Early Detection of Systemic Disorders in the Optometric Office

Ocular signs frequently precede the classic symptoms and signs of systemic disorders: part 1 of 2.

By Hashim Ali-Khan, BSOpt, and Fatima Iqbal, OD

The eyes are the windows to the soul. These windows let optometrists peer into the souls of their patients and discover hidden maladies. Numerous systemic conditions can affect the ocular tissues in a variety of ways. Conversely, the ocular tissues can offer crucial clues to as yet undetected systemic diseases. At times, an ophthalmic finding may be the earliest signal of a systemic disorder or may precede the classic clinical signs and symptoms. This article presents three case reports and commentary illustrating that eye care providers may be the first to identify serious systemic conditions.

CASE No. 1

A 16-year-old female presented with a complaint of transient visual blur for 3 months. Her medical, family medical, and ocular histories were unremarkable. Her uncorrected and best-corrected visual acuity was 0.8 Snellen decimal in each eye. Color vision, pupil testing, and extraocular motilities were all normal.

Anterior segment examination was unremarkable except for mild conjunctival pallor OU. Her IOP measured 16 mm Hg OU. Dilated fundus examination showed multiple hemorrhages with white centers on the posterior pole OU (Figure 1).

Figure 1. Multiple Roth spots on posterior pole.

An array of tests, including complete blood count (CBC) and peripheral smear, erythrocyte sedimentation rate, liver function test, renal function test, and general physical examination, were recommended. Physical examination and echography confirmed severe hepatosplenomegaly. The blood testing revealed decreased glycosylated hemoglobin level, high total leukocyte count, and a complete spectrum of granulocytes, suggesting a myeloproliferative condition.

The patient was consequently diagnosed with chronic myeloid leukemia and referred to a hematology-oncology service where, after extensive investigations, she was treated with hydroxyurea and maintained on nilotinib (Tasigna; Novartis). Ocular examination after 3 months of treatment revealed normal ocular tissues. A recent blood workup showed near normal values.

Figure 2. Algorithm of workup for Roth spots.


Intraretinal hemorrhages with white or pale centers (Roth spots) are seen in various hematologic disorders, infectious diseases, and vascular conditions. Although initially believed to be pathognomonic signs of infectious endocarditis, Roth spots are now considered to be nonspecific signs of blood dyscrasias.

White-centered retinal hemorrhages discovered during fundus examination should raise the eye care physician’s suspicion for systemic conditions including anemia, thrombocytopenia, leukemia, subacute infectious endocarditis, diabetes mellitus (DM), hypertension, anoxia, preeclampsia, human immunodeficiency virus, arteriovenous malformation, collagen vascular disease, and multiple myeloma.1

Taking a detailed history and noting associated symptoms and signs at the physical examination may help the doctor choose appropriate investigations. CBC should be considered in all patients, as it can disclose many hidden diseases and provide grounds for further testing (Figure 2).

Figure 3. Fluorescein angiogram of retinal capillary hemangiomas before (left) and after laser photocoagulation.

CASE No. 2

A 23-year-old woman visited for a comprehensive eye exam. Her ocular history was remarkable for an exudative retinal detachment OD 5 years previous. Subsequent to the detachment, the patient was diagnosed with Coats disease and treated with intravitreal bevacizumab (Avastin, Genentech) and cryotherapy. Unfortunately, the globe shrank a few weeks after she received the treatment. A recent ocular examination at another facility, two weeks before our seeing her, did not suggest any abnormality OS. Her medical history was significant for hypertension controlled with atenolol 50 mg twice daily.

On examination, her BCVA was 20/20 OS. The patient could not see the brightest flashlight OD. Slit-lamp examination showed grade IV phthisis bulbi OD and a normal anterior segment OS. Dilated fundus examination exhibited two small retinal capillary hemangiomas (RCHs) in the left superotemporal retinal periphery. Fundus fluorescein angiography showed minimal leakage from the lesions (Figure 3). The patient was referred for magnetic resonance imaging of the brain, renal ultrasonography, and spinal x-ray.

Ultrasound and nephrology consultation confirmed that pheochromocytomas on both kidneys were the cause of the hypertension. The patient underwent surgery for pheochromocytomas and laser photocoagulation to the RCHs at different intervals. The patient is now on a schedule of biannual optometric follow-up and annual nephrologic and neurologic examination.

Family screening for von Hippel-Lindau (VHL) tumors was positive for a cerebral hemangioblastoma in an elder sister and multiple RCHs in a first-degree maternal cousin.


RCH is a well-defined, round, orange-red benign vascular tumor supplied by a pair of dilated and tortuous vessels and often found in the peripheral retina. Ten percent to 15% of RCHs occur in the peripapillary or juxtapapillary retina.2 The size of the tumor may range from 10 to 3,000 µm.3 The natural course is variable. The lesions may remain stable, regress, or enlarge and progress to cause exudation, tractional retinal detachment, neovascular glaucoma, and phthisis bulbi.3-5

RCH may occur sporadically or as part of VHL syndrome. Discovery of RCH on fundus examination must direct the clinician’s attention to the possibility of VHL disease. VHL disease (Online Mendelian Inheritance in Man entry No. 193300) is a rare, dominantly inherited, multisystem neoplastic disorder caused by a defect on the VHL gene. The VHL gene is a tumor suppressor gene mapped to 3p25-p26. The spectrum of disease includes hemangioblastoma throughout the craniospinal axis, renal cell carcinoma, pheochromocytoma, visceral cyst, and other tumors.6

Presence of either a central nervous system hemangioblastoma or a pheochromocytoma, in patients with a positive family history of VHL disease, satisfies the diagnosis. In the absence of a family history, two or more hemangioblastomas or one hemangioblastoma with a visceral cyst must be present.7

RCH is the most common presenting sign of VHL disease, occurring in up to 60% of patients.6,8 Multiple bilateral lesions indicate VHL disease. RCH may remain silent for several years. Nonetheless, most tumors progress slowly, causing retinal exudation (37%), tractional retinal detachment (22%), neovascular glaucoma (5%), and phthisis bulbi.4,9 Depending on the situation, RCH may be followed or treated with laser photocoagulation, cryotherapy, and anti-VEGF agents.

In identifying RCH in a patient, the optometrist may plan a proper workup, make appropriate referrals, and monitor for ocular complications, thus preventing the vision- and life-threatening complication of VHL. In addition, the optometrist can educate the patient about prognosis and possible complications and can screen family members for the VHL phenotype.

CASE No. 3

A 10-year-old boy was referred by his pediatrician for a diabetic retinopathy exam. He had DM of about 2 years duration, controlled with insulin. He was born to a marriage of first-degree consanguineous cousins, and his birth history was normal. A recent glycosylated hemoglobin report indicated good glycemic control. His general health otherwise was good. His ocular history was remarkable for a gradual visual decline during 2 years. He had never had an ocular exam before this visit.

Upon examination, his BCVA was 20/200 OU. Confrontation visual fields with careful finger counting were constricted; however, confrontation testing was unreliable because of poor patient cooperation. Extraocular motilities were full OU. The pupils were equally round but poorly responsive to light. Intraocular pressure measured 12 mm Hg OU. Anterior segments were normal OU. Dilated fundus examination was unremarkable except for pale, atrophic optic nerve heads OU.

In collaboration with the referring pediatrician, a detailed workup was ordered to rule out diabetes insipidus and other systemic abnormalities. Laboratory investigations including CBC, liver function test, renal function test, serum electrolytes, and urine and serum osmolalities all were normal. An endocrinology consult was negative for diabetes insipidus. An otolaryngology consult, however, was remarkable for high frequency hearing loss of more than 60 dB. Magnetic resonance imaging of the brain was within normal limits.


In cases of optic atrophy in young children, all causes of inherited neuropathies—compressive, nutritional, and toxic causes—should be considered (Table 1).

Wolfram syndrome (WS) is a rare spectrum of juvenile onset DM, diabetes insipidus, optic atrophy, and deafness, also known as DIDMOAD syndrome. It is caused by mutations of the WS gene (WFS1), mapped to chromosome 4p16, which encodes for the Wolframin protein. This protein plays a role in survival of islet beta cells and neurons and in membrane trafficking, protein regulation, and calcium homeostasis in the endoplasmic reticulum. Deficiencies in Wolframin increase stress within the endoplasmic reticulum, impair the cell cycle, alter calcium channel homeostasis, and cause apoptosis.10 Recent theories suggest that a mitochondrial dysfunction secondary to central nuclear mutations contributes to the overall phenotype.11

The minimal criteria for a diagnosis of WS are nonimmune-mediated DM type 1 and optic atrophy.12 DM in WS is typically of juvenile onset, insulin-dependent, and of nonimmune origin. It is the earliest manifestation in 84% of patients. Mean age at onset is 6.3 ±3 years.13 Diabetic retinopathy in WS patients is less frequent, less severe, and progresses more slowly than in other patients, perhaps because of easier and better controllability of DM in WS.14

In WS, optic atrophy usually develops after DM. The Washington University Wolfram Study Group found optic atrophy in 94% of patients, with average age at diagnosis of 7.5 years in males and 9.3 years in females.13 The mean duration from visual dysfunction to legal blindness has been reported to be 6.7 years, but rapid and severe visual dysfunction may rarely be encountered.15

Diabetes insipidus in WS is cranial in nature and caused by loss of vasopressin-producing neurons in the hypothalamus. It affects up to 73% of patients by a mean age of 15.5 years.16 Bilateral, symmetric, high-tone sensory hearing loss occurs at an average age of 14.6 (range 1-29) years.15 It affects 26% of patients in the second decade of life and progresses slowly.16


A wide range of systemic diseases and disorders can affect the ophthalmic apparatus in a variety of ways. These include neurological disorders, infection, inflammation, vascular disease, endocrine problems, hematologic abnormalities, and multisystem syndromes.

Commonly, the ocular signs of systemic disorders precede the classic systemic symptoms and signs. The familiarity of eye care providers with such signs and their associations may not only aid to establish a timely diagnosis but also help to avoid complications. This in turn increases the trust of patients in their eye care providers, promotes interaction with other specialists, and engenders more referrals from other health care providers (Table 2).

Several superb resources detailing the ocular aspects and impacts of systemic diseases are readily available. Clinical Medicine in Optometric Practice, 2nd Edition (Philadelphia: Elsevier) is an excellent textbook written by Bruce Muchnick, OD. Specifically written to meet the requirements of optometrists, it explains basic concepts, physical examination methods, and the significance of these investigations in optometric practices.

Eye care providers with a better understanding of systemic diseases and of ocular signs with systemic associations may save not only the vision and eyes of their patients, but also their lives.

“Whosoever saves a life, saves the entire human race.”



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14. Cano A, Molines L, Valero R, et al. Microvascular diabetes complications in Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness [DIDMOAD]): an age- and duration-matched comparison with common type 1 diabetes. Diabetes care. 2007;30(9):2327-2330.

15. Kinsley BT, Swift M, Dumont RH, Swift RG. Morbidity and mortality in the Wolfram syndrome. Diabetes care. 1995;18(12):1566-1570.

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Hashim Ali Khan, BSOpt, FAAO
• Consultative Optometrist at SEHHAT Foundation Hospital, Gilgit, Pakistan, specializing in retinal disorders • retinadr.hashimalikhan@gmail.com

Fatima Iqbal, OD
• Full-time faculty at University of Faisalabad School of Optometry, Pakistan
• Private practice at Abdullah Memorial Hospital Faisalabad