Neuro-ophthalmic manifestations of diabetes1

Guest Editorial Neuro-ophthalmic Manifestations of Diabetes The neuro-ophthalmic manifestations of diabetes not only involve different locations in the brain, but also occupy disparate areas in the field of neuro-ophthalmology. This editorial considers many aspects of this complex disease by dividing the neuro-ophthalmic manifestations of diabetes into four systems. Diabetes-associated pathology may affect (1) the afferent visual system; (2) the pupillary and accommodative reflexes; (3) the efferent system; and (4) the orbit and its associated structures. Juvenile diabetic papillitis is appropriately described as diabetic papillopathy (DP) because there is no significant inflammatory component and it also occurs in older patients with type II diabetes.1 Diabetic papillopathy usually presents with a slower progression and milder optic nerve dysfunction than anterior ischemic optic neuropathy (NAION) or optic neuritis.1 Visual acuities are usually 20/40 or better, the visual field shows central scotomas or peripheral constriction, and the fundus examination may show hemorrhagic disc swelling of one or both optic discs. The optic disc may be slightly blurred and the blood vessels tortuous and telangiectatic.2 These findings may be difficult to distinguish from those seen in NAION. Disc edema with severe, persistent poor vision should suggest NAION. Disc surface telangiectasia may be so prominent as to convey a false impression of neovascularization. Telangiectasia probably reflects the shunting of blood from the prelaminar to peripapillary ischemic areas. The differential diagnosis of DP also includes papilledema, hypertensive papillopathy, and papillophlebitis. Systemic corticosteroids are of questionable benefit and will aggravate blood sugar control. Optic disc edema and telangiectatic changes generally resolve over a period of several months, although mild optic atrophy may persist. Nonarteritic anterior ischemic optic neuropathy is a common (3 per 100,000-population/year) acute optic neuropathy, usually seen in older patients. There may be an abrupt and profound loss of vision, color vision and brightness sense deficits, an afferent pupillary defect, and a characteristic altitudinal visual field defect. The sectoral optic disc edema will resolve over several weeks, leaving an atrophic disc. The pathogenesis of NAION probably involves a structural crowding of the optic disc (the “disc at risk”) in which symptoms are triggered by a vasculopathy such as hypertension or diabetes.3 The most important differential diagnosis to NAION is arteritic AION (temporal arteritis), treated effectively with corticosteroids. Idiopathic optic neuritis, particularly in patients under the age of 45 and more exotic causes of optic nerve head inflammation, such as sarcoidosis or syphilis, may also have to be considered.2 There is no known effective treatment for NAION. Spontaneous improvement in the range of approximately 3 Snellen lines is seen in approximately one fourth of NAION patients.4 Central retinal artery occlusion (CRAO) presents with severe, painless, and abrupt loss of vision. Early diagnosis is possible due to the characteristic fundus findings of a whitened retina with a prominent central “cherry red spot,” arteriolar attenuation, and the “boxcarring” segmentation of blood flow. One fourth of all patients with CRAO have diabetes. Ocular ischemic syndrome reflects the variable spectrum of signs and symptoms that come from chronic ocular hypoperfusion. Terms such as venous stasis retinopathy may be confused with nonischemic central vein occlusion and should be avoided. Ocular ischemic syndrome is often caused by severe carotid artery obstruction. The visual loss may be mild or severe and generally progresses gradually and may also involve the anterior segment. Fluorescein angiography may demonstrate delayed choroidal and retinal circulation times. More than half of all patients with ocular ischemic syndrome have diabetes.5 Optic nerve hypoplasia (ONH) is now recognized as a relatively common cause of blindness in children. This congenital abnormality is associated with a subnormal complement of axons in the optic nerve. It is most often seen in children born to mothers who were diabetic or exposed to certain medications (especially anticonvulsants).6 Optic atrophy reflects the permanent loss of retinal ganglion cell axons produced by a variety of causes. At least two mild forms of optic atrophy are directly due to diabetic retinopathy.7 First, multiple nerve fiber layer infarcts will accumulate over time, manifested as temporal pallor or general diffuse optic atrophy. Second, while panretinal photocoagulation (PRP) is usually sufficiently peripheral as to not involve the concentration of retinal ganglion cells and their axons near the macula, many retinal ganglion cells are destroyed. Patients with longstanding diabetes, particularly juvenile onset diabetes, may develop a moderately dilated pupil with light/near dissociation even though they preserve good central vision. This slightly dilated tonic pupil may resemble Adie syndrome, except that there is usually no segmental denervation of the iris sphincter notable on slit-lamp examination. The likely explanation for the diabetic pupil is a form of peripheral neuropathy involving the parasympathetic supply to the pupil. Difficulties with accommodation may be manifested as either a reduced range of accommodation (premature presbyopia) or a decreased speed of accommodation. Additionally, changes in the refractive power of the lens may be induced by the hyperglycemia and lens swelling. The most common neuro-ophthalmic problems in the diabetic patient are those of ocular motility. Patients generally present with complaints of diplopia from a complete or partial paresis of cranial nerves III, IV, or VI. In the elderly such palsies are often due to a microvascular lesion associated with diabetes. Diabetes is not the only risk factor for microvascular lesions of this sort; age and hypertension also contribute to atherosclerosis. All adult patients with sudden ophthalmoplegia are suspect for diabetes, and a glucose tolerance test usually should be obtained. The differential diagnosis in an adult with an isolated third, fourth, or sixth nerve palsy includes microvascular infarction, vasculitic infarction, a compressive lesion, trauma, inflammation, and in the young, ophthalmoplegic migraine.1 The risk of aneurysm is much higher for an isolated third nerve palsy but almost always involves the pupil. Trauma is also a frequent cause of fourth nerve palsy. A sixth nerve paresis may be nonlocalizing and reflect increased intracranial pressure.8 Involvement of one of these three cranial nerves causes the patient to present with sudden onset of diplopia, unless, in the case of third nerve palsy, ptosis blocks vision. Notwithstanding what is often taught to residents, microvascular cranial nerve palsies may present with orbital pain in up to 20% of cases.8 Most patients with isolated pupil-sparing third, as well as fourth or sixth nerve palsies, can be followed conservatively for the first 2 to 3 months, by which time there usually is a dramatic or even complete recovery. A more extensive work-up (including scans) may be delayed up to 3 or 4 months in the absence of recovery. However, the prudent clinician should remember six important caveats: (1) Pupil

Modified from notes for Diabetes and the Eye, January 1998, Long Beach Memorial Hospital. Course Director, Jerry Sebag, MD.

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Ophthalmology Volume 106, Number 6, June 1999 involvement in a third nerve palsy implies a compressive lesion, particularly a posterior communicating artery aneurysm. Urgent neuroradiologic work-up is indicated; (2) Beware of the simultaneous presentation of two or more cranial nerves. Multiple nerve involvement is a clear indication that something other than a diabetic microvascular lesion is occurring; (3) Patients under the age of 45 with an isolated cranial nerve palsy do not have a microvascular infarct even if they have longstanding juvenile- or adult-onset diabetes; (4) Temporal arteritis may present as a microvascular insult to a cranial nerve or eye muscle as well as to the optic nerve. Hence, in the elderly, it is crucial to investigate by history and physical examination all of the factors that might suggest this treatable diagnosis. Erythrocytic sedimentation rate, a complete blood count, and a C-reactive protein test can be very helpful. If in doubt, obtain a temporal artery biopsy while covering the patient with corticosteroids. In diabetics, the biopsy should be done as soon as possible so that the patient’s blood sugar control is not upset by unnecessary corticosteroids; (5) The general rule that a pupil-sparing third nerve palsy is not due to an aneurysm or other compressive lesion has one important exception. If the isolated third nerve palsy is incomplete, it may still be “in evolution”; and (6) There should be at least partial recovery of the diabetic microvascular cranial nerve palsy by 2 or 3 months. Most authors advocate initiating a comprehensive work-up only if there is no recovery by 3 to 6 months.9 With these six considerations in mind, the clinician can generally spare the patient and his third-party payer the time and cost of more extensive investigations by awaiting the spontaneous resolution of these cranial nerve palsies. Even more than diabetic retinopathy, ocular motor lesions may be sentinels of poor blood sugar control. Patients with diabetes mellitus have a partly compromised immune system. Particularly if they are in acidosis, these patients are vulnerable to infections, particularly fungal infections. In a diabetic patient presenting with an orbital apex syndrome manifested by proptosis, ophthalmoplegia, or visual loss, orbital mucormycosis must be considered. It is critical to make this diagnose early because mucormycosis is known for its ability to rapidly invade arterial vessels, which can thrombose and facilitate the rapid spread of infection and necrosis. Acidosis appears to be more important than the hyperglycemia found in diabetics in this frequently fatal syndrome. The keys to diagnosis are suspicion, neuroimaging, and biopsy. Early diagnosis, the correction of acidosis, and aggressive surgical debridement with treatment using amphotericin B gives hope of survival. Even today, the overall mortality rate in mucormycosis exceeds 50%.10 Readers should not mistake this brief summary for a comprehensive review of a complex topic. Its value relates to helping interested clinicians recognize the myriad neuro-ophthalmic manifestations of diabetes. In a larger context, this unusual approach may help us come to the view that each of these very distinct neuro-ophthalmic syndromes is but a different manifestation of one disease. References 1. Regillo CD, Brown GC, Savino PJ, et al. Diabetic papillopathy. Patient characteristics and fundus findings. Arch Ophthalmol 1995;113:889 –95. 2. Arnold AC. Ischemic optic neuropathy, diabetic papillopathy, and papillophlebitis. In: Yanoff M, Duker JS, Augsburger JJ, et al, eds. Ophthalmology. London; Philadelphia: Mosby, 1998;7.1–7.6. 3. Sadun AA, Rubin RM. The anterior or visual pathways [review]. J Neuroophthalmol 1996;16:137–51. 4. Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. The Ischemic Optic Neuropathy Decompression Trial Research Group. JAMA 1995;273:625–32. 5. Sivalingam A, Brown GC, Magargal LE, Menduke H. The ocular ischemic syndrome. II. Mortality and systemic morbidity. Int Ophthalmol 1989;13:187–91. 6. Nelson M, Lessell S, Sadun AA. Optic nerve hypoplasia and maternal diabetes mellitus. Arch Neurol 1986;43:20 –5. 7. Sadun AA. Optic atrophy and papilledema. In: Albert JM, Jakobiec FA, eds. Principles and Practice of Ophthalmology: Clinical Practice. Philadelphia: W. B. Saunders, 1994; V.4, chap 200. 8. Moster M. Paresis of isolated and multiple cranial nerves and painful ophthalmoplegia. In: Yanoff M, Duker JS, Augsburger J, et al, eds. Ophthalmology. London; Philadelphia: Mosby, 1998;16.1–16.12. 9. Savino PJ, Hilliker JK, Casell GH, Schatz NJ. Chronic sixth nerve palsies: Are they really harbingers of serious intracranial disease? Arch Ophthalmol 1982;100:1442– 4. 10. Parfrey NA. Improved diagnosis and prognosis of mucormycosis: A clinicopathologic study of 33 cases. Medicine (Baltimore) 1986;5:113–23.

ALFREDO A. SADUN, MD, PHD Los Angeles, California

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