Introduction

Neurofibromatosis type I, also known as von Recklinghausen’s disease, is an autosomal dominant disorder and one of the most common genetic diseases, affecting one in approximately 3000 persons [19]. Because its pathogenesis involves neural crest-derived melanocytes, Schwann cells, prevertebral ganglion and sympathetic neurons, it is considered a neurocristopathy [3, 12, 21]. Clinically, the disease is characterized by cafe-au-lait spots, freckle-like deposits in the skin, and neurofibroma. Ophthalmologic manifestations include Lisch nodules and optic nerve glioma [19]. Choroidal changes in the fundus have been reported [13, 18], but pathologic choroidal changes are difficult to detect by routine clinical examination under visible light [5]. Scanning laser ophthalmoscopy with near-infrared light is useful in detecting choroial changes. Near-infrared light penetrates more deeply into the choroid than visible light, and the confocal nature of direct-mode of a scanning laser ophthalmoscopy provides better contrast than is possible with a fundus camera by eliminating scattered light from the choroid [5]. We reported previously that patients with neurofibromatosis type I have a high incidence of choroidal abnormalities detected by scanning laser ophthalmoscopy. These abnormalities appear as hypofluorescent patches in the early phase of indocyanine-green angiography and as bright patchy lesions under infrared monochromatic light; they are not seen in conventional ophthalmoscopic examination or by means of fluorescein angiography [22]. We studied choroidal abnormalities to determine whether a relation exists between age and the number of abnormalities. We also studied patterns of anatomic distribution in the fundus.

Materials and methods

We examined the fundus of 28 eyes in 14 patients with neurofibromatosis type I. Patients ranged in age from 2 to 38 years and were examined between April 2001 and April 2002 by confocal scanning laser ophthalmoscopy (Heidelberg Retinal Angiogram, Heidelberg, Germany) with infrared monochromatic light (780 nm wavelength) under mydriasis. The angle of photography was 30°. After the posterior fundus was photographed, the confocal scanning laser ophthalmoscope was adjusted to capture regions superior, supero-temporal, temporal, infero-temporal, inferior, infero-nasal, nasal, and supero-nasal to the posterior region within the retinal vascular arcade, in that order. After the images of each region were printed, the fundus was divided into five regions (a region within the arcade, and supero-temporal, infero-temporal, supero-nasal, and infero-nasal regions) (Fig. 1). Lesions on the border between regions were assigned to the region that contained the greater part of the lesion. The correlation between the total number of choroidal abnormalities and age and the patterns of anatomic distribution in the fundus were analyzed.

Fig. 1
figure 1

Regions of the fundus, as defined in our study

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The correlation between patient age and the total number of choroidal abnormalities was calculated by the Spearman rank correlation coefficient. Trends in the number of choroidal abnormalities and distribution by location within the fundus were evaluated by adding the choroidal abnormalities in both eyes in a given region and testing the data by two-way analysis of variance (ANOVA) and Scheffe’s multiple comparisons test. Difference in the number of choroidal abnormalities between the left eye and the right eye was analyzed by the appropriate t-test. P-values of 0.05 or less were considered significant.

Results

The number of choroidal abnormalities per region for each of the 14 patients is shown in Table 1. The total number of choroidal abnormalities increased significantly with age, and there was a positive correlation (correlation coefficient, r=0.6209; P=0.0178) (Fig. 2). Choroidal abnormalities occurred significantly more often within the arcade region than in any of the other four regions (ANOVA, Scheffe’s multiple comparisons test; P<0.001) (Table 2). There was no difference in the number of choroidal abnormalities between the left and right eyes (paired t-test; P=0.1304) (Figs 3 and 4).

Table 1 Number of choroidal abnormalities per region
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Fig. 2
figure 2

Correlation between the number of choroidal abnormalities and patient age (r=0.6209, P=0.0178)

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Table 2 Statistical analysis of the distribution of choroidal abnormalities
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Fig. 3
figure 3

Photographs obtained of patient 1, a 2-year-old child, during infrared-laser examination with a confocal scanning laser ophthalmoscope. Choroidal abnormalities are seen as bright patchy regions

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Fig. 4
figure 4

Photographs obtained of patient 12, a 23-year-old man, during infrared-laser examination with a confocal scanning laser ophthalmoscope. Many bright patchy regions are seen

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Discussion

Among the National Institutes of Health diagnostic criteria of neurofibromatosis type I, features known to increase in number with age are neurofibromas [9] and Lisch nodules [10]. Although café-au-lait lesions and axillary or inguinal freckling have been confirmed to increase with age, such changes cannot be verified in geriatric patients because they become hidden by neurofibromas [9]. As with the Lisch nodules, unidentified bright objects seen on magnetic resonance images and thought to be hamartomas are seen in 60–90% of pediatric patients [1, 4, 7, 11]. However, there are no reports that the number of unidentified bright objects increases with age [4, 7], and, in fact, unidentified bright objects disappear in patients by the age of 20–30 years [11]. What is the basis for the age-related increase in the neurofibromas, Lisch nodules, and similarly in the choroidal abnormalities? It has been proposed that ultraviolet (UV) light is involved in the formation of Lisch nodules [14], which are proliferating melanocytic tissues. In the patient reported by Nichols et al., with a plexiform neurofibroma of one eye associated with complete ptosis, there was left-right asymmetry in the formation of Lisch nodules: only one was seen in the eye with complete ptosis, but 32 were seen in the unaffected eye [15]. The authors postulated that UV light, which is a melanocyte mitogen, was the underlying cause. Similarly, Nicolas et al. studied the distribution of Lisch nodules in the irises of 369 patients with neurofibromatosis type I and found that in 80% of cases, the nodules were located in the lower portion of the iris, where exposure to UV light is greater [16]. However, with regard to the location and development of choroidal abnormalities, UV light of 100–400 nm wavelength is essentially absorbed by the cornea, lens, and vitreous and thus does not reach the retina [2], so involvement of UV is unlikely. In neurofibromatosis type I patients, the choroid shows a proliferation of neural crest-derived melanocytes and neural cells, thickening the posterior fundus [14]. Of the two proliferating cell types, neural cells and melanocytes, melanocytes are rich in melanin, which absorbs near-infrared lights and at the same time causes the near-infrared light to be strongly backscattered due to Mie scattering from melanosomes [17]. Melanin in human skin is reported to provide strong contrast by the increased backscattering of infrared light such that the cytoplasm in heavily pigmented cells images brightly under confocal scanning laser microscopy [17]. Similarly, the densely packed, proliferating melanocytes in the choroid may appear as bright patchy lesions due to strong backscattering of the 780-nm wavelength near infrared light from melanosomes under confocal scanning laser ophthalmoscopy.

In the choroidal lesions of densely packed, proliferated neural cells and melanocytes, there might be a decrease in the volumetric percentage of blood components including hemoglobin, oxygenated hemoglobin, and water. Because these three blood components can absorb scattered near-infrared light [5], the relative decrease of the absorbers might cause the choroidal lesions to appear brighter than the surrounding choroid.

Anatomically, the choroid in the posterior region of the fundus is 0.22 mm thick; in the peripheral regions, it is only 0.10–0.15 mm thick [6, 8, 20]. There are numerous branches of short ciliary nerves and abundant melanocytes in the choroid of the posterior region. It is for these reasons that we believe these choroidal abnormalities are seen more frequently in the arcade region.

Conclusion

The choroidal abnormalities that are specific to neurofibromatosis type I appear to increase significantly with age and are most frequently observed within the vascular arcade.