History
A 4-year-old spayed female American Staffordshire Terrier mix was presented for a multiple-week history of progressive ataxia and collapsing episodes. Approximatively 2 weeks prior to presentation, the owner reported that the dog started slightly dragging the pelvic limbs and kicking up grass during running. By 1 week prior to presentation, the dog was reportedly swaying when walking and was collapsing after running about 20 feet. The patient was current on vaccinations with an otherwise unremarkable medical history.
On presentation, the patient’s general physical examination was unremarkable. The patient appeared to experience episodes of collapse during activity but, after resting for short periods, recovered uneventfully (Supplementary Video S1). At presentation, a neurological examination was performed.
Assessment
Anatomic diagnosis
In this dog, the collapse after short periods of activity could be suggestive of a neuromuscular condition. However, tetraparesis or systemic weakness was not consistently seen, making a neuromuscular condition less likely. Collapse could also occur due to a loss of balance from vestibular or cerebellar disease and may coincide with leaning, falling, or a wide-based stance. In this case, the collapse was noted to occur with sudden movements of the head. Additionally, the intermittent hypermetria, ataxia, and swaying of the head, neck, and trunk suggest a cerebellovestibular ataxia, consistent with a cerebellar lesion.
Likely location of the lesion
The cerebellum was considered the most likely location of the lesion.
Etiologic diagnosis
Differential diagnoses for progressive cerebellar disease included autoimmune (meningoencephalitis of unknown etiology) or infectious (bacterial encephalitis, fungal encephalitis [Cryptococcus neoformans or Coccidioides immitis], viral encephalitis [canine distemper virus or rabies virus], or parasitic [Toxoplasma gondii or Neospora caninum] infection) diseases. Given the patient’s age, neoplastic diseases (such as medulloblastoma and lymphoma) and degenerative diseases (such as cerebellar cortical degeneration of American Staffordshire Terriers) were considered. Acquired myasthenia gravis was considered unlikely but could not be completely ruled out as a potential concurrent disease, to explain the episodes of exercise-related collapse.
Diagnostic Test Findings
Clinicopathologic analyses (CBC and serum biochemical analyses including creatine kinase levels) as well as thoracic radiography were performed and were all within normal limits. Serum acetylcholine receptor antibody titers were sent out for quantification.
MRI of the brain and cervical spinal cord was performed with a high-field MRI scanner (3T; Philips). Sagittal (Figure 1) and transverse T2-weighted images as well as sagittal, transverse, and dorsal T1-weighted images (before and after gadolinium contrast administration) were obtained. Transverse images were also acquired using T2* gradient recalled echo, T2-weighted FLAIR, diffusion weighted imaging, and apparent diffusion coefficient map sequences. MRI revealed diffuse cerebellar cortical atrophy. Based on the MRI findings, the top differential was cerebellar cortical degeneration of American Staffordshire Terriers. Blood was submitted for genetic testing. To further rule out other causes, CSF was collected from the cerebellomedullary cistern and was normal. On recovery from anesthesia, a transient spontaneous horizontal nystagmus was appreciated. The patient was discharged the following day to the owners’ care with plans to monitor for signs of progression.
Sagittal T2-weighted MRI images from a 4-year-old spayed female Staffordshire Terrier (A) that was evaluated for progressive ataxia and episodes of collapse that localized to the cerebellum. Note the cerebellar cortical atrophy characterized by secondary widening of the cerebellar sulci with CSF, outlining hypointense white matter tracts (*). These findings are consistent with cerebellar cortical degeneration of American Staffordshire Terriers. Sagittal T2-weighted MRI from an age- and weight-matched clinically normal Labrador Retriever (B) with idiopathic (suspected genetic) epilepsy showing normal cerebellar structure for comparison. Note the abundance of visible cerebellar cortex (**) between hypointense white matter tracts, with minimal CSF in the cerebellar sulci.
Citation: Journal of the American Veterinary Medical Association 261, 10; 10.2460/javma.23.04.0194
Sagittal T2-weighted MRI images from a 4-year-old spayed female Staffordshire Terrier (A) that was evaluated for progressive ataxia and episodes of collapse that localized to the cerebellum. Note the cerebellar cortical atrophy characterized by secondary widening of the cerebellar sulci with CSF, outlining hypointense white matter tracts (*). These findings are consistent with cerebellar cortical degeneration of American Staffordshire Terriers. Sagittal T2-weighted MRI from an age- and weight-matched clinically normal Labrador Retriever (B) with idiopathic (suspected genetic) epilepsy showing normal cerebellar structure for comparison. Note the abundance of visible cerebellar cortex (**) between hypointense white matter tracts, with minimal CSF in the cerebellar sulci.
Citation: Journal of the American Veterinary Medical Association 261, 10; 10.2460/javma.23.04.0194
Sagittal T2-weighted MRI images from a 4-year-old spayed female Staffordshire Terrier (A) that was evaluated for progressive ataxia and episodes of collapse that localized to the cerebellum. Note the cerebellar cortical atrophy characterized by secondary widening of the cerebellar sulci with CSF, outlining hypointense white matter tracts (*). These findings are consistent with cerebellar cortical degeneration of American Staffordshire Terriers. Sagittal T2-weighted MRI from an age- and weight-matched clinically normal Labrador Retriever (B) with idiopathic (suspected genetic) epilepsy showing normal cerebellar structure for comparison. Note the abundance of visible cerebellar cortex (**) between hypointense white matter tracts, with minimal CSF in the cerebellar sulci.
Citation: Journal of the American Veterinary Medical Association 261, 10; 10.2460/javma.23.04.0194
Sagittal T2-weighted MRI images from a 4-year-old spayed female Staffordshire Terrier (A) that was evaluated for progressive ataxia and episodes of collapse that localized to the cerebellum. Note the cerebellar cortical atrophy characterized by secondary widening of the cerebellar sulci with CSF, outlining hypointense white matter tracts (*). These findings are consistent with cerebellar cortical degeneration of American Staffordshire Terriers. Sagittal T2-weighted MRI from an age- and weight-matched clinically normal Labrador Retriever (B) with idiopathic (suspected genetic) epilepsy showing normal cerebellar structure for comparison. Note the abundance of visible cerebellar cortex (**) between hypointense white matter tracts, with minimal CSF in the cerebellar sulci.
Citation: Journal of the American Veterinary Medical Association 261, 10; 10.2460/javma.23.04.0194
Sagittal T2-weighted MRI images from a 4-year-old spayed female Staffordshire Terrier (A) that was evaluated for progressive ataxia and episodes of collapse that localized to the cerebellum. Note the cerebellar cortical atrophy characterized by secondary widening of the cerebellar sulci with CSF, outlining hypointense white matter tracts (*). These findings are consistent with cerebellar cortical degeneration of American Staffordshire Terriers. Sagittal T2-weighted MRI from an age- and weight-matched clinically normal Labrador Retriever (B) with idiopathic (suspected genetic) epilepsy showing normal cerebellar structure for comparison. Note the abundance of visible cerebellar cortex (**) between hypointense white matter tracts, with minimal CSF in the cerebellar sulci.
Citation: Journal of the American Veterinary Medical Association 261, 10; 10.2460/javma.23.04.0194
Acetylcholine receptor antibody titers were later confirmed to be normal at a concentration of 0.01 nmol/L (reference range, < 0.6 nmol/L), further helping rule out myasthenia gravis. Genetic testing for cerebellar cortical degeneration of American Staffordshire Terriers confirmed the patient had 2 mutant copies of the ARSG gene. The patient was euthanized 2 months following diagnosis due to progressively worsening cerebellar dysfunction such that the patient could minimally ambulate at time of euthanasia. Necropsy was performed, and histopathology confirmed cerebellar cortical atrophy with loss of Purkinje neurons and hypocellularity within the granule cell layer (Figure 2). Pigment accumulation was identified within the remaining Purkinje neurons and stained positive on periodic acid–Schiff stain. These findings were consistent with a degenerative lysosomal storage disorder: cerebellar cortical degeneration of American Staffordshire Terriers.
Low-magnification photomicrographs of cerebellar folia from the affected dog (A and B) and a clinically normal age- and breed-matched control (C). A and C: H&E stain; bar = 140 μm. B: Periodic acid–Schiff (PAS) stain; bar = 140 μm. Note the overall pallor in the cerebellar cortex on H&E stain and loss of Purkinje neurons in A compared with C. The few existing Purkinje neurons show PAS stain uptake (white arrowheads). High-magnification photomicrographs of the cerebellar cortex from the affected dog (D and E) and the normal age- and breed-matched control (F). D and F: H&E stain; bar = 25 μm. E: PAS stain; bar = 25 μm. Note the vacuolation and relative lack of granule cells (black arrowhead) and Purkinje neurons (*) in D, compared with F. The remaining Purkinje neurons (white arrowhead; E), show PAS-positive granules consistent with lysosomal storage products.
Citation: Journal of the American Veterinary Medical Association 261, 10; 10.2460/javma.23.04.0194
Low-magnification photomicrographs of cerebellar folia from the affected dog (A and B) and a clinically normal age- and breed-matched control (C). A and C: H&E stain; bar = 140 μm. B: Periodic acid–Schiff (PAS) stain; bar = 140 μm. Note the overall pallor in the cerebellar cortex on H&E stain and loss of Purkinje neurons in A compared with C. The few existing Purkinje neurons show PAS stain uptake (white arrowheads). High-magnification photomicrographs of the cerebellar cortex from the affected dog (D and E) and the normal age- and breed-matched control (F). D and F: H&E stain; bar = 25 μm. E: PAS stain; bar = 25 μm. Note the vacuolation and relative lack of granule cells (black arrowhead) and Purkinje neurons (*) in D, compared with F. The remaining Purkinje neurons (white arrowhead; E), show PAS-positive granules consistent with lysosomal storage products.
Citation: Journal of the American Veterinary Medical Association 261, 10; 10.2460/javma.23.04.0194
Low-magnification photomicrographs of cerebellar folia from the affected dog (A and B) and a clinically normal age- and breed-matched control (C). A and C: H&E stain; bar = 140 μm. B: Periodic acid–Schiff (PAS) stain; bar = 140 μm. Note the overall pallor in the cerebellar cortex on H&E stain and loss of Purkinje neurons in A compared with C. The few existing Purkinje neurons show PAS stain uptake (white arrowheads). High-magnification photomicrographs of the cerebellar cortex from the affected dog (D and E) and the normal age- and breed-matched control (F). D and F: H&E stain; bar = 25 μm. E: PAS stain; bar = 25 μm. Note the vacuolation and relative lack of granule cells (black arrowhead) and Purkinje neurons (*) in D, compared with F. The remaining Purkinje neurons (white arrowhead; E), show PAS-positive granules consistent with lysosomal storage products.
Citation: Journal of the American Veterinary Medical Association 261, 10; 10.2460/javma.23.04.0194
Comments
Lysosomal storage disorders are neurodegenerative, autosomal recessive disorders where a patient is deficient in specific enzymes associated with lysosomal catabolic pathways.1,2 This leads to accumulation of various toxic materials within neurons, with cerebellar Purkinje neurons being especially sensitive due to their high metabolic demands.2,3 Clinical signs often present in young animals < 6 months of age, but select conditions in specific breeds have been associated with a later onset of signs.3
American Staffordshire Terriers experience a late-onset lysosomal storage disorder secondary to a mutation of the ARSG gene.1,2 This condition was originally called cerebellar cortical degeneration of American Staffordshire Terriers and is colloquially known as cerebellar abiotrophy or cerebellar ataxia; however, it since has been reclassified several times.1–4 Initially, it was thought to be a form of neuronal ceroid lipofuscinosis and was termed NCL-4A.1 However, recent research with ARSG knockout mice has suggested that this disease is a type of mucopolysaccharidosis.4 Due to the multiple reclassifications and continued research on this disorder, the terminology throughout the literature remains inconsistent. However, it is important to consider this condition when working with juvenile to older American Staffordshire Terriers with progressive cerebellar disease.
In American Staffordshire Terriers with this disease, the age of onset of clinical signs has been reported to vary from 18 months to 9 years, with the majority of patients developing neurological signs between the ages of 4 and 6 years.3 Most commonly, these patients are initially identified by owners as stumbling especially when attempting to navigate stairs, corners, and hills and jumping up onto objects.3 The patient may also display mild sway of the head, neck, and trunk; intermittent recumbency with opisthotonus or full-body jerks; and stiffening during sleep.3 As signs progress, they display thoracic and/or pelvic limb hypermetria, a wide-based stance, truncal sway, falls when moving or shaking their heads, and markedly worsening signs with sudden movements and excitement due to overcompensation.3 Some patients also develop spontaneous or positional nystagmus or an intermittent head tilt.3 Most notably, patients have an otherwise unremarkable cranial nerve examination, have no conscious proprioceptive deficits, and appear normal when walked in a straight line without sharp movements or inclines.3
MRI findings reveal generalized cerebellar cortical atrophy with increased CSF between the folia of the cerebellum.3 CSF analysis is classically unremarkable, and histopathology reveals marked loss of Purkinje neurons within the cerebellum.3 A strong clinical suspicion and working diagnosis can be made based on MRI findings and genetic testing antemortem.5 Unfortunately, there is no treatment available at this time, and patients with this disorder are usually euthanized within 6 months to 6.5 years due to loss of the ability to ambulate.3
In this report, neurolocalization based on examination findings was made to the cerebellum due to the intermittent hypermetria, generalized cerebellovestibular ataxia, and sway of the head, neck, and trunk. As the patient was seen to collapse during activity, initially neuromuscular disease such as myasthenia gravis was also considered. However, with further careful gait examination outdoors, the amount of activity prior to collapse was variable, and collapse was consistently seen following sudden head and neck movements (Supplementary Video S1). In some instances of cerebellar disease, dysregulation of the vestibular and cerebellar systems can occur, resulting in loss of balance and overcompensation, especially with sudden turns or movements of the head. This may cause collapse or recumbency with or without opisthotonos, as seen in the patient of this report. A thorough neurological examination, including gait assessment in various environments, such as up and down inclines, or walking with the head raised, can be helpful in further differentiating collapse due to cerebellar dysfunction from exercise-induced weakness due to neuromuscular disease and other causes.
This report highlights the presentation and diagnosis of a relatively common lysosomal storage disorder as well as the importance of a thorough neurological examination and diagnostic workup, including genetic testing.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org
Acknowledgments
The authors declare that there are no conflicts of interest. No third-party funding or support was received in connection with this case or the writing or publication of the manuscript.
References
- 1.↑
Abitbol M, Thibaud JL, Olby NJ, et al.A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A. 2010;107(33):14775-14780.
- 2.↑
Katz ML, Rustad E, Robinson GO, et al.Canine neuronal ceroid lipofuscinoses: promising models for preclinical testing of therapeutic interventions. Neurobiol Dis. 2017;108:277-287.
- 3.↑
Olby N, Blot S, Thibaud J-L, et al.Cerebellar cortical degeneration in adult American Staffordshire Terriers. J Vet Intern Med. 2004;18(2):201-208.
- 4.↑
Kowalewski B, Heimann P, Ortkras T, et al.Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III). Hum Mol Genet. 2015;24(7):1856-1868.
- 5.↑
Kwiatkowska M, Pomianowski A, Adamiak Z, Bocheńska A. Magnetic resonance imaging and brainstem auditory evoked responses in the diagnosis of cerebellar cortical degeneration in American Staffordshire Terriers. Acta Vet Hung. 2013;61(1):9-18.
