What Is Your Neurologic Diagnosis?

Brittany N. Lucchetti Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Marc Kent Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Renee M. Barber Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Bridgette Wells Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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Kristina Meichner Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

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A 2-year-old 32.1-kg (70.6-lb) sexually intact male Bernese Mountain Dog was evaluated because of dull mentation following an episode of status epilepticus. For 1 week prior to the episode of status epilepticus, the dog had a decreased appetite. Twenty-four hours prior to the episode of status epilepticus, the dog became severely lethargic. The duration of the episode was 10 minutes. Following cessation of status epilepticus, the dog was evaluated at a local emergency practice where it was treated IV with mannitol and hypertonic saline (7.5% NaCl) solution (dosages unknown). Results of a CBC and serum biochemical analysis were considered normal except for hyperglobulinemia (5.1 g/dL; reference range, 2.5 to 4.5 g/dL). Despite treatment, the dog's mentation remained dull and it was referred for further evaluation. Historically, the dog had had multiple infections of the ears and skin and an upper respiratory tract infection. The dog had free access to the property where it lived, on which chickens also resided. On general physical examination, the dog was tachycardic (150 beats/min); rectal temperature and respiratory rate were within reference ranges. The dog was obtunded and thin (body condition score, 3/9). A 2 × 4 × 1-cm, firm, nonpainful subcutaneous mass was present on the right lateral aspect of the thorax. Funduscopic examination findings were normal with the exception of a 1-mm-diameter beige lesion in the left retina. The remainder of the physical examination findings were unremarkable. A neurologic examination was performed.

What is the problem? Where is the lesion? What are the most probable causes of this problem? What is your plan to establish a diagnosis? Please turn the page.

Assessment Anatomic diagnosis

ProblemRule out location
SeizuresProsencephalon
Transient circling to the rightRight prosencephalon or right vestibular dysfunction
Depressed mentationProsencephalon or reticular activating system
Tetraparesis, proprioceptive ataxia, and decreased postural reactions in all limbsFocal or diffuse lesion involving the brainstem or the C1 to T2 spinal cord segments
Transient positional ventral strabismus of the left eyeLeft vestibular dysfunction (less likely left cranial nerve III or its nucleus in the midbrain)
Absent menace response and mydriasis with reduced pupillary light reflexes in both eyesRetina or optic nerve bilaterally, optic chiasm, or less likely optic tracts bilaterally
Signs of neck painInflammation (skin, muscles, or the joints; vertebrae, or intervertebral disks of the cervical vertebral column; meninges, spinal nerves or roots; or spinal cord) or compression of the meninges, spinal cord, or spinal nerves or roots.

Likely location of 1 lesion

Multifocal lesion distribution including prosencephalon; brainstem; retina, optic nerve, or optic chiasm; and meninges, spinal nerves or roots, or spinal cord within the cervical vertebral column

Etiologic diagnosis—Differential diagnoses considered for the dog included infectious diseases (bacterial, fungal [Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, or Coccidioides immitis], viral [canine distemper virus or rabies], protozoal [Neospora caninum or Toxoplasma gondii], or rickettsial [Erhlichia canis or Rickettsia rickettsii] infection), noninfectious inflammatory disease (immune-mediated meningoencephalomyelitis or steroid-responsive meningitis arteritis), congenital disease or malformation, metabolic or toxic encephalopathy, or less likely vascular disease (ischemia or stroke), lysosomal storage disease, or neoplasia. The diagnostic plan included a minimum database (hematologic and serum biochemical analyses and urinalysis), assessments of venous blood gas concentration and serum ammonia concentration after food withholding to assess for causes of metabolic encephalopathies and to identify signs of systemic inflammation or infection, collection of fine-needle aspirate specimens from the subcutaneous mass for cytologic examination to rule out neoplasia (primary or metastatic) or an infectious or noninfectious cause, and 3-view thoracic radiography to screen for evidence of an infectious or a neoplastic cause. Following these preliminary diagnostic tests, MRI of the head with a 3-T MRI unita was planned to obtain multiplanar sequences (T2-weighted, T1-weighted, and T2-fluid attenuated inversion recovery images). Additional T1-weighted images would be obtained following IV administration of contrast medium. Subsequent diagnostic testing such as CSF analysis or serum antigen or antibody assays for infectious causes was to be guided by the compilation of results.

Diagnostic test findings—The minimum database, venous blood gas concentration, and serum ammonia concentration after food withholding were considered normal with the exception of hypocarbia (Paco2, 25.8 mm Hg; reference range, 29.7 to 46.0 mm Hg). Thoracic radiography revealed tracheobronchial lymphadenopathy. Cytologic examination of fine-needle aspirate specimens of the subcutaneous mass revealed macrophages and reactive fibroblasts with many round to oval yeast organisms consistent with a Cryptococcus spp. The dog's owners were notified of the likelihood of a systemic mycosis underlying the neurologic deficits; MRI evaluation of the head was undertaken. On MRI images, the olfactory bulbs and peduncles were enlarged and had ill-defined heterogeneous signal intensity that was T2-hyperintense and T1-hypointense. The T2-hyperintensity extended into the rostral aspects of the cerebral hemispheres, ventral aspect of the internal capsule, and ventral portion of the diencephalon bilaterally. A focal region of T2-hyperintensity also was identified in the ventral aspect of the midbrain. Following IV contrast medium administration, there was heterogeneous contrast enhancement of the olfactory bulbs and peduncles and a pial pattern of contrast enhancement.1 In addition, there was marked enlargement of the retropharyngeal and mandibular lymph nodes (Figure 1). Analysis of a CSF sample obtained from the cisterna magna revealed an eosinophilic pleocytosis (530 WBCs/μL; reference range, 0 to 5 WBCs/μL) and high protein content (173 mg/dL; reference range, 15 to 35 mg/dL) with numerous yeast organisms similar to those detected cytologically in the fine-needle aspirate specimens of the subcutaneous mass. A latex agglutination test for cryptococcal capsular antigen revealed a high titer (800; reference range, < 8), which confirmed the diagnosis of cryptococcosis. Results of fungal culture of tissue from the subcutaneous mass were consistent with C neoformans

Figure 1—
Figure 1—

Magnetic resonance images of the brain of a 2-year-old Bernese Mountain Dog that was evaluated because of dull mentation following an episode of status epilepticus. A—Transverse T2-weighted image. At the level of the rostral cerebrum, hyperintensity is observed in the white matter of the internal capsule and areas of the lentiform nuclei bilaterally (arrows) The hyperintense signal of the CSF normally present in the sulci is absent, suggesting brain swelling. B—Transverse T1-weighted image obtained at the same level as that in panel A after administration of contrast medium. There is a leptomeningeal pattern of contrast enhancement wherein meningeal enhancement is present within sulci of the cerebrum (large open arrowhead) and along the cerebral longitudinal fissure (small open arrowhead). A small well-defined round lesion consistent with a granuloma is adjacent to the meninges overlying the piriform lobe (small arrow). Hypointensity within the internal capsule is consistent with edema (large arrows). C—Dorsal T1-weighted image obtained at the level of the mid diencephalon after administration of contrast medium. The olfactory bulbs and rostral aspect of the cerebral hemispheres are heterogeneously contrast enhancing (arrowhead). Enhancement along the meninges within the cerebral longitudinal fissure (small arrow) is observed. D— Midline sagittal T2-weighted image. The olfactory bulb and rostral aspect of the cerebrum are hyperintense, and there is a loss of delineation of the sulci (large arrow). The lateral ventricle is compressed. There is a focal hyperintensity in the midbrain (small white arrowhead).

Citation: Journal of the American Veterinary Medical Association 253, 1; 10.2460/javma.253.1.39

Comments

Cryptococcosis is a globally distributed mycotic disease caused by organisms of the Cryptococcus gattii-C neoformans species complex. These fungi have undergone several shifts in nomenclature resulting in categorization of the fungi into 7 species instead of2 or 3 species with several serotypes.2 Cryptococci are found in decaying organic matter; C neoformans has also been detected in avian droppings, and C gattii is present in some live trees.2 Cats are more commonly infected with C gattii, which typically affects the respiratory system. Dogs are more commonly infected with C neoformans, which typically affects the CNS.3 The suspected route of infection in dogs and cats is inhalation of desiccated yeast or basidiospores through the nasal cavity and possible direct penetration into the CNS via the cribriform plate. In dogs and cats, infection may be limited to the CNS or may involve other organ systems and tissues.

Among dogs, cryptococcosis typically develops in young, large-breed animals.4 Central nervous system involvement is observed in 30% of affected dogs. In the dog of the present report, a subcutaneous mass also was present. Dermal lesions are uncommon (6% of affected dogs). Central nervous system signs include altered mentation, vestibular dysfunction, paresis or plegia, seizures, and signs of neck pain.5

Diagnostically, hematologic and serum biochemical analyses and urinalysis often reveal nonspecific changes reflective of systemic inflammation and the degree of organ involvement in affected animals. Definitive diagnosis requires cytologic or histologic observation or PCR assay detection of the organism in appropriate specimens or positive results of serologic testing for Cryptococcus spp. The latex agglutination procedure for detection of cryptococcal capsular antigen can be performed on samples of body fluids, such as serum, urine, or CSF, and is a highly sensitive and specific test for diagnosis of cryptococcal infection.6

The mainstay of treatment for cryptococcosis is administration of antifungal drugs. Commonly used antifungal drugs include azole antifungals and amphotericin B, which selectively interfere with fungal cell membranes via inhibition of synthesis or binding of ergosterol, a component of the cell wall of fungi. These antifungals are fungistatic, necessitating long-term treatment (durations of months to years). Antifungal administration is continued until affected animals are seronegative. Regular serologic monitoring (4 to 6 times each year) should be performed to guide treatment until clinical remission and seronegativity are achieved.

In some affected animals, corticosteroids administered at anti-inflammatory dosages also may be judiciously used to improve clinical signs. Corticosteroids also may improve survival rate by ameliorating inflammation, which can intensify related to die-off of fungi during treatment. In humans with CNS cryptococcosis, corticosteroid administration may be used to improve signs related to new lesions, enlargement of previous lesions, or perilesional edema that may develop after starting antifungal treatment.7

The dog of the present report was treated in the hospital with fluconazole (10 mg/kg [4.5 mg/lb], PO, q 12 h), phenobarbital (2 mg/kg [0.9 mg/lb], PO, q 12 h), dexamethasone sodium succinate (0.1 mg/kg [0.045 mg/lb], IV, q 24 h), and gabapentin (10 mg/kg, PO, q 8 h). After 3 days of phenobarbital administration, the dog's ataxia worsened. Consequently, the phenobarbital dosage was reduced to 1 mg/kg (0.45 mg/lb), PO, every 12 hours, which resulted in resolution of the ataxia. The dog was discharged from the hospital, and the owners were instructed to continue treatment with the same medications, with the exception of dexamethasone sodium phosphate, which was changed to prednisone (1 mg/kg, PO, q 24 h). Mentation and ataxia improved within 6 days after hospital discharge. Four weeks following hospital discharge, a neurologic examination of the dog revealed no abnormalities; the dog had had no further seizures and had gained weight. At that time, the dog's cryptococcal capsular antigen latex agglutination titer had improved to 200.

Despite appropriate antifungal treatment, ≥ 50% of affected dogs die, with CNS involvement being a predictor of death.5,8 The median survival time in dogs with cryptococcal CNS infection is 7 days from the time of diagnosis.9 In dogs that survive the first 4 days of treatment, median survival time is 190 days.

Footnotes

a.

Magnetom 3.0-T MRI Skyra, Siemens AG, Munich, Germany.

References

  • 1. Mellema LM, Samii VF, Vernau KM, et al. Meningeal enhancement on magnetic resonance imaging in 15 dogs and 3 cats. Vet Radiol Ultrasound 2002;43:1015.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Vorathavorn VI, Sykes JE, Feldman DG. Cryptococcosis as an emerging systemic mycosis in dogs. J Vet Emerg Crit Care (San Antonio) 2013;23:489497.

    • Search Google Scholar
    • Export Citation
  • 3. Trivedi SR, Sykes JE, Cannon MS, et al. Clinical features and epidemiology of cryptococcosis in cats and dogs in California: 93 cases (1988–2010). J Am Vet Med Assoc 2011;239:357369.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. O'Brien CR, Krockenberger MB, Wigney DI, et al. Retrospective study of feline and canine cryptococcosis in Australia from 1981 to 2001: 195 cases. Med Mycol 2004;42:449460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Duncan C, Stephen C, Campbell J. Clinical characteristics and predictors of mortality for Cryptococcus gattii infection in dogs and cats of southwestern British Columbia. Can Vet J 2006;47:993998.

    • Search Google Scholar
    • Export Citation
  • 6. Malik R, McPetrie R, Wigney DI, et al. A latex cryptococcal antigen agglutination test for diagnosis and monitoring of therapy for cryptococcosis. Aust Vet J 1996;74:358364.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Chen SC, Korman TM, Slavin MA, et al. Antifungal therapy and management of 211 complications of cryptococcosis due to Cryptococcus gattii. Clin Infect Dis 2013;57:543551.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. O'Brien CR, Krockenberger MB, Martin P, et al. Long-term outcome of therapy for 59 cats and 11 dogs with cryptococcosis. Aust Vet J 2006;84:384392.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Sykes JE, Sturges BK, Cannon MS, et al. Clinical signs, imaging features, neuropathology, and outcome in cats and dogs with central nervous system cryptococcosis from California. J Vet Intern Med 2010;24:14271438.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Figure 1—

    Magnetic resonance images of the brain of a 2-year-old Bernese Mountain Dog that was evaluated because of dull mentation following an episode of status epilepticus. A—Transverse T2-weighted image. At the level of the rostral cerebrum, hyperintensity is observed in the white matter of the internal capsule and areas of the lentiform nuclei bilaterally (arrows) The hyperintense signal of the CSF normally present in the sulci is absent, suggesting brain swelling. B—Transverse T1-weighted image obtained at the same level as that in panel A after administration of contrast medium. There is a leptomeningeal pattern of contrast enhancement wherein meningeal enhancement is present within sulci of the cerebrum (large open arrowhead) and along the cerebral longitudinal fissure (small open arrowhead). A small well-defined round lesion consistent with a granuloma is adjacent to the meninges overlying the piriform lobe (small arrow). Hypointensity within the internal capsule is consistent with edema (large arrows). C—Dorsal T1-weighted image obtained at the level of the mid diencephalon after administration of contrast medium. The olfactory bulbs and rostral aspect of the cerebral hemispheres are heterogeneously contrast enhancing (arrowhead). Enhancement along the meninges within the cerebral longitudinal fissure (small arrow) is observed. D— Midline sagittal T2-weighted image. The olfactory bulb and rostral aspect of the cerebrum are hyperintense, and there is a loss of delineation of the sulci (large arrow). The lateral ventricle is compressed. There is a focal hyperintensity in the midbrain (small white arrowhead).

  • 1. Mellema LM, Samii VF, Vernau KM, et al. Meningeal enhancement on magnetic resonance imaging in 15 dogs and 3 cats. Vet Radiol Ultrasound 2002;43:1015.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Vorathavorn VI, Sykes JE, Feldman DG. Cryptococcosis as an emerging systemic mycosis in dogs. J Vet Emerg Crit Care (San Antonio) 2013;23:489497.

    • Search Google Scholar
    • Export Citation
  • 3. Trivedi SR, Sykes JE, Cannon MS, et al. Clinical features and epidemiology of cryptococcosis in cats and dogs in California: 93 cases (1988–2010). J Am Vet Med Assoc 2011;239:357369.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. O'Brien CR, Krockenberger MB, Wigney DI, et al. Retrospective study of feline and canine cryptococcosis in Australia from 1981 to 2001: 195 cases. Med Mycol 2004;42:449460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Duncan C, Stephen C, Campbell J. Clinical characteristics and predictors of mortality for Cryptococcus gattii infection in dogs and cats of southwestern British Columbia. Can Vet J 2006;47:993998.

    • Search Google Scholar
    • Export Citation
  • 6. Malik R, McPetrie R, Wigney DI, et al. A latex cryptococcal antigen agglutination test for diagnosis and monitoring of therapy for cryptococcosis. Aust Vet J 1996;74:358364.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. Chen SC, Korman TM, Slavin MA, et al. Antifungal therapy and management of 211 complications of cryptococcosis due to Cryptococcus gattii. Clin Infect Dis 2013;57:543551.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8. O'Brien CR, Krockenberger MB, Martin P, et al. Long-term outcome of therapy for 59 cats and 11 dogs with cryptococcosis. Aust Vet J 2006;84:384392.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. Sykes JE, Sturges BK, Cannon MS, et al. Clinical signs, imaging features, neuropathology, and outcome in cats and dogs with central nervous system cryptococcosis from California. J Vet Intern Med 2010;24:14271438.

    • Crossref
    • Search Google Scholar
    • Export Citation

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