Advanced visual field loss secondary to optic nerve head drusen: Case report and literature review

Transcription

1 Optometry (2009) 80, Advanced visual field loss secondary to optic nerve head drusen: Case report and literature review Robert W. Morris, O.D., a Joy M. Ellerbrock, O.D., b Ania M. Hamp, O.D., a Jeffrey T. Joy, O.D., a Philip Roels, O.D., a and Charles N. Davis, Jr., O.D. a a W.G. Hefner VA Medical Center, Salisbury, North Carolina; and b TLC Eyecare of Michigan, Jackson, Michigan. KEYWORDS Optic nerve head drusen; Optic disk drusen; Autofluorescence; B-scan ultrasonography; Computed tomography imaging; Visual field; glaucoma Abstract BACKGROUND: Optic nerve head drusen (ONHD) is a relatively uncommon condition that results from calcific degeneration of axons within the optic nerve. The abnormal drusen bodies can enlarge, compressing normal nerve structures, and ultimately may result in vision loss. Drusen often are discovered through clinical evaluation with a dilated funduscopic examination. Ancillary testing, including computed tomographic (CT) imaging, B-scan ultrasonography, autofluorescence imaging, nerve fiber layer imaging, and threshold visual field evaluation are helpful to confirm the existence of ONHD and to evaluate for progression of this condition. CASE REPORT: This case report discusses the clinical presentation of a patient with advanced visual field loss from ONHD and the ancillary testing used to confirm the diagnosis. A complete review of literature on ONHD is discussed. CONCLUSIONS: Currently, there is no cure or direct treatment for progressive vision loss or complications that may develop from ONHD. Useful diagnostic tools include serial automated threshold visual fields, nerve fiber layer analysis, and fundus photography. It is suggested that ocular hypotensive agents be used to lower intraocular pressure prophylactically to prevent further nerve fiber layer and optic nerve damage. Optometry 2009;80: The first report of what is now referred to as optic nerve head drusen (ONHD) was a histologic description by Muller in He described crystalline, fatty-appearing granules in the optic nerve head 2 5 to 1,000 mm in size, 3 which were found intra- and extracellularly. 2,3 The first clinical description of the condition was published 10 years later by Liebrich. 4 Modern terminology is derived from Nieden who used the term Drusenbildung (drusen buildup) in 1878 to describe this clinical condition. 5 The term druse originates from German and is the singular form of Corresponding author: Robert W. Morris, O.D., Salisbury VA Medical Center, 1601 Brenner Avenue (11i), Salisbury, North Carolina robert.morris2@va.gov drusen, applying to a crystal-lined hollow space in a rock widely used in the mining industry in the 16th century. 1 The first reported case of visual field defects associated with ONHD was published in Historically, the literature includes other terminology such as colloid or hyaline bodies to describe optic nerve head deposits. 1 Case report A 59-year-old white man presented for his initial evaluation to the eye clinic at the Salisbury VA Medical Center. His chief complaint was that he felt his peripheral vision had changed, causing him to run into things. His last eye examination was approximately 1 year prior, and he denied /09/$ -see front matter - This is a U.S. government work. There are no restrictions on its use. Published by Elsevier, Inc. on behalf of the American Optometric Association. doi: /j.optm

2 84 Optometry, Vol 80, No 2, February 2009 any remarkable findings from that examination other than an update in his spectacle prescription. His personal and family ocular history was unremarkable. Medical history included medical treatment for depression, hyperlipidemia, seasonal allergies, history of kidney stones, and previous right carotid endarterectomy. His social history included a 1-pack per day cigarette smoking habit. Entering visual acuities with habitual correction were 20/ 20 in the right eye (O.D.), 20/40 in the left eye (O.S.). Pupils were equal, round, and reactive to light without afferent pupillary defect. Extraocular motility was full without restriction or overaction. Confrontation visual fields were constricted in both eyes (OU), with severe constriction to finger counting O.D. An updated refraction showed no improvement in visual acuity. External examination findings were unremarkable and anterior segment evaluation found mild bulbar conjunctival injection OU; clear corneas; deep and quiet anterior chambers; and normal lids, lashes, and irides OU. Tonometry by applanation measured 15 mmhg O.D. and 15 mmhg O.S. at 9:41 AM. Dilated fundus examination found a mild nuclear sclerotic cataract in each eye. Evaluation of the optic nerve showed small nerves with a 0.1 cup-to-disk ratio OU. Careful examination of the optic nerves found small, bright yellow deposits, more prominent in the temporal region of both nerves, with slightly irregular disk margins OU. The nerves were not inflamed or edematous but did appear full with peripapillary atrophy OU. The macula was clear in each eye, and vessels were of normal course and caliber. The retinal periphery was flat and intact 360 OU. At this point, the main concerns for the ocular health of this gentleman were the visual field defects detected by confrontation visual fields, the reduced vision in the left eye, and the full-appearance of the optic nerves OU. An automated visual field test was ordered to further investigate the visual field defects. The results confirmed the advanced constriction of the right eye greater than left. It also helped to substantiate the central vision loss O.S. caused by the fixation splitting defect (see Figures 1 and 2) Based on the advanced visual field loss in each eye and the subjective patient complaint of progressive peripheral field loss, an urgent magnetic resonance imaging (MRI) test was ordered to investigate the visual pathway for any pathology. Baseline fundus and optic nerve photography with autofluorescence was additionally obtained. The leading differential at this point was ONHD. A B-scan ultrasound scan would have been valuable to finalize the diagnosis; however, a B-scan was not available in our clinic at that time. Fundus imaging of the posterior poles and optic nerves are shown in Figures 3 and 4. Figure 5 shows a higher magnification of the optic nerve of the left eye allowing better visualization of the bright yellow deposits noted on dilated fundus examination. Retinal images were taken with both the barrier and exciter filters in place looking for autofluorescence. The optic nerve of both the right and left eye showed autofluorescence, giving strong evidence that the small yellow deposits were ONHD (see Figure 6 for an example of autofluorescence from another patient with ONHD). Ten days later, the MRI of the brain and orbits was performed and showed no evidence of an acute infarct, pituitary mass, suprasellar mass, intracranial mass or extraaxial collection. Scans through the orbits showed no evidence of an optic nerve signal abnormality, abnormal enhancement, or mass within either orbit. The MRI of the brain and orbits was considered negative. Based on the clinical appearance of the optic nerves, which showed autofluorescence, the advanced visual field defects and the clean MRI, a diagnosis of ONHD was made. The patient was told that his vision loss was a result of nerve damage from ONHD and that currently no proven treatments were available to reverse his vision loss or halt any progression. A repeat visual field was completed to confirm the original field defects. The subsequent visual field verified the extent and depth of the defects found on initial testing. Topical ocular hypotensive treatment was initiated to decrease intraocular pressure (IOP) prophylactically to attempt to preserve the health of the optic nerve. Given the patient s tubular fields, a low vision evaluation also was ordered. The main goal of this evaluation and rehabilitation was to increase awareness of his physical surroundings to improve his mobility. At a follow-up visit, optical coherence tomography (OCT) was utilized to further evaluate the optic nerve. The fast optic disk scan protocol showed shadowing of the deep optic nerve consistent with ONHD (see Figure 7). The fast retinal nerve fiber layer thickness scan and analysis measured advanced thinning of each eye, which is not definitive for ONHD but can help show the general health of the optic nerve (see Figure 8). The advanced nerve fiber thinning did support the degree of field loss found on visual field testing. The patient had been ordered to return every 6 months for dilated fundus examinations, automated visual fields, and retinal nerve fiber analysis to monitor for progression. When the B-scan unit became available, it was to be used to confirm calcification of the optic nerves. Unfortunately, repeated attempts to have the patient return for follow-up care were unsuccessful. Demographics and epidemiology Optic nerves with drusen can change appearance over time and have been detected in patients of all ages. Optic nerve head drusen found in children are typically buried and more difficult to visualize. 7,8 The youngest child reported with ONHD detected by B-scan ultrasonography was 3.8 years old, but the drusen did not become clinically visible for 2 years after detection by ultrasound scan. 9 With time, drusen can enlarge and migrate to a more superficial, visible position. In adults, the drusen often are described as having a lumpy, bumpy appearance and usually are located in the nasal half of the optic disk. 7,8 The prevalence of ONHD in the

3 Morris et al Clinical Research 85 Figure 1 Humphrey 24-2 visual field of the right eye at presentation shows severely constricted field loss greater than the left eye. adult population has been reported to be 0.34% by Lorentzen, 8 which is similar to the 0.4% found in children reported by Erkkila. 10 Histologic studies, however, have reported the prevalence to be 0.5%, 11 1 to 2%, 12 and 2.4% 13 in the adult population with 60% of the drusen located deep in the optic nerve. 11 It is important to note these epidemiologic studies were completed before the emergence of B-scan ultrasonography as a diagnostic tool for detection of ONHD in Optic nerve head drusen generally are bilateral with reports ranging from 66.6% to 91.2% 15 with a female predilection ranging from 57.6% to 71%. 16,17 Optic nerve head drusen are found to be more prevalent in whites than other races. 18 Mansour and Hamed 17 reported racial variation of optic nerve diseases in a 1991 report that included 85 cases of ONHD. They reported 80 of 85 (94.1%) patients with ONHD were white, and 5 of 85 (5.9%) were black (see Table 1). With regard to refractive error, several studies have shown that refractive error for patients with ONHD is similar to that of the general population. 7-10,19-22 Inheritance Many studies have investigated the inheritance pattern of ONHD. In 1961, Lorentzen studied 909 relatives of patients with ONHD and found 28 individuals with the condition

4 86 Optometry, Vol 80, No 2, February 2009 Figure 2 Humphrey 24-2 visual field of the left eye at presentation shows near-complete inferior hemianopsia and superior nasal defects. (3.1%), which is approximately 10 times the rate found in the general population. 23 As a result, he concluded ONHD are inherited in an irregularly dominant fashion. 23 A more recent article by Antcliff and Spalton 24 in 1999 studied 27 relatives of 7 unrelated patients with bilateral ONHD. They discovered only 1 of the 27 relatives had buried ONHD (3.7%) as detected by B-scan ultrasonography. They also described 30 of 53 (57%) eyes as having anomalous vessels (defined as trifurcation of the arterioles within or adjacent to the optic disk or the presence of cilioretinal vessels), and 26 eyes (49%) had no optic cup at all. They concluded the primary pathology of ONHD is most likely an inherited dysplasia of the optic disk and its blood supply, which predisposes to ONHD formation in some individuals. 24 Twenty to forty percent of eyes with ONHD have been observed to have cilioretinal arteries. 1 For comparison, the prevalence of cilioretinal arteries in the normal population has been reported at 15% 25,26 and 24%. 8 As a result of the irregularly inherited autosomal dominant pattern of ONHD, Spencer et al. 27 suggested ONHD is the most commonly inherited optic neuropathy. Forsius and Eriksson 28 found a 3.7% prevalence rate in 403 patients in the genetically isolated community in the Aland archipelago, which is roughly 10 times the percentage found in the normal population. This higher prevalence rate supports Lorentzen s theory of an irregularly dominant

5 Morris et al Clinical Research 87 Figure 3 Color fundus photography of the right eye shows superficial ONHD and peripapillary atrophy. inheritance pattern resulting in approximately 10 times the prevalence rate found in the general population. Abnormal vessels It has long been recognized that eyes with ONHD have anomalous vascular patterns in addition to structural anomalies. Some of these anomalies include bi- and trifurcations, 1 vessel tortuosity, 1 optociliary shunt vessels, 1 relatively large blood vessels connecting the superficial and deep disk circulation, 29 increased disk capillarity, 29 and cilioretinal vessels. 25,26 Auw-Haedrich et al. 30 theorized that coalescence of ONHD could lead to collateral vessel formation, and as drusen enlarge with age, shunt vessels become more apparent. 31 Lorentzen 8 described optociliary shunts as collateral networks that form between the retinal venous system and the choroidal network as a result of increased central retinal venous pressure. Based on the popular theory that a small scleral canal is typically found in these eyes as well as the ability for drusen to Figure 5 Higher magnification optic nerve photograph of the left eye shows superficial ONHD. expand within the crowded optic nerve, it is possible for increased central retinal venous pressure to contribute to optociliary shunt formation. However, the small scleral canal theory has recently been challenged by Floyd et al. 32 as a possible cause for development of ONHD. Further investigation is needed to determine the role of scleral canal size in the development of ONHD and how that may relate to optociliary shunt vessel formation in eyes with ONHD. Visual field As a result of progressive drusen formation, it is common to have visual field defects associated with ONHD. The prevalence of the visual field defects in adults has been reported to range from 24% to 87%. 8,20,23,33-36 The types of visual field defects reported in eyes with ONHD include Figure 4 Color fundus photography of the left eye shows superficial ONHD and peripapillary atrophy. Figure 6 Preinjection angiography photograph of another patient with ONHD shows autofluorescence of the superficial ONHD.

6 88 Optometry, Vol 80, No 2, February 2009 Figure 7 the scan. Optical coherence tomography optic nerve head analysis report for fast optic disk scan O.D. shows elevation of the nerve and deep shadowing on nerve fiber bundle defects, 33 arcuate defects, 34,37,38 enlargement of the blind spot, 8,20 and concentric narrowing. 35,39 Visual field defects are found to be more prevalent in eyes with superficial or visible drusen 34,35,40 and can appear during childhood, even preceding the clinical appearance of ONHD. 10 Hoover et al. 9 reported the mean age for detection of objective visual field defects was 14 years old. Katz and Pomeranz 41 reported that visual field defects are uncommon in eyes with buried drusen. They speculated that only when buried drusen are associated with other visible drusen does visual field loss occur. However, they also found focal retinal nerve fiber loss in patients without visual defects, which suggests ganglion cell damage that has not yet manifested as a visual field defect. Visual field defects generally progress at a very slow rate, often without patient awareness. A study of 6 patients with progressive visual field defects showed the shortest time to detect progression was 2.5 years, with an average time of 9 years. 42 Auw-Haedrich et al. 1 proposed the following pathogenetic mechanisms leading to visual field defects: 1) impaired axonal transport in an eye with a small scleral canal leading to gradual attrition of optic nerve fibers, 3,43 2) direct compression of prelaminar nerve fibers by drusen, 8,42 and 3) ischemia within the optic nerve head. 44 By testing the visual field with Goldmann perimetry, defects associated with ONHD were historically described as nerve fiber bundle defects. 45 These defects were reported to affect the inferior nasal quadrant most frequently. More recently, the percentage of visual field defects described as blind spot enlargement has been reported as 23% by Pietruschka and Priess, 20 60% by Lorentzen, 8 and 88.1% by Mustonen. 34 Auw-Haedrich et al. 1 suggested an alternative mechanism for enlargement of the blind spot found in eyes with ONHD. They reported this mechanism is most likely caused by leaking vessels and concomitant papilledema. In contrast to other reports of multiple types of visual field defects occurring in eyes with ONHD, they reported arcuate defects are the main (possibly only) type of visual field loss in drusen and are responsible for peripheral vision loss. When arcuate defects are very fine they may not be detected by routine automated perimetry. 1 Impact on visual acuity Several studies have reported the visual acuity impairment associated with ONHD (see Table 2). These studies show that drusen alone can cause a mild reduction in visual

7 Morris et al Clinical Research 89 Figure 8 Optical coherence tomography retinal nerve fiber layer thickness average analysis for fast retinal nerve fiber layer thickness scan shows significant retinal nerve fiber layer loss in both eyes. acuity but generally do not lead to severe vision loss. A 2004 study by Wilkins and Pomeranz 46 found that 70% of subjects with buried and visible disk drusen had a visual acuity of 20/20 or better, with an acuity of 20/50 being the worst visual acuity attributed to ONHD. Another report described a higher prevalence of severe vision loss caused by vascular occlusions, which were associated with deep ONHD. 47 In this study, deep drusen were associated with vascular accidents of the disk more often than superficial drusen. It is thought that deep drusen located near the lamina cribrosa may have more compressive effects on vascular structures than superficial drusen. If this is the case, many cases of anterior ischemic optic neuropathy (AION) or central retinal artery occlusion (CRAO) may be caused by ONHD that are not visible clinically. In a study of 40 children with ONHD, 35 had a bestcorrected Snellen visual acuity of 20/25 or better in both eyes. One child had reduced acuity in 1 eye caused by subretinal neovascularization, another had reduced acuity caused by steroid-induced posterior subcapsular cataracts, and the remaining 3 children had unilateral reduced acuity caused by amblyopia. 9 In cases in which visual acuity is severely impaired, advanced visual field defects generally are the culprit. That being said, transient amaurosis 44,48,49 or even permanent monocular blindness 20,50 caused by ONHD can also occur without signs of vascular complications. It is important to rule out other potential causes of vision loss in patients with ONHD, as compressive mass lesions have been masked by the presence of ONHD in patients with severe visual field and visual acuity loss. 1 Central visual loss can also be a result of another ocular condition; for example, there are numerous cases of vision loss caused by choroidal neovascularization membrane (CNVM) or subretinal hemorrhage. Pathogenesis Several theories have been proposed for the mechanism of optic nerve drusen development. Histochemical studies by Seitz and Kersting 51 in 1962 concluded that drusen originate from axoplasmic derivatives of disintegrating nerve fibers. They also made the important discovery that drusen develop by a slow degenerative process rather than a rapid process. In 1977 Sacks et al. 29 evaluated angiograms of optic nerves with drusen. When compared with normal controls

8 90 Optometry, Vol 80, No 2, February 2009 Table 1 Literature review of race association with ONHD Author (year published) No. white (%) No. black (%) Hoyt and Pont 19 (1962) 28/28 (100) 0/28 (0) Wise et al. 123 (1974) 16/17 (94.1) 1/17 (5.9) Boyce (1978) 39/46 (84.8) 7/46 (15.2) Rosenberg et al. 21 (1979) 128/133 (96.2) 5/133 (3.8) Hoover et al. 9 (1988) 37/40 (92.5) 3/40 (7.5) Mansour and Hamed 17 (1991) 80/85 (94.1) 5/85 (5.9) Adapted from Mansour and Hamed. 17 without drusen, the disks with drusen had the following vascular abnormalities: abnormal branching pattern on the disk, relatively large blood vessels connecting the superficial and deep disk circulation, and increased disk capillarity. As a result of these findings, Sacks et al. 29 concluded a congenital abnormality of the optic nerve vasculature that allowed deposition of extracellular materials was the reason for ONHD formation. One year later, Spencer 43 presented his findings during an Edward Jackson Memorial Lecture on the possible pathogenesis of ONHD. He proposed an alteration in axonal transport as the anatomic substrate for formation of disk drusen. In familial cases, the cause of axonal transport alteration may be related to the presence of a genetically determined, small, crowded optic nerve head. In 1981 Tso 3 reported the first ultrastructural study of ONHD in a correlative study of 18 cases. This report stated that abnormal axonal metabolism leads to intracellular mitochondrial calcification. Some axons may rupture, extruding mitochondria into the extracellular space. Small, calcified microbodies are produced, and calcium continues to deposit on the surface of the nidi, forming drusen. 3 From this study, he concluded that drusen are definitively related to axonal degeneration of the optic nerve head. Auw-Haedrich et al. 1 supported the axonal origin of drusen formation proposed by Tso 3 based on 3 factors: 1) drusen are located anterior to the lamina cribrosa, where intra-axonal material accumulates in all forms of disk edema; 2) evolution (slow increase in size caused by accumulation of axoplasma followed by later calcification, which should be preceded by axonal interruption); and 3) clinical and histopathologic similarity at a very early stage (before calcification) to lesions in the optic disk known to be caused by processes that chronically obstruct axonal transport, such as papilledema and enlarging melanocytoma. Kapur et al. 52 reported histologic findings of ONHD after surgical excision. They found the drusen material stained positively with periodic acid-schiff and von Kossa stains by light microscopy. They also reported that energydispersive spectroscopy showed emission peaks corresponding to calcium and phosphorous, suggesting that Ca 3 (PO 4 ) 2 was the salt present in ONHD. The emission peak was similar to an enucleated specimen with incidental ONHD. In addition, no axonal elements or blood vessels were identified by histopathologic evaluation. Kapur et al. 52 also noted that the discovery of Ca 3 (PO 4 ) 2 as the likely salt has implications on the pathogenesis of neuronal cell death in ONHD. Stasis of axoplasmic flow may contribute to ONHD formation, and certain patients with ONHD may be more prone to ischemia. Ischemia is a known trigger for phosphate-dependent calcium accumulation in neural mitochondria. The phosphate component of the Ca 3 (PO 4 ) 2 salt may derive from axonal cytoplasm. Furthermore, Ca 3 (PO 4 ) 2 precipitation in the mitochondria can then trigger further events leading to cell death. As a result, the presence of Ca 3 (PO 4 ) 2 may suggest an ischemic component to the etiopathogenesis of ONHD. Mullie and Sanders 53 reported the diameter of ONHD scleral canals was 20% to 33% smaller than the scleral canal diameter of normal optic nerves. In a 1991 report, Mansour and Hamed 17 explained that a small optic disk leads to crowding of the nerve fibers passing through a tight scleral canal. The crowding of nerve axons may lead to abnormal axonal metabolism and therefore drusen formation. In addition to reports of smaller scleral canals, patients with ONHD also have smaller optic disks than those of the average population. 53,54 The smaller scleral canal and optic nerve diameter may help explain why ONHD develops in whites more frequently than blacks. It has been reported that in addition to a smaller optic disk diameter, the scleral canal in whites is smaller than that of blacks, which adds Table 2 Visual impairment in eyes with ONHD Author (year published) No. of eyes studied No. of eyes with visual impairment No. of eyes with visual acuity impairment related to optic nerve drusen Lorentzen 8 (1966) Mustonen 22 (1983) Scholl et al. 90 (1992) * Boldt et al. 47 (1991) Percentage of eyes with visual acuity impairment due to ONHD * Scholl explained this by including more severely affected and symptomatic patients than other studies. Boldt reported 6 eyes evaluated for acute vision loss caused by CRAO or AION. Unilateral deep drusen was detected echographically in 5 of 6 of these eyes.

9 Morris et al Clinical Research 91 support to the theory of drusen formation caused by an anatomic predisposition. 55,56 The optic nerve scleral canal size was evaluated in a 2005 report by Floyd et al. 32 In their study, OCT was used to measure the optic disk and scleral canal of patients with ONHD by detecting the termination of the retinal pigment epithelium (RPE) and Bruch s membrane. The average area of the scleral canal in normal eyes was mm 2, the average area of the unaffected eye in patients with unilateral drusen was mm 2, and the average area for eyes with ONHD was mm 2. Based on the observation that disk size is inherited and bilaterally similar, 57,58 this study brings the compression theory of small scleral canal causing formation of drusen into question. Floyd et al. 32 offered the following alternate explanations for their observation of larger scleral canal sizes in patients with ONHD: 1) The calcified drusen bodies obscure the underlying RPE and Bruch s membrane making these structures appear to terminate prematurely, resulting in a larger measured scleral canal diameter. 2) As the optic nerves with drusen become distended, they cause circumferential displacement of the RPE and Bruch s membrane, which may result in the appearance of a larger diameter scleral canal without any actual change in the anatomical structure. 3) Optical coherence tomography measurements perpendicular to the incident light may be affected by the optics of the instrument or the eye. Floyd s most persuasive evidence that scleral canal size is not a factor in the development of ONHD is the nearnormal scleral canal size measured in the unaffected eye of patients with unilateral ONHD. They also observed that first-degree relatives of patients with ONHD have scleral canal size as large as or larger than normal, unaffected eyes. Because of this evidence, Floyd et al. 32 felt that a compressive etiology because of small scleral size seemed unlikely. Further studies will help clarify the role of scleral canal size and relation to optic nerve head drusen development. Common differentials Optic nerve head drusen can often give the appearance of a full or edematous optic nerve. In this case, it is reasonable to classify it as pseudopapilledema because the nerve is not truly edematous. It is important to consider other reasons for this appearance when evaluating a suspected case of ONHD (see Table 3). The most common clinical differentials are true papilledema and AION. It has been reported that some cases of ONHD cannot be differentiated from intrapapillary refractile bodies that occasionally form in cases of chronic papilledema. 59,60 According to Auw-Haedrich et al., 1 in cases of papilledema, the occurrence of refractile bodies precedes or coincides with vision decline and disappears as optic atrophy supervenes. These refractile bodies are thought to be residual exudates 61 or possibly incipient drusen caused by chronic axonal disturbance without calcification 43 and do not exhibit calcification by Table 3 Differential diagnosis of optic disk edema Papilledema Pseudotumor cerebri Ischemic optic neuropathy Arteritic and nonarteritic optic neuropathy Space-occupying lesions (e.g., astrocytic hamartoma) Optic neuritis Central retinal vein occlusion Optic nerve head drusen Uveitis Optic neuropathy Diabetic papillopathy Papillitis 145 Optic disk vasculitis 145 Infiltration of the nerve 145 (e.g., sarcoidosis, leukemia, lymphoma, tuberculous granuloma, metastasis, other inflammatory disease or tumor) Leber optic neuropathy 145 Optic nerve sheath meningioma 145 Graves ophthalmopathy 145 Amiodarone toxicity 145 Spinal tumors 146 Acute idiopathic polyneuropathy 146 (Guillain-Barre syndrome) Mucopolysaccharidoses 146 Craniosynostoses 146 Foreign body lodged at the optic nerve 47 Adapted from Gay and Boyer. 96 either CT or B-scan ultrasonography. Clinical features of ONHD and papilledema are compared in Table 4. The echographic appearance of ONHD has limited differentials. A foreign body lodged at the optic nerve could appear similar to that of ONHD. 47 Other conditions that have calcification could appear similar echographically to that of ONHD, including granuloma, a vascular lesion of the optic nerve, or a small astrocytoma. 47 Unfortunately, testing for an afferent pupillary defect (APD) would not help discriminate between ONHD and papilledema, as an APD has been reported as the rule rather than the exception in the setting of unilateral or asymmetric visual field loss from ONHD without loss of visual acuity. 46,62-65 The other most common differential to consider is AION. It is possible for AION to develop in eyes with ONHD; this typically occurs at a younger age than is usually seen in patients with AION without ONHD and is even found in teens and young adults. 31 These patients do not typically suffer from the usual risk factors associated with AION. 21,44,40,48,66-70 Purvin et al. 71 proposed 2 possible explanations for AION occurring at a younger age in patients with ONHD: 1) drusen bodies themselves act directly on healthy optic disk vessels to cause infarction, and 2) progressive thinning of the nerve fiber layer in eyes with nerve head drusen may make the disk less crowded and therefore less susceptible to infarction later in life. The infarction theory corresponds with that of Auw-Haedrich 1 and Gittinger, 67

10 92 Optometry, Vol 80, No 2, February 2009 Table 4 Comparing signs of true papilledema and ONHD Clinical feature True papilledema ONHD Nerve fiber layer edema Present 1 Absent 125 Superficial optic nerve vessels Ectasia of superficial optic nerve vessels 1 Lack of telangiectatic superficial disk vessels 125 Obscuration of retinal vessels at Present 96 Absent 61 disk margin Cotton wool spots Present 31,96 Absent Hemorrhages Multiple hemorrhages around optic disk 31 Splinter, optic nerve head hemorrhages extending into the vitreous, deep papillary and deep peripapillary that may extend into macula; 2% to 10% Hyperemia Hyperemia 31 Absent Venous congestion Present 31 Absent Patton s lines Present 31 Absent Exudates Present 31 Absent Increased intracranial pressure Present 31 Absent Visual field defects Visual acuity Enlarged blind spot and peripheral constriction 147 Usually not affected unless papilledema is severe, long-standing, or accompanied by macular edema or hemorrhage 147 Nerve fiber bundle defects, arcuate defects, enlarged blind spot, and concentric narrowing Rarely affected by ONHD alone Transient vision loss Classic symptom of papilledema 147 Generally absent, but reported in up to 8.6% Double vision Present Absent Nausea and vomiting Present Absent Spontaneous venous pulse Absent Present Headache Present Absent but the theory of a less-crowded disk caused by nerve fiber layer thinning offers a unique perspective into the lower rate of AION in older eyes with ONHD. Sarkies and Sanders 72 reported that up to 8.6% of patients with ONHD report transient visual obscurations (TVO). Sadun et al. 73 also reported TVO to be a well-described observance in those with ONHD. In comparison, TVO is quite uncommon in patients with nonarteritic ischemic optic neuropathy. In contrast to previous reports that describe visual field loss as the culprit in case of severe vision loss, Gittinger et al. 67 reported vision loss in patients with ONHD as most commonly associated with AION, and this ischemic event is in part caused by an anatomic predisposition and disk crowding over time. 67 Farah and Mansour 74 stated both AION and disk drusen share a similar pathophysiology of axonal crowding from a tight scleral canal. Auw-Haedrich et al. 1 further reported that this occurs because the prelaminar and laminar pial and choroidal nourishing arteries may develop ischemia because of the increasing size of the drusen within the optic nerve. Diagnosis and imaging Multiple imaging methods have been described to detect drusen, but currently there is no standard protocol for diagnosing ONHD. The most common method for detection of ONHD is through a dilated funduscopic evaluation. Methods to aid in diagnosis or to monitor for progression include disk photography, preinjection fluorescein angiogram (autofluorescence), B-scan ultrasonography, CT imaging, serial nerve fiber layer analysis, automated threshold visual field evaluation, and electrodiagnostic testing. The ability of some methods to detect drusen is dependent on the depth of the drusen. Utilization of B-scan ultrasonography to detect ONHD was described in the mid 1970s and can detect both superficial and deeply buried drusen of the optic nerve head B-scan ultrasonography is able to identify the presence of drusen because of its ability to detect calcium deposits and is the most reliable method to detect ONHD. 76 The drusen show up as an echo of extremely high reflectivity at, or within, the optic nerve head with acoustic shadowing in the medium-gain setting. 48,80,81 Another pathognomonic sign of ONHD is the posterior cone of shadowing that occurs as a result of the highly reflective nature of the drusen. 18 The easiest ultrasound approach is axial, but has the limitation of a weaker signal, as the ultrasound beam passes through the lens twice. For improved resolution, the transverse and longitudinal approaches bypass the lens and are able to more clearly show the highly reflective calcified drusen at lower gain settings. 47,82 One of the advantages of B-scan as a diagnostic tool is its ability to scan the entire area of the optic nerve allowing

11 Morris et al Clinical Research 93 Table 5 Differential diagnosis of posterior pole calcifications as seen on CT scan 85 Diagnosis Location CT appearance Other CT scan signs ONHD Optic nerve head Well defined, small Elevated optic nerve Astrocytic hamartoma Optic nerve head Similar to ONHD, but larger Prepapillary tumor Retinoblastoma Retina and vitreous body Large, floccular Intraocular tumor Optic nerve glioma Optic nerve Punctiform or nodular Optic nerve enlarged Choroidal osteoma Juxtapapillary choroid Crescentic None Scleral calcification Sclera Crescentic, discontinuous None Retrolental fibroplasia Choroid Crescentic Lens calcification Phthisis bulbi Diffuse Small, calcified, ocular globe Globe atrophy more reliable and accurate results. 76 A disadvantage is that some false-positive results can occur with B-scan ultrasonography in the presence of other optic nerve disorders including pseudodrusen in chronic papilledema, calcified granuloma of the optic disk, a vascular lesion, or an astrocytoma. 76 In 1978, Frisen et al. 83 were the first to describe buried ONHD that were not evident clinically but could be imaged by CT. Ramirez et al. 84 described the typical CT appearance of ONHD as discrete, rounded calcifications that were confined to the superficial layers of the optic disk. 84 With the appropriate slice thickness, CT is capable of precisely disclosing the location of the drusen in the optic nerve head. 85 Some disadvantages of CT imaging for ONHD include the significantly higher cost of the study, the additional exposure to ionizing radiation, and the risk of not imaging the drusen between the scan slices. When considering CT imaging to detect calcification of the drusen, a clinician needs to be aware of other causes of posterior pole calcification to accurately determine if calcification observed on CT imaging is truly caused by the presence of ONHD or by other pathology (see Table 5). CT imaging can be more useful than imaging with an MRI when it is necessary to rule out an intracranial mass in the presence of ONHD because it can detect the calcium deposits in the drusen. However, an MRI is a more sensitive method to detect intracranial lesions. Kurz-Levin and Landau 76 compared B-scan ultrasonography, CT, and autofluorescence imaging techniques for diagnosing ONHD. They found no cases in which a B-scan failed to diagnose drusen that were identified by either autofluorescence or CT imaging. The B-scan was able to correctly identify 21 of 21 eyes with ONHD, whereas CT imaging correctly identified 9 of 21 (42.9%), and autofluorescence identified 10 of 21 (47.6%) eyes with ONHD. Although CT imaging is capable of detecting drusen of the optic nerve, it was the least reliable method tested in their study. The most common reason for misdiagnosis with CT imaging is scanning with thick slices, thus missing the drusen. However, orbital CT scans did prove more reliable than autofluorescence in detecting buried drusen. Based on their findings, autofluorescence is best suited for confirming superficial drusen of the optic nerve but is not a reliable method for detecting buried drusen. When attempting to identify suspected buried drusen, a B-scan was able to identify 39 of 82 (47.6%) eyes with ONHD, whereas autofluorescence only identified 15 of 82 (18.3%) eyes with buried ONHD. From their experience, Kurz-Levin and Landau 76 suggested that B-scan ultrasonography be the examination of first choice for suspected drusen of the optic nerve head as a noninvasive, inexpensive and easy-to-learn imaging technique. B-scan ultrasonography offers the highest sensitivity to detect drusen in all layers of the optic nerve head as well as a simple, rapid, and reliable testing method. It has also been reported that an additional major advantage of echography is that a standard A-scan can be utilized to evaluate the retrobulbar optic nerve to rule out other concomitant optic nerve disorders. 47 This report described the additional benefit of A-scan, as it was found to be helpful in diagnosing pseudotumor cerebri and optic neuritis in patients initially thought to have ONHD. 47 Autofluorescence can be a useful tool to aid in the diagnosis of visible, superficial drusen but is of little value for buried drusen of the optic nerve head or in patients with media opacities. In the Kurz-Levin and Landau study, 76 autofluorescence was able to detect 96% of superficial drusen compared with only 27% with buried drusen. Autofluorescence has also been described as preinjection fluorescein angiography. To perform this technique, the exciter and barrier filters used in fluorescein angiography are in place, but the images are taken without the injection of fluorescein. If drusen are present, the drusen will appear lighter and almost glow. (Autofluorescence is not diagnostic for ONHD, as there are other optic nerve conditions that can autofluorescedfor example, astrocytic hamartoma.) Newer digital imaging techniques have been reported to be useful in the evaluation of ONHD. Many of these methods measure the nerve fiber layer in a quantifiable and repeatable way. This can be helpful because nerve fiber layer loss is a pathologic finding observed with progressive nerve head drusen. 31 Scanning laser ophthalmoscopy (SLO) has been described as a method of imaging ONHD. 86 Kurz-Levin and Landau 76 found imaging with the SLO to be valuable because the associated anomalous disk features could be demonstrated; however, it does not seem to be superior to B-scan because this additional information is only of limited value once

12 94 Optometry, Vol 80, No 2, February 2009 Table 6 Ocular disorders found by chance in association with ONHD Aneurysm of the opththalmic artery Astrocytic hamartoma Atrophic gyrata Birdshot chorioretinopathy and Cacchi-Ricci syndrome Congenital night blindness Familial macular dystrophy Glaucoma Nanophthalmos 148 Peripapillary central serous retinopathy Pigmented paravenous retinochoroid atrophy Thick cornea Central and branch retinal artery occlusion Central and branch retinal venous occlusion Retinitis pigmentosa Angioid streaks Adapted from Auw-Haedrich et al. 1 drusen have been detected. Haynes et al. 86 reported a series of 12 eyes with ONHD scanned with SLO. 86 They reported that SLO is an excellent method for the diagnosis of optic disk drusen and its associated nerve head abnormalities even in the presence of significant lens opacity. This is in comparison with their report of poor demonstration of typical drusen features using B-scan ultrasonography in an eye with significant media opacities. Optical coherence tomography of ONHD has been shown to show elevation of the optic nerve head and shadows on imaging and can be useful in the management of ONHD by following nerve fiber layer changes over time. 87 Roh et al. 88 measured the nerve fiber layer using OCT in 30 patients with ONHD and found localized nerve fiber layer thinning in quadrants in which the drusen were aggregated. These areas corresponded to visual field defects on perimetry. Similarly, Mustonen and Nieminen 89 and Stevens and Newman 36 found visible ONHD were usually associated with thinning or atrophy of the peripapillary nerve fiber bundles. This thinning correlated with visual field defects but did not always correlate with the degree of visual field loss. Electrodiagnostic testing is not commonly used for eyes with ONHD but can provide some useful information. The electroretinogram (ERG) is most useful when the nerve fiber layer and visual acuity are subnormal. 31 Scholl et al. 90 studied 24 eyes that had ONHD and found 79% had a reduced pattern ERG or absent N95 component. These findings suggest poor ganglion cell layer function. 90 Stevens and Newman 36 reported abnormal visual evoked potential (VEP) in 95% of eyes with ONHD caused by peripapillary nerve fiber layer malfunction. It is also reported that the p100 latency is prolonged, similar to those found in optic nerves with demyelinating disease. An abnormal VEP alone should not be used to automatically diagnose demyelinating disease, as similar findings can be found in cases with ONHD. 91 Associated ocular complications Optic nerve head drusen have been reported to occur in eyes with other ocular disorders not necessarily linked to the drusen. 1 Ocular disorders found by chance in association with ONHD are listed in Table 6. Retinitis pigmentosa The association between ONHD and retinitis pigmentosa has long been known. 92 The prevalence of this combination has been reported to be between 0% and 10%. 8,93 However, many reports find that eyes with ONHD associated with retinitis pigmentosa have normal-sized disks and scleral canals, 94,95 and there is no disk elevation. 43 This is in comparison with idiopathic ONHD that may have smaller disks and scleral canals and can have elevated optic nerves. 31 Further investigation into patients with retinitis pigmentosa and ONHD finds individuals with Usher syndrome, which involves concurrent hearing impairment and retinitis pigmentosa. The 2 types of Usher syndrome exhibit a different prevalence of ONHD. 96 Usher type I manifests with severe hearing loss, unintelligible speech, and absent vestibular responses. Type II Usher syndrome has less severe hearing loss, intelligible speech, and positive vestibular responses with caloric testing. Drusen of the optic nerve was found in 35% of patients with type I Usher syndrome and 8% in type II Usher syndrome. 97 Vascular occlusions All types of vascular occlusions have been reported to occur in eyes with ONHD 20,34,35,47,51,74,93, and generally are thought to be caused by vascular compression at or within the optic nerve. CRAO in patients with ONHD has been reported in children as well as adults, 48,74,104 but the pathophysiology in these cases is evidently not just drusen alone. 31 Systemic hypertension, 106 migraine, 34,105,107 oral contraceptives, 105 atrioseptal defects, 108 and high altitude 108 all have been implicated as contributing factors for CRAO in eyes with ONHD. Farah and Mansour 74 proposed a dual mechanism for CRAO in the case of a 39-year-old white man with ONHD and CRAO. 74 This report proposed both external and internal compression as the mechanisms of the CRAO. The external pressure on the hereditary small optic disk leads to further crowding of nerve fibers passing through a tight scleral canal. The internal pressure is caused by the unyielding properties of the drusen that compresses the retinal vasculature. Their proposed mechanism of external pressure on a tight scleral canal contributing to ONHD

13 Morris et al Clinical Research 95 development conflicts with the more recent report by Floyd et al. 32 that state patients with ONHD may not have a smaller tight scleral canal. Seitz and Kersting 51 reported 2 of 7 cases studied had central retinal vein occlusion (CRVO) with ONHD. They postulated that drusen enlargement gradually leads to compression of the central retinal vein resulting in occlusion. Some CRVOs associated with ONHD were suggested to be associated with hormonal contraception similar to that reported in CRAO. 109,110 From an anatomic perspective, the central retinal vein normally narrows as it traverses the lamina cribrosa. 111 The risk of a CRVO increases in the presence of any material or condition that might cause increased turbulence or further narrowing of the vein as in the case of ONHD. 112 Boldt et al. 47 reported 6 of 48 patients with ONHD had vascular occlusions at the level of the optic nerve. They found unilateral deep drusen on the side of the occlusion in 5 of these patients, lending further support to the mechanical compressive theory of vascular structures by ONHD. Choroidal neovascular membrane Choroidal neovascular membranes (CNVMs) have been reported in eyes with ONHD in children as well as young adults. 1,31,38, The youngest reported case of CNVM in an eye with ONHD was a 3-year-old child. 116 In other reports of CNVMs in eyes with ONHD, ages ranged from 8 to 24 years. 113,114,117,118 Mustonen 22 reported on 2 children with subretinal neovascularization with ONHD in a series of 200 patients studied. Choroidal neovascularization is typically located near the optic nerve, occasionally extending toward the macula but rarely involving the macula. 1 Any peripapillary CNVM has the potential to cause central vision loss in 3 ways: 119 1) subfoveal progression of the CNVM, 2) serous macular detachment, and 3) submacular hemorrhage. Different treatment strategies are discussed in the literature including observation, laser photocoagulation, photodynamic therapy (PDT) and surgical removal of CNVMs in eyes with ONHD. Observation has been suggested for CNVMs that are not threatening vision because many CNVMs in eyes with ONHD resolve on their own with potential for good visual recovery. Choroidal neovascular membranes associated with ONHD occasionally hemorrhage, and the resulting visual symptoms usually resolve with mild to moderate vision loss without requiring treatment. 31 Harris et al. 114 described 6 of 7 patients with CNVM with ONHD who regained visual acuity of at least 20/40 without treatment. 114 They proposed avoiding routine photocoagulation of peripapillary CNVMs secondary to optic disk drusen. Laser photocoagulation was recommended only for CNVMs that cause hemorrhage or chronic serous macular detachments and for extensive CNVMs. Combining reports of CNVMs that involved the macula, Wise, 123 Brown, 113 Saudax, 117 and Mateo 119 reported on cases that included 9 CNVM eyes that did not receive any treatment. 119 Five of the 9 (56%) ended up with 20/ 60 or better visual acuity, and 4 of the 9 (44%) regressed in 20/200 or worse vision. Delyfer et al. 120 reported on 2 patients with CNVM associated with ONHD that were treated with laser photocoagulation. Both patients had subretinal hemorrhages extending into the macula that threatened macular function and vision. Visual acuity pretreatment was 20/100 in each case and returned to 20/20 and 20/30 after 10 months. No recurrence was noted in either case after 24 months of follow-up. Mateo et al. 119 discussed PDT for CNVMs associated with ONHD. 119 When treating the whole CNVMs, which are often juxtapapillary in the case of ONHD, the optic nerve would often be included in the treatment area. This could lead to either incomplete coverage of the CNVM or optic nerve damage. As a result, they could not recommend PDT in the treatment of CNVM localized within 200 mm of the optic nerve. Mateo et al. 119 also reported surgical removal in 4 cases of CNVMs associated with ONHD. Preoperatively, vision loss in 3 of the cases was caused by subfoveal extension of the neovascular membrane, and one had a serous-hemorrhagic retinal detachment. The 4 patients in this study showed significant visual recovery after surgical removal of the CNVMs without any evidence of recurrence during 12 to 42 months of follow-up. They concluded that surgical removal is a reasonable management option for central vision loss caused by CNVM associated with ONHD. Hemorrhages Retinal hemorrhages have been discovered in eyes with ONHD without impact on visual acuity 114 ; these generally have a good visual prognosis. 1 The prevalence of retinal hemorrhages ranges from 2% to 10%. 21,22,100,114,115 Theories on the pathomechanism of retinal hemorrhages include 1) erosion of disk vessels by enlarging drusen, 2) congestion and venous stasis of retinociliary venous communications, 69 and 3) ischemia. 121 Four types of hemorrhages have been described in eyes with ONHD: 1) splinter hemorrhages in the nerve fiber layer, 2) hemorrhages of the optic nerve head extending into the vitreous, 3) deep papillary hemorrhages, and 4) deep peripapillary hemorrhages with or without extension into the macula. 1,31 Flame hemorrhages associated with ONHD tend to present individually on or adjacent to the disk and are visually insignificant. 34,122 This is in contrast to splinter hemorrhages found with papilledema, which typically are multiple flame hemorrhages in the nerve fiber layer and can obstruct vision. 13,31 Deeper hemorrhages associated with ONHD can appear surrounding the optic nerve in the subretinal or subretinal pigment epithelial spaces 31 and may be caused by occult neovascularization, direct venous compression, or vascular wall erosion by sharp-edged drusen. 69,123