Intraoperative Floppy Iris Syndrome and Management of Small Pupils
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Introduction and disease entity
Intraoperative floppy iris syndrome (IFIS) is a clinical entity originally described by Chang and Campbell in 2005. This syndrome is known to cause a poor pupillary dilation, intraoperative complications during cataract surgery and is characterized by the following triad of intraoperative signs:
- Billowing of a flaccid iris stroma in response to ordinary intraocular fluid currents;
- Propensity for iris prolapse toward the phaco and/or the side-port incisions;
- Progressive pupil constriction.
A grading system for IFIS was suggested based on the presence of the previously described intraoperative signs as follows: no IFIS (stable iris without significant miosis), mild IFIS (noticeable floppy iris only), moderate IFIS (floppy iris and miosis) and severe IFIS (floppy iris, significant miosis and strong tendency to iris prolapse). Two additional pupil features may be present in IFIS:
- Poor preoperative pupil dilation;
- Elasticity of pupil margin.
In contrast to other causes of small dilated pupil and progressive intraoperative miosis (e.g. diabetes), IFIS is characterized by an elastic iris which does not dilate with mechanical stretching. Therefore, it is important to anticipate IFIS and use pupil expansion devices as a preventive measure in the beginning of surgery rather than after IFIS has developed and the capsulorrhexis is already completed (which might compromise its integrity).
The reported overall prevalence of IFIS in patients undergoing phacoemulsification is variable, ranging from 2% in the Chang and Campbell report in 2005, up to 12.6% in later studies. This wide range of prevalence might be due to the subjective clinical definition of this syndrome and its manifestations being a continuum of severity with variability between patients and between eyes of the same patient. The prevalence also varies among countries and is significantly increased in groups of patients with clinical factors positively correlated with IFIS.
Currently in more recent studies, there is a tendency for higher rates of IFIS, perhaps due to the increasingly high prescription rate of medications associated with IFIS and also because of higher awareness and recognition of milder IFIS signs by surgeons.
The most likely pathogenic mechanism for IFIS is the antagonism of α1-adrenergic receptors within the dilator muscle of the iris, which prevent the iris from dilation during surgery. This inhibition can happen with the use of some types of medications, such as the most commonly prescribed α1-adrenegic receptor antagonist (α1-ARA) tamsulosin used for the management of benign prostatic hyperplasia (BPH).
There are 3 subtypes of α1-adrenergic receptors: α1-A, α1-B and α1-D. The subtype α1-A is the main regulator of smooth muscle tone of the urinary system and of iris dilator muscle. α1-B controls blood pressure through arterial smooth muscle relaxation and is highly present in the choroid (a highly vascularized tissue). α1-D contributes for spinal cord innervation and bladder muscle contraction.
There is evidence that blocking α1 adrenergic receptors results in relaxation of the iris dilator muscle, with poor pupillary tone. Furthermore, it was proposed that the long-term intake of α1-ARA may cause anatomical variations that are permanent and cannot be completely reversed with interruption of medication and is maintained despite the use of preoperative pharmacological dilation with topical cyclopentolate, phenylephrine and ketorolac. A study also reported drug-melanin interaction, which causes iris dilator muscle atrophy and therefore to IFIS.
Pharmacological inhibition of α1-ARA reduces the muscular tone and thus the pressure within prostatic urethra, and it is nowadays the first line medical approach to BPH. With the continuing longer life expectancy, along with the increased diagnosis of BPH in older men, it is expected that patients on α1-ARA treatment requiring cataract surgery will continue to rise. 
- Tamsulosin – is the most commonly prescribed medication for BPH and it is an α1-A subtype selective blocker. In addition to its effects in the prostate, tamsulosin selectively blocks the iris dilator muscle, in which the α1-A receptor subtype predominates. This drug has a half-life of 48-72h, and it has been proposed that its constant blockade effect can result in disuse atrophy of the iris dilator muscle and loss of normal smooth muscle tone, explaining why IFIS manifestations may occur even after its discontinuation. Furthermore, smooth muscle tone in iris dilator muscle may be necessary for the overall iris rigidity observed during surgery, suggesting that iris billowing and prolapse in IFIS may be due to loss of the dilator muscle tone. A 2010 study of iris tissue found α1-A receptors in iris arteriolar muscularis, and suggested that tamsulosin-induced dysfunction may include vascular dysfunction of iris vessels. This can lead to loss of vessels' ability to coil, resulting in iris flaccidity and inability to reach normal pupil dilatation. Incidence of IFIS among tamsulosin users was reported to be 37.9-90.0%, with high odds and relative risk ratios, showing strong positive correlations between tamsulosin use and IFIS (OR 206.5; RR 99.3). Additionally, tamsulosin blocks α1-A receptors with the highest affinity, compared to the other α1-ARAs.
- Alfuzosin, doxazosin, prazosin and terazosin – these are non-selective α1-ARAs. They have lower affinity for α1-A and are less associated with IFIS compared to tamsulosin, and therefore are considered a safer choice in cases of expected IFIS undergoing cataract surgery. However, being non-selective blockers, these drugs may have other potential side effects such as postural hypotension. Alfuzosin is considered an alternative to tamsulosin when considering men with BPH requiring cataract surgery, with a 30 times less probable development of IFIS than with tamsulosin.
- Silodosin and naftopidil are new selective α1-ARAs with a similar pharmacological profile to tamsulosin. Further studies are needed to characterise the risk of IFIS with the intake of these new uroselective drugs. Some reports state the possible causative role of silodosin in some patients with IFIS.
Some drugs may have a similar effect on the iris and cause some IFIS manifestations, nevertheless its mechanism is not yet fully explained. The incidence and association with IFIS are not as strong as with tamsulosin.  These include: Finasteride, Saw palmetto (Serenoa repens) as a herbal BPH remedy, Angiotensin II receptor inhibitors (e.g. losartan), Benzodiazepines, Donepezil, Duloxetine, Naftopidil and antipsychotics (quetiapine, chlorpromazine, zuclopenthixol, aripiprazole and risperidone).
It is not yet clear whether gender is a risk factor for IFIS. Most studies report higher frequency and correlation between IFIS and male gender, which may be attributed to the treatment of BPH with α1-ARA. However, α1-ARA are also prescribed in women for urinary retention and hypertension. In addition, female gender has been associated with increased intraoperative complications when compared to male gender, such as posterior capsular rupture, nucleus dropping and vitreous loss. 
The risk for IFIS may increase with aging due to iris vasculature dysfunction and altered potency of norepinephrine in iris dilator muscles (which is proportional to receptor reserve).
High blood pressure
It remains controversial whether the increased incidence of high blood pressure in IFIS patients is due an independent risk factor (blood pressure) or due to an association with antihypertensive drugs.
The cause is an autonomic neuropathy partially denervating both the sphincter and the dilator muscles.
Surgery (phacoemulsification) duration
Higher mean duration of surgery was found to be associated with IFIS, which might reflect a more difficult procedure in these patients, not necessarily being a risk factor for IFIS.
Diameter of dilated pupil
Regardless of α1-ARA intake, decreased preoperative dilated pupil diameter has been associated with increased risk of IFIS. A dilated pupil with 6.5 mm or smaller is predictive of IFIS in cases of tamsulosin intake.
Several reports found no correlation between the risk of developing IFIS and diabetes mellitus, pseudoexfoliation syndrome, glaucoma, eye colour, coronary heart disease or cerebrovascular disease. 
Preoperative evaluation and preventive measures
Concerning the clinical features of IFIS, as well as other causes for small pupils, there are several problems during surgery with poor pupil dilation:
- Restriction of the diameter of capsulorrhexis, which increases the risk of pupillary border and capsular edge trauma with the phaco tip.
- Impaired visualization of the lens and of the capsular bag, as it reduces the intensity of the red reflex.
- Difficult hydrodissection due to peripheral lens and capsular hiding by the iris and difficult removal of subincisional cortex.
Risk assessment and classification systems remain unavailable for IFIS; therefore, it is important to evaluate the patients’ preoperative medication history, among with the other possible risk factors (particularly advanced age and small dilated pupil).
Preoperative measures to prevent IFIS include:
- Discontinuation of medication: no clear evidence demonstrates that discontinuation of drugs associated with IFIS prior to surgery fully eliminates the risk of intraoperative events nor the severity of IFIS. Tamsulosin has a long half-life and may cause irreversible iris atrophy, hence there is not an apparent benefit in its withdrawal. Chang and Campbell suggested discontinuation of tamsulosin 4-7 days before the surgery, although they stated it does not prevent IFIS completely. Other authors recommend switching to other α1-ARA like alfuzosin which seems to have a better profile regarding the risk of developing IFIS.
- Pupillary dilation: instillation of 1% atropine drops qid for 1 week preoperatively is useful in patients taking tamsulosin. Standard measures for preoperative dilation are recommended, which include the application of topical mydriatics (such as high concentration cyclopentolate 2% and phenylephrine 10%). Some studies favour the addition of preoperative epinephrine and topical nonsteroidal anti–inflammatory drugs (e.g. flurbiprofen, ketorolac), due to its advantage in the blockage of prostaglandins which cause miosis during surgery.
Intraoperative preventive measures
Strategies for managing progressive miosis and iris stroma billowing during surgery in IFIS patients include:
- Irrigation of epinephrine: preservative-free solution of epinephrine 1:10.000 may increase pupil diameter when injected the anterior chamber at the start of surgery.
- Intracameral injection of epinephrine and phenylephrine: promote maximal dilation, augment iris muscular tone and therefore reduce the propensity for billowing and subsequent prolapse in cases of IFIS. They may be used in the beginning or during the surgery, depending on pupil behaviour. Despite few reports of adverse reactions, attention is advised to potential toxicities: local toxicity to endothelium, systemic side effects such as spikes in blood pressure, cystoid macular oedema and toxic anterior segment syndrome.
- Intracameral epinephrine: avoid reserved solutions and use a diluted mixture to avoid corneal endothelial damage [e.g. dilution 1:3 with balanced salt solution (BSS), resulting in a 1:4.000 epinephrine solution].
- Intracameral phenylephrine: protocols for accurate preparation and dosing are inconsistent, so clinical use may be variable. Solutions should be preservative and bisulfite free. It has been proposed that 0.25 mL of phenylephrine 2.5% (Minims) should be increased to 2.0 mL using BSS prior to use; they also recommend that at least 30 seconds be allowed for maximal effect.
- Sub-Tenon injection of 2.5 ml of 2% lidocaine was found to decrease the incidence of IFIS features in patients taking oral α-adrenergic inhibitors when compared to intracameral lidocaine.
Surgical technique modifications
Multiple technique modifications may be employed during cataract surgery in IFIS and small pupil cases, which have been proposed to reduce overall complication rates:
- Creation of appropriately sized tunnels and entry anterior to the iris root, reducing wound leak.
- Use of ophthalmic viscosurgical devices (OVDs): viscomydriasis using high concentration sodium hyaluronate (such as Healon5®) has been used in IFIS with high success. This cohesive OVR has the ability to dilate the small pupil effectively and also to create a physical barrier to decrease iris billowing and prolapse through the incisions. However, the latter effect depends on Healon5 to remain in the anterior chamber throughout the procedure, which requires measures like the use of low aspiration flow and vacuum settings. If high vacuum settings are needed (e.g. dense nucleus), a dispersive OVR may be injected peripherally, followed by central injection of Healon5, so the former remains in the anterior chamber closer to the cornea and provides stability of intraoperative mydriasis – this technique is known as modified soft-shell technique.
- Careful hydrodissection: it is important to ensure that the anterior chamber is not overfilled with OVDs in order to prevent iris prolapse during hydrodissection. In IFIS, hydrodissection and hydrodelineation are two of the surgical maneuvers which represent more risk of iris prolapse. Attempts should be made to ensure decreased irrigation and aspiration flow rates and direct irrigation currents above the iris plane and away from the pupillary margin to reduce the degree of anterior displacement of the lens–iris diaphragm, preventing the iris from prolapsing. In the presence of iris prolapsing tendency, it has been suggested to bowl out a small portion of central endonucleus, followed by hydrodelineation from inside-out, resulting in an ability to rotate the endonucleus and then chop the residual endonuclear bowl in the usual manner.
- Bimanual microincision phacoemulsification: useful in soft to moderate nuclear densities due to the small sized incisions, making iris prolapse thought the incisions then less likely. Combination of this technique with the use of Healon5 is very advantageous in cases of dense nuclei, where the pupil may remain dilated and enable larger capsulorrhexis. The irrigator should be kept in an anterior position when removing the remaining cortical material with the phacoemulsification needle, in order to maintain a posterior placed iris and hindering its billowing and concomitant pupil constriction.
- IOL implantation: the cartridge of the injection system should be turned bevel-up while introducing it to avoid prolapse of iris into the cartridge, as well as after the lens is placed in the bag and exiting the eye.
- Pupil enlargement devices: they provide dilation of the small pupil, prevent constriction of the pupil and restrain the iris from prolapsing. They are recommended in cases with predictive factors of severe IFIS (e.g. poor preoperative pupil dilation).
- Pupil expansion rings – generally easy to insert and remove from the eye, less traumatic than iris retractors as they do not overstretch the iris, require less surgery time and do not require additional incisions. Currently available designs include Morcher Pupil Ring®, Milvella Perfect Pupil® and Malyugin Ring®. The rings are introduced following incision completion and injection of dispersive viscoelastic. It is important to ensure correct position of the ring prior to removing it with the injector after IOL implantation, in order to prevent injury to intraocular ocular contents.
- Iris retractors/hooks – very commonly used in the management of IFIS, these devices maintain a constant pupil size during surgery, have lower costs than pupil rings and offer a better safety profile in shallow anterior chambers. There are different techniques for placing the hooks. Placing four hooks in a diamond configuration demonstrates advantages in IFIS as suggested by the American Society of Cataract and Refractive Surgery committee. In addition to maximization of pupillary dilation in front of the phaco tip and thus facilitation of cataract space removal, this configuration includes a subincisional retractor inserted through a separate plane. Thus, it allows the iris to be pulled posteriorly and away from the phaco tip and incision, preventing iris prolapse and iatrogenic iris trauma. There are disposable (6-0 nylon manufactured material) and reusable retractors (4-0 polypropylene) available, the latter being the same size and rigidity as an IOL haptic and thus more easily manipulated. Moreover, iris retractors are advantageous during the placement of a toric IOL, since two of the retractors being used can be aligned with the astigmatic axis.
- Combination strategies: as there are no reliable methods to predict the severity of IFIS in advance, different modalities may have complementary advantages when combined, particularly because clinical circumstances may change during surgery. In more challenging cases, such as a small pupil with concomitant tamsulosin use, pseudoexfoliation and shallow anterior chamber, it may be preferable to undergo 25-gauge pars plana vitrectomy as the first step of the surgery.
As initially reported in 2005, sphincterotomies (including partial thickness) and mechanical stretching of the pupil are not effective and may exacerbate IFIS. 
Management of small pupils
There are other clinical entities which may present with small pupils without the other features of IFIS, mainly pseudoexfoliation, diabetes mellitus and glaucoma. In these cases, there are several surgical techniques available which may facilitate pupil dilation and visualization during phacoemulsification.
In addition to the anteriorly described strategies, intraoperative efficient options to mechanically stretch the pupil are available for small pupils unrelated to IFIS. The latter techniques are not advantageous and may exacerbate IFIS.
Methods for mechanical stretching of the pupil include the following:
- When poor dilation is caused by posterior synechiae and there is normal zonular support, the synechiae should be lysed with a metallic spatula or cannula, followed by the injection of OVR to disrupt the irido-capsular adhesions if needed. Following dissection of the synechiae, additional dispersive OVR may be injected in the centre of the pupil to achieve greater pupillary dilation.
- Manipulation of phacoemulsification instruments: it is possible to retract the pupil and increase its size through the incisions, but it is highly dependent on experienced surgeons with the correct technique to avoid thermal injury and focal depigmentation.
- Bimanual pupil stretching technique of Luther Fry: it requires two hooks engaged at opposite pupillary ends to create a 5-6 mm pupilar diameter, with the adjunctive use of an OVR to protect the anterior lens capsule.
- Beehler pupil dilator: single instrument which provides a pupil diameter of 6–7 mm by making microsphincterotomies circumferentially around the pupil and can be mechanically reduced at the end of the procedure. This technique preserves a functional pupil size and is particularly useful in cases where pupil margin is fibrotic (e.g. with chronic use of pilocarpine). However, some cases require a miotic agent after surgery to prevent the formation of synechiae.
- Iris sphincterotomy: examples include proximal superior small segment excision, midiris iridectomy followed by sphincterotomy and multiple partial thickness cuts in iris sphincter using intraocular microscissors prior to stretching.
Complications during phacoemulsification surgery in IFIS patients vary in severity, including iatrogenic iris injury, wound dehiscence, hyphema, iridodialysis, nuclear drop, posterior capsule rupture and vitreous loss. Furthermore, the propensity of the iris to prolapse towards the phaco tip and to the incisions increases the risk of postoperative uveitis and permanent pupil distortion with glare and photophobia. Other long-term consequences include retinal-detachment, cystoid macular oedema and limited visual recovery due to endophthalmitis. Adequate preoperative evaluation and use of preventive measures anticipating IFIS significantly reduces the rates of complications. 
IFIS remains highly attributable to the drug-induced blockage of α1-1A receptor found in the iris dilator muscle, with a large proportion of patients under or with history of previous treatment with tamsulosin. It is important to recognize the rising frequency of women taking these drugs mainly for urinary retention and hypertension, constituting potential IFIS cases. Primary care physicians and urologists should likewise be aware of the association between tamsulosin and increased complication rate in cataract surgery. Discontinuing tamsulosin prior to surgery has no significant benefit and does not prevent IFIS.
Anticipation of IFIS before surgery should be part of ophthalmologists' preoperative assessment in order to achieve appropriate preparation for the procedure. Lack of preoperative prophylaxis is linked to higher rate of complications and worse visual outcomes. Moreover, further clinical trials and studies are needed to create a standardised assessment that stratifies the risk and predicts IFIS, as well as to compare the efficacy and safety profile of the different management options for IFIS.
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