Introduction
Meningoencephalitis of unknown origin (MUO) encompasses a group of noninfectious inflammatory conditions of the CNS. It is the most frequently diagnosed immune-mediated disorder affecting the canine CNS, representing almost half of such disorders in a recent retrospective cohort study.1 The exact etiology and pathophysiology are not fully understood, but underlying immune system disturbances are thought to be responsible, resulting in different histological patterns of inflammation, including granulomatous meningoencephalitis, necrotizing leukoencephalitis, and necrotizing meningoencephalitis.2 A definitive diagnosis can be established by conducting a histopathological examination on a biopsy sample3 or postmortem tissue. A presumptive diagnosis is more frequently achieved by considering epidemiological data, clinical abnormalities, cerebrospinal fluid (CSF) analysis, negative testing for infectious agents, and MRI examination.4–6 A poor prognosis is commonly attributed to MUO, as 56% to 60% of affected dogs die or are euthanized because of the disease.7,8 According to various studies,7,8 early death is frequent, as 33% and 25% of dogs die or are euthanized within 3 and 7 days after diagnosis, respectively. More recently, obtundation has been found as a risk factor for early death, with a decreasing risk over time.9 Various biomarkers have been studied in blood and/or CSF in MUO cases, as distinct immunoglobulin-family autoantibodies (eg, IgA, IgC, IgM), specific autoantibodies (eg, GFAP, TG2), cytokine activity (CCL19), micro-ARN activity,5 and more recently oligoclonal bands.10 Some of these markers appear promising in the diagnostic approach of MUO but are challenging to implement in practical settings.
C-reactive protein (CRP) is a positive acute-phase protein that is easily measurable using on-site analyzers or in a laboratory setting. CRP concentration increases with high sensitivity but low specificity in several inflammatory (eg, infectious, immune-mediated) or noninflammatory conditions (eg, neoplasia) in dogs.11 In the field of veterinary neurology, CRP has been reported as a diagnostic biomarker in steroid-responsive meningitis and arteritis12–15 and bacterial discospondylitis.16,17 CRP was also evaluated in dogs suffering from bacterial meningitis or meningoencephalitis without empyema and was increased in all cases in which the test was performed.18 While some studies included MUO cases for comparison with steroid-responsive meningitis arteritis (SRMA), there is a lack of substantial evidence regarding concentrations of CRP in blood and CSF in dogs with MUO. The objectives of the present study were to determine the proportion of dogs with MUO exhibiting an increased blood CRP and detectable CRP in CSF; identify any epidemiological, clinical, diagnostic laboratory, or radiological factor associated with abnormal CRP level in blood; and, lastly, investigate the predictive value of blood CRP level for mortality. Our main hypotheses were (1) a low proportion of dogs with MUO would have a CRP concentration increase in blood and a detectable CRP level in the CSF, (2) a blood CRP concentration increase would potentially be associated with lesions diffusely distributed within the cerebral parenchyma or in proximity to the meninges based on MRI findings, and (3) there would be no correlation between CRP levels and long-term survival.
Methods
Study design
The study was a prospective cohort observational study. It was conducted at the Neurology Department of the Veterinary Hospital Languedocia between September 3, 2019, and December 25, 2022.
Ethical considerations
For affected dogs, all study procedures were realized as part of the diagnostic workup regardless of the study. No additional samples were taken from dogs, as only CSF and plasma excesses were used. According to European Union law (Directive 2010/63/UE), no ethical approval had to be sought. Informed owner consent was obtained at the time of the animal’s admission. For healthy dogs, all were presented for blood donation for clinical purposes, and owners were informed about the study procedures and gave their consent.
Animals
Dogs were included in the group of MUO if they fulfilled all the following inclusion criteria4: (1) dogs older than 6 months, (2) neurological examination consistent with a focal or multifocal encephalopathy, (3) MRI showing intra-axial focal or multifocal hyperintense (relative to normal gray matter) lesions on T2 and T2-weighted FLAIR images, (4) CSF analysis showing a pleocytosis (ie, total nucleated cell count [TNCC] > 5/μL) with > 50% mononuclear cells, and (5) exclusion of local infectious encephalopathy by serology titer in serum or PCR in CSF (Toxoplasma gondii, Neospora caninum, Leishmania infantum, and Ehrlichia sp). If a dog died within the 3 months after the initial investigations, histopathological confirmation of MUO was necessary to keep the dog included in the group. Otherwise, if a different cause was identified or histopathology was not conducted, the dog was removed from the group. Dogs were included in the group of SRMA if the following criteria were respected: (1) < 5 years of age at first; (2) general clinical signs consistent with the disease, such as pyrexia and/or cervical hyperesthesia and/or reluctance to move; (3) examination, using cross-sectional imaging modalities (CT ± MRI), of the entire vertebral column without abnormalities except a possible meningeal enhancement; and (4) CSF analysis demonstrating a neutrophilic pleocytosis (> 50% of TNCC) and increased protein concentration. This group was considered a positive control group. The negative control group consisted of healthy dogs presented for blood donation. The same blood work as for affected dogs was performed, and a search for infectious agents in blood was conducted as part of the blood donation process.
In all groups, dogs had to be free of digestive clinical signs suggestive of gastroenteropathy and clinical signs consistent with urinary or respiratory disorders. Dogs that received glucocorticoids within 3 weeks before the admission were not included in the study. Pregnant bitches19 and Miniature Schnauzers20 were not included because of slightly higher serum CRP concentration in comparison with nonpregnant bitches and other breeds, respectively.
Procedures
All dogs underwent a general and neurological examination by a board-certified neurologist or a resident in neurology under supervision. Breed, age, sex, clinical signs, and seizure activity were recorded. A CBC and biochemistry panel were performed for each dog. Blood samples were collected by venipuncture and immediately disposed in a lithium heparin tube. After centrifugation at 5,000 X g for 5 minutes, plasma was used to perform the initial biochemistry profile. The remaining excess of plasma was kept for plasmatic CRP concentration measure. All dogs underwent general anesthesia preparatory to cross-sectional imaging examination (eg, CT or MRI for the SRMA group and MRI for the MUO group) and CSF sampling. Premedication was administered IV after placement of an intravenous catheter. For dogs that exhibited pain and those that were painless, methadone (0.3 mg/kg) and butorphanol (0.3 mg/kg) were administered, respectively. Anesthesia was induced by a combination of propofol (1 to 2 mg/kg) and midazolam (0.2 mg/kg) and maintained by isoflurane delivered by oxygen through an endotracheal tube. CSF sampling was collected in lateral recumbency from the subarachnoid space at the cerebellomedullary cistern for most dogs. Otherwise, if the cisterna magna collection was contraindicated (indentation of the cerebellum through the foramen magnum, occipital-atlanto-axial misarticulation), CSF was taken from the lumbar subarachnoid space. Cell count was performed immediately after CSF collection by the attending clinician with a hemocytometer chamber. The remaining sample was sent to an external laboratory to perform cell differentiation and infectious agent testing. CRP concentration measurement in CSF was performed if the remainder volume was sufficient. Otherwise, the dog was not included in the study. Since healthy dogs were not anesthetized for blood donation and CSF analysis was not included in blood donor analyses, no CSF collection was performed.
Magnetic resonance imaging—All dogs included in the MUO group underwent a brain MRI examination with a 0.25-T magnet (Vet-MR Grande; Easote) in ventral recumbency. The same protocol was used for all dogs. T2-weighted fast spin echo images were acquired in the sagittal and transverse planes, T2 FLAIR and T1-weighted fast spin echo images were acquired in the transverse plane. Gadolinium-based contrast agent was used at a dose of 0.25 mmol/kg IV (gadoterate meglumine [Dotarem; Guerbet]). T1 postcontrast administration images were acquired in the transverse plane. A single board-certified radiologist (LB) who was blinded to the results of the CRP measurements interpreted the images. MRI lesions were evaluated according to various characteristics for each individual case. First, the lesion distribution influence on CRP concentration was assessed by classifying them as focal or multifocal and noting whether the telencephalon, the brainstem, and the cerebellum were affected. If telencephalic lesions were noticed, the number of cortices affected (ie, frontal, parietal, temporal, or occipital) was used to investigate the influence of lesion extent. Then, close contact with surrounding meninges and with ventricles was mentioned as present or not. The margins of the lesions were defined as smooth, ill-defined, or mixed if both types were noticed. Contrast enhancement was defined as absent, slight, or severe to investigate an altered blood-brain barrier or increased vascularization. The enhancement was described as homogenous if it was comparable among enhancing areas or heterogeneous otherwise. Loss of brain tissue suggestive of chronicity and defined as focal areas of T1-weighted hypointensity or T2-weighted hyperintensity suppressed on T2 FLAIR within the brain parenchyma was described. The presence of mass effect was documented by noting specific type of lesion, including midline shift, foramen magnum, subfalcine, and transtentorial herniation (Supplementary Table S1).
CRP measurements—Plasma and CSF samples obtained for CRP analysis were assayed within 24 hours after collection. CRP was analyzed with Randox cCRP assay (Advia 1800 analyzer; Siemens Healthcare Diagnostics Inc) as previously validated in blood.21 The normal reference range in plasma was < 7 mg/L. A value of 0.1 mg/L was attributed to CRP concentrations below the detection limit of 0.1 mg/L.
Treatment and outcome
At the time of diagnosis of MUO, dogs received a single initial dose of dexamethasone (0.1 to 0.2 mg/kg, IV) followed by prednisone (0.5 mg/kg, PO, q 12 h). While infectious agent research was pending, clindamycin was given at a dose of 12.5 mg/kg, PO, q 12 h. Once the results returned negative, all dogs received an immunosuppressive therapy (corticosteroid alone or in combination with another immunosuppressive treatment). Dogs were followed for at least 6 months after the diagnosis. Death or euthanasia related to the disease was recorded and represented the outcome data.
Statistical analysis
Quantitative data were evaluated for normality by the Shapiro-Wilk test. If they were skewed, they were presented as the median and range. Categorical variables were described as counts and percentages. The Mann-Whitney test was used to compare median blood CRP concentration between MUO and control groups. In the MUO group, associations between an increased blood CRP concentration and epidemiological data, clinicopathological findings, and MRI criteria were assessed. The χ2 test was used regarding history of seizures, sex, breed, leukocytosis, and all MRI criteria except the number of affected telencephalic cortices. The Mann-Whitney U test was used for age, duration of clinical signs, neutrophil-to-lymphocyte ratio, albumin-to-globulin ratio, TNCC, CSF protein concentration, and the number of affected telencephalic cortices. Because the immunofluorometric method has not been validated with CSF as the assay matrix, no statistical analysis was conducted to compare the groups or investigate an association with the other studied factors. Only descriptive data for each group are provided. The receiver operator characteristic analysis was used to determine the predictive power of CRP in identifying surviving patients at 6 months after diagnosis. Areas under the curve of < 0.7 were considered poor, 0.7 to 0.8 was considered fair, 0.8 to 0.9 was considered good, and 0.9 to 1.0 was considered excellent.22 Statistical analyses were carried out with IBM SPSS Statistics, version 27 (SPSS Inc). A significance threshold of P < .05 was used for all tests.
Results
Sixty dogs were included in the study. Thirty dogs were enrolled in the MUO group. The median age of dogs with MUO was 4.3 years (range, 0.75 to 11.8 years). There were 11 females, 7 spayed females, 6 males, and 6 neutered males. Breeds included Chihuahua (n = 13; 43.3%), Yorkshire Terrier (7; 23.3%), French Bulldog (4; 13.3%), Pug (2; 6.3%), and 1 (3.3%) dog of each of the following breeds: Brittany Spaniel, Golden Retriever, Miniature Spitz, and Spitz. Nineteen other dogs were diagnosed with MUO but were not included because of prior corticosteroid treatment (n = 10), insufficient CSF volume (4), unsuccessful CSF collection (3), and both corticosteroid treatment and unsuccessful CSF collection (2). Fifteen dogs were enrolled in the SRMA positive control group. The median age of dogs with SRMA was 0.8 years (range, 0.5 to 3.6 years). There were 3 females, 2 spayed females, 6 males, and 4 neutered males. Types of dogs included Beagle (n = 5; 33.3%), Boxer (3; 20%), crossbreed (2, 13.3%), and 1 (6.7%) dog of each of the following breeds: Bernese Mountain, Border Collie, Golden Retriever, Labrador Retriever, and Belgian Shepherd. Fifteen healthy dogs were enrolled, and their age ranged from 1.8 to 4.2 (median, 3.2 years). There were 2 females, 6 spayed females, 2 males, and 5 neutered males. Types of dogs included Australian Shepherd (n = 3; 20%), crossbreed (3; 20%), Golden Retriever (2; 13.3%), Dogo Argentino (2; 13.3%), and 1 (6.7%) dog of each of the following breeds: Newfoundland, Border Collie, Labrador Retriever, Beauceron, and Belgian Shepherd.
In the MUO group, the median CRP concentration in blood and CSF was 0.1 mg/L (range, 0.1 to 102 mg/L) and 0.1 mg/L (range, 0.1 to 7.3 mg/L), respectively. In the blood, it was considered increased (> 7 mg/L) in 9 of 30 (30%) dogs. Three (10%) dogs had a detectable CRP concentration in the CSF (higher than 0.1 mg/L). All these dogs had an increased CRP concentration in the blood. In the SRMA positive control group, the median CRP concentration in the blood and the CSF was 145 mg/L (range, 42 to 278 mg/L) and 0.1 mg/L (range, 0.1 to 23 mg/L), respectively. All dogs in this group had an increased CRP concentration in the blood. Nine (60%) dogs had a detectable CRP concentration in the CSF. In the healthy group, the median CRP concentration in blood was 0.1 mg/L (range, 0.1 to 5.3 mg/L). Blood CRP concentration for dogs with MUO was significantly lower than for dogs with SRMA (P < .001). No significant difference in the CRP values measured in blood was observed between the MUO group and the healthy group.
For dogs with MUO, the median duration of clinical signs was 12 days (range, 1 to 1,095 days). The median duration of clinical signs in dogs with MUO with normal and increased blood CRP concentration was 8.5 days (range, 1 to 56 days) and 47.5 days (range, 4 to 1,095 days), respectively. An increased blood CRP concentration was significantly associated with a longer duration of clinical signs (P = .007; Figure 1). Of the 30 dogs, 10 (33%) had a history of seizures at the time of first evaluation. No significant associations were observed between blood CRP concentrations and breed, sex, age, and epileptic seizure activity.
Comparison of duration of clinical signs between dogs that had meningoencephalitis of unknown origin with normal and elevated blood C-reactive protein (CRP) levels. Box-and-whisker plots represent mean ± 95% CI, with asterisks representing outliers.
Citation: Journal of the American Veterinary Medical Association 262, 4; 10.2460/javma.23.11.0606
None of the MRI findings were significantly associated with an increased CRP concentration in blood (Supplementary Table S1).
Leukocytosis was identified in only 1 dog with MUO (3.3%). The median blood neutrophil-to-lymphocyte ratio was 4.5 (range, 1.9 to 11.2). The median albumin-to-globulin ratio was 1.1 (range, 0.5 to 1.3). Blood CRP concentration was not significantly associated with leukocytosis, neutrophil-to-lymphocyte ratio, or albumin-to-globulin ratio.
In the MUO group, CSF samples were obtained from the cisterna magna in 11 dogs (37%) and from the lumbar subarachnoid space in 19 dogs (63%). The median TNCC was 25.5 cells/μL (range, 6 to 1,700 cells/μL). The median total RBC count was 3 cells/μL (range, 0 to 430 cells/μL). The median protein concentration in CSF was 0.4 and 0.7 g/L for CSF sampled from the cisterna magna and the lumbar subarachnoid space respectively (range, 0.1 to 1.9 g/L). Protein concentration was increased in 17 samples (reference interval, < 0.25 g/L for CSF obtained from the cisterna magna and < 0.45 g/L for CSF obtained from the lumbar subarachnoid space). No parameter in CSF was significantly associated with CRP value in blood.
Twenty-three dogs with MUO received a combination of prednisolone (0.9 to 1 mg/kg, PO, q 12 h for 1 week, then tapering the dose by 25% every 4 weeks to the lowest effective dose) and cytosine arabinoside (200-mg/m2 continuous rate infusion over 12 to 24 hours or 400 mg/m2 divided in 4 SC injections, q 12 h, every 3 to 4 weeks for 6 cycles), 2 dogs received prednisolone (0.9 to 1.1 mg/kg, PO, q 12 h for 1 week, then tapering the dose by 25% every 4 weeks to the lowest effective dose) and cyclosporine (5 mg/kg, PO, q 12 h for 2 months and 5 mg/kg, PO, q 24 h, for the 4 following months), and 4 dogs received prednisolone (0.9 to 1.1 mg/kg, PO, q 12 h for 1 week, then tapering the dose by 25% every 4 weeks to the lowest effective dose) alone. In 2 dogs, a third immunosuppressant, mycophenolate mofetil, was administered because of a relapse of clinical signs during treatment with prednisolone and cytosine arabinoside. One dog was euthanized at the time of diagnosis and was excluded from the analysis of the outcome. Six months after diagnosis, 22 dogs exhibited a positive response to treatment and remained alive, while the remaining 7 dogs were euthanized due to a lack of significant response to treatment. Two dogs died within 3 months following diagnosis, and histopathological analysis identified necrotizing leukoencephalitis for one dog and granulomatous meningoencephalitis for the other dog. The predictive power regarding survival at 6 months presented as area under the curve was 0.60 (95% CI, 0.40 to 0.81) for blood CRP concentration, which means a poor predictive value (Figure 2).
Results of receiver operator characteristic curve analysis to determine the predictive value of CRP concentration in blood for survival at 6 months. The area under the curve is 0.60 (95% CI, 0.40 to 0.81). The 45° diagonal line represents the line of no discrimination.
Citation: Journal of the American Veterinary Medical Association 262, 4; 10.2460/javma.23.11.0606
Discussion
The present study was undertaken to evaluate the concentration of CRP in blood and CSF in dogs diagnosed with MUO.
In this cohort of dogs affected by MUO, the median value of CRP in the blood was 0.1 mg/L, a value falling within the lower end of the reference range and mostly representing a nondetectable level. Thirty percent of dogs showed an increased CRP concentration in the blood. CRP is classified as an acute-phase protein in dogs due to its substantial increase in response to inflammatory stimuli.11 The lack of systematic blood CRP elevation in dogs affected by MUO does not support the development of a systemic inflammatory response in the pathophysiology of the disease, as it is demonstrated for SRMA in other studies13–15,23 and corroborated in our positive control group. The absence of leukocytosis, except in 1 dog, and the normal median albumin-to-globulin ratio measured in the MUO group support this fact. Consequently, with the lack of association between the median albumin-to-globulin ratio and blood CRP levels, it becomes challenging for veterinarians to predict which patient might exhibit increased blood CRP levels at the time of diagnosis based on other blood examination results.
In humans, multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the CNS typically presenting in either a relapsing-remitting or progressive form.24,25 MUO shares clinical26 and pathological features27,28 with MS and appears to be comparable to the progressive clinical form of the disease. CRP levels have been studied as a potential biomarker of MS. Some studies29,30 support a high concentration of CRP in serum of individuals affected by MS compared to healthy individuals. Similarly, during clinical relapses with the expression of specific signs, CRP concentration in serum may be higher than in individuals in remission.31,32 In our cohort of MUO dogs, the association between the duration of clinical signs and an increase in blood CRP at the time of diagnosis could potentially reflect a variable progression of the disease. Possibly, some owners of dogs with increased blood CRP opted to seek the neurology department because their dog exhibited more severe acute signs, occurring in the context of a chronic progression with subtle signs, reminiscent of clinical relapse observed in humans with MS. To support this hypothesis, it would have been informative to have a blood CRP value from a few weeks before the presentation. However, none of the included dogs with increased CRP at the time of diagnosis had this assay performed, due to the prospective nature of the study. Nevertheless, there is a lack of consistent findings in the utility of CRP as a reliable biomarker in MS.33 Based on our results, blood CRP doesn’t represent a promising diagnostic biomarker of MUO in dogs. Furthermore, the analysis does not indicate any predictive power in survival at 6 months for concentration of CRP in blood and CSF. Neutrophil-to-lymphocyte ratio tends to be a better biomarker of MS activity.33 This ratio has also been studied in dogs with MUO34 and seems to be an interesting diagnosing biomarker. A cutoff of 4.16 has a sensitivity of 71.1% and a specificity of 83.9% to differentiate MUO dogs from the dogs with other forebrain diseases. The median value of the neutrophil-to-lymphocyte ratio in our MUO dogs approximates this cutoff value. However, no correlation between this ratio and the elevation of blood CRP was demonstrated in our study.
Several other possible reasons remain to explain CRP increase in 30% of dogs with MUO. First, despite the absence of clinical signs suggestive of respiratory, digestive, or urinary disorders being an inclusion criterion, we could not have excluded the presence of a subclinical condition that might have influenced blood CRP value. Second, even though no infectious agent was identified in the pathophysiology of MUO,35,36 increased blood CRP in dogs with acute clinical signs could potentially be the result of a recent systemic inflammation that might have contributed to the onset of this immune-mediated disease. Finally, since histopathological analysis was not conducted in all cases, it could not have been ruled out that cases of other encephalopathies might have been included.
The median value of CRP concentration in CSF of MUO dogs is 0.1 mg/L, with only 10% of them showing a clear distinguishable value. CRP is traditionally known as an acute-phase protein produced in the liver, but a local production by CNS-resident cells like astrocytes or neurons has been demonstrated in humans affected by Alzheimer disease.37,38 Given that all dogs with measurable CRP levels in the CSF also exhibited increased blood CRP levels, it is more likely that the observed CRP in the CSF originates from the liver, potentially crossing the altered blood-brain barrier, or due to slight blood contamination. Detectable CSF CRP concentration is reported in 82% to 100% of dogs with SRMA with a value not exceeding 9.1 to 13.6 mg/L, depending on studies.23,39 A CSF CRP value was detected in our SRMA group, which was moderately lower than in the 2 other studies.
While MRI abnormalities detected in MUO cases can vary in terms of location, weighting features, and enhancement, none of the studied criteria were associated with an increased CRP concentration in blood. In humans, the same results are observed in MS with MRI analysis at the time of diagnosis and during the disease progression.31,40
One of the limitations of this study was the relatively small number of cases included in the MUO group, which is partially explained by stringent inclusion criteria. The absence of influence of glucocorticoid treatment on blood production of CRP is demonstrated in healthy dogs,41 a situation not comparable to the dogs included in this study, as they suffered from an immune-mediated neurological disorder. It also seems that glucocorticoid treatment does not affect CRP levels at the time of SRMA diagnosis,23 but no treatment duration before CRP measurement is reported in this study. Therefore, cases previously treated with glucocorticoids within 3 weeks were not included to mitigate this potential confounding factor. Additionally, a moderate number of cases could not be included due to the inability to measure CRP in CSF because of insufficient quantity or unsuccessful tap. Finally, strict inclusion criteria reinforced the suspicion of MUO. However, dogs in which CSF analysis is unremarkable, potentially accounting for up to 25.9% of cases, or dogs with MRI missing as many as 40% of lesions, were not included.26,42 The use of the immunoturbidimetric technique represents a limitation, as it was not specifically validated for CSF as the assay medium. Variability in results in CSF due to the technique should be considered. Therefore, no statistical analysis regarding CRP in the CSF was conducted to prevent misinterpretation of statistical differences that could be related to the measurement method. Nevertheless, results obtained in the SRMA group were consistent with results obtained in previous studies using the same laboratory technique12 or ELISA.23 Thus, all dogs with MUO that had measurable CRP in the CSF had an increased blood CRP. This result supported that the assay can measure CRP in CSF when its concentration is high enough by an altered blood-CSF barrier or slight blood contamination. The time-resolved immunofluorometric assay, which was validated in CSF,43 was not used because it was not commercially available according to the authors’ knowledge. Further studies would be necessary to validate the immunoturbidimetric technique in CSF and to compare the agreement between the 2 techniques. Another limitation is the absence of a healthy population for CSF CRP measurement, which is linked to the fact that the dog cohort exclusively comprises privately owned dogs, and no unnecessary procedures were performed on healthy dogs. Lastly, not all dogs received the same treatment following MUO diagnosis, although a combination of cytosine arabinoside and corticosteroids was used in a large majority. The lack of treatment homogeneity could have potentially influenced the survival rate.
In summary, CRP concentration in blood of dogs with MUO was mostly within normal range and might be increased, with a higher probability in patients exhibiting chronic clinical signs. No other epidemiological, clinical, MRI, or CSF features appeared to be associated with an increase in blood CRP concentration. CRP measured in CSF with Randox cCRP assay provides limited information and seemed to be consecutive to a small quantity of protein crossing the blood-CSF barrier from the blood. Lastly, blood CRP concentration was not predictive of outcome in MUO patients in our study.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to disclose.
References
- 1.↑
Gonçalves R, De Decker S, Walmsley G, Butterfield S, Maddox TW. Inflammatory disease affecting the central nervous system in dogs: a retrospective study in England (2010-2019). Front Vet Sci. 2022;8:819945. doi:10.3389/fvets.2021.819945
- 2.↑
Talarico LR, Schatzberg SJ. Idiopathic granulomatous and necrotising inflammatory disorders of the canine central nervous system: a review and future perspectives. J Small Anim Pract. 2010;51(3):138-149. doi:10.1111/j.1748-5827.2009.00823.x
- 3.↑
Flegel T, Oevermann A, Oechtering G, Matiasek K. Diagnostic yield and adverse effects of MRI-guided free-hand brain biopsies through a mini-burr hole in dogs with encephalitis. J Vet Intern Med. 2012;26(4):969-976. doi:10.1111/j.1939-1676.2012.00961.x
- 4.↑
Granger N, Smith PM, Jeffery ND. Clinical findings and treatment of non-infectious meningoencephalomyelitis in dogs: a systematic review of 457 published cases from 1962 to 2008. Vet J. 2010;184(3):290-297. doi:10.1016/j.tvjl.2009.03.031
- 5.↑
Andersen-Ranberg E, Berendt M, Gredal H. Biomarkers of non-infectious inflammatory CNS diseases in dogs—where are we now? part I: meningoencephalitis of unknown origin. Vet J. 2021;273:105678. doi:10.1016/j.tvjl.2021.105678
- 6.↑
Flegel T. Breed-specific magnetic resonance imaging characteristics of necrotizing encephalitis in dogs. Front Vet Sci. 2017;4:203. doi:10.3389/fvets.2017.00203
- 7.↑
Lowrie M, Thomson S, Smith P, Garosi L. Effect of a constant rate infusion of cytosine arabinoside on mortality in dogs with meningoencephalitis of unknown origin. Vet J. 2016;213:1-5. doi:10.1016/j.tvjl.2016.03.026
- 8.↑
Cornelis I, Volk HA, Van Ham L, De Decker S. Prognostic factors for 1-week survival in dogs diagnosed with meningoencephalitis of unknown aetiology. Vet J. 2016;214:91-95. doi:10.1016/j.tvjl.2016.05.008
- 9.↑
Lawn RW, Harcourt-Brown TR. Risk factors for early death or euthanasia within 100 days of diagnosis in dogs with meningoencephalitis of unknown origin. Vet J. 2022;287:105884. doi:10.1016/j.tvjl.2022.105884
- 10.↑
Prümmer JK, Stein VM, Marti E, et al. Assessment of oligoclonal bands in cerebrospinal fluid and serum of dogs with meningoencephalitis of unknown origin. PLoS One. 2023;18(1):e0280864. doi:10.1371/journal.pone.0280864
- 11.↑
Malin K, Witkowska-Piłaszewicz O. C-reactive protein as a diagnostic marker in dogs: a review. Animals (Basel). 2022;12(20):2888. doi:10.3390/ani12202888
- 12.↑
Lowrie M, Penderis J, Eckersall PD, McLaughlin M, Mellor D, Anderson TJ. The role of acute phase proteins in diagnosis and management of steroid-responsive meningitis arteritis in dogs. Vet J. 2009;182(1):125-130. doi:10.1016/j.tvjl.2008.05.001
- 13.↑
Andersen-Ranberg E, Berendt M, Gredal H. Biomarkers of non-infectious inflammatory CNS diseases in dogs: where are we now? Part 2—steroid responsive meningitis-arteritis. Vet J. 2021;273:105692. doi:10.1016/j.tvjl.2021.105692
- 14.
Indzhova V, Czopowicz M, Kilpatrick S, Gutierrez-Quintana R, Brocal J. Signalment and C-reactive protein values in dogs with immune-mediated polyarthritis and steroid responsive meningitis arteritis. Front Vet Sci. 2023;10:1091318. doi:10.3389/fvets.2023.1091318
- 15.↑
de la Fuente C, Monreal L, Cerón J, Pastor J, Viu J, Añor S. Fibrinolytic activity in cerebrospinal fluid of dogs with different neurological disorders. J Vet Intern Med. 2012;26(6):1365-1373. doi:10.1111/j.1939-1676.2012.00991.x
- 16.↑
Nye G, Liebel FX, Harcourt-Brown T. C-reactive protein in dogs with suspected bacterial diskospondylitis: 16 cases (2010-2019). Vet Rec Open. 2020;7(1):e000386. doi:10.1136/vetreco-2019-000386
- 17.↑
Trub SA, Bush WW, Paek M, Cuff DE. Use of C-reactive protein concentration in evaluation of diskospondylitis in dogs. J Vet Intern Med. 2021;35(1):209-216. doi:10.1111/jvim.15981
- 18.↑
Rawson F, Foreman M, Mignan T, Galer J, Fraser A, Crawford A. Clinical presentation, treatment, and outcome of 24 dogs with bacterial meningitis or meningoencephalitis without empyema (2010-2020). J Vet Intern Med. 2023;37(1):223-229. doi:10.1111/jvim.16605
- 19.↑
Kuribayashi T, Shimada T, Matsumoto M, et al. Determination of serum C-reactive protein (CRP) in healthy Beagle dogs of various ages and pregnant Beagle dogs. Exp Anim. 2003;52(5):387-390. doi:10.1538/expanim.52.387
- 20.↑
Wong VM, Kidney BA, Snead EC, Myers SL, Jackson ML. Serum C-reactive protein concentrations in healthy Miniature Schnauzer dogs. Vet Clin Pathol. 2011;40(3):380-383. doi:10.1111/j.1939-165X.2011.00336.x
- 21.↑
Klenner S, Bauer N, Moritz A. Evaluation of three automated human immunoturbidimetric assays for the detection of C-reactive protein in dogs. J Vet Diagn Invest. 2010;22(4):544-552. doi:10.1177/104063871002200408
- 22.↑
Safari S, Baratloo A, Elfil M, Negida A. Evidence based emergency medicine, part 5: receiver operating curve and area under the curve. Emerg (Tehran). 2016;4(2):111-113.
- 23.↑
Bathen-Noethen A, Carlson R, Menzel D, Mischke R, Tipold A. Concentrations of acute-phase proteins in dogs with steroid responsive meningitis-arteritis. J Vet Intern Med. 2008;22(5):1149-1156. doi:10.1111/j.1939-1676.2008.0164.x
- 24.↑
Dobson R, Giovannoni G. Multiple sclerosis - a review. Eur J Neurol. 2019;26(1):27-40. doi:10.1111/ene.13819
- 25.↑
Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43. doi:10.1038/s41572-018-0041-4
- 26.↑
Jeffery N, Granger N. New insights into the treatment of meningoencephalomyelitis of unknown origin since 2009: a review of 671 cases. Front Vet Sci. 2023;10:1114798. doi:10.3389/fvets.2023.1114798
- 27.↑
Church ME, Ceja G, McGeehan M, et al. Meningeal B cell clusters correlate with submeningeal pathology in a natural model of multiple sclerosis. J Immunol. 2021;207(1):44-54. doi:10.4049/jimmunol.2000514
- 28.↑
Greer KA, Wong AK, Liu H, et al. Necrotizing meningoencephalitis of Pug dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis. Tissue Antigens. 2010;76(2):110-118. doi:10.1111/j.1399-0039.2010.01484.x
- 29.↑
Hossain MJ, Morandi E, Tanasescu R, et al. The soluble form of toll-like receptor 2 is elevated in serum of multiple sclerosis patients: a novel potential disease biomarker. Front Immunol. 2018;9:457. doi:10.3389/fimmu.2018.00457
- 30.↑
Farrokhi M, Jahanbani-Ardakani H, Eskandari N, Shaygannejad V, Ghafari S. Cerebrospinal fluid and serum markers of inflammation in patients with multiple sclerosis. Adv Neuroimmune Biol. 2017;6(3-4):149-152. doi:10.3233/nib-170121
- 31.↑
Nazeri M, Bazrafshan H, Abolhasani Foroughi A. Serum inflammatory markers in patients with multiple sclerosis and their association with clinical manifestations and MRI findings. Acta Neurol Belg. 2022;122(5):1187-1193. doi:10.1007/s13760-021-01647-9
- 32.↑
Soilu-Hänninen M, Koskinen JO, Laaksonen M, Hänninen A, Lilius EM, Waris M. High sensitivity measurement of CRP and disease progression in multiple sclerosis. Neurology. 2005;65(1):153-155. doi:10.1212/01.wnl.0000167129.90918.f5
- 33.↑
Olsson A, Gustavsen S, Gisselø Lauridsen K, et al. Neutrophil-to-lymphocyte ratio and CRP as biomarkers in multiple sclerosis: a systematic review. Acta Neurol Scand. 2021;143(6):577-586. doi:10.1111/ane.13401
- 34.↑
Park J, Lee D, Yun T, et al. Evaluation of the blood neutrophil-to-lymphocyte ratio as a biomarker for meningoencephalitis of unknown etiology in dogs. J Vet Intern Med. 2022;36(5):1719-1725. doi:10.1111/jvim.16512
- 35.↑
Nessler JN, Jo WK, Osterhaus ADME, Ludlow M, Tipold A. Canine meningoencephalitis of unknown origin—the search for infectious agents in the cerebrospinal fluid via deep sequencing. Front Vet Sci. 2021;8:645517. doi:10.3389/fvets.2021.645517
- 36.↑
Hoon-Hanks LL, McGrath S, Tyler KL, Owen C, Stenglein MD. Metagenomic investigation of idiopathic meningoencephalomyelitis in dogs. J Vet Intern Med. 2018;32(1):324-330. doi:10.1111/jvim.14877
- 37.↑
Mulder SD, Hack CE, van der Flier WM, Scheltens P, Blankenstein MA, Veerhuis R. Evaluation of intrathecal serum amyloid P (SAP) and C-reactive protein (CRP) synthesis in Alzheimer’s disease with the use of index values. J Alzheimers Dis. 2010;22(4):1073-1079. doi:10.3233/JAD-2010-100888
- 38.↑
Yasojima K, Schwab C, McGeer EG, McGeer PL. Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer’s disease. Brain Res. 2000;887(1):80-89. doi:10.1016/S0006-8993(00)02970-X
- 39.↑
Lowrie M, Penderis J, McLaughlin M, Eckersall PD, Anderson TJ. Steroid responsive meningitis-arteritis: a prospective study of potential disease markers, prednisolone treatment, and long-term outcome in 20 dogs (2006-2008). J Vet Intern Med. 2009;23(4):862-870. doi:10.1111/j.1939-1676.2009.0337.x
- 40.↑
Giovannoni G, Miller DH, Losseff NA, et al. Serum inflammatory markers and clinical/MRI markers of disease progression in multiple sclerosis. J Neurol. 2001;248(6):487-495. doi:10.1007/s004150170158
- 41.↑
Martínez-Subiela S, Ginel PJ, Cerón JJ. Effects of different glucocorticoid treatments on serum acute phase proteins in dogs. Vet Rec. 2004;154(26):814-817. doi:10.1136/vr.154.26.814
- 42.↑
Suñol A, Garcia-Pertierra S, Faller KME. Cerebrospinal fluid analysis in dogs: main patterns and prevalence of albuminocytological dissociation. Vet Rec. 2021;188(5):e27. doi:10.1002/vetr.27
- 43.↑
Martínez-Subiela S, Caldin M, Parra MD, et al. Canine C-reactive protein measurements in cerebrospinal fluid by a time-resolved immunofluorimetric assay. J Vet Diagn Invest. 2011;23(1):63-67. doi:10.1177/104063871102300109
