Clinical approach to Uveitis

Parthopratim Dutta Majumder,MS, Department of Uveitis, Sankara Nethralaya,Chennai,India

 

CLASSIFICATION OF UVEITIS


Proper classification of uveitic entities is essential to avoid confusion and misinterpretation among ophthalmologists. There have been many classifications proposed for uveitis. This section deals with the various available classification systems of uveitis.


Pathological or Woods Classification:
One of the oldest classification of uveitis is Woods classification (also known as pathological or clinicopathological classification). This was proposed by Alan Churchill Woods.  Uveitis is classified as granulomatous or nongranulomatous on the basis of the predominant clinical characteristics.

Granulomatous Uveitis

Nongranulomatous Uveitis

Insidious onset and chronic course

Sudden onset and acute course

Absent or mild congestion

Severe episcleral congestion

Iris nodules (Keoppe’s and Bussaca’s nodules) are common

Iris nodules are uncommon

Medium to large keratic precipitates ( Mutton fat KPs) are seen

Fine, small keratic precipitates are seen

Posterior segment involvement is common

Posterior segment involvement is uncommon 

Table 1 :  Difference between granulomatous and nongranulomatous Uveitis

IUSG classification:
International Uveitis Study Group (IUSG) classification of uveitis was originally devised by the International Uveitis Study Group, accepted at the XXV International Congress of Ophthalmology, and published in 1987. This classification is largely based on the anatomic position of the inflammation within the eye. Though this classification system permits the description of the physical location of the uveitis, it does not attempt to describe the cause of the uveitis.

Anterior uveitis

Iritis, Anterior cyclitis, Iridocyclitis

Intermediate uveitis

Pars planitis, Posterior cyclitis, Hyalitis, Basal retinochoroiditis

Posterior uveitis

Focal, multifocal, or diffuse choroiditis, chorioretinitis, retinochoroiditis, or neurouveitis

Panuveitis

 

Table 2:  IUSG classification of uveitis

Standardization of Uveitis Nomenclature (SUN) Classification:
Most recent and widely accepted version of classifying uveitis is the Standardization of Uveitis Nomenclature (SUN) Classification. This classification was proposed in a workshop in Baltimore, Maryland, USA in 2004 under the aegis of International Uveitis Study group to devise a set of uniform criteria for classifying and grading of uveitis. According to SUN classification, uveitis was divided in to anterior, intermediate, posterior, and panuveitis according to their primary site of inflammation (table 3).

Type

Primary site of inflammation

Includes

Anterior uveitis

Anterior chamber

Iritis, Iridocyclitis, Anterior cyclitis

Intermediate uveitis

Vitreous

Pars planitis, Posterior cyclitis, Hyalitis

Posterior uveitis

Retina/Choroid

Focal, multifocal, diffuse choroiditis
Chorioretinitis, Retinochoroiditis, Retinitis, Neuroretinitis

Panuveitis

Anterior chamber, vitreous and retina or choroid

 

Table 3 SUN classification of uveitis

Unlike the previous classification systems of uveitis, SUN classification has addressed various ambiguities of the uveitic nomenclature.

Various descriptors for defining onset, duration, and course of uveitis have been proposed in SUN classification (table 2).

Category

Descriptor

Description

Onset

Sudden

Acute onset

Insidious

Slow onset

Duration

Limited

≤3 months duration

Persistent

>3 months duration

Course

Acute

Episode characterized by sudden onset and limited duration

Recurrent

Repeated episodes separated by periods of inactivity without treatment <3 months in duration

Chronic

Persistent uveitis with relapse in <3 months after discontinuing treatment

Table 4 SUN Classification: Descriptors of uveitis

Grading of cells and flare was also addressed in SUN classification (Discussed in section 1.4).While grading cells in anterior chamber in inflammation, 0.5+ was advocated over the term “trace” and separate documentation of  the presence or absence of a hypopyon was recommended. Though no consensus could be reached on a standard grading system for vitreous cells. The National Eye Institute system for grading vitreous haze was adopted in this classification. Based on these parameters, terminology regarding activity of a uveitic entity has been depicted (table 1.1.3).

Term

Description

Inactive

Grade 0 cells (anterior uveitis)

Worsening activity

Two step increase in level of inflammation (e.g. anterior chamber cells, vitreous haze) or increase from grade 3 to 4

Improved activity

Two step decrease in level of inflammation (e.g. anterior chamber cells, vitreous
haze) or decrease to grade 0

Remission

Inactive disease for 3 months after discontinuing all treatments for eye disease

Table 5 SUN classification: Activity of uveitis

Further reading:
Standardization of Uveitis Nomenclature for Reporting Clinical Data. Results of the First International Workshop. Am J Ophthalmol 2005; 140:509–516.

 HISTORY TAKING IN UVEITIS


An elaborate history taking is the corner stone of the management of a case of uveitis. It has been estimated that more than 75 % of diagnoses can be made on the basis of the medical history and a thorough systemic examination. Because of frequent association of uveitis with rheumatologic, infectious diseases it is very important to look beyond the eye and to perform a thorough physical examination and to obtain a meticulous history to clinch the diagnosis.

1. Demographics:
 Age: Age is an important factor in history taking as few conditions are known to occur more predominantly in some age group.

Age Group

Clinical entities commonly seen

Children

Juvenile rheumatoid arthritis, retinoblastoma, toxocariasis, Masquerade syndrome

Young adults

Pars planitis, multiple sclerosis, and Fuchs' heterochromic iridocyclitis

Middle age

Reiter's syndrome, Ankylosing spondylitis, Acute multifocal posterior placoid epitheliopathy, Vogt-Koyanagi-Harada syndrome, Behçet's disease

Old age

Large cell lymphoma or choroidal melanoma, Endogenous endophthalmitis, Masquerade syndrome

However it should be kept in mind that certain diseases like toxoplasmosis, sarcoidosis and tuberculosis can be found at any age.
Gender:
Uveitis associated with juvenile rheumatoid arthritis is found much more frequently in females, while uveitis associated with ankylosing spondylitis and Reiter's syndrome is usually seen in males. Most of the patients with Behçet’s disease are males.

Male predominance

Juvenile rheumatoid arthritis, Rheumatoid arthritis

Female predominance

Ankylosing spondylitis , Reiter's syndrome, Behçet’s disease

Race:
Conditions like Ankylosing spondylitis, Reiter's syndrome, and other HLA-B27-associated arthritides are common in whites and Sarcoidosis occurs most commonly in blacks. Vogt-Koyanagi-Harada syndromes are most prevalent in Asians. In the Mediterranean countries, Behçet's disease is more common.

Geographical location:                
Geographical location of the patient often helps us in diagnosis of certain conditions as few clinical entities are more commonly seen in the some specific parts of the world. For example Behcet’s disease is more common in countries situated along the old Silk Road, a trade route used for centuries by Greeks, Romans and Chinese. Reported rates of the disease is higher the countries, situated along this route and highest in two ends of the old silk road – Turkey and Japan.

Tuberculosis

Developing countries

Histoplasmosis

Mississippi-Ohio-Missouri River Valleys

Coccidioidomycosis

Southwest United States ,Central and South America

Birdshot Choroiditis

USA

Lyme disease

USA

Behcets Disease

Turkey, Iraq, Saudi Arabia, Iran, Afganisthan, Pakistan, Northern Chiana, Mongolia, The Koreas and Japan

Diet, Domestic and Personal Factors:

Systemic History and examination:
A detailed history of various systemic diseases should be taken. History of tuberculosis should be taken in patients with vasculitis, choroiditis etc.  Endogenous endophthalmitis is more common in old patients with diabetes mellitus, renal failure and with patients on immunosuppressant. It is of paramount importance to look for the evidence of septic foci like boil, carbuncle, abscess etc. in such patients.
Arthralgia: An elaborate history of joint pain should be taken especially in patients presenting with nongranulomatous uveitis. Information on type of joint involved, onset, timings and nature of the joint pain often provides useful clue to the diagnosis of a case of uveitis.

Signs

Uveitic entities

Arthralgias

Behçet disease, sarcoidosis, SLE, juvenile idiopathic arthritis (JIA), Lyme disease, syphilis, psoriatic arthritis, Reiter syndrome, ulcerative colitis

Skin lesions: Rashes can be seen in various conditions with uveitis. Malar butterfly rashes can be seen in patients with systemic lupus erythematous (SLE).Thickening of skin can be seen in patients with scleroderma. Increased cutaneous sensitivity can be seen in various conditions including SLE, Behçet’s disease. Acne-like eruptions are often seen in certain conditions like Behçet’s disease and it should be differentiated from similar skin lesions seen in patient on oral corticosteroid therapy.

Skin Lesions

Uveitis Entities

Nodules

Sarcoidosis, SLE, leprosy, Crohn disease, ulcerative colitis

Rash

Syphilis, Lyme disease, Reiter syndrome, leprosy, sarcoidosis, herpes zoster, Behçet disease, psoriasis, SLE, Kawasaki disease

Erythema nodosum

Behçet disease, sarcoidosis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), tuberculosis

Vitiligo, Poliosis

Vogt-Koyanagi-Harada syndrome (VKH)

Keratoderma blennorrhagicum

Reactive arthritis

Hair loss: Hair loss can be seen in patient with Vogt-Koyanagi-Harada syndrome (VKH), SLE and syphilis. Abnormalities like poilosis is common in VKH patients and madarosis can be seen in leprosy patients. Increased sensitivity to hair is often complained by patients with VKH.
Oral ulcer: Aphthous ulceration can be seen in patients with Behcet’s disease, reactive arthritis, SLE, herpes simplex, Reiter syndrome, ulcerative colitis etc.

Central nervous system:
Neurological signs are common during prodromal stage of Vogt-Koyanagi-Harada syndrome (VKH) and can include neck stiffness, headache and confusion. Patients of VKH can have auditory symptoms like tinnitus, dysacusis (difficulty in processing details of sound due to distortion in frequency or intensity), vertigo etc. Similarly demyelinating diseases like multiple sclerosis should be ruled out in cases with intermediate uveitis, retinal vasculitis etc.

Signs

Uveitic entities

Headache

Vogt-Koyanagi-Harada syndrome (VKH), tuberculosis, herpes zoster, large cell lymphoma, Cryptococcus meningitis, toxoplasmosis

Auditory/vestibular

VKH disease

Cranial neuropathy

Lyme disease, sarcoidosis, multiple sclerosis, syphilis, herpes simplex virus

Cerebral vasculitis

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE)

Examination of Ear, Nose and Throat:
Examination of ear, nose and throat is also important. Relapsing polychondritis is a rare small-vessel vasculitis which predominantly affect cartilaginous structures of the body such as pinna of the ear, nasal cartilage, larynx and trachea. Relapsing polychondritis should be ruled out in patients with episcleritis and scleritis. Saddle nose deformity is characterized by a loss of height of the nose, because of collapse of the nasal bridge. Saddle nose deformity in a patient of uveitis should give rise to the suspicion of conditions like Wegener’s granulomatosis, leprosy, syphilis or relapsing polychondritis.

Signs

Uveitic entities

Bilateral ear pinna inflammation

Relapsing polychondritis

Saddle nose deformity

Syphilis, Wegener granulomatosis (SLE), relapsing polychondritis

Sinusitis

Sarcoidosis, Wegeners granulomatosis

Salivary/lacrimal gland swelling

Sarcoidosis, lymphoma

Lymphadenopathy

Lymphoma, HIV

 

Gastrointestinal
Though uncommon, uveitis can be associated with Crohn disease, ulcerative colitis.

Pulmonary:
Pulmonary involvement is common in various uveitic conditions, especially granulomatous uveitic entities. It is very important to elicit a proper history regarding symptoms like hemoptysis, dyspnea, cough, sputum, chest pain and fatigue.

Signs

Uveitic entities

Cough/breathlessness

Tuberculosis, sarcoidosis, Pneumocystis carinii, Wegener granulomatosis

Nodules/hilar adenopathy/infiltrates

Ocular histoplasmosis, sarcoidosis (hilar adenopathy), malignancy, tuberculosis, Pneumocystis carinii pneumonia

Genitourinary system:
Examination of genitourinary system is important as many uveitic entities can have genitourinary involvement which can help one to clinch the diagnosis. However history taking or examination of genitourinary system should be conducted tactfully so that the patient does not become embarrassed, or offended. Recurrent genital ulcer is a common feature of Behcet’s disease, but urethritis is not common feature of the disease. Presence of urethritis in a uveitic patient with joint pain can give clue to the diagnosis of reactive arthritis (previously called Reiter’s Syndrome). Also circinate balanitis is a common feature of reactive arthritis. Circinate balanitis is a form of skin inflammation where skin around the shaft and tip (glans) of the penis become inflamed and scale.

Signs

Uveitic Entities

Genital ulcers

Behçet disease, Reiter syndrome, syphilis

Hematuria

Wegener granulomatosis, polyarteritis nodosa (PAN), systemic lupus erythematosis (SLE)

Circinate balanitis

Ankylosing spondylitis, Reiter syndrome

Nephritis

PAN, Wegener granulomatosis, tubulointerstitial nephritis and uveitis (TINU)

 

SYMPTOMS OF UVEITIS


The symptoms in a case of uveitis depend on various factors. These are: part of the uveal tract involved, presentation and course of the uveitic entity (acute or chronic) and onset (sudden and insidious). For example a case of anterior uveitis can present with an acute, chronic, or recurrent form. The severity of symptoms can range from very severe symptoms in a case of sudden onset acute uveitis to nil or minimal symptoms in a case of insidious-onset chronic anterior uveitis.
Ocular Pain
The pain in iridocyclitis is due to ciliary spasm. The ciliary body is innervated by the trigeminal nerve, and pain caused by irritation of the nerve endings by the product of inflammation. The pain in uveitis can be variable and mostly described as a dull aching or a throbbing pain localized to the eye. Sometimes it can be associated with referred pain which seems to radiate over a larger area served by the trigeminal nerve.
Pain in scleritis is typically dull and boring in nature, exacerbated by eye movement, is worse at night often interfering with sleep, and characteristically wakens the patient from sleep.
Photophobia:
Photophobia or intolerance to bright light is often accompanied by tearing (watering) and blepharospasm. Photophobia is usually caused by ciliary muscle spasm but can also be due to with pupillary muscle involvement or corneal involvement.
Redness of eye:
Redness of the eye in uveitis is primarily due to ciliary injection or circumcorneal injection, or "ciliary flush." It is manifest by a ring of dilated or engorged episcleral vessels radiating from the limbus.
Blurred vision and floaters:
Blurred vision is usually caused by cloudy media. Intermediate uveitis most often presents with floaters and blurred vision. Floaters occur because of shadows cast by the products of inflammation in vitreous like vitreous cells, debris etc. Most common cause of decreased vision in these patients is cystoid macular edema (CME).
Posterior uveitis usually presents with decreased vision, floaters, photopsias, metamorphopsia, scotomata, nyctalopia or a combination of these. The decreased vision may be due to the primary effects of inflammation involving retina and choroid, often directly affecting macular function or due to the complications of inflammation like CME, epiretinal membrane (ERM), Retinal ischemia, choroidal neovascular membrane (CNVM).

1.4 EXAMINATION OF A PATIENT OF UVEITIS

1. External examination and examination of lid and adnexa:
A careful examination of lid and adnexa can provide important clue in patients with uveitis.

2. Ocular examination:
A. Examination of conjunctiva:

Ciliary Injection

Conjunctival Hyperemia

Engorgement of episcleral vessels

Engorgement of anterior and posterior conjunctival vessels

Bright reddish violet in color

Bright red in colour

Radially arranged blood vessels

Irregular branching vessels

Most intense near limbus

Most intense in fornix

Blood vessels do not move with conjunctiva

Moves with conjunctiva

Blood flow is from limbus to fornix

Blood flow is from fornix to limbus.

 

B. Examination of Anterior chamber:
Cells: Cells in the aqueous humor is generally seen after inflammation of the iris and ciliary body. Cells in the anterior chamber are counted using slit-lamp with a beam of 1 x 1 mm slit and graded according the SUN Working Group Grading Scheme (table 1.3.1).

Grade

Cells in Field of 1 mm by 1 mm slit beam.

0

< 1

0.5+

1–5

1+

6–15

2+

16–25

3+

26–50

4+

> 50

Table SUN Working Group Grading Scheme for Cells
  • Polymorphonuclear leucocytes are the predominant cells in an acute case and in chronic cases, lymphocytes, plasma cells, monocytes and macrophages are seen.
  • Larger cells are generally swollen macrophages or clumps of lymphocytes
  • Inflammatory anterior chamber cells are generally white in colour and should be not be confused with pigmented cells. Pigmented cells can be iris pigments, dead erythrocytes, or macrophages filled with pigment like melanin.
  • Iris pigments can be seen in the anterior chamber after dilatation and should be distinguished from cells.
Cells in aqueous humor migrate across the iris and ciliary vessels and depending on the nature and severity of inflammation, their numbers and types varies. In the aqueous, the cells are seen circulating due to the convection current.

Flare:             In normal condition aqueous humor is optically empty and if a slit- lamp beam is passed through it, it cannot be seen.  In case of inflammation, when breakdown of the blood-aqueous barrier occurs, there is increased protein content in the aqueous and if slit beam is obliquely aimed across the anterior chamber, the path of the beam can be seen, which is termed flare. Flare is graded according to the scheme proposed by SUN classification (Table 1.3.2).

Grade

Description

0

None

1+

Faint

2+

Moderate (iris and lens details clear)

3+

Marked (iris and lens details hazy)

4+

Intense (fibrin or plastic aqueous)

Table SUN Working Group Grading Scheme for flare

Flare is often the first sign of uveitis and it may persist despite adequate control of inflammation.

Flare can also be measured using a laser flare photometry, which quantifies anterior chamber protein by measuring light scattering of a helium-neon laser beam in the anterior chamber.

Hypopyon:  Often the inflammatory circulating cells particularly leucocytes can deposit at the bottom of the anterior chamber and can form hypopyon. Thus it is very essential to examine the area of the inferior limbus in uveitic patient. SUN classification has recommended that presence or absence of a hypopyon should be recorded separately while documenting a case of uveitis.  It should be kept in mind that hypopyon frequently occurs in patients with endophthalmitis and should always be ruled out especially in patients who had undergone recent intraocular surgery.

Causes of Hypopyon:
  • HLA B 27 ant Uveitis
  • Ankylosing spondylitis
  • Behçet’s disease
  • Endophthalmitis
  • Drugs: rifabutin

Hypopyon seen in Behçet’s disease is mobile and often visible only during gonioscopy (microhypopyon). Often retained lens fragments, tumor cells can deposit in anterior chamber and mimic hypopyon .These are known as Pseudohypopyon.

Hyphema: In some rare cases erythrocyte can sediment in anterior chamber causing hyphema. The causes of hyphema are listed below.

Causes of Hyphema
  • Viral uveitis
  • Trauma
  • Malignancies
  • Fuchs
  • Chronic uveitis with rubeosis
  • Any severe uveitis
  • Post anterior chamber taps

C. Examination of cornea:

Keratic precipitates: Due to the convection current in anterior chamber, the circulating inflammatory cells can deposit in corneal endothelium which is known as keratic precipitates (KPs). KPs are normally deposited in inferior half of the cornea in base down triangle shaped configuration (Arlt’s triangle).

Band shaped keratopathy: Deposition of calcium hydroxyapatite in Bowman's layer can be seen in condition like chronic uveitis, juvenile idiopathic arthritis. It typically begins at the periphery of the interpalpebral region and spread centrally. If visual axis is involved it can cause marked diminution of vision. On slit-lamp examination, small clear dot like areas are observed giving "Swiss cheese" appearance to band keratopathy. These clear small dot like areas represent the location where corneal nerves penetrate Bowman's layer.
Scar or Ulceration:

D. Examination of pupil:

Posterior synechiae can lead to pupillary block glaucoma and peripheral anterior synechiae can cause  secondary angle closure glaucoma

E. Examination of Iris:

Causes of iris atrophy

  • Viral infections
  • Anterior segment ischemia,
  • Leprosy,
  • syphilis
  • Previous attacks of angle-closure glaucoma.
  • Iatrogenic (previous intraocular surgery)

F. Intraocular pressure (IOP):

 The cause of rise of intraocular pressure in uveitis can be due to:

  • clogging of trabecular meshwork with inflammatory cells,
  • inflammation of  trabecular meshwork fibers (“trabeculitis”),
  • Peripheral anterior synechiae  
  • Pupillary block from posterior synechiae, and
  • Corticosteroid-induced IOP rise (steroid responder).

G. Examination of lens:

H. Examination of vitreous:

0

nil

0.5+

trace

1+

Few opacities, mild blurring

2+

Significant blurring, but still visible

3+

Optic nerve visible, no vessels visible

4+

Dense opacity obscures optic nerve head

Table National eye institute grading system for vitreous haze (adopted by SUN classification)

 

I. Examination of Fundus:

Arterial involvement (arteritis)

Venous involvement (phlebitis)

  • Acute retinal necrosis ,
  • Systemic lupus erythematosus
  • Behçet's disease
  • Sarcoidosis
  • Frosted branch angiitis

 

Retinitis

Choroiditis

  • Appears as a whitish patch
  • Ill-defined margins.
  • Superficial
  • Appears as yellowish patches
  • Relatively well defined margins
  • Deeper(deep to the retinal blood vessels)

 

 

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 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 anterior chamber is a common complication following recurrent attack 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:

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. 

Type of Glaucoma

Causes

Secondary open angle glaucoma

  • Mechanical obstruction of the trabecular meshwork by products of inflammation or due to swelling of the trabecular lamellae due to inflammation
  • Biochemical and structural changes in the trabecular meshwork induced by corticosteroid
  • Inflammation induced

Secondary angle closure glaucoma

  • Pupillary block due to 3600 posterior synechiae
  • PAS
  • Rotation of ciliary body due  to oedema and inflammation or ciliochoroidal effusion

Combined mechanism

  • Combination of the above two mechanism

 

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:

Intraocular Inflammation

Corticosteroid induced catractogenesis

  • Impaired nutrition  to the lens
  • Formation of inflammatory membrane over pupillary area

• Disulphide bond formation
• Increased cation permeability
• Decreased G6PD activity
• Binding of steroids to lens proteins
• Increased glucose concentration in lens

 

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 retinal surface which gradually progresses to form irregular, shiny sheet of 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. 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 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

Type of retinal Detachment associated with uveitis

Common causes

Exudative (Serous) retinal detachment

Vogt-Koyanagi-Harada syndrome, Sympathetic ophthalmia, Posterior scleritis

Combination of rhegmatogenous and tractional retinal detachment

Toxoplasmic retinochoroiditis, Pars planitis
Behçet's disease, Acute retinal necrosis syndrome, Cytomegalo virus retinitis, Ocular toxocariasis

 

Combined Tractional and Rhegmatgenous 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 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 are required to repair the detachment and remove the epiretinal membranes. When PVR is present, combined sclera buckling and PPV is 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 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. The clinical features and characteristics of exudative detachment have described with relation to specific entities elsewhere in this book.
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

Infectious uveitic entities

Noninfectious uveitic entities

Toxoplasmosis, Toxocariasis,, Tuberculosis, viral retinopathies, Presumed ocular histoplasmosis syndrome

Punctate inner choroidopathy (PIC), Multifocal choroiditis (MFC), Acute posterior multifocal placoid pigment epitheliopathy (APMPPE), Vogt-Koyanagi-Harada (VKH) disease, Behçet’s disease, Serpiginous choroiditis

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