Racecadotril induced bilateral uveal effusion: a case report

Abstract

Background

Uveal effusion is a sight threatening condition, due to possible acute angle-closure glaucoma and maculopathy. We present a case of bilateral uveal effusion after taking racecadotril, an enkephalinase inhibitor used as a medical treatment for diarrhea. Uveal effusion after the use of racecadotril has not been described in literature.

Case presentation

A 76-year-old woman presented with blurred vision in both eyes. Fundoscopy and B-scan ultrasound showed bilateral choroidal effusion. The anterior chamber was narrow, but the intra ocular pressure remained normal. The medication review showed that the only recently added medication was racecadotril. Other potential causes of uveal effusion were excluded. Topical steroids and atropine were started. After cessation of racecadotril, a complete resolution of the uveal effusion was observed.

Conclusions

This case of bilateral uveal effusion was probably caused by racecadotril, since this was the only recently started drug, and we observed a complete resolution of the effusion after cessation of the drug. It is possible that the increase in enkephalins caused by racecadotril intake, leads to changes in the choroid, causing choroidal effusion. It is important to recognize uveal effusion as a rare side effect of racecadotril, because of its possible sight threatening character.

Background

Uveal effusion is a condition that consists of abnormal collection of fluid that expands the suprachoroidal space, leading to choroidal swelling. This results in anterior displacement of the lens–iris diaphragm, which can lead to acute angle-closure glaucoma [1]. The uveal effusion itself can also cause severe visual loss, due to chronic submacular fluid and secondary RPE (retinal pigment epithelium) changes [2].

The causes of uveal effusion are diverse and include hypermetropia/nanophthalmia, trauma, chronic uveitis, and intraocular surgery. It is prevalent after glaucoma surgery but these cases are usually self-limited and localized [3]. It is also known that uveal effusion can be drug-induced. Sulfonamides like topiramate, acetazolamide and hydrochlorothiazide can be the causational drug, but also serotonergic medications like escitalopram can be the culprit [1].

In this article we describe a case of bilateral uveal effusion following the use of racecadotril (Tiorfix^®). Racecadotril is a treatment option for acute diarrhea. As far as we know, uveal effusion after taking this medication has not been described in literature.

Case presentation

A 76-year-old lady presented to the ophthalmology department with blurry vision since five days in both eyes, more pronounced in the left eye. She also described a mild pressure above both the eyes. The only relevant ophthalmological history is cataract surgery on the left eye, more than five years ago. Her general medical history involves achalasia, treated with multiple ablations. She is also known with mild chronic obstructive pulmonary disease (COPD), atrial fibrillation, episodes of autoimmune hemolytic anemia and prurigo nodularis.

The patient was recently hospitalized with a pulmonary infection, treated with amoxicillin and clavulanic acid. The antibiotics were given intravenous for four days and continued orally for three days. She developed acute diarrhea secondary to the antibiotics, which was treated with Tiorfix^® (racecadotril) 100 mg, three times a day. Racecadotril was prescribed for five days, but was continued by the patient because the diarrhea persisted. Eight days after the initiation of this treatment, she started to experience ophthalmological symptoms. She described a blurry vision and mild pressure on the eyes, more pronounced in the left eye.

Her best corrected visual acuity (BCVA) was 20/50 in the right eye and 20/67 in the left eye. Biomicroscopy showed a narrow anterior chamber and conjunctival injection in both eyes. Intraocular pressure (IOP) was 18mmHg on the right eye and 17mmHg on the left eye. There was no anterior chamber inflammation. Fundoscopic examination revealed an extensive bilateral choroidal detachment, most pronounced in the nasal quadrant, not involving the macula (Fig. 1). A B-scan ultrasound was performed in both eyes, showing choroidal detachment, with normal scleral thickness (Fig. 2). In the right eye three quadrants of the retina were involved, in the left eye four quadrants.

Fig. 1.

Fundoscopy at presentation showing bilateral choroidal effusion

Fig. 2.

B-scan ultrasound at presentation, A: Right eye and B: Left eye, showing serous choroidal effusion

Because of the normal scleral thickness and the absence of pain (only discomfort), the clinical picture was not typical for scleritis, and a diagnosis of uveal effusion was proposed. Treatment started with topical steroids drops, dexamethasone 0.1% four times a day. The patient was reviewed three days later, with little to no response to treatment. There was a stable choroidal effusion on fundoscopy and ultrasound. IOP remained normal.

A detailed medication review (Table 1) showed that racecadotril was the only recently added medication. Atropine 1% drops two times daily were added to the treatment scheme. Dexamethasone drops were continued. Instructions were given to the patient to stop Tiorfix^® (racecadotril).

Table 1.

Medication review, generic names

- Amitriptyline - Amoxicillin with clavulanic acid (finished one week before start of ocular symptoms) - Apixaban - Beclometasondipropionaat/formoterolfumaraatdihydraat/glycopyrronium (inhalation) - Bisoprolol - Bumetanide (stopped two weeks before start of ocular symptoms) - Clobetasol-17-propionaat (corticosteroid crème, local application) - Dapagliflozine

- Dixogine - Ipratropiumbromide anhydraat/fenoterolhydrobromide (inhalation, in case of dyspnea) - Lormetazepam - Omeprazole - Paracetamol - Racecadotril (started one week before start of symptoms) - Spironolactone (stopped two weeks before start of symptoms)

Re-evaluation after one week showed marked improvement of the condition. There was a subjective decrease in blurred vision. The BCVA was 20/29 in the right eye and 20/50 in the left eye. IOP stayed normal. The anterior chamber was less narrow and fundoscopy showed a clear decrease in the extent of the choroidal effusion (Fig. 3).

Fig. 3.

Fundoscopy one week after discontinuation of racecadotril, showing a decrease of the bilateral choroidal effusion

The last check-up was done four weeks later. The patient had no complaints anymore. BCVA was 20/33 in the right eye and 20/29 in the left eye. Fundoscopy showed a resolution of the choroidal effusion in both eyes (Fig. 4). In the left eye there were still some pigmentary changes visible at the place of the past choroidal detachment. B-scan ultrasound showed a complete resolution of the choroidal detachment, with normal sclera (Fig. 5). The axial length was measured and was 23.17 mm on the right and 23.05 mm on the left.

Fig. 4.

Fundoscopy at the last visit, showing complete resolution of the choroidal effusion

Fig. 5.

B-scan ultrasound at the last visit, A right eye and B left eye, showing complete resolution of the choroidal effusion

Discussion and conclusions

There are many known causes of uveal effusion. When the etiology of the effusion remains unknown, the term uveal effusion syndrome (UES) is used [2]. This is a diagnosis of exclusion, which means that other causes should be excluded first. UES can be divided into two groups, with or without hypermetropia/nanophthalmia. Our patient had no significant refractive error, and her axial length was normal. If no other cause is found, the diagnosis of an idiopathic UES can be made.

There was no recent intra-ocular surgery, trauma or laser treatment in the history of the patient. Intra-ocular inflammation was absent and there was no significant macular oedema present, so chronic uveitis as a cause did not seem plausible. Moreover, we measured a normal IOP, which excluded hypotony as a cause. Primary angle closure as a cause (in the right eye), was also excluded because of the normal IOP.

Another possible cause of uveal effusion is scleritis. This disease usually presents with unilateral symptoms, such as periocular pain, headache and pain with ocular movements, with a thickened sclera and a T-sign on B-scan ultrasound [4]. Our patient presented with bilateral disease, without the typical pain pattern of scleritis, with normal scleral thickness on ultrasound, so scleritis did not seem plausible in our case.

Drug-induced uveal effusion is another possibility. Several drugs are known to cause a uveal effusion, such as sulfonamides and serotonergic agents [1]. A recent case report described a myopic shift after a single dose of acetazolamide 250 mg and 23 similar cases were found in the literature, half of which showed uveal effusion [5]. Another recent article reported sildenafil-induced bilateral ciliochoroidal effusion for the first time in literature [6]. A very recent case report described bilateral uveal effusion in a ten year old patient taking amoxicillin for pneumonia [7].

The medication review of our patient showed that racecadotril was the only recently added medication that she was still taking at the time of the presentation of the symptoms. She was taking two diuretics (bumetanide and spironolactone), which were both stopped two weeks before her ophthalmological symptoms started. Amitriptyline is a tricyclic antidepressant with anti-cholinergic properties, causing pupil dilation and possible pupillary block, leading to angle closure and acute glaucoma, but amitriptyline is not known to cause uveal effusion. She also received a course of amoxicillin with clavulanic acid, which was finished one week before the development of ophthalmological symptoms. As mentioned above, there is one article reporting uveal effusion in a child taking amoxicillin [7]. Given that our patient finished the course of amoxicillin one week before the onset of the symptoms, it seems unlikely that this was the causative agent, but it is a possibility.

Racecadotril is a weak inhibitor of neutral endopeptidase, also known as enkephalinase. It is used as a medical treatment for acute diarrhea and has similar efficacy but greater tolerability, particularly less constipation and abdominal discomfort, as compared to loperamide [8]. Adverse effects of racecadotril in studies were low and comparable to placebo [8]. Uveal effusion after the use of this medication has not been described in literature.

The mechanism by which racecadotril could cause uveal effusion is not clear. There are multiple factors contributing to the pathogenesis of UES, summarized in the major review of Elagouz et al., including vortex vein compression, reduced scleral protein permeability, reduced scleral hydraulic conductivity and increased choroidal permeability [2].

The antidiarrheal activity of racecadotril derives from the drug’s pure antisecretory action, without influencing the transit time [9]. After taking racecadotril, secretion of fluids into the intestines is decreased, resulting in a higher retention of fluids in the blood stream causing a decrease in serum protein concentration, such as albumin. This would lead to a high albumin concentration in the suprachoroidal space. The process of transscleral macromolecular diffusion contributes to the transport of protein across the sclera, but if transscleral macromolecular diffusion were reduced, then this would tend to retain protein, and thus fluid, in the suprachoroidal space [2]. A cause of a reduction in transscleral protein diffusion could be a swollen sclera. Our patient did not show a thickened sclera on B-scan ultrasound, so this hypothesis is not completely suitable.

Racecadotril is an enkephalinase inhibitor, so it inhibits the breakdown of enkephalins, which are endogenous opioids. There is data available showing the presence of functional opioid receptors in vascular smooth muscle and this implicates a direct impact of opioids on vascular contractile tone [10]. It is not clear if this plays a role in the vessels of the choroidea.

Opioid peptides and their receptors are expressed in the mammalian retina and research suggests that endogenous opioid signaling in the retina contributes to the regulation of the pupillary light reflex [11]. However, in the choroid, neither endogenous opioids nor their receptors have been reported [12].

Endogenous opioids, such as enkephalin and endorphin, are released in response to stress, and they help coping with a stressor by inhibiting the over-activation of HPA axis [13]. Psychological stress may also play an important role in the etiopathogenesis of the pachychoroid-related changes leading to central serous chorioretinopathy (CSCR) [14]. Taking this information into account, it is possible there is a common pathway whereby stress or medications, such as racecadotril, increase endogenous opioids, leading to changes in the choroid which cause pathology such as CSCR and choroidal effusion.

Applying the Naranjo criteria, this case scored a six out of fourteen on the Adverse Drug Reaction Probability Scale [15]. We scored two point because the adverse reaction appeared after the drug was administered, one point because adverse event improved when the drug was discontinued, two points because alternative causes were excluded, and one point because the adverse event was confirmed by objective evidence. This means that it is probable that racecadotril was the cause of bilateral choroidal effusion.

In summary, we presented a case of bilateral uveal effusion which was probably drug-induced. Symptoms started eight days after starting treatment with racecadotril and the choroidal effusion decreased rapidly after cessation. Uveal effusion after taking racecadotril has not been described in literature before. It is possible that the increase in enkephalins caused by racecadotril intake, leads to changes in the choroid, causing choroidal effusion. It is important to recognize uveal effusion as a rare side effect of racecadotril, because of its possible sight threatening character.

Abbreviations

ANA

Antinuclear antibodies

BCVA

Best corrected visual acuity

COPD

Chronic obstructive pulmonary disease

CSCR

Central serous chorioretinopathy

HPA

Hypothalamic-pituitary-adrenal

IOP

Intraocular pressure

RPE

Retinal pigment epithelium

UES

Uveal effusion syndrome

Author contributions

JC did a literature review and wrote a draft of the manuscript. PS gave insights into the possible mechanisms of the uveal effusion. PS and JVC helped with revising and writing the manuscript. JVC supervised writing the manuscript. All authors read and approved of the final manuscript.

Funding

None.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

Ethics approval and patient consent were obtained. The ethics committee that gave approval was the ‘EC Onderzoek UZ/KU Leuven’.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report.

Competing interests

The authors declare no competing interests.