A Rare Case of Recurrence of Bilateral Corneal Edema Secondary to Amantadine

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doi: 10.62055/35835045Sl

ABSTRACT

Background

Amantadine hydrochloride has been used as a prophylactic agent for the treatment of Influenza A in adults since 1959. It is also commonly used to reduce the symptoms of Parkinson’s disease and has been shown to be effective in relieving fatigue in multiple sclerosis (MS) patients. However, it can induce corneal edema, which can be reversible after cessation of the medication.

Case Report

A 49-year-old Caucasian female presented with complaints of blurry vision for two weeks. She had a pertinent history of an episode of corneal edema secondary to amantadine use four years prior to exam. The anterior segment was remarkable with corneal findings of central microcystic 3+ corneal edema with endothelial folds and a 1 mm paracentral area of bullae in the right eye along with central microcystic 2+ corneal edema with endothelial folds in the left eye. The corneal edema was determined to be secondary to amantadine use; discontinuation of the medication resulted in resolution of the edema and recovery of vision.

Conclusion

This case demonstrates the role of a thorough patient history in the early diagnosis of corneal edema secondary to amantadine. The ophthalmic adverse effects are uncommon but well documented. The use of amantadine may be easily overlooked. The etiology of corneal edema needs to be determined with careful review of the patient’s medications and medical history to ensure timely diagnosis and appropriate treatment to prevent unnecessary treatment.

Keywords: amantadine, corneal edema, pachymetry

INTRODUCTION

Amantadine hydrochloride has been used as a prophylactic agent for the treatment of Influenza A in adults since 1959. ^1,2,3,4 It is also commonly used to reduce the symptoms of Parkinson’s disease, drug-induced extrapyramidal syndromes, and tardive dyskinesia. ^5,1,2,3,4 In addition, amantadine has shown to be effective in relieving fatigue in multiple sclerosis (MS) patients, but the exact mechanism is still unknown.^5,2 Corneal edema is a very rare side effect of amantadine toxicity and if recognized early, the visual prognosis is good upon discontinuation of the medication.⁶ This case report discusses a patient who developed a recurrence of bilateral corneal edema secondary to amantadine treatment.

CASE REPORT

A 49-year-old Caucasian female presented for an eye exam due to blurry vision. Her medical history was positive for hypertension, diabetes, multiple sclerosis, major depressive disorder, anxiety disorder, chronic obstructive pulmonary disorder (COPD) and asthma. She was taking furosemide, propranolol, hydrochlorothiazide, and lisinopril for hypertension, metformin and insulin glargine for diabetes, glatiramer acetate for multiple sclerosis, buspirone, bupropion lorazepam, venlafaxine for major depressive disorder and anxiety disorder, and albuterol, busdesonide formoterol, and prednisone for asthma and COPD. Four years prior to this exam, the patient was prescribed amantadine for her MS but it was discontinued due to the development of corneal edema two weeks into treatment. Despite this history, the patient was restarted on amantadine by her neurologist three months prior to this exam.

Her past ocular history was positive for dry eyes with superficial punctate epithelial erosions attributed to the use of her CPAP mask. Artificial tears were prescribed at a previous exam to be instilled four times a day and a lubricating ointment at bedtime in both eyes. She had no drug allergies, no family history of ocular diseases and did not use tobacco, alcohol, or illicit drugs.

She presented with complaints of blurry vision for two weeks. Her corrected visual acuities were 20/125 OD and OS without improvement by pinhole OU. Pupils were equal, round and reactive to light without a relative afferent pupillary defect OU. Visual fields were full to confrontation OU. Extraocular muscles were unrestricted and had a full range of motion in all gazes. The cornea of the right eye had central microcystic edema and a 1 mm paracentral area of bullae with grade 3+ stromal edema with endothelial folds. The cornea of the left eye had central microcystic edema with grade 2+ stromal edema with endothelial folds (Figures 1-3). Corneal pachymetry revealed central corneal thicknesses of 764 um OD and 771 um OS. The iris was unremarkable in each eye and the anterior chambers were deep and quiet. The crystalline lenses were clear both centrally and peripherally. The IOP was OD 13 mmHg and 11 mmHg. Funduscopic assessment revealed flat optic nerves with distinct disc margins and cup-to-disc ratios of 0.35/0.35 OU with healthy rim and normal macula OU. The peripheral retina was flat and intact OU.

Figure 1. Slit lamp photo of the right eye revealing corneal edema and folds

Figure 2. AS-OCT of the right eye revealing corneal edema and folds

Figure 3. AS-OCT of the left eye revealing corneal edema and folds.

Differential diagnoses include: herpes simplex keratitis, herpes zoster keratitis, iritis, iridocorneal endothelial (ICE) syndrome, Fuch’s endothelial dystrophy and iatrogenic from systemic and ophthalmic drugs. Herpes simplex keratitis is typically unilateral with photophobia, pain, decreased vision.⁷ Corneal findings are typically dendritiform ulcerations in the epithelium with club-shaped terminal bulbs at the end of each branch.⁷ There was no evidence of any dendritic pattern in either eye of this patient. Herpes zoster keratitis is characterized by painful, unilateral, vesicular skin lesions that are spread in a dermatomal distribution.⁸ The corneal findings are typically epithelial pseudodendrites or punctate epitheliopathy. The patient in this case did not present with vesicular skin lesions or epithelial pseudodendrites. Iritis is inflammation of the iris and ciliary body. Neither eye had circumlimbal flush nor cells or flare.Patients with ICE syndrome have an abnormal corneal endothelial cell layer, which can grow across the anterior chamber angle and secondary angle closure can result from contraction of this tissue.⁹ Slit lamp examination did not show any findings consistent with ICE.⁹ Fuch’s endothelial dystrophy appears with corneal guttae with stromal thickening and edema.¹⁰ There was no evidence of corneal guttae in this patient. Several systemic and ophthalmic drugs can cause corneal edema. Given that all of the above differentials were ruled out and corneal edema is a documented side effect of amantadine, this was deemed the most likely diagnosis.

One treatment for corneal edema is the use of desiccating agents including sodium chloride hypertonic ophthalmic solution and/or ointment. These agents were not used due to the high suspicion of amantadine as the cause of the corneal edema. After a neurology consultation, amantadine was discontinued and was documented as an adverse event on the patient’s chart. The patient was scheduled to return for follow-up in two weeks.

Follow up

The patient did not return until six weeks later and reported that her vision became clear a week before. Her corrected visual acuity was 20/20 OD and OS. The intraocular pressure was 14 mmHg OD and 13 mmHg OS with Goldmann tonometry. The anterior segment was unremarkable, with no corneal edema, folds, or superficial punctate keratitis OU (Figures 4 and 5). Corneal pachymetry revealed central corneal thicknesses of 509um OD and 507um OS. The bilateral corneal edema had resolved.

Figure 4. Slit lamp photo of the right eye at six-week follow-up reveals resolved corneal edema.

Figure 5. Slit lamp photo of the left eye at six-week follow-up reveals resolved corneal edema.

DISCUSSION

This case is an example of drug-induced corneal edema. Amantadine is a non-competitive antagonist at the phencyclidine site within the N-methyl-D-aspartate (NMDA) receptor at therapeutic concentrations.^5,2 It is known to augment the release of dopamine and delay its reuptake.¹¹ Dopamine is less associated with corneal toxicity than amantadine.¹²

Several case reports have found that amantadine induces superficial punctate keratitis, punctate epithelial opacities, and epithelial and stromal edema.^{12,13,14,11,5,14,16,17} Although rare, amantadine-related corneal edema is now considered a possible adverse reaction to this treatment. Several reports have found that patients with Parkinson’s disease taking amantadine reported visual blur and/or foreign body sensation with sudden onset of bilateral corneal edema.^12,1,2 When amantadine was discontinued, corneal edema resolved and resulted in improved in visual acuity.^12,11,1,2 In these cases, if amantadine was restarted, the corneal edema recurred.^13,11

A timeline for the initial onset of corneal edema is highly variable, and it has been reported to occur from 25 days after initiating therapy to after 6 years of treatment.¹² Ophthalmic adverse effects are rare. A 2007 Veterans Health Administration retrospective database review of patients on amantadine found an incidence of 0.27% of corneal edema, with a relative risk of 1.7 times greater than non-amantadine users.⁶ It is also believed that amantadine-induced corneal edema may be underreported because many patients are diagnosed with idiopathic corneal edema or Fuch’s endothelial dystrophy.¹⁷

The pathophysiology for amantadine-induced corneal endothelial changes resulting in edema is unknown, but corneal deposition of the drug is one hypothesis.¹² Amantadine is present in the tear film from the lacrimal gland, and these secretions cause corneal edema and keratitis. Dose-dependent effects are suspected.² The prognosis is better if caught early before serious corneal changes occur, and the condition is generally reversible upon discontinuation of the medication. The long-term use of amantadine therapy may cause stress to endothelial cells and thus is associated with greater variation of endothelial cell area (poylmegethism).^12,14,5 To date, no study has been conducted to determine the prevalence of these ocular signs in patients treated with amantadine. Irreversible endothelial changes are noted with continuous therapy.¹⁴ Permanent loss of endothelial cells have been noted with atrophy of the endothelial layer and decreased endothelial density.^15,16,17

Early discontinuation of amantadine usually results in a complete resolution of edema, but consultation with the prescribing neurologist is recommended before discontinuation. This is a rare condition, and the management frequency will be variable depending on each case. The current literature does not indicate how soon the corneal edema will resolve. Muro-128 or topical steroids are commonly used for managing corneal edema but are not required if amantadine alone is the suspected etiology.

Gradual loss of endothelial cell count and eventual corneal decompensation is a concern with chronic use of amantadine.¹² If corneal changes begin and the therapy is not discontinued promptly, permanent corneal endothelial damage could result, and lead to the need for corneal transplant surgery in some cases.¹

CONCLUSION

The adverse ophthalmic effects of amantadine are not well-known, and this case demonstrates the important role of patient history and clinical observation in the early diagnosis of corneal edema secondary to amantadine. The etiology of corneal edema needs to be determined with careful review of the patient’s medications and medical history to ensure timely diagnosis and appropriate treatment to prevent long-term complications. Finally, in cases of iatrogenic adverse events, it’s vital to let the patient know which medication caused the problem and to document it in the EHR allergy assessment to prevent future use of the offending medication.

REFERENCES

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2. Kubo S, Iwatake A, and et al. Visual impairment in Parkinson’s disease treated with amantadine: Case report and review of the literature. Parkinsonism and Related Disorders. 2008;14:166-169.

3. Blomquist PH. Ocular Complications of Systemic Medications: UT Southwestern Medical Center. The American Journal of the Medical Sciences. 2011;342:62-69.

4. Fraunfelder FT, Fraunfelder FW, Chambers WA. “Drug-Induced Ocular Side Effects.” Clinical Ocular Toxicology: Drugs, Chemicals and Herbs. Philadelphia, PA: Elsevier, 2008. 194-195.

5. Jeng BH, Galor A, Lee MS and et al. Amantadine-Associated Corneal Edema Potentially Irreversible Even after Cessation of the Medication. Ophthalmology. 2008;115.

6. French D, Margo CE. Postmarketing Surveillance of Corneal Edema, Fuchs Dystrophy, and Amantadine Use in the Veterans Health Administratin. Cornea 2007;26:1087–89.

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8. Yanoff M and Duker J. “Herpes Zoster Ophthalmicus.” Ophthalmology. Philadelphia, PA: Elsevier, 2014. 180-182.

9. Krachmer JH, Mannis MJ and Holland EJ. “ Iridocorneal Endothelial Syndrome.” Cornea. St. Louis: Mosby, 2011. 889-899.

10. Gault JA. “Corneal Dystrophies” Ophthalmology Secrets in Color. Philadelphia, PA: Elsevier, 2016. 114-122.

11. Hughes B, Vahid Feiz V, Flynn SB, and et al. Reversible Amantadine-Induced Corneal Edema in an Adolescent. Cornea. 2004;23:823–824.

12. Chang KC, Kim MK, Wee WR , et al. Corneal Endothelial Dysfunction Associated with Amantadine Toxicity. Cornea. 2008;27:1182-85.

13. Deogaonkar M, Wilson K, Vitek, J. Amantadine induced reversible corneal edema. Case Reports / Journal of Clinical Neuroscience. 2011;18:298-299.

14. Esquenazi S. Bilateral Reversible Corneal Edema Associated With Amantadine Use. Journal of Ocular Pharmacology and Therapeutics. 2009;25: 567-569.

15. Kim YE, Yun JY, Yang H and et al. Amantadine Induced Corneal Edema in a Patient with Primary Progressive Freezing Gait. Journal of Movement Disorders 2013;6:34-36.

16. Aksoy D, Ortak H, and et al. Central corneal thickness and its relationship to Parkinson’s disease severity. Can J Ophthalmol. 2014;49:152-156.

17. Yang Y, Teja S, and Baig K. Bilateral corneal edema associated with amantadine. CMAJ. 2015;15:1155-58.

Dipti Singh, OD, MPH, FAAO, ABCMO

Audie Murphy VA Hospital | San Antonio, TX

Dr. Dipti Singh graduated from Southern College of Optometry in 2001. After graduation, she completed Residency in Primary Care Optometry with Emphasis in Ocular Disease at James H. Quillen Department of Veterans Affairs Medical Center in 2002. She is currently working at the South Texas Veterans Health Care System in San Antonio, TX. Dr. Singh is the Ocular Disease Coordinator for Residency in Ocular Disease with an emphasis in Brain Injury and Rehabilitation at the Audie Murphy VA Hospital.

Gregg Wentworth, OD MBA, FAAO, ABCMO

South Texas Veterans Health Care System | San Antonio, TX

A graduate of the University of Houston College of Optometry, Dr. Gregg Wentworth is a retired U.S. Air Force officer and Optometric Glaucoma Specialist with over 30 years of experience. He currently serves as Chief of Optometry at the South Texas Veterans Health Care System and Residency Coordinator for the Residency in Ocular Disease with an emphasis in Brain Injury and Rehabilitation. He is also an adjunct faculty member at the University of Houston College of Optometry, University of the Incarnate Word Rosenberg College of Optometry, and the Massachusetts College of Pharmacy and Health Sciences.