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

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40.Hood DC, Odel JG, Chen CS, Winn BJ (2003) The multifocal electroretinogram. J Neuroophthalmol 23:225–235

41.Hood DC, Zhang X, Greenstein VC, Kangovi S, Odel JG (2000) An interocular comparison of the multifocal VEP: a possible technique for detecting local damage to the optic nerve. Invest Ophthalmol Vis Sci 41:1580–1587

42.Hood DC, Thienprasiddhi P, Greenstein VC, Winn BJ, Ohri N, Liebmann JM, Ritch R (2004) Detecting early to mild glaucomatous damage: a comparison of the multifocal VEP and automated perimetry. Invest Ophthalmol Vis Sci 45:492–498

43.Greenstein VC, Thienprasiddhi P, Ritch R, Liebmann JM, Hood DC (2004) A method for comparing electrophysiological, psychophysical, and structural measures of glaucomatous damage. Arch Ophthalmol 122:1276–1284

44.Rodarte C, Hood DC, Yang EB, Grippo T, Greenstein VC, Liebmann JM, Ritch R (2006) The effects of glaucoma on the latency of the multifocal visual evoked potential. Br J Ophthalmol 90:1132–1136

45.Parisi V, Miglior S, Manni G, Centofanti M, Bucci MG (2006) Clinical ability of pattern electroretinograms and visual evoked potentials in detecting visual dysfunction in ocular hypertension and glaucoma. Ophthalmology 113:216–228

46.Hood DC (2003) Objective measurement of visual function in glaucoma. Curr Opin Ophthalmol 14:78–82

47.Bach M, Unsoeld AS, Philippin H, Staubach F, Maier P, Walter HS, Bomer TG, Funk J (2006) Pattern ERG as early glaucoma indicator in ocular hypertension – a long-term prospective study. Invest Ophthalmol Vis Sci 47:4888–4894

References 159

48.Halliday AM, McDonald WI, Mushin J (1972) Delayed visual evoked response in optic neuritis. Lancet 1:982–985

49.Hood DC, Odel JG, Zhang X (2000) Tracking the recovery of local optic nerve function after optic neuritis: a multifocal VEP study. Invest Ophthalmol Vis Sci 41:4032–4038

50.Guillery RW (1986) Neural abnormalities in albinos. Trends Neurosci 18:364–367

51.Apkarian P, Reits D, Spekreijse H, van Dorp D (1983) A decisive electrophysiological test for human albinism. Electroenceph Clin Neurophysiol 55:513–531

52.Hoffmann MB, Lorenz B, Morland AB, Schmidtborn LC (2005) Misrouting of the optic nerves in albinism: estimation of the extent with visual evoked potentials. Invest Ophthalmol Vis Sci 46:3892–3898

53.Creel D, Spekreijse H, Reits D (1981) Evoked potentials in albinos: efficacy of pattern stimuli in detecting misrouted optic fibers. Electroencephalogr Clin Neurophysiol 52:595–603

54.Hoffmann MB, Tolhurst DJ, Moore AT, Morland AB (2003) Organization of the visual cortex in human albinism. J Neurosci 23:8921–8930

55.Aine CJ, Supek S, George JS, Ranken D, Lewine J, Sanders J, Best E, Tiee W, Flynn ER, Wood CC (1996) Retinotopic organization of human visual cortex: departures from the classical model. Cereb Cortex 6:354–361

10.1Autoimmune Disease Overview

Autoimmune diseases occur when the body’s immune response is directed against self antigens. The natural endpoint of a normal immune response (non-autoimmune) to a foreign antigen is to rid the body of the antigen. This cannot be achieved in autoimmunity, and thus the immune response to self antigen results in a sustained process which generally causes chronic inflammation and tissue damage. Specifically, damage can occur through local inflammation, immune complex formation, damage to cells bearing antigen, or stimulation or blockage of cell receptor function. Both antibodies and T-cells play a role in autoimmune disease. There are multiple mechanisms by which autoantibodies can cause

tissue damage. Binding of autoantibody to autoantigens on cell surfaces can trigger complementmediated destruction of the cell. Autoantibodies may also bind to receptors, either blocking or stimulating receptor function. Graves’ disease provides an example of autoantibody stimulation of receptor function. Thyroid hormone production is stimulated by autoantibodies binding to thyroid stimulating hormone receptors on thyroid cells. In myasthenia gravis, receptor function is blocked. Autoantibodies to the acetylcholine receptor in the neuromuscular junction bind to the receptor and block neuromuscular transmission, as well as causing depletion of the receptors. Autoantibodies can less commonly be directed against extracellular matrix molecules, as in Goodpasture’s syndrome, where they are directed against the basement membrane of the

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renal glomeruli. Although it is more difficult to demonstrate T-cell involvement than antibody involvement in the autoimmune response, T-cells have been implicated in the disease processes of Type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. A further distinction among autoimmune processes is whether they are organ specific, i.e., affecting only one organ such as the retina in cancer-associated retinopathy, or whether they affect multiple organ systems, as in systemic lupus erythematosus, sarcoidosis, or Wegener’s granulomatosis. Molecular mimicry is a common mechanism of autoimmune disease. Similarity between a foreign antigen and a self antigen stimulates an immune response against the self antigen (cross-reactivity), which continues to propagate due to the continued presence of the self antigen.

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10.2Autoimmune Retinopathy Overview

Many diseases affecting the retina are postulated or known to have an autoimmune component. The presentation of a subset of these disorders overlaps with the presentation of disorders affecting the optic nerve, such as compressive or inflammatory lesions, toxic, hereditary or nutritional optic neuropathies, and, in the cancer patient, direct spread of the malignancy, toxic effects of the treatment (chemotherapy or radiation), or carcinomatous meningitis. These entities can present with subacute vision loss and little or no findings on fundus examination. Autoimmune retinopathies that can present in a similar fashion include: paraneoplastic retinopathies such as cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and bilateral diffuse uveal melanocytic proliferation (BDUMP); non-paraneoplastic autoimmunerelated retinopathy and optic neuropathy (ARRON); acute outer retinopathies with blind spot enlargement [acute idiopathic blind spot enlargement (AIBSE), multiple evanescent white dot syndrome (MEWDS), and acute zonal occult outer retinopathy (AZOOR)] (Table 10.1). There are multiple other retinal disorders with confirmed or suspected autoimmune etiologies

that generally have a more distinguishing presentation, history, or associated systemic disease making them less likely to find their way into the neuroophthalmic differential diagnosis, including: birdshot retinochoroidopathy; sarcoid panuveitis; Behçet’s syndrome; diabetic retinopathy; retinopathies associated with systemic lupus erythematosus; periphlebitis retinae and pars planitis associated with multiple sclerosis, among others (Table 10.2).

10.3 Paraneoplastic Retinopathies

There are multiple ways in which cancer can affect the visual system: directly; through cancer treatments; or remotely. Direct effects include metastasis, or secondary invasion of tumors located in or near the orbit or any part of the visual pathway. Cancer treatments, both chemotherapy and radiation, can cause vision loss. The third way that cancer can have an impact on vision is via a remote, or paraneoplastic, process in which autoimmune or possibly hormonal processes affect the retina or optic nerve secondary to a neoplasm located elsewhere in the body. This is thought to be mediated via molecular mimicry; similarity between a tumor antigen and a component of the target organ results in misplaced, antibody-mediated attack by the immune system on the target organ. Specific paraneoplastic syndromes have been identified in which the target organ is the retina or choroid, including cancerassociated retinopathy (CAR), melanoma-asso- ciated retinopathy (MAR) and bilateral diffuse uveal melanocytic proliferation (BDUMP). Although BDUMP is thought to be paraneoplastic, an autoimmune etiology has not been demonstrated.

10.3.1Cancer-Associated Retinopathy

Cancer-associated retinopathy (CAR) is most often associated with small cell lung cancer (twothirds of cases). Multiple other cancers have been associated with CAR including ovarian, cervical, uterine, and breast. Less common associations

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include lymphoma, prostate, bladder, laryngeal, colon and hepatocellular cancers [9, 10]. In about half of the cases, CAR is diagnosed prior to the malignancy.

10.3.1.1 Clinical Presentation

Cancer-associated retinopathy typically presents with subacute vision loss, photopsias, and night-blindness. The clinical examination may appear normal, or there may be some narrowing of retinal vessels and/or vitritis (Fig. 10.1).

10.3.1.2.2 Electroretinogram (ERG)

The ERG shows diffuse loss, most marked under scotopic conditions.

Fig. 10.1. Attenuated retinal vessels in cancer-associ- ated retinopathy

10.3.1.2.3 Laboratory Testing

Cancer-associated retinopathy has been associated with multiple antibodies, but primarily with an autoantibody to a 23-kDa protein identified as recoverin. A commercial test is available for this antibody. The diagnosis of CAR is a clinical one, however, and should not rely on the identification of this antibody.

10.3.1.3 Pathophysiology

Keltner and associates [31] first proposed an autoimmune mechanism for paraneoplastic retinopathy in 1983, when they demonstrated that the serum from a patient with cervical cancer and progressive blindness, with ring scotomas and a flat electroretinogram (ERG), contained antibodies that reacted with human retinal photoreceptors [31]. Subsequently, Western blot and enzyme-linked immunosorbent assays identified a 23-kDa antigen that bound to antibodies from serum of patients with CAR [48]. This protein, which became known as the CAR antigen, was further characterized using antibodies from the serum of patients with CAR to identify the gene that encoded it from a cDNA library of human retina. Analysis of the nucleotide sequence revealed 90% homology with a bovine homolog of the protein recoverin, a calcium-binding protein found in photoreceptor cells [50]. Recoverin production has been demonstrated in small cell lung neoplasms, providing a basis for the molecular mimicry mechanism of autoimmunity [36]. Recoverin, a member of the EF-hand superfamily of calcium-binding proteins, plays a role in the visual transduction cycle [46]. Evidence suggests that recoverin functions in the termination of the transduction cascade via regulation of rhodopsin phosphorylation [46]. Its role was previously thought to involve the recovery phase of the cycle via activation of guanylate cyclase in response to declining intracellular calcium levels. This role, however, has recently been attributed not to recoverin, but to a family of guanylate cyclase activating proteins [46]. Recoverin functions in a calcium-dependent manner, to inhibit rhodopsin phosphorylation, which is a step in the termination of the phototransduction cascade. Direct interaction between recoverin and rhodopsin

kinase, the molecule that directly regulates rhodopsin phosphorylation, has been demonstrated in vitro [8]. Inhibition of rhodopsin phosphorylation by recoverin has also been demonstrated in vitro [30].

Recoverin antibodies have been shown to cause photoreceptor cell death by apoptosis. The apoptosis occurs in vitro via a mitochondrial pathway mediated by entry of all or part of the antibody into retinal cells [45]. It is coupled to an antibody-mediated increase in intracellular calcium, which is common component of apoptotic pathways. Adamus and associates [2] demonstrated that exposure of retinal cells to the anti-recoverin antibody causes an increase in intracellular calcium in vitro. Other mediators of apoptosis identified via in vitro studies of retinal cells treated with anti-recoverin antibody included bcl-2 family proteins, cytochrome c, caspase 9 and caspase 3 [2]. Caspase enzymes (cys- teine-containing aspartate-specific proteases) are commonly involved in apoptotic pathways in general, although of the 14 subtypes found in human cells, select subtypes are involved depending on cell type and inciting event. Elucidating the pathway of recoverin-antibody-induced cell death allows for the potential development of protective agents, such as calcium channel blockers and caspases inhibitors, which are under investigation. Retinal cells exposed to the calcium channel blocker nifedipine and anti-recoverin antibody were found to have a blunted increase in intracellular calcium, modified changes in the mitochondrial pathway, and ultimately decreased

apoptosis [2]. Calcium channel blockers therefore hold promise as therapeutic agents against CAR. Caspase inhibitors, which have been shown to diminish cell death in animal models, are another class of potential therapeutic agents [34].

The recoverin antibody is present in the serum of most patients with CAR, and its pathogenicity has been well characterized. However, additional factors are involved which are not fully understood. While most patients with CAR have autoantibodies to recoverin, other antigens have been identified in these patients, including alpha-enolase and heat shock cognate protein 70 (HSC70), although only the recoverin antibody hasbeendemonstratedtocausephotoreceptorcell death [13]. Additionally, tumors can produce recoverin and not cause CAR [40, 44]. An explanation is also needed for how the CAR antibody crosses the blood–retina barrier to reach photoreceptor cells, if the in vitro studies demonstrating endocytosis of the antibody as a prerequisite for apoptosis hold true in vivo. Bazhin and associates [4] have suggested that this issue may explain why CAR is such a rare condition. They conjecture that a second event may be needed to allow access of these molecules beyond the blood–retinal barrier, and this may explain why not all patients with the CAR antibody develop retinopathy, and may also provide a role for the other antibodies identified in CAR patients. Another explanation for the presence of CAR antibodies in patients without CAR may be attributable to the particular epitope to which the antibody is directed.

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10.3.1.4 Treatment

Currently, the mainstay therapy for CAR, and indeed for all of the paraneoplastic retinopathies, is systemic corticosteroids. Reported cases indicate that steroids may cause a mild transient improvement in visual fields and/or acuities, or arrest further deterioration [9]. Other treatment modalities include intravenous immunoglobulins (IVIg) and plasmapheresis. Scattered case reports are inconclusive as to the effectiveness of these treatments. Treatment of the primary tumor does not appear to alter the course of the retinopathy [9]. Possible future therapies include calcium channel blockers and caspase inhibitors. Patients with CAR should be followed with serial visual fields, acuities, ERG and antibody titers. Unfortunately, the course of CAR, although variable, is generally characterized by rapidly progressive vision

10 loss resulting in severe bilateral vision loss, often within weeks or months of onset.

10.3.2Melanoma-Associated Retinopathy

Melanoma-associated retinopathy (MAR) is a paraneoplastic retinal degeneration associated with cutaneous melanoma. The diagnosis of melanoma generally occurs months to years prior to the onset of MAR. A series of 62 patients with MAR revealed an average time from diagnosis of melanoma to diagnosis of MAR of 3.6 years [32]. Two of these patients were diagnosed with melanoma subsequent to the onset of MAR. One patient has been reported to develop MAR 19 years after resection of cutaneous melanoma [41]. The average age on onset was 57.5 years, with a range of from 30 to 78 years. Men were affected more than women (33/40 versus 7/40; the gender was not known for 22 of the patients) [32]. Most patients with MAR have metastatic melanoma although in a review of 12 MAR patients, 3 had no evidence of metastasis [32].

Summary for the Clinician

■Most common association: small cell lung cancer.

■Also associated with cancers of the female reproductive tract.

■May be diagnosed prior to malignancy.

■Presents with subacute vision loss, photopsias, night-blindness.

■May have normal fundus, narrowing of vessels, or vitritis.

■Visual field: mid-peripheral defects progressing to ring scotoma.

■ERG: diffuse loss particularly under scotopic conditions.

■Antibody to photoreceptor cell antigen, recoverin (“CAR antigen”) commonly involved.

■Commercialtibody.” test available for “CAR an-

■Treatment: corticosteroids.

■Possible future treatments: calcium channel blockers, caspase inhibitors.

■Course: rapidly progressive bilateral vision loss.

10.3.2.1 Clinical Presentation

Patients with MAR present with acute onset of night-blindness, photopsias, and floaters. Vision at presentation is usually better than 20/40. In Keltner’s review [32], 82% had presenting visual acuity better than 20/60. Dyschromatopsia, vitritis, retinal vessel attenuation and optic nerve pallor may be apparent.

10.3.2.2 Diagnostic Studies

10.3.2.2.1 Visual Field

Visual field testing at presentation can reveal central scotomas, generalized constriction, or arcuate defects.

10.3.2.2.2 ERG/EOG

The ERG findings in MAR are highly specific, showing a normal a-wave and the absence of the b-wave under dark-adapted conditions (socalled electronegative ERG). This pattern is suggestive of bipolar cell dysfunction. The pattern is

similar to the ERG pattern seen in patients with congenital stationary night-blindness. A subset of MAR patients show decreased a- and b-wave amplitudes, suggesting photoreceptor dysfunction in addition to bipolar cell dysfunction [32]. Some MAR patients have abnormal EOGs [31].

10.3.2.3 Pathophysiology

The mechanism of MAR is largely conjecture at this point. There is compelling evidence that autoimmune attack of retinal bipolar cells plays a central role. Serum from patients with MAR has been shown by immunocytochemical techniques to react with retinal bipolar cells [6, 37]. Histologic examination of the retina in MAR patients demonstrates bipolar cell degeneration [21, 49]. Serum from patients with MAR injected into monkeys induces retinal bipolar cell degeneration [33]. Consistent with these findings is a typical decreased ERG b-wave in MAR patients. Although no MAR-specific antigen has been identified, a mechanism based on molecular mimicry, as in CAR, has been postulated. Decreased ERG a- and b-wave amplitudes and serum reactivity with photoreceptor cells in some MAR patients suggest that a subset of these patients has photoreceptor dysfunction in addition to bipolar cell dysfunction [7, 32].

10.3.2.4 Treatment

As with CAR, the mainstay of treatment is with systemic corticosteroids. Again, while other therapies have been tried, there has been no rigorous evaluation. Keltner and colleagues [32] found 7/62 patients to have visual improvement on a various therapies, including IVIg, cytoreductive surgery, and prednisone. These authors find cytoreductive surgery to be a promising direction for future therapy, citing four patients who had visual improvement following either cytoreductive surgery alone, or cytoreductive surgery in combination with IVIg. Suggesting a theoretical basis for this therapy, they note that decreasing the tumor load, and thereby decreasing tumor production of antigens that may mimic retinal antigens, may decrease serum levels of pathogenic

antibodies [32]. However, antibody production may persist despite lowering of tumor load due to continued propagation by the self-antigen in the retina, as is frequently the case in autoimmune disease. One concern regarding treatment for MAR, and indeed all of the paraneoplastic retinopathies, with immunomodulatory agents is that although they may decrease circulating antibodies that are harmful to the retina, these same antibodies may be effective tools fighting against the malignancy. It is not clear whether antibodies induced by these tumors are helpful or harmful to the cancer.

The course of MAR is generally more moderate than that of CAR. Patients should be followed with serial visual fields, visual acuities and ERGs. Table 10.3 compares characteristics of MAR and CAR.

Summary for the Clinician

■Associated with cutaneous melanoma.

■Usually diagnosed after malignancy.

■Presents with acute onset night-blind- ness, photopsias, floaters.

■May have normal fundus, narrowing of vessels, vitritis, or optic nerve pallor.

■Visual field: central, arcuate or generalized constriction.

■ERG: absence of b-wave under scotopic conditions.

■Unidentified antibody to bipolar cells.

■Treatment: corticosteroids.

■Course: slower progression than CAR.

10.3.3Bilateral Diffuse Uveal Melanocytic Proliferation

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic retinopathy with 28 cases reported in the literature [42]. Among these cases, the mean age of diagnosis was 64, ranging from 34 to 89 years [42]. It is most commonly associated with lung and retroperitoneal cancers in men, and cancers of the reproductive tract in women. Diagnosis of BDUMP may occur prior to that of the primary cancer. In

one review, 10/16 cases presented 3–12 months prior to diagnosis of the primary cancer [19]. The pathophysiology of BDUMP is not clearly understood; compelling evidence of an autoimmune etiology is lacking.

10.3.3.1 Clinical Presentation

Patients generally present with subacute loss of vision. The classic fundus findings are bilateral subtle red retinal pigment epithelial lesions which often precede development of multiple subretinal pigmented and non-pigmented slightly elevated melanocytic uveal tumors, which may appear similar to choroidal nevi. Serous retinal detachments, uveitis, and rapidly progressing cataracts may develop subsequently [19]. Dilated episcleral vessels, pigmented cells in the anterior chamber and/or vitreous, pigmented keratic precipitates, a shallow anterior chamber and glaucoma may also be apparent [3, 19, 43]. Patients may also develop pigmented lesions of the skin or mucous membranes. Out of the 28 reported

cases of BDUMP, 26% of patients exhibited such lesions [42].

10.3.3.2 Diagnostic Studies

10.3.3.2.1Fluorescein Angiography

Early hyperfluorescence of the subtle, red retinal pigment epithelial lesions is classic, and virtually pathognomonic [19].

10.3.3.3 Pathophysiology

The underlying mechanism of BDUMP involves multifocal areas of retinal pigment epithelium (RPE) destruction (red patches) and uveal proliferation of melanocytes (elevated lesions), although the pathogenesis is not clear. The degree of retinal pigment epithelial destruction is out of proportion to the amount of underlying choroidal infiltration. Gass and colleagues [19] suggest that