Inherited Disorders With Neuro-Ophthalmic Signs

Myopathies

The extraocular muscles are affected by several inherited conditions that result in mitochondrial dysfunction.

Chronic progressive external ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is an inherited mitochondrial myopathy characterized by slowly progressive, symmetric ophthalmoplegia with or without ptosis (Fig 14-4). The majority of patients with CPEO have a mitochondrial DNA (mtDNA) point deletion, but nuclear DNA mutations that drive mtDNA mutation can also cause CPEO. Thus, the mode of inheritance can be mitochondrial (maternal), autosomal, or sporadic, and the disorder may not be transmissible to the next generation. Patients often initially present with ptosis and, because the ophthalmoplegia is usually symmetric, do not generally complain of diplopia. However, the majority of patients have difficulty with visual impairment and reading. At presentation, myasthenia gravis may be considered in the differential diagnosis but, in contrast to patients with CPEO, MG patients typically have variable signs and symptoms. Clinical findings are usually evident by the second decade of life. Systemic symptoms may include generalized muscle weakness. Genetic testing is available for detection of abnormalities in the mtDNA. Histologic examination of muscle biopsy specimens shows the characteristic “ragged red fibers” (Fig 14-5) and mitochondrial proliferation, and electron microscopic studies show inclusion body abnormalities of the affected mitochondria.

Figure 14-4 A 42-year-old with a 2-year history of progressive ptosis and ophthalmoplegia. Biopsy of the deltoid muscle showed ragged red fibers consistent with CPEO. (Courtesy of Steven A. Newman, MD.)

Figure 14-5 Histologic examination of a muscle biopsy specimen from a patient with Kearns-Sayre syndrome shows ragged red fibers (arrows). Specimen stained with modified Gomori trichrome stain. (Courtesy of Eric Eggenb erger, DO.)

The Kearns-Sayre syndrome is also an inherited mitochondrial myopathy. It includes CPEO, pigmentary retinopathy, and cardiac conduction abnormalities, and it variably includes cerebellar ataxia, deafness, and elevated CSF protein levels. Cardiac evaluation is essential to rule out conduction defects.

Yu Wai Man CY, Smith T, Chinnery PF, Turnbull DM, Griffiths PG. Assessment of visual function in chronic progressive external ophthalmoplegia. Eye (Lond). 2006;20(5):564–568.

Oculopharyngeal dystrophy

Oculopharyngeal dystrophy is a hereditary condition, usually autosomal dominant, with onset in the fifth and sixth decades of life. The typical presentation is progressive dysphagia followed by proximal muscle weakness and ptosis. Most patients have an external ophthalmoplegia that, when asymmetric, may be accompanied by diplopia. Pathologic studies show a vacuolar myopathy. The disease is classically observed in patients of French-Canadian ancestry. The only causative mutation described to date is a triplet repeat expansion consisting of 2–7 additional base triplets in a repeat

sequence in exon 1 of the polyadenine binding protein, nuclear 1 (PABPN1) gene.

Myotonic dystrophy

Myotonic dystrophy, a dominantly inherited multisystem disorder, also produces ophthalmoplegia that may mimic CPEO. Two types have been identified: type 1, due to mutation on chromosome 19, and type 2, due to mutation on chromosome 3. Blood test results for these mutations can confirm the diagnosis. Symptoms usually start in late childhood or early adulthood with myotonia that is exacerbated by excitement, cold, and fatigue. The myotonia is easily detected by asking the patient to shake hands; the patient will not be able to quickly release his or her grasp. This myopathy is unusual in that it affects distal limb musculature first. Wasting of the temporalis and masseter muscles produces the typical “hatchet face.” The myopathic facies, frontal balding, and ptosis cause a distinct and remarkably characteristic appearance.

Ocular findings include ptosis, pigmentary retinopathy, ophthalmoparesis, and polychromatic lenticular deposits (“Christmas tree” cataracts). The pupils are miotic and respond sluggishly to light. Other features include low intelligence, insulin resistance, hearing loss, cardiomyopathy, cardiac conduction abnormalities, testicular atrophy, and uterine atony. Electromyographic studies provide the definite diagnosis by demonstrating the typical myotonic discharges.

Neurocutaneous Syndromes

Neurocutaneous syndromes, or phakomatoses, are disorders characterized by the presence of hamartomas involving different organ systems, such as the skin, eyes, CNS, and viscera. Six entities are classically grouped under this category:

1.neurofibromatosis (NF)

2.tuberous sclerosis (Bourneville syndrome)

3.cerebrofacial angiomatosis (Sturge-Weber syndrome)

4.retinal angiomatosis (von Hippel disease)

5.ataxia-telangiectasia (Louis-Bar syndrome)

6.Wyburn-Mason syndrome

Klippel-Trénaunay-Weber syndrome is included by some authors. A syndrome of cavernous hemangioma of the retina associated with CNS angiomas (von Hippel–Lindau) is yet another variant of the phakomatoses. The phakomatoses are discussed at length in BCSC Section 6, Pediatric Ophthalmology and Strabismus. In this chapter, we emphasize the neuro-ophthalmic features of these conditions.

These disorders are characterized by tumors formed from normal tissue elements: hamartomas and choristomas. A hamartoma is composed of elements normally found at the involved site; hamartomas are not true neoplasms, as they are anomalies of tissue formation that lack the capability for limitless proliferation. The glial retinal tumors of tuberous sclerosis are a type of hamartoma. Choristomas are tumorlike growths composed of tissue not normally present at the site of growth. All phakomatous lesions are hamartomas or choristomas.

Neurofibromatosis

The 2 most common forms of NF are von Recklinghausen neurofibromatosis (NF1) and bilateral

acoustic neurofibromatosis (NF2). NF1 is the more common form of the disease. It is inherited in an autosomal dominant manner and has been linked to chromosome 17. General features include multiple neurofibromas, pigmented skin lesions, osseous malformations, and associated tumors. The disease is defined by the presence of multiple cutaneous pigmented macules (café-au-lait spots), neurofibromas, and iris (Lisch) nodules (Fig 14-6). Mild cases may show only iris nodules associated with café-au- lait spots.

Figure 14-6 The most common ocular finding in neurofibromatosis type 1 (NF1) is the presence of iris (Lisch) nodules. These are often light-colored in a patient with dark irides (A) but may be relatively darker in patients with light irides (B). The diagnosis is often suggested by cutaneous findings, including café-au-lait spots (C) or skin neurofibromas (D). (Part A

courtesy of Mark J. Greenwald, MD; parts B–D courtesy of Steven A. Newman, MD.)

Neurofibromas are histologically benign and may take the form of either fibroma molluscum or plexiform neurofibromas. They may involve the eyelid and face, occasionally causing marked deformities (see Chapter 11, Fig 11-1). Lisch nodules are pigmented iris hamartomas present in 94%– 97% of patients with NF1 who are over the age of 6 years. These nodules do not become symptomatic, but their presence may prove helpful in establishing the diagnosis, especially when discovered in asymptomatic relatives.

Other ocular involvement in NF includes congenital glaucoma and retinal astrocytomas. Osseous defects may involve the orbit, commonly the greater wing of the sphenoid, with associated orbital encephalocele. Vertebral and long-bone defects are observed as well. Multiple tumors of the brain, spinal cord, and meninges, as well as of the cranial, peripheral, and sympathetic nerves, may be encountered in these patients. Optic nerve or chiasmal gliomas in children are frequently associated

with NF. These lesions cause proptosis and vision loss but are rarely life threatening. Treatment for these lesions is controversial. Additional neoplastic associations include pheochromocytoma and meningioma. See Chapter 4 for a discussion of gliomas and meningiomas of the optic nerve.

NF2 is less common than NF1. Also transmitted as an autosomal dominant trait, NF2 is linked to chromosome 22. Only about 60% of patients with NF2 have café-au-lait spots or peripheral neurofibromas, and Lisch nodules are not a feature of this disease. Bilateral acoustic neuromas usually present symptomatically in young adulthood. Other CNS tumors may occur but not as frequently as in NF1. Other ocular findings may include combined retinal–retinal pigment epithelial hamartomas and posterior subcapsular cataracts.

Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty-first century perspective. Lancet Neurol. 2007;6(4):340– 351.

Savar A, Cestari DM. Neurofibromatosis type 1: genetics and clinical manifestations. Semin Ophthalmol. 2008;23(1):45–51.

Tuberous sclerosis

Also known as Bourneville syndrome, tuberous sclerosis is transmitted as an autosomal dominant trait. There are 2 tuberous sclerosis genes: 1 at chromosome 9q34 (TSC1), and the other at 16p13.3 (TSC2). The gene products tuberin (TSC1) and hamartin (TSC2) form a heterodimer that inhibits cell growth and proliferation. The exact mechanism by which mutations in these genes result in tuberous sclerosis is unclear. The disorder has classically been characterized by the triad of adenoma sebaceum, cognitive deficiency, and epilepsy, although presentation shows great variability. Most patients have seizures, but many have normal mentation. The so-called sebaceous adenomas are actually hamartomatous angiofibromas that commonly appear in a butterfly distribution over the nose and cheeks (Fig 14-7). Other skin lesions include periungual fibromas, café-au-lait spots, and shagreen patches (large, leatherlike, hyperpigmented, raised patches that are typically located on the trunk). The ash-leaf spot, a leaf-shaped area of skin depigmentation that fluoresces under a Wood lamp, is considered pathognomonic for tuberous sclerosis.

Figure 14-7 A, Hamartomatous angiofibromas (previously called adenoma sebaceum) are a hallmark of tuberous sclerosis and involve the cheek, particularly in the area of the nasolabial fold. Other classic skin findings include the presence of an ash-leaf spot (B), best observed with ultraviolet light, and subungual lesions (C). D, Ophthalmic findings include the presence of astrocytic hamartomas on funduscopic examination. E, Intracranial hamartomas often line the subependymal surface. They frequently calcify, becoming obvious on CT scan. (Parts A, B courtesy of Mark J. Greenwald, MD;

parts C, E courtesy of Steven A. Newman, MD; part D reprinted from Kline LB, Foroozan R, eds. Optic Nerve Disorders. 2nd ed. Ophthalmology Monograph 10. New York: Oxford University Press, in cooperation with the American Academy of Ophthalmology; 2007:164.)

Calcified astrocytic hamartomas (brain stones) are frequently evident on plain skull x-ray and CT scan. Other visceral involvement that has been described includes cardiac rhabdomyomas, renal cysts, and angiomyolipomas. The characteristic ocular finding is an astrocytic hamartoma of the retina or optic disc.

Cerebrofacial (encephalotrigeminal) angiomatosis

The inheritance pattern of cerebrofacial angiomatosis, or Sturge-Weber syndrome, is sporadic. The characteristic skin lesion in Sturge-Weber syndrome is nevus flammeus (portwine stain), an angioma involving skin and subcutaneous tissues that usually follows the distribution of CN V (the trigeminal nerve) (Fig 14-8). This lesion is present from birth, usually unilateral, and commonly associated with a parieto-occipital leptomeningeal hemangioma ipsilateral to the facial vascular hamartoma. Calcification of the cortex underlying the hemangioma can be observed radiographically. A CT scan is best for showing the calcification, but MRI scans will demonstrate leptomeningeal enhancement typical of this condition. Seizures are a major problem for these patients.

Figure 14-8 Sturge-Weber syndrome. A, This 1-year-old exhibits a port-wine stain involving the V1 and V2 distributions on the right side, a classic finding in Sturge-Weber syndrome. These patients often have congenital glaucoma. B, In an infant with congenital glaucoma, the globe may enlarge significantly (buphthalmos). C, MRI scan showing cortical vascular malformations following the gyral pattern (arrow), which may also be present. Diffuse choroidal hemangiomas may also occur, causing increased hyperemia and redness of the choroid. D, Fundus photograph showing choroidal hemangioma

and E, the contralateral normal eye. (Parts A, B courtesy of Steven A. Newman, MD; part C courtesy of Mark J. Greenwald, MD; parts D, E courtesy of James J. Augsb urger, MD.)

Unilateral congenital open-angle glaucoma is observed in 30%–70% of patients with SturgeWeber syndrome and is usually associated with an angioma of the upper eyelid. Onset of glaucoma may occur at any time; tonometry should be performed early and repeated periodically. Heterochromia iridis has been described. The characteristic fundus lesion is a choroidal hemangioma, a solitary, yellow-orange, moderately elevated mass located in the posterior pole of up to 50% of these patients (see Fig 14-8). More diffuse uveal involvement can give the fundus a confluent “tomato ketchup” appearance. Exudative retinal detachments may occur in association with these lesions.

Klippel-Trénaunay-Weber syndrome may be a variant of cerebrofacial angiomatosis. Nonocular findings include cutaneous nevus flammeus and hemangiomas, varicosities, associated hemihypertrophy of the limbs, and intracranial angiomas. The cutaneous lesions and vascular anomalies are sometimes amenable to laser treatment. Ocular involvement, usually congenital glaucoma and conjunctival telangiectasia, is uncommon.

Retinal angiomatosis

Also known as von Hippel disease, retinal angiomatosis is transmitted by autosomal dominant inheritance. The disease may also occur sporadically. The characteristic ocular lesion is a retinal capillary angioma: a globular, smooth-surfaced, pink retinal tumor fed by a single dilated, tortuous retinal artery and drained by a similar-appearing vein (Fig 14-9). These lesions are often multiple and are bilateral in 50% of cases. Serous exudation can cause retinal detachment.

Figure 14-9 Fundus photograph of a patient with von Hippel syndrome, showing a characteristic angioma of the retina.

(Courtesy of Steven A. Newman, MD.)

Cerebellar hemangioblastomas are present in approximately 25% of patients with retinal angiomatosis, and this association is known as von Hippel–Lindau disease. Hemangioblastomas may also occur in the brainstem or spinal cord and may be associated with syrinxes in these regions.

Patients with cerebellar angiomas may also have renal, pancreatic, hepatic, or epididymal cysts and pheochromocytomas or renal cell carcinoma. Several of these multisystem manifestations are potentially lethal. Early detection of the retinal abnormality by the ophthalmologist should prompt referral of the patient for a thorough systemic investigation.

Ataxia-telangiectasia

Ataxia-telangiectasia, or Louis-Bar syndrome, is considered the most common cause of progressive ataxia in early childhood. It is characterized by progressive cerebellar ataxia and oculocutaneous telangiectasia. Thymic hypoplasia, with defective T-cell function and immunoglobulin deficiency, predisposes patients to recurrent sinopulmonary infections. The genetic abnormality is localized to chromosome 11, and the inheritance pattern is generally autosomal recessive. This genetic defect results in inactivation of a critical protein kinase that regulates the response to DNA double-strand breaks. Clinical manifestations of ataxia-telangiectasia occur because of this resultant defective DNA damage signaling. Conjunctival telangiectasia is almost always observed, especially as the child ages

(Fig 14-10). Ocular motility deficits are the classic eye findings—specifically, horizontal and vertical supranuclear gaze palsies. At first, the patient shows an inability to initiate saccades, which may be associated with head thrusting and abnormalities of the fast phase of optokinetic nystagmus. Pursuit becomes impaired, and eventually the disease leads to total ophthalmoplegia. However, oculocephalic responses remain intact. Patients who do not succumb to recurrent infections have a high incidence of malignancy.

Figure 14-10 Photograph of the left eye of a child with ataxia-telangiectasia, showing abnormally dilated and tortuous

conjunctival vessels. (Courtesy of Mark J. Greenwald, MD.)

Wyburn-Mason syndrome

Wyburn-Mason syndrome refers to the association of an intracranial arteriovenous malformation (AVM) with an AVM of the ipsilateral retina (racemose angioma) (Fig 14-11). The inheritance pattern is sporadic. The AVM consists of direct communications between the arteries and the veins without an intervening capillary bed. The vessels are usually fully developed and may involve any part of the posterior pole. They are usually increased in number, size, and tortuosity. Spontaneous hemorrhage from these lesions may cause decreased vision. Because of the association between retinal and intracranial AVMs, an MRI scan of the brain should be obtained for patients with a retinal AVM. Associated AVMs may be observed in the midbrain, basofrontal region, or posterior fossa, and they may be associated with spontaneous intracranial hemorrhage or convulsions. AVMs can also involve the maxilla, pterygoid fossa, or mandible. Orbital AVMs may be associated with mild