Mitomycin-C in Glaucoma Filtering Surgery

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Mitomycin-C in Glaucoma Filtering Surgery Powered By Docstoc
					                                                                                                       TREATMENT FOCUS

                                                                                                  for primary open angle glaucoma.
Mitomycin-C in Glaucoma                                                                           However, such procedures are not with-
                                                                                                  out complications.

Filtering Surgery                                                                                     The first reported adverse effects of
                                                                                                  MMC were scleral changes, such as
                                                                                                  scleral melting in cases of pterygium
   PT Hung                                                                                        excision. Complications may appear
   Department of Ophthalmology, National                                                          early, or as late as 15 to 20 years after
   Taiwan University Hospital, Taipei,                                                            MMC application (figure 2). MMC can
   Taiwan, Republic of China                                                                      also cause ocular complications and
                                                                                                  toxicity in glaucoma surgery. Eye sur-
                                                                                                  geons must therefore exercise caution
Introduction                                  ophthalmology as a topical drop for pre-            to avoid serious complications when
                                              vention of recurrent pterygium. 2 In 1981,          performing MMC procedures.

          ew concepts in glaucoma             Chen, a former student of Kunitomo, was
                                              the first to use MMC intra-operatively for          Indications                                   21
          therapy have led to remarkable
          achievements in the 20th cen-       refractory glaucoma.3 This first patient            www
tury. Recently-introduced drugs not           had lost one eye in a traffic accident and          In 1990, Chen et al. demonstrated that
only reduce intraocular pressure (IOP),       had refractory high IOP in the remaining            intra-operative MMC application is
but also aim to provide neuroprotection       eye after cataract extraction, corneal              indicated for treatment of patients for
and increased retinal circulation. How-       transplant, and repeated filtering surgery          whom filtering surgery carries a high
ever, the practical approach remains          (figure 1).                                         risk of failure. 4 Their study of MMC
the gold standard of glaucoma treat-               Adjunctive MMC application during              and fibroblast inhibition indicated that
ment, i.e. reduction of IOP by means of       filtering surgery has since been popular-           activated fibroblasts are one of the
medication, laser surgery, or conventional    ised for refractory glaucoma, and has been          major factors leading to failed filtering
surgery to obtain a safe target pressure.     reported to maintain the filtering effect           surgery.
The surgical filtering procedure with         in patients with childhood glaucoma                      The indications for MMC set forth in
adjunctive antimetabolites is still an        and secondary glaucoma, as well as                  their series included failure of previous
excellent choice for reducing IOP in          when used in initial surgical approaches            filtering operations, previous intraocular
patients with advanced glaucoma.
    A variety of antimetabolites, including
mitomycin-C (MMC) and 5-fluorouracil
(5-FU), are available for reducing IOP.
Since MMC was first introduced for
ophthalmologic use, and has been
studied in-depth at the Department of
Ophthalmology, at the National Taiwan
University Hospital, this brief review
will focus on MMC.
    MMC was first developed in 1955 by
Hata et al., from Streptomyces caespito-
sus.1 MMC inhibits cell mitosis by inter-
rupting DNA synthesis, and probably
also acts on the vascular endothelium.
The late Kunitomo of the National Taiwan      Figure 1. First application of adjunctive mitomycin-C in refractory glaucoma, 1981.3 Photograph
University first introduced this agent to     reproduced courtesy of Professor Chen.

Asian Journal of OPHTHALMOLOGY and Asia-Pacific Journal of Ophthalmology                                         Volume 2, Numbers 1, 2, 2000

     Figure 2. Necrotising scleritis after application of mitomycin-C eye drops for prevention of pterygium   after MMC treatment ranges from 1.5 to
     recurrence after excision.
                                                                                                              35%, while approximately 4 to 10% of
                                                                                                              patients develop hypotonous maculo-
                                                                                                              pathy following various forms of MMC
                                                                                                              application. Such hypotonous maculo-
                                                                                                              pathy is seen frequently in young and
                                                                                                              myopic patients. The treatments for
                                                                                                              hypotonous maculopathy include auto-
                                                                                                              blood bleb injection, scleral patching, and
                                                                                                              cryotherapy.8 However, the best approach
                                                                                                              is to prevent hypotony by regulation of
                                                                                                              the concentration and duration of MMC
                                                                                                              application, which can be accomplished
                                                                                                              with the use of releasable sutures or other
                                                                                                              methods (described below).
                                                                                                              Dose and Duration
                                                                                                              of Mitomycin-C
     surgery, high scar tendency related to               years later, in the original pterygium
     race, and a strong inflammatory reaction             excision site include scleral melting
                                                                                                              Chen et al. originally reported that appli-
     in patients with secondary glaucoma.4                and necrotising scleritis (figure 2).
                                                                                                              cation of MMC at a concentration of 0.2
     However, a recent study indicated that               Such scleral complications prompted
                                                                                                              to 0.4 mg/ml for 5 minutes is adequate,
     intra-operative application of MMC can               Rubinfeld et al. to suggest that MMC
                                                                                                              and poses little risk of severe complica-
     increase the success rate of initial trabecu-        should not be used to prevent pterygium
                                                                                                              tions such as hypotony.4 However, Chen
     lectomy for patients with primary glau-              recurrence in patients with poor ocular
                                                                                                              et al. also suggested that 0.2 mg/ml
     coma, even for younger age groups.5 The              healing, as in those with Sjögren’s syn-
                                                                                                              for 5 minutes may be the safest effective
     indications for adjunctive MMC appli-                drome, herpetic keratitis, or keratocon-
                                                                                                              dose. In North America, an initial report
     cation in filtering surgery may therefore            junctivitis sicca.6                                 indicated that application of 0.5 mg/ml
     expand to include treatment of childhood                 With increasing experience of the               MMC for 5 minutes could result in se-
     glaucoma.                                            application of intra-operative MMC                  vere hypotony associated with maculo-
                                                          during the past decade, the minor com-              pathy. In our department, the dose of
     Complications                                        plications of punctuate corneal erosion,            MMC for intra-operative application
     www                                                  poor conjunctival wound healing or                  ranges from 0.2 to 0.3 mg/ml with
     Past studies of postoperative application            leakage, and elongation of postoperative            durations ranging from 2 to 5 minutes
     of MMC eye drops in pterygium ex-                    wound reaction have become almost                   according to the risk factors for bleb
     cision provide valuable insight into the             negligible.                                         closure; these risk factors include patient
     potential complications of intraocular                   The most serious complications of               age, previous operation, duration of
     MMC use. In subtropical areas such                   MMC application include ciliary body                antiglaucoma drug medication, and a
     as Taiwan, recurrent pterygium is so                 toxicity and long-term hypotony of less             tendency for wound scarring.
     common that 0.04% MMC solution is                    than 5 mm Hg, which may induce macu-                    It is encouraging that a lower con-
     usually applied 4 times daily after pter-            lar change. Our stereoscopic fluorescein            centration of 0.02% twice daily has been
     ygium excision. Poor wound healing,                  angiography study in 1992 showed only               recommended for prevention of recurrent
     scleral ulcer, and even perforations may             2 cases of maculopathy in 30 eyes 18                pterygium.9 In addition, some institutes
     occur as early complications of MMC                  months after MMC surgery.7 Moreover,                have shortened the duration of MMC
     therapy. Serious long-term complica-                 MMC-related maculopathy may be revers-              application to 2 minutes when used for
     tions, usually appearing more than 10                ible. The reported frequency of hypotony            adjunctive trabeculectomy.10

     Volume 2, Numbers 1, 2, 2000                                                   Asian Journal of OPHTHALMOLOGY and Asia-Pacific of Ophthalmology
                                                                                                      TREATMENT FOCUS

    Because of the high prevalence of        Figure 3. Subconjunctival mitomycin-C solution injection 24 hours prior to trabeculectomy.

primary angle closure glaucoma in
Asia, trabeculectomy with releasable
sutures is probably safe for treatment of
shallow anterior chamber glaucoma,
with the goal of early restoration of the
anterior chamber. Therefore, the concen-
tration and duration of MMC application
are also important in trabeculectomy
for primary angle closure glaucoma.
MMC application can also yield effective
bleb formation after restoration of the
chamber followed by releasing suture
and digital pressure.

Subconjunctival                                                                                                                                  23
With intra-operative application and         injection prior to trabeculectomy in                of back-flow of MMC intracamerally via
washing techniques, the amount of            patients with refractory glaucoma in                a fistula during intra-operative use, and
MMC left in the eye is quite variable;       1995.14 The total dose of MMC injection             the fact that it improves the ease of the
it may also vary considerably among          was 1 to 3 µg (0.05 ml of a 0.02 mg/ml              fornix-based conjunctival flap procedure.
surgeons. Because of the potential           solution), 24 hours to 5 days prior to              However, the procedure can be difficult
adverse effects of MMC in pterygium          filtering surgery. The 27-gauge needle              in patients with a very thin conjunctiva
surgery, as well as the possible cyto-       was inserted more than 1 cm away from               or thick conjunctival scarring, and MMC
toxicity of MMC in the ciliary body, a       the limbus to reach the planned trabecu-            can be difficult to place in the infrascleral
variety of approaches have been tried        lectomy site, and the subconjunctival               lamella.
to precisely control the MMC dose.           MMC solution was spread using the same
Although drug carriers and controlled        needle (figure 3). During the follow-up             Conclusion
delivery implants have been used in an       period of more than 12 months, we                   www
attempt to control the MMC dose more         observed significant IOP control and                This brief review has described the
precisely, simple subconjunctival injec-     typical MMC blebs with diffuse, non-                background of intraoperative MMC
tion appears to be most practical and        vascular appearance. Complications                  application in ophthalmic procedures,
least invasive method.11,12                  were minor.                                         as well as its indications and possible
    In 1992, we first reported the use of         The most important consideration               complications. Because of the potential
simultaneous sclerostomy and sub-            in pre-operative subconjunctival MMC                complications, the concentration and
conjunctival MMC injection.11 The scle-      injection for filtering surgery is optimisa-        duration of MMC application must be
rostomy was performed with a THC:            tion of the MMC dose. Ando et al. showed            carefully controlled; a new approach,
YAG laser probe subconjuctivally in          that when 0.2 mg/ml MMC is injected                 pre-operative subconjunctival injection,
rabbits, and IOP and bleb survival were      subconjunctivally, followed by thorough             appears to have great advantage in this
monitored. This procedure proved to be       washing 5 minutes later, approximately              regard. The development of MMC and
effective in enhancing bleb filtration. A    3 µg of MMC remains in the eye.15                   other antimetabolites has started a
similar rabbit experiment was reported            Subconjunctival administration of              new era for glaucoma filtering surgery.16
in 1994 by Karp et al.13                     MMC prior to filtering surgery appears              However, the risk-benefit ratio for the
    Using the results of these animal        to be a safe and easy procedure. Its                patient should be carefully weighed
studies as a starting point, we investi-     advantages include exact control of the             prior to surgery using MMC or similar
gated the use of MMC subconjunctival         amount of MMC delivered, prevention                 agents.

Asian Journal of OPHTHALMOLOGY and Asia-Pacific Journal of Ophthalmology                                        Volume 2, Numbers 1, 2, 2000

     References                                            Ophthalmol Vis Sci 1992;33 (Suppl. 4):     15. Ando H, Kondom Y, Yamamoto T,
                                                           1271.                                          Kitazawa Y. Intraoperative mitomycin-C
     www                                             8.    Liebmann JM, Sokol J, Ritch R.                 uptake by the eye in vivo and contribu-
     1. Hata T, Sugawara R, Kanamori K, et al.             Management of chronic hypotony after           tory factors. Invest Ophthalmol Vis Sci
        A new antibiotic from streptomyces.                glaucoma surgery. J Glaucoma 1996;             1994;35 (Suppl. 4):1426.
        J Antibiotic (Tokyo) 1956;Ser. A, 9:               5:210-220.                                 16. Loon SC, Chew PT. A major review of
        141-146.                                     9.    Lee CH, Kim DC. Recurrence rate of             antimetabolites in glaucoma surgery.
     2. Kunitomo N, Mori S. Studies on                     pterygium with respect of mitomycin-C          Ophthalmologica 1999;213:234-245.
        pterygium, Report IV. A treatment of the           concentration in primary pterygium
        pterygium by mitomycin-C. Acta Soc                 operation. Invest Ophthalmol Vis Sci
        Ophthalmol Jpn 1963;67:601-607.                    1999;40 (Suppl. 4):5913.                     This study was supported in part
     3. Chen CW. Medical innovation in the           10.   Singh K. Intraoperative 5-fluorouracil       by grants NSC89-2314-B002-240
        effect of fistulizing operation. Proc Chin         (5 FU) vs. mitomycin-C (MMC). The
                                                           primary anti-metabolite study. Invest
                                                                                                        and NSC89-2314-B002-243 from
        Med Assoc (Taipei) 1983;30:15.
     4. Chen CW, Huang HD, Bair JS, et al.                 Ophthal Vis Sci 1999;40 (Suppl. 4): 84.      the National Council of Science,
        Trabeculectomy with simultaneous             11.   Wang TH, Hung PT, HO TC. THC:YAG             Executive Yuan, Republic of China.
        topical application of mitomycin-C in              laser sclerostomy with preoperative
        refractory glaucoma. J Ocular                      mitomycin-C subconjunctival injection in
        Pharmacol 1990;6:175-182.                          rabbits. J Glaucoma 1992;2:260-265.
     5. El-Rasheed S. Initial trabeculectomy         12.   Schwartz M, Yoles E, Solomon A. A
                                                                                                           Address for correspondence:
        with intraoperative mitomycin-C                    potential treatment of glaucoma. J
        application in primary glaucoma.                   Glaucoma 1996;5:473-483.
24                                                   13.   Karp CL, Higginbotham EJ, Griffin EO.
                                                                                                                   Prof. PT Hung
        Ophthalmic Surg Lasers 1999;30:
        360-366.                                           Adjunctive use of transconjunctival            Department of Ophthalmology
     6. Rubinfeld RS, Pfister RR, Stein RM,                mitomycin-C in ab externo diode laser        National Taiwan University Hospital
        et al. Serious complications of topical            sclerostomy surgery in rabbits. Ophthal-
        mitomycin-C after pterygium surgery.               mic Surg 1994;25:22-27.                          7 Chung-Shan South Road
        Ophthalmology 1992;9:1647-1654.              14.   Hung PT, Lin LLK, Hsieh JW, Wang TH.                        Taipei
     7. Ho TZ, Hung PT, Wang TH. Intra-                    Preoperative mitomycin-C subconjuncti-
        operative application of mitomycin-C               val injection and glaucoma filtering
        and stereoscopic fluorescein angio-                surgery. J Ocular Pharmacol 1995;11:                  Republic of China
        graphy study of hypotony. Invest                   233-241.

                                                 Glaucoma: An Asian Theme
                              Inaugural Meeting of the Southeast Asian Glaucoma Interest Group
                                        (SEAGIG is a part of the Asian-Oceanic Glaucoma Society, AOGS)

                                                        Date: 27-28 November 2000
                                            Venue: Siam Intercontinental Hotel, Bangkok, Thailand
                                                     Contact: Prin Rojanapongpun, MD
                                        Department Ophthalmology, Chulalongkorn University & Hospital
                                                   1873 Rama 4 Road, Bangkok, Thailand
                                                            Tel: (66 2) 256 4423
                                                           Fax: (66 2) 252 8290

     Volume 2, Numbers 1, 2, 2000                                             Asian Journal of OPHTHALMOLOGY and Asia-Pacific of Ophthalmology

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