S E C T I O N
11 Phakomatoses
103 ANGIOMATOSIS RETINAE 759.6
(Angiomatosis of the Retina and Central Nervous System, Retinal and Optic Disk Capillary Hemangiomas, Retinal Capillary Hamartoma, Retinal Hemangioblastoma, von Hippel–Lindau Disease, von Hippel’s Disease)
Shiyoung Roh, MD
Boston, Massachusetts
John J. Weiter, MD, PhD
Boston, Massachusetts
ETIOLOGY/INCIDENCE
Angiomatosis retinae (von Hippel’s disease) is characterized by congenital capillary angiomatous hamartomas of the retina and optic nerve. The retinal angiomas usually are diagnosed when the patient is between 10 and 30 years of age. Central nervous system (CNS) and visceral tumors are commonly noted after the ocular symptoms become manifest; if the CNS and viscera are involved, the condition is termed von Hippel–Lindau disease.
The disorder is transmitted by autosomal dominant inheritance with incomplete penetrance and variable expressivity; there is no well-established predilection for gender or race. The retinal tumors often are multiple and are bilateral in more than 50% of cases; about 20% of patients with retinal angiomas develop CNS tumors.
DIAGNOSIS
Clinical signs and symptoms
Ocular
●Angiomas of retina or optic nerve or both.
●Disk edema.
●Retinal or optic disk exudates, circinate exudative retinopathy.
●Epiretinal membranes.
●Dilated, tortuous retinal vessels.
●Macular star exudation.
●Retinal hemorrhage.
●Retinal detachment.
●Vitreous hemorrhage.
●Proliferative vitreoretinopathy.
●Phthisis bulbi.
●Secondary glaucoma.
●Vision loss.
The ocular angiomas may develop in the retina (usually from the inner layers, as discrete angiomas – endophytic angiomas), in the optic nerve head, in the peripapillary retina (frequently from the outer layers – exophytic angiomas) where they are diffuse, or in the retrobulbar portion of the optic nerve.
Histologic findings
●Masses of capillaries exhibit an embryonic appearance (hemangioblastoma), often with abnormal fenestrations.
●Glial proliferation (of astrocytes) separates the vascular channels.
●Vascular channels frequently contain large lipid-filled vacuoles, most likely representing astrocytic phagocytosis of leaking plasma.
CLINICAL COURSE/PROGNOSIS
Retinal tumors are usually at the equator or in the periphery, with a propensity for the temporal side. The tumor typically remains stable or grows very slowly. With gradual tumor growth, arteriovenous shunting occurs within the mass, resulting in an increasingly dilated, tortuous feeding artery and draining vein. With time, subretinal fluid and yellow exudate accumulate around the lesion and very often in the macula. Visual change resulting from the macular pooling of exudates often is the presenting sign.
Endophytic tumors often produce vitreous traction that may lead to vitreous hemorrhage or tractional retinal detachment (rhegmatogenous or nonrhegmatogenous).
Peripapillary angiomas tend to be exophytic and relatively flat, without feeding and draining vessels, resembling outer retinal telangiectasia.
Multiple tumors tend to occur in the same retinal quadrant. The earliest endophytic tumors tend to be in the peripheral retina, with subsequent tumors appearing proximally in the same quadrant, having the same feeding and draining vessels. Fluorescein angiography shows arteriovenous shunting of blood through the tumor or tumors with an associated relative hypoperfusion of the retina peripheral to the tumor, suggestive of a vascular steal syndrome. Although not proven, the subsequent, more proximal angiomas may well represent a ‘neovascular angiomatous’ reaction in a susceptible vascular bed.
Hemangiomas of the optic disk often mimic papilledema or disk edema; untreated retinal angiomatosis often leads to vitre-
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ous hemorrhage, total retinal detachment, secondary glaucoma, and phthisis bulbi.
TREATMENT
Surgical
Angiomatosis retinae is usually a progressive disease, so therapy should begin as soon as diagnosis is made. The treatment selected depends on the size and location of the tumor or tumors, the clarity of the ocular media, and the associated ocular complications. In treating smaller tumors with a clear medium, argon laser photocoagulation has proven effective; treatment should consist of a large spot size and low-intensity and long-duration burns directed at the angioma itself. Multiple treatment sessions should be planned for all but the smallest tumors. The endpoint should be the obliteration of the tumor both by clinical observation and by fluorescein angiography. Once the tumor becomes yellowish (secondary to gliosis and lipid ingestion), photocoagulation becomes difficult because of poor penetration of the laser light.
Anterior angiomas and larger posterior angiomas may be treated successfully with cryotherapy using a repetitive freezethaw technique. Only two or three freeze-thaw cycles should be used at each therapy session to minimize the risk of hemorrhage. Multiple treatment sessions usually are required. Eradication of the tumor or tumors by cryotherapy or photocoagulation usually results in resolution of the macular edema and improved visual acuity.
For larger angiomas, angiomas unresponsive to cryotherapy or photocoagulation, and those associated with retinal detachment, penetrating diathermy under a lamellar scleral bed has proven effective. If there is extensive subretinal exudation, the fluid should be drained and a scleral buckling procedure considered. Frequently, large tumors develop surface membranes and vitreous traction that can lead to vitreous hemorrhage or rhegmatogenous retinal detachment; these complications may be amenable to treatment using the following:
●Vitreous surgery techniques;
●Endodiathermy;
●Scleral buckling procedures.
The peripapillary and optic disk angiomas are difficult to treat without destroying useful central vision; diffuse exophytic peripapillary hemangiomas with associated visual loss may be considered for laser photocoagulation, using a wavelength that spares the inner retina and is well absorbed by blood; treatment should be conservative and aimed at the foci of greatest leakage.
tumor and to associated complications at the time therapy is initiated. Early detection of a peripheral tumor results in a good prognosis, whereas large tumors with an associated retinal detachment or angiomas of the optic nerve have a less favorable prognosis.
These tumors are often multiple or bilateral or both, so close follow-up is important. Furthermore, because there is a familial tendency, other family members should be evaluated. The retinal angioma is the earliest and most common manifestation detected in screening examinations of families documented to have von Hippel–Lindau disease.
COMMENTS
About 20% of patients presenting with retinal angiomas develop multiple systemic involvement (von Hippel–Lindau disease), so patients with angiomatosis retinae should have a thorough systemic evaluation. Cerebellar hemangioma is the typical CNS tumor in von Hippel–Lindau disease and it tends to occur somewhat later than the retinal angioma. The cerebellar tumor is similar to the retinal angioma in histologic appearance and in having large feeding and draining vessels.
In von Hippel–Lindau disease, angiomas also may be found in the medulla oblongata, spinal cord, liver, or kidney. Cysts of the liver, pancreas, kidney, and epididymis occasionally are found as well, as is an elevated incidence of pheochromocytoma and renal cell carcinoma. In patients with von Hippel–Lindau disease, renal cell carcinoma is the most common cause of death, followed closely by cerebellar hemangioblastoma.
Vasoproliferative angiomatous lesions are not infrequently found in the peripheral retina and can mimic von Hippel’s angiomas. There is evidence that both are related to upregulation of vascular endothelial growth factor (VEGF), and both may be amenable to treatment in the future with anti-VEGF agents.
The gene for von Hippel–Lindau disease recently has been mapped to the short arm of chromosome 3 (3p25-p26) and appears to function at the molecular level as does the retinoblastoma gene-that is, as a recessive tumor-suppressor gene. Early detection is important for genetic counseling, and it improves the visual prognosis by allowing early treatment of retinal angiomas. Diagnosis using DNA markers allows relatives at low risk to be screened less often, thus enabling a focus on affected individuals and high-risk relatives.
SUPPORT GROUPS
See internet www.vhl.org or email at info@vhl.org.
PRECAUTIONS
Because these tumors are highly vascular, any form of treatment may cause further leakage or hemorrhage before the vascular channels are obliterated. This may result in further visual loss from macular exudation, vitreous hemorrhage and retinal detachment. Proliferative vitreoretinopathy frequently occurs after treatment of large tumors. Most of these complications are only exacerbations of the normal course of the disease process; however, many complications can be minimized by treating the angioma in multiple sessions rather than performing an aggressive single-session treatment.
Treatment is best accomplished when the tumor is small. Prognosis for vision is related to the size and location of the
REFERENCES
Annesley WJ, Jr, Leonard BC, Shields JA, et al: Fifteen-year review of treated cases of retinal angiomatosis. Trans Am Acad Ophthalmol Otolaryngol 83:446–453, 1977.
Filling-Katz MR, Choyke PL, Oldfield E, et al: Central nervous system involvement in von Hippel-Lindau disease. Neurology 41:41–46, 1991.
Gass JDM, Braunstein R: Sessile and exophytic capillary angiomas of the juxtapapillary retina and optic nerve head. Arch Ophthalmol 98:1790– 1797, 1980.
Hardwig P, Robertson DM: von Hippel-Lindau disease: a familial, often lethal, multi-system phakomatosis. Ophthalmology 91:263–270, 1984.
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Lindau A: Zur Frage der Angiomatosis Retinae und ihrer Hirnkomplikationen. Acta Ophthalmol 4:193–209, 1926.
Machemer R, Williams JM, Sr: Pathogenesis and therapy of traction detachment in various retinal vascular diseases. Am J Ophthalmol 105:170– 181, 1988.
Machmichael IM: von Hippel-Lindau’s disease of the optic disc. Trans Ophthalmol Soc UK 90:877–885, 1970.
Maher ER, Bentley E, Yates JRW, et al: Localization of the gene for von Hippel-Lindau disease to a small region of chromosome 3 confirmed by genetic linkage analysis. Genomics 10:957–960, 1991.
Maher ER, Yates JRW, Harries R, et al: Clinical features and natural history of von Hippel-Lindau disease. QJ Med 77:1151–1163, 1990.
Miyagawa Y, Nakazawa, M, Noda Y, et al: von Hippel-Lindau disease type 2A in a family with a duplicated 21-base-pair-in frame insertion mutation in the VHL gene. Graefes Arch Clin Exp Ophthalmol 241:241–244, 2003.
Moore AT, Maher ER, Rosen P, et al: Ophthalmological screening for von Hippel-Lindau disease. Eye 5:723–728, 1991.
Neumann HP, Wiestler OD: Clustering of features of von Hippel-Lindau syndrome: Evidence for a complex genetic locus. Lancet 337:1052– 1054, 1991.
Nicholson DH, Green WR, Kenyon KR: Light and electron microscopic study of early lesions in angiomatosis retinae. Am J Ophthalmol 82:193–204, 1976.
Shields JA: Diagnosis and management of intraocular tumors. St Louis, CV Mosby, 1983:534–556.
von Hippel E: Uber eine sehr seltene Erkrankung der Netzhaut; Klinische Beobachtungen. Graefes Arch Clin Exp Ophthalmol 59:83–97, 1904.
Welch RB: von Hippel-Lindau disease: The recognition and treatment of early angiomatosis retinae and the use of cyrosurgery as an adjunct to therapy. Trans Am Ophthalmol Soc 68:367–424, 1970.
Wing GL, Weiter JJ, Kelly PJ, et al: von Hippel-Lindau disease angiomatosis of the retina and central nervous system. Ophthalmology 88:1311– 1314, 1981.
104 NEUROFIBROMATOSIS TYPE 1
237.7
(NF1, von Recklinghausen’s Disease, Peripheral Variant of Neurofibromatosis)
Nastaran Rafiei, MD
Baltimore, Maryland
Cameron F. Parsa, MD
Baltimore, Maryland
ETIOLOGY/INCIDENCE
Neurofibromatosis (NF) is an autosomal dominant disorder predominantly affecting neuroectodermal derived tissue. It is characterized, thus, by the development of hamartomas of the skin and nervous system, increasing in number and size throughout life. In 1988, neurofibromatosis was reclassified into two distinct variants, NF1 and NF2.
NF1 occurs in approximately 1 in 4000 individuals and generally features multiple café-au-lait spots, cutaneous neurofibromas and iris hamartomas (Sakurai–Lisch nodules). Half of affected individuals inherit the disease, while the others have novel mutations of predominantly paternal origin (with no apparent relation to paternal age).
The genetic mutation responsible for NF1 is in a tumor suppressor gene has been mapped to chromosome 17q11.2. The protein encoded by the gene, neurofibromin, is expressed at reduced levels in NF1, resulting in down-regulation of the ras protein (a protein that is involved in cell growth and differentiation) and dysregulated cell growth. Deletion of a second copy of this tumor-suppressing gene is necessary for development of malignancies.
COURSE AND PROGNOSIS
Expressivity is highly variable and many patients with NF1 lead a normal life. Others, however, may have tumors of the central nervous system, structural abnormalities, or secondary malignancies. Visual prognosis depends on the presence or absence of optic pathway gliomas and orbital plexiform neurofibromas.
DIAGNOSIS
Clinical signs and symptoms
The 1988 National Institute of Health Consensus Development Statement has suggested the presence of two or more of the following criteria for the diagnosis of NF1:
●Six or more café-au-lait spots, 5 mm or larger in prepubertal children, 15 mm or larger after puberty;
●Two or more neurofibromas of any type (e.g. placoid, nodular, pedunculated), or one plexiform neurofibroma;
●‘Freckles’ in intertriginous areas;
●Glioma involving the anterior visual pathways;
●Two or more Sakurai–Lisch nodules;
●A distinctive osseous lesion such as sphenoid dysplasia or thinning of the cortex of the long bone (with or without pseudoarthrosis);
●A first-degree relative who has NF1 by these criteria.
Cutaneous manifestations
Cutaneous manifestations include café-au-lait spots, neurofibromas and plexiform neurofibromas. Although over 10% of the general population may have one to three café-au-lait spots, nearly 99% of individuals with NF1 have multiple café-au-lait spots increasing in number and size with age. Neurofibromas are benign tumors consisting of Schwann cells admixed with nerve fibers, perineural cells and fibroblasts in various ratios accounting for differences in morphology. They grow around the time of puberty, continuing to enlarge throughout life. They contain increased numbers of mast cells and may be associated with pain, tenderness, or itchiness. Plexiform neurofibromas have markedly enlarged nerves surrounded by a thickened perineural sheath, and possess a ‘bag of worms’ consistency. Malignant degeneration of neurofibromas occurs in 5% of individuals.
Nervous system
Juvenile pilocytic astrocytomas are common. While MRI studies have demonstrated the presence of gliomas in over 25% of patients with NF1, clinical symptoms occur in only a fraction of these. Occasionally, ependymomas, meningiomas and primitive neuroectodermal tumors may develop.
Occasionally, mild cognitive impairment may result in various learning disabilities.
104TypeERCHAPNeurofibromatosis •
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FIGURE 104.1. Multiple tan-colored and dome-shaped melanocytic hamartomas, Lisch–Sakurai nodules, are highly suggestive of NF1. They increase in number with age and may develop more commonly on the inferior aspect of the iris. The morphologic appearance, however, varies widely.
Optic nerve gliomas associated with NF1 often develop a perineural arachnoidal hyperplasia. The high water content of this tissue produces an image on T2-weighted MR imagery that looks like an expanded CSF space around the nerve. This socalled ‘pseudo-CSF signal’ is a specific marker of NF1.
Although the NF1 gene has been cloned and characterized, its high mutation rate has limited the sensitivity and diagnostic value of laboratory-based genetic testing.
Differential diagnosis
Ten times less frequent than NF1, NF2 (‘central’ or ‘acoustic’ neurofibromatosis) is characterized by vestibular schwannomas (acoustic neuromas) and the development of tumors typically involving neural coverings (meningiomas, schwannomas and ependymomas). Combined hamartomas of the retinal pigment epithelium and retina may be present. Sakurai–Lisch nodules are generally absent, but most affected individuals have presenile posterior lens opacities. Optic disc gliomas are rare, but highly suggestive of NF2. There is a relative lack of cutaneous findings. The genetic mutation has been mapped to the long arm of chromosome 22.
Ophthalmic involvement
Sakurai–Lisch nodules, smooth, dome-shaped pigmented hamartomas of the iris, are not noted at birth, but are usually seen by age 10 years, and by age 30, are present in essentially all individuals with NF1. Although not pathognomonic, the presence of Sakurai–Lisch nodules is highly suggestive of NF1 and screening of family members is often warranted (Figure 104.1).
Hamartomas of the conjunctiva, uveal tract or retina, and corkscrew retinal vascular abnormalities may be present. Indocyanine green angiography reveals hypofluorescent areas of the choroid.
Proptosis may be present due to optic nerve glioma, orbital neurofibroma, or sphenoid bone defects. Periocular plexiform neurofibromas may cause glaucoma, ptosis and amblyopia.
Musculoskeletal involvement
Musculoskeletal abnormalities include progressive kyphoscoliosis, pseudoarthrosis (often of the tibia), and hypoplasia of the sphenoid bone.
Other manifestations
Other tumors of neural-crest origin such as pheochromocytoma and neuroblastoma also occur with increased frequency. However, as for the musculoskeletal manifestations of NF1 and for reasons not yet well understood, non-neural crest derived conditions such as rhabdomyosarcoma and myelogenous leukemia are also associated. Neurofibromin is expressed in endothelial cells and the NF1 gene plays an essential role in endothelial development with an increased incidence of congenital heart disease in those who harbor a mutation. Secondary hypertension occasionally develops from pheochromocytoma or renal artery stenosis.
Laboratory findings
T2-weighted MRI images demonstrate multiple ‘bright lesions’ in the basal ganglia, cerebellum and brain stem in up to 80% of affected children — these decrease with age. Although a quarter of children imaged may also have gliomas, routine MR imaging for screening purposes is not recommended since the findings may not assist in management.
TREATMENT
Observation with supportive treatment is generally recommended for optic pathway gliomas, which can regress spontaneously. Due to germline tumor-suppressor gene haploinsufficiency, treatment of NF1-associated tumors with alkylating agent chemotherapy and irradiation can produce somatic mutations throughout the body leading to subsequent malignant neoplasms.
Plexiform neurofibromas affecting the orbit are generally diffuse and not fully excisable, with residua often leading to recurrences. Despite the cosmetic disfigurement, such tumors are often best left alone.
Mast cell stabilizers such as oral ketotifen may reduce the itchiness, tenderness and pain associated with neurofibromas, and retard their growth. Occasionally, excision may be required. Anticipation and management of NF1 associated conditions such as secondary hypertension and malignancies is an important aspect of care, as is family counseling.
REFERENCES
Arun D, Gutmann DH: Recent advances in neurofibromatosis type 1. Curr Opin Neurol 17:101–105, 2004.
Beauchamp GR: Neurofibromatosis type 1 in children. Trans Am Ophthalmol Soc 93:445–472, 1995.
Brodsky MC: The ‘pseudo-CSF’ signal of orbital optic glioma on magnetic resonance imaging: a signature of neurofibromatosis. Surv Ophthalmol 38:213–218, 1993.
Critler AD, Zhu Y, Ismat FA, et al: NF1 has an essential role in endothelial cells. Nat Genet 33:75–79, 2003.
DiMario FJ Jr, Ramsby G, Greenstein R, et al: Neurofibromatosis type 1: magnetic resonance imaging findings. J Child Neurol 8:32–39, 1993.
Jadayel D, Fain P, Upadhyaya M, et al: Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature 343:558–559, 1990.
Muci-Mendoza R, Ramella M, Fuenmayor-Rivera D: Corkscrew retinal vessels in neurofibromatosis type 1: report of 12 cases. Br J Ophthalmol 86:282–284, 2002.
Riccardi VM: A controlled multiphase trial of ketotifen to minimize neu- rofibroma-associated pain and itching. Arch Dermatol 129:577–581, 1993.
Sakurai T: Multiple neurofibroma patient showing multiple flecks on the anterior surface of the iris. Acta Soc Ophthal Jpn 39:87–93, 1935.
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