Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

Figure 8: Fundus photograph showing an epiretinal membrane over macula in a case of chronic pars planitis

Figure 9: Slit lamp photograph showing band shaped keratopathy in a case of pars planitis

have to be explained to the patient. The complication rate is quite high in these patients. The most common complications are posterior subcapsular cataract and cystoid macular oedema. Band shaped keratopathy (Figure 9) and secondary glaucoma due to peripheral anterior synechiae are rare complications.17

In the healing stages, several changes can occur in pars planitis. Pars plana exudates in the periphery can transform into fibroglial mass. Racemose neovascularisation can occur in the late stages which can bleed (Figure 10). Vitreous haemorrhage has been reported in about 3% cases. Vitreoretinal traction can give rise to tractional as well as rhegmatogenous retinal detachment. Occasionally one may see optic disc

Figure 10: Fundus drawing showing Neovascularisation at the pars plana in a case of pars planitis

changes such as optic disc oedema, optic atrophy, and neovascularisation. Optic disc neovascularisation has been reported in 9 out of 163 eyes (5.5%) in a series.18 We have noted neovascularisation of the disc (NVD) in very few cases of pars planitis compared to this series.

DIFFERENTIAL DIAGNOSIS

The disease in various stages mimics other conditions. Table 3 lists the conditions which should be considered in the differential diagnosis.

Table 3: Differential diagnosis

SPECIFIC ENTITIES THAT CAN PRESENT AS AN INTERMEDIATE UVEITIS

Specific entities can present as an intermediate uveitis even with the occurrence of the typical snow banks. Granulomatous signs have to be searched as tuberculosis and sarcoidosis can present as an intermediate uveitis. The presence of only a few or even one granulomatous keratic precipitate (KP) is enough to exclude the entity of pars planitis or idiopathic uveitis. Another sign that has to orient the clinician towards a specific diagnosis and is incompatible with the diagnosis of pars planitis are irido-lenticular or posterior synechiae.

Other specific diagnoses that can cause intermediate uveitis are sarcoidosis, tuberculosis, multiple sclerosis, Lyme disease (USA) and HTLV type I viral infection (Japan). Zierhut et al14 found that 9.7% of patients with “pars planitis” had sarcoidosis. Other than idiopathic cases, sarcoidosis and tuberculosis are common associations with intermediate uveitis in our set up. Apart from pulmonary manifestations such as hilar lymphadenopathy, patients with sarcoidosis were proven by biopsy of the conjunctival or skin granuloma, or by bronchoalveolar lavage. Most of these patients present with granulomatous uveitis. A report indicates a 14.8% incidence of multiple sclerosis in “pars planitis” patients in a follow up period of more than 7.5 years.17 We have a young patient with repeated recurrences of intermediate uveitis who has a demyelinating disease though not proven definitively as multiple sclerosis. In case of patients with optic neuritis, such association was found to be 22.2%. Increased HLA DR2 antigen was also found in these patients. It is interesting to note that HLA DR2 antigen is seen in patients with multiple sclerosis.22

In a prospective study of 53 patients with pars planitis by Raja et al,22a an association was found with the human leukocyte antigen DR15 (HLA-DR15) antigen, a suballele of HLA-DR2. This has the highest association with intermediate uveitis presenting in 64.3 to 72% in comparison to 20-28% in controls. This supports previous studies showing a similar relationship.

Lyme disease, a spirochaetal infection caused by Borrelia burgdorferi and transmitted by Ixodes damini tick can be associated with pars planitis. Friedman23 reported five cases of pars planitis with Lyme disease. Breeveld and coworkers24 reported a case of chronic intermediate uveitis with classic snow banking and severe cystoid macular oedema probably due to

Lyme borreliosis. The patient responded to intravenous ceftriaxone treatment. Mochizuki et al25 found a 44.8% incidence of positive serology for human. Lymphotrophic virus type I in idiopathic intermediate uveitis, in comparison to 9.3% controls in Japanese patients.

DIAGNOSIS

ANCILLARY TESTS

Fundus photography, Fluorescein angiography and OCT are quite useful in the management of intermediate uveitis especially in the detection of cystoid macular oedema (CMO). FA is also very useful in detecting subtle vasculitic patches or neovascularisation. Patchy staining of major retinal veins has been observed in a study.16 Arellanes and associates26 demonstrated the evidence of several angiographic features in pars planitis patients. This includes capillary hyper-fluorescence, optic disc hyperfluorescence, staining of the vessel walls and fern pattern radial hyper-fluorescence surrounding the optic disc. OCT can demonstrate cystoid spaces in the macula. Accurate quantification of macular oedema is possible by measuring the central macular thickness which is very helpful in follow-up. OCT being noninvasive, thus has better role in follow-up.

ULTRASOUND BIOMICROSCOPY

Ultrasound biomicroscope – 50 MHZ (Humphrey, USA) can be used in cases of small pupil or dense cataract where visualisation of fundus examination is difficult due to small pupil or dense cataract to detect exudates or membranes over the pars plana (Figure 11).27

ELECTROPHYSIOLOGICAL TESTS

Electrophysiological testing may indicate widespread dysfunction of retina in some patients of intermediate uveitis. In a study by Cantrill and associates28 abnormal b-wave implicit time and reduction or absence of scotopic b-wave oscillation were seen in patients with pars planitis of duration of over 2 years.

OPTICAL COHERENCE TOMOGRAPHY

Intermediate uveitis, by nature is recurrent and needs to be followed up at frequent intervals. Macular

Figure 11: Ultrasound biomicroscopic photograph using 50 MHZ probe showing exudates at pars plana and vitreous base (arrow)

Figure 12: OCT showing cystoid spaces at macula and increased macular thickness in a case of intermediate uveitis

oedema is the main cause of defective vision in patients with intermediate uveitis and has to be detected and treated early as it may lead to chronic changes which are resistant to treatment. OCT can detect subtle macular changes better than other modalities of investigations. It is also helpful in quantifying macular oedema thus very helpful in follow-up and titrating the therapy (Figure 12).

OCT can also detect causes of vision loss due to other chronic changes in patients with intermediate

Figure 13: OCT scan showing a full thickness macular hole in a case chronic intermediate uveitis

Figure 14: OCT performed with the OTI OCT/SLO instrument showing an epiretinal membrane with tenting of the macula after longstanding intermediate uveitis (right image). On the left SLO image of the fundus showis dark shadows from vitreal snow ball opacities (Courtesy Carl P. Herbort, Lausanne, Switzerland (SRD))

uveitis like epiretinal membrane, macular hole, etc. (Figures 13 and 14).

LABORATORY INVESTIGATIONS

The diagnosis of intermediate uveitis is clinical. Laboratory investigations are not always helpful as they are mostly idiopathic. However one may order tests for tuberculosis, sarcoidosis or Lyme disease, e.g. in case of granulomatous anterior uveitis with pars planitis. Tuberculosis as a possible cause should always be kept in mind especially in developing nations. Increased association with HLA DR2 antigen has been found in pars planitis as well as multiple sclerosis. Positive HLA DR2 antigen may indicate an underlying multiple sclerosis in suspected cases. Common laboratory tests that may be helpful in diagnosis is outlined in Table 4.

Flow chart 1 shows a systemic diagnostic approach to perform a differential diagnosis in intermediate uveitis.

PATHOLOGY29,30

Pathological studies of pars planitis cases are limited. On gross examination extensive scarring over the pars plana was seen (Figure 17). Microscopic study of the snow ball opacities showed epithelioid cell granulomas. Pathological study of the ‘snow bank’ showed condensed vitreous, spindle cells, blood vessels and hyperplastic non-pigmented epithelium of the pars plana with a few scattered lymphocytes. Such paucity of inflammatory cells indicates that the presence of ‘snow bank’ is rather suggestive of a chronic inflammation with reactive changes, than an acute inflammation (Figure 18).

IMMUNOLOGY

There have been various studies on the immunohistochemistry of the snow bank in pars planitis.31 Wetzig et al32 have examined a family in which to brothers with identical HLA typing had pars planitis with snowbanking. Their findings suggest that the snowbank could be formed by the glial elements of the peripheral retina. The chronic inflammation in pars planitis appeared to consist of helper T cells, both in the pars plana, and the retinal vasculature.

Various studies have shown several immunological abnormalities in the serum of pars planitis patients. Rahi et al33 found significantly decreased levels of a

Figure 15: Chest X ray showing typical lambda sign (right paratracheal and bilateral lymphadenopathy in a case of suspected sarcoid intermediate uveitis (I would leave this figure out as sarcoidosis is only a marginal diagnosis in IU)

Figure 16: CT chest – In a case of suspected sarcoidosis or malignancy (please give more explanations)

particular complement (C3) in the serum of pars planitis patients. Kaplan34 observed a relatively increased number of B cells and null cells in comparison to T cells in the aqueous and vitreous of patients with pars planitis. It was concluded that the normal T cells regulation of B cell function is deranged in this condition. However, in another study using fluorescein labelled monoclonal antibodies against cell surface molecules, Nolle and Eckardt35 have demonstrated T cells in vitreous of patients with

Figure 17: Cut section showing pars plana membranes

Figure 18: Microphotograph showing fibroglial tissue adhered to the pars plana with a few chronic inflammatory cells (haematoxylin and eosin, X 100) (Courtesy Prof Narsing A Rao, Doheny Eye Institute. USA). (please give more explanations with arrows at least to situate where we are)

intermediate uveitis as the most common cells followed by macrophages and B-lymphocytes.

Human leukocyte antigens have been associated with several uveitic entities, e.g. acute anterior uveitis (HLA B27), Birdshot retinochoroidopathy (HLA A29), Behçet’s disease (HLA B51), etc.36 Malinowski, et al37 found a 67.5% incidence of HLA DR2 antigen in intermediate uveitis due to multiple sclerosis. Other interesting immunologic findings are raised intercellular adhesion molecules (ICAM-1) in the serum of patients with pars planitis.38

Bora et al39 reported elevated levels of a protein (P36) in the serum of active pars planitis patients in

comparison to the control and healed pars planitis. The protein was also cloned from a human spleen cDNA library.40 The role of this protein in pars planitis is still to be determined but its correlation with disease activity may provide an important marker for diagnosis and therapy.

Immunological study of the snow bank over pars plana showed a ratio of helper/inducer cells (CD4) to suppressor/cytotoxic cells (CD8) of approximately 10:1. Similar pattern of ratio of CD4+ T cells to CD8+ T cells was noticed in multiple sclerosis which is often associated with pars planitis. Most of these lymphocytes were found to bear class II HLA antigens. Type IV collagen and laminin were found to be the major glycoprotein in the exudates.32

Murphy et al have studied the Systemic CD4 T cell phenotype and activation status in intermediate uveitis and concluded that ”the expression of CD 69 and TNF alpha by peripheral blood CD 4 lymphocytes of patients with idiopathic intermediate uveitis and presumed sarcoid intermediate uveitis was significantly higher than controls”.41

HEREDITY

There are several reports of familial occurrence of this disease and we have also reported intermediate uveitis of the pars planitis type in identical twins.42

PATHOGENESIS

The exact etiopathogenesis of this disorder is yet to be ascertained. Several investigators (Gärtner43; Bec7 and Lützen-Drecoll44) have demonstrated the presence of anatomic features that can promote inflammation in the region. Cell breakdown products in the vitreous base and probably embryonic vitreous can act as antigens. Relative ischemia in this area can also make it prone to inflammation. In addition, vitreous base rich in cellular elements and debris might act as antigenic stimuli. Relative low oxygen tension has also been noted.

Systemic diseases, e.g. sarcoidosis, tuberculosis and Lyme disease can present as intermediate uveitis with snow balls and snowbanks. Dernouchamps and Tassignon reported four cases of intermediate uveitis associated with extraocular infectious diseases where

antibiotic therapy of extraocular infection resulted in remission of pars planitis.45 Ormerod and associates46 reported a case in which the patient developed persistent pars planitis following cataract extraction and Propionibacterium acne was isolated from vitreous specimen. The case indicates that postoperative P. acnes infection can masquerade as pars planitis.

As no specific aetiology is found for idiopathic intermediate uveitis or intermediate uveitis of the pars planitis type, the treatment of this condition remains nonspecific. This disease is by nature slowly progressive and often self-limiting. Although aetiology of idiopathic intermediate uveitis is still not understood, it is possible that an immune mediated response against hyaluronic acid, a principal vitreous humour protein, could be involved. Further research is needed to elucidate the exact aetiopathogenesis.

TREATMENT

There are two schools of thought regarding treatment of intermediate uveitis. One school of though is that, treatment of intermediate uveitis is indicated only when the patient’s vision is diminished to 6/12 or less, or if there is evidence of cystoid macular oedema. While the general consensus is that intermediate uveitis needs to be treated inspite of a patient’s presenting vision of better than 6/9. Since there is always a risk of the increase in the inflammation progressively, which itself can be associated with the development of cystoid macular oedema, this school of though seems to be the more logical one. The degree of treatment may vary based on the vision and the nature of inflammation. Kaplan47 decribed a 4 step approach which is no longer to be recommended as ophthalmologists have more experience with the use of immunosuppressives and as new biological treatments are now available. Cryotherapy has practically be abondoned nowadays.48

Graded approach of the treatment idiopathic intermediate uveitis and/or intermediate uveitis of the pars planitis type

Step 1 – Periocular depot steroids (triamcinolone) Step 2 – Systemic steroids

Step 3 – Addition of immunosuppressives Step 4 – Biological agents (TNF-alpha blockers) Step 5 - Vitrectomy

1.PERIOCULAR DEPOT STEROIDS POSTERIOR SUBTENON INJECTION

Posterior subtenon injection of depot steroids for example, methyl prednisolone (40 mg) or triamcinolone acetonide (40 mg) is preferred in the initial stage of the disease. The injection is given preferably in the upper temporal quadrant. This can be repeated earliest only after 3-4 weeks. Two to four such injections at intervals of three weeks to one month often lead to resolution of an active pars planitis. In a recent series improvement of 2 Snellen’s lines or more were seen in 67% of patients with intermediate uveitis at median of 3 weeks following injection of triamcinolone acetonide.49

Our preferred technique of subtenon’s injection is the technique described by Smith et al.50 The patient is asked to look down and in. The eyelid is lifted up. A cotton tip applicator soaked in 4% lidocaine hydrochloride is applied over the conjunctiva. Using a 27 gauge, 5/8 inch disposable needle with the bevel end looking up, the conjunctiva is entered deep in the superotemporal quadrant (Figure 9). The needle is advanced posteriorly with a broad side-to-side and slow posterior movement, carefully following the curve of the globe, to make sure that the sclera is not engaged. If the needle engages the sclera the globe will move with the movement of the needle. The bevel end of needle is then rotated downwards and 0.5 ml of depot steroid is injected. Care is taken to avoid inadvertent intraocular injection. Injection is given as much as possible in the posterior region. Anterior injection has got more risk of developing steroid induced glaucoma. Increase of intraocular pressure following posterior subtenon injection of triamcinolone acetonide has been observed in up to 30% of patients in different series.48,50-53 The patient should be informed about this potential complication and periodic check up of intraocular pressure should be done following such injection. Other complications like ptosis, globe perforation, necrotizing scleritis and skin hyperpigmentation are rare.

Intravitreal triamcinolone injection usage for cystoid macular oedema is widely reported. We have found extremely good results in the short term follow up. We have found that there is a need for repeat injections as the macular oedema can recur after intravitreal injections. Strict aseptic precautions and

intraocular pressure monitoring is crucial with this form of therapy. However this should remain an emergency procedure when essential structures such as the macula have to be saved and gives time to organize the long term management.

2. SYSTEMIC STEROIDS

Oral prednisolone is the next step given in the dose of 1 to 1.5 mg/kg body weight, with a loading full dose and tapered by 10 mg weekly. If the patient has active and severe bilateral pars planitis, systemic corticosteroids 60 to 80 mg/day can be given alone or in combination with periocular injection of depot steroid preparation.

3 & 4. IMMUNOSUPPRESSIVE THERAPY AND BIOLOGICAL AGENTS

In cases resistant to oral or periocular steroids, or in recurrent intermediate uveitis, immunosuppressive agents can be used. Various immunosuppressive agents can be used but our preferred immunosuppressive is azathioprine because of its cost effectiveness and relatively low side effects. The initial dose should be from 2.3 to 2.8 mg/kg. It should be remembered that this agent needs 4-6 weeks to become effective and quick acting inflammation suppressive therapy such as corticosteroids should be given in parallel during 6-8 weeks until azathioprine can be expected to take the relay. Classical therapy should be given for 8-12 months, followed by tapering over 2-4 months. Total white blood cells, platelet count and liver function tests are monitored four weekly under the care of a physician. Nussenblatt and Palestine54 described the indication and efficacy of cyclosporine in treatment of patients with pars planitis.

Methotrexate and mycophenolate mofetil are the other drugs which can also be used in this situation.

Other new drugs with anti-TNF-alpha activity are used for refractory posterior uveitis and can be thought of in refractory cases.

5. PARS PLANA VITRECTOMY

Cases not responsive to medical therapy and which develop chronic vision threatening sequelae like dense vitreous membranes and/or tractional retinal detachment may benefit from pars plana vitrectomy. In fact, vitrectomy plays an important role in the

treatment of CMO in pars planitis. Hikichi and Trempe54 found that in the presence of posterior vitreous detachment (PVD) CMO is present in 38% cases, whereas in the absence of PVD, CMO is seen in 78% cases in a follow up period of 5 years. Inflammatory cells and mediators can gain access to the macula through the vitreous, increasing the risk of development of CMO. Dugel et al55 reported the beneficial role of vitrectomy in CMO in pars planitis resistant to corticosteroid therapy. In an earlier study in our institute, vitrectomy was done in seven cases of pars planitis, four patients had complicated cataract with dense vitreous membrane. One patient had vitreous haemorrhage, unresolved vitreous opacity, tractional retinal detachment with macular pucker and neovascularisation. Five patients had a visual improvement of more than two lines. One patient had resolution of inflammation following cataract extraction and vitrectomy but had marked oedema of the optic disc and macula causing impairment of vision. One patient was lost to follow-up.

In contrast to four step therapy by Kaplan, we recommend immunosuppressive therapy prior to cryotherapy to vitreous base or vitrectomy.

The guidelines of therapy in pars planitis, which we follow at our institute57 are given in the Flow chart 2.

CATARACT EXTRACTION IN PARS PLANITIS

Special precaution is to be taken if cataract extraction is done in cases of pars planitis.58,59 The eye should be quiet for at least 3 months prior to surgery. We prefer to operate in the ‘burnt out’ stage of the disease. Preoperative topical, systemic and periocular steroid is given to prevent an exacerbation of inflammation due to surgical trauma. We recommended starting preoperative systemic steroid 40 mg/day 3 days before surgery. In addition, a posterior subtenon injection of depot steroid is given three to four days prior to surgery.

Michelson et al,60 in a series of 15 patients, reported 60% of the cases as having a vision of 6/12 or better after extracapsular cataract extraction with posterior chamber IOL combined with pars plana vitrectomy. They reported a persistent veil of debris accumulated over the posterior and anterior surface of the IOL. We have reported results of cataract extraction in 39 cases

Flow chart 2:

of pars planitis, 20 of whom had extracapsular extraction alone. Twelve had IOL implantation in addition and seven patients had lensectomy. Ten per cent of them had fibrin reaction in the first postoperative week. The most significant postoperative complication was posterior capsule opacification and cystoid macular oedema. A visual acuity of more than 6/12 was seen in 51% of the patients.61

Phacoemulsification with intraocular lens implantation (in the bag – foldable hydrophobic acrylic) is the surgery of choice.

We have studied results of phacoemulsification with IOL implantation in patients with intermediate uveitis and found good results. Ninety one per cent of the patients had better visual acuity than preoperative values.62

This indicates that for a successful cataract surgery with intraocular lens implantation especially in patients with intermediate uveitis, effective control of preoperative inflammation and proper selection of intraocular lens type and positioning is important. Judicious selection of patients, meticulous surgery with in the bag placement of intraocular lenses and vigilant postoperative care can produce good visual recovery

in patients with complicated cataract surgery due to intermediate uveitis.

PARS PLANITIS IN CHILDHOOD

Intermediate uveitis accounts for 15.3% of all uveitis diagnoses in childhood.63 In children it has to be differentiated from other common causes of uveitis like Juvenile idiopathic arthritis (JIA). In childhood, the disease is largely asymptomatic64 until in a well advanced stage with markedly reduced vision. Lack of early diagnosis and treatment may lead to a permanent visual loss due to complications of uveitis and also due to amblyopia.

A recent study by Ben Ezra65 et al on uveitis in children and adolescents – noted that intermediate uveitis to be the commonest cause of uveitis in childhood (in 41.7% patients – 115 out of 276).

Jain66 et al studied 26 patients of intermediate uveitis in children below 16 years of all patients and found good results with topical and periocular steroids in most of them. Eight patients required systemic steroids, four of whom also required cyclosporine. Six of these children had successful disease control and maintained a visual acuity of 6/9 in at least one affected eye. They thus concluded that the variation in disease severity prompts the use of individually tailored immunosuppressive regimens.

KEY POINTS

•“Intermediate uveitis is an anatomical classification which includes a diverse group of entities and poses a significant challenge to the ophthalmologist as a large proportion of such patients is still of undetermine etiology.

•Its varied clinical course and its tendency to involve the macula adds to the difficulty. Meticulous examination of the parsplana region by indirect ophthalmoscopy with scleral depression is a must in all cases of uveitis.

•Associated clinical signs of a granulomatous variety helps in establishing the underlying systemic diagnosis of a tuberculosis or sarcoidosis.

•Idiopathic intermediate uveitis (without snowbanking) or parsplantitis (featuging snowbanks) can even be self limiting showing resolution without treatment in some cases. Visual acuity is affected usually when there is associated cystoid macular oedema and has to be treated aggressively with periocular and systemic steroids along with immunosuppressive agents.

•Laser photocoagulation and/or vitrectomy may be required in the management of the complications. Early diagnosis and treatment helps in salvaging the vision in majority of the eyes.

ACKNOWLEDGEMENT

We would like to thank Mrs. Sowmyalakshmi, Secretary in the Dept. of Ocular Pathology and Uvea for her kind assistance in helping us completing this chapter in time.

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