Dear Editor

I was delighted to read Dr Okada’s reply to my letter.[1] At the risk of transgressing from the point of the original article [2] that dealt with a novel technique to administer triamcinolone to a wide group of patients with uveitis, I would like to reply:

1. The WHO guidelines are indeed silent on the treatment of latent tuberculosis which can be defined as merely positive mantoux tests with no clinical, microbiological, or radiographic evidence of active tuberculosis (TB).[3] These patients may be treated with single or two drug therapy to prevent progression to active TB [4] but patients with an active uveitis would not fall within this definition and probably should be treated as patients with active extrapulmonary TB irrespective of the detection or otherwise of an infective focus. The absence of a detectable focus of systemic TB (usually pulmonary) should not lead to a diagnosis of latent tuberculosis. In patients suspected of ocular TB, the findings of systemic TB especially in those patients with infective manifestations (like choroidal tubercles) , suggests the need to receive the full four drug regime but considerable latitude exists in those patients in whom there is neither a detectable systemic focus or microbiologic evidence. As ocular TB has been known to occur even in the absence of systemic foci,[5] it may be prudent to advise a full four drug course rather than one/ two drug regimes. Inadequate regimes would lead to the development of microbial resistance and subsequent therapeutic difficulties.

2. The authors theorize that certain cases may be due to an immune reaction to sequestered mycobacterial antigen. Recent mouse models have demonstrated an initial pulmonary infection followed by the appearance of bacteria at the draining lymph nodes, at which stage a T cell immune response is generated.[6] Does this response lead to the release of antigen into the bloodstream leading to the sequence of events we describe as ocular TB? A mantoux test would probably be positive in these patients indicating recent infection (but not necessarily active disease) but whether they would need antitubercular (as opposed to only immunosuppressive agents) drugs remains unknown.

References

1. Okada AA and Wakabayashi T. Trans-Tenon's retrobulbar triamcinolone infusions in uveitis [electronic response to Okada et al. Trans-Tenon’s retrobulbar triamcinolone infusion for the treatment of uveitis] http://bjo.bmjjournals.com/cgi/eletters/87/8/968#210

2. AA Okada, T Wakabayashi, Y Morimura, S Kawahara, E Kojima, Y Asano and T Hida. Trans-Tenon’s retrobulbar triamcinolone infusion for the treatment of uveitis. Br J Ophthalmol 2003; 87:968-971.

3. American Thoracic Society. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. Am. J. Respir. Crit. Care Med 2000; 161(4): 1376-1395.

4. Small PM. Fujiwara PI. Management of Tuberculosis in the United States. N Engl J Med. 2001; 345:189-200.

5. Sarvananthan N, Wiselka M, Bibby K. Intraocular tuberculosis without detectable systemic infection. Arch Ophthalmol. 1998;116(10):1386-8.

6. Chackerian AA, Alt JM, Perera TV, Dascher CC, Behar SM. Dissemination of Mycobacterium tuberculosis Is Influenced by Host Factors and Precedes the Initiation of T-Cell Immunity. Infection and Immunity.2002, 70(8): 4501-4509.

Dear Editor

I thank Dr Okada et al for replying to my letter to the editor regarding their article "Trans-Tenon's retrobulbar triamcinolone infusion for the treatment of uveitis".[1] While speculating that the cause of the lack of therapeutic response to sub-tenon’s corticosteroids may be because of placement at a site relatively far from the target zone, I had quoted only the article by Freeman et al.[2] I fully agree that the article by Jennings et al.[3] had ensured reliable drug placement. This study was quoted only to highlight the point that injection of steroids by the sub-tenon’s route did not consistently affect the blood-retinal barrier permeability and that there was no diffusion of the steroids into the eye in therapeutically meaningful concentrations, despite accurate drug placement.

References

(1) AA Okada, T Wakabayashi, Y Morimura, S Kawahara, E Kojima, Y Asano and T Hida. Trans-Tenon’s retrobulbar triamcinolone infusion for the treatment of uveitis. Br J Ophthalmol 2003;87:968-971.

(2) Freeman WR, Green RL, Smith RE. Echographic localization of corticosteroids after periocular injection. Am J Ophthalmol 1987 Mar; 15;103(3 Pt 1):281-8.

(3) Jennings T, Rusin MM, Tessler HH, Cunhavaz JG. Posterior sub-tenon’s injections of corticosteroids in uveitis patients with cystoid macular edema. Jpn J Ophthalmol 1988;32:385-391.

Dear Editor

We appreciate the interest and many comments we have received regarding our recent article on "Trans-Tenon's retrobulbar triamcinolone infusion for the treatment of uveitis."[1]

In reply to the comments by Dr Vedantham, we acknowledge the paucity of experimental data to actually prove that accurate placement of corticosteroids into the sub-Tenon's space provides good drug penetration into the eye. However, the studies to the contrary cited by Dr Vedantham have all used needles to make such "accurate placement" including the study by Jennings et al.[2] which utilized the technique described by Tessler.[3] Use of needles represents not only a potential hazard to the eye in terms of accidental globe penetration, but also makes it much more difficult to place any sub- Tenon's injection under the posterior Tenon's capsule near the macula and/or around the optic nerve. It has been shown that many injections intended for the sub-Tenon's space merely end up somewhere in the orbit outside of Tenon's capsule.[4] We believe that our method using a 23 gauge blunt, curved, long cannula (the one we used was #HS-2764 by Handaya Co., Ltd., Tokyo, Japan) assures accurate placement into the target space.

However, we are in agreement with Dr Vedantham, in that ultimately corticosteroid placed outside of the eye may be no match for the efficacy that may be obtained by corticosteroid placed inside the eye. Yet, we have found such a high efficacy rate for the trans-Tenon's retrobulbar infusion of triamcinolone in uveitis, that we can conceive of no reason why this treatment should not be tried before procedures such as intravitreal injections that carry risks of severe complications are considered. For example, as also pointed out by Dr Vedantham, the risks of intravitreal corticosteroid injections even include development of a rare form of mycobacterial endophthalmitis.[5] We strongly encourage all uveitis and retina specialists who have up until now been disappointed with the efficacy of their sub-Tenon's corticosteroid injections, to make the effort in obtaining an appropriate cannula and revising their technique before jumping to intravitreal procedures.

In reply to the first comment by Dr Mehta, we acknowledge the current WHO guidelines, revised for 2003, that include recommendations for extrapulmonary tuberculosis.[6] However, we would also like to amend Dr Mehta's comment, in that the WHO admits in those guidelines that there are many regimens with reported efficacy including a 6-month regimen of rifampicin (with streptomycin also given in the initial phase only) for meningeal tuberculosis. Furthermore, the WHO recommendations are for active extrapulmonary tuberculosis that has been diagnosed by specimen examination or strong clinical evidence, and give no recommendations for latent infection. As we have previously reported in a series on intraocular tuberculosis, systemic work-up failed to identify a focus of active tuberculosis in the majority of our patients,[7] and we have come to suspect that the uveitis we observed may be an immune response to latent tuberculosis antigen sequestered elsewhere. Therefore, the patients we described were given a diagnosis of "presumed intraocular tuberculosis," that is with uveitis presumed to be related to the Mycobacterium tuberculosis organism. Furthermore, we would like to clarify that in the cases of presumed ocular tuberculosis that received trans- Tenon's retrobulbar triamcinolone infusion,[1] this treatment was judged to be effective in 2 of 3 eyes. Regardless, since the focus of active or latent tuberculosis was never identified in our patients, a two-drug regimen of isoniazid and rifampicin was used as a therapeutic trial for anti-tuberculosis therapy. A similar therapeutic trial for ocular tuberculosis, albeit with isoniazid alone, has been previously advocated in Japan by Ishihara and Ohno.[8]

With regards to the second comment, among the 16 patients who were receiving some form of systemic immunosuppressive therapy, we did not notice any difference in outcome when compared to patients who were not on immunosuppressive therapy. In other words, the efficacy of trans-Tenon's retrobulbar triamcinolone infusion was the same. However, we suspect that the recurrence rate after triamcinolone infusion may be different, and we are currently investigating this possibility.

References

(1) Okada AA, Wakabayashi T, Morimura Y, et al. Trans-Tenon's retrobulbar triamcinolone infusion for the treatment of uveitis. Br J Ophthalmol 2003;87:968-971.

(2) Jennings T, Rusin MM, Tessler HH, Cunha-Vaz JG. Posterior sub-Tenon's injections of corticosteroids in uveitis patients with cystoid macular edema. Jpn J Ophthalmol 1988;32:385-391.

(3) Tessler H. Uveitis. In: Peyman GA, Sanders DR, Goldberg MF, eds. Principles and Practice of Ophthalmology, Vol 2, First edition. Philadelphia: Saunders, 1980;1554-1629.

(4) Freeman WR, Green RL, Smith RE. Echographic localization of corticosteroids after periocular injection. Am J Ophthalmol 1987;103:281- 288.

(5) Benz MS, Murray TG, Dubovy SR, et al. Endophthalmitis caused by Mycobacterium chelonae abscessus after intravitreal injection of triamcinolone. Arch Ophthalmol 2003;121:271-273.

(6) World Health Organization. Case definitions (p. 24) and Standardised treatment regimens (p. 35-36) In: Treatment of Tuberculosis: Guidelines for National Programmes. Third edition. (WHO/CDS/TB/2003.313) Accessed on 13 October 2003. Geneva: World Health Organization.

(7) Morimura Y, Okada AA, Kawahara S, et al. Tuberculin skin testing in uveitis patients and treatment of presumed intraocular tuberculosis in Japan. Ophthalmology 2002;109:851-857.

(8) Ishihara M, Ohno S. [Ocular tuberculosis] Nippon Rinsho 1998;56:3157- 3161.

Dear Editor

I read with great interest the article by Okada et al,[1] reporting the efficacy and complications of trans-tenon’s retrobulbar infusion of triamcinolone acetonide for posterior uveitic inflammation. The authors have to be commended for the excellent description of this novel technique.

The efficacy of various modalities of corticosteroid injection has always been a matter of debate with different studies giving different results. McCartney et al.[2] showed that the major route of penetration of steroids after subconjunctival injection was directly through the adjacent sclera, choroid and retina. In addition, the authors described methods to inject steroids in the sub-tenon’s space and concluded that the injections should be placed immediately adjacent to the site of intraocular inflammation that was under treatment. In contrast, in a study on rabbit eyes, Wilson et al.[3] have elegantly demonstrated that injection of corticosteroids by the sub-tenon’s route does not show a significant effect on the blood-retinal barrier owing to inadequate penetration. The authors analysed the severity of blood-retinal barrier breakdown following panretinal photocoagulation, using rapid sequential MRI with contrast. Of note, in this study the authors have taken particular care to ensure the accurate placement of the needle in the sub-tenon’s space. A similar result was obtained in a study on the efficacy of posterior sub-tenon’s injections in patients with cystoid macular edema due to uveitis by Jennings et al.[4] The authors found that the injection of steroids by the sub-tenon’s route did not consistently affect the blood-retinal barrier permeability in such patients and that there was no diffusion of the steroids into the eye in therapeutically meaningful concentrations. This is of particular concern since it is the breakdown in the blood-retinal barrier that leads to influx of serum/serum components leading to macular edema, epiretinal membrane and other sequelae.

Sub-tenon’s injections when compared to intravitreal injections have the disadvantage of probably a decreased and difficult drug penetration through the sclera and choroid and a rapid removal of the drug by the choroidal circulation after penetration with the resultant shortened duration of action. This is probably the reason why sub-tenon’s route of injection of steroids has not become popular in diabetic macular edema in contrast to the gaining popularity of the intravitreal steroid injections.

Interestingly, Freeman et al.[5] have postulated that the lack of therapeutic response to sub-tenon’s corticosteroids may be because of placement at a site relatively far from the target zone. They determined the location of repository corticosteroid after sub-tenon’s injection by echography and showed that the steroid was deposited within the sub- tenon’s space over the macula in only 11 of 24 cases. They hence concluded that the therapeutic response manifested by improvement in macular function may be related to the proximity of the corticosteroid to the macular area. The impressive efficacy reported in the study by Okada et al.[1] could probably be due to reliable drug placement thanks to the visual confirmation of cannula entry into sub-tenon’s space, as the authors speculate. However, it is important to note that most of the patients in this study continued to receive topical steroid drops. Whether these drops had an additive effect is unclear.

It would probably be worthwhile to consider a planned, primary intravitreal injection of corticosteroids under aseptic conditions that has the distinct advantage of getting distributed into a much larger volume for selected conditions. There would be no cases of “therapeutic failures” that are seen after injection of steroids into the sub-tenon’s space and the resultant confusion as to whether the unsatisfactory response is secondary to the disease process or failure to inject the steroid into the sub-tenon’s space or the debated lower efficacy of this route of injection. The procedure is simpler than the described trans- tenon’s retrobulbar infusion (no special cannula is required), but the risk of endophthalmitis is daunting.[6]

References

(1) AA Okada, T Wakabayashi, Y Morimura, S Kawahara, E Kojima, Y Asano and T Hida. Trans-Tenon’s retrobulbar triamcinolone infusion for the treatment of uveitis. Br J Ophthalmol 2003;87:968-971.

(2) McCartney HJ, Drysdale IO,Gornall AG, Basu PK. An autoradiographic study of the penetration of subconjunctivally injected hydrocortisone into normal and inflamed rabbit eyes. Invest Ophthalmol 1965;4: 297.

(3) Wilson CA, Berkowitz BA, Sato Y, Ando N, Handa JT, deJuan E. Treatment with intravitreal steroid reduces blood-retinal barrier breakdown due to retinal photocoagulation. Arch Ophthalmol 1992;110:1155-9.

(4) Jennings T, Rusin MM, Tessler HH, Cunhavaz JG. Posterior sub-tenon’s injections of corticosteroids in uveitis patients with cystoid macular edema. Jpn J Ophthalmol 1988;32:385-391.

(5) Freeman WR, Green RL, Smith RE. Echographic localization of corticosteroids after periocular injection. Am J Ophthalmol 1987 Mar; 15;103(3 Pt 1):281-8.

(6) Benz MS, Murray TG, Dubovy SR, Katz RS, Eifrig CW. Endophthalmitis caused by Mycobacterium chelonae abscessus after intravitreal injection of triamcinolone. Arch Ophthalmol 2003;121(2):271-3.

Dear Editor

I read with great interest the article by Okada et al.[1] I would like to make the following comments:
(1) The authors describe three patients of tubercular uveitis who are being treated with isoniazid and rifampicin for a month prior to their treatment with trans-tenons triamcinolone. However, current WHO guidelines recommend an initial phase of 2 months with four drugs (isoniazid, rifampicin, ethambutol and pyrazinamide )followed by a longer continuation phase (four months of isoniazid and rifampicin or six months of isoniazid and ethambutol) for both the severe and the less severe forms of extrapulmonary tuberculosis.[2] Could the non-resolution of their uveitis be due to inadequate anti-tubercular therapy?

(2) 16 of the described 37 patients were on systemic immunomodulators (corticosteroids/cyclosporine) prior to their treatment with triamcinolone. Did the authors notice any differences in the outcome between those patients who were being treated with systemic drugs initially versus those who were not?

References

(1) A A Okada, T Wakabayashi, Y Morimura, S Kawahara, E Kojima, Y Asano, and T Hida. Trans-Tenon’s retrobulbar triamcinolone infusion for the treatment of uveitis. Br J Ophthalmol 2003;87:968-971.

(2) World Health Organization. Standardized treatment regimes, Chapter 4:27-38. In Treatment of tuberculosis: guidelines for national programmes (WHO/CDS/TB/2003.13) Third Edition. Available Online Accessed on 31 July 2003. Geneva: World Health Organization.