Dear Editor,

Antiproliferative treatment following glaucoma surgery includes subconjunctival 5-fluorouracil (5-FU) injections as a routine procedure. Cumulative dosage during the postoperative period is adjusted to individual needs ranging from 5 to 75 mg.

We report the case of a 68-year-old male Caucasian patient who underwent uneventful trabeculectomy for advanced primary open-angle glaucoma with intraoperative application of Mitomycin C. Under topical anesthesia with tetracaine eye drops, a subconjunctival injection of 5 mg 5-FU was administered on postoperative day 4. A few minutes later, a generalized tonic and clonic seizure occurred lasting for 3 min that ended spontaneously. A second episode of seizures happened 3 h later. The patient did not retain any memory of the episode and amnesia was observed for the immediate postictal period. However, epilepsy was hitherto unknown in this patient nor did his medical history give any hints as to such a condition. Known systemic conditions included arterial hypertension, coronary heart disease, congenital aortic coarctation, hyperlipidemia, and prostate hyperplasia. Neurologic examination including electroencephalography and cranial imaging revealed spike wave complexes, but no specific focus. Thirteen days later, two more subconjunctival injections of 5 mg 5-FU were applied without complications under anticonvulsive therapy with Valproic acid 300 mg twice a day. No more seizures occurred in the domestic environment.

When trabeculectomy was performed on the fellow eye 4 months later, 5 mg 5-FU was again applied to prevent bleb scarring without obvious complications. Upon a 5-h interval after the second injection, two more grand-mal convulsions occurred despite permanent therapy with gabapentin 300 mg three times a day and acute therapy with lorazepam 1 mg after the first seizure. Afterwards, the therapy was modified to Valproic acid 600 mg twice a day.

5-fluorouracil is a pyrimidine antimetabolite that prevents DNA synthesis and inhibits RNA processing and function. It quickly penetrates the blood–brain barrier and achieves significant concentrations within the cerebrospinal fluid.

Observed neurotoxicity of 5-FU as a commonly used, systemic chemotherapy agent is estimated <1% [1–3], but also up to 5.7% [4, 5] in high-dose chemotherapy. Acute neurotoxicity is dose-related and generally reversible [6]. It typically manifests as encephalopathy with somnolence and confusion or cerebellar syndrome. However, seizures are described in a few cases [3, 6], and in only one case as isolated generalized tonic-clonic seizures [7].

The exact pathways of neurotoxicity are not completely understood. The most plausible pathogenetic mechanism for developing seizures or paresis-like symptoms may be the Krebs cycle blockade by fluoroacetate and fluorocitrate, which results in a reduction of high-energy adenosine triphosphate [2, 8, 9]. Other proposed mechanisms are thiamine deficiency and inherited deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), which metabolizes about 80% of fluorouracil [2, 7]. An animal model demonstrated that systemic 5-FU causes acute damage by induction of apoptosis to neuronal cells and delayed damage to myelinated tracts [10].

A supposed pathomechanism might be a rise in concentration in brain and cerebrospinal fluid (CSF) due to the close and direct communication between the subconjunctival/sub-Tenon space and the optic nerve sheath as part of the CSF system [11]. Through avoiding a significant systemic distribution of 5-FU, the DPD activity is thought to be of secondary importance, and a test for DPD activity was not performed in our patient.

The subconjunctival injection itself may also be a conceivable trigger for seizures. This, however, would imply an immediate temporal correlation to the injection in all events and there still would not be an explanation for the delayed onset of the third episode. Nevertheless, such an association has not been described in the literature yet. To the best of our knowledge, this is the first report of epileptic seizures following subconjunctival 5-FU application.