Phacoanaphylaxis/lens-induced uveitis occurs in the setting of a ruptured or degenerative lens capsule and is characterized by a granulomatous antigenic reaction to lens protein.[1, 2, 3, 4, 5, 6] Before the modern era of microsurgery, this disease was more common, and the diagnosis was often made histologically, as eyes with phacoanaphylaxis were often enucleated for intractable inflammation and secondary glaucoma.[7, 8, 9]
With improved microsurgical techniques, especially with the introduction of extracapsular cataract extraction and phacoemulsification, the incidence of phacoanaphylaxis has decreased dramatically and rarely occurs in its originally described form. However, chronic postoperative uveitis following phacoemulsification with retained lens material is still a well-known complication of cataract surgery and is the result of the same pathophysiology as the classically described entity of phacoanaphylaxis.[10, 11]
While lens fragments may be retained in the anterior or posterior chamber during seemingly uncomplicated cataract surgery, they also may be dislocated posteriorly into the vitreous cavity during phacoemulsification of the nucleus, usually after zonular dehiscence or posterior capsule rupture. Lens-induced uveitis may develop, and the degree of intraocular inflammation in these patients often is governed by the size of the retained lens fragment, the time since cataract surgery, the patient's individual inflammatory response, and the extent of other intraocular manipulations.
Lens proteins are most likely immunologically privileged, and they may initiate an immunologic sensitization only after entering the aqueous humor. This privilege is probably because of numerous factors, as follows: lens proteins are isolated from the fetal circulation early in embryonic life, the lens is devoid of innervation, and the adult lens is completely avascular. However, the immunopathogenesis of lens-induced uveitis is not precisely understood.
The lens is an epithelial structure as it is derived from primitive ectoderm. By virtue of its capacity to synthesize alpha crystallins, the lens epithelium may become strongly antigenic.[12, 13, 14, 15, 16, 17, 18, 19] The protein concentration within the lens is higher than that of any other tissue in the body.
Early experiments inferred that lens antigens are shared among a number of animal species, and they can provoke the formation of homologous antibodies.[16, 20] Halbert et al found that lens proteins might be autoantigenic when they escape from their position of immunological isolation in the lens capsule.[21] Each of the crystallin protein groups of lens cortical fibers contains a number of subtypes with distinct antigenic characteristics. Autologous lens proteins are only weakly antigenic, but fractionated crystallins are much more effective in stimulating an antibody response. The conversion process from soluble crystallins to insoluble proteins during aging of the lens also may result in an increased antigenic effect of proteins from mature or hypermature cataracts.
The classic histologic picture is one of zonal granulomatous inflammation.[22, 12, 21, 23, 24] Polymorphonuclear leukocyte infiltration around degenerate lens remnants is surrounded by a palisade of macrophages, including epithelioid cells and multinucleated giant cells (see the images below).
View Image | Gross photomicrograph for eye enucleated with penetrating injury. |
View Image | Gross photomicrograph for eye enucleated with penetrating injury. Note marked inflammatory reaction consisting of polymorphonuclear cells around lens .... |
View Image | Low (X25) photomicrograph of phacoanaphylactic reaction to lens protein in eye enucleated with penetrating injury. Note polymorphonuclear leucocytes a.... |
Eosinophils may be prominent, and, eventually, fibroblastic granulation tissue develops together with prominent lymphocyte and plasma cell infiltration. The uveitis principally affects the iris, with the choroid being only secondarily involved. Retinal perivasculitis and papillitis may develop because of the presence of cross-reacting antigens in these tissues. Although a zonal granulomatous inflammation is the classic histopathologic description, a nongranulomatous uveitis also has been observed (see the image below).
View Image | High (X50) photomicrograph of phacoanaphylactic reaction to lens protein in eye enucleated with penetrating injury. Note polymorphonuclear leucocytes .... |
The term phacoanaphylaxis is probably inappropriate because no evidence exists of a classic type I immunoglobulin E (IgE) mediated anaphylactic reaction. The immunopathogenesis of lens-induced uveitis is believed to be the result of autosensitization to lens proteins. After a break in the lens capsule and sensitization to lens proteins, an immune complex–mediated phenomenon develops, which can be transferred by hyperimmune serum. Type II, III, and IV hypersensitivity reactions may be involved in the pathogenesis.
The disease most likely is induced by altered tolerance to lens protein and not as a result of a rejection phenomenon of sequestered foreign materials. The specific type of immunological reaction in lens-induced uveitis may vary from patient to patient, and it may depend on the type of surgery or injury, the amount of retained lens in the vitreous cavity, and the previous immunological status of both the patient and the eye.
International
The incidence of both phacoanaphylaxis and lens-induced uveitis is unknown. The best estimate of the incidence of posteriorly displaced lens fragments during phacoemulsification is 0.3-18% (the latter figure reported by a surgeon learning to use phacoemulsification). The incidence of retained lens fragments has increased as phacoemulsification has become more popular for cataract surgery. Although data are lacking, the authors' clinical impression is that about 50% of patients with retained lens material after cataract surgery have lens-induced uveitis. The incidence of lens-induced uveitis following penetrating injury is unknown.
Lens-induced uveitis may cause or may be associated with cystoid macular edema, hypotony, phthisis, and secondary glaucoma.[25, 26, 27, 28] Complications also may be the result of medical or surgical treatment of lens-induced uveitis.
No racial predilection exists.
No sexual predilection exists.
Phacoanaphylactic endophthalmitis and lens-induced uveitis are more common in the elderly population, with a peak incidence in the sixth to seventh decades. The main exception is traumatic cataract and related complications, which are more common in younger age groups.
Phacoanaphylactic uveitis/lens-induced uveitis typically develops 1-14 days after traumatic or surgical perforation of the lens capsule. In rare instances, the inflammation may develop several months after the disruption of the lens capsule. In the large pathologic study by Thatch and Marak, there was no history of trauma or histopathologic evidence of a penetrating wound in about 20% of cases where phacoanaphylaxis was verified histopathologically.[29]
Clinical symptoms may include severe light sensitivity, epiphora, pain, floaters, decreased vision, and redness of the eye.
Decreased vision may be due to refractive error (myopic or hyperopic shift) associated with such factors as macular edema, hypotony, or change in lens position.
Visual acuity in patients with phacoanaphylactic uveitis is quite variable, ranging from 20/20 to no light perception.
Typically, the onset of lens-induced uveitis occurs 1-14 days after traumatic or surgical capsular disruption. However, unusual cases have been reported where the reaction occurred as early as several hours or as late as several months following capsular rupture.
The inflammation can vary from a mild anterior uveitis to a fulminant endophthalmitis. Typically, the inflammation is unilateral and involves only the traumatized eye.
The most important clinical signs of lens-induced uveitis are lid swelling, perilimbal or diffuse injection, corneal haze, keratic precipitates (nongranulomatous or mutton fat), cells and flare, fibrin in the anterior chamber (occasionally), peripheral anterior synechiae, posterior synechiae, pupillary membrane, and iris nodules.
In the posterior segment, lens fragments, inflammatory cells, traction bands in the vitreous, retinal edema, inflammatory cuffing of blood vessels[30] , cystoid macular edema, and epiretinal membrane formation can be observed.
If untreated, lens-induced uveitis/phacoanaphylactic endophthalmitis may result in chronic cystoid macular edema, cyclitic membrane formation, tractional retinal detachment, and phthisis bulbi.
Phacoanaphylactic endophthalmitis/lens-induced uveitis is usually the result of traumatic or surgical disruption of the lens capsule and liberation of lens proteins into the aqueous or into the vitreous cavity.[31, 7, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41] Posterior capsular rupture during phacoemulsification is the most common cause of posterior displacement of lens fragments. This complication is more common in patients with pseudoexfoliation syndrome, zonular dehiscence, a small pupil, friable iris, and hard nuclei or hypermature cataracts.[42]
Penetrating injury of the globe may result in severe lens-induced uveitis. The uveitis may remain undiagnosed clinically because of hyphema, decreased corneal clarity, and inflammation related to the trauma. A small punctured perforation site may remain unnoticed initially (see the images below), and severe inflammation and cataract will be present 1 week later.
View Image | High (X50) photomicrograph of phacoanaphylactic reaction to lens protein in eye enucleated with penetrating injury. Note polymorphonuclear leucocytes .... |
View Image | Phacoanaphylactic reaction to penetrating injury of lens. This patient was a 25-year-old woman whose eye was penetrated with a 27-gauge needle during .... |
View Image | Same patient as in Media file 5. Notice cortical cataract at perforation site. |
Early and total removal of the lens material may prevent trauma-related phacoanaphylaxis and should be performed if the lens capsule is disrupted and a high probability of cataract exists.
Aqueous paracentesis in subtle or early cases may reveal inflammatory cells and particulate lens proteins without bacteria. This procedure is performed more efficiently at the time of anterior chamber washout and vitrectomy to remove the inciting lenticular antigens. In cases of suspected bacterial endophthalmitis, intraoperative aqueous and vitreous specimens may establish the diagnosis of phacoanaphylaxis in the absence of positive cultures.
If the media opacity prevents an appropriate fundus examination, echography with A-scan and B-scan may be helpful when evaluating the posterior pole.[63]
Suspicion for acute endophthalmitis, intraocular foreign body, dropped lens nucleus, thickening of the choroid, retinal detachment, and choroidal effusion are all indications for echography if the anterior segment changes hinder examination of the posterior segment.
The shape, position, and thickness of the traumatized lens; the presence of focal echogenic areas; and, sometimes, even the entrance and exit wounds are recognizable by ultrasound. It is clinically important to diagnose the isolated rupture of the posterior capsule of the lens by echography. Such ruptures are characterized by the irregular extension of the highly reflective posterior capsule toward the vitreous with significantly increased thickness of the lens.
Ultrasound biomicroscopy (UBM) may have an important role in the evaluation of lens-induced uveitis after extracapsular cataract extraction, revealing hidden lens particles in the posterior chamber causing inflammation as well as lens-particles creating secondary glaucoma.[64, 65]
Histopathology of phacoanaphylactic endophthalmitis is characterized by a zonal granulomatous inflammatory reaction consisting of polymorphonuclear neutrophils, numerous epithelioid cells, and occasional giant cells. The inflammatory reaction is around the lens material or lens capsule (see the images below). Associated cells include eosinophils, plasma cells, and histiocytes containing phagocytized lens material.
View Image | Gross photomicrograph for eye enucleated with penetrating injury. |
View Image | Gross photomicrograph for eye enucleated with penetrating injury. Note marked inflammatory reaction consisting of polymorphonuclear cells around lens .... |
View Image | Low (X25) photomicrograph of phacoanaphylactic reaction to lens protein in eye enucleated with penetrating injury. Note polymorphonuclear leucocytes a.... |
Minimal histopathologic diagnostic criteria include neutrophil-associated lens damage accompanied by a granulomatous response associated with the lens material. A paucity of neutrophils may be present in late cases. Isolated giant cells without neutrophils and associated lens damage may create difficulty in distinguishing phacoanaphylactic endophthalmitis from a foreign body granuloma since lens material or the Descemet membrane may induce giant cells.
Treatment of phacoanaphylaxis may be medical or surgical. Medical therapy of phacoanaphylactic uveitis includes topical corticosteroids and may include cycloplegics and medication for elevated intraocular pressure as needed. Treatment should be tailored to the individual patient and adjusted according to response. Patient age, immune status, and tolerance for adverse effects always must be taken into account.
Topical cycloplegics break or prevent the formation of posterior synechiae, stabilize the blood-aqueous barrier leading to reduced leakage of plasma proteins, increase uveoscleral outflow, and provide mild relief of ciliary spasm pain. The stronger the inflammatory reaction, the more frequently applied or stronger the cycloplegic.
Corticosteroids block the formation of arachidonic acid from cell membrane precursors by inhibiting the action of phospholipase-A2, cyclooxygenase, and lipoxygenase. Thus, arachidonic acid is the premier precursor of potent inflammatory mediators, such as prostaglandins, thromboxane, and leukotrienes. Corticosteroids frequently are used in uveitis therapy. Topical steroid drops are given in dosages ranging from once daily to hourly. They also can be given in an ointment form. Periocular corticosteroids generally are given as depot-steroid injections when a more prolonged effect is needed or when a patient is noncompliant or poorly responsive to topical administration.
Nonsteroidal anti-inflammatory agents typically block the formation of cyclooxygenase. They are useful in the management of cystoid macular edema and anterior segment inflammation. Their anesthetic properties increase patient comfort. They can be used in conjunction with corticosteroids.
When phacoanaphylaxis is associated with high intraocular pressure (see the image below), aqueous suppressants are indicated. Beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors are used to lower the pressure.
View Image | Patient with persistently elevated intraocular pressure after cataract surgery was found to have retained lens material and low-grade inflammation. Ey.... |
If persistent or uncontrolled inflammation or elevated intraocular pressure is not responsive to medical therapy or if such a large amount of exposed lens material is present that medical therapy is likely to fail, then surgical removal of the exposed lens material is indicated (see the image below).
View Image | Typical clinical picture of retained lens material following cataract surgery. White cortical material is easily visible in the pupillary space. |
The most common situation leading to this is posterior capsular rupture with the loss of lens fragments into the vitreous cavity during phacoemulsification (see the images below). Removal of retained lens fragments by pars plana vitrectomy may restore good visual function and reverse many complications in these patients.[66, 67, 68, 69, 70, 71, 72]
View Image | Patient with persistently elevated intraocular pressure after cataract surgery was found to have retained lens material and low-grade inflammation. Re.... |
View Image | Typical appearance of retained lens fragments in posterior vitreous cavity. Lens material is a whitish substance that obscures fundus details. |
View Image | Another view of a retained lens fragment, noted inferiorly. |
Surgical removal of retained lens material may be necessary depending upon the degree of inflammation, the size of the retained lens particle, and the presence of increased intraocular pressure. Observation is indicated when the lens fragments are small and the inflammation can be controlled.
Several studies demonstrate no advantage to early surgery; therefore, the cataract surgeon may treat patients with retained lens fragments conservatively, and then refer the patient to a vitrectomy surgeon after an appropriate period of observation and medical therapy, unless the patient develops retinal detachment, highly elevated intraocular pressure, or some other condition in which posterior segment surgery is indicated more urgently.[74]
A review by Schaal et al found that about one third of patients with retained lens fragments may be managed conservatively (ie, medical therapy alone) with good results; however, vitrectomy and lensectomy with removal of the offending lens particles were indicated in those patients not responding to topical and systemic medications.[71] Moreover, Schaal et al found that surgery could be successfully delayed in many patients.[71]
Various techniques have been reported for use by the cataract surgeon at the time of lens fragment loss.[75, 76, 66, 77, 78] However, no apparent advantage exists for immediate removal of retained lens fragments, and such attempts are to be discouraged.
A complete limbal vitrectomy should be performed before any lens placement, and the absence of vitreous to the wound or other anterior structures should be confirmed at the time of wound closure. The recommendation from most retina surgeons is to place the IOL in the posterior chamber if there is adequate capsular support and to place anterior chamber lenses if there is inadequate capsular support at the time of the cataract surgery. If the eye is left aphakic at the time of the cataract surgery, secondary IOL insertion is possible at the time of pars plana vitrectomy. Sutured IOL with transscleral fixation may increase the risk of retinal detachment, endophthalmitis, and cystoid macular edema.
Kim suggests that the final visual acuity is probably more dependent on the extent of manipulations during the initial cataract surgery than the type of IOL placed or subsequent surgery.[68]
Borne et al found perfluorocarbon liquids not to be protective against poor visual outcome.[76] They reported no statistically significant retinal detachment rates in eyes where perfluorocarbon liquid was used compared with eyes in which only vitrectomy was performed to remove retained lens fragments. However, the study conducted by Ross found that patients with retained lens fragments in whom posterior chamber lenses were implanted had a better outcome than patients with anterior chamber lenses, and both groups of pseudophakic patients fared better than aphakic patients. Other studies have failed to find a correlation between IOL placement, type of IOL placed (anterior or posterior chamber IOL), and final visual outcome.
The final visual acuity after vitrectomy for retained lens fragments was 20/40 or better in 60-70% of patients and worse than 20/200 in 10-15% of patients in 2 large retrospective studies.[79]
Postoperative complications related to vitrectomy include corneal edema, glaucoma, persistent uveitis, cystoid macular edema, retinal detachment, and endophthalmitis. The same complications are associated with complicated cataract surgery and may coexist before and after pars plana vitrectomy.
Retinal detachment is the major cause of a poor visual outcome in the management of retained lens fragments. The frequency of retinal detachment is higher in eyes in which ultrasonic phacofragmentation was used (24%) compared to the eyes in which it was not used (12%), although the difference is not statistically significant. The cumulative incidence of retinal detachment is 15-17% when large series of vitrectomy for retained lens fragment are analyzed.
In the postoperative period of complicated cataract surgery or pars plana vitrectomy, patients are instructed not to bend over, to avoid extreme physical activities, and to protect the operated eye (eg, glasses, Fox-shield at night) for a minimum of 2 weeks.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. See Medical Care.
Clinical Context: Blocks muscle of ciliary body and sphincter muscle of iris from responding to cholinergic stimulation, thus causing mydriasis and cycloplegia.
Cyclopentolate, atropine sulfate, homatropine, and scopolamine break or prevent formation of posterior synechiae; stabilize the blood-aqueous barrier, leading to reduced leakage of plasma proteins; increase uveoscleral outflow; and provide mild relief of ciliary spasm pain. The stronger the inflammatory reaction, the more frequently applied or stronger the cycloplegic.
Clinical Context: Treats acute inflammations following eye surgery or other types of insults to eye.
Decreases inflammation and corneal neovascularization. Suppresses migration of polymorphonuclear leukocytes and reverses increased capillary permeability.
In cases of bacterial infections, concomitant use of anti-infective agents is mandatory; if signs and symptoms do not improve after 2 days, reevaluate patient. Dosing may be reduced, but advise patients not to discontinue therapy prematurely.
Block formation of arachidonic acid from cell membrane precursors by inhibiting action of phospholipase-A2. Corticosteroids frequently are used in uveitis therapy. Topical corticosteroids are given in dosages ranging from once daily to hourly. They also can be given in an ointment form. Periocular corticosteroids generally are given as depot-steroid injections when a more prolonged effect is needed or when a patient is noncompliant or poorly responsive to topical administration.
Clinical Context: Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclooxygenase, which, in turn, decreases formation of prostaglandin precursors. May facilitate outflow of aqueous humor and decreases vascular permeability.
Inhibit cyclooxygenase pathway that controls prostaglandin biosynthesis. NSAIDs have both topical analgesic and anti-inflammatory effects. Although NSAIDs currently do not have a significant role in uveitis therapy beyond the treatment of macular edema, they may have a synergistic effect with topical corticosteroids, and, because of minimal adverse effects, they often are used in cases of intraocular inflammation.
Clinical Context: Ocular hypotensive medication that lowers intraocular pressure by reducing aqueous humor production. Reduces cardiac output, decreases heart rate and blood pressure, produces beta-adrenergic receptor blockade in bronchi and bronchioli, and has little or no effect on pupil size and accommodation.
Decrease production of aqueous humor by the ciliary epithelium, resulting in decreased intraocular pressure. Beta-blockers reduce aqueous formation by 24-48%.
Clinical Context: Relatively selective alpha2-adrenergic agonist. Has dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow.
Clinical Context: Formulated for topical ophthalmic use. Inhibition of carbonic anhydrase in ciliary processes decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is decreased intraocular pressure.
Clinical Context: Used for adjunctive treatment of glaucoma. Reduces aqueous humor formation by 20-40% with no significant change in outflow facility. Approximately 90% is bound to plasma proteins and excreted by urine largely unmetabolized. Maximal effect is noted 2-4 h after oral administration and 10-15 min after IV administration.
These agents are nonbacteriostatic sulfonamides that inhibit enzyme carbonic anhydrase (eg, topical dorzolamide, brinzolamide, systemic methazolamide, acetazolamide). This action reduces the rate of aqueous humor production, resulting in decreased intraocular pressure.
Follow-up care of patients with phacoanaphylaxis or retained lens material should be scheduled according to the severity of symptoms and the preoperative or postoperative condition of the patient.
The incidence of cystoid macular edema after complicated cataract surgery with retained lens material has been reported to be approximately 7%.[26, 80]
The incidence of secondary glaucoma related to retained lens fragment was 30% in one study and 52% in another study.
Leakage of lens proteins through the injured lens capsule with or without leakage of serum proteins from uveal blood vessels in lens-induced uveitis may block the trabecular outflow causing secondary glaucoma.[27]
Trabecular meshwork obstruction may occur with the accumulation of white blood cells (macrophages and activated T lymphocytes) or their aggregations. These may cause peripheral anterior synechiae and subsequent closed-angle glaucoma.
Obstruction may arise from inflammatory debris (eg, proteins, fibrin, high molecular weight proteins) and from lens particles. These proteins increase the aqueous viscosity, which may contribute to increased intraocular pressure.
The incidence of retinal detachment after cataract surgery complicated by retained lens material is 7-11%. This is not a result of damage to the retina from sharp lens fragments or the inflammation associated with phacoanaphylaxis but is related to complications of the cataract surgery, such as vitreous loss.
Vigorous attempts to retrieve the lens fragments from the vitreous cavity via an anterior segment incision during phacoemulsification have been associated with giant retinal tears and poor prognosis.[81]
Prognosis of phacoanaphylaxis without surgical treatment is dismal. With appropriate surgical and medical treatment, the prognosis of retained lens material is much more favorable, especially with today's state-of-the-art surgical techniques.
Several series reported visual acuities of 20/40 or better in 60-82% of patients with retained lens material after vitrectomy.[79]
Postoperative complications related to vitrectomy may be difficult to distinguish from complications related to the initial cataract surgery. (See Surgical Care.)
The prognosis in trauma cases is highly correlated to the extent of trauma and the visual acuity at the time of initial evaluation.
Phacoanaphylactic reaction to penetrating injury of lens. This patient was a 25-year-old woman whose eye was penetrated with a 27-gauge needle during an attempt to anesthetize the eyelid for chalazion removal. One week later, a marked uveitis was present. Notice perforation site and posterior synechiae.
Phacoanaphylactic reaction to penetrating injury of lens. This patient was a 25-year-old woman whose eye was penetrated with a 27-gauge needle during an attempt to anesthetize the eyelid for chalazion removal. One week later, a marked uveitis was present. Notice perforation site and posterior synechiae.