Aqueous misdirection is a challenging form of secondary angle closure that presents with elevated intraocular pressure (IOP) and shallowing of the central and peripheral anterior chamber despite the presence of a peripheral iridotomy. Aqueous misdirection is a diagnosis of exclusion, and requires exclusion of other clinical entities such as choroidal hemorrhage, choroidal effusion, and pupillary block.
Elevation of intraocular pressure and axial shallowing of the anterior chamber from posterior pressure characterize aqueous misdirection. Von Graefe described the condition in 1869 using the phrase “malignant glaucoma”  but in this article we will use the term aqueous misdirection. Other common terms that are used to describe the entity are cilary block glaucoma or lens block glaucoma. The exact mechanism resulting in aqueous misdirection is unknown but appears to be related to the relationship between the ciliary body, anterior hyaloid, and lens as well as the permeability of the vitreous. The pressure is often elevated but can be normal or low. Appropriate timely medical intervention with cycloplegics and ocular antihypertensives needs to be initiated to avoid progression to blindness. Miotics should be avoided as they can worsen the condition. If medical therapy should fail, surgical management may eventually be required.
Aqueous misdirection classically occurs during the early post-operative period after incisional surgery for acute angle closure with an incidence of 0.6 to 4%. A recent retrospective review of 24 eyes found the incidence to be 2% after glaucoma surgery; the condition was also found to be more common in females (which may coincide with higher incidence of angle closure in women). The condition can also occur in other postoperative states, including after cataract surgery, surgical iridotomy, and after laser iridotomy. The condition typically presents unilaterally, reflecting the fact that it is usually a postoperative complication. However, occurrence of aqueous misdirection in one eye significantly raises the risk of the misdirection presenting in the contralateral eye in the context of ocular surgery. Aqueous misdirection can occur in phakic as well as pseudophakic eyes.  It occurs with increased frequency in hyperopic eyes, especially those with a history of primary angle closure. Aqueous misdirection can occur outside the post-operative setting as remotely as months to years upon discontinuing cycloplegics. Other conditions more infrequently associated with aqueous misdirection include post pars plana vitrectomy, post diode laser cyclophotocoagulation , post trabeculectomy bleb needling, and post instigation of miotic therapy in non-operated  or operated eyes . Other ocular disorders that have been more rarely associated with malignant glaucoma include trauma, inflammation, fungal keratomycosis endophthalmitis, Nocardia asteroides endophthalmitis, retinopathy of prematurity, and in corneal hydrops.
The precise underlying mechanism of aqueous misdirection is unknown. Generally, it is felt to result from diversion of aqueous flow into the posterior segment. This diversion of fluid results from an abnormal relationship between the ciliary body processes, lens, and anterior vitreous. Several theories for the pathogenesis of aqueous misdirection have been proposed. One theory is that overfiltration in the immediate post op period leads to shallowing of the anterior chamber and anterior rotation of the ciliary body as a consequence of posterior pressure (i.e. from pressure differential between anterior and posterior chamber) . Whatever the cause, a malignant cycle is created whereby pressure incrementally rises in the posterior chamber but the fluid build-up cannot decompress or exit to balance anterior chamber pressure resulting in forward movement of the lens-iris diaphragm.
Axial hyperopia and a history of chronic angle closure with peripheral anterior synechiae are risk factors that predispose a patient to aqueous misdirection. The risk is present whether there is partial or total closure of the anterior chamber angle and regardless of whether there is a patent iridectomy or iridotomy. Furthermore, aqueous misdirection can rarely develop in eyes without any known risk factors.
There are a number of theories as to the underlying cause for this condition though the exact mechanism is unknown. Chandler and Grant hypothesized that weakness or laxity in the zonules in combination with posterior pressure resulted in axial shallowing of the anterior chamber . Shaffer proposed that aqueous humor pooled in the posterior chamber behind a posterior vitreous detachment (PVD) leading to anterior displacement of the ciliary body, lens, and iris . Quigley proposed that choroidal expansion results in intraocular pressure elevation and increased aqueous outflow which results in a pressure gradient leading to movement of aqueous posteriorly . The reasons as to why the aqueous is directed posteriorly and why it continues to flow posteriorly, however, are not fully clear. One possible theory hypothesizes that the ciliary body processes rotate forward with the tips subsequently abutting the lens equator (or the anterior hyaloid in aphakic patients). This contact then obstructs anterior aqueous flow. Another theory is that the anterior hyaloid may act as a one-way valve with increased resistance to flow which traps fluid within the vitreous when compressed against the ciliary body, lens, and iris preventing further forward flow and creating posterior pressure. Posterior flow of fluid is thought to occur through breaks in the hyaloid face near the vitreous base. This is supported by animal studies by Fatt where the fluid conductivity of the vitreous decreased with an increased pressure differential . So in summary, although there is no consensus as to the exact mechanism, there is agreement that an abnormal relationship exists between the ciliary processes, lens (crystalline or intraocular implant), and anterior vitreous/hyaloid face. This abnormality leads to posterior diversion of aqueous. Furthermore, decreased permeability of the vitreous or anterior hyaloid is likely a central factor in the development and perpetuation of the disorder .
As the exact underlying mechanism has yet to be fully elucidated, there are no guidelines for primary prevention. However, since there is increased risk of developing aqueous misdirection in the fellow eye, it has been proposed that either a prophylactic iridotomy be placed, and/or that the patient be maintained on cycloplegics-mydriatics. Patients with history of angle closure should be placed on cycloplegics post-operatively. The effectiveness of these measures remains unknown. Other possible measures that serve to eliminate the risk in this population include intentional violation of the anterior hyaloid during cataract extraction, placement of a glaucoma shunt in the posterior chamber with pars plana vitrectomy, and/or opting to perform non-penetrating glaucoma surgery when incisional surgery is indicated. Prophylactic pars plana vitrectomy has been advised in high risk fellow eyes during cataract surgery .
A thorough documentation of prior incisional or laser procedures, angle closure attacks, eye infections and/or inflammation, and prior episodes of aqueous misdirection are very important in taking the patient’s history. Also, notation of past or current eye drop usage is vital.
Physical examination includes evaluation of intraocular pressure, anterior chamber, iris, and retina. Intraocular pressure tends to be elevated but can be within normal limits or low in the presence of a filtering bleb . Slit lamp examination demonstrates shallowing of both the peripheral and central anterior chamber typically in aqueous misdirection. The iris configuration is also important to evaluate concomitantly with the anterior chamber. If a peripheral iridotomy is present, its patency should be assessed. A ciliary body process can at times be visible through the iridotomy in apposition to the lens. Choroidal detachment and suprachoroidal hemorrhage should be ruled out with a dilated fundus exam if the cornea allows a view of the fundus. If filtration surgery is present a Seidel test should be performed to exclude a wound leak, particularly if the intraocular pressure is not significantly elevated.
Symptoms can include redness, eye pain, and decreasing vision (especially in patients with an ocular history of angle closure, eye procedures/surgeries, inflammation or infection). Prior to these symptoms, patients may note an improvement in near vision secondary to the myopic shift from forward rotation of the lens-iris complex.
- B-scan ultrasonography can help to exclude choroidal detachments and suprachoroidal hemorrhage, which are two important differential diagnoses. B-scan is particularly helpful in cases where corneal clouding precludes direct retinal examination.
- Ultrasound biomicroscopy (UBM) also can also be used to image the anterior chamber angle, iris configuration, and lens configuration. UBM can help supplement history and physical exam.
- Anterior segment optical coherence tomography (OCT) can be used to measure anterior chamber depth and configuration in cases where the cornea is sufficiently clear.
There are no laboratory tests to diagnosis malignant glaucoma.
- Pupillary Block Glaucoma: An important distinguishing factor comparing the two entities includes a moderately deep central anterior chamber with bowing of the peripheral iris in pupillary block (unlike the significant shallowing of the central anterior chamber in aqueous misdirection). However, pupillary block glaucoma is unlikely if there is a patent iridotomy or if the patient is pseudophakic or aphakic. In the rare case where aqueous misdirection is suspected in a phakic eye without a previous iridotomy or iridectomy, placement of an iridotomy is a reasonable first therapeutic (and diagnostic) step.
- Choroidal Detachment: After glaucoma filtering procedures, hypotony may be associated with a shallow anterior chamber and a serous choroidal detachment, along with a tendency to over-estimate the IOP, which can mimic aqueous misdirection. Of note, Liebmann, Weinreb, and Ritch presented a case series of an occult annular ciliary body detachment causing angle-closure glaucoma that clinically mimicked malignant glaucoma . Choroidal detachment can be diagnosed by dilated fundus exam and/or ultrasonography. As stated, though, patients with choroidal detachments typically present with low IOP.
- Suprachoroidal Hemorrhage: Post-operatively, suprachoroidal hemorrhage can also cause shallow anterior chamber, pain, and elevated IOP. On dilated fundus exam, elevated choroidals that are hemorrhagic are typically reddish-brown and will be more echogenic on ultrasound.
- Secondary Angle Closure: Scleral buckle placement may result in an anterior chamber depth reduction that mimics aqueous misdirection. However, this can be distinguished from aqueous misdirection by its moderate, non-progressive features. These patients also have a high frequency of choroidal effusions.
In general, most of the strategies to treat aqueous misdirection are directed at restoring the normal anatomic relationship between the ciliary body, lens, and iris as well as restoring anterior flow of the aqueous and controlling IOP. The condition can be refractory and recur making the entity challenging to say the least. Conservative measures or a stepwise approach is therefore taken. However, as noted above, having or performing an iridotomy is often the first step in diagnosis and treatment along with the interventions presented below.
Medical management is effective in roughly half of cases of aqueous misdirection within five days, after which surgical intervention should strongly be considered . Medical management involves concomitant use of cycloplegics-mydriatics, aqueous suppressants, and hyperosmotics, as using only one class of therapy oftentimes is not as effective as using them in combination. In Dr. Simmons’ 1972 case series, medical therapy consisted of phenylephrine and atropine, oral acetazolamide, and oral or intravenous glycerol or mannitol. Anti-inflammatory agents may also be required for post-operative inflammation. Within two or three days of starting treatment, the anterior chamber was reformed in half of patients; in a single case, the anterior chamber reformed five days after combined therapy and thus five days was used as a cut-off prior to pursuing surgical management . These medications function together to reverse the clinical manifestations of aqueous misdirection. Cycloplegics inhibit contraction of the muscle fibers of the ciliary body causing tightening of zonules, which in turn pulls the lens backward. Hyperosmotic agents draw fluid out from the posterior chamber thereby decreasing the vitreous volume and pressure and may also increase vitreous permeability. Aqueous suppressants decrease the flow of aqueous that can precipitate aqueous misdirection. A combination of topical atropine, topical or oral carbonic anhydrase inhibitors, topical alpha-2 agonists and beta-blockers or intravenous mannitol can potentially break an attack of aqueous misdirection. Mydriatics may help by eliminating lens-iris apposition in combination with cycloplegics. Recurrences may be decreased by maintenance on topical atropine. If the medications are successful, osmotics are typically withdrawn first, followed by ocular antihypertensives. Cycloplegics are usually withdrawn last but may be required long term. If medications are not successful, then more invasive measures are required as described below.
If medical management is unsuccessful, the next approach to treatment includes laser therapy. The goal of laser therapy is to establish a conduit for flow between the vitreous cavity and the anterior chamber.
- If the patient is pseudophakic, Nd:YAG laser  is performed to disrupt the anterior vitreous face and allow misdirected aqueous to flow anteriorly from the posterior chamber. Nd:YAG laser can be applied to the anterior vitreous face through the visual axis or optic of the lens. In theory, if the iridotomy is large enough, Nd:YAG could be applied through this opening.
- Laser photocoagulation using argon laser to photocoagulate ciliary processes directly or transscleral diode laser cyclophotocoagulation (CPC) can also help treat an acute attack of malignant glaucoma. The laser may result in result in shrinkage of the ciliary processes, which may decrease cilio-hyaloidal apposition and decrease posterior aqueous flow .
Surgical therapy is frequently necessary to definitively manage aqueous misdirection. In a retrospective review of 26 eyes from 24 patients with aqueous misdirection from a single center, all but one case required surgery eventually within 3 months of presentation. If the patient is refractory to both medical and laser management of aqueous misdirection, surgery is necessary to disrupt the anterior vitreous face or remove vitreous, thereby increasing aqueous flow to the anterior chamber.
- Transcorneal needling can be performed at the slit lamp through a patent iridotomy that is peripheral to the lens . This procedure is again designed to disrupt the anterior vitreous face and was done in conjunction with reformation of the anterior chamber.
- The next simplest surgical option aside from transcorneal needling is to create a posterior sclerotomy to disrupt the anterior hyaloid. A small amount of fluid is aspirated from the vitreous through the sclerotomy along with reformation of the anterior chamber with air .
- Another approach is anterior vitrectomy via pars plana approach  and/or in combination with reformation of the anterior chamber with air. The purpose of the vitrectomy is again to disrupt the anterior hyaloid face and release fluid trapped within the vitreous. Anterior vitrectomy may require lens extraction or may be combined with laser treatment of ciliary processes .
- Recurrences can occur with the above techniques, so for patients who are pseudophakic, reports have shown success with iridectomy-hyaloido-zonulectomy combined with anterior vitrectomy whether anteriorly via the iridectomy or pars plana . In phakic patients, a vitrectomy-phacoemulsification-vitrectomy (with zonulo-hyaloidectomy-iridectomy) has shown preliminary success (i.e. limited core vitrectomy is done prior to cataract extraction to decompress vitreous followed by a more thorough complete vitrectomy after lens extraction) . In refractory cases, a complete pars plana vitrectomy along with lens removal is likely required with thorough removal of the entire hyaloid face as well as creation of vitrectomy tunnel (defined by an iridectomy-hyaloidectomy-zonulectomy . A pars plana tube may also be considered .
Aqueous misdirection can represent a clinical challenge. Though the etiology is unclear it demonstrates how an imbalance in the dynamic between the lens, cilary body and vitreous can cause a potentially vision threatening condition. However, with prompt diagnosis and initiation of treatment, aqueous misdirection can be resolved. Furthermore, steps can be taken to prevent occurrence in the fellow eye.
- ↑ Graefe, v., Beitrage zur pathologie und therapie des glaucoms. Arch Fur Ophthalmol, 1869. 15: p. 108.
- ↑ 2.0 2.1 2.2 Epstein, D.L., et al., Experimental perfusions through the anterior and vitreous chambers with possible relationships to malignant glaucoma. Am J Ophthalmol, 1979. 88(6): p. 1078-86.
- ↑ Ruben, S., J. Tsai, and R.A. Hitchings, Malignant glaucoma and its management. Br J Ophthalmol, 1997. 81(2): p. 163-7.
- ↑ 4.0 4.1 4.2 Weiss, D.I. and R.N. Shaffer, Ciliary block (malignant) glaucoma. Trans Am Acad Ophthalmol Otolaryngol, 1972. 76(2): p. 450-61.
- ↑ Epstein, D.L., Pseudophakic malignant glaucoma--is it really pseudo-malignant? Am J Ophthalmol, 1987. 103(2): p. 231-3.
- ↑ Tomey, K.F. and C.E. Traverso, The glaucomas in aphakia and pseudophakia. Surv Ophthalmol, 1991. 36(2): p. 79-112.
- ↑ 7.0 7.1 Lippas, J., Mechanics and the Treatment of Malignant Glaucoma and the Problem of a Flat Anterior Chamber. Am J Ophthalmol, 1964. 57: p. 620-7.
- ↑ 8.0 8.1 8.2 Greenfield, D.S., et al., Aqueous misdirection after glaucoma drainage device implantation. Ophthalmology, 1999. 106(5): p. 1035-40.
- ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Chandler, P.A., R.J. Simmons, and W.M. Grant, Malignant glaucoma. Medical and surgical treatment. Am J Ophthalmol, 1968. 66(3): p. 495-502.
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Simmons, R.J., Malignant glaucoma. Br J Ophthalmol, 1972. 56(3): p. 263-72.
- ↑ Lowe, R.F., Malignant glaucoma related to primary angle closure glaucoma. Aust J Ophthalmol 1979. 7: p. 11.
- ↑ 12.0 12.1 Debrouwere, V., et al., Outcomes of different management options for malignant glaucoma: a retrospective study. Graefes Arch Clin Exp Ophthalmol, 2012. 250(1): p. 131-41.
- ↑ Aminlari, A. and J.W. Sassani, Simultaneous bilateral malignant glaucoma following laser iridotomy. Graefes Arch Clin Exp Ophthalmol, 1993. 231(1): p. 12-4.
- ↑ 14.0 14.1 14.2 Saunders, P.P., et al., Bilateral malignant glaucoma. Can J Ophthalmol, 1992. 27(1): p. 19-21.
- ↑ Cashwell, L.F. and T.J. Martin, Malignant glaucoma after laser iridotomy. Ophthalmology, 1992. 99(5): p. 651-8; discussion 658-9.
- ↑ DM, L., Ciliary block glaucoma, in Focal Points: Clinical Modules for Ophthalmologist1999: San Francisco.
- ↑ Azuara-Blanco, A. and H.S. Dua, Malignant glaucoma after diode laser cyclophotocoagulation. Am J Ophthalmol, 1999. 127(4): p. 467-9.
- ↑ Mathur, R., G. Gazzard, and F. Oen, Malignant glaucoma following needling of a trabeculectomy bleb. Eye (Lond), 2002. 16(5): p. 667-8.
- ↑ Pecora, J.L., Malignant glaucoma worsened by miotics in a postoperative angle-closure glaucoma patient. Ann Ophthalmol, 1979. 11(9): p. 1412-4.
- ↑ Lass, J.H., et al., Exogenous Nocardia asteroides endophthalmitis associated with malignant glaucoma. Ann Ophthalmol, 1981. 13(3): p. 317-21.
- ↑ Kushner, B.J., Ciliary block glaucoma in retinopathy of prematurity. Arch Ophthalmol, 1982. 100(7): p. 1078-9.
- ↑ Jacoby, B., J.W. Reed, and L.F. Cashwell, Malignant glaucoma in a patient with Down's syndrome and corneal hydrops. Am J Ophthalmol, 1990. 110(4): p. 434-5.
- ↑ Simmons, R.J., Malignant glaucoma. 3rd edition ed. Chandler and Grant's Glaucoma, ed. D.L. Epstein1986, Philadelphia: Lea & Febiger.
- ↑ 24.0 24.1 Quigley, H.A., Angle-closure glaucoma-simpler answers to complex mechanisms: LXVI Edward Jackson Memorial Lecture. Am J Ophthalmol, 2009. 148(5): p. 657-669 e1.
- ↑ Schwartz, A.L. and D.R. Anderson, Malignant glaucoma" in an eye with no antecedent operation or miotics. Arch Ophthalmol, 1975. 93(5): p. 379-81.
- ↑ Chandler, P.A. and W.M. Grant, Mydriatic-cycloplegic treatment in malignant glaucoma. Arch Ophthalmol, 1962. 68: p. 353-9.
- ↑ 27.0 27.1 Shaffer, R.N., The role of vitreous detachment in aphakic and malignant glaucoma. Trans Am Acad Ophthalmol Otolaryngol, 1954. 58(2): p. 217-31.
- ↑ Quigley, H.A., Malignant glaucoma and fluid flow rate. Am J Ophthalmol, 1980. 89(6): p. 879-80.
- ↑ 29.0 29.1 Shaffer, R.N. and H.D. Hoskins, Jr., Ciliary block (malignant) glaucoma. Ophthalmology, 1978. 85(3): p. 215-21.
- ↑ Fatt, I., Hydraulic flow conductivity of the vitreous gel. Invest Ophthalmol Vis Sci, 1977. 16(6): p. 565-8.
- ↑ Chaudhry, N.A., et al., Pars plana vitrectomy during cataract surgery for prevention of aqueous misdirection in high-risk fellow eyes. Am J Ophthalmol, 2000. 129(3): p. 387-8.
- ↑ Liebmann, J.M., R.N. Weinreb, and R. Ritch, Angle-closure glaucoma associated with occult annular ciliary body detachment. Arch Ophthalmol, 1998. 116(6): p. 731-5.
- ↑ Epstein, D.L., R.F. Steinert, and C.A. Puliafito, Neodymium-YAG laser therapy to the anterior hyaloid in aphakic malignant (ciliovitreal block) glaucoma. Am J Ophthalmol, 1984. 98(2): p. 137-43.
- ↑ 34.0 34.1 Herschler, J., Laser shrinkage of the ciliary processes. A treatment for malignant (ciliary block) glaucoma. Ophthalmology, 1980. 87(11): p. 1155-9.
- ↑ 35.0 35.1 Weber, P.A., et al., Argon laser treatment of the ciliary processes in aphakic glaucoma with flat anterior chamber. Am J Ophthalmol, 1984. 97(1): p. 82-5.
- ↑ 36.0 36.1 Stumpf, T.H., et al., Transscleral cyclodiode laser photocoagulation in the treatment of aqueous misdirection syndrome. Ophthalmology, 2008. 115(11): p. 2058-61.
- ↑ AlQahtani RD, Al Owaifeer AD, AlShahwan S, et al. Outcomes of Medical and Surgical Management in Aqueous Misdirection Syndrome. Clin Ophthalmol, 2023. 17:797-806.
- ↑ Francis, B.A. and D. Babel, Malignant glaucoma (aqueous misdirection) after pars plana vitrectomy. Ophthalmology, 2000. 107(7): p. 1220-2.
- ↑ Chandler, P.A., A New Operation for Malignant Glaucoma: A Preliminary Report. Trans Am Ophthalmol Soc, 1964. 62: p. 408-24.
- ↑ Koerner, F.H., Anterior pars plana vitrectomy in ciliary and iris block glaucoma. Albrecht Von Graefes Arch Klin Exp Ophthalmol, 1980. 214(2): p. 119-27.
- ↑ Byrnes, G.A., et al., Vitrectomy for ciliary block (malignant) glaucoma. Ophthalmology, 1995. 102(9): p. 1308-11.
- ↑ Bitrian, E. and J. Caprioli, Pars plana anterior vitrectomy, hyaloido-zonulectomy, and iridectomy for aqueous humor misdirection. Am J Ophthalmol, 2010. 150(1): p. 82-87 e1.
- ↑ Lois, N., D. Wong, and C. Groenewald, New surgical approach in the management of pseudophakic malignant glaucoma. Ophthalmology, 2001. 108(4): p. 780-3.
- ↑ Sharma, A., et al., Vitrectomy-phacoemulsification-vitrectomy for the management of aqueous misdirection syndromes in phakic eyes. Ophthalmology, 2006. 113(11): p. 1968-73.
- ↑ Azuara-Blanco, A., et al., Pars plana tube insertion of aqueous shunt with vitrectomy in malignant glaucoma. Arch Ophthalmol, 1998. 116(6): p. 808-10.