Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

39.Landau K, Winterkorn JMS, Mailloux LU et al (1996) 24-hour blood pressure monitoring in patients with anterior ischemic optic neuropathy. Arch Ophthalmol 114:570–575

40.Liozon E, Herrmann F, Ly K et al (2001) Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients. Am J Med 111:211–217

41.Liu GT, Glaser JS, Schatz NJ et al (1994) Visual morbidity in giant cell arteritis. Ophthalmology 101:1779–1785

42.Macaluso DC, Shults WT, Fraunfelder FT (1999) Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 127:610–612

43.Mack HG, O’Day J, Currie JN (1991) Delayed choroidal perfusion in giant cell arteritis. J Clin Neuroophthalmol 11:221–227

44.Mojon DS, Hedges TR 3rd, Ehrenberg B et al (2002) Association between sleep apnea syndrome and nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol 120:601–605

45.Muller M, Kessler C, Wessel K et al (1993) Lowtension glaucoma: a comparative study with retinal ischemic syndromes and anterior ischemic optic neuropathy. Ophthalmic Surg 24:835–838

46.Nesher G, Berkun Y, Mates M et al (2004) Lowdose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 50:1332–1337

47.Olver JM, Spalton DJ, McCartney ACE (1990) Microvascular study of the retrolaminar optic nerve in man: the possible significance in anterior ischemic optic neuropathy. Eye 4:7–24

48.Pianka P, Almog Y, Man O et al (2000) Hyperhomocystinemia in patients with nonarteritic anterior ischemic optic neuropathy, central retinal artery occlusion, and central retinal vein occlusion. Ophthalmology 107:1588–1592

49.Pless M, Rizzo JF, Lamkin JC et al (2000) Concordance of bilateral temporal artery biopsy in giant cell arteritis. J Neuroophthalmol 20:216–218

50.Pomeranz HD, Bhavsar AR (2005) Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol 25:9–13

51.Purvin VA (1995) Anterior ischemic optic neuropathy secondary to interferon alfa. Arch Ophthalmol 113:1041–1044

52.Repka MX, Savino PJ, Schatz NJ et al (1983) Clinical profile and long-term implications of anterior ischemic optic neuropathy. Am J Ophthalmol

96:478–483

54.Sadda SR, Nee M, Miller NR et al (2001) Clinical spectrum of posterior ischemic optic neuropathy. Am J Ophthalmol 132:743–750

55.Salomon O, Huna-Baron R, Steinberg DM et al (1999) Role of aspirin in reducing the frequency of second eye involvement in patients with nonarteritic anterior ischaemic optic neuropathy. Eye 13:357–359

56.Salomon O, Huna-Baron R, Kurtz S et al (1999) Analysis of prothrombotic and vascular risk factors in patients with nonarteritic anterior ischemic optic neuropathy. Ophthalmology 106:739–742

57.Salomon O, Rosenberg N, Steinberg DM et al (2004) Nonarteritic anterior ischemic optic neuropathy is associated with a specific platelet polymorphism located on the glycoprotein Ibalpha gene. Ophthalmology 111:184–188

58.Siatkowski RM, Gass JDM, Glaser JS et al (1993) Fluorescein angiography in the diagnosis of giant cell arteritis. Am J Ophthalmol 115:57–63

59.Soheilian M, Koochek A, Yazdani S et al (2003)

Transvitreal optic neurotomy for nonarteritic anterior ischemic optic neuropathy. Retina 23:692–697

60.Tesser RA, Niendorf ER, Levin LA (2003) The morphology of an infarct in nonarteritic anterior ischemic optic neuropathy. Ophthalmology 110:2031–2035

61.Weger M, Stanger O, Deutschmann H et al (2001) Hyperhomocysteinaemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic anterior ischaemic optic neuropathy. Br J Ophthalmol 85:803–806

emic optic neuropathy, central/branch retinal artery or vein occlusion.

■The most sensitive diagnostic test for ODD is B-scan ultrasound.

■There is currently no therapy for ODD.

3.1 Introduction

Optic disc drusen (ODD) represent a frequent cause of optic neuropathy. Despite numerous publications since the first histopathological description of ODD in 1858 [40], followed 10 years later by its clinical description [32], the problem of ODD remains unresolved. Two major reviews were recently published, providing a clear overview of ODD [3, 11].

Most frequently the affected patients are asymptomatic and ODD are incidentally found during ocular fundus examination. However, certain cases can represent a diagnostic chal-

showed exposed ODD at age 12.

Summary for the Clinician

■Buried (deep) drusen most likely represent an earlier stage of optic disc drusen (ODD), and become exposed (visible) later on.

■Ongoing calcification of ODD and progressive thinning of the nerve fiber layer contribute to the evolution of buried ODD to exposed (visible) drusen.

3.2 Epidemiology

There is no sex predilection for ODD, but there is a racial predilection. Patients of African ancestry rarely present ODD and this may result from the overall larger optic disc size amongst this ethnic

group. Various studies have previously reported an overall prevalence of ODD varying between 0.4% and 3.7% within a normal population and an autosomal-dominant pattern with variable penetrance has been assumed for years. Recently, a study was conducted to determine the incidence of ODD as well as the incidence of optic disc anomalies amongst seven families of seven unrelated probands. The authors found only 1 of 27 examined relatives to exhibit ODD (incidence 3.7%), whereas 30/53 eyes had anomalous optic disc vasculature (57%) and 26/53 eyes had absent optic disc cupping (49%) [1]. The authors proposed that the primary pathology could be an inherited optic disc dysplasia, predisposing to the formation of ODD in susceptible patients.

3.3 Pathology

Optic disc drusen result from a slow degenerative process, and originate from axoplasmic derivatives of disintegrating nerve fibers. This mechanism was proposed more than 40 years ago and remains the accepted physiopathology of ODD [49, 50, 53]. In his Edward Jackson Memorial Lecture, Spencer proposed that a blockade of axoplasmic flow occurs at the lamina cribrosa, initially at the optic disc periphery, and that the Bruch’s membrane might act as a mechanical barrier to axoplasmic flow [53]. A few years later, Tso [56] published an outstanding paper on the histopathology of 18 patients with ODD and presented the only electron microscopy study of OND published

to date. He proposed that an abnormal axonal metabolism leads to mitochondrial calcification. Axons eventually rupture, and calcium is then heavily deposited in the now extracellular mitochondria. They form small calcified microbodies which further calcify and coalesce into ODD. Optic disc drusen are found only in the prelaminar portion of the optic nerve, supporting the proposal that blockade of axoplasmic flow occurs at the lamina cribrosa. Tso [56] also showed that some patients with ODD exhibited vascular alterations within the optic nerve head, in the vicinity of ODD (enlargement of the perivascular space, endothelial cells and pericyte degeneration).

A more recent histopathological study reported results from 18 patients with ODD (18/3395 autopsies; 0.5% incidence) [20]. Their results confirmed the prelaminar location of ODD, showed that the papillary arterial and venous vessels are displaced in severe cases of ODD, and also suggested that mechanical constriction by a tight Bruch’s membrane might play a role in the formation of ODD.

An interesting study from Germany attempted to correlate visual function with the pattern of retinal ganglion cells [19]. They compared the results from 1 patient with ODD to 10 normal retinae. They found a drastic loss of retinal ganglion cells in the ODD patient: the total retinal ganglion cell count was reduced by 75% in the right eye (RE) and by 58% in the left eye (LE), which correlated grossly with visual dysfunction in both eyes, more pronounced in the right eye. However, there was no correlation between visual field loss and the topography of retinal ganglion cell loss. The greatest loss of retinal ganglion cells occurred in the paracentral and mid-peripheral retinal regions, and the least was found in the far periphery. Small retinal ganglion cells were more susceptible to die in ODD. Counting the central retinal ganglion cells (0.8 mm eccentricity from the foveola) showed that 43% of retinal ganglion cells remained in the right eye while 64% were present in the left eye. Such a loss was compatible with visual acuity reduced to 0.8 RE but maintained at 1.0 LE.

Summary for the Clinician

■Mitochondrial dysfunction at the prelaminar level of the optic nerve head seems to be the primary event in the formation of ODD.

■Mitochondria calcify, axons rupture and extracellular mitochondria further calcify.

■Vascular alterations in the vicinity of ODD are also found.

3.4 Optic Canal Size

Since the first clinical descriptions of ODD, a small crowded optic disc without cupping has been frequently reported. In 1984, a photographic retrospective study was performed, comparing the optic disc size between a group of 13 emmetropic eyes with ODD and 19 normal emmetropic eyes [41]. These authors found that the optic disc size in ODD was statistically significantly smaller than in normal eyes. Also, 10/13 eyes with ODD showed vascular anomalies. They concluded that a mesodermal dysgenesis resulted in a small scleral canal, a prerequisite for developing ODD.

This widely accepted point of view was recently challenged by Floyd et al. [18]. These authors designed a prospective study to determine whether patients with ODD presented a smaller optic canal as compared to normal subjects. They used optical coherence tomography (OCT) to determine the size of the scleral canal in 25 ODD patients, 13 unaffected first-degree relatives, and 17 normal subjects. The size of the inner aspect of the scleral canal was measured based on the detection of the retinal pigment epithelium and Bruch’s membrane around the optic disc. They found a statistically significantly larger optic canal size in the ODD group when compared to either the normal or the first-degree relative groups. They mentioned but refuted the possibility that ODD would obscure or displace the retinal pigment epithelium and/or the Bruch’s membrane, therefore providing falsely large numbers in the ODD group. It is nonetheless interesting to

40

3

scription of an association of ODD with nanophthalmos, and the present case might have well resulted from RP alone.

One case of ODD in a patient with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) was recently reported [13]. Although there is no explanation for the presence of ODD in POEMS syndrome, one might postulate that the chronic optic disc swelling (present in 50% of POEMS cases) might be the cause of ODD in such cases.

Wollenhaupt et al. [59] reported a single case of ODD associated with trisomy 15q. They reported the presence of bilateral hypoplastic but nonelevated optic discs at age 2, with subsequent development of optic disc swelling and ultrasound evidence for ODD at age 5. This association had never been reported before.

Summary for the Clinician

■The incidence of ODD is higher amongst patients with retinitis pigmentosa, Usher syndrome, pseudoxanthoma elasticum, or angioid streaks alone.

■Other associations are anecdotal.

3.6 Paraclinical Investigations

Diagnosing ODD may be easy when ODD are exposed (superficial). In that situation, ocular fundus examination might be sufficient, and autofluorescence is often present (Fig. 3.2). When ODD are buried (deep), the diagnosis relies more importantly on paraclinical examinations, such as B-scan ultrasound, fluorescein angiography, and CT scan (Figs. 3.2, 3.3). Recently, newer imaging techniques have been used in diagnosing and/or staging the degree of optic nerve dysfunction in ODD.

3.6.1 B-Scan Ultrasound

There is no doubt that the most sensitive way to detect ODD, buried or exposed, is B-scan ultra-

sound, as has been demonstrated on several occasions (Fig. 3.2). Most of these studies evaluated various diagnostic procedures.

Pierro et al. [44] demonstrated that ultrasound was the most sensitive test to detect the presence of ODD, followed by ophthalmoscopy, and fluorescein angiography in a series of 116 eyes with angioid streaks [44].

Kheterpal et al. [29] studied prospectively four patients with swollen optic discs using CT-scan, magnetic resonance imaging (MRI), fundus autofluorescence, and B-scan ultrasound. Only B- scan ultrasound was able to detect ODD in all four patients, whereas the other techniques correctly diagnosed ODD in only one patient each. MRI is not recommended to investigate potential ODD.

A nice study was published by Kurz-Levin and Landau [30]. They performed a retrospective study of 261 eyes (142 patients) referred for suspicion of ODD. Of 261 eyes, 36 were investigated with B-scan ultrasound, CT scan and preinjection control photograph looking for autofluorescence of the optic disc. Only B-scan ultrasound correctly identified all 21 patients with ODD, fewer than 50% of ODD being identified by CT scan or showing autofluorescence. Further, amongst 82 eyes with suspected buried ODD, 39 eyes showed ODD by B-scan ultrasound and only 15 eyes showed optic disc autofluorescence. No diagnosis of ODD was missed by B-scan ultrasound, and 50% of all ODD cases were diagnosed only by B-scan ultrasound. Autofluorescence was positive in 96% of exposed ODD, but in only 27% of buried ODD.

3.6.2Scanning Laser Ophthalmoscope

Haynes et al. [23] performed a prospective study of 12 eyes with swollen optic discs, using scanning laser ophthalmoscope (SLO) and B-scan ultrasound. Both techniques correctly identified ODD in 10/12 eyes. The advantages of SLO over B-scan ultrasound reside in the fact that SLO is able to provide a clear image of the fundus even in the presence of significant lens opacity (Fig. 3.2). However, SLO is not readily available to most ophthalmologists.

3.6.3Optical Coherence Tomography

Optical coherence tomography (OCT) is a newly developed objective technique allowing the measurement of retinal nerve fiber layer (NFL) thickness. Several studies recently addressed the question of NFL loss in patients with ODD.

In a prospective study, Roh et al. [46] concluded that OCT was a sensitive and early indicator of NFL thinning in ODD, when compared

to red-free photography and computerized visual field results. Further they also demonstrated that buried ODD were not as damaging to the optic nerve as exposed ODD, as there was no NFL thinning in the buried ODD group.

Another group of authors studied the evolution of NFL thickness in ODD patients over an average of 18 months [43]. In this prospective study of 23 eyes with ODD, mean retinal NFL thickness did not change. The authors stressed the difficulties of obtaining comparable optic

44

3

Optic Disc Drusen

nerve measurements with OCT and also the fol- low-up time, which might have been too short.

Amongst 58 eyes with buried ODD, Katz and Pomeranz [28] found only 3 eyes (5%) with visual field defects. Twenty one patients with normal visual field underwent OCT, and all eyes showed a normal average NFL thickness. Only 4/21 eyes had some sectorial NFL loss, and 4 others were borderline. Most patients with buried ODD had no visual field defects, and only 20% showed some mild abnormalities of NFL thickness. Optical coherence tomography can also be used to directly image the optic nerve head. In the presence of ODD, the irregular “lumpy bumpy” appearance of the optic nerve head is readily apparent (Fig. 3.2).

3.6.4 Scanning Laser Polarimetry

Scanning laser polarimetry (SLP) is also an objective technique recently developed to assess NFL thickness. In a prospective study of 38 eyes with ODD, the authors found a good correlation between SLP and functional loss: the average NFL thickness was decreased in eyes with abnormal visual field results [38]. However, SLP results could not differentiate patients with buried ODD from patients with exposed ODD.

Similar results were found amongst 23 eyes with exposed ODD: NFL thickness was decreased in ODD patients as compared to normals [55]. Furthermore, NFL thickness loss was more pronounced when the clinical grading of ODD was higher.

3.6.5 Electrophysiology

Electrophysiology is not really needed to diagnose ODD, but can be helpful to stage the degree of optic neuropathy. In a prospective study of 29 eyes with ODD, the P100 latency of the pattern visual-evoked potentials was prolonged in 12 eyes (41%) whereas a reduced amplitude or the absence of the N95 component of the pattern electroretinogram (pERG) was detected in 79% (19/29 eyes) [48]. The abnormality of the pERG was more frequently found than any other test performed in this group (visual acuity, color vi-

sion, visual field, flash or pattern visual-evoked potentials). Pattern ERG might then be a very sensitive way to detect preclinical dysfunction of the retinal ganglion cells in ODD.

3.6.6 Retinal Angiography

Fluorescein angiography (FFA) has been used for several years in investigating ODD. It can prove helpful sometimes, when a differential diagnosis with true papilledema (elevated intracranial pressure) is not clear. In patients with ODD, there is neither dilatation nor leakage from the papillary capillaries. In the late phase of FFA, there is however staining of the drusen by the dye, and frequently hyperfluorescence is more pronounced nasally (Fig. 3.3). In our experience, indocyanine green angiography (ICGA) is not helpful in diagnosing ODD. With ICG, the optic nerve stays hypofluorescent even during the late phases.

Summary for the Clinician

■B-scan ultrasound is widely accepted as the most sensitive means to confirm the presence of ODD.

■Scanning laser ophthalmoscopy was recently reported to be as sensitive as ultrasound, offering also a good direct imaging of the optic nerve head in the presence of opaque media.

■Fluorescein angiography can be helpful, mostly to distinguish ODD from true papilledema. Indocyanine green angiography and MRI are not helpful for diagnosing ODD, as calcifications do not appear on MRI.

3.7 Complications

3.7.1 Visual Field Defects

Visual field defects are a common, frequently incidental, finding amongst patients with ODD (Fig. 3.4). In children, the incidence of visual field defect varies between 11% and 51% [15, 24],

whereas it has been reported to be as high as 87% in the adult population with ODD [34, 47]. The increased frequency of visual field defect with age seems to parallel the evolution of ODD from buried (children) to exposed (adults). It also confirms the slowly progressive nature of the optic neuropathy of ODD.

A retrospective study recently addressed the question of the rate of visual field loss in ODD patients [31]. The authors determined that the rate of visual field loss was 1.6% per year, based on Goldmann visual field measurements of 32 patients followed for 36 months. There was no sex difference.

Recently, Wilkins and Pomeranz [57] published an interesting paper on the visual manifestations of ODD. They retrospectively compared the results from 33 patients with exposed ODD to those of 46 patients with ultrasonographically proven buried ODD [57]. They found an overall prevalence of 49% of visual field defects, nerve fiber bundle defect being the most frequent (73%, mostly infero-nasally), followed by generalized constriction only (20%), and enlarged blind spot only (7%). There was an obvious increased prevalence of defects within the exposed ODD group (73%) versus the buried ODD (36%). However, the type and severity of visual field defects did not significantly differ between the two groups. They also interestingly noticed that more than half of their patients were symptomatic (decreased visual acuity, blurriness of vision, dim vision).

More recently in another study of patients with buried ODD, only 5% of patients (3/51 eyes) presented a visual field defect [28].

Sudden visual field constriction can occur in ODD, as it was reported by Moody et al. [39]. They described two patients who suddenly and painlessly presented permanent monocular peripheral visual loss, with preserved visual acuity and a relative afferent pupillary defect. No definite explanation could be provided. As compared to other optic neuropathies, preservation of visual acuity and central visual field suggests that the small fibers of the papillomacular bundle seem to be relatively resistant in ODD. This conclusion contradicts the only study to examine the regional loss of retinal ganglion cells in a patient with ODD [19].

Fig. 3.4a–d.  Visual field defects in patients with optic disc drusen (ODD). a Mild asymmetrical visual field defect in an asymptomatic 54-year-old woman with buried ODD. Visual acuity was 10/10 in both eyes. The defect is nasal inferior in both eyes. b Moderate and asymmetrical visual field defect in a 24-year-old man with exposed ODD. Visual acuity was 10/10 in both eyes. The defect was still purely nasal. c Severe visual field defect in a symptomatic 49-year-old woman with exposed ODD. Visual acuity was reduced to 4/10 in the right eye with a mild dyschromatopsia (6/13 Ishihara), whereas the left eye visual acuity and color vision were normal (10/10, 13/13 Ishihara). Dense arcuate scotomata surround the macula. d Very severe visual field defect in a symptomatic 39-year-old man with exposed ODD. Visual acuity was 10/10 in the right eye and 6/10 in the left eye. Only a central island of vision remained in both eyes, more so in the right eye, with a temporal superior island of vision partially remaining in the left eye