Introduction

Canine distemper virus (CDV) is an RNA virus of the genus Morbillivirus within the Paramyxoviridae family. The virus is typically transmitted via inhalation or ingestion of respiratory secretions of clinically or subclinically affected dogs. Following exposure, the virus replicates within lymphoid tissue. The incubation period ranges from 1 to 4 wk or more.^1–7 Infected dogs that mount an immune response will recover with mild to no clinical signs. If a sufficient immune response is not mounted, then a secondary viremia results in dissemination of the virus to epithelial cells of multiple organs including the central nervous system (CNS).^3,6,7 Infection with CDV can lead to severe, multisystem disease including the gastrointestinal, respiratory, and CNS disease in dogs.^2,6,7 An estimated 30% of dogs infected with CDV ultimately develop neurological dysfunction, which may be observed 1–6 wk after the onset of initial clinical signs.² Puppies at 3–6 mo old with declining maternal antibodies and an immature immune system are most susceptible to the disease and tend to develop polioencephalopathies causing forebrain dysfunction.^1,3,4 Previously reported signs of CNS disorder include abnormal mentation, partial or generalized seizures, myoclonus, paresis, paralysis, proprioceptive deficits, circling, behavioral changes, and vestibular dysfunction.^1,2,5 Clinical signs of myelopathy, particularly lower motor neuron signs and hyperesthesia, in acute CDV infection of the CNS are uncommonly reported.

This case report describes a unique presentation of canine distemper encephalomyelitis in a young dog that caused focal lower motor neuron signs and hyperesthesia. There is a paucity of current literature on CNS CDV infection. To the authors’ knowledge, these clinical signs are poorly described in the literature, and imaging findings have not been previously documented.^5,8,9

Case Report

A 4 mo old spayed female mixed-breed dog was presented to the Ohio State Veterinary Medical Center (OSUVMC) Emergency Service with a 2 day history of right thoracic limb lameness that had progressed from mild limping to toe-dragging. There was no known history of trauma. She had a history of mild intermittent vomiting since adoption at 10 wk of age, including once the morning prior to presentation. Six days prior to presentation at the OSUVMC, the dog had been spayed by the referring veterinarian, at which time, an abdominal exploratory was performed as a result of the history of vomiting and biopsies of enlarged abdominal lymph nodes were collected. Histopathology of the enlarged lymph nodes reportedly demonstrated normal lymph nodes, and the lymphadenopathy was determined to be consistent with the dog’s young age. She tested negative for parvovirus by the referring veterinarian. All of her foot pads were documented as thickened and cracked at the time of her ovariohysterectomy. Two days prior to presentation at the OSUVMC the dog was evaluated for the lameness by the referring veterinarian. Radiographs of the right thoracic limb were unremarkable, and she was treated with gabapentin (6.6 mg/kg orally every 24 hr) and carprofen (5 mg/kg orally every 24 hr). She had previously received two distemper, adenovirus, parvovirus, parainfluenza vaccines by the referring veterinarian but had not completed the vaccination series.

On presentation, she was mildly febrile (102.7°F) and displayed a quiet but normal mentation. Physical examination revealed moderate muscle atrophy of the right thoracic limb, particularly over the scapula, and moderate hyperkeratosis with fissuring of the foot pads. Orthopedic examination demonstrated hyperesthesia on palpation of the right axillary region but no underlying orthopedic cause of the hyperesthesia. Abnormalities on neurological evaluation included a right thoracic limb monoplegia with flaccid muscle tone, absent conscious proprioception in the right thoracic limb, weak to absent withdrawal in the right thoracic limb with intact pain perception, and an absent cutaneous trunci reflex on the right side of the patient. The neuroanatomic localization was the right brachial plexus or C6–T2 spinal cord segments.

Indirect blood pressure measurement in both the right and left thoracic limbs revealed mild hypertension (175 mm Hg systolic in both thoracic limbs). This hypertension was attributed to pain and stress of being in the hospital. A complete blood count and serum biochemistry panel identified a leukocytosis (18.8 × 10⁹/L; reference range, 4.1–15.4 × 10⁹/L) with a mature neutrophilia (16.5 ×10⁹/L; reference range, 3.0–10.4 × 10⁹/L), minimally elevated creatine kinase (413 IU/L; reference range, 50–400 IU/L), and hypercholesterolemia (319 mg/dL; reference range, 80–315 mg/dL).

The dog was sent home with medical management. The owner was instructed to discontinue the carprofen and continue with the previously prescribed gabapentin. A fentanyl patch was applied to the right pelvic limb and owners were instructed to discontinue carprofen in anticipation of starting prednisone therapy following a washout period. She was also prescribed clindamycin (10 mg/kg orally every 12 hr), sucralfate (0.5 g orally every 8 hr), and tramadol (3.3 mg/kg orally every 8–12 hr).

The dog re-presented to the OSUVMC Emergency Service within 24 hr for being laterally recumbent, mentally inappropriate, and incessantly vocalizing. It was suspected that her inappropriate mentation was related to dysphoria from the fentanyl patch, and the dog’s mentation improved following removal of the fentanyl patch and reversal with naloxone (0.03 mg/kg IV once). Abnormalities on neurological evaluation were consistent with the previous visit and included a right thoracic limb monoplegia with flaccid muscle tone, absent conscious proprioception in the right thoracic limb, weak to absent withdrawal in the right thoracic limb with intact pain perception, and an absent cutaneous trunci reflex on the right side of the patient. The neuroanatomic localization was the right brachial plexus or C6–T2 spinal cord segments. Indirect blood pressure measurement revealed normotension (136 mm Hg systolic). A biochemistry panel^a identified a mild acidemia (pH 7.332; reference range, 7.35–7.47) mild hyperlactatemia (2.5 mg/dL; reference range, 0–2 mg/dL), and a mild hypokalemia (3.8 mg/dL; reference range, 3.9–4.9 mg/dL). At this time, the dog was admitted to the hospital for further diagnostics and therapy.

MRI of the dog’s brain and cervical spine were performed using a 3 Tesla magnet^b. The MRI sequences included T1- and T2-weighted images of the brain and cervical spinal cord. Additional sequences included Spectral presaturation with inversion recovery sagittal images of the brain and cervical spinal cord, and fluid-attenuated inversion recovery transverse images of the brain and cervical spinal cord from mid C4 to mid C6. Intravenous gadodiamide^c was administered at 0.1 mL/kg (0.2 mL/kg) and transverse and sagittal TI-weighted images of the brain and cervical spinal cord from mid C4 to mid C6 were repeated. Within the spinal cord from the caudal aspect of C4 to the caudal aspect of C5 there was an ill-defined, slightly right-sided, 2.5 cm long, 0.4 cm diameter region of T2-weighted hyperintensity and T1-weighted isointensity. The lesion was noncontrast-enhancing (Figure 1). An MRI of the brain was unremarkable. Imaging differential diagnoses included edema, myelitis, noncontrast-enhancing neoplasia, and gliosis. After the MRI, a cerebrospinal fluid (CSF) sample was obtained from the cerebellomedullary cistern for analysis and demonstrated a mild lymphocytic pleocytosis (total nucleated cell count 10/μL; reference range <5/uL, 78% well-differentiated lymphocytes). CSF protein and red blood cell count were normal (protein 19 mg/dL, reference range <25 mg/dL; red blood cell count 0/μL, reference range 0/μL). No etiologic agents or atypical cells were noted. Differential diagnoses included infectious or sterile meningomyelitis or less likely neoplasia such as lymphoma. Whole blood was submitted to Auburn University College of Veterinary Medicine for Toxoplasma gondii titers and Neospora Indirect Fluorescent Antibody test. The Neospora Indirect Fluorescent Antibody test was negative. There was a significant Toxoplasma immunoglobulin (Ig)G titer (1:1280) and a borderline IgM titer (1:40). A parvovirus test^d and Cryptococcus antigen Latex Agglutination test^e were negative. Polymerase chain reaction (PCR)^f on CSF for CDV was positive and negative for all other infectious agents (West Nile Virus, Borrelia burgdorferi, neospora hughesi and caninum, T gondii, Anaplasma phagocytophilum, Ehrlichia canis, and Rickettsia sp. including Rocky Mountain Spotted Fever). Blastomyces quantitative enzyme immunoassay^g was negative on urine. While awaiting infectious testing results, the dog was hospitalized for 4 days and treated empirically for myelitis. Treatments included continuation of the previously prescribed clindamycin (10 mg/kg orally every 12 hr), sucralfate (0.5 gram orally every 8 hr), gabapentin (7 mg/kg orally every 8–12 hr), and tramadol (3.3 mg/kg orally every 8–12 hr), in addition to famotidine (0.5 mg/kg IV every 12 hr), metronidazole (10 mg/kg IV every 12 hr), and acepromazine (0.01 mg/kg IV as needed for anxiety). On her third day of hospitalization, the dog received one dose of dexamethasone sodium phosphate (2.1 mg IV). The dog was discharged from the hospital with gabapentin (7 mg/kg orally every 8–12 hr), metronidazole (9 mg/kg orally every 12 hr), clindamycin (10 mg/kg orally every 12 hr), omeprazole (1.4 mg/kg orally every 24 hr), and a tapering dose of prednisone (starting at 0.5 mg/kg orally every 12 hr).

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The dog’s clinical signs waxed and waned, and 4 days later, the dog re-presented to the OSUVMC Neurology Service for progression of her neurological signs. On presentation, she was febrile (103.3°F) and had an obtunded mentation. Neurological evaluation revealed an ambulatory tetraparesis with right thoracic limb monoplegia, absent conscious proprioception in both thoracic limbs, decreased flexor withdrawal and poor extensor muscle tone in all limbs, and lumbar spinal hyperesthesia. While in the hospital, the dog had a focal seizure. The neuroanatomic lesion localization was most consistent with prosencephalic disease and a diffuse myelopathy or peripheral neuropathy affecting all four limbs.

As a result of the progression of her disease, the dog was humanely euthanized and submitted for a complete necropsy. At gross examination, the most significant finding was marked hyperkeratosis with fissuring of all the digital paw pads as well as the carpal and metacarpal pads (Figure 2A). Histologically, the C5 spinal cord had marked increase in cellularity and pallor of the right dorsal and ventral horns, as well as similar less severe changes in the left gray matter. The increase in cellularity was comprised of lymphohistiocytic and rare plasmacytic infiltrates expanding the Virchow-Robbins space with inflammatory infiltrates also permeating into the parenchyma (Figure 2B). An increased number of astrocytes and activated microglia characteristic of gliosis was also present. Both intranuclear and intracytoplasmic eosinophilic viral inclusions were evident within astrocytes and intracytoplasmic inclusions within neurons and oligodendrocytes.

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Gray matter cytotoxic edema, single cell necrosis, and chromatolysis was appreciated as well as dilated axon sheaths, digestion chambers, and axon swelling in the adjacent white matter, particularly the ventral right column consistent with secondary demyelination. (Figure 2C). The lumbar spinal cord had similar histologic changes most prominent in the left dorsal horn. The periventricular gray and white matter of the pons and cerebellum respectively demonstrated similar mononuclear Virchow-Robbins space expansion as well as rare eosinophilic intranuclear and intracytoplasmic viral inclusions within astrocytes and oligodendrocytes.

Immunohistochemistry of the C5 and lumbar spinal cord tissues had strong nuclear and cytoplasmic brown staining for CDV and no staining for T gondii (Figure 2D). The histopathologic findings were characteristic of CDV infection.

Discussion

This case report documents the occurrence of lower motor neuron signs and hyperesthesia in a young mixed-breed dog secondary to canine distemper infection. The diagnosis was based on the clinical history of the patient, positive PCR for CDV in CSF, and positive immunohistochemistry for CDV with the presence of eosinophilic intranuclear and intracytoplasmic inclusion bodies within the cerebellum, brainstem, and spinal cord.

On initial presentation, this dog’s focal lower motor neuron signs were suspected to be due to a lesion within the right brachial plexus or C6–T2 spinal cord segments. The initial differential diagnoses for this case included a neuritis or myelitis of infectious or immune-mediated etiology, hemorrhage, or less likely, a neoplastic process. Because the dog was currently vaccinated for CDV and did not demonstrate some of the more common signs of CDV (respiratory signs, seizures, myoclonus), distemper myelitis was considered unlikely. However, the dog did have footpad hyperkeratosis, which is a nonspecific sign but frequently seen in dogs with distemper encephalomyelitis.⁷ The dog also had only received two of three distemper vaccinations that are normally recommended for young dogs because she was too young to have completed the vaccination series. Therefore, it is possible that the dog had not mounted an adequate immune response. Also, current vaccination status does not rule out CDV infection. In one study, 34–41% of dogs with CDV encephalitis were currently vaccinated for CDV.⁹

The acute phase of CDV infection of the CNS in young dogs more commonly causes signs of forebrain dysfunction including either generalized or focal seizures.^4,7 “Chewing gum” seizures, a type of focal seizure, are considered a common sign of CDV CNS infection.^2,3,7 Other intracranial signs include myoclonus, altered mentation, vestibular and cerebellar signs, and behavioral changes. The dog in this report had one seizure shortly prior to euthanasia but otherwise did not demonstrate signs of intracranial disease even though there were histopathologic changes in her brain on necropsy examination. Lower motor neuron signs and hyperesthesia were the initial clinical signs in the dog in this report. Our belief is that this dog’s lower motor neuron signs came from disease within the spinal cord gray matter rather than disease affecting the nerve roots. This theory is supported by the histopathologic changes on necropsy affecting the gray matter in the cervical and lumbar spinal cord segments. The progression of this dog’s clinical signs to lower motor neuron signs in all four limbs is an unusual presentation for CDV myelitis. Clinical signs in dogs who develop meningomyelitis are poorly described but include proprioceptive deficits, paresis, and ataxia.^1–3,7 Lower motor neuron signs are infrequently reported in the literature.^1–3,7–9 In one study, 7 of 84 dogs diagnosed with CDV encephalomyelitis demonstrated fibrilliation potentials on electomyogaphy, suggesting involvement of lower motor neurons.⁸ However, 3 of the 7 dogs had concurrent protozoal myositis, which could account for the electomyogaphy changes as well, and lower motor neuron involvement was not confirmed. One dog in the study was diagnosed with neurogenic atrophy secondary to neuritis related to CDV.⁸ In a retrospective study of inflammatory CNS diseases in dogs, a subset of dogs with CDV demonstrated lower motor neuron signs with hyporeflexia and CDV was identified in the gray matter of the spinal cord.⁹ None of these reports describe hyperesthesia, which was a significant clinical sign in this dog. The pain on right thoracic limb and axillary manipulation in this dog was an unusual finding for CDV. Although a definitive cause of the hyperesthesia was not found on necropsy, meningeal or nerve root inflammation may have been responsible. Nerve root inflammation was not noted in the necropsy report but may have been present in nerve roots that were not evaluated histopathologically. Another explanation could include a functional paresthesia that could not be qualified histopathologically due to dysfunction of the sensory portion of the nerve root. In humans, paresthesias are reported as a result of neuropathies with no known cause in ∼20% of cases.¹³ Bone lesions have been documented in experimentally and naturally CDV infected, 3–6 mo old, large-breed dogs, most commonly at the metaphysis of long bones.⁷ However, these dogs did not display hyperesthesia or other clinical signs related to these lesions.¹⁴

The dog in this report had MRI of the brain with normal findings even though she had clinical signs of prosencephalic disease and histopathologic changes within the pons and cerebellum. There are few references in the veterinary literature documenting MRI findings in the brain of dogs with acute CDV encephalitis. MRI of the brain in acutely affected dogs may demonstrate T2 hyperintense lesions with loss of distinction between the gray and white matter due to necrosis, demyelination, gliosis and cytotoxic edema.^7,10,11 A case series of five young dogs with acute CDV encephalitis demonstrated that four of the five dogs had asymmetrical lesions within the gray matter of the forebrain with the temporal lobe being most commonly affected. The fifth dog had a T2 hyperintense lesions in the brainstem and cerebellum. Interestingly, histopathological examination only revealed demyelination within the cerebellum and not within the forebrain. The changes in the temporal lobe may be attributed to inflammation, gliosis, axonal loss or cytotoxic edema.¹²

The T2 hyperintensity seen in the spinal cord in the dog in this report was suspected to be due to demyelination and cytotoxic edema and less likely as a result of inflammatory infiltration because there was no contrast enhancement noted on T1-weighted images. To the authors’ knowledge, there are no reports evaluating MRI findings in the spinal cord with acute CDV myelitis, although it is likely the findings would be similar to those found in the brain as a result of similar histopathologic changes.

A lymphocytic pleocytosis was identified in the dog in this report. This has been reported previously as have normal CSF findings.² A study of eight dogs with acute CDV encephalomyelitis had CSF analyses characterized as a lymphocytic pleocytosis with normal protein concentrations.⁵ Reverse-transcriptase PCR can be sensitive and specific for detection of CDV.³ The dog also had a positive PCR for CDV in the CSF confirming active infection. The dog had a significant IgG titer and borderline IgM titer for T gondii, suggesting a recent antigenic stimulation by the organism. However, immunohistochemistry for Toxoplasma was negative on necropsy and therefore these titers were likely a result of a previous exposure. Histologically, noninflammatory demyelination in the brain is the hallmark of acute CDV infection.^3,6 Acute infections often do not demonstrate perivascular cuffing as opposed to other CNS infections and noninfectious inflammatory diseases.^6,7 However, CD8+ lymphocytes are found scattered through the brain parenchyma in conjunction with demyelinating lesions. As CNS CDV infections become chronic, perivascular cuffing with lymphocytes, plasma cells and monocytes occurs.⁶ This finding in the dog in this case leads us to believe the disease was becoming chronic despite the acute presentation of clinical signs. In the previously described case series of five dogs with CNS CDV, all dogs had demyelinating lesions found predominantly in the cerebellum.¹² The dog in this report did have histologic changes in the cerebellum consistent with CDV infection even though she did not demonstrate signs of cerebellar dysfunction, nor did she have imaging changes noted within the cerebellum.

The prognosis for dogs with acute neurological signs due to CDV is poor.² The dog in this report failed to respond to all therapy including corticosteroids. Antiviral treatment was not pursued, and currently this is no antiviral therapy that has been demonstrated to prevent the progression of neurologic disease.⁴ In one study, only 3 of 13 dogs with CDV infection recovered.¹ In addition, those that did recover did not display progressive neurologic signs.

Conclusion

This report describes an atypical presentation of thoracic limb monoplegia and hyperesthesia progressing to diffuse lower motor neuron signs secondary to CDV encephalomyelitis. Although signs of forebrain dysfunction are most common, this report demonstrates that CDV encephalomyelitis can have different clinical presentations and should remain a differential diagnosis in young dogs displaying neurological abnormalities including lower motor neuron signs and hyperesthesia.