Amantadine-Induced Corneal Edema

Key Points at a Glance

Key Points of This Disease

• Rare bilateral corneal edema caused as a side effect of amantadine (Symmetrel®).
• It is thought to be due to dose-dependent toxicity to corneal endothelial cells.
• Typically presents as bilateral, centrally predominant corneal edema without corneal guttata or anterior chamber inflammation.
• In most cases, recovery occurs within 30 days after discontinuing the drug, but it may become irreversible with long-term use.
• Daily doses exceeding 100 mg or concomitant use of dopamine agonists increase the risk.

1. What is amantadine-induced corneal edema?

Amantadine is an NMDA-type glutamate receptor antagonist, originally developed as a prophylactic agent for influenza A. It is currently used to treat tremor associated with Parkinson’s disease (PD), levodopa-induced dyskinesia, and fatigue in multiple sclerosis (MS).

A rare side effect of this drug is bilateral corneal edema. In a literature review of 33 cases, 70% of patients were women, with a median age of 52 years ¹⁾. A two-year surveillance study by the Veterans Health Administration found corneal edema in 0.27% of patients taking amantadine. A longitudinal study in Taiwan reported a relative risk (RR) of 1.98 for corneal edema with amantadine use in PD patients.

Q Can corneal edema occur with dopamine agonists other than amantadine?

A

Similar corneal edema has been reported with other dopamine agonists such as methylphenidate, ropinirole, and bupropion. In all cases, recovery occurred after discontinuation, and concomitant use of multiple dopamine agonists may increase risk due to additive effects.

2. Main symptoms and clinical findings

Subjective symptoms

The main symptom is slowly progressive bilateral blurred vision over weeks to months. Onset often occurs weeks to months after starting the drug, but cases have been reported years after treatment initiation ¹⁾. In a literature review, the median visual acuity at onset was 20/200 (worse eye) ¹⁾.

Clinical findings (findings confirmed by physician examination)

• Corneal edema: Bilateral, centrally predominant diffuse corneal edema with Descemet’s membrane folds
• Absence of guttata: Unlike Fuchs’ endothelial corneal dystrophy, no guttata are present
• Absence of anterior chamber inflammation: No keratic precipitates or anterior chamber inflammation
• Corneal sensation: Usually normal, useful for differentiating from viral keratitis
• Corneal endothelial examination: Specular microscopy shows a marked decrease in endothelial cell density. In the literature review, the median endothelial cell density was 759 cells/mm²¹⁾
• Advanced cases: May present with bullous keratopathy or epithelial bullae

3. Causes and Risk Factors

The following risk factors for amantadine toxicity have been reported.

Dose dependency

Daily dose: The RR was 2.71 for patients taking more than 100 mg/day, compared to 1.69 for those taking 100 mg/day or less

Cumulative dose: Patients with higher lifetime cumulative doses tend to have lower endothelial cell density

Chronic effects on the endothelium

Prospective study: Patients taking amantadine had a greater annual decrease in corneal endothelial cell density (1.51%/year) compared to non-medicated PD patients (0.94%) and healthy individuals (0.55%)

Higher doses have greater effect: The decrease in hexagonality and increase in coefficient of variation increased in a dose-dependent manner

Prevention and daily care

• If you are taking amantadine long-term, consider having regular specular microscopy evaluations of the corneal endothelium.
• If you notice decreased vision or blurred vision, promptly see an ophthalmologist.
• Inform your primary care physician (e.g., neurologist) about the possibility of ocular symptoms.

4. Diagnosis and Examination Methods

IVCM findings of amantadine-induced corneal edema

Buzzi M, Vagge A, Traverso CE, et al. Ocular Surface Features in Patients with Parkinson Disease on and off Treatment: A Narrative Review. Life (Basel). 2022 Dec;12(12):2141. Figure 1. PMCID: PMC9783883. License: CC BY.

Numerous hyperreflective round deposits are scattered at the corneal epithelial level, indicating intraepithelial deposits reported in amantadine-related corneal toxicity. This image supplements subtle findings that are difficult to capture with slit-lamp alone.

The diagnosis of amantadine-induced corneal edema is made clinically. After excluding other causes of corneal edema, the association with amantadine use is confirmed.

Diagnostic Procedure

• History taking: Confirm the dose and duration of amantadine, and history of concomitant use of other dopaminergic agents.
• Slit-lamp examination: Evaluate the distribution of corneal edema (central predominance), Descemet’s membrane folds, and the presence of guttae or anterior chamber inflammation.
• Specular microscopy: Measure corneal endothelial cell density, hexagonality (EH), and coefficient of variation (CoV).
• Corneal sensitivity test: Confirm normal sensitivity to rule out viral keratitis.

Differential Diagnosis

• Fuchs endothelial corneal dystrophy (with guttae)
• Posterior polymorphous corneal dystrophy (PPCD)
• Iridocorneal endothelial syndrome (ICE syndrome, unilateral)
• Herpetic corneal endotheliitis (with keratic precipitates and anterior chamber inflammation)
• Interstitial keratitis
• Pseudophakic bullous keratopathy (with history of intraocular surgery)

Q What are the points of differentiation from Fuchs endothelial corneal dystrophy?

A

In Fuchs endothelial corneal dystrophy, specular microscopy or slit-lamp microscopy characteristically reveals corneal guttata, whereas amantadine-induced corneal edema does not show guttata. Additionally, Fuchs is chronic and progressive, but amantadine-induced edema often resolves after discontinuation of the drug.

5. Standard Treatment

Discontinuation of Amantadine

The mainstay of treatment is prompt discontinuation of amantadine. In a literature review, the majority of cases showed resolution of corneal edema within 30 days (median 30 days, interquartile range 14–35 days) after drug cessation, with visual acuity recovering to a median of 20/25 ¹⁾. Coordinate with the attending neurologist to consider switching to an alternative medication.

Symptomatic Treatment

Hypertonic saline (5% sodium chloride) eye drops may be used as symptomatic treatment for corneal edema. However, since the underlying issue is endothelial dysfunction, the effect is limited. If it progresses to bullous keratopathy, bandage contact lenses for pain management and prophylactic antibiotic eye drops may be used.

Corneal Transplantation

In a literature review, corneal transplantation was required in 5 of 33 cases (10 eyes) ¹⁾. Descemet membrane endothelial keratoplasty (DMEK) or Descemet stripping automated endothelial keratoplasty (DSAEK) may be selected. There are reports of non-immune graft failure if corneal transplantation is performed while continuing amantadine use, so the drug should be discontinued before transplantation.

Precautions in Treatment

• In long-term use (especially over 10 years), corneal edema may become irreversible even after drug discontinuation. Early detection is extremely important.
• Discontinuation of amantadine should be done in consultation with the attending neurologist. Abrupt cessation may lead to worsening of the underlying disease.
• If amantadine is resumed after corneal transplantation, there is a risk of graft failure.

6. Pathophysiology and Detailed Mechanism

The exact mechanism is unknown, but dose-dependent toxicity to corneal endothelial cells is considered the main cause. Corneal endothelial cells have a pump function that removes water from the corneal stroma into the anterior chamber via ion transporters such as Na⁺-K⁺ ATPase and SLC4A11, as well as a barrier function through tight junctions. These functions maintain constant corneal hydration and transparency.

Histopathological examination of cases requiring corneal transplantation for amantadine-induced corneal edema revealed moderate to complete loss of corneal endothelial cells without guttata or inflammation. It is presumed that drug-induced stress on corneal endothelial cells, when exceeding a threshold, leads to progressive endothelial dysfunction and loss, and the resulting decrease in pump function causes fluid accumulation in the corneal stroma, leading to edema.

Dose-dependent chronic toxicity is considered the main mechanism rather than an idiosyncratic reaction (onset within 1 month of starting the drug). A literature review found that only 9.7% of cases developed within 1 month ¹⁾.

Q Can corneal endothelial cells recover once they decrease?

A

Human corneal endothelial cells have little regenerative capacity; damaged cells are compensated by flattening and enlargement of surrounding cells. Even after corneal edema resolves upon discontinuation of amantadine, endothelial cell density often remains low, posing a risk of future corneal decompensation. Therefore, long-term follow-up is recommended.

---

7. References

1. Raharja A, Mina W, Ashena Z. Amantadine-induced corneal edema: A case and literature review. Am J Ophthalmol Case Rep. 2023;32:101881.
2. Kim YE, Yun JY, Yang HJ, Kim HJ, Kim MK, Wee WR, et al. Amantadine induced corneal edema in a patient with primary progressive freezing of gait. J Mov Disord. 2013;6(2):34-6. PMID: 24868424.
3. Hughes B, Feiz V, Flynn SB, Brodsky MC. Reversible amantadine-induced corneal edema in an adolescent. Cornea. 2004;23(8):823-4. PMID: 15502485.