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

additional immune or toxic factors may account for the extensive outer retinal and RPE damage. Whether the melanocytic lesions have malignant potential is controversial. In most cases, pathologic specimens reveal a benign-appearing proliferation of spindle-shaped cells. A minority, however, have an appearance suggestive of malignancy [42]. The lack of any reported cases of metastasis supports a benign nature to these proliferations. This could, however, be related to the poor prognosis associated with this disease, and therefore the short time over which metastasis could declare itself. The mean survival time of these patients is 16 months [19]. Additionally, a protein commonly overexpressed in uveal melanomas, p53, does not appear to be associated with BDUMP melanocytic proliferation, as evidenced by lack of staining with antibodies to p53 [35]. Histologic specimens reveal diffuse uveal tract thickening [42]. Neither the stimulus for melanocytic proliferation nor the explanation for retinal pigment epithelial and choroidal destruction out of proportion to the underlying uveal tumor has been determined. Normal uveal melanocytes rarely, if ever, proliferate. However, it is not uncommon to find nevus cells, pigmented or unpigmented, in the uveal tract that do have the capacity to proliferate, often in response to hormonal signals. Gass and colleagues [19] have suggested that BDUMP patients may have congenital, bilateral, non-pigmented, melanocytic uveal nevi that proliferate secondary to hormones secreted by the distant carcinoma. They suggest that the extent of RPE and outer retinal changes needs an explanation in addition to the presence of underlying melanocytic proliferation, and is possibly due to toxic and/or immune factors secondary to interplay between the carcinoma, uveal tumors and outer retinal/RPE elements.

10.3.3.4 Treatment

Radiation or systemic steroids may cause transient improvement in the serous retinal detachment. However, no effective treatment has yet been found to halt the characteristic progressive visual loss, which may proceed despite treatment of the primary cancer [19].

Summary for the Clinician

■Autoimmune?

■Associated with lung and retroperitoneal cancers in men, cancers of the reproductive tract in women.

■Presents with subacute loss of vision.

■Early: subtle red retinal pigment epithelial lesions.

■Later: multiple subretinal pigmented and non-pigmented elevated lesions.

■Serous retinal detachments, uveitis, cataracts may develop.

■Fluorescein angiography: early hyperfluorescence of red RPE lesions.

■Treatment: systemic corticosteroids may improve serous retinal detachments.

■Course: progressive vision loss.

10.4AutoimmuneRelated Retinopathy and Optic Neuropathy

The term autoimmune-related retinopathy and optic neuropathy (ARRON) has been used to describe a number of patients with a clinical presentation, ERG findings, and disease course similar to CAR or MAR, but no underlying cancer [23, 34, 38, 52]. Disease progression is generally slower than in CAR [38]. One or multiple anti-retinal antibodies have been identified in these patients, including anti-recoverin antibodies, although their pathogenic significance is in question. One such patient, described by Whitcup et al. [52], was found to have anti-recoverin antibodies and serum which demonstrated immunohistochemical staining of photoreceptor cells, bipolar cells, and the outer plexiform layer. Heckenlively and associates [23] described ten CAR-like patients who carried the diagnosis of retinitis pigmentosa, and demonstrated immunoreactivity against multiple retinal antigens, including recoverin. Mizener and colleagues [38] reported two patients with a CAR-like syndrome whose serum demonstrated antibody staining the retinal inner plexiform layer. While reports of such cases emerge, this syndrome

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is not well understood, and the role of autoimmunity has been challenged [1]. The patients described by Heckenlively et al. [23] possessed serum antibodies against a variety of proteins; Adamus [1] suggests that this differentiates them from typical CAR, and calls into question the pathogenic importance of any particular antibody. She also notes the common correlation between disease activity and autoantibody levels in autoimmune disease in general, and CAR in particular, and contrasts this with the lack thereof demonstrated in the cohort described by Heckenlively et al. [23]. It is also possible that, despite diligent search, a cancer remains undiscovered in these patients. Indeed it would be prudent to search exhaustively for a malignancy in a patient that presents with vision loss, photopsias, visual field defects, and ERG abnormalities, particularly if anti-recoverin antibodies are identified.

10

Summary for the Clinician

■Similar to CAR or MAR but no associated malignancy.

■Multiple antibodies identified, including “CAR antibody.”

■GenerallyCAR. progresses more slowly than

10.5Acute Outer Retinopathies with Blind Spot Enlargement

Several disorders of the retina and/or choroid are associated with enlarged blind spots (Table 10.4). While some of these conditions have examination findings sufficient to explain this visual field defect, such as a markedly edematous or optic nerve (displacing peripapillary retina), ophthalmoscopically apparent choroidal or retinal peripapillary abnormalities, some of the outer retinopathies do not [5]. In fact, acute idiopathic blind spot enlargement (AIBSE), multiple evanescent white dot syndrome (MEWDS), and acute zonal occult outer retinopathy (AZOOR) often have minimal fundus findings. These disorders have a place in the neuroophthalmologist’s differential diagnosis of vision loss with a relatively normal fundus exam. There is continued controversy over whether AIBSE, MEWDS, and AZOOR, and indeed several other syndromes including acute macular neuroretinitis (AMN), multifocal choroiditis (MFC), puncatate inner choroidopathy (PIC), and presumed ocular histoplasmosis are part of a spectrum of a single disease or distinct disease entities.

10.5.1Acute Idiopathic

Blind Spot Enlargement

10.5.1.1 Clinical Presentation

In 1988, Fletcher and associates [15] reported seven patients who presented with enlarged blind spots and photopsias with no significant disc swelling. All of these patients had normal fluorescein angiograms, two had abnormal multifocal ERGs, and two had peripapillary pigmentary abnormalities. This constellation of findings became known as AIBSE, and is characterized by acute onset of photopsias and enlarged blind spot without marked disc swelling. The condition tends to be unilateral. The majority of patients are young women. In a review by Volpe and colleagues [51] of 27 patients with AIBSE, all were women, ranging in age from 19 to 53 years. Though decreased vision is a common presenting complaint, 16/27 patients in this review had normal visual acuity. Patients may have dyschromatopsia (9/27), an afferent pupillary defect (APD) (8/27), mild disc edema, hyperemia or peripapillary pigmentary changes, and, occasionally, multiple white lesions similar to those seen in MEWDS (5/27).

There is a high rate of misdiagnosis in AIBSE. Other conditions that can be confused with AIBSE, and in fact should be in the differential diagnosis, include: migraine (photopsias); optic neuritis (sudden onset of visual field defect in young woman); papilledema (enlarged blind spot); and chiasmal lesion (temporal field defect).

10.5.1.2 Diagnostic Studies

10.5.1.2.1 Visual Field

All patients with AIBSE have enlarged blind spots (Figs. 10.3, 10.4). There is wide variability in the size of the blind spot; however, steep borders of the field defect are characteristic of this disorder. The enlarged blind spot seen in AIBSE can appear similar to a temporal defect seen in chiasmal disease.

10.5.1.2.2 ERG

Full-field ERG amplitudes are generally within normal in patients with AIBSE. However, intereye asymmetry has been observed, with the affected eye having lower amplitudes [51] (Fig. 10.5). Focal ERGs directed at the peripapillary retina tend to be abnormal [15, 51]. In the review by Volpe and associates [51], eight out of the nine patients who had focal ERGs showed such abnormalities.

10.5.1.2.3Fluorescein Angiography

Fluorescein angiography may show disc staining, which may not correlate with clinically apparent optic disc edema. Out of 27 patients in the Volpe review [51], 12 had disc staining on fluorescein angiography, while 3 of these 12 and normal appearing discs by ophthalmoscopy. Late-staining retinal pigment lesions may also be seen. These lesions do not correspond to white lesions sometimes seen on examination.

10.5.1.3 Pathophysiology

Abnormal ERG results from focal ERGs directed at the peripapillary retina suggest that retinal dysfunction in this region is responsible for the enlarged blind spot. The pathophysiology of AIBSE is poorly understood. It has been known to occur in members of the same family; however, no defined heritable pattern has been identified. The acute presentation and sporadic occurrence of AIBSE have led to speculation of an autoimmune or infectious etiology. The prevalence among young women and occasional recurrence (6 out of 27 patients had recurrences in the review by Volpe and colleagues [51]) fit the profile of autoimmune disease, although perhaps a higher recurrence rate would be expected in an autoimmune condition. No specific antibody or infectious agent has been identified. The common finding of disc staining on fluorescein angiography suggests the possibility of optic nerve inflammation in addition to presumed

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outer retinal dysfunction. This staining, however, may simply represent increased vascularity secondary to contiguous inflammation.

10.5.1.4 Treatment

There is no treatment for AIBSE. The photopsias tend to resolve over time. The enlarged blind spot, while occasionally improving, generally persists.

Summary for the Clinician

■Unilateral.

■Usually affects young women.

■Presents with photopsias and enlarged blind spot.

■May have mild disc edema.

■May have an APD and/or dyschromatopsia.

■Visual field: enlarged blind spot with steep borders.

■ERG: abnormal focal ERG directed at peripapillary retina.

■Etiology:genetic. suspected autoimmune/viral/

■Treatment: none.

■Course: persistence of blind spot.

10.5.2Multiple Evanescent White Dot Syndrome

10.5.2.1 Clinical Presentation

Multiple evanescent white dot syndrome (MEWDS) was first described in 1984, by two independent research groups: Jampol et al. [28] and Takeda et al. [47]. They reported series of patients presenting with acute unilateral vision loss, scotomas, and multiple, white fundus lesions. The majority of patients were women: 10 of the 11 patients were women in Jampol’s series [28]. A recent review of the literature shows 51 out of 62 reported cases to be women, with an average age of 27 years, ranging from 14 to 47 years [12]. In Jampol et al.’s study, nearly half of 11 patients with MEWDS had had a flu-like ill-

ness prior to developing MEWDS [28]. In addition to complaining of decreased vision and dark spots, most patients describe photopsias (flickering lights). Fundus exam may reveal, often subtle, multiple white lesions, often extending centripetally from the disc, with particular concentration between the arcades, however sparing the fovea. The lesions tend to disappear altogether within 4–6 weeks, and during this time may fade and reappear in other locations. They have been described as “dots and spots” where the dots are smaller, measuring approximately 100 µm, and the spots are larger, at approximately 200 µm in diameter. Clinical examination in conjunction with fluorescein or indocyanin green angiography and ocular coherence tomography (OCT) suggests involvement of the neurosensory retina, RPE, and choroid [22, 26]. Other examination findings include foveal granularity of the RPE, and less commonly mild disc edema, vascular sheathing, or vitritis (Figs. 10.6, 10.7). An afferent papillary defect may be present. Patients may have dyschromatopsia.

10.5.2.2 Diagnostic Studies

10.5.2.2.1 Visual Field

Visual field testing may reveal an enlarged blind spot. Other less common defects include central, cecocentral or arcuate scotomas. As with AIBSE, the field defect is generally more extensive than would be expected based on the clinical appearance of the retina or optic nerve.

10.5.2.2.2Fluorescein Angiography

The classic finding on fluorescein angiography is a middle-phase wreath-like pattern of hyperfluorescence surrounding the fovea, corresponding to the white lesions seen on ophthalmoscopy, although more lesions are evident angiographically. Gross and colleagues [22] demonstrated hyperfluorescence of most dots during the cho- roidal-filling stage, localizing them to the RPE or inner choroid; however, some dots fluoresced during the retinal arteriolar filling stage, suggesting a more anterior location in the retina. The

Fig. 10.6. Foveal granularity in multiple evanescent white dot syndrome (MEWDS)

angiographic appearance of the larger lesions, “spots,” was variable in this study.

10.5.2.2.3Indocyanine Green Angiography

Indocyanine green (IGC) angiography demonstrates multiple hypofluorescent lesions larger and more numerous than those evident clinically. These may be indicative of inflammatory lesions in the choriocapillaris [24, 39]. Some patients with blind spot enlargement exhibit peripapillary hypofluorescence, the resolution of which corresponds to the resolution of their field defect [12].

10.5.2.2.4 ERG

Full-field ERG may show diffuse photoreceptor dysfunction during the acute phase of the illness, implicating involvement of the photoreceptor/ RPE complex in the disease process.

10.5.2.2.5Ocular Coherence Tomography

Jampol [26] reported OCT findings suggestive of transient accumulation of material in the subretinal space corresponding to white lesions (domeshaped reflective lesion), with underlying, persis-

Fig. 10.7. Higher magnification of foveal granularity

tent deep choroidal reflectivity. Seven weeks after presentation, the subretinal lesion was resolved; however, the choroidal reflectivity remained 5 months after presentation, suggesting greater choroidal involvement in this disorder than previously thought. Kanis and van Norren [29] report evidence of temporary disruption of foveal cones by both OCT and foveal reflection analyzer techniques.

10.5.2.3 Pathophysiology

The pathogenesis of MEWDS is incompletely understood.Aviraltriggerhasbeenpostulatedbased on the acute onset and a frequent preceding viral illness.Anautoimmuneetiologywouldfitwiththis scenario, and is supported further by the tendency to occur in young women, sporadic occurrence, and occasional recurrence. Although elevated levels of immunoglobulins have been detected in the serum of patients with MEWDS, no histochemical evidence of antibody binding to retinal proteins has been demonstrated [11, 25]. Additional pieces of the puzzle that remain to be united include ICG angiography and OCT findings suggestive of choroidal inflammation, and OCT, fluorescein angiography, ERG, and reflection analyzer techniques findings indicative of transient outer retinal disturbances [22, 26, 29]. Additionally, the optic nerve may be involved in MEWDS either via direct inflammation or secondary inflammation. Dyschromatopsia, visual

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field defects, an afferent papillary defect, and optic nerve head staining on fluorescein angiography, which may be present in patients with MEWDS, could be explained by extensive retinal involvement; however, direct inflammation of the nerve/ retinal ganglion cell layer, or secondary inflammation due to adjacent retinal/vascular inflammation could also be responsible.

10.5.2.4 Treatment

Most patients with MEWDS recover fully over 3– 10 weeks. Some may experience persistent field defects. MEWDS occasionally recurs: 5 out of 62 patients have been reported to experience recurrences [12]. There is currently no effective treatment; however, in a report of one patient who had multiple recurrences of MEWDS (nine recur-

10 rences over 7 years) cyclosporin therapy was found to reduce the recurrence rate. Over a 2- year period, recurrences occurred only when the cyclosporin was discontinued or when the dose was decreased [14].

Summary for the Clinician

■Unilateral.

■Usually affects young women.

■Presents with acute unilateral vision loss, scotomas, and photopsias.

■Subtle, transient white fundus lesions.

■May have foveal granularity, mild disc edema, vascular sheathing, vitritis.

■May have an APD and/or dyschromatopsia.

■Visual field: enlarged blind spot common. May have central, cecocentral or arcuate defect.

■ERG: full-field ERG may show diffuse photoreceptor dysfunction.

■Fluorescein angiography: middle-phase wreath pattern surrounding fovea.

■Etiology:genetic. suspected autoimmune/viral/

■Treatment: none.

■Course: generally full recovery in 3– 10 weeks.

10.5.3Acute Zonal Occult Outer Retinopathy

10.5.3.1 Clinical Presentation

Acute zonal occult outer retinopathy (AZOOR) was first described in 1993 by Gass, who reported a series of 13 patients, 10 of whom were young women, who presented with acute loss of peripheral vision in one or both eyes, photopsias, and minimal or no fundus abnormalities. The syndrome was further characterized by recurrences in the same or fellow eye, ERG abnormalities, and persistence of both photopsias and visual field defects, sometimes associated with fundus changes later in the disease course [17, 20]. While the term AZOOR sometimes refers to a complex of diseases including variably MEWDS, AIBSE, multifocal choroiditis, punctuate inner choroidopathy, acute macular neuroretinopathy; and pseudo-presumed ocular histoplasmosis syndrome, Gass and colleagues [20] reviewed 51 patients with AZOOR, in 2002, excluding all of the above conditions excepting AIBSE. 20% of these patients had a preceding viral-like illness days or weeks prior to the onset of the visual symptoms [20]. Vision loss was often described as “dark blind spots.” Other findings include: 88% of the patients described photopsias; 90% of the patients were aware that their vision was worse in the bright light; and 24% had an APD within a few weeks of presentation [20]. While no patients had vitritis within 1 week of onset, vitreous cell was observed in 57% of eyes weeks to months later [20]. No fundus changes related to AZOOR were noted in 91% of eyes in this review [20].

10.5.3.2 Diagnostic Studies

10.5.3.2.1 Visual Field

Visual field defects in AZOOR are variable, and include from most frequent to least frequent: blind spot enlargement, ring scotomas, hemianopic scotomas, generalized constriction, arcuate defects, and multiple isolated scotomas. The blind spot was involved in 87% of eyes in the review by Gass et al [20].

10.5.3.2.2 ERG

In the original cohort described by Gass [17], most eyes showed mild to moderate reduction in rod and cone amplitudes. Out of 13 of these patients, 11 had the ERG more than a month into the disease course [17]. In their review of 51 patients, Gass and colleagues report variable ERG findings with 55/90 eyes showing scotopic and photopic dysfunction, and 16/55 showing photopic dysfunction, and 8/55 eyes showing only scotopic dysfunction [20]. Jacobson et al. [25] reported full-field ERG abnormalities on a cohort of 24 patients with the AZOOR complex of disease, including MEWDS, multifocal choroiditis, acute macular neuroretinopathy, and pseudo-presumed ocular histoplasmosis syndrome [25]. Francis and associates [16] reported an ERG and EOG analysis of 28 patients who fit the criteria for AZOOR originally presented by Gass in 1993. These patients were predominantly young females (86% female), whose condition was characterized by persistent, usually temporal field loss, photopsias, and normal appearing fundus at presentation. Involvement of both eyes occurred in 46%; 4 out of the 15 who presented unilaterally subsequently developed second eye involvement, and 46% of these patients carried a previous diagnosis of a white dot syndrome [16]. ERG findings demonstrated diffuse RPE/photoreceptor dysfunction, and were suggestive of greater cone than rod involvement [16]. Francis et al. [16] additionally postulated inner retinal involvement based on the abnormal 30 Hz flicker ERG results.

young women is suggestive of an autoimmune etiology. This is further supported by the presence of at least one autoimmune disease in 28% of the 51 patients reviewed by Gass et al [20]. This is compared to no autoimmune disease noted in an ageand sex-matched control group [20]. No immunocytochemical studies have directly linked AZOOR with an autoimmune etiology. Gass has postulated that AZOOR may be precipitated by a virus infecting photoreceptor cells. Photoreceptor destruction may then be triggered by a delayed host immune response to the virus [18]. It is relevant to this hypothesis that 20% of patients in Gass’s review of 51 patients with AZOOR had an antecedent viral-like illness [20].

10.5.3.4 Treatment

As with MEWDS and AIBSE, there is no proven effective treatment for AZOOR. One out of six patients in the original report by Gass showed improvement with corticosteroids. In the review of 51 patients with AZOOR, 39 out of 113 episodes were treated with corticosteroids [20]; 11 episodes were also treated with acyclovir or valacyclovir. Of the 51 patients, 13 showed improvement in vision. Of these, 9 had no treatment, 4 had been treated with steroids, and 2 of the 4 had also been given acyclovir. Visual loss generally stabilizes within 6 months following an episode of AZOOR (77% of 90 eyes in the review by Gass et al [20]). Recurrences may occur in approximately 25% of patients [27]. (See Table 10.5 for a comparison of AIBSE, MEWDS, and AZOOR.)

10.5.3.2.3 EOG

Gass and colleagues [20] report abnormal EOG results in 9/13 eyes tested. Francis et al. [16] found consistently abnormal EOG results, which, they note in the context of their ERG findings, is suggestive of RPE involvement in this disease [16].

10.5.3.3 Pathophysiology

The pathogenesis of AZOOR is unknown. As with MEWDS and AIBSE, the predominance among

10.5.3.5AZOOR Complex of Disease

Controversy continues over whether AZOOR, MEWDS, AIBSE, as well as other white dot syndromes, variably including punctuate inner choroidopathy, acute macular neuroretinopathy, multifocal choroiditis, and presumed ocular histoplasmosis, are separate diseases, or comprise one disease with variable presentation. Proponents of one unifying disease cite similar demographics, the overlap of signs and symptoms, and the occurrence of several of

these different entities in one person as evidence for a single condition. All of these enti- 10 ties tend to occur in young, otherwise healthy women. Presentation is similar, consisting of an acute onset of photopsias and visual field defects with minimal if any fundus changes, and an abnormal ERG. While these various conditions do have distinguishing features, such as the multiple evanescent dots in MEWDS, Gass has proposed that this could be explained by differences in individuals’ genetic and immune system make-up [18]. On the other hand, these very differences can be considered reason to consider these as separate diseases until a single etiology is determined. Becker has proposed a “genetic hypothesis of autoimmune/inflammatory disease” that could explain the similar demographic and character of these syndromes [27]. His hypothesis proposes a genetic predisposition to autoimmune disease that may develop into specific autoimmune disease depending on environmental triggers such as viral illness. Individuals with this predisposition may be susceptible to multiple autoimmune/ inflammatory diseases, explaining the occurrence of several of these diseases in one person.

More investigation is required to further refine this hypothesis; however, there is some evidence to support allelic associations with multiple autoimmune diseases [27].

Summary for the Clinician

■Unilateral or bilateral.

■Tends to recur.

■Usually affects young women.

■Presents with acute peripheral vision loss in one or both eyes and photopsias.

■Normal fundus. May have vitritis weeks to months after onset.

■May have an APD.

■Visual field: enlarged blind spot common. May have ring scotoma, hemianopic scotoma, constriction, arcuate, or multiple isolated defects.

■ERG: may show diffuse reduction of rod and cone amplitudes.

■Etiology:genetic. suspected autoimmune/viral/

■Treatment: none.

■Course: stabilization of field defect within 6 months of onset. Recurrences in 25% of patients.

10.6 Summary

Paraneoplastic retinopathies and acute outer retinopathies with blind spot enlargement can present with subacute vision loss, photopsias, visual field defects, and minimal fundus changes. An APD and/or dyschromatopsia may be present.