathogenesis
Table 5.1 Microscopic and ultrastructural observations in primary congenital glaucoma Location
Finding
Iris
Anterior insertion (with open angle configuration)8,10,11–14 Iris processes (also called pectinate ligaments16) present14,17 Longitudinal fibers of ciliary muscle insert directly onto trabecular meshwork, because scleral spur not yet developed10,12,13,18,19,41
Trabecular meshwork
Trabecular beams thicker than normal10,11 Deeper trabecular sheets compressed with decreased intertrabecular spaces9–11
Schlemm’s canal
Amorphous material in the subendothelial region10,11 Few Holmberg15 vacuoles (vesicles) on endothelial surface of Schlemm’s canal, presumably due to decreased flow of aqueous10,11 Some cases reported of faulty development or absence of Schlemm’s canal.20–22 Congenital absence of canal is very rare, if it exists at all. Most often, canal is compressed and difficult to identify
Ciliary processes
Anteriorly displaced and pulled inward due to enlarging globe with non-enlarging lens10,13,18,19,41
Membrane
Instead of imperforate membrane, proposed by Barkan1–7 and Worst,8 most observers have documented compact mass of compressed trabecular tissue, giving the illusion of a continuous membrane.10,11,14
C
AC TM I
Figure 5.1 Microscopic appearance of the anterior chamber angle in a patient with primary congenital glaucoma. There is an anterior insertion of the iris (I), which extends over the poorly developed trabecular meshwork (TM). Schlemm’s canal is present adjacent to the trabecular meshwork. The ciliary muscle and the rudimentary scleral spur insert into the trabecular meshwork. C = cornea, AC = anterior chamber. Periodic acidSchiff (PAS) stain, original magnification ×100. Original photograph provided courtesy of William R. Morris, MD.
and discontinuous hyperreflective structures overhanging the endothelial layer at the level of Descemet’s membrane. The endothelium showed severe polymegethism, pleomorphism, and a markedly decreased cell density, with focal cellular lesions.27
Histopathological observations in secondary glaucoma Cases of secondary glaucoma associated with other neonatal or developmental anomalies include anterior chamber cleavage syndrome of Axenfeld and Rieger and Peters anomaly 24
(iridocorneotrabeculodysgenesis), encephalotrigeminal angiomatosis (Sturge–Weber syndrome), neurofibromatosis (Von Recklinghausen disease), maternal rubella syndrome, and retinopathy of prematurity. The pathogenesis in most of these disorders is different from that in primary infantile glaucoma, as evidenced by the poor response of these secondary glaucomas to classic infantile glaucoma surgery, such as goniotomy or trabeculotomy ab externo. The occasional association of trabecular dysgenesis with other anomalies may be explained by a common neural crest cell origin of the affected tissue.28 Although Axenfeld–Rieger syndrome is characterized by a prominent, anteriorly displaced line of Schwalbe with attachment of tissue strands of peripheral iris, several reports have documented structural alterations in the trabecular meshwork and Schlemm’s canal29–31 similar to that seen in primary congenital glaucoma. Shields has postulated that the changes in the anterior segment of the eyes in patients with Axenfeld–Rieger syndrome result from an arrest in the development of the tissues derived from neural crest cells that occurs late in gestation.29,30 Peters anomaly is characterized by a spectrum of changes in the anterior segment structures. Only a few studies have been reported on the structure of the trabecular meshwork and Schlemm’s canal in patients with Peters anomaly. In one patient who had total peripheral anterior synechia, Schlemm’s canal and the trabecular meshwork could not be identified.32 Kupfer et al33 studied the trabeculectomy specimen from the eye of a 2-year-old child with Peters anomaly and reported that the trabecular beams showed thickening, with the presence of ‘curly’ collagen. The endothelial cells contained an abnormal amount of phagocytosed pigment granules. Again, the authors suggested that the structural alterations could have resulted from a failure of differentiation of neural crest-derived cells that were destined to form the trabecular and corneal endothelial cells.33,34 In some cases of Sturge–Weber syndrome, the anterior chamber angle is histologically identical to that in primary
Conclusion infantile glaucoma. Phelps35 and Weiss36 have suggested that elevated episcleral venous pressure may be an additional problem in the etiology of the glaucoma in this condition. Trabeculectomy specimens from patients with Sturge–Weber syndrome revealed not only a compact trabecular meshwork with thickening and hyalinization of the trabeculae, but also the presence of amorphous material and abnormal collagen. The juxtacanalicular region showed an excess of extracellular elements (granuloamorphous material, basal lamina material, banded and non-banded structures), and degenerative changes were noted in the cellular component.37 These alterations in patients with Sturge–Weber syndrome suggested premature aging of the trabecular meshwork and Schlemm’s canal. The defect in the aqueous outflow pathway can arise early in the development of the anterior chamber, because some of these patients have glaucoma and even buphthalmos soon after birth. In the maternal rubella syndrome, the anterior chamber angle resembles that in primary infantile glaucoma both clinically and histopathologically.12 Indeed, several cases of reported primary infantile glaucoma were actually cases of maternal rubella syndrome, which were either inapparent or subclinical.12 Retinopathy of prematurity has been associated with a shallow anterior chamber and angle-closure glaucoma.38 However, gonioscopic observation in infants with stage IV and V retinopathy of prematurity has identified structural abnormalities of the anterior chamber angle that may have developmental origin.39
Causes of elevated intraocular pressure Clinical evidence supports the theory that the obstruction to aqueous flow with a resultant increase in intraocular pressure is located at the trabecular meshwork area. Incision into the trabecular meshwork by goniotomy or trabeculotomy relieves the obstruction and normalizes the intraocular pressure in the majority of cases. The surgical incision may relieve the compaction of the trabecular sheets and allow the trabecular spaces to open. Surgical success with goniotomy is achieved by a superficial incision into the trabecular meshwork.40 The iris root drops backward as the blade incises the meshwork. It may be that the thickened cords of uveal meshwork hold the iris anteriorly. Superficial incision of the thickened uveal meshwork will allow the iris root to drop posteriorly with accompanying posterior rotation of the scleral spur. This might allow opening of the corneoscleral trabecular sheets with improved outflow of aqueous. Schlemm’s canal has been found to be open both histologically and clinically, and does not appear to be the site of obstruction to aqueous flow.10,41 Tissue abnormalities adjacent to or involving the internal wall of Schlemm’s canal are a less likely source for the resistance to aqueous flow as it is unlikely that goniotomy incisions consistently cut this tissue. Incisions at various heights along the meshwork have all been found to relieve the resistance to outflow.42
Effects of elevated intraocular pressure in the infant eye During the first 3 years of life, the extracellular fibers of the eye are softer and more elastic than in older individuals. Thus, elevation of the intraocular pressure causes rapid enlargement of the globe, which is especially apparent as a progressive corneal and limbal enlargement. The normal neonatal horizontal corneal diameter of 10.0 to 10.5 mm may be enlarged to as much as 16 to 18 mm. As the cornea and limbus enlarge, Descemet’s membrane and the corneal endothelium are stretched. This can result in linear ruptures (Haab’s striae), which in turn can lead to corneal scarring if the problem is chronic. The thinned endothelium may also decompensate in adult life, despite a normal intraocular pressure, when aging changes are superimposed upon the initial endothelial damage.43 As the eye enlarges, the iris is stretched and the overlying stroma may appear thinned. The scleral ring through which the optic nerve passes also enlarges with elevated intraocular pressure, which can lead to an enlargement of the optic cup even in the absence of loss of optic nerve fibers.44 The disc is cupped more quickly in the infant as compared to the adult eye, and reversal of the enlargement can also occur rapidly after normalization of the intraocular pressure. This is probably related to the increased elasticity of the connective tissues of the optic nerve head in the infant eye, which allows an elastic or compression response to fluctuation in intraocular pressure.45,46 Eyes with advanced disease are enlarged in all dimensions. The root of iris and trabecular meshwork are degenerated and thinned, and Schlemm’s canal may not be evident. The ciliary body is atrophic, as are the retina and choroid. The zonules may be degenerated and the lens displaced.43 The optic nerve may show complete cupping.
Conclusion There are certain similarities in the morphologic features of the trabecular meshwork and Schlemm’s canal in most of the disorders associated with the developmental glaucoma. This disorder usually manifests itself as an anterior iris insertion with thickening of the trabecular beams caused by increased amounts of extracellular components, a consequent reduction of the intertrabecular spaces, and an attenuation of the endothelium. These findings have been described as nondifferentiation of the trabecular meshwork or as persistence of embryonic characteristics. Observations strongly suggest developmental immaturity of the trabecular meshwork and Schlemm’s canal system, which renders it functionally incompetent. The more extensive the immaturity, the earlier the glaucoma appears.
References 1. Barkan O. Technique of goniotomy. Arch Ophthalmol 1938; 19:217. 2. Barkan O. Operation for congenital glaucoma. Am J Ophthalmol 1942; 25:525. 3. Barkan O. Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol 1948; 32:701.
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Pathology and pathogenesis 4. Barkan O. Techniques of goniotomy for congenital glaucoma. Arch Ophthalmol 1949; 41:65. 5. Barkan O. Surgery of congenital glaucoma. Review of 196 eyes operated by goniotomy. Am J Ophthalmol 1953; 36:1523–1534. 6. Barkan O. Pathogenesis of congenital glaucoma. Gonioscopic and anatomic observation of the angle of the anterior chamber in the normal eye and in congenital glaucoma. Am J Ophthalmol 1955; 40:1–11. 7. Barkan O. Goniotomy. Trans Am Acad Ophthalmol 1955; 59:322–332. 8. Worst JGF. Congenital glaucoma. Remarks on the aspect of chamber angle, ontogenic and pathogenic background, and mode of action of goniotomy. Invest Ophthalmol 1968; 7:127–134. 9. Hansson HA, Jerndal T. Scanning electron microscopic studies on the development of the iridocorneal angle in human eyes. Invest Ophthalmol 1971; 10:252–265. 10. Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–465. 11. Maul E, Strozzi L, Munoz C, Reys C. The outflow pathway in congenital glaucoma. Am J Ophthalmol 1980; 89:667–673. 12. Anderson DR. Pathology of the glaucomas. Br J Ophthalmol 1972; 56:146–157. 13. Maumenee AE. The pathogenesis of congenital glaucoma: a new theory. Trans Am Ophthalmol Soc 1958; 56:507–570. 14. Sampaolesi R, Argento C. Scanning electron microscopy of the trabecular meshwork in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 1977; 16:302–314. 15. Holmberg AS. Schlemm’s canal and the trabecular meshwork. An electron microscopic study of the normal structures in man and monkey (Cereopithecus ethops). Doc Ophthalmol 1965; 19:339–373. 16. Barishak YR. The development of the angle of the anterior chamber in vertebrate eyes. Doc Ophthalmol 1978; 45:329–360. 17. Sampaolesi R, Zarate JO, Caruso R. Congenital glaucoma light and scanning electron microscopy of trabeculectomy specimens. In: Leydhecker W, Krieglstein GK, eds. International Glaucoma Symposium, Nara, Japan, 1978: Glaucoma Update. Springer Verlag: New York; 1979:39–51. 18. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Trans Am Ophthalmol Soc 1962; 60:140–146. 19. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176. 20. Shaffer RN. Pathogenesis of congenital glaucoma. Gonioscopic and microscopic anatomy. Trans Am Acad Ophthalmol Otolaryngol 1955; 59:297–308. 21. Ikui H, Iwaki S. Histological studies on the development of narrow angle glaucoma (Preliminary report). Acta Soc Ophthalamol Jpn 1959; 63:2412. 22. Crombie AL, Cullen JF. Hereditary glaucoma occurrence in five generations of an Edinburgh family. Br J Ophthalmol 1964; 48:143–147. 23. Bakunowicz-Lazarczyk A, Sulkowska M, Sulkowski S, Urban B. Ultrastructural changes in the trabecular meshwork of congenital glaucoma. J Submicrosc Cytol Pathol 2001; 33:17–22. 24. Speakman JS, Leeson TS. Pathological findings in a case of primary congenital glaucoma compared with normal infant eyes. Br J Ophthalmol 1964; 48:196–204.
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25. Hoskins HD Jr, Hetherington J Jr, Shaffer RN, Welling AM. Development glaucomas: diagnosis and classification. In: Symposium on glaucoma. Trans New Orleans Acad Ophthalmol. St. Louis, 1981. 26. Tawara A, Inomata H. Developmental immaturity of the trabecular meshwork in congenital glaucoma. Am J Ophthalmol 1981; 92:508–525. 27. Mastropasqua L, Carpineto P, Ciancaglini M, Nubile M, Doronzo E. In vivo confocal microscopy in primary congenital glaucoma with megalocornea. J Glaucoma 2002;11:83–89. 28. Kupfer C, Kaiser-Kupfer MI. Observations on the development of the anterior chamber angle with reference to the pathogenesis of congenital glaucomas. Am J Ophthalmol 1979; 88(3 Pt 1):424–426. 29. Shields MB. Axenfeld-Rieger syndrome: a theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc 1983; 81:736–784. 30. Shields MB, Buckley E, Eleintworth G, Threshwer R. Axenfeld-Rieger syndrome: a spectrum of developmental disorders. Surv Ophthalmol 1985; 29:387–409. 31. Wolter JR, Somdall GS, Fraliek FB. Mesodermal dysgenesis of anterior eye with a partially separated posterior embryotoxon. J Pediatr Ophthalmol 1967; 4:41. 32. Scheie HG, Yanoff M. Peter’s anomaly and total posterior coloboma of retinal pigment epithelium and choroid. Arch Ophthalmol 1972; 87:525–530. 33. Kupfer C, Kuwabara T, Stark W. The histopathology of Peters anomaly. Am J Ophthalmol 1975; 80:653. 34. Kupfer C, Kaiser-Kupfer MI. New hypothesis of developmental anomalies of the anterior chamber associated with glaucoma. Trans Ophthalmol Soc UK 1978; 98:213. 35. Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome. Trans Ophthalmol Soc UK 1978; 98:213. 36. Weiss DI. Dual origin of glaucoma in encephalotrigeminal haemangiomatosis. Trans Ophthalmol Soc UK 1973; 93:477–493. 37. Cibis GW, Tripathi RC, Tripathi BJ. Glaucoma in Sturge-Weber syndrome. Ophthalmology 1984; 91:1061–1071. 38. Pollard ZF. Secondary angle-closure glaucoma in cicatricial retrolental fibroplasia. Am J Ophthalmol 1980; 89:651–653. 39. Hartnett ME, Gilbert MM, Richardson TM, et al. Anterior segment evaluation of infants with retinopathy of prematurity. Ophthalmology 1990; 97:122–130. 40. Shaffer RN, Weiss DI. Congenital and pediatric glaucomas. CV Mosby: St. Louis; 1970. 41. Maumenee AE. The pathogenesis of congenital glaucoma: a new theory. Am J Ophthalmol 1959; 47:827–858. 42. Hoskins HD Jr, Kass MA. Becker-Shaffer’s diagnosis and therapy of the glaucomas. CV Mosby: St. Louis; 1989. 43. Spencer WH. Ophthalmic pathology, an atlas and textbook. WB Saunders: Philadelphia; 1985. 44. Quigley H. Childhood glaucoma, results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–226. 45. Quigley HA. The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 1977; 84:358–370. 46. Wu SC, Huang SC, Kuo CL, Lin KK, Lin SM. Reversal of optic disc cupping after trabeculectomy in primary congenital glaucoma. Can J Ophthalmol 2002; 37:337–341.
Chapter 6 Primary congenital glaucoma Introduction Clinical features The diagnostic examination Conditions with overlapping signs of epiphora and ‘red-eye’ Conditions with overlapping signs of corneal enlargement Conditions with overlapping signs of corneal edema and opacity Conditions with overlapping signs of optic nerve abnormalities Conditions associated with increased intraocular pressure Conclusion
Introduction Primary congenital glaucoma refers to a specific form of developmental glaucoma, which has an isolated maldevelopment of the trabecular meshwork (isolated trabeculodysgenesis) not associated with other developmental ocular anomalies or ocular disease that can raise the intraocular pressure. The term primary infantile glaucoma has the same meaning as primary congenital glaucoma. It is the most common form of developmental glaucoma, occurring in about 1 in 10 000 live births. Primary congenital glaucoma is typically bilateral, although a significant intraocular pressure elevation may
occur in only one eye in 25 to 30% of the cases. In this chapter, we will discuss the clinical features, the diagnostic examination and the differential diagnosis of the disease.
Clinical features Primary congenital glaucoma may present with a classic triad of symptoms (Fig. 6.1A-C).1 These symptoms include epiphora (excessive tearing), photophobia (hypersensitivity to light), and blepharospasm (squeezing of the eyelids). Any combination of these symptoms should arouse suspicion of glaucoma in an infant or child. These symptoms are secondary to the corneal irritation that accompanies corneal epithelial edema caused by elevated intraocular pressure. Epiphora may at first be attributed to a non-patent tear drainage system, which is a common condition. Photophobia commonly occurs and may be of gradual or sudden onset. The parents may first notice that their baby keeps the eyes closed when exposed to sunlight, and their usual reaction is to provide some shade, in the belief that the baby is merely showing normal sensitivity to light. Moderate photophobia may be noticed indoors as well; the baby will often keep the eyes closed even while eating. Severe photophobia will cause the baby to keep the eyes closed constantly or to hide the face from bright lighting or even from ordinary lighting. During the period of apparent discomfort, the baby may also be seen to rub the eyes frequently.2 Primary infantile glaucoma may also present as a ‘red eye,’ mimicking conjunctivitis and delaying the correct diagnosis.1,3,4 Enlargement of the eye occurs under the influence
A B
Figure 6.1 Symptoms of primary congenital glaucoma include: tearing (A), photophobia (B), and blepharospasm (C).
C
27
Primary congenital glaucoma of the elevated intraocular pressure, with the major enlargement occurring at the corneoscleral junction. A hazy appearance of the cornea can be intermittent in the early stages and precede breaks in Descemet’s membrane.
Ocular enlargement Ocular enlargement occurs because the neonatal globe is still distensible (Fig. 6.2). The corneal and scleral collagen have not hardened sufficiently to prevent their expansion with increased intraocular pressure. This change includes stretching in all parts of the infant eye, including the cornea, the anterior chamber angle, the sclera, the optic nerve, the scleral canal, and the lamina cribrosa.1,3 The normal neonatal horizontal corneal diameter is approximately 10 to 10.5 mm, increasing an additional 0.5 to 1.0 mm in the first year of life.5 Enlargement of the corneal diameter to greater than 12 mm in the first year of life is highly suspicious of developmental glaucoma.1 This enlargement is more obvious in asymmetric cases. Corneal enlargement from increased intraocular pressure predominantly occurs before the age of three years,6,7 but the sclera may be deformable until approximately age 10 years.8 The increased intraocular pressure stretches the corneal endothelium and Descemet’s membrane, resulting in breaks in these layers, first described by Haab in 1863 (Fig. 6.3).4,7 As the edge of the rupture in Descemet’s membrane contracts into scrolls and ridges,7 infiltration of the aqueous humor causes localized corneal edema, compounding any diffuse edema that may also be present simply because of the elevated intraocular pressure. Haab’s striae form as endothelial cells lay down new basement membrane (Descemet’s membrane) and hyaline ridges develop.4,7 Haab’s striae are typically horizontal and linear when they occur centrally in the cornea, but parallel or curvilinear to the limbus when they occur peripherally.4,6,7,9 They do not seem to occur in corneas smaller than 12.5 mm in diameter. Breaks in the Descemet’s membrane from increased intraocular pressure rarely occur after the age of three years.7 Haab’s striae occur in approximately 25% of patients who have primary infantile
Figure 6.2 Infant with megalocornea and corneal edema due to primary congenital glaucoma. 28
A
B Figure 6.3 Slit lamp biomicroscopy of Haab’s striae with diffuse illumination (A) and retroillumination (B).
glaucoma at birth and are evident in over 60% of infants presenting with primary infantile glaucoma at 6 months of age.10,11 The initial corneal edema in primary infantile glaucoma is simple epithelial edema due to elevated intraocular pressure. In chronic primary infantile glaucoma, there is permanent stromal edema.14,15 Persistence and progression of primary infantile glaucoma may lead to permanent sequelae, such as stromal scarring, chronic stromal corneal edema, and irregular corneal astigmatism12,13 Younger children are more likely to present to the ophthalmologist with corneal edema and haze, while older children will more commonly present with frank corneal enlargement or buphthalmos.16 The sclera also expands slowly under the influence of elevated intraocular pressure. The associated scleral thinning causes an increased visibility of the underlying uveal tissue in the neonate and a ‘blue-sclera’ appearance (Fig. 6.4). With the gradual deposition of additional extracellular connective tissue that occurs during growth,17 no further expansion of sclera occurs. Once buphthalmos has developed, the globe usually does not return to normal size with normalization
Clinical features
A
B Figure 6.4 Child with congenital glaucoma and ‘blue-sclera’ appearance due to buphthalmos and scleral thinning.
Figure 6.5 Glaucomatous optic nerve damage in congenital glaucoma with elevated intraocular pressure. Note the enlarged optic nerve cup with an intact neural rim (A). End-stage cupping (B).
of the intraocular pressure.17 As the axial length of the globe increases, myopia and astigmatism result.18,19 Myopic astigmatism and anisometropia are particularly common in cases of unilateral or asymmetric primary infantile glaucoma.
Optic nerve cupping The optic nerve changes in primary congenital glaucoma are different from those occurring in adults with glaucoma. Optic nerve cupping may occur rapidly and early in infants (Fig. 6.5).17,20–23 Also, cupping of the optic nerve head may be reversible with normalization of intraocular pressure (Fig. 6.6),24,25 whereas this is uncommon in the adult with glaucomatous induced optic nerve head damage.17 Several hypotheses have been proposed to explain the optic nerve head cupping in infants. First, it has been suggested that astroglial cell loss may be induced by elevated intraocular pressure.21 Second, extracellular fluid shifts in the optic nerve head may contribute to changes in the cup at different levels of intraocular pressure.26 Third, posterior displacement of the lamina cribrosa and enlargement of the scleral canal may account for changes in the cup size with fluctuation of intraocular pressure during infancy.17,27 The third explanation
Figure 6.6 Appearance of the optic nerve of a child with congenital glaucoma after surgical treatment and normalization of the intraocular pressure. The cup shows mild concentric enlargement with increased vertical cup-to-disc ratio and an intact neural rim.
currently seems most reasonable, based on the fact that the connective tissue of the lamina cribrosa is not yet mature during early neonatal life.17 Reversibility of cupping in infantile glaucoma appears to be due to incomplete development of connective tissue in the lamina cribrosa, which allows posterior movement of the 29
Primary congenital glaucoma optic disc tissue in response to elevated intraocular pressure, with an elastic return to normal when the pressure is lowered.17 In those cases in which the damage to a neonatal optic nerve head is not partially or completely reversible upon normalization of intraocular pressure, either a portion of the stretching is permanent with remolding of the connective tissue, or there has been a loss of glia and axons.17 If the intraocular pressure is not controlled, tearing, photophobia, and blepharospasm may worsen. Continued enlargement of the cornea with more tears of Descemet’s membrane may lead to corneal scarring, erosion, and ulcerations. Stretching and rupture of the zonules can cause lens subluxation. Blunt trauma in these enlarged eyes can lead to hyphemas, retinal detachment, and rupture of the globe, and phthisis bulbi may be the final outcome.
A
The diagnostic examination The history of blepharospasm, photophobia, and tearing is very useful in arousing the suspicion of glaucoma and in distinguishing it from other conditions. Other historical information of importance is the family history of glaucoma, associated congenital defects, maternal history of infection (rubella) during pregnancy, and birth history.13
Initial examination During the initial office visit, the examiner may be able to observe the degree of photophobia, blepherospasm, and tearing. Ideally, the examiner captures the infant’s open-eyed attention with a slowly blinking flashlight or a gentle jingle of keys and then can observe the corneal size and clarity without touching the baby’s face. The effort may be unavoidably impossible, and often the inexperienced examiner aggravates the difficulty by moving too quickly or frightening the child with a loud clatter of keys, whistling and clicking sounds, and perhaps a futile effort to pry open the lids. Meanwhile, the anxious mother, realizing the importance of the examination and sensing the examiner’s desire for a close look, frantically pats and rocks the baby. As the baby cries, the mother and the examiner not only feel frustrated in their efforts, but become tense. The examiner with insight will avoid making the examination more difficult than it is already. At this point, the examiner may have determined that there is an enlarged or cloudy cornea, and that the patient has photophobia, blepharospasm, and tearing. The diagnosis of primary infantile glaucoma may be sufficiently obvious or likely that it is almost certain that examination and possible surgery under general anesthesia is going to be required. In any event, it should be kept in mind that the goal of the office examination is to accomplish an examination sufficient to rule out glaucoma making examination under anesthesia unnecessary; or to gather enough information to establish the suspicion of primary infantile glaucoma, justifying administration of general anesthesia for a more complete ocular examination and probable surgery. Usually, a complete ocular examination, including slit-lamp examination, applanation tonometry, gonioscopy, and optic 30
B Figure 6.7 Distracting an awake child with a bottle or pacifier can permit accurate measurement of intraocular pressure and a thorough examination. Many children are cooperative with an office examination (A, B). In these photographs, the intraocular pressure is measured using an electronic (Tonopen) tonometer.
nerve evaluations can be performed in the office in children over the age of 5 years and, with some training, in children as young as 3 years. Timing the examination of an infant to occur when the child is placated by a bottle feeding can be helpful in allowing a complete examination (Fig. 6.7). If necessary, in an older child, a mild sedative such as chloral hydrate syrup (25 to 50 mg/kg body weight) can be given (Fig. 6.8). Chloral hydrate can mildly lower the intraocular pressure, and this approach is usually not necessary if patience and gentleness are exercised. Visual field examination can be performed at 5 to 6 years of age, but the patient’s short attention span and poor fixation often prevent a detailed study. The older and more cooperative the child, the more detailed the examination. By the age of 8 to 10 years, most children can cooperate for a full quantitative visual field examination.
Figure 6.8 A mild sedative such as chloral hydrate can allow complete examination, and avoid deep anesthesia (examination under anesthesia) requiring respiratory support. This child’s anterior segment and anterior chamber angle is examined using Koeppe gonioscopy.
The diagnostic examination A reasonably good office examination can sometimes be performed in infants younger than 3 months of age using the infant diagnostic lens of Richardson–Shaffer or a small diameter Koeppe lens. The lens assists in examination of the anterior segment, and enables the physician to perform gonioscopy and visualize the optic disc. It is well tolerated when placed on the eye with topical anesthesia, and, with a direct ophthalmoscope set at approximately +10.0 diopters, a very good view of the posterior pole can be obtained even with small pupils and mild corneal haze.
Examination under anesthesia (EUA) The examination under anesthesia, when necessary, provides an opportunity to thoroughly examine the eye. Anesthesia should be administered in the operating room by skilled individuals who have experience with pediatric patients. For a brief examination, oftentimes administration of intravenous and mask anesthesia is sufficient. For more prolonged examination and treatment, an endotracheal tube may be necessary. The basic equipment required to perform an adequate examination under anesthesia to ascertain the diagnosis of primary infantile glaucoma is shown in Table 6.1.
Corneal clarity and corneal diameter The cornea is examined to document the presence or absence of corneal edema, breaks in Descemet’s membrane (Haab’s striae), and corneal enlargement in order to distinguish the glaucomatous signs from other corneal abnormalities. The corneal diameter is measured along the horizontal and vertical meridian. The vertical meridian may be difficult to measure accurately due to encroachment of sclera at the superior limbus. Corneal diameter can be measured with calipers, but a problem with calipers is that it may be difficult to judge the actual diameter when the examiner is measuring meridian length. Kiskis and coworkers28 introduced a series of transparent plastic plates (templates) with holes of different diameters in quarter-millimeter increments to fit close to the eye so that the location of the limbus can accurately be
aligned. A corneal diameter greater than 12 mm in the first year of life is highly suggestive of infantile glaucoma.1 With an increase in the horizontal diameter above 13 mm, the limbus becomes indistinct, making measurement difficult. However, the measurement should be recorded accurately, even when it is clearly abnormal, to serve as a baseline to allow determination of further corneal enlargement at later examinations.
Refraction Determination of refractive error, including the astigmatic change by streak retinoscopy, is used as a diagnostic method to recognize ocular enlargement and distortion. Assessment of the refractive error also establishes a baseline which can be helpful to judge future progression.
Intraocular pressure measurement Tonometry can be performed with a Schiotz tonometer, Perkins hand-held applanation tonometer, or electronic (Tonopen) tonometer (Fig. 6.9). One method is usually sufficient, although, in cases where uncertainty exists, checks can be performed with other instruments. All anesthetics alter the intraocular pressure of patients with primary infantile glaucoma,29 seemingly in relation to the level of anesthesia29 and as a direct function of their effect on cardiovascular tone.13 A rapid lowering occurs particularly with halothane (Fluothane) anesthesia,13,24,29 which may produce readings 15 to 20 mm below the ‘true’ measurement.29 The intraocular pressure may be at least transiently elevated by cyclopropane or succinylcholine.13 Anesthetic drugs that achieve only light anesthesia and those that induce deeper anesthesia only slowly, such as diethyl ether, cyclopropane,13 or ketamine, allow the intraocular pressure to be measured somewhere between the artificially elevated intraocular pressure of ‘excitement’ stage of anesthesia and the artificially
Table 6.1 Equipment for examination under anesthesia (EUA) 1. Pediatric lid speculum 2. Balanced salt solution 3. Tonometer (Perkins and/or Tonopen) 4. Direct ophthalmoscope 5. Retinoscope 6. Koeppe goniolens and light source 7. Calipers or templates with different sized holes (to measure corneal diameter) *8. Portable hand-held slit-lamp *9. Ultrasound (A- or B-mode; ultrasound biomicroscope, [UBM]) *10. Hand-held Kowa camera or a specially adapted fundus camera (for optic disc and possibly fundus photographs) *Optional
Figure 6.9 An examination under anesthesia (administered by mask). The intraocular pressure is measured using the Perkins hand-held applanation tonometer. 31
Primary congenital glaucoma lowered intraocular pressure of deep anesthesia observed with halothane. Standardization of anesthesia for intraocular pressure measurement for diagnosis and follow-up of primary infantile glaucoma is obviously highly desirable, and inconsistent readings should always be interpreted with consideration of the patient’s general state of anesthesia and the specific anesthetic used.13 The normal intraocular pressure in an infant under halothane anesthesia is said to be approximately 9 to 10 mmHg30 and a pressure of 20 mmHg or more should arouse suspicion.30 The most reliable method of measuring the intraocular pressure is probably with the child awake, if cooperation permits, and the Perkins tonometer has been found to be particularly suitable in this situation.31 In one study, the mean intraocular pressure in unanesthetized newborns was 11.4 ± 2.4 mmHg.32 Another potential source of error is the method of tonometry itself. Schiotz tonometry, a commonly used method for measurement of the intraocular pressure in the operating room, is affected by corneal edema and swelling, corneal surface distortion and irregularities, and by changes in corneal curvature and ocular rigidity, conditions that all exist in primary infantile glaucoma.33,34 In cases of scarred or edematous corneas, the Mackay–Marg tonometer is considered to be more accurate.35–37 The electronic (Tonopen) tonometer is useful, but the mires observed using the Perkins applanation tonometer may be helpful in assessing the accuracy of the measurement. The normal intraocular pressure in an infant is slightly lower than in an adult, but 21 mmHg remains a useful upper limit. There is no one way of measuring intraocular pressure that is ideal. Our preference is the hand-held Perkins applanation tonometer used at that earliest stage of inhalation anesthesia before intubation to reduce errors related to anesthesia, relying on the rest of the examination to interpret the importance of the intraocular pressure reading.
Slit lamp examination This portion of the examination is best performed with a portable hand-held slit lamp. The corneal findings are judged with magnification and stereopsis. The anterior chamber in primary congenital glaucoma is characteristically deep, especially when distention of the globe is present. The iris is typically normal, although it may have stromal hypoplasia with loss of the crypts.
Gonioscopy Evaluation of the anterior chamber angle is essential for the accurate diagnosis of the developmental glaucomas. The Koeppe 14 to 16 mm lens with a Barkan light and hand-held binocular microscope provides the surgeon with the appropriate view of the angle (Fig. 6.10). Alternatively, the handheld slit lamp, if available, may be used to visualize the angle through the Koeppe lens. The Goldmann lens may also be used for viewing the angle through the operating microscope. If corneal clouding is marked, the view may be improved 32
Figure 6.10 The Koeppe lens is useful for assessing the anterior segment and the anterior chamber angle, especially during an examination under anesthesia. An excellent view of the disc and macula, also, may be obtained using the Koeppe lens and a direct ophthalmoscope.
by instilling topical glycerine solution or, if necessary, by removing the epithelium with a surgical blade38 or applying a 70% alcohol solution with a cotton applicator. The anterior chamber angle in childhood differs significantly from that of adults. In the normal newborn eye, the iris usually inserts posterior to the scleral spur. The anterior extension of the ciliary body is seen as a distinct band anterior to the iris insertion. The iris insertion into the angle is flat, because the angle recess has not yet formed. The trabecular meshwork appears thicker and more translucent than that of the adult. Absence of acquired pigmentation of the trabecular meshwork is normal in the infant eye. Illuminating the angle from the side with a slit beam may help determine the location of the trabecular meshwork posterior to the area where the light beam narrows at the end of the cornea. The formation of the angle recess, characteristic of the adult angle, in which the iris turns slightly posteriorly before inserting into the ciliary body, develops in the first 6 to 12 months of life. The normal infant eye may have some thinning of the peripheral iris.2 Gonioscopy of the eye with primary congenital glaucoma reveals an anterior insertion of the iris directly into the trabecular meshwork (Fig. 6.11).39,40 This iris insertion is most commonly flat, although a concave insertion may also be seen. In a concave insertion, the plane of the iris is posterior to the level of the scleral spur, but the anterior stroma of the iris sweeps upward to insert into the trabecular meshwork. The level of the iris insertion may vary at different areas of the angle, with some portions of the iris inserting anterior and other areas posterior to the scleral spur. The surface of the trabecular meshwork may have a stippled appearance and the meshwork may appear thicker than normal. There is no pigmented band present, but a thin section of the ciliary body may be visible through the thickened trabeculum. The peripheral iris may show a thinning of the anterior stroma.
The diagnostic examination
Figure 6.11 Gonioscopic appearance of the anterior chamber angle in an infant with primary congenital glaucoma. Note the high insertion of the iris. There is no definite visible scleral spur.
Although the angle is usually avascular, loops of vessels from the major arterial circle may be seen above the iris, which has been called the ‘Loch Ness Monster phenomenon.’41 In addition, the peripheral iris may be covered by a fine, fluffy tissue that has been referred to as ‘Lister’s morning mist.’41 Sometimes exposure of the radial iris vessels may exist in normal blue-eyed infants or in the eyes with hypoplasia of the anterior iris stroma. In such eyes there is no vascular anomaly even though the vessels are easily seen.42
Ophthalmoscopy Evaluation of the optic disc is an essential part of the examination. Ophthalmoscopy under general anesthesia is most easily performed through a semi-dilated pupil (Fig. 6.12). Mydriasis can be obtained by using a drop of 2.5% phenyl-
ephrine and 1% cyclopentolate. This seldom influences intraocular pressure or systemic blood pressure.43 If surgery is contemplated, ophthalmoscopy should be done without dilatation. One can use the hand-held direct ophthalmoscope to obtain monocular clues of optic nerve head cupping or enlargement. A good view can be facilitated by the use of a Koeppe contact lens, which neutralizes irregular corneal reflexes and also improves the view of the optic disc through a small pupil. The optic nerve head in normal newborns is typically pink, but may have slight pallor, and a small physiological cup is usually present.44 In most cases, the physiologic cupping is bilaterally symmetric, and asymmetry is suggestive evidence of glaucoma. Cup-to-disc ratios greater than 0.3 are rare in normal infants but common in infants with glaucoma and must be considered suspicious. Cupping of the optic nerve is an early sign of increased pressure. Optic nerve cupping occurs much more quickly and at lower pressures than in adults. The infant glaucomatous cup usually has a configuration different from adult glaucomas. Although it can be oval, it is more commonly round, steep walled, and central, surrounded by a uniform pink rim. The cup tends to enlarge circumferentially with glaucomatous progression, which probably results from a stretching of the scleral canal. A decrease in cupping can occur within hours or days after intraocular pressure control in the very young. This is especially marked in infants below 1 year of age.17,29 If therapy is successful, the cup will either remain stable or decrease in size. Evidence of increased cup size is indicative of uncontrolled glaucoma in an individual of any age. To provide records for future comparison, it is best to make a careful drawing or to take photographs of the optic nerve head. Robin and associates19 examined in detail the features of the optic nerve head in their 59 patients with primary infantile glaucoma by stereophotographs when possible and by careful drawings. They found that the average vertical cup/disc ratio was 0.68 ± 0.24 and the average horizontal cup/disc ratio was 0.65 ± 0.24.19 In addition, they found that 14 (25%) of involved eyes had loss of neuroretinal rim tissue at the superior and inferior poles, as in adult glaucomatous optic nerve heads, and 12 (21%) had slit defects in the arcuate area of the nerve fiber layer. Finally, they documented three prognostic factors regarding cupping. First, males tended to lose more of the neuroretinal rim tissue compared with females. Second, eyes of bilaterally involved primary infantile glaucoma patients had larger cups than unilaterally glaucomatous patients. Third, the older the patient at the time of the initial diagnosis, the greater the cupping (P < 0.001).19
Ocular fundus photography
Figure 6.12 Examination of the disc is an essential part of the examination under anesthesia. This is also the best opportunity for photographic documentation of the appearance of the optic nerve.
Ocular fundus photography is very useful in keeping a record of the appearance of the optic disc. This is best done when the infant is anesthetized, using a hand-held Kowa camera or a fundus camera placed vertically to obtain fundus pictures. Sometimes it is necessary to put a special contact lens on the eye to see through the small pupil, such as a Koeppe lens without a dimple, or use a Kowa hand-held camera and an indirect lens. 33
Primary congenital glaucoma
Ultrasonography Ultrasonic ocular biometry has been recommended by some investigators for routine use in the diagnosis and follow-up of congenital glaucoma.45,46–48 A-scan measurements can determine axial length, depth of anterior chamber, and lens thickness. The normal axial length in an infant ranges from 17.5 to 20 mm and increases to 22 mm in length by 1 year of age. Several studies have indicated that ultrasonic measurement of the axial length of the eye in infants and children is a highly valuable parameter in the diagnosis of congenital glaucoma. Results confirmed the clinical value of ultrasonic biometry for both the diagnosis of congenital glaucoma in cases with borderline intraocular pressures and to detect glaucoma in the fellow eye of patients with presumed unilateral disease.44,45 Also, the method was effective in the follow-up45–48 of patients with congenital glaucoma who had undergone surgery. It has been reported that the axial length may decrease up to 0.8 mm following surgical reduction of the intraocular pressure.48 The values of the measurements of the anterior chamber depth, the length of the vitreous body, and the axial length are significantly higher in glaucomatous eyes. An interesting finding is that the lens thickness of glaucomatous eyes is notably reduced.46 This is an important contributing factor in the emmetropization of the glaucomatous eye, the axial length of which, when considered as an isolated factor, would predict a higher myopia than observed in glaucomatous eyes.46 In congenital glaucoma, although myopia is a common finding, its magnitude does not usually reach the expected value based on the enlargement of the eyeball. The final refraction will also be influenced by other changes induced by the disease in other eye structures. The enlargement of the eye and the cornea is associated with flattening of the cornea, which reduces myopia. Also, the lens decreases in thickness, probably due to expansion of the scleral ring adjacent to the ciliary body and stretching of the zonular fibers thereby decreasing the lens thickness. Furthermore, the deepening of the anterior chamber due to posterior positioning of the lens as the eye and cornea enlarge can influence the refraction in eyes with congenital glaucoma. All of these factors contribute to the so-called emmetropization, which involves harmonization of the different and interdependent parameters that have an influence on ocular refraction. B-scan ultrasonography can support A-scan measurements in buphthalmic eyes by depicting a generalized enlargement of the globe. When the media are opaque (corneal edema, cataract), B-scan examination can delineate structural abnormalities such as retinal or choroidal detachment, or unsuspected mass lesion. High frequency ultrasound examination of the anterior segment (ultrasonic biomicroscopy or UBM) uses higher resolution imaging to depict the cornea, anterior chamber, iris and angle. UBM has been used to determine angle development values for various post-conceptual age and birth weights, including those of premature infants.49,50 In eyes with trabeculodysgenesis, elongated and anteriorly placed 34
ciliary processes may be noted.51 In congenital glaucoma patients with dense corneal opacities, this technique may be useful in delineating the extent of anterior segment abnormalities to aid in surgical planning.51
Interpretation of examination findings In most cases, after completion of the examination under anesthesia, the findings of corneal enlargement, optic nerve head changes, and buphthalmos are so typical of primary congenital glaucoma that there is little doubt about the diagnosis and the need for surgery. If the intraocular pressure is normal and the other findings are present, one can assume the intraocular pressure is artifactually lowered under anesthesia, and still secure the diagnosis and proceed with surgery. If ocular enlargement and optic nerve cupping are not typical or are absent, then it is appropriate to postpone diagnosis and therapy for 3 to 4 weeks, repeating the examination under anesthesia at that time to see if any changes have occurred to allow a clinical diagnosis. It is important to inform the parents of the possibility of a diagnosis of primary infantile glaucoma before the examination under anesthesia and obtain consent for a possible surgical procedure. If the diagnosis is confirmed, goniotomy or trabeculotomy (or combined trabeculotomy–trabeculectomy) can be performed immediately. This spares the patient another inhalation anesthesia, and allows the clinician to proceed with the definitive procedure for the disease as early as possible.
Differential diagnosis Some of the clinical features of primary congenital glaucoma are also found in other conditions, and these must be considered in the differential diagnosis. Several clinical entities deserve mention, to differentiate them from primary infantile glaucoma. Most have one of the signs or symptoms of primary infantile glaucoma, but none are completely characterized by photophobia, tearing, blepharospasm, and generalized ocular enlargement (buphthalmos) with optic nerve cupping.33 A differential diagnosis for congenital glaucoma is provided in Table 6.2.
Conditions with overlapping signs of epiphora and ‘red-eye’ The most common cause of epiphora in the infant is obstruction of the nasolacrimal drainage system. Photophobia is not associated with this problem and other signs typical of congenital glaucoma are absent. The epiphora of nasolacrimal duct obstruction is distinguished from that of infantile onset glaucoma in that the former condition is usually associated with fullness of the lacrimal sac and often has chronic mucopurulent discharge. Any of several causes of conjunctivitis1,3,4 in the infant can present with redness and tearing. Chemical conjunctivitis secondary to silver nitrate prophylaxis is a common cause in
Conditions with overlapping signs of corneal edema and opacity
Table 6.2 Differential diagnosis of primary congenital glaucoma Conditions with overlapping signs of epiphoria and ‘red eye’ Nasolacrimal duct obstruction Conjunctivitis Corneal epithelial defect, abrasion Meesman’s corneal dystrophy Reis–Buckler’s corneal dystrophy Ocular inflammation (e.g., keratitis, iridocyclitis) Conditions with overlapping signs of corneal enlargement Axial myopia Megalocornea Conditions with overlapping signs of corneal edema or opacity Sclerocornea Tears in Descemet’s membrane (e.g., obstetric trauma) Ulcers (e.g., congenital neonatal corneal herpes infection, congenital syphilis) Metabolic diseases (e.g., oculocerebrorenal syndrome of Lowe, mucopolysaccharidoses, cystinosis, mucolipidoses, amyloidosis, Fabry’s disease, glucose-6-phosphatase deficiency) Peters anomaly Endothelial dystrophies (e.g. posterior polymorphous dystrophy, congenital heriditary endothelial dystrophy) Congenital hereditary stromal dystrophy Dermoid (central corneal dermoid) Conditions with overlapping signs of optic nerve abnormalities Congenital malformation of the disc (e.g., pits, colobomas, hypoplasia) Tilted disc Large physiologic cups Conditions with overlapping signs of increased intraocular pressure Maternal rubella syndrome Secondary infantile glaucoma due to anterior chamber cleavage syndromes, phakomatoses (e.g., Sturge–Weber syndrome, Von Recklinghausen’s disease, Von Hippel–Lindau syndrome, nevus of Ota), and other secondary glaucomas Modified from Raab.33
the newborn. Bacterial, chlamydial, and viral infections are usually associated with a mucoid or mucopurulent discharge and must be ruled out. Corneal epithelial defects or abrasions are frequent causes of acute ocular irritation in children and are diagnosed by history and external examinations. Meesman’s corneal dystrophy usually presents in the first several months of life with ocular irritation. Examination reveals multiple clear to gray-white, punctate opacities of the corneal epithelium, which are intra-epithelial cysts. The condition is bilateral, dominantly inherited, and is the probable equivalent of Stocker–Holt dystrophy. Reis–Buckler dystrophy can present in the first few years of life with ocular pain secondary to recurrent epithelial erosion. Examination reveals irregular patches of opacity in the region of Bowman’s layer, with progression to a diffuse reticular pattern associated with an anterior stromal haze. Congenital hereditary endothelial dystrophy can also present with tearing and photophobia along with corneal edema. Inflammatory disease, such as keratitis and iridocyclitis, can cause corneal edema and clouding associated with pain, redness and watering. Rubella keratitis may occur in newborn patients.
Conditions with overlapping signs of corneal enlargement High degrees of axial myopia can present with large eyes, including large corneas. The other symptoms and signs of glaucoma are not present. The posterior pole findings serve to distinguish this condition from primary congenital glaucoma. A tilted appearance of the optic nerve head, peripapillary scleral halo (‘myopic crescent’), and choroidal mottling are characteristic of axial myopia, and are rarely seen in primary congenital glaucoma. Megalocornea1,5 is a condition of marked corneal enlargement, often to diameters of 14.0 to 16.0 mm. Other signs of congenital glaucoma, such as elevated intraocular pressure, abnormal cupping of the optic disc nerve head, or tears in Descemet’s membrane, are not present. These eyes have deep anterior chambers and may have iridodonesis secondary to stretched zonules and a loose lens. On gonioscopic examination, one may find a normal angle, prominent iris processes, or a broad dense area of pigmented trabecular meshwork.24 The inheritance appears to be sex-linked, with ninety percent of cases occurring in males. Families have been reported in which some members have megalocornea and others have primary infantile glaucoma.19,52 Indeed, some have considered megalocornea a forme fruste of primary infantile glaucoma.49 These patients, while not in need of treatment, must be followed carefully for possible intraocular pressure changes indicative of primary infantile glaucoma.4,5,52
Conditions with overlapping signs of corneal edema and opacity In sclerocornea, opaque scleral tissue extends into the cornea. Vessels usually accompany the tissue in this typically bilateral (90%), non-hereditary disease. Obstetric trauma can cause rupture of the Descemet’s membrane with resultant corneal edema and clouding. The tears in Descemet’s membrane may mimic the Haab’s striae of primary infantile glaucoma.7 There is no unequivocal way of determining whether breaks in the Descemet’s membrane are due to birth trauma or increased intraocular pressure. It has often been stated that Descemet’s membrane breaks from birth trauma are vertically oriented while those caused by increased intraocular pressure are horizontal.7,53 However, they are also frequently curvilinear and often can run diagonally across the cornea as well. Obstetric corneal trauma is usually unilateral and more commonly affects the left eye because of the higher incidence of left occiput anterior presentation of the infant’s head at birth. There are attendant signs of periorbital skin changes as a result of trauma (bruising), normal intraocular pressure, and no corneal enlargement.7 Congenital or neonatal ocular herpes infections are extremely rare. Ocular herpes in the newborn include one or all of the following: conjunctivitis, epithelial keratitis, epithelial ulcer, stromal immune reaction, cataracts, and necrotizing chorioretinitis.54,55 In congenital ocular herpes, the infection may be acquired in utero via the transplacental route. Neonatal ocular herpes is almost invariably secondary to direct 35
Primary congenital glaucoma exposure to HSV-2 in the birth canal during the late prenatal period or during passage of the baby through an infected canal at birth itself. Corneal involvement in congenital syphilis may manifest as bilateral interstitial keratitis and ulceration. Several metabolic diseases can produce corneal clouding mimicking the corneal edema of primary congenital glaucoma. Other disorders may be associated with glaucoma, although they can be distinguished from primary congenital glaucoma. For example, oculocerebrorenal syndrome of Lowe, an X-linked recessive condition of renal tubular acidosis and cataracts, may be associated with glaucoma.3,4 However, other stigmata of the disease, especially cataracts and nephropathy, differentiate Lowe syndrome from primary congenital glaucoma.3 Mucopolysaccharidoses (MPS) are inborn errors of metabolism characterized by excessive storage of mucopolysaccharides and defective degradation due to deficiencies of lysosomal acid hydrolases. In these diseases, excessive keratan sulfate appear in the cornea. In MPS I-H (Hurler syndrome), corneal clouding is a prominent feature of the disease (Fig. 6.13), which helps to differentiate it from Hunter’s syndrome. The opacities are located first in the anterior stroma and consist of fine gray punctate opacities. Later the posterior stroma and endothelium become involved. Histologically, ballooned macrophages are found in the cornea. MPS I-S (Scheie syndrome) is a variant of Hurler syndrome. The corneal haze that is often present at birth is very slowly progressive. The cornea appears thickened and somewhat edematous. The cloudiness is more marked in the corneal periphery. MPS II (Hunter syndrome) has clinical and biochemical features similar to those of Hurler syndrome, except Hunter syndrome is less severe. Corneal clouding is generally considered to be absent in Hunter syndrome, although exceptions in some older patients have been recorded. Corneal cloudiness does not occur in MPS III (Sanfilippo syndrome); however, corneal clouding is observed in MPS IV (Morquio syndrome). Corneal opacities occur in MPS VI (Maroteax–Lamy syndrome), but slit-lamp examination may be necessary to see them. Corneal clouding is absent or mild in MPS VII (Sly syndrome), which is due to β-glucuronidase deficiency. Cystinosis (Lignae–Fanconi syndrome) is a rare autosomal recessive genetic disorder of cystine storage. The lysosomal cystine transport system is defective. In some cases, cystine crystals may be deposited in the cornea and conjunctiva as the only manifestation of cystinosis. However, in the nephropathic type, patients may also develop renal failure and a ‘salt and pepper’ retinopathy. In the cornea, the crystals are glistening, polychromatic, needlelike to rectangular, and distributed throughout the anterior stroma with a slight predilection for the periphery. They appear early as 6 months of age and can cause intense photophobia. Crystals may be found throughout the entire thickness of the cornea,56 if they are extensive, and visual acuity may be reduced. Intracellular crystals have been demonstrated within corneal stromal cells as well as in cells of the iris, ciliary body, choroid, and retinal pigment epithelium. 36
A
B Figure 6.13 Hurler syndrome (MPS I-H). This condition is a mucopolysaccharidosis that may be associated with corneal clouding (A), which may lead to initial consideration of the diagnosis of congenital glaucoma. The habitus of the same patient with MPS I-H (B).
The mucolipidoses are inherited metabolic diseases caused by defects in glycoprotein oligosaccharide degradation or biosynthesis that result in abnormal accumulation of acid mucopolysaccharides, sphingolipids and glycolipids. Progressive corneal clouding is due to accumulation of abnormal storage material around stromal keratocytes. Other ophthalmic manifestations include retinal pigmentary degeneration, a cherry-red spot, and optic atrophy. Psychomotor retardation and other systemic abnormalities are associated with this group of diseases. Amyloid is an eosinophilic material that has an affinity for dyes such as Congo red. Amyloid can be deposited in various tissues of the body, including the eyes, as part of a localized or systemic disease. A specialized form of amyloid deposition in the cornea is seen in lattice corneal dystrophy. Amyloid may be deposited in the cornea as the result of chronic inflammation. The corneas in amyloidosis may show corneal scarring and opacification. Familial amyloidosis of the cornea has also been described.
Conditions with overlapping signs of optic nerve abnormalities Sphingolipidoses are caused by a deficiency of lysosomal enzymes required for the metabolism of sphingolipids, including gangliosides, cerebrosides, and sphingomyelin. In these disorders, sphingolipids accumulate in lysozymes of cells, which can be identified by electron microscopy as multimembranous inclusion bodies (zebra bodies). Corneal clouding may occur in Fabry disease and metachromatic leukodystrophy. Fabry disease is an X-linked recessive sphingolipidosis caused by a lack of alpha-galactosidase, which results in accumulation of ceramide trihexoside. The most typical ocular feature is a fine, whorl-like superficial corneal opacity (cornea verticillata). It resembles the corneal opacities found after administration of chloroquine and amiodarone. Corneal opacities have been seen as early as 6 months of age and are presumably caused by the accumulation of sphingolipids in the corneal epithelium. Visual acuity is generally unaffected. Metachromatic leukodystrophy is an autosomal recessive disorder caused by a defect of acylsulfatase A, leading to accumulation of cerebroside sulfate. Corneal clouding may be observed and, unlike Fabry disease, macular grayness or a cherry-red spot and optic atrophy may be observed. In glucose-6-phosphatase deficiency (Von Gierke disease), the cornea may show a faint brown peripheral clouding. In general, metabolic disorders with corneal clouding or opacity are associated with normal intraocular pressure and no corneal enlargement, which clinically differentiates them from primary congenital glaucoma. In addition to metabolic disorders, corneal dystrophies may be associated with corneal clouding at an early age. Congenital hereditary stromal dystrophy is an autosomal dominant disease that appears at birth as a bilateral, symmetrical, non-progressive clouding of the central superficial corneal stroma. The epithelium is unaffected, and the stromal opacity is flaky, feathery and diffuse, fading in intensity as it approaches the periphery. This dystrophy was described by Witschel and associates in 1978.57 Posterior polymorphous dystrophy, described by Koeppe in 1916, has an autosomal dominant inheritance pattern with good penetrance and can be asymmetric. The opacities can occur anywhere in the posterior cornea and may either remain stationary or progress slowly. Polymorphous opacities, typically vesicular, are located at the level of Descemet’s membrane. In some cases, when viewed by retro-illumination, the posterior cornea has the appearance of beaten metal. In severe cases, there may be stroma and epithelial edema with or without elevated intraocular pressure58 and peripheral anterior synechiae.59 Congenital hereditary endothelial dystrophy (CHED) was described by Laurence in 1863. It may have autosomal dominant and recessive inheritance patterns with a variable expressivity ranging from minimal posterior corneal changes to severe corneal edema. In contrast with congenital hereditary stromal dystrophy, the corneal thickness is usually increased. Congenital hereditary endothelial dystrophy can present at birth or in the first 1 to 2 years of life. Descemet’s membrane appears thickened and gray, and has a peau d’orange texture. The endothelial mosaic may be absent or
irregular. The patient may present with diffuse, bilaterally symmetric corneal edema associated, in some patients, with tearing and photophobia (Figure 6-14). To avoid unnecessary glaucoma surgery, it is crucial to differentiate this disease from congenital glaucoma. A mistaken diagnosis of congenital glaucoma is unlikely because there is no corneal enlargement, the intraocular pressure is normal, and corneal stromal thickness can be up to three times the normal in congenital hereditary endothelial dystrophy.1,5 Congenital hereditary endothelial dystrophy may be associated with glaucoma.60,61 Patients usually are identified when corneal edema persists after surgical treatment for glaucoma and normalization of intraocular pressure. After treatment with penetrating keratoplasty, histopathological studies of the corneal button showed changes of Descemet’s membrane and attenuation of the endothelium typical of congenital hereditary endothelial dystrophy.60,61 In patients with congenital glaucoma who have persistent and total corneal opacification that persists after normalization of intraocular pressure, the combination of congenital hereditary endothelial dystrophy and congenital glaucoma should be suspected. Other causes of corneal opacification in early childhood are not commonly confused with congenital glaucoma. Corneal dermoid is a hamartoma that is a rare cause of congenital corneal opacification. They may contain mesodermal elements including fibrous tissue, fat, muscle, cartilage, and bone. The severity may vary greatly, from the least severe and most common limbal variety to those that involve the entire cornea and anterior chamber.8 In the milder variety, only the superficial cornea is involved. Peters anomaly is a posterior corneal defect, frequently associated with iris
A
B Figure 6.14 Congenital hereditary endothelial dystrophy (CHED) may be associated with diffuse, bilaterally symmetric corneal edema, which must be distinguished from congenital glaucoma. CHED in an eye, viewed with diffuse illumination (A). Another eye with CHED, viewed by slit beam illumination (B). 37
Primary congenital glaucoma strands connected to the edge of the defect, which causes central corneal opacification at birth.
Conditions with overlapping signs of optic nerve abnormalities Congenital malformations of the optic disc must be distinguished from disc changes caused by glaucoma. These pseudoglaucomatous anomalies include congenital optic nerve pits, optic nerve colobomas, and optic nerve hypoplasia.62 The tilted disc syndrome may be associated with hypopigmentation and staphylomatous ectasia in the direction of the tilt. Axial myopia can be associated with a large optic nerve cup or even a tilted disc and accompanying scleral crescent. Optic nerve hypoplasia is associated with a small disc, but difficulties in interpretation of the appearance of the disc may be caused by the abnormal termination of the retinal pigment epithelium in the peripapillary area, known as the ‘double ring sign.’ A variant of optic nerve hypoplasia associated with large cups and periventricular leukomalacia may be observed in premature infants.63 Large physiologic cups must also be distinguished from pathological cupping caused by glaucoma. This is not a common problem in the infant where accompanying signs and symptoms are evident, but it can be a problem in the child over 3 years of age who is too young for precise visual field testing and in whom the changes secondary to globe elasticity are not evident. Careful examination is essential, and follow-up examination may be required before a definitive diagnosis can be made. Examination of the family members can be helpful as this may reveal similar optic cups in several members.64
Conditions associated with increased intraocular pressure Inflammatory disease such as maternal rubella syndrome may cause an angle anomaly virtually indistinguishable from that seen in primary infantile glaucoma, with identical clinical stigmata, and a good response to goniotomy (Fig. 6.15). However, the other ocular manifestations of the rubella syndrome in the neonate, including deafness, cardiac anomalies (patent ductus arteriosus, atrial and ventricular septal defects), mental retardation, and cataracts should distinguish this syndrome from primary infantile glaucoma.5 When rubella viremia occurs in the third trimester, anterior chamber angle involvement and glaucoma may occur, without other signs of rubella infection. These cases may be mistakenly identified as primary infantile glaucoma.4 A transient or permanent corneal edema has been observed in infants with maternal rubella syndrome, even without elevated intraocular pressure.4 Primary congenital glaucoma is diagnosed by the finding of glaucoma in a child with isolated trabeculodysgenesis and no other ocular diseases that could result in an increased intraocular pressure. The differential diagnosis of primary congenital glaucoma should also include developmental 38
Figure 6-15 Maternal rubella syndrome. The clinical presentation in this child resembles the appearance of primary infantile glaucoma.
glaucomas with associated anomalies, as well as childhood glaucomas secondary to systemic or other ocular disorders, which will be discussed in the subsequent chapter.
Conclusion The clinical features, the diagnostic examination, and the differential diagnosis of primary congenital glaucoma has been discussed. Early diagnosis is important to prevent glaucomatous damage. Any child with tearing, photophobia, blepharospasm, corneal cloudiness, or ocular enlargement should be examined with the possibility of congenital glaucoma in mind. Pressure measurements in all children old enough to cooperate will provide a low yield of glaucoma because of the rarity of this disease in childhood. Nevertheless, when the diagnosis can be made before advanced field loss occurs, it is extremely gratifying. Even in children who can not cooperate for pressure measurements, it is a simple matter to examine at the optic nerve head. A cup-to-disc ratio exceeding 0.3 indicates a need for further investigation. Prevention of visual loss is the goal in the treatment of glaucoma. Early diagnosis is essential to accomplish this goal.
References 1. Hoskins HD Jr, Kass MA. Becker-Shaffer’s diagnosis and therapy of the glaucomas, 6th edn. CV Mosby: St. Louis; 1989. 2. Walton DS. Glaucoma in infants and children. In: Harley RD, ed. Pediatric ophthalmology, 2nd edn. WB Saunders: Philadelphia; 1983. 3. Kwitko ML. The pediatric glaucomas. Int Ophthalmol Clin 1981; 21:199–222. 4. Shaffer RN, Weiss DI. The congenital and pediatric glaucomas. CV Mosby: St Louis; 1973. 5. Kwitko ML. Glaucoma in infants and children. Appleton-Century-Crofts: New York; 1973. 6. Scheie HG. Symposium on congenital glaucoma: Diagnosis, clinical course and treatment other than goniotomy. Trans Am Acad Ophthalmol Otolaryngol 1955; 59: 309. 7. Waring GO, Laibson PR, Rodriguez M. Clinical and pathological alteration of Descemet’s membrane with emphasis on endothelial metaplasia. Surv Ophthalmol 1974; 18:325–368.
References 8. Mann I. Developmental abnormalities of the eye. JB Lippincott: Philadelphia; 1957. 9. Maumenee AE. Further observations on the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176. 10. Morin JD. Congenital glaucoma. Trans Am Ophthalmol Soc 1980; 78:123. 11. Morin JD, Bryars JH. Causes of loss of vision in congenital glaucoma. Arch Ophthalmol 1980; 98:1575–1576. 12. Hass JS. End results of treatment. Trans Am Acad Ophthalmol Otolaryngol 1955; 59:333. 13. Hass J. Principles and problems of therapy in congenital glaucoma. Invest Ophthalmol 1968; 7:140. 14. Barkan O. Goniotomy. Trans Am Acad Ophthalmol 1955; 59:322–332. 15. Scheie HG. Management of infantile glaucoma. Arch Ophthalmol 1959; 62:35. 16. Morin JD, Merin S, Sheppard RW. Primary congenital glaucoma. A survey. Can J Ophthalmol 1974; 9:17–28. 17. Quigley HA. The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 1977; 84:358–370. 18. Broughton WL, Parks MM. An analysis of treatment of congenital glaucoma by goniotomy. Am J Ophthalmol 1981; 91:566–572. 19. Robin AL, Quigley HA, Pollack IP, et al. An analysis of visual acuity, visual fields and disc cupping in childhood glaucoma. Am J Ophthalmol 1979; 88:847–858. 20. Richardson KT, Shaffer TN. Optic-nerve cupping in congenital glaucoma. Am J Ophthalmol 1966; 62:507–509. 21. Shaffer RN. New concepts in infantile glaucoma. Can J Ophthalmol 1967; 2:243. 22. Shaffer RN. New concepts in infantile glaucoma. Trans Ophthalmol Soc UK 1967; 87:581–590. 23. Shaffer RN, Hetherington J Jr. Glaucomatous disc in infants. A suggested hypothesis for disc cupping. Trans Am Acad Ophthalmol Otolaryngol 1969; 73:929–935. 24. Chandler PA, Grant WM. Glaucoma. Lea and Febiger: Philadelphia; 1980. 25. Iwata K, Sobuek, Imai A, Sakurai I. On the reversibility of glaucomatous disc cupping and the visual field. Jpn J Clin Ophthalmol 1977; 31:759. 26. Hetherington J, Shaffer RN, Hoskins HD. The disc in congenital glaucoma. In: Etienne R, Patterson GD, eds. XXII Congress Internationale Ophthalmologie. International glaucoma symposium, Albi, France, 1974, Varseille, France, Diffusion Generale de Librarie, 1975. 27. Anderson DR. Glaucomatous disc changes in infants. In: Symposium on Glaucoma. Trans New Orleans Acad Ophthalmol. CV Mosby: St Louis; 1975:104–155. 28. Kiskis AA, Markowitz SN, Morin JD. Corneal diameter and axial length in congenital glaucoma. Can J Ophthalmol 1985; 20:93–97. 29. Quigley HA. Childhood glaucoma: Results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–226. 30. Dominguez A, Banos S, Alvarez G, Contra GF, Quintela FB. Intraocular pressure measurements in infants under general anesthesia. Am J Ophthalmol 1974; 78:110–116. 31. Van Buskirk EM, Palmer EA. Office assessment of young children for glaucoma. Ann Ophthalmol 1979; 11:1749–1751. 32. Radtke ND, Cohen BF. Intraocular pressure measurement in the newborn. Am J Ophthalmol 1974; 78:501–504. 33. Raab EL. Congenital glaucoma. Pers Ophthalmol 1978; 2:35. 34. Ytteborg J. Investigations of the rigidity coefficient in children’s eyes. Acta Ophthalmol 1960; 38:658–674. 35. Kaufman HE, Wind CA, Waltman SR. Validity of Mackay-Marg electronic applanation tonometer in patients with scarred irregular corneas. Am J Ophthalmol 1970; 69:1003–1007. 36. McMillan F, Forster RK. Comparison of Mackay-Marg, Goldmann, and Perkins tonometers in abnormal corneas. Arch Ophthalmol 1975; 93:420–424. 37. West CE, Capella JA, Kaufman HE. Measurement of intraocular pressure with pneumatic applanation tonometer. Am J Ophthalmol 1972; 74:505–509.
38. Hoskins HD, Shaffer RN. Evaluation techniques for congenital glaucomas. J Pediatr Ophthalmol Strabismus 1971; 8:81. 39. Anderson DR. Pathology of the glaucomas. Br J Ophthalmol 1972; 56:146–157. 40. Anderson DR. The development of the trabecular meshwork and its abnormality in primary infantile glaucoma. Trans Am Ophthalmol Soc 1981; 79:458–485. 41. Worst JGF. The pathogenesis of congenital glaucoma, an embryological and goniosurgical study. CC Thomas: Springfield; 1966. 42. Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classification of the developmental glaucomas. Arch Ophthalmol 1984; 102:1331–1336. 43. Khoo BK, Koh A, Cheong P, Ho NK. Combination cyclopentolate and phenylephrine for mydriasis in premature infants with heavily pigmented irides. J Pediatr Ophthalmol Strabismus 2000; 37:15–20. 44. Khodadaust AA, Ziai M, Biggs SL. Optic disc in normal newborns. Am J Ophthalmol 1968; 66:502–504. 45. Reibaldi A. Biometric ultrasound in the diagnosis and follow-up of congenital glaucoma. Ann Ophthalmol 1982; 14:707–708. 46. Sampaolesi R, Caruso R. Ocular echometry in the diagnosis of congenital glaucoma. Arch Ophthalmol 1982; 100:574–577. 47. Buschmann W, Bulth K. Ultrasonographic followup examination of congenital glaucoma. Graefe’s Arch Ophthalmol 1983; 61:618. 48. Tarkkanen A, Uusitalo R, Mianowicz J. Ultrasonographic biometry in congenital glaucoma. Acta Ophthalmol 1983; 61:618–623. 49. Kobayashi H, Kiryu J, Kobayashi K, Kondo T. Ultrasound biomicroscopic measurement of anterior chamber angle in premature infants. Br J Ophthalmol 1997; 81:460–464. 50. Kobayashi H, Ono H, Kiryu J, Kobayashi K, Kondo T. Ultrasound biomicroscopic measurement of development of anterior chamber angle. Br J Ophthalmol 1999; 83:559–562. 51. Azuara-Blanco A, Spaeth GL, Araujo SV, et al. Ultrasound biomicroscopy in infantile glaucoma. Ophthalmology 1997; 104:1116–1119. 52. Kolker AE, Hetherington J. Diagnosis and therapy of glaucoma, 4th edn. CV Mosby: St Louis; 1976:276–321. 53. Duke-Elder S. System of ophthalmology, Vol III, Pt 2, Congenital deformities. CV Mosby: St Louis; 1969:548–565. 54. Cibis A, Bunde R. Herpes Simplex virus-induced congenital cataracts. Arch Ophthalmol 1971; 85:220–223. 55. Hagler WS, Walters PV, Nahmias AJ. Ocular involvement in neonatal herpes simplex virus infection. Arch Ophthalmol 1969; 82:169–176. 56. Yamamoto GK, Schulman JD, Schneider JA, Wong VG. Long-term ocular changes in cystinosis: observations in renal transplant recipients. J Pediatr Ophthalmol 1979; 16:21–25. 57. Witschel H, Fine BS, Grutzner P, McTigue JW. Congenital hereditary stromal dystrophy of the cornea. Arch Ophthalmol 1978; 96:1043–1051. 58. Grayson M. The nature of hereditary deep polymorphous dystrophy of the cornea: its association with iris and anterior chamber dysgenesis. Trans Am Ophthalmol Soc 1974; 72:516–559. 59. Cibis GW, Krachmer JH, Phelps CD, Weingeist TA. Iridocorneal adhesions in posterior polymorphous dystrophy. Trans Sect Ophthalmol Acad Ophthalmol Otolaryngol 1976; 81:770–777. 60. Pedersen OO, Rushood A, Olsen EG. Anterior mesenchymal dysgenesis of the eye. Congenital hereditary endothelial dystrophy and congenital glaucoma. Acta Ophthalmol (Copenh) 1989; 67:470–476. 61. Mullaney PB, Risco JM, Teichmann K, Millar L. Congenital hereditary endothelial dystrophy associated with glaucoma. Ophthalmology 1995; 102:186–192. 62. Campbell DG, Netland PA. Stereo atlas of glaucoma. Mosby: St. Louis; 1998. 63. Jacobson L, Hellstrom A, Flodmark O. Large cups in normal-sized optic discs: a variant of optic nerve hypoplasia in children with periventricular leukomalacia. Arch Ophthalmol 1997; 115:1263–1269. 64. Netland PA, Wiggs JL, Dreyer EB. Inheritance of glaucoma and genetic counseling of glaucoma patients. Int Ophthalmol Clin 1993; 33:101–120.
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Chapter 7 Secondary congenital glaucoma Introduction Axenfeld–Rieger syndrome Peters anomaly Aniridia Glaucoma in the phakomatoses Metabolic diseases Persistent hyperplastic primary vitreous Retinopathy of prematurity (retrolental fibroplasia) Chromosomal anomalies Broad thumb syndrome (Rubenstein–Taybi syndrome) Conclusion
Introduction There are several conditions characterized by developmental defects of the anterior chamber angle with additional ocular and systemic abnormalities, which may be associated with glaucoma. These disorders are typically bilateral, are usually diagnosed at birth or in early childhood, and most have a genetic basis. Furthermore, a large number of other syndromes with ocular and systemic abnormalities may be associated with developmental glaucoma. All these conditions have been grouped under the term secondary congenital glaucoma. The purpose of this chapter is to outline the characteristics of these conditions wherein glaucoma plays a significant role.
Axenfeld–Rieger syndrome Axenfeld described, in 1920, a patient with a white line in the posterior aspect of the cornea, near the limbus, and tissue strands extending from the peripheral iris to this prominent line. Beginning in the mid-1930s, Rieger reported cases with similar anterior segment anomalies, but with additional changes in the iris, including corectopia, atrophy, and hole formation. It was also discovered that some of these patients had associated non-ocular developmental defects, especially of the teeth and facial bones. Axenfeld referred to his case as ‘posterior embryotoxon of the cornea,’ while Rieger used the term ‘mesodermal dysgenesis of the cornea and iris.’ In current nomenclature, these conditions are commonly designated by three eponyms. Axenfeld’s anomaly is limited to peripheral anterior segment defects. Rieger’s anomaly includes peripheral anterior segment abnormalities with additional changes in the iris. Rieger syndrome includes ocular
anomalies plus non-ocular developmental defects. Within each category, glaucoma occurs in approximately half the cases. The similarity of anterior chamber angle abnormalities in Axenfeld’s anomaly, Rieger’s anomaly, and Rieger syndrome has led most investigators to agree that these three arbitrary categories represent a spectrum of developmental disorders.1,2 The overlap of ocular anomalies is such that the traditional classification is difficult to apply in all patients. For example, the degree of iris stromal atrophy is so slight in some patients that it is hard to know whether the term Axenfeld’s anomaly or Rieger’s anomaly should be used. Indeed, Axenfeld described mild stromal atrophy of the iris in his patient, further compounding the difficulty of clearly separating this entity from Rieger’s anomaly. In addition, the association between ocular and non-ocular abnormalities is not always as clear as the traditional classification would imply. Although most patients with non-ocular developmental defects have changes in the central iris, as with Rieger’s anomaly, some have only the peripheral ocular abnormalities of Axenfeld’s anomaly3 or no ocular changes at all.4 There are also families in which the ocular and non-ocular anomalies vary considerably among family members. These observations have led many investigators to place all of these conditions within a single diagnostic category. There seems to be no advantage in splitting this spectrum of disorders into sub-categories, since the entire group of patients, irrespective of ocular manifestations, shares the same general features. First, there is a bilateral, developmental disorder of the eyes. Second, there is frequently a family history of the disorder (with an autosomal dominant mode of inheritance). Third, there is no sex predilection. Fourth, there are frequent non-ocular developmental defects. Fifth, there is a high incidence of secondary glaucoma. A single diagnostic category has the advantage not only of eliminating the difficulty of selecting an arbitrary subclassification, but also of reminding the physician to search for additional ocular and non-ocular disorders in all cases. Most of the names for this spectrum of anomalies were based on presumed common developmental mechanisms, which in turn were dependent upon a particular concept of the related embryology. The terms used include ‘anterior chamber cleavage syndrome,’1 ‘mesodermal dysgenesis of the cornea and iris (dysgenesis mesodermalis corneae et iridis),’5 and ‘primary dysgenesis mesodermalis of the iris.’6 However, the concepts of normal development on which the above terms were based no longer appear to be entirely correct. It was for this reason that the alternative title ‘Axenfeld–Rieger 41
Secondary congenital glaucoma syndrome’ was proposed. This term retains reference to the traditional subclassifications, but is not dependent upon a particular concept of development, knowledge of which is still incomplete.
The age at which Axenfeld–Rieger syndrome is diagnosed ranges from birth to adulthood, with most cases recognized during infancy or childhood. The diagnosis may result from discovery of an abnormal iris or other ocular anomaly, signs of congenital glaucoma, reduced vision in older patients, or non-ocular anomalies. Other cases are diagnosed during a routine examination, which may have been prompted by a family history of the disorder. There is no apparent racial or sex predilection.5 The family history is often positive for the spectrum of disorders, typically with an autosomal dominant mode of inheritance, although sporadic cases are also common.3 Ocular defects in Axenfeld–Rieger syndrome are typically bilateral. The structures most commonly involved are the peripheral cornea, anterior chamber angle, and iris. The characteristic abnormality of the peripheral cornea is a prominent, anteriorly displaced Schwalbe’s line. This appears on slit-lamp examination as a white line on the posterior cornea near the limbus. In some cases, the line is incomplete, usually limited to the temporal quadrant, while in other patients it may be seen for 360 degrees. Strands of peripheral iris stroma may occasionally be seen by slit-lamp biomicroscopy extending to the prominent Schwalbe’s line. While a prominent Schwalbe’s line is a typical feature of Axenfeld–Reiger syndrome, it is neither a consistent nor pathognomonic finding. In some cases, the prominent line can only be seen by gonioscopy. A rare case may have other ocular and non-ocular abnormalities of this spectrum of disorders, with grossly normal Schwalbe’s lines.4 More commonly, a patient may have a prominent Schwalbe’s line with no other evidence of the Axenfeld– Rieger syndrome (Fig. 7.1). This isolated defect has been referred to by the term, originally given by Axenfeld, as ‘posterior embryotoxon.’ The prevalence of this condition has been reported ranging from 8%5 to 15%.7,8 While a prominent
Schwalbe’s line, as an isolated finding, may represent a forme fruste of Axenfeld–Rieger syndrome, it is not included within this spectrum of anomalies, because it is neither associated with an increased incidence of secondary glaucoma nor with non-ocular anomalies. In addition to the isolated finding, a prominent Schwalbe’s line is occasionally seen in patients with primary congenital glaucoma9 or the iridocorneal endothelial syndrome.10 The cornea is otherwise normal in the typical case of Axenfeld–Rieger syndrome, with the exception of occasional patients with variation in the overall size or shape of the cornea. Microcornea may be seen, although megalocornea, in the absence of known intraocular pressure elevation, is more common. Congenital opacities of the central cornea have also been observed in a few of these cases. The corneal endothelium is typically normal, with the exception of occasional subtle changes consistent with age or longstanding intraocular pressure elevation. The corneal endothelial appearance by specular microscopy reveals distinct cell margins, although mild to moderate variation in the size and shape of the endothelial cells is commonly observed. These changes are more prominent in older patients and in those longstanding glaucoma or previous intraocular surgery. Gonioscopic examination typically reveals a prominent Schwalbe’s line, although there is considerable variation among the patients in the extent to which Schwalbe’s line is enlarged and anteriorly displaced. In occasional cases, the line is suspended from the cornea in some areas by a thin membrane.3,11 Tissue strands bridge the anterior chamber angle from the peripheral iris to the prominent ridge (Fig. 7.2). These strands range in size from threadlike structures to broad bands extending nearly 15 degrees of circumference. In some eyes, only one or two tissue strands are seen, while others have several per quadrant. In addition to the characteristic gonioscopic features of Axenfeld–Rieger syndrome, a more subtle abnormality has also been noted in the anterior chamber angle.3,5,7,8 Beyond the tissue strands, the anterior angle is open and the trabecular meshwork is visible, but the scleral spur is typically obscured by peripheral iris which inserts into the posterior portion of the meshwork. This alteration is distinctly different from the coarser strands of tissue that bridge the angle. In
Figure 7.1 Posterior embryotoxon. The prominent Schwalbe’s line is indicated by the arrow.
Figure 7.2 Axenfeld’s anomaly. The arrowhead indicates the tissue strands that bridge the anterior chamber from the peripheral iris to the prominent Schwalbe’s line (indirect gonioscopic view).
Clinical features
42
Axenfeld–Rieger Syndrome
Figure 7.3 Rieger’s anomaly. Iris abnormalities include iris hole formation with polycoria.
some eyes, this abnormality is continuous for 360 degrees, while in others it involves only one or more quadrants. Aside from peripheral abnormalities, the iris is normal in some eyes with Axenfeld–Rieger syndrome. In other cases, defects of iris range from mild stromal thinning to marked atrophy with hole formation, corectopia and ectropion uvea (Fig. 7.3). When corectopia is present, the pupil is usually displaced toward a prominent peripheral tissue strand, which is often visible by slit-lamp biomicroscopy. The atrophy and hole formation typically occur in the quadrant away from the direction of the corectopia. In a small number of patients with Axenfeld–Rieger syndrome, abnormalities of the central iris have been observed to progress.3,12,13 This is more often seen during the first years of life, but may occur at a later time. The progressive changes usually consist of displacement or distortion of the pupil and occasional thinning or hole formation of the iris. Abnormalities of the peripheral iris or anterior chamber angle do not appear to progress after birth, except for occasional thickening of iridocorneal tissue strands.3 Aside from abnormalities of the cornea, anterior chamber angle, and iris, no additional ocular anomalies occur with sufficient regularity to be included as typical features of the Axenfeld–Rieger syndrome. However, many additional ocular abnormalities have been reported in one or more cases or pedigrees. Strabismus has been reported, although it is difficult to know whether this is a primary muscle imbalance or is secondary to reduced visual acuity from the glaucoma. Other rarely associated ocular anomalies include limbal dermoids, cataracts of many types (including congenital), peripheral spoke-like transillumination defects of the iris, retinal detachment, macular degeneration, chorioretinal colobomas, choroidal hypoplasia, and hypoplasias of the optic nerve head.3,5,8 Slightly more than half of the patients with Axenfeld– Rieger syndrome develop glaucoma. This may become manifest during infancy, although it more commonly appears in childhood or young adulthood. Glaucoma seems to occur more often in patients with central iridic changes, although the extent of the defects does not correlate precisely with the presence or severity of the glaucoma. The abundance or paucity of peripheral tissue strands does not correlate with the presence or absence of glaucoma, whereas high insertion of peripheral iris into the trabecular meshwork is associated
with glaucoma.3 The glaucoma associated with Axenfeld– Rieger syndrome is typically difficult to control, often leading to significant optic nerve head damage and vision loss. Rare cases have been reported to regress spontaneously. The systemic anomalies most commonly associated with the Axenfeld–Rieger syndrome are developmental defects of the teeth and facial bones. The dental abnormalities include a reduction in crown size (microdontia), a decreased but evenly spaced number of teeth (hypodontia), and a focal absence of teeth (oligodontia or anodontia).14 The teeth most commonly missing are anterior maxillary primary and permanent central incisors. Facial anomalies include maxillary hypoplasia with flattening of the mid-face, a receding upper lip and a prominent lower lip, especially in association with dental hypoplasia. Hypertelorism, telecanthus and a broad flat nose have also been described.5 Anomalies in the region of the pituitary gland are not common, but may be a significant finding associated with the Axenfeld–Rieger syndrome. A primary empty sella syndrome has been documented in several patients,3,15 and one case of congenital parasellar arachnoid cyst has been reported.3 Growth hormone deficiency and short stature have also been described in association with this entity.16,17 Other abnormalities reported in association with the Axenfeld–Rieger syndrome include redundant periumbilical skin, hypospadias,18 oculocutaneous albinism,19 heart defects, middle ear deafness, mental deficiency, and a variety of neurologic and dermatologic disorders.5
Histopathologic features The central cornea is typically normal, while the peripheral cornea has the characteristic prominent, anteriorly displaced Schwalbe’s line. The Schwalbe’s line is composed of dense collagen and ground substance covered by a monolayer of spindle-shaped cells with basement membrane.3,7,11 The peripheral iris is attached in some areas to the corneoscleral junction by tissue strands which usually connect with the prominent Schwalbe’s line. Occasionally, however, the adhesions insert either anterior or posterior to Schwalbe’s line or on both sides of the ridge.3 The strands consist of either iris stroma, a membrane composed of a monolayer of spindleshaped cells and/or a basement membrane-like layer, or both. A membrane, similar to that seen in association with the iridocorneal tissue strands, has also been observed on the iris, usually on the portion towards which the pupil is distorted.3,5,20 In the quadrants away from the direction of pupillary displacement, the stroma of the iris is often thin or absent, exposing pigment epithelium that may also contain holes. The iris peripheral to the iridocorneal adhesions inserts into the posterior aspect of the trabecular meshwork. The meshwork may be composed of a scant number of attenuated lamellae, which extend from beneath peripheral iris to the prominent Schwalbe’s line and are often compressed, especially in the outer layers. Transmission electron microscopic examination suggests that the apparent compression may be due to incomplete development of the trabecular meshwork. Schlemm’s canal is either rudimentary or absent. 43
Secondary congenital glaucoma
Differential diagnosis The condition most frequently confused with Axenfeld– Rieger syndrome is another spectrum of disorders that has been referred to as the iridocorneal endothelial syndrome.21 Indeed, similarities of certain clinical and histopathologic features of the two disorders have led some investigators to suggest a common mechanism.22 However, comparison of the clinical features of the Axenfeld–Rieger and the iridocorneal endothelial syndromes suggest that these are two distinctly separate entities (Table 7.1).23 The ICE syndrome is composed of three major clinical variations. In Chandler’s syndrome, there are corneal endothelial changes while iris changes are mild to absent.24 In progressive (essential) iris atrophy, iris changes predominate, with marked corectopia, atrophy, and hole formation. In Cogan–Reese (or iris nevus) syndrome, nodular, pigmented lesions of the iris are the hallmark, and may be seen with the entire spectrum of corneal or other iris abnormalities.25,26 In each type of iridocorneal endothelial syndrome, the condition is typically unilateral, usually becomes manifest in young adulthood, and has a predilection for women. There is rarely a positive family history and no additional ocular or systemic abnormalities are associated with the disease.10,27 In all variations, there is an abnormality of the corneal endothelium which frequently leads to edema of the cornea.28 The specular microscopic appearance of the endothelial cells is virtually pathognomonic in the iridocorneal endothelial syndrome, with pleomorphism in shape and size, dark areas within the cells (causing a reversal of the normal shading pattern), and loss of hexagonal margins.29 Ultrastructural studies of corneas with advanced edema reveal markedly abnormal cells lining a thickened, multilayered Descemet’s membrane.28 A characteristic feature common to all forms of the iridocorneal endothelial syndrome is peripheral anterior synechiae, which often extend to or beyond Schwalbe’s line. Progressive closure of the anterior chamber angle leads to secondary glaucoma in a high percentage of patients. The appearance
of the angle and the associated glaucoma are features that may be confused with the Axenfeld–Rieger syndrome, although a prominent Schwalbe’s line is rarely seen in the ICE syndromes.10 Another similarity between the Axenfeld– Rieger and iridocorneal endothelial syndrome is the range of changes observed in the iris. Progressive iris atrophy is characterized by marked corectopia and atrophy of the iris with hole formation, which may also be observed in advanced cases of the Axenfeld–Rieger syndrome. Patients with Cogan– Reese syndrome may have any degree of iris changes, as well as fine nodules or diffuse nevi on the stromal surface.25,26,30 Such nodules are not a typical feature of the Axenfeld–Rieger syndrome, although the association has been described.31 Histopathological studies of the iridocorneal endothelial syndrome have demonstrated a membrane, composed of a single layer of endothelial cells and a basement membrane, extending from the cornea, across the anterior chamber angle, and onto the surface of the iris.32–35 The similarity between this membrane and those seen in Axenfeld–Rieger syndrome is the main feature leading some investigators to suspect a common mechanism for these two syndromes. There may be, however, a difference in the origin of the membranes in these syndromes. According to the theory proposed by Campbell and co-workers for the iridocorneal endothelial syndrome, the fundamental defect is an abnormality of the corneal endothelium which leads to proliferation of the endothelial layer across the anterior chamber angle and over the iris. Subsequent contraction of the membrane pulls the peripheral iris to the anterior chamber angle, forming peripheral anterior synechia and frequently causing secondary glaucoma.32,36,37 The theory of pathogenesis of Axenfeld–Rieger syndrome differs from the mechanism proposed for iridocorneal endothelial syndrome because the membrane is derived not from abnormal corneal endothelium but from retention of the primordial endothelial layer lining the anterior chamber angle during gestation. Several observations are believed to support this concept. In contrast with the iridocorneal endothelial syndrome, the specular microscopic appearance of
Table 7.1 Differences between the Axenfeld–Rieger (A–R) and iridocorneal endothelial (ICE) syndromes and posterior polymorphous dystrophy (PPD) Characteristics
44
A–R syndrome
ICE syndrome
PPD
Age of presentation
Birth
Young adulthood
Birth
Sex predilection
None
Women
None
Laterality
Bilateral
Unilateral
Bilateral
Familial pattern
Frequently
Rarely
Typically
Prominent Schwalbe’s line
Typical
Rarely
Rarely
Non-ocular disorders
Frequent
No
No
Corneal edema
No
Frequent
Occasional
Corneal endothelium
Normal
Abnormal
Abnormal
Proposed origin of membrane
Retention of primordial tissue
Proliferation from abnormal corneal endothelium
Proliferation from abnormal corneal endothelium
Proposed mechanism of secondary glaucoma
Maldevelopment of aqueous outflow system
Outflow obstruction by membrane or peripheral anterior synechiae
Maldevelopment (as in A–R) or membrane-induced (as in ICE)
Axenfeld–Rieger syndrome the corneal endothelium in Axenfeld–Rieger syndrome is within normal limits, allowing for age, chronic intraocular pressure elevation, and surgical intervention. In addition, continuity in the membrane between the iris and the peripheral cornea was rarely observed in histopathologic specimens from patients with the Axenfeld–Rieger syndrome. This is in contrast with the iridocorneal endothelial syndrome, in which the membrane is typically continuous, from the peripheral cornea across the anterior chamber angle and onto the iris.32 In the theories of mechanism for both Axenfeld–Rieger and iridocorneal endothelial syndrome, contraction of a membrane is believed to be the principal cause of the iris changes. The situation in the anterior chamber angle is not the same, however, since the tissue strands in the iridocorneal endothelial syndrome are believed to develop at some point after birth, as the membrane pulls peripheral iris into the angle, while those in the Axenfeld–Rieger syndrome are congenital but may become thicker and shorter by contraction of the associated membrane. Furthermore, the mechanism of the glaucoma differs in the two conditions, in that the membrane over the trabecular meshwork or the peripheral anterior synechia are believed to cause the secondary glaucoma in the iridocorneal endothelial syndrome, whereas maldevelopment of the trabecular meshwork and Schlemm’s canal, and the associated tissue strands, cause the secondary glaucoma in the Axenfeld–Rieger syndrome. Posterior polymorphous dystrophy represents yet another broad spectrum of abnormalities involving the cornea, anterior chamber angle and iris, which may be confused with both the Axenfeld–Rieger and iridocorneal endothelial syndromes (Table 7.1).38 posterior polymorphous dystrophy resembles the Axenfeld–Rieger syndrome in that it is congenital, typically with autosomal dominant inheritance, has bilateral ocular involvement, and has no significant race or sex predilection.39 It resembles the iridocorneal endothelial syndrome, however, in that association of glaucoma is usually not recognized until adulthood and corneal edema may be present.40,41 The common feature throughout the spectrum of posterior polymorphous dystrophy is an abnormality of the corneal endothelium and Descemet’s membrane, giving the slitlamp appearance of blisters or vesicles on the posterior surface of the cornea, which are often linear or in groups and surrounded by an area of gray haze (Fig. 7.4).40,41 Most patients remain asymptomatic, although secondary stromal and epithelial edema occurs in some cases. An even smaller
number of patients may have broad iridocorneal adhesions, occasionally with corectopia, ectropion uvea, and rarefaction of the iris.41,42 Some of these cases will be associated with glaucoma, while other patients with posterior polymorphous dystrophy may have glaucoma in the absence of these anterior chamber angle and iris changes. In those cases with glaucoma and iridocorneal adhesions, ultrastructural studies have revealed a layer of Descemet’s membrane and transformed endothelial cells with epithelial characteristics covering the trabecular beams and iris.35 It has been postulated that this layer extends down from the abnormal corneal endothelium and that subsequent contraction leads to the secondary synechiae formation and iris changes,40 similar to that which has been proposed for the iridocorneal endothelial syndrome.32 In the other form of glaucoma associated with posterior polymorphous dystrophy, a high insertion of the iris into the posterior trabecular meshwork has been observed by gonioscopy and microscopic examination, and ultrastructural examination revealed collapse of the trabecular beams.43 These changes resemble those seen in primary congenital glaucoma5 and Axenfeld– Rieger syndrome,3 suggesting a developmental anomaly of the anterior chamber angle in this variation of posterior polymorphous dystrophy.43 It may be that this abnormality of the angle represents a common pathway, which leads to glaucoma in several developmental disorders. Distinctions between the Axenfeld–Rieger and iridocorneal endothelial syndromes and the posterior polymorphous dystrophy are summarized in Table 7.1. Peters anomaly is a developmental abnormality involving the central cornea, iris, and the lens. Similar changes have been reported in association with the peripheral iris and angle abnormalities of the Axenfeld–Rieger syndrome, and the two conditions were once included in a single category of developmental disorders.1,2 However, this association is rare and the mechanisms for the two groups of developmental disorders are distinctly different. Patients may have congenital hypoplasia of the iris without the anterior chamber angle defect of Axenfeld–Rieger syndrome or any other ocular abnormality. Iris hypoplasia has also been reported in association in juvenile-onset glaucoma with autosomal dominant inheritance. Congenital ectropion uvea is a rare, non-progressive anomaly characterized by the presence of pigment epithelium on the stroma of the iris.44–47 It may be an isolated finding, or may occur in association with ptosis (Fig. 7.5). Congenital
Figure 7.4 Posterior polymorphous dystrophy associated with glaucoma. Opacities resembling blisters or vesicles may be identified on the posterior surface of the cornea (A). The opacities at the level of Descemet’s membrane may form a linear pattern (B).
A
B
45
Secondary congenital glaucoma
A
B
C
Figure 7.5 Congenital ectropion uvea. A non-progressive extension of pigment epithelium onto the anterior surface of the iris (A). The anterior surface of the iris may have a smooth appearance (B), and may occur in association with ptosis (C).
ectropion uvea may also occur in association with systemic anomalies, including neurofibromatosis, facial hemiatrophy, and the Prader–Willi syndrome.44 Glaucoma is present in a high percentage of cases, and ectropion uvea may be confused with that found in some cases in the Axenfeld–Rieger syndrome. The extent of ectropion uvea usually remains unchanged, but progressive changes have been identified.48 In iridoschisis, there is bilateral separation and dissolution of the stromal layers of the iris, which may be associated with glaucoma.49 Iridoschisis differs from Axenfeld–Rieger syndrome and other abnormalities of the iris by the age of onset in the 6th or 7th decade of life. The rudimentary iris and anterior chamber abnormalities with associated glaucoma in aniridia may, in some cases, lead to confusion with the Axenfeld–Rieger syndrome. Ectopia lentis et pupillae is an autosomal recessive condition that is characterized by bilateral displacement of the lens and pupil,50 with the two structures typically displaced in opposite directions. The corectopia in this disorder may resemble that of the Axenfeld–Rieger syndrome, but the absence of anterior chamber angle defects is a differentiating feature. In oculodentodigital dysplasia, the dental abnormalities are similar to those seen in the Axenfeld–Rieger syndrome. In addition, these patients may occasionally have mild stromal hypoplasia of the iris, anterior chamber angle defects, microophthalmia, and glaucoma.51
Management of Axenfeld–Rieger syndrome The primary concern regarding the management of ocular defects in a patient with the Axenfeld–Rieger syndrome is detection and control of the associated glaucoma. Intraocular pressure elevation most often develops between childhood and early adulthood, but may appear in infancy, or in rare cases, not until the elderly years.3 Therefore, patients with the Axenfeld–Rieger syndrome must be followed for suspicion of glaucoma throughout their life. Patients should also be examined for associated ocular and systemic abnormalities.52 46
With the exception of infantile cases, medical therapy should usually be tried before surgical intervention is recommended. Pilocarpine and other miotics are often ineffective, and drugs which reduce aqueous production, such as betablockers and carbonic anhydrase inhibitors are most likely to be beneficial. Laser surgery has not been found effective in managing the glaucoma in the Axenfeld–Rieger syndrome. Options for conventional surgery include goniotomy, trabeculotomy, and trabeculectomy. The former two have been utilized in infantile cases with limited success. Goniotomy may be impeded due to iris strands. Trabeculectomy is the surgical procedure of choice for most patients with glaucoma secondary to the Axenfeld–Rieger syndrome. Difficulty with intraoperative airway management has been described in a child with Axenfeld–Rieger syndrome.53
Peters anomaly In 1897, Von Hippel reported a case of buphthalmos with bilateral central corneal opacities and adhesions from these defects to the iris. Peters, beginning in 1906, described similar patients with what has been generally known as Peters anomaly.
General features Most cases are sporadic, although there is evidence of autosomal recessive inheritance, and chromosomal defects have been described.54 The condition is present at birth and is usually bilateral. It typically occurs in the absence of additional abnormalities, although rare associations with various systemic and other ocular anomalies have been reported.
Clinicopathologic features The hallmark of Peters anomaly is a central defect in Descemet’s membrane and corneal endothelium with thinning and opacification of the corresponding area of corneal stroma (Fig. 7.6).55–58 Adhesions may extend from the borders of this
Aniridia
Glaucoma anomaly
associated
with
Peters
Approximately half of the patients with Peters anomaly will develop glaucoma, which is frequently present at birth. The mechanism of the glaucoma is uncertain. The anterior chamber angle is usually grossly normal by clinical examination. One histopathological report of the eye of a young child with Peters anomaly described changes in the trabecular meshwork that are characteristic of aging.61 Patients with glaucoma may be at increased risk for other systemic abnormalities.62 A
Differential diagnosis
B Figure 7.6 Schematic representation of Peters anomaly (A). Abnormalities include a central defect in Descemet’s membrane and the corneal endothelium, adhesions extending from the borders of this defect to the iris and lens, and frequently cataract. Clinical appearance of an infant with Peters anomaly (B). A central corneal leukoma is present. The day before the photograph, the child underwent trabeculotomy combined with trabeculectomy for marked elevation of intraocular pressure despite medical therapy.
defect to the iris. Bowman’s membrane may also be absent centrally.57,58 The disorder has been subdivided into three groups, each of which may have more than one pathogenic mechanism: those not associated with keratolenticular contact or cataract, those associated with keratolenticular contact or cataract, and those associated with Axenfeld– Rieger syndrome.56 The association of Peters anomaly with Axenfeld–Rieger syndrome is rare. Some cases of Peters anomaly are not associated with keratolenticular contact or cataract. In these cases, the defect in Descemet’s membrane may represent primary failure of corneal endothelium to develop. However, rare cases may be secondary to intrauterine inflammation,59 which was originally postulated by Von Hippel and gave rise to the term ‘Von Hippel’s’ internal corneal ulcer. Other cases are associated with keratolenticular contact or cataract. Most histopathologic studies of this variation suggest that the lens developed normally and was then secondarily pushed forward against the cornea by one of several mechanisms, causing the loss of Descemet’s membrane.56,57,60 It is also possible that some cases may result from incomplete separation of the lens vesicle from the surface ectoderm.
The corneal clouding of Peters anomaly must be distinguished from primary congenital glaucoma, birth trauma, the mucopolysaccharidoses, and congenital hereditary corneal dystrophy. In addition, posterior keratoconus may be confused with Peters anomaly. Posterior keratoconus is a rare disorder that is characterized by a thinning of the central corneal stroma, with excessive curvature of the posterior corneal surface and variable overlying stromal haze.2,63 An ultrasound study revealed a multilayered Descemet’s membrane with abnormal anterior banding and localized posterior excresences. Glaucoma is rarely associated with posterior keratoconus. Congenital corneal leukomas and staphylomas represent severe forms of central dysgenesis of the anterior ocular segment and are frequently associated with glaucoma.
Management All infants and children with cloudy corneas must be examined carefully for the possibility of associated glaucoma, which usually requires surgical intervention. Initial trabeculectomy may offer the best chance of success. Penetrating keratoplasty is also frequently necessary. Visual outcomes are poor due to the presence of congenital anterior and posterior segment anomalies, structural defects of the central nervous system, cognitive dysfunction, and amblyopia, as well as postoperative complications such as graft failure, cataract, inoperable retinal detachment, and phthisis.64,65
Aniridia Aniridia (Greek: absence of iris) is a bilateral, uncommon panocular disorder affecting not only the iris, but also the cornea, anterior chamber angle, lens, retina and optic nerve. The name ‘aniridia,’ however, is a misnomer, since a small portion of the iris tissue can be present. The term ‘iridemia’ better describes the condition than does ‘aniridia.’ Since Barrata’s first description of aniridia in 1818, the ophthalmic literature has contained many scattered reports on the subject. Most cases are inherited by autosomal dominant transmission,66 although sporadic cases also occur. Other patients, especially those with mental retardation, have an autosomal 47
Secondary congenital glaucoma recessive mode of inheritance. No significant sexual or racial predilection for aniridia has been described. Four phenotypes of aniridia have been identified on the basis of associated ocular and systemic abnormalities.67 One phenotype is aniridia with predominant iris changes and normal visual acuity. Another phenotype is aniridia associated with foveal hypoplasia, nystagmus, corneal pannus, glaucoma, and reduced vision. The third type is aniridia associated with Wilm’s tumor (the aniridia–Wilm’s tumor syndrome) or other genitourinary anomalies. The fourth phenotype is aniridia associated with mental retardation.
Clinical manifestations Decreased vision is generally associated with aniridia.68–72 The majority of ophthalmic manifestations occurring with aniridia are the result of various associated ocular abnormalities, including cataracts, glaucoma, corneal dystrophy, nystagmus, photophobia, strabismus, ectopia lentis, optic nerve hypoplasia, and poor foveal reflex. Poor foveal development may occur in the postnatal period in some cases. The ophthalmic complications associated with aniridia, especially cataracts, glaucoma, and corneal opacification, are often responsible for progressive loss of vision. Photophobia is often present in affected patients, and is due to absence of a normal pupil and excessive light stimulation. A characteristic facial expression in many children is narrowing of the palpebral fissure and furrowing of the brow (Fig. 7.7).73,74 There is variability in the iris configuration in aniridia, ranging from almost total absence to mild hypoplasia of the iris (Fig. 7.8). Although early reports described cases in which the iris appeared to be completely missing clinically, complete gonioscopic examination was not performed. Ocular colobomas associated with aniridia have been reported among individuals in the same family in the early literature. Aniridia is still considered by some to be one of the colobomatous disorders.75 Congenital glaucoma with or without buphthalmos is rare in infants with aniridia; however, the reported incidence of glaucoma later in childhood is 6% to 75%. The higher
Figure 7.7 Aniridia. Photophobia with narrowing of the palpebral fissure and furrowing of the brow.
figures were reported from glaucoma centers and probably represent an overestimation of the true incidence because of the referral nature of the institutions. Routine gonioscopic examination is important to detect anatomic changes in the angle structures that may progress to angle closure. During the first few years of life, the trabecular meshwork appears open and is not covered by iris tissue. Grant and Walton found that progressive change in the angle structures may occur during the first two decades of life in those patients who will develop glaucoma.74,76 These changes include attachment of the rudimentary iris to an anterior position, thereby covering the filtration area of the trabecular meshwork. Most of the filtration area is covered by the iris remnant in patients who will develop glaucoma. Glaucoma secondary to intumescent lens changes or ectopia lentis has been reported in aniridia. Ectopia lentis has been reported, ranging from 0% up to 56% of patients with aniridia. Failure to detect mild subluxations of the lens may be the reason ectopia lentis has not been reported by some investigators. Hypoplastic ciliary processes have been reported in pathologic specimens from patients with aniridia, but no defects in zonules or the pars plana have been reported.73 Cataracts occur frequently and at a young age in aniridia.67,70 Lens opacities develop in 50% to 85% of patients, usually during the first two decades of life. Although many aniridics have poor vision during adolescence secondary to foveal Figure 7.8 Aniridia. An iris remnant is present. The lens and cornea are clear in the right eye (A). There is corneal edema due to elevated intraocular pressure in the left eye (B). The corneal edema is more prominent centrally.
A
48
B
Glaucoma in the Phakomatoses hypoplasia and corneal opacification, cataracts may further compromise vision. Frequently, at birth, small anterior and posterior lens opacities may be noted, but these do not usually cause significant visual difficulty. Cortical, subcapsular, and lamellar opacities often develop by the teenage years and may require lens extraction. Corneal abnormalities are common in aniridia. In a high proportion of patients, a corneal pannus and opacity begins in the peripheral cornea in early life and advances towards the center of the cornea with increasing age. Because the corneal abnormality in aniridia is vascularized and inflamed, it is not included among the group of diseases known as dystrophies. Microcornea77 has been reported in association with aniridia. Increased central corneal thickness has been reported in patients with aniridia,78 which may lead to inaccuracy (overestimation) of applanation tonometry measurement of intraocular pressure in some patients. Layman and coworkers70 suggested that the majority of aniridia patients have optic nerves that are hypoplastic. However, optic nerve hypoplasia is often difficult to document in the aniridia patient because of nystagmus and poor visibility secondary to cornea and lens involvement. Poor retinal and macular development seen in many aniridics probably contributes to or is entirely responsible for the optic nerve hypoplasia. Pendular nystagmus is present in the majority of patients with aniridia. Most investigators believe the nystagmus is secondary to macular hypoplasia.67,70 Strabismus is common in aniridic patients, often an esotropia. High refractive errors are common and a careful cycloplegic refraction is necessary in affected children. Asymmetric visual loss in aniridic children may occur from amblyopia secondary to strabismus or anisometropia. Aniridia has also been reported in association with Marfan syndrome, Hallerman–Streiff syndrome, and sometimes with ptosis. Different mechanisms have been proposed for the elevation of intraocular pressure in aniridic patients. There may be abnormal function of the anterior chamber angle, with or without absence of Schlemm’s canal. Peripheral anterior synechiae may cause secondary angle closure.74,76 Secondary angle closure may develop following cataract extraction or glaucoma procedure. The anterior chamber angle may be open, with elevation of intraocular pressure. Unsuccessful argon laser trabeculoplasty may also be associated with elevated intraocular pressure.
most cases. Aniridic glaucoma requiring surgical treatment occurs in up to half of patients. Goniotomy is of limited value in advanced cases, but early goniotomy to separate the iris and the trabecular meshwork may prevent the development of glaucoma.66,76,79 Initial trabeculotomy80 or trabeculotomy combined with trabeculectomy81 may also be effective. Trabeculectomy alone is often unsuccessful,82 although trabeculectomy with mitomycin C may be a useful option.83 A glaucoma drainage implant may have a lasting benefit in some cases.82,84 Cyclophotocoagulation may have a role in some patients with intractable glaucoma as a temporizing or adjunctive measure.85
Glaucoma in the phakomatoses The phakomatoses (phakos = birthmark) or disseminated hamartomatoses, are a group of ophthalmologically important hereditary disorders exhibiting variable penetrance and expressivity. These disorders are characterized by the formation of hamartias and hamartomas in the eye, central nervous system, skin, and viscera. The classic features of the phakomatoses include nontumorous growths on the skin or mucous membranes that arise from cells normally found in the tissue at the involved site of growth (hamartias). Also, there are localized tumors arising from cells normally found in the tissue at the site of growth (hamartomas). There may be true neoplasms originating from undifferentiated embryonic cells of differentiated mature cells as well as other associated congenital abnormalities. In phakomatoses, derivatives of all three embryonic layers may be affected. Some of the phakomatoses are commonly associated with glaucoma, whereas others are occasionally or rarely associated, or not associated with glaucoma (Table 7.2). Sturge–Weber syndrome (encephalotrigeminal angiomatosis) is commonly associated with glaucoma (Fig. 7.9). Glaucoma is occasionally a manifestation of other phakomatoses, including neurofibromatosis (Von Recklinghausen), angiomatosis retinae (Von Hippel–Lindau), and oculodermal melanocytosis (nevus of Ota, Fig. 7.10). Glaucoma in the phakomatoses86 can develop through a number of different mechanisms, even within a single disease entity. Table 7.2 Glaucoma associated with phakomatoses Commonly associated with glaucoma Encephalotrigeminal angiomatosis (Sturge–Weber syndrome)
Differential diagnosis of aniridia Aniridia must be differentiated from other disorders, including iris coloboma (typical or atypical), corectopia, iridocorneal endothelial syndrome, anterior chamber cleavage syndromes, and colobomatous microphthalmia.
Management of glaucoma in aniridia Conventional medical therapy may control the intraocular pressure initially, but eventually proves to be inadequate in
Occasionally associated with glaucoma Neurofibromatosis (Von Recklinghausen) Angiomatosis retinae (Von Hippel–Lindau) Oculodermal melanocytosis (nevus of Ota) Rarely associated with glaucoma Basal cell nevus syndrome Tuberous sclerosis (Bourneville) Klippel–Trenaunay–Weber (in pure form) Diffuse congenital hemangiomatosis Unassociated with glaucoma Ataxia–telangiectasia (Louis–Bar) Racemose angioma of the retina (Wyburn–Mason)
49
Secondary congenital glaucoma
B
A
C
Figure 7.9 Sturge–Weber syndrome (encephalotrigeminal angiomatosis). Amblyopia therapy in a child with unilateral nevus flammeus associated with glaucoma in the left eye (A). Bilateral is less common than unilateral involvement (B). The soft palate may be affected (C). Note the soft tissue hypertrophy in the upper lip on the affected side (C). Prominent episcleral vessels in a patient with Sturge–Weber syndrome (D).
D
B Figure 7.10 Nevus of Ota (oculodermal melanocytosis). Bilateral periocular hyperpigmentation (A), which is less common compared with uniocular involvement. Episcleral melanosis may have a slate gray appearance (B), in contrast with the brown appearance of the superficial pigmentation immediately adjacent to the limbus. A
Diagnosis of glaucoma is frequently straightforward, based on the presence of elevated intraocular pressure, buphthalmos, and other signs of glaucoma in infancy or early childhood, and based on elevated intraocular pressure in children and adults. Optimal treatment, however, often depends on the determination and analysis of the underlying mechanisms of the glaucoma. Although there is no universal mechanism to explain the pathogenesis of glaucoma in the phakomatoses, there 50
are similarities among the syndromes. Tissue hypertrophy and developmental abnormalities have been postulated to cause ocular hypertension in both neurofibromatosis and encephalotrigeminal angiomatosis, or melanocytes in oculodermal melanocytosis. A ciliary body or choroidal neurofibroma or an iris hemangioma may cause the iris to obstruct the angle. Neovascular glaucoma has been reported in neurofibromatosis, encephalotrigeminal angiomatosis, angiomatosis retinae, and tuberous sclerosis. Elevated
Retinopathy of prematurity (retrolental fibroplasia) episcleral venous pressure may occur in encephalotrigeminal angiomatosis, which may increase the risk of complications associated with glaucoma surgery.
Metabolic diseases Oculocerebrorenal syndrome of Lowe Oculocerebrorenal syndrome (Lowe syndrome) features increased organic aciduria, systemic acidosis, ketonuria, glycosuria, proteinuria, emotional irritability, and mental retardation. The blood shows a decreased carbon dioxide and a decrease in serum phosphorus. The inheritance pattern is X-linked recessive, and mothers who are carriers of the trait may have characteristic punctate lens opacities. The ophthalmic findings include congenital cataracts, nystagmus, blue sclera, and, in patients with glaucoma, corneal edema and bilateral corneal opacification (Fig. 7.11). Glaucoma is noted in approximately two-thirds of the patients. Patients may have microphthalmia, which may present with elevated intraocular pressure. The mechanism of the glaucoma is related to faulty development of the filtration angle. Gonioscopy reveals minor anatomic defects, including poor visualization of the scleral spur and a narrow ciliary body band. Ophthalmic treatment includes cataract extraction and control of glaucoma. Glaucoma may respond to goniotomy or trabeculotomy, although filtering surgery may be required. Comanagement with a pediatrician is required for the metabolic disorder.
Homocystinuria Homocystinuria is a metabolic abnormality with a defect in the enzyme cystathionine synthetase. It is inherited as an autosomal recessive disorder. The patients are characteristically lightly pigmented with blond hair and blue eyes. Ocular abnormalities include ectopia lentis,87 retinal detachment, and glaucoma. The lens is usually subluxated inferiorly, but may move anteriorly, resulting in pupillary block glaucoma.
Figure 7.11 Lowe’s syndrome (oculocerebrorenal syndrome). This infant had bilateral cataracts and renal tubular dysfunction (Fanconi syndrome). He subsequently manifested elevated intraocular pressure, hypotonia, frontal bossing, and developmental delay. His mother had punctate lens opacities, most apparent after dilation of the pupil with retroillumination.
When the dislocated lens causes angle closure, treatment consists of dilatation of the pupil and peripheral iridectomy to break the pupillary block. If possible, iridectomy should be done with laser, because patients may have an increased risk of thromboembolic phenomena with general anesthesia. Lens extraction is required if the lens has dislocated into the anterior chamber.
Sulfite oxidase deficiency Sulfite oxidase deficiency is characterized by severe neurological abnormalities, mental retardation, and dislocation of the lens. The syndrome is due to defective activity of the enzyme that normally catalyzes the conversion of sulfite to sulfate. Death usually occurs in early childhood. Glaucoma is managed in the same fashion as in homocystinuria.
Persistent hyperplastic primary vitreous Persistent hyperplastic primary vitreous typically occurs unilaterally in a microphthalmic eye. It results from failure of atrophy of the primary vitreous and its vascular structures. A retrolental fibrovascular membrane can attach to the posterior aspect of the lens, as well as to the ciliary processes. The membrane may appear as a whitish mass in the pupil, giving rise to leukocoria. Secondary angle closure glaucoma can occur because of swelling of the lens and contraction of the retrolental membrane, which pushes the lens further forward. Hemorrhages into the eye may also result in glaucoma. Removal of the lens and membrane may prevent closure of the angle and is indicated if the angle is narrowing. Peripheral iridectomy can delay the need for lens extraction, but the angle must be observed carefully for progressive closure.
Retinopathy of prematurity (retrolental fibroplasia) Retinopathy of prematurity is often associated with prematurity of the newborn and oxygen therapy. It is typically bilateral and fairly symmetric, although it can present asymmetrically. Occasionally the disease occurs in full-term infants and in those without any oxygen therapy. Retinal blood vessels reach the ora serrata nasally at eight months gestation but do not vascularize the temporal retina until shortly after birth. The retinal vessels only appear susceptible to oxygen damage before their complete vascularization, which accounts for the propensity for retrolental fibroplasia to occur temporally. The initial effect of oxygen on the retinal blood vessels is vasoconstriction. When the infant is placed in normal air, vascular endothelial proliferation may occur adjacent to vessels that were constricted and closed during oxygen therapy. Regression is common in the earlier stages of the process, but with more advanced disease neovascularization may develop through the internal limiting membrane onto the retinal 51
Secondary congenital glaucoma surface and into the vitreous. If these advanced stages are reached, vitreous hemorrhage and fibrosis, and retinal detachment may occur. The development of these retrolental fibrotic membranes can cause a forward displacement of the lens and iris, which may lead to angle closure glaucoma, usually with some degrees of pupillary block.88 Iridectomy can be helpful in relieving the pupillary block.89 Lens removal with removal of the retrolental membranes may be indicated in selected cases.
Chromosomal anomalies Several types of chromosomal defects are often associated with developmental glaucoma. These include Trisomy 21 (Down syndrome), Trisomy D (13–15) syndrome, Trisomy 18 (Edward syndrome), and Turner syndrome (XO). Multiple ocular and systemic defects may be evident, in association with a large variety of presentations. The necessity for surgical and medical management must be individualized to each patient because some of these patients have a limited life expectancy. If isolated trabeculodysgenesis is evident on examination, a goniotomy or trabeculotomy would be the initial procedure.
Broad thumb syndrome (Rubenstein–Taybi syndrome) Broad thumbs and great toes are the most evident abnormalities in this syndrome. They may occur in association with mental and motor retardation, lid colobomata, cataract, as well as congenital glaucoma.90 Large physiologic optic disc cupping without glaucoma also can be seen in these patients. In patients with glaucoma, goniotomy or trabeculotomy can be successful in controlling the glaucoma.
Conclusion The diagnosis and management of some of the important secondary congenital glaucomas have been discussed in this chapter. In the management of the secondary congenital glaucomas, identification of the underlying mechanism for the glaucoma determines the appropriate therapeutic strategy. The necessity for surgical and medical management must be individualized to each patient, and a multidisciplinary approach must be undertaken whenever necessary.
References 1. Reese AB, Ellsworth RM. The anterior chamber cleavage syndrome. Arch Ophthalmol 1966; 75:307–318. 2. Waring GO III, Rodrigues MM, Liabson PR. Anterior chamber cleavage syndrome: a stepladder classification. Surv Ophthalmol 1975; 20:3–27. 3. Shields MB. Axenfeld Rieger syndrome. A theory of mechanism and distinctions from the iridocorneal endothelial syndrome. Trans Am Ophthalmol Soc 1983; 81:736–784. 4. Chisholm IA, Chundley AE. Autosomal dominant iridogoniodysgenesis with associated somatic anomalies: four generation family with Rieger’s syndrome. Br J Ophthalmol 1983; 67:529–531. 5. Allkemade PPH. Dysgenesis mesodermalis of the iris and cornea: A study of Rieger’s syndrome and Peters anomaly. Van Goreum: Assen, The Netherlands; 1969.
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6. Rieger H. Dysgenesis mesodermalis corneae et iridis. Z Augenheilkd 1935; 86:333. 7. Burian HM, Braley AE, Allen L. External and gonioscopic visibility of the ring of Schwalbe and the trabecular zone: an interpretation of the posterior corneal embryotoxon and the so-called congenital hyaline membranes on the posterior corneal surface. Trans Am Ophthalmol Soc 1954; 51:389–428. 8. Burian HM, Braley AE, Allen L. Visibility of the ring of Schwalbe and the trabecular zone: an interpretation of the posterior corneal embryotoxon and the so-called congenital hyaline membranes on the posterior corneal surface. Arch Ophthalmol 1955; 53:767–782. 9. Maumenee AE. Further observations of the pathogenesis of congenital glaucoma. Am J Ophthalmol 1963; 55:1163–1176. 10. Shields MB, Campbell DG, Simmons RJ. The essential iris atrophies. Am J Ophthalmol 1978; 85:749–759. 11. Wolter JR, Sandall GS, Fralick FB. Mesodermal dysgenesis of anterior eye with a partially separated posterior embryotoxon. J Pediatr Ophthalmol 1967; 4:41–46. 12. Cross HE, Jorgenson RJ, Levin LS, Kelly TE. The Rieger syndrome: an autosomal dominant disorder with ocular, dental and systemic abnormalities. Perspect Ophthalmol 1979; 3:3–16. 13. Dark AJ, Kirkham TH. Congenital corneal opacities in a patient with Rieger’s anomaly and Down’s syndrome. Br J Ophthalmol 1968; 52:631–635. 14. Wesley RK, Baker JD, Golnick AL. Rieger’s syndrome (oligodontia and primary mesodermal dysgenesis of the iris): clinical features and report of an isolated case. J Pediatr Ophthalmol Strabismus 1978; 15:67–70. 15. Kleinmann RE, Kazarian EL, Raptopoulos V, Braverman LE. Primary empty sella and Reiger’s anomaly of the anterior chamber of the eye: a familial syndrome. N Engl J Med 1981; 304:90–93. 16. Feingold M, Shiere F, Fogels HR, Donaldson D. Rieger’s syndrome. Pediatrics 1969; 44:564–569. 17. Sadeghi-Nejad A, Senior B. Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger’s syndrome). J Pediatr 1974; 85:644–648. 18. Jorgenson RJ, Levin LS, Cross HE, Yoder F, Kelly TE. The Rieger syndrome. Am J Med Genet 1978; 2:307–318. 19. Lubin JR. Oculocutaneous albinism associated with corneal mesodermal dysgenesis. Am J Ophthalmol 1981; 91:347–350. 20. Troeber R, Rochels R. Histological findings in dysgenesis mesodermalis iridis et corneae Rieger. Albrecht Von Graefes Arch Klin Exp Ophthalmol 1980; 213:169–174. 21. Yanoff M. Discussion of Shields MB, McCracken JS, Klintworth GK, Campbell DG: corneal oedema in essential iris atrophy. Ophthalmology 1979; 86:1549–1550. 22. Kupfer C, Kaiser-Kupfer MI, Datiles M, McCain L. The contralateral eye in the iridocorneal endothelial (ICE) syndrome. Ophthalmology 1983; 90:1343–1350. 23. Shields MB. Axenfeld-Rieger and iridocorneal endothelial syndromes: two spectra of disease with striking similarities and differences. J Glaucoma 2001; 10 (Suppl 1):S36–S38. 24. Chandler PA. Atrophy of the stroma of the iris: endothelial dystrophy, corneal edema, and glaucoma. Am J Ophthalmol 1956; 41:607–615. 25. Cogan DG, Reese AB. A syndrome of iris nodules, ectopic Descemet’s membrane, and unilateral glaucoma. Doc Ophthalmol 1969; 26:424–433. 26. Scheie HG, Yanoff M. Iris nevus (Cogan–Reese) syndrome. A cause of unilateral glaucoma. Arch Ophthalmol 1975; 93:963–970. 27. Shields MB. Progressive essential iris atrophy, Chandler’s syndrome, and the iris nevus (Cogan-Reese) syndrome: a spectrum of disease. Surv Ophthalmol 1979; 24:3–20. 28. Shields MB, McCracken JS, Klintsworth GK, et al. Corneal edema in essential iris atrophy. Ophthalmology 1979; 86:1533–1548. 29. Hirst LW, Quigley HA, Stark WJ, et al. Specular microscopy of iridocorneal endothelial syndrome. Am J Ophthalmol 1980; 89:11–21. 30. Shields MB, Campbell DG, Simmons RJ, et al. Iris nodules in essential iris atrophy. Arch Ophthalmol 1976; 94:406–410. 31. Theil R. Atlas of disease of the eye, Vol 2. Elsevier: New York; 1963:222–223. 32. Campbell DG, Shields MB, Smith TR. The corneal endothelium and the spectrum of essential iris atrophy. Am J Ophthalmol 1978; 86:317–324. 33. Rodrigues MM, Streeten BW, Spaeth GL. Chandler’s syndrome as a variant of essential iris atrophy: a clinicopathological study. Arch Ophthalmol 1978; 96:643–652. 34. Eagle RC Jr, Font RL, Yanoff M, et al. Proliferative endotheliopathy with iris abnormalities: the iridocorneal endothelial syndrome. Arch Ophthalmol 1979; 97:2104–2111. 35. Rodrigues MM, Phelps CD, Krachmer JH, et al. Glaucoma due to endothelialization of the anterior chamber angle: a comparison of posterior polymorphous dystrophy of the cornea and Chandler’s syndrome. Arch Ophthalmol 1980; 98:688–696.
References 36. Campbell DG. Formation of iris nodules in primary proliferative endothelial degeneration. Presented at the meeting of the Association for Research in Vision and Ophthalmology, Sarasota, FL, April 30–May 4, 1979. 37. Eagle RC Jr, Font RL, Yanoff M, et al. The iris nevus (Cogon-Reese) syndrome: light and electron microscopic observations. Br J Ophthalmol 1980; 64:446–452. 38. Anderson NJ, Badawi DY, Grossniklaus HE, Stulting RD. Posterior polymorphous membranous dystrophy with overlapping features of iridocorneal syndrome. Arch Ophthalmol 2001; 119:624–625. 39. Waring GO III, Rodrigues MM, Laibson PR. Corneal dystrophies II. Endothelial dystrophy. Surv Ophthalmol 1978; 23:147–168. 40. Cibis GW, Krachmer JH, Phelps CD, Weingeist TA. The clinical spectrum of posterior polymorphous dystrophy. Arch Ophthalmol 1977; 95:1529–1537. 41. Grayson M. The nature of hereditary deep polymorphous dystrophy of the cornea: its association with iris and anterior chamber dysgenesis. Trans Am Ophthalmol Soc 1974; 72:516–559. 42. Cibis GW, Krachmer JH, Phelps CD, Weingeist TA. Iridocorneal adhesions in posterior polymorphous dystrophy. Trans Am Acad Ophthalmol Otolarygnol 1976; 81:770–777. 43. Bourgeois J, Shields MB, Thresher R. Open angle glaucoma associated with posterior polymorphous dystrophy. Ophthalmology 1984; 91:420–423. 44. Ritch R, Forbes M, Hetherington J Jr, Harrison R, Podos SM. Congenital ectropion uveae with glaucoma. Ophthalmology 1984; 91:326–331. 45. Gramer E, Krieglstein GK. Infantile glaucoma in unilateral uveal ectropion. Graefe’s Arch Ophthalmol 1979; 211:215–219. 46. Dowling JL Jr, Albert DM, Nelson LB, Walton DS. Primary glaucoma associated with iridotrabecular dysgenesis and ectropion uveae. Ophthalmology 1985; 92:912–921. 47. Mandal AK. Late-onset unilateral primary developmental glaucoma associated with iridotrabecular dysgenesis, congenital ectropion uveae and thickened corneal nerves: a new neural crest syndrome? Ophthalmic Surg Lasers 1999; 30:567–570. 48. August PS, Niederberger H, Helbig H. Progression of congenital ectropion uveae. Arch Ophthalmol 2003; 121:1511. 49. Cross HE, Maumenee AE. Progressive spontaneous dissolution of the iris. Surv Ophthalmol 1973; 18:186. 50. Cross HE. Ectopia lentis et pupillae. Am J Ophthalmol 1979; 88:381–384. 51. Judisch GF, Martin-Casals A, Hanson JW, Olin WH. Oculodentodigital dysplasia. Four new reports and a literature review. Arch Ophthalmol 1979; 97:878–884. 52. Ozeki H, Shirai S, Ikeda K, Ogura Y. Anomalies associated with AxenfeldRieger syndrome. Graefe’s Arch Clin Exp Ophthalmol 1999; 237:730–734. 53. Asai T, Matsumoto H, Shingu K. Difficult airway management in a baby with Axenfeld-Rieger syndrome. Paediatr Anaesth 1998; 8:444. 54. Bateman JB, Maumenee IH, Sparkes RS. Peters anomaly associated with partial deletion of the long arm of chromosome 11. Am J Ophthalmol 1984; 97:11–15. 55. Townsend WM. Congenital corneal leukomas. 1. Central defect in Descemet’s membrane. Am J Ophthalmol 1974; 77:80–86. 56. Townsend WM, Font RL, Zimmerman LE. Congenital corneal leukomas. 2. Histopathologic findings in 19 eyes with central defect in Descemet’s membrane. Am J Ophthalmol 1974; 77:192–206. 57. Stone DL, Kenyon KR, Green WR, Ryan SJ. Congenital central corneal leukoma (Peters anomaly). Am J Ophthalmol 1976; 81:173–193. 58. Nakanishi I, Brown SI. The histopathology and ultrastructure of congenital, central corneal opacity (Peters anomaly). Am J Ophthalmol 1971; 72:801–812. 59. Polack FM, Graue EL. Scanning electron microscopy of congenital corneal leukomas (Peters anomaly). Am J Ophthalmol 1979; 88:169–178. 60. Heckenlively J, Kielar R. Congenital perforated cornea in Peters anomaly. Am J Ophthalmol 1979; 88:63–65. 61. Kuper C, Kuwabara T, Stark WJ. The histopathology of Peters anomaly. Am J Ophthalmol 1975; 80:653–660. 62. Ozeki H, Shirai S, Nazaki M, et al. Ocular and systemic features of Peters anomaly. Graefe’s Arch Clin Exp Ophthalmol 2000; 238:833–839.
63. Wolter JR, Haney WP. Histopathology of keratoconus posticus circumscriptus. Arch Ophthalmol 1963; 69:357–362. 64. Yang LL, Lambert SR. Peters anomaly. A synopsis of surgical management and visual outcome. Ophthalmol Clin North Am 2001; 14:467–477. 65. Yang LL, Lambert SR, Lynn MJ, Stulting RD. Surgical management of glaucoma in infants and children with Peters anomaly: long-term structural and functional outcome. Ophthalmology 2004; 111:112–117. 66. Walton DS. Glaucoma in aniridia. In: Ritch R, Shields MB, eds. The secondary glaucomas. CV Mosby Co: St Louis; 1982. 67. Elsas FJ, Maumenee IH, Kenyon KR, Yoder F. Familial aniridia with preserved ocular function. Am J Ophthalmol 1977; 83:718–724. 68. Grove JH, Shaw MW, Bourge G. A family study of aniridia. Arch Ophthalmol 1961; 65:81–84. 69. Hudson AC. Congenital aniridia treated by sclerocorneal trephining. Trans Ophthalmol 1961; 65:81–84. 70. Layman PR, Anderson DR, Flynn JT. Frequent occurrence of hypoplastic optic disc in patients with aniridia. Am J Ophthalmol 1974; 77:513–516. 71. Shaffer RN, Cohen JS. Visual reduction in aniridia. J Ped Ophthalmol 1975; 12:220–222. 72. Shaw MW, Falls HF, Neil JV. Congenital aniridia. Am J Hum Genet 1960; 12:389–415. 73. Neher EM. Aniridia congenita, iridermia. Am J Ophthalmol 1938; 21:293–298. 74. Walton DS. Aniridia with glaucoma. In: Chandler PA, Grant WM, eds. Glaucoma. Lea & Febiger: Philadelphia; 1979:351–354. 75. Pagon AR. Ocular coloboma. Surg Ophthalmol 1981; 25:223–236. 76. Grant WM, Walton DS. Progressive changes in the angle in congenital aniridia with development of glaucoma. Am J Ophthalmol 1974; 18:842–847. 77. David R, MacBeath L, Jenkins T. Aniridia associated with microcornea and subluxated lenses. Br J Ophthalmol 1978; 62:118–121. 78. Brandt JD, Casuso LA, Budenz DL. Markedly increased central corneal thickness: an unrecognized finding in congenital glaucoma. Am J Ophthalmol 2004; 137:348–350. 79. Chen TC, Walton DS. Goniosurgery for prevention of aniridic glaucoma. Arch Ophthalmol 1999; 117:1144–1148. 80. Adachi M, Dickens CJ, Hetherington J Jr, et al. Clinical experience of trabeculotomy for the surgical treatment of aniridic glaucoma. Ophthalmology 1997; 104:2121–2125. 81. Mullaney PBB, Selleck C, Al-Awad A, Al-Mesfer S, Zwaan J. Combined trabeculotomy and trabeculectomy as an initial procedure in uncomplicated congenital glaucoma. Arch Ophthalmol 1999; 117:457–460. 82. Wiggins RE Jr, Tomey KF. The results of glaucoma surgery in aniridia. Arch Ophthalmol 1992; 110:503–505. 83. Mandal AK, Prasad K, Naduvilath TJ. Surgical results and complications of mitomycin C-augmented trabeculectomy in refractory developmental glaucoma. Ophthalmic Surg Lasers 1999; 30:473–480. 84. Arroyave CP, Scott IU, Gedde SJ, Parrish RK 2nd, Feuer WJ. Use of glaucoma drainage devices in the management of glaucoma associated with aniridia. Am J Ophthalmol 2003; 135:155–159. 85. Kirwan JF, Shah P, Khaw PT. Diode laser cyclophotocoagulation: role in the management of refractory pediatric glaucomas. Ophthalmology 2002; 109:316–323. 86. Weiss DS, Ritch R. Glaucoma in the phakomatoses. In: Ritch R, Shields MB, Krupin T, eds. The glaucomas, Vol. II, Ch 52. CV Mosby: St. Louis; 1989:905–929. 87. Lieberman TW, Podos SM, Hartstein J. Acute glaucoma, ectopia lentis and homocystinuria. Am J Ophthalmol 1966; 61:252–255. 88. Pollard ZF. Secondary angle-closure glaucoma in cicatricial retrolental fibroplasia. Am J Ophthalmol 1980; 89:651–653. 89. Smith J, Shivitz I. Angle-closure glaucoma in adults with cicatricial retinopathy of prematurity. Arch Ophthalmol 1984; 102:371–372. 90. Roy FH, Summit RL, Hiatt RL, Hughes JG. Ocular manifestations of the Rubinstein-Taybi syndrome. Case report and review of the literature. Arch Ophthalmol 1968; 79:272–278.
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Chapter 8 Overview of the management of developmental glaucomas Introduction Overview of clinical management Factors influencing therapeutic decisions Conclusion
Introduction The primary objective in the management of the developmental glaucomas is to normalize and permanently control the intraocular pressure, thereby preventing loss of visual acuity, preserving visual field and ocular integrity, and stimulating the development of binocular stereoscopic vision. In 1939, J. Ringland Anderson1 stated that ‘the future of children with hydrophthalmia [primary infantile glaucoma] is bleak... with little hope of preserving sufficient sight to permit the earning of a livelihood.’ Today a much more optimistic outlook has been reached. It is rare to see a neglected patient with a poor outcome (Fig. 8.1). The improved prognosis of the developmental glaucomas is due to accurate and early diagnosis, as well as prompt and effective treatment. Glaucoma in the infant is an uncommon disease, but the impact on the visual development is profound. Any vision during the child’s formative years is worth fighting for, even if it is ultimately lost in severe cases, because appropriate and early therapy of this relatively uncommon condition may improve the child’s visual future. This chapter provides an overview of the management of the developmental glaucomas, and highlights the factors influencing therapeutic decisions in the child with glaucoma.
Overview of clinical management Medical therapy usually provides a supportive role to reduce the intraocular pressure temporarily, to clear the cornea, and to facilitate surgical intervention. Most patients who require long term medical therapy have severe disease that has not responded to surgical therapy. Medical therapy for pediatric glaucomas is described in detail in Chapter 9. Laser therapy has a limited role in the treatment of developmental glaucomas. The effective and definitive form of treatment of most of the developmental glaucomas is surgical. Primary surgical treatment is usually with goniotomy or trabeculotomy, although combined trabeculotomy and trabeculectomy may be useful in certain populations with a high risk for failure of goniotomy or trabeculotomy (Chapter 10). Some patients will not respond well to initial surgery for developmental glaucoma. As described in Chapter 12, these patients may respond to a variety of surgical treatments, including trabeculectomy with antifibrosis drugs, glaucoma drainage implants, and cyclodestructive procedures.
Factors influencing therapeutic decisions The choice of surgical therapy in the developmental glaucomas is dependent on a variety of factors (Table 8.1). Most important of these is the structural defect2,3 associated with the elevated intraocular pressure. In addition, age, corneal clarity, and associated systemic syndromes can influence the choice of therapy.
Structural defects Isolated trabeculodysgenesis is the hallmark of primary developmental glaucoma. In most instances, abnormal development of the trabecular meshwork increases the resistance
Table 8.1 Factors influencing clinical treatment Structural defects Age Systemic syndromes Corneal clarity Figure 8.1 Untreated congenital glaucoma. Untreated patients are uncommon, and the prognosis of congenital glaucoma has improved with more effective diagnosis and treatment.
Severity of glaucoma Corneal diameter
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Overview of management to aqueous outflow, which causes the elevated intraocular pressure. This condition is highly responsive to both goniotomy and trabeculotomy ab externo. The classic operation for the treatment of primary infantile glaucoma is Barkan’s goniotomy,4 a procedure which has changed little since its original description. In recent years, however, there has been a trend toward trabeculotomy ab externo.5–7 In iridotrabeculodysgenesis, the success rate for goniotomy and trabeculotomy decreases. When the only iris defect is hypoplasia of the anterior stroma, good response to goniotomy or trabeculotomy has been noted. However, when the iris defect includes abnormal vessels that appear to wander somewhat irregularly across the surface of the iris, then the prognosis is poor. In such cases, multiple surgeries are usually needed. If the angle can be easily visualized, goniotomy may be attempted, but trabeculotomy is probably the better initial procedure of choice. When there are extensive iris structural defects, careful evaluation of the angle is necessary. In aniridia, Grant and Walton8 noted gradual folding up of the peripheral stump of the iris over the trabecular meshwork forming the peripheral anterior synechia that blocks aqueous outflow. They believe this is a common cause of glaucoma in aniridia, and recommend prophylactic goniotomies to prevent the adhesion. Hoskins and associates frequently noted an anterior insertion of iris stroma in patients with aniridia, which is not an acquired process but present at birth. The stroma of the stump of the iris seems to sweep up across the angle. In the presence of this developmental anomaly, we prefer trabeculotomy ab externo for the initial operation when medical therapy fails. In iridocorneotrabeculodysgenesis, the prognosis for surgical treatment is poor. Often medical therapy is unsuccessful, and surgical intervention becomes necessary. Ab externo combined trabeculotomy and trabeculectomy may be useful as the initial operation in these patients to control the intraocular pressure. Angle-closure glaucoma is uncommon in childhood, but is important to recognize when it occurs. The surgical treatments for open-angle glaucoma are not effective for angleclosure glaucoma. Closure of the angle may be secondary to an underlying problem, which should be corrected.
Systemic syndromes In Sturge–Weber syndrome, the glaucoma can be present at birth or appear at anytime from infancy to adulthood. The mechanism of the glaucoma remains controversial9,12 and these patients show varying response to surgical therapy according to their age. When glaucoma is present in infancy, the developmental anomaly that obstructs aqueous outflow may predominate, which resembles the situation in primary congenital glaucoma.9 Many surgeons prefer goniotomy or trabeculotomy as the operation of choice but report that the rate of success is consistently lower than that with primary congenital glaucoma.10,11 When glaucoma in Sturge–Weber syndrome has its onset in later life, it is thought to be primarily due to elevated episcleral venous pressure.9 The angle defect is less severe and is sometimes minimal. In such patients, medical therapy should be tried first. If medical therapy fails, some surgeons feel that filtering procedures, such as trabeculectomy, should be performed on these eyes.12–14 We often use a technique combining ab externo trabeculotomy and trabeculectomy in such cases. The trabeculotomy is performed to remove the possible obstruction to aqueous outflow by a congenital angle deformity, while the trabeculectomy is included to bypass the episcleral venous system. In other words, the combined procedure may address both possible mechanisms of glaucoma association in this disease.15 There may be a rapid accumulation of a massive amount of suprachoroidal fluid during the operative procedure (Fig. 8.2).11,14 This will produce flattening of the anterior chamber, hardening of the globe, and difficulty in repositing a prolapsed iris when the sclerotomy is made. After the iridectomy is done, it may be difficult to reposit ciliary processes that rotate anteriorly into the sclerostomy, and vitreous may be lost. These complications can be avoided or minimized if, before entering the anterior chamber, two posterior radial sclerotomies or a triangular sclerotomy are made in the inferior quadrants of the globe. This enables the suprachoroidal effusion to drain out of the eye as it forms.
Age The age of the child at the onset of glaucoma is also a factor in choosing the appropriate therapy. In general, children under the age of 3 years are best treated surgically. Those with isolated trabeculodysgenesis respond well to both goniotomy and trabeculotomy ab externo. It has been observed that goniotomy is less successful after the age of 3 years, whereas trabeculotomy may be successful until later in life. Children over 3 years of age deserve a trial of medical therapy unless the specific defect of trabeculodysgenesis is seen (including an anterior insertion of the iris, a thickened trabeculum, or a wrapround type of anterior iris stromal insertion). Such patients may be treated with trabeculotomy ab externo.
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Figure 8.2 Choroidal effusion during the immediate postoperative period in a patient with Sturge–Weber syndrome.
Systemic syndromes To help avoid the complications of conventional glaucoma surgery in eyes with increased episcleral venous pressure, filtration techniques that do not require entry into the anterior chamber have been recommended by some surgeons. These include sinusotomy16 and non-penetrating trabeculectomy with or without Nd:YAG laser trabeculotomy.16,17 Oculocerebrorenal syndrome of Lowe is a rare syndrome, which may be associated with glaucoma and trabeculodysgenesis.18 Hemorrhage may accompany surgery and, therefore, medical therapy should be tried initially. The success of surgery is reduced compared with the success for primary developmental glaucoma. In homocystinuria, secondary glaucoma associated with angle closure may occur, due to subluxation of the lens. Laser or surgical iridotomy or lens removal are surgical options in this situation. Intravascular thrombosis has been reported with anesthesia in patients with homocysteinuria.19 In trisomy 13, congenital glaucoma resulting from poor differentiation of the angle structures has been reported.20 However, most of these patients die within the first few weeks of life, with only 18% of patients surviving the first year. Thus, in this syndrome and in others that have a high mortality rate, surgical intervention is warranted only in eyes that have a good prognosis and patients in whom longevity is likely to be good. Consultation with the pediatrician is useful in deciding management for these patients. In chronic childhood uveitis, goniotomy is a useful initial surgical procedure. Freedman and coworkers described the efficacy of goniotomy in 12 patients with childhood uveitic glaucoma and found an overall success of 75% with a mean follow-up of 32 months.21 Ho and coworkers reported experience with 54 goniotomies performed in 40 eyes of 31 patients, the majority with a diagnosis of juvenile rheumatoid arthritisassociated uveitis.22 Overall surgical success was achieved in 29 eyes (72%). Surgical outcome was adversely affected by increased age, peripheral anterior synechiae, prior surgeries, and aphakia.
Figure 8.3 Corneal edema due to elevated intraocular pressure in a patient with aniridia. The opacity of the cornea is associated with a poor gonioscopic view of the angle, which precludes goniotomy.
until they were a week or so of age to reduce anesthetic risk. With current anesthetic techniques, surgery can be safely performed on the second or third day of life. We feel that early surgery has salvaged more eyes than with delayed surgery.
Corneal diameter Some authors have had the impression that corneal enlargement was a poor prognostic factor in trabeculotomy.25 However, this has not been the experience of Luntz and Livingston in a prospective study of 86 treated eyes.23,26 Quigley27 reported a success rate of 67% in eyes with corneal diameter greater than 14 mm compared to 100% success in eyes less than 14 mm. However, McPherson and McFarland28 noted that corneal diameter had little effect on the final outcome of the external trabeculotomy. The success of goniotomy is decreased in eyes with significant buphthalmos (Fig. 8.4). Barkan29 felt that eyes with corneal diameters greater that 15 mm were not suitable for goniotomy. Similarly, Robertson30 reported 13 of 15 successes in non-buphthalmic eyes compared with only 3 of 10
Corneal clarity In situations where corneal clouding prevents adequate visualization of the trabecular meshwork by gonioscopy, trabeculotomy ab externo has to be performed in children with developmental glaucoma as the initial surgical procedure (Fig. 8.3).23,24
Severity of glaucoma In advanced cases of developmental glaucomas, initial goniotomy or trabeculotomy may be tried, but has a high failure rate. In this situation, combined trabeculotomy and trabeculectomy may offer a higher success rate than goniotomy or trabeculotomy. If the initial surgical procedure fails, it may be necessary to perform trabeculectomy with an adjunctive antifibrosis drug or glaucoma drainage implant. Patients who appeared at birth with bilateral cloudy corneas and severe glaucoma often had surgery delayed
Figure 8.4 Buphthalmos in a child with bilateral congenital glaucoma. Severe corneal enlargement and buphthalmos is associated with decreased success of goniotomy and may be associated with increased risk of surgical complications.
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Overview of management successes in buphthalmic eyes. In patients with a significant increase in corneal diameter, goniotomy is technically difficult to perform and the initial procedure of choice should be trabeculotomy or ab externo combined trabeculotomy and trabeculectomy. Our impression has been that complications may occur with increased frequency in eyes with severe corneal enlargement and buphthalmos. Additional precautions to avoid complications improve safety during the postoperative period. These precautions include tightly sutured trabeculectomy flap and two stage glaucoma drainage device implantation, in order to minimize postoperative hypotony.
Conclusion Surgical therapy is the most effective and definitive form of treatment for the developmental glaucomas. The choice of surgical therapy is influenced by a variety of factors, including the structural defect, age of the patient, corneal clarity, and associated systemic syndromes. Consideration of these factors may guide the clinician toward more effective treatment strategies.
References 1. Anderson JR. Hydrophthalmia or congenital glaucoma. Cambridge University Press: London; 1939:14–16. 2. Hoskins HD Jr, Shaffer RN, Hetherington J. Anatomical classification of the developmental glaucomas. Arch Ophthalmol 1984; 102:133–136. 3. Hoskins HD Jr, et al. Developmental glaucoma: diagnosis and classification. In: The New Orleans Academy of Ophthalmology Symposium on Glaucoma. CV Mosby: St. Louis; 1981. 4. Barkan O. Technique of goniotomy. Arch Ophthalmol 1938; 19:217–221. 5. Burian HM. A case of Marfan’s syndrome with bilateral glaucoma with a description of a new type of operation for developmental glaucoma. Am J Ophthalmol 1960; 50:1187–1192. 6. Smith R. A new technique for opening the canal of Schlemm. Br J Ophthalmol 1960; 44:370–373. 7. Burian HM, Allen L. Trabeculotomy ab externo; a new glaucoma operation: technique and results of experimental surgery. Am J Ophthalmol 1962; 53:19–26. 8. Grant WM, Walton DS. Progressive changes in the angle in congenital aniridia, with development of glaucoma. Am J Ophthalmol 1974; 78:842–847.
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9. Weiss DL. Dual origin of glaucoma in encephalotrigeminal hemangiomatosis. Trans Ophthalmol Soc UK 1973; 93:477–491. 10. Barkan O. Goniotomy for glaucoma associated with nevus flammeus. Am J Ophthalmol 1957; 43:545–549. 11. Christensen GR, Records RE. Glaucoma and expulsive hemorrhage mechanism in the Sturge-Weber syndrome. Ophthalmology 1979; 86:1360–1366. 12. Phelps CD. The pathogenesis of glaucoma in Sturge-Weber syndrome. Ophthalmology 1978; 85:276–286. 13. Keverline DO, Hills DA. Trabeculectomy for adolescent glaucoma in Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus 1977; 13:144–148. 14. Bellows AR, Chylark LT, Epstein DL, et al. Choroidal effusion during glaucoma surgery in patients with prominent episcleral vessels. Arch Ophthalmol 1979; 97:493–497. 15. Board RJ, Shields MB. Combined trabeculotomy-trabeculectomy for the management of glaucoma associated with Sturge-Weber syndrome. Ophthalmic Surg 1981; 12:813–817. 16. Krasnov MM. Microsurgery of the glaucomas. CV Mosby: St Louis; 1979. 17. Zimmerman TJ, Kooner KS, Ford VJ, et al. Trabeculectomy vs nonpenetrating trabeculectomy: a retrospective study of two procedures in phakic patients with glaucoma. Ophthalmic Surg 1984; 15:734–740. 18. Curtin VT, Joyce EE, Ballin N. Ocular pathology in the oculo-cerebro-renal syndrome of Lowe. Am J Ophthalmol 1967; 64(3); Suppl:533–543. 19. Komrower GM, Wilson VK. Homocystinuria. Proc R Soc Med 1963; 56:996–997. 20. Lichter PR, Schmickel RD. Posterior vortex vein and congenital glaucoma in a patient with trisomy-13 syndrome. Am J Ophthalmol 1975; 80:939–942. 21. Freedman SF, Rodriguez-Rosa RE, Rojas MC, Enyedi LB. Goniotomy for glaucoma secondary to chronic childhood uveitis. Am J Ophthalmol 2002; 133:617–621. 22. Ho CL, Wong EYM, Walton DS. Goniosurgery for glaucoma complicating chronic childhood uveitis. Arch Ophthalmol 2004; 122:838–844. 23. Luntz MH, Livingston DG. Trabeculotomy ab externo and trabeculectomy in congenital and adult-onset glaucoma. Am J Ophthalmol 1977; 83:174–179. 24. Hoskins HD, Shaffer RN, Hetherington J. Goniotomy vs trabeculotomy. J Pediatr Ophthalmol Strabismus 1984; 21:153–158. 25. Gregerson E, Kessing SVV. Congenital glaucoma before and after the introduction of microsurgery. Results of ‘Macro-surgery’ 1943–1963 and of microsurgery (Trabeculotomy/ectomy) 1970–1974. Acta Ophthalmol 1977; 55:422–430. 26. Luntz MH. Primary buphthalmos (infantile glaucoma) treated by trabeculotomy ab externo. S Afr Arch Ophthalmol 1974; 2:319–334. 27. Quigley HA. Childhood glaucoma: results with trabeculotomy and study of reversible cupping. Ophthalmology 1982; 89:219–225. 28. McPherson SD, McFarland D. External trabeculotomy for developmental glaucoma. Ophthalmology 1980; 87:302–305. 29. Barkan O. Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol 1948; 32:701–728. 30. Robertson EN Jr. Therapy of congenital glaucoma. AMA Arch Ophthalmol 1955; 54:55–58.
Chapter 9 Medical therapy of pediatric glaucoma Introduction Beta-blockers Carbonic anhydrase inhibitors Prostaglandin-related drugs Alpha-2 agonists Other adrenergic agonists Cholinergic drugs Osmotic drugs Conclusion
Introduction In pediatric patients, medical therapy is usually accorded a supportive role to reduce the intraocular pressure temporarily, to clear the cornea, and to facilitate surgical intervention. Definitive treatment of primary congenital glaucoma is usually accomplished with surgical intervention. Most patients who require long-term medical therapy have severe disease that has not responded to surgical therapy. Although regulatory agencies worldwide usually do not include children in antiglaucoma drug approval studies, clinicians have found these medications useful in children with elevated intraocular pressure (Table 9.1). Some children with congenital glaucoma and elevated intraocular pressure respond to medical therapy. In 161 eyes with congenital glaucoma, medical therapy alone reduced the intraocular pressure to less than 21 mmHg in 12% of eyes in the short-term and 10% of eyes in the long term.1 When
Table 9.1 Glaucoma medications in common usage in pediatric patients Beta-blockers Timolol solution 0.25% (qd, bid) Timolol gel-forming solution 0.25% (qd) Levobunolol 0.25% (qd, bid) Betaxolol 0.25% (qd, bid) Carbonic anhydrase inhibitors Dorzolamide 2% (bid, tid) Brinzolamide 1% (bid, tid) Acetazolamide elixir 5–15 mg/kg/day in divided doses (bid, tid) Prostaglandin-related drugs Latanoprost 0.005% (qd) Travoprost 0.004% (qd) Bimatoprost 0.03% (qd)
contemplating medical therapy in children, clinicians should evaluate the risks and benefits of the individual medications, use the minimum dosages required to achieve a therapeutic benefit, and monitor children for ocular and systemic side effects.2,3
Beta-blockers The response to adjunctive treatment with timolol has been studied in patients with a variety of pediatric glaucomas. In 34 patients with childhood glaucoma, timolol was added to other medical therapy, causing a definite improvement in 29%, a modest or equivocal improvement in 32%, and no improvement in 39%.4 In 38 eyes treated with timolol as adjunctive therapy, 37% of eyes were controlled at 22 mmHg or less.5 In 89 eyes with various types of pediatric glaucoma, an intraocular pressure lowering effect was observed only in 20% of eyes.6 Similarly, in 100 eyes with childhood glaucoma treated with timolol, 31% experienced a reduction of intraocular pressure (Fig. 9.1).7 After the initial response, increased an intraocular pressure over time may occur.5 Plasma timolol levels in children after treatment with 0.25% timolol greatly exceed those in adults after instillation of 0.5% timolol, especially in infants.8 Increased plasma timolol levels in children are explained by the volume of distribution of the drug, which is much smaller in children compared with adults. Higher plasma levels of drug would be expected to be associated with an increased risk of systemic side effects in children, especially young children, compared with adults. In children over 5 years old, reduction in resting pulse rates have been identified and are comparable to those observed in adults.4 Side effects have occurred in 4% to 13% of children,5,6 and timolol therapy has been discontinued in 3% to 7% of patients.4,5 Serious adverse events such as apnea, have been reported, especially in younger children with smaller body mass and blood volume for drug distribution compared with adults.9–11 Provocation of asthma may occur with topical timolol treatment. It is not known whether betaxolol, a selective beta-blocker, reduces the risk of pulmonary side effects in children compared with timolol. The effects of long-term use of topical beta blockers in children are not reported. Timolol in 0.25% and 0.5% solutions may be used cautiously in young glaucoma patients. The drug should be used with extreme caution in neonates, due to the possibility of apnea and other systemic side effects. A detailed pediatric examination should precede the use of this drug, to elicit the 59
Medical therapy of pediatric glaucoma
A
A
35 30 IOP (mmHg)
Additional treatment required
No added treatment
20
*
*
15 10 5
0
20
40 Percent Eyes
60
0
80
Baseline
B
Acetazolamide
Dorzolamide
> 10 1 to 10
-1 to -10 < -10 0
10
20 30 Percent Eyes
40
50
Figure 9.1 Timolol in pediatric glaucomas. (A) In a series of 100 eyes treated with timolol maleate, the majority (60%) required additional surgery or medications. (B) The change from baseline intraocular pressure (IOP) in the 40 eyes receiving timolol therapy without additional surgery or medications. Of the 40 eyes that received timolol therapy without additional surgery or medications, 31 (78%) demonstrated reduced IOP after timolol treatment. (Adapted with permission from Hoskins HD Jr, Hetherington J Jr, Magee SD, Naykhin R, Migliazzo CV. Clinical experience with timolol in childhood glaucoma. Arch Ophthalmol 1985; 103:1163–1165. Copyright © (1985) American Medical Association. All rights reserved.)
presence of systemic abnormalities such as bronchial asthma and cardiac disease. In these cases, beta blockers are contraindicated. Use of 0.25% timolol rather than 0.5% timolol is strongly recommended in order to minimize the risk of side effects. Once daily dosing with timolol 0.25% in gel-forming solution may help simplify medical regimens.
Carbonic anhydrase inhibitors Systemic carbonic anhydrase inhibitors would be expected to have similar side effects in children compared with adults. In addition, growth suppression in children has been associated with oral acetazolamide therapy,12 and infants may experience a severe metabolic acidosis.13 Side effects due to systemic carbonic anhydrase inhibitors in infants and young children are not commonly reported, although these patients may not verbalize these side effects to parents or health care providers. Oral administration of acetazolamide suspension in a dosage of 10 (range 5–15) mg/kg/day given in divided doses (three times daily) is safe and well tolerated by children, lowers intraocular pressure, and may reduce corneal edema as a prelude to surgery.14,15
Dorzolamide (% Decrease IOP)
Change IOP (mmHg)
B
No Change
60
25
55 45 35 25 15 5 -5
0
10
20 30 40 50 Acetazolamide (% Decrease IOP)
60
Figure 9.2 Carbonic anhydrase inhibitors in pediatric patients treated with beta blocker at baseline. (A) Intraocular pressure (IOP) was significantly reduced from baseline (on topical beta blocker alone) after addition of acetazolamide (mean ± standard deviation decrease of 35.7 ± 15.6%) or dorzolamide (27.4 ± 17.1%). Y error bars indicate standard error of mean (SEM). Asterisk indicates P < 0.01 compared with baseline. (B) Correlation between efficacy of oral and topical carbonic anhydrase inhibitor therapy. The percentage reduction of intraocular pressure (IOP) in 8 eyes on topical beta-blocker therapy was similar after addition of acetazolamide (oral) or dorzolamide (topical) treatment (r = 0.94). (Adapted with permission from Portellos M, Buckley EG, Freedman SF. Topical versus oral carbonic anhydrase inhibitor therapy for pediatric glaucoma. J AAPOS 1998; 2:43–47.)
Topical versus oral carbonic anhydrase inhibitor therapy has been evaluated for pediatric glaucoma in a crossover design study.16 The mean intraocular pressure was reduced by 36% and 27% compared with baseline after treatment with oral acetazolamide and topical dorzolamide, respectively (Fig. 9.2). All eyes showed an increase in intraocular pressure when switched from acetazolamide to dorzolamide, with a mean increase of 3.7 mmHg. Although not as effective as acetazolamide in this group of patients, topical dorzolamide caused a significant reduction of intraocular pressure and was well tolerated. At present, topical carbonic anhydrase inhibitors are more commonly prescribed compared with systemic carbonic anhydrase inhibitors. Many clinicians recommend twice daily dosing, in order to minimize discomfort to the parent and child associated with three times daily dosing. For older children, the fixed combination of dorzolamide with timolol
Alpha-2 agonists may simplify medical regimens, reducing the number of drops instilled per day.
A prostaglandin-related drug, specifically latanoprost, has been evaluated in studies of a variety of glaucoma diagnoses, including glaucoma associated with Sturge–Weber syndrome.17–21 In 31 eyes with a variety of glaucoma diagnoses, 6 (19%) of treated eyes responded with a decrease of intraocular pressure averaging 8.5 mmHg (34% reduction), whereas the majority of eyes were nonresponders (Fig. 9.3).17 Responders were more likely to have juvenile-onset openangle glaucoma and to be older than nonresponders. The drug was well tolerated in this short-term study. In glaucoma associated with Sturge–Weber syndrome, 17% to 28% of eyes treated with latanoprost responded with a reduction of intraocular pressure.18,19 Increased episcleral venous engorgement was noted, and one patient (6%) discontinued therapy because of intolerable conjunctival hyperemia.19
Nonresponders Responders
N=25
B 35
IOP (mmHg)
30
Nonresponders Responders
0.4 0.2 0.0
0
1
2
3 4 Follow-up (months)
5
6
Figure 9.4 Kaplan–Meier survival curve showing response to latanoprost in patients with Sturge–Weber syndrome and glaucoma. A successful response to latanoprost was defined as a reduction of intraocular pressure of at least 20% from baseline without additional medical or surgical therapy and no adverse events related to latanoprost therapy. Medical therapy can be effective in patients with Sturge–Weber syndrome, but patients often require additional therapy. (Reproduced with permission from Altuna JC, Greenfield DS, Wand M, et al. Latanoprost in glaucoma associated with Sturge–Weber syndrome: benefits and side effects. J Glaucoma 1999; 8:199–203.)
Alpha-2 agonists
25 20 * 15 10 Baseline
0.6
Although a declining success rate occurs over time, half of the patients were controlled at 1 year follow-up following a trial of latanoprost as adjunctive therapy (Fig. 9.4).20 Although the majority of children do not respond well to latanoprost, some children may have a significant ocular hypotensive effect with latanoprost treatment.21 Side effects are infrequent and mild, and the dosage schedule is convenient. Parents and patients should be advised about the possibility of local side effects, including iris pigmentation change, eyelash growth, and hyperemia. When medical therapy prior to surgery or other short-term medical therapy is planned, these local side effects are generally not a problem. However, the prevalence and types of side effects associated with long-term therapy are not known.
A
N=6
0.8 Success
Prostaglandin-related drugs
1.0
Latanoprost
Figure 9.3 Latanoprost in pediatric glaucomas. (A) In a series of 31 eyes, the majority of children (25) were non-responders (
