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CASE REPORT
Bilateral Reversible Corneal Edema as a Novel
Side-Effect of Levetiracetam – A Case Report
Kimberly Caruana
*, Matthew Ellul*, Andre Grixti*
Department of Ophthalmology, Mater Dei Hospital, Imsida, MSD, 2090, Malta
*These authors contributed equally to this work
Correspondence: Kimberly Caruana, Ophthalmology Outpatients, Mater Dei Hospital, Imsida, MSD, 2090, Malta, Email kimberly.caruana27@gmail.com
Purpose: We present a case of levetiracetam-induced corneal edema. To the best of our knowledge, this is the first documented case
of bilateral reversible corneal edema secondary to levetiracetam use.
Patients and Methods: A 59-year-old woman was referred to the ophthalmology department with a few weeks’ history of bilateral
blurring of vision. She is a known case of secondary progressive multiple sclerosis, and she was started on levetiracetam by her
neurologist a few weeks prior to referral in view of new seizure activity. Examination revealed bilateral clinically evident corneal
edema, which was documented on corneal topography.
Results: Upon levetiracetam dose reduction, symptoms started to improve and eventually the medication was stopped altogether. The
patient’s vision and corneal edema normalized on follow-up.
Conclusion: This novel side effect should be kept in mind when a patient who is on levetiracetam presents with corneal edema as this
can avoid misdiagnosis and unnecessary interventions.
Keywords: blurred vision, corneal thickening, multiple sclerosis
Introduction
We present a case of levetiracetam-induced corneal edema. To the best of our knowledge, this is the first documented
case of this medication side-effect. Levetiracetam is an anti-epileptic medication that is used both as monotherapy in the
treatment of focal epilepsy and as an add-on agent for complex or generalised epilepsy. Its mechanism of action is still
not completely understood. One of its modes of action is mediated via adherence to synaptic vesicle 2A. This mediates
calcium-dependent neurotransmitter release. 1,2
Case Report/Case Presentation
We present a case of a 59-year-old lady with a twelve-year history of secondary progressive multiple sclerosis who was
referred to ophthalmology with a few weeks’ history of bilateral blurring of vision.
The patient had no past ophthalmic history and no drug history other than the anti-epileptic medications related to her
multiple sclerosis. Previously documented ophthalmic examinations did not reveal any signs of Fuchs' endothelial
corneal dystrophy, and the patient has no family history of corneal pathology.
The patient had been on amantadine therapy at a dose of 100mg twice daily for the past 7 years and was started on
levetiracetam 250mg twice daily as an add-on agent. Visual deterioration was experienced shortly after commencement
of levetiracetam therapy for a breakthrough seizure.
On examination, the patient’s best corrected visual acuity was 0.5 logMAR right eye and 0.5 logMAR left eye. Slit-
lamp examination revealed corneal edema (shown in Figure 1) involving both eyes and absence of uveitis. Corrected
intraocular pressures were 16mmHg right eye and 18mmHg left eye. Corneal topography was performed which
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Open Access Full T ext Article
Received: 21 September 2024
Accepted: 18 December 2024
Published: 23 December 2024
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confirmed bilateral significant corneal thickening with a right central corneal thickness of 936μm and left central corneal
thickness of 1134μm (shown in Figure 2). The rest of the eye examination was normal.
Since amantadine is a known cause of corneal edema, 3,4 it was agreed with the patient and her caring neurologist to
switch from amantadine to lamotrigine. Levetiracetam therapy was continued at this stage. No improvement in vision
was noted two months after this change in treatment. The patient expressed the wish to temporarily stop levetiracetam on
a trial basis in view of the direct temporal association between the onset of symptoms and the commencement of the
medication.
Amantadine was re-introduced, while levetiracetam dose was tapered. Improvement in vision was noted a few days after
levetiracetam dose reduction. Levetiracetam was stopped altogether, and the patient remained on amantadine and lamo -
trigine. A provisional diagnosis of levetiracetam-induced corneal edema was made at this stage. Her vision normalized and
repeat corneal topography six months after stopping the levetiracetam showed a right central corneal thickness of 567μm
and a left central corneal thickness of 573μm, (shown in Figure 3) and a visual acuity of 0.2 logMAR both eyes. Slit-lamp
examination confirmed clear cornea and the absence of corneal guttata in either eye (shown in Figure 4).
The patient was examined again thirteen months after the first presentation. No further changes in her medications
were made, and her vision had remained stable at 0.2 logMAR in both eyes. Repeat corneal topography showed no
further changes.
Discussion
The primary function of corneal endothelium (CEN) is maintenance of constant corneal thickness and transparency. This
is achieved via tight junctions that form a barrier to diffusion of electrolytes and water from the anterior chamber across
the CEN to the corneal stroma, and via active transport of electrolytes (and passive flow of water) from the corneal
stroma to the anterior chamber. 5
It has been shown in different corneal models (bovine, rabbit and human) that calcium is involved in endothelial
regulation of ion and fluid transport.6 Exposure to a hypotonic environment triggers cells to perform a regulatory volume
decrease, which is mediated via calcium release from intracellular stores. On the other hand, perfusion with a calcium-
free medium results in disruption of endothelial tight junctions, resulting in loss of barrier function with consequent
corneal edema.5
Since some calcium channel blockers influence corneal endothelial calcium levels, these agents have been used
experimentally to elucidate corneal function. While some agents clearly diminish corneal endothelial function and may
Figure 1 Right corneal picture showing corneal oedema with descemet membrane folds. Patient on levetiracetam.
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Figure 2 Corneal topography of the patient on levetiracetam treatment showing generalised increased corneal thickness. ( A) Corneal topography right eye showing right
apical thickness of 936 μm (B) Corneal topography left eye showing left apical thickness of 1134 μm.
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Figure 3 Corneal T opography of patient off levetiracetam treatment showing normal corneal thickness. ( A)Corneal topography right eye showing right apical corneal
thickness of 572μ (B)Corneal topography left eye showing left apical corneal thickness of 577 μm.
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consequently cause corneal edema (for example, nifedipine and diltiazem), other calcium channel blockers have no effect
on the corneal endothelium. These results suggest that L-type calcium channels are the type predominantly expressed in
corneal endothelial cells. 5
In this case, the two drugs of interest were amantadine and levetiracetam. There are documented cases of amantadine-
associated corneal endothelial cell dysfunction with resultant cornea edema 3,4 in the literature and, therefore, amantadine
was stopped first. The patient’s symptoms did not improve after stopping this medication. Since the patient started
experiencing blurred vision shortly after starting levetiracetam, amantadine was re-started and she underwent
a levetiracetam cessation trial, which resulted in resolution of her symptoms and reversal of her corneal edema. The
exact time interval between the initiation of levetiracetam and the development of corneal oedema cannot be accurately
ascertained since the patient presented for an ophthalmic consultation after having been symptomatic for a few weeks.
However, her symptoms improved within days of stopping the levetiracetam.
The temporal correlation between the initiation and cessation of levetiracetam treatment, the onset and resolution of
symptoms, and the clinical and topographic corneal findings points towards a direct association between corneal edema
and levetiracetam use.
Levetiracetam is a newer generation anti-epileptic agent with high bioavailability. It is excreted unchanged in the
kidneys with no effect on the cytochrome P450 enzyme system and therefore has very low interaction with other
medications.7,8 For these reasons, its use in seizure control is increasing, both as a sole agent and as an add-on
medication.7
While the mechanisms of action of levetiracetam are incompletely understood, it has been shown that one mechanism
of action of levetiracetam is inhibition of N, P and L-type calcium channels in the brain, which results in reduced calcium
release from intracellular stores and consequently reduced intracellular calcium levels. 7 Given the key roles played by
calcium in corneal endothelial physiology, this mechanism of action of levetiracetam is a plausible mechanism, which
can explain the corneal side-effect experienced by our patient when the medication was used. Specular microscopy of the
patient, performed after resolution of her corneal edema showed a right corneal endothelial cell count of 1357 cells/mm 2
and a left corneal endothelial cell count of 1299 cells/mm 2 (endothelial cell count normal range: 1500–3500 cells/mm 2).
Taking into consideration the low corneal endothelial cell count, our patient may have been at higher predisposition to
medication-induced corneal edema than patients with normal endothelial cell counts. Moreover, other factors, such as
genetic variables cannot be excluded in this case.
Figure 4 Right corneal picture showing clear cornea. Patient off levetiracetam.
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Conclusion
This case is of value as it is the first documented case of corneal edema that was associated with levetiracetam use.
Awareness of this side-effect is vital to avoid misdiagnosis and unnecessary interventions. Corneal transplant surgery,
with all its associated risks, was being considered in this case since primary corneal failure was the main differential
diagnosis.
Abbreviations
CEN, corneal endothelium.
Ethical Statement
Institutional ethical approval was not required for publication.
Informed consent
Patient’s verbal and written consent was obtained to publish this data. Any person identifying information was not
included.
Funding
This study was not supported by any sponsor or funder.
Disclosure
The authors declare no conflict of interest or financial support.
References
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findings, case report and revision of literature. BMC Ophthal. 2022;22(1):10.1186/s12886–022–02410–1. doi:10.1186/s12886-022-02410-1
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5. Kraus D, Kaiserman I, Frucht-Pery J, Rahamimoff R. Calcium–an “all- round player” in the cornea. Israel Med Ass J . 3(4):269–274.
6. Green K, Cheeks L, David SH. Effects of calcium channel blockers on rabbit corneal endothelial function. Current Eye Rese . 13(6):401–408.
doi:10.3109/02713689408999867
7. Contreras-García IJ, Cárdenas-Rodríguez N, Romo-Mancillas A, et al. Levetiracetam Mechanisms of Action: from Molecules to Systems.
Pharmaceutica. 2022;15(4):475. doi:10.3390/ph15040475
8. Wright C, Downing J, Mungall D, et al. Clinical pharmacology and pharmacokinetics of levetiracetam. Front Neurol. 2013;4:192. PMID: 24363651.
doi:10.3389/fneur.2013.00192
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