Use of anti-coronavirus antibody testing of cerebrospinal fluid for diagnosis of feline infectious peritonitis involving the central nervous system in cats

Irene C. Boettcher Clinic of Small Animal Medicine, Ludwig-Maximilians-University, Veterinaerstr. 13, 80539 Munich, Germany

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Tanja Steinberg Clinic of Small Animal Medicine, Ludwig-Maximilians-University, Veterinaerstr. 13, 80539 Munich, Germany

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Kaspar Matiasek Chair of General Pathology and Neuropathology, Institute of Veterinary Pathology, Ludwig-Maximilians-University, Veterinaerstr. 13, 80539 Munich, Germany

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Craig E. Greene Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7371

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Katrin Hartmann Clinic of Small Animal Medicine, Ludwig-Maximilians-University, Veterinaerstr. 13, 80539 Munich, Germany

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Andrea Fischer Clinic of Small Animal Medicine, Ludwig-Maximilians-University, Veterinaerstr. 13, 80539 Munich, Germany

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Abstract

Objective—To assess the use of measuring anti-coronavirus IgG in CSF for the diagnosis of feline infectious peritonitis (FIP) involving the CNS in cats.

Design—Prospective study.

Sample Population—CSF and serum samples from 67 cats.

Procedures—CSF and serum samples were allocated into 4 groups: cats with FIP involving the CNS (n = 10), cats with FIP not involving the CNS (13), cats with CNS disorders caused by diseases other than FIP (29), and cats with diseases other than FIP and not involving the CNS (15). Cerebrospinal fluid was evaluated for concentrations of erythrocytes, leukocytes, and total protein. Anti-coronavirus IgG was measured in CSF and serum by indirect immunofluorescence assay.

Results—CSF IgG (range of titers, 1:32 to 1:4,096) was detected in 12 cats, including 6 cats with neurologic manifestation of FIP, 4 cats with FIP not involving the CNS, and 2 cats with brain tumors. Cerebrospinal fluid IgG was detected only in cats with correspondingly high serum IgG titers (range, 1:4,096 to 1:16,384) and was positively correlated with serum IgG titers (r = 0.652; P < 0.01), but not with any other CSF parameter. Blood contamination of CSF resulted in ≤ 333 erythrocytes/μL in cats with CSF IgG.

Conclusions and Clinical Relevance—The correlation between serum and CSF IgG and the fact that CSF IgG was detected only in strongly seropositive cats suggested that CSF anti-coronavirus IgG was derived from blood. Measurement of anti-coronavirus IgG in CSF was of equivocal clinical use.

Abstract

Objective—To assess the use of measuring anti-coronavirus IgG in CSF for the diagnosis of feline infectious peritonitis (FIP) involving the CNS in cats.

Design—Prospective study.

Sample Population—CSF and serum samples from 67 cats.

Procedures—CSF and serum samples were allocated into 4 groups: cats with FIP involving the CNS (n = 10), cats with FIP not involving the CNS (13), cats with CNS disorders caused by diseases other than FIP (29), and cats with diseases other than FIP and not involving the CNS (15). Cerebrospinal fluid was evaluated for concentrations of erythrocytes, leukocytes, and total protein. Anti-coronavirus IgG was measured in CSF and serum by indirect immunofluorescence assay.

Results—CSF IgG (range of titers, 1:32 to 1:4,096) was detected in 12 cats, including 6 cats with neurologic manifestation of FIP, 4 cats with FIP not involving the CNS, and 2 cats with brain tumors. Cerebrospinal fluid IgG was detected only in cats with correspondingly high serum IgG titers (range, 1:4,096 to 1:16,384) and was positively correlated with serum IgG titers (r = 0.652; P < 0.01), but not with any other CSF parameter. Blood contamination of CSF resulted in ≤ 333 erythrocytes/μL in cats with CSF IgG.

Conclusions and Clinical Relevance—The correlation between serum and CSF IgG and the fact that CSF IgG was detected only in strongly seropositive cats suggested that CSF anti-coronavirus IgG was derived from blood. Measurement of anti-coronavirus IgG in CSF was of equivocal clinical use.

Feline infectious peritonitis is a common cause of neurologic disease in cats.1–3 Manifestation of FIP in the CNS is characterized by a pyogranulomatous meningoencephalitis and meningomyelitis.4–6 A tentative diagnosis of neurologic FIP is often made on the basis of results of a combination of hematologic and serum biochemical findings, CSF analysis, and diagnostic imaging. Definite diagnosis requires detection of intracellular antigen in macrophages in samples obtained from effusions or histologic examination of organ biopsy specimens revealing characteristic perivascular pyogranulomatous inflammatory reactions or immune-mediated vasculitis7–9; however, biopsy specimens may not be available in cats with disease restricted to the CNS.10

In 1 study,11 it had been stated that the measurement of anti-coronavirus antibody titers in the CSF could be used to confirm the CNS manifestation of FIP, and this premise has been subsequently cited by others.12–17 However, this finding was unexpected because the mere presence of anti-coronavirus antibody titers in serum had been found to be of little diagnostic relevance for FIP.9,18 In addition, the former study used a small number of control cats and most cats with FIP not involving the CNS had been experimentally infected.

The purpose of the study reported here was, therefore, to provide additional data to assess the diagnostic use of measuring anti-coronavirus IgG in CSF for the diagnosis of FIP involving the CNS in cats. Special emphasis was placed on a large number of control cats, including cats naturally infected with FIP not involving the CNS, cats with CNS disorders caused by diseases other than FIP, and cats with diseases other than FIP and not involving the CNS.

Materials and Methods

Sample collection—Blood for serum and CSF samples were obtained nonselectively from cats that died or were euthanized at the Clinic of Small Animal Medicine, Ludwig-Maximilians-University of Munich, from 2001 to 2003. Only cats in which an extensive clinical workup and necropsy had been performed were included in the study. Gross and histologic examinations, including examinations of the CNS, were performed at the Department of Pathology and Neuropathology, Ludwig-Maximilians-University of Munich.

Samples from 67 cats were included in the study. Samples were allocated into the following 4 groups: samples from cats with FIP involving the CNS (group 1; n = 10), samples from cats with FIP not involving the CNS (group 2; 13), samples from cats with CNS disorders caused by diseases other than FIP (group 3; 29), and samples from cats with diseases other than FIP and not involving the CNS (group 4; 15).

At necropsy, brain, spinal cord, and samples from all visceral organs were immediately immersed in neutral-buffered 10% formalin. Sections were processed routinely in an automatic tissue processor, embedded in paraffin, sectioned at 5 to 8 μm, and stained with hemalaun-eosin. According to histopathologic appearance, certain samples underwent special neuropathologic staining and immunohistochemical investigation. All sections were placed on 0.1% polylysine–coated slides and were treated with a mounting medium.

Postmortem diagnoses of cats in group 1 were based on characteristic histopathologic features such as pyogranulomatous cell infiltration of leptomeninges, choroid plexuses, ependyma and superficial brain parenchyma, and Arthus-like inflammation of small cerebral blood vessels.4 In cats in group 2, the CNS appeared histopathologically inconspicuous, but pyogranulomatous infiltrates with or without effusion were detected outside the CNS. Postmortem diagnoses of cats in groups 3 and 4 are summarized (Appendices 1 and 2, respectively).

Blood for serum was collected via venous puncture at the time of CSF collection and stored at −20°C for 2 weeks, followed by storage at −70°C. Cerebrospinal fluid was collected aseptically from the cerebellomedullary cistern in all but 1 cat in which a lumbar puncture was performed. Samples were processed within 30 minutes. Erythrocytes and leukocytes in CSF were counted by use of a Fuchs-Rosenthal chamber. Cerebrospinal fluid was centrifuged, and the supernatant was subsequently stored as described for serum. The total protein concentration in CSF was measured by nephelometry with trichloracetic acid. As many as 3 leukocytes/μL and 0.3 g of protein/L in the CSF were considered normal. Similar reference limits have been reported in the literature.19–21

Anti-coronavirus IgG was measured in CSF and serum by use of an indirect immunofluorescence assay.a Feline coronavirus American Type Culture Collection VR-990 FIP virus strain WSU-1 146 was used as antigen and was grown in Crandell-Rees feline kidney cells. An antibody-conjugate consisting of fluorescein-labeled anti-cat IgG from goatsb was used for detection of anti-coronavirus IgG by use of a fluorescence microscope.

Dilutions of samples from cats started at 1:32 in CSF and 1:128 in serum and ended at 1:16,384. The highest dilution in which fluorescence was detectable was considered as the final titer.

Data analysis—Age, breed, and sex; concentrations of erythrocytes, leukocytes, and total protein in CSF; and anti-coronavirus IgG titers in serum and CSF were analyzed for each group. Data were reported as median and range. Differences between groups were assessed by use of 1-way ANOVA and the Scheffé test for age and CSF parameters and by the Kruskal-Wallis test and Mann-Whitney U test for anti-coronavirus IgG antibody titers in CSF and serum. Correlations were calculated by use of the Spearman correlation coefficient. Sensitivity, specificity, PPV, and NPV described the diagnostic use of anti-coronavirus IgG in CSF. Values of P < 0.05 were considered significant.

Results

Cats with FIP (groups 1 and 2) were significantly (P < 0.01) younger than cats with other diseases (groups 3 and 4). The median age of cats in groups 1 and 2 was 1 year (range, 0.3 to 5 years) and 2 years (range, 0.3 to 12 years), respectively, whereas cats in groups 3 and 4 had median ages of 14 years (range, 0.2 to 20 years) and 11 years (range, 0.6 to 19 years), respectively. The age of 2 cats was not known.

There were more male than female cats in groups 1, 2, and 4 (7/10, 9/13, and 9/15 cats, respectively). Fifty-four percent of cats in group 3 were females. Sex of 1 cat was not recorded.

Fifty-seven cats (86%) were domestic shorthair cats. Breeds of remaining cats included Russian Blue, Persian, British Shorthair, Angora cross, Devon Rex, Siamese, and Maine Coon. The proportion of pedigreed cats was highest in group 1 (3/10 cats) and lowest in group 2 (1/13 cats). Three of 28 cats in group 3 and 2 of 15 cats in group 4 were pedigreed cats. Breed of 1 cat in group 3 was not known.

Leukocytes were counted in CSF of 59 cats (Table 1). The highest leukocyte numbers in CSF were detected in cats with neurologic manifestations of FIP (group 1; 1 to 295 leukocytes/μL; median, 28 leukocytes/μL). The difference between this group and all other groups was highly significant (P < 0.01). The leukocyte count in CSF of 2 cats in group 1 was not remarkable.

Table 1—

Median (range) number of erythrocytes and leukocytes and total protein concentration in CSF samples obtained from cats with FIP with (group 1; n = 10) and without (group 2; 13) involvement of the CNS, with CNS disorders caused by diseases other than FIP (group 3; 29), and with diseases other than FIP and not involving the CNS (group 4; 15).

GroupErythrocytes (RBCs/μL)Leukocytes (WBCs/μL)Protein (g/L)
112 (1–330)28 (1–295)0.26 (0.06–10.9)
25 (0–84)0 (0–4)0.08 (0.06–0.21)
335 (0–4,373)4 (0–182)0.24 (0.06–3.45)
43 (0–471)1 (0–2)0.10 (0.06–0.22)

Erythrocytes were counted in CSF samples from 58 cats (Table 1). No significant differences were detected between groups. Most samples (38/58 [65%]) contained < 33 erythrocytes/μL. Erythrocyte numbers in CSF were positively correlated with leukocyte numbers (r = 0.625; P < 0.01) and total protein concentration (r = 0.447; P < 0.01) in CSF. No significant correlation was detected between the number of erythrocytes in CSF and anti-coronavirus IgG titers in CSF. None of the samples with a detectable anti-coronavirus IgG titer in CSF contained > 333 erythrocytes/μL.

The total protein concentration in CSF was measured in 60 samples and was high only in cats with CNS disease (groups 1 and 3; Table 1). In group 1, only 4 of 10 cats had a protein concentration greater than the reference range (0.3 g/L). Statistically, there was no difference between groups.

All cats with neurologic manifestations of FIP (group 1) also had typical extracerebral lesions. Effusions were detected in 4 of 10 cats, whereas the noneffusive form of FIP was detected in the remaining cats (6/10). In each cat in group 1, microscopic inflammatory changes of the CNS appeared in more than 1 location or compartment or both. In particular, meningitis was detected in 9 cats, additional inflammation of the choroid plexuses was detected in 5 cats, additional ventriculitis was detected in 2 cats, and infiltration progressed to the neuroparenchyma in 5 cats. Hydrocephalus of the lateral ventricles and the fourth ventricle was identified in 1 cat. In those cats, infiltrations mainly resembled type B lesions, consisting of demarcated or confluent granulomas with or without a necrotic center.22 These lesions were associated with remarkable inflammation of small veins and venules and had a pyogranulomatous character. Reactive microglia and astrocytes were commonly detected in neuroparenchymal lesions.

Three of 10 cats with histopathologic lesions in the brain (group 1) had no abnormalities on neurologic examination. In those cats, inflammatory lesions in the CNS were graded as mild. In one of those cats, the pathologic process was restricted to the temporal lobe of 1 side. In the remaining 7 cats in group 1, results of neurologic examination localized the lesion to the brainstem (n = 4) because of gait dysfunction, altered proprioception, apathy, central vestibular signs, and cranial nerve deficits or to the forebrain (1) because of generalized seizures. Results of neurologic examination indicated multifocal intracranial disease in 2 cats.

In group 2, 11 of 13 cats had gelatinous serosanguinous exudate within pleural or peritoneal cavities. Histopathologic lesions of serosal surfaces in those cats were consistent with type A lesions consisting of diffuse serosal inflammation with fibrinous exudation, necrosis, perivasculitis, and vasculitis.22 Two other cats had the noneffusive form of FIP with type B–like granuloma formation indicative of delayed-type hypersensitivity.22 Histopathologic examination confirmed or completed the clinical diagnosis of cats in groups 3 and 4 (Appendices 1 and 2).

Anti-coronavirus IgG titers were measured in serum of 63 cats and in the CSF of 67 cats. Thirty-five (56%) cats had measurable serum anti-coronavirus IgG titers. Serum IgG titers ranged from 1:128 to 1:16,384. Anti-coronavirus IgG was detected in CSF samples from 12 (18%) cats. Anti-coronavirus IgG titers in CSF samples ranged from 1:32 to 1:4,096.

Six of the 12 cats with detectable anti-coronavirus IgG in CSF were in group 1 (6/10 cats), 4 cats were in group 2 (4/13), and 2 cats were in group 3 (2/29). In the latter group, brain tumors (meningioma and astrocytoma) were diagnosed. None of the cats in group 4 had measurable anti-coronavirus IgG in CSF. Anti-coronavirus IgG titers in CSF samples from cats in group 1 were significantly (P < 0.05) higher than those in group 3, but there was no significant difference in anti-coronavirus IgG titers between groups 1 and 2.

Six of the 35 seropositive cats were in group 1 (6/9 cats tested), 12 cats were in group 2 (12/12), 11 cats were in group 3 (11/28), and 6 cats were in group 4 (6/14). Serum IgG titers were significantly higher in samples from cats in group 1 (P < 0.05) and group 2 (P < 0.01), compared with samples from cats in groups 3 and 4.

Anti-coronavirus IgG was detected only in CSF samples from seropositive cats. In addition, antibodies were detected only in CSF from cats with high serum IgG titers ranging from 1:4,096 to 1:16,384 (Figure 1).

Figure 1—
Figure 1—

Corresponding pairs of anti-coronavirus antibody titers in CSF and serum from 63 cats obtained for assessment of the diagnostic use of anti-coronavirus antibody testing for detection of FIP. Number in parentheses is the number of cats with the same CSF-serum pair.

Citation: Journal of the American Veterinary Medical Association 230, 2; 10.2460/javma.230.2.199

Anti-coronavirus IgG titers in CSF were positively correlated with serum IgG titers (r = 0.652; P = 0.000), but not with any other CSF parameter.

For all 67 cats, detection of anti-coronavirus IgG in CSF had a sensitivity of 60% and specificity of 90% for diagnosis of the CNS manifestation of FIP. The PPV and NPV were 50% and 93%, respectively. Because in a clinical setting one would perform CSF collection and analysis only in cats with neurologic disease, calculation was repeated for groups 1 and 3. Considering only the 39 cats with CNS alterations (groups 1 and 3), detection of anti-coronavirus IgG in CSF had a sensitivity of 60% and specificity of 93% for the diagnosis of FIP within the CNS. The PPV increased to 75%, and the NPV was 87%.

Discussion

The purpose of the study reported here was to provide additional data to assess the diagnostic use of anti-coronavirus IgG titers in CSF for the diagnosis of FIP involving the CNS in cats. Anti-coronavirus IgG titers in CSF were measured simultaneously with serum IgG titers in 10 cats with neurologic manifestation of FIP and 57 control cats, including cats with FIP not involving the CNS, other diseases involving the CNS, and diseases other than FIP and not involving the CNS. Anti-coronavirus IgG titers were detected in CSF samples from 12 cats. Results of our study, which involved a comprehensive control group, were different from those in another study11 and make recommendations to measure anti-coronavirus antibodies in CSF questionable.

In our investigation, 50% of the measurable anti-coronavirus IgG in CSF was detected in control cats. Anti-coronavirus IgG was detected in CSF samples from 6 of 10 cats with FIP involving the CNS, 4 of 13 cats with FIP not involving the CNS, 2 of 29 cats with CNS diseases other than FIP, and no cats with diseases other than FIP and not involving the CNS (n = 15). No FIP-associated CNS lesions were detected via histologic examination in any control cats.

In general, anti-coronavirus IgG was detected only in CSF of cats with high serum anti-coronavirus IgG titers, and CSF titers were always lower than the corresponding serum antibody titers. Antibody titers in serum and CSF differed by a magnitude of 3 to 9 dilutions in a given cat. Cats with anti-coronavirus IgG in CSF had serum antibody titers ≤1:4,096. A significant (r = 0.652; P = 0.000) correlation between serum and CSF antibody titers was detected. These findings suggest that anti-coronavirus IgG in CSF is not specifically synthesized in the CNS, but that most of the antibodies in CSF are derived from blood. These results are not in agreement with results of 1 study11 and extensively cited12–17 data. In the former study,11 anti-coronavirus antibodies in CSF were detected in 15 of 16 cats with FIP-associated CNS disease and not in any control cats. Additionally, in that study, anti-coronavirus antibodies were detected in CSF of cats with low serum anti-coronavirus antibody titers and there was no correlation between serum and CSF antibody titers. In 2 cats, the anti-coronavirus antibody titer in CSF was equivalent to the serum antibody titer. These findings are indicative of intrathecal production of anti-coronavirus antibodies in cats in which the blood-brain barrier is intact.

The divergent results between our study and the study by Foley et al11 cannot be explained easily and may be attributable to a more diverse and larger control group, as used in our study. The disease status of cats with FIP may have been different in both studies. Factors that influence course and severity of disease include dosage and virulence of the virus and the immune response and physical characteristics of infected cats.4,23 Another explanation for the discrepancy between the 2 studies may be that the low number of cats in each group (affected vs control groups) is not representative for a specific disease in both studies. In addition, in the study by Foley et al,11 control cats had considerably lower serum antibody titers than cats in our study, making comparison difficult. In that study, 5 of the 8 control cats with FIP not involving the CNS had been experimentally infected and had a peracute course with low serum titers (≤1:400) and no measurable CSF antibody titers. The beginning dilution and titration end point of CSF and serum antibody titers were not similar in both studies. One important limitation of the previous study11 suggesting that CSF antibody titers are diagnostically useful for detection of CNS manifestation of FIP in cats is the lack of information on whether the CSF had been assessed for contamination with seropositive blood.

Results of the study reported here suggest that anti-coronavirus IgG in CSF is derived from seropositive blood. Antibodies in CSF can result from seropositive blood contamination during sample collection or leakage into the CSF from an impaired blood-brain barrier or altered CSF flow rate. Results of 1 study24 indicate that contamination of 1 mL of CSF with 0.001 μL of strongly seropositive blood can result in detectable antibodies in the CSF. In the study reported here, blood contamination resulted in ≤333 erythrocytes/L in cats that had measurable anti-coronavirus IgG titers in CSF, and < 33 erythrocytes/L were detected in 50% of all samples. We consider blood contamination as an unlikely cause for the appearance of CSF antibodies in our study because serum IgG titers (1:256, 1:512, and 1:1,024) of the only 3 cats with 467 to 4,373 erythrocytes/μL of CSF did not result in detectable antibody titers in the CSF. In addition, there was no significant correlation between erythrocyte numbers and anti-coronavirus antibody titers in CSF.

In our study, an impaired blood-brain barrier or blood-CSF barrier could have resulted in detection of anti-coronavirus IgG in CSF. The blood-brain barrier in cats with FIP involving the CNS has not been specifically evaluated, but an impaired status is presumed.25 Generally, in infection and inflammation of the CNS, cytokines attract leukocytes and adhesion molecules facilitate leukocyte migration into tissue. Release of metalloproteinases, nitric oxide, and other mediators leads to alterations of the tight junctions, basal membrane, and cerebrovascular endothelium.25–27 In addition to morphologic barrier dysfunction, a reduced CSF flow rate is sufficient to explain increased protein concentrations in CSF without any structural alteration. The influx of proteins from blood follows the laws of diffusion. A reduced CSF flow rate results in higher molecular flux into the CSF, compared with normal CSF flow.28–30

Vasculitis is one of the prominent findings in cats with FIP.12,31 It is caused by initial infiltration of monocytes32 and subsequent deposition of immune complexes and fixation of complement, resulting in a pyogranulomatous inflammatory reaction.32–34 In addition to these morphologic indicators of blood-brain barrier disruption, changes in CSF pressure and flow characteristics caused by inflammatory products are suspected in cats with FIP.5

Considering the pathogenesis of FIP, we postulate that an impaired blood-brain barrier or CSF flow rate influenced our results. The correlation between serum and CSF antibody titers and the fact that serum antibody titers were always higher than CSF antibody titers emphasizes a blood-brain or blood-CSF barrier dysfunction.

Alternatively, increased CSF antibody titers may result from local production of antibodies. Results of the study by Foley et al11 indicate that anti-coronavirus antibodies were produced intrathecally. Locally produced antibodies originate from B-lymphocytes that migrate into the CNS during an inflammatory reaction.35,36 In cats with FIP, migration of B-lymphocytes into the CNS has not yet been determined, but can be assumed because coronavirus antigen11,33,37 and plasma cells with coronavirus-specific antibodies33 have been detected histopathologically in brains of cats with FIP. Additionally, sensitized lymphocytes may also migrate into the CNS and cause a specific immune response without the presence of the infectious agent.38 The appearance of antibodies in the CSF may be part of any systemic immune response. Antibodies in CSF have been detected after parenteral application of ovalbumin,39 in clinically healthy foals born to mares that were seropositive for Sarcocystis neurona,40 and after vaccination of adult horses against S neurona.41 In the study reported here, anti-coronavirus IgG detected in the CSF may have also been produced in the CNS because the CNS may have participated in a systemic immune response. This may explain the detection of CSF antibodies in cats with FIP in which no histologic lesions were detected in the CNS.

In humans, calculation of the specific antibody index has been recommended for evaluation of local synthesis of antibodies in the CNS.42 Use of this method is based on the assumption that a specific immunoglobulin has the same blood-brain barrier permeability as all other immunoglobulins of the same class. The CSF-toserum ratio for a specific antibody is greater than the CSF-to-serum ratio of total IgG in cases of intrathecal production of this specific antibody. Local production is indicated with a specific antibody index > 1.5 (> 4 when titers are given).43,44 Recently, the antibody index has been interpreted as the association between a specific antibody and total IgG in blood and CSF.45 In veterinary medicine, specific antibody indices have been calculated in Toxoplasma gondii infection38,46 and in canine distemper encephalitis,47,48 but it has been determined that even increased specific antibody indices > 1 do not necessarily imply active infection of the CNS.38 The same has been detected in humans with multiple sclerosis, which is associated with a polyspecific immune response in the CNS and with increased specific antibody indices against multiple antigens without the antigen actually being present in the CNS.43,45,49

Histologic examination has been used as the gold standard for confirmation or exclusion of FIP in the CNS. Therefore, 3 cats in which results of neurologic examinations were considered normal were allocated into group 1 because of histopathologic lesions characteristic of FIP in the CNS. In clinical conditions, cats would be allocated into groups according to their clinical signs. Histologic examination was preferred because subclinical lesions could influence CSF parameters. In addition, cats with FIP not involving the CNS may not represent a true control group. Unexpectedly, in 4 of those cats (group 2), anti-coronavirus IgG was detected in low concentrations in CSF. This may result from migration of activated B-lymphocytes into the CNS as part of a systemic immune response without the coronavirus antigen being present in the CNS. However, the presence of small, scattered inflammatory lesions that may not have been detected during histologic examination of the CNS could have resulted in blood-brain barrier dysfunction or specific intrathecal antibody production and cannot be ruled out. Use of immunohistochemistry or PCR assay for confirmation of FIP in mildly affected cats was not performed in our study.

Our study had a few limitations. Cats with FIP involving the CNS should have been compared with control cats with other inflammatory CNS diseases. In control cats with CNS disorders caused by diseases other than FIP (group 3), only 2 cats had CNS inflammation, of which 1 cat had protozoal meningoencephalitis and a meningioma and the other had polioencephalitis. Unfortunately, 1 of those 2 cats was seronegative, and the other had a low serum anti-coronavirus IgG titer. Neither cat had CSF IgG titers. In these cats, we do not know whether a high serum antibody titer would have resulted in CSF antibody titers because of inflammatory changes of the blood-brain barrier. There were only 2 cats with measurable CSF antibody titers in group 3. Those cats had serum anti-coronavirus IgG titers of 1:4,096 and 1:8,192, respectively, and had a meningioma and an astrocytoma. Four other cats in group 3 had serum anti-coronavirus IgG titers between 1:1,024 and 1:2,048, but no antibodies were detected in the CSF. In those cats, histologic changes indicated uremic encephalopathy, cortical and hippocampal necrosis, oculomotor tract degeneration, and an astrocytoma. Astrocytomas are known to have a variable effect on the blood-brain barrier in humans. Astrocytomas with low malignancy have little or no effect on the blood-brain barrier, whereas highly malignant forms lead to disruption.50,51 Blood-brain barrier dysfunction has been described in cats with experimentally induced astrocytomas.52 Similarly, meningiomas can break into the Virchow-Robin space and disrupt the blood-brain barrier.53 Uremic encephalopathy, necrosis, and oculomotor tract degeneration are less likely to be associated with a disrupted blood-brain barrier than brain tumors and inflammatory disease; therefore, the absence of CSF antibodies is not unexpected in those cats.

Results of our study indicated that anti-coronavirus antibodies may be detected in CSF of cats with FIP involving the CNS, but not every cat with CNS manifestation of FIP had measurable CSF antibody titers. Alternatively, measurable anti-coronavirus antibodies were detected in CSF of control cats. Therefore, we conclude that the clinical use of CSF anti-coronavirus antibodies is as equivocal as that determined for serum antibodies.18,54,55 The significant correlation between serum and CSF antibody titers and the fact that CSF antibodies were detected only in cats with high serum antibody titers suggest that CSF antibodies were derived from blood. However, on the basis of results of our study and another study,11 the definite origin of anti-coronavirus antibodies in CSF of cats with FIP remains unknown. Future studies may therefore address the origin of anti-coronavirus antibodies in CSF by measurement of the albumin quotient for the assessment of the blood-brain and blood-CSF barriers and by calculation of the specific antibody index as an indicator of intrathecal antibody production.

ABBREVIATIONS

FIP

Feline infectious peritonitis

PPV

Positive predictive value

NPV

Negative predictive value

a.

Infectious Diseases Laboratory, Department of Medical Microbiology and Parasitology, College of Veterinary Medicine, University of Georgia, Athens, Ga.

b.

ICN FITC goat anti-cat IgG, whole molecule, MP Biomedicals, Cappel, Aurora, Ohio.

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    Munana KR. Head tilt and nystagmus. In:Platt SR, Olby NJ, ed.BSAVA manual of canine and feline neurology. 2nd ed.Quedgeley, UK: British Small Animal Veterinary Association, 2004;155171.

    • Search Google Scholar
    • Export Citation
  • 17.

    Vite CH. Inflammatory diseases of the central nervous system. In:Vite CH, ed.Braund's clinical neurology in small animals: localization, diagnosis and treatment. Ithaca, NY: International Veterinary Information Service, 2005. Available at: www.ivis.org. Accessed Oct 14, 2006.

    • Search Google Scholar
    • Export Citation
  • 18.

    Hirschberger J, Hartmann K, Wilhelm N, et al. Clinical symptoms and diagnosis of feline infectious peritonitis. Tieraerztl Prax 1995;23:9299.

    • Search Google Scholar
    • Export Citation
  • 19.

    Rand JS, Parent J, Jacobs R, et al. Reference intervals for feline cerebrospinal fluid: biochemical and serologic variables, IgG concentration, and electrophoretic fractionation. Am J Vet Res 1990;51:10491054.

    • Search Google Scholar
    • Export Citation
  • 20.

    Rand JS, Parent J, Jacobs R, et al. Reference intervals for feline cerebrospinal fluid: cell counts and cytologic features. Am J Vet Res 1990;51:10441048.

    • Search Google Scholar
    • Export Citation
  • 21.

    Tipold A. Cerebrospinal fluid. In:Vite CH, ed.Braund's clinical neurology in small animals: localization, diagnosis and treatment. Ithaca, NY: International Veterinary Information Service, 2003. Available at: www.ivis.org. Accessed Oct 14, 2006.

    • Search Google Scholar
    • Export Citation
  • 22.

    Berg AL, Ekman K, Belak S, et al. Cellular composition and interferon-γ expression of the local inflammatory response in feline infectious peritonitis (FIP). Vet Microbiol 2005;111:1523.

    • Search Google Scholar
    • Export Citation
  • 23.

    Foley JE, Poland A, Carlson J, et al. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. J Am Vet Med Assoc 1997;210:13131318.

    • Search Google Scholar
    • Export Citation
  • 24.

    Miller MM, Sweeney CR, Russell GE, et al. Effects of blood contamination of cerebrospinal fluid on western blot analysis for detection of antibodies against Sarcocystis neurona and on albumin quotient and immunoglobulin G index in horses. J Am Vet Med Assoc 1999;215:6771.

    • Search Google Scholar
    • Export Citation
  • 25.

    Webb AA, Muir GD. The blood-brain barrier and its role in inflammation. J Vet Intern Med 2000;14:399411.

  • 26.

    Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical interpretation. Neurobiol Dis 2004;16:113.

    • Search Google Scholar
    • Export Citation
  • 27.

    Zameer A, Hoffmann SA. Increased ICAM-1 and VCAM-1 expression in the brains of autoimmune mice. J Neuroimmunol 2003;142:6774.

  • 28.

    Reiber H. Flow rate of cerebrospinal fluid (CSF)—a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci 1994;122:189203.

    • Search Google Scholar
    • Export Citation
  • 29.

    Reiber H. Cerebrospinal fluid physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases. Mult Scler 1998;4:99107.

    • Search Google Scholar
    • Export Citation
  • 30.

    Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci 2003;21:7996.

    • Search Google Scholar
    • Export Citation
  • 31.

    McReynolds C, Macy D. Feline infectious peritonitis. Part I. Etiology and diagnosis. Compend Contin Educ Pract Vet 1997;19:10071014.

  • 32.

    Kipar A, May H, Menger S, et al. Morphologic features and development of granulomatous vasculitis in feline infectious peritonitis. Vet Pathol 2005;42:321330.

    • Search Google Scholar
    • Export Citation
  • 33.

    Kipar A, Bellmann S, Kremendahl J, et al. Cellular composition, coronavirus antigen expression and production of specific antibodies in lesions in feline infectious peritonitis. Vet Immunol Immunopathol 1998;65:243257.

    • Search Google Scholar
    • Export Citation
  • 34.

    Wolfe LG, Griesemer RA. Feline infectious peritonitis: review of gross and histopathologic lesions. J Am Vet Med Assoc 1971;158:987993.

    • Search Google Scholar
    • Export Citation
  • 35.

    Male DK. Immunology of brain endothelium and the blood-brain barrier. In:Bradbury MWB, ed.Physiology and pharmacology of the blood-brain barrier. Berlin: Springer-Verlag Berlin Heidelberg, 1992;397404.

    • Search Google Scholar
    • Export Citation
  • 36.

    Tipold A, Pfister H, Vandevelde M. Determination of the IgG index for the detection of intrathecal immunoglobulin synthesis in dogs using an ELISA. Res Vet Sci 1993;54:4044.

    • Search Google Scholar
    • Export Citation
  • 37.

    Tammer R, Evensen O, Lutz H, et al. Immunohistological demonstration of feline infectious peritonitis virus antigen in paraffin-embedded tissues using feline ascites or murine monoclonal antibodies. Vet Immunol Immunopathol 1995;49:177182.

    • Search Google Scholar
    • Export Citation
  • 38.

    Lappin MR, Chavkin MJ, Munana KR, et al. Feline ocular and cerebrospinal fluid Toxoplasma gondii-specific humoral immune responses following specific and nonspecific immune stimulation. Vet Immunol Immunopathol 1996;55:2331.

    • Search Google Scholar
    • Export Citation
  • 39.

    Furr M. Antigen-specific antibodies in cerebrospinal fluid after intramuscular injection of ovalbumin in horses. J Vet Intern Med 2002;16:588592.

    • Search Google Scholar
    • Export Citation
  • 40.

    Cook AG, Maxwell VB, Donaldson LL, et al. Detection of antibodies against Sarcocystis neurona in cerebrospinal fluid from clinically normal foals. J Am Vet Med Assoc 2002;220:208211.

    • Search Google Scholar
    • Export Citation
  • 41.

    Witonsky S, Morrow JK, Leger C, et al. Sarcocystis neurona-specific immunoglobulin G in the serum and cerebrospinal fluid of horses administered S neurona vaccine. J Vet Intern Med 2004;18:98103.

    • Search Google Scholar
    • Export Citation
  • 42.

    Andiman WA. Organism-specific antibody indices, the cerebro-spinal fluid-immunoglobulin index and other tools: a clinician's guide to the etiologic diagnosis of central nervous system infection. Pediatr Infect Dis J 1991;10:490495.

    • Search Google Scholar
    • Export Citation
  • 43.

    Derfuss T, Hohlfeld R, Meinl E. Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20% of multiple sclerosis patients and might be linked to a polyspecific B-cell response. J Neurol 2005;252:968971.

    • Search Google Scholar
    • Export Citation
  • 44.

    Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem 1991;37:11531160.

    • Search Google Scholar
    • Export Citation
  • 45.

    Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 1998;4:111117.

    • Search Google Scholar
    • Export Citation
  • 46.

    Munana KR, Lappin MR, Powell CC, et al. Sequential measurement of Toxoplasma gondii-specific antibodies in the cerebrospinal fluid of cats with experimentally induced toxoplasmosis. Progr Vet Neurol 1995;6:2731.

    • Search Google Scholar
    • Export Citation
  • 47.

    Johnson GC, Fenner WR, Krakowka S. Production of immunoglobulin G and increased antiviral antibody in cerebrospinal fluid of dogs with delayed-onset canine distemper viral encephalitis. J Neuroimmunol 1988;17:237251.

    • Search Google Scholar
    • Export Citation
  • 48.

    Vandevelde M, Zurbriggen A, Steck A, et al. Studies on the intrathecal humoral immune response in canine distemper encephalitis. J Neuroimmunol 1986;11:4151.

    • Search Google Scholar
    • Export Citation
  • 49.

    Petereit HF, Reske D. Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients—follow-up and clinical implications. Cerebrospinal Fluid Res 2005;2:3. Available at: www.cerebrospinalfluidresearch.com/content/2/1/3. Accessed Oct 14, 2006.

    • Search Google Scholar
    • Export Citation
  • 50.

    Davies DC. Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 2002;200:639646.

  • 51.

    Schneider SW, Ludwig T, Tatenhorst L, et al. Glioblastoma cells release factors that disrupt blood-brain barrier features. Acta Neuropathol 2004;107:272276.

    • Search Google Scholar
    • Export Citation
  • 52.

    Bayens-Simmonds J, Boisvert DP, Castro ME, et al. A feline model for experimental studies of peritumor brain edema. J Neurooncol 1988;6:371378.

    • Search Google Scholar
    • Export Citation
  • 53.

    Moore GJ, Bagley RS, Harrington ML, et al. Intracranial tumors. Vet Clin North Am Small Anim Pract 1996;26:759777.

  • 54.

    Hartmann K. Feline infectious peritonitis. Vet Clin North Am Small Anim Pract 2005;35:3979.

  • 55.

    Sparkes AH, Gruffydd Jones TJ, Harbour DA. An appraisal of the value of laboratory tests in the diagnosis of feline infectious peritonitis. J Am Anim Hosp Assoc 1994;30:345350.

    • Search Google Scholar
    • Export Citation

Appendix 1

Postmortem and histologic diagnoses for 29 cats with CNS disorders caused by diseases other than FIP (group 3) from which CSF samples were obtained for assessment of the diagnostic use of anticoronavirus antibody testing for diagnosis of FIP involving the CNS.

Postmortem diagnosis (No. of cats)Histologic diagnosis (No. of cats)
CNS neoplasia (11)Meningioma (4)
Astrocytoma (3)
CNS manifestation of malignant lymphoma (3)
Metastasis of hemangiosarcoma (1)
Unclassified, FIP excluded (10)Degenerative encephalopathy (2)
Uremic encephalopathy (1)
Neuronal degeneration (1)
Systemic final permeability alteration (1)
Oculomotor tract degeneration (1)
Condensation of vestibular neurons (1)
Hypoxia (1)
Unidentified, contrast enhancement detected during computed tomography (1)
Spongiform degeneration (1)
Necrosis (3)Cortical and hippocampal necrosis (2)
Cortical necrosis (1)
Metabolic (2)Hepatoencephalopathy (2)
Inflammatory (2)Meningitis and polioencephalitis (FIP excluded; 1)
Protozoal encephalitis and meningioma (1)
Neurovascular (1)Subdural bleeding after thromboembolism in spinal cord (1)

Appendix 2

Postmortem and histologic diagnoses for 15 cats with diseases not associated with FIP and not involving the CNS (group 4) from which CSF samples were obtained for assessment of the diagnostic use of anti-coronavirus antibody testing for diagnosis of FIP involving the CNS.

Postmortem diagnosis (No. of cats)Histologic diagnosis (No. of cats)
Neoplasia (7)Malignant lymphoma (3)
Adenocarcinoma (3)
Squamous cell carcinoma (1)
Cardiomyopathy (3)Restrictive cardiomyopathy (2), not performed (1)
Hepatopathy (1)Liver cirrhosis (1)*
Enteropathy (1)Catarrhal enteritis (1)
Inflammatory (1)Pyometra and peritonitis (1)
Endoparasitosis (1)Lung worms (1)
Unclassified, FIP excluded (1)Chronic myeloproliferative disease of bone marrow (1)

Esophageal malignant lymphoma was an incidental finding at necropsy.

  • Figure 1—

    Corresponding pairs of anti-coronavirus antibody titers in CSF and serum from 63 cats obtained for assessment of the diagnostic use of anti-coronavirus antibody testing for detection of FIP. Number in parentheses is the number of cats with the same CSF-serum pair.

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    Munana KR. Head tilt and nystagmus. In:Platt SR, Olby NJ, ed.BSAVA manual of canine and feline neurology. 2nd ed.Quedgeley, UK: British Small Animal Veterinary Association, 2004;155171.

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    • Export Citation
  • 17.

    Vite CH. Inflammatory diseases of the central nervous system. In:Vite CH, ed.Braund's clinical neurology in small animals: localization, diagnosis and treatment. Ithaca, NY: International Veterinary Information Service, 2005. Available at: www.ivis.org. Accessed Oct 14, 2006.

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    • Export Citation
  • 18.

    Hirschberger J, Hartmann K, Wilhelm N, et al. Clinical symptoms and diagnosis of feline infectious peritonitis. Tieraerztl Prax 1995;23:9299.

    • Search Google Scholar
    • Export Citation
  • 19.

    Rand JS, Parent J, Jacobs R, et al. Reference intervals for feline cerebrospinal fluid: biochemical and serologic variables, IgG concentration, and electrophoretic fractionation. Am J Vet Res 1990;51:10491054.

    • Search Google Scholar
    • Export Citation
  • 20.

    Rand JS, Parent J, Jacobs R, et al. Reference intervals for feline cerebrospinal fluid: cell counts and cytologic features. Am J Vet Res 1990;51:10441048.

    • Search Google Scholar
    • Export Citation
  • 21.

    Tipold A. Cerebrospinal fluid. In:Vite CH, ed.Braund's clinical neurology in small animals: localization, diagnosis and treatment. Ithaca, NY: International Veterinary Information Service, 2003. Available at: www.ivis.org. Accessed Oct 14, 2006.

    • Search Google Scholar
    • Export Citation
  • 22.

    Berg AL, Ekman K, Belak S, et al. Cellular composition and interferon-γ expression of the local inflammatory response in feline infectious peritonitis (FIP). Vet Microbiol 2005;111:1523.

    • Search Google Scholar
    • Export Citation
  • 23.

    Foley JE, Poland A, Carlson J, et al. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. J Am Vet Med Assoc 1997;210:13131318.

    • Search Google Scholar
    • Export Citation
  • 24.

    Miller MM, Sweeney CR, Russell GE, et al. Effects of blood contamination of cerebrospinal fluid on western blot analysis for detection of antibodies against Sarcocystis neurona and on albumin quotient and immunoglobulin G index in horses. J Am Vet Med Assoc 1999;215:6771.

    • Search Google Scholar
    • Export Citation
  • 25.

    Webb AA, Muir GD. The blood-brain barrier and its role in inflammation. J Vet Intern Med 2000;14:399411.

  • 26.

    Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical interpretation. Neurobiol Dis 2004;16:113.

    • Search Google Scholar
    • Export Citation
  • 27.

    Zameer A, Hoffmann SA. Increased ICAM-1 and VCAM-1 expression in the brains of autoimmune mice. J Neuroimmunol 2003;142:6774.

  • 28.

    Reiber H. Flow rate of cerebrospinal fluid (CSF)—a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci 1994;122:189203.

    • Search Google Scholar
    • Export Citation
  • 29.

    Reiber H. Cerebrospinal fluid physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases. Mult Scler 1998;4:99107.

    • Search Google Scholar
    • Export Citation
  • 30.

    Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci 2003;21:7996.

    • Search Google Scholar
    • Export Citation
  • 31.

    McReynolds C, Macy D. Feline infectious peritonitis. Part I. Etiology and diagnosis. Compend Contin Educ Pract Vet 1997;19:10071014.

  • 32.

    Kipar A, May H, Menger S, et al. Morphologic features and development of granulomatous vasculitis in feline infectious peritonitis. Vet Pathol 2005;42:321330.

    • Search Google Scholar
    • Export Citation
  • 33.

    Kipar A, Bellmann S, Kremendahl J, et al. Cellular composition, coronavirus antigen expression and production of specific antibodies in lesions in feline infectious peritonitis. Vet Immunol Immunopathol 1998;65:243257.

    • Search Google Scholar
    • Export Citation
  • 34.

    Wolfe LG, Griesemer RA. Feline infectious peritonitis: review of gross and histopathologic lesions. J Am Vet Med Assoc 1971;158:987993.

    • Search Google Scholar
    • Export Citation
  • 35.

    Male DK. Immunology of brain endothelium and the blood-brain barrier. In:Bradbury MWB, ed.Physiology and pharmacology of the blood-brain barrier. Berlin: Springer-Verlag Berlin Heidelberg, 1992;397404.

    • Search Google Scholar
    • Export Citation
  • 36.

    Tipold A, Pfister H, Vandevelde M. Determination of the IgG index for the detection of intrathecal immunoglobulin synthesis in dogs using an ELISA. Res Vet Sci 1993;54:4044.

    • Search Google Scholar
    • Export Citation
  • 37.

    Tammer R, Evensen O, Lutz H, et al. Immunohistological demonstration of feline infectious peritonitis virus antigen in paraffin-embedded tissues using feline ascites or murine monoclonal antibodies. Vet Immunol Immunopathol 1995;49:177182.

    • Search Google Scholar
    • Export Citation
  • 38.

    Lappin MR, Chavkin MJ, Munana KR, et al. Feline ocular and cerebrospinal fluid Toxoplasma gondii-specific humoral immune responses following specific and nonspecific immune stimulation. Vet Immunol Immunopathol 1996;55:2331.

    • Search Google Scholar
    • Export Citation
  • 39.

    Furr M. Antigen-specific antibodies in cerebrospinal fluid after intramuscular injection of ovalbumin in horses. J Vet Intern Med 2002;16:588592.

    • Search Google Scholar
    • Export Citation
  • 40.

    Cook AG, Maxwell VB, Donaldson LL, et al. Detection of antibodies against Sarcocystis neurona in cerebrospinal fluid from clinically normal foals. J Am Vet Med Assoc 2002;220:208211.

    • Search Google Scholar
    • Export Citation
  • 41.

    Witonsky S, Morrow JK, Leger C, et al. Sarcocystis neurona-specific immunoglobulin G in the serum and cerebrospinal fluid of horses administered S neurona vaccine. J Vet Intern Med 2004;18:98103.

    • Search Google Scholar
    • Export Citation
  • 42.

    Andiman WA. Organism-specific antibody indices, the cerebro-spinal fluid-immunoglobulin index and other tools: a clinician's guide to the etiologic diagnosis of central nervous system infection. Pediatr Infect Dis J 1991;10:490495.

    • Search Google Scholar
    • Export Citation
  • 43.

    Derfuss T, Hohlfeld R, Meinl E. Intrathecal antibody (IgG) production against human herpesvirus type 6 occurs in about 20% of multiple sclerosis patients and might be linked to a polyspecific B-cell response. J Neurol 2005;252:968971.

    • Search Google Scholar
    • Export Citation
  • 44.

    Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. Clin Chem 1991;37:11531160.

    • Search Google Scholar
    • Export Citation
  • 45.

    Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 1998;4:111117.

    • Search Google Scholar
    • Export Citation
  • 46.

    Munana KR, Lappin MR, Powell CC, et al. Sequential measurement of Toxoplasma gondii-specific antibodies in the cerebrospinal fluid of cats with experimentally induced toxoplasmosis. Progr Vet Neurol 1995;6:2731.

    • Search Google Scholar
    • Export Citation
  • 47.

    Johnson GC, Fenner WR, Krakowka S. Production of immunoglobulin G and increased antiviral antibody in cerebrospinal fluid of dogs with delayed-onset canine distemper viral encephalitis. J Neuroimmunol 1988;17:237251.

    • Search Google Scholar
    • Export Citation
  • 48.

    Vandevelde M, Zurbriggen A, Steck A, et al. Studies on the intrathecal humoral immune response in canine distemper encephalitis. J Neuroimmunol 1986;11:4151.

    • Search Google Scholar
    • Export Citation
  • 49.

    Petereit HF, Reske D. Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients—follow-up and clinical implications. Cerebrospinal Fluid Res 2005;2:3. Available at: www.cerebrospinalfluidresearch.com/content/2/1/3. Accessed Oct 14, 2006.

    • Search Google Scholar
    • Export Citation
  • 50.

    Davies DC. Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 2002;200:639646.

  • 51.

    Schneider SW, Ludwig T, Tatenhorst L, et al. Glioblastoma cells release factors that disrupt blood-brain barrier features. Acta Neuropathol 2004;107:272276.

    • Search Google Scholar
    • Export Citation
  • 52.

    Bayens-Simmonds J, Boisvert DP, Castro ME, et al. A feline model for experimental studies of peritumor brain edema. J Neurooncol 1988;6:371378.

    • Search Google Scholar
    • Export Citation
  • 53.

    Moore GJ, Bagley RS, Harrington ML, et al. Intracranial tumors. Vet Clin North Am Small Anim Pract 1996;26:759777.

  • 54.

    Hartmann K. Feline infectious peritonitis. Vet Clin North Am Small Anim Pract 2005;35:3979.

  • 55.

    Sparkes AH, Gruffydd Jones TJ, Harbour DA. An appraisal of the value of laboratory tests in the diagnosis of feline infectious peritonitis. J Am Anim Hosp Assoc 1994;30:345350.

    • Search Google Scholar
    • Export Citation

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