Phakomatoses-Neurocutaneous Syndromes




von Recklinghausen disease

 Tuberous sclerosis

Boumeville disease

 Cerebroretinal angiomatosis

von Hippel–Lindau disease

 Encephalotrigeminal angiomatosis

Sturge–Weber syndrome

Less accepted

 Ataxia telangiectasia

Louis–Bar syndrome

 Racemose angiomatosis

Wyburn–Mason syndrome Bonnet–Dechaume–Blanc syndrome

 Angioosteohypertrophy or Hypertrophic haemangiectasia

Klippel–Trenaunay–Weber syndrome

 Incontinentia pigmenti

Bloch–Sulzberger syndrome

Hamartomas are tumors composed of cells normally present in the involved tissue. For example, the vascular tumors associated with encephalotrigeminal angiomatosis arise from blood vessels normally found at the involved site. Similarly, the glial retinal tumors seen in neurofibromatosis and tuberous sclerosis arrive from astrocytes normally present in the retina. In contrast to hamartomas, choristomas are composed of cells not normally present at the involved site. Limbal and orbital dermoids are the most common choristomas seen by ophthalmologists.

Ocular involvement occurs frequently in the phakomatoses. Recognition of characteristic eye lesions in the context of related skin and systemic abnormalities may be crucial to making the diagnosis of a specific neurocutaneous syndrome [5]. Also, ocular involvement in these conditions may at times lead to blindness, especially without early diagnosis and treatment. The purpose of this chapter is to review the ophthalmologic and systemic findings characteristic of these neurocutaneous syndromes, commonly termed phakomatoses.


The neurofibromatosis are a diverse group of genetic conditions consisting of three subgroups: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis. Schwannomatosis , originally reported as neurofibromatosis type 3 is a rare form of neurofibromatosis characterized by multiple cutaneous neurilemmomas and schwannomas but without characteristic ocular lesions, acoustic tumors or other signs of NF1 or NF2, and therefore will not be further discussed in this chapter [3, 21, 22].

NF1 and NF2 patients have characteristic melanocytic and neuroglial cell lesions derived from neural crest mesenchyme tissue [23]. These lesions are characterized as hamartomas but may be indistinguishable histologically from low-grade neoplasms. NF1 and NF2 have significant genetic, clinical and management considerations which will be addressed in this chapter.

Neurofibromatosis Type I


Specific diagnostic criteria were established for Neurofibromatosis Type I at the National Institute of Health consensus conference in 1988 (Table 16.2). The individual associated physical features can be determined by a combination of clinical inspection and specific tests (see Diagnostics below). Initial examination can reveal café au lait macules, skinfold and axillary/inguinal freckling as well as Lisch nodules, which are pathognomonic for NF1 [31].

Table 16.2
Diagnostic criteria for neurofibromatosis type I

Two or more of these features are necessary to meet the diagnostic criteria

• Six or more café au lait macules (>0.5 cm in children or >1.5 cm in adults)

• Two or more cutaneous/subcutaneous neurofibromas or one plexiform neurofibroma

• Axillary or groin freckling

• Optic pathway glioma

• Two or more Lisch nodules (iris hamartomas seen on slit lamp examination)

• Bony dysplasia (sphenoid wing dysplasia, bowing of long bone ±pseudarthrosis)

• First degree relative with NF1

NIH consensus development conference 1988

Because family history is a diagnostic criterion, the majority of familial cases are clinically identified by 1 year of age. Almost all de novo cases are clinically apparent by 8 years of age [32].

NF1 is caused by a mutation in the NF1 gene located (17 q11.2). Neurofibromin interacts with Ras leading to increased downstream activation of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling. These pathways are related to the increased tumorgenesis and glial proliferation seen in affected individuals. Current testing identifies ~95 % of the mutation, with the majority (>90 %) of these resulting from sequence variants. An additional 4–5 % are detectable via deletion/duplication analysis, and <1 % via cytogenic analysis of larger scale rearrangements.


Dr. Robert William Smith first described this disease in 1849 in his “A Treatise on the Pathology, Diagnosis and Treatment of Neuroma” [24]. This work received little attention in the medical community which resulted in multiple neurofibromatosis becoming synonymous with the brilliant German pathologist von Recklinghausen who described the main features of this nosological entity in his classical paper of 1882 [25].


The incidence of NF1 is estimated to be approximately 1 in 2500–3500 births [26, 27]. As such, it is the most common single-gene disorder affecting the nervous system. There is no sex or race predilection. The disease is inherited through an autosomal dominant inheritance with almost 100 % penetrance [28] and variable expressivity. Approximately 50 % of cases are sporadic, likely from new mutations [29].

A diagnosis can still be established without molecular confirmation (Table 16.2) [30]. Half of all cases result from a de novo mutation, while the other half are familial.

Systemic Manifestations

Cutaneous involvement in NF1 may result from melanocytic or neuroglial cell involvement or a combination of both neural crest mesenchyme sources. The principal cutaneous lesions are cafe-au-lait spots and neurofibromas of both the diffuse and plexiform type. Cafe-au-lait spots are flat, uniformly hyperpigmented lesions, with sharply demarcated borders of varying size and shape. They are usually present on the trunk, but may occur anywhere on the body. Cafe-au-lait spots are often the earliest clinical sign to present (Fig. 16.1). Histopathologically, the cafe-au-lait spots reveal hyperpigmentation resulting from an increase in the total amount of melanin, scattered, abnormally large melanin granules, and an increased concentration of melanocytes which are metabolically more active [33]. Whereas normal individuals may have 1–3 café au lait spots , the majority of NF1 patients will have 6 or more café au lait spots. The number of cafe-au-lait spots increases through childhood and puberty, followed by a period of relative stability which in turn is replaced by a decrease in pigmentation [26]. Clusters of small cafe-au-lait spots and/or freckling in the axillae or groin regions is highly supportive of the diagnosis, this has been termed “Crowe’s sign” (Fig. 16.2) [34].


Fig. 16.1
Multiple café’ au lait macules


Fig. 16.2
Axillary freckling, Crowe’s sign

The most common neuroglial NF1 lesions are the neurofibromas and optic pathway gliomas. Neurofibromas rarely occur as an isolated solitary non-NF1 lesion. They are present in 30–50 % of NF1 patients. Neurofibromas are benign Schwann cell tumors that arise from the fibrous tissue surrounding peripheral nerve sheaths and are composed of Schwann cells, fibroblasts, perineural cells, and mast cells, classified according to their appearance and location: focal or diffuse cutaneous, subcutaneous, nodular or diffuse plexiform and spinal [35]. The multiple cutaneous tumors of NF1 in most cases appear in late childhood/adolescence and gradually increase in size and number through adulthood. They are usually skin-colored, and are either semiglobular or pedunculated (Figs. 16.3 and 16.4) [33].


Fig. 16.3
Diffuse cutaneous neurofriboma (Courtesy Dr Frank Judisch collection U of Iowa)


Fig. 16.4
Diffuse cutaneous neurofibroma (Courtesy Dr Frank Judisch collection U of Iowa)

Optic gliomas are the most common intracranial tumor (see Ophthalmic Manifestations); however other low grade gliomas may also be found in addition to other radiographic abnormalities.

Plexiform neurofibromas , arise from multiple nerve fascicles, and tend to grow along the length of the nerve . The diffuse proliferation within the nerve sheath produces a grossly thickened and tortuous nerve [9]. They usually have a soft consistency, often described as like a “bag of worms” [8]. They may involve multiple nerve branches and plexuses potentially causing significant morbidity. These lesions can appear in the skin as an irregularly bordered patch or finely papillated plaque, sometimes with coarse terminal hair growth overlying (Fig. 16.5). Since plexiform neurofibromas extend into surrounding structures including skin, fascia, muscle, bone, and internal organs, they may cause pain. The neurofibromas may become large and disfiguring. Enlargement of a particular part of the body with neurofibromatosis is called elephantiasis neuromatosa, representing a diffuse proliferation outside the nerve sheath [9]. Approximately 50 % of patients with NF1 develop plexiform neurofibromas, and they are most often internal without associated cutaneous manifestations. They tend to be slow-growing, although occasionally rapid growth has been noted (particularly in early childhood) [36, 37].


Fig. 16.5
Multiple café’ au lait macules with plexiform neurofibroma

Patients with plexiform neurofibromas and persistent pain lasting greater than 1 month, significant sleep disruption, new or unexplained neurologic deficit, or rapid increase in neurofibroma size should prompt evaluation for a malignant peripheral nerve sheath tumor (MPNST) [35, 37, 38]. A malignant peripheral nerve sheath tumor, (previously described as “Malignant schwannoma,” “Neurofibrosarcoma,” and “Neurosarcoma”) is a cancer of the connective tissue surrounding nerves. Given its origin and behavior it is classified as a sarcoma. These tumors usually arise from pre-existing plexiform neurofibromas but a minority (36 %) arise de novo [38, 39]. The lifetime risk for an MPNST in patients with neurofibromatosis type 1 is 8–13 % [38]. About half the cases are diagnosed in people with neurofibromatosis. The median age of diagnosis of this tumor in NF1 is 26 years, with a 5-year survival rate of 21 % (lower than observed in sporadic cases of MPNST) [38].

Besides MPNST and optic pathway gliomas , NF1 remains a risk factor for development of other tumors and malignancies. There is a predilection for low-grade gliomas in the brainstem and cerebellum, as well as the tectum (dorsal midbrain). Compared to sporadic occurrences of these tumors in children without NF1, there is a possibility of spontaneous regression. Therefore, treatment is typically reserved for symptomatic tumors or concerning radiographic progression. The reported incidence of malignant transformation of neurofibromas ranges between 2.4 % and 16.5 % [40, 41]. Malignant transformation occurs most commonly in neurofibromas of large nerve trunks and only rarely in cutaneous neurofibromas [42]. There is an increased risk for both gastrointestinal stromal tumors and a 3.5-fold incidence in rates of breast cancer (with increased likelihood of diagnosis before age 50 years) [43]. There are several reports of rare NF1 associations with juvenile xanthogranuloma and juvenile myelomonocytic leukemia , a rare malignancy. Juvenile xanthogranulomas present as small pink papules, gradually becoming yellow/orange in color over time and eventually spontaneous involute, over the time course of several years. NF1 patients with juvenile xanthogranuloma are at significantly higher risk (20–32 times higher) of developing juvenile myelomonocytic leukemia than the general population [44].

Academic difficulties and school failure are the most common reported complication of NF1, with ~50 % of children performing poorly on tasks in reading, spelling, and mathematics. Formal neuropsychologic testing identifies an intellectual disability (FSIQ < 70) in ~7 %. An additional 20 % were diagnosed with a specific learning disability. Other neurocognitive problems are more prevalent, as almost 2/3 demonstrate difficulties with attention, with 38 % meeting criteria for a diagnosis of attention deficit-hyperactivity disorder (ADHD) . The most consistent areas of difficulty were within the domains of visuospatial/perceptual skills, executive functioning, and attention. Language was less significantly impaired, and memory was relatively preserved [45]. NF1 patients also have a higher incidence of autism spectrum disorders , behavioral abnormalities and psychosocial issues [35].

Macrocephaly in the absence of hydrocephalus, is present in 30–50 % of children with NF1. MRI of the brain identifies diffuse enlargement of both grey and white matter (including corpus callosum), suggesting that macrocephaly is driven by megencephaly. There is no apparent correlation between brain volume and cognitive ability [46]. There is also evidence that optic pathway gliomas are associated with macrocephaly significantly more often when compared to NF1 patients without optic pathway gliomas [47].

Headaches are another common neurologic manifestation, with 61 % of individuals reporting recurrent headaches (90 % of these with one or more headaches/month), and the majority of these individuals reported onset before the age of 10 years. One-third of individuals with recurrent headache had migraineous features (nausea, photo/phonophobia, throbbing/pulsatile quality, and/or visual scotoma). Migraine was more common with adolescents, but was also seen at a high rate in children <10 years (25 %). The majority of individuals did not have intracranial pathology that could potentially account for headache symptoms, with <3 % having either tumor or hydrocephalus. The majority of these individuals did have non-specific radiographic changes that were felt not to be related [48].

Seizures have been reported in ~10 % of individuals, with confirmed epilepsy in 6 % [49, 50]. The majority of these cases present during childhood (77 %). At least one quarter of those with seizures had intracranial tumors (dysembryoplastic neuroepithelial tumor, low-grade glioma) other than optic pathway gliomas, and some of these neoplasms were new findings compared to prior neuroimaging. The majority of seizures are focal in onset, although some individuals have had a primary generalized epilepsy syndrome (including childhood absence epilepsy, juvenile myoclonic epilepsy) [49].

Myelin vacuolization (also called spongioform myelinopathy , formerly ‘unidentified bright objects’ or UBOs) is often incidentally identified on MRI brain, and registers as T2 hyperintense signal, most commonly in the brainstem, basal ganglia, thalamus, and cerebellum. They increase in number in early childhood with a natural history of spontaneous remission in adolescence; this finding is considered rare after the age of 20 years. These do not evolve into tumors, and as such, do not exert any mass effect. These generally do not correspond to clinical symptoms, and the incidence is similar in individuals with NF-1 (~70 %) irregardless of the presence of seizures [50]. T2 hyperintense lesions in other locations (cortical, juxtacortical) should prompt consideration of low grade tumor or developmental dysplasia rather than presumed myelin vacuolization [50, 51]. The number and distribution of T2 hyperintensities does not correlate with cognitive disability; however, well defined, discrete lesions in the thalamus (seen in ~8 % of children with NF1) are associated with global intellectual dysfunction, with mean FSIQ 18 points lower than the general NF1 population [52].

The osseous manifestations of NF1 may consist of either intraosseous neurofibromatosis or erosive defects caused by the pressure of adjacent neurofibromas on bone. Scoliosis affects 10 % to 26 % of patients [53]. The most severe form, dystrophic scoliosis, occurs in fewer than 10 % of patients but is marked by earlier onset, rapid progression and need for early spinal fusion with potential for spinal cord compression [5456]. Spinal dislocation has been described [57]. As a result of spinal cord compression, patients may suffer from bladder and bowels dysfunction as well as limb paralysis [58]. Although nonspecific bone lesions such as increased length of long bones may occur, decreased height is more of a concern with 14 % of NF1 patients two standard deviations below the mean height for chronological age [59, 60].

NF1 has been associated with congenital bowing of the tibia and subsequent pseudoartbrosis or “false joint” formation from repetitive fracture and poor healing [61]. This long bone tibial dysplasia is typically identified in infancy and manifests as anteriolateral bowing of the leg secondary to cortical thinning and pathologic fractures with weight bearing [62].

Cardiovascular disease is an important consideration in the evaluation of NF1 patients. Vasculopathy , hypertension and congenital heart disease are the principal considerations. Vasculopathy, which includes stenosis, aneurysm and arteriovenous malformations, ranks as the second leading cause of death in NF1 [63]. Renal artery stenosis, the most common vasculopathy, is estimated to occur in at least 1 % of patients. Therefore, any NF1 patient with hypertension should have consideration for renal arteriography [64]. Cerebrovascular disease is another important vasculpathic consideration with pathology resulting from stenosis or occlusion. Patients with sudden onset neurologic changes or a history of headaches, weakness, seizures or involuntary movements should be evaluated for cerebrovascular disease [64]. The underlying histopathology lesion for both the renal artery stenosis and the cerebrovascular lesions show fibromuscular dysplasia with intimal thickening and proliferation of Schwann sells without atherosclerosis [63, 64].

Hypertension in NF1 patients is most frequently caused by renal artery stenosis. Other possible differential considerations are coarctation of the aorta and pheochromocytoma. Pheochromocytomas occur in 0.1–5.7 % of patients with neurofibromatosis [65]

Congenital heart disease occurs at a higher frequency for NF1 patients than noted in the general population. Pulmonary artery stenosis represents 25 % of the congenital heart disease lesions [64]. Murmurs require cardiology and echocardiography evaluation [64]

Other clinical features of NF1 include hamartomas of the gastrointestinal tract which can cause gross hemorrhage, occult blood loss with chronic anemia and pain [66, 67]. Additionally, neurofibromas have been demonstrated in the bladder, mouth, larynx, renal artery and vagina [68, 69].

Ophthalmic Manifestations

The effects of neurofibromatosis on the eye and ocular adnexae are diverse, involving virtually every conceivable structure (Table 16.3) [4, 6, 70]. Symptoms depend on the location and extent of the tumors.

Table 16.3
Ocular manifestations of neurofibromatosis



 – Plexiform neurofibroma

 – Neurilemoma (schwannoma)

 – Proptosis

 – Displacement of the globe

 – Pulsation of the globe synchronous with pulse but no bruit

 – Enlargement of the optic foramen

 – Underdevelopment of the orbital bones

 – Absence of the greater wing of sphenoid

 – Optic nerve gliomas

 – Neurofibromas of the ciliary nerves


 – Ptosis

 – Cafe-au-lait spots

 – Neurofibroma of the eyelid



 – Neurofibromata

 – Thickening of the conjunctival nerves


 – Nodular swelling of the ciliary nerves


Anterior segment

 – Nodular swelling of the corneal nerves

 – Medullated/myelinated corneal nerves

 – Posterior embryotoxon

 – Unilateral keratoconus

 – Glaucoma (congenital secondary)

 – Dense abnormal tissue in the chamber angle

 – Defects of Schlemm Canal

 – Focal iris (Lisch) nodules/hamartomas

 – Neurofibroma of the iris

 – Congenital extropion uveae

 – Iris neovascularization


 – Cataract

 – Neurofibroma of the ciliary body


 – Choroidal ganglioneuroma

 – Diffuse neurofibroma of choroid

 – Diffuse and nodular involvement with thickening consisting of neurofibroma, fibroblasts, spindle cells containing pigment, ovoid corpuscles of convoluted nerve fibers

 – Uveal malignant melanoma

 – Choroidal nevi (multiple)

 – Near infra-red detected choroidal lesions


 – Hamartoma of the retina

 – Cafe-au-lair spots of the retina

 – Sectorial retinal pigmentation

 – Sectorial chorioretinal scar

 – Myelinated/medullated nerve fibers

 – Typical peripheral retinoschisis

 – Congenital hypertrophy of the RPE

Optic nerve

 – Optic nerve drusen

 – Hamartoma of optic disc

 – Neurofibroma of the optic disc

 – Primary optic atrophy due to tumor pressure

 – Secondary atrophy due to papilledema

 – Glioma of optic nerve head


 – Extraocular muscle palsies

 – Strabismus

 – Juvenile xanthogranuloma

Skin, Lids and Orbit

Eyelid abnormalities consisting of punctate neurofibroma, plexiform neurofibroma or café au lait spots of the lids occur in 25 % of NF1 patients [71]. The skin of the affected lids often has a brawny and bronzed appearance. Plexiform neurofibroma of the lid results in a characteristic enlargement producing an S-shaped deformity and proptotic appearance (Fig. 16.6) [72]. Patients may have significant facial asymmetry. Elephantiasis can result from involvement of the eyelids. “Box-like enlargement of the sella turcica” has been associated with thickening of the lids due to plexiform neurofibroma [73]. Other associated cranial orbital anomalies abnormalities include bony defects of the sphenoid bone and absence of the orbital roof. The defects in the bony walls of the orbit may be congenital or may be attributable to a secondary erosion by a neurofibroma [4]. Plexiform neurofibromas of the orbit can produce enlargement of the involved orbit. A non-expansile pulsating exophthalmos synchronous with the radial pulse and not associated with a bruit is characteristic. Pulsating exophthalmos not associated with carotid-cavernous fistula most often arises as a result of neurofibromatosis [73]. Proptosis in NF1 represents congenital absence/dysplasia of the greater wing of the sphenoid bone, optic glioma or orbital neurofibroma (Fig. 16.7) [72]. Sphenoid wing dysplasia is most often detected in asymptomatic individuals as a unilateral defect affecting the orbital plate and frontal bone, although some patients have pulsating exophthalmos with cerebral herniation into the orbit [60, 62].


Fig. 16.6
Plexiform neurofibroma


Fig. 16.7
Proptosis and strabismus from orbital tumor (Courtesy Dr Frank Judisch collection U of Iowa)

Orbital tumors not only produce proptosis but may result in decreased visual acuity, visual field defects, optic disc edema and atrophy , relative afferent pupillary defects and secondary strabismus.

Anterior Segment

Involvement of the anterior segment is common in neurofibromatosis. Hamartomatous conjunctival lesions have been described as painless salmon-pink growths on the bulbar surface which may infiltrate the cornealscleral limbus [73, 74]. Prominent corneal nerves are present in up to 25 % of patients, with posterior embryotoxin less frequent [72, 73]. Lisch nodules , melanocytic hamartomas , are the most characteristic iris findings [73]. They are typically multiple, bilateral and up to 2 mm in diameter (Figs. 16.8 and 16.9). These are present in 92 % of in NF1 patients over the age of 6 years [71]. The presence of Lisch nodules is correlated to age. They are found in 5 % of NF1 patients younger than 3 years of age, 42 % of 3–4-year-olds, 55 % of 5–6-year-olds and virtually all adults over 21 years of age [75]. Their absence, particularly in children, does not exclude the diagnosis of neurofibromatosis.


Fig. 16.8
Lish nodules (Courtesy Dr Frank Judisch collection U of Iowa)


Fig. 16.9
Lisch nodules, high magnification (Courtesy Dr Frank Judisch collection U of Iowa)

Multiple juvenile xanthogranuloma lesions are transiently present in almost 40 % of children with NF1. They are difficult to diagnose and are often missed by clinicians other than dermatologists since the lesions disappear before 5 years of age [76]

Segmental neurofibromatosis , also called mosaic or localised neurofibromatosis , describes a person in which the signs for NF1 are limited to a particular area of their body. This affects one in 36,000 patients. Segmental neurofibromatosis is generally thought to result from a postzygotic NF1 gene mutation [77]. In segmental NF1 the iris hamartomas are unilateral and ipsilateral to the side of cutaneous involvement when the eye is in the affected segment.

Glaucoma is infrequent in NF1 patients. It may be present at birth or as a juvenile glaucoma. Congenital ectropion uveae increases glaucoma risk and warrants continued observation for the development of glaucoma and disorders of neural crest origin (Fig. 16.10) [78]. Unilateral glaucoma has been documented in approximately 50 % of patients with plexiform neurofibroma of the ipsilateral upper lid and face [79]. The triad of unilateral buphthalmos and hydophthalmos, homolateral plexiform neuroma of the eyelid, and homo lateral facial hemi-hypertrophy has been termed the Francois syndrome [80, 81]. Glaucoma may be present at birth before any abnormality of the lid is observed [82]. Distinctive angle findings have been described as avascular dense, opaque, light brown tissue (resembling a Barkan membrane) covering and obscuring the angle structure in neurofibromatosis and childhood glaucoma [79].


Fig. 16.10
Pupillary ectropion uveae

Three main theories have been postulated to explain the glaucoma associated with neurofibromatosis: (1) obstruction to the outflow of aqueous humor by neurofibromatous tissue or by a developmental anomaly in the chamber angle; (2) closure of the angle by tumor involving the ciliary body and anterior choroid; and (3) a secondary fibrovascular membrane in the iridocorneal angle and the formation of peripheral anterior synechiae (neovascular glaucoma) [4, 79, 83].

Posterior Segment

Choroid and ciliary body neurofibromatosis changes may be found at routine autopsy in individuals without NF1 ocular symptoms [73]. Choroidal hamartomas may be single or multiple flat ill-defined lesions varying from yellow-white to light brown scattered throughout the posterior pole [71, 84]. Reports show the number of lesions varying from 1 to 18 and occurring in up to 51 % of patients studied [71]

Bright patchy choroidal lesions visible by infrared light confocal scanning laser ophthalmoscopy, iridocyanine-green fundus angiorgraphy and more recently infrared reflectance optical coherence tomography (OCT) have been found to be highly specific to NF1 patients [8588] (Fig. 16.11). Interestingly, these lesions are not visible by traditional ophthalmoscopy, autofluorescence, fluorescein angiography or red-free testing [87]. The lesions increase in number over time and have an increased tendency to accumulate in the posterior pole between the arcades with an earlier appearance than Lisch nodules [86, 88]. They rarely occur in non NF1 subjects and typically one a solitary lesion would be found as compared to multiple lesions in NF1. There is no visual consequence from these choroidal lesions , but it has been suggested that they represent a new diagnostic criterion for NF1 [87, 88]


Fig. 16.11
Choroidal lesion posterior pole with near infrared reflectance OCT (Courtesy of Dr Alex V. Levin)

Uveal involvement may show diffuse neurofibroma thickening, consisting of a mixture of spindle-shaped Schwann cells and fibrocytes with variable number of melanocytes, ganglion cells and ovoid bodies [89]. The ovoid bodies consist of concentric layers of Schwann cells with nerves present [90, 91]. A limited number of eyes with diffuse neurofibromatosis of the uvea have demonstrated a marked increase of plump dendritic melanocytes with the uveal melanocytes over shadowing the neurofibromatous elements. This has suggested these patients may have a higher incidence of malignant melanoma of the uvea than the general population [4].

A number of disparate retinal lesions occur in NF1. Lesions include large retinal astrocytic hamartomas , multiple retinal capillary hemangiomas, and combined hamartomas of the retina and retinal pigment epithelium, which may result in rubeotic glaucoma, vitreous hemorrhage, and retinal detachment [92]. Astrocytic hamartomas may cause retinal dialysis and retinal detachment [84]. Retinal vasoproliferative tumors are uncommon benign vascular tumors in NF1 that may result in vision loss secondary to retinal fibrosis, subretinal exudation and neovascular glaucoma [93]. Myelinated nerve fiber layers have also been reported in patients with neurofibromatosis but it is not clearly established that the frequency of occurrence is greater than the normal population [4, 73, 92].

Optic disc “tumors” have been described in NF1 patients [9496]. These mulberry like masses involving the optic nerve head are not true glial neoplasms but histologically a hamartomatous malformation composed mainly of fibrillary astrocytes and frequently exhibiting dystrophic secondary dystrophic calcification [4]. Pathologically the lesion is a neuroma containing many cystic spaces and clefts consisting of groups of neurocytes and neurofibrils with areas of degeneration. Papilledema may be present as a result of increased intracranial pressure [73]. Optic atrophy develops when glioma occurs within the nerve or chiasm or it may result from long-standing papilledema or nerve compression by non intraneural tumor [73].

Optic pathway gliomas (OPGs) are the most common type of intracranial malignancy in patients with NF1 and typically consist of low-grade pilocytic astrocytomas [97]. Although considered a usually slow-growing, relatively benign neoplasm (astrocytoma) and considered by some to be a hamartoma, evidence suggests that optic pathway gliomas fall on a continuous scale from benign to malignant differentiation [98, 99]. NF1 OPGs appear more indolent and are more often located along the optic nerves as opposed to sporadic OPGs found more frequently in the chiasmal or postschiasmal regions [100, 101]. Most of these tumors develop in the first 6 years of life in approximately 15 % of children with NF1. Fifty to 75 % of patients are asymptomatic at time of diagnosis and approximately 30–50 % develop visual symptoms with the majority having a benign course [73, 97, 100, 102104]. When symptomatic, OPGs can cause vision loss, visual field loss, proptosis and precocious puberty [60]. Chiasmal tumor involvement is associated with precocious puberty (12–40 % of children) from tumor expansion and hypothalamic encroachment [60, 101]

Strabismus , including congenital esotropia, partially accommodate esotropia, alternating esotropia, overacting inferior oblique muscles, and rotary nystagmus occur in approximately 10 % of patients with NF1 [103]


Clinical criteria (Table 16.2) can establish a diagnosis of NF1 without confirmation by molecular genetics. Histopathology remains important for characterization of masses and other cutaneous manifestations. MRI and other functional imaging studies remain important adjuncts to evaluate for diagnostic findings, characterize/categorize abnormal findings, and potentially monitor growth. Neurofibromas are benign tumors consisting of Schwann cells, axons, fibroblasts, perineural cells, and mast cells [39, 105]. Cutaneous and dermal neurofibromas have characteristic appearances and typically appear during late childhood or early adolescence, rarely cause pain or neurologic deficits but may pose local discomfort or cosmetic disfiguration [106, 107]. Diagnoses are by means of clinical appearance or histopathology .

Although usually present at birth, plexiform neuromas develop from multiple nerve fascicles with growth along the length of the nerve in an unpredictable growth pattern and if located more internally may remain undetected for many years [36, 107]. The development of pain or a new neurologic deficit could represent either growth of an existing plexiform neurofibroma, but could also be the heralding signs of transformation to a malignant peripheral nerve sheath tumor (MPNST) . This tumor typically presents with pain and/or rapid growth, with 38 % occurring internally without any cutaneous signs. MRI and PET scan may be useful in distinguishing the two; although a histologic diagnosis remains the gold standard. Specifically, MRI may be used to determine volumetric measurements of plexiform neurofibromas permitting tumor growth calculations, response to treatment or with monitoring for transformation into MPNST [36, 37].

Pediatricians in particular need a heightened awareness of the multiple skeletal associations with NF1. These include scoliosis, congenital bone defects leading to pseudoarthrosis, short stature, macrocephaly and sphenoid wing dysplasia [35]. Careful assessment of linear growth, head growth, spinal curvature and symmetry as well as early identification of limb anomalies with anterolateral bowing or repeated fractures are necessary.

Cardiovascular abnormality associations require specific diagnostic testing. NF1 patients should have a cardiac examination and blood pressure measurement at the time of diagnosis. Any sign of murmur or hypertension warrants a cardiologist evaluation with consideration of echocardiography [64]. Examination for possible renal artery stenosis as a cause of hypertension is necessary since this occurs in at least 1 % of patients with NF1, potentially requiring renal arteriography [64]. Additionally, since pheochromocytoma occurs at a higher rate in NF1 patients than the general population, catecholamine testing may be necessary [108]. Intracranial vascular disease evaluation should be considered for children with onset of headache, seizures, weakness, involuntary movements or any sudden onset neurologic deficit [63, 64].

Every patient with NF1 must have a complete ophthalmology examination. The characteristic skin lesions involving lids and face, café au lait macules, cutaneous and plexiform neurofibroma changes and proptosis or strabismus, should be recognizable through direct examination. Intraocular pressure should be measured to monitor for glaucoma. Biomicroscopy using the slitlamp will establish the presence of prominent corneal nerves and/or Lisch nodules. Careful dilated fundus examination should identify optic nerve changes such as edema or atrophy and presence of retinal lesions. Fundus photography , angiography and ocular coherence tomography (OCT) may need to be utilized to make an accurate diagnosis of characteristic lesions. Optic pathway gliomas demand special attention and consideration. Any evidence of visual acuity change, visual field loss or endocrine dysfunction would warrant MRI evaluation of the orbits and brain. Baseline MRI testing attempting to detect asymptomatic optic pathway gliomas is not indicated [101]. MRI studies for identification of unidentified bright objects [50, 51, 109] and OCT for identification for choroidal abnormalities may become instrumental in the diagnosis of NF1 [8588]. Asymptomatic patients can be evaluated yearly. This is especially important for children less than 6 years of age when vision changes may not be recognized and they are at greatest risk for developing optic pathway glioma [97, 101].


The skin freckling and café au lait macules may be followed since there is no tendency for malignant transformation. For those concerned with the appearance, cosmetic makeup and dermabrasion are available, but there is no strong recommendation for laser removal [107]. Neurofibromas may cause significant skin irritation and pruritus treated by antihistamine , mast cell stabilizers and emollients [107, 110]. Patients with cutaneous neurofibromas causing cosmetic disfigurement and discomfort may have removal by an experienced surgeon, but should be aware of the risk for increased scarring and tumor recurrence [107, 111]. Additionally, removal of subcutaneous neurofibromas and spinal neurofibromas may result in neurologic deficit with both sensory and motor components [107, 112].

Plexiform neurofibromas are more difficult to treat because of their diffuse infiltrative nature which may prevent successful resection. Local recurrence is common due to incomplete resections. Neurologic deficit related to surgical treatment remains a risk. There is evidence that early removal may prevent complications later in life and prevent the greater growth demonstrated in young children [36, 113]. Radiotherapy is contraindicated due to a risk for inducing malignant peripheral nerve sheath tumors [38]. Treatment for MPNST consists of wide surgical excision with postoperative radiotherapy. This regimen does not improve long-term survival rates but does delay the time for local recurrence. Chemotherapy as a second treatment option is controversial [114].

Treatment of neurologic manifestations is symptomatic, with standard anti-seizure and migraine/headache medications tailored to the clinical situation (e.g. seizure or headache type). Individuals with neuropathic pain symptoms may be treated with either gabapentin or pregabalin as first-line agents. There should be a low threshold for screening for ADHD symptoms, with early implementation of behavioral and pharmacologic treatments . All children with a diagnosis of NF1 deserve a 504 plan to ensure early evaluation of learning difficulties within the school. If educational difficulties arise, complete psychometric testing should be completed to best tailor the child’s individual education plan.

Patients with scoliosis may benefit from early brace treatment to prevent progression when there is mild change and corrective surgery for more severe cases. Dystrophic scoliosis, recognized as the most severe form, demonstrates rapid progression and the need for early spinal fusion [54]. Pseudoarthroses frequently respond poorly to surgical management with patients progressing to limb amputation. Bisphosphonate therapy when used early in the disease progression has demonstrated positive effect [53]. An exercise regimen directed at strengthening bone may prevent some of the long-term loss of bone mineral density and predisposition for osteoporosis and fractures [53, 115]. Sphenoid wing dysplasia with pulsating proptosis may require surgical reconstruction [116].

The cardiovascular manifestations of congenital heart disease, hypertension and vasculopathy are treated as directed by the underlying diagnosis. Specific findings of ischemia, stenosis, hypertension, cardiac disease, cerebrovascular disease and pheochromocytoma direct the further investigation and treatment modalities.

Optic pathway glioma is typically diagnosed and considered for treatment when an NF1 patient has vision, visual field or endocrinologic signs and symptoms [101]. When indicated, the optic pathway glioma is treated with chemotherapy (combination of carboplatin and vincristine) [117]. Radiation therapy is discouraged because of concerns for radiation-induced second malignancies and vascular stenosis [100, 118]. Surgical excision of an optic nerve glioma generally results in the sacrifice of all vision in that eye [119, 120]. Optic pathway gliomas may also occur in the brain stem, diencephalon and cerebellum (3.5 %) of NF1 patients [107, 118]. These tumors show a more indolent course with potential for spontaneous regression, but must be followed carefully for aggressive tumor characteristics. Surgery is not recommended unless there are excessive growth characteristics or deterioration of the patient’s clinical state [107, 121].

Neurofibromatosis Type 2


The central or type 2 form of neurofibromatosis (NF2) is an autosomal dominant multiple neoplasia syndrome characterized by tumors of the eighth cranial nerve (usually bilateral), meningiomas of the brain, and schwannomas of the dorsal roots of the spinal cord .

Neurofibromatosis type 2 is caused by mutation in the (NF2) gene (22q12.2) encoding neurofibromin-2, which is also called merlin [134]. Approximately 50 % are familial and demonstrate autosomal dominant inheritance. Of the de novo cases, 25–33 % result from somatic mosaicism, which may result in atypical clinical presentations or inability to detect a mutation in leukocytes (mutations confirmed in tumor). Among mosaics, recurrence risk to offspring appears low if no mutations are identified in leukocytes [135]. Genetic testing is 93 % sensitive, combining sequencing and deletion/duplication analysis [136].


Neurofibromatosis type 2 was previously called central neurofibromatosis or bilateral acoustic neurofibromatosis. Despite an initial NF2 description in 1882 (a patient with deafness and tumors of the brain, dura matter and skull), it was clinically incorporated within the diagnosis of the more common neurofibromatosis type 1 or peripheral neurofibromatosis for decades [122124].

In 1920, three generations of a single-family were reported with vestibular schwannomas demonstrating the heritable nature of NF2 [125]. In 1930, 38 members of a single-family across five generations were found to have acoustic neuromas. By 1970 more than 100 members of this same family were affected demonstrating autosomal dominant transmission [126, 127]. NF1 and NF2 were localized to two different chromosomes by genetic linkage analysis in 1987 firmly establishing the existence of two separate disease entities [128130].


The incidence of neurofibromatosis type 2 is 1 in 25,000 live births [131]. It has wide phenotypic variability and nearly 100 % penetrance by 60 years of age [132, 133]. NF2 has few of the hallmarks of the peripheral or type 1 form of neurofibromatosis.

Systemic Manifestations

Diagnostic criteria for NF2 include presence of either bilateral vestibular schwannomas, or an affected first degree relative and unilateral vestibular schwannoma, or two of the following : schwannoma, glioma, meningioma, ependymoma, posterior subcapsular cataract (Table 16.4) [137]. With distinct features from NF 1, more than 6 café-au-lait macules are uncommon, learning disabilities are not a feature and malignant tumors are not increased in frequency in NF2. Vestibular schwannomas present with tinnitus, hearing loss and trouble with balance. In the setting of NF2, these tumors arise early—often in the second decade of life, as opposed to occurring later in life which is typical of idiopathic presentations of this tumor. Schwannomas can also affect the other cranial nerves as well as cutaneous nerves. When affecting cutaneous nerves, skin-colored to slightly hyperpigmented papules and plaques with increased overlying hair growth are the presenting signs (Fig. 16.12) [138].

Table 16.4
Findings in NF2

Ophthalmological lesions

Cataracts 60–81 %

Epiretinal membranes 12–40 %

Retinal hamartomas 6–22 %

Neurological lesions

Schwannomas 24–95 %

Intracranial meningiomas 45–58 %

Spinal tumours 63–90 %

Cutaneous lesions

Skin tumours 59–68 %

Skin plaques 41–48 %

Subcutaneous tumours 43–48 %

Intradermal tumours rare

Modified from Asthagiri AR, Parry DM, Butman JA, et al. Neurofibromatosis type 2. Lancet 2009;373:1974–86


Fig. 16.12
Soft skin-colored nodule with overlying hypertrichosis consistent with schwannoma in NF2

Spinal tumors are present in ~2/3 of individuals. Most often, these are schwannomas of the dorsal root seen in the intravertebral canal. Multiple tumors are often identified with surveillance imaging, although many remain asymptomatic. Other tumors include intramedullary astrocytomas or ependymomas (present in 5–33 %). 50–80 % of patients will have one or more meningiomas, most typically with an intracranial location, although they can occur in the spine [139]. Symptoms correspond to size and location, but symptoms can include headache, visual loss, or focal weakness.

Mononeuropathy without tumor involvement may be seen, and common features include facial droop, oculomotor palsy, or a foot/wrist drop, and may be more common with childhood presentation [140]. In contrast, an axonal polyneuropathy has been demonstrated in nerve conduction studies in adults with NF2, although the contribution of this finding to clinical well-being and function is uncertain [141].

Ocular Abnormalities

Ocular abnormal findings include cataracts, epiretinal membranes, and retinal hamartomas. Lisch nodules, iris hamartomas that are frequently found in NF1, are typically not found in NF2 [142].

Cataracts are present in 60–81 % of NF2 patients [133, 141, 143, 144]. The cataracts are characteristically posterior subcapsular, capsular or peripheral cortical opacifications with onset under 30 years of age [145, 146]. The cataracts frequently predate symptoms of bilateral acoustic neurofibromatosis [142]. The association of peripheral cortical lens opacities with NF2 has been found to be statistically significant being present in approximately 38 % of patients [145]. Although lens opacities are an important marker for NF2, the majority do not interfere with vision such that 10–25 % of patients might need cataract extraction [144, 145, 147]. The cataract association is strong enough that NF2 should be considered in young persons without NF1 but with mild skin findings of NF or CNS tumors with posterior capsular opacities. Additionally, the presence of posterior capsular opacities in a relative of persons with NF2 is suggestive of NF2 [148].

Epiretinal membranes are present in 12–40 % of NF2 patients [146, 147]. These are characterized as translucent, semi-translucent or gray white lesions with well demarcated borders located in the posterior pole. Dysplastic Muller cells might be a major component of NF2-associated epiretinal membrane [149]. The epiretinal membranes are typically not a cause of significant vision impairment [150]

Retinal hamartomas are present in 6–22 % of NF2 patients [144, 146, 148]. They consist of slightly raised masses frequently identified in the macula that often reduce visual acuity [144, 146, 148]. They are characterized by enhanced pigmentation and varying amounts of thickened, grey–white retinal and epiretinal tissue [145].

Combined pigment epithelial and retinal hamartoma (CEPRH) and intrascleral schwannomas have also been described in NF2 [149, 151].

There are multiple considerations for potential visual loss in NF2. Progressive cataract, damage to the optic pathways, optic sheath meningiomas, macular hamartomas and corneal opacities secondary to fifth or seventh cranial nerve damage are prime considerations. Fifth cranial nerve lesions resulting corneal hypoesthesia and seventh cranial nerve damage may cause lagophthalmos and decreased lacrimal secretion [152].


NF2 should be considered in any child presenting with meningioma, vestibular schwannoma, or cutaneous symptoms such as neurofibroma or schwannoma, especially if they have fewer than 6 cafe-au-lait patches and therefore do not fulfill the diagnostic criteria for NF1 [140]

Historically, four separate diagnostic criteria evolved to assist in making the diagnosis of NF2: the NIH Consensus Development Conference [153], the Consensus Development Panel of the NIH [154] the Manchester Group [133] and the National Neurofibromatosis Foundation (NNFF) criteria [137]. None of the criteria were adequate in making the diagnosis in individuals with negative family history of NF2 and without bilateral vestibular schwannomas [155].

The Baser criteria (2011) was developed incorporating a diagnostic system that utilizes genetic testing and weighted characteristic clinical features that occur before 30 years of age. The Baser criteria have been found to have increased diagnostic sensitivity to 79 % (9–15 % greater than previous sets of criteria) while maintaining 100 % specificity at the age of onset of the first characteristic sign of NF2 [156].

Multispecialty evaluation by dermatology, neurology and ophthalmology is necessary for both initial diagnostic evaluation and ongoing clinical monitoring monitoring of NF2 patients.


Early detection of vestibular schwannomas is important and this is best done with MRI, though auditory brainstem evoked response testing may also be helpful. Management of these tumors may involve surgery or stereotactic radiation. Auditory brainstem implants may be helpful in restoring hearing [157]. The other associated tumors—meningeomas and other schwannomas—are managed surgically [138].

NF2 patients require ophthalmology evaluation and monitoring for visual acuity status with special attention to cataract formation and posterior segment epiretinal membrane formation.

Sturge-Weber Syndrome (Encephalo-Trigeminal Angiomatosis)


The Sturge-Weber Syndrome (SWS, encephalo-trigeminal angiomatosis) is a congenital vascular disorder characterized by the following features: leptomeningeal vascular malformations (usually over the posterior parietal and occipital lobes), facial capillary malformation (port-wine birthmark—PWS) most often in the cutaneous distribution of the first and second divisions of the trigeminal nerve, ipsilateral choroidal vascular malformation which may lead to glaucoma [158]. Partial forms of SWS may occur with only eye findings, or only CNS involvement [159, 160]. SWS has been classified into three types based on the presence or absence of these vascular malformations [161].

  • Type I: individual has a facial port-wine birthmark, leptomeningeal angioma, and may have glaucoma

  • Type II: individual has a facial port-wine birthmark, no leptomeningeal angioma, and may have glaucoma

  • Type III: individual has leptomeningeal angiomatosis, no facial port-wine birthmark, and rarely, glaucoma

A somatic mosaic mutation of the GNAQ gene is the underlying genetic etiology of Sturge-Weber syndrome. As the gene mutation is not present in the germline in affected individuals, the inheritance pattern is sporadic [166]. There have been no reported cases of familial recurrence or parental consanguinity [167, 168].


The triad of findings which bear the eponyn of Sturge-Weber Syndrome was described clinically by Sturge in 1879 when he described a patient with epilepsy, buphthalmos and a facial capillary malformation with suspected vascular brain anomalies [162]. The underlying brain vascular abnormalities and intracranial calcifications were further clarified by Kalischer, Durck, Volland, Krabbe and Parkes Weber [163, 164]. There may be isolated single symptom forms—facial angioma, meningeal angioma, or isolated choroidal angioma, and incomplete forms exhibiting two of three complete signs have been described [159, 160].


Sturge Weber syndrome is a rare neurocutaneous disorder which has an incidence of 1/50,000 live births with no racial predilection and equal male to female distribution [165].


The combination of cutaneous and cerebral angiomas is thought to result from maldevelopment of the vasculature at 4–8 weeks gestational age, when the ectoderm that will form the upper part of the face closely apposes the neural tube that will form the occipital lobe and adjacent cerebrum [158]. Morgan notes that the development of the blood supply to the brain in the primordial vascular system splits into an inner layer which supplies the brain and the retina and an outer layer which supplies the meninges, choroid, and face. Morgan feels that this common derivation of the meningeal, choroidal, and facial vessels may explain the congenital vascular malformation of SWS [160]

The territory of the ocular branch of the trigeminal nerve is classically used to describe the distribution of the majority of PWM in SWS; however, embryoinic development of facial vasculature occurs independently of neural innervation of the face. Interestingly, a recent article by Waelchli et al. challenges the classic teaching that the V1 distribution is a good description of the location of PWM in SWS and thoughtfully proposes using a forehead distribution (bordered inferiorly by a line from upper eyelid to top of the ear) as a more accurate way to predict infants at risk for SWS [169]. The proposed forehead distribution covers territory from all three branches of the trigeminal nerve but corresponds well to embryonic vasculature development. In order to remain consistent with other published texts and majority of literature on SWS we will utilize the branches of the trigeminal nerve as anatomic landmarks.

Nearly all patients with SWS have a PWM in the distribution of the ocular branch of the trigeminal nerve (V1) (Fig. 16.13). Patients with V1 PWM have an approximate 8–10 % chance of developing SWS [170]. Unilateral V1 is most common PWM location but ipsilateral V2 and V3 and contralateral dermatomes may additionally be affected. When this is the case, risk of SWS is elevated beyond 8–10 % and presentation tends to be more severe.


Fig. 16.13
Port wine birthmark V1 and some V2 distribution

The cutaneous feature of the SWS is the “port-wine birthmark,” which is a capillary malformation. These lesions are present at birth as flat, vascular patches. They tend to evolve overtime to a deep red to purple color and surface can thicken, become irregular, or nodular with age. Histopathologic examination of PWM shows a normal numbers of ectatic vessels in the superficial dermis. The nasal mucosa and buccal mucosa may also be affected, and localized hemiphypertrophy of the involved tissues may develop over time [4]

The cerebral vascular malformation in SWS is leptomeningeal angiomatosis, demonstrated as meningeal enhancement on contrast MRI of the brain. Progressive calcification of the cortex underlying the angiomatosis can occasionally be seen as early as infancy [4]; however, by age 20 years, most patients have cortical calcifications that appear radiographically as double densities resembling “railroad tracks.” [171]

The vascular malformation results in progressive cerebral changes due to impaired blood flow, with chronic hypoperfusion and hypometabolism. Perfusion studies suggest venous stasis results in decreased arterial perfusion, and there can be significant progression of this process over the first year of life [170]. Functional imaging through PET and magnetic resonance spectroscopy (MRS) show a broader distribution of abnormalities than might be predicted by the delineation of the angiomatosis alone, and these functional disturbances can fluctuate with the degree of underlying seizure control [172]. Chronic changes have been recognized radiographically with both cortical and subcortical atrophy [173]. There are increasing reports of associated dysplastic lesions of the cortex adjacent to the malformation (focal cortical dysplasia type IIa, polymicrogyria), which have epileptogenic potential independent of chronic perfusion abnormalities [174].

The most common neurologic manifestations include seizures , “stroke-like episodes,” headache, hemiparesis, visual field cuts, and cognitive disability. In a patient with facial PWM, if the child has normal development, neurologic examination, absence of seizures, and normal MRI brain with contrast after 1 year of age, it is unlikely that there is any cerebral involvement.

Seizures are reported in 80 % (71 % with unilateral and 87 % with bilateral PWM) [175]. Approximately 75 % of those develop within the first year of life (range birth to 23 years) [175]. The development of seizures at <6 months of age correlates with development of a more severe hemiparesis [176]. Seizures are most commonly described as focal clonic seizures +/− impairment of consciousness. Progression to generalized convulsion may occur, and other seizure types (e.g. atonic) are reported less frequently.

Recurrent headaches are reported in 44 % of patients and over half of these were consistent with the International Headache Society classification for migraine. There is also a proclivity towards complicated migraine, with 58 % of those with migraine reporting an associated neurologic deficit [177]. Headaches often begin in early childhood (mean onset = 8 years), and duration can be prolonged with a median duration of 12 h. Migraines are five-fold more likely in individuals who experience stroke-like events [178].

“Stroke-like events” in SWS differ from classic acute arterial ischemic strokes , in that symptom progression may be more gradual, and symptoms are potentially reversible. Recurrent thrombotic venous occlusion has been postulated as the underlying mechanism. An episode starts with subacute to acute onset of contralateral weakness, sensory loss, cognitive impairment or visual field loss. The symptoms may last hours to days, and recovery may be gradual (weeks) but potentially incomplete. The consequence of multiple events can be a step-wise decline in function. These events are distinct from post-ictal deficits after a seizure, which should result in complete return to neurologic baseline within minutes to a few hours. Mild head trauma has been reported as a potential trigger for stroke-like events, most prevalent in toddlers [179]. Both seizures and headache can co-occur with stroke-like events, with repeated descriptions of headache preceding stroke-like events and/or stroke symptoms preceding onset of seizures.

Neurodevelopmental effects are frequent and include emotional/behavioral difficulties, learning disabilities, and intellectual disability. Approximately 50–60 % of individuals meet diagnostic criteria for intellectual disability (FSIQ < 70) [180182]. This statistic underestimates the prevalence of any cognitive effects, which include milder attention deficits or specific learning disabilities despite intelligence scores in the normal or borderline range [175]. In a survey of 171 SWS individuals, 58 % were involved in special education, while 83 % were noted to have some developmental or academic problem. Progressive functional declines have been observed, mostly with recurrent stroke-like episodes or status epilepticus. However, there has been no observed association between lower IQ scores with increasing age [180] suggesting that the progressive aspect of cognitive disability may occur prior to the age where neuropsychologic can be performed reliably. Bilateral angiomatosis and earlier presentation of treatment-resistant seizures are both risk factors for more severe intellectual disability [175, 183].

Other viscera in which angiomas may develop include the lung, thymus, testes, lymph nodes, pituitary gland, and liver, and gastrointestinal tract [184186].


The characteristic cutaneous facial lesion seen in SWS is the PWM which is present at birth. The PWS is a vascular lesion at the level of the dermis [186188]. It begins as a well-defined pink smooth macular lesion which blanches with pressure, helping to distinguish PWM from capillary hemangioma [189]. With time, the area changes color from pink to red to purple with associated hypertrophy of the involved skin [190].

SWS patients develop PWM along the trigeminal nerve distribution V1 through V 3, with the most frequent distribution involving the ophthalmic V1 upper lid distribution [191, 192]. Adjacent conjunctiva may also be involved [160]. Episcleral hemangioma and iris heterochromia may also be present with PWM and when found have a high correlation with glaucoma (45 % and 50 % respectively) [189]. Several cases of SWS have been associated with oculocutaneous melanosis [193]. Up to 37 % of SWS patients have bilateral PWM facial lesions [194]. Additionally, 40–50 % of patients with SWS have choroidal hemangiomas, and 50 % of all choroidal hemangiomas occur in SWS patients (Table 16.5 for ocular findings) [7].

Table 16.5
Ocular manifestations of SWS



– Proptosis

– Lids

– Ptosis

– Port-wine birthmark of eyelid



– Nevoid marks or vascular dilation of the episclera

– Large, anomalous vessels in the episclera

– Dilation and tortuosity of episcleral vessels

– Episcleral hemangiomas


– Conjunctival telangiectasia

– Conjunctival hemangiomas

– Dilatation and tortuosity of conjunctival vessels

– Large anomalous vessels in the conjunctiva


Anterior segment

– Increased corneal diameter

– Iris discoloration

– Telangiectasia of the iris with heterochromia

– Dilation and tortuosity of iridic vessels

– Sluggish pupils

– Anisocoria or other disturbances in pupil reaction

– Deep anterior chamber angle

– Glaucoma

– Ectopia lentis


– Choroidal hemangioma

– Angioid streaks


– Dilation and tortuosity of retinal vessels

– Retinal arteriovenous aneurysm

– Varicosity of retinal veins

– Glioma

– Retinal detachment

– Central retinal vein occlusion

Optic nerve

– Arteriovenous angiomas

– Papilledema

– Optic atrophy

– Optic nerve cupping

– Optic nerve drusen




Loss of vision (any degree)

Cortical blindness

Abnormal visual field due to lesion in visual pathway


Choroidal hemangiomas may be discrete or diffuse. The discrete lesions are yellowish, elevated, circular areas which disappear or decrease with scleral depression, in contrast to the diffuse “tomato catsup” hemangioma which is often flat, involving the posterior pole and more difficult to observe. The diffuse type occurs more commonly in SWS patients, and the age of onset of ocular symptoms with the diffuse hemangioma is noted earlier (median, 7.6 years) than with the discrete or solitary type (38.7 years) [194]. In SWS, choroidal hemangiomas are typically unilateral, and ipsilateral to the angiomatous malformation of the skin [195]. The examiner may be able to see beyond the lesion with the indirect ophthalmoscope and note the border of the striking color change. The appearance of an optic nerve buried in a “sea of tomato catsup” is described as a pathognomonic fundus picture in SWS (Fig. 16.14) [196]. In unilateral disease there is a dramatic color difference between the two fundi with the involved eye seen as a bright red fundus reflex compared to the normal contralateral fundus. Bilateral choroidal hemangiomas may be difficult to appreciate.


Fig. 16.14
Diffuse choroidal hemangiomas. Note absence of choroidal markings (Courtesy Dr Frank Judisch collection U of Iowa)

Patients with diffuse choroidal hemangiomas are at risk for developing secondary retinal detachment with shifting subretinal fluid layers [195, 197]. They may also develop visual loss from changes in refractive error, foveal distortion, and exudative retinal detachment [198].

Histologically, the diffuse hemangioma engorgement of pre-existing vessels is intermixed with the vascular tumor, presenting the picture of diffuse hemangiomatosis of the choroid [199]. The choroidal hemangioma may induce changes in the adjacent and overlying choroid and in the overlying retina and retinal pigment epithelium (RPE) . In 11 eyes enucleated for suspicion of malignant melanoma, the eyes were found to have irregular pigmentation over and at the margin of the tumor caused by compressed choroidal melanocytes and hyperplastic RPE. Additionally, fibrous tissue proliferation from hyperplastic RPE was observed in half of the diffuse hemangiomas [200]. This fibrous tissue is thought to be responsible for the grayish-white appearance of many of these lesions [199]. Ossification in association with hyperplastic RPE was observed in 64 % of diffuse hemangiomas [200]. Breakdown of the blood ocular barrier at the level of the RPE leads to cystic changes in the outer layers of the overlying retina and retinal detachment, and eventually to degeneration of the entire photoreceptor cell layer [199].

Glaucoma occurs in approximately 68–71 % [189, 201] of patients and is more common when the PWS involves the eyelids or when there is episcleral hamangioma, iris hterrochromia or choroidal hemangioma [168, 189]. Stevenson and Morin reviewed 50 patients with PWM and found that when PWM involves the area of both the first and second sensory branches of the trigeminal nerve, there is a 15 % chance of diagnosing definite glaucoma, and a 30 % chance of diagnosing a patient as a glaucoma suspect [202]. The Great Ormond Street Hospital experience with 216 PWM patients demonstrated that glaucoma was more common in bilateral PWM compared to unilateral PWM patients, 47.2 % versus 12.2 % [189]. They also showed that the incidence of glaucoma in PWS patients with episclaeral hemangioma was 45 %, iris heterochromia patients 50 % and those with choroidal hemangioma 40 % [189].

In SWS patients, glaucoma develops in a bimodal pattern with approximately 60 % of cases appearing in early childhood with a higher risk of developing buphthalmos , and a later childhood or early adult form which does not develop buphthalmos [4, 168, 201, 203205]. The early form is attributed to immature or anomalous angle anatomy with trabeculodysgenesis with an anterior insertion of the longitudinal muscle of the ciliary body on the trabecular meshwork and incomplete cleavage of the chamber angle with persistence of the uveal part of the meshwork [204206]. The later onset glaucoma is related to increased venous pressure and possibly anomalous angle anatomy changes [204206]. Phelps described 16 of 21 SWS patients with glaucoma and episcleral vascular hamartoma, in which 11 had elevated episcleral venous pressure [207]. Vascular malformations in the episclera and limbal conjunctiva may result in an elevated episcleral venous pressure, impeding the outflow of aqueous from the anterior ciliary veins [205, 207209].

Glaucoma mechanisms also include occlusion of the anterior chamber angle by peripheral anterior synechiae (PAS) and malformation of the anterior chamber angle [4, 168]. PAS most often occurs in persons with choroidal hemangioma and retinal detachment with development of secondary neovascularization and rubeosis. Cibis and co-workers reviewed the histolopathology of trabeculectomy specimens from three eyes with SWS and suggested that a premature aging of the trabecular meshwork Schlemm’s canal complex is the primary cause for the later onset juvenile glaucoma [206].


SWS is suspected in any patient with PWM along the facial distribution of V1-V2. Clinical investigation and diagnostic confirmation frequently involves dermatology, radiology, neurology and ophthalmology services. A complete ophthalmologic evaluation with frequent consideration for ancillary ultrasound and ocular coherence tomography (OCT) testing is necessary to determine ocular associations and potential vision loss from glaucoma or choroidal hemangioma changes. The central nervous system concerns require neurologic investigation with consideration for EEG for seizure evaluation and computerized tomography and/or magnetic resonance imaging for leptomeningeal angiomas. The PWS needs early evaluation and timely treatment by dermatology to prevent chronic more disfiguring changes.


It is well-established that individuals with facial disfigurement have an altered social experience resulting in negative psychological consequences thus providing significant motivation for treatment of facial PWM in SWS [210]. Additionally, early treatment of PWM can prevent the superficial thickening and nodularity that tends to occur over time. Pulsed dye laser (PDT) is the treatment of choice for PWM. Pulsed dye lasers (PDL) emit a wavelength of light between 585–595 nm that can penetrate up to 1.2 mm [211]. This wavelength targets superficial blood vessels causing intravascular coagulation and subsequent vessel involution. Side effects of PDL include postoperative bruising that persists for 1–2 weeks and transient pigmentary alterations. There is a low risk of scarring. It is controversial as to when exactly laser treatment should be initiated for this condition, but with most agreeing on at least early childhood if not infancy given the progressive nature of this lesion. Rarely does laser treatment completely fade the cutaneous malformation. A widely accepted goal of therapy is 70 % lightening and prevention of thickening/nodularity. On-going, intermittent treatment for maintenance is needed.

Treatment of seizures associated with SWS remains symptomatic, and choice of medication does not differ significantly from other causes of epilepsy. A rescue medicine such as rectal valium (DiastatTM ) should be available for clustering or prolonged seizures (>5 min). Migraine treatments are also symptomatic, and consist of both preventive medications and abortive medications. A survey of patients with SWS indicated that both categories of medicine are used effectively in this population. Those taking preventive medications were less likely to report a negative impact of headaches on quality of life (42 % vs 85 %). Approximately 22 % of migraineurs with SWS reported using triptans, and overall reported that triptans were more effective as an abortive than over-the-counter analgesics (42 % vs 20 %) [212]. The safety of triptans in the SWS population has not been evaluated. Triptans could potentially precipitate a stroke, and some experts advise against triptan use in individuals experiencing neurologic deficits (weakness, sensory loss, aphasia) during their migraine, although there is insufficient data to determine the absolute risk. 2/16 individuals in the Kosoff study reported reversible unilateral weakness with a migraine in which a triptan was used.

Treatment with low-dose aspirin (3–5 mg/kg/day) remains controversial as there have been no randomized controlled trials for this treatment. Anti-platelet therapy has been proposed to reduce recurrent microthrombosis and improve perfusion. A retrospective survey of families indicates a reduction in monthly stroke-like events and seizures in children who were taking daily aspirin [213]. Of 26 individuals reporting stroke-like events before and after aspirin use, there was a reduction from a mean number of monthly events from 1.1 to 0.3 (p = 0.014). There was a statistically significant reduction in the number of reported seizures (from 3/month to 1/month), even though the majority of these families subjectively felt there was no change in seizure burden. In cases of medically-resistant epilepsy and/or progressive cognitive decline, hemispherectomy is an option, with noted improvements in cognitive outcome and seizure burden [214].

Medical management of SWS associated glaucoma is difficult and often unsuccessful. Aqueous suppressants are more an adjunct to surgery in the early onset glaucoma patients and often the initial treatment modality in the later onset glaucoma group. Oral propranolol has also been used to produce a temporary intraocular pressure lowering treatment for SWS glaucoma patrients, but is not indicated as a primary treatment modality [215]

Surgical treatment should probably be individualized based on the gonioscopic appearance of the anterior chamber angle at the time of examination under anaesthesia. Numerous surgical procedures have been advocated, including goniotomy, trabeculotomy, full-thickness filtration surgery, partial-thickness filtration surgery (trabeculectomy), combined trabeculotomy-trabeculectomy, argon laser trabeculoplasty, neodymium:yttrium-aluminum-garnet (Nd:YAG) laser goniotomy, seton procedures, and transpupillary thermotherapy (infrared diode laser) [216].

Goniotomy and trabeculotomy are considerations for the early onset group. A combined trabeculectomy and trabeculotomy may have theoretical advantages, since it should provide treatment for both a congenitally abnormal angle and increased episcleral venous pressure [205, 217]. Cibis and co-workers site the success of trabeculectomy, trabeculotomy, and goniotomy in controlling lOP as proof that a primary block in the trabecular meshwork and Schlemm’s canal system is the main cause of SWS glaucoma [206]. SWS patients with infantile glaucoma have also been successfully treated with combined trabeculectomy and cyclocryotherapy [218].

In view of the expulsive hemorrhage risk with open procedures in SWS glaucoma, goniotomy or trabeculotomy should be considered as a primary procedure. Cibis and co-workers have anectotally noted a poor response to goniotomy and have done trabeculotomies as the primary procedure for SWS glaucoma [206]. YAG laser goniotomy has been employed in an eye with juvenile primary developmental glaucoma associated with SWS [219]. Cycloablative procedure, either with cryotherapy or laser, can eliminate the risks of open surgical procedures. Induction of a low intraocular pressure preoperatively and careful cauterization of the dilated subconjunctival and episcleral vessels would seem to be prerequisites for avoiding complications of hemorrhage, expulsion or prolapse of intraocular contents as much as possible.

Complications of glaucoma surgery in SWS patients are significant. Ciliary processes , lens zonule and vitreous prolapse into the trabeculectomy wound has been described [220]. Cilioretinal artery occlusion has been reported with glaucoma drainage device surgery in SWS [221]. Expulsive hemorrhage, choroidal effusion, prolonged persistence of flat anterior chambers and excessive anterior chamber hemorrhages are well documented serious complications in open eye surgery in SWS glaucoma cases [206, 222224]. This had led same surgeons to take measures to preplace sutures and scleral flaps and posterior sclerotomies in order to permit rapid closure with prevention of hemorrhage, effusion or expulsive hemorrhage although this is less common in children. One recent report has demonstrated that this risk may be very low and preventive measures are not necessary [225].

Management of the choroidal hemangiomas presents a therapeutic challenge for the treating ophthalmologist. These vascular malformations frequently produce an exudative retinal detachment leading to vision loss, intractable secondary glaucoma, and increased potential for enucleation [4, 168]. Treatment modalities, including diathermy, photocoagulation, cryotherapy, radiotherapy, proton beam stereotactic radiotherapy, photodynamic therapy (PDT) and plaque radiation therapy, have produced favorable results treating exudative retinal detachment associated with choroidal hemangioma especially when initiated prior to the development of significant exudation [6, 195, 197, 216, 226233]. Treatment with argon laser over the area of tumor may be effective in reducing or eliminating associated retinal detachment, even those involving the macula [234]. Bevacizumab has also been effective in treating serous retinal detachment associated with choroidal hemangioma [232].

PDT is suggested as the treatment of choice for discrete choroidal hemangioma but has good short-term results in limited case reports with the diffuse choroidal hemangioma form as well (2002, [235]). In eyes where the exudative retinal detachment precludes photocoagulation, treatment by percutaneous radiotherapy has resulted in successful reattachment [236, 237].

Potential treatment complications include radiation retinopathy, optic neuropathy, macula ischemia, and subretinal fibrosis in addition to the secondary formation of choroidal effusion after laser treatment for choroidal hemangioma [195, 227].

Tuberous Sclerosis Complex


Tuberous sclerosis complex (TSC) is a multisystem disease characterized by disordered proliferation, migration, and differentiation due to dysregulation of the mammalian Target of rapamycin (mTor) pathway . Common manifestations include hamartomas and other abnormalities in the skin, brain, eye, kidney, heart, lung, and liver.


In 1880 Bourneville described the case of a 15 year-old girl who had seizures since childhood, psychomotor delay, and an eruption vascular papules on her nose, cheeks, and forehead [238]. At autopsy, multiple sclerotic nodules were observed in the cerebral cortex and kidney, which Bourneville associated with skin lesions he had observed [4]. In 1808, Bourneville published another paper about a 4 year-old boy who had intractable seizures, intellectual disability, and a heart murmur who was found to have tubers of his heart, brain, and kidneys, at autopsy [239]. Although tuberous sclerosis bears the eponym “Bourneville’s disease,” it was not until 1908 that Vogt established the classic triad of epilepsy, low intelligence, and angiofibromas of TSC (although less than 1/3 of patients have all three symptoms) [7, 240]

The term “epiloia” has often been used in the past to designate this triad. The term was coined by Sherlock as a contraction of the words epilepsy and anoia, meaning mindlessness [4, 8]. Although obsolete now, an attempt was made by Gorlin in 1981 to suggest a more useful interpretation of the term epiloia as an acronym for the disease with epilepsy, low intelligence, and adenoma sebaceum (the term “angiofibroma” is now preferred for these lesions) [241]. In 1920 van der Hoeve first established that retinal tumors are present in some cases of TSC and called these “phakomas,” now termed astrocytic hamartomas [2, 4].


The current estimated birth incidence is 1/6000 person, with a population prevalence of approximately 1/20,000 [242]. The disease shows no sexual or racial predilection.

Tuberous sclerosis is a single gene disorder that may be inherited in a dominant fashion from an affected parent (~1/3) or arise sporadically as a de novo mutation (~2/3). 85 % of cases have an identifiable mutation in the TSC1 (31 % 9q34) and TSC2 (69 % 16p13.3) genes, which code for the proteins hamartin and tuberin, respectively. Mutations cause constitutive activation of the mammalian target of rapamycin complex 1(mTORC1), which result in multi-system hamartomas in addition to the other sequelae described in this disorder [243, 244]. Although the penetrance of the gene is high, there can be variable expressivity within a family with some individuals having multiple or severe findings and others expressing only a single sign.

Somatic mosaicism is present in ~5 % of individuals without a known mutation (1 % of all individuals with TSC). If the gonadal cell line carries the mutation, these individuals could have affected children [245]

Although not absolute, TSC2 mutations and sporadic inheritance have been associated with more severe multisystem disease.

Clinical Diagnosis

The diagnostic criteria for TSC was most recently revised at the 2012 International Tuberous Sclerosis Complex Consensus Conference (Table 16.6). A diagnosis can be established either by genetic or clinical criteria. For a clinical diagnosis, definite TSC diagnosis requires presence of two major or one major plus ≥2 minor features. Possible TSC diagnosis is made by one major or ≥2 minor features [242].

Table 16.6
Updated diagnostic criteria for tuberous sclerosis complex 2012 [242]

Genetic diagnostic criteria

Major features

Minor features

TSC1 or TSC2 DNA mutation (Identification of mutation serves as independent diagnostic criterion)

1. Hypomelanotic macules (≥3, at least 5-mm diameter. Poliosis may count as hypomelanotic macule)

1. “Confetti” skin lesions

2. Angiofibromas-major feature in child (≥3) or fibrous cephalic plaque

2. Dental enamel pits (≥3)

3. Ungual fibromas (≥2)

3. Intraoral fibromas (≥2)

4. Shagreen patch

4. Retinal achromic patch

5. Multiple retinal hamartomas

5. Multiple renal cysts

6. Cortical dysplasias

6. Nonrenal hamartomas

7. Subependymal nodules

*Angiofibromas, multiple with adult onset, considered a minor feature

8. Subependymal giant cell astrocytoma

**Bone cysts no longer a diagnostic criterion

9. Cardiac rhabdomyoma

10. Lymphangioleiomyomatosis (LAM)

11. Angiomyolipomas (≥2)

Genetic testing can also provide a definite diagnosis, as 85 % will have a known pathogenic mutation in either the TSC1 or TSC2 gene. Genetic testing may yield a variant of unknown significance or no identifiable mutation, and clinical criterial would be necessary to establish the diagnosis.

Systemic Features

Cutaneous manifestations are frequently the first signs of TSC and occur in nearly all patients. Four different cutaneous manifestations are independent major criteria for a diagnosis of TSC: hypopigmented macules , angiofibromas , a shagreen patch, and periungual fibromas . Hypopigmented macules are usually present at birth and occur in 90–100 % of TS patients (Fig. 16.15). These can be difficult to appreciate in lightly pigmented infants, and so may not become obvious until months or years of life as the surrounding normal pigmentation darkens over time in these individuals. They can present in numerous shapes and sizes including 1–2 mm macules called “confetti” macules (a minor feature) or larger lesions. These may have one rounded and one tapered end, resembling the leaf of an Eastern Mountain ash tree, from which these characteristic “ash leaf” macules take their name. Hypopigmented macules and patches , sometimes called nevus depigmentosus, are not an infrequent occurrence in healthy children (approximately 1–4 % of children have at least one); however, more than three hypopigmented macules is highly specific for TSC and therefore has been adopted as a major criterion for the disease [242, 246]


Fig. 16.15
Hypopigmented macules in TSC (Courtesy Dr Frank Judisch collection U of Iowa)

Unlike hypopigmented macules, angiofibromas are not present at birth but develop over the first 2–10 years of life and occur in approximately 75 % of TS patients [247]. Angiofibromas were called “adenoma sebaceum” until it was discovered that these tumors were neither adenomatous nor derived from sebaceous glands. The prototypical angiofibromas are numerous red-brown firm shiny dome-shaped papules located on bilateral cheeks and forehead (Fig. 16.16). In mosaic TSC, facial angiofibromas may be unilateral. A variant of angiofibromas is the fibrous plaque of the forehead which histologically resembles an angiofibroma but arises as a single, slowly growing plaque.


Fig. 16.16
Angiofibroma in TSC (Courtesy Dr Frank Judisch collection U of Iowa)

Another cutaneous manifestation of TSC is a connective tissue nevus or shagreen patch. These occur in about half of TS patients and typically present around 2 years of life. The shagreen patch most often manifests as an uneven firm skin-colored, pink, or brown plaque with depressions at follicular orifices resulting in an appearance likened to that of pig skin or an orange peel (peau de’ orange). Shagreen patches are commonly in the lumbosacral area.

The final cutaneous finding that is a major criterion for TS diagnosis is periungual fibromas or Koenen tumors (Fig. 16.17). Periungual fibromas in association with TSC were first described by Richard Kothe in 1903; however, it was not until Koenen published a paper on a family of TSC patients with pictures of periungual fibromas that this finding was definitively linked with TSC [247]. These are skin-colored, firm papules found on the skin around the nails. Periungual fibromas are more commonly found on toes than fingers and on occasion can present at a linear distortion of the nail plate without visible tumor. Periungual fibromas are found in 15 % of TSC patients and develop later than other cutaneous manifestations, with onset in late childhood and extending throughout adulthood [248]


Fig. 16.17
Periungual fibromas

Multiple randomly distributed dental enamel pits and gingival fibromas are also common in TSC patients and are both minor criteria for TSC diagnosis [249]

Several other cutaneous lesions have been associated with TS but are not part of the diagnostic criteria. These include poliosis (a circumscribed patch of depigmented hair), soft fibromas in flexural areas, cafe-au-lait spots (tan patches of skin, and port-wine stains (capillary malformations).

Neurologic manifestations of TSC include frequent epilepsy and intellectual disability. The most common anatomic findings, which are all considered major diagnostic criteria, include areas of cortical dysplasia (i.e. tubers), subependymal nodules, and subependymal giant cell astrocytomas (SEGA).

Epilepsy occurs in ~85 % of individuals with TSC, although periods of remission are possible [250]. A broad range of seizure types may be seen, with an elevated risk for development of infantile spasms.

Intellectual disability occurs in 50–60 % of individuals with TSC. Other neurodevelopmental disabilities are also more frequently seen, including specific impairment of attention, executive function, other learning disabilities, and/or behavior problems. Autism spectrum disorders have been reported in ~40 %. The presence of bilateral tubers and seizure onset < 6 months are risk factors for intellectual disability [251] as is the development of infantile spasms [252].

The cortical/subcortical tubers are T2-hyperintense lesions on brain MRI, often multifocal in distribution. They are present in >70 % of patients with TSC. Pathologically, these reflect areas of disrupted cortical architecture with a mixture of dysplastic neurons and astroglial cells, disoriented pyramidal cells, and reactive astrocytes [253]. Functionally, there is abnormal expression of excitatory glutatmate receptors [254]. This combination of abnormal architectural and physiologic features predisposes the risk for seizures, although some tubers remain physiologically quiescent. The disrupted connectivity (cortico-cortical and cortico-subcortical networks) may also underlie neurodevelopmental disabilities, which correlate with increased tuber burden. Tubers with cystic qualities are more likely to be associated with TSC2 mutations, the development of infantile spasms, and refractory epilepsy [255]

Subependymal nodules are benign hamartomatous growths of the lateral and third ventricle wall. These were first associated with TSC in two separate reports published in 1881 by Bourneville and Hartdegen [256]. It is now known that these are present in 90 % of TSC patients and are detectable prenatally via ultrasound or MRI [257, 258]. Nodules can transform to subependymal giant cell astrocytmas (5–20 %), which are slow-growing tumors most commonly detected in childhood or adolescence. SEGAs occur predominantly near the foramen of Monro, and mass effect can cause obstructive hydrocephalus as the primary complication [259]. Progressive calcification of the tubers or subependymal nodules over time is often incidentally noted.

The heart, lungs, and kidneys can also be affected in TSC. Cardiac rhabdomyomas are a major criterion for diagnosis and can be seen prenatally or after birth by echocardiography or MRI. They are often largest in the neonatal period. When detected they confer at least an 80 % risk of having TSC [260, 261]. Fortunately, cardiac rhabdomyomas do not often have major functional ramifications and they have the propensity to involute in the first years of life. Rarely, they can be associated with outflow obstruction and congestive heart failure in the neonatal period and the incidence of cardiac arrhythmias including Wolff-Parkinson-White syndrome is significantly higher in TSC patients [262]. Lymphangioleiomyomytosis (LAM) is the major criterion for TS diagnosis associated with pulmonary manifestations. LAM is an infiltration of all lung structures with benign appearing smooth muscle cells resulting in cystic changes in lung parenchyma, subsequent pneumothoraces, and symptoms of progressive dyspnea [263]. This condition occurs in about 30 % of TSC patients, at a five to ten fold higher incidence than sporadic LAM [264266].

Angiomyolipomas and multiple renal cysts are the major and minor criterion, respectively, for TSC involving the kidneys. Angiomyolipomas, as their name implies, are benign tumors composed of vascular, smooth muscle, and adipose tissue. They are often asymptomatic and can occur in organs other than the kidney. Interestingly, TSC patients can have multiple renal cysts due to a contiguous gene deletion syndrome resulting from loss of both TSC2 and polycystic kidney disease 1 (PKD1) genes as they are immediately adjacent on chromosome 16 [267]. More commonly, however, cysts occur as single or multiple small asymptomatic lesions. Over time, these benign lesions can grow enough to cause life-threatening bleeding and can replace enough normal renal parenchyma to cause end-stage renal disease. Malignant angiomyolipoma and renal cell carcinoma are also possible. Overall, renal disease is the second leading cause of early death in TSC patients.

Ophthalmic Features

The ophthalmic manifestations of TSC may be divided into retinal and non-retinal findings (Table 16.7). Retinal lesions are the most frequent findings. Four different retinal lesions have been described: a flat, grey, non-calcified translucent hamartoma, a raised multnodular (mulberry) calcified hamartoma, an “in between” transitional retinal hamartoma with features of the first two hamartoma types and a punched out or depigmented achromic patch (non-astrocytic hamartoma) typically noted in the midperiphery [268271]. Hyperpigmented areas thought to be congenital retinal pigment epithelium hypertrophy may also be present [272]

Table 16.7
Ocular manifestations of tuberous sclerosis



– Proptosis

– Fibrous dysplasia of orbit


– Adenoma sebaceum (angiofibroma)

– Poliosis (hypopigmented lashes)

– Nevus flammeus



– Small pediculate whitish-gray tumors on palpebral conjunctiva

– Subconjunctival nodules

Anterior Segment

– Corneal opacities with subepithelial haze

– Lens opacities

– Depigmented sectors of iris

– Hypopigmented iris spots

– Coloboma of iris

– Megalocornea

– Posterior embryotoxon


– Vitreous cloudy

– Vitreous hemorrhage (from hamartoma)


– Diffuse angiomatosis

– Angioid streaks (single finding)

– Coloboma of choroid

– Punched-out chorioretinal defects


– Retinal mushroom-like tumor of grayish-white color

– Yellow-white plaques with small hemorrhages and cystic changes

– Neurofibrilloma

– Neurocystoma

– Retinal glioneuroma

– Glial hamartoma

– Pigmentary changes

– “Ash-leaf” patches

– Atypical retinitis proliferans

– Retinal telangiectasis

– Retinal angioma

– Exophytic retinal astrocytoma

Optic Nerve

– Optic atrophy

– Papilledema

– Pseudopapilledema

– Disc drusen

– Glial hamartoma anterior to the lamina cribosa (giant drusen)





Phthisis bulbi

Progressive external ophthalmoplegia

Astrocytic hamartomas of the retina are the most common finding being present in 30–50 % of patients and it is common to find multiple lesions in the same patient [268, 270, 273, 274]. Flat non calcified glial hamartomas of the retina have a smooth, spongy appearance with fuzzy borders. They are gray-white and may be mistaken for retinoblastoma. In the absence of other systemic evidence of TSC, observation over time may be necessary to rule out this malignancy [5]

The raised hamartomas appear condensed and have an irregular surface (Figs. 16.18 and 16.19). These lesions are white and resemble a mulberry. The lesions are frequently multiple and vary in size from 0.25 to 4.0 disc diameters [268, 274]. Retinal hamartomas vary in number from one to a dozen or more in the two eyes and can occur anywhere in the fundus, although there seems to be a predilection for the posterior pole, along the arcades and adjacent to the optic nerve [5, 274].


Fig. 16.18
Astrocytic hamartoma (Courtesy Dr Frank Judisch collection U of Iowa)


Fig. 16.19
Astrocytic hamartoma (Courtesy Dr Frank Judisch collection U of Iowa)

These lesions are not related to the surrounding vasculature and cause little reaction in the adjacent retina. If there is growth, it is extremely slow and the general impression is that these lesions are congenital or present very soon after birth and are stable over time [8, 268, 275].

In general, although the earlier conception that flat hamartomas develop into multi-nodular hamartomas over time is incorrect, there are reports of astrocytic hamartoma transformation with more aggressive growth causing exudative retinal detachment and neovascular glaucoma [268, 276, 277]. Vitreous seeding rarely occurs with retinal hamartomas, but can result in overlying vitreous inflammation and hemorrhage [278, 279].

The astrocytic hamartomas in TSC differ from those found in neurofibromatosis type I in that the TSC hamartomas are intraocular and do not involve the orbit, the optic nerve or produce increased glaucoma risk [5].

The actual prevalence of retinal hamartoma in the general population is not known, but suspected to be very low. The rarity of this lesion in non-TSC patients was demonstrated by a study which performed perinatal ocular examinations on 3573 healthy full-term newborns with only two astrocytic hamartomas noted in this population [280]. Diagnostically, the presence of two retinal hamartomas is necessary to meet the major diagnostic criterion.

Retinal hamartomas have similar histologic features to the tubers located in the brains of TSC patients [268, 274]. Histologically, the retinal hamartomas are composed of large, fusiform astrocytes separated by a coarse and nonfibrillated, or finer and fibrillated, matrix formed from the astrocytic cell processes. The retinal tumors are generally sparsely vascularized or nonvascularized [9]. Microscopically, these are astrocytic hamartomas of the nerve fiber layer, and fluorescein angiographic studies have demonstrated associated abnormal vessels [7, 281].

Retinal achromic patches have been determined a minor diagnostic feature [242]. Retinal achromic patches are basically areas of hypopigmentation on the retina. These patches have been noted to occur in 39 % of TSC patients [268, 282]. Incidence in the general population is estimated at 1 in 20,000 [245].

The non-retinal ocular findings of TSC represent a collection of diverse physical features. Sectorial hypopigmentation of the iris [268, 283] as well as more subtle hypopigmented iris spots have been reported [271, 284]. Lens colobomas [268] megalocomea [285] posterior embryotoxon [286], poliosis, with hypopigmented lashes set amongst normally pigmented lashes [287] strabismus [268, 272] and isolated cases of progressive external ophthalmoplegia may occur [288].

Cutaneous angiofibromata may develop with the, formation of small salmon-colored nodules in the lid and under the conjunctiva (39 %) [268, 287, 289291]. Retinitis pigmentosa has been associated with optic disc hamartoma, however, it is uncertain whether these patients had TSC or isolated hamartoma [292294].

In general, the ocular lesions found in TSC do not interfere with vision development or function.

The unfortunate development of a large hamartoma of the central macula would be an exception with the potential for significant vision loss [5]. Vision loss in TSC patients is more likely to result from disruption of the visual pathway. Intracranial tumors (tubers) can damage the optic nerves, chiasm or visual pathways from direct compression [5]. Additionally, posterior fossa tumor involvement can produce hydrocephalus and increased intracranial pressure leading to papilledema and optic atrophy [5, 270, 295].


The updated genetic and diagnostic clinical features are listed in Table 16.6 [242, 246].

The current consensus is that “identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue” or presence of two major or one major and two or more minor feature indicates a definite TSC diagnosis. One major feature or two or more minor features is a possible TSC diagnosis. Since TSC has great variability of disease expressivity, patients with neurologic (epilepsy) or neurodevelopmental conditions (learning disorders and developmental delay) without specific etiology should be considered for investigation [296]. Evaluation of first-degree relatives, parents and siblings of TSC patients requires participation by multiple specialties including pediatrics, dermatology, ophthalmology, and radiology [297].


The 2012 International Tuberous Sclerosis Complex Consensus Conference published updated guidelines for screening and management and a summary of their recommendations by the Tuberous Sclerosis Alliance appears in Table 16.8www.​tsalliance.​org [297].

Table 16.8
Pediatric surveillance and management of tuberous sclerosis syndrome [242]

Newly diagnosed or suspected

Diagnosed definite or suspected tuberous sclerosis


+ testing/counseling

+ testing/counseling





MRI abdomen, renal fxn

MRI abdomen, renal fxn


Baseline pulmonary fxn

Specific testing per findings


Dermatology evaluation

dermatology evaluation


baseline dental exam

dental evaluation every 6 months


EKG baseline

EKG every 1–3 years


Complete examination for baseline

Yearly examination

Neurologic treatment of seizures remains largely symptomatic and a broad array of anti-seizure medications may be used; however, there is a specific indication for the use of vigabatrin in the treatment of infantile spasms due to tuberous sclerosis. Using vigabatrin in TS yields spasms remission rates as high as 95 %, which is significantly higher than remission rates seen with standard steroidal treatments or for spasms due to other etiologies [298]. For cases of medically refractory epilepsy, surgical resection of a tuber has been successfully pursued in cases where the seizure burden is primarily attributable to a single focus .

Everolimus , an mTor inhibitor, is a non-surgical option for decreasing the volume of SEGAs, thereby reducing the likelihood of obstructive hydrocephalus. The majority of patients have a >30 % volume reduction that appears sustainable for up to 3 years (longer follow-up not available) [299]. MTor inhibitors are also clinically used for treatment of renal angiomyolipomas, lymphangioleiomyomatosis, and facial angiofibromas. Discontinuation of therapy can result in regrowth of tumors and other lesions. There are small case series supporting a potential decrease in seizure burden while taking everolimus [300]; further investigation via randomized controlled trial is ongoing.

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Jul 20, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Phakomatoses-Neurocutaneous Syndromes

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