Signalment:  

6-year-old male Newfoundland Dog, Canis familiarsThe animal presented to the small animal hospital at the University of Glasgow with acute tetraparesis following development of left thoracic limb lameness. MR imaging revealed the brainstem to be moderately atrophied with uneven margins. In addition MR imaging revealed that the cervical spinal cord was markedly atrophied with uneven and distorted margins, with an associated compensatory increase of surrounding CSF and faint intramedullary changes most apparent centrally within the cord.

Gross Description:  

On macroscopic examination, the brain was unremarkable but the brainstem and cervical spinal cord were moderately to markedly atrophic with increased CSF within the cervical region in concordance with MRI findings.

Histopathologic Description:

Large numbers of ovoid to irregular, eosinophilic, intra-astrocytic hyaline structures consistent with Rosenthal fibers were distributed throughout the cerebellum, brainstem and spinal cord and to a lesser extent within supratentorial regions. Rosenthal fibers were most prominent within the subependymal and perivascular areas and within the subpial glia limitans, as would be expected for areas which ordinarily contain dense networks of astrocytic processes. Rosenthal fibers were found predominantly within the white matter but also to a lesser extent within the grey matter. Within affected areas, especially in the most severely affected areas of white matter there are also moderate numbers of abnormal astrocytes with large amounts of eosinophilic cytoplasm and marked karyomegaly. Occasional binucleate astrocytes were also noted in severely affected areas. Areas of white matter exhibiting the highest numbers of Rosenthal fibers, including the cerebellum, dorsal medulla oblongata, dorsal cervical spinal cord and piriform lobe, were also characterized by severe rarefaction of the surrounding white matter. 

Rosenthal fibers, particularly at their periphery, show moderate GFAP immunostaining and moderate to strong ubiquitin immunostaining. 

Morphologic Diagnosis:  

Brain, cerebellum, brainstem and spinal cord: Encephalomyelopathy, multifocal, severe with subpial, perivascular and periependymal Rosenthal fiber accumulation, astrocytosis and astrocytic hypertrophy, consistent with Type II Alexander disease.

Condition:  

Rosenthal fibers encephalopathy

Contributor Comment:  

The presence of Rosenthal fiber accumulation within the CNS is not a pathognomonic lesion of Alexander-like disease. Rosenthal fibers may be found in a variety of conditions including reactive astrocytosis and in some astrocytomas and the diagnosis of an Alexander-like disease must be based on recognition of the distribution of Rosenthal fibers within the CNS most prominently within the subpial glia limitans and in perivascular and periependymal locations. (13)

Alexanders disease in man is a primary astrocytic disorder with approximately 95% of patients harboring mutations in the GFAP gene. The age of onset is variable with cases reported from the prenatal period through until the sixth decade of life. (7) Alexanders disease is classically divided into infantile (0-2 years), juvenile (2-12 years) and adult (>12 years) onset forms however more recently a new classification limited to two categories (type I and type II) has been proposed focusing on lesion distribution and clinical presentation. (10) In the case of the two category classification, system age of onset remained a powerful predictor of disease type. It has been shown that phenotypic pattern and disease course alone more accurately classify cases of Alexander disease and whereas all type I cases presented at an early age, type II cases occurred at all ages although generally with a later onset than type I cases. Type I disease is typically characterized by early onset commonly with seizures, spasticity, or developmental delays and diagnosis can be made based on the presence of at least four of the following five features on MR imaging: extensive cerebral white matter changes with a frontal predominance, a periventricular rim with high signal on T1-weighted images and low signal on T2-weighted images, abnormalities of the basal ganglia and thalami, brain stem abnormalities, and contrast enhancement of the ventricular lining, periventricular tissue or white matter of the frontal lobes, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, or brain stem structures.(10,12) Type II disease is typically later in onset and more often presents with signs of hindbrain dysfunction such as ataxia, palatal myoclonus and dysphagia. MR findings in type II disease show hindbrain predominance with atrophy of the medulla oblongata and cervical spinal cord. (4,5,8,9)

There have been seven previous reports of Alexander disease in the dog, all of which predate the new human classification system.(1,2,3,6,11,14) Due to the distribution of lesions in this case with pronounced atrophy of the cervical spinal cord, Type II Alexander disease was diagnosed.

JPC Diagnosis:  

Cerebellum: Hypertrophy, astrocytic processes, with accumulation of intermediate filament (Rosenthal fibers), diffuse, severe, with Purkinje and granular cell loss. Spinal cord, cervical: Hypertrophy, astrocytic processes, dorsal funiculi and subependymal, with accumulation of intermediate filament (Rosenthal fibers), moderate. 

Conference Comment:  

This is a rarely reported disease in the veterinary literature, thus much of its understanding is derived from the documented cases in people where a functional mutation of the dominant GFAP gene has been identified.(1) The genetic equivalent in dogs has not been determined, although the similarities in presentation between animals and people strongly suggests a correlation. Rosenthal fibers consist of three major chemical components: GFAP, small heat shock proteins, and ubiquitin.(1) Their presence translates into increased expressivity with immunohistochemistry for GFAP, and coupled with their perivascular and periependymal location, are diagnostic for Alexanders disease (AD).(1) In AD, the mutant GFAP proteins are unable to form intermediate filaments and precipitate in aggregrates to cause derangements of astrocytic functions.(9) With the multiple functions of astrocytes, to include regulating the microenvironment of the CNS, repairing injured nervous tissue, and providing structural support;(15) it is reasonable to conclude their dysfunction can result in a variety of central nervous clinical manifestations. Among cases reported in dogs, depression, generalized tremors, progressive tetraparesis, spinal reflex deficits, and ataxia have all been observed.(1,11,14) The contributor described the different classifications of AD, and all previously reported cases in the dog could be considered the juvenile, or type II, form.(1)

References:

1. Alema+�-� N, Marcaccini A, Espino L, et al. Rosenthal fiber encephalopathy in a dog resembling Alexander disease in humans. Vet Pathol. 2006; 43: 1025-1028

2. Andrews EJ, Ward BC, Altman NH. Spontaneous animal models of human disease Elsevier; 1980

3. Cox NR, Kwapien RP, Sorjonen DC, et al. Myeloencephalopathy resembling Alexanders disease in a Scottish terrier dog. Acta Neuropathol. 1986; 71: 163-166

4. Farina L, Pareyson D, Minati L, et al. Can MR imaging diagnose adult-onset Alexander disease? AJNR Am J Neuroradiol 2008; 29: 1190-1196

5. Graff-Radford J, Schwartz K, Gavrilova RH, et al. Neuroimaging and clinical features in type II (late-onset) Alexander disease. Neurology 2014; 82: 49-56

6. Ito T, Uchida K, Nakamura M, et al. Fibrinoid leukodystrophy (Alexanders disease-like disorder) in a young adult French bulldog. J Vet Med Sci. 2010; 72: 1387-1390

7. Messing A, Brenner M, Feany MB, et al. Alexander disease. J Neurosci. 2012; 32: 5017-5023

8. Namekawa M, Takiyama Y, Honda J, et al. Adult-onset Alexander disease with typical tadpole brainstem atrophy and unusual bilateral basal ganglia involvement: a case report and review of the literature. BMC neurology 2010; 10: 21

9. Pareyson D, Fancellu R, Mariotti C, et al. Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature. Brain 2008; 131: 2321-2331

10. Prust M, Wang J, Morizono H, et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 2011; 77: 1287-1294

11. Richardson JA, Tang K, Burns DK. Myeloencephalopathy with Rosenthal fiber formation in a miniature poodle. Vet Pathol. 1991; 28:536-538

12. van der Knaap MS, Naidu S, Breiter SN, et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiolv 2001; 22: 541-552

13. Vandevelde M, Higgins R, Oevermann A. Veterinary Neuropathology: Essentials of Theory and Practice. John Wiley and Sons; 2012

14. Weissenbock H, Obermaier G, Dahme E. Alexanders disease in a Bernese mountain dog. Acta Neuropathol 1996; 91: 200-204

15. Zachary JF. Nervous system. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Elsevier Mosby; 2012:776-777.