Ciclosporin use in multi-drug therapy for meningoencephalomyelitis of unknown aetiology in dogs

OBJECTIVE: To evaluate the efficacy and safety of ciclosporin therapy alone or in combination with corticosteroids and/or ketoconazole in dogs with diagnosis of meningoencephalomyelitis of unknown aetiology. METHODS: Medical records of 10 dogs diagnosed with meningoencephalomyelitis of unknown aetiology and treated with ciclosporin therapy alone or in combination with corticosteroids and/or ketoconazole were reviewed at the Veterinary Medical Teaching Hospital, University of Wisconsin-Madison. Laboratory abnormalities, side effects, clinical and cerebrospinal fluid responses to treatment and association between blood ciclosporin level and response to treatment were evaluated. Histopathological diagnosis was available in three patients. RESULTS: No significant abnormalities were detected on serial complete blood count and serum chemistry panel in any of the dogs. Side effects of ciclosporin therapy included excessive shedding, gingival hyperplasia and hypertrichosis. Overall median survival time for all dogs in the study was 930 days (range, 60 to more than 1290 days). In all dogs, serial cerebrospinal fluid analysis showed a marked improvement in the inflammation. CLINICAL SIGNIFICANCE: Results suggest that ciclosporin either alone or in combination with ketoconazole may be a safe and effective treatment for meningoencephalomyelitis of unknown aetiology in dogs.     

Idiopathic hypertrophic pachymeningitis in six dogs: MRI, CSF and histological findings, treatment and outcome

Idiopathic hypertrophic pachymeningitis has been described in humans as a rare, chronic progressive non-specific inflammatory and fibrotic disease of the dura mater. This is a case series of six canine cases of presumptive or confirmed intracranial idiopathic hypertrophic pachymeningitis. These dogs were included in this retrospective study, based on magnetic resonance imaging findings. All presented with pachymeningeal thickening and enhancement without involvement of the leptomeninges on magnetic resonance imaging and no underlying cause identified on cerebrospinal fluid analysis, complete blood count, serum biochemistry and infectious disease titres. Histopathological examination was available in one case. Response to immunomodulatory treatment (corticosteroids and cytosine arabinoside) was achieved in five cases. Idiopathic hypertrophic pachymeningitis should be considered as a possible differential diagnosis for dogs with pachymeningeal thickening on magnetic resonance imaging and no identified underlying cause. The prognosis appears to be fair to poor.     

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.     

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.     

RETROSPECTIVE STUDY EVALUATING ASSOCIATIONS BETWEEN MIDLINE BRAIN SHIFT ON MAGNETIC RESONANCE IMAGING AND SURVIVAL IN DOGS DIAGNOSED WITH MENINGOENCEPHALITIS OF UNKNOWN ETIOLOGY

Difficulty has been encountered when trying to identify ante mortem prognostic indicators for dogs with meningoencephalitis of unknown etiology (MUE). Identifying MRI imaging parameters associated with prognosis may impact treatment decision‐making for clinician and owner. Our hypotheses for this retrospective cohort study are that dogs diagnosed with MUE that had midline shift on brain MRI would have a poorer survival compared to dogs without midline shift; and that younger age, lower weight, and low cerebrospinal fluid (CSF) cell count would be correlated with improved survival. Medical records were reviewed from two institutions. Inclusion criteria included: clinical signs referable to intracranial disease, brain MRI at presentation, abnormal CSF analysis, and negative infectious disease testing. Magnetic resonance imaging scans were evaluated for midline shift using the T2‐weighted transverse image at the interthalamic adhesion and at the site of maximal deviation. Fifty‐two dogs met the inclusion criteria. Median midline deviation was 0.12 cm. Median survival for dogs with no shift was 906 days and with shift was 84 days. Survival was not significantly different between groups (P = 0.11). This remained true when correcting for age (P = 0.22) and CSF TNCC (total nucleated cell count) (P = 0.12). Age at the time of diagnosis (P = 0.02) and CSF TNCC (P = 0.03) were significantly associated with survival. Cerebrospinal fluid protein value (P = 0.84) and weight (P = 0.82) were not significantly associated with survival. In this study of 52 dogs with MUE, MRI evidence of midline brain shift between 0.04 and 0.3 cm at the level of the interthalamic adhesion was not associated with shorter survival.     

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.     

Long-term immunosuppressive therapy with cyclosporine plus prednisolone for necrotizing meningoencephalitis in a Pekingese dog

A 4-year-old intact female Pekingese dog was presented with ataxia and seizure episodes. Based on magnetic resonance imaging and cerebrospinal fluid analysis results, meningoencephalitis of unknown etiology was suspected. The present case survived for 1,096 days under cyclosporine plus prednisolone therapy and was definitively diagnosed with necrotizing meningoencephalitis. This report describes the clinical findings, serial magnetic resonance imaging characteristics and pathologic features of a necrotizing meningoencephalitis and long-term survival after cyclosporine with prednisolone therapy.     

COMPUTED TOMOGRAPHY OF NECROTIZING MENINGOENCEPHALITIS IN 3 YORKSHIRE TERRIERS

A necrotizing meningoencephalitis of Yorkshire terriers has recently been reported in 6 dogs in Switzerland, 1 dog in Japan and 1 dog in the United States. The purpose of this report is to describe the computed tomographic (CT) findings in 3 dogs with this disease, and to correlate the CT abnormalities with the clinical and pathologic findings in each case. Three Yorkshire Terriers between 2 and 10 years old were evaluated. Physical and neurologic examinations, complete blood count (CBC), serum biochemistry profile, cerebrospinal fluid analysis, and CT scan were performed on all 3 dogs. Brainstem auditory evoked responses (BAER) were evaluated for 2 dogs. Two dogs were euthanized at the owners' request and necropsies were performed. Neurologic examination findings were consistent with a multifocal/diffuse encephalitis involving the cerebrum and brainstem in all 3 dogs. Complete blood count and biochemistry profiles were normal. Elevated protein concentration and a mononuclear pleocytosis were demonstrated in 2 of 3 dogs on cerebrospinal fluid evaluation. Multifocal, extensive areas of decreased opacity throughout the cerebral hemispheres, asymmetric ventriculomegaly, and lack of contrast enhancement were appreciated on CT images of all three dogs. No mass effect was seen. These findings correlated well with pathologic findings at necropsy, which included multiple malacic cavitations within the brain, representing areas of locally extensive necrosis. CT abnormalities in combination with signalment, clinical findings and cerebrospinal fluid analysis should facilitate a presumptive diagnosis of Yorkshire Terrier necrotizing meningoencephalitis.     

Meningoencephalitis associated with Staphylococcus warneri in a dog

A case of meningoencephalitis in a dog caused by Staphylococcus warneri is reported here. The history and clinical signs were suggestive of possible central nervous system infection. Analysis of cerebrospinal fluid documented a neutrophilic pleocytosis (890 cells/mul) and the presence of occasional intracellular cocci. Staphylococcus warneri was isolated from the microbiological culture of the cerebrospinal fluid. Treatment consisted of intravenous antibiotics, supportive care and anticonvulsants for the generalised seizures that developed after admission. Histological assessment confirmed the location and extension of bacterial meningoencephalitis. Thrombotic meningoencephalitis associated with Staphylococcus warneri infection has not, to the authors' knowledge, been previously reported in dogs.     

Treatment of 11 dogs with meningoencephalomyelitis of unknown origin with a combination of prednisolone and cytosine arabinoside

The records of 11 dogs with evidence of meningoencephalomyelitis of unknown origin were reviewed. Two of them had had a focal form of the disease and the other nine a disseminated form. The forebrain was involved in five of the nine dogs with disseminated disease, the brainstem in all nine and the cerebellum in one. They had been treated with courses of cytosine arabinoside every three weeks and immunosuppressive doses of prednisolone. Their response to the treatment, in terms of quality of life, was judged by their owners and referring veterinarians to have been excellent in five, good in five and poor in one; their survival times ranged from 78 days to more than 603 days. The cumulative probability of survival at two years was 58.4 per cent. No signs of myelosuppression or other side effects associated with cytosine arabinoside were observed.     

Clinical signs, imaging features, neuropathology, and outcome in cats and dogs with central nervous system cryptococcosis from California

Background: Cryptococcus spp. is a fungal pathogen with a predilection for the central nervous system (CNS). Objectives: To compare the clinical, advanced imaging, and neuropathologic findings in dogs and cats with CNS cryptococcosis, and to evaluate outcome of treatment in these animals. Animals: Twenty‐six cats and 21 dogs with CNS cryptococcosis. Methods: Medical records were reviewed for clinical findings and results of CNS imaging. Archived cerebrospinal fluid and CNS tissue specimens were reviewed for pathology. Findings in cats were compared with those in dogs and the effects of variables on survival were determined by survival curve analysis. Results: When present, pain was localized to the cervical region in dogs and was generalized or localized to the thoracolumbar spine or pelvic limbs in cats. Magnetic resonance imaging (MRI) findings were variable but correlated with CNS histopathological findings of meningitis, meningitis with gelatinous pseudocyst formation, and granulomatous mass lesions. Peripherally enhancing brain lesions were seen only in cats. Histopathologically, the inflammatory response was milder in cats compared with dogs. Remissions of ≥1 year occurred in 32% of treated animals. Altered mentation was associated with negative outcome. Glucocorticoid use after diagnosis was associated with improved survival in the first 10 days. Conclusions and Clinical Importance: Lesions seen on MRI reflected neuropathological findings and were similar to those reported in human patients. The immune response to infection may differ between cats and dogs, or relate to the infecting cryptococcal species. Long‐term (>6 month median survival time) survival may be possible in animals surviving ≥4 days after diagnosis.     

Presumptive meningoencephalitis secondary to extension of otitis media/interna caused by Streptococcus equi subspecies zooepidemicus in a cat

A 5-year-old castrated male domestic longhair cat was presented with neurological signs consistent with a central vestibular lesion and left Horner's syndrome. Computed tomography images revealed hyperattenuating, moderately contrast-enhancing material within the left tympanic bulla, most consistent with left otitis media/interna. Marked neutrophilic pleocytosis was identified on cerebrospinal fluid analysis. Streptococcus equi subspecies zooepidemicus (SEZ) was isolated from the cerebrospinal fluid. Intracranial extension of otitis media/interna is relatively infrequent in small animals. There are no reports of otitis media/interna caused by SEZ in dogs or cats. This is the first report of otitis media/interna and presumptive secondary meningoencephalitis caused by SEZ in a cat.     

Streptococcal meningoencephalitis in a dog.

A 5.5-year-old French bulldog was presented with acute neck pain and a short history of central vestibular syndrome. A marked neutrophilic pleocytosis and numerous gram-positive cocci were evident on cerebrospinal fluid (CSF) cytology. Streptococcus pneumoniae, a pathogen of humans, was isolated upon CSF microbiological culture. Treatment consisted of intravenous antibiotics, supportive care, and anticonvulsants for the generalized seizures which developed shortly after admission. The dog responded to therapy and two years later exhibited only a mild, residual head tilt. The pathogenesis and treatment of bacterial meningoencephalitis in dogs are reviewed.     

Canine multicentric lymphoma 2: Comparison of response to two chemothera-peutic protocols

This paper describes the chemotherapeutic response of 90 cases of canine multicentric lymphoma. All the dogs were treated with a combination protocol using cyclophosphamide, vincristine and prednisolone. Forty-seven dogs received additional intravenous cytosine arabinoside on the first four days of treatment. Eighty-eight per cent of all cases had shown either a complete or partial response to this treatment at six weeks from the start of treatment and the overall mean survival time was 37 weeks (SD = 35.8). There was no significant difference in response or survival rates between the two treatment groups. The age and sex of the patient, the clinical stage of the disease and previous treatment with corticosteroids were all analysed to determine whether these parameters were of prognostic significance. Those dogs in clinical stages 4 and 5 carried a worse prognosis than those in stages 1 to 3. Previous treatment with corticosteroids adversely affected both tumour response and patient survival rates.     

Central nervous system lymphosarcoma in the dog

Central nervous system lymphosarcoma was diagnosed in 8 dogs with seizures and clinical signs compatible with multifocal central nervous system involvement. Cerebrospinal fluid analysis showed high white cell counts with abnormal lymphoid cells in all dogs, and high protein concentration in 5 dogs. Two dogs were given systemic anticancer chemotherapy, and 4 dogs were given a combination of systemic chemotherapy, intrathecal cytosine arabinoside, and craniospinal irradiation, resulting in marked improvement of the clinical signs.     

Acquired amegakaryocytic thrombocytopenia--four cases and a literature review

Acquired amegakaryocytic thrombocytopenla was diagnosed in four dogs. Initial platelet counts in all four dogs were less than 50,000 x 10(9)/litre and initial bone marrow examinations revealed megakaryocytic hypoplasia with minimal changes in the erythroid and myeloid cell lines. Two dogs had evidence of idiopathic immune-mediated disease and two dogs had evidence of associated infectious disease. One dog had a positive antibody titre to Borrella burgdorferi, and one dog had positive titres to both Ehrlichia canis and B. burgdorferi. Treatment consisted of prednisone and cyclophosphamide for the dogs with presumptive immune-mediated disease, and prednisone and tetracycline for the dogs with positive antibody titres to the Infectious organisms. Both dogs with evidence of associated infectious disease responded to treatment. A postmortem examination did not reveal the underlying aetiology in the two dogs with presumptive idiopathic immune-mediated disease.     

Idiopathic eosinophilic meningoencephalitis in a Dutch Warmblood gelding

An increased content of eosinophils in cerebrospinal fluid (CSF) and eosinophilic infiltration of brain tissue are observed in eosinophilic meningoencephalitis (EME). After exclusion of various infectious diseases and further known causes of EME in other species, the diagnosis idiopathic EME was made at necropsy in the case reported here. To the authors' knowledge, this is the first report of idiopathic EME in a horse similar to the disorder occurring in dogs.     

Comparison of COAP and UW-19 protocols for dogs with multicentric lymphoma

BACKGROUND: Various chemotherapy protocols for treating lymphoma in dogs have been published; however, comparison of protocols from different studies is difficult, especially when evaluating survival time and toxicoses. HYPOTHESIS: The choice of COAP (C, cyclophosphamide; O, vincristine; A, cytosine arabinoside; P, prednisone) and a modified University of Wisconsin 19-week (UW-19) induction protocol has no influence on overall survival times in dogs with lymphoma. ANIMALS: One hundred and one dogs with multicentric lymphoma. METHODS: Retrospective study (2001-2006). Dogs induced with either an 8-week COP-based protocol (C, cyclophosphamide; O, vincristine; and P, prednisone) with maintenance therapy (COAP group) or a 19-week CHOP (C, cyclophosphamide; H, doxorubicin; O, vincristine; and P, prednisone) based protocol (UW-19 group) were compared in terms of the duration of first remission, survival time, toxicoses, and cost. RESULTS: There were 71 dogs in the COAP group and 30 dogs in the UW-19 group. Various protocols were used after the first relapse. The median duration of the first remission for the COAP and UW-19 groups were 94 days (range, 6-356 days) and 174 days (28-438 days), respectively (P < .01). The median survival times for dogs in the COAP and UW-19 groups were 309 days (6-620 days) and 275 days (70-1102+ days), respectively (P = .09). Dogs in the COAP group had a hazard ratio of 1.9 (95% CI 1.1-3.4) for death relative to the UW-19 group (P = .03), after controlling for the confounders (World Health Organization clinical stage, age, sex, use of doxorubicin during reinduction). The severity of neutropenia and gastrointestinal toxicoses were significantly higher in the UW-19 group than in the COAP group (P = .01 and P < .01, respectively). CONCLUSION AND CLINICAL IMPORTANCE: Use of a long-term doxorubicin-containing sequential combination chemotherapy protocol is associated with a decreased risk of relapse and death relative to a non-doxorubicin-containing protocol.     

Chemotherapeutic responses in dogs with lymphosarcoma and hypercalcemia

Twelve dogs with lymphosarcoma and hypercalcemia were treated over a period of 36 months. Signs and laboratory findings were referable to hypercalcemia and azotemia. All dogs were staged, classified histologically, and given cytoreductive chemotherapy, using 5 drugs (vincristine sulfate, cytosine arabinoside, cyclophosphamide, L-asparaginase and prednisone). For azotemia, symptomatic therapy (0.9% NaCl solution and furosemide) was given. Seven dogs responded completely, with marked reduction of lymphadenopathy and return of serum calcium concentration to normal. Median duration of remission in this group was 48 days (range, 14 to 93), and median survival time was 112 days (range, 85 to 153). Five nonresponding dogs had less than 50% reduction in measurable tumor mass, although serum calcium concentration returned to normal. The median survival time for this group was 34 days (range, 23 to 68). Two of the nonresponders died from sepsis and another from disseminated intravascular coagulation. Response to therapy did not appear to be influenced by age, breed, sex, initial calcium concentration, degree of azotemia, or histologic classification.     

Long-term treatment of dogs with steroid-responsive meningitis-arteritis: clinical, laboratory and therapeutic results

Steroid-responsive meningitis-arteritis is an immunopathological disease in dogs characterised by neck pain, pleocytosis of the cerebrospinal fluid (CSF) and increased serum and CSF immunoglobulin (Ig) A levels. A long-term treatment protocol (four to 20 months) with prednisolone was applied in 10 dogs with the condition. Clinical side effects, changes in blood and CSF values and long-term outcome were evaluated retrospectively. Eight of the 10 dogs were without clinical signs up to 29 months after the treatment was terminated. Long-term glucocorticosteroid treatment appears to result only in mild clinical side effects, such as polyuria/polydipsia, polyphagia and weight gain. All clinical and laboratory changes were reversible after the therapy was discontinued. Elevated serum and CSF IgA levels did not decrease to normal values during prednisolone treatment and were still slightly increased after the therapy was discontinued. A marked decrease in the cell count of the CSF was observed after therapy was initiated, although pleocytosis increased again during relapses of the disease. Monitoring of CSF cell count in dogs with this condition seems to be a sensitive indicator of success of treatment. In addition, older dogs with high IgA levels in the CSF and frequent relapses seem to require a longer duration of therapy and have a less favourable prognosis long term. The reason for high systemic and intrathecally produced IgA levels remains unknown, but seems not to be influenced by prednisolone treatment.