RETINAL DISEASE

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CHAPTER 24 RETINAL DISEASE

The retina reflects many of the pathophysiological processes that occur in the central nervous system (CNS). Indeed the retinal appearances may be diagnostic but, conversely, can be nonspecific; for example, pigmentary retinal changes are part of the diagnostic criteria for Kearns-Sayre syndrome but are also present in many other diseases. Furthermore, in other diseases, the retina may appear clinically normal, but psychophysical and electrophysiological testing reveal abnormalities.

In this chapter, both neurological diseases with retinal involvement that patients would tend to present with to a neurologist, as well as diseases that patients would tend to present with to an ophthalmologist but that have neurological involvement, are discussed. Disorders of the choroid that might be apparent on funduscopy are also discussed.

The following is a brief description of the embryology, anatomy, and physiology of the retina, highlighting its similarities to the CNS. There is also an explanation of some of the ophthalmological terms that are used in this chapter.

The eyeball consists of three layers, which, starting from the outside, are a fibrous layer, a vascular pigmented layer, and a nervous layer. The fibrous layer consists of the sclera, which makes up the posterior five sixths of the eyeball and is opaque, and the cornea, which forms the anterior one sixth and is transparent. The vascular pigmented layer is also known as the uveal tract and consists of the choroid, which is a very vascular layer; the ciliary body; and the iris. The retina constitutes the nervous layer. The cavity behind the cornea and in front of the iris is the anterior chamber, and it is filled with aqueous humor. The vitreous humor fills the eyeball behind the lens.

Embryologically, the ectoderm that is derived from the neural tube gives rise to the retina, the fibers of the optic nerve, and the smooth muscle of the iris. The choroid is derived from mesenchyme and is homologous in its embryonic origin with the pia mater and arachnoid tissue.

The photoreceptors, consisting of rod and cone cells, are located near the outer surface of the retina. In the process of phototransduction, light energy is absorbed by specialized visual pigments within the outer segments of the photoreceptors, which results in hyperpolarization and the generation of an electrical signal. After photoreception, the signal is conducted to the bipolar cells in the inner nuclear layer, which in turn transmit their signals to the ganglion cells. The axons of the ganglion cells are collected on the inner surface of the retina and form the optic nerve. There are many interneuronal connections and a variety of neurotransmitters and neuromodulators such as acetylcholine, γ-amino butyric acid (GABA), glutamate, and dopamine, which are involved in the signal processing.

At the extreme outer layer of the retina is the retinal pigment epithelium, which is in contact with the outer segments of the photoreceptors. This layer is in contact with Bruch’s membrane, which is the inner layer of the choroid. The choroid provides the blood supply for the outer layers of the retina, including the photoreceptors, whereas the inner layers are supplied by branches of the central retinal artery.

The macula lutea is a yellowish, oval area located at the center of the posterior part of the retina. It has a central depression, the fovea centralis.

Uveitis, inflammation of the uveal tract, can occur in association with neurological disease. In this chapter, the classification recommended by the Standardization of Uveitis Nomenclature Working Group is used.¹ In this classification, the primary site of inflammation in anterior uveitis is the anterior chamber. For intermediate uveitis, it is the vitreous humor. The primary site of inflammation in posterior uveitis can be the retina or choroid. Panuveitis is used when there is no predominant site of inflammation, but inflammation occurs in the anterior chamber, vitreous humor, and retina and/or choroid.

UVEOMENINGEAL SYNDROMES

The uveomeningeal syndromes are a heterogeneous group of disorders that share involvement of the uveal tract (which comprises the iris, the ciliary body, and the choroid), retina, and meninges. Causes of this syndrome include infectious, inflammatory, and neoplastic disorders. The infectious and neoplastic causes are discussed elsewhere; in this section, syndromes caused by inflammatory disease are discussed.

Sarcoidosis

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can affect the eye and the CNS, as well as the lungs, skin, and other organs. Of all patients with sarcoidosis, 25% to 60% have ocular involvement, which may be the manifesting sign. Sarcoidosis can affect most ocular tissues, but the most common ocular manifestations are uveitis and conjunctival nodules. Uveitis can occur in about 30% of patients before nonocular signs.²

A 10-year follow-up study of patients with uveitis caused by sarcoidosis or presumed sarcoidosis revealed that over this period, the disease spread most often to the CNS.³ Posterior segment involvement is frequently associated with neurological disease.^4,⁵ It may be more common in white patients, especially elderly women,² although this has not been confirmed by all studies.⁶ The optic nerve may become swollen because of intraocular inflammation, when visual acuity is usually preserved, or it may be involved either directly by granulomas or as a result of meningeal changes, when loss of visual acuity and field result from compressive optic neuropathy.

The classic sign of retinal involvement by sarcoidosis is retinal periphlebitis (Fig. 24-1),⁷^–⁹ which may be described as similar to candle wax dripping. Other vascular changes include retinal hemorrhages, vein occlusions, neovascularization, and possibly retinal arteriolitis with aneurysm or ectasia formation.¹⁰ Focal subretinal lesions have been described, but these do not appear to affect vision.⁹ Confluent choroidal infiltrates have been described.¹¹ Appearances similar to that of a multifocal choroiditis (Fig. 24-2),^12,¹³ and a serpiginous choroidopathy have been described.¹⁴ Multiple sclerosis may include a similar ocular inflammatory manifestation, but the choroid is not involved.

Figure 24-1 Retinal periphlebitis.

Figure 24-2 Choroidal lesions in sarcoidosis.

Behçet’s Disease

Behçet’s disease is characterized by recurrent episodes of orogenital aphthae and by systemic and retinal venous thrombosis. It remains a clinical diagnosis, and diagnostic criteria have been published.¹⁵ The CNS manifestations of Behçet’s disease can be categorized into parenchymal and nonparenchymal involvement (neurovascular Behçet’s disease). Parenchymal CNS manifestations include brainstem and hemisphere involvement, spinal cord lesions, and meningoencephalitis. Nonparenchymal involvement includes dural sinus thrombosis, arterial occlusion, and arterial aneurysms. These categories have different clinical and prognostic properties.¹⁶ The ocular manifestations in the parenchymal category include optic neuritis and ischemic optic neuropathy.¹⁷^–¹⁹ Papilledema caused by intracranial hypertension secondary to dural sinus thrombosis occurs in neurovascular Behçet’s disease^20,²¹ and can result in significant visual loss. Intracranial hypertension can, however, occur in the absence of venous sinus thrombosis or meningitis.¹⁸

Inflammatory eye disease occurs in approximately 70% of all patients who may have additional neurological or neuro-ophthalmological disease. The inflammation usually occurs after the onset of oral aphthosis, but the delay between the two may be as long as 14 years.²² In approximately 10% of patients, intraocular inflammation is the manifesting feature,²³ and in rare cases, neither oral nor genital ulcers may occur at all.²⁴ Usually the involvement is bilateral.

The main ocular finding is panuveitis, although there may be differing degrees of anterior and posterior segment involvement. The anterior uveitis may be so severe that the inflammatory cells precipitate in the inferior portion of the anterior chamber, forming a hypopyon. Retinal vein occlusion is the most characteristic fundal sign, but others include retinal perivasculitis and retinal infiltrates. The perivasculitis involves mainly the veins and less frequently the arteries. The retinal infiltrates are collections of lymphocytes in the superficial retina and are pathognomonic of Behçet’s disease (Fig. 24-3). They resolve spontaneously and carry no visual morbidity. However, recurrent retinal vein occlusions can result in total attenuation of all vessels and consequent optic atrophy. Macular edema may also cause visual loss. Unfortunately, the visual prognosis is poor in spite of the development of new immunosuppressive therapies. Up to 15% of patients are unresponsive to these therapies,²⁵ and the disease may remain active for many years.

Figure 24-3 A peripapillary retinal infiltrate and a vein occlusion superior to the optic disc.

Vogt-Koyanagi-Harada Disease

Vogt-Koyanagi-Harada (VKH) disease is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin of unknown etiology. VKH disease usually affects darkly pigmented Asian, American Indian, Hispanic, or African-American adults.

Like Behçet’s disease, it is diagnosed on clinical findings. Diagnosis can be difficult because there are no specific tests and the clinical features are dependent on the stage of the disease at which the patient is examined. Diagnostic criteria have been published.²⁶ One of the following neurological features has to be present for the diagnosis of VKH: meningismus, tinnitus or cerebrospinal pleocytosis. The ocular features have been divided into early and late manifestations of the disease. In the early manifestation, the retinal and choroidal features are mainly in the form of serous retinal detachments. In the late manifestations, choroidal depigmentation that results in a mottled “sunset glow” appearance, nummular chorioretinal depigmented scars, and retinal pigment epithelium clumping and/or migration²⁶ may be present (Fig. 24-4). Recurrent or chronic uveitis also occurs in the late stage of VKH. The criteria include the presence of bilateral ocular involvement. The integumentary findings are alopecia, poliosis, or vitiligo. A further neurological association with VKH is Guillain-Barré syndrome. Three patients who developed VKH within 3 months of having Guillain-Barré syndrome have been reported.²⁷

Figure 24-4 Pigmentary changes in Vogt-Koyanagi-Harada disease.

RHEUMATOLOGICAL DISEASES AND THE SYSTEMIC VASCULITIDES

Rheumatoid arthritis is associated with corneal and sclera changes but not usually retinal ones. Retinal involvement is, however, a common ocular feature of systemic lupus erythematosus. Indeed, the presence of ocular features may mirror disease activity elsewhere.^28,²⁹ Retinal arteriolar occlusion may occur, and multiple cotton-wool spots may be seen (Fig. 24-5). In rare cases, venulitis develops. Choroidal involvement can also occur. A postmortem study of patients with systemic lupus erythematosus affecting the brain and eye demonstrated vasculitis in the brain and the choroidal vessels.³⁰ A number of retinal arterioles were occluded with thrombus, but there was no evidence of inflammation of the retinal vessels. Emboli from a diseased heart valve or deposition of immune complexes may have caused the occlusion.

Figure 24-5 Multiple cotton-wool spots in systemic lupus erythematosus.

A number of the vasculitides affect the retina. This, however, is not always caused primarily by the vasculitis, but it can result from other complications of the disease, such as hypertension. The diseases are discussed according to the size of vessel they affect.

Large Artery

Giant cell arteritis is a necrotizing vasculitis targeting large and medium-sized arteries and affects mainly white patients older than 50 years. Anterior ischemic neuropathy is the most common cause of visual loss in giant cell arteritis, but patients can suffer from either central retinal artery occlusions or, less commonly, branch retinal artery occlusions. Compromised blood flow to the retina may result in signs of ischemia such as cotton-wool spots and hemorrhages. Posture can also affect the ischemia in that vision may be reduced in the upright position, in relation to lying down.³¹ Poor perfusion of the choroid may result in reduced vision, which can be reversible, but permanent infarction can occur (Fig. 24-6). Treatment is aimed primarily at preventing both visual loss in the second eye and the development of stroke.

Figure 24-6 Choroidal insufficiency in giant cell arteritis.

Takayasu’s disease is another disease of the large vessels. Retinal disease is present in fewer than 50% of patients with Takayasu’s disease.³² The retinal changes include vessel dilation, tortuosity of vessels, arteriovenous anastomoses, and hemorrhages. In many patients, hypertension is probably the major cause of retinal changes; in some patients, however, the changes may result from reduced flow to the retinal circulation (i.e., a hypotensive retinopathy).³²

Medium-Sized Artery

Ocular involvement occurs in 10% to 20% of patients with polyarteritis nodosa. Retinal artery occlusion, ischemic retinopathy, exudative retinal detachment,³³ and choroidal infarcts have been described.³⁴ Kawasaki’s disease tends not to affect the retina, although one postmortem study did yield evidence of retinal ischemia.³⁵

Medium-Sized and Small Vessels

Wegener’s granulomatosis is characterized by a systemic vasculitis and necrotizing granulomatous lesions that may be found in the respiratory tract, kidney, orbit, and brain. Between 30% and 50% of patients with Wegener’s granulomatosis have neurological involvement.^36,³⁷ The patterns of neurological involvement have been described as granulomatosis invasion of the orbit, granulomas of the brain and meninges, and vasculitis of the nervous system.³⁶ The orbital involvement usually is from the extension of disease in the paranasal sinuses. Orbital involvement may be the initial sign of the disease, manifesting with orbital pain, rapidly progressing proptosis, and limited eye movements with associated granulomatosis infiltration of adjacent structures. Cranial nerves may also be involved; the optic nerve, the abducens nerve, and the facial nerve are the most commonly affected.³⁷ Retinal and choroidal involvement is rare but may manifest as retinitis, vein occlusion, or an intermediate uveitis.³⁸ Some of these changes, however, may have been secondary to hypertension or cytomegalovirus–associated retinitis. A number of patients taking cyclophosphamide for Wegener’s granulomatosis have developed cytomegalovirus-associated retinitis (Fig. 24-7).³⁹^–⁴¹ In patients with the limited form of Wegener’s granulomatosis, the neuro-opthalmological features may, again, be the earliest feature of the disease.⁴² A similar pattern of neuro-ophthalmological involvement is seen, the orbit being affected more frequently than the retina.⁴³

Figure 24-7 Cytomegalovirus-associated retinitis.

Ocular involvement in the Churg-Strauss syndrome can be in the form of either chronic orbital pseudotumor or ischemic vasculitis. The retinal manifestations of the latter group include retinal artery occlusions.⁴⁴ Cotton-wool spots in the retina have been described in a patient with microscopic polyangiitis. The patient also had a very severe uveitis that resulted in a hypopyon.⁴⁵

MULTIPLE SCLEROSIS

Manifestations of multiple sclerosis in the eye other than optic neuritis include uveitis and retinal changes, such as periphlebitis or sheathing or cuffing of the retinal veins by lymphocytes and plasma cells.⁴⁶^–⁴⁹ This may occur in isolation or as part of an intermediate uveitis. Periphlebitis may occur in up to 36% of patients with multiple sclerosis ^50,⁵¹ and is usually asymptomatic. These changes are often in the peripheral retina and so cannot be viewed through a direct ophthalmoscope trained on an undilated pupil. Indeed, the changes may be visible only on fluorescein angiography (Fig. 24-8).⁵² Focal perivenous hemorrhage can also occur. The presence of vascular changes and/or ocular inflammation in patients with optic neuritis is associated with a greater risk of developing multiple sclerosis.^52,⁵³ It has been suggested that periphlebitis is a marker for disease activity,^50,⁵⁴ but this has not been confirmed.⁵⁵ Vascular sheathing can occur in other diseases such as sarcoidosis, systemic lupus erythematosus, Wegener’s granulomatosis, and Behçet’s disease.⁵⁶ Multiple sclerosis can be differentiated from sarcoidosis inasmuch as it is not associated with choroidal lesions.

Figure 24-8 Vascular changes in multiple sclerosis seen on fluorescein angiography.

Uveitis

Studies of records of patients at multiple sclerosis clinics have revealed that 1% to 2% have uveitis, which is a higher frequency than in the general population.^57,⁵⁸ Asymptomatic uveitis has been found in a range from none⁵⁹ to 18%⁶⁰ of patients with multiple sclerosis. This range probably reflects the difference in disease activity of the patients in the studies. All types of uveitis are observed; one form of intermediate uveitis, pars planitis, is probably the most common,^57,^61,⁶² but this has not been found in all studies.⁵⁹

There does not seem to be any correlation between the type of multiple sclerosis and uveitis or between the degree of neurological disability and the type of uveitis,^57,⁵⁹ although the presence of optic atrophy may be protective against uveitis.⁶⁰

Visual Loss

In patients with multiple sclerosis and uveitis, visual loss cannot be assumed to result from optic neuritis, because the complications of uveitis such as macular edema ^63,⁶⁴ and retinal vasculitis with associated neovascularization^63,⁶⁵ can also result in visual loss. The features that suggest a diagnosis of uveitis rather than optic neuritis include photophobia, floaters, redness of the eye, and the absence of a relative afferent pupillary deficit. Nevertheless, many patients with multiple sclerosis–associated uveitis retain useful vision if it is treated appropriately.⁶²

Neuroretinitis

Neuroretinitis is a descriptive term for optic disc swelling and macular exudates (Fig. 24-9) that classically results from infective causes (discussed in the next section). One study has suggested that the presence of neuroretinitis indicated that the patient did not have demyelinating disease.⁶⁶ Thus, neuroretinitis should be differentiated from cases of optic neuritis that manifest with papillitis. However, in a retrospective review of 35 patients with neuroretinitis, 3 patients were found to have multiple sclerosis, although they also had received interferon β therapy.⁶⁷

Figure 24-9 Neuroretinitis.

INFECTIONS

A number of various infectious agents can cause both retinal and neurological disease. Some, however, usually do so only in the presence of immunosuppression, most often caused by human immunodeficiency virus (HIV) infection. This section therefore deals with infections both in immunocompetent individuals and in those with HIV infection.

Infectious Causes of Neuroretinitis

As discussed, the presence of a swollen disc and macular exudates in a starlike pattern is known as neuroretinitis and is classically caused by infection. However, other causes such as hypertension can result in the same clinical picture. A number of infections are classically associated with neuroretinitis and can have neurological associations. These include cat-scratch disease, Lyme disease, and syphilis. In very rare cases, toxoplasmosis manifests this appearance.⁶⁸ The ocular features of these other conditions are discussed as follows, except for toxoplasmosis, which is discussed elsewhere.

Cat scratch fever is caused by Bartonella henselae. There may be an associated uveitis, and the other fundal appearances include discrete retinal or choroidal lesions, which are more common than in classic neuroretinitis.⁶⁹

Lyme disease is a spirochetal infection that results from tickborne transmission of Borrelia burgdorferi. Conjunctivitis is the most common ocular manifestation of early Lyme disease and occurs in approximately 10% of cases. Uveitis is a relatively rare manifestation of Lyme disease, but it may occur in the later stages. Vitritis, choroiditis optic neuritis, and motility problems have also been described.⁷⁰^–⁷⁴ Exudative detachment associated with the choroiditis⁷⁴ has been reported, as has a case of retinal vasculitis.⁷⁵

Syphilis is caused by Treponema pallidum. Between 1995 and 2003, the increase in the incidence of syphilis in the United Kingdom has been more than 10-fold.⁷⁶ Ocular disease typically occurs in secondary syphilis but is also observed in tertiary syphilis. Uveitis is the most common ocular manifestation in both these stages of the disease.^77,⁷⁸ The retinal changes are essentially similar in both secondary and tertiary syphilis. In keeping with its moniker, the “great imitator,” the disease can affect all structures of the eye. The combination of good visual acuity, reasonable visual fields, mild panuveitis, swollen disc, and afferent papillary defect is highly suggestive of syphilitic infection.

In addition to neuroretinitis, the retinal findings include chorioretinitis, retinal vasculitis, serous retinal detachment, and necrotizing retinitis (Fig. 24-10). The necrotizing retinitis may be such that it is difficult to clinically distinguish from acute retinal necrosis (ARN) (discussed later in this chapter). The diagnosis is established by the presence of other systemic features.⁷⁹ The association with HIV is discussed elsewhere in this chapter.

Figure 24-10 Peripheral retinal changes in syphilis.

Tuberculosis

Choroidal involvement is probably the most common form of ocular involvement in tuberculosis. Usually it is in the form of choroidal tubercles that are white, gray, or yellow lesions (Fig. 24-11). The patient neither has to be seriously unwell nor has to have miliary tuberculosis for ocular disease to be present.^80,⁸¹ The ocular disease may manifest many years after the tuberculosis has been found and treated elsewhere in the body.⁸² Other manifestations include multifocal choroiditis or serpiginous-like choroiditis.

Figure 24-11 Choroidal changes in tuberculosis.

Retinal involvement can result from either choroidal extension or bloodborne spread. Retinal involvement can be either as tubercles or as a diffuse retinitis. Neovascularization and retinal vasculitis can also occur.^83,⁸⁴

Whipple’s Disease

Whipple’s disease is characterized by arthralgia, abdominal pain, and weight loss. The causative organism is Tropheryma whippelii. Oculomasticatory myorrhythmia is believed to be pathognomonic, but fundal changes also occur. These include vitreous opacities, diffuse chorioretinal inflammation with capillary involvement, and retinitis.⁸⁵^–⁸⁹

Herpetic Infections

Herpesviruses cause ARN. The clinical characteristics for the diagnosis are focal, well-demarcated areas of retinal necrosis, which progresses in a rapid and circumferential manner; occlusive vasculopathy; and a prominent inflammatory reaction (Fig. 24-12).⁹⁰ ARN may occur in isolation or in association with other forms of herpes infection, such as herpes zoster ophthalmicus. ARN may also be present in association with either meningitis or encephalitis. It appears that encephalitis, either concurrent or past, is more likely to be associated with herpes simplex virus type 1 infection, whereas herpes simplex virus type 2 is more likely to be involved in the presence of meningitis, whether past or concurrent.⁹¹ Genotypical analysis in two patients who had ARN after encephalitis revealed identical strains of herpes simplex virus type 1 in the brain and eye, suggestive of brain-to-eye transmission of the infection in these patients.⁹² ARN may occur concurrently with encephalitis or up to 20 years later.⁹³ A case of cerebral vasculitis in which ARN was the only manifestation of any herpetic infection has been reported.⁹⁴

Figure 24-12 Areas of retinal necrosis in acute retinal necrosis.

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis can occur months to years after measles infection. It usually affects children or young adults, but a case in a 49-year-old man has been described.⁹⁵ Ocular involvement occurs in about 50% of cases and most often develops at the same time as neurological symptoms. Chorioretinitis with subsequent scarring is the most common retinal appearance. In rare cases, the ocular signs precede the neurological ones.⁹⁶

Human Immunodeficiency Virus

The retinal manifestations of HIV can be subdivided into those resulting primarily from the HIV infection, from associated infections, and from malignancies. The incidence of many of these conditions appears to have decreased since the introduction of highly active antiretroviral therapy.⁹⁷ Diagnosis can be difficult because the ocular signs may differ from those in an immunocompetent individual, and there may be two concurrent infections. Also interesting is that although HIV has contributed to the increase in incidence of tuberculosis, this may not have been mirrored by an increase of ocular tuberculosis. An autopsy study of eyes from 235 patients with HIV infection revealed intraocular tuberculosis in only two eyes.⁹⁸

Retinal Manifestations of HIV Infection

Microvasculopathy is the most common ocular manifestation of HIV infection, being present in 40% to 60% of patients,⁹⁹ and appears to be inversely related to the CD4 count.¹⁰⁰ In the retina, it is most frequently represented by cotton-wool spots, which are usually asymptomatic and resolve after about 6 weeks. Hemorrhages may occur, particularly in patients with low platelet counts or diabetes. They are a response to the HIV infection. Less commonly, patients may develop macular ischemia,¹⁰¹ which is also probably caused by the primary infection. Large retinal vessel disease has been described,¹⁰² but this is rare. Progressive visual loss has been described in a patient with HIV infection who had a clinically normal retina but abnormal photoreceptor function on electrophysiological testing.¹⁰³ This process continued even when the viral load was undetectable.

Cytomegalovirus-Associated Retinitis

Cytomegalovirus-associated retinitis is the commonest ocular infection in patients with acquired immunodeficiency syndrome (Fig. 24-7). However, its incidence has dropped since the introduction of highly active antiretroviral therapy.¹⁰⁴ It rarely occurs in patients with a CD4 count lower than 50.¹⁰⁰ Cytomegalovirus-associated retinitis occurs mainly in patients with HIV infection but can occur in patients who are immunocompromised for other reasons.^41,¹⁰⁵ There are two main forms of clinical presentation: a fulminant form and an indolent form. The fulminant form is characterized by confluent retinal necrosis with hemorrhage that in most cases develops in the posterior retina, whereas the indolent form has a more granular form. Up to 15% of patients with cytomegalovirus-associated retinitis are asymptomatic; therefore, screening is required for patients with HIV infection who have low CD4 counts and positive cytomegalovirus serological profiles.

Fungal Infections

A number of fungi can affect the brain and the retina. These are most often present in patients who are immunocompromised. The incidence of ocular fungal infections, such as Pneumocystis and Cryptococcus organisms, in HIV-seropositive patients appears to have decreased since the introduction of highly active antiretroviral therapy.⁹⁷

Mucormycosis

Mucormycosis is an acute fungal infection that is rapidly invasive and carries a high mortality rate. Diabetes is a common predisposing factor. There are a number of clinical forms of mucormycosis, the most common being rhino-orbito-cerebral. This form affects the eye, and a necrotic eschar of the nose or hard palate is a characteristic sign. Although orbital cellulitis is the most common form of ocular involvement, serous retinal detachment and retinitis ¹¹⁹ and choroidal ischemia have been described.^120,¹²¹

Candida Albicans

A fluffy white chorioretinal lesion with overlying vitreous haze is the typical lesion of C. albicans–related endophthalmitis. The infection may extend into the vitreous humor, causing cotton ball–like opacities characteristic of candidal infection. Progressive retinochoroiditis with satellite lesions may also occur.

Cryptococcus

Cryptococcal infection occurs mainly in patients who are HIV-seropositive. Up to 25% of patients with cryptococcal meningitis have neuro-ophthalmological lesions, which makes it the most common cause of acquired immunodeficiency syndrome–related neuro-ophthalmological lesions.⁹⁹ Cryptococcal choroiditis is, however, rare. It may be may be multifocal, solitary, or confluent (Fig. 24-14).¹²² The lesions may initially be asymptomatic. Progressive visual loss may occur as a result of papilledema and also fungal optic nerve sheath invasion.¹²³

Figure 24-14 Cryptococcal choroiditis with a swollen optic disc.

Pneumocystis Carinii

One of the ocular features of P. carinii is choroiditis.¹²⁴ It is classically bilateral and multifocal. The lesions are distinctive, being yellowish and well demarcated. They are slowly progressive, and usually vision is unaffected. There is not usually any associated ocular inflammation.^124,¹²⁵ In HIV-seropositive patients with presumed P. carinii choroidopathy, the majority had used inhaled pentamidine as prophylaxis against recurrent Pneumocystis-related pneumonia.¹²⁵

MITOCHONDRIAL DISEASES

Pigmentary changes in the retina may occur in patients with mitochondrial disease. These can take a variety of forms and include appearances that have been described as pigment clumping, atrophy, salt-and-pepper retinopathy, and appearances of classic retinitis pigmentosa (Fig. 24-15). Involvement of the macula can occur, as can vascular attenuation. The most common appearance is that of a salt-and-pepper retinopathy. There does not, however, appear to be any link between the presence or type of retinal pigmentary change, the type of genetic defect, biochemical abnormality, and any clinical features.

Figure 24-15 Retinitis pigmentosa.

A pigmentary retinopathy is a major diagnostic criterion for the diagnosis of Kearns-Sayre syndrome (the other features being a chronic progressive external ophthalmoplegia; onset before the age of 20; and cardiac conduction abnormalities, elevated cerebrospinal fluid protein levels, or cerebellar dysfunction). Retinal pigmentary degeneration can also be present in patients with chronic progressive external ophthalmoplegia and no other neurological or systemic abnormalities, as well as in otherwise unaffected relatives.¹²⁶

Pigmentary retinopathy is also a major diagnostic feature of the syndrome of neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP). However, patients who have no retinopathy, no subtle pigmentary retinopathy, and no severe bone spicule pattern have been identified with the same mutation.¹²⁶ Furthermore, a patient in whom the retinal changes progressed from an initial salt-and-pepper retinopathy to typical retinitis pigmentosa over an 8-year period has been described.¹²⁷

Other mitochondrial diseases in which retinal changes have been reported include the syndrome of myoclonic epilepsy and ragged red fibers and the syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS). The retinal changes in MELAS are in the form of pigmentary changes in the macula.^128,¹²⁹ MELAS is associated with the 3243 mutation, which can also manifest as maternally inherited diabetes and deafness. Macular changes similar to those in MELAS have also been reported in these patients,^130,¹³¹ which demonstrates the marked overlap between clinical syndromes.

Funduscopic abnormalities may be present in patients with Leber’s hereditary optic neuropathy and in their asymptomatic maternal relatives. Especially during the acute phase of visual loss, there may be hyperemia of the optic nerve head, dilation and tortuosity of vessels, hemorrhages, circumpapillary telangiectatic microangiopathy, or circumpapillary nerve fiber layer swelling (pseudoedema). There may be cupping of the optic disc and arterial attenuation.¹²⁶ In 2 of 20 patients with Leber’s hereditary optic neuropathy, pigmentary changes were noted at the retina.¹²⁸

NEOPLASIA

Metastatic Disease

Metastases are probably the most common form of intraocular malignancy and can be associated with concurrent neurological involvement. They tend to involve the choroid but can affect the retina or vitreous humor (Fig. 24-16).^132,¹³³ Lung and breast carcinoma are the most common sources of ocular metastases and may be the manifesting sign of the disease.

Figure 24-16 Metastatic deposits with associated retinal detachment.

Lymphoma

Primary intraocular lymphoma may occur in isolation, without involvement of the CNS. However, because the ocular and the CNS components show identical cytological features and phenotypical expression, the two entities are often considered as one entity: primary CNS lymphoma. Involvement of the eyes in this condition has been reported to occur in 12% to 25% of cases,¹³⁴^–¹³⁷ and 56% to 80% of patients with intraocular lymphoma eventually develop intracranial involvement.¹³⁸^–¹⁴² As yet, it is unknown whether lymphoma cells from the eye can invade the CNS or whether the disease arises multifocally, in the eye and CNS. Experimental data from an animal model suggest that invasion of the CNS from the eye does not occur.¹⁴³

The clinical features are dependent on the site of lymphoma involvement. The only sign of the disease may be vitreous cellular infiltration with resulting floaters and reduction of acuity. Because this is typically the appearance of a posterior uveitis, ocular lymphomas are described as being one of the masquerade syndromes. Diagnosis at this stage can therefore be difficult. The classic lesions are creamy yellow subretinal infiltrates (Fig. 24-17), with overlying retinal pigment epithelial detachments,¹⁴² but they may take on many forms, such as discrete white lesions, suggestive of ARN or toxoplasmosis¹⁴⁴; branch retinal artery obstruction with coexistent multifocal chorioretinal scars¹⁴⁵; and retinal vasculitis.

Figure 24-17 Ocular lymphoma. The hazy view is caused by vitreal inflammation.

If patients have combined CNS and eye involvement, therapy for the eyes is typically accomplished as part of the overall treatment plan, including the use of intravitreal methotrexate in some cases. An important question that has not been answered is whether apparently clinically isolated ocular disease is adequately treated with only local therapy or requires treatment of the entire CNS presumptively.

Paraneoplastic Syndromes

Paraneoplastic visual syndromes represent visual dysfunction in the setting of known or suspected malignancies, without direct involvement of the eye or nervous system by tumor, antineoplastic agent toxicity, or opportunistic infection. They are rare, and the fundus may appear normal on presentation. Furthermore, because some patients may present before the diagnosis of a neoplasm, diagnosis can be difficult. These syndromes are characterized by elevated serum levels of autoantibodies directed against tumor antigen that cross-react with retinal proteins, resulting in retinal dysfunction.

Carcinoma-Associated Retinopathy

Carcinoma-associated retinopathy (CAR) was first described in 1976.¹⁴⁶ It is associated most commonly with small cell lung cancer and next most commonly with gynecological and breast cancers. Cases associated with other cancers such as non–small cell lung, colon, pancreatic, prostate, larynx, and bladder cancers and lymphoma have also been reported. Overall, the incidences among men and women are equal. Visual loss is usually subacute and bilateral, preceding tumor diagnosis in about 50% of cases. Patients may complain of positive visual phenomena, visual field loss, and night blindness. Initially there may be no retinal signs, but arteriolar narrowing and pigmentary retinal changes develop. Sheathing of the retinal vessels may develop. Electrophysiological testing demonstrates that both rods and cones are affected.

The first antigen shown to represent the source of autoimmunity in patients with CAR was the 23-kD protein recoverin.^147,¹⁴⁸ This is a calcium-binding protein that regulates phosphorylation of the visual pigment rhodopsin during visual transduction. A number of other antigens have since been reported to be associated with CAR. The next most commonly found antigen is the 46-kD protein enolase,¹⁴⁹ although a number have now been identified (see review by Chan¹⁵⁰).

However, the presence of neither antirecoverin nor antienolase antibodies is diagnostic for CAR. A few patients with antirecoverin antibodies but with no evidence of malignancy have been described.^151,¹⁵² Up to two thirds of patients with antienolase antibody–associated retinopathy have no evidence of malignancy.^153,¹⁵⁴ Furthermore, in patients with antienolase antibodies, the retinopathy often develops after the detection of cancer, and the disease course is usually less severe than in patients with antirecoverin antibodies.¹⁵⁴

Melanoma-Associated Retinopathy

Because of the relatively greater decrease in incidence of lung cancers in comparison with melanomas, it has been suggested that melanoma-associated retinopathy (MAR) is becoming more common than CAR.¹⁵⁰ There are a number of differences between MAR and CAR. In MAR, the diagnosis of melanoma has often been made before the development of visual problems, and the incidence of MAR is higher in men. Patients tend to complain of shimmering vision and night blindness. The degree of visual loss is less severe than in CAR. As in CAR, the initial retinal appearances may be normal, but retinal pigment epithelial irregularity, retinal arteriolar attenuation, and optic disc pallor are present in cases in which the symptoms have been present for some time. Vitritis and retinal periphlebitis have been reported.¹⁵⁵

Autoantibodies from MAR sera were shown to stain rod bipolar cells in the human retina.¹⁵⁶ The specific antigen responsible has not been identified. Retinal cells other than bipolar cells have implicated, and antibodies against a variety of antigens have been identified (see Chan¹⁵⁰).

Paraneoplastic Optic Neuritis with Retinitis

Paraneoplastic ophthalmological syndromes are usually retinopathies, but in rare cases, the optic nerve is affected. In some patients, both paraneoplastic optic neuritis and a retinopathy coexist. This has been described in patients with small cell lung carcinoma. None had antirecoverin antibodies, but all had a distinct immunoglobulin G marker antibody to collapsing response-mediator protein-5.¹⁵⁷

Bilateral Diffuse Uveal Melanocytic Proliferation

This rare condition often precedes the diagnosis of cancer. Patients present with visual loss and are found to have many round or oval red patches at the level of retinal pigment epithelium and pigmented and nonpigmented melanocytic lesions of the uveal tract. An ultrasonogram reveals extremely thickened choroid. Retinal detachment and cataracts may develop.¹⁵⁸ Approximately 25% of patients develop pigmentation of their skin or mucous membranes.¹⁵⁹ The most commonly associated neoplasms are ovarian cancers in women and lung and pancreas cancers in men, although it has also been reported in kidney, colon, breast, and esophageal cancers.^159,¹⁶⁰

MOVEMENT DISORDERS AND ATAXIA

Most often the neuro-ophthalmological findings in patients with movement disorders are those of the oculomotor system. Patients with Parkinson’s disease often complain of blurred vision. Retinal appearances are normal, however, but functional abnormalities are present on psychophysical and electrophysiological testing. Some of these are reversible with levodopa (see Jackson and Owsley ¹⁶¹ for a review). Patients with Huntington’s disease also demonstrate abnormalities of retinal function on psychophysical testing.¹⁶² However, about 50% of patients with Guam amyotrophic lateral sclerosis–parkinsonism–dementia complex (Lytico-Bodig disease) do have retinal pigmentary changes.¹⁶³

A number of rare movement disorders are associated with retinal changes. Pantothenate kinase–associated neurodegeneration (formerly known as Hallervorden-Spatz syndrome),¹⁶⁴ which is caused by a mutation in the PANK2 gene, is characterized by dystonia, parkinsonism, iron accumulation in the brain, and occasionally retinopathy. Electrophysiological abnormalities have been observed in affected patients who have clinically normal eyes.¹⁶⁵ The syndrome of hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration, which is also caused by a PANK2 mutation,¹⁶⁶ also has a pigmentary retinopathy.

Aceruloplasminemia is a rare condition that was first described in 1987.¹⁶⁷ It also results in iron overload in the brain, retina, and pancreas. The first patient described was Asian, and the retinal changes were noted in the midperipheral region.¹⁶⁷ Subsequently a case was described in a white patient, but the changes were at the macula.¹⁶⁸

In Wilson’s disease, there is also a deficiency of ceruloplasmin, but the biochemical problem relates to copper metabolism. Retinal changes have been reported in addition to the familiar Kayser-Fleischer rings in the cornea. However, it is unclear whether these were caused by long-term therapy with pencillamine.¹⁶⁹

A number of the ataxias are also associated with retinal pigmentary changes. These include Bassen-Kornzweig disease,¹⁷⁰ Refsum’s disease,¹⁷¹ and adult-onset spinocerebellar syndrome with idiopathic vitamin E deficiency.¹⁷² A deficiency of vitamin E may cause the initial retinopathy; the treatment of these conditions includes vitamin E supplementation.¹⁷³

Although there are many forms of spinocerebellar ataxia with oculomotor abnormalities, spinocerebellar ataxia type 7 can be differentiated from the other forms by the associated retinal changes. These take the form of progressive macular changes with visual loss (Fig. 24-18).¹⁷⁴ Electrophysiological studies have demonstrated that the functional defects are greater than expected from the clinical appearance.¹⁷⁵

Figure 24-18 Macular changes in spinocerebellar ataxia type 7.

MUSCLE DISEASES

Patients with facioscapulohumeral muscular dystrophy often have retinal telangiectasia. In rare cases, this can have significant visual consequences, such as exudative retinal detachment.¹⁷⁶ Myotonic dystrophy is most frequently associated with cataract, but retinal pigmentary changes are also present. They can be peripheral or affect the macula and may slowly progress.¹⁷⁷ The classic neuro-ophthalmological feature of dermatomyositis is the heliotrope rash of the eyelids, but a vasculitic retinopathy with retinal hemorrhages and cotton-wool spots may occur. With immunosuppression, visual recovery is usually but not always complete.¹⁷⁸

PHACOMATOSES

The phacomatoses are a group of disorders that feature multiple hamartomas of the nervous system, eye, skin, and viscera.

Neurofibromatosis

Neurofibromatosis Type 1

The diagnostic criteria for neurofibromatosis type 1 include optic gliomas and Lisch nodules, which are hamartomas of the pigment epithelium. Nevertheless, retinal involvement is rare and generally nonspecific. The retinal lesions include a pigmentary retinopathy,¹⁷⁹ retinal hamartomas,^180,¹⁸¹ and capillary hemangiomas and combined hamartomas of the retina and pigment epithelium.¹⁸¹ Mild pigmentary changes that resemble cutaneous café au lait spots have been described.¹⁸⁰ Myelinated fibers may be present more frequently than in the normal population,¹⁸² and vascular occlusions have also been reported,¹⁸³ but it is unclear whether these are merely coincidental. Neurofibromas of the uveal tract can occur in up to 50% of patients.^182,¹⁸⁴^–¹⁸⁹ These are usually pale yellow nodules, but the entire uvea may be thickened by a diffuse neurofibroma. Choroidal nevi may occur more frequently in patients with neurofibromatosis type 1 than in the normal population.¹⁹⁰

Neurofibromatosis Type 2

Cataracts and retinal changes are common in patients with neurofibromatosis type 2, whereas Lisch nodules are not as common as in neurofibromatosis type 1.¹⁹¹^–¹⁹⁶ Indeed, the ocular findings may be the first manifestation of the disease.¹⁹⁴ The retinal changes can take the forms of epiretinal membranes,¹⁹⁶^–¹⁹⁸ hamartomas of the retina,^194,¹⁹⁵ and combined pigment epithelial and retinal hamartomas.^191,^193,¹⁹⁸ Retinal hamartomas are not exclusively associated with severe neurofibromatosis type 2, and neither the type nor the location of the germline neurofibromatosis type 2 mutation is the sole determinant of retinal abnormalities, which can be variably expressed in families with neurofibromatosis type 2.¹⁹⁹

Tuberous Sclerosis

Hamartomas of the retina are the most prominent ocular manifestation of tuberous sclerosis, present in about 50% of patients and bilateral in 25% of cases. They arise from the ganglion cell layers and infiltrate all layers of the retina. They do not tend to grow or interfere with vision. The appearances are varying, ranging form semitransparent structures to opaque multinodular lesions (Fig. 24-19). Although most lesions remain stable, becoming calcified over time, they can develop in areas of previously normal-appearing retina.²⁰⁰ A case of a patient with a giant cell astrocytoma of the retina with atypical histopathological features and local aggressive behavior has been reported.²⁰¹ Depigmented pigment epithelial lesions may be present. These can have a shape similar to that of cutaneous mountain ash leaf spots.²⁰²^–²⁰⁴

Figure 24-19 Astrocytic hamartoma.

Von Hippel-Lindau Disease

The retinal capillary hemangioma is the most frequent and the earliest manifestation of von Hippel-Lindau disease (Fig. 24-20).²⁰⁵^–²⁰⁹ The other systemic features include hemangiomas of the CNS; renal cell carcinoma; pheochromocytoma; and renal, pancreatic, and epididymal cysts. The retinal capillary hemangioma is usually an orange-red, circumscribed round lesion. It can enlarge and develop a feeder vessel, and fluid may extravasate, leading to a retinal detachment. Thus, patients should have an annual ophthalmological assessment with dilated funduscopy, because the lesions may be small and situated in the retinal periphery. Retinal capillary hemangiomas can also develop around the optic disc. A rare retinal feature of von Hippel-Lindau disease are retinal “twin vessels,”²¹⁰ defined as a paired retinal arteriole and venule that are separated by less than the diameter of one venule. Twin vessels are of normal caliber and look like normal retinal vessels except for their course. Retinal capillary hemangiomas not associated with von Hippel-Lindau disease do occur but at a later age (48 years) than in patients with von Hippel-Lindau disease (25 years).²¹¹ Nevertheless, the systemic features of von Hippel-Lindau disease must be ruled out in patients presenting with a solitary capillary hemangioma. The presence of multiple retinal capillary hemangiomas (two or more) indicates the presence of underlying von Hippel-Lindau disease.²¹²

Figure 24-20 Retinal capillary angioma.

Sturge-Weber Syndrome

The chief components of the Sturge-Weber syndrome are a cutaneous hemifacial angioma and an ipsilateral angioma of the leptomeninges and brain. Glaucoma is the most common ocular association. Choroidal angiomas are also present; these can affect one or both eyes. Most commonly the angiomas are diffuse, obscuring the normal choroidal markings.²¹³ More rarely, they are localized and may be associated with a serous retinal detachment.²¹⁴ The retinal vasculature may be abnormal.²¹⁵

Wyburn-Mason Syndrome

The classic Wyburn-Mason syndrome consists of an intracranial arteriovenous malformation and a separate retinal one. The retinal arteriovenous malformation has also been described as an arteriovenous aneurysm or racemose angioma. It is usually unilateral and involves the posterior pole, thus affecting the vision. Often it is stable, but it may enlarge (Fig. 24-21).^216,²¹⁷

Figure 24-21 Racemose angioma.

Other Phacomatoses

The classic ophthalmological lesion of ataxia telangiectasia is telangiectasia of the conjunctiva, and the retina is spared. In Klippel-Trénaunay-Weber syndrome, varicosities of the retinal vasculature and choroidal angiomas have been described.²¹⁸

CEREBROVASCULAR DISEASE

Retinopathy

The retinal and cerebral arterioles share common anatomy and physiology. Because the retina is readily visualized, it provides an opportunity to assess the retinal and, by inference, the cerebral circulation. Studies in people with hypertension have shown that signs of retinopathy are associated with both subclinical and clinical stroke.²¹⁹^–²²² Retinal digital photography has been used in large population-based studies to investigate the relationship between retinal findings and systemic disease, including stroke. The images are analyzed in a standardized manner and are used to look for features of retinopathy such as microaneurysms, retinal hemorrhages, cotton-wool spots, arteriovenous nicking, and arteriolar narrowing. The studies include the Atherosclerosis Risk in Communities study, the Beaver Dam Eye Study, and the Blue Mountains Eye Study.

The Atherosclerosis Risk in Communities study has demonstrated that after controlling of stroke risk factors such as diabetes and hypertension, the presence of retinopathy was predictive of an incident stroke.²²³ Retinopathy was also associated with cognitive decline²²⁴ and with magnetic resonance imaging findings such as white matter lesions²²⁵ and cerebral atrophy.²²⁶ The risk of stroke was higher in patients who had both retinopathy and changes noted on cerebral magnetic resonance imaging.²²⁵

Retinal Emboli and Arteriolar Occlusion

Retinal emboli are usually present at the bifurcation of retinal arterioles and may be reflective or nonreflective. A variety of emboli have been described, but clinically a reliable distinction cannot always be made (Fig. 24-22).²²⁷ Emboli are also present in up to about 40% of central retinal artery occlusions (Fig. 24-23) and 70% of branch retinal artery occlusions.^228,²²⁹ The emboli usually originate from the carotid arteries or a cardiac source. The carotid vessels are the commonest source of emboli in patients with amaurosis fugax or retinal artery occlusion and of asymptomatic emboli,²³⁰ but often no embolic source is found.^230,²³¹ In elderly patients, the absence of an embolus in a retinal artery occlusion necessitates the exclusion of giant cell arteritis as a diagnosis. Furthermore, the presence of an embolus that is asymptomatic²³² or in association with a retinal artery occlusion²³³ is not a good predictor of carotid artery stenosis. This may be because the emboli result from plaques and are not associated with stenosis per se.²³²

Figure 24-22 Retinal embolus.

Figure 24-23 Central retinal artery occlusion with the appearance of a cherry-red spot.

Emboli may be asymptomatic. It has been shown that for men with asymptomatic cholesterol emboli, there is an increased risk of stroke, but not myocardial infarction,²³⁴ and that patients with an embolus, symptomatic or not, have a reduced survival rate.²²⁸ Again, the analysis of digital photographs in large populations has added further information about emboli. The Beaver Dam Eye study found that for asymptomatic retinal emboli, the 10-year cumulative incidence was 1.5%.²³⁵ The incidence rose with age, from 1.0% in subjects aged 43 to 54 years to 2.2% in those aged 65 years or older at baseline. They are more common in men than in women. They appear to be transitory, and in approximately 30% of affected eyes, they are multiple. Bilateral ocular involvement is rare. The presence of asymptomatic retinal emboli is associated with carotid artery disease²³⁶ and an increased risk of death from stroke, independent of any other risk factors.²³⁵

Ocular Ischemic Syndrome and Other Ocular Associations with Carotid Artery Disease

Severe carotid stenosis is associated with venous stasis retinopathy. In this condition, there is an insidious onset of blurred vision in the affected eye. Patients may complain of episodes of transient monocular visual loss precipitated by exercise, eating, or bright lights. Examination reveals dilated and tortuous retinal veins, peripheral hemorrhages, and an easily induced pulsation of the central retinal artery with digital pressure.^237,²³⁸

Venous stasis retinopathy may progress to ocular ischemic syndrome. This is a severe form of chronic ischemia caused by hypoperfusion of the eye, which affects both its anterior and posterior segments. Neovascularization of the iris, disc, and retina may occur. In patients with minimal or no neovascular changes, carotid endarterectomy appears to improve blood flow through the ophthalmic and central retinal arteries.²³⁹ It also appears to prevent progression of ocular ischemic syndrome, if not improve vision in all patients.²³⁹ Percutaneous angioplasty and stenting have also been used effectively in a number of patients who had lesions that were not amenable to endarterectomy.²⁴⁰

Patients with carotid occlusive disease may develop neurological symptoms at the same time as a central retinal artery occlusion.²⁴⁰ Carotid artery dissection is classically associated with a painful Horner’s syndrome, but both central and branch retinal artery occlusions can be present in this condition.²⁴¹^–²⁴³ Carotid artery disease is also associated with retinal vein occlusions.²³⁶

Retinal Vasculitis and Stroke

One form of retinal vasculitis is localized to the eye, and fluorescin angiography demonstrates ischemic retinal changes. This condition, known as idiopathic ischemic retinal vasculitis, has a worse visual prognosis than does retinal vasculitis with no associated ischemia.²⁴⁴ Furthermore, after a minimum follow up of 5 years, almost one third of patients in one study had suffered a stroke and/or myocardial infarction.²⁴⁵

Secondary Causes of Stroke

Coagulopathies that are associated with stroke, such as hyperhomocysteinemia and antiphospholipid syndrome, also have retinal manifestations such as retinal artery and vein occlusions.^246,²⁴⁷

Cerebral Small-Vessel Disease

The most common form of cerebral small-vessel disease is acquired degenerative small-vessel disease, and this usually is not clinically manifest before the sixth decade of life. There are, however, a number of other cerebral microangiopathies, several of which affect the eye. These include Susac’s syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and a number of hereditary diseases.

Susac’s Syndrome

Susac’s syndrome consists of the triad of encephalopathy, branch retinal artery occlusions, and hearing loss, which occurs most commonly in affected young women.^248,²⁴⁹ The branch retinal artery occlusions are often bilateral and may be the manifesting features of the illness, or they may occur later in the clinical course. Fluorescein angiography may reveal focal leakage from retinal arterioles even in the absence of frank occlusion (Fig. 24-24). Such leakage can be used to measure disease activity. The encephalopathy manifests with headache, confusion, memory loss, behavioral changes, dysarthria, and occasional mutism. The hearing loss is usually bilateral and frequently associated with tinnitus and vertigo. Although the presence of encephalopathy, branch retinal artery occlusions, and hearing loss is pathognomonic for Susac’s syndrome, not all elements may be present initially. The condition usually stabilizes after a period of 2 to 4 years. On magnetic resonance images, lesions of the corpus callosum are often present.²⁵⁰

Figure 24-24 An area of focal leakage from a retinal arteriole on fluorescein angiography.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

CADASIL is caused by mutations of the Notch3 gene, which is located on chromosome 19. In patients with CADASIL vision is usually preserved, although retinal findings such as peripapillary arteriolar sheathing, arteriolar narrowing, ateriovenous nicking,²⁵¹ and cotton wool spots²⁵² may be present. Visual loss may take the form of a hemianopic defect caused by stroke²⁵² or anterior ischemic optic neuropathy.²⁵³ In asymptomatic patients, there may be electrophysiological evidence of retinal dysfunction.²⁵⁴ A histopathological study of four eyes from two patients with CADASIL demonstrated loss of vascular smooth muscle cells in the central retinal artery and its branches, as well as the optic disc. The choroidal circulation was spared, which demonstrated a differential involvement of small blood vessels.²⁵⁵

Other Hereditary Diseases of the Small Vessels

There are other rare hereditary conditions that affect the retinal and cerebral circulation. Patients with autosomal dominant vascular retinopathy, migraine, and Raynaud’s phenomenon may have a retinopathy that appears very similar to that of diabetic retinopathy. Indeed, a few patients may develop retinal neovascularization, which results in poor vision.^256,²⁵⁷ Three other diseases with retinopathy have been linked to the same locus on chromosome 3p21. These are cerebroretinal vasculopathy; the syndrome of hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS); and hereditary vascular retinopathy.²⁵⁸ The retinal vascular abnormality constitutes part of the disease title in the syndrome of hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy.²⁵⁹ Fabry’s disease is also accompanied by retinal vascular changes.²⁶⁰ The practical implication of these findings is that all patients with small-vessel disease probably require ophthalmoscopy.²⁶¹ Finally, of interest is that a high prevalence of migraine has been in reported in CADASIL; HERNS; hereditary vascular retinopathy; and the syndrome of hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy.

Terson’s Syndrome

Vitreous hemorrhage occurring in association with subarachnoid hemorrhage is known as Terson’s syndrome.²⁶² However, intraocular hemorrhages of any type (retinal, subhyaloid, or vitreous) have been documented in 10% to 40% of individuals with subarachnoid hemorrhage,²⁶³ and reports have not always made a distinction between such types of hemorrhage (Fig. 24-25).²⁶⁴ Furthermore, preretinal hemorrhage may precede vitreous hemorrhage.^263,²⁶⁵ Terson’s syndrome is present in between 3% and 13% of patients with a subarachnoid hemorrhage²⁶⁶ and carries an increased mortality rate in relation to patients who have had a subarachnoid hemorrhage but not vitreous hemorrhage.²⁶⁶ It has also been suggested that mild retinal hemorrhages are associated with a better prognosis than are large preretinal hemorrhages or vitreous hemorrhages.²⁶⁷ An urgent vitrectomy may be required for visual rehabilitation in patients with bilateral vitreous hemorrhage.

Figure 24-25 Retinal hemorrhages in a patient with a subarachnoid hemorrhage.

METABOLIC DISEASES IN CHILDREN

A variety of ophthalmological features may occur in these diseases, all of which may contribute to visual problems. Thus, it can be difficult to determine the precise cause of visual loss. For example, patients with Hunter’s syndrome may have corneal clouding, pigmentary retinal degeneration, and optic atrophy. Furthermore, there may also be mucopolysaccharide deposition in the occipital cortex.

The most common retinal findings are the presence of a macular cherry-red spot (an appearance similar to that of a central retinal artery occlusion; see Fig. 24-23) and pigmentary retinopathy. The cherry-red spot is classically associated with Tay-Sachs disease. However, a form of this finding is present in many of the metabolic diseases, although not necessarily in all patients affected by them. Also, in other conditions it may have prognostic significance; for example, in Farber’s disease, its presence may be correlated with disease severity.²⁶⁸ Pigmentary retinopathy is also present in a number of conditions, although, again, not in all affected individuals. The clinical pattern of the retinopathy is variable. There are a few striking changes associated with the metabolic diseases, such as the absence of retinal pigmentation observed in phenylketonuria and the presence of bilateral parafoveal ringlets observed in hyperoxaluria type 1.²⁶⁹

The cherry-red spot tends to be present in the lysosomal storage diseases such as Tay-Sachs disease, Sandhoff’s disease, type 1 GM₁ gangliosidosis, Farber’s disease, Niemann-Pick disease type A, and the sialidoses (namely types 1 and 2), as well as in metachromic leukodystrophy.

Retinal pigmentary changes can be present in a number of the following conditions:

1. The mucopolysaccharidoses: namely, Hurler’s syndrome, Hunter’s syndrome, Scheie’s syndrome, and Sanfilippo’s syndrome. It is rarely present in Morquio’s syndrome and is not present in Maroteaux-Lamy or Sly’s syndrome.

2. The disorders of peroxisomes, such as Zellweger’s cerebrohepatorenal syndrome, neonatal adrenoleukodystrophy, infantile Refsum’s disease, and X-linked adrenoleukodystrophy.

3. The juvenile and infantile neuronal ceroid lipofuscinoses.

4. A few other conditions such as mucolipidosis type IV, GM₁ gangliosidosis type 2 (in which a cherry-red spot is not present).

KEY POINTS

• The brain and retina share much in terms of anatomy and physiology.

• Retinal disease may be the primary manifestation of systemic disease, including inflammation, infection, and metabolic and degenerative disorders.

• Retinal changes can be diagnostic of a wide range of neurological diseases, from demyelinating to neuromuscular.