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Use of topical allogenic fresh-frozen plasma drops in the treatment of ligneous conjunctivitis

Published:November 09, 2021DOI:https://doi.org/10.1016/j.jcjo.2021.09.017
      Ligneous conjunctivitis is a rare inflammatory condition characterized by chronic and recurrent deposition of fibrin-rich pseudomembranes on the palpebral conjunctiva.
      • Shamim MM
      • Weissman HM
      • Al-Mohtaseb ZN
      Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
      Firm membranes with a characteristic ‘woody’ induration usually occur bilaterally presenting since childhood.
      • Shamim MM
      • Weissman HM
      • Al-Mohtaseb ZN
      Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
      ,
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      The formation of fibrinous pseudomembranes is caused by a mutation in the PLG gene, leading to deficient levels of type 1 plasminogen.
      • Shamim MM
      • Weissman HM
      • Al-Mohtaseb ZN
      Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
      Plasminogen is a precursor of plasmin, a molecule involved in the degradation of fibrin.
      • Shamim MM
      • Weissman HM
      • Al-Mohtaseb ZN
      Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
      Pseudomembrane formation has been reported after trauma, surgery, contact with ocular foreign bodies, and infection.
      • Shamim MM
      • Weissman HM
      • Al-Mohtaseb ZN
      Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
      Lesions may also occur in other mucous membranes.
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      There is no standardized treatment for ligneous conjunctivitis. Several topical and systemic therapeutic options have been used to prevent pseudomembrane recurrence post-operatively. These include antibiotics, corticosteroids, immunosuppressants, heparin, plasminogen and fresh frozen plasma as well as amniotic membrane transplantation, with varied outcomes.
      • Shamim MM
      • Weissman HM
      • Al-Mohtaseb ZN
      Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
      ,
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      They characteristically tend to recur shortly after surgical excision.
      • Shamim MM
      • Weissman HM
      • Al-Mohtaseb ZN
      Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
      Pseudomembranes may be debilitating and may result in vision-threatening complications.
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      A two-year-old female patient presented to our Pediatric Ophthalmology clinic with bilateral pseudomembranes and clear, watery discharge. The patient was otherwise healthy. She was born term and had no complications during pregnancy or delivery. Immunizations were up-to-date. There was no previous ocular history, and family history was not contributory. No history of consanguinity was reported.
      On examination, visual acuity was 6/6 bilaterally using Cardiff cards. There was mild left upper lid swelling. Thick pseudomembranes were present along the palpebral conjunctival surfaces bilaterally. The rest of the anterior and posterior exam was unremarkable bilaterally.
      Cultures of the palpebral conjunctiva were positive for Haemophilus influenza. The patient was treated with topical tobramycin, fluorometholone (FML), and tobramycin/dexamethasone.
      After two weeks, there was complete resolution of the pseudomembranes on the right palpebral conjunctival surfaces. In the left eye, a thick, pale yellow, firmly adherent pseudomembrane persisted over the entire upper and three quarters of the lower palpebral conjunctival surface.
      The lesions on the left palpebral conjunctiva were surgically excised in the operating room with minimal bleeding. The patient was given topical tobramycin/dexamethasone. Unfortunately, pseudomembranes recurred two weeks post-operatively on both left palpebral surfaces (Figure 1).
      Figure 1
      Figure 1Colour photograph of the left eye of a two-year-old female with ligneous conjunctivitis showing: A) worm's-eye view of a thick pseudomembrane covering most of the (everted) upper palpebral conjunctival surface; and B) en-face view of the same large pseudomembrane over the upper palpebral conjunctiva and a smaller pseudomembrane over the lower palpebral conjunctiva post-resection on a regimen of topical tobramycin/dexamethasone. Credit: Dr. Dorothy Bautista, 2016.
      Histopathological examination demonstrated acellular fibrinous material with chronic inflammation, in keeping with ligneous conjunctivitis. Plasminogen level was 0.2U/mL (normal range 0.8-1.2U/mL). The diagnosis of Type 1 Plasminogen deficiency was confirmed by genetic testing, which demonstrated a homozygous pathogenic mutation in the PLG gene, c.112A>G (previously denoted as p. Lysine19Glutamic Acid or p. Lys19Glu), where a negatively charged amino acid is switched for a positively charged one.).
      The pseudomembranes remained stable on a topical regimen of FML and cyclosporine. A trial discontinuation of steroid drops resulted in a prolonged episode of keratitis, which eventually resolved with increased lubrication and resumption of the steroid drop regimen.
      At age five, the patient began to develop mild ptosis of the left upper eyelid and mild astigmatism secondary to pseudomembrane size (Figure 2A). The patient also presented increased intraocular pressure and early lens opacity in the left eye secondary to prolonged steroid use. Corrective glasses were prescribed, and the patient was placed on timolol.
      Figure 2
      Figure 2Colour photograph of the everted left eye of a five-year-old female with ligneous conjunctivitis showing: A) a chronic thick pseudomembrane covering most of the upper palpebral conjunctiva on a regimen of topical FML and cyclosporine post-recurrence three years prior; and B) scarring of left upper palpebral conjunctiva but no sign of pseudomembrane recurrrence ten months post-resection after a five-month regimen of slowly tapered topical allogenic fresh frozen plasma drops, cyclosporine and tobramycin/dexamethasone. Credit: Dr. Dorothy Bautista, 2019-2020.
      A second surgical excision of the left upper palpebral conjunctival pseudomembrane was performed. The pseudomembrane on the left lower palpebral conjunctiva was too small to warrant excision. In post-operative week one, there was a small recurrence of the pseudomembrane on the left upper eyelid; however, the pseudomembrane completely regressed by post-operative week two, leaving a small linear fibrotic conjunctival scar.
      The patient was placed on a post-operative regimen of topical allogenic fresh frozen plasma (FFP) drops hourly, cyclosporine drops four times a day, and tobramycin/dexamethasone drops four times a day with a prolonged taper over five months.
      FFP was prepared from pooled plasma by the Canadian Blood Services. FFP was stored frozen in vials, which contained approximately 3-4 doses each. The vials were stored in a refrigerator once opened.
      The taper involved continuing FFP drops hourly only while awake and decreasing to every 3 hours while asleep on post-operative day five. The frequency of FFP was slowly decreased over five months. Tobramycin/dexamethasone and cyclosporine drops were discontinued after three weeks and four months, respectively.
      Ten months post-operatively (i.e. five months after discontinuation of topical drop regimen), there was scarring of the left upper palpebral conjunctiva but there was no sign of pseudomembrane recurrence. The pseudomembrane on the left inferior palpebral conjunctiva decreased in size and remained stable (Figure 2B). The patient had corrected distance visual acuity of 6/6 bilaterally, with normal ocular alignment, normal motility, and excellent stereopsis. Corneas were clear bilaterally, and the early lens opacity noted in the left eye was unchanged.
      Many aspects of our patient's presentation followed a course characteristic of ligneous conjunctivitis. The patient presented with a first episode of ligneous conjunctivitis in childhood, carried a homozygous mutation in the PLG gene, possessed a low level of plasminogen, and had recurrence of pseudomembranes after surgical resection. In this patient, infection was identified as a precipitating factor in the development of pseudomembranes, which has been reported in the literature.
      • Shamim MM
      • Weissman HM
      • Al-Mohtaseb ZN
      Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
      ,
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      Homozygous mutations in p. Lys19Glu have been associated with a higher residual PLG activity; and therefore, a milder clinical course of Type 1 Plasminongen deficiency. This may explain the complete absence of systemic disease, characterized by pseudomembrane formation in other organ systems, in our patient. The patient continues to have annual evaluations to monitor for the formation of pseudomembranes in the oral cavity, nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and the cerebral ventricular system.
      The size of pseudomembranes may predict response to treatment. During our patient's original presentation, the smaller pseudomembranes on the right palpebral conjunctiva completely resolved with a course of topical antibiotics and steroids, whereas the larger one on the left palpebral conjunctiva persisted. This is an interesting outcome as ligneous conjunctivitis-associated pseudomembranes have been extensively reported to be non-responsive to antibiotic and steroid therapy.
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      • Ku JY
      • Lichtinger A
      • Yeung SN
      • Kim P
      • Cserti-Gazdewich C
      • Slomovic AR.
      Topical fresh frozen plasma and heparin treatment of ligneous conjunctivitis in a Canadian hospital setting.
      • Gürlü VP
      • Demir M
      • Alimgil ML
      • Erda S.
      Systemic and topical fresh-frozen plasma treatment in a newborn with ligneous conjunctivitis.
      • Putri SC
      • La Distia NR
      • Made S
      Response of Plasminogen Deficiency Associated Ligneous Conjunctivitis to Topical Fresh frozen Plasma with Heparin.
      In addition, the pseudomembrane present on the left lower palpebral conjunctiva, which was not resected a second time due to its small size, decreased in size over five months on a course of topical allogenic fresh frozen plasma, cyclosporine, and tobramycin-dexamethasone with taper. This is also an interesting outcome as fresh frozen plasma has only been reported to prevent recurrence of pseudomembrane formation after surgical excision, but the ability to decrease the size of existing pseudomembranes has not been reported.
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      • Ku JY
      • Lichtinger A
      • Yeung SN
      • Kim P
      • Cserti-Gazdewich C
      • Slomovic AR.
      Topical fresh frozen plasma and heparin treatment of ligneous conjunctivitis in a Canadian hospital setting.
      • Gürlü VP
      • Demir M
      • Alimgil ML
      • Erda S.
      Systemic and topical fresh-frozen plasma treatment in a newborn with ligneous conjunctivitis.
      • Putri SC
      • La Distia NR
      • Made S
      Response of Plasminogen Deficiency Associated Ligneous Conjunctivitis to Topical Fresh frozen Plasma with Heparin.
      The use of topical fresh frozen plasma drops may be a suitable option for the treatment of ligneous conjunctivitis flare-ups. Our case suggests that topical fresh frozen plasma is successful in preventing the recurrence of pseudomembranes
      • Ku JY
      • Lichtinger A
      • Yeung SN
      • Kim P
      • Cserti-Gazdewich C
      • Slomovic AR.
      Topical fresh frozen plasma and heparin treatment of ligneous conjunctivitis in a Canadian hospital setting.
      ,
      • Putri SC
      • La Distia NR
      • Made S
      Response of Plasminogen Deficiency Associated Ligneous Conjunctivitis to Topical Fresh frozen Plasma with Heparin.
      without the need of its subconjunctival or systemic administration.
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      ,
      • Gürlü VP
      • Demir M
      • Alimgil ML
      • Erda S.
      Systemic and topical fresh-frozen plasma treatment in a newborn with ligneous conjunctivitis.
      The results of our case also suggest that topical fresh frozen plasma may be useful in reducing the size of existing pseudomembranes. Topical administration of fresh frozen plasma decreases the likelihood of adverse outcomes including anaphylaxis, transfusion-related acute lung injury, and haemolysis related to its systemic administration.
      • Gürlü VP
      • Demir M
      • Alimgil ML
      • Erda S.
      Systemic and topical fresh-frozen plasma treatment in a newborn with ligneous conjunctivitis.
      The use of topical medication also eliminates the need for hospitalization, intravenous access, and the short half-life of intravenous fresh frozen plasma.
      • Gürlü VP
      • Demir M
      • Alimgil ML
      • Erda S.
      Systemic and topical fresh-frozen plasma treatment in a newborn with ligneous conjunctivitis.
      Our case adds to the growing body of evidence suggesting that the use of frozen plasma, in combination with other topical medications, represents an acceptable treatment for the management of ligneous conjunctivitis. Fresh frozen plasma has shown to be a more accessible and cost-efficient treatment compared to topical plasminogen.
      • Watts P
      • Agha SH
      • Mameesh M
      • et al.
      Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
      ,
      • Putri SC
      • La Distia NR
      • Made S
      Response of Plasminogen Deficiency Associated Ligneous Conjunctivitis to Topical Fresh frozen Plasma with Heparin.

      References

        • Shamim MM
        • Weissman HM
        • Al-Mohtaseb ZN
        Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.
        J Pediatr Ophthalmol Strabismus. Aug 2018; 55: e30-e32https://doi.org/10.3928/01913913-20180806-01
        • Watts P
        • Agha SH
        • Mameesh M
        • et al.
        Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.
        J AAPOS. 2019; 23 (02e1): 42-45https://doi.org/10.1016/j.jaapos.2018.05.011
        • Ku JY
        • Lichtinger A
        • Yeung SN
        • Kim P
        • Cserti-Gazdewich C
        • Slomovic AR.
        Topical fresh frozen plasma and heparin treatment of ligneous conjunctivitis in a Canadian hospital setting.
        Can J Ophthalmol. Oct 2012; 47: e27-e28https://doi.org/10.1016/j.jcjo.2012.03.025
        • Gürlü VP
        • Demir M
        • Alimgil ML
        • Erda S.
        Systemic and topical fresh-frozen plasma treatment in a newborn with ligneous conjunctivitis.
        Cornea. May 2008; 27: 501-503https://doi.org/10.1097/ICO.0b013e318162a8e0
        • Putri SC
        • La Distia NR
        • Made S
        Response of Plasminogen Deficiency Associated Ligneous Conjunctivitis to Topical Fresh frozen Plasma with Heparin.
        Journal of Case Reports. 2015; 5: 132-136https://doi.org/10.17659/01.2015.0033