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Corneal Morphology and Sensitivity in Lattice Dystrophy Type II (Familial Amyloidosis, Finnish Type)

¹ From the Department of Ophthalmology, University of Helsinki, Finland; ² Instituto de Neurociencias, Universidad Miguel Hernández–Consejo Superior de Investigaciones, Campus de San Juan de Alicante, Spain; and ³ The Netherlands Ophthalmic Research Institute, Amsterdam.

	Abstract

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PURPOSE. To describe the corneal abnormalities and to measure different modalities of corneal sensitivity in corneal lattice dystrophy type II (familial amyloidosis, Finnish type, also known as gelsolin-related amyloidosis and originally as Meretoja syndrome).

METHODS. Twenty eyes of 20 patients were examined by in vivo confocal microscopy and noncontact gas esthesiometry.

RESULTS. Pleomorphism of, and dense deposits between or posterior to, the basal epithelial cells were frequently observed, as well as a reduction of long nerve fiber bundles in the subbasal nerve plexus. The anterior stroma was altered in most cases, with fibrosis and abnormal extracellular matrix. In 15 corneas, thick anterior and midstromal filaments, corresponding to lattice lines, and in 11 corneas, thin undulated structures were observed. The average mechanical sensitivity threshold of 12 subjects was increased, and in the remaining 8 subjects there was no response, even to the highest intensity of stimuli used. Three patients did not respond to CO₂, 11 to heat, and 2 to cold, but those patients who responded had normal thresholds. Patients with more long nerve fiber bundles per confocal microscopic image had better mechanical and cold sensitivity than patients with fewer nerve fiber bundles.

CONCLUSIONS. Lattice lines seem to be related to amyloid material and not to corneal nerves. However, the subbasal nerve density appears reduced, which results mainly in a decrease in mechanical and, to a lesser extent, thermal sensitivity. The location of stromal filaments and undulated structures changes with increasing age.

	Introduction

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Familial amyloidosis, Finnish type (FAF), also known as gelsolin-related amyloidosis and originally as Meretoja syndrome, is an autosomal dominant systemic disease that appears in early adulthood and predominantly affects cornea, skin, and cranial nerves.¹ The disease results from a point mutation in the gelsolin gene, wherein aspartic acid is replaced by asparagine.² The corneal findings of stromal lattice lines and deposits are described as corneal lattice dystrophy type II. The other recognized types of lattice dystrophy (types I, III, IIIA, and IV) are not associated with systemic disease. Mutations of a completely different gene cause at least three of these entities (for a recent review on the molecular genetics of corneal dystrophies see Reference ³ ).

In general, patients with FAF primarily display ocular changes. They usually have reduced corneal sensitivity, and frequently show epithelial erosions after the fourth decade of life.^{1 4} Clinically, they often have dry eye syndrome. Their visual acuity is often decreased, and visual loss after 60 years of age is not uncommon.⁵

Several histochemical studies of corneas have been conducted in patients with FAF.^{6 7 8} The main findings include lines of amyloid material in the anterior and midstroma, an almost continuous deposition of amyloid material under Bowman’s layer and sometimes at the level of the epithelial basement membrane, and formation of scar tissue with occasional amyloid deposits invading the subepithelial space.⁷ Anti-FAF antiserum immunoreacts with the lattice lines and the amyloid deposits around Bowman’s layer, as well as with amyloid streaks between the corneal lamellae.⁷ Recently, two confocal microscopic studies concerning lattice dystrophy have been published: one on type I and III⁹ and one on type I.¹⁰

The purpose of this study was to describe the confocal microscopic findings in patients with FAF/corneal lattice dystrophy type II and to examine by a recently developed noncontact gas esthesiometer¹¹ the different modalities of corneal sensitivity in this condition.

	Methods

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Patients
Twenty eyes of 20 patients (15 women and 5 men) aged 23 to 72 years (mean age ± SEM, 50 ± 3 years) with previous diagnosis of FAF (lattice dystrophy type II) were included in the study. Thirteen attending subjects had at least one relative in the group. The patients had been aware of the diagnosis for between 2 weeks and 30 years. Sixteen patients used moisturizing eye drops occasionally, and two patients used ß-blockers for glaucoma. Three patients had recurrent epithelial erosions, and another patient also reported keratitis or erosion of unknown origin that had occurred 20 years ago. Two patients had undergone laser trabeculoplasty, and one of these patients had undergone trabeculectomy as well. The best corrected visual acuities varied between 0.1 and 1.3. Clinical characteristics of patients are summarized in Table 1 .

Sensitivity measurements of 10 eyes of five healthy volunteers (three women, two men; mean age ± SEM, 22 ± 1 years) were used as controls.

In Vivo Confocal Microscopy
After topical anesthesia (Oftan Obucain; Santen, Tampere, Finland) the central area of the cornea was examined using a tandem scanning confocal microscope (TSCM; model 165A; Tandem Scanning, Reston, VA). Gel of 2.5% hydroxymethylcellulose was used as a coupling medium, and after the examination the gel was washed out with artificial tears (Tears Naturale; Alcon, Puurs, Belgium). The setup and operation of the confocal microscope have been described previously.^{12 13} Briefly, a x24, 0.6-numeric-aperture, variable-working-distance objective lens was used. The field of view with this lens is 450 x 360 µm, and the z-axis resolution is 9 µm. Images were detected using a low-light-level camera (VE1000; Dage, Michigan City, IN) and recorded on S-VHS tape. In addition, confocal microscopy through-focusing (CMTF) scans were obtained as previously described.^{13 14} Video images of interest were digitized using a computer-based imaging system with custom software (University of Texas, Southwestern Medical Center at Dallas, TX), and printed (Stylus Color 800 printer; Epson Seiko, Nagano, Japan). Using the custom software, the CMTF data were digitized onto the computer, and intensity profile curves were calculated. From each scan, the corneal thickness was measured. On average, there were three acceptable CMTF scans per eye. In one eye, no acceptable CMTF profiles could be produced because of the patient’s inability to fixate steadily; these scans were not included in the analysis. The average values of the measurements were used for the statistical calculations.

Special attention was paid to the morphology of the subbasal nerves and stromal filaments. From the recorded tapes the highest number of long nerve fiber bundles per confocal microscopic field was counted in each patient, and findings were classified according to the nerve count: no nerves, absence of long subbasal nerve fiber bundles; few nerves, one to three long nerve fiber bundles; and many nerves, four to six long nerve fiber bundles (which equals the normal nerve fiber count).¹⁵ Branches shorter than half of the screen were not included in the calculations.

Noncontact Gas Esthesiometry
A gas esthesiometer previously described¹¹ and patented (but not yet commercially available), was used to perform selective mechanical, chemical, and thermal stimulation of the cornea. Gas jets of 3 seconds’ duration, separated by 2-minute pauses, were applied to the corneal surface. The selective mechanical stimulation consisted of a series of pulses of air at flows ranging from 0 to 330 ml/min. For selective chemical stimulation, pulses of a mixture of air and CO₂ at different concentrations (0%–80% CO₂) were used. Selective thermal stimulation was tested by applying pulses of air of different temperatures (-10°C–80°C), that induced a variation in corneal surface temperature between -5°C and +3°C around its control value (34.4°C).¹¹ For selective chemical and thermal stimulation, flows below mechanical threshold of each subject were used. To prevent corneal temperature changes during selective mechanical and chemical stimulation, the air was heated up to 50°C at the tip of the probe.¹¹ The protocol was completed in a single session.

The esthesiometer probe was placed on a slit lamp table, and its tip was placed perpendicular to the center of the cornea, at a distance of 5 mm from the ocular surface. Immediately after each pulse, the subject evaluated the several components of the sensation experienced (intensity, irritation, stinging and burning components of the irritation, and warming or cooling thermal components) in six separate continuous horizontal visual analog scales (VASs). In the VAS, 0 was assigned to no sensation, and 10 to maximal sensation. The subjects were also in each case asked to describe in their own words the quality attributes of the sensation evoked by each stimulus.

Intensity–response curves for the various parameters of the sensation were constructed. Sensitivity thresholds for mechanical, chemical, and thermal stimulation were determined with the method of the minimum stimulus—-that is, the lowest intensity of stimulus that evoked a response of 0.5 or more VAS units.¹⁶

Statistical Analysis
Statistical analyses were performed by computer (SPSS, ver. 8.0 for Windows; SPSS, Chicago, IL; Sigma Stat, ver. 2.03 for Windows; Jandel Scientific, San Raphael, CA). Data are expressed as mean ± SEM. Pearson’s correlation was used to determine the stimulus–response relationship. A t-test or Mann–Whitney test was used for comparison of sensitivity thresholds between patients and control subjects. A nonparametric Kruskal–Wallis test was used for comparison of age and of the different sensitivity thresholds among patients grouped in three subgroups based on the appearance of the subbasal nerve plexus in the central cornea. In patients in whom thresholds could not be measured because of severely decreased sensitivity, the values of the highest stimuli tested (or lowest, when measuring cold sensitivity) were used to include all patients in this part of the statistical analysis.

	Results

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Corneal Morphology
The main pathologic findings are summarized in Table 2 . In 19 of the 20 examined corneas the surface epithelium appeared normal. In one cornea there was a ridge, where, in the same image section, both surface and basal epithelial cells of normal size were visible (image not shown). In 5 corneas there was pleomorphism of the basal epithelial cells (Fig. 1A ), and in 13 corneas there were dense deposits between or posterior to these cells (Fig. 1B) . The region immediately behind the basal epithelium was characterized by irregular dark and light patches and appeared to be opaque in most cases (Fig. 1C) . In general, the number of long nerve fiber bundles in most patients was reduced when compared with control corneas. Only one cornea (in a 30-year-old woman) had a normal-looking subbasal nerve plexus, with six thick parallel nerve fiber bundles (Fig. 1D) , and another one had four thick, unusual, undulated nerve fiber bundles (Fig. 1E) . Thirteen corneas showed one to three long nerve fiber bundles, and five corneas had only short branches or no main nerve fiber bundles (Fig. 1F) . Two corneas showed normal keratocyte appearance in the anterior stroma, whereas in one cornea the anterior keratocytes were hyperreflective and irregular in shape (Fig. 2A ). In the remaining corneas, the anterior parts of the stroma seemed fibrotic or scarred (Fig. 2B) , and in five of these corneas dense hyperreflective scar tissue was observed (Figs. 2C 2D) . In 15 of 20 corneas thick anterior and midstromal filaments, corresponding to lattice lines visible on biomicroscopy were observed (Fig. 2E) . They were thicker than normal stromal nerves and appeared to be located between collagen lamellae. In addition, thin, undulated, unspecified structures were observed in the stroma of 11 corneas (Figs. 2F 2G) . In only six corneas were stromal nerves with normal caliber and an oblique pattern noted (Fig. 2H) . The endothelium turned out to be normal in 17 corneas and was not visualized at all in one cornea. One cornea showed small endothelial pits, and another had a precipitate-like aggregation on the endothelium (images not shown). The total central corneal thickness varied between 489 and 573 µm (mean value 530 ± 6 µm).

View larger version (133K): [in this window] [in a new window]   Figure 1. Confocal microscopic images in patients with corneal lattice dystrophy type II. (A) The basal epithelial cells of five patients were pleomorphic. (B) In 13 corneas highly reflective deposits were observed in or under the basal epithelial cells. (C) Immediately under the basal cells of the epithelium, Bowman’s layer was irregular and thicker, seen as differences in grayscale in most patients. This may have been due to accumulation of amyloid. (D) Only in one patient a control-like subbasal nerve plexus was observed with many parallel-running nerve fiber bundles, and (E) in one cornea the subbasal nerves had loops and abnormal undulations. In 13 patients only a few long nerve fiber bundles were visible, whereas (F) in five patients only short branches were observed.

View larger version (106K): [in this window] [in a new window]   Figure 2. Confocal microscopic images in patients with corneal lattice dystrophy type II. (A) The anterior keratocytes were relatively normal, with only moderately increased reflectivity, in a young woman with FAF. (B) Because of the increase in extracellular matrix individual anterior keratocytes could not be discerned in 12 patients. (C, D) In addition, five had severe scarring in this region. (E) Fifteen had thick straight stromal filaments (most probably amyloid in origin) between the collagen lamellae in the central cornea. (F, G) In 11 corneas, there were unspecified undulating, thinner structures, apparently interacting with the keratocytes, in the midstroma. (H) Only a few stromal nerves were noted.

Corneal Sensitivity
The average flow of air (at neutral temperature, 50°C), required to evoke a sensation in the cornea of 12 subjects was established at 208 ± 20 ml/min, which was significantly higher (P < 0.01) than in the healthy control subjects (121 ± 21 ml/min). In the remaining eight subjects there was no response to the highest flow used (330 ml/min). The CO₂ concentration necessary to evoke a sensation was 28% ± 4% (range, 20%–80%) in 17 of the subjects, whereas the 3 remaining subjects did not detect the 80% CO₂ pulse. When thresholds were measurable, they were within the range of normality (control values, 22% ± 4%). Threshold sensations evoked by CO₂ were defined by patients as irritating with a stinging component. The heat threshold was 67°C ± 3°C at the tip of the probe for nine of the subjects, which is within normal limits (control values, 65°C ± 3°C), whereas 11 did not detect the most intense pulse used (80°C). Heat stimulation evoked, when detected, a slightly burning, irritating sensation. The cooling threshold was established at 11°C ± 4°C (range, 25°C to -10°C) in 17 of the subjects, whereas two of the remaining three subjects did not detect the coolest pulse used, and in one subject cooling was not explored at all. The responding patients had similar values to control subjects (16°C ± 6°C). Cold stimulation was described as a cooling sensation.

When the patients with previous ocular surgery or ß-blocker use, which would possibly affect corneal sensitivity, were excluded from the analysis, the sensitivity threshold averages were established as follows: mechanical 202 ± 24 ml/min, chemical 30% ± 5%, heat 63°C ± 3°C, and cold 11°C ± 4°C. A statistically significant difference in mechanical threshold was still found between patients with amyloidosis and control subjects (P = 0.02). The other differences were statistically nonsignificant.

The intensity–response (VAS) curves for mechanical, chemical, and thermal stimulation in patients with FAF are shown in Figure 3 . Graphs of control subjects have recently been published.¹⁷ A significant correlation was found between the intensity of the stimulus and the subjective intensity reported by the subjects for mechanical (r = 0.898, P = 0.006) and cold (r = -0.993, P = 0.007) stimulation. Only VAS values of irritation with some stinging and burning pain were obtained for the chemical stimulation with CO₂. A slightly burning component was assigned for the hotter pulses used. Only the thermal component of the sensation was assigned for cold stimulation, the magnitude of the cooling component being in proportion to the intensity of the stimulus.

View larger version (19K): [in this window] [in a new window]   Figure 3. Intensity–response curves for the most important components of sensation caused by mechanical (top), chemical (middle), and thermal (bottom) stimulation. VAS ratings account for the subjective feeling of sensation and are shown as mean ± SEM (in patients with FAF) for each intensity of stimulus.

	Discussion

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As early as in 1972 Meretoja reported that healthy corneal nerves usually are absent in FAF and that the disease manifests itself with corneal anesthesia.⁴ In our study an abnormality of the subbasal nerve plexus was frequently observed, whereas the earlier confocal microscopic studies on lattice type I and III dystrophy did not report anything about the subbasal nerves.^{9 10} Only one of our youngest patients had a normal distribution of six long nerve fiber bundles, and another patient had four visible nerve fiber bundles. The remaining patients had fewer or no nerve fiber bundles. The mechanism of altered gelsolin in relation to nerve fiber injury is still unknown,⁵ but myelin loss in small-diameter peripheral nerve fibers,²⁴ as well as axonal neuropathy,^{25 26} have been reported. In the cornea, nerve fiber bundles lose their myelin sheath in the limbal area before penetrating the anterior third of the stroma,^{27 28} and it may be that demyelination leads to degeneration of nerve fibers and consequently a reduction in numbers of subbasal nerve fiber bundles. It is, however, also possible that accumulation of amyloid material results in irregularity of the stromal surface and, subsequently, poor visualization of subbasal nerve structures.

It is interesting that many undulated hyperreflective structures were seen in the immediate vicinity of stromal keratocyte nuclei in 11 patients. These structures were different from normal stromal nerves, and different from the filaments considered to be lattice lines. They may have represented new local amyloid deposits or altered nerve structures. It has been suggested that parts of the stromal nerves are surrounded by thick amyloid deposits,⁴ although electron microscopic studies have not confirmed these findings.²⁹ We speculate that the undulated structures are not related to large stromal nerves, because they appear to be intralamellar rather than obliquely running. The amyloid fibrils in this familial amyloidosis correspond to an internal degradation product of human gelsolin.^{2 30 31 32 33} In healthy cornea antigelsolin immunoreactivity has been found most intensely in the basal epithelial cell layer and sometimes in the anterior stromal keratocytes.^{6 7} This is also in favor of a local production of amyloid in the anterior part of the cornea. The observed stimulated keratocytes in the vicinity of amyloid deposits in lattice dystrophy type I have already led to speculation that stromal keratocytes produce amyloid.^{34 35 36} The frequently observed anterior stromal fibrosis in our patients points to increased production of amyloid or other abnormally arranged extracellular matrix components. Intense scarring was not seen in patients who had had epithelial erosions, whereas the patient who recalled an episode of keratitis showed severe fibrosis. The mean total corneal thickness was normal in the corneas examined, although previous ex vivo results by Meretoja suggested a mean corneal thickness of as much as 0.8 to 1.3 mm.⁴

In this confocal microscopic study, 15 patients showed midstromal filaments with diffuse borders, most likely representing lattice lines, in the center of the cornea. Lattice lines were observed in all patients by slit lamp examination. The fact that central confocal microscopic images of 450 x 360 µm did not reveal filaments in all patients supports the observation that the most central area of the cornea in lattice dystrophy type II often is devoid of these changes.⁴ We speculate that with time the undulated structures change to become larger and more diffuse filaments located in the more posterior stroma. This theory is substantiated by the fact that undulated structures were more frequently seen in younger patients and filaments with diffuse borders in elderly patients.

Only three eyes in our study had had temporary corneal erosions, whereas earlier studies report that approximately one third of the patients had spontaneous erosions.³⁷ Because corneal nerves are known to play important roles in maintaining corneal epithelial integrity^{38 39} and tear secretion,⁴⁰ the reduction in number of subbasal nerves most probably accounts for the development of epithelial erosions. All three patients with a history of erosions had deposits in the basal epithelial cells, and one had pleomorphism of these cells. Mutation of the gelsolin gene and disturbed function of the produced protein could also interfere with attachment of epithelial cells to the underlying stroma and thereby lead to erosions.

Based on their stimulation response, three types of neurons innervating the cornea have been characterized: mechanosensory, polymodal, and cold sensory neurons.⁴¹ FAF severely affects mechanical sensitivity in almost all patients, and apparently also thermal sensitivity in some patients. Chemical sensitivity seems best preserved. When the results were more thoroughly analyzed on the basis of nerve fiber density, it was observed that patients without long nerve fiber bundles on confocal microscopy had severely reduced corneal mechanical sensitivity, although they detected chemical stimuli and very cold pulses. One of them also detected hot air. On the contrary, patients with some long nerve fiber bundles or a normal amount of them showed normal chemical and thermal sensitivity, although the mechanical sensitivity still was reduced. Our results suggest that, with progression of the disease, corneal sensitivity and the amount of visible nerve fiber bundles decrease, because older patients appeared to have fewer nerve fiber bundles. The difference in age did not reach statistical significance, however. Trabeculectomy, topical glaucoma medication, or dry eye syndrome could have affected the sensitivity measurements in some of the patients, but all these components are firmly linked to the disease, and thus no patients were originally excluded from the study. When the patients with topical ß-blockers or previous ocular surgery were excluded from the statistics, we found that the threshold results did not change markedly. Thus, the disease itself appears to cause sensory loss. Statistical significance was just missed, however, when these patients were excluded from the nerve statistics concerning mechanical and cold sensitivity, which may in part have been due to the reduction in the number of patients. The difference in age between the control subjects and the patients with amyloidosis may also have affected the results, but differences in threshold averages (when a reaction was present) were not found in most modalities of sensitivity.

The present results suggest that FAF causes a progressive loss of corneal sensory nerves, resulting in impairment of corneal sensory modalities. Tear secretion is impaired after corneal sensory denervation⁴⁰ and production of cytokines by the lacrimal gland appear to be related to corneal (and neural) damage.⁴² A number of cytokines are supposed to influence either the maintenance and healing of the corneal epithelium or keratocyte transformation in the stroma.^{43 44} Consequently, the typical features of FAF—dry eye and spontaneous epithelial erosions and perhaps, at a later stage, stromal fibrosis—could be natural consequences of the neural damage. On the other hand, local production of amyloid by the stromal keratocytes may cause disturbance of structure and fibrosis as well. The current treatment modalities such as wetting agents and lubricants do not completely control the biologic degenerative changes and leave space for more specific therapeutic innovations.

	Acknowledgements

 
The authors thank Alcon, Finland, and Pirjo Vesterinen for providing artificial tears.

	Footnotes

 
Supported by Finska Läkaresällskapet (Medical Society of Finland); the Finnish Eye Foundation; the Dorothea Olivia, Karl Walter, and Jarl Walter ;2>Perklens Minne Foundation; the Finnish Eye and Tissue Bank Foundation; the Ella and Georg Ehrnrooth Foundation; the Mary and Georg C. Ehrnrooth Foundation; the University of Helsinki; The State EVO Grant; The Friends of the Blind, Finland; and the Instrumentarium Scientific Foundation.

Submitted for publication July 28, 2000; revised October 27, 2000; accepted November 8, 2000.

Commercial relationships policy: P (JG); N (MER, TMTT, MCA, LJM, JAOM, AHAT, MHV).

Corresponding author: Maria E. Rosenberg, Department of Ophthalmology, University of Helsinki, Eye Bank, PO Box 220, Fin-00029 HUS, Finland. maria.rosenberg{at}hus.fi

	References

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