In Vivo Confocal Microscopic Architecture of Corneal Nerves in a Case of Multiple Endocrine Neoplasia Type 2b.

A detailed ocular examination and in vivo confocal microscopy (IVCM) using the Heidelberg retinal tomograph 3 with Rostock cornea module were performed in a patient with multiple endocrine neoplasia (MEN) 2b syndrome. Ocular findings included ptosis secondary to thickening of the lid margins, subconjunctival and perilimbal neuromas, and prominent corneal nerves extending up to the pupillary area. IVCM demonstrated structural alterations of both the main nerve trunks and the smaller branches. The main nerve trunks were grossly thickened while the smaller fibers were present in an intertwining manner in the anterior stroma. Some fibers showed prominent looping and nodular dilatations at irregular intervals along the length of the nerves. These nodular dilatations were in all probability ganglioneuromas of corneal nerves demonstrated by histopathology in earlier reports of MEN 2b. IVCM may be potentially useful in detecting the nerve alterations in MEN 2b even before other ocular or systemic features become apparent clinically.

Introduction

Multiple endocrine neoplasia (MEN) syndromes are a group of inherited hamartoneoplastic syndromes, which affect different endocrine glands in varying combinations. Traditionally, MEN syndromes have been categorized into three different patterns - MEN 1, MEN 2a, and MEN 2b. MEN 2b is characterized by medullary thyroid carcinoma, pheochromocytoma, and multiple mucosal neuromas. It is a potentially life-threatening condition with almost 100% progression to medullary thyroid carcinoma very early in life.[1] Ocular manifestations can often precede other systemic features and recognition of these may help in the diagnosis of this syndrome at a premalignant stage. Varying ocular manifestations in MEN 2b syndrome have been reported. Perilimbal neuromas are quite characteristic of the disorder while prominent corneal nerves are seen in many other ocular and systemic conditions.[2] To the best of our knowledge, the literature reports only one case of the confocal microscopic findings of the corneal nerves in MEN 2b.[3] We present the structural alterations of corneal nerves by in vivo confocal microscopy (IVCM) in a case of MEN 2b syndrome.

Case Report

A 25-year-old male already a diagnosed with MEN 2b syndrome was referred to the ophthalmology department by the internists for complaints of thickening of both upper lids. A review of his medical records revealed that the patient had bilateral pheochromocytoma, medullary carcinoma of the thyroid gland with metastasis to the cervical lymph nodes, and multiple mucosal neuromas. A detailed slit lamp biomicroscopic examination was performed for both eyes followed by bilateral IVCM using the Heidelberg retinal tomograph 3 with Rostock cornea module.

Results

Ocular examination revealed an unaided visual acuity of 20/20 bilaterally. The patient had mild symmetrical ptosis with thickening of the lateral parts of both upper eyelids [Figure 1a]. The meibomian glands were normal in appearance, and the patient had no signs or symptoms of dry eye disease. Both eyes had gelatinous, worm-like subconjunctival masses suggestive of neuromas on the bulbar conjunctiva [Figure 1b]. The limbus was diffusely and irregularly thickened 360° due to the presence of perilimbal neuromas which appeared as nodular lesions and were associated with prominent vascularization, especially at the inner edge [Figure 1c and d]. These neuromas were encroaching 1–1.5 mm into the peripheral cornea. Prominent corneal nerves reaching to the pupillary area were present bilaterally [Figure 1d]. Fundus examination was unremarkable in both eyes.

Figure 1

Slit lamp photographs of ocular manifestations. (a) Thickening of lateral part of the right upper lid. (b) Subconjunctival neuromas (black arrows). (c) Perilimbal thickening with neuromatous tissue (black arrows). (d) Prominent corneal nerves reaching up to pupillary area (white arrows) and perilimbal neuroma with prominent vascular arcade at inner edge (black arrow)

IVCM of the cornea indicated normal appearing epithelium and endothelium in both eyes. The subbasal epithelial nerve plexus and anterior stroma had an increased number of nerves fibers present that were intertwined [Figure 2a]. The average nerve fiber width was 31.1 μ (range 28.7–32.9 μ) oculus dextrus (OD) and 30.2 μ (range 28.4–31.8 μ) oculus sinister (OS). Some of these nerve fibers looped in varying patterns and had prominent nodules at irregular intervals along the entire course of the fibers [Figure 2b]. Apart from the network of intertwining smaller nerve fibers, obviously thickened main nerve trunks [Figure 2c] appearing as bright, hyperreflective rod-like structures were also seen in the midstroma.

Figure 2

In vivo confocal images of the cornea. (a) Nerve fibers in anterior stroma present in an intertwining manner. (b) Nerve fibers forming loops and showing nodular dilatations (white arrows). (c) Thickened main corneal nerve trunk appearing as a bright, hyperreflective structure (white arrow)

Discussion

A wide spectrum of ocular manifestations occurring with varying degree of frequency has been reported in MEN 2b syndrome and include in decreasing order of frequency prominent corneal nerves (100%), eyelid thickening or neuromas (88%), subconjunctival neuromas (79%), decreased basal tear production (48%), rostral displacement of cilia (12%), and poor pupillary dilatation (12%).[4] The present case showed lid thickening, prominent corneal nerves, subconjunctival and perilimbal neuromas. Prominent corneal nerves have been reported in other systemic disorders including MEN 2a syndrome, neurofibromatosis, leprosy, ectodermal dysplasia, primary amyloidosis, congenital ichthyosis, ectodermal dysplasia, and Refsum's disease. Prominent corneal nerves can be found in some ocular conditions including keratoconus, Fuchs’ endothelial dystrophy, posterior polymorphous dystrophy, herpes simplex, and herpes zoster infections.[5] Although prominent corneal nerves are present in the majority of patients with MEN 2b syndrome, these are not a specific ocular sign for the syndrome. In contrast, the development of perilimbal nodular changes in association with the neovascular corneal arcade, has not been described for other differential diagnosis of prominent corneal nerves and has been suggested by Puvanachandra and Aroichane to represent a key distinguishing feature of MEN type 2b.[2] These perilimbal nodules have been shown by biopsy to be neuromatous tissue positive for S100 and have been postulated to be an extension of the corneal nerve thickening.[6]

To our knowledge, there is only one previous report describing the confocal microscopic findings in a case of MEN 2b.[3] Javadi et al.[3] have described the presence of thickened subbasal epithelial nerves with a maximum diameter of 26.7 μm OD and 32.4 μm OS. Our findings were similar with a mean nerve fiber width of 31.1 μ OD and 30.2 μ OS. The morphological features of intertwining, looping, and nodular thickenings along the length of the nerve fibers, visualized by IVCM in our case have, however, not been reported earlier in MEN 2b syndrome. Postmortem light and electron microscopic ocular examination has shown the presence of ganglioneuromas of the nerves in the limbus, trabecular meshwork, uveal tract, and posterior ciliary nerves in a case of MEN 2b.[7] The nodular thickening of the nerve fibers seen by IVCM in the present case, likely represents the ganglioneuromatous transformation of the corneal nerves.

To summarize, we describe the ocular features and architectural alterations of the corneal nerves studied by IVCM in a case of MEN 2b. The nodular dilatations of the corneal nerves as seen on IVCM in the present case may help to differentiate this condition from other ocular or systemic causes of prominent corneal nerves and may be useful in screenings or detecting cases suspected to be MEN 2b syndrome even prior the other ocular features of lid, subconjunctival or perilimbal neuromas become apparent clinically.

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Conflicts of interest

There are no conflicts of interest.