Occlusion of the central retinal artery after the iatrogenic migration of filler materials is typically associated with a poor outcome for the vision system because of the anastomotic nature of the facial and ophthalmic vasculatures and the end artery of the retinal circulation.1,2 Multiple branches of the ophthalmic artery that project outside the ocular area and onto the nose and forehead are prone to exposure to retinal damage because of central retinal artery occlusion and optic nerve infarction caused by compromised retrograde collateral circulation of the ophthalmic artery.3,4
There is no proven effective treatment for blindness following cosmetic filler injection, but hyaluronidases have the potential to reverse hyaluronic acid filler–associated occlusion of the ophthalmic system.5 A major factor in filler-associated blindness is the retinal ischemic tolerance time, which is estimated to be 90 minutes or shorter.6,7 A proposed practical route for time-sensitive administration is the percutaneous injection of high-dose hyaluronidase directly into the orbit (retrobulbar space) to recover the blood flow within the retinal vascular system. However, this procedure requires caution because of the potential risks of ophthalmic artery perforation, vitreous loss, or optic nerve injury.8 The present study aimed to provide a rationale to facilitate the technique of administering hyaluronidase retrobulbarly to salvage central retinal artery occlusion, based on the detailed anatomy of the central retinal artery related to the optic nerve.
MATERIALS AND METHODS
This study conformed to the World Medical Association Declaration of Helsinki (June of 1964) and subsequent amendments. Sixty-six orbits of 41 formalin-embalmed cadavers were investigated. The donors had a mean age ± SD of 74.0 ± 11.9 years (range, 47 to 95 years) at death, and they had signed documents agreeing to their participation in the body donation program of the medical school and the use of their body for clinical studies. The orbital contents were extracted from the bony structures and dissected meticulously in consecutive order to preserve all branches of the ophthalmic artery. The accompanying veins and fascia of the optic nerve composed of loose connective tissues were removed. After identifying the central retinal artery ramification from the ophthalmic artery, the distance from the posterior margin of the eyeball and entry point of the central retinal artery into the dural sheath of the optic nerve was measured (Fig. 1). Specimens without intact vascular structures of the orbits because of previous surgery were excluded.
To define the three-dimensional structure of the central retinal artery inside the optic nerve, 11 optic nerves were immersed in 4% phosphate-buffered formalin (pH 7.4), and processed using routine histologic methods. Ten-micron-thick sections cut transversely and serially at 100-μm intervals underwent Masson trichrome and hematoxylin and eosin staining. All of the stained sections were photographed using a digital charge-coupled device camera (2048 × 1536 pixels) (DP70; Olympus, Tokyo, Japan). All vessels, stroma of the optic nerve, and dural sheaths of the optic nerve were reconstructed for each specimen (Fig. 2), and Reconstruct software (http://synapseweb.clm.utexas.edu/software-0) was used to produce three-dimensional images.
The ophthalmic artery is the first intracranial branch of the internal carotid artery, entering the optic canal with the optic nerve and then crossing under the optic nerve. The central retinal artery supplying the retina originates from the ophthalmic artery before it courses in a superior and diagonal direction with extensive arborization. This topography means that there is less vascularization in the inferolateral (inferotemporal) quadrant of the orbit than in the other quadrants (Fig. 1, above). In this part, the optic nerve is surrounded by the meningeal sheath, which consists of the dura mater, arachnoid mater and pia mater, and cerebrospinal fluid in the subarachnoid space.9 The dural sheath of the optic nerve—composed of thick, dense connective tissue—keeps the optic nerve separate from the environment of the orbital structures (Fig. 1, below).
The central retinal artery in periorbital tissues pierces the optic nerve sheath and travels within the subarachnoid space between the optic nerve sheath and optic nerve, and then penetrates again the stroma of the optic nerve in a vertical direction to reach the retina (Fig. 2). The distance from the posterior margin of the eyeball to the point where the central retinal artery enters the optic nerve sheath was 8.7 ± 1.7 mm (Table 1), with no sex- or side-related difference.
Table 1. -
Distance from the Posterior Margin of the Eyeball and Entry Point of the Central Retinal Artery into the Optic Nerve Sheath
|Mean distance ± SD, mm
||8.7 ± 1.7
||8.8 ± 2.0
||8.5 ± 1.8
||8.8 ± 1.8
||8.6 ± 2.0
Vision loss caused by central retinal artery occlusion is a rare but devastating complication of filler injection that can occur even in the hands of experienced operators.10 The presumed mechanism of embolization and vision compromise is vascular anastomoses between the external carotid–derived facial arteries and the internal carotid–derived ophthalmic artery systems.11,12 The signature features of periocular embolism are instant-onset and simultaneous blindness and ocular pain, which contrasts with nonocular ischemia of the facial skin that manifests as blanching followed by delayed pain.10,13–15 The need for an immediate ophthalmologic intervention and comprehensive therapy has been argued, because every passing minute increases the possibility of irreversible retinal damage.6 Physicians might encounter this situation whenever they are injecting filler materials for augmentation of the glabella, nose, nasolabial folds, and marionette lines, which is where the course of the facial artery is shared with the collateral circulation of the ophthalmic artery.
The crucial factor in a time-sensitive management strategy for retinal ischemia is a thorough understanding of the orbital anatomy. There are no proven effective therapeutic interventions for central retinal artery occlusion following filler injection, but the treatment mainstay for hyaluronic acid–based filler complications is hyaluronidase, an enzyme that degrades hyaluronic acid.16–23 Although it remains uncertain whether the blindness can be treated, the immediate injection of hyaluronidase seems to be the most promising step in managing this devastating complication.1 In case of a vascular accident, urgent and repeated flushing of the ischemic area with high doses of hyaluronidase is required because hyaluronic acid can cross the obstructed arterial walls, disperse through the tissue, and degrade the hyaluronic acid gel filler.16,19 If the filler has traveled to a location distant from the original injection site, hyaluronidase must be injected as close to the embolism as possible.15 The direct intraarterial injection of hyaluronidase into the ischemic area might be ideal, but this is challenging and probably unrealistic in most cases.8
Another delivery technique is retrobulbar hyaluronidase injection, which is strongly advocated in the literature.1–3 The developmental process of eye formation accompanies protrusion of the brain tissue. Inevitably, the optic nerve is surrounded by dural sheets composed of two layers of tough connective tissue latticed obliquely, consisting of clusters of fibroblasts.9,24,25 In cases of central retinal artery occlusion, a region remote from where the arteries are occluded might be an inappropriate target because of the countercurrent against ophthalmic artery pulsation, and the thick dural sheath surrounding the optic nerve disturbs the permeation of hyaluronidase into the bloodstream supplying the retina. Anatomical studies show that the central retinal artery lumen is the narrowest where it pierces the dural sheath of the optic nerve.26 Therefore, this study suggested that the entry point of the central retinal artery into the optic nerve could be an appropriate target for hyaluronidase administrations not hampered by dense fibrous intersections of extracellular matrix produced by dural fibroblasts.25
The dissections of the eyeball performed in the present study revealed that the mean distance between the posterior margin of the eyeball and the dural entry point of the central retinal artery to the optic nerve was 8.7 mm. This value is within the range found in previous studies (7.5 to 12.5 mm),27–30 but is expected to be more accurate because the present specimens extracted from the orbit were dissected directly. Considering that the mean diameter of the eyeball is 25 mm31 and the eyeball protrudes 1.7 mm from the inferior orbital margin,32 the ideal depth to reach the central retinal artery in the retrobulbar space for flushing by hyaluronidase is speculated to be 3.0 to 3.5 cm, which is not interfered with by the optic nerve sheath composed of tough connective tissues (Fig. 3, left). Practically, inserting a 5-cm-long cannula approximately 3 cm along the inferior orbital margin will ensure that its tip is appropriately located at the entering point of the central retinal artery. During procedures of confirming a depth of the cannula insertion by remaining length, gentle movement of the cannula could prevent the eyeball or optic nerve from involvement (Fig. 3, right). The exact location of the disposition relative to the eyeball could differ somewhat according to the degree of eyeball protrusion, such as because of the orbit being deeper in Caucasians than in Asians and shallower in female subjects than in male subjects.2 The present study provides a rationale for treatment flushing of the ischemic area in the presence of remote vascular occlusion of the central retinal artery aiming at the inferotemporal quadrant of the orbit.
The different commercial hyaluronic acid fillers have various molecular weights, cross-linking properties, and particle sizes ranging from 20 to 1000 μm, which also influence their longevity in the bloodstream.12,13,33 The retrograde arterial displacement of hyaluronic acid materials when injecting them with a force greater than the systolic arterial pressure will ensure that they are carried distally in the normal direction of blood flow,34 and progressively into smaller vessels until the hyaluronic acid materials can no longer pass any further distally, resulting in complete obstruction.19 The complicated anatomy of the central retinal artery penetrating the dural sheath of the optic nerve with a zigzag appearance predisposes the retina to inadvertent occlusion by large hyaluronic acid particles whose diameters are similar to that of the artery (Fig. 4). The awareness of iatrogenic central retinal artery occlusion and the need for immediate treatment needs to be popularized among injectors to prevent complications.35 Further investigations are needed to determine the optimal dosage of hyaluronidase for effective reperfusion, because different brands of hyaluronic acid fillers have different sensitivities to degradation by different members of the hyaluronidase family.13,36,37 Future studies are needed to improve retrobulbar procedures for recovering ophthalmic complications during facial interventions involving the injection of hyaluronic acid fillers.
The central retinal artery in periorbital tissues entered the optic nerve at a mean distance of 8.7 mm from the posterior margin of the eyeball. The reliable access route of hyaluronidases by a retrobulbar approach for central retinal artery reperfusion is suggested to be at a depth of 3.0 to 3.5 cm from the border of the inferolateral orbital rim, based on consideration of the orbital anatomy.
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