Int Ophthalmol DOI 10.1007/s10792-014-0008-8
ORIGINAL PAPER
Clinical Profile of Uveitis-Related Ocular Hypertension Deepankur Mahajan • Reetika Sharma Sat Pal Garg • Pradeep Venkatesh • Ramanjit Sihota • Tanuj Dada
•
Received: 2 August 2014 / Accepted: 3 October 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract The purpose of this article is to study the clinical and demographic profile of uveitis-related ocular hypertension (OHT) and evaluate risk factors predisposing to development of OHT in uveitis. Two hundred patients (200 eyes) with uveitis were evaluated for type of uveitis and the presence of OHT [IOP [ 21 mmHg]. All patients underwent a complete ophthalmic examination and appropriate systemic evaluation. Patients with OHT were started on appropriate antiglaucoma medication and were followed up for minimum of 6 months. Forty-two eyes (21 %) were found to have OHT. Anterior uveitis alone was seen in 22 (52.4 %), granulomatous uveitis was seen in 8 (19.1 %) eyes, while 13 eyes (30.9 %) had active uveitis. On multiple logistic regression, age greater than 60 years (p = 0.025), peripheral anterior synechiae (PAS) [ 180° (p = 0.029), and steroid use (p \ 0.001) were found to have significant association with OHT. Mean IOP at baseline was 24.6 ± 10.1 mmHg which decreased to 17.3 ± 4.5 mmHg at 6 months (p \ 0.001). At 6 months, 30 eyes were medically controlled (71.4 %), 5 eyes underwent trabeculectomy with MMC (11.9 %), and in 7 eyes, antiglaucoma medication could be discontinued. One-fifth of eyes
D. Mahajan R. Sharma S. P. Garg P. Venkatesh R. Sihota T. Dada (&) Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Room No. S1, 1st Floor, New Delhi 110029, India e-mail: [email protected]
with uveitis had OHT. Risk factors for IOP elevation included increased age, PAS [ 180°, and corticosteroid use. Keywords Uveitis Ocular hypertension Glaucoma Secondary glaucoma
Introduction Elevated intraocular pressure (IOP) is a recognized complication of uveitis [1, 2]. Terminology such as ‘‘secondary glaucoma’’ (SG), ‘‘uveitic glaucoma’’ (UG), or ‘‘ocular hypertension’’ (OHT) has been used to refer to elevated IOP in uveitic cases, in a roughly interchangeable fashion. However, strictly speaking, it might be incorrect to use the terminology of ‘‘glaucoma’’ in the absence of disk or field changes suggestive of glaucoma. Various studies have reported prevalence ranging from 5.2 [3] to 41.8 % [4] which vary with disease patterns or case definition of OHT/ SG related to uveitis used. Certain risk factors are known to have a higher tendency to develop elevated IOP. These include elderly patients [4, 5], anterior uveitis [6, 7], granulomatous uveitis [6, 8], active uveitis [6–8], chronic uveitis [4, 6, 9, 10], prolonged disease duration [4, 9], and steroid use [4, 7, 9, 11]. Although several retrospective reports have described the prevalence of and various risk factors for elevated IOP in patients with uveitis, prospective
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studies looking at the anterior chamber angle are lacking.
Table 1 Type of uveitis associated with ocular hypertension Type of uveitis
Frequency in uveitis patients (%)
Materials and Methods The study was performed at uvea clinic of tertiary eye care centre. Two hundred non-consecutive patients of uveitis were included in the study after written and informed consent was obtained. The study conformed to the tenets of Declaration of Helsinki. Patients with postoperative uveitis, post-traumatic uveitis, lens induced uveitis, masquerade syndromes, significant corneal pathology, and pre-existing primary glaucoma were excluded. Detailed history was recorded, especially the details of medication, both systemic and topical, that patient had received in the past or were currently on, for uveitis or elevated IOP. Complete ophthalmic examination including slit-lamp biomicroscopy, gonioscopy, dilated fundus examination, and IOP measurements with Goldmann Applanation tonometer were carried out. All patients underwent systemic investigations as per clinical suspicion of etiology on a case to case basis. Cases were classified as anterior, intermediate, posterior uveitis, and panuveitis [12, 13]. Cases were further classified as granulomatous or non-granulomatous, as active or healed and as acute, recurrent or chronic, with specific etiological diagnoses when possible [13]. Uveitis-related OHT was defined as a documented IOP greater than 21 mmHg on at least two occasions. Patients with OHT were evaluated for glaucomatous neuropathy with stereoscopic evaluation of the optic nerve head with a 90D lens and visual field defects on Humphrey Visual Field (HVF 30-2 SITA Standard protocol). Patients with evidence of glaucomatous neuropathy on either of the two investigations were labeled as having SG related to uveitis. The diagnosis of steroid-induced (SI) OHT was made based on an IOP rise in parallel with administration of steroids and a decrease in the IOP with discontinuation of steroids. All the clinical details were recorded on a preset case proforma. Patients with OHT or SG were followed up for a minimum of 6 months. For OHT (i.e., IOP [ 21 mmHg), treatment with appropriate ocular hypotensive agents (topical, systemic, or both) was initiated. If IOP was not controlled medically, patients underwent
123
Frequency in patients with ocular hypertension (%)
Anatomical type of uveitis Anterior Intermediate
105 (52.5) 36 (18.0)
0.613 22 (52.4) 10 (23.8)
Posterior
31 (15.5)
6 (14.3)
Panuveitis
28 (14.0)
4 (9.5)
Healed
90 (45.0)
29 (69.1)
Active
110 (55.0)
13 (30.9)
Activity of disease
0.001
Character of uveitis
0.237
Granulomatous
27 (13.5)
8 (19.1)
Nongranulomatous
173 (86.5)
34 (80.9)
Chronology in anterior uveitis Acute Recurrent
50 (47.7656) 37 (35.2)
Chronic
18 (17.2)
0.016 5 (22.7) 12 (54.6) 5 (22.7)
Angle of anterior chamber Open
p-value (p \ 0.05 considered significant)
0.001
140 (70.0)
20 (47.6)
Partly closed (PAS \ 180°)
36 (18.0)
11 (26.2)
Closed (PAS [ 180°)
24 (12.0)
11 (26.2)
trabeculectomy with Mitomycin C (MMC). Target IOP was kept at 18 mmHg or below during follow-up in eyes with OHT. For patients with SG, treatment was titrated to a target pressure based on existing optic nerve damage or visual field defect on perimetry. The response to therapy was evaluated in terms of IOP control, visual acuity, and number of medications. Statistical Analysis Only one eye from each patient was enrolled for analysis. In case both the eyes of patient satisfied the inclusion criteria, right eye was included in the study. Statistical tests including Fisher’s exact, Chi square, t test, Wilcoxon rank-sum test, and Mann–Whitney U were used to test the level of significance (p value) of relationship between patient and disease variables with SG. Unadjusted and adjusted odds ratio (OR) was calculated using logistic regression and multiple
Int Ophthalmol
11
1
9.1
Herpetic iridocyclitis
9
3
33.3
Serpiginous choroiditis
8
2
25
Toxoplasma retinochoroiditis
5
1
20
Posner schlossman syndrome
3
3
100
(9.5 %), respectively. Granulomatous uveitis was seen in 8 (19.1 %) eyes and 13 (30.9 %) had active uveitis at the time of examination. Gonioscopy revealed that 20 eyes (47.6 %) had anatomically open angle, while 11 (27.2 %) had peripheral anterior synechiae (PAS) of greater than 180° (Table 1). SI OHT was diagnosed in 9 out of 42 eyes with OHT (21.4 %). SG was diagnosed in 12 cases (28.6 %). Etiological diagnosis of uveitis was established in 76 (38 %) out of 200 cases in study population of uveitic patients, while in patients of uveitic OHT, etiology was established in 12 out of 42 patients (28.6 %). The prevalence data for the same is shown in Table 2.
Fuchs heterochromic iridocyclitis
3
1
33.3
Risk Factors for Uveitic Glaucoma
Seronegative rheumatoid arthritis
1
1
100
There was a significant difference between the means of age of uveitic patients with and without OHT (p = 0.0331, t-test). Sex of patient (p = 0.258, Chi square) did not show any significant association with OHT. Anatomical distribution of uveitis (p = 0.613, Chi square) and pattern of uveitis, that is, granulomatous or non-granulomatous (p = 0.241, Chi square), did not reveal any statistically significant association with raised IOP. OR of developing OHT in healed uveitis was determined to be 3.55 (95 % CI 1.71–7.35) compared to active uveitis. Among the patients of anterior uveitis, the course of disease, determined as acute, recurrent, or chronic, was found to be associated with raised IOP (p = 0.016, Chi square). The odds of developing OHT in recurrent and chronic uveitis was determined to be 4.90 (95 % CI 1.54–15.59) and 3.61 (95 % CI 0.91–14.42), respectively, when compared to acute uveitis. However, mean number of recurrences in the former and total disease duration in the latter revealed no association with raised IOP. Overall, mean total duration of disease was higher in eyes with OHT (36.5 ± 60.4 months) as compared to others (20.5 ± 48.6 months), but this was not significant statistically (p = 0.235, Wilcoxon rank-sum test). Analysis of gonioscopic findings revealed statistically significant association between the presence of PAS and OHT (p \ 0.001, Chi square). The OR of developing OHT was 5.08 (95 % CI 2.00–12.89) with PAS greater than 180° and 2.64 (95 % CI 1.13–6.19) with PAS less than 180° when compared to open angle seen on gonioscopy.
Table 2 Ocular hypertension in uveitis patients (Etiology specific) Disease entity
Presumed ocular tuberculosis
Other etiologies Idiopathic
No. of cases
No. of patients with ocular hypertension
36
0
124
30
Prevalence (%)
0 24.19
logistic regression analysis, respectively. Repeated measure two-way ANOVA (Analysis of variance) and Friedman test were used to calculate the level of significance of change in variables like IOP and best corrected visual acuity (BCVA) over the follow-up duration. A p value of \0.05 was considered as statistically significant. Stata SE 9 software was used.
Results Clinical and Demographic Profile of Examined Patients The mean age of the study population was 31.6 ± 12.2 years (Range 9–75 years). Of 200 patients of uveitis, 123 were males (61.5 %) and bilateral involvement was seen in 92 cases (46 %). The distribution of uveitis type is as shown in Table 1. Uveitic OHT was seen in 42 study eyes yielding a prevalence of 21 %. The mean age for patients with OHT was 35.1 ± 13.6 years (Range 18–75 years) with 29 males (69.1 %). Anterior uveitis was seen in 22 (52.4 %) patients followed by intermediate, posterior, and panuveitis in 10 (23.8 %), 6 (14.3 %), and 4
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Int Ophthalmol Table 3 Risk factors for developing ocular hypertension in uveitis
Table 4 Antiglaucoma treatment profile of uveitis-related ocular hypertension patients
Logistic Regression
[Odds Ratio]
Intervention
Closed Angle (PAS [ 180°)
[5.08]
Number of patients at baseline (%)
Number of patients at 6-m follow-up (%)
Medical
23 (54.8 %)
30 (71.4 %)
Recurrent Uveitis
[4.90]
Steroid Use
[4.04]
Healed Uveitis
[3.55]
Partly Closed Angle (PAS \ 180°)
[2.64]
Age Multiple Logistic Regression Age [ 60 yrs
One topical drug
7
8
Two topical drugs
5
16
Three topical drugs
2
6
Systemic drugs
9
0
2 (4.8 %) 17 (40.4 %)
5 (11.9 %) 7 (16.7 %)
Surgical No Treatment
Closed angle (PAS [ 180°) Steroid Use
The presence of OHT was significantly more common in patients with history of steroid use (topical or periocular or systemic or any combination of these) (p \ 0.001, Chi square) with OR of 4.04 (95 % CI 1.92–8.5) (Table 3). This significant difference was valid individually for the use of topical (p = 0.050), systemic (p = 0.004), and periocular (p \ 0.001) steroids with OR of developing glaucoma being 1.98, 2.90, and 4.625, respectively, for the three modes of use of steroid. Using multiple logistic regression analysis, age greater than 60 years (p = 0.025), closed angles (PAS greater than 180°) on gonioscopy (p = 0.029), and steroid use (p \ 0.001) were found to have significant association with OHT related to uveitis (Table 3).
At baseline, 23 patients (54.8 %) were already on ocular hypotensive medication, and 2 patients had history of undergoing surgery (trabeculectomy with MMC). At 6-month follow-up, 30 eyes (71.4 %) were on medical treatment. None of the eyes required systemic medication at the end of 6 months. IOP recorded in eyes on medical management decreased from 24.3 ± 8.6 mmHg to 17.3 ± 3.6 mmHg at 6-month follow-up (p \ 0.001 repeated measure ANOVA). Overall, 5 eyes (11.9 %) had undergone trabeculectomy with MMC at a follow-up duration of 6 months. IOP in these eyes decreased from 33.4 ± 10.9 mmHg (on topical and systemic ocular hypotensive medication) to 12.2 ± 2.6 mmHg at 6-month follow-up (p = 0.05 repeated measure ANOVA). None of these eyes were on any ocular hypotensive medication after surgery. Remaining 7 eyes (16.7 %) did not require any ocular hypotensive medication at 6 months of follow-up (Table 4).
Follow-up of Patients With OHT Eyes with uveitic OHT were followed up on average for 7.4 ± 2.3 months (range 6–13 months). Overall, there was reduction in mean IOP level from 24.6 ± 10.1 mmHg at baseline examination to 17.3 ± 4.5 mmHg at 6-month follow-up (p \ 0.001 repeated measure ANOVA). Median BCVA in patients with ocular hypertension ranged from 6/12 to 6/60 on Snellen visual chart, while those without OHT ranged from 6/6 to 6/12 (p = 0.003 on Mann–Whitney) at baseline. It revealed significant improvement in patients with ocular hypertension over follow-up duration of 6 months (p \ 0.001 with Friedman test) so as to be placed in the group with Snellen acuity ranging from 6/6 to 6/12.
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Discussion Glaucoma represents a severe and potentially sight threatening complication of uveitis. Uveitis is a fairly common cause of SG [14]. An important difference with patients having primary glaucoma is that in secondary uveitic glaucoma, the damaging mechanism is nearly always raised IOP, and hence treatment is guided toward controlling IOP alongwith inflammation in these cases [2]. However, raised IOP associated with uveitis is a challenging condition to manage, often with poor visual outcome [6]. The present study was conducted in a tertiary eye care centre in India and 200 patients of uveitis patients were
Int Ophthalmol
included. OHT was defined as documented IOP of greater than 21 mmHg on at least two occasions. Out of 200 eyes of 200 patients evaluated in the study, OHT was diagnosed in 42 eyes (21 %). Many studies have reported similar prevalence of raised IOP in uveitis. Merayo-Lloves et al. in their study found the prevalence of uveitic patients with IOP greater than 21 mmHg to be 17 % [6]. Takahashi et al. reported SG in 293 eyes (18.3 %) of 217 patients (19.6 %) in a retrospective study of 1,099 patients (1,604 eyes) from Japan [7]. Panek et al. found 23 patients (31 eyes) out of 100 patients (161 eyes) to have SG by criteria of IOP alone yielding prevalence of 23 % (19.3 % of eyes) [10]. Mean age in patients who developed OHT related to uveitis was found to be higher when compared to uveitic patients who did not have raised IOP. This was also confirmed on multivariate analysis. Similar results have been cited by Herbert et al. [4] and Barton et al. [5]. The effects of age probably represent an imbalance between trabecular meshwork function and the inflammatory load reflecting on declining trabecular meshwork function with increasing age, where even a nominal inflammatory attack will unmask compromised trabecular meshwork function [15]. Similar to previous studies, anterior uveitis was the predominant clinical type associated with OHT which might be expected as anterior uveitis is the most common type of uveitis seen [6, 16]. The possible inflammatory load and trabeculitis associated with this type of uveitis is more making it the predominant type associated with OHT. The present study did not find any significant association between raised IOP and anatomical distribution of uveitis, which too has been reported in few previous studies. [4, 9, 11] It may be that the propensity to increased use of steroids with intermediate and posterior uveitis will act to mask any significant association of raised IOP with anatomical location of inflammation per se. Granulomatous uveitis is usually said to be associated with greater propensity of posterior and PAS formation and hence greater risk of elevated IOP [6, 8] in these cases, but we did not find the same. This was probably due to lower prevalence of granulomatous uveitis cases noted in this study (eight cases) and hence, larger numbers will probably be needed to establish or discard a significant relationship. Neri et al. in their study found posterior synechiae to be seen more frequently in patients with SG but we could not find any such association [9].
Presence of healed uveitis was noted as another risk factor for raised IOP in uveitis. Previous studies, however, have noted raised IOP to be in phase with intraocular inflammation, [7, 8] but few have suggested for this factor to be interpreted with caution in view of marginally significant association [4]. The association of healed uveitis with raised IOP probably reflects cumulative effect of restoration of secretory function of the ciliary body, the longer duration of the disease process, and the effects of corticosteroids given as therapy. Failure to establish an association on multivariate analysis reflects on the same hypothesis. In patients with anterior uveitis, recurrent and chronic patterns of uveitis were found to be associated with raised IOP. Overall, patients with OHT had longer mean duration of disease process. Previous studies have reported chronic and recurrent course of uveitis as to be predominantly associated with SG [4, 6, 9, 10]. Increasing prevalence of glaucoma with recurrent pattern of uveitis, chronicity, and longer duration reflects the cumulative detrimental effect of inflammation and probably the consequence of chronic corticosteroid therapy on an initially normal trabecular meshwork [15]. Although angles were open in most cases of OHT, presence of PAS on gonioscopy were found to be risk factors for SG in uveitis. Open angles have been reported in majority of eyes with SG in past [6, 7]. To the best of our knowledge, no previous study reports the association of the extent of PAS seen on gonioscopy to raised IOP in uveitis. Presence of PAS on gonioscopy may be predisposing to OHT due to obstruction of outflow pathway especially when grossly open angle is already compromised by the effects of trabecular inflammation, scarring, pigment deposition, steroid response, and so on. Noting the location of PAS is also important pre-operatively to decide the site for glaucoma filtration surgery. Again, there was significant association seen between steroid use and raised IOP which was maintained on multivariate analysis. Previous studies support association between raised IOP and steroid use however; usually lower prevalence has been reported [4, 7, 9–11]. It is generally accepted that the steroid dose should be tapered as soon as possible, according to clinical criteria, to avoid serious side effects. It is postulated that a treatment of more than 6 months represent an additional risk to develop glaucoma [9].
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At the end of 6 months of follow-up, there was significant reduction in mean IOP. Nearly 90 % patients were controlled on either without ocular hypotensive agents or with topical agents alone, without requirement of systemic antiglaucoma medication. Only 5 out of 42 patients (11.9 %) with OHT had undergone trabeculectomy with MMC. Takahashi et al. reported the use of surgical therapy in 12.7 % of patients with uveitic glaucoma with IOP controlled in 89.5 % eyes at a mean follow-up duration of 71.6 ± 47.1 months [7] which is similar to our study. In a retrospective review by Neri et al., 11.1 % patients of chronic uveitis and 7.6 % patients with acute uveitis developed SG and 7 patients (12.5 %) of the former group required trabeculectomy, while none of the patients in the latter group required any surgery [9]. In conclusion, OHT is a commonly encountered problem in patients with uveitis, seen in nearly one out of every five patients. Risk factors for OHT in uveitis include increasing age, healed uveitis, recurrent uveitis, presence of PAS on gonioscopy, and steroid use. Anterior chamber anatomy using gonioscopy needs to be studied as PAS is an indicator to higher chance of developing OHT. Steroid use by any route also remains a significant risk factor for IOP elevation in uveitis, and hence treatment needs to be monitored. Patients with these risk factors should be monitored closely and raised IOP should be treated promptly. Medical management is able to control IOP in nearly 90 % of patients, hence a good evaluation and follow-up is needed. Conflict of Interest
None.
References 1. Ritch R (1981) Pathophysiology of glaucoma in uveitis. Trans Ophthalmol Soc UK 101:321–324 2. Moorthy RS, Mermoud A, Baerveldt G, Minckler DS, Lee PP, Rao NA (1997) Glaucoma associated with uveitis. Surv Ophthalmol 41:361–394
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3. Kanski JJ, Shun-Shin GA (1984) Systemic uveitis syndromes in childhood: an analysis of 340 cases. Ophthalmology 91:1247–1252 4. Herbert HM, Viswanathan A, Jackson H, Lightman SL (2004) Risk factors for elevated intraocular pressure in uveitis. J Glaucoma 13:96–99 5. Barton K, Pavesio CE, Towler HM, Lightman S (1994) Uveitis presenting de novo in the elderly. Eye 8(Pt 3):288–291 6. Merayo-Lloves J, Power WJ, Rodriguez A, Pedroza-Seres M, Foster CS (1999) Secondary glaucoma in patients with uveitis. Ophthalmologica 213:300–304 7. Takahashi T, Ohtani S, Miyata K, Miyata N, Shirato S, Mochizuki M (2002) A clinical evaluation of uveitis-associated secondary glaucoma. Jpn J Ophthalmol 46:556–562 8. Saouli N, Bre´zin AP (1999) Ocular hypertension and uveitis. J Fr Ophtalmol 22:943–949 9. Neri P, Azuara-Blanco A, Forrester JV (2004) Incidence of glaucoma in patients with uveitis. J Glaucoma 13:461–465 10. Panek WC, Holland GN, Lee DA, Christensen RE (1990) Glaucoma in patients with uveitis. Br J Ophthalmol 74:223–227 11. Sijssens KM, Rothova A, Berendschot TT, de Boer JH (2006) Ocular hypertension and secondary glaucoma in children with uveitis. Ophthalmology 113:853–859 12. Bloch-Michel E, Nussenblatt RB (1987) International study group recommendations for the evaluation of intraocular inflammatory disease. Am J Ophthalmol 103:234–235 13. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group (2005) Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 140:509–516 14. Agarwal HC, Sood NN, Kalra BR, Ghosh B (1982) Secondary glaucoma. Indian J Ophthalmol 30:121–124 15. Kok H, Barton K (2002) Uveitic glaucoma. Ophthalmol Clin North Am 15:375–387 16. Gadia R, Sihota R, Dada T, Gupta V (2008) Current profile of secondary glaucomas. Indian J Ophthalmol 56:285–289
ORIGINAL PAPER
Clinical Profile of Uveitis-Related Ocular Hypertension Deepankur Mahajan • Reetika Sharma Sat Pal Garg • Pradeep Venkatesh • Ramanjit Sihota • Tanuj Dada
•
Received: 2 August 2014 / Accepted: 3 October 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract The purpose of this article is to study the clinical and demographic profile of uveitis-related ocular hypertension (OHT) and evaluate risk factors predisposing to development of OHT in uveitis. Two hundred patients (200 eyes) with uveitis were evaluated for type of uveitis and the presence of OHT [IOP [ 21 mmHg]. All patients underwent a complete ophthalmic examination and appropriate systemic evaluation. Patients with OHT were started on appropriate antiglaucoma medication and were followed up for minimum of 6 months. Forty-two eyes (21 %) were found to have OHT. Anterior uveitis alone was seen in 22 (52.4 %), granulomatous uveitis was seen in 8 (19.1 %) eyes, while 13 eyes (30.9 %) had active uveitis. On multiple logistic regression, age greater than 60 years (p = 0.025), peripheral anterior synechiae (PAS) [ 180° (p = 0.029), and steroid use (p \ 0.001) were found to have significant association with OHT. Mean IOP at baseline was 24.6 ± 10.1 mmHg which decreased to 17.3 ± 4.5 mmHg at 6 months (p \ 0.001). At 6 months, 30 eyes were medically controlled (71.4 %), 5 eyes underwent trabeculectomy with MMC (11.9 %), and in 7 eyes, antiglaucoma medication could be discontinued. One-fifth of eyes
D. Mahajan R. Sharma S. P. Garg P. Venkatesh R. Sihota T. Dada (&) Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Room No. S1, 1st Floor, New Delhi 110029, India e-mail: [email protected]
with uveitis had OHT. Risk factors for IOP elevation included increased age, PAS [ 180°, and corticosteroid use. Keywords Uveitis Ocular hypertension Glaucoma Secondary glaucoma
Introduction Elevated intraocular pressure (IOP) is a recognized complication of uveitis [1, 2]. Terminology such as ‘‘secondary glaucoma’’ (SG), ‘‘uveitic glaucoma’’ (UG), or ‘‘ocular hypertension’’ (OHT) has been used to refer to elevated IOP in uveitic cases, in a roughly interchangeable fashion. However, strictly speaking, it might be incorrect to use the terminology of ‘‘glaucoma’’ in the absence of disk or field changes suggestive of glaucoma. Various studies have reported prevalence ranging from 5.2 [3] to 41.8 % [4] which vary with disease patterns or case definition of OHT/ SG related to uveitis used. Certain risk factors are known to have a higher tendency to develop elevated IOP. These include elderly patients [4, 5], anterior uveitis [6, 7], granulomatous uveitis [6, 8], active uveitis [6–8], chronic uveitis [4, 6, 9, 10], prolonged disease duration [4, 9], and steroid use [4, 7, 9, 11]. Although several retrospective reports have described the prevalence of and various risk factors for elevated IOP in patients with uveitis, prospective
123
Int Ophthalmol
studies looking at the anterior chamber angle are lacking.
Table 1 Type of uveitis associated with ocular hypertension Type of uveitis
Frequency in uveitis patients (%)
Materials and Methods The study was performed at uvea clinic of tertiary eye care centre. Two hundred non-consecutive patients of uveitis were included in the study after written and informed consent was obtained. The study conformed to the tenets of Declaration of Helsinki. Patients with postoperative uveitis, post-traumatic uveitis, lens induced uveitis, masquerade syndromes, significant corneal pathology, and pre-existing primary glaucoma were excluded. Detailed history was recorded, especially the details of medication, both systemic and topical, that patient had received in the past or were currently on, for uveitis or elevated IOP. Complete ophthalmic examination including slit-lamp biomicroscopy, gonioscopy, dilated fundus examination, and IOP measurements with Goldmann Applanation tonometer were carried out. All patients underwent systemic investigations as per clinical suspicion of etiology on a case to case basis. Cases were classified as anterior, intermediate, posterior uveitis, and panuveitis [12, 13]. Cases were further classified as granulomatous or non-granulomatous, as active or healed and as acute, recurrent or chronic, with specific etiological diagnoses when possible [13]. Uveitis-related OHT was defined as a documented IOP greater than 21 mmHg on at least two occasions. Patients with OHT were evaluated for glaucomatous neuropathy with stereoscopic evaluation of the optic nerve head with a 90D lens and visual field defects on Humphrey Visual Field (HVF 30-2 SITA Standard protocol). Patients with evidence of glaucomatous neuropathy on either of the two investigations were labeled as having SG related to uveitis. The diagnosis of steroid-induced (SI) OHT was made based on an IOP rise in parallel with administration of steroids and a decrease in the IOP with discontinuation of steroids. All the clinical details were recorded on a preset case proforma. Patients with OHT or SG were followed up for a minimum of 6 months. For OHT (i.e., IOP [ 21 mmHg), treatment with appropriate ocular hypotensive agents (topical, systemic, or both) was initiated. If IOP was not controlled medically, patients underwent
123
Frequency in patients with ocular hypertension (%)
Anatomical type of uveitis Anterior Intermediate
105 (52.5) 36 (18.0)
0.613 22 (52.4) 10 (23.8)
Posterior
31 (15.5)
6 (14.3)
Panuveitis
28 (14.0)
4 (9.5)
Healed
90 (45.0)
29 (69.1)
Active
110 (55.0)
13 (30.9)
Activity of disease
0.001
Character of uveitis
0.237
Granulomatous
27 (13.5)
8 (19.1)
Nongranulomatous
173 (86.5)
34 (80.9)
Chronology in anterior uveitis Acute Recurrent
50 (47.7656) 37 (35.2)
Chronic
18 (17.2)
0.016 5 (22.7) 12 (54.6) 5 (22.7)
Angle of anterior chamber Open
p-value (p \ 0.05 considered significant)
0.001
140 (70.0)
20 (47.6)
Partly closed (PAS \ 180°)
36 (18.0)
11 (26.2)
Closed (PAS [ 180°)
24 (12.0)
11 (26.2)
trabeculectomy with Mitomycin C (MMC). Target IOP was kept at 18 mmHg or below during follow-up in eyes with OHT. For patients with SG, treatment was titrated to a target pressure based on existing optic nerve damage or visual field defect on perimetry. The response to therapy was evaluated in terms of IOP control, visual acuity, and number of medications. Statistical Analysis Only one eye from each patient was enrolled for analysis. In case both the eyes of patient satisfied the inclusion criteria, right eye was included in the study. Statistical tests including Fisher’s exact, Chi square, t test, Wilcoxon rank-sum test, and Mann–Whitney U were used to test the level of significance (p value) of relationship between patient and disease variables with SG. Unadjusted and adjusted odds ratio (OR) was calculated using logistic regression and multiple
Int Ophthalmol
11
1
9.1
Herpetic iridocyclitis
9
3
33.3
Serpiginous choroiditis
8
2
25
Toxoplasma retinochoroiditis
5
1
20
Posner schlossman syndrome
3
3
100
(9.5 %), respectively. Granulomatous uveitis was seen in 8 (19.1 %) eyes and 13 (30.9 %) had active uveitis at the time of examination. Gonioscopy revealed that 20 eyes (47.6 %) had anatomically open angle, while 11 (27.2 %) had peripheral anterior synechiae (PAS) of greater than 180° (Table 1). SI OHT was diagnosed in 9 out of 42 eyes with OHT (21.4 %). SG was diagnosed in 12 cases (28.6 %). Etiological diagnosis of uveitis was established in 76 (38 %) out of 200 cases in study population of uveitic patients, while in patients of uveitic OHT, etiology was established in 12 out of 42 patients (28.6 %). The prevalence data for the same is shown in Table 2.
Fuchs heterochromic iridocyclitis
3
1
33.3
Risk Factors for Uveitic Glaucoma
Seronegative rheumatoid arthritis
1
1
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There was a significant difference between the means of age of uveitic patients with and without OHT (p = 0.0331, t-test). Sex of patient (p = 0.258, Chi square) did not show any significant association with OHT. Anatomical distribution of uveitis (p = 0.613, Chi square) and pattern of uveitis, that is, granulomatous or non-granulomatous (p = 0.241, Chi square), did not reveal any statistically significant association with raised IOP. OR of developing OHT in healed uveitis was determined to be 3.55 (95 % CI 1.71–7.35) compared to active uveitis. Among the patients of anterior uveitis, the course of disease, determined as acute, recurrent, or chronic, was found to be associated with raised IOP (p = 0.016, Chi square). The odds of developing OHT in recurrent and chronic uveitis was determined to be 4.90 (95 % CI 1.54–15.59) and 3.61 (95 % CI 0.91–14.42), respectively, when compared to acute uveitis. However, mean number of recurrences in the former and total disease duration in the latter revealed no association with raised IOP. Overall, mean total duration of disease was higher in eyes with OHT (36.5 ± 60.4 months) as compared to others (20.5 ± 48.6 months), but this was not significant statistically (p = 0.235, Wilcoxon rank-sum test). Analysis of gonioscopic findings revealed statistically significant association between the presence of PAS and OHT (p \ 0.001, Chi square). The OR of developing OHT was 5.08 (95 % CI 2.00–12.89) with PAS greater than 180° and 2.64 (95 % CI 1.13–6.19) with PAS less than 180° when compared to open angle seen on gonioscopy.
Table 2 Ocular hypertension in uveitis patients (Etiology specific) Disease entity
Presumed ocular tuberculosis
Other etiologies Idiopathic
No. of cases
No. of patients with ocular hypertension
36
0
124
30
Prevalence (%)
0 24.19
logistic regression analysis, respectively. Repeated measure two-way ANOVA (Analysis of variance) and Friedman test were used to calculate the level of significance of change in variables like IOP and best corrected visual acuity (BCVA) over the follow-up duration. A p value of \0.05 was considered as statistically significant. Stata SE 9 software was used.
Results Clinical and Demographic Profile of Examined Patients The mean age of the study population was 31.6 ± 12.2 years (Range 9–75 years). Of 200 patients of uveitis, 123 were males (61.5 %) and bilateral involvement was seen in 92 cases (46 %). The distribution of uveitis type is as shown in Table 1. Uveitic OHT was seen in 42 study eyes yielding a prevalence of 21 %. The mean age for patients with OHT was 35.1 ± 13.6 years (Range 18–75 years) with 29 males (69.1 %). Anterior uveitis was seen in 22 (52.4 %) patients followed by intermediate, posterior, and panuveitis in 10 (23.8 %), 6 (14.3 %), and 4
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Int Ophthalmol Table 3 Risk factors for developing ocular hypertension in uveitis
Table 4 Antiglaucoma treatment profile of uveitis-related ocular hypertension patients
Logistic Regression
[Odds Ratio]
Intervention
Closed Angle (PAS [ 180°)
[5.08]
Number of patients at baseline (%)
Number of patients at 6-m follow-up (%)
Medical
23 (54.8 %)
30 (71.4 %)
Recurrent Uveitis
[4.90]
Steroid Use
[4.04]
Healed Uveitis
[3.55]
Partly Closed Angle (PAS \ 180°)
[2.64]
Age Multiple Logistic Regression Age [ 60 yrs
One topical drug
7
8
Two topical drugs
5
16
Three topical drugs
2
6
Systemic drugs
9
0
2 (4.8 %) 17 (40.4 %)
5 (11.9 %) 7 (16.7 %)
Surgical No Treatment
Closed angle (PAS [ 180°) Steroid Use
The presence of OHT was significantly more common in patients with history of steroid use (topical or periocular or systemic or any combination of these) (p \ 0.001, Chi square) with OR of 4.04 (95 % CI 1.92–8.5) (Table 3). This significant difference was valid individually for the use of topical (p = 0.050), systemic (p = 0.004), and periocular (p \ 0.001) steroids with OR of developing glaucoma being 1.98, 2.90, and 4.625, respectively, for the three modes of use of steroid. Using multiple logistic regression analysis, age greater than 60 years (p = 0.025), closed angles (PAS greater than 180°) on gonioscopy (p = 0.029), and steroid use (p \ 0.001) were found to have significant association with OHT related to uveitis (Table 3).
At baseline, 23 patients (54.8 %) were already on ocular hypotensive medication, and 2 patients had history of undergoing surgery (trabeculectomy with MMC). At 6-month follow-up, 30 eyes (71.4 %) were on medical treatment. None of the eyes required systemic medication at the end of 6 months. IOP recorded in eyes on medical management decreased from 24.3 ± 8.6 mmHg to 17.3 ± 3.6 mmHg at 6-month follow-up (p \ 0.001 repeated measure ANOVA). Overall, 5 eyes (11.9 %) had undergone trabeculectomy with MMC at a follow-up duration of 6 months. IOP in these eyes decreased from 33.4 ± 10.9 mmHg (on topical and systemic ocular hypotensive medication) to 12.2 ± 2.6 mmHg at 6-month follow-up (p = 0.05 repeated measure ANOVA). None of these eyes were on any ocular hypotensive medication after surgery. Remaining 7 eyes (16.7 %) did not require any ocular hypotensive medication at 6 months of follow-up (Table 4).
Follow-up of Patients With OHT Eyes with uveitic OHT were followed up on average for 7.4 ± 2.3 months (range 6–13 months). Overall, there was reduction in mean IOP level from 24.6 ± 10.1 mmHg at baseline examination to 17.3 ± 4.5 mmHg at 6-month follow-up (p \ 0.001 repeated measure ANOVA). Median BCVA in patients with ocular hypertension ranged from 6/12 to 6/60 on Snellen visual chart, while those without OHT ranged from 6/6 to 6/12 (p = 0.003 on Mann–Whitney) at baseline. It revealed significant improvement in patients with ocular hypertension over follow-up duration of 6 months (p \ 0.001 with Friedman test) so as to be placed in the group with Snellen acuity ranging from 6/6 to 6/12.
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Discussion Glaucoma represents a severe and potentially sight threatening complication of uveitis. Uveitis is a fairly common cause of SG [14]. An important difference with patients having primary glaucoma is that in secondary uveitic glaucoma, the damaging mechanism is nearly always raised IOP, and hence treatment is guided toward controlling IOP alongwith inflammation in these cases [2]. However, raised IOP associated with uveitis is a challenging condition to manage, often with poor visual outcome [6]. The present study was conducted in a tertiary eye care centre in India and 200 patients of uveitis patients were
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included. OHT was defined as documented IOP of greater than 21 mmHg on at least two occasions. Out of 200 eyes of 200 patients evaluated in the study, OHT was diagnosed in 42 eyes (21 %). Many studies have reported similar prevalence of raised IOP in uveitis. Merayo-Lloves et al. in their study found the prevalence of uveitic patients with IOP greater than 21 mmHg to be 17 % [6]. Takahashi et al. reported SG in 293 eyes (18.3 %) of 217 patients (19.6 %) in a retrospective study of 1,099 patients (1,604 eyes) from Japan [7]. Panek et al. found 23 patients (31 eyes) out of 100 patients (161 eyes) to have SG by criteria of IOP alone yielding prevalence of 23 % (19.3 % of eyes) [10]. Mean age in patients who developed OHT related to uveitis was found to be higher when compared to uveitic patients who did not have raised IOP. This was also confirmed on multivariate analysis. Similar results have been cited by Herbert et al. [4] and Barton et al. [5]. The effects of age probably represent an imbalance between trabecular meshwork function and the inflammatory load reflecting on declining trabecular meshwork function with increasing age, where even a nominal inflammatory attack will unmask compromised trabecular meshwork function [15]. Similar to previous studies, anterior uveitis was the predominant clinical type associated with OHT which might be expected as anterior uveitis is the most common type of uveitis seen [6, 16]. The possible inflammatory load and trabeculitis associated with this type of uveitis is more making it the predominant type associated with OHT. The present study did not find any significant association between raised IOP and anatomical distribution of uveitis, which too has been reported in few previous studies. [4, 9, 11] It may be that the propensity to increased use of steroids with intermediate and posterior uveitis will act to mask any significant association of raised IOP with anatomical location of inflammation per se. Granulomatous uveitis is usually said to be associated with greater propensity of posterior and PAS formation and hence greater risk of elevated IOP [6, 8] in these cases, but we did not find the same. This was probably due to lower prevalence of granulomatous uveitis cases noted in this study (eight cases) and hence, larger numbers will probably be needed to establish or discard a significant relationship. Neri et al. in their study found posterior synechiae to be seen more frequently in patients with SG but we could not find any such association [9].
Presence of healed uveitis was noted as another risk factor for raised IOP in uveitis. Previous studies, however, have noted raised IOP to be in phase with intraocular inflammation, [7, 8] but few have suggested for this factor to be interpreted with caution in view of marginally significant association [4]. The association of healed uveitis with raised IOP probably reflects cumulative effect of restoration of secretory function of the ciliary body, the longer duration of the disease process, and the effects of corticosteroids given as therapy. Failure to establish an association on multivariate analysis reflects on the same hypothesis. In patients with anterior uveitis, recurrent and chronic patterns of uveitis were found to be associated with raised IOP. Overall, patients with OHT had longer mean duration of disease process. Previous studies have reported chronic and recurrent course of uveitis as to be predominantly associated with SG [4, 6, 9, 10]. Increasing prevalence of glaucoma with recurrent pattern of uveitis, chronicity, and longer duration reflects the cumulative detrimental effect of inflammation and probably the consequence of chronic corticosteroid therapy on an initially normal trabecular meshwork [15]. Although angles were open in most cases of OHT, presence of PAS on gonioscopy were found to be risk factors for SG in uveitis. Open angles have been reported in majority of eyes with SG in past [6, 7]. To the best of our knowledge, no previous study reports the association of the extent of PAS seen on gonioscopy to raised IOP in uveitis. Presence of PAS on gonioscopy may be predisposing to OHT due to obstruction of outflow pathway especially when grossly open angle is already compromised by the effects of trabecular inflammation, scarring, pigment deposition, steroid response, and so on. Noting the location of PAS is also important pre-operatively to decide the site for glaucoma filtration surgery. Again, there was significant association seen between steroid use and raised IOP which was maintained on multivariate analysis. Previous studies support association between raised IOP and steroid use however; usually lower prevalence has been reported [4, 7, 9–11]. It is generally accepted that the steroid dose should be tapered as soon as possible, according to clinical criteria, to avoid serious side effects. It is postulated that a treatment of more than 6 months represent an additional risk to develop glaucoma [9].
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At the end of 6 months of follow-up, there was significant reduction in mean IOP. Nearly 90 % patients were controlled on either without ocular hypotensive agents or with topical agents alone, without requirement of systemic antiglaucoma medication. Only 5 out of 42 patients (11.9 %) with OHT had undergone trabeculectomy with MMC. Takahashi et al. reported the use of surgical therapy in 12.7 % of patients with uveitic glaucoma with IOP controlled in 89.5 % eyes at a mean follow-up duration of 71.6 ± 47.1 months [7] which is similar to our study. In a retrospective review by Neri et al., 11.1 % patients of chronic uveitis and 7.6 % patients with acute uveitis developed SG and 7 patients (12.5 %) of the former group required trabeculectomy, while none of the patients in the latter group required any surgery [9]. In conclusion, OHT is a commonly encountered problem in patients with uveitis, seen in nearly one out of every five patients. Risk factors for OHT in uveitis include increasing age, healed uveitis, recurrent uveitis, presence of PAS on gonioscopy, and steroid use. Anterior chamber anatomy using gonioscopy needs to be studied as PAS is an indicator to higher chance of developing OHT. Steroid use by any route also remains a significant risk factor for IOP elevation in uveitis, and hence treatment needs to be monitored. Patients with these risk factors should be monitored closely and raised IOP should be treated promptly. Medical management is able to control IOP in nearly 90 % of patients, hence a good evaluation and follow-up is needed. Conflict of Interest
None.
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