A 4-year-old 6.2-kg (13.6-lb) castrated male terrier-Poodle mixed-breed dog was evaluated because of a 6-month history of bruxism (initially occurring only during stressful events, but progressively worsening), falling, stumbling, bumping into walls and objects, head tremors, pecking motions, behavior changes, urinating and defecating in the house, and not sleeping at night (restlessness and barking). Prior to the referral evaluation, a CBC and serum biochemical profile revealed no abnormalities; an oral cavity examination performed when the dog was sedated did not identify the cause of the bruxism. The dog had been treated with gabapentin (8 mg/kg [3.6 mg/lb], PO, 2 hours before a stressful event), which caused lethargy. Gabapentin administration was discontinued 14 days prior to the referral evaluation. Neurologic examination revealed bright mentation with hyperreactivity to stimuli around the face, absent menace response in the right eye (intermittently absent in the left eye), normal to minimal pupillary light reflexes bilaterally, intermittent right or left head tilt, intention tremors, vestibular and cerebellar ataxia, delayed postural reactions in all 4 limbs, and normal withdrawal reflexes in all 4 limbs.
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Assessment Anatomic diagnosis
Problem | Rule out location |
---|---|
Bruxism | Basal ganglia, cranial nerve V (motor nucleus of mandibular branch in the pons), muscles of mastication, or oral cavity |
Vestibular and cerebellar ataxia | Caudal fossa (vestibular nuclei of medulla and cerebellum); less likely, bilateral involvement of the peripheral vestibular system |
Intermittent right and left head tilt | Caudal fossa (vestibular nuclei of medulla and cerebellum); less likely, bilateral involvement of the peripheral vestibular system |
Absent menace response in the right eye | Right cranial nerve II, optic chiasm, optic tract, prosencephalon or thalamocortex, or right region of the cerebellum |
Intention tremors | Cerebellum |
Hyperreactivity to stimuli or hyperesthesia of the face | Cranial nerve V or caudal fossa |
Delayed hopping and postural reactions in all 4 limbs | Multifocal lesion of the prosencephalon, midbrain, pons, or medulla or C1-C5 myelopathy |
Likely location of 1 lesion
Clinical signs could be attributed to a lesion in the caudal fossa or a lesion with a multifocal intracranial localization (prosencephalon, midbrain, pons, medulla, cerebellum, and caudal fossa).
Etiologic diagnosis—Differential diagnoses for a progressive onset of cerebellar, central vestibular, and prosencephalic signs included degenerative disease, infectious or inflammatory process, or neoplasia. Given the dog's young age, a degenerative disease such as a lysosomal storage disorder was considered to be more likely and neoplasia was considered to be less likely. Differential diagnoses for the bruxism included a lesion associated with the oral cavity or temporomandibular joint or a behavioral response to stress and anxiety. Clinicopathologic analyses and an oral cavity examination had been performed at the referring veterinary hospital. In addition, the dog had been tested for circulating Dirofilaria immitis antigen and antibodies against Anaplasma phagocytophilum, Anaplasma platys, Borrelia burgdorferi, Ehrlichia canis, and Ehrlichia ewingii, and the results were all negative. The initial diagnostic plan included MRI of the brain to investigate for abnormalities, followed by analysis of a CSF sample if indicated.
Diagnostic test findings—The dog underwent MRI of the brain with a 1.5-T unit,a and sagittal plane T2-weighted images; transverse plane T2-weighted, fluid-attenuated inversion recovery, T1-weighted, T1-weighted with contrast agentb administration, T2-weighted gradient echo, diffusion-weighted, and apparent diffusion coefficient images; and dorsal plane T1-weighted and T1-weighted postcontrastb images were obtained.
The MRI examination revealed severe dilation of the lateral, third, and fourth ventricles and diffuse widening of the cerebral sulci (Figure 1). The thalamus and basal nuclei were also considered small. On the sagittal plane T2-weighted images, the interthalamic adhesion appeared irregular in shape and atrophied and the cerebellum was small and had markedly prominent folia surrounded by an increased amount of CSF. In addition, the interthalamic adhesion thickness was decreased (2.5 mm on T2-weighted images and 3.0 mm on T1-weighted images; mean thickness, 2.75 mm), compared with the thickness expected in clinically normal dogs (reported range,1 6.09 to 7.49 mm). Overall, the MRI examination findings were indicative of severe cerebral and cerebellar atrophy. The presumptive diagnosis for this dog was degenerative disease, and imaging was most consistent with neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder.
In the absence of specific treatment options for dogs with NCL apart from supportive care, the dog was treated with gabapentin (2 mg/kg [0.9 mg/lb], PO) and trazodone (2 mg/kg, PO) as needed for anxiety. The overall prognosis for the dog was poor but variable with regard to the rates of disease progression and decline of clinical status. Recommendations were made to monitor the dog for worsening of neurologic signs and potential development of seizures. Five months after the referral evaluation (approx 1 year since initial onset of signs), the dog was euthanized (by an intravenous injection of euthanasia solution) because of progression of the disease and poor quality of life; a necropsy was performed.
Histopathologic findings included an atrophied cerebral cortex with secondary dilation of the lateral ventricles and widening of the sulci. Diffusely in the cerebral cortical, cerebellar, and spinal cord gray matter, there was moderate to severe neuronal degeneration and nearly all neurons contained abundant globular eosinophilic cytoplasmic pigment (intracytoplasmic granular pigment) that stained positively with periodic acid-Schiff stain. There was mild gliosis and multifocal spongiosis of the forebrain with rare neuronal necrosis. The white matter throughout the spinal cord had mild multifocal Wallerian degeneration. On the basis of the appearance and distribution of the pigment and associated lesions, these findings were most consistent with NCL, although definitive diagnosis would have required genetic testing of the dog or electron microscopic examination of affected tissue specimens.
Comments
Neuronal ceroid lipofuscinoses are a group of rare, inherited, neurodegenerative lysosomal storage diseases that are characterized by the presence of brain atrophy and accumulation of intracellular fluorescent storage cytosomes that resemble the lipopigments ceroid and lipofuscin.2 Neuronal ceroid lipofuscinosis is a disease of humans and other animals and has been identified in cattle, sheep, goats, cats, and dogs of several breeds including American Bulldogs, Dalmatians, English Setters, Dachshunds, Salukis, Border Collies, Australian Cattle Dogs, and Chihuahuas.2 There are different types of NCL and each type may behave differently; in humans, NCL has been classified into the acute infantile, acute late infantile, chronic juvenile (Batten disease), and chronic or subacute adult types among several others.3
Genetic mutations causing NCL have been found in Dachshunds, Border Collies, Australian Cattle Dogs, English Setters, American Bulldogs, and Chihuahuas.4–9 Age of onset of the disease has been documented to vary from 6 months to 4 to 6 years of age and, in some cases, 6 to 8 years of age.2 Typical clinical signs of NCL may include blindness, changes in personality, loss of learned behaviors, tremors, cerebellar ataxia, decline in cognitive and motor function, sleep disturbance, and seizures.10
The case described in the present report was interesting because the dog was a mix of breeds (unknown terrier type and Poodle). In Tibetan Terriers, a genetic mutation has been identified as the cause of NCL; however, Poodles may develop suspected NCL with an unknown genetic cause or no molecular genetic confirmation.10 The dog's age at onset of clinical signs, nature of the clinical signs, and MRI findings were consistent with previous reports of NCL.2,11,12 For the dog of the present report, the ventriculomegaly, dilation of cerebral sulci, and cerebral and cerebellar atrophy were very similar to MRI findings for 3 longhaired Chihuahuas with NCL.12 However, it is interesting to note that those Chihuahuas had an earlier onset of clinical signs (at 16 to 18 months of age) and died at 23 or 24 months of age as a result of disease progression12; in contrast, the dog of the present report did not have an onset of clinical signs until approximately 3.5 years of age and was euthanized at 4.5 years of age.
Another unique feature of the case described in the present report was the dog's initial clinical sign of bruxism. Bruxism has not typically been described for or associated with NCL in dogs, although it has been noted to develop in sheep with NCL.13 For humans in general, 2 theories (ie, peripheral or local vs central problems) have been proposed regarding the cause of bruxism or teeth grinding, namely occlusion or nonfunctional contact of mandibular and maxillary teeth (peripheral or local theory), or CNS disturbances such as imbalances of circuit processing in the area of the basal ganglia (central theory).14 That second theory is favored in cases of sleep-related bruxism because the basal ganglia have a role in sleep, and an imbalance in basal ganglia circuit processing may lead to muscle hyperactivity, such as sleep-related bruxism.14 The dog of the present report also had signs of sleep disturbances at home, including restlessness and barking at night. On the assumption that bruxism is associated with basal ganglia disturbances in humans, it is interesting to consider whether the bruxism of the dog of the present report could have been attributed to the small thalamus and basal nuclei, as detected by MRI. Bruxism has also been described for a human following a thalamic and caudate infarct.15
For dogs with NCL, prognosis is poor, and times from initial onset of clinical signs to disease progression leading to euthanasia can range from weeks to months to a few years; survival times are variable because of the diversity of NCL subtypes and their biological behaviors.10 The disease is rare, and there may be difficulties in diagnosis of NCL if diagnostic investigations, such as MRI, are not performed prior to euthanasia of affected dogs. Progression of the disease and poor prognosis may also play a role in clients’ decisions to pursue or decline further diagnostic testing of their dogs. Veterinarians should be able to recognize the common clinical signs associated with NCL in dogs and include the disease in the differential diagnosis list for canine patients when appropriate.
Footnotes
GE LX 1.5-T MR scanner, GE Healthcare, Milwaukee, Wis.
Magnevist (gadopentetate dimeglumine), Bayer HealthCare Pharmaceuticals, Wayne, NJ.
References
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