Retained, Non-Dissolving, Tubular Foreign Bodies in the Vitreous Cavity after Intravitreal Dexamethasone (Ozurdex) Implantation

Abstract

Purpose:

To describe the retention of large, tubular, non-dissolving foreign bodies as a complication of the intravitreal dexamethasone implant (Ozurdex).

Methods:

This is a single center, retrospective chart review of patients who were found to have retained, non-dissolvable tubular foreign bodies in the vitreous cavity greater than 6 months (the expected dissolution time of the implants) after Ozurdex injections. Ocular symptomatology and multimodal imaging were reviewed.

Results:

Five patients had retained, non-dissolvable tubular foreign bodies in the vitreous that persisted for months (mean 28.2 months, range 9–67 months) after intravitreal injection of Ozurdex. Two patients were symptomatic due to the foreign bodies and chose alternate local therapy, but none of the patients opted for surgical explantation.

Conclusion:

Persistent, non-dissolving, tubular foreign bodies can be seen in the vitreous cavity for years after injection of the Ozurdex implant. Clinicians should be aware of this complication, which has the potential to cause visual symptoms and ocular morbidity.

Brief Summary Statement:

Intravitreal dexamethasone implant (Ozurdex) is in everyday use for the treatment of diabetic macular edema, cystoid macular edema with retinal vein occlusion, and non-infectious posterior uveitis. Here we describe the ocular findings of five patients who had retained, non-dissolving, tubular intravitreal foreign bodies after injection of Ozurdex.

The dexamethasone intravitreal implant (Ozurdex®; Allergan Inc., Irvine, CA) is a sustained-release injectable implant effective in the treatment of diabetic macular edema, retinal vein occlusion with macular edema, and noninfectious uveitis affecting the posterior segment.^1–3 In October 2018, the manufacturer recalled 22 lots of Ozurdex manufactured from 2016–18 due to retained particulate matter.² These particles were described as round and small (300 micron diameter) and confirmed to originate from the silicone sleeve lining the pre-packaged injection needle. However, the intravitreal delivery of a tubular, non-dissolving foreign body after Ozurdex has not been described. Here, we report five patients who have persistent, tubular foreign bodies in the vitreous cavity up to five years following their last Ozurdex injection. These foreign bodies are much larger than the particulate silicone debris described in the recall and thought to result from intravitreal injection of a silicone sleeve lining the injection needle.

Methods

This is a single center, retrospective case series of patients with retained foreign bodies after Ozurdex implantation seen from October 18, 2018 (the date of the manufacturer’s recall) to August 19, 2019. The research adhered to the tenets of the Declaration of Helsinki and was conducted in accord with regulations set forth by the Health Insurance Portability and Accountability Act. Patients with retained, tubular intravitreal foreign bodies were identified and examined by fellowship-trained retina specialists (JCF, ICH). Clinical data including demographic information, examination findings, and results of multimodal imaging were reviewed.

Results

Five patients were found to have retained, non-dissolving tubular foreign bodies in the vitreous that persisted for months (mean 28.2 months, range 9–67 months) after intravitreal injection of Ozurdex. Two patients were symptomatic due to the foreign bodies. A summary of the patients is included in Table 1, and case details with representative images from each patient are presented below.

Table 1. Summary of patients with retained, non-dissolving intravitreal foreign bodies after Ozurdex injection.

Visual acuity and intraocular pressure (IOP) are from the most recent follow up visit. CME = cystoid macular edema. Symptoms of floater refers to whether the patient was bothered by the Ozurdex-related intravitreal foreign body.

	Age	Gender	Diagnosis	Systemic Immunosuppression	Active Uveitis	Visual Acuity	IOP	Lens Status	Indication for Ozurdex	Symptoms of Floater
Case 1	61	F	Multifocal choroiditis	Mycophenolate mofetil	No	20/30	17	Phakic	CME	Yes
Case 2	45	F	Multifocal choroiditis	Tacrolimus	No	20/25	15	Pseudophakic	CME	No
Case 3	60	F	Idiopathic panuveitis	None	No	20/40	17	Pseudophakic	CME	No
Case 4	32	F	Multifocal choroiditis	None	Yes	20/20	23	Pseudophakic	CME	No
Case 5	80	F	Idiopathic panuveitis, rheumatoid arthritis	Methotrexate, Infliximab	No	20/40	10	Pseudophakic	CME	Yes

Case 1:

A 61-year-old phakic woman with multifocal choroiditis received a single Ozurdex injection in the right eye at an outside institution in November 2015. Since then, she has been bothered by a large floater, most noticeable on down gaze and interfering with reading. Fundus examination revealed a prominent tubular structure in the anterior vitreous (Figure 1). Despite persistent visual symptoms on most recent follow up in August 2019 (45 months after her last injection), the patient opted to observe the foreign body without intervention.

Figure 1: Detailed image of a tubular foreign body in the anterior vitreous (Patient 1).

Red reflex slit lamp photograph of the right eye demonstrates a translucent, tubular foreign body with adjacent particulate material in the anterior vitreous of Patient 1. The photograph was taken over 3 years since her last Ozurdex injection.

Case 2:

A 45-year-old pseudophakic woman with multifocal choroiditis and panuveitis was initially seen at our clinic in March 2017. She had received two previous Ozurdex implants in the right eye at an outside institution, most recently in December 2013. Fundus examination revealed a tubular foreign body bent at a ninety-degree angle in the inferior vitreous, with multiple adjacent smaller fragments. These foreign bodies persisted with the same appearance and location, including at her most recent visit in July 2019 (67 months after her last injection) (Figure 2A). She had no related visual symptoms, and the fragments were observed.

Figure 2: Ultra-widefield pseudocolor photographs of persistent tubular, intravitreal foreign bodies (Patients 2–4).

(A, with inset) Image of the right eye of Patient 2, taken 5 years since her last Ozurdex injection, demonstrates a long tubular foreign body with multiple, adjacent smaller fragments. (B, with inset) Image of the right eye of Patient 3, taken 9 months after last Ozurdex injection, demonstrating a tubular foreign body in the inferior vitreous. (C, with inset) Image of the right eye of Patient 4, taken 9 months after her last Ozurdex injection, showing a segmented, hollow, tubular foreign body in the vitreous.

Case 3:

A 60-year-old pseudophakic woman with idiopathic, non-infectious panuveitis and recurrent cystoid macular edema received four intravitreal Ozurdex injections in the right eye from 2011 to 2018, with last injection in December 2018. Since then, she has had two tubular foreign bodies in the inferior vitreous (Figure 2B), including at her most recent visit in August 2019 (9 months after her last injection). She had no visual symptoms secondary to the retained foreign bodies.

Case 4:

A 32-year-old pseudophakic woman with multifocal choroiditis and panuveitis received ten Ozurdex implants in the right eye from July 2015 to November 2018. At her most recent visit in July 2019 (9 months after her last injection), two translucent tubes were seen in the inferior vitreous (Figure 2C). She was not visually symptomatic from the tubes but chose alternate local therapy with the fluocinolone acetonide 0.18 mg intravitreal implant for her active uveitis.

Case 5:

An 80-year-old pseudophakic woman with chronic idiopathic panuveitis in the setting of rheumatoid arthritis received seven intravitreal Ozurdex implants in the left eye from September 2016 to September 2018. She had a prior pars plana vitrectomy in 2016 for repair of a macula-involving retinal detachment in the same eye. She was bothered by a large vitreous floater in her left eye after her last Ozurdex injection. Examination revealed a translucent, hollow, freely-mobile tube in the vitreous cavity that was visible on the macula with the patient supine (Figure 3). The tubular structure ultimately settled in the inferior vitreous base (i.e., out of her visual axis) on most recent follow up in August 2019 (11 months after her last injection). However, she has since chosen alternate local therapy with topical difluprednate 0.05% drops for her active uveitis due to the prior bothersome floater.

Figure 3: En face near-infrared reflectance and cross-sectional optical coherence tomography images of tubular foreign body lying on the macula (Patient 5).

En face near-infrared reflectance images (A, with inset) showing a hollow (i.e., no remnant dexamethasone drug) tubular structure lying on the macula in the left eye of Patient 5. OCT of axial (B) and cross-sectional (C) line scans through the silicone sleeve. These images were taken 6 months after her last intravitreal Ozurdex injection with the patient supine using a custom built armature to invert and suspend the OCT camera head over the patient.

Discussion

The Ozurdex is an injectable, sustained-release, rod-shaped implant comprised of a biodegradable co-polymer and micronized dexamethasone pre-packaged with a disposable applicator and spring-loaded plunger. The implant is 6-mm in length and delivered using a thin-walled, 22-gauge hyperdermic needle that includes a colored, siliconized rubber sleeve that is fit around the outside of the needle and secured by an O-ring to the needle hub (Supplemental Digital Content 1).^5,6 The needle is then externally lubricated with silicone oil. The dexamethasone implant itself is water-soluble, and once in the eye, the polymer components degrade by backbone hydrolysis into lactic and glycolic acid, which are metabolized into carbon dioxide and water.

The pharmacokinetics of Ozurdex, including the degradation rate of the implant, has been relatively well-described through animal models and in human clinical trials. The implant lasts up to 4 months in rabbits and 6 months in monkeys.^7,8 Concentrations of dexamethasone peak by 2 months, and >90% of the implant is dissolved by 3 months.⁵ In human patients, the duration of effect is up to 6 months^1–3 and has been shown to be similar in vitrectomized and non-vitrectomized eyes.⁹ When used to treat uveitis macular edema, the efficacy of Ozurdex varies widely but is typically less than 3 months.^10–16 The implant is typically mobile within the vitreous cavity, but few reports have demonstrated its appearance when trapped or attached to the macula.^17–19 In one such case, Kim and colleagues used longitudinal optical coherence tomography to beautifully demonstrate the dissolution of an Ozurdex implant attached to the macula over 6 months.¹⁹ The absorption of the implant is expontential, and in their case, the length of the remaining implant was less than 2 millimeters by 3 months and less than 1 millimeter by 6 months.

Each patient in this report was noted to have hollow, non-dissolving tubular structures in the vitreous cavity for longer than the typical duration of the implant, including up to 67 months since the last injection. The appearance of these foreign bodies has not changed on follow-up examination for any of the reported patients. These foreign bodies are distinct from the white particles typically seen with dissolution of the drug itself, and their persistence for months after implantation is inconsistent with PLGA polymer material, which is known dissolve within 6 months by backbone hydrolysis on contact with water, as described above. Two of the five patients had floaters from the intravitreal foreign bodies that interfered with daily activities. Although neither patient opted for surgical explantation with pars plana vitrectomy, two patients opted for alternate therapy other than Ozurdex for treatment of macular edema. In no case did the tubes appear to contribute to ocular inflammation or cause visible retinal damage. All patients were either phakic or pseudophakic with intact posterior capsules, and none of the tubes migrated to the anterior chamber.

The exact composition of these tubular foreign bodies is unclear, but we suspect that they are comprised of silicone based on their translucent appearance and their non-dissolvable nature. Numerous prior reports have described silicone oil droplets in the vitreous cavity after intravitreal injection of pegaptanib sodium, ranibizumab, triamcinolone acetonide, or bevacizumab.^20–24 These silicone oil droplets have been shown to originate from the siliconized syringe barrel, lubricated needle, or plunger tip.^25–27 Recently, the drug manufacturer of Ozurdex recalled multiple lots due to retained intravitreal silicone particles confirmed to originate from the outer sleeve of the needle. In contrast to the particles described in the recall, however, which were small (less than 300 microns) and round, the foreign bodies observed in these patients were long and tubular.⁴ The Ozurdex implants in Patients 1 and 2 were not on the recall list as they pre-dated the manufactured dates of the recalled lots. However, all four of the Ozurdex implants injected in Patient 3 [lots E79366 (2 implants), E82847 (2 implants)], five of the ten implants in Patient 4 (lots E78729, E79233, E80122, E81273, E82852), and four of the seven in Patient 5 [lots E79233 (2 implants), E81273, E82741] were from lots that were eventually recalled.⁴

We suspect that these retained tubular foreign bodies may be related to the same manufacturing defects that prompted the recall. Based on their estimated length and diameter, we surmise that the foreign bodies may originate from the exposed portion of the injection needle (see Supplemental Figure 1), which enters the eye during the injection procedure. This portion is coated with silicone for lubrication, and defects in manufacturing may have resulted in an abnormally thick “false sleeve” of silicone over the needle. As part of standard injection techniques, most clinicians will depress over the injection site (e.g., with a cotton-tipped applicator) to help seal the wound and prevent vitreous prolapse, and we postulate that firm depression may unsheathe the false silicone sleeve into the eye.

To the best of our knowledge, this is the first report of retained, tubular, non-dissolving foreign bodies with Ozurdex injections. These tubes are large enough to cause visual symptoms, but overall there appears to be a low risk of vision loss. While the foreign bodies may be safely observed in the vitreous cavity, as with the Ozurdex implant itself, they have the theoretical potential to migrate into the anterior chamber, particularly in cases where the posterior capsule may not be intact. As in our cases, the visual symptoms of a persistent floater may alter management decisions in treatment of ongoing disease. Clinicians should be aware of this potential complication with Ozurdex injections and consider including it in discussion of the potential risks when consenting patients for Ozurdex treatment.