Veterinary Ophthalmology (2009) 12, 4, 248–253 Blackwell Publishing Inc
CASE REPORT
Ligneous conjunctivitis in a plasminogen-deficient dog: clinical management and 2-year follow-up María-Dolores Torres, Marta Leiva, María-Dolores Tabar, Carolina Naranjo, Josep Pastor and Teresa Peña Departament de Medicina i Cirurgia Animals, Facultat de Veterinària, Universitat Autònoma de Barcelona, Barcelona, Spain
Address communications to: M.-D. Torres Tel.: 34-93-285-8400 Fax: 34-93-285-8401 e-mail:
[email protected]
Abstract A 1-year-old-female Yorkshire Terrier was referred to the Veterinary Teaching Hospital of the Autonomous University of Barcelona (VTH-UAB) (Spain) with a 6-month history of unilateral chronic proliferative conjunctivitis and intermittent vomiting and cough. Several medical and surgical treatment efforts to manage conjunctival lesions had resulted in no improvement of the clinical signs. Complete general and ophthalmic examinations revealed several proliferative ‘wood-like’ masses in the conjunctiva, oral cavity and an interscapular subcutaneous nodule. Conjunctival and buccal biopsies were performed as diagnostic procedures. A diagnosis of ligneous conjunctivitis was made on the basis of histopathology findings and clinical presentation. The only biochemical abnormalities found were severe proteinuria and low plasminogen activity in plasma. No other analytical abnormalities were observed. Topical treatment with heparin and anti-inflammatory and immunosuppressive drugs have controlled the ophthalmological clinical signs. To our knowledge, this is the first case report of a dog with plasminogen deficiency and ligneous conjunctivitis with a long survival period and 2-year follow-up. Key Words: conjunctiva, dysplasminogenemia, heparin, hypoplasminogenemia, pseudomembranes, systemic manifestations
INTRO DUC T IO N
Ligneous conjunctivitis (LC) is a rare and unusual form of chronic membranous or pseudomembranous conjunctivitis described in humans, dogs and mice.1–4 The first detailed histological description of pseudomembranous conjunctivitis in humans was reported in 1924,5 and in 1933 the current name ‘ligneous conjunctivitis’ was introduced.6 In human medicine, LC is characterized by amorphous fibrin accumulation in the palpebral conjunctiva.7 It usually begins after local injury and is caused by a systemic plasminogen disorder.8 Although the disease may appear at any gender and at any age, a clear sexual predisposition in young females has been described.1,3,4,9–20 Usually the disease starts in early infancy, with conjunctival redness that progress to pseudomembranes formation on the palpebral conjunctival surface. Thick ‘woodlike’ masses, replacing the normal mucosa and limiting palpebral aperture, appear with disease progression and, in some cases, induce blindness due to corneal involvement.3 In 1996, Ramsey et al. described LC in four Doberman pinschers, three of them females.1 Recently, McLean et al. have described a case of LC in a young female Golden Retriever.4
The objective of the present case report is to describe, for the first time, a 2-year follow-up period in a case of LC with systemic involvement in a 1-year-old female Yorkshire Terrier dog. C A S E R E P O RT
A 1-year-old intact female Yorkshire Terrier, weighing 1 kg, with a history of chronic OD conjunctivitis, was referred to the Ophthalmology Service of the Autonomous University of Barcelona Veterinary Teaching Hospital (UAB-VTH). Clinical signs appeared at 4 months of age and were refractive to various previous topical treatments, progressing to chronic proliferative conjunctivitis. Palpebral/conjunctival surgery had been performed in the eye, but no data concerning surgical procedure or biopsy results were available. After surgery, the conjunctival masses relapsed in a short period of time and topical treatment with dexamethasone 0.1% QID (Maradex® Laboratorios L.O. Oftalmi, Caracas, Venezuela), and tacrolimus 0.1% BID (Protopic® 0.1% ointment, Astellas Pharma GmbH, München, Germany) was administered with no improvement. Additional clinical signs were sporadic vomiting and nonproductive cough. © 2009 American College of Veterinary Ophthalmologists
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Figure 2. Mild palpebral involvement on the OS.
Figure 1. (a) Severe ectropion secondary to proliferative conjunctival masses on the OD. (b) Corneal dystrophy and meibomianitis associated.
At the time of referral, a complete ophthalmic examination was performed. The Schirmer tear test I (Schering-Plough Animal Health Corp., Union, NJ) was within the reference range for OU. Menace response and pupillary light reflexes were normal. The biomicroscopic examination (Kowa SL-15, Kowa Company, Tokyo, Japan) showed proliferative red masses in the upper and lower palpebral conjunctiva of the OD, causing secondary ectropion associated with mild meibomianitis (Fig. 1a,b). The conjunctiva of the OS was also involved but to a lesser degree, with diffuse redness and conjunctival pseudomembranous proliferation of the upper eyelid (Fig. 2). Other biomicroscopic anomalies included mild bilateral corneal lipid epithelial dystrophy and right persistent pupillary membranes (iris to iris). Intraocular pressure, measured by applanation tonometry (Tonopen XL®, Mentor, Norwell, MA) was within reference range. Indirect funduscopic examination (Heine Omega® 180, Herrsching, Germany) showed no abnormalities. General physical examination showed proliferative masses in the oral mucosa (Fig. 3), buccal ulcers associated with periodontal disease (Fig. 4) and an interscapular subcutaneous nodule. No other abnormalities were detected at that moment.
Figure 3. Proliferative masses at the oral mucosa.
Fine needle aspiration of the nodule yielded fibrin accumulation. Initial work-up included complete blood count (CBC), complete biochemical and coagulation panel with plasma d-dimer analysis, urinalysis, serological testing against Leishmania spp. and Erhlichia spp., abdominal ultrasound and thoracic radiographs. Mild leukocytosis (18 040 μL; reference range 6000–17 000 μL) and mild ALT elevation (135 UI/L; reference range 21–102 UI/L) were the only clinical pathologic findings seen in the bloodwork, with normal creatinine and urea values. Urinalysis showed marked proteinuria, with urine protein : creatinine ratio (UPCR) of 10 (normal reference range < 0.5) and negative urine culture. ELISA testing for Leishmania spp. and Erhlichia spp. was negative for both. Mild peritoneal effusion, intestinal mucosa hyperechogenicity, and cervix distension were seen in the abdominal ultrasound. Thoracic radiographs showed no alterations. At that time, the differential diagnoses for
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Figure 4. Buccal ulcers associated with periodontal disease.
the chronic bilateral proliferative conjunctival masses with renal involvement were systemic amyloidosis or ligneous conjunctivitis. Other differential diagnoses for ocular signs were conjunctival granulomas (associated with a foreign body, protozoa [Leishmania spp.] or fungi [Blastomyces dermatitidis]), and primary or metastatic neoplasia. To make a definitive diagnosis, oral mucosa and conjunctival biopsies, associated with a temporal protective tarsorraphy of the OD, were proposed. Before performing the biopsy, and in order to manage the renal process, a trial with ramipril (Vasotop® 1.25 mg, Laboratorios Intervet S.A., Salamanca, Spain) 0.25 mg/kg SID was given. Although the next urinalysis performed 21 days after starting the treatment with ramipril showed improvement in the UPCR (UPCR of 5.4), the reference values were never achieved. Oral mucosa and conjunctival biopsy samples (Fig. 5) were obtained and processed routinely, fixed with 10% buffered formalin, sectioned at 6 μm and stained with H&E. Hyperplastic epithelial lamina of the basal membrane with eosinophilic, amorphous and hyaline material within the substantia propria, and mild perivascular lymphoplasmacytic infiltrate were observed (Fig. 4) in the conjunctiva. Similar findings were found in the oral mucosa. Special stains were used to identify the hyaline material. Gram stain, PAS, and Congo red stains ruled out, respectively, bacterial, fungal and parasitic conjunctivitis, as well as conjunctival amyloidosis. A Mallory PTAH stain demonstrated the presence of fibrin in the samples. Based on clinical signs and histopathological findings, a definitive diagnosis of ligneous conjunctivitis was made. Topical heparin (10 mg/mL, three times a day) was added to the previous topical treatment (topical dexamethasone 0.1% QID and tacrolimus 0.1% BID) in accord with human literature.21 To further investigate the LC and systemic involvement, antithrombin III and plasminogen activity (PLGa) were studied. Antithrombin III was within normal limits (115% with reference range of 85–120%). For PLGa detection, a human plasminogen (PLG) kit was used (Kit Coanatic® Plasminogen, Chromogenix Laboratory). To
Figure 5. Photomicrographs of: (a) conjunctival specimen and (b) oral specimen. ‘*’ Hyperplastic epithelial lamina of the basal membrane with eosinophilic, amorphous and hyaline material within the substantia propria and mild perivascular lymphoplasmacytic infiltrate (H&E, original magnification ×20).
optimize the test, serum samples from 12 healthy dogs were taken and mixed, assigning to this mix the value of 100% of activity (reference range in human literature 55–145%17). Three other healthy dogs were used as controls (range 97– 105%). PLGa value in our patient was extremely diminished at 2% and plasminogen deficiency was confirmed. One week after the biopsy procedure, the conjunctival proliferation on the OD had mostly disappeared but topical treatment was maintained (topical dexamethasone 0.1%, tacrolimus 0.1% and heparin dilution 10 mg/mL). One month later the clinical signs in the OD recurred. No further biopsies were undertaken and only topical and systemic treatments (ramipril 0.25 mg/kg SID) were maintained. Two years after initial clinical presentation, the topical treatment consisting of topical heparin, anti-inflammatory and immunosuppressive drugs, has controlled ocular relapses, although renal proteinuria persists, even with systemic treatment.
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DISC USSIO N
Ligneous conjunctivitis (LC) appears to have similar clinical presentation in humans, mice and dogs.1–4,10,13,17–20 Despite the limited veterinary literature,1,4 the predisposition of females and the early age of presentation seems to be similar to what is described in human medicine. LC is related to PLG deficiency, and in most humans systemic involvement is observed. There are two types of PLG alteration in humans affected by LC: hypoplasminogenemia and dysplasminogenemia. In hypoplasminogenemia, or severe type I PLG deficiency, both the PLGa and the immunoreactive PLG level are decreased, with ocular and systemic signs usually present.18 In dysplasminogenemia only PLGa is reduced, and normally no clinical signs are associated.17 Fibrin is necessary in wound healing, providing a matrix for cell migration. Abnormalities in fibrin metabolism produce defective wound healing. PLG, which is synthesized by liver and other extra-hepatic tissues as cornea,22 is very important in fibrin metabolism, acting directly in its degradation.23 In affected patients fibrin is not degradated, due to the low amount of plasminogen, and it tends to accumulate in the more external mucosae such as the conjunctival, oral, respiratory and genital, giving the characteristic clinical presentation. In cases of hypoplasminogenemia, accumulation of fibrin provides the characteristic clinical presentation of amorphous conjunctival masses and fibrin deposition in different mucosae. In human beings, an initial trauma seems to be needed for clinical signs develop in affected patients.3 According to this theory, there is a clear predisposition for the more external mucosas to be affected. Two different clinical phases (acute and chronic) are described in the human literature.3,24 During the acute phase, systemic signs (fever and associated secondary infections) are important, and they involve the conjunctiva, gingiva,25–29 skin,10 middle ear,24,30 respiratory tract,13,31 female genital tract,17,24 and kidneys.32 The chronic phase is usually asymptomatic and is characterized only by recurrence of the conjunctival lesions. The clinical presentation of the case described here shows a resemblance to human ligneous conjunctivitis. Characteristic conjunctival and oral lesions were confirmed with histopathology. The renal involvement in this case could be related to the PLG deficiency, but no further investigations, such as renal biopsy, were performed due to the pathogenesis of the disease. Other systemic alterations revealed by abdominal ultrasound were cervix and intestinal involvement, which may be related to the same entity, but no definite diagnosis was made. Some authors have described systemic involvement in the dog.1,4 Most of the canine cases affected with LC described in the veterinary literature lived only for a short time after diagnosis, due to systemic involvement.1,4 Some of them were humanely euthanized. To our knowledge, this is the first case of LC in a dog with long-term survival. Even though systemic signs are difficult to manage, and chronic medication is required, the dog is still alive with acceptable quality of life.
In human medicine, PLGa alteration has been described without a relationship between the degree of PLGa deficiency and the severity of clinical signs.3 In the veterinary literature, only one previous report has described PLGa deficiency associated with LC and systemic involvement.4 In that case, similar to human patients, the degree of PLGa deficiency does not seem to be related to the clinical outcome. In the case presented here, the PLGa was lower than in the one reported by McLean et al. but the follow-up was longer with no worsening of clinical signs. In human medicine,3,7 diagnosis of LC is achieved with the characteristic clinical presentation, the typical histopathological findings and, eventually, a positive family history. Histopathological findings are characterized by thinned or eroded epithelium with superficial or subepithelial deposits of amorphous hyaline eosinophilic material and foci of persisting granulation tissue with accompanying inflammatory cells, such as lymphocytes, plasma cells and granulocytes.3 This amorphous material can be confused with amyloid, but a negative Congo red rules out systemic amyloidosis as the origin of clinical signs. Reported cases in dogs, including the one reported here, present a similar histopathological pattern.1,4 In our patient, although systemic involvement was seen, only histopathological confirmation of the conjunctival and oral lesions was obtained. Positive Mallory stain and negative Congo red were conclusive for the definitive diagnosis, ruling out suspicion of systemic amyloidosis as the principal etiology. No further biopsies were considered due to the pathogenesis of the disease, the possibility of relapses and the worsening of initial clinical signs. In humans it has been reported that local excision or injuries may trigger the clinical signs and may be an initial event for development of systemic symptoms.3 Due to the consistent histopathology results, presenting clinical signs and low PLGa, hypoplasminogenemia was suspected as the most likely cause of LC; dysplasminogenemia was ruled out because in human medicine it has never been associated with clinical signs, although immunoreactivity was not studied.33 PLG consumption as the possible cause of low PLGa was also ruled out based on a normal coagulation panel, lack of detection of plasma d-dimer and normal antithrombin III values.34 Topical anti-inflammatory and immunosuppressive drugs have been proposed as standard treatment in humans and dogs affected with LC. Their use seems to improve clinical signs without complete resolution.1,3 Another reported therapy in humans is topical heparin, which diminishes fibrin accumulation due to its antithrombotic activity.34 Topical heparin accelerates the activity of antithrombin III, which inhibits thrombin formation and activity, reducing the conversion of fibrinogen to fibrin.21 In our case, topical heparin at 10 mg/mL concentration was used in association with the primary topical treatment instituted at time of referral. Improvement in ophthalmic signs was observed when topical heparin was added. Systemic treatment for LC in humans has been focused on hormones, immunosuppressant
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and fresh frozen plasma administration.1,3,4,8,12,15,21,28,35–37 Hormonal stimuli may up-regulate PLG synthesis as happens in Cushing’s syndrome, and during pregnancy and treatment with oral contraceptives.15 In only one dog, Danazol and diethylstilbestrol has been used without a significant improvement.4 Systemic immunosuppressive treatment was effective in the treatment of one of the five previously canine reported cases.1 Administration of systemic immunosuppressive drugs in our case was not instituted due to significant proteinuria and the potential worsening of the renal involvement. In human medicine, the best clinical results have been obtained with frozen PLG.11 The reported administration routes are systemic, topical and intralesional.18,20,35–37 The systemic route is the best approach for controlling clinical signs in human medicine, but PLG has a short lifetime and repeated intravenous doses are needed,35 which is a difficult treatment option in canine cases. The topical route seems to diminish the conjunctival proliferations, but even with intensive treatment doses, it is not curative.36 The intralesional route has been tested only in one young woman, in whom complete ocular resolution was observed.37 Association of surgical resections with plasma transfusions in acute proliferative cases is also described for human therapy.37 In our clinical case, heparin and anti-inflammatory/ immunosuppressive therapies were used as the only topical treatment, with partial resolution of local clinical signs. No systemic treatment was used to control systemic involvement other than an angiotensin converting enzyme inhibitor for the renal problem. The prognosis in human medicine is directly related to the degree of systemic involvement, the worst cases being associated with hydrocephalus. The congenital occlusive hydrocephalus has been described in humans and mice. The pathophysiological mechanism could be fibrin deposition in the cerebral ventricular system causing impaired circulation of the fluid in the aqueduct region; however, the exact pathogenesis is still unclear.23,31,36,38 In veterinary medicine, four of the five previously described cases died or were euthanized, and in only one dog was mild hydrocephalus described.4 Our case is the first one reported with a 2 years of follow-up, probably because the systemic clinical signs were mild and have not progressed to a more severe presentation. Neither in human nor veterinary medicine are the factors affecting the progression of the disease well understood.3,4 To our knowledge, this is the first case report of a dog with PLG deficiency and LC with a long survival period and 2-year follow-up. Future studies will be needed to focus on the inheritability of the disease and mutations in the PLG gene; in human medicine an autosomal recessive inheritance is suspected, associated with a mutation in the long arm of chromosome 6 or 2.9,23,32,39 In canine patients due to the low number of cases reported, no inheritability has as yet been proven, so further familial investigation of affected dogs is needed.
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31. Çiftçi E, Ince E, Akar N et al. Ligneous conjunctivitis, hydrocephalus, hydrocele, and pulmonary involvement in a child with homozygous type I plasminógeno deficiency. European Journal of Pediatrics 2003; 162: 462– 465. 32. Schuster V, Seindenspinner S, Zeitler P et al. Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis. Blood 1999; 93: 3457–3466. 33. Ichinose A, Espling ES, Takamatsu J et al. Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis. Proceedings of the National Academy of Sciences USA 1991; 88: 115–119. 34. Chen S, Wishart M, Hiscott P. Ligneous conjunctivitis: a local manifestation of a systemic disorder? American Association for Pediatric Ophthalmology and Strabismus 2000; 4: 313–315. 35. Schott D, Demplfle CE, Beck P et al. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. New England Journal of Medicine 1998; 339: 1679–1686. 36. Watts P, Suresh P, Mezer E et al. Effective treatment of ligneous conjunctivitis with topical plasminogen. American Journal of Ophthalmology 2002; 133: 451– 455. 37. Tabbara KF. Prevention of ligneous conjunctivitis by topical and subconjunctival fresh frozen plasma. American Journal of Ophthalmology 2004; 138: 299–300. 38. Mingers AM, Heimburger N, Lutz E. Familiärer homozygoter und heterozygoter Typ I-Plasminogenmangel. In: (eds Scharrer I, Schramm W) 25. Hämophilie-Symposium. Hamburg, Berlin, Germany, 1994. 39. Murray JC, Buetow KH, Donovan M et al. Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26–6q27. American Journal of Human Genetics 1987; 40: 228–350.
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