Central Nervous System Dysfunction Associated With Rocky Mountain Spotted Fever Infection in Five Dogs
Five dogs from the northeastern United States were presented with clinical signs of neurological disease associated with Rocky Mountain spotted fever (RMSF) infection. Four of the five dogs had vestibular system dysfunction. Other neurological signs included paresis, tremors, and changes in mentation. All of the dogs had an elevated indirect fluorescent antibody titer or a positive semiquantitative enzyme screening immunoassay titer for Rickettsia rickettsii at the time of presentation. Although a higher mortality rate has been reported for dogs with neurological symptoms and RMSF infection, all of the dogs in this study improved with appropriate medical therapy and supportive care.
Introduction
Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii (R. rickettsii). It is transmitted principally by the wood tick (Dermacentor andersoni) in the western United States and the American dog tick (Dermacentor variabilis) in the eastern United States.1 Clinical signs in dogs are variable and may include lethargy, anorexia, fever, hyperesthesia, petechial hemorrhages of the retina and skin, limb edema, and renal, cardiopulmonary, and nervous system dysfunction.2 In general, the prognosis for dogs with RMSF is good following treatment, although fatalities do occur.1 One study in dogs reported a 4% mortality rate; however, dogs with cardiovascular complications, active bleeding, or neurological dysfunction may have a higher mortality rate.1,3
Signs of neurological dysfunction occur in as many as 43% of canine cases of RMSF, and dogs with a high antibody titer at the time of presentation may have a higher incidence of severe neurological disease.3,4 Neurological manifestations of disease in dogs include paraparesis, tetraparesis, vestibular dysfunction, seizures, hyperesthesia, stupor, and coma.5 Of these, vestibular dysfunction may be the most common specific neurological abnormality seen with RMSF infection.3
The purpose of this report is to describe five dogs with neurological dysfunction associated with RMSF that were presented over a 3-year period.
Materials and Methods
The medical records of cases examined between 1993 and 2003 at the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania (VHUP) were searched for dogs with a discharge or necropsy diagnosis of RMSF and neurological signs. Nine cases were identified that met these selection criteria.
Active infection with R. rickettsii in this study was defined by a single high indirect fluorescent antibody (IFA) titer of ≥1:512, by an increase in paired enzyme-linked immunosorbent assay (ELISA) titers performed 10 to 14 days apart, or by an elevation in semiquantitative titers to detect immunoglobulin G (IgG) antibodies to R. rickettsii in serum.a,1,3 Four of the nine original cases failed to meet these criteria, leaving five cases in the study. These five cases were presented to the hospital within a 3-year period (2000 to 2003). The diagnosis of RMSF was further supported by 1) compatible clinical signs; 2) compatible laboratory abnormalities including thrombocytopenia, hypoalbuminemia, and leukocytosis; 3) elevated serum antibodies to R. rickettsii; and 4) response to treatment with doxycycline.
Case Reports
Case No. 1
An 8-month-old, female Yorkshire terrier was presented in August with a 1-week history of listlessness, fever, and abdominal pain that was unresponsive to treatment with amoxicillin/clavulanic acid,b carprofen,c and aminopentamide hydrogen sulfate.d There was no known history of recent tick exposure. Blood work performed by the referring veterinarian 2 days prior to presentation revealed thrombocytopenia (30,000/μL platelets; reference range 170,000 to 400,000/μL), hypoproteinemia (3.8 g/dL, reference range 5.0 to 7.4 g/dL), hypoalbuminemia (1.7 g/dL, reference range 2.7 to 4.4 g/dL), and elevated alkaline phosphatase (ALP) activity (259 U/L, reference range 5 to 131 U/L). Urinalysis revealed a 3+ proteinuria and an elevated urine protein/creatinine ratio of 7.4 (reference range <1.0). Treatment with prednisone (1 mg/kg per os [PO] q 12 hours), azathioprinee (2.2 mg/kg PO q 24 hours), and doxycyclinef (10 mg/kg PO q 24 hours) was initiated 2 days prior to referral. The dog began to vomit, developed neurological signs, and was referred for further diagnostics and treatment.
Physical examination indicated mild dehydration. Laboratory tests revealed thrombocytopenia, leukocytosis, mild anemia, hypoproteinemia, hypoalbuminemia, and elevated ALP activity [Table 1]. A resting blood ammonia level was within normal limits. A complete coagulation profile revealed a normal prothrombin time (PT) of 6.9 seconds (reference range 6.8 to 10.2 seconds) and a prolonged partial thromboplastin time (PTT) of 17.4 seconds (reference range 10.7 to 16.4 seconds). A coagulation profile repeated on the third day of hospitalization was within normal limits.
A neurological examination revealed a tendency to stumble and turn to the right, an intermittent truncal sway, and a 30° right head tilt. A menace response was absent in the left eye. Also noted were a right positional ventral strabismus and a rotary resting nystagmus with a fast phase to the left that became more brisk when the animal was changed to dorsal recumbency [Table 2]. Proprioception was normal in all four limbs, although limb placement and hopping reactions were diminished in the right thoracic and right pelvic limbs. Segmental spinal reflexes were within normal limits, and no pain was elicited on spinal palpation or manipulation. Ocular fundic examination was unremarkable. Neurological examination suggested a right-sided lesion within the caudal fossa.
On the second day of hospitalization, urinalysis revealed a urine specific gravity of 1.021 with a +3 proteinuria. A screening semiquantitative ELISA assay for R. rickettsii was positive (+3). Serum titers for Ehrlichia canis (E. canis), Toxoplasma gondii (T. gondii), and Neospora caninum (N. caninum) were negative. Treatment with doxycycline (5 mg/kg intravenously [IV] q 12 hours) was initiated. By the fourth day of hospitalization, the platelet count had improved to 90,000/μL, and the albumin had increased to 1.9 mg/dL. By the fifth day of hospitalization, the platelet count was within the normal range. The dog was alert and eating and drinking well. The nystagmus had resolved, and a menace response was present in both eyes. A right head tilt and mild ataxia persisted at the time of discharge. The dog was discharged from the hospital after 5 days of hospitalization, and doxycycline (5 mg/kg PO q 12 hours) was continued.
Follow-up examination by the referring veterinarian was performed 2 weeks after discharge. The platelet count (359,000/μL platelets, reference range 170,000 to 400,000/μL) and albumin (3.3 g/dL, reference range 2.7 to 4.4 g/dL) had returned to normal. The urine protein to creatinine ratio was also within normal limits. A serum IFA titer for R. rickettsii was 1:16,384.
Case No. 2
A 3-year-old, castrated male Labrador retriever was presented in May with a 6-day history of lethargy, anorexia, full-body tremors, and an elevated rectal temperature (105.8°F). There was no known history of tick exposure. The referring veterinarian found hookworms and coccidia on fecal examination, and blood work revealed mild thrombocytopenia (132,000/μL platelets, reference range 200,000 to 500,000/μL) and a mild increase in ALP activity (154 U/L, reference range 10 to 150 U/L). Treatment with amoxicillin,g carprofen, pyrantel pamoate,h and sulfadimethoxinei was initiated; but lethargy, anorexia, and weakness worsened, and the dog began to vomit. The dog also developed mental dullness, ataxia, and episodes of head shaking, jaw tremors, stiffness in all four limbs, and moaning that lasted 30 to 60 seconds.
Physical examination at presentation revealed ataxia that progressed to nonambulatory tetraparesis. Treatment with doxycycline (4 mg/kg IV q 12 hours) was initiated. Laboratory abnormalities included thrombocytopenia, leukocytosis, hyponatremia, hypochloremia, hypoproteinemia, hypoalbuminemia, and elevated ALP activity [Table 1]. A coagulation profile was within normal limits.
On the second day of hospitalization, a neurological examination revealed a stuporous, nonambulatory, tetra-paretic dog [Table 2]. A menace response was difficult to elicit in either eye, and both pupils were miotic with intact pupillary light responses. A positional ventral strabismus of the left eye was noted. No resting or positional nystagmus was seen; however, the fast phase of the physiological nystagmus was absent. Jaw tone was markedly increased. Postural reactions were absent. Segmental spinal reflexes were normal in the thoracic limbs and brisk in the pelvic limbs. Muscle tone was increased in all limbs. No pain was elicited on spinal palpation. A complete ocular fundic examination could not be performed, owing to the degree of sedation and miosis. One episode of agitation, characterized by vocalization and a side-to-side weaving motion of the head, was observed during the neurological examination. Intermittent opisthotonus was also noted. Neurological examination suggested a lesion in the caudal fossa. Involvement of the prosencephalon was also suspected.
Urinalysis performed on the second day of hospitalization revealed a urine specific gravity of 1.025 with a +2 proteinuria. A serum IFA titer for R. rickettsii was 1:2560. A serum titer for E. canis was negative.
On the fourth day of hospitalization, the dose of doxycycline was increased to 10 mg/kg IV q 12 hours, and enrofloxacinj was added (10 mg/kg IV q 24 hours). The episodes of flailing and vocalization increased in frequency, and treatment with phenobarbital was initiated (3 mg/kg IV q 12 hours). The dose of phenobarbital was decreased over the next 3 days as the episodes of agitation diminished, and the drug was discontinued on the seventh day. An antiinflammatory dose of dexamethasonek was also initiated on the fourth day of hospitalization (0.1 mg/kg IV q 24 hours) and was discontinued on the sixth day.
On the seventh day of hospitalization, the platelet count improved to 158,000/μL, and the albumin increased to 2.7 mg/dL. Elevations were found in the alanine transferase (ALT; 743 U/L, reference range 16 to 91 U/L), aspartate transferase (AST; 301 U/L, reference range 23 to 65 U/L), and ALP activities (1065 U/L, reference range 24 to 174 U/L). The dose of doxycycline was decreased to 5 mg/kg PO q 12 hours.
On the eighth day of hospitalization, the dog walked with assistance. A good menace response was elicited bilaterally. By the ninth day, the dog ate and drank well, and the platelet count had returned to the normal range. The ALT (1967 U/L) and the ALP activities (4194 U/L) were higher, and the total bilirubin was also elevated (4.5 mg/dL, reference range 0.3 to 0.9 mg/dL). A resting blood ammonia level was within normal limits. Ultrasonography of the liver and gallbladder revealed no abnormalities.
On the 11th day of hospitalization, the dog was discharged. Laboratory assays performed by the referring veterinarian 3 days after discharge revealed persistent elevations in ALP (5730 U/L, reference range 5 to 131 U/L) and ALT (7030 U/L, reference range 12 to 118 U/L), as well as elevated total bilirubin (2.0 mg/dL, reference range 0.1 to 0.3 mg/dL). Repeat testing performed 2 months after discharge revealed normal liver enzymes. At this time, the owners described the dog as slightly uncoordinated and consistently leaning to the right while walking, but otherwise normal in attitude and mentation.
Case No. 3
A 4.5-year-old, spayed female, mixed-breed dog was presented in October with a 7-day history of lethargy, neck and shoulder pain, and reluctance to go up stairs. There was no known history of tick exposure. The dog’s pain increased, despite medication with phenylbutazonel and butorphanol tartrate,m and she became anorexic on the day prior to presentation.
Physical examination at presentation revealed general hyperesthesia on manipulation, bilateral carpal and tarsal edema, petechiation of the skin of the ears and limbs, and bilateral subconjunctival hemorrhages. Initial laboratory tests showed thrombocytopenia, leukocytosis, anemia, hyponatremia, hypoproteinemia, hypoalbuminemia, and elevated ALP activity [Table 1]. Urinalysis revealed a urine specific gravity of 1.037 and +3 proteinuria.
Neurological examination showed a depressed but aggressive animal, with a left head tilt and a tendency to fall and lean to the left. A left ventrolateral strabismus and a resting rotary nystagmus with the fast phase to the right (that changed to vertical with a change in head position) were also seen [Table 2]. Postural reaction deficits of the left thoracic and pelvic limbs were noted. Segmental spinal reflexes were within normal limits, and no pain was elicited on spinal manipulation. Ocular fundic examination was unremarkable. Neurological examination suggested a lesion in the left caudal fossa, with suspected involvement of the prosencephalon as well.
On the second day of hospitalization, a bone marrow aspirate showed an adequately cellular marrow characterized by myeloid hyperplasia and megakaryocytic and erythrocytic hypoplasia. Cerebrospinal fluid (CSF) was collected from the cisterna magna, and analysis revealed elevated total protein and nucleated cell count [Table 3]. A screening R. rickettsii semiquantitative ELISA titer was positive (+3). Serum titers for E. canis and T. gondii were negative. Treatment with doxycycline was initiated at 4 mg/kg IV q 24 hours and was increased to 10 mg/kg PO q 24 hours on the third day. Prednisone was also added to the treatment protocol (0.5 mg/kg PO q 12 hours) on the third day of hospitalization.
On the fifth day of hospitalization, the dog’s platelet count had increased to 142,000/μL. The albumin remained low (1.6 g/dL). A resting nystagmus persisted, but the dog’s ataxia and appetite were improved. The dog was discharged on doxycycline (10 mg/kg PO q 12 hours) and a 10-day tapering course of prednisone.
Reexamination 3 days later revealed decreased proprioception in the right pelvic and right thoracic limbs, and discomfort on palpation of the neck. A residual left head tilt, with an associated left positional ventral strabismus, was present. Cranial nerve responses were otherwise normal. Laboratory tests revealed thrombocytosis (444,000/μL platelets) and a serum albumin of 2.3 g/dL.
Reexamination 10 days after discharge revealed marked improvement in the neurological signs. The semiquantitative R. rickettsii ELISA titer had increased (+4). The dog had also developed ulcerative lesions on the dorsal nasal planum that were presumed to be secondary either to a vasculitis and necrosis from antigen-antibody deposition, or a drug reaction.6 The doxycycline was discontinued, and pentoxifyllineo was initiated at 400 mg PO q 8 hours.
Case No. 4
A 3.5-year-old, spayed female, mixed-breed dog was presented in July with a 7-day history of an abnormal pelvic limb gait that progressed to quadriparesis and signs of vestibular dysfunction on the day prior to presentation. The dog also had an abnormal ocular discharge. Two weeks prior to presentation, the dog was covered with ticks. The ticks were removed by the owner, and the dog was treated with fipronil.p Referring laboratory results showed thrombocytopenia (62,000/μL, reference range 175,000 to 500,000/μL), leukocytosis (28,500/μL, reference range 6000 to 16,900/μL), anemia (hematocrit 28%, reference range 37% to 55%), hypoalbuminemia (2.13 g/dL, reference range 2.7 to 3.8 g/dL), elevated ALP (350 U/L, reference range 23 to 212 U/L), hypercholesterolemia (441.2 mg/dL, reference range 110 to 320 mg/dL), and hyponatremia (138 mmol/L, reference range 144 to 160 mmol/L). Treatment initiated by the referring veterinarian (i.e., prednisone [0.5 mg/kg PO q 12 hours] and doxycycline [4 mg/kg PO q 12 hours]) failed to resolve the clinical signs.
Physical examination at presentation revealed a mild ocular discharge, increased respiratory rate, and an irregular heart rate characterized by occasional bradycardia. Neurological examination revealed profoundly depressed mentation. The dog was nonambulatory with a tendency to roll and tilt the body and head to the left. Occasional tremors of the head, body, and neck were also observed. A positional, left medial, ventral strabismus was present. A resting nystagmus was also present [Table 2]. Postural reactions were absent in all four limbs. Segmental spinal reflexes were normal to increased. Muscle tone was normal to decreased. No spinal pain was elicited. Retinal hemorrhage was evident on fundic examination of the left eye. Neurological examination suggested a lesion in the left caudal fossa.
Laboratory tests revealed thrombocytopenia, leukocytosis, hyponatremia, hypochloremia, hypoproteinemia, hypoalbuminemia, elevated ALP, and hypercholesterolemia [Table 1]. A coagulation profile was within normal limits.
On the second day, treatment with clindamycinq (10 mg/kg IV q 8 hours), doxycycline (12 mg/kg IV q 24 hours), and cefazolinr (20 mg/kg IV q 6 hours) was initiated. Electrocardiography showed a sinus arrhythmia with occasional second-degree atrioventricular block and a variable PR interval (Mobitz type 1). Fluid was collected from the cisterna magna, and CSF analysis revealed elevated total protein and nucleated cell count [Table 3]. Serum titers for T. gondii, E. canis, and N. caninum were negative. A canine distemper virus serum neutralization test performed on the CSF was positive at 1:64. Culture of the CSF yielded no aerobic growth. Cryptococcal latex agglutination performed on the CSF was negative. A semiquantitative R. rickettsii ELISA titer was positive (+4). Electrodiagnostic testing revealed normal nerve conduction velocities of the sciatic, ulnar, and radial nerves; normal F waves; and no decremental response to repetitive stimulation. Fibrillation potentials and positive sharp waves were seen in muscles below the elbow and stifle, which suggested axonal disease affecting the extremities, or localized muscle disease.
On the third day of hospitalization, the platelet count improved to 97,000/μL. The dose of doxycycline was increased (10 mg/kg PO q 12 hours). By the fifth day of hospitalization, the platelet count returned to normal, and the dog was ambulatory with assistance. The bradycardia and the resting nystagmus resolved. The dog was discharged on the sixth day on doxycycline (10 mg/kg PO q 24 hours). On reexamination 9 days later, the head tilt had resolved, and the cranial nerve examination was within normal limits. The dog had a slightly short-stride gait and mild proprioceptive deficits. An IFA titer for R. rickettsii performed at the time of reexamination was positive at 1:512.
Case No. 5
A 15-month-old, spayed female Labrador retriever was presented in July with an 8-day history of lethargy, fever, muscle spasms, intention tremors, difficulty prehending food, difficulty rising, and a behavioral change characterized by disorientation, increased anxiety, and fighting with another dog in the house. One month prior to presentation, the dog was covered with ticks. The clinical signs had progressed despite treatment with amoxicillin (14.3 mg/kg PO q 12 hours) and etodolacs (13 mg/kg PO q 24 hours). Blood work done by the referring veterinarian showed mild thrombocytopenia (147,000/μL platelets, reference range 175,000 to 500,000/μL), but results were otherwise unremarkable.
Neurological examination at presentation revealed a tendency to circle compulsively to the left, and a right hemi-paresis with decreased to absent proprioception in the right thoracic and right pelvic limbs. Menace response was absent on the right side. Segmental spinal reflexes were within normal limits. Fundic examination revealed multifocal, hyper-reflective lesions and small, gray, indistinct lesions in both retinae. Neurological examination suggested a lesion in the left prosencephalon and possible chorioretinitis.
Laboratory tests showed moderate thrombocytopenia, mild anemia, and leukocytosis [Table 1]. Fluid was collected from the cisterna magna, and CSF analysis revealed an elevated total protein and nucleated cell count [Table 3]. Serum titers for T. gondii, E. canis, and N. caninum were negative. A canine distemper virus serum neutralization test performed on the CSF was positive at 1:6. Cryptococcal latex agglutination performed on the CSF was negative. A serum IFA titer for R. rickettsii was positive at 1:20,480. Doxycycline was started (10 mg/kg IV q 24 hours).
On the third day of hospitalization, the platelet count had improved to 142,000/μL. The dog circled less to the left, and the menace response in the right eye had returned. Postural reaction deficits persisted on the right side. On the fifth day of hospitalization, the dog had a normal neurological examination and was discharged on doxycycline (10 mg/kg PO q 24 hours). Recheck examination was performed 2 weeks after discharge, at which time the dog had a normal neurological examination, and the platelet count was normal. The behavioral changes noted by the owner prior to initial presentation were also rapidly improving. A convalescent IFA titer for R. rickettsii was positive at 1:40,960.
Discussion
Neurological dysfunction has been reported in dogs actively infected with R. rickettsii, and tetraparesis or paraparesis with ataxia and vestibular abnormalities have been the most common neurological signs of disease.4,5 In a retrospective study of 30 dogs with RMSF, 20% had signs of vestibular dysfunction, 33% were tetraparetic, and 30% were ataxic.4 Other published reports of RMSF have described vestibular signs and generalized hyperesthesia in dogs.7–9
Neurological dysfunction, including seizures, vestibular signs, and changes in mentation, has also been found in dogs experimentally infected with R. rickettsii.10 In these dogs, postmortem examination revealed acute meningoencephalitis caused by disseminated necrotizing vasculitis.10 Neutrophilic and lymphocytic perivascular accumulations were present, and small, focal glial nodules were noted.10 Necropsies performed on clinical cases showed a vasculitis in multiple organs involving capillaries, arteries, veins, and small venules, and characterized by neutrophilic and mononuclear cell infiltration.7 Focal hemorrhages and malacia in the brain were described secondary to the vasculitis and thrombosis.7 Postmortem examination on one dog with vestibular signs and seizures revealed a severe vasculitis in the cerebrum, thalamus, hippocampus, cerebellum, and medulla.7
The dogs in this case series were ≥4 years of age, which was typical of RMSF in dogs.1 Four of the five cases were presented from May to August, which also was typical.1 All dogs in this case series had laboratory abnormalities commonly associated with RMSF, including thrombocytopenia (n=5), leukocytosis (n=5), anemia (n=4), elevated ALP activity (n=4), hypoalbuminemia (n=5), and hyponatremia (n=3).4 These abnormalities, together with the high initial R. rickettsii titer (or rise in convalescent titer), suggested a diagnosis of active infection with R. rickettsii.1
Signs of vestibular dysfunction, changes in mentation, paresis, ataxia, and tremors were commonly seen in the dogs reported here. Four of the five dogs had evidence of central vestibular disease. Disease of the caudal fossa was suspected based on findings of vestibular dysfunction (e.g., head tilt, nystagmus, strabismus, loss of balance), in addition to other signs of brain stem dysfunction (e.g., depressed mentation, spinal ataxia, and spastic paresis). The remaining dog had a history of intention tremors and difficulty rising that suggested caudal fossa involvement. Vestibular signs may be more common in dogs with RMSF than in humans, because the disease may progress further in dogs before treatment is initiated. In contrast, people generally present for medical treatment with myalgia and headache that are unresponsive to nonprescription analgesic therapy.11 It is also possible that R. rickettsii preferentially affects the vestibular system in dogs as opposed to humans.
Although many of the clinical signs in these five dogs may be explained by inflammation of the brain stem, it was likely that multifocal disease was responsible for the clinical signs in this study. Involvement of the prosencephalon was suspected in three animals based on behavioral changes, inappropriate mentation, and/or inconsistent or absent menace responses. Three of the dogs had tremors of the head and trunk, which may have arisen from involvement of the cerebellum or prosencephalon. Tremors also may have been associated with fever or pain. Cerebellar disease may explain the menace deficit seen in case no. 1, although the side of the menace deficit did not correspond to the side of the head tilt and postural reaction deficits. On the day of presentation, this dog had bilateral menace deficits and a brisk nystagmus with a fast phase to the right, suggesting bilateral disease of the caudal fossa. One dog (case no. 4) had decreased muscle tone and electrophysiological evidence of peripheral axonal disease or muscle disease affecting the extremities. The vasculitis associated with RMSF may preferentially affect the skeletal muscle.10 Unfortunately, no biopsies were taken to further characterize nerve or muscle involvement.
The neurological signs reported here were consistent with previous reports of vestibular dysfunction associated with RMSF.4,5 Unlike previous reports, however, spinal pain and seizures were not features of disease in the dogs reported here.1,4,5 Three dogs in this report (case nos. 2, 4, 5) developed neurological signs (e.g., tremors, ataxia, and behavioral change) concurrent with the onset of systemic signs of illness. This was distinct from previous reports of a 5- to 10-day period of lethargy, anorexia, and fever prior to the development of neurological signs.5,7,12
Pain is a common clinical sign of RMSF in humans, with 92% of humans experiencing headaches (often accompanied by intense myalgia) and 18% experiencing meningismus.11,13 In a retrospective study of 30 dogs with RMSF, myalgia was described in <10%, and hyperesthesia was present in 32% of the dogs.4 The presence and location of pain were difficult to assess in the dogs reported here. A discrete focus of pain was not elicited on spinal, muscle, or bony palpation of any dog, although four animals were depressed or stuporous upon presentation to the hospital. Cardiovascular parameters, sometimes used to evaluate pain in dogs, were generally within normal limits. One dog was diffusely hyperesthetic on manipulation. Two additional dogs had a history of appearing painful to the owner prior to presentation. The remaining two dogs had episodic, full-body tremors that may have indicated pain or discomfort.14
Definitive diagnosis of RMSF in this study was difficult, as all of the dogs survived, and tissue biopsies or necropsies were not performed. Diagnosis was based largely on clinical signs, supportive laboratory abnormalities, elevated serum antibody titers to R. rickettsii, and a positive response to treatment.
Production of IgG antibodies to R. rickettsii occurs within 1 to 3 weeks in exposed individuals; therefore, animals tested early in the course of infection may not have elevated IgG antirickettsial titers. In such cases, a titer should be repeated in 2 to 4 weeks to confirm infection.1 According to some authors, a single high IFA titer >1:512 implies active disease in dogs residing in the eastern United States.1 Other reports have suggested that a single high IFA titer >1:1024 is required to indicate active disease; however, seronegative beagles that developed clinical signs of disease after experimental inoculation with R. rickettsii had peak titers ≥1:160 in one study.3,10 Use of the semiquantitative assay to detect IgG antibodies to R. rickettsii in serum provides a rapid result and initial guide to treatment, especially when IFA testing is not performed in-house. Ideally, IFA testing is performed following a positive result on the screening test, and a second (convalescent titer) should be obtained. At VHUP, treatment is often initiated on the basis of a positive semiquantitative test. If the animal responds favorably to treatment, the semiquantitative test is not always followed by an IFA test. Case no. 3 in this series did not have an IFA test performed, but the animal did have a rise in semiquantitative titers, characteristic skin lesions, compatible laboratory abnormalities, and a rapid response to treatment for RMSF.
Analysis of CSF was used as a diagnostic tool in three of the five dogs. All three fluid analyses revealed a moderate elevation in total protein and cell count. Cytology of the CSF of all three dogs showed a mixed cellular pleocytosis, although the differential cytology in case no. 3 was predominantly neutrophilic. These cytology results were consistent with the mononuclear and neutrophilic cell infiltrations noted on postmortem examination of previously reported clinical cases.7 One study of RMSF in 30 dogs reported abnormal CSF analyses characterized by an elevated protein and/or cell count in five of seven CSF samples, but the differential cytology was not reported.4 A neutrophilic pleocytosis and a lymphocytic pleocytosis have been reported in individual dogs.5 A predominantly mononuclear pleocytosis was described in another report.15 Differences in CSF cytology likely resulted from the predominant cell infiltrate associated with the vasculitis caused by RMSF, which has been characterized as neutrophilic, lymphocytic, mononuclear, or mixed, and which may vary with the stage and severity of the disease process.7,10
Two dogs had positive CSF titers to canine distemper virus. These positive titers may have reflected the vaccination status of the dogs rather than an active distemper infection. The vasculitis associated with RMSF may have allowed leakage of distemper antibody from the blood into the CSF. Aerobic culture was performed on the CSF of only one dog (case no. 4) and revealed no bacterial growth. At VHUP, CSF for culture is not routinely submitted unless bacterial encephalitis is strongly suspected or infectious disease titers are negative in the face of an inflammatory CSF analysis.
All five of the dogs in this case series responded promptly to treatment with doxycycline. In some cases, an initial IV dose of doxycycline was administered, owing to the severity of clinical signs and the inability of the dogs to pre-hend food. Providing therapy early in the course of disease, rather than at high doses, is crucial in both human and canine cases of RMSF.4,11,13 Combination therapy with enrofloxacin and doxycycline has been previously reported in dogs, and this was attempted in case no. 2 because of an initial poor response to treatment.4 However, there is no conclusive evidence to support that a higher dosage of antibiotics or combination antibiotic therapy is efficacious in dogs that do not initially respond to therapy.
One dog (case no. 2) had an elevation in liver enzymes during treatment with doxycycline, and these elevations resolved after the medication was withdrawn. Hepatotoxicity associated with doxycycline administration in humans has been reported.16 Three dogs were discharged on the fifth day of hospitalization, one on the 6th day, and one on the 11th day of hospitalization. The mean duration of hospitalization was 6.4 days. Three of the five animals had normal platelet counts, and two animals had near-normal platelet counts at the time of discharge. All animals were ambulatory, with a normal menace response and normal or near-normal mentation at the time of discharge. By the time of reexamination (i.e., 10 to 14 days after discharge), the neurological status of all the dogs was markedly improved or normal.
Conclusion
This case series supported the previous findings that central vestibular disease may be the most common specific neurological abnormality seen in dogs with RMSF. In addition to vestibular dysfunction, tetraparesis with ataxia and generalized or focal prosencephalic involvement often accompanied the vestibular signs. The onset of neurological abnormalities in three dogs occurred at the beginning of the clinical course of illness, and seizures and spinal pain were not features of the neurological disease associated with RMSF. The prognosis with prompt and appropriate treatment was good; all five dogs recovered within 15 days.
INDX Canine Multi-Test Dip S-Ticks; PanBio InDx Inc., Baltimore, MD 21227
Clavamox; Pfizer Animal Health, New York, NY 10017
Rimadyl; Pfizer Animal Health, New York, NY 10017
Centrine; Fort Dodge Animal Health, Overland Park, KS 66225
Imuran; Faro Pharmaceuticals, Bedminster, NJ 07921
Doxycycline; Bedford Laboratories, Bedford, OH 44146
Amoxi-Tabs; Pfizer Animal Health, New York, NY 10017
Nemex; Pfizer Animal Health, New York, NY 10017
Albon; Pfizer Animal Health, New York, NY 10017
Baytril; Bayer Corporation, Shawnee Mission, KS 66201
Azium; Schering-Plough Corporation, Kenilsworth, NJ 07083
Butazolidin; Schering-Plough Corporation, Kenilsworth, NJ 07083
Torbutrol; Fort Dodge Animal Health, Overland Park, KS 66225
Hetastarch 6% in 0.9% NaCl; Abbott Laboratories, North Chicago, IL 60086
Trental; Aventis, Bridgewater, NJ 08807
Frontline Top Spot; Merial, Duluth, GA 30096
Antirobe; Pfizer Animal Health, New York, NY 10017
Cefazolin Sodium; West-Ward Pharmaceutical Corporation, Eatontown, NJ 07724
EtoGesic; Fort Dodge Animal Health, Overland Park, KS 66225
