Pif Tratamiento Neurologico
Pif Tratamiento Neurologico
Pif Tratamiento Neurologico
DOI: 10.1111/jvim.15780
CASE REPORT
1
Department of Surgical and Radiological
Sciences, School of Veterinary Medicine, Abstract
Davis, California, USA Feline infectious peritonitis (FIP) is caused by a mutant biotype of the feline enteric coro-
2
Veterinary Medical Teaching Hospital, School
navirus. The resulting FIP virus (FIPV) commonly causes central nervous system (CNS)
of Veterinary Medicine, Davis, California, USA
3
Department of Ophthalmology and Vision and ocular pathology in cases of noneffusive disease. Over 95% of cats with FIP will suc-
Science, University of California-Davis, Davis, cumb to disease in days to months after diagnosis despite a variety of historically used
California, USA
4
treatments. Recently developed antiviral drugs have shown promise in treatment of non-
Department of Pathology, Microbiology and
Immunology, School of Veterinary Medicine, neurological FIP, but data from neurological FIP cases are limited. Four cases of naturally
Davis, California, USA
occurring FIP with CNS involvement were treated with the antiviral nucleoside analogue
5
Center for Companion Animal Health, School
of Veterinary Medicine, Davis, California, USA
GS-441524 (5-10 mg/kg) for at least 12 weeks. Cats were monitored serially with physi-
cal, neurologic, and ophthalmic examinations. One cat had serial magnetic resonance
Correspondence
Peter J. Dickinson, Department of Surgical and
imaging (MRI), cerebrospinal fluid (CSF) analysis (including feline coronavirus [FCoV])
Radiological Sciences, University of California- titers and FCoV reverse transcriptase [RT]-PCR) and serial ocular imaging using Fourier-
Davis, School of Veterinary Medicine, Davis,
CA 95616.
domain optical coherence tomography (FD-OCT) and in vivo confocal microscopy
Email: [email protected] (IVCM). All cats had a positive response to treatment. Three cats are alive off treatment
Funding information
(528, 516, and 354 days after treatment initiation) with normal physical and neurologic
Center for Companion Animal Health (CCAH), examinations. One cat was euthanized 216 days after treatment initiation following
University of California, Davis School of
Veterinary Medicine; SOCK FIP
relapses after primary and secondary treatment. In 1 case, resolution of disease was
defined based on normalization of MRI and CSF findings and resolution of cranial and
caudal segment disease with ocular imaging. Treatment with GS-441524 shows clinical
efficacy and may result in clearance and long-term resolution of neurological FIP.
Dosages required for CNS disease may be higher than those used for nonneurological FIP.
KEYWORDS
Abbreviations: AG, albumin:globulin; CNS, central nervous system; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; FCoV, feline coronavirus; FD-OCT, Fourier-domain
optical coherence tomography; FeLV, feline leukemia virus; FIP, feline infectious peritonitis; FIPV, feline infectious peritonitis virus; FIV, feline immunodeficiency virus; HIV, human
immunedeficiency virus; IFA, indirect immunofluorescence assay; IgG, immunoglobulin G; IgM, immunoglobulin M; IVCM, in vivo confocal microscopy; LM, large mononuclear; MRI, magnetic
resonance imaging; OD, oculus dexter, right eye; OS, oculus sinister, left eye; OU, oculus uterque, both eyes; PLR, pupillary light reflex; RT-PCR, reverse transcriptase polymerase chain reaction;
SM, small mononuclear; TNCC, total nucleated cell count; TP, total protein.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
reference interval, 2.6-3.9 g/dL; globulin, 9.7 g/dL; reference interval, 18.87. Tests for FeLV and FIV were negative. Serum biochemistry
3.0-5.9 g/dL). Tests for FeLV and FIV were negative, and FCoV and CBC abnormalities included a total protein concentration of
antibody titer was positive at 1:6400. Abdominal ultrasound exami- 8.5 g/dL (reference interval, 6.6-8.4 g/dL), an AG ratio of 0.37
nation showed hepatosplenomegaly, small kidneys with indistinct (albumin, 2.3 g/dL; reference interval, 2.2-4.6 g/dL; globulin, 6.2 g/
corticomedullary junctions and enlarged mesenteric lymph nodes. dL; reference interval, 2.8-5.4 g/dL), a total bilirubin concentration
The cat was treated with 5 mg/kg GS-441524 SC, once daily for of 0.5 mg/dL (reference interval, 0.0-0.2 mg/dL), anemia (hemato-
15 weeks. After 1 month of treatment, uveitis was improved but still crit, 25.8%; reference interval, 30-50%) and lymphopenia (835/μL;
present, and the cat was ambulatory paraparetic with normal seg- reference interval, 1000-7000/μL). Abdominal ultrasound examina-
mental reflexes. The cat weighed 3.3 kg and the AG ratio was 0.55. tion showed hyperechoic kidneys and retroperitoneal fat, several
After 2 months of treatment, subtle signs of active cranial uveitis enlarged lymph nodes and mild peritoneal effusion. On ophthalmic
were present OD, but there was only moderate improvement in the examination, FD-OCT and IVCM, cranial uveitis was found with
ambulatory paraparesis. Body weight had increased to 3.7 kg and the keratic precipitates and caudal synechiae present OU; ocular hyper-
AG ratio was 0.67. After 15 weeks of treatment, there was minimal tension (25 mmHg OD, 11 mmHg OS) and chorioretinitis also were
evidence of uveitis OD and improvement in the ambulatory para- identified OD (Figure 2). The cat was treated with 5 mg/kg GS-
paresis that had been static for the preceding 4 weeks. The cat 441524 SC, once daily for 4 weeks and with prednisolone acetate
weighed 4.0 kg and AG ratio was 0.76. After cessation of treatment, 1% eye drops OU q8h and dorzolamide 2% eye drops OD q8h for
lethargy, inappetence, and anisocoria recurred within 36 hours. the first 3 weeks of GS-441524 treatment. Activity and mentation
Treatment was reinstituted with 5 mg/kg GS-441524 SC, once daily improved within 24 hours of treatment. After 4 weeks, ophthalmic
and signs resolved within 24 hours. Signs remained static during the disease was markedly improved (Figure 2), but ataxia was still pre-
12 weeks of the second round of treatment, but decreased activity sent, and the cat had lost 0.2 kg body weight (Figure 3). Serum total
recurred again after cessation of treatment. The cat was euthanized protein concentration was still increased (8.6 g/dL) with an
in part because of increased resistance to drug administration. Histo- improved AG ratio of 0.72; lymphopenia and anemia had resolved.
pathological assessment after necropsy showed multifocal chronic Because of the lack of weight gain and continued neurological defi-
nonsuppurative meningitis, encephalomyelitis and ventriculitis, cits, the GS-441524 dosage was increased to 8 mg/kg SC, once
lymphocytic, histiocytic uveitis and choroiditis OU and interstitial daily for an additional 10 weeks (14 weeks in total). The cat also
nephritis. Positive coronavirus immunohistochemical immunoreactiv- was given a 2-week course of prednisolone 1 mg/kg PO q24h.
ity (FIP-V3-70 antibody, Custom Monoclonals International, Sacra- Increased activity and willingness to jump onto elevated surfaces
mento, California) was identified within lesion-associated histiocytes was seen within 24 hours, and 1 week after cessation of GS-
in the brain, kidney, and eye. 441524 treatment, neurological examination was unremarkable
and no active ophthalmic disease was detected. Body weight had
increased to 3 kg and serum total protein concentration was normal
5 | CASE 4 (7.6 g/dL) with an AG ratio of 0.8. Repeat MRI (Figure 1) showed minimal
meningeal contrast enhancement, but ventriculomegaly had increased.
A 7-month-old spayed female domestic shorthair cat adopted from an Repeat CSF RT-PCR for FCoV RNA was negative, and CSF TNCC was
animal shelter presented with a 3-week history of lethargy and inap- decreased from the previous count, but still high at 224/μL. Because of
petence and a 2-week history of ataxia and crouching gait. On neuro- CSF analysis evidence that the infection was still active, GS-441524 dos-
logical examination the cat had an ataxic gait which was worse in the age was further increased to 10 mg/kg SC, once daily for an additional
pelvic limbs. Postural reactions were decreased in the pelvic limbs. 5 weeks (19 weeks in total). The cat remained clinically normal with
Anisocoria (midrange OD, miotic OS) was present with incomplete increased activity over this period and body weight increased to 4.7 kg
PLRs OU. Menace responses, dazzle reflexes, and vision were present (Figure 3). Immediately after cessation of treatment, neurological and
OU. The cat weighted 2.7 kg. Magnetic resonance imaging of the ophthalmologic examinations remained unchanged, and repeat MRI was
brain showed multifocal T2-weighted hyperintensities throughout unremarkable other than persistent ventriculomegaly. Repeat CSF analy-
the parenchyma, most severe in the midbrain and thalamus. sis showed a continued decrease in TNCC (8 cells/μL) and total protein
Postcontrast T1-weighted images showed diffuse thickening and concentration (85 mg/dL), negative RT-PCR for FCoV RNA and a
enhancement of the meninges of the cerebrum and brainstem, with decreased FCoV antibody titer of 1:128. Approximately 8 months after
marked ventriculomegaly (Figure 1). Cerebrospinal fluid collected initiation of treatment, and 3 months after cessation of treatment,
from the cerebellomedullary cistern was xanthochromic with a total MRI was unchanged from the previous imaging other than less
nucleated cell count (TNCC) of 888/μL (reference interval, <3 cells/ severe ventriculomegaly. Cerebrospinal fluid analysis showed a
μL) and a CSF total protein concentration of 1790 mg/dL (reference TNCC of 6 cells/μL, total protein concentration of 52 mg/dL, nega-
interval, <25 mg/dL). Serum and CSF FCoV antibody titers both tive RT-PCR for FCoV RNA and a static FCoV antibody titer of
were positive at >1:20 480 and real-time TaqMan RT-PCR for 1:128. Serum total protein concentration was 7.1 g/dL with an AG
FCoV in CSF was positive with a threshold cycle (Ct) value of ratio of 0.97. On ophthalmic examination, no signs of active
4 DICKINSON ET AL.
F I G U R E 1 Sequential magnetic resonance imaging from Case 4. Rows represent selected postcontrast (gadolinium) T1-weighted transverse
images of the brain acquired in a single imaging sequence. Routine analysis from cerebrospinal fluid analysis at the time of imaging is presented in
white for each imaging time point: TNCC = CSF total nucleated cell count (cells/μL); TP = CSF total protein (mg/dL); N = neutrophils, SM = small
mononuclear, LM = large mononuclear. Characteristic neutrophilic pleocytosis resolved over the course of the treatment. Additional CSF analyses
relating to FCoV detection are presented in yellow for each time point: PCR = FCoV RT-PCR result [positive (+) or negative (−)]; Dilution
ratio = cerebrospinal fluid FCoV antibody titer. Time points and doses of GS-1441524 delivered before imaging time points are described for
each imaging sequence. Initial pronounced meningeal contrast enhancement resolves after GS-144524 treatment and does not recur after
cessation of treatment. Ventriculomegaly that is present after initial response to treatment, resolved slowly on subsequent imaging. Decreasing
abnormalities in CSF analysis findings paralleled decreased abnormalities on MR imaging
DICKINSON ET AL. 5
F I G U R E 2 Sequential multimodal imaging of the cranial and caudal segments from Case 4. At presentation (A, B) predilatation and (G, H)
postdilatation cranial segment photographs showing mild diffuse corneal edema, pigmented keratic precipitates, rubeosis iridis, obscured detail of
the iris because of aqueous flare, and incomplete dilatation OU; dyscoria with incomplete pupillary dilatation because of caudal synechia OS
(H) was also observed. Keratic precipitates were also visualized OS with slit lamp biomicroscopy (V), corneal FD-OCT (M), and IVCM of the
endothelium (X, arrows); increased corneal thickness was also observed with FD-OCT (X). Imaging of the retina and choroid with FD-OCT
revealed cellular infiltrate in the choroid (P, arrow) that was visible as a hyporeflective lesion with infrared photography (S). At 0.8 months after
initiation of GS-441524 treatment, pre- (C,D) and postdilatation (I,J) cranial segment photographs demonstrated clear corneas and cranial
chambers OU, isocoria, decreased rubeosis iridis, and complete pupillary dilatation OS. A marked decrease in pigmented keratic precipitates was
noted with slit lamp biomicroscopy (W), corneal FD-OCT (N), and IVCM of the endothelium (Y, arrow). Normal retinal and choroidal morphology
is observed with FD-OCT (Q) although the hyporeflective lesions remain with infrared imaging (T). At 7.6 months, pre- (E,F) and postdilatation
(K, L) cranial segment photographs demonstrated clear corneas and cranial chambers OU, isocoria, normal iris morphology, and postinflammatory
pigment on the cranial lens capsule OS. Keratic precipitates are absent with corneal FD-OCT (O). With FD-OCT and infrared imaging, thinning of
the dorsal peripheral retina was present (R, arrow) with loss of the normal layering but no cellular infiltrate or retinal separation (U)
6 DICKINSON ET AL.