completely encloses the RCH. Cryotherapy can be repeated, but usually not within 2 months of the previous application [116]. Cryotherapy is more effective and less likely to induce ablation fugax than photocoagulation in larger RCHs. In general, cryotherapy can be considered for lesions up to 4.5 mm in size.

7.3.20  Protoporphyrin

Derivative Therapy

Experience with photodynamic therapy in the treatment of RCH is limited. Barbazetto and Schmidt-Erfurth reported two cases with only partial occlusion and fibrosis with 12 months follow-up [126].

7.3.21  Plaque Radiotherapy

RCHs larger than 4.5 mm show poor response to laser photocoagulation and cryotherapy. Plaque radiotherapy has been tried with good success in these cases [110, 127, 128]. Kreusel et al reported a series of 25 RCHs treated with b-radiation emitting Ruthenium 106/Rhodium-106 plaque; 23 tumors regressed [128]. The lesion size ranged from 1.5 to 7.8 mm with a mean of 3.8 mm, and regression occurred within 5–14 months. In 16 (64%) eyes, visual acuity greater than 20/200 and retinal attachment was observed. Radiationinduced complications were not significant.

7.3.23  Pars Plana Vitrectomy, Retinal

Detachment Repair, and Other

Related Procedures

Pars plana vitrectomy (PPV) and other related procedures are adjuvant treatment methods to the therapeutic options discussed above. PPV is usually required for large lesions complicated by rhegmatogenous or tractional retinal detachment [130, 131, 132]. Peeling of preretinal fibrosis secondary to RCH should be performed after the lesion is treated and is stable for at least 6 months.

7.3.24  Enucleation

Total exudative or tractional retinal detachments associated with advanced disease can cause secondary changes such as cataract formation, phthisis bulbi, neovascular glaucoma, and painful blind eye. These end-stage complications may eventually necessitate enucleation.

7.3.25  Social and Family Impact

Patient with established diagnosis of or suspected to have VHL disease should undergo formal genetic counseling. The patients should understand the genetic nature of the disease and autosomal dominant inheritance with 50% risk of transmission to their progeny. Patients should be informed about family support groups such as American VHL Family Alliance (www.VHL.org)

7.3.22  Proton Beam Radiotherapy

A series of five patients with juxtapapillary RCH treated with proton beam radiation has been reported [129]. The largest lesion was 3 mm in diameter. Radiation was delivered over four or five fractions with a total dose of 28–54 Gray. All lesions responded within 6 weeks to 6 months, although two lesions required additional photocoagulation and penetrating diathermy. Proton beam irradiation-related complications were not observed.

7.4  Tuberous Sclerosis Complex

7.4.1  Introduction

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartoma formation in many organs, particularly the CNS, skin, and retina. The most common neurological manifestations include childhood epilepsy, mental retardation, and

behavioral problems. The skin findings are of diagnostic significance. Ocular involvement presents as single or multiple astrocytic hamartoma of the retina.

7.4.2  Historical Context

The term tuberous sclerosis was coined by a French physician, Desire Magloire Bourneville. In 1880, Bourneville described a case with seizures, hemiplegia, mental subnormality, and renal tumors. He based the terminology on the neuropathologic observations of multiple potato-like (tubers) lesions in the brain [132].

7.4.3  Overview with Clinical Significance

TSC presents as a wide spectrum of disease characterized by hamartomatous growth in various organs. Astrocytoma and ependymoma of the CNS lead to seizures, cognitive impairment, and behavior abnormalities. Facial angiofibromas, subungual fibromas, hypomelanotic macules, and Shagreen’s patches are diagnostic skin findings. Ocular involvement is limited to retinal astrocytic hamartoma. Visceral hamartomas most commonly involve the lungs, kidney, and heart [133]. Although many clinical manifestations of tuberous sclerosis are benign lesions, invasive neoplasms do occur, particularly in the kidneys and brain [134]. Depending on the specific organ involved, patients may experience significant morbidity and mortality [134–138].

7.4.4  Classification

Two types of TSC (TSC 1 and TSC 2) result from distinct mutations on two separate chromosomes. However, the phenotype of TSC 1 and TSC 2 is similar except that TSC 1 is milder with a reduced risk of mental retardation [139]. Seizures, facial angiofibroma, retinal hamartomas, and renal involvement are also less frequent and severe in TSC 1 than TSC 2 [140].

7.4.5  Genetics

TSC is an autosomal dominant multisystem disorder with 95% penetrance (p102). However, 65–85% of cases are sporadic, arising via spontaneous mutations [141, 142]. Genetic abnormalities responsible for TSC were found on two chromosomal loci: 9q34 (TSC 1) and 16p13 (TSC 2) [143]. TSC1 are small deletions and nonsense mutations. TSC 2 mutations are large deletions, rearrangements, and mis-sense mutations and are more common in sporadic cases [144]. TSC 2 gene is adjacent to the gene for adult polycystic kidney disease (PKD 1). With the exception of contiguous gene deletion syndrome involving TSC 2 and PKD 1, TSC 1 and TSC 2 phenotypes are considered identical [145].

TSC 1 and TSC 2 genes encode hamartin and tuberin, respectively [146]. Hamartin and tuberin are coexpressed in a wide variety of normal human tissues including neurons and astrocytes [147]. Hamartin and tuberin interact with each other and influence a common cellular pathway [147]. These findings provide the basis for identical clinicopathologic manifestations of TSC 1 and TSC 2 that result when either of these proteins is inactivated [145].

There is no strict correlation between genotype and phenotype. Individuals with the same genotype can have wide variations in the extent and severity of clinical manifestations [148]. Individuals with TSC 2 mutations generally have more severe epilepsy, mental retardation, cortical tubers, renal angiomyolipomas, retinal hamartomas, and facial angiofibromas than those with TSC 1 mutations [140, 149–152]. The mutation detection rate in patients with TSC is about 85–90% using a combination of molecular genetic techniques [152]. Patients with undetectable mutations have milder manifestations than those with detectable mutations.

Before diagnosing a case of TSC as a sporadic mutation, the possibility of mosaicism should be considered. When unaffected parents have more than one affected child, germ-line mosaicism must be excluded. Parents may have only mild manifestations of TSC and they should be examined and imaged to exclude TSC as an integral part of genetic counseling. In one study, the exclusion of TSC in the parents of a patient with TSC reduced the chance of mosaicism from 10 to 2% [153].