Ординатура / Офтальмология / Английские материалы / Applied Pathology for Ophthalmic Microsurgeons_Naumann, Holbach, Kruse_2008

Latest results of Heiduschka, Thanos and colleagues (2005) show that, at least in cats, under certain circumstances the regeneration of axons in a crash model of the optic nerve can be demonstrated.

We have tried to sketch the basic principles of anatomy and pathology of the optic nerve in the context of ocular and non-ocular diseases.

References (see also page 379)

Annesley W, Brown G, Bolling J, Goldberg R, Fisher D. Treatment of retinal detachment with congenital optic pit by krypton laser photocoagulation. Graefes Arch Clin Exp Ophthalmol 1987. 225;5: 311 – 314

Brodsky MC. Morning glory disc anomaly or optic disc coloboma? Arch Ophthalmol 1994. 112;2: 153

Burk RO, Rendon R. Clinical detection of optic nerve damage. Surv Ophthalmol 2004. 45;3: 297 – 303

Cohen AI. Is there a potential defect in the blood retinal barrier at the choroidal level of the optic nerve canal? Invest Ophthal 1973; 12: 513

Corbett JJ, Thompson HS. The rational management of idiopathic intracranial hypertension. Arch Neurol 1989. 46; 10: 1049 – 1051

Dichtl A, Jonas JB, Holbach L, Naumann GOH. Retinal nerve fiber layer thickness in human eyes. Graefes Arch Clin Exp Ophthalmol 1999. 237; 6: 474 – 479

Eller AW, Friberg TL, Mah F. Migration of silicone oil into the brain. Am J Ophthalmol 2002; 133: 429-438

Evans JM, Batts KP, Hunder GG. Persistent giant cell arteritis despite corticosteroid treatment. Mayo Clin Proc 1994. 69;11: 1060 – 1061

Friedmann SM, Margo CE. Bilateral subinternal limiting membrane hemorrhage with Terson syndrome. Am J Ophthalmol 1997. 124;6: 850 – 851

Gandorfer A, Kampik A. Role of vitreoretinal interface in the pathogenesis and therapy of macular disease associated with optic pits. Ophthalmologe 2000. 97; 4: 276 – 279

Glaser JS, Teimory M, Schatz NJ. Optic nerve sheath fenestra-

Fig. 5.7.14. Radiation arteriopathy: cross section through a posterior ciliary artery (Masson trichrome) 2 years after radiation of an ethmoidal and maxillary cell carcinoma, resulting in an ischemic ophthalmopathy. Note the irregular wall thickening, narrowed lumen with thrombosis, and concentric myointimal proliferation

tion for progressive optic neuropathy. Results in second series consisting of 21 eyes. Arch Ophthalmol 1994. 112;8: 1047 – 1050

Green WR, Chan CC, Hutchins GM, Terry JM. Central vein occlusion: A prospective histopathologic study of 29 eyes in 28 cases. Retina 1981. 1;1: 27 – 55

Heiduschka P, Fischer D, Thanos S. Recovery of visual evoked potentials after regeneration of cut ganglion cell axons within the ascending visual pathway in rats. Restorative Neurology and Neuroscience 2005. 23; 5 – 6: 303 – 312

Hinzpeter EN, Naumann GOH. Ischemic papilledema in giant cell arteriitis. Mucopolysaccharide deposition with normal intraocular pressure. Arch Ophthalmol 1976; 94: 624 – 628

Horio N, Horiguchi M. Retinal blood flow and macular edema after radial optic neurotomy for central retinal vein occlusion. Am J Ophthalmol 2006. 141;1: 31 – 34

Hotta K. Unsuccessful vitrectomy without gas tamponade for macular retinal detachment and retinoschisis without optic disc pit. Ophthalmic Surg Lasers Imaging. 2004 JulAug;35(4):328 – 31

Irvine AR, Crawford JB, Sullivan JH. The pathogenesis of retinal detachment with morning glory discs and pit. Retina 1986. 6; 3: 146 – 150

Ishikawa K, Terasaki H, Mori M, Sugita K, Miyake Y. OCT before and after vitrectomy with internal limiting membrane removal in a child with optic pit maculopathy. Jpn J Ophthalmol 2005. 49;5: 411 – 413

Jacobs DS, Foster CS. Temporal arteriitis. In: Alber DM, Jacobiec FA (eds) Principles and practice of ophthalmology, vol.5. Philadelphia: Saunders 1994; 2901 – 2908

Jonas JB, Berenshtein E, Holbach L. Lamina cribrosa thickness and spatial relationships between intraocular space and cerebrospinal fluid space in highly myopic eyes. Invest Ophthalmol Vis Sci 2004. 45;8: 2660 – 2665

Jonas JB, Naumann GOH. The optic nerve: Its embryology, histology and morphology. In: Varma R, Spaeth GL (eds) The optic nerve in glaucoma. Philadelphia: Lippincott 1993; pp 3 – 26

Jonas JB, Schmidt AM, Müller-Bergh JA, Schlötzer-Schrehardt UM, Naumann GOH. Human optic nerve fiber count and optic disc size. Invest Ophthalmol Vis Sci 1992. 33; 6: 2012 – 2018

Kearns TP, Hollenhorst RW. Venous stasis retinopathy of occlusive disease of the carotid artery. Majo Clinic Proc 1963;38:304

Kim TW, Lee SJ, Kim SD. Comparative evaluation of radial optic neurotomy and panretinal photo coagulation in the management of central vein occlusion. Korean J Ophthalmol 2005. 19;4: 269 – 274

Konno S, Akiba J, Sato E, Kuriyama S, Yoshida A. OCT in successful surgery of retinal detachment associated with optic nerve head pit. Ophthalmic Surg Lasers 2000. 31; 3: 236 – 239 Kubota T, Holbach L, Naumann GOH. Corpora amylacea in glaucomatous and non-glaucomatous optic nerve and reti-

na. Graefes Arch Clin Exp Ophthalmol 1993. 231;1: 7 – 11 Kubota T, Jonas JB, Naumann GOH. Direct clinico-histological

correlation of parapapillary chorioretinal atrophy. Br J Ophthalmol 1993. 77; 2: 103 – 106

Kuhn F, Morris R, Witherspoon CD, Mester V. Terson syndrome. Results of vitrectomy and the significance of vitreous hemorrhage in patients with subarachnoid hemorrhage. Ophthalmology 1998. 105;3: 472 – 477

Lippe von der I, Wuermeling MJ, Naumann GOH. Akute druckabhängige Veränderungen des neuroretinalen Randsaums in einer juvenilen Glaukompapille – Messungen mittels Laser Scanning Tomographie und planimetrischer Papillometrie. Klin Monatsbl Augenheilkd 1994; 204:126 – 130

Naumann GOH, Mardin CY, Bergua A. Bedeutung und Perspektive der Glaukom-Mikrozirkulationsforschung. Klin Monatsbl Augenheilkd 1993; 203: 286

Naumann GOH. Benign melanocytoma of the optic nerve papilla. Doc Ophthalmol. 1966;20: 468 – 483

Okinami S, Ohkuma M, Tsukahara I. Kuhnt intermediary tissue as a barrier between the optic nerve and retina. Albrecht v Graefes Arch klin exp Ophthal 1977; 201: 57

Opremcak EM, Rehmar AJ, Ridenour CD, Kurz DE. Radial optic neurotomy for central retinal vein occlusion: 117 consecutive cases. Retina 2006. 26;3: 297 – 305

Postel EA, Pulido JS, McNamara JA, Johnson MW. The etiology and treatment of macular detachment associated with optic nerve pits and related anomalies. Trans Am Ophthalmol Soc 1998; 96:73 – 88

Quigley HA. The pathogenesis of reversible cupping in congenital glaucoma. Am J Ophthalmol 1977;84:358

Richardson KT, Shaffer RN. Optic nerve cupping in congenital glaucoma. Am J Ophthalmol 1966;62:507

Risco JM, Grimson BS, Johnson PT. Angioarchitecture of the ciliary artery circulation of the posterior pole. Arch Ophthalmol 1981. 99; 5: 864 – 868

Seiff SR, Shah L. A model for the mechanism of optic nerve fenestration. Arch Ophthalmol 1990. 108; 9: 1326 – 1329 Sharma T, Gopal L, Biswas J, Shanmugam MP, Bhende PS,

Agrawal R, Shetty NS, Sanduja N. Results of vitrectomy in Terson’s syndrome. Ophthalmic Surg Lasers 2002. 33;3: 195 – 199

Traboulsi EI, O’Neill JF. The spectrum in the morphology of the so called morning glory disc anomaly. J Pediatr Ophthalmol Strabismus 1988. 25;2: 93 – 98

Tsai JC, Petrovich MS, Sadun AA. Histopathological and ultrastructural examination of optic nerve sheath decompression. Br J Ophthalmol 1995. 79;2: 182 – 185

Vogel A, Holz G, Loeffler KU. Histopathologic findings after radial optic neurotomy in central retinal vein occlusion. Am J Ophthalmol 2006. 141;1: 203 – 205

Wenkel H, Michelson G. Korrelation der Ultraschallbiomikroskopie mit histologischen Befunden in der Diagnostik der Riesenzellarteriitis. Klin Monatsbl Augenheilkd 1996; 210: 48 – 52

Wenkel H, Naumann GOH. Retrolaminäre Infiltration des Nervus opticus durch als intraokulare Tamponade verwendetes Silikonöl. Klin Monatsbl Augenheilkd 1999; 214: 120 – 122

Wietholter S, Steube D, Stotz HP. Terson syndrome: A frequently missed ophthalmologic complication in subarachnoid hemorrhage. Zentrabl Neurochir 1998. 59;3: 166 – 170 Wrede J, Varadi G, Volcker HE, Dithmar S. Radial optic neurotomy for central retinal vein occlusion – how deep should it

be. Ophthalmologe 2006. 103; 4: 321 – 324

Yokoi M, Kase M, Hyodo T, Horimoto M, Kitagawa F, Nagata R. Epiretinal membrane formation in Terson’s syndrome. Jpn J Ophthalmol 1997. 41;3: 168 – 173

Most generalized diseases lead to manifestations also in the ocular tissues. In this chapter we shall briefly review the intraocular consequences of the following common generalized diseases of relevance for ocular microsurgery: (1) diabetes mellitus, (2) arterial hypertension and “vis a tergo,” (3) pseudoexfoliation syndrome (PEX) and its intraocular and systemic manifestations andcomplications, (4) infectious diseases, and

(5) hematologic disorders. – The intraocular pathology

of PEX shall be reviewed in more detail because of its significantly increased risks for intraand postoperative complications.

In addition, neurologic diseases, e.g., multiple sclerosis and Parkinson’s disease, and muscular problems like myotonic dystrophy and endocrine orbitopathy as manifestations of thyroid disease require the conscious cooperation of the entire surgical team, anesthesiologist and their consultants.

G.O.H. Naumann

This very common metabolic disorder currently affects 170 million people and will concern an estimated 370 million people by 2030. Not only the population in the industrialized part of the world but particularly the inhabitants in the lowand middle-income countries are suffering from this “pandemic.” More than 75 % of those suffering from diabetes mellitus for over 20 years will have some sort of retinopathy. “Metabolic control matters!” Well controlled glucose and Hb1Ac levels are most important for the prevention or delayed onset of the late microangiopathy involving the sensory retina, kidney and peripheral nerves. Proper medical therapy can reduce the risk of blindness and moderate vision loss significantly, but does not totally prevent it.

The following manifestations are of particular significance for the ophthalmic microsurgeon.

6.1.1

Diabetic Retinopathy

Retinopathia diabetic simplex involves the capillaries of the sensory retina by formation of microaneurysms due to loss of pericytes and finally capillary occlusion. The resulting hypoxic and ischemic areas in the sensory retina induce release of vasoproliferative factors leading to preretinal proliferating retinopathy and to rubeosis iridis and cyclitic membrane (see Chapters 2, 5.6). Awareness of such neovascularization is necessary, particularly in open eye surgery.

6.1.2

Diabetic Iridopathy

Persisting glucose levels above 200 mg % lead to accumulation of glycogen in the pigment epithelium of the iris (Fig. 5.3.7). These ballooned cells are often an obstacle for satisfactory mydriasis for diagnostics and laser therapy. Glycogen deposits in the iris pigment epithelium make it friable and during iris movements cause rupture and induce secondary melanin granule dispersion syndrome (Tables 5.3.1, 5.3.3, 5.3.11) and

melanin phagocytosis in the corneal and trabecular endothelium. The multifocal loss of melanin leads to the appearance of a “starry sky” on retroillumination. Ruptured cell bodies of the iris pigment epithelium pose a risk for posterior synechiae. Melanin granules are also phagocytized by the corneal endothelium, which may induce heat damage during laser coagulation of the retinal periphery or trabeculoplasty (see 5.2).

6.1.3

Recurrent Corneal Erosions

Markedly thickened basement membranes of the corneal epithelium and decreased corneal sensitivity from diabetic neuropathy loosen the hemidesmosomes of the corneal epithelium with an increased risk of recurrent erosions. This concerns not only patients wearing contact lenses but also all diagnostic or therapeutic manipulations of the corneal surface during microsurgery. In view of the risks of bacterial infections from blepharitis and increased bacterial contamination of the tear film, the risk of complicating bacterial ulcers of the cornea is a real threat (see Chapter 5.1).

6.1.4 Cataracts

Diabetic cataract in juvenile diabetes: They present the pathognomic “snowflake” phenotype (Fig. 5.5.20).

Earlier Manifestation of Age-Related Cataracts in Adult

Onset Diabetes

The mechanisms of this common entity are poorly understood. Secondary cataract after extracapsular cataract extraction (ECCE) seems to be less frequent than, e.g., in pseudoexfoliation (PEX) syndrome (see Chapter 5.5; 6.3; Küchle et al., 1997).

Intraoperative control of arterial blood pressure and choice of anesthesia are particularly relevant in wide open eye surgery (see Chapter 2 and 4).

Uncontrolled arterial hypertension is associated with an increased risk of spontaneous and intra-/post- operative hemorrhage in all organs. An important distinguishing feature of intraocular versus extraocular surgery includes the forward movement of the iris lens diaphragm by increased blood filling of the choroid – “vis a tergo” – with any opening of the eye as soon as the intraocular pressure falls. In its extreme expression as

expulsive hemorrhage it may lead to loss of the eye (see Chapter 2). Prevention of such potential catastrophic complications is of the utmost importance: During the phase of the open eye the systemic arterial blood pressure should be well controlled and ideally should be around 100 mm Hg systolic in demanding and difficult intraocular surgery, e.g., block excision and penetrating corneal grafts (see Chapters 5.1, 5.4).

Preexisting arterial hypertension requires close cooperation with the internist and anesthesiology team to evaluate the individual situation.

6.3.1 Introduction

Pseudoexfoliation* (PEX) syndrome is a common age-related, although often overlooked disorder that predisposes to a number of conditions requiring intraocular surgery, most notably cataract and glaucomas but also corneal endothelial decompensation. It has been estimated that the number of people with PEX syndrome in the world varies between 60 and 100 million (Ritch and Schlötzer-Schrehardt 2001). With a rising mean age not only in western populations, PEX syndrome is increasing in prevalence, although it is not an integral part of ageing but represents a distinct clinical entity (Naumann et al. 1998). PEX syndrome is presently acknowledged as the most common identifiable cause of open-angle glaucoma, accounting for the majority of glaucoma in some countries and for about 25 % of all open-angle glaucomas worldwide (Ritch 1994a). The condition is characterized by an abnormal turnover of extracellular matrix material resulting in the deposition of an abnormal fibrillar substance (PEX material) in virtually all tissues of the anterior segment of the eye (Naumann et al. 1998). Despite its clinical significance and extensive research, the precise etiology and pathogenesis of PEX syndrome remain unclear; however, there is evidence for a genetic basis of the disease (Damji et al. 1998; Orr et al. 2001).

Although concepts of PEX are often dominated by its association with chronic open-angle glaucoma and by the visible changes on the anterior lens capsule

*The current terminology is very unsatisfactory. The term “exfoliation” implies a “minus” of tissue as it really occurs in “glassblowers’ cataract” (infrared exposure lens capsule exfoliation). “Pseudoexfoliation” is the correct ophthalmopathologic description for the newly produced material (a “plus”) deposited on the intact lens capsule and other structures of the anterior segment. However, to use the prefix “pseudo” for a serious and common entity may appear misleading. We suggest to use both terms to sustain awareness that details are important to understand the manifestations and complications. A new nomenclature will be suggested as soon as we better understand the etiology and pathogenesis of this puzzling entity.

(Lindberg 1989) depicted by Vogt almost 100 years ago (Vogt 1925), lens capsule involvement is only one aspect of the various ocular manifestations of PEX syndrome (Naumann et al. 1998). There is also direct in situ involvement of the ciliary body and zonular apparatus, the juxtacanalicular and trabecular tissue, the corneal endothelium, and virtually all cell populations of the iris, predisposing to a number of intraocular complications including phacodonesis and lens subluxation, pupillary block angle-closure glaucoma, melanin dispersion, insufficient mydriasis, bloodaqueous barrier dysfunction and pseudouveitis, anterior segment hypoxia, posterior synechiae as well as corneal endothelial decompensation (Table 6.3.1) (Naumann et al. 1998; Ritch and Schlötzer-Schrehardt 2001).

The pathological changes also explain the spectrum of complications that occur in association with intraocular surgery on PEX patients (Table 6.3.1). At our institution, approximately 15 % of patients undergoing cataract surgery and 40 % of patients undergoing glaucoma filtering surgery have PEX. In relation to these procedures, numerous studies have reported a wide range of intraand postoperative complications including zonular dehiscence, vitreous loss, posterior capsular rupture, intraocular hemorrhage, corneal endothelial failure, postoperative inflammation and intraocular pressure spikes, secondary cataract, and luxation of intraocular lens implants (Naumann et al. 1988; Küchle et al. 1997).

Moreover, recent evidence indicates that the ocular features of PEX syndrome are actually only one facet of a broader systemic process, since typical PEX material deposits have been identified in the skin and in connective tissue portions of various visceral organs including lungs, kidney, gallbladder, liver and heart (SchlötzerSchrehardt et al. 1992; Streeten et al. 1992). Although the clinical consequences of these systemic deposits await further clarification, PEX syndrome has been repeatedly associated with cardiovascular and cerebrovascular disease, such as aneurysms of the abdominal aorta, transient ischemic attacks, and a history of angina pectoris, hypertension, myocardial infarction or stroke (Mitchell et al. 1997; Schumacher et al. 2001).

Hyperhomocysteinemia has been suggested as one possible cause for an increased vascular risk in PEX patients (Vessani et al. 2003; Bleich et al. 2004). However, the mortality rate appears not to be increased in PEX patients (Shrüm et al. 2000). Other investigators reported on an association of PEX syndrome and hearing loss or Alzheimer’s disease.

6.3.2

Pathobiology of PEX Syndrome

The exact pathogenesis of PEX syndrome is still not known. However, the pathologic process is characterized by the progressive accumulation of an abnormal fibrillar matrix product, which is either the result of an excessive production and/or an insufficient breakdown, and which is regarded as pathognomonic for the disease based on its unique light microscopic and ultrastructural criteria (Fig. 6.3.1a–d) (Naumann et al. 1998; Ritch and Schlötzer-Schrehardt 2001). The characteristic fibrils, which are composed of microfibrillar subunits resembling elastic microfibrils (Fig. 6.3.1e), contain predominantly epitopes of elastic fibers, such as elastin, tropoelastin, amyloid P, vitronectin, and components of elastic microfibrils, such as fibrillin-1, mi- crofibril-associated glycoprotein MAGP-1, and the latent TGF- q binding proteins LTBP-1 and LTPB-2

(Fig. 6.3.1f). These immunohistochemical and recent molecular biologic data, confirming an overexpression of fibrillin-1 and LTBP-1/2 mRNA in most cell types involved (Schlötzer-Schrehardt et al. 2001; Zenkel et al. 2005), give strong support to the elastic microfibril theory of pathogenesis, which explains PEX syndrome as a type of elastosis affecting elastic microfibrils (Streeten 1993). The PEX fibrils appear to be multifocally produced by various intraand extraocular cell types including the preequatorial lens epithelium, nonpigmented ciliary epithelium, trabecular endothelium, corneal endothelium, vascular endothelial cells, and virtually all cell types in the iris, by active fibrillogenesis involving all anterior segment tissues (Figs. 6.3.1g, h, 6.3.2). This fibrillogenesis is accompanied by a destruction of the normal extracellular matrix of the cells, normally represented by their basement membrane, and is followed by a degeneration of the cells involved due to a disturbed cell-matrix interaction (degenerative fibrillopathy).

The currently acknowledged pathogenetic concept describes PEX syndrome as a specific type of a stressinduced elastosis, an elastic microfibrillopathy, associated with the excessive production of elastic microfibrils and their aggregation into typical PEX fibrils by a variety of potentially elastogenic cells in intraand extraocular locations (Ritch and Schlötzer-Schrehardt 2001; Ritch et al. 2003; Schlötzer-Schrehardt and Nau-

mann 2006). Growth factors, particularly TGF- q 1, increased cellular and oxidative stress, but also the stable aggregation of misfolded stressed proteins, appear to be involved in this fibrotic process. Due to an imbalance of matrix metalloproteinases (MMPs) and their inhibitors TIMPs and extensive cross-linking processes involved in PEX fiber formation, the newly formed material is not properly degraded but progressively accumulates within the tissues over time with potentially deleterious effects.

* *

In a recent landmark study, polymorphisms in the lysyl oxidase-like 1 (LOXL1) gene located on chromosome 15q24 have been shown to be associated with PEX syndrome and PEX glaucoma in two Scandinavian populations (Thorleifsson et al., 2007). LOXL1 is a member of the lysyl oxidase familiy of enzymes that are necessary for the stabilizaton of elastic fibers by cross-linking tropoelastin molecules to mature elastin. These genetic variants may contribute to the elastotic process characteristic of PEX syndrome.

ciliary body

vitreous body

Table 6.3.2. Clinical stages of pseudoexfoliation (PEX) syndrome

Suspect

Early PEX (precapsular diffuse dewy layer on anterior lens surface)

”Masked PEX” (posterior synechiae without other obvious cause)

Definite

”Mini-PEX” (focal defects in precapsular layer, mostly nasal superiorly)

Manifest PEX (characteristic target-like pattern of PEX material deposition)

6.3.3

Clinical Diagnosis and Early Recognition

Several clinical stages of PEX syndrome can be recognized (Table 6.3.2, Fig. 6.3.3).

6.3.3.1

Manifest PEX Syndrome

The most important diagnostic criteria of PEX syndrome are the whitish flake-like deposits of PEX material on anterior segment structures, particularly on the anterior lens surface (Fig. 6.3.4a, b) and the pupillary margin (Fig. 6.3.4c, d), occasionally also on the posterior surface of the cornea (Fig. 6.3.4e), on the surface of intraocular lens implants, and on the anterior vitreous face in aphakic eyes. The characteristic target-shaped pattern on the lens, consisting of a rather homogeneous central disc, an intermediate clear zone, and a periph-

Fig. 6.3.3. Schematic representation of clinical classification of PEX syndrome based on morphologic alterations of the anterior lens surface

eral granular zone, can be only seen after pupillary dilation (Fig. 6.3.4a). In routine examinations without pupillary dilation, the diagnosis may be easily missed, because the central disc may be very subtle or even absent in 20 – 50 % of cases (Fig. 6.3.4b). However, the ma-