There is a wide range of severity of IFIS reported within the literature. Mild cases have minimal billowing of the iris and dilate well, which permits any of the recommended treatment techniques to be successful in controlling the undesirable iris behavior during the surgery. However, severe cases demonstrating marked iris billowing, extensive and repetitive iris prolapse, and marked intraoperative miosis require use of iris retractors, hooks, or expanders to complete the surgery comfortably.1–7
Naturally, this great variability in severity of IFIS, and its unpredictability, even within one patient, make comparisons between individual cases and reports of different treatments and their relative effectiveness difficult. Therefore, because of the existing evidence in the literature, decisions concerning the optimum preventative measures and treatments are difficult to make and definitive studies of the prevention and treatment of the syndrome are difficult to design.
Simply discontinuing use of an α-blocker treatment regimen prior to surgery is usually not an effective remedy, because IFIS has been associated with the use of adrenergic antagonists even after they have been discontinued years prior to the surgery.1,5
Some believe that the persistence of IFIS long after discontinuing the associated drug reflects permanent anatomic changes within the iris.16,17
This suggestion begs the question, Is there any evidence within the literature that anatomic changes can occur within the eye following the use of autonomic drugs?
EVIDENCE FOR ANATOMIC STRUCTURAL CHANGES ASSOCIATED WITH DRUGS ACTIVE UPON THE AUTONOMIC NERVOUS SYSTEM
There is clinical and laboratory evidence that anatomic changes can be associated with the topical and systemic administration of drugs used to manipulate the autonomic nervous system. Topically applied parasympathomimetic drugs have long been recognized to break down the blood-aqueous barrier and even result in a fibrinous iritis.18
This tendency to break down the blood-aqueous barrier has clinical significance for surgery for glaucoma patients and the success of trabeculectomy.19
Furthermore, permanently miotic pupils and anatomically changed sphincter muscles have accompanied the long-term use of the parasympathomimetics during therapy for glaucoma. These miotic changes make cataract surgery more challenging.
In addition to parasympathomimetics, topically administered sympathomimetic drugs have been associated with an increase in floating cells within the anterior chamber of the human eye that can be mistaken for a persistent iritis.20
Furthermore, patients treated with sympathomimetics achieving a satisfactory mydriasis on one day will often demonstrate a rebound miosis resulting in a clinically significant decrease in dilatation of 30% to 40% on the following day.21
For this reason, many retinal and cataract surgeons discourage the use of sympathomimetics for dilation of patients on the day prior to surgery. Therefore, there are reports of clinical examples of autonomic drugs inducing grossly visible anatomic changes within human eyes following their topical administration.
In addition to these clinical observations, laboratory studies provide evidence that anatomic structural change can accompany both topical and systemic sympathomimetic drug treatments in experimental animals and humans. Topically applied 6-hydroxydopamine (6-OHDA), owing to its structural similarity to norepinephrine, can be taken up by postganglionic sympathetic nerve terminals, resulting in nerve terminal destruction.22
This chemical sympathectomy results in decreased nerve terminal uptake of not only endogenous norepinephrine but also exogenously applied epinephrine, and an enhancement of the therapeutic activity from topically applied epinephrine is achieved. This supersensitive pharmacologic state has been used, clinically, during the treatment of glaucoma to enhance the clinical effects of topically applied epinephrine.23
Subsequently, in an effort to prove that the biphasic onset of action of epinephrine on intraocular pressure is a reflection of supersensitivity, epinephrine was studied for an ability to damage adrenergic postganglionic nerve terminals. It was reasoned, insofar as norepinephrine is the endogenous postganglionic sympathetic neurotransmitter within the iris, that exogenous epinephrine, recognized as foreign to these nerve terminals, might induce destructive changes within them, similar to those degenerative changes observed following use of 6-OHDA. Evidence supporting this hypothesis has been provided using electron microscopy, catecholamine radioenzyme assays, and histofluorometric techniques.24–30
These laboratory investigations culminated in the demonstration of degenerative anatomic structural changes induced by the administration of epinephrine 1% during the treatment of glaucoma.30
The clinical significance of these pharmacologic observations for the treatment of glaucoma and their relationship to the pharmacodynamics or therapeutic effects of epinephrine remain obscure.
Nevertheless, this demonstration of anatomic changes following use of sympathomimetics in several species, including humans, provides a precedent for the possibility of structural changes following the systemic administration of exogenous sympathomimetic and sympatholytic agents, and this, in turn, could explain the long-lasting effects following termination of treatment. Phenoxybenzamine (1 mg/kg), a nonspecific α1
- and α2
-blocker, was used in one of these studies to enable cats to tolerate supralethal doses of epinephrine.24
This nonspecific α-blocker treatment was not associated with evidence of anatomic structural changes compared to untreated controls. Although this observation does not provide evidence for structural changes associated with α-blockers, it does not rule out the possibility that anatomic changes may occur in patients treated for longer durations with more specific α1
-antagonists. Clearly, all of these observations simply suggest a potential pathogenesis related to structural damage as a possible explanation for the prolonged effects of α-blockers that have been described, by providing a precedent, but not proof, which would require a more definitive study.
STUDIES WITH TAMSULOSIN IN HUMANS
Light microscopy was performed on 14 eyes removed from patients treated with tamsulosin prior to death and compared to specimens taken from untreated controls. Mean iris dilator muscle thickness was significantly less in tamsulosin-treated patients (P
= .004) compared to controls, without differences noted within the stroma.31
There was no correlation with dose of the α-blocker. The presence of diabetes or lens changes did not influence the results. In addition, transmission electron microscopy showed decreased myofibrils and increased vacuoles in the tamsulosin-treated eyes. The investigators concluded that this provides evidence for dilator muscle atrophy related to treatment with this α-blocker.
In different experiments, the eyes of 29 patients treated with tamsulosin were compared to untreated controls with special attention to their irises using ocular coherence tomography (OCT). A significantly decreased dilator muscle thickness was noted in irises of tamsulosin-treated patients (P
= .001) compared to controls. This appeared to be dose-related.32,33
These observations have been considered further evidence for muscle atrophy related to α-blockers.
Although both studies report decreased iris dilator muscle thickness in tamsulosin-treated patients, which may coexist with muscle atrophy, these observed findings could simply reflect the pharmacologic effect of the α-blocker. More specifically, α-blockers produce miosis, which is accompanied by a measurable thinning of the dilator muscle as the pupil becomes smaller and the dilator muscle stretches from its insertion. In contrast, sympathomimetics are associated with a measurable thickening of the dilator muscle as this radial muscle contracts, enlarging the pupil. In addition, decreased myofibrils and increased vacuoles do not necessarily indicate muscular atrophy.
In conclusion, there are clinical observations that reflect anatomic changes that can accompany the use of autonomic drugs, including evidence for breakdown of the blood-ocular barriers and permanent changes in the iris sphincter muscle. Furthermore, there is evidence using several experimental and laboratory techniques, including electron microscopy, catecholamine radioenzyme assays, and histofluorescence, that drugs used to manipulate the autonomic nervous system can induce anatomic changes within tissues of the eye, including the iris, that persist long after the drug is discontinued. Finally, two clinical studies report observations from humans demonstrating decreased iris dilator muscle thickness in tamsulosin-treated patients, which can coexist with atrophy. In spite of these different lines of evidence, we await a definitive study. For example, a potentially more conclusive study might compare tamsulosin-treated eyes having demonstrated IFIS to tamsulosin-treated eyes that have not manifested the syndrome, looking for a greater effect on iris dilator muscle thickness in treated eyes compared to controls. This comparison would be more relevant to the question of drug-induced atrophy within the dilator muscle that might explain the long duration of IFIS following cessation of the α-blocker. Therefore, the pathogenesis underlying the long duration of IFIS, even present years after cessation of α-blocker treatment, remains a conundrum.
AN ALTERNATIVE TREATMENT FOR BPH: ALPHA-REDUCTASE INHIBITORS
Finasteride is a 5α-reductase inhibitor that blocks the production of endogenous dihydrotestosterone, which helps reduce the size of enlarged prostates, thereby providing relief from symptoms of BPH. It is commercially available as Proscar (Merck & Co Inc, Whitehouse Station, New Jersey) and is approved by the US Food and Drug Administration for relief of the symptoms that accompany BPH. The Prostate Cancer Prevention Trial,34
sponsored by the National Cancer Institute and Merck & Co Inc, was a prospective, placebo-controlled, randomized trial that followed 19,000 men 55 years of age or older for 7 years looking for the pharmacologic effects, beneficial and detrimental, of finasteride. Recent analysis of the data reports that this treatment not only benefits symptoms of BPH, but it reduces the risk of prostate cancer by 30% and is not associated with prostate cancers that are more aggressive, as originally suggested.35–38
This medication is available in an inexpensive generic form. These findings provide an incentive to consider finasteride as a first-line treatment for BPH. Side effects include reduced hair loss (the FDA approved a lower-strength finasteride marketed as Propecia, Merck & Co Inc, for this indication) and a low incidence of decreased libido, which diminishes with time.38
A recent editorial39
provides a good rationale for trying finasteride as a first-line treatment for BPH symptoms, whether or not cataracts are present, and strongly advocates educating both patients and our internal medicine colleagues about BPH treatment and its relationship to cataract surgery.
What should the surgeon do when a patient is using tamsulosin? Discontinuing any α-blocker for 1 or 2 weeks prior to surgery may help but does not prevent IFIS. In fact, a prospective study5
reported that discontinuation of tamsulosin before cataract surgery did not decrease the severity of IFIS. Therefore, it is less than prudent to discontinue α-blockers used for BPH abruptly prior to surgery without careful discussion with the patient and urologist. Discontinuing α-blockers in patients with BPH can result in urinary retention, which will be further exacerbated during surgery by the use of concurrent drugs with parasympathomimetic activity, particularly atropine.
IFIS can be prevented and treated by maintaining mydriasis and restraining the iris from prolapsing during cataract surgery. This can be accomplished by mechanical and pharmacologic treatments and the use of intraoperative proper phacoemulsification fluidic parameters. The most reliable method of maintaining an adequate pupil during cataract surgery in severe cases of IFIS is the use of iris hooks, iris retractors, or expansion rings. Iris retractors and hooks are best placed in diamond configuration with incision just posterior to clear corneal incision. Useful pharmacologic agents described in the literature include preoperative atropine at various intervals prior to surgery and intraoperative phenylephrine or epinephrine injected under iris. Modifying phacoemulsification fluidic parameters to include lower aspiration flow (<22 mL/min) and lower vacuum (<200 mm Hg) is helpful. Finally, viscoelastic agents, ideally used with lower phacoaspiration and vacuum settings, can be effective, often requiring repeated injections. Unfortunately, it is difficult to study the relative effectiveness of these techniques, because IFIS is so variable in its relationship to α-blockers and in its severity when manifest even within the same patient. It is not surprising that studies simply conclude that retracting iris or expanding the pupil by some means is the only reliable method to manage severe IFIS.5
Recently, members of the American Society of Cataract and Refractive Surgery were surveyed for their opinions. A response from 957 of 6,000 members who were e-mailed the survey revealed that 95% agreed that tamsulosin appears to make cataract surgery more difficult and 77% believed that it increases the risk of surgery.40
Complications such as iris trauma (52%) and posterior capsule rupture (23%) were reported as more common in eyes with IFIS. Furthermore, 90% believed that IFIS is more likely to accompany tamsulosin use as compared to the nonspecific α1
-antagonists. A significant percentage (64%) polled would avoid tamsulosin themselves if they had early cataracts or would even have the cataract removed before initiating treatment with tamsulosin. Many members (33%) use a combination of techniques and strategies to manage the syndrome, particularly in severe IFIS. Finally, 91% believe physicians prescribing α1
-antagonists should be better educated about the syndrome, and 59% would recommend an ophthalmic evaluation for any patient with known cataracts or decreased vision prior to initiating treatment with the α-blocker.