Uveitis associated with septic peritonitis in a cat

Objective – To report a case of bilateral uveitis believed to be a consequence of septic peritonitis in a 19‐month‐old cat. Case Summary – Bilateral anterior uveitis with suspicion of extension to the posterior segment was documented in a previously healthy young cat during hospitalization for severe septic peritonitis. Based on medical history and other findings uveitis was believed to result from concurrent abdominal sepsis, due either to metastatic seeding of bacterial organisms or to effects of bacterial toxins and inflammatory mediators on the blood‐aqueous barrier. The cat was surgically and medically managed, and made a full recovery with respect to both his ocular and his abdominal disease. New or Unique Information Provided – Ocular complications secondary to systemic sepsis are well documented in people but seldom reported in the veterinary literature. To the authors' knowledge this is the first report of uveitis linked to septic peritonitis in any veterinary species and the first to report sepsis‐related uveitis in a cat. Ocular inflammatory disease in the context of critical illness deserves attention as a potential significant source of morbidity. The development of ocular inflammatory disease may serve as a sentinel lesion for systemic sepsis and other life‐threatening conditions.     

Bartonella vinsonii subspecies berkhoffi as a possible cause of anterior uveitis and choroiditis in a dog

A 2-year old, neutered, female spaniel mixed breed was referred to the North Carolina State University Veterinary Teaching Hospital for evaluation of bilateral anterior uveitis. The dog was febrile and, in addition to anterior uveitis, multifocal hyporeflective lesions were present in the tapetal fundus of both eyes. The antibody titer for Bartonella vinsonii subspecies berkhoffi was positive (1 : 512). Aqueous paracentesis was performed for PCR in an attempt to detect B. vinsonii in the eye but was unsuccessful. The ocular manifestations of Bartonella infection in humans are currently expanding as more sensitive serologic and PCR techniques are being developed to identify Bartonella spp. In addition to optic neuritis and neuroretinitis, retinochoroidal lesions are one of the most common manifestations of B. henselae infection, and are frequently accompanied by vitreous or anterior segment inflammation. Diagnosis of a Bartonella infection in humans can be made on serology alone, in conjunction with ocular examination findings. The ultimate proof of B. vinsonii (berkhoffi) as a direct cause of ocular disease would be detection of the infectious agent in the eye. However, it is unknown at this time whether Bartonella causes ocular disease primarily, secondarily via an autoimmune reaction, or both. Due to the difficulties associated with culture of Bartonella spp. and the limitations of PCR, serology is currently the most useful tool for screening dogs for possible Bartonella spp. infection. In the case presented here, even though the PCR was negative, the clinical signs of anterior uveitis and choroiditis might reasonably be associated with B. vinsonii (berkhoffi) seroreactivity, which was repeatable on three separate occasions. Clinical improvement was also accompanied by a post-treatment decrease in B. vinsonii (berkhoffi) seroreactivity, potentially supporting resolution of Bartonella infection in this dog. This is the first reported case of a possible association between uveitis, choroiditis and Bartonella infection in the dog, without clinical manifestations of other organ or tissue involvement. Future studies based on PCR analysis of intraocular fluids may clarify the involvement of B. vinsonii (berkhoffi) in dogs with intraocular inflammatory disease. Furthermore, performing fluorescein angiography in dogs with elevated Bartonella titers may also prove useful in the identification and characterization of lesions.     

Equine recurrent uveitis: A review of clinical assessment and management

Equine recurrent uveitis (ERU) is a vision‐threatening ocular disease that practitioners must be able to identify and manage. Although not every case of acute uveitis will develop into ERU, if 2 or more episodes of uveitis are observed, a diagnosis of ERU can be made. Patient outcomes improve with early diagnosis, appropriate therapy and client education. Recent advances in surgical options and treatment of horses with ERU have improved success in managing this condition. New therapeutic strategies under investigation may further enhance results and reduce the development of complicating factors.     

Effects of ophthalmic disease on concentrations of plasma fibrinogen and serum amyloid A in the horse

Reasons for performing study: There is little scientific information available about the ability of ocular disease to cause a systemic inflammatory response. Horses are frequently affected with ocular disease and ensuring their systemic health prior to performing vision saving surgery under anaesthesia is essential for the successful treatment of ophthalmic disease. Hypothesis: Ocular disease will cause elevations in the concentration of the acute phase proteins fibrinogen and serum amyloid A in peripheral blood. Methods: Whole blood and serum samples were obtained from 38 mature horses with ulcerative keratitis or uveitis and no evidence of systemic disease, 9 mature horses with no evidence of ocular or systemic disease (negative controls) and 10 mature horses with systemic inflammatory disease and no evidence of ocular disease (positive controls). Blood samples were assayed for concentrations of the acute phase proteins fibrinogen and serum amyloid A. Results: Fibrinogen and serum amyloid A were significantly different in the positive control group compared to the negative control, corneal disease and uveitis groups (P<0.126). There was no significant difference between the negative control, corneal disease and uveitis groups (P<0.001). Conclusions: Ulcerative keratitis and anterior uveitis are not associated with elevated concentrations of the acute phase proteins fibrinogen and serum amyloid A in peripheral blood. Potential relevance: When the clinician is presented with a patient with ocular disease and elevated plasma fibrinogen or serum amyloid A concentrations, a nonocular inflammatory focus should be suspected.     

Uveitic glaucoma in the horse

Glaucoma is a serious complication of anterior uveitis that can result in significant ocular discomfort and loss of vision. As glaucoma is insidious and mostly asymptomatic until late in the course of disease, it is often undiagnosed. Equine recurrent uveitis is the most common underlying disorder: it is a disease of high prevalence, characterised by recurrent‐remitting episodes of ocular inflammation. Here, the inflammatory cells and mediators they release alter the normal anatomic structure of the anterior chamber and aqueous drainage pathways of the eye. These changes alter the homeostatic mechanisms of intraocular pressure control. Management of glaucoma secondary to uveitis can be challenging due to the difficulties of managing the underlying disorder and its effects on the eye. This article reviews the pathogenesis of uveitic glaucoma in the horse and medical and surgical management options.     

Diagnosis of Borrelia‐associated uveitis in two horses

Borrelia burgdorferi, the etiologic agent of Lyme disease is a tick born spirochetal infection. Clinical signs of Lyme borreliosis are uncommon in horses, but when present they are often vague and nonspecific. In horses, Lyme borreliosis has been implicated in musculoskeletal, neurological, reproductive, and ocular disorders, including uveitis, but definitive diagnosis can be challenging as the causative agent is rarely isolated and serologic tests can be unreliable and do not confirm active disease. Here, we report two cases of equine uveitis associated with B. burgdorferi based on the identification of spirochetes within ocular fluids and confirmed with PCR testing. The two cases illustrate some of the challenges encountered in the recognition and diagnosis of equine Lyme borreliosis. Although only one of many possible causes of equine uveitis, Lyme disease should be considered a differential diagnosis, especially in endemic areas. Given the possibility for false negative results of serum tests during uveitis associated with B. burgdorferi and the failure of such tests to confirm active infection, a combination of cytologic assessment, antibody, and/or PCR testing of ocular fluids may be worthwhile if the clinical suspicion for Lyme uveitis is high.     

Clinical ocular findings in cows with malignant catarrhal fever: ocular disease progression and outcome in 25 cases (2007-2010)

Objective To describe the ocular clinical signs in a group of cows diagnosed with sheep associated malignant catarrhal fever (MCF), and to investigate a possible correlation between the severity and progression of certain typical clinical signs and disease outcome. Procedure This prospective study involved cows diagnosed with MCF between 2007 and 2010, and included cows enrolled in a larger clinical trial. Signalment of affected cows, presence and progression of ocular lesions, as well as disease outcome were recorded. Cows were divided into two groups based on the disease outcome: (1) survival and (2) nonsurvival. The degree of corneal edema at first examination was statistically compared between groups. The progression of corneal edema, uveitis and the examining ophthalmologists’ subjective assessment of disease progression between the first and last examination were also compared between groups. Results Twenty‐five cows (22 F, 3 M) of six different breeds and one mixed breed were included. Median age was 21 months (range 8–113). Ten cows survived, 13 cows were euthanized, and two died. No statistical association was identified between the degree of corneal edema at the first examination and the disease outcome. Deterioration of corneal edema was not noticed in any of the surviving animals. Anterior uveitis improved in all 10 surviving cows. Conclusions The degree of corneal edema at first examination had no prognostic value for the disease outcome. The results of this study suggest that the progression of corneal edema correlates well with disease outcome, and that nonimprovement of uveitis is a bad prognostic sign.     

Canine adenovirus: its role in renal and ocular disease: a review

Hypersensitivity reactions to live attenuated and virulent field strains of canine adenovirus can produce renal and ocular disease. The renal lesion is a focal interstitial nephritis which is probably a Type IV hypersensitivity reaction; it has not so far been shown to be of any clinical significance. The ocular lesion, thought to be a Type III immune complex hypersensitivity reaction, is characterized by anterior uveitis and corneal oedema. It is usually transitory but occasionally results in permanent eye defects.     

Ocular and periocular manifestations of leishmaniasis in dogs: 105 cases (1993-1998)

The purpose of this retrospective study was to determine the prevalence, type, and prognosis of ocular lesions associated with leishmaniasis in dogs. One hundred and five dogs (24.4% of all cases of leishmaniasis diagnosed during the study period) had ocular or periocular leishmaniasis, and 16 dogs (15.2% of ocular cases) had only ocular lesions and systemic signs were not apparent. Anterior uveitis was the most common manifestation and other prevalent findings included blepharitis and keratoconjunctivitis. Several distinct variations of eyelid lesions were seen including a dry dermatitis with alopecia, diffuse blepharedema, cutaneous ulceration, and discrete nodular granuloma formation. In some cases with keratoconjunctivitis, corneal lesions clinically resembled nodular granulomatous episclerokeratitis. Twenty-seven of the 34 cases with ocular lesions had improvement in signs following systemic antiprotozoal and topical anti-inflammatory therapy, although many cases with anterior uveitis required long-term topical therapy. Response of ocular signs correlated highly with overall, systemic response to therapy. Ophthalmic manifestations of systemic leishmaniasis are common in the dog, and this disease should be considered in the differential diagnosis of most adnexal and anterior segment ocular inflammatory lesions in dogs in endemic areas.     

Ocular signs of canine monocytic ehrlichiosis: a retrospective study in dogs from Barcelona, Spain

Canine monocytic ehrlichiosis (CME) is a tick-borne disease caused by the rickettsia Ehrlichia canis. Ocular lesions are a common feature of the disease and can be present in all stages. The purpose of this retrospective study was to determine the prevalence, type and response to treatment of ocular lesions associated with monocytic ehrlichiosis in 46 affected dogs presented to the Autonomous University of Barcelona-Veterinary Teaching Hospital (UAB-VTH) from January 2000 to December 2002. Dogs were included in the study only if they had a positive serologic test for E. canis and information about the clinical outcome was available. Eighteen breeds were represented, with the German Shepherd dog (n = 6) being the most common. There were 25 intact and three castrated males, and 16 intact and two neutered females. Twenty dogs (43.4%) were between 5 and 10 years old. Seventeen dogs (37% of all cases of monocytic ehrlichiosis diagnosed during the study period) had ocular signs, and 11 dogs (64.7% of the ocular cases) had only ocular lesions without apparent systemic signs. Exudative retinal detachment was the most common ocular manifestation; other prevalent findings included anterior exudative uveitis and optic neuritis. Five of the 17 cases with ocular lesions (29.4%) had ocular bleeding disorders (hyphema or retinal hemorrhages). All the dogs with ocular disease presented with bilateral signs. Dogs with posterior segment disease had titers against E. canis that were > or = 1 : 320, while lower titers were noted in dogs with anterior exudative uveitis. Two dogs presented with chronic autoimmune panuveitis after ehrlichiosis treatment. Canine ehrlichiosis should be considered in the differential diagnosis of exudative retinal detachment and anterior uveal inflammatory lesions.     

Toxoplasmosis.

Toxoplasmosis in dogs and cats can cause chorioretinitis, anterior uveitis, or both. Ocular lesions are a common manifestation of generalized toxoplasmosis. The prevalence of toxoplasmosis as a cause of idiopathic anterior uveitis in cats is not clear, although there is a significant association between exposure to T. gondii and feline anterior uveitis. The pathogenesis of ocular toxoplasmosis may be different in humans and cats, and the anterior uveitis may represent a type of immune-mediated inflammation. A diagnosis is made by observing compatible clinical findings and obtaining supportive findings on serologic tests. Despite improved diagnostic techniques, including determination of IgM class antibodies and PCR testing, definitive diagnosis of ocular toxoplasmosis remains a challenge. Topical anti-inflammatory therapy should be used in cats with anterior uveitis, a positive serum titer, and no concurrent systemic signs. Systemic clindamycin should be given to cats with ocular and systemic signs and to cats with suggestive serology and idiopathic anterior uveitis that fails to respond to topical therapy alone.     

Prevalence of serum antibodies against Bartonella species in the serum of cats with or without uveitis

Bartonella henselae has been implicated as a causative agent of chronic uveitis in people and in some cats. The objective of this study was to determine whether Bartonella species seroprevalence or titer magnitude varies among cats with uveitis, cats without ocular diseases recorded and healthy cats, while controlling for age and risk of flea exposure based on state of residence. There was no difference in seroprevalence rates or titer magnitude between cats with uveitis and cats with non-ocular diseases. Healthy cats were more likely to be seropositive for Bartonella species than cats with uveitis. The median Bartonella species titer was 1:64 for all groups, although healthy cats were more likely to have higher titers than cats with uveitis and cats with non-ocular disease. The results suggest that serum antibody tests alone cannot be used to document clinical uveitis associated with Bartonella species infection.     

Causes of uveitis in dogs: 102 cases (1989-2000)

Uveitis is one of the most common ocular diseases and one of the most common causes of blindness in dogs. The purpose of this retrospective study was to correlate the signalment, history, clinical signs and ophthalmic findings of dogs with uveitis with the underlying etiology. We conducted a retrospective study of 102 dogs presented to the NCSU-VTH from 1989 to 2000 with clinical signs of uveitis. Medical records of dogs presented for uveitis were reviewed. Dogs were included in the study only if a complete diagnostic work-up database was collected, if sufficient follow-up was documented, and if the uveitis was not secondary to trauma or a hypermature cataract. The mean age +/- SD of all dogs in this study was 6.2 +/- 3.6 years. There were 33 intact and 16 castrated males, and 14 intact and 27 neutered females. Fourteen breeds were represented, with the Golden Retriever (n = 14) most common. Fifty-nine dogs (58%) were diagnosed with idiopathic/immune-mediated uveitis, neoplasia was diagnosed in 25 dogs (24.5%) and 18 dogs (17.6%) were diagnosed with infectious causes of uveitis. Aqueous flare was the most common clinical sign, occurring in 88 dogs (86%). The most common infectious organisms associated with uveitis in the dogs of this study were Ehrlichia canis (n = 7). Lymphosarcoma (n = 17) was the most common neoplasm. In approximately 60% of dogs presenting for uveitis an underlying cause was not found, and a diagnosis of immune-mediated or idiopathic uveitis was made. However, approximately 25% of dogs had ocular and/or systemic neoplasia (with 17% of cases having lymphosarcoma) and 18% with an underlying infectious cause for uveitis. Because of the high percentage of systemic disease associated with uveitis in dogs, extensive diagnostic testing is recommended before instituting symptomatic anti-inflammatory therapy.     

Septic implantation syndrome in dogs and cats: a distinct pattern of endophthalmitis with lenticular abscess

Objective To summarize the clinical and pathologic findings in a group of dogs and cats with progressive clinical ocular disease, which were diagnosed with suppurative endophthalmitis and lens capsule rupture. Animals studied Twenty cats and forty‐six dogs that underwent unilateral enucleation or evisceration for intractable uveitis and/or glaucoma. Procedure Biopsy submission requests and microscopic case material were evaluated for clinical and histological features, including history of ocular trauma, duration of ocular disease, pattern of inflammation, and the presence of intralenticular microorganisms. Results The median duration for cats and dogs was 6 and 5 weeks, respectively. A history of trauma was reported for four (20%) cats and 18 (39%) dogs. All confirmed cases of trauma—three in cats and 14 in dogs—were caused by a cat scratch. Microscopically, all cases had suppurative endophthalmitis centered on the lens, lens capsule rupture, cataract, and lenticular abscess. Infectious organisms were identified by Gram stain within the lens of 14 (70%) cats and 30 (65%) dogs. Gram‐positive cocci were seen most commonly. Male cats were overrepresented as compared to females. There were no apparent gender, age or breed predilections in dogs. Conclusions A unique pattern of slowly progressive or delayed‐onset endophthalmitis with lens capsule rupture, lenticular abscess, and frequently intralenticular microorganisms is associated with traumatic penetration of the globe and lens capsule. The term Septic Implantation Syndrome (SIS) is favored in lieu of ‘phacoclastic uveitis’ to avoid confusion with phacolytic uveitis and to clearly implicate the role of intralenticular microorganisms in the pathogenesis.     

Cataract surgery. Current approaches

Cataract surgery in the dog can be a highly successful and rewarding technique for restoring vision to the cataract patient. Coexisting ocular conditions can complicate cataract surgery or be a contraindication for lens removal; these include KCS, uveitis, glaucoma, lens subluxation, and retinal disease. Techniques for cataract surgery include intracapsular cataract extraction, extracapsular cataract extraction, and phacofragmentation, both extracapsular and endocapsular (intercapsular). Phacofragmentation is probably the most successful technique in the dog at this time. Postoperative complications include uveitis, hyphema, glaucoma, capsular opacities, corneal endothelial damage, and retinal detachments. Newer methods of dealing with these problems include the use of viscoelastic materials and IOL implants intraoperatively and the use of the Nd:YAG laser for posterior capsulotomies postoperatively.     

Equine pectinate ligament descemetization is associated with age

Purpose

To evaluate the correlation between equine pectinate ligament descemetization and ocular disease.

Methods

The pathology database of the North Carolina State University Veterinary Medical Center was searched from 2010–2021 for all equine globes. Disease status was then assigned as affected by glaucoma, uveitis, or “other” based upon clinical records. The iridocorneal angles (ICA) of each globe were evaluated for the presence of pectinate ligament descemetization, the length of descemetization, as well as for the degree of angle collapse and the extent of cellular infiltrate or proteinaceous debris. One slide from each eye was evaluated by two separate, blinded investigators (HW & TS).

Results

A total of 66 eyes from 61 horses were identified, with a total of 124 sections of ICA of sufficient quality to review. 16 horses were affected by uveitis, 8 by glaucoma, 7 by both glaucoma and uveitis, and 30 horses by other ocular disease, most commonly ocular surface disease or neoplasia, which served as controls. Pectinate ligament descemetization was most prevalent in the control group compared to the glaucoma and uveitis groups. Pectinate ligament descemetization length was positively correlated with age, with an increase of 13.5 μm per year of age (p = .016). Infiltrate scores and angle closure scores were higher in both the glaucoma and uveitis group compared to the control group (p < .001).

Conclusions

Equine pectinate ligament descemetization appears to be correlated with increased age and should not be used as a histologic marker for the presence of glaucoma.     

Three cases of feline ocular coccidioidomycosis: presentation,clinical features,diagnosis, and treatment

Objective To describe clinical and diagnostic features of ocular coccidioidomycosis in cats and the response to fluconazole and anti‐inflammatory therapy. Animals studied Three cats with naturally acquired coccidioidomycosis. Procedure Cats were treated with topical or systemic corticosteroids and systemic fluconazole, an antifungal of unproven efficacy against feline ocular coccidioidomycosis. Results Two cats presented for periocular swellings, either subpalpebral or periorbital, with systemic signs including weight loss, unkempt hair coat, and lethargy. One cat presented for apparent blindness with no systemic signs. Clinical ophthalmologic abnormalities were bilateral in each cat and included hyperemic, conjunctival masses, fluid‐filled periorbital swellings, granulomatous chorioretinitis, nonrhegmatogenous retinal detachments, and anterior uveitis. Cats were diagnosed with coccidioidomycosis using a combination of clinical findings, serology and, in two cases, visualization of Coccidioides spherules by either aspiration cytology or biopsy. Active anterior uveitis and periocular swelling were resolved in all cats during treatment. Chorioretinal granulomas, although persistent, significantly decreased in size. Conclusions Coccidioidomycosis should be considered as a differential diagnosis for cats with a travel history to the southwestern United States that demonstrate periocular swelling, anterior uveitis, or granulomatous chorioretinitis, with or without evidence of systemic disease. Aspiration cytology or biopsy of suspicious conjunctival or skin lesions, if present, may aid in diagnosis. A combination of corticosteroids and fluconazole may be effective in treating ocular coccidioidomycosis, although chorioretinal granulomas may persist and long‐term fluconazole therapy may be necessary.     

Ocular manifestations of natural canine monocytic ehrlichiosis (Ehrlichia canis): a retrospective study of 90 cases

OBJECTIVE: To investigate the spectrum, prevalence and treatment response rate of ocular manifestations associated with natural canine monocytic ehrlichiosis (CME) due to Ehrlichia canis. METHODS: The medical records of 90 dogs that were admitted for primary ocular problems and reacted positive for E. canis serum antibodies were reviewed. All the dogs were treated with oral doxycycline. In 79 dogs, a combination of systemic corticosteroids and/or topical anti-inflammatory, mydriatics/cycloplegics and antibacterial agents were applied. RESULTS: The dogs ranged from 0.5 to 15 years in age; 55 were male and 35 female. A total of 19 breeds were represented. In the majority of dogs, ocular abnormalities were noticed in conjunction with other CME-induced clinical signs. In 30/90 dogs, ophthalmic signs were the sole presenting complaint. Unilateral (22/90, 24.5%) and bilateral (68/90, 75.5%) uveitis was the most common ophthalmic diagnosis and was classified as anterior, posterior or panuveitis in 58 (64.5%), 8 (8.9%) and 24 (26.6%) of the dogs, respectively. Bilateral uveitis was significantly more common than unilateral uveitis (P < 0.0001), and anterior significantly more common than posterior uveitis (P < 0.0001) or panuveitis (P < 0.0001). In addition, corneal ulceration (12/90, 13.3%), necrotic scleritis (10/90, 11.1%), low tear production (8/90, 8.9%) and orbital cellulitis (3/90, 3.3%) were seen. Of the 45 (50%) dogs with a satisfactory follow-up, 25 (55.5%), 11 (24.5%), and 9 (20%) showed complete, partial and poor response to treatment, respectively. The number of dogs exhibiting complete resolution of the ocular manifestations was significantly higher than those with partial (P < 0.0001) or poor (P < 0.0001) response. CONCLUSIONS: CME should be considered a major differential for a wide range of ocular manifestations exhibited by dogs residing in the endemic areas of the disease. Anterior bilateral uveitis appears to be the most prevalent ocular lesion and a favorable outcome to systemic and topical treatment may be expected in the majority of the affected dogs.     

Feline systemic fungal infections.

Systemic fungal diseases are important diagnostic considerations in all sick cats, particularly in cats with ocular symptoms. The most common ocular manifestation of these diseases is posterior uveitis (choroiditis); however, anterior uveitis is sometimes present and is usually secondary to the inflammation in the posterior segment. Occasionally, adnexal diseases such as blepharitis, inflammation of the nictitating membrane, and ocular discharge may be present in cats with systemic mycoses. The prognosis for cats with systemic fungal diseases has changed with the advent of the triazole antifungal drugs. In the past, the prognosis was guarded to poor for survival of the cat. Today, with prolonged antifungal therapy, many cats recover completely from their disease. The prognosis for return of vision for eyes affected with systemic fungal disease is still guarded. Often, even if the infection is controlled systemically, the retina is severely damaged and may remain nonfunctional.     

Encephalitozoon cuniculi infection in rabbits

The microsporidian parasite Encephalitozoon cuniculi commonly infects rabbits. Most infections are initially asymptomatic, but for reasons yet to be explained, many rabbits subsequently develop disease as a result of infection with this organism. Three common forms of this disease are recognized, and they can occur individually or in combination. The ocular form is associated with cataracts and when there is extensive damage to the lens, uveitis. The neurological form can vary from a mild change in the rabbit’s behavior to severe vestibular disease. The signs associated with the renal form of the disease are those of chronic progressive renal disease. Definitive diagnosis of encephalitozoonosis in the rabbit is difficult. Animals with encephalitozoonosis are expected to be seropositive, but many apparently healthy rabbits are also seropositive, so this assay is not specific and its results must be considered in the light of other diagnostic findings. The absence of antibody, however, should cause the practitioner to consider other differentials. Drugs proven to be efficacious for E. cuniculi infections include albendazole and fenbendazole. Supportive care and treatment with antiinflammatory medications may also be necessary in some forms of encephalitozoonosis. Lens removal or removal of the lens contents is indicated in some rabbits with E. cuniculi-induced ocular disease.