Just because a disease is rare doesnt mean it wont end up in your chair. As a result, you must be knowledgeable of the rare systemic conditions that have ocular manifestations so you are not misled to make a diagnosis based solely on the appearance of a particular corneal or retinal finding. This article discusses three such rare systemic diseases: Fabrys disease, Churg- Strauss syndrome and Susacs syndrome (see Diseases at a Glance, below.), and stresses the importance of looking past the eye and considering the patients entire body.

Diseases at a Glance

Disease Etiology Sex Predominance  Treatment
Fabrys Sex-linked recessive 
metabolic disorder 
M>F Agalsidase 
beta IV 
infusion q2 weeks 
 Churg-Strauss     ANCA-positive vasculitis  M>F Steroid + cytotoxic agent
Susacs Unknown F>M steroid

Fabry"s Disease

Fabrys disease, also known as Anderson-Fabry disease or angio-keratoma corporis diffusum, is an X-linked recessive metabolic disorder occurring in 1 in 40,000 males.1 It is the second most prevalent metabolic storage disease of humans, affecting all ethnicities, with an incidence of 1 in 117,000 in the general population.2,3 Men with Fabrys disease (hemizygotes) are predominantly affected, but many female carriers (heterozygotes) have similar clinical involvement.4,5 Patients as young as five years of age may present with early intermittent symptoms (to be discussed below). But, because the disease often goes unrecognized by physiciansbecause it causes many varied symptoms affecting different body parts, the mean age of diagnosis for the illness is around 29 years.3,6

Fabrys disease is caused by an inborn error of glycosphinogolipid metabolism, which results from the defective activity of the lysosomal hydrolase, a-galactosidase A (a-GAL). This deficiency of the enzyme a-GAL leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide (GL-3), within vascular endothelium, smooth muscle cells and visceral organs.7 GL-3 can be found in renal epithelium, myocardium, dorsal root ganglia, the brain and the autonomic nervous system.8

The classic systemic findings begin in childhood or adolescence and include intermittent episodes of burning and aching pains in the hands and feet (acroparesthesias); abdominal pain, hypohidrosis or anhidrosis (impaired ability to perspire); heat, cold and exercise intolerance; episodic fevers; and dark reddish-purple, non-blanching lesions (angiokeratomas)usually seen in a bathing suit distribution around the umbilicus, buttocks, groin and upper thighs (though these lesions may also involve the eyelids).1,7,8

The classic systemic findings of Fabrys disease include dark reddish-purple, non-blanching lesions (angiokeratomas) usually seen in a bathing suit distribution around the umbilicus, buttocks, groin and upper thighs, as shown above. Still, these lesions may also involve the eyelids.

The potential lethality of Fabrys disease results from damage to the kidneys and heart. Renal dysfunction often leads to uremia and hypertension, which progresses to end-stage kidney failure and death. Common cardiac manifestations include ventricular hypertrophy, valvular disease, congestive heart failure, arrhythmias and myocardial infarction.1,7 Cardiomyopathy and renal insufficiency often result in death by the patients fifth decade.9

Gastrointestinal symptoms in patients who have Fabrys disease include episodic diarrhea, post-prandial bloating and pain, and weight loss.7 Bronchitis, dyspnea and wheezing are not uncommon.1 Various cerebrovascular events, such as stroke, transient ischemic attacks, hemiparesis, vertigo/dizziness and dementia can also occur.1,7

The most common and first ocular sign of Fabrys disease: bilateral corneal diffuse yellow epithelial haziness that gradually becomes concentrated into dense rays that radiate from the center of the cornea into dense bronze to cream-colored streaks arranged in a vortex or star-shaped pattern (whorl-like or verticillata).8,9 These opacities appear to be in the subepithelial or Bowmans layer of the cornea.8 Corneal involvement occurs in over 90% of these patients, and, in one study, this involvement was present in all female carriers over the age of 10 years.10,11 In my experience, I have found that these opacities are best seen by transillumination and can mimic similar findings that may occur in patients who take amiodarone (an antiarrhythmic), chloroquine (used to prevent and treat malaria and liver disease), or chlorpromazine (used to treat psychotic disorders, such as delusions).

In Fabrys disease, bilateral corneal diffuse yellow epithelial haziness eventually becomes dense bronze to  cream-colored streaks arranged in a vortex or star-shaped pattern (whorl-like or verticillata).

You can further diagnose this disorder by using your slit-lamp to inspect the conjunctival vessels, and look for signs of dry eye. The small vessels of the conjunctiva in Fabrys disease often show aneurysmal dilatations, tortuosity and kinking.12 Peripheral nerve damage (autonomic dysfunction) results in decreased tear production in approximately 50% of Fabrys disease cases.13

The small vessels of the conjunctivea in Fabry"s disease often show aneurysmal dilations, tortuosity, and kinking.

Two different types of lens opacities have been noted in Fabrys patients. Cream-colored anterior capsular deposits in the lens (sometimes distributed like a propeller) are less common than the whitish, granular spoke-like deposits on the posterior of the lens (known as Fabrys cataracts).7 The posterior Fabrys cataracts, best observed by retroillumination, are found in 37% of hemizygotes and 14% of heterozygotes.11

Retinal vascular changes are more prevalent in hemizygous males (70% vs. 25% in heterozygous females).8 These vascular changes may present as segmental sausage-like dilation of the veins or corkscrew-like diffuse tortuosity.8 Other retinal findings include hemorrhages, hypertensive retinopathy, perimacular edema and central retinal artery occlusion.8,9,11,12

Ocular abnormalities may also occur secondary to neurologic disease and include nystagmus, diplopia from extraocular muscle palsies or internuclear ophthalmoplegia, disc edema, anterior ischemic optic neuropathy, hemianopsia and pupil abnormalities.8,9,11,12 (See Ocular Signs and Symptoms of Fabrys Disease," below.)

Ocular Signs and Symptons of Fabry"s Disease 

Eyelid and Periorbita 



Aneurysmal dilation, tortuosity 
     and kinking of venules


Diffuse yellow epithelial 
     progressing to whorled

     or spoke-like pattern


Anterior capsular propeller

Posterior subcapsular
     Fabry cataract


Sausage-like dilation of veins
Retinal or preretinal

Perimacular edema

Corkscrew-like diffuse vascular

Central retinal artery

Hypertensive retinopathy


Extraocular muscle palsies

Internuclear ophthalmoplegia

Hypertensive disc edema

Anterior ischemic optic

Homonymous hemianopsia

Pupil abnormalities


Decreased tear production

Aside from the clinical evaluation and a positive family history of the disease, laboratory findings of a marked decrease in activity of the enzyme a-GAL  help confirm the diagnosis of Fabrys disease. In 2003, the FDA approved the re-combinant human a-GAL enzyme Fabrazyme (agalsidase beta, Genzyme) as a replacement therapy in Fabrys disease patients. This drug has been shown to reduce GL-3 deposition and slow the progression of the disease process.14 It is administered as an intravenous in-fusion every two weeks.14 If the cataracts are affecting the patients vision, they should be surgically removed. Treat the patients dry eye with ocular lubricants and/or punctal plugs. Unfortunately, the other aforementioned ocular complications cannot be treated.


Churg-Strauss Syndrome

Churg-Strauss syndrome (CSS), also known as allergic granulomatous angiitis, is a distinct vasculitic syndrome belonging to the pauci-immune antineutrophil cytoplasmic antibody (ANCA) positive vasculitides.15 It is an uncommon condition characterized by asthma, eosino-philia and a recurrent necrotizing vasculitis.15,16

CSS affects men twice as often as women, and the age of onset varies from 15 to 70 years, with a mean age of about 40 years.17 The cause is unknown. The distinct nature of CSS distinguishes it from polyarteritis nodosa, a disease of small-sized and medium-sized arteries.15

Several stages of CSS can usually be identified:

Prodromal stage. This can persist for years and is manifested by symptoms of allergic disease with rhinitis, nasal polyps, bronchitis with shortness of breath, fever and asthma.16,18

Infiltration stage. This occurs when blood eosinophil levels become elevated, and the skin, lungs and gastrointestinal tract are infiltrated by these cells (eosinophils).18

Vasculitis stage. This is generalized (symptoms affect many different organ systems) and accompanied by weight loss, malaise, fever, arthralgias, myalgias and cutaneous vasculitis. More severe manifestations occur with persistent perivascular eosinophilic infiltration. These manifestations include cardiac and renal failure, convulsions and coma.18

Ocular involvement of CSS is uncommon, although eosinophilic granulomas may develop on the eyelids and conjunctiva.16,19 Similar granulomatous lesions can cause episcleritis, scleritis and panuveitis.15 Marginal corneal ulceration can also occur.16 Neuro-ophthalmologic findings include episodes of transient monocular visual loss, retinal ischemia, branch and central retinal artery occlusion, ischemic optic neuropathy and various cranial neuropathies including ocular motor nerve palsies.20

If the disease is diagnosed early, the outlook is relatively good, meaning treatment may halt organ damage or slow the disease process. Treatment consists of a combination of oral or intravenous steroids with a cytotoxic agent, such as oral cyclophosphamide.17,18 If left untreated, CSS is frequently fatal.16 An eyelid or conjunctival biopsy of involved tissue helps identify any eosinophilic granulomas and therefore helps in the diagnosis. Laboratory tests in a complete uveitis work-up should also be done to verify the diagnosis if these tests show eosinophilia > 10% or > 400/ml in peripheral blood and presence of antineutrophil cytoplasmic antibodies.


Susac"s Syndrome

Susacs syndrome was first described in 1979 and is defined by a triad of multiple branch retinal arterial occlusions, brain microangiopathy causing encephalopathy, and sensorineural hearing loss.21 This condition usually occurs in young women but can affect 15% to 20% of men.22,23 The age range for both men and women is from eight to 59 years with a mean age of 28.1 years and a median age of 29 years.22 No racial trend is noted.22 Its etiology is not known.

The retinopathy seen in Susacs syndrome is characterized by multiple peripheral retinal arteriolar branch occlusions that can be seen on funduscopy or retinal fluorescein angiography. The occlusions may be quite extensive or very subtle.22,24 Aside from the retinal arteriolar occlusions and their accompanying vessel narrowing, boxcar segmentation of the blood column may be seen beyond the point of occlusion in the affected arterioles, pointing to thrombosis as a possible mechanism for the occlusions.25 Iritis and vitritis are not seen, and there is usually no periarteriolar inflammation or sheathing.25,26

Retinal fluorescein angiography typically shows retinal arterial wall hyperfluorescence.27 The hyperfluoresence serves as an indicator of active disease and can precede the actual arterial occlusion.22 Vessel wall hyperfluoresence may be seen at sites distant from and unassociated with those of retinal arterial occlusion. Fluorescein angiography should always be performed on patients suspected of having Susacs syndrome, as the more subtle branch arterial occlusions may only be detected by doing this procedure. Other signs seen with fluorescein angiography: arterial constriction, leakage and perivascular sheathing.22,27

The retinopathy seen in Susacs syndrome is characterized by multiple peripheral retinal arteriolar branch occlusions that can be seen on funduscopy or retinal fluorescein angiography.

Other ophthalmic manifestations of Susacs syndrome: vision loss (57%), nystagmus (7%), gaze palsies (7%) and ptosis (2%).22 Vision loss is bilateral in 33% of cases and often permanent. This can occur because the branch retinal arterial occlusions frequently occur bilaterally.21,24 When vision loss does occur, it is usually segmental and not hemianopic.23 Some patients may complain of scintillating scotomas in their field of vision, while others may have no visual complaints even though they have evidence of funduscopic changes. This may be due to either encephalopathy, which prevents the patient from experiencing or reporting the visual disturbance, or the retinal infraction may be either too small or located in the periphery, and the patient does not notice it.23,28 On the other hand, occlusions at the posterior pole or adjacent to the optic disc cause profound vision loss.

Hearing loss in these patients is often acute, unilateral or bilateral, asymmetrical and associated with tinnitus, vertigo, vomiting, nausea and unsteady gait.27,23 The vertigo may be accompanied by nystagmus.27 The progression of the hearing loss is variable during the active phase of the illness. Some patients experience rapid progression and deafness, whereas others have significant improvement of previously impaired cochlear function on one side and subsequent involvement contralaterally.29

The encephalopathy may be acute or subacute and is frequently seen with psychiatric features of personality change and bizarre behavior.29 Common neuropsychiatric signs and symptoms include global brain microangiopathy, memory loss, headache (often with migrainous features), impaired cognition, ataxia, dysarthria, hemiparesis, hemisensory changes and brain atrophy.22,29

Magnetic resonance imaging (MRI) is the neuro-imaging technique of choice for identifying the etiology of the encephalopathy. The MRI findings show multiple small foci of abnormality. These appear both in the gray and white matter of the brain as hyperintensities.29 These lesions, which enhance on contrast dye (gadolinium) injection, are ischemic infarctions.30

The disease has a spontaneous remitting-relapsing course. The neuropsychiatric symptoms may resolve completely, but any hearing loss or visual changes usually do not improve. The mainstay of treatment is a minimum of 1 mg/kg oral prednisone (up to 80mg daily) with slow taper over two weeks, preceded by three days of intravenous methylprednisolone in severe cases. A total of 87% to 91% of patients have a response to prednisone treatment.22

Since retinal changes usually mirror a neurologic brain disease, weekly funduscopic exams are recommended for the first month, followed by monthly exams. Disease activity can also be assessed by monthly or quarterly MRIs and hearing evaluations. New lesions seen on MRI will enhance brightly than older lesions, indicating disease progression.29,31

Awareness of the aforementioned rare systemic diseases that have ocular manifestations will ensure that you ask patients who present with these particular corneal or retinal findings the proper questions during the history portion of their exam. This is crucial to
help you make the correct diagnosis, and prescribe the appropriate treatment. Again, just because its rare, that doesnt mean it wont end up in your chair.

Dr. Skorin is the staff osteopathic ophthalmologist at Albert Lea Eye ClinicMayo Health System, Albert Lea, Minn.


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