Amantadine Keratopathy

Etiology

The acute onset of corneal edema with amantadine treatment and the resolution with discontinuation of the drug shows a causal relationship.[1][2][3][4] Studies show that amantadine keratopathy occurs in a cumulative and dose-dependent manner.[5][6] There is a negative correlation between the duration of treatment and endothelial cell density (ECD).[1] The greatest relative risk of corneal edema is seen in patients who are given 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 in corneal edema.[6] Amantadine could 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 ECD is not a highly reliable marker of clinical outcomes, patients with decreased baseline ECD may be at increased risk of amantadine keratopathy. ECD decreases linearly throughout one's lifetime, and the standard deviation of ECD increases in later decades of life.[8][9] A study of corneas from a large cornea donor database showed that prevalence of ECD <2000 was substantially increased in the eyes of patients >75 years old (odds ratio (OR)=24.6), eyes 65-74 years old (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 known as the majority of studies exclude patients with ocular comorbidities (e.g., glaucoma, prior history of corneal edema) where amantadine keratopathy may have an increased prevalence. Amantadine keratopathy has 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 dystrophy in patients prescribed amantadine is 1.79 when compared to the general population. Over this period, 36 (0.27%) of the 13,137 patients receiving amantadine (99% of whom received a prescription of 100 mg BID) were diagnosed with Fuchs dystrophy or corneal edema.[10] 

There is an increased incidence of amantadine keratopathy within months of treatment initiation, but cases have been reported as late as 6 years after starting therapy, so the relative risk is likely greater than this.[6][10][11] The largest retrospective cohort study conducted on amantadine keratopathy showed that patients prescribed amantadine for Parkinson's disease specifically have an increased risk of developing amantadine keratopathy when compared to individuals taking amantadine for other reasons (RR=1.97).[6] This increased risk is likely due to long term treatment. The same study calculates a RR of 1.97 over a 15-year period for Parkinson's patients on amantadine when compared to healthy controls not taking amantadine.[6]

Pathophysiology

Amantadine causes permanent damage to the corneal endothelium and a decrease in corneal endothelial cell density by unknown mechanisms.[4][11][12] Bovine cornea cell cultures showed no signs of corneal endothelial cell apoptosis, although the duration of incubation may not have been sufficient to induce such a change.[13] Corneal endothelial cells are located in a monolayer posterior to Descemet's membrane and the stroma. These cells function to dehydrate and thus maintain the clarity of the cornea via sodium-potassium adenosine triphosphatase (Na/K ATPase) pumps. Loss of corneal endothelium led to edema and blurred vision at a cell density of about 500 cells/mm. Corneal edema in amantadine keratopathy frequently causes loss of visual acuity to 20/200 or hand motion.[2][3][4][11][12] 

Because damage to the corneal endothelium is permanent, edema may persist even after discontinuation of the drug, and a corneal transplant may be necessary to restore vision.[12] The primary action of amantadine as a neurologic drug is through an indirect increase in extracellular dopamine by non-competitive inhibition of NMDA receptors. Recent case reports of corneal edema with a similar clinical picture have been attributed to memantine, a drug with similar structure and mechanism of action.[14] Amantadine also has several off-target effects that may contribute to corneal edema.[13][15] In a study on bovine cornea cultures, amantadine was shown to inhibit K channels similar to the effect of the K channel blocker clotrimazole. Cells in cultures showed an increase in area and cell volume consistent with edema, and gap junctions between cells were disrupted.[13] 

Another recent case study showed that the dopaminergic agonists ropinirole, methylphenidate, and resiniferatoxin induced corneal edema with a similar clinical presentation to amantadine keratopathy.[15] Dopamine D1 receptors (DRD1) have been found on corneal endothelial cells, and dopamine sensitivity has been linked to decreased 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 that ultimately disrupt intracellular fluid osmolarity and corneal endothelial cell organization. Damage to the endothelium has been measured by different parameters, including a decrease in endothelial cell density (ECD), a decrease in cell hexagonality (CH), and an increase in the coefficient of variation (CoV).[1][4][5] 

Endothelial cell size variation (CoV) demonstrates that some endothelial cells are enlarging to fill gaps and compensate for the loss of surrounding endothelial cells. 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 pre-operative risk in patients with intrinsic disease of corneal endothelium such as Fuchs endothelial corneal dystrophy (FECD). Corneal endothelium damage may be present in eyes without corneal edema or decreased visual acuity in patients on amantadine therapy.[1][5] Regardless of whether or not keratopathy develops, endothelial cells do not regenerate after amantadine toxicity occurs.[4][5][11] It is likely that amantadine keratopathy occurs in a dose-dependent fashion, with significant variation among individuals in the concentration of amantadine that is ultimately present in the aqueous, even when the prescribed dose of amantadine is the same.[4][6]

History and Physical

In almost all case reports of amantadine keratopathy, the patient describes a sudden onset of painless, bilateral blurring of vision with progressive worsening in the following months. Many patients have a visual acuity of 20/200 or worse at the time of presentation to an ophthalmologist. This history in patients with no past ocular disease, and 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 patient's risk of amantadine keratopathy. It is important to consider undiagnosed ocular pathologies that may be contributing to visual loss, as amantadine keratopathy is a very rare diagnosis with a nonspecific presentation.

In a patient with vision loss taking amantadine, possible comorbid ocular pathologies should be ruled out by extensive slit lamp examination of the anterior segment, retina, and optic nerve. Slit-lamp examination of the cornea shows diffuse stromal edema with Descemet's folds and absent guttae. Microcystic epithelial edema and loosened epithelia have also been described.

Evaluation

Further studies, such as pachymetry, can be used to confirm the presence of corneal edema, monitor disease progression and resolution with discontinuation of amantadine. Specular microscopy studies can be performed to assess the extent of endothelial damage and ECD.

Treatment / Management

The majority of reported cases of amantadine keratopathy have shown complete resolution of corneal edema and visual acuity with discontinuation of amantadine.[2][3][4][11] There have been a few reported cases where corneal edema did not resolve after discontinuation of amantadine.[7][12] In these cases, visual acuity returned to normal following corneal transplant surgery. It is also possible that comorbid corneal pathologies may have caused further damage to the cornea, preventing the resolution of the disease even with discontinuation of therapy.[16] A more recent case report showed that a patient with a history of amantadine keratopathy was able to continue using the drug with topical steroids without recurrence of edema or a decrease in endothelial cell density.[17] Although topical steroids have not been shown to decrease corneal edema, they could be useful as a prophylactic measure in susceptible individuals.(B3)

Currently, there is little to no evidence to stratify a patient’s risk of developing amantadine keratopathy. Decreased vision following initiation of treatment should undoubtedly prompt a referral to an ophthalmologist by the prescribing neurologist. Patients with a history of ocular trauma, ocular surgery, corneal or anterior segment disease, and possibly those of a certain age may necessitate a consultation by a corneal specialist prior to initiation of amantadine therapy. However, further research is needed to elucidate guidelines for such practice. Increased corneal backscatter on slit-lamp examination and CCT have been shown to have weak predictive value in the prognosis of FECD.[18][19] It is unlikely that these data points would be helpful for ophthalmologists in evaluating patients before initiating amantadine therapy. Newer forms of analysis of the cornea, including Scheimpflug tomography, show significant promise in predicting the need for future interventions in FECD prior to the loss of visual acuity.[18] Scheimpflug tomography could be an effective screening method for amantadine keratopathy, although no research has been conducted on this topic.(B2)

Differential Diagnosis

Fuchs endothelial dystrophy (FECD): Fuchs endothelial dystrophy has the most similar pathophysiology and presentation to amantadine keratopathy. Differentiating features include the presence of guttata on slit-lamp examination and persistence following discontinuation of amantadine.

Band keratopathy: Calcium deposition in the anterior stroma can look similar to the stomal edema associated with amantadine keratopathy, and the epidemiology is similar due to the age-related progression and association with chronic disease. Patients will generally have a sub-acute or chronic progression of corneal opacification as opposed to that in amantadine keratopathy, and there is an increased association with ocular comorbidities. Like FECD, band keratopathy will not resolve with discontinuation of amantadine.

Prognosis

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

Complications

Misdiagnosis could lead to unnecessary surgeries and medical interventions as well as significant distress for patients who fail to improve. Because amantadine keratopathy causes permanent damage to the corneal endothelium, failure to recognize this disease or individuals who are susceptible could lead to permanent loss of vision.