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Alzheimer disease (AD) is the most common type of dementia and a growing public health concern. Its estimated prevalence in the United States is 5.2 million cases and is projected to exceed 13 million cases by 2050.1 With no cure available, therapy is palliative via modulation of acetylcholine and glutamate. Current treatment patterns favor cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, respectively.2
Memantine (Namenda) is indicated for moderate to severe AD.2,3 It is 1-amino-3,5-dimethyladamantane,3 an NMDA receptor antagonist related to amantadine (1-aminoadamantane; Figure 1).4 Amantadine has been implicated in corneal endothelial dysfunction manifested as bilateral corneal edema, endothelial cell loss, and nonimmunologic keratoplasty failures.5,6 To our knowledge, this is the first reported case of memantine-associated corneal endothelial dysfunction.
The chemical structures of amantadine (A) and its congener memantine (B), which possesses additional methyl groups (red) at the 3- and 5-carbon positions. NH2 indicates amine group.
Report of a Case
A woman in her mid-80s with AD and Fuchs endothelial dystrophy was referred for Descemet membrane endothelial keratoplasty (DMEK) in her right eye to optimize her vision after complications from Descemet stripping automated endothelial keratoplasty (DSAEK) resulted in visual acuity of hand motions OS. The DSAEK graft had detached repeatedly and severe optic neuropathy from pupil block occurred while receiving 3 air reinjections during the first 3 consecutive postoperative days. She was pseudophakic in the right eye with best-corrected visual acuity of 20/60, central corneal thickness of 616 μm, and no measurable endothelial cells.
Two days after uncomplicated DMEK in the right eye, the graft was diffusely detached and would not reattach after multiple air reinjections (Figure 2A). Visual acuity was counting fingers and corneal thickness was 1 mm. The clinical picture was consistent with primary graft failure, so the patient underwent repeated DMEK 1 week later. The second graft was also diffusely detached and refractory to air reinjections (Figure 2B). Two weeks later, a third DMEK was performed. When this third graft became diffusely detached and refractory to air reinjections (Figure 2C), we investigated surgeon and donor factors.
A-C, While the patient was being treated with memantine, all grafts were diffusely detached (arrowheads) on their respective second postoperative days. Multiple air injections failed prior to memantine washout. D, After memantine washout and intracameral air injection, the third graft (C) attached and edema resolved in the recipient (D).
Finding no issues, we considered the recipient. We confirmed the patient’s compliance with postoperative instructions. Re-review of her lifestyle, diet, and medications revealed no known risk factors. However, she was taking memantine, 10 mg/d, and we recognized its structural similarities to amantadine. Memantine undergoes partial hepatic metabolism and renal excretion with an elimination half-life of 60 to 80 hours.3 The patient and her prescribing physician agreed to discontinue memantine for 2 weeks (4 half-lives), whereupon an air reinjection successfully reattached and rescued the third DMEK graft (Figure 2D). One month later, her best-corrected visual acuity improved to 20/50, central corneal thickness improved to 511 μm, and endothelial cell density improved to 1570/mm2. She is now receiving donepezil hydrochloride monotherapy for AD.
We present a case of post-DMEK corneal endothelial dysfunction possibly associated with memantine use. This case suggests that memantine may be toxic to corneal endothelium because corneal endothelial dysfunction abates when memantine is withheld and because a related medication, amantadine, is accepted to have similar effects.5,6 Because reversible bilateral corneal edema has been associated with other NMDA receptor antagonists (eg, ethanol and ketamine), amantadine- and memantine-associated corneal endothelial dysfunction may represent a broader class effect, pending further study. Fortunately, dysfunction is rare with these agents,5 and we have performed DMEK and DSAEK successfully in other patients receiving memantine.
In summary, decreased endothelial function of DMEK grafts may be associated with memantine use and may mimic primary graft failure. Recognition of this possible risk factor for graft detachment may avoid additional or unnecessary surgery. We recommend counseling before endothelial keratoplasty or after unexplained poor outcomes in patients receiving memantine. A trial discontinuation of memantine should be discussed, including with the prescribing physician. If possible, we suggest a washout period of 2 weeks based on 4 half-lives of 72 hours each.3 After graft attachment, the patient and prescribing physician should decide whether and when to resume memantine therapy.
Corresponding Author: Matthew T. Feng, MD, Price Vision Group, 9002 N Meridian St, Ste 100, Indianapolis, IN 46260 (firstname.lastname@example.org).
Published Online: August 6, 2015. doi:10.1001/jamaophthalmol.2015.2476.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Feng MT, Price FW, McKee Y, Price MO. Memantine-Associated Corneal Endothelial Dysfunction. JAMA Ophthalmol. 2015;133(10):1218–1220. doi:10.1001/jamaophthalmol.2015.2476
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