globular concretions, often collected in larger, multilobulated agglomerations. Individual drusen usually exhibit a concentrically laminated structure that is not encapsulated and contains no cells or cellular debris.357 Drusen are often most concentrated in the nasal portion of the disc. The optic disc axons are atrophic adjacent to large accumulations of drusen.56,177,357 Drusen take up calcium salts and must be decalcified before being cut into sections for histological study.357

Pathogenesis

The primary developmental expression of the genetic trait for drusen may be a smaller-than-normal scleral canal.367,396 The peripapillary sclera forms after the optic stalk is complete.396 Mesenchymal elements from the sclera then invade the glial framework of the primitive lamina, reinforcing it with collagen.396 An abnormal encroachment of sclera, Bruch’s membrane, or both, on the developing optic stalk would narrow the exit space of optic axons from the eye. The absence of a central cup in affected eyes is consistent with the existence of axonal crowding. Drusen are often first detected clinically and histopathologically at the margins of the optic disc, which raises the possibility that the rigid edge of the scleral canal may be an aggravating factor in producing a relative mechanical interruption of axonal transport.396

In 1962, Seitz and Kersting498 first suggested that disc drusen may be the product of chronic degenerative changes in ganglion cell axons. In 1968, Seitz496 concluded from a series of histochemical studies that drusen originate from axonal derivatives of disintegrating nerve fibers resulting from a slow degenerative process. Sacks et al476 advanced an alternative hypothesis that formation of drusen is secondary to the associated abnormal disc vascular pattern, which is conducive to leakage of nonformed elements such as plasma proteins from the blood. According to Sacks, these elements serve as a nidus for the deposition of other materials in the perivascular space, which then gradually increase in size and coalesce.

Spencer528 hypothesized that axonal crowding may provide the anatomical substrate for impaired axoplasmic transport anterior to the lamina cribrosa that, over years, leads to intracellular mitochondrial calcification, axonal rupture, extrusion of mitochondria into the extracellular space, and the appearance of drusen on the surface of the disc. Tso favored a similar mechanism but believed that abnormal axonal metabolism, rather than axonal transport, was responsible for the accumulation of disc drusen.388,549 The lower prevalence of optic disc drusen in African Americans, who have a larger disc area with less potential for axonal crowding, is consistent with the notion of axonal crowding as a fundamental anatomical substrate for formation of disc drusen.286

Although previous studies have indicated that eyes with optic disc drusen have a small scleral canal,273,396 a more recent

OCT study162 failed to show this association. Alternatively, Antcliff and Spalton18 found optic disc drusen in only 1 of 27 relatives of 7 probands with bilateral optic disc drusen. However, 57% had anomalous vessels and 49% had no optic cup. They concluded that the primary pathology of optic disc drusen is likely to be an inherited dysplasia of the optic disc and its blood supply, which predisposes to the formation of optic disc drusen. Figure 3.24 summarizes our current understanding of the pathogenesis of optic disc drusen and their attendant complications.366

Ocular Complications

Optic disc drusen should not be viewed as an innocuous condition. While the finding of disc drusen is generally compatible with preservation of good visual function, patients rarely experience acquired progressive loss of visual field or visual acuity via a number of different mechanisms. Acquired visual loss in eyes with drusen is rare in childhood but may afflict young adults. As such, it is appropriate to inform patients that, while disc drusen rarely cause blindness, there

Fig. 3.24  Pathogenesis of optic disc drusen. Adapted from Tso549

is a remote possibility that affected patients may develop visual symptoms later in life.

Visual field defects have been detected in 71–87% of eyes with visible disc drusen and in 21–39% of eyes with pseudopapilledema but no visible drusen.357,400,486 In most cases, the asymptomatic nature of the defects reflects the insidious attrition of optic nerve fibers over decades.486 Less common but equally recognized is the abrupt visual field loss that may accompany vascular occlusions or hemorrhagic phenomena.486

Using Goldmann perimetry, Savino et al486 found field defects in 71% of patients with visible drusen, as opposed to only 21% with buried drusen. Visual field defects fall into three general categories: (1) nerve fiber bundle defects; (2) enlargement of the blind spot; and (3) concentric field constriction.174 Several studies noted inferonasal steps to be the most common nerve fiber bundle defect, but arcuate defects and sector defects are not uncommon.356,357,486,530 Mustonen found an afferent pupilary defect associated with asymmetrical visual field defects in 14 of 200 patients with optic disc drusen.398,399 Miller380 stated that an afferent pupillary defect is the rule rather than the exception in the setting of unilateral or asymmetrical visual field loss from optic disc drusen without visual acuity loss. Although concentric constriction of the visual field is recognized as a chronic phenomenon, three adults have recently been documented to have sudden severe visual field constriction with preservation of central vision.382,388 There was no disc swelling or retinal edema to suggest an ischemic process in these patients.

Visual field defects are uncommon in eyes with buried optic disc drusen.284 The pathogenesis of visual field loss in eyes with disc drusen could involve one or more of the following mechanisms: (1) an abnormality in axoplasmic flow leading to dysfunction of nerve fibers (the formation of drusen has been postulated to be related to axonal degeneration from altered axoplasmic flow),528,549 (2) compression of nerve fibers by the drusen, or (3) ischemia in the optic nerve head.41 The visual field defects often fail to correspond to the position of the visible drusen on the disc.483,484 The presence of disc drusen also does not preclude superimposition of field defects from other ocular or intracranial diseases.486

Transient visual loss was reported in 8.6% of the patients with disc drusen in Lorentzen’s study.357 Episodes of transient visual loss may be a harbinger of vascular occlusions in some patients.407

Superficial splinter or flame-shaped hemorrhages on the surface of the disc or peripapillary area may be seen in eyes with optic disc drusen.398,481 Splinter hemorrhages associated with optic disc drusen tend to be single and prepapillary in location, in contrast to the multiple hemorrhages in the nerve fiber layer that characterize papilledema.244 They are not visually significant but may cause diagnostic confusion if they arouse suspicion of papilledema.174 Large superficial hemorrhages rarely extend into the vitreous.

Deep peripapillary hemorrhages have been documented in children with disc drusen.147,467 These hemorrhages may be subretinal or subpigment epithelial and are typically circumferentially oriented around the disc. The question of whether these hemorrhages can be caused by compression of thinwalled veins by drusen conglomerates or by erosion of the vessel wall by the sharp edge of the druse remains unsettled.278 Wise et al584 postulated that enlarging disc drusen could result in circulatory compromise and local hypoxia, which might stimulate the growth of new vessels between the RPE and Bruch’s membrane, which are prone to hemorrhage. Peripapillary pigmentary disruption may remain following resolution of subretinal hemorrhage. Subretinal hemorrhage may also occur in papilledema, but its occurrence in early papilledema is rare and should suggest the possibility of disc drusen.244

Peripapillary subretinal neovascularization is a recognized complication in eyes with disc drusen (Fig. 3.25). Peripapillary subretinal neovascularization may manifest as a peripapillary subpigment epithelial hemorrhage and may be associated with either transient or permanent visual disturbances.584 In severe cases, this complication may simulate a neuroretinitis (Fig. 3.22). Harris et al227 found subretinal neovascularization in seven eyes of 57 patients with optic disc drusen. They also noted that hemorrhages occurring in the absence of choroidal vascularization produced no symptoms and resolved without sequelae, while hemorrhages resulting from choroidal neovascularization commonly produced visual symptoms. In their study, six of seven eyes with neovascular membranes retained visual acuities of 20/40 or better. On the basis of their findings, they recommended observation rather than laser photocoagulation for peripapillary choroidal neovascularization associated with disc drusen.

Fig. 3.25  Ten-year-old child with buried drusen and subretinal neovascular membrane simulating neuroretinitis. Courtesy of Stephen C. Pollock, M.D.

Vascular occlusions have been reported in patients with disc drusen. The most common of these causes ischemic optic neuropathy, which may occur as a single episode or as successive episodes of discrete visual loss over years.483 Karel et al278 documented ischemic optic neuropathy in three patients (including one 13-year-old boy) with optic disc drusen. Branch retinal artery occlusion, central retinal artery occlusion, and central retinal vein occlusion have also been reported. Retinal vascular occlusions can occur in young adulthood, and rare cases in children have been documented.407,437

The mechanism by which disc drusen produce vascular occlusion is uncertain.407 The following theories have been advanced:

·· Vascular anomalies are commonly associated with intrapapillary drusen, and it has been suggested that these tortuous vessels with abnormal branching patterns and loops are more susceptible to disrupted hemodynamics.407

·· Disc drusen are associated with small, cupless discs, which may predispose to crowding of the vasculature and vascular compromise. The association of ischemic optic neuropathy with small, cupless discs is well established.483 ·· Drusen are hard, unyielding structures that may directly

compromise adjacent vessels.407

Peripapillary central serous choroidopathy has been described in association with disc drusen.371 Fluorescein angiography showed a bright hyperfluorescent spot superonasal to the disc. The detachment resolved following focal laser photocoagulation of the RPE defect.

Ischemic optic neuropathy. Ischemic optic neuropathy is a rare complication of optic disc drusen that seems to be confined to the adult population. It has been attributed to the small scleral canal that foreordains optic disc drusen.286,350,406,439

Loss of central acuity has been reported as a rare complication of disc drusen. In most cases, this follows a series of episodic, stepwise events that progressively diminish the peripheral visual field.41,312 Loss of visual acuity should only be attributed to disc drusen after potential intracranial causes have been ruled out.

Systemic Associations

Retinitis pigmentosa. Globular excrescences of the optic nerve head are occasionally seen in patients with retinitis pigmentosa. They differ in appearance from typical disc drusen in that the disc does not appear elevated, and they often lie just off the disc margin in the superficial retina. Some investigators have documented an increase in size, leading to the conjecture that they may be hamartomas rather than drusen.119,430 More recent histopathological examination has confirmed that the globular excresences of the optic nerve in

retinitis pigmentosa are indeed drusen.436 Children with retinitis pigmentosa and buried drusen may present with optic disc elevation and masquerade as having neurological disease.235 The combination of vitreous cells with optic disc elevation may masquerade as uveitis in a child with retinitis pigmentosa. In this setting, the finding of attenuated retinal arterioles provides an important (and easily overlooked) clue to the diagnosis, which is confirmed by electroretinography.235 A distinct autosomal recessive syndrome of nanophthalmos, retinitis pigmentosis, foveoschisis, and optic disc drusen caused by mutation in the MFRP gene has also been

recognized.112

Pseudoexanthoma elasticum. The incidence of optic disc drusen in patients with pseudoxanthoma elasticum is 20–50 times greater than in the general population.95 Disc drusen may be the earliest clinical manifestation of pseudoxanthoma elasticum.95 Coleman et al95 postulated that an abnormal aggregation of macromolecules with a high affinity for calcium (which affects elastin in the dermis, arterial walls, and Bruch’s membrane) may also develop at the lamina cribrosa, disrupting axonal transport and leading to disc drusen formation. The association of angioid streaks with disc drusen should suggest the systemic diagnosis of pseudoxanthoma elasticum.

Megalencephaly. Hoover et al249 found megalencephaly in 3 of 40 children with pseudopapilledema and cautioned that such children can be misdiagnosed as having hydrocephalus.

Migraine headaches. Migraines are said to occur with increased frequency in patients with disc drusen.400,564 Some have pointed out that the concurrence of migraine and optic disc drusen probably reflects the frequent and often expedited referral of patients with headache and elevated discs for specialty evaluation.407

Pigmented paravenous retinochoroidal atrophy. Disc drusen were recently noted in a patient with pigmented paravenous retinochoroidal atrophy.593 This association may be fortuitous.

Growth Hormone Deficiency. It has been proposed that pseudopapilledema may be associated with growth hormone deficiency and suggested that this association should be considered before diagnosing children receiving recombinant human growth hormone as having IIH.96

Miscellaneous. Pseudopapilledema with or without optic disc drusen may be seen in association with a variety of chromosomal syndromes.53,92,58a5

Natural History and Prognosis

The evolution of disc drusen is a dynamic process that continues throughout life. It is rare to see visible drusen or significant optic disc elevation in an infant. During childhood, the involved optic discs begin to appear “full” and acquire a tan,