Cynthia Mattox, MD and Priti Batta, MD
The phakomatoses (Table 50-1) are a diverse group of dis orders. The categorization of many disorders under the heading of the phakomatoses has created controversy and confusion since the term was first introduced by Dutch ophthalmologist Jan van der Hoeve in the early 20th century.1,2 Van der Hoeve first described tuberous sclerosis3,4 (Bourneville’s disease) and neurofibromatosis (NF; von Recklinghausen’s disease) as phakomatoses in his earliest publications on the subject, then later added von Hippel-Lindau2 and Sturge-Weber syndromes.4–6 The common denominator seemed to be the congenital nature of multisystem tumors. Jan van der Hoeve called them phakomata after the Greek name for motherspot, indicating the congenital nature of the conditions. Others later interpreted this to mean that the phakomatoses had a birthmark that indicated an underlying multiorgan condition.7 In a more contemporary interpretation of the meaning behind grouping these diverse conditions, Hogan and Zimmerman8 described the phakomatoses as disseminated hamartomas affecting the eye, central nervous system (CNS), skin, and internal organs. Hamartomas are tumorous masses that arise from tissue elements normally found at the site, as opposed to choristomas, which are tumors derived from elements not normally found at the site. Others9 have proposed that the phakomatoses may be disorders of the regulation of paracrine growth factors.
Glaucoma is a common feature of encephalotrigeminal angiomatosis (Sturge-Weber syndrome) and is occasionally found in NF type 1 and von Hippel-Lindau disease. The other phakomatoses rarely have an associated glaucoma, although a secondary glaucoma may be present as a complication of the other ocular manifestations of the disease.
STURGE-WEBER SYNDROME (ENCEPHALOTRIGEMINAL ANGIOMATOSIS)
In 1860, Schirmer10 described a patient with glaucoma and a facial angioma. Sturge11 presented a case in 1879 of a child with a “port-wine stain” angioma involving half the face and head, with ipsilateral buphthalmos, congenital glaucoma, as well as seizure disorder. He also noticed the choroid of the involved eye was a darker red and hypothesized that the choroid was involved with a vascular lesion similar to the face. In 1922, Weber12 reported the characteristic intracranial calcifications seen radiographically in patients with the syndrome and suggested the parallel streaks were a result of a meningeal angioma. The syndrome became known as the Sturge-Weber syndrome and in its full presentation includes a facial hemangioma, with an ipsilateral intracranial angioma, an ipsilateral choroidal hemangioma, and congenital glaucoma.13 Incomplete forms occur, but all have the characteristic facial angioma or nevus flammeus. The syndrome has no racial or gender predilection. Unlike the other phakomatoses, Sturge-Weber does not have any identifiable hereditary pattern.
The facial angioma (Figure 50-1) is usually unilateral in the distribution of the first and second divisions of the trigeminal nerve. The lesion occurs bilaterally in 10% to 30% of cases.14–16 It appears deep burgundy in color, and facial hyper trophy of varying degrees of the involved area occurs frequently. Histopathologically, the angioma is composed of dilated, telangiectatic capillaries lined by a single layer of endothelial cells in the dermis.17 Some success has been achieved using laser therapy to diminish the appearance of the lesion.
A racemose leptomeningeal hemangioma is the intracranial lesion of Sturge-Weber syndrome. It is usually ipsilateral to the facial angioma and is located over the parietooccipital region. Progressive calcification of the angioma occurs during childhood.18 Adjacent atrophy of the underlying cerebral cortex is frequent and may result in varying degrees of intellectual deficit and mental retardation in about 60% of patients.19 Contralateral focal motor seizures occur in 85% of patients and usually begin after the age of 1 year, but become more generalized with age.19 Permanent hemiparesis, hemiplegia, and homonymous hemianopsia may occur as a consequence of the seizures.
The lids, orbit, episclera (Figure 50-2), conjunctiva, iris, and ciliary body may be involved with a hemangioma. Al though exceptions occur, if the upper eyelid is involved with hemangioma, there is intraocular involvement according to Anderson’s rule.18 The iris, if involved, will be hyperchromic in about 7% of cases.20
Choroidal hemangiomas are the most frequent ocular manifestation of Sturge-Weber syndrome. They have been found in 40% to 50% of patients upon pathologic examination.21,22 In young children, the lesion may simply appear as a darker red choroidal hue in the ipsilateral eye, called the tomato-catsup fundus.23 However, as it slowly grows, it will appear as a mildly elevated, orange-yellow diffuse mass involving the posterior pole, and usu ally more than half the choroid. Histopathologically, the lesions are mixed-type hemangiomas, with elements of both capillary and cavernous hemangiomas.24 Vision loss may occur in young adulthood due to a degeneration of the overlying choriocapillaris, retinal pigment epithelium, and photoreceptors.17 Serous detachment of the retina can occur.
Glaucoma in Sturge-Weber Syndrome
Glaucoma develops in a reported 30% to 70% of patients with Sturge-Weber syndrome. Approximately 60% present as congenital glaucomas with buphthalmos, whereas 40% present in later childhood or adulthood.20,25 Usually, the upper eyelid is involved by the hemangioma. The most common presentation is unilateral and congenital, before the age of 2 years, on the side of the facial angioma. Bilateral glaucoma can occur, although usually in the presence of a bilateral facial hemangioma.
Many theories have been put forth to explain the mechanism of glaucoma in Sturge-Weber syndrome. Early theories proposed that abnormal sympathetic innervation might cause a loss of regulation of the normal uveal capillary bed, which then results in stasis and glaucoma.26 Others20,27,28 proposed that transudation of fluid from the choroidal hemangioma might cause congestion of the choroid or change the composition of aqueous. These theories have largely been disproven or discounted, as later studies29–31 (discussed in the following text) revealed structural as well as functional alterations in Sturge-Weber eyes that seemed to correlate with development of glaucoma.
The congenital glaucoma that is associated with Sturge-Weber syndrome is usually associated with immature angle development, as in primary congenital glaucoma. Careful gonioscopic examination will reveal indistinct angle structures with a high iris insertion. Histopathologic specimens have shown changes consistent with developmental anomalies, such as poorly developed scleral spur, thickened uveal meshwork, and an anteriorly displaced iris root.18,21,29,32–34 Others have found few structural angle abnormalities. Cibis and colleagues30 examined 3 trabeculec tomy specimens from 2 patients with Sturge-Weber syndrome, both of whom had episcleral hemangiomas; the overall architecture of the trabecular meshwork and Schlemm’s canal were found to be well preserved.30 However, the individual trabecular beams were thickened and showed signs of degeneration, which the authors proposed were primary changes associated with premature aging.
Weiss29 proposed that glaucoma in Sturge-Weber syndrome was a result of 2 mechanisms. In clinical experience, the congenital glaucoma cases had anomalous-appearing angles as opposed to cases with later-onset glaucoma that had normal-appearing angles; evidence of episcleral or conjunctival angiomas was found in all patients examined. Weiss29 proposed that increased episcleral venous pressure from the episcleral angioma contributed to the congenital glaucoma cases, in addition to an angle abnormality, whereas juvenile and adult-onset cases without angle malformations were secondary to the elevated episcleral venous pressure. Phelps,31 and then Bellows and colleagues,35 later measured episcleral venous pressure and found it elevated in patients with Sturge-Weber syndrome and glaucoma.
Management depends on the presentation of the glaucoma. Congenital cases and those with buphthalmos, im plying congenital onset, can initially be managed surgically with goniotomy or trabeculotomy. The advantage of goniotomy/trabeculotomy over filtering surgery is the reduction in the risk of sudden intraoperative or prolonged postoperative hypotony that can precipitate choroidal effusions or suprachoroidal hemorrhages in these eyes. However, these procedures are frequently ineffective, and many eyes eventually require filtering surgery. The angle dysgenesis in Sturge-Weber syndrome is clinically indistinguishable from primary con genital glaucoma, but the surgical success rate is lower. One retrospective review34 of 30 cases (28 goniotomies and 2 trabeculotomies) found a surgical failure rate of 60%. Iwach and colleagues25 found the stable interval of control after a single goniotomy to be only a median of 8 months in patients with Sturge-Weber syndrome presenting before 4 years of age. Interestingly, in these same patients, multiple goniotomies plus medical therapy al lowed stability for almost 9 years. Olsen and colleagues36 published a study of 16 Sturge-Weber syndrome eyes with early-onset glaucoma treated with one or more goniotomies or trabeculotomies; 10 of these patients had good control of intraocular pressure (IOP) over a median of 5.4 years of follow-up. However, the majority of their patients required more than one surgical procedure for adequate control also. Mandal37 has suggested performing combined trabeculotomy-trabeculectomy to address both mechanisms of early-onset glaucoma in Sturge-Weber. The addition of filtering surgery bypasses the elevated episcleral venous pressure that may be playing a secondary role in the pathogenesis of congenital glaucoma in these patients. In 10 of the patients described by Mandal who underwent primary combined trabeculotomy-trabeculectomy, all had good IOP control over a mean follow-up of 27.6 months.
Older patients are often managed with medical therapy for as long as possible, but in most cases medical therapy eventually fails. Laser trabeculoplasty was performed in 6 of 16 older-onset glaucoma eyes by Iwach and colleagues25and was effective in 5 of the 6 for approximately 2 years, but such efficacy has unfortunately not been our experience. When surgical intervention is indicated, older patients are more likely to receive a trabeculectomy. The rationale for using trabeculectomy in older patients stems from Weiss’s29 theory that the primary mechanism in these patients is increased episcleral venous pressure, rather than angle dysgenesis. The trabeculectomy will bypass the episcleral venous system, whereas goniotomy, trabeculotomy, or laser trabeculoplasty will not. Though it remains the treatment of choice for late-onset cases, the success rates of trabeculectomy have been variable in children, presumably due to their more vigorous healing response, causing scarring and thereby preventing adequate filtration. There have been limited reports38,39 suggesting favorable success rates for filtering surgery with antimetabolites such as 5-fluorouracil and mitomycin C in children. However, a number of these patients developed bleb-related infections.39 Glaucoma drainage implants have also been used in Sturge-Weber syndrome eyes. Budenz and colleagues40 published their results on a 2-staged Baerveldt implant procedure in 10 Sturge-Weber eyes with late-onset glaucoma.41 All displayed adequate IOP control over a mean follow-up of 35 months with no cases of intraoperative choroidal hemorrhage. Performing the surgery in 2 stages allows time for encapsulation of the implant plate prior to placement of the filtering tube into the anterior chamber. This prevents hypotony and will help to avoid the most dreaded complication of all filtration surgeries in eyes with elevated episcleral venous pressure: sudden massive intraoperative choroidal effusion or expulsive hemorrhage.21,25,35,41 The rapid transudation of fluid from the intravascular to the extravascular space in the setting of sudden hypotony and increased venous pressure is thought to be responsible for the effusion. Bel lows and associates35 reported success in minimizing the intraoperative complications from the effusion by creating a posterior sclerotomy prior to entering the anterior chamber. A more recent study42 suggests that the incidence of intraoperative or postoperative choroidal detachment or hemorrhage may not be as high as previously suggested and that prophylactic sclerotomies may be unnecessary. To help prevent potentially devastating hemorrhages and effusions, the IOP should be reduced as much as possible prior to surgery and controlled intraoperatively with viscoelastic or anterior chamber maintainers, and the postoperative period requires slow, controlled lowering of IOP to avoid their development after surgery.
In 1900, Klippel and Trenaunay43 described a syndrome of cutaneous hemangioma of the extremities and face, with varicosities and hypertrophy of bone and soft tissues in the affected limb. Weber44 later described the same disorder and reported the association of arteriovenous fistulas. Seizures, mental retardation, and cerebral hemangiomas may also occur in patients. Many features of this syndrome are similar to Sturge-Weber syndrome.
Ophthalmic involvement is occasionally found and may include orbital varices or hypertrophy, conjunctival telangiectasias, heterochromia iridis, choroidal angiomas, retinal varicosities or vascular tumors, disc anomalies, and glaucoma with or without buphthalmos.45–48 The glaucoma is associated with an ipsilateral facial hemangioma, but the incidence appears to be less frequent than in Sturge-Weber syndrome. One eye has been examined histopathologically and found to have an anomalous development of the anterior chamber angle.49
NEUROFIBROMATOSIS (VON RECKLINGHAUSEN’S DISEASE)
In a classic monograph by the German pathologist Freidrich Daniel von Recklinghausen in 1882, NF was described. NF is inherited as an autosomal dominant disease with nearly 100% penetrance but highly variable expressivity. Neuroectodermal elements of the skin, eyes, and CNS are involved with the development of hamartomas that grow in size and number throughout life. The hamartomas may be present at birth, later in childhood, or adulthood.
Two forms of NF are recognized. NF-1 is the classic form of von Recklinghausen’s NF and is more common. The diagnosis of NF-1 is made if the patient has 2 or more of the following:
- Six or more café-au-lait macules over 5 mm in greatest diameter in prepubertal individuals, or over 15 mm in greatest diameter in postpubertal individuals
- Two or more neurofibromas of any type or 1 plexiform neurofibroma
- Freckling in axillary or inguinal regions
- Optic glioma
- Two or more Lisch nodules
- A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis
- A first-degree relative with NF-1 by the above criteria50
NF-1 occurs at a frequency of about 1/3000 to 1/4000, with no known racial or gender predilection.51,52 The NF-1 gene has been isolated on the long arm of chromosome 17 and encodes for a protein related to guanosine diphosphatase-activating protein.53–55 Guanosine diphosphatase-activating protein regulates another protein, Ras, that signals cells to grow. Mutation of the NF-1 gene is thought to inactivate the gene.55
NF-2, also called bilateral acoustic neurofibromatosis, was first described by Henneberg and Koch56 in 1902. The National Institutes of Health diagnostic criteria requires bilateral acoustic neuromas or a first-degree relative with NF-2 and a unilateral acoustic neuroma or 2 of the following: meningioma, glioma, schwannoma, neurofibroma, or presenile posterior sub capsular lens opacity.50 NF-2 is present in only 1 out of 50,000 population. The NF-2 locus has been isolated to near the center of the long arm of chromosome 22, but the molecular genetics have not been elucidated yet.57,58
The skin is the most commonly involved organ in NF-1.18 Café-au-lait spots are brown macules usually found on the trunk. Fibroma molluscum are isolated, pedunculated, pigmented nodules that are found to have enlarged cutaneous nerves, Schwann’s cells, and connective tissue elements, histopathologically. Plexiform neurofibromas are groups of enlarged nerves with thickened perineural sheaths that may feel like a bag of worms on palpation. These lesions often appear or worsen around puberty and may increase in size and number with age. Hypertrophy of the involved areas may occur. NF-2 has very little skin involvement.
CNS tumors are common in both NF-1 and NF-2. CNS tumors in NF-1 and NF-2 include neurofibromas of the nerve roots or spinal cord, meningiomas, and intracranial or spinal cord gliomas. Acoustic neuromas in NF-2 usually present in the second or third decades when hearing loss, tinnitus, or balance problems are noted. In individuals with a family history of NF-2, early detection with screen ing tests is possible.
Skeletal problems in patients with NF-1 include rapidly progressive kyphoscoliosis and pseudoarthroses, or non-healing fractures.17 Pheochromocytomas are 10 times more common in patients with NF than the general population.59 Other organs may be involved by hamartomas or malignant tumors.
The eyelids are frequently involved by neurofibromas and may produce a characteristic S-shaped upper eyelid contour (Figure 50-3). Any of the other characteristic skin lesions may present in the eyelids or surrounding periorbital area and may develop in approximately 25% of patients.60 Rarely, the conjunctiva or orbit may develop neurofibromas, while some patients have prominent corneal nerves visible on slit-lamp examination. The greater wing of the sphenoid bone at the orbital apex may be absent, allowing the frontal lobe to herniate into the orbital apex.
Optic nerve glioma has been reported to occur in 15% of NF-1 patients, although many are asymptomatic.61,62 Optic nerve gliomas tend to grow slowly and extremely rarely develop malignant transformation, al though they can be very destructive locally. Optic nerve gliomas are the primary cause of visual loss in NF. Tumors that invade intracranially into the chiasm have a much poorer prognosis than optic nerve gliomas that involve the orbital portion of the optic nerve. Symptoms and signs of optic nerve glioma include decreased visual acuity, proptosis, strabismus, visual field loss, and optic atrophy. Contrast-enhanced computed tomography (CT) scanning or magnetic resonance imaging (MRI) will demonstrate enlargement and kinking of the optic nerve anywhere along its course and into the chiasmal region, although MRI may be able to detect intracanalicular and chiasmal masses better.63
Lisch nodules are melanocytic hamartomas of the iris and are found in more than 90% of patients with NF-1 older than 5 years of age.64 Patients younger than 2 years of age rarely have any Lisch nodules, and they are not present in unaffected first-degree relatives.60,65 Lisch nodules are avascular, smooth, dome-shaped gelatinous nodules found on the iris surface. They may be mildly translucent to dark brown in color, ranging up to 2 mm in size.
Patients with NF-2 have a high incidence of posterior sub capsular cataract occurring at a young age.66 This association has not been seen with NF-1. Choroidal hamartomas have been reported in a series of White patients with NF but were not seen in Black patients with NF.60 Occasionally, retinal astrocytic hamartomas or combined retinal and retinal pigment epithelial hamartomas have been seen in patients with NF-1.
Glaucoma in Neurofibromatosis
Congenital glaucoma and glaucoma presenting somewhat later in childhood have been reported in cases of NF-1. The actual incidence of glaucoma in NF is unknown. Buphthalmos in the absence of elevated IOP has been reported as a manifestation of regional giantism.67 Care must be taken to distinguish this condition from true congenital glaucoma in NF. Two presentations of glaucoma in NF are recognized.
Infants and toddlers have presented with unilateral buphthalmos and elevated IOP, usually with a plexiform neurofibroma formation of the upper eyelid and hemihypertrophy of the face (Francois syndrome), and are subsequently diagnosed with NF-1.68,69 It is reported that glaucoma is present in 50% of eyes with a plexiform neurofibroma of the upper lid,70 though more recently Morales and colleagues71 report a rate of glaucoma of only 23% in patients with orbitofacial NF-1. In their study of 80 patients with NF-1, glaucoma presented only in patients with orbitofacial NF-1, and the majority were diagnosed with glaucoma prior to 3 years of age. Glaucoma in these patients was consistently associated with severe globe enlargement.