Amantadine Keratopathy

Etiology

The acute onset of corneal edema with amantadine treatment and its resolution upon discontinuation of the drug show a causal relationship.[1][2][3][4] Studies show that amantadine keratopathy occurs in a cumulative and dose-dependent manner.[5][6] A negative correlation exists between treatment duration and endothelial cell density.[1] The highest relative risk (RR) of corneal edema is observed in patients who receive a high dose for a short period (2000 mg within 30 days, RR=2.38).[6] A 4000 mg cumulative dose prescribed within 30 days led to a 3-fold increased risk of corneal edema.[6] Amantadine may act synergistically with other medications that are toxic to the cornea, increasing the risk for corneal edema and permanent damage in these patients.[2][7]

Although endothelial cell density is not a highly reliable marker of clinical outcomes, patients with decreased baseline cell density may be at increased risk of amantadine keratopathy. Endothelial cell density decreases linearly with age , and the standard deviation increases in later decades of life.[8][9] A study using a large corneal donor database showed that the prevalence of endothelial cell density less than 2000 cells/mm² was significantly higher in eyes from patients older than 75 (odds ratio [OR]=24.6), patients aged 65 to 74 (OR=17.8), and eyes with a previous history of cataract surgery (OR=4.8).[9]

Epidemiology

The incidence and prevalence of amantadine keratopathy in the general population are not well established, as most studies exclude patients with ocular comorbidities (eg, glaucoma or a history of corneal edema), in whom the condition may be more prevalent. Amantadine keratopathy appears to have an equal preponderance in males and females.[6][10] In a phase IV post-marketing surveillance study, the 2-year relative risk (RR) of developing corneal edema or Fuchs endothelial dystrophy among patients prescribed amantadine was 1.79 compared with the general population. During this period, 36 (0.27%) of the 13,137 patients receiving amantadine (99% of whom received a prescription of 100 mg twice daily) were diagnosed with Fuchs dystrophy or corneal edema.[10]

The incidence of amantadine keratopathy increases within the first few months of treatment initiation, although cases have been documented as late as 6 years after therapy onset. Consequently, the cumulative relative risk may be higher than initially estimated.[6][10][11] The largest retrospective cohort study conducted on amantadine keratopathy showed that patients prescribed amantadine for Parkinson disease have a higher risk of developing amantadine keratopathy compared to those taking amantadine for other indications (RR=1.97).[6] This increased risk is likely related to long-term exposure. The same study calculated a RR of 1.97 over 15 years for patients with Parkinson disease receiving amantadine compared to healthy individuals not taking the medication.[6]

Four cases of amantadine-induced corneal edema have been reported in the pediatric population, especially those with underlying psychiatric and developmental impairment.[12][13][14][15] All cases demonstrated a resolution in corneal edema and recovery of visual acuity to baseline. However, 1 patient had persistently low endothelial cell density (1395/mm² in the right eye and 1054/mm² in the left eye).[13] In another case, transient visual impairment was associated with delays in academic and developmental milestones.[12]

Pathophysiology

Amantadine has been associated with permanent damage to the corneal endothelium and a decrease in corneal endothelial cell density through mechanisms that remain incompletely understood.[4][11][16] Studies using bovine corneal endothelial cell cultures showed no evidence of apoptosis, although the duration of incubation may not have been sufficient to induce such changes.[17] However, another study demonstrated that higher concentrations (2000 μΜ) induced apoptosis and increased sub-G1 phase growth arrest.[18] At concentrations 200 μM or higher, amantadine attenuated proliferation and arrested the cell cycle at the G1 phase; at higher concentrations (≥1000 μM), it induced endothelial hyperpermeability and DNA damage in bovine corneal endothelial cells.

Corneal endothelial cells are located in a monolayer posterior to the Descemet membrane and stroma. These cells function to dehydrate and thus maintain corneal clarity via sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) pumps. Loss of corneal endothelial cells can lead to edema and blurred vision, typically occurring when cell density declines to approximately 500 cells/mm². Corneal edema in amantadine keratopathy may result in loss of visual acuity to 20/200 or hand motion.[2][3][4][11][16] Endothelial damage may persist after discontinuation of the drug, and in severe cases, corneal transplantation may be required to restore vision.[16]

The primary neurologic action of amantadine involves an indirect increase in extracellular dopamine through noncompetitive inhibition of N-methyl-D-aspartate receptors. Similar cases of corneal edema have been reported with memantine, a structurally related drug with a comparable mechanism of action.[19] Amantadine also has several off-target effects that may contribute to corneal edema.[20][21] In bovine corneal endothelial cell cultures, amantadine was shown to inhibit K+ channels similar to the effect of the K+ channel blocker clotrimazole. Cells in culture showed increased area and cell volume consistent with edema, accompanied by disruption of intercellular gap junctions.[20]

Additional reports have described corneal edema associated with dopaminergic agents such as ropinirole, methylphenidate, and resiniferatoxin, producing a clinical presentation similar to amantadine keratopathy.[21] Dopamine D1 receptors have been found on corneal endothelial cells, and dopaminergic activity has been associated with reduced corneal transparency. Based on these studies, it is likely that acute corneal edema in amantadine keratopathy occurs secondary to interactions with multiple corneal endothelial cell receptors, ultimately disrupting intracellular fluid osmolarity and corneal endothelial cell organization. Damage to the endothelium has been assessed using several parameters, including decreased endothelial cell density, decreased hexagonality, and increased coefficient of variation.[1][4][5]

An increased coefficient of variation reflects endothelial cell size variability, which indicates compensatory enlargement of remaining cells to fill gaps after cell loss. The percentage of hexagonal cells decreases in response to chemical, mechanical, or hypoxic stress. These parameters are frequently used as markers of endothelial cell viability and preoperative risk in patients with intrinsic corneal endothelial disease, such as Fuchs endothelial corneal dystrophy. Subclinical endothelial changes may be present in patients receiving amantadine even in the absence of corneal edema or visual symptoms.[1][5] Regardless of whether keratopathy develops, endothelial cells do not regenerate after amantadine toxicity.[4][5][11] Amantadine keratopathy likely occurs in a dose-dependent manner, with significant variation in aqueous humor concentrations of amantadine, even when the prescribed dose is consistent.[4][6]

History and Physical

In most reported cases of amantadine keratopathy, patients describe a sudden onset of painless, bilateral, blurred vision that progressively worsens over subsequent months. Many patients have a visual acuity of 20/200 or worse. This presentation in patients with no past ocular disease and a negative family history of ocular disease should prompt an extensive workup of medical history and medication exposure. If a patient is taking amantadine, the duration and dosage of treatment should be determined to stratify the risk of amantadine keratopathy. Undiagnosed ocular pathologies that may contribute to visual loss should be considered, as amantadine keratopathy is a rare condition with a nonspecific presentation.

In a patient with vision loss taking amantadine, possible comorbid ocular pathologies should be ruled out through a comprehensive slit-lamp examination of the anterior segment, retina, and optic nerve. Slit-lamp examination of the cornea typically shows diffuse stromal edema with Descemet's folds and absent guttae. A study found that corneal edema initially appears centrally and, in some cases, progresses to diffuse edema.[22] The involvement may also be asymmetrically bilateral. Microcystic epithelial edema and loosened epithelia have also been described. 

Evaluation

Additional testing, such as pachymetry, may be used to confirm the presence of corneal edema, monitor disease progression, and resolution after discontinuation of amantadine. Specular microscopy studies can be performed to evaluate the extent of endothelial damage and assess endothelial cell density.

Treatment / Management

Most reported cases of amantadine keratopathy demonstrate complete resolution of corneal edema and recovery of visual acuity after discontinuation of amantadine.[2][3][4][11] However, a small number of cases have described persistent corneal edema despite drug cessation.[7][16] In these cases, visual acuity returned to normal following corneal transplant surgery. Comorbid corneal pathologies may have further damaged the cornea, preventing resolution of the disease even with therapy discontinuation.[23] A prior case report described a patient with a history of amantadine keratopathy who was able to continue amantadine therapy with concurrent topical steroid treatment without recurrence of edema or a decrease in endothelial cell density.[22] Although topical steroids have not been shown to reduce corneal edema, they may be useful as a prophylactic measure in susceptible individuals.(B3)

Currently, little to no evidence exists to guide risk stratification for the development of amantadine keratopathy. Decreased vision following initiation of treatment should prompt the prescribing neurologist to refer the patient to an ophthalmologist. Patients with a history of ocular trauma, ocular surgery, corneal or anterior segment disease, and possibly advanced age may necessitate a consultation with a corneal specialist before initiation of amantadine therapy. However, further research is needed to elucidate formal guidelines.

Increased corneal backscatter on slit-lamp examination and central corneal thickness have shown weak predictive value for the prognosis of Fuchs endothelial dystrophy.[24][25] These parameters are unlikely to be useful in assessing patients before initiating amantadine therapy. Newer methods of corneal analysis, including Scheimpflug tomography, show significant promise in predicting the need for future interventions in Fuchs endothelial dystrophy before visual acuity declines.[24] A study showed that Scheimpflug tomography can effectively characterize specific patterns of corneal edema and monitor its resolution.[22] This method may represent a potential screening modality for amantadine keratopathy, although no studies have specifically evaluated its role in this context.(B2)

Differential Diagnosis

Fuchs Endothelial Dystrophy

Fuchs endothelial dystrophy has a pathophysiology and clinical presentation most similar to amantadine keratopathy. Distinguishing features include the presence of guttata on slit-lamp examination and persistence of corneal edema despite discontinuation of amantadine.

Band Keratopathy

Band keratopathy is characterized by calcium deposition in the anterior stroma, which can resemble the stromal edema associated with amantadine keratopathy. The epidemiology is also similar due to the age-related progression and association with chronic disease. However, band keratopathy typically demonstrates a subacute or chronic course of corneal opacification rather than the more acute presentation observed with amantadine keratopathy, and it is more strongly associated with underlying ocular comorbidities. Like Fuchs endothelial dystrophy, band keratopathy does not resolve with discontinuation of amantadine.

Prognosis

The majority of reported cases have shown complete resolution of corneal edema and a return of visual acuity to baseline upon discontinuation of amantadine, particularly in those with no prior ocular history. In patients with preexisting low endothelial cell density, a corneal transplant or Descemet membrane endothelial keratoplasty may be indicated.

Complications

Misdiagnosis may lead to unnecessary surgical and medical interventions and significant distress for patients who fail to improve. Although amantadine keratopathy may be reversible with early recognition and drug discontinuation, failure to recognize this disease or continued exposure can result in irreversible corneal endothelial damage and permanent vision loss.