High risk and low prevalence diseases: Orbital cellulitis.

INTRODUCTION: Orbital cellulitis is an uncommon but serious condition that carries with it a potential for significant morbidity. OBJECTIVE: This review highlights the pearls and pitfalls of orbital cellulitis, including presentation, diagnosis, and management in the emergency department (ED) based on current evidence. DISCUSSION: Orbital cellulitis refers to infection of the globe and surrounding soft tissues posterior to the orbital septum. Orbital cellulitis is typically caused by local spread from sinusitis but can also be caused by local trauma or dental infection. It is more common in pediatric patients compared to adults. Emergency clinicians should first assess for and manage other critical, sight-threatening complications such as orbital compartment syndrome (OCS). Following this assessment, a focused eye examination is necessary. Though orbital cellulitis is primarily a clinical diagnosis, computed tomography (CT) of the brain and orbits with and without contrast is critical for evaluation of complications such as abscess or intracranial extension. Magnetic resonance imaging (MRI) of the brain and orbits with and without contrast should be performed in cases of suspected orbital cellulitis in which CT is non-diagnostic. While point-of-care ultrasound (POCUS) may be useful in differentiating preseptal from orbital cellulitis, it cannot exclude intracranial extension of infection. Management includes early administration of broad-spectrum antibiotics and ophthalmology consultation. The use of steroids is controversial. In cases of intracranial extension of infection (e.g., cavernous sinus thrombosis, abscess, or meningitis), neurosurgery should be consulted. CONCLUSION: An understanding of orbital cellulitis can assist emergency clinicians in diagnosing and managing this sight-threatening infectious process.

Non-visual complications of orbital cellulitis (NVCOC) in pediatric vs adult populations.

PURPOSE: There have been many publications evaluating the visual outcomes of patients treated for orbital cellulitis. The aim of this study was to evaluate non-visual complications of post-septal orbital cellulitis (NVCOC) present 30 days after discharge from index hospitalization. METHODS: This was an IRB-approved, retrospective chart review. RESULTS: Ninety patients (45 pediatric, 45 adults) were identified with OC. NVCOC were significantly more common in adult patients as compared to children (40.0% vs 15.6% respectively; p < 0.05). The most common NVCOC among children was persistent ptosis, while clinically significant scarring was most common in adults. NVCOC were less persistent in children as compared to adults with 71.4% of complications in children resolving spontaneously by 6 month follow up as compared to 11.1% adults. (p < 0.05). The only statistically significant risk factor identified for the development of NVCOC in children and adults was the presence of ICE (intracranial extension) during index hospitalization (p < 0.05) and the presence of an infected orbital implant (p < 0.05) respectively. CONCLUSIONS: Adult patients experience NVCOC complications more often than children. Furthermore, the nonvisual complications in children are more likely to resolve spontaneously than those in adults. The intracranial spread of infection is a significant risk factor for late complications in children. The presence of an orbital wall/floor implant is a significant risk factor for late complications in adults. There are many differences in the etiology, pathophysiology, and course of NVCOC in children and adults, so information on these two populations should be reported separately.

Orbital cellulitis and cavernous sinus thrombosis with contralateral sinus disease in a COVID-19 positive adolescent patient.

Patients with COVID-19 have been reported to have elevated coagulation factors, which is a well-documented cause of venous thromboembolism events such as deep vein thrombosis and pulmonary embolism. Other venous thrombotic events, however, such as cavernous sinus thrombosis (CST) have been less commonly observed, specifically in combination with primary orbital cellulitis. Due to its unique anatomic location, the cavernous sinus is susceptible to thrombophlebitis processes including septic thrombosis and thrombosis most commonly from sinusitis. Many studies have shown that in the antibiotic era thromboembolic events of the cavernous sinus are less common due to infection spread from the orbit or facial region. This case report describes a 17-year-old COVID-19 positive male who presented with a left-sided primary orbital cellulitis with CST without radiographic evidence of ipsilateral sinus disease.

Factors Associated with Surgery and Imaging Characteristics in Severe Orbital Infections.

OBJECTIVES: To evaluate risk factors associated with surgical intervention and subperiosteal/orbital abscess in hospitalized children with severe orbital infections. STUDY DESIGN: We conducted a multicenter cohort study of children 2 months to 18 years hospitalized with periorbital or orbital cellulitis from 2009 to 2018 at 10 hospitals in Canada. Clinical details were extracted, and patients were categorized as undergoing surgical or medical-only management. Primary outcome was surgical intervention and the main secondary outcome was clinically important imaging. Logistic regression was used to identify predictors. RESULTS: Of 1579 patients entered, median age was 5.4 years, 409 (25.9%) had an orbital/subperiosteal abscess, and 189 (12.0%) underwent surgery. In the adjusted analysis, the risk of surgical intervention was associated with older age (age 9 to <14: aOR 3.9, 95% CI 2.3-6.6; and age 14 to ≤18 years: aOR 7.0, 95% CI 3.4-14.1), elevated C-reactive protein >120 mg/L (aOR 2.8, 95% CI 1.3-5.9), elevated white blood cell count of 12-20 000/µL (aOR 1.7, 95% CI 1.1-2.6), proptosis (aOR 2.6, 95% CI 1.7-4.0), and subperiosteal/orbital abscess (aOR 5.3, 95% CI 3.6-7.9). There was no association with antibiotic use before hospital admission, sex, presence of a chronic disease, temperature greater than 38.0°C, and eye swollen shut. Complications were identified in 4.7% of patients, including vision loss (0.6%), intracranial extension (1.6%), and meningitis (0.8%). CONCLUSIONS: In children hospitalized with severe orbital infections, older age, elevated C-reactive protein, elevated white blood cell count, proptosis, and subperiosteal/orbital abscess were predictors of surgical intervention.

Clinical, advanced imaging data and outcome of inflammatory and neoplastic orbital disease in 81 dogs and 16 cats in Australia (2010-2019).

OBJECTIVE: To characterize the clinical presentation, advanced imaging features, and outcome of orbital disease in a referral population of dogs and cats that underwent computed tomography (CT) or magnetic resonance imaging (MRI). ANIMALS STUDIED: Client-owned animals. PROCEDURES: Animals referred for orbital disease undergoing ophthalmic examination and either head MRI or CT were included. Demographic and imaging features were compared between animals diagnosed with inflammatory disease and neoplastic disease using Mann-Whitney U and Fischer's exact tests. RESULTS: Ninety-seven animals (81 dogs and 16 cats) were included. Eighty-four and 13 patients underwent CT and MRI scanning, respectively. Inflammatory orbital disease was more frequently detected than neoplasia in dogs (59% vs. 41%) and cats (62% vs. 39%). Orbital cellulitis was the most common diagnosis in dogs (36/81, 44.4%) and cats (8/16, 80%). A foreign body was suspected in 36.1% of dogs with orbital cellulitis but only 3 were retrieved during orbitotomy. Multi-drug resistant bacteria were identified in 3 samples and influenced treatment plans. The most common neoplasms were sarcoma (10/30) and carcinoma (7/30) in dogs and lymphoma in cats (3/6). Imaging findings of osteolysis (p = 0.0002) and intracranial extension (p = 0.0001) were significantly associated with neoplasia in dogs. In contrast, osteolysis extension was present in cats with both inflammatory (7/10) and neoplastic (6/6) orbital disease. CONCLUSIONS: Inflammatory disease, particularly orbital cellulitis, was more common than neoplasia in dogs and cats with orbital disease in our population. We recommend including bacterial culture and susceptibility as part of the diagnostic work up when orbital cellulitis is suspected.

Orbital Metastasis From Gastric Cancer Presenting as Orbital Cellulitis With Ptosis.

ABSTRACT: We report a rare case of orbital metastasis that originated from gastric carcinoma, which presented as orbital cellulitis with ptosis. Orbital metastasis accounts for about only 1% to 13% of orbital tumors. Orbital metastasis in orbital soft tissue or bony structures is very uncommon.A female patient with advanced gastric cancer with multiple metastases was referred to our clinic. She showed mild swelling and ptosis in her left eye. Contrast enhanced computed tomography imaging suggested orbital metastasis from gastric cancer in the superolateral aspect of the orbit. Based on her general condition and after consulting with an oncologist, we determined that fine needle biopsy and excisional biopsy for pathological diagnosis should not be performed as a therapeutic treatment.It is important to distinguish orbital metastasis from orbital cellulitis with ptosis especially for patients with family or personal history of cancer. Clinicians should collect a through medical history from patients and suggest contrast enhanced computed tomography for appropriate diagnosis. Assessing quality of life and aggressive treatment options is crucial for determining the best treatment for orbital metastasis.

Fusobacterium necrophorum-induced orbital cellulitis with intracranial involvement: a case report and review of the literature.

We report a case of a 17-year-old female who presented with orbital cellulitis and meningeal involvement secondary to severe paranasal sinusitis with positive blood culture for Fusobacterium necrophorum. The patient recovered after a 2-month course of systemic antibiotics and functional endoscopic sinus surgery.Fusobacterium necrophorum-induced orbital cellulitis is a rare entity, with only 5 previous cases reported in the literature, which are reviewed here as well. This review reveals that Fusobacterium necrophorum is an aggressive pathogen in orbital cellulitis and therefore we suggest that affected patients may require a correspondingly aggressive medical management. Furthermore, we advise additional workup to rule out Lemierre's syndrome, a severe complication of Fusobacterium necrophorum infection, including transthoracic echocardiogram, chest radiograph, upper extremities' venous duplex and magnetic resonance venography.

Orbital cellulitis secondary to sinusitis in upstate New York: current incidence, seasonality, severity, management and outcomes.

PURPOSE: While sinusitis carries a seasonal variation, the temporal features of sinusitis-related orbital cellulitis (SRC) are unclear. This study analyzes the incidence, seasonality, management, and outcomes of SRC in northeastern New York. METHODS: A retrospective review of 79 patients was performed from January 2008 - December 2018. Cases of orbital cellulitis without comitant sinusitis were excluded. Demographic, radiographic, clinical features, month at presentation, interventions (surgical and nonsurgical), microbiology, and hospitalization duration were recorded. Fisher-exact test, Mann-Whitney test, and Kruskal Wallis test statistical analyses were performed in consultation with our institution's statistician via a dedicated software package (vassarstats.net). RESULTS: 79 patients were admitted for SRC. 25 patients were treated with antibiotics only, 31 underwent orbitotomy exclusively and 23 received combined orbitotomy and functional endoscopic sinus surgery (FESS). Of the 31 patients who underwent orbitotomy only, 8 (26%) returned to the operating room. In contrast, of those who underwent concomitant orbitotomy and FESS, only one patient (4.3%) required re-operation (fisher exact test, p = .021). The median length of stay for the antibiotic-only group (4 days), orbitotomy-only group (6 days), and combined surgery group (5 days) were statistically different (Kruskal Wallis, p = .004, Figure 3). Interestingly, there was no significant relationship of incidence or severity of SRC related to seasonality (fisher-exact test, p = .76). CONCLUSION: Our findings suggest that cases requiring surgical management for SRC should undergo coinitial orbitotomy with FESS to reduce re-operation rates. Additionally, SRC incidence and severity did not correlate with season.

Orbital abscess: 20 years' experience at a tertiary eye care center.

PURPOSE: To study the clinical, microbiological profile and management outcomes of orbital abscess at a tertiary care center in South India. MATERIAL AND METHOD: In a retrospective interventional case series, we reviewed all patients diagnosed with orbital cellulitis from 2000-2020. The data analyzed included demographic profile, clinical and radiological features, microbiological profile, and management outcome. RESULTS: A total of 921 cases of orbital and periorbital infections were reviewed. Seventy-two cases were diagnosed as orbital cellulitis. Thirty-four cases (47.22%) had radiological evidence of orbital abscess. The median age was 20.63 years. Three patients (8.82%) were neonates. A male preponderance was noted (23, 67.65%). Sinusitis (10, 29.41%) and diabetes (5, 14.7%), were the most common predisposing factors. Optic neuropathy was seen in 15 (44.11%) patients, cavernous sinus thrombosis in two patients (5.88%), and septicemia in one patient (2.94%) Multiple orbital abscesses were noted in 7 (20.59%) cases. All patients underwent surgical drainage. Methicillin-sensitive Staphylococcus aureus was the most common organism isolated in 14 patients (41.18%). Vision improvement or stabilization was seen in all except 3 (8.82%). CONCLUSION: Orbital abscess is a potential sight-threatening orbital infection. The infective process can spread and ascend up to involve cavernous sinus thereby becoming life-threatening. A timely diagnosis and intervention can halt the disease process and help restore vision in many cases.

Point-of-Care Ultrasound Findings in a Case of Orbital Cellulitis: A Case Report.

BACKGROUND: Ophthalmologic complaints are common in the emergency department. The utility of point-of-care ultrasound (POCUS) as an accessible, noninvasive modality to evaluate ocular pathology is of great value-particularly in settings where resources are limited or where ophthalmologic consultation may not be readily available. CASE REPORT: A 21-year-old woman presented to the emergency department with periorbital edema, erythema, and drainage that was worsening despite topical and oral antimicrobial therapy. Mild proptosis was present on examination. POCUS was performed to investigate her symptoms further. A modified ocular ultrasound revealed prominence and edema of the retro-orbital soft tissue with echogenic fat, consistent with the diagnosis of orbital cellulitis. These findings were corroborated with computed tomography imaging. Why Should an Emergency Physician Be Aware of This?: Few reports describe the utility of POCUS in evaluating patients for orbital cellulitis. This case emphasizes the value of POCUS in assessing patients presenting to the emergency department with ocular complaints and demonstrates ultrasound-specific findings that may lead the clinician toward the diagnosis of orbital cellulitis. © 2021 Elsevier Inc.

Bilateral orbital cellulitis in an infant: An unusual case.

Bilateral orbital cellulitis is an uncommon presentation in infants, and its association with rhinosinusitis has been scantily reported in the literature. An infant underwent bilateral uncinectomy and right ethmoidal decompression for bilateral orbital cellulitis with right ethmoidal sinusitis, after a period of non-recovery with conservative treatment. Mixed infection with Escherichia coli and methicillin-sensitive Staphylococcus aureus was observed. The right eyelid swelling began to resolve; however, the left lower eyelid showed an increase in the fluctuant swelling. Transconjunctival incision and drainage of pus was done in the left eye subsequently. The patient showed marked clinical recovery and is doing well. A multidisciplinary management approach can avert potentially life-threatening sequelae of this condition.

Factors Associated With Increased Risk of Pediatric Orbital Cellulitis-Who Should Be Scanned?

BACKGROUND: Evaluation of a child with POC/OC is complicated due difficulties in physical examination and risks of imaging by computed tomography. METHOD: Retrospective review of children 0-16 years admitted to the pediatric emergency department for POC/OC from 2009 to 2019. RESULTS: Ten years study period, 243 children younger than 16 years presented to the pediatric emergency department with a diagnosis of POC/OC. OC was documented in 51 (20.6%) patients. The mean age was 7.8 years (±4.3 years). Fever (80.4%), upper respiratory tract infection (43%), swelling of both eyelids (96%), proptosis (33.3%), and tenderness on percussion (24.5%) were more common in comparison to POC (P = 0.0001, 0.03, 0.0001, 0.0001, 0.0001 respectively). All children with suspected diagnosis of OC underwent computed tomography scan. POC accounted for 196 patients. Mean age was 4.6 (±4.3) years. Twenty percent of the cases were recorded as local trauma or insect bite in the infected eye.Mean leukocyte count in the OC group had higher mean of 15.2 (109/L) versus 13.4(109/L) (P = 0.05), absolute neutrophil count was significantly higher in the OC 11.3(109/L) versus 7.2(109/L) (P = 0.0001) whereas the lymphocyte count was higher in the POC 4.5(109/L) versus 2.4(109/L) (P = 0.0001), NLR of 0.318 correlates with orbital cellulitis with sensitivity of 75.5% and specificity of 77.4%.Patients with OC had mean C-reactive protein levels of 11.7 (mg/dL) versus 4.9(mg/dL) (P = 0.0001), erythrocyte sedimentation rate was elevated in the OC 53.6 (cm/h) versus 36.4 (cm/h) (P = 0.02).Based on the aforementioned study a risk calculator for OC was formulated with 6 major variables. CONCLUSIONS: Differentiation between POC/OC is cardinal. This study highlights the importance of ancillary laboratory tests especially C-reactive protein in the assessment of infections of the eye.

Orbital Cellulitis-When Computed Tomography Imaging Is Falsely Reassuring.

ABSTRACT: An 8-year-old male presented to the pediatric emergency department with subjective fever, blurry vision, and left eye pain. On physical examination, there was mild left lower lid erythema and a subtle left eye elevation deficit. Computed tomography demonstrated preseptal soft tissue swelling without orbital involvement; however, there was varying amounts of paranasal sinus opacification. Despite the negative scan, a diagnosis of orbital cellulitis associated with sinusitis was made and treatment with intravenous antibiotics was initiated. A magnetic resonance imaging performed subsequently revealed orbital fat stranding and inferior rectus enlargement and enhancement near the orbital apex, indicating the presence of orbital cellulitis. This case demonstrates the utility of magnetic resonance imaging when initial computed tomography imaging is negative in patients with concern for orbital cellulitis.

Orbital cellulitis, sinusitis and intracranial abnormalities in two adolescents with COVID-19.

We review two cases of adolescents with orbital cellulitis, sinusitis and SARS- CoV-2 infection presenting to emergency departments within a 24 hour period. SARS-CoV-2 samples obtained within 24 hours were positive, supporting prior infection despite relatively limited early symptoms of COVID-19. Unusual clinical and radiographic characteristics included hemorrhagic abscess with blood of varying age in the first, intracranial epidural abscess in the second, radiographic signal consistent with hemorrhagic or thrombotic phenomena, retro-maxillary antral fat changes, and meningeal enhancement or extension in both cases. Radiographic findings thereby mimic fungal infection, although final cultures and ancillary investigation for allergic and invasive fungal disease have remained negative. These cases highlight two unusual orbital presentations of cellulitis occurring in the context of SARS-CoV-2 co-infection.

Impact of superior ophthalmic vein thrombosis: a case series and literature review.

Purpose: To present nine new cases of superior ophthalmic vein thrombosis (SOVT) and compare these with the literature, and to assess the impact of SOVT for the clinician. Methods: Using the data bases of the Department of Ophthalmology of the AMC, we searched for patients with radiologically evidenced SOVT between January 2006 and December 2014. In addition, a PubMed search, using the mesh term 'superior ophthalmic vein thrombosis', was done. Results: We found nine patients with SOVT. In three patients, SOVT was related to dural arteriovenous fistulae. In one patient, it was caused by the acute reversal of warfarin by vitamin K. In two patients, an infectious cause was found. In three patients, the cause of SOVT was not found despite screening for coagulation and other disorders. All patients presented with eyelid swelling, proptosis, and/or motility impairment. We found complete recovery in four patients. Three patients had mild sequelae and two patients had severe visual impairment. In the literature, we found 60 cases reporting on SOVT with various aetiologies. Clinical presentation, treatment modalities, and outcomes were comparable to our findings. Conclusion: Our case series and literature review show that SOVT can occur simultaneously with cavernous sinus thrombosis (CST) but can also be a separate entity. Clinical presentation can mimic orbital cellulitis (OC) or CST and when no signs of OC can be found, an alternative cause for SOVT should be sought. When timely and adequate treatment is conducted, the prognosis is predominantly favourable.

Elevated Optic Disc Height and Increased Optic Nerve Sheath Diameter on Bedside Ultrasound in a Pediatric Patient With Orbital Cellulitis: More Than Meets the Eye.

BACKGROUND: Orbital cellulitis is an uncommon ophthalmological emergency in children, but rapid emergency department (ED) diagnosis is essential. CASE REPORT: A 13-year-old boy presented to our pediatric ED with left orbital cellulitis secondary to pansinusitis. Emergency bedside ocular ultrasonography was used to evaluate and expedite his management. Besides inflammatory changes observed on ultrasound of his affected orbit, the patient had an elevated optic disc height and increased nerve sheath diameter, which were not commonly reported in published literature on orbital cellulitis. Emergent computed tomography of the orbits and head showed orbital cellulitis without complications of orbital abscess or cavernous sinus thrombosis. Despite initiating early appropriate antibiotics, there was rapid progression of his disease and he developed intraconal abscess and cavernous sinus thrombosis the following day. After emergency surgical drainage of his pansinusitis, antibiotics, and anticoagulation, he was discharged well after a 2-week hospitalization. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: There are important advantages of using bedside ultrasonography for diagnosis of pediatric orbital cellulitis in the ED setting. Further research should be done to evaluate the clinical significance of an enlarged optic nerve sheath diameter and raised optic disc height in pediatric orbital cellulitis.

True abscess formation is rare in bacterial orbital cellulitis; consequences for treatment.

BACKGROUND: Pre- or retroseptal bacterial orbital cellulitis (pOC/rOC) is not an uncommon orbital disease. Treatment consists of antibiotics with or without surgical drainage. Several questions regarding course, complications and outcome of treatment are unanswered and the indication for surgery is not well defined. The aim of this study is to: 1. describe the outcome of orbital cellulitis (OC) in a large cohort, 2. assess the significance of Chandler's classification, 3. assess the incidence of abscess formation in OC, and 4. redefine criteria for surgery. METHODS: Retrospective case series of patients with OC seen between 1-1-2007 and 1-1-2014 in a tertiary referral center. RESULTS: Sixty-eight patients presented with (presumed) bacterial pOC. Two out of these 68 developed rOC. All 68 patients had a full recovery. Forty-eight patients presented with rOC. Four out of 48 (8%) had intracranial extension of the infection at the time of admission. No admitted patient developed distant seeding. Only four (8%) patients with rOC had a true orbital abscess. In the other 92% we found a diffuse orbital inflammation or a subperiosteal empyema. Forty-four (92%) patients with rOC had a full recovery. CONCLUSIONS: 1. The prognosis of both pOC and rOC nowadays is generally favorable. 2. Chandler's classification is of little use. 3. True abscess formation in OC is rare. 4. The indication for surgical intervention must be based on the clinical presentation and the assessment of true orbital abscess formation.

Orbital Cellulitis Following Orbital Blow-out Fracture.

Orbital cellulitis and abscess have been described in the literature as complication that usually occur secondary to infection in the maxillary, ethmoidal, and frontal sinuses. If left untreated, it can lead to blindness, cavernous sinus thrombosis, meningitis, or cerebral abscess. Orbital fractures are a common sequela of blunt orbital trauma, but are only rarely associated with orbital cellulitis. So, the authors present rare orbital cellulitis after orbital blow-out fracture. A 55-year-old Asian complains of severe orbital swelling and pain on the left side. These symptoms had started 2 days earlier and worsened within the 24 hours before hospital admission resulting in visual disturbances such as diplopia and photophobia. Contrast-enhanced computed tomography scan showed considerable soft tissue swelling and abscess formation on the left side. Patient was subjected to surgical drainage under general anesthesia in the operation room. In this case, the postoperative period was uneventful and the rapid improvement of symptoms was remarkable. In conclusion, the abscess of the orbit is a surgical emergency in patients whose impairment of vision or ocular symptoms cannot be controlled with medical therapy using antibiotics. In our case, orbital cellulitis can occur after blunt orbital trauma without predisposing sinusitis. Early and prompt diagnosis and surgical drainage before severe loss of visual acuity rescue or recover the vision in case of orbital cellulitis.

Orbital Cellulitis Presenting as Giant Cell Arteritis: A Case Report.

PURPOSE: To present a case of orbital cellulitis initially mimicking giant cell arteritis. CASE REPORT: An 80-year-old man with a history of hypertension and type 2 diabetes mellitus was referred with a prominent progressive headache over the right temporal and periorbital areas. Non-contrast brain CT results were normal, but ESR was elevated. Giant cell arteritis was suspected initially. However, the symptoms progressed under oral corticosteroid therapy. The subsequent brain MRI with contrast revealed extensive contrast enhancement along the right optic nerve and optic canal with a rim-enhancing lesion in the posterior aspect of the optic nerve. Treatment included intravenous antibiotics and surgical drainage. Culture of the drainage revealed growth of Pseudomonas aeruginosa. CONCLUSION: Orbital cellulitis should be considered in patients with progressive headache over the unilateral temporal and periorbital areas, in addition to giant cell arteritis. Brain imaging with contrast should be performed for detecting occult orbital infection or other intracranial etiologies.

Orbital abscess following posterior subtenon injection of triamcinolone acetonide.

Orbital cellulitis is a serious sight threatening and potentially life threatening condition which can be complicated by orbital abscess formation. Posterior subtenon (PST) injection of corticosteroid is commonly used in the treatment of posterior segment inflammation including post-operative macular oedema. We report a case of orbital abscess formation as a late complication of PST triamcinolone acetonide and discuss the presentation, diagnosis and management.