A 6-year-old 24.1-kg (53.0-lb) neutered male Treeing Walker Coonhound was presented because of a 3-day history of progressive dull mentation and gait change. Two days earlier, the dog acutely appeared dull and developed a hypermetric gait in the thoracic limbs. The dog was treated with carprofen (unknown dosage) by the primary veterinarian. The following day, the dog developed tremors and was treated with methocarbamol (1.74 mg/kg [0.79 mg/lb], PO, q 12 h). On the third day, the dog began stumbling and falling to the left side. Because of progressive worsening of the dog's condition, a referral evaluation was scheduled. At the evaluation, physical examination findings were within reference limits with the exception of tachypnea. A neurologic examination was performed.
Neurologic examination
Assessment
Anatomic diagnosis
| Problem | Rule out location |
|---|---|
| Obtundation | Ascending reticular activating system (ARAS) or prosencephalon |
| Postural reactions (all 4 limbs) | Ipsilateral brainstem or cervical spinal cord or contralateral prosencephalon |
| Tetraparesis (all 4 limbs) | Brainstem or cervical spinal cord |
| Pleurothotonus (left sided) | Left side of the prosencephalon or rostral portion of the midbrain |
| Left head tilt | Left-sided peripheral vestibular system (receptors in the inner ear or cranial nerve VIII) or central vestibular system (rostral portion of the medulla or cerebellum) |
| Vestibular ataxia | Peripheral vestibular system (receptors in the inner ear or cranial nerve VIII) or central vestibular system (rostral portion of the medulla or cerebellum) |
| Cerebellar ataxia | Cerebellum |
| Cervical hyperesthesia | Cervical region (meninges, nerve roots, vertebrae, or epaxial musculature) or referred signs associated with an intracranial lesion |
Likely location of 1 lesion
Multifocal lesion affecting anatomic structures of the left caudal fossa (pons, medulla, and cerebellum) and left side of the prosencephalon or left rostral portion of the midbrain.
Etiologic diagnosis
The differential diagnosis considered for a sudden-onset, progressive course of multifocal neurologic deficits included inflammation, such as immune-mediated meningoencephalitis (meningoencephalitis of unknown etiopathogenesis [MUE]) or an infectious cause (protozoal encephalitis [infection with Toxoplasma gondii or Neospora caninum], fungal encephalitis [infection with Cryptococcus neoformans, Blastomyces dermatidis, or Coccidioides immitis], viral encephalitis [canine distemper encephalitis or rabies encephalitis], or bacterial encephalitis), or a neoplastic process (primary CNS neoplasm [lymphoma or histiocytic sarcoma] or metastatic neoplasm [extra-CNS or primary CNS neoplasm, such as choroid plexus carcinoma]). The initial diagnostic plan included a CBC, serum biochemical profile, urinalysis, and 3-view thoracic radiography to evaluate for evidence of systemic inflammation or an underlying extra-CNS neoplasm. Depending on the results of initial diagnostic testing, MRIa of the brain was considered. Evaluation of a sample of CSF would be determined on the basis of the MRI findings.
Diagnostic test findings
Results of the CBC, serum biochemical profile, urinalysis, and 3-view thoracic radiography were within reference limits. On the MRI images of the brain, the brainstem (thalamus, midbrain, pons, and medulla) and cranial cervical portion of the spinal cord were hyperintense on T2-weighted (Figures 1 and 2) and T2-weighted FLAIR sequences and isointense on T1-weighted sequences, and those regions did not enhance following IV administration of contrast medium. Analysis of a CSF sample collected from the cisterna magna revealed mononuclear pleocytosis (91 cells/µL; reference range, 0 to 5 cells/µL) and high protein concentration (199.0 mg/dL; reference range, 15.0 to 35.0 mg/dL). A 100-cell differential cell count revealed 84 small mononuclear cells, 11 large mononuclear cells, and 5 nonregenerative neutrophils. The MRI and CSF analysis results were consistent with MUE or, less likely, protozoal or fungal infection or neoplasia. Owing to financial constraints, the owner declined infectious disease testing and treatment for presumptive MUE was initiated with prednisone (0.8 mg/kg [0.36 mg/lb], PO, q 24 h) and mycophenolate mofetil (10.5 mg/kg [4.8 mg/lb], PO, q 12 h).
Magnetic resonance image of the brain of a 6-year-old Treeing Walker Coonhound that was evaluated because of a 3-day history of progressive dull mentation and gait change. On this midline sagittal T2-weighted image, there is moderate to severe, ill-defined hyperintensity in the brainstem from the midbrain (solid arrow) through the pons (solid arrowhead) and medulla (open arrowhead) and extending into the cranial cervical portion of the spinal cord (open arrow).
Citation: Journal of the American Veterinary Medical Association 258, 2; 10.2460/javma.258.2.141
Representative transverse T2-weighted MR images at the level of the mid-diencephalon (A), midbrain (B), pons (C), rostral portion of the medulla (D and E), and caudal portion of the medulla (F). Ill-defined hyperintensity (arrows) is seen throughout the brainstem.
Citation: Journal of the American Veterinary Medical Association 258, 2; 10.2460/javma.258.2.141
Comments
The case described in the present report highlighted several notable observations that reflect the multifocal nature of MUE, namely obtundation, head tilt, head and neck turn, abnormal gait, delayed postural reactions, and cervical hyperesthesia. An abnormal mental state intuitively necessitates an anatomic diagnosis that involves the brain. Specifically, abnormal mentation reflects dysfunction of either the prosencephalon (cerebrum or thalamus [or both]) or the ARAS. The ARAS is a network of neurons distributed in the central core of the brainstem from the medulla to the rostral portion of the thalamus. Nearly all sensory systems destined for conscious recognition by the prosencephalon extend collateral axons that synapse on the neurons that make up the ARAS. In turn, the neurons of the ARAS project axons to the rostral portion of the thalamus; thalamic neurons send axons that project to the entire cerebral cortex to awaken the cerebrum.1 Consequently, lesions that affect the prosencephalon or the ARAS can affect the mental state of a patient. Levels of ARAS dysfunction may be categorized with terms such as alert, dull, obtunded (ie, a state of being less responsive to normal environmental stimuli, such as a loud noise, compared with the responsiveness typically observed in animals of that species), stuporous (responsive to only noxious stimuli), and comatose (nonresponsive to noxious stimuli).
A subtle but crucial finding in the case described in the present report was observation of both a head tilt and head turn (pleurosthotonus). A head tilt is defined as a rotation of the head along the long axis of the body whereby one ear is positioned closer to the ground than the other. A head tilt is a quintessential finding with dysfunction of the vestibular system,2 which was supported by the presence of a vestibular ataxia in the dog of the present report. Because the dog's gait also had qualities of cerebellar ataxia, a lesion involving the cerebellum could not be excluded. On the other hand, pleurosthotonus is defined as deviation or turning of the head and neck in a plane parallel to the ground. Prosencephalic or rostral midbrain lesions cause pleurosthotonus as well as propulsive behavior, including wide circling and pacing toward the side of the lesion. This behavior is known as adversive (to turn to) syndrome.1
In addition, the dog of the present report had postural reaction deficits in all limbs. The pathway for postural reactions involves the entire neurologic system; information is received by the sensory afferents of the limb and is carried by the nerves to the ascending long tracts that traverse the spinal cord and brainstem to the contralateral portion of the prosencephalon and ipsilateral portion of the cerebellum.3 In turn, upper motor neurons descend to modulate function of lower motor neurons to move the limbs.3 Therefore, postural reactions are a sensitive marker for neurologic disease but are nonspecific for any region of the CNS or peripheral nervous system.3
During the neurologic examination, the dog of the present report had evidence of marked hyperesthesia during cervical palpation. For this dog, cervical hyperesthesia could have been related to the presence of meningitis, as evidenced by the results of CSF sample analysis. Alternatively, intracranial disease has been reported to be associated with signs of neck pain, which may be attributed to stretching of nociceptors in the dura or vasculature or to central pain syndrome. Central pain syndrome is thought to be secondary to a direct disruption of the nociceptive pathways of the CNS.4
The abnormal gait, mentation change, and vestibular system dysfunction observed in the dog of the present report suggested central vestibular dysfunction secondary to a caudal brainstem lesion, whereas the pleurosthotonus suggested a disorder affecting the rostral portion of the thalamus. Consequently, the dog's neurologic deficits could not be explained by a single lesion and therefore necessitated an anatomic diagnosis of a multifocal localization. Causes of multifocal disease include immune-mediated meningoencephalitis, infectious diseases, neoplasia, and vascular disease.
Meningoencephalitis of unknown etiopathogenesis is an encompassing term that describes a heterogeneous group of idiopathic inflammatory brain diseases.5 This group includes 3 subtypes, namely granulomatous meningoencephalomyelitis, necrotizing meningoencephalomyelitis, and necrotizing leukoencephalomyelitis, which are clinically challenging to distinguish from each other.
Clinical signs of MUE can vary dramatically on the basis of the distribution of inflammation; inflammation can be focal or multifocal and involve the brain or spinal cord (or both).6 Typically, young to middle-aged small-breed dogs are affected.6,7 Granulomatous meningoencephalomyelitis typically affects females of terrier and toy breeds with a mean age of onset of 4.5 years.8 Necrotizing meningoencephalomyelitis primarily affects Pugs, Chihuahuas, and Maltese with a mean age of onset of 2.5 years.8 Necrotizing leukoencephalomyelitis is commonly reported as affecting Yorkshire Terriers and French Bulldogs with a mean age of onset of 4.5 years.8
Although MUE is considered most commonly associated with small-breed dogs, dogs of any size, breed, or age group can be affected. Large-breed dogs may account for 25% of canine cases of MUE.9 Although definitive diagnosis and classification of MUE into subtype requires histologic examination of appropriate specimens,6 a presumptive diagnosis can be made of the basis of signalment and results of MRI and CSF sample analysis. The MRI findings include focal, multifocal, or diffuse hyperintense lesions in the brain or spinal cord (or both) that are hyperintense on T2-weighted images and iso- to hypointense on T1-weighted images and have variable degrees of contrast enhancement.8 Analysis of a CSF sample from an affected dog generally reveals pleocytosis with a predominance of monocytic or lymphocytic cell populations (> 50% of the total nucleated cell count).10 Protein content in the CSF sample is often high and may range from 30 mg/dL to > 1,500 mg/dL.10
Although the etiopathogenesis of MUE is not yet fully understood, current theories suggest an excessive immunologic response is involved; therefore, treatment is comprised of immunosuppressive therapies,5,11 often with administration of multiple drugs including corticosteroids, cytosine arabinoside, cyclosporine, azathioprine, lomustine, procarbazine, leflunomide, and mycophenolate mofetil.12,13 Treatment of affected dogs with corticosteroids in conjunction with another immunosuppressive or cytotoxic drug results in improved survival times (range, 250 to 1,834 days), compared with survival times for dogs treated with corticosteroids alone (range, 28 to 602 days).12,13,14 To the authors' knowledge, no prospective study has investigated direct comparisons between secondary immunomodulatory medications.6 Without treatment, MUE in dogs is considered fatal.7
For the dog of the present report, the combination of multifocal neurologic deficits referable to the brainstem, MRI findings, and results of CSF sample analysis supported a diagnosis of MUE. Owing to the severity of the dog's signs and the owner's financial constraints, infectious disease testing was forgone and immunosuppressive therapy was initiated. Twenty-four hours after immunosuppressive therapy was begun, marked improvement of the dog's clinical signs was noted. At 2 and 6 weeks after initiation of immunosuppressive therapy, the dog's neurologic examination findings were unremarkable. Over a 6-month period following the diagnosis, treatment with prednisone was slowly tapered and discontinued. At 7 months following the diagnosis, the dog was being treated with mycophenolate mofetil and remained neurologically normal.
This feature is published in coordination with the American College of Veterinary Internal Medicine on behalf of the specialty of neurology. Contributors to this feature should contact Dr. Helen L. Simons (hsimons@avma.org) for case submission forms. Submissions will be sent to Dr. Karen Kline, DVM, DACVIM, for her review, except when Dr. Kline is an author.
Footnotes
3.0-T MRI, Siemens Skyra MRI, Erlangen, Germany.
References
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Cornelis I, Volk HA, De Decker S. Clinical presentation, diagnostic findings and long-term survival in large breed dogs with meningoencephalitis of unknown aetiology. Vet Rec 2016;179:147.
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Cornelis I, Van Ham L, Gielen I, et al. Clinical presentation, diagnostic findings, prognostic factors, treatment and outcome in dogs with meningoencephalomyelitis of unknown origin: a review. Vet J 2019;244:37–44.
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Kipar A, Baumgärtner W, Vogl C, et al. Immunohistochemical characterization of inflammatory cells in brains of dogs with granulomatous meningoencephalitis. Vet Pathol 1998;35:43–52.
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Woolcock AD, Wang A, Haley A, et al. Treatment of canine meningoencephalomyelitis of unknown aetiology with mycophenolate mofetil and corticosteroids: 25 cases (2007–2012). Vet Med Sci 2016;2:125–135.
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Wong MA, Hopkins AL, Meeks JC, et al. Evaluation of treatment with a combination of azathioprine and prednisone in dogs with meningoencephalomyelitis of undetermined etiology: 40 cases (2000–2007). J Am Vet Med Assoc 2010;237:929–935.
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Jung DI, Kang BT, Park C, et al. A comparison of combination therapy (cyclosporine plus prednisolone) with sole prednisolone therapy in 7 dogs with necrotizing meningoencephalitis. J Vet Med Sci 2007;69:1303–1306.
