Ophthalmic Surgery, Lasers and Imaging Retina

The articles prior to January 2012 are part of the back file collection and are not available with a current paid subscription. To access the article, you may purchase it or purchase the complete back file collection here

Case Report 

Amantadine-Associated Corneal Edema Treated with Descemet’s Stripping Automated Endothelial Keratoplasty

Christopher T. Hood, MD; Roger H. S. Langston, MD; Lynn R. Schoenfield, MD; William J. Dupps, MD, PhD

Abstract

The authors report the successful use of Descemet’s stripping automated endothelial keratoplasty (DSAEK) to treat a 45-year-old woman with amantadine-associated corneal edema. Discontinuation of the medication and treatment with corticosteroids did not result in resolution of the edema. The patient underwent sequential phakic DSAEK in both eyes with significant anatomic, visual, and functional improvement. Histopathologic analysis of Descemet’s membrane by light microscopy revealed a paucity of endothelial cells. This case highlights the importance of considering amantadine toxicity in the differential diagnosis of corneal edema without an identifiable ocular cause and suggests the utility of DSAEK in the treatment of this rare condition.

Abstract

The authors report the successful use of Descemet’s stripping automated endothelial keratoplasty (DSAEK) to treat a 45-year-old woman with amantadine-associated corneal edema. Discontinuation of the medication and treatment with corticosteroids did not result in resolution of the edema. The patient underwent sequential phakic DSAEK in both eyes with significant anatomic, visual, and functional improvement. Histopathologic analysis of Descemet’s membrane by light microscopy revealed a paucity of endothelial cells. This case highlights the importance of considering amantadine toxicity in the differential diagnosis of corneal edema without an identifiable ocular cause and suggests the utility of DSAEK in the treatment of this rare condition.

Amantadine-Associated Corneal Edema Treated with Descemet’s Stripping Automated Endothelial Keratoplasty

From the Cole Eye Institute (CTH, RHSL, WJD); the Transplant Center, Surgery Institute (RHSL, WJD); and the Departments of Anatomic Pathology (LRS) and Biomedical Engineering (WJD), Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Supported in part by grant 1KL2RR024990 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and a Research to Prevent Blindness Challenge Grant to the Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Dupps is a recipient of a Research to Prevent Blindness Career Development Award.

The authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to William J. Dupps, Jr., MD, PhD, Cleveland Clinic Cole Eye Institute, 9500 Euclid Avenue/i-32, Cleveland, OH 44195. E-mail: bjdupps@sbcglobal.net

Received: June 28, 2009
Accepted: April 23, 2010
Posted Online: July 29, 2010

Introduction

Amantadine was developed for short-term use as an antiviral drug against influenza A, but it is also used chronically to treat tremors and stiffness in Parkinson’s disease and fatigue associated with multiple sclerosis. The mechanism of action is not well understood. Reported ocular side effects include visual loss, hallucination, oculogyric crisis, and mydriasis.1 Corneal side effects include superficial punctuate keratitis, punctuate subepithelial opacities, and epithelial and stromal edema.1 It has recently been reported that discontinuation of amantadine may not result in the resolution of corneal edema, and penetrating keratoplasty has been employed successfully in these cases.1 We describe a case of amantadine-associated corneal edema treated with sequential bilateral phakic Descemet’s stripping automated endothelial keratoplasty (DSAEK) and report the histopathologic features on light microscopy.

Case Report

A 45-year-old woman presented to the Cole Eye Institute for management of corneal edema. She described 6 months of blurry vision in both eyes, but denied having redness, pain, or photophobia. She was being treated with sodium chloride ointment four times daily in the right eye on referral.

She denied any ocular history of trauma, surgery, or inflammatory disease. Her medical history was significant for a longstanding diagnosis of multiple sclerosis, for which she was taking baclofen, Concerta (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Titusville, NJ), Copaxone (Teva Pharmaceutical Industries, Ltd., Tikva, Israel), Neurontin (Pfizer, New York, NY), Lexapro (Forest Pharmeceuticals, New York, NY), and Wellbutrin (GlaxoSmithKline, Middlesex, UK). She was prescribed amantadine 17 months prior to the presentation in our clinic and approximately 6 months prior to onset of visual symptoms. She denied any family history of eye disease.

On examination, best spectacle-corrected visual acuity was 10/400 in the right eye and 20/400 in the left eye. Pupils were equal in size and reactivity without an afferent pupillary defect. Extraocular movements were full. Intraocular pressures were 12 mm Hg in the right eye and 10 mm Hg in the left eye. Anterior segment examination demonstrated normal eyelids, sclera, and conjunctiva. Bilateral diffuse stromal and epithelial edema was observed with marked Descemet’s membrane folds and pre-Descemet’s membrane opacification without guttae (Fig. 1). Bullous epithelial changes were present in the right eye. Central corneal thicknesses were 867 microns in the right eye and 700 microns in the left eye by ultrasound pachymetry. The anterior chambers were deep and quiet with a normal iris in each eye. There was no evidence of cataractous changes in either lens. Dilated fundus examination of both eyes was unremarkable.

(A) Slit-Lamp Photograph of the Patient’s Right Eye on Presentation, Demonstrating Diffuse Stromal and Bullous Epithelial Corneal Edema Secondary to Amantadine Use. (B) A Slit-Beam Demonstrates Marked Descemet’s Membrane Folds. No Guttae Were Visible. Similar Findings Were Present in the Left Eye.

Figure 1. (A) Slit-Lamp Photograph of the Patient’s Right Eye on Presentation, Demonstrating Diffuse Stromal and Bullous Epithelial Corneal Edema Secondary to Amantadine Use. (B) A Slit-Beam Demonstrates Marked Descemet’s Membrane Folds. No Guttae Were Visible. Similar Findings Were Present in the Left Eye.

The differential diagnosis included Fuchs’ endothelial corneal dystrophy and posterior polymorphous dystrophy, as well as viral endotheliitis associated with the herpes virus family (herpes zoster ophthalmicus, herpes simplex virus, and cytomegalovirus). However, a lack of guttae on examination combined with absence of ocular inflammation and a history of progressive bilateral corneal decompensation after amantadine use led to the diagnosis of amantadine-associated endothelial dysfunction. With the approval of the patient’s neurologist, amantadine was discontinued and the patient was observed for 6 weeks with minimal improvement of the bilateral corneal edema. Prednisolone acetate 1% was initiated four times daily in both eyes and the patient was observed for an additional 6 weeks. Although she demonstrated initial improvement, best-corrected visual acuity was 20/200 in both eyes.

The patient was offered DSAEK in the right eye. After informed consent was obtained, she underwent uncomplicated surgery 6 months after cessation of amantadine. The patient, who had no appreciable nuclear sclerosis, was left phakic and was given topical pilocarpine 1% preoperatively. Descemet’s stripping was performed under air and a donor lenticula was prepared on an artificial anterior chamber and punched to 8.5 mm just prior to insertion. Controlled tamponade of the graft against the host stroma was performed with air infusion and air–fluid exchange as described previously,2 and irregular central epithelium due to bullous edema was debrided. Histopathologic analysis by routine light microscopy of Descemet’s membrane revealed scant endothelial cells and no guttae, consistent with endothelial cell loss secondary to amantadine toxicity (Fig. 2). No further improvement in corneal edema or visual acuity occurred in the left eye, so 3 months later the patient underwent phakic DSAEK in the left eye by the same surgeon (WJD) as described above.

A Photomicrograph of Stripped Descemet’s Membrane in the Right Eye Demonstrates the Presence of Rare Endothelial Cells. No Guttae Were Present (hematoxylin–Eosin, Original Magnification ×40).

Figure 2. A Photomicrograph of Stripped Descemet’s Membrane in the Right Eye Demonstrates the Presence of Rare Endothelial Cells. No Guttae Were Present (hematoxylin–Eosin, Original Magnification ×40).

Sixteen months after surgery on her right eye and 11 months after surgery on her left eye, the patient’s best-corrected visual acuity was 20/25 in the right eye (−2.50 + 2.00 × 080) and 20/40 in the left eye (−2.25 + 1.75 × 090). The cornea was clear and compact in the right eye and the posterior donor lenticule was well centered (Fig. 3). The graft was clear centrally in the left eye with mild stromal haze present. Throughout follow-up, intraocular pressure remained under 15 mm Hg and the crystalline lens remained clear in both eyes.

Three Months After Descemet’s Stripping Automated Endothelial Keratoplasty Surgery in the Right Eye, the Donor Lenticula Was Well Centered. The Patient’s Best-Corrected Visual Acuity Was 20/25.

Figure 3. Three Months After Descemet’s Stripping Automated Endothelial Keratoplasty Surgery in the Right Eye, the Donor Lenticula Was Well Centered. The Patient’s Best-Corrected Visual Acuity Was 20/25.

Discussion

Corneal edema may occur from weeks to many years after commencing amantadine therapy.1,3–5 Clinical examination demonstrates bilateral, diffuse stromal, and microcystic epithelial edema without guttae or inflammatory signs. Initial management consists of discontinuing amantadine, which results in the resolution of corneal edema in most cases.1,3–6 However, it has recently been reported that corneal edema may be irreversible, and penetrating keratoplasty has been employed successfully in such patients.1

The pathophysiology of amantadine-associated corneal edema is not fully understood, but the medication is thought to damage endothelial cells, as evidenced by the presence of rare endothelial cells on routine light microscopy and areas of denuded endothelial cells on scanning electron microscopy.1 The presence of a posterior collagenous layer by transmission electron microscopy supports the hypothesis that amantadine leads to endothelial stress.1,7 No inflammatory cells have been observed by histopathologic examination.1 Other authors have demonstrated a low endothelial cell density by specular microscopy after discontinuation of amantadine, even in corneas that cleared and returned to normal thickness.3 It remains unclear why only a small fraction of patients treated with amantadine develop corneal edema.

DSAEK, a partial thickness transplantation of the posterior corneal surface, is emerging as the preferred procedure for managing endothelial dysfunction in the absence of stromal opacities because of its more predictable refractive outcomes, faster visual recovery, and preservation of the structural integrity of the eye. Although most commonly used for Fuchs’ dystrophy and pseudophakic or aphakic bullous keratopathy, DSAEK has also been used in cases of iridocorneal endothelial syndrome.8,9 To our knowledge, this is the first case in which DSAEK was employed for amantadine-associated corneal edema. It should be noted that when performing DSAEK in the presence of the crystalline lens, the anterior chamber may be slightly shallower than in a pseudophakic patient and could affect the ease with which the donor graft unfolds. No difficulties were encountered in this particular case. This case highlights the importance of considering amantadine toxicity in the differential diagnosis of corneal edema without an identifiable ocular cause and suggests the utility of DSAEK in the treatment of this rare condition.

References

  1. Jeng BH, Galor A, Lee MS, et al. Amantadine-associated corneal edema potentially irreversible even after cessation of the medication. Ophthalmology. 2008;115:1540–1544. doi:10.1016/j.ophtha.2008.03.011 [CrossRef]
  2. Meisler DM, Dupps WJ Jr, Covert DJ, Koenig SB. Use of an air-fluid exchange system to promote graft adhesion during Descemet’s stripping automated endothelial keratoplasty. J Cataract Refract Surg. 2007;33:770–772. doi:10.1016/j.jcrs.2006.11.033 [CrossRef]
  3. Chang KC, Kim MK, Wee WR, Lee JH. Corneal endothelial dysfunction associated with amantadine toxicity. Cornea. 2008;27:1182–1185. doi:10.1097/ICO.0b013e318180e526 [CrossRef]
  4. Hughes B, Feiz V, Flynn SB, Brodsky MC. Reversible amantadine-induced corneal edema in an adolescent. Cornea. 2004;23:823–824. doi:10.1097/01.ico.0000130417.91438.7e [CrossRef]
  5. Kubo S, Iwatake A, Ebihara N, Murakami A, Hattori N. Visual impairment in Parkinson’s disease treated with amantadine: case report and review of the literature. Parkinsonism Relat Disord. 2008;14:166–169. doi:10.1016/j.parkreldis.2007.03.003 [CrossRef]
  6. Pond A, Lee MS, Hardten DR, Harrison AR, Krachmer JH. Toxic corneal oedema associated with amantadine use. Br J Ophthalmol. 2009;93:281, 413. doi:10.1136/bjo.2007.135731 [CrossRef]
  7. Waring GO III, . Posterior collagenous layer of the cornea: ultrastructural classification of abnormal collagenous tissue posterior to Descemet’s membrane in 30 cases. Arch Ophthalmol. 1982;100:122–134.
  8. Price MO, Price FW Jr, . Descemet stripping with endothelial keratoplasty for treatment of iridocorneal endothelial syndrome. Cornea. 2007;26:493–497. doi:10.1097/ICO.0b013e318030d274 [CrossRef]
  9. Jeng BH, Dupps WJ Jr, Meisler DM, Schoenfield L. Epithelial debridement for the treatment of epithelial basement membrane abnormalities coincident with endothelial disorders. Cornea. 2008;27:1207–1211. doi:10.1097/ICO.0b013e3181814c74 [CrossRef]
Authors

From the Cole Eye Institute (CTH, RHSL, WJD); the Transplant Center, Surgery Institute (RHSL, WJD); and the Departments of Anatomic Pathology (LRS) and Biomedical Engineering (WJD), Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.

Supported in part by grant 1KL2RR024990 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and a Research to Prevent Blindness Challenge Grant to the Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Dupps is a recipient of a Research to Prevent Blindness Career Development Award.

The authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to William J. Dupps, Jr., MD, PhD, Cleveland Clinic Cole Eye Institute, 9500 Euclid Avenue/i-32, Cleveland, OH 44195. E-mail: bjdupps@sbcglobal.net

10.3928/15428877-20100726-11

Sign up to receive

Journal E-contents