Combined cytosine arabinoside and prednisone therapy for meningoencephalitis of unknown aetiology in 10 dogs

OBJECTIVES: The differential diagnosis for young to middle-aged dogs with progressive neurological signs, focal or multifocal computed tomography/magnetic resonance imaging lesions, mononuclear cerebrospinal fluid pleocytosis and negative infectious titres includes granulomatous meningoencephalomyelitis, breed-specific meningoencephalitis, infectious meningoencephalitis of unknown origin and central nervous system neoplasia. The terminology meningoencephalitis of unknown aetiology may be preferable for cases that lack histopathological diagnoses. The safety and efficacy of a combination of cytosine arabinoside and prednisone protocol is evaluated, in this study, for the treatment of meningoencephalitis of unknown aetiology in 10 dogs. METHODS: Cases were selected based on neuroanatomical localisation, negative regional infectious disease titres, cerebrospinal fluid pleocytosis and brain imaging. Clinical response was gauged through follow-up examinations, owner and referring veterinarian surveys and review of medical records. RESULTS: Partial or complete remission was achieved in all dogs; the median survival time for the 10 dogs was 531 days (range 46 to 1025 days), with five of the 10 dogs alive at the time of writing. CLINICAL SIGNIFICANCE: Prednisone/cytosine arabinoside is a safe empirical therapy for dogs with meningoencephalitis of unknown aetiology; this drug combination may prolong survival time.     

Procarbazine as adjunctive therapy for treatment of dogs with presumptive antemortem diagnosis of granulomatous meningoencephalomyelitis: 21 cases (1998-2004)

BACKGROUND: Granulomatous meningoencephalomyelitis (GME) is an idiopathic inflammatory disease of the central nervous system. Remission often is short-lived in dogs treated with glucocorticoids. Procarbazine is T cell-specific and crosses the blood-brain barrier. HYPOTHESIS: Dogs with presumptive antemortem diagnosis of GME given procarbazine as adjunctive therapy to prednisone will have improved long-term outcome compared with dogs given no treatment or glucocorticoids alone. ANIMALS: Two groups were studied: (1) Dogs with presumptive antemortem diagnosis of GME treated with procarbazine and prednisone (n = 21); (2) Dogs that had a histologic diagnosis of GME at postmortem examination and received no treatment (n = 11). METHODS: Dogs with presumptive GME treated with procarbazine were identified retrospectively from medical records of 2 veterinary referral hospitals. Selection criteria required all dogs have a neurologic examination, blood work, cerebrospinal fluid analysis, and brain imaging (MRI or CT). RESULTS: Median survival time for all dogs studied was 5.0 months. Median survival time for dogs treated with procarbazine was 14.0 months and for untreated dogs, 0.73 months. Treatment with procarbazine was significantly correlated with survival time (P < .001). Procarbazine was the only independent predictor of survival. Prednisone was reduced in dosage or discontinued in 17 dogs. Adverse reactions to procarbazine therapy included myelosuppression in 7 dogs and hemorrhagic gastroenteritis in 3 dogs. CONCLUSION: These data suggest that procarbazine treatment of presumptive GME may result in greater improved long-term outcome than has been previously reported for glucocorticoid treatment alone and may complement other immunomodulatory therapies. Procarbazine-treated dogs must be monitored for adverse reactions.     

Comparison of Two Regimens for the Treatment of Meningoencephalomyelitis of Unknown Etiology

Background: The optimal treatment for meningoencephalomyelitis of unknown etiology (MUE) remains unknown, despite the widespread use of a variety of immunosuppressive drugs.
Objective/Hypothesis: To compare the efficacy of prednisolone combined with either vincristine and cyclophosphamide (COP group; n = 10) or with cytosine arabinoside (AraC group; n = 9).
Animals: Nineteen dogs with neurological deficits, neuroimaging, and cerebrospinal fluid abnormalities consistent with a diagnosis of MUE.
Methods: Prospective, blinded, and randomized clinical trial. Dogs fulfilling the inclusion criteria were randomly allocated to receive 1 drug regimen.
Results: Four of 10 dogs in the COP group and 5/9 in the AraC group survived > 12 months but neither the survival time nor the time-to-treatment failure differed between the 2 groups. Treatment with COP resulted in an unacceptable incidence of adverse effects.
Conclusions: The adverse effects of COP make it an unsuitable treatment for MUE. Although survival of animals treated with AraC was broadly similar to that reported in recently published studies describing this treatment, it remains unclear whether it confers any benefit over using prednisolone alone.     

Safety of intrathecal administration of cytosine arabinoside and methotrexate in dogs and cats

The objective of the study was to retrospectively evaluate the short‐term safety of intrathecal administration of cytosine arabinoside alone or in combination with methotrexate in dogs and cats. One hundred and twelve dogs and eight cats admitted between September 2008 and December 2013, diagnosed with suspected inflammatory (meningoencephalomyelitis of unknown aetiology) or neoplastic disease affecting brain or spinal cord and treated with an intrathecal administration of cytosine arabinoside alone or in combination with methotrexate were included in the study. Recorded information regarding possible adverse events during administration while recovering from anaesthesia and during hospitalization period were evaluated. The results showed that one patient developed generalized tonic‐clonic seizure activity after administration of cytosine arabinoside and methotrexate during recovery from anaesthesia, however responded to intravenous administration of diazepam. On the base of our results we can conclude that intrathecal administration of cytosine arabinoside alone or in combination with methotrexate is a safe procedure in dogs and cats.     

Management of 13 cases of canine respiratory disease using inhaled corticosteroids

OBJECTIVES: To determine the value of inhaled corticosteroids in the management of chronic inflammatory airway disease in dogs. METHODS: Medical records of dogs that were presented for the investigation of respiratory disease were reviewed retrospectively. Criteria for inclusion were knowledge of previous medical treatment including side effects, diagnosis of the underlying disease, use of inhaled corticosteroids and at least two-months follow-up data.RESULTS: Thirteen dogs that fulfilled the criteria were identified. Ten dogs were diagnosed with chronic bronchitis and three with eosinophilic bronchopneumopathy. Four dogs had not previously received corticosteroid treatment for their respiratory disease, and all these showed a reduction or a resolution of clinical signs without obvious side effects after inhaled corticosteroid therapy. Nine dogs had previously received oral or parenteral corticosteroids for treatment of their respiratory disease, and all had exhibited side effects. Five of these dogs were treated with inhaled corticosteroids alone, and all exhibited an improvement in clinical signs without observable side effects. The remaining four dogs were treated with a combination of inhaled and oral corticosteroids, and all showed improvement in clinical signs and reduction in side effects. Inhaled medication was well tolerated in all dogs. CLINICAL SIGNIFICANCE: Inhaled corticosteroids were used for the management of chronic bronchitis and eosinophilic bronchopneumopathy in 13 dogs, and these may have the advantage of reducing side effects associated with oral corticosteroids.     

Frequency of urinary tract infection in dogs with inflammatory skin disorders treated with ciclosporin alone or in combination with glucocorticoid therapy: a retrospective study

Background – Few studies have investigated the frequency of urinary tract infection (UTI) in dogs receiving long‐term ciclosporin therapy. Hypothesis/Objectives – The goal of the study was to investigate the frequency of UTI in dogs receiving ciclosporin with or without glucocorticoids. A secondary goal was to determine whether bacteriuria, pyuria and urine specific gravity were good predictors of UTI, and if ciclosporin dose, concurrent ketoconazole therapy, sex or duration of therapy affected the frequency of UTI. Animals – Eighty‐seven dogs with various inflammatory skin disorders and 59 control dogs with inflammatory skin conditions that had not received glucocorticoids or ciclosporin for 6 months were enrolled. Methods – This study was retrospective. The first urine culture from dogs receiving ciclosporin was compared with control dogs using Fisher’s exact test. A logistic mixed model was used to test for association between a positive bacterial culture and duration of treatment, dose of ciclosporin, concurrent ketoconazole therapy and sex. The sensitivities and specificities for bacteriuria, pyuria and urine specific gravity were determined. Results – Twenty‐six of 87 (30%) ciclosporin‐treated dogs had at least one positive culture. Compared with 3% positive control samples, 15% were positive in treated dogs (P = 0.027). The sensitivity and specificity were, respectively, 64.1 and 98.1% for bacteriuria, 74.4 and 70.9% for pyuria, and 56.4 and 65.3% for urine specific gravity. All other analysed parameters were not significantly different. Conclusions and clinical importance – The results suggest that routine urine cultures and assessment of bacteriuria by cystocentesis should be part of the monitoring for dogs on long‐term ciclosporin with and without glucocorticoids.     

Granulomatous meningoencephalomyelitis in dogs: A review

: Granulomatous meningoencephalomyelitis (GME) is an inflammatory disease of the central nervous system in dogs that is characterised by focal or disseminated granulomatous lesions within the brain and/or spinal cord, non-suppurative meningitis and perivascular mononuclear cuffing. The aetiology of the disease remains unknown, although an immune-mediated cause is suspected. This article reviewed the typical history, clinical signs and pathology of the condition along with current opinions on pathogenesis. The potential differential diagnoses for the disease were discussed along with current treatment options.     

A prospective study of clopidogrel therapy in dogs with primary immune-mediated hemolytic anemia

Background: A major cause of death in dogs with primary immune‐mediated hemolytic anemia (pIMHA) is thrombotic disease. Ultralow‐dose aspirin (ULDA) is commonly used to prevent thrombosis in dogs with pIMHA; however, the efficacy of antiplatelet agents in dogs with pIMHA is unknown. Hypothesis: The use of clopidogrel (CL), alone or in combination with ULDA, would improve survival to discharge and at 90 days without important adverse effects compared with ULDA alone in dogs with pIMHA treated with standard immunosuppressive therapy. Animals: Twenty‐four client‐owned dogs with pIMHA. Methods: Prospective, positive‐controlled, unmasked clinical trial with dogs randomized in 3 treatment groups to receive PO ULDA or CL or both. Results: There was no identifiable adverse reaction, evidence of hemorrhage, or increase in transfusion requirements associated with CL therapy, either alone or combined with ULDA, compared with ULDA alone. There was no significant difference between treatment groups with respect to survival to discharge and at 90 days. Conclusions and Clinical Importance: This study suggests that CL therapy, alone or in combination with ULDA, was safe and had similar short‐term survival compared with ULDA alone in a small group of dogs with pIMHA able to tolerate oral medications and treated with standard immunosuppressive treatment.     

Evaluation of Brain Tissue or Cerebrospinal Fluid with Broadly Reactive Polymerase Chain Reaction for Ehrlichia,Anaplasma, Spotted Fever Group Rickettsia,Bartonella, and Borrelia Species in Canine Neurological Diseases (109 Cases)

Background: Vector‐transmitted microorganisms in the genera Ehrlichia, Anaplasma, Rickettsia, Bartonella, and Borrelia are commonly suspected in dogs with meningoencephalomyelitis (MEM), but the prevalence of these pathogens in brain tissue and cerebrospinal fluid (CSF) of dogs with MEM is unknown. Hypothesis/Objectives: To determine if DNA from these genera is present in brain tissue and CSF of dogs with MEM, including those with meningoencephalitis of unknown etiology (MUE) and histopathologically confirmed cases of granulomatous (GME) and necrotizing meningoencephalomyelitis (NME). Animals: Hundred and nine dogs examined for neurological signs at 3 university referral hospitals. Methods: Brain tissue and CSF were collected prospectively from dogs with neurological disease and evaluated by broadly reactive polymerase chain reaction (PCR) for Ehrlichia, Anaplasma, Spotted Fever Group Rickettsia, Bartonella, and Borrelia species. Medical records were evaluated retrospectively to identify MEM and control cases. Results: Seventy‐five cases of MUE, GME, or NME, including brain tissue from 31 and CSF from 44 cases, were evaluated. Brain tissue from 4 cases and inflammatory CSF from 30 cases with infectious, neoplastic, compressive, vascular, or malformative disease were evaluated as controls. Pathogen nucleic acids were detected in 1 of 109 cases evaluated. Specifically, Bartonella vinsonii subsp. berkhoffii DNA was amplified from 1/6 dogs with histopathologically confirmed GME. Conclusion and Clinical Importance: The results of this investigation suggest that microorganisms in the genera Ehrlichia, Anaplasma, Rickettsia, and Borrelia are unlikely to be directly associated with canine MEM in the geographic regions evaluated. The role of Bartonella in the pathogenesis of GME warrants further investigation.     

A multicentre placebo‐controlled clinical trial on the efficacy of oral ciclosporin A in the treatment of canine idiopathic sebaceous adenitis in comparison with conventional topical treatment

Canine idiopathic sebaceous adenitis (ISA) is an inflammatory reaction of sebaceous glands, potentially resulting in their complete loss. It is considered a T‐cell‐mediated disease, but its precise pathogenesis is still unknown. Topical treatment with oil soaks, humectants and shampoos is effective but laborious. Ciclosporin A (CsA), an immunomodulatory drug, has recently been shown to ameliorate the clinical picture of ISA and to reduce inflammation greatly. It is, however, an expensive treatment option. The objective of this multicentre, partly double‐blinded, randomized controlled study was to evaluate the efficacy of ciclosporin A, either alone or with topical therapy, in comparison to conventional topical treatment alone, as measured by the primary end‐points alopecia and scaling, and multiple histopathological secondary objectives. Thirty‐four dogs with an established diagnosis were treated for 4–6 months and were evaluated before, during and after therapy. Both CsA and topical therapy demonstrated efficacy in this study. Differences between the treatment protocols were marginal. Topical treatment, both alone and in combination with CsA, appeared to reduce scaling more effectively than CsA alone. Both therapies reduced alopecia. There is evidence of a synergistic benefit on both scaling and alopecia, if both treatment options are combined. Inflammation of the sebaceous glands is also best reduced by a combination of both CsA and topical therapy. There is evidence that regeneration of sebaceous glands is best achieved by CsA, either given alone or in combination with topical treatment.     

Cerebrospinal Fluid Analysis and Clinical Outcome of Eight Dogs With Eosinophilic Meningoencephalomyelitis

Eight dogs, 14 weeks to 5.5 years of age, had signs of diffuse or multifocal meningoencephalomyelitis. The total white cell counts of the cerebrospinal fluid (CSF) ranged from 11 to 5,550 cells/microliters; the percentage of eosinophils ranged from 21% to 98%. The total CSF protein content range was 19 to 1,430 mg/dl. On necropsy, two dogs had granulomatous encephalomyelitis due to protozoan infection. The other six dogs, of which three were Golden Retriever dogs, appeared to have an idiopathic eosinophilic meningoencephalitis; four of these dogs recovered. The significance of eosinophils in CSF and the possible emergence of a new encephalitic syndrome of dogs involving a hypersensitivity to an unknown agent is also discussed.     

Adverse effects of ketoconazole in dogs--a retrospective study

Although ketoconazole has been used extensively in dogs for the treatment of various fungal infections, information about adverse effects is mainly anecdotal. Common adverse effects in humans include dose-dependant anorexia, nausea and vomiting, allergic rashes and pruritus. Drug-induced hepatitis is very rare, but potentially fatal. The aim of this study was to evaluate the type and frequency of adverse effects associated with ketoconazole therapy in dogs treated for skin diseases and any possible influence of dosage, duration of therapy, signalment or concurrent medication. The medical records of 632 dogs treated with ketoconazole (2.6–33.4 mg/kg) were reviewed. Adverse effects occurred in 14.6% (92 dogs) and included vomiting (7.1%), anorexia (4.9%), lethargy (1.9%), diarrhea (1.1%), pruritus (0.6%), erythema (0.3%) and other adverse effects (2.5%). Of the dogs with other adverse effects, four of 16 (25%) were ataxic and three of these received concurrent ivermectin. Adverse effects were significantly more often recorded in dogs concurrently treated with ciclosporin ( P =  0.034) or ivermectin ( P =  0.007). Increased liver enzyme levels were reported rarely, and icterus was not seen in any of the dogs. However, monitoring liver enzymes during therapy is recommended, although this might not necessarily prevent severe idiosyncratic hepatotoxicity.     

Opportunistic fungal infections in dogs treated with ciclosporin and glucocorticoids: eight cases

Glucocorticoids are the standard of care for the treatment of immune‐mediated disorders, and ciclosporin is increasingly being used off‐label as an adjunct immunosuppressive drug in dogs. However, opportunistic infections can develop during combination immunosuppressive regimens. This case series describes atypical fungal infections in eight dogs treated with immunosuppressive dosages of glucocorticoids and ciclosporin. The median duration of combined treatment prior to the identification of fungal infection was 31 (range, 13 to 201) days, although two dogs received glucocorticoids for prolonged periods prior to the addition of ciclosporin. The estimated prevalence of serious fungal infections with this drug combination appears to be low (approximately 1 · 67%), but these infections led directly or indirectly to death or euthanasia in five of eight (63%) dogs. These cases highlight the need for frequent clinical monitoring of dogs receiving immunosuppressive dosages of glucocorticoids and ciclosporin.     

Cardiovascular device infections in dogs: report of 8 cases and review of the literature

BACKGROUND: Infection is an infrequent but major complication of cardiovascular device implantation. HYPOTHESIS: Treatment of patients with cardiovascular implant infection with antibiotic therapy and removal of the device is superior to antibiotic therapy alone. METHODS: Medical records were reviewed for dogs that received a cardiovascular device from June 2001 to August 2006 at the University of Minnesota Veterinary Medical Center and the University of Missouri Veterinary Medical Teaching Hospital. RESULTS: Six of 63 (9.5%) pacemaker systems and 2 of 47 (4.3%) patent ductus arteriosus (PDA) occlusion devices became infected. Median time from procedure to diagnosis of implant infection was 62 days (range, 5 to 419). Median age of dogs with pacemaker infections was 8.5 years (range, 6.2 to 11.9). Pseudomonas aeruginosa and Staphylococcus spp were the most commonly cultured isolates. Four dogs were treated with antibiotics and pacemaker replacement. All 4 recovered completely from their infections. One was alive at the end of the study period, and 3 had been euthanized. However, the reasons for euthanasia were unrelated to pacemaker infection. In contrast, both dogs with infected pacemakers that were treated with antibiotics alone were euthanized because of complications attributable to infection. Infection of PDA occlusion devices occurred in puppies < 16 weeks of age, and Pasteurella spp were isolated from both. One was successfully treated with a combination of antibiotics and surgery, and the other was euthanized without treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Antibiotic therapy alone is associated with chronic complications in patients with cardiovascular implants and is unlikely to effect a cure.     

Cyclosporin and ketoconazole interaction for treatment of perianal fistulas in the dog

OBJECTIVE: To assess the use of concurrent ketoconazole and low dose cyclosporin administration in a group of dogs with clinical evidence of perianal fistulas, and to determine if this combination could be used to manage perianal fistulas effectively. DESIGN: Prospective clinical trial PROCEDURE: Sixteen dogs with clinical evidence of perianal fistulas were given ketoconazole (10 mg/kg once daily) and cyclosporin (1 mg/kg twice daily initially) for 16 weeks. Blood cyclosporin assays were performed regularly and cyclosporin doses were altered to achieve a stable blood level above 200 ng/mL. Regular examinations assessed the dogs' general health, changes in clinical behaviour, fistula size and number. A complete blood count and serum biochemical analysis was performed in all dogs before and after the treatment period, and after 8 weeks of treatment in 12 dogs. Dogs were assessed for recurrence of lesions at 1, 3 and 12 months after the trial. RESULTS: All dogs showed marked improvement in lesions and behaviour within 14 days of the medication. Fourteen dogs completed the trial. Two dogs were excluded due to concurrent disease. Thirteen dogs (93%) showed complete resolution of fistulas during the treatment period. Seven dogs (50%) had no recurrence after 12 months. Recurrence was seen in three dogs (21%) at 8, 10 and 12 months after treatment, and in three dogs (21%) within 1 month of treatment. The medication was well tolerated. Side effects included transient anorexia, vomiting and lethargy in some dogs, increased shedding of hair and gingival hyperplasia. Ketoconazole administration allowed a dramatic reduction in cyclosporin dose (over 90% in 12 dogs and 80% in the other two) compared to previously reported cases treated with cyclosporin alone. CONCLUSION: The use of combined ketoconazole and cyclosporin provided an effective treatment for perianal fistulas. Outcomes were similar to those seen with cyclosporin alone, but allowed a significant reduction in cyclosporin dose and, therefore, cost. The use of immunosuppressive therapy in the treatment of perianal fistulas was effective and avoided many of the problems associated with surgical treament.     

Granulomatous meningoence-phalomyelitis in 21 dogs

Granulomatous meningoencephalomyelitis (GME) is a well recognised disease entity affecting dogs. It manifests in a wide variety of clinical syndromes. The lesion is characterised by focal or disseminated non-caseating granulomas in the brain and spinal cord, non-suppurative meningitis and marked perivascular lymphoid cuffing. The clinical signs can be acute and rapidly progressive or can manifest as a chronic relapsing disease. In this survey, 12 clinical cases were referred to Murdoch University Veterinary Hospital and nine cases were submitted for necropsy. While cerebrospinal fluid examination in seven of these cases suggested inflammatory disease, necropsy confirmed the presence of GME. An immunohistochemical technique for detection of distemper virus antigen failed to identify the presence of distemper virus antigen in any of the cases. It was concluded that distemper virus was not involved in the aetiology of these 21 cases all of which were confirmed by post mortem examination.     

A comparison of combination therapy (cyclosporine plus prednisolone) with sole prednisolone therapy in 7 dogs with necrotizing meningoencephalitis

Administration of immunosuppressive doses of glucocorticosteroids is the traditional primary treatment in necrotizing meningoencephalitis (NME) in dogs. However, response is variable and clinical signs often recur quickly with tapering dosage. Prognosis is poor and long-term therapy causes many complications. In the present study, we compared the long-term effects of combination (cyclosporine plus prednisolone) therapy with sole prednisolone therapy in management in dogs with NME. All NME cases in this study were examined with magnetic resonance imaging and cerebrospinal fluid analysis, and confirmed by histopathologic examination. The mean survival time of combination therapy group was 305.7 +/- 94.7 days. The mean survival time of sole prednisolone therapy group was 58.3 +/- 30.5 days. This case report demonstrates that combination treatment of cyclosporine with prednisolone is more effective in survival time than administration of only prednisolone in NME cases.     

Cerebrospinal Fluid Eosinophilia in Dogs

Background: Marked eosinophilic meningitis or meningoencephalomyelitis (EME) is rarely reported in dogs and the cause is usually undetermined. Long-term prognosis for dogs with cerebrospinal fluid (CSF) eosinophilia is variable.
Animals: Twenty-three client-owned dogs.
Methods: Retrospective case series. Dogs with eosinophilic CSF, defined as total nucleated cell count (TNCC) >3 cells/μL with >20% eosinophils, were identified by a computerized search of all dogs having cisternal and/or lumbar CSF analyzed as part of the diagnostic workup between 1992 and 2007.
Results: TNCC in CSF ranged from 4 to 4,740 cells/μL (median 84 cells/μL, reference range ≤3 cells/μL), with 22 to 95% (median 78%) eosinophils in the differential count. An infectious agent was identified on necropsy in 4 of 23 (17%) dogs ( Cryptococcus neoformans [n = 2], Neospora caninum [n = 1], and Baylisascaris procyonis [n = 1]). Each of these dogs had progressive neurologic deterioration. Sixteen dogs had idiopathic EME. Magnetic resonance imaging (MRI) findings were abnormal in 7 of 13 dogs with EME; 2 dogs had focal lesions and 5 dogs had multifocal lesions. Clinical signs in 12 of 16 (75%) dogs with idiopathic EME resolved with prednisone treatment. Three dogs with acute intervertebral disc herniations recovered after decompressive surgery alone.
Conclusions: Idiopathic EME is a common cause of eosinophilic pleocytosis in dogs. MRI findings are variable. Infectious causes of EME were less common and had a poor prognosis.     

Therapy of a horse with diarrhoea of unknown aetiology.

A 5 year old Thoroughbred stallion with diarrhoea of unknown aetiology was referred to Davis. Treatment was aimed at terminating diarrhoea and restoring normal fluid status. Laboratory aids were utilised to establish where inbalance and deficits were present. Antibiotics and corticosteroids were used as an adjunct to fluid therapy. The case history and rationale of treatment of fluid disorders resulting from diarrhoea are discussed.