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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
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.
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.
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
To my patients and their families, my colleagues and trainees, and my supportive family and friends.
Peter A. Netland
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
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.
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.
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
Figure 1.1 Otto Barkan (1887–1958). Reprinted with permission from Cordes FC, Otto Barkan, MD. Trans Am Ophthalmol
1958; 56:3–4.
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
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.
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.
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
defined by Shaffer and Weiss. In other areas, however, the term infantile retains its intended meaning, indicating glaucoma occurring at birth.3
Classification
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.
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
Table 2.1 Shaffer–Weiss (1970) classification of congenital glaucoma
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
2.Anomalous superficial vessels
C.Structural anomalies
1.Holes
2.Colobomata
3.Aniridia
III.Cor neoiridotrabeculodysgenesis (malformation of trabecular meshwork with iris and corneal anomalies)
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
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.
Iridotrabeculodysgenesis
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
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 2mm 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
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.
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.
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.
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.
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).
Table 3.1 Contributions of neural crest-derived mesenchyme and mesodermal mesenchyme to human ocular structures
ANeural crest cell derivatives
1Sclera (except caudal portion)
2Cornea
aEndothelium
bKeratocytes
3 Uveal tract
aFibroblasts of choroid
bCiliary body muscles
cStromal cells of iris
dMelanocytes
4 Iridocorneal angle
aTrabecular meshwork endothelium
5Vascular system a? Pericytes
BMesodermal cell derivatives
1Caudal region of sclera
2Vascular endothelium, including Schlemm’s canal
3Extraocular 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
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 24mm 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
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.)
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.
Retina
Optic cup
Optic stalk
Embryonic fissure
Lens vesicle
Epithelium
Retina
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 normallypresent at birth but develops in the first year of life.
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
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.)
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
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
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
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
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.
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.
25.Tawara A, Inomata H. Developmental immaturity of the trabecular meshwork in congenital glaucoma. Am J Ophthalmol 1981; 92:508–525.
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.
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.
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.
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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.
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Chapter 4 Epidemiology and genetics of developmental glaucomas
Introduction
Incidence
Heredity
Genetic studies
Genetic counseling
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 10000 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 10000 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
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.
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
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.
Table 4.1 Known genetic loci for primary congenital glaucoma Mutated gene
LocusLocationInheritance(MIM)Reference
GLC3A2p21AR CYP1B1 (601771)14
GLC3B1p36AR Unknown15
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.
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
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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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.
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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.
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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
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.
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30.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.
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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,
Table 5.1 Microscopic and ultrastructural observations in primary congenital glaucoma
Location Finding
Iris
Trabecular meshwork
Schlemm’s canal
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 beams thicker than normal10,11
Deeper trabecular sheets compressed with decreased intertrabecular spaces9–11
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
Membrane
Anteriorly displaced and pulled inward due to enlarging globe with non-enlarging lens10,13,18,19,41
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
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
(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
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 10.5mm may be enlarged to as much as 16 to 18mm.
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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Varnish, 232, 239, 249, 293, 294 f., 309.
‘Vasajo,’ origin of Vasari family name, 156.
Vasari, the family, 156.
Vasari, Giorgio, the elder (‘Vasajo’), 156 f.
Vasari, Giorgio: his character and gifts, 4, 15 f.: his life and art, 5, 7, 33, 59, 106, 291: his visits, 56, 103, 237: his method of mural painting in oil, 233 f.: his writings; Letters, 3, 6, 111;
Lives of the Artists, 1, 2, 5, 7, and passim; Ragionamenti, 3; Editions of, 1, 2, 7; Translations of, 2 f.;
Text, printed, possible mistakes in, see ‘Text.’
Vaults; brick, 86; stucco, 85, 170; in St. Peter’s, 54.
Vellino, river, 88.
Venetians, the, 14, 212.
Venice: colour printing, 281: enamels of, 278: frescoes at, 234: glass work at, 268: mosaics at, 252, 254, 268: Ducal Palace, 236, 237: Church of S. Marco, 111, 112; mosaics at, 252: Library of S. Marco, 56, 237: Palace of S. Marco, see ‘Ducal Palace’: Panattiera, 56: Piazza di S. Marco, 56:
Piazzetta, 56: Scuola di S. Rocco, 234: Zecca (Mint), 56, 65.
Veniziano, Domenico, 229.
‘Venus’; crouching, in Louvre, 194; Medici, 105; of Milo, 195; and Cupid, 112.
‘Verdaccio,’ 242.
‘Verde’; ‘Antico,’ 35; ‘di Prato,’ 35, 118, 127.
Verdun, 266.
Verhaecht, 227.
Verona; marble, 39; S. Maria in Organo, 306.
Verrocchio, 199; his ‘Boy with a Dolphin,’ 33; his sarcophagus in S. Lorenzo, 112; his Colleoni statue, 200.
Versiglia, the, 125.
‘Via dei Magistrati,’ see ‘Florence,’ ‘Uffizi.’
Victoria and Albert Museum, 136, 156, 189, 311, 313. Vignola, 81. Villa; Careggi, 33, 228; Farnesina, 301, 171; of Hadrian, 303; Madama, 89; Medici, 40, 105, 107, 109; Papa Giulio, 108;
Walnut wood; for carving, 174; as ground for inlays, 262.
Wax; its use by the modeller, 148, 188 f.; by the bronze founder, 160 f.; coloured, its preparation and use, 148 f., 188 f.; as setting for portable mosaics, 136.
Westminster Abbey, waxen effigies at, 188.
Wheel, the, for working hard stones, 112, 167, 168.
White; of egg, 234, 249; for fresco (bianco Sangiovanni), 221; lead white (biacca), 221, 230, 236; for tempera, 224.
Whitening, 241, 242, 294.
Wilkinson, Sir Gardner, 102.
Wilson, Charles Heath, Life of Michelangelo, 310.
Winckelmann, 104.
Wire-drawing plate, 280.
Wolf, porphyry, 28, 107.
Wood; carving, 173 f.; engraving, 281 f.; inlaying, see ‘Tarsia.’
Yellow stain for glass, 270, 311.
‘Zeus,’ of Pheidias, 181.
Zinc, ingredient in bronze, 164.
Zirkel, Petrographie, 49.
Zobi, Notizie ... dei Lavori ... in Pietre Dure, 109, 114 f.
GLASGOW: PRINTED AT THE UNIVERSITY PRESS BY
ROBERT MACLEHOSE AND CO. LTD.
1. Berenson, The Drawings of the Florentine Painters, London, 1903, 1, p. 18, says that Vasari ‘ was an indifferent connoisseur and a poor historian; but he was a great appreciator ... and a passionate anecdote-monger. Now the Anecdote must have sharp contrasts....’
2. The materials for our knowledge of Vasari and his works are derived from his own Autobiography and his notes on himself in the Lives of other artists, as well as from the Ragionamenti and from the Letters, printed by Milanesi in the eighth volume of the Sansoni edition of Vasari’s writings, or previously printed by Gaye in the third volume of the Carteggio.
3. Before Vasari published his Lives, at least eight editions of Vitruvius had appeared. The Editio Princeps, ‘curante Jo. Sulpitio Verulano,’ is believed to have been issued at Rome about 1486, and in 1496 and 1497 reprints were published at Florence and at Venice. In 1511 appeared the important edition, with emendations and illustrations, by the famous architect Fra Giocondo of Verona, and this was reprinted in the Giunta edition at Florence in 1513. Other editions saw the light in 1522, 1523, 1543, and 1550. An Italian translation was published in 1521, a French one in 1547, and in 1548 one in German. The reverence of the architects of the Renaissance for Vitruvius was unbounded, and Michelangelo is said to have remarked that if a man could draw he would be able by the help of Vitruvius to become a good architect.
4. Leon Battista Alberti shares with Brunelleschi the distinction of representing in its highest form the artistic culture of the early age of Humanism. His principal work De Re Aedificatoria, or, as it is also called, De Architectura, was published after his death, in 1485. It is divided, like the work of Vitruvius, into ten books, and is an exceedingly comprehensive treatise on the architectural art both in theory and practice, and on the position of architecture in relation to civilization and to society at large. It is written in a noble and elevated style, and, as the title implies, in Latin. It was translated into Italian by Bartoli and into English by J. Leoni (three volumes, folio, 1726). Alberti also wrote shorter tracts on Sculpture and Painting, as well as other works of a less specially artistic order.
5. See Note on ‘Porphyry and Porphyry Quarries’ at the close of the ‘Introduction’ to Architecture, postea, p. 101, and A on the Frontispiece, which gives representations in colour of the stones Vasari mentions in these sections, omitting those familiarly known.
6. If a stone be comparatively soft when quarried and become harder after exposure to the air, this is due to the elimination in the air of moisture that it held when in the earth. In a dry climate like that of Egypt there is little or no moisture for stones to hold, and the Egyptian porphyry, Mr W. Brindley reports, is quite as hard when freshly quarried as after exposure. Vasari repeats this remark when he is dealing with granite in § 6, postea, p. 41. He has derived it from Alberti, who in De Architectura, bk. II, ch. vii, notices perfectly correctly that the question is one of the comparative amount of moisture in the stone.
7. ‘Temple of Bacchus’ was the name given at the Renaissance to the memorial chapel containing the tomb of Constantia, daughter of Constantine the Great, on the Via Nomentana close to S. Agnese, and now known as S. Costanza. The name was suggested by the mosaics with vintage scenes on the barrel vault of the aisle, which are of great interest and beauty. In Vasari’s time this still contained the porphyry sarcophagus where Constantia was laid, and of this he goes on to speak. In 1788 Pius VI transferred it to his new Sala a Croce Greca in the Vatican, where it now stands.
8. This is the second of the two vast cubical porphyry sarcophagi in the Croce Greca, and it is believed that it served once to contain the mortal remains of Helena, mother of Constantine. It is much finer in execution than the other, and exhibits a large number of figures in high relief, though incoherently composed. The subject may be the victories of Constantine. It was originally in the monument called ‘Torre Pignattara,’ the supposed mausoleum of Helena on the Via Labicana, and was transported in the twelfth century by Anastatius IV to the Lateran, whence Pius VI had it transferred to the Vatican. The restoration of these huge sarcophagi cost an immense amount in money and time. Massi (Museo Pio-Clementino, Roma, 1846, p. 157) states that the second one absorbed the labour of twenty-five artificers, who worked at it day and night for the space of nine years. Strzygowski, Orient oder Rom, 1901, notices the sarcophagi.
9. Urns, or, as the Italians called them, ‘conche,’ of porphyry, basalt, granite and marble existed in great abundance in the Roman Thermae where they were used for bathing purposes. From the seventh century onwards the Christians adopted these for sepulchral use and placed them in the churches, where many of them are still to be seen (Lanciani, Storia degli Scavi, Roma, 1902, I, 3, and Marangoni, Delle Cose Gentilesche, etc., Roma, 1744). Hence Vasari speaks of the porphyry urn of the Piazza della Rotonda (the Pantheon) as of sepulchral origin, and it was indeed rumoured to have held the ashes of Agrippa, and to have stood once on the apex of the pediment of the Pantheon portico. It was however an ancient bath vessel, and was found when Eugenius IV, 1431–39, first excavated and paved the piazza in front of the Pantheon. It was placed with two Egyptian lions in front of the portico, where it may be seen in the view of the Piazza della Rotonda in G. F. Falda’s Vedute delle Fabbriche, etc., of 1665. Clement XII, 1730–40, who was a Corsini, had it transported for his own sepulchre to the Corsini chapel in the
Lateran, where it now stands, with a modern cover. Vasari evidently admired this urn, and he mentions it again in the life of Antonio Rossellino, where he says of the sarcophagus of the monument of the Cardinal of Portugal in S. Miniato, ‘La cassa tiene il garbo di quella di porfido che è in Roma sulla piazza della Ritonda.’ (Opere, ed. Milanesi, III, 95.) See Lanciani, Il Pantheon, etc., Prima Relazione, Roma, 1882, p. 15, where the older authorities are quoted. Of all the bath vases of this kind now visible in Rome, the finest known to the writers is the urn of green porphyry, a rare and beautiful stone, behind the high altar of S. Nicola in Carcere. It is nearly six ft. long, and on each side has two Medusa heads in relief worked in the same piece, with the usual lion’s head on one side at the bottom for egress of water. The workmanship is superb. It may be noted that the existing baptismal font in St. Peter’s, in the first chapel on the left on entering, is the cover of the porphyry sarcophagus of Hadrian turned upside down. It measures 13 ft. in length by 6 ft. in width.
10. In chapter VI of the ‘Introduction’ to Architecture, postea, p. 93, Vasari writes of the ‘ casa di Messer Egidio et Fabio Sasso’ as being ‘in Parione.’ See Note at the end of the ‘Introduction’ to Architecture on ‘The Sassi, della Valle, and other Collections of Antiques of the early part of the sixteenth century,’ postea, p. 102 f.
11. This is the ‘Apollo’ at Naples, No. 6281. See Note as above.
12. See Note above mentioned.
13. Now lost.
14. Now in the Boboli Gardens at Florence. See Note on the Sassi, etc., Collections.
15. See Note on ‘The Revival of Sculpture in Porphyry,’ postea, p. 110 f.
16. Reciprocating saws of the kind Vasari mentions, mostly of soft steel or iron, and also circular saws, are in use at the present day, the abrasives being emery, or a new material called ‘carborundum.’ This consists in minute crystals of intense hardness gained by fusing by an electric current a mixture of clay and similar substances. See The Times, Engineering Supplement, Oct. 31, 1906.
17. It needs hardly to be said that the ancients had no ‘secrets’ such as Vasari hints at. Mr W. Brindley believes that the antique methods of quarrying and working hard stones were ‘precisely the same as our own were until a few years ago, ’ that is to say that the blocks were detached from the quarry and split with metal wedges, dressed roughly to shape with large and small picks, and ‘rubbed down with flat stone rubbers and sand, then polished with bronze or copper rubbers with emery powder’ (Transactions, R.I.B.A., 1888, p. 25). At a very early date in Egyptian history, even before the dynastic period, the hardest stones (not excepting porphyry) were successfully manipulated, and vases and bowls of these
materials cut with exquisite precision. Professor Flinders Petrie found evidence that at the epoch of the great pyramids tubular drills and bronze saws set with gem-stones (corundum) were employed by the Egyptians in hollowing basalt sarcophagi and cutting the harder stones (The Pyramids and Temples of Ghizeh, London, 1883, p. 173 f.). There is however no evidence of the use of these advanced appliances by the Greeks or Romans. It must not be forgotten that even before the age of metals the neolithic artificers of western Europe could not only cut and bore, but also ornament with patterns, stone hammer-heads of the most intractable materials, with the aid only of pieces of wood twirled or rubbed on the place and plentifully fed with sand and water. The stone axe- and hammer-heads so common in pre-historic collections were bored with tubular drills, made probably from reeds, which cut out a solid core. Such cores can still be seen in partly-pierced hammer-heads in the Museum at Stockholm, and elsewhere.
18. Fig. 1 shows the inscription of which Vasari writes and the situation of it on the riser of the step is seen on Plate II. The porphyry slab is 3 ft. 5 in. long and 5½ in. high. The tongues at the ends are in separate pieces. The letters, nineteen not eighteen in number, are close upon 2 in. in height and are cleanly cut with Vshaped incisions. The illustration shows the form of the letters which Vasari justly praises. The name ‘Oricellario’ or -us was derived by the distinguished Florentine family that bore it from the plant Oricello, orchil, which was employed for making a beautiful purple dye, from the importation of which from the Levant the family gained wealth and importance. The shortened popular form of the name ‘Rucellai’ is that by which the family is familiarly known. Giovanni Rucellai gave a commission to Alberti to complete the façade of S. Maria Novella, which was carried out by 1470. The Bernardo Rucellai of the inscription, the son of Giovanni, was known as a historian, and owned the gardens where the Platonic Academy had at one time its place of meeting. Fineschi, in his Forestiero Istruito in S. Maria Novella, Firenze, 1790, says that Bernardo desired to be buried in front of the church and had the inscription cut for sepulchral purposes. The existence of sepulchral ‘avelli’ of distinguished Florentine families at the front of the church makes this seem likely, and in this case the lettering would be after Alberti’s time, though as Fineschi believes, the earliest existing work of the kind in hard stone at Florence. See Rev. J. Wood Brown, S. Maria Novella, Edinburgh, 1902, p. 114.
19. After the fashion of an ordinary carpenter’s ‘brace.’
20. See Note on ‘The Porphyry Tazza of the Sala Rotonda of the Vatican,’ at the close of the ‘Introduction’ to Architecture, postea, p. 108.
21. See Note at the end of the ‘Introduction’ to Architecture, postea, p. 110 f., on ‘Francesco del Tadda and, the Revival of Sculpture in Porphyry.’
22. About 4 ft. 9 in. In a letter of May 1557 in Gaye, Carteggio, II, 419, Vasari mentions the work as nearly finished.
23. The palace in question is the well-known Palazzo Vecchio at Florence, which was adapted for the Grand-ducal residence largely by Vasari himself under the Grand Dukes Cosimo and his successor Francesco. The fountain is the one at present in the courtyard of the palace, carrying the beautiful bronze figure of a boy with a dolphin, by Verrocchio. This ‘putto’ was brought in from the famous Medicean Villa at Careggi, the seat of the Platonic Academy, for the purpose of completing the fountain of which Vasari here gives an account. The porphyry work, both in design and execution, is worthy of the beautiful bronze that surmounts it. The basin rests on a well-turned dwarf pillar of porphyry and this on a square base of the same material. The surfaces are true and the arrises sharp, and the whole is carried out in a workmanlike manner, and by no means betrays a ‘prentice hand.’
24. See Vasari’s Life of Michelangelo, Opere, ed. Milanesi, VII, 260.
25. That is Cosimo ‘Pater Patriae,’ who died at Careggi in 1464. The portrait in question is shown on Plate III. For what is known about this and other works by Francesco del Tadda, see postea, p. 113 f.
26. See Note on ‘Porphyry and Porphyry Quarries,’ postea, p. 101.
27. This remark is evidently derived by Vasari from Leon Battista Alberti, who writes as follows in De Re Aedificatoria, Lib. II, ‘At nos de porphirite lapide compertum habemus non modo flammis non excoqui, verum et contigua quaeque circumhereant saxa intra fornacem reddere ut ignibus ne quidquam satis exquoquantur.’ The sense of ‘excoqui’ in this passage, and of Vasari’s ‘ cuocer, ’ is somewhat obscure, but can be interpreted by reference to old writings on stones, in which great importance is given to their comparative power of resistance to fire. See Pliny, Hist. Nat., XXXVI, 22, etc., etc. Theophrastus, Περι ̀ Λίθων, § 4, has the following: ‘Stones have many special properties ... for some are consumed by fire and others resist it ... and in respect of the action of the fire and the burning they show many differences....’ The ‘excoqui’ of Alberti probably refers to the resistance of porphyry to the fire as compared with the submission to it of stones like limestone, which are ‘burnt out’ or calcined by the heat. Vasari’s ‘ non si cuoce ’ is not an adequate translation of Alberti’s word ‘ excoqui.’ With a blast heat porphyry fuses to a sort of obsidian or slag, but a moderate heat only causes it to lose its fine purple hue and become grey. This is the ‘ rawness ’ implied in Vasari’s word ‘incrudelisce.’ To us rawness suggests raw meat which is redder in colour than cooked, but the Italians, who are not great meat eaters, would have in their minds the action of fire on cakes and similar comestibles that darken when baked, and an Italian artist would think too of the action of fire on clay, ‘che viene rossa quando ella è cotta’ as he says in chapter XXV of the ‘Introduction’ to Painting. See Frontispiece, where A1 , compared with A, shows the effect of fire on the stone.
28. The two porphyry columns, that stand one on each side of Ghiberti’s Old Testament gates at the eastern door of the Baptistry of Florence, serve to point a moral about the untrustworthiness of popular sayings. When these apply to
monuments it usually happens that the monument itself hopelessly discredits the saying. The porphyry columns in question are perfectly normal in colour and show no recognizable trace of the action of fire. Villani (Chronicle, bk. IV, ch. 31) says of these columns ‘The Pisani sent them to Florence covered with scarlet cloth, and some said that before they sent them they put them in the fire for envy. ’ If we rationalize a little we can imagine that the scarlet cloth, the use of which by the Pisans in connection with porphyry shows a most lamentable absence of taste in colour, would at first sight seem to take the colour out of the porphyry and make it look grey through contrast. Hence may have arisen the impression which gave rise to the saying. Boccaccio, in his commentary on the passage in Dante (Inferno, XV, 67), in which the ‘blindness’ of the Florentines is referred to, notices this affair of the columns as one explanation of this accusation against his countrymen.
29. On the subject of serpentine some misapprehension exists. Mineralogists apply the term to a soft stone of a green hue with long curling markings through it, which in their form suggest lacertine creatures and account for the name of the stone. It derives its colour from the presence of a large percentage of manganese in union with silica, and contains twelve or so per cent. of water. A penknife scores it easily. The ‘Verde di Prato,’ a dark stone used in bands on Tuscan buildings, of which there is question in a subsequent section, postea, p. 43, is a species of true serpentine.
On the other hand the word ‘serpentine’ is in common use for a dark green stone of quite a different kind, that occurs very commonly in ancient Roman tesselated pavements, and it is this false serpentine that Vasari has in view. It is very hard indeed, and a penknife does not mark it. Professor Bonney describes it as ‘ a somewhat altered porphyritic basalt,’ and it is full of scattered crystals of a paler green composed of plagioclasic felspar. These crystals average about the size of grains of maize and they sometimes cross each other, thus justifying Vasari’s description of them. A specimen is B, on the Frontispiece. This stone was found in Egypt, and it is probably the ‘Augustan’ and ‘Tiberian’ stone mentioned by Pliny, Hist. Nat., XXXVI, 7. See Transactions, R.I.B.A., 1888, p. 9. The chief quarry of it however was in the Peloponnesus to the south of Sparta, and the produce of this is called by Pliny, loc. cit., ‘Lacedaemonium viride.’ It should be noted that ‘Verde Antico,’ a green marble of which the chief quarries are in Thessaly, is distinct from both the true and the false ‘serpentine.’
30. Cipollaccio. It is not clear what is the difference, if any exist, between the stone thus called and the ‘Cipollino’ which Vasari discusses in a later section, postea, p. 49. The latter is a name in universal employment, but the term ‘Cipollaccio’ is not known to Cavaliere Marchionni, the courteous Director of the Florentine State Manufactory of Mosaics, nor is it recognized at Carrara. On the other hand it is given as the name of a marble in Tomaseo’s Dizionario (though probably only on the strength of this mention in Vasari) and a stone worker at Settignano claimed to know and use the word. On the material see the Note on
