Complications of Uveitis

COMPLICATIONS OF UVEITIS

Band keratopathy

Long-standing chronic iridocyclitis or intraocular inflammation, especially in children, can result in deposition of calcium hydroxyapatite in the cornea at the level of Bowman's membrane, giving rise to a condition known as band keratopathy. Band keratopathy usually starts as grayish-white opacities at the periphery of the interpalpebral region. It is typically limited to the corneal periphery at the 3 o’clock and 9 o’clock positions. Gradually the opacification spreads centrally and forms a complete band within the interpalpebral zone. Bowman's layer does not extend to the limbus, the reason a lucid interval is noted between the band keratopathy and the limbus. Small clear areas are noted in the band keratopathy, giving rise to   characteristic "Swiss cheese" appearance. These small clear areas represent penetration or entry point of corneal nerves into Bowman's layer.
Profound band keratopathy can lead to the diminution of vision in patients with chronic anterior uveitis, especially in children. Thus it is of paramount importance to treat vision-robbing cases of band keratopathy in children with chronic anterior uveitis to prevent ambrosia.
 

Anterior segment fibrosis and adhesions

Iridolenticular adhesion or synechia following intense inflammation in the anterior chamber is a common complication following the recurrent attacks of acute anterior uveitis. In severe cases of such inflammation, there can be formation of a fibrotic membrane over the pupil. This membrane can occlude the pupillary aperture and can obstruct the aqueous outflow, leading to the formation of iris bombe and acute glaucoma. Formation of peripheral anterior synechiae in chronic anterior uveitis can also cause secondary glaucoma.
 

Glaucoma:

Glaucoma is a common complication of uveitis. The incidence of glaucoma is relatively more common in chronic than in acute uveitis.
During acute attack of uveitis, the IOP is often reduced because of ciliary body inflammation and increased uveoscleral outflow. With ongoing inflammation, various other mechanisms come in to play, leading to increase the resistance to aqueous outflow and subsequent rise in IOP.
The causes of elevated IOP include:

• Posner-Schlossman’s syndrome
• Herpetic uveitis
• Toxoplasmosis
• Fuchs’ heterochromic iridocyclitis
• Sarcoidosis
• Iridocyclitis with secondary angle closure glaucoma
• Secondary to treatment with steroids.

Identifying the exact mechanism of glaucoma in uveitic patients is challenging. Broadly secondary glaucoma in uveitis can be divided into three groups:  secondary open angle glaucoma, secondary angle closure glaucoma and combination of the two. 

Steroid-induced glaucoma

The therapeutic use of corticosteroids can lead to the rise of intraocular pressure (IOP).Increased IOP can occur as a consequence of any form of corticosteroid therapy - oral, intravenous, inhaled, topical, periocular, or intravitreal corticosteroid therapy. When treated with topical steroids for 4–6 weeks, 5% of the population demonstrates a rise in IOP greater than 16 mmHg and 30% shows a rise of 6–15 mmHg. Children and older patients are at increased risk of developing increased IOP in response to corticosteroid. Also patients with pre-existing POAG, glaucoma suspect, or history of POAG in first-degree relative are important risk factors and any form corticosteroid should be used judiciously and under proper monitoring. There are variable reports on time taken to show rise of IOP in response to corticosteroid and varies with mode of administration of corticosteroid. The rise of IOP usually occurs over a period of 4 to 6 weeks when used topically in majority of the patients. It is of paramount importance to understand that there is never a ‘safe’ period in patients on any form of corticosteroid, after which IOP monitoring becomes unnecessary. Usually IOP almost always returns to normal within days or weeks of disconnection of the corticosteroid treatment.

How does steroid cause glaucoma?
• Increased glycosaminoglycan in trabecular meshwork,
• Inhibition of phagocytic activity of meshwork cells,
• Inhibition of prostaglandins

The primary mechanism of corticosteroid-induced ocular hyper-tension is increased aqueous outflow resistance. Corticosteroids are believed to induce physical and mechanical changes in the microstructure of the trabecular meshwork causing decreased outflow of aqueous humor.

Corneal Decompensation

Corneal decompensation in patients with uveitis is rare. It is can be rarely seen in uveitis associated with corneal endotheliitis and in herpetic keratouveitis and is a well-recognized feature of chronic cytomegalovirus (CMV) anterior uveitis.

Phthisis

Phthisis is the dreaded complication of uveitis. Long standing inflammation can lead to deposition of exudates and cyclitic membrane over the ciliary body surface leading to diminished function or destruction ciliary processes. This can result into decrease or cessation of aqueous production resulting in hypotony. The definition of ocular hypotony is debatable, but it can probably be considered when IOP reduces to less than 6 mmHg. Patient experiences diminution in vision mostly due to massive fluctuating astigmatism  and fundus examination can show macular choroidal folds with or without disc edema often termed as  hypotonous maculopathy. The collapsing of the scleral wall causes a wrinkling of the choroid and the retina which can be attributed to the cause of hypotonous maculopathy. If not treated, can lead to phthisis of the globe. A physical globe often assumes a quadrilateral shape because of the action of four recti muscles on a hypotonous eyeball. 

Cataract

Cataract is one of the common complication of uveitis. Cataract formation in uveitic patient can be attributed to   intraocular inflammation or as a side effect of the treatment with corticosteroid. 
Posterior subcapsular cataract are most common, but complicated cataract with nuclear, cortical, and capsular opacities are also seen.  Often they are associated with posterior synechiae and pupillary membranes.
Cataract can also obscure the view of the fundus, making the evaluation of posterior segment very difficult. Also it is very important to determine whether vision loss is due to the cataract or due to some pathologies in posterior segment prior to any surgical intervention.

Cause of cataract in uveitis:

Macular Edema: 

Cystoid macular edema (CME) is caused by cystic accumulation of intraretinal fluid in the outer plexiform and inner nuclear layers of the retina as a result of the breakdown of the blood–retinal barrier. CME can cause profound visual loss and is one of the major causes of decreased vision in patients with uveitis. It can complicate virtually any type of acute or chronic, anterior or posterior uveitis. Common causes of uveitic CME are intermediate uveitis, pars planitis, Behçets disease.
The exact pathogenesis of uveitic CME remains unclear. Usually CME develops when excess fluid accumulates within the retina of macular region (both extracellularly and intracellularly), which is primarily thought to occur following disruption of the blood-retinal barrier. This fluid accumulation disturbs cell function and retinal architecture. In uveitic eyes, this disruption of blood retinal barrier believed to occur with the release of inflammatory mediators.
Müller cells function as metabolic pumps and are thought to play an important role in keeping the macula dehydrated. Intracellular fluid accumulation in these Müller cells cause significant damage to the metabolic pump action of retina and further reduce macular retinal function. Vitreous traction at the macula also has been proposed as another causative factor for the development of uveitic CME.
Fundus fluorescein angiography (FFA) is an important tool for the diagnosis and management of eyes with uveitic CME as it is more sensitive than clinical examination.   However, patients’ visual acuity has been found to correlate with the extent of macular thickening and not the severity of dye leakage on a FFA. Thus, the gold standard of assessing and following up patients with uveitic CME is with serial Optical coherence tomography (OCT).  

Epiretinal membrane:

Epiretinal membrane (ERM) is an avascular, fibrocellular membrane that proliferates on the inner surface of the retina and produces various degrees of visual impairment.  Long-standing intraocular inflammation can lead to ERM formation, surface wrinkling and vitreomacular traction.  
Epiretinal membranes contain glial cells, retinal pigment epithelial (RPE) cells, macrophages, fibrocytes, and collagen fibers. ERM starts as small patchy areas of reflection from the retinal surface which gradually progresses to form irregular, shiny sheets of the membrane. In severe cases, it may lead to surface wrinkling and potentially to massive retinal folding. Most of the time these membranes are asymptomatic. The most common presenting symptoms of ERM are decreased visual acuity, metamorphosis, micropsia and macropsia . The severity of symptoms is related to the involvement of macula and the thickness of ERM.
During biomicroscopical examination of fundus with a +90D or +78D lens,  an ERM is seen as a glistening transparent, translucent membrane. Retinal changes associated with ERM can be surface wrinkling, vasculature distortion, cystoid macular oedema or pseudohole. A fundus examination with a blue filter is often helpful.

ERM has been classified into three grades:
Grade 1:  cellophane membrane causing irregular wrinkling of the inner retina+ no elevated edge of ERM
Grade 2: ERM with full-thickness retinal distortion+ elevated edge of ERM elevated+ less than half of ERM is opaque causing obscuration of underlying retina and vasculature;
Grade 3:  Thick opaque membrane + half of the ERM opaque, causing marked obscuration and distortion of the underlying retina and vasculature

Fundus fluorescein angiography (FFA) has a limited role in the diagnosis and follow-up of an ERM. Optical coherence tomography (OCT) is very useful to monitor the progression of the membrane.

Retinal detachment:

Retinal detachment in uveitis can be of

• Exudative (Serous) retinal detachment can present as a part of the inflammatory process e.g. Vogt-Koyanagi-Harada syndrome
• Rhegmatogenous or tractional retinal detachment caused by traction secondary to intraocular inflammation e.g. Acute retinal necrosis syndrome 

Combined Tractional and Rhegmatogenous retinal detachment in Uveitis:

Abnormal vitreoretinal adhesions and tissue shrinkage are the two important components of retinal detachment in uveitis. In intraocular inflammation, abnormal adhesions exist between the vitreous and inflammatory fibrous or neovascular tissue. Shrinkage of fibrous tissue can result in the detachment of retina. Contraction of these fibrous bands can cause a retinal tear which in turn causes a rhegmatogenous detachment.

Panuveitis and infectious uveitic entities are most frequently associated with the combination of rhegmatogenous and tractional retinal detachment. Any substantial posterior uveitis can result into vitreoretinal traction which can lead to tractional retinal detachment. Rhegmatogenous detachment can supervene if traction is adequate and it becomes very difficult to identify the sole mechanism of detachment in such cases. Usually, vitreoretinal traction, resulting from intraocular inflammation can often cause retinal elevations that are characteristically self-limiting with adequate control of inflammation.  Tractional change is a characteristic feature of ocular toxocariasis. Retinal vasculitis has a tendency to produce traction specifically along the line of large retinal vessels. ARN and CMV retinitis frequently lead to retinal detachments that are difficult to repair because of multiple, large, posterior retinal breaks.  Pars plana vitrectomy (PPV) and endolaser treatment with silicone oil tamponade is required to repair the detachment and remove the epiretinal membranes. When PVR is present, combined sclera buckling and PPV are often required. Thus, the prognosis in eyes with uveitis and retinal detachment is particularly poor. Also, it is important to note that a chronic rhegmatogenous retinal detachment can often lead to the development of intraocular inflammation.
Exudative retinal detachment is typically a feature of severe choroidal inflammation, for example, sympathetic uveitis or VKH syndrome and posterior scleritis.  

Retinal ischemia and neovascularization

Intraocular inflammation can affect retinal circulation and sometimes can lead to vascular occlusion.  The most important factor for development of retinal neovascularization is retinal hypoxia which can result from vascular occlusion. Vascular occlusion is manifested clinically by capillary closure and loss of the retinal capillary bed. 
Retinal angiogenesis, the pathophysiological process behind the process of neovascularization, is   controlled by the release of a complex family of stimulatory and inhibitory growth factors from hypoxic retina which stimulates neovascularization on the retina, optic disc or choroid.  The most important factor is vascular endothelial growth factor (VEGF) which targets mainly vascular endothelial cells but can also act on RPE cells.
Neovascularization most frequently arises at the disc or the capillary bed at the edge of an infarcted area of retina, most commonly from the wall of a thickened venule and often begin as a tuft of fine vessels. When these new vessels  arise on or within one disc diameter of the optic nerve they are known as neovascularization of the disc ( NVD) and  the new vessels arising one disc diameter away from the optic disc are called neovascularization elsewhere( NVE ).
All these new blood vessels lack barrier properties and rapidly and intensively leak fluorescein during angiography. These vessels are sight-threatening because they are fragile and tend to bleed to obscure the media. They are also associated with fibrosis and membrane formation which can lead to traction retinal detachment.

Choroidal neovascular membrane:

Choroidal neovascular membrane (CNVM) is one of the most severe causes of visual impairment in patients with uveitis. A uveitic CNVM or inflammatory CNVM usually occur adjacent to any post-inflammatory outer retinal or subretinal scar. CNVM secondary to uveitis can occur in both infectious and noninfectious uveitic entities. Common causes inflammatory CNVM are listed in table

The majority of the inflammatory CNVMs are predominantly classical, and fundus fluorescein angiography is, therefore, excellent for diagnosis and monitoring.