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Sir,

Tadalafil (Cialis) is a potent phosphodiesterase-type-5-inhibitor, which has been shown to be effective in the treatment of erectile dysfunction in men. It shares its mechanism of action with sildenafil (Viagra). In concurrence with recent reports of nonarteritic anterior ischaemic optic neuropathy (NAION) associated with the use of sildenafil, we describe a previously undocumented occurrence of NAION following the use of the more recently licensed and longer acting drug tadalafil, in the absence of any known systemic or local risk factors.

Case report

A healthy, nonsmoking 59-year-old man with no known vasculopathic risk factors was prescribed tadalafil for the treatment of erectile dysfunction following a radical prostatectomy for adenocarcinoma of the prostate. Within 7 days of ingesting 20 mg of tadalafil, he began to experience a generalised headache and blurring of vision associated with ‘blue areas’ and flashing lights in the visual field of the left eye. It is unknown whether or not an erection occurred or if he participated in sexual intercourse.

Ophthalmology examination 3 weeks later revealed snellen visual acuity of 6/6 and 6/9 in the right and left eye, respectively, with decreased left colour vision on Ishihara testing. There was a left relative afferent pupillary defect. Static perimetry revealed a global reduction in the left eye (Figure 1). Dilated fundoscopy showed a swollen left optic disc with an otherwise normal retina, consistent with ischaemic optic neuropathy (Figure 2). The right eye had a healthy retina and optic nerve head (ONH), with normal cup–disc ratio. The remainder of the ophthalmic examination was unremarkable. There were no symptoms or signs of temporal arteritis and an ESR was 7 mm. Fundus fluorescein angiography confirmed the diagnosis of left anterior ischaemic optic neuropathy (Figure 3). Blood pressure (BP) measured 122/70 mmHg, and in view of the absence of any vascular risk factors, further investigations such as 24-h BP monitoring were not performed.

Figure 1
figure 1

24-2 Humphrey visual field perimetry of the left eye showing global field reduction.

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Figure 2
figure 2

Left AION showing oedematous left optic disc with multiple splinter haemorrhages.

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Figure 3
figure 3

Fundus fluorescein angiography of left eye during acute phase of NAION showing diffuse disc hyperfluorescence.

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Ophthalmic examination 4 months after presentation revealed pallor of the left ONH with persistent global reduction of sensitivity of the left visual field.

Comment

Six of the seven recent reports of sildenafil-associated anterior ischaemic optic neuropathy (AION) have occurred in patients with anatomically vulnerable optic discs with or without vasculopathic risk factors. 1, 2, 3 Our patient had no underlying risk factors for AION, and is the first documented report of such a case associated with the use of tadalafil.

Penile erection during sexual stimulation involves the local release of nitric oxide (NO) in the corpus cavernosum, which stimulates the synthesis of cyclic guanosine monophosphate (cGMP), thus producing relaxation of smooth muscle in the corpus cavernosum and penile arteries, therefore increasing penile blood flow. Tadalafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE 5), which is responsible for the degradation of cGMP in the corpus cavernosum. The subsequent increased levels of cGMP results in enhanced erectile function. Both tadalafil and sildenafil exert their effects by this mechanism; however, the former has a significantly longer duration of action, effective for up to 36 h.4 When compared to sildenafil, tadalafil also exhibits a 70-fold greater selectivity for PDE5 than for PDE6 (responsible for retinal phototransduction), possibly accounting for its documented lower incidence of transient changes in perception of colour.5, 6

NAION is known to occur typically in patients with small vessel occlusive cerebrovascular disease, including hypertension, diabetes mellitus, raised cholesterol or fibrinogen levels, and cigarette usage.7 The mechanism of action is thought to involve the reduced perfusion pressure in the posterior ciliary arteries supplying the optic disc, leading to ischaemia. Local factors such as structural predisposition to ischaemic damage by the presence of an optic disc with a small physiological cup (cup-disc ratio of less than 0.1), the classic ‘disc at risk’ (Burdle8), are thought to play an important role. Systemic circulatory factors are also thought to be involved in the development of critical ischaemia to the ONH. Systemic arterial or nocturnal hypotension may be a possible aetiology, especially in the context of a structurally crowded ONH. As with other PDE5 inhibitors, tadalafil is known to have systemic vasodilatory properties that may result in transient decreases in blood pressure,9 which may be sufficient to serve as a trigger for ischaemia in the anatomically predisposed optic disc. As it is unknown whether the patient developed an erection or went on to participate in sexual activity, a steal phenomenon cannot be postulated as the cause of the hypotensive event to his optic nerve. By way of increasing local levels of NO, a potent vasodilator, disrupted auto regulation of microvasculature may also compromise ONH perfusion. Another potential mechanism is drug-induced potentiation of NO resulting in a toxic optic neuropathy.1

The association of tadalafil and NAION in a patient with no known systemic or local risk factors, combined with the lower dose of the drug, its greater selectivity for PDE5 and longer duration of action, may suggest that it is associated with a higher risk of the development of ONH ischaemia, compared to its predecessor. Although it is not possible to be confident about a causal association between tadalafil and NAION, this case, combined with previous reports of the condition in the context of PDE5 inhibitor usage, is strongly suggestive of one. The development of an animal model for NAION would provide an experimental paradigm in which to test the relationship between this poorly characterised condition and PDE5 inhibitors.