Cranial vena cava syndrome secondary to cryptococcal mediastinal granuloma in a cat

Abstract

The successful management of cranial vena cava syndrome with suspected secondary chylothorax due to mediastinal cryptococcal granuloma in a 4-year-old male domestic shorthair cat is described. Treatment included long-term antifungal medication, short-term corticosteroids, intermittent thoracocentesis, rutin, octreotide, and enalapril.

A 4-year-old male neutered domestic shorthair cat was referred for evaluation of a mediastinal mass, jugular distension, and swelling of the head and neck. The cat was initially evaluated for non-progressive facial edema, pyrexia, and regurgitation. Empiric therapy was attempted with enrofloxacin (Baytril; Bayer Healthcare, Toronto, Ontario), 2.5 mg/kg body weight (BW), PO, q12h, ketoprofen (Anafen; Mérial Canada, Baie d’Urfé, Québec), 1 mg/kg BW, PO, q24h, vitamin E, 8 IU/kg BW, PO, q12h, and metoclopramide (Metoclopramide HCl injectable; Sandoz Canada, Boucherville, Québec), 0.4 mg/kg BW, PO, q8h without significant improvement, although the pyrexia resolved. The cat was negative for feline immunodeficiency virus and feline leukemia virus (SNAP FIV/FeLV Combo Test; Idexx Canada, Markham, Ontario). A complete blood (cell) count (CBC) and serum chemistry panel (Service de diagnostic, Faculté de médecine vétérinaire, St-Hyacinthe, Québec) were unremarkable and the cat was started on a 4-day course of furosemide (Apo-Furosemide; Apotex, Toronto, Ontario), 1 mg/kg BW, PO, q12h. When the cat failed to respond to furosemide therapy it was referred to the teaching hospital for further workup, 11 days following the initial presentation.

Case description

On presentation to the teaching hospital the cat was bright and alert, with stertor, mild dyspnea, and increased lung sounds bilaterally. Severe edema of the head and neck prevented palpation of mandibular lymph nodes. The heart rate (HR), respiratory rate (RR), and rectal temperature were 200 beats/min (BPM), 36 breaths/min and 38.2°C, respectively. Thoracic radiographs revealed compression of the trachea and esophagus, as well as thickening of the soft tissues in the ventral thorax, most compatible with edema. Thoracic ultrasound revealed a large, highly vascular, bi-lobed cranial mediastinal mass measuring approximately 3.7 cm × 7 cm, which caused compression of the cranial vena cava. Ultrasound-guided fine-needle aspiration and cytology of the mass revealed the presence of a large population of non-degenerate neutrophils, macrophages with cytoplasmic vacuolization, rare lymphocytes, numerous round to oval yeast with thick colorless capsules and occasional narrow-based buds. Cytological findings were consistent with a Cryptococcus infection. Cryptococcus antigen titer (Cryptococcus Antigen Latex Agglutination Test System, Immuno-Mycologics, Norman, Oklahoma, USA) was 1:512. A CBC, serum biochemistry panel, and urinalysis (Service diagnostic, Faculté de médecine vétérinaire, St-Hyacinthe, Québec) were within normal reference limits, with the exception of a decreased serum glucose concentration [1.90 mmol/L; reference interval (RI): 3.80 to 7.90 mmol/L]. Treatment for cryptococcal mediastinal granuloma was initiated. An intravenous catheter was placed and 0.45% NaCl with 2.5% dextrose and 20 mEq/L of potassium chloride at a rate of 6 mL/h was started. Ketoconazole (Apo-Ketoconazole; Apotex), 8 mg/kg BW, PO, q12h and dexamethasone (Dexamethasone 2; Vétoquinol, Lavaltrie, Québec), 0.1 mg/kg BW, IM, q24h were administered. Given the degree of edema, signs of regurgitation and tracheal compression, surgical excision/debulking of the mass was recommended, but declined due to financial constraints. During the first 2 d of hospitalization, the cat improved considerably. Stertor, dyspnea, and regurgitation resolved. The edema of the head and neck improved, although mild edema persisted. Repeat thoracic radiographs showed persistence of the mediastinal granuloma with resolution of the tracheal compression. Abdominal ultrasonography performed 3 d post admission revealed a heterogeneous and slightly enlarged spleen, mottled liver, and markedly increased size of both kidneys (left: 5.06 cm; right: 5.25 cm). Fine-needle aspirates were performed, and cytology of spleen, liver, and kidneys aspirates were unremarkable. Because of marked improvement, the cat was discharged 4 d post-admission. Dexamethasone and ketoconazole were discontinued and itraconazole (Itrafungol; Vétoquinol), 8 mg/kg BW, PO, q12h was prescribed. Over the following 12 wk serial radiographs showed the mediastinal mass decreased in size by approximately 15% to 20%. The cat remained asymptomatic and liver enzymes remained within reference limits.

Fourteen weeks following discharge the cat was again presented to the teaching hospital due to a 2-week history of progressive dyspnea (RR: 66 breaths/min). Thoracic radiographs revealed severe bilateral pleural effusion. Five hundred milliliters of fluid were removed bilaterally from the thorax. Pleural fluid cytology revealed predominance of small lymphocytes (49%) with a large number of nondegenerate neutrophils (43%). Total protein (TP) was 44 g/L, cholesterol 1.93 mmol/L, and triglycerides 10.50 mmol/L, most consistent with chylous effusion. There was no evidence of cryptoccoccal organisms or neoplastic cells in the pleural effusion. Although organisms were not seen, their presence could not be ruled out without culture. Cryptococcal antigen titer was 1:2048. A CBC and serum biochemistry were unremarkable, except for a mild hypoalbuminemia (28.6 g/L; RI: 29 to 39 g/L). Echocardiography revealed marked thickening of the right ventricle with mild thickening of the right atrium, increased echogenicity of the right ventricular free wall and systolic anterior motion. Itraconazole was discontinued and replaced by fluconazole (Itrafungol; Vétoquinol), 8 mg/kg BW PO, q12h. Surgical exploration of the thoracic cavity was recommended, but declined due to financial constraints. The cat was discharged to the care of his owner with rutin (General Nutrition Centers, Pittsburgh, Pennsylvania, USA) 42 mg/kg BW, PO, q8h, enalapril (Enacard^®; Merial Canada) 0.4 mg/kg BW, PO, q24h, and a low fat diet after 2 days of hospitalization.

The cat returned 2 wk later for recurrence of acute respiratory distress (RR: 56 breaths/min). Heart rate and rectal temperature were 210 BPM and 38.7°C, respectively. Approximately 500 mL of pinkish-white opaque pleural fluid was removed via ultrasound-guided thoracocentesis. The fluid had no detectable microorganisms, had protein concentration of 56 g/L, and had 9.63 × 10⁹ nucleated cells/L. Differential cell count of the fluid revealed 63% nondegenerate neutrophils, 33% lymphocytes, 1% macrophages, and 3% eosinophils. Emergency blood test results [lactate, blood glucose, blood urea nitrogen (BUN), hematocrit, TP] were within reference limits. Three-view thoracic radiographs revealed the presence of a moderate amount of pleural effusion which obscured visualization of the mediastinal mass. Thoracic ultrasound revealed stable cardiac findings and the mediastinal mass measured 2.5 cm in diameter. A left-sided Argyle™ chest tube (Covidien Canada, Saint-Laurent, Québec) was placed using aseptic technique under general anesthesia. Fluconazole, rutin, and enalapril therapies were continued as previously prescribed and octreotide (Novartis, Dorval, Québec) was initiated at 12 μg/kg BW, SC, q8h for 14 d. Fluid removal via the thoracic tube was minimal despite continued presence of fluid on repeat thoracic radiographs. Thoracic ultrasound revealed the presence of multiple pockets of fluids, which likely explained the difficulty in draining fluid via the thoracostomy tube. The drain was removed and intermittent ultrasound-guided thoracocentesis was performed. The cat was discharged to the care of his owner 9 d after presentation.

Periodic thoracocentesis was done to remove pleural effusion over the following 12 wk. The cat’s RR and effort remained within reference limits (20 to 30 breaths/min). Cryptococcus antigen titer obtained after 16 wk of this therapy was 1:126 and became negative after another 4 wk of fluconazole therapy. Although a small amount of pleural effusion continued to be detected on thoracic radiographs, the cat did not have respiratory distress and required no further thoracocentesis. All medications but enalapril were discontinued and the cat remained non-clinical with a negative antigen titer despite the presence of chronic pleural effusion. Total duration of antifungal therapy was 34 wk and 4 d, with 4 days of ketoconazole, 14 wk of itraconazole, and 20 wk of fluconazole.

Discussion

To the authors’ knowledge, this is the first report of non-fatal feline cranial vena cava syndrome in the veterinary literature. Meadows et al (1) described a fatal case of cranial vena cava syndrome, chylous effusion, and fungal mediastinal granuloma secondary to Cryptococcus neoformans in a 10-year-old spayed female domestic shorthair cat. The case was treated with ketoconazole (10 mg/kg BW PO, q12h), thoracic drainage, and furosemide (3 mg/kg PO IV, q24h), but died from cardiopulmonary arrest, 10 d after initiation of therapy (1). The other case report of cranial vena cava syndrome in a cat with invasive mediastinal lymphosarcoma, which despite therapy (cyclophosphamide, 300 mg/m² IV and furosemide, 4 mg/kg IV) arrested 24 h after diagnosis (2). The cat in the current case, which also had cranial vena cava syndrome and chylous effusion secondary to a mediastinal fungal granuloma, was treated with a regime of ketoconazole for 4 d, itraconazole for 14 wk, fluconazole for 20 wk, dexamethasone for 4 d, rutin for 20 wk, enalapril long-term, octreotide for 14 d, and thoracic drainage, which led to resolution of clinical signs and negative fungal antigen titers, although chronic low-grade pleural effusion remained.

Cranial vena cava syndrome, which is rare in veterinary patients, should not be confused with caval syndrome, which is a more common serious, life-threatening disease characterized by the presence of a large number of heartworms, which leads to severe pulmonary hypertension, decreased cardiac output, and hemoglobinemia and hemoglobinuria secondary to retrograde migration of heartworms into the main pulmonary arteries, right atrium, right ventricle, and cranial vena cava (3–5). Cranial vena cava syndrome, on the other hand, results from impairment of blood flow to the right atrium secondary to obstruction via external compression, invasion, or intrinsic blockage of the cranial vena cava. Impaired venous return causes increased hydrostatic pressure, which leads to an elevated net driving pressure for filtration and excessive fluid leakage from the capillaries into the interstitial compartment and subsequent subcutaneous edema of the cranial anatomy, particularly the head and neck, and in some cases pleural effusion (6–10). In the present case, cranial vena cava syndrome likely developed secondary to external compression of the vena cava secondary to fungal granuloma, which compromised venous return leading to extravasation of fluid and subsequent interstitial edema of the head and neck. Differential diagnoses for cranial vena cava syndrome in cats and dogs include mediastinal neoplasia, mediastinal fungal granuloma, and cranial vena cava thrombosis (i.e., secondary to hyperocagulable states, tumor emboli, jugular catheters). Although not reported in small animals, ectopic parathyroid tissue, and mediastinal abscess have been suggested as possible differentials for cranial vena cava syndrome (11).

Cranial vena cava syndrome in the current case appeared to be secondary to cryptococcal infection. Antigen testing, cytology, histopathology, polymerase chain reaction, or culture can be used to help confirm the diagnosis of cryptococcal infection (12–14). Subclinical infection cannot be distinguished from active disease by antibody testing; therefore, antibody detection alone cannot be recommended as the sole diagnostic test (12). The diagnosis of Cryptococcus infection was based on the presence of the organism in the sample and on antigen testing. Although cultures are not required to confirm a diagnosis of Cryptococcus, they are recommended to allow identification of specific Cryptococcus subspecies and for antifungal susceptibility testing. Fungal cultures and molecular typing were not performed in this case and it remains speculative if the resolution of clinical signs may have been hastened if cultures and fungal sensitivity testing had been performed.

When the diagnosis of cranial vena cava syndrome secondary to mediastinal cryptococcal granuloma was made, in conjunction with initiation of ketaconazole therapy, the cat received a 4-day course of dexamethasone to help manage suspected upper airway edema/swelling and to prophylactically manage any further inflammation that might result following initiation of antifungal medications. In human patients with superior vena cava syndrome, steroids are often used as a temporary measure in symptomatic patients in whom airway edema is believed to contribute to the symptoms. However, no data documenting the effectiveness and dose of steroids for this purpose are available (15). Corticosteroids are also used in several fungal infections to decrease the inflammatory response associated with the primary disease and its therapy, which may contribute to the pathogenesis and clinical signs (16).

The cat was started on ketaconazole due to availability of this drug, which, in combination with 4 dexamethasone injections led to rapid resolution of dyspnea and marked reduction of the head and neck edema. The cat was then switched to itraconazole when this drug became available (not in stock initially) as it was felt to have better tissue penetration with fewer side effects. Tissue penetration and efficacy are better with fluconazole and itraconazole than with ketoconazole, and adverse effects are less commonly reported (17). The cat was then switched to fluconazole after 14 wk of itraconazole therapy due to continued presence of the mediastinal granuloma (20% reduction in size, which had become static), persistent elevations in fungal titers, and development of chylous effusion. Fluconazole was continued in conjunction with serial antigen titers until the titers became negative. Serial antigen titers allow the response to treatment to be monitored. Clinical improvement with a decrease in antigen titer suggests adequate treatment, and therapy should ideally be continued until the titer reaches zero. It should be noted, however, that reductions in titer typically lag behind clinical improvement and there is no apparent correlation between pre-treatment antigen titer and outcome (18).

The prognosis for cats with localized cryptococcosis is usually good to excellent. When patients exhibit neurological signs, the prognosis is guarded, although outcomes seem to vary depending on the host immune response and the cryptococcal strain involved (18,19). Identification of the Cryptococcus subspecies and strain may improve initial prognostic accuracy; however, response to therapy must also be considered. Amphotericin B, in combination with an azole and/or flucytosine, is usually recommended for severe, disseminated cryptococcosis, and central nervous system involvement (12,20,21), but was not used in this case. Although this cat responded to therapy with fluconazole, the addition of amphotericin B may have hastened the resolution of his clinical signs. Combination therapy and amphotericin B was considered but not used due to financial constraints.

Although the serum triglyceride concentration was not measured and bacterial culture and susceptibility were not performed in this case, the pleural effusion appeared to be chylous based on its gross appearance, a lymphocyte predominance among the total nucleated cells, the high triglyceride concentration, and the cholesterol: triglycerides ratio (0.8). Chylous or exudative effusions occur in most human patients with superior vena cava syndrome, and chylous effusion has been reported with cranial vena cava syndrome in dogs secondary to pacemaker implantation, thymoma, blastomycosis, mediastinal granuloma, and cranial caval thrombosis (22–29). There is only 1 previously reported case in the cat describing chylous effusion in association with cranial vena cava syndrome (1). The suspected chylous effusion in the cat of the current case was likely the result of the mediastinal fungal granuloma disrupting systemic venous pressures and the emptying of the thoracic duct or impairment of lymphatic drainage by compression and/or invasion of the lymphatics. However, echocardiography showed changes in the right heart and evidence of hypertrophic cardiomyopathy with a component of diastolic dysfunction and systolic anterior motion, which may also have contributed to development of pleural effusion and suspected chylothorax. These cardiac changes may have been present in the cat at the time of initial presentation, but an echocardiogram was not performed at that time. It is also possible that the cardiac changes may have been secondary to cryptococcal myocarditis. Cryptococcal myocarditis has been reported in humans with acquired immunodeficiency syndrome or following immunosuppressive therapy or procedures (30–32). To the authors’ knowledge, cryptococcal myocarditis has not been described in veterinary patients.

The presumed chylothorax was treated with intermittent pleural drainage, rutin, octreotide, and treatment of the mediastinal granuloma with antifungal therapy, which was the presumptive underlying cause. Octreotide has been used in veterinary patients for management of chylothorax, with variable results (33). The mechanism of action of this synthetic analogue of somatostatin in the treatment of chylous effusion is not fully understood but it may induce vasoconstriction of the splanchnic vessels, thereby reducing gastrointestinal secretions and absorption, and subsequently reducing the flow of chyle (34,35). A study in dogs and cats treated with octreotide revealed a success rate of 40% (33). The mechanism of action of rutin, a benzopyrone extract from plants, is also unknown; however, it is hypothesized to enhance macrophage phagocytosis of chyle, increase proteolysis and remove protein from tissues, and reduce leakage from blood vessels. Although the efficacy of rutin has not been demonstrated in cats, there are case reports that suggest it may play a role in the resolution of chylothorax (36). The role of octreotide and rutin in the near resolution of the chylous effusion in current case is unknown. If medical management of chylothorax is unsuccessful or not an option, other therapies such as surgery or interventional radiologic therapy may be indicated. Surgery was recommended in an attempt to manage the recurrent chylous effusion and to further manage the presumptive underlying cause (fungal mediastinal granuloma); however, surgery was not an option due to financial constraints.

This case report suggests that successful medical management of cranial vena cava syndrome in cats is possible depending on the underlying cause. Prolonged antifungal therapy, short-term corticosteroid therapy, intermittent thoracocentesis, rutin, octreotide, and enalapril led to almost complete resolution of the clinical signs, including secondary cranial vena cava syndrome and suspected chylous effusion. The best combination of therapies in such cases remains speculative, and the positive outcome in this case was most likely attributed to a reversible underlying cause of the cranial vena cava syndrome: mediastinal fungal granuloma. CVJ