Progressive ataxia due to central demyelination in Rottweiler dogs

Veterinary Quarterly ISSN: 0165-2176 (Print) 1875-5941 (Online) Journal homepage: https://www.tandfonline.com/loi/tveq20 Progressive ataxia due to central demyelination in Rottweiler dogs W. Wouda & J. J. van Nes To cite this article: W. Wouda & J. J. van Nes (1986) Progressive ataxia due to central demyelination in Rottweiler dogs, Veterinary Quarterly, 8:2, 89-97, DOI: 10.1080/01652176.1986.9694028 To link to this article: https://doi.org/10.1080/01652176.1986.9694028 Copyright Taylor and Francis Group, LLC Published online: 01 Nov 2011. Submit your article to this journal Article views: 243 Citing articles: 11 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalinformation?journalcode=tveq20

ORIGINAL PAPERS Progressive ataxia due to central demyelination in Rottweiler dogs W. Wouda' and J. J. van Nes2 SUMMARY A clinicopathological study of a neurologic disease in Rottweiler dogs was conducted. Clinical data were available on 16 dogs, 11 of which were examined pathologically. All dogs had a history of progressive gait abnormalities, which had commenced insidiously at an agevarying from 1.5 to 3.5 years. In most dogs the fore limbs were affected prior to the hind limbs. At neurologic examination ataxia of all 4 limbs was seen, in some instances accompanied by an apparent paresis. Proprioceptive positioning was delayed whereas spinal reflexes were often hyperactive. Plain and contrast radiographs of the spine did not reveal any compressive lesions in 5 dogs examined. Cerebrospinal fluid analysis in 4 dogs was normal. Electrodiagnostic testing in 3 dogs revealed no abnormalities. At pathologic examination demyelinating lesions were found in thecentral nervous system. These were largely confined to the cervical spinal cord and brain stem and had a rather characteristic more or less symmetric distribution. Pedigree data suggested that the disease is transmitted genetically. INTRODUCTION A newly recognized neurologic disease in Rottweiler dogs has been reported in the Netherlands (1). This disease is characterised clinically by progressive gait abnormalities in all 4 limbs, and pathologically by the presence of symmetric areas of demyelination in the spinal cord and brain. A leukoencephalomyelopathy, which has been recently described in 2 Rottweiler dogs from the USA (2), appears to represent the same entity. The present paper gives the results of a clinicopathologic study of this disease. Sixteen Rottweiler dogs were used for this study, eleven of which were available for pathologic examination. A pedigree analysis suggests that the disease has a genetic basis. MATERIALS AND METHODS Fourteen Rottweiler dogs were examined at the Small Animal Clinic, State University of Utrecht from 1978-1984. Nine of these dogs were necropsied, 3 dogs were not available for post-mortem examination, and 2 dogs are still alive. Two dogs with similar clinical signs were euthanatised by private practitioners and were submitted for pathologic examination. General physical and neurologic examinations as well as routine haematologic and blood chemical examinations were carried out in most dogs. Cerebrospinal fluid was examined in dogs 1, 6, 7, and 11. Plain and contrast radiographs of the spine were made in dogs 1, 2, 5, 6, and 10. Routine needle electromyographic examinaion and motor and sensory conduction studies were performed under general inhalation anaesthesia in dogs 2, 6, and 11. Dogs were euthanatised with an overdose of barbiturates. At post-mortem examination the brain and spinal cord as well as samples of various other tissues including peripheral nerves and muscles were immersed in 10% buffered formalin. Routine histological sections were made after paraffin embedding. Special stains used on CNS tissues were luxol fast blue-cresyl echt violet, and Holmes-luxol fast blue. RESULTS Signalments and histories All dogs were purebred Rottweilers, with the exception of dog 5, which was a crossbred Rottweiler. There were 4 males and 12 females. All dogs had received vaccinations against canine distemper and infectious canine hepatitis. I Department of Veterinary Pathology, State University of Utrecht, Yalelaan 1, 3508 TD Utrecht, The Netherlands. Present address: Gezondheidsdienst voor Dieren Noord Nederland, PO Box 361, 9200 AJ Drachten, The Netherlands. 2 Small Animal Clinic, State University of Utrecht, Yalelaan 1, 3508 TD Utrecht, The Netherlands. THE VETERINARY QUARTERLY, VOL. 8, No. 2, APRIL 1986 89

Table I. Main neurologic symptoms and distribution of demyelinating lesions of Rottweiler dogs in the present study. Dog number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Sex 9 d 9 9 9 d d 9 9 9 9 9 9 9 9 d Age at onset of signs (years) S' y incoordination M proprioceptive deficit P M T hypermetria O paresis S hyperreflexia D SPINAL CORD I s dorsal T dorsolaternl (superficial) n 2.9 3.2 1.8 1.6 1.7 1.5 1.5 1.9 2.5 3.5 2.5 1.9 2.2 2.1 2.5 2.5 + + + + + + + + + + + + + + + + + + NE NE + + + + + + + + + + + + + - - - + - + + - - + - - + + - + - - + + - - + - + -. + NE NE + - - - + + + + + - + + + + + + + + - NA NA - NA NA + NA + +x _ + _ + + - + x I dorsolateral (deep) + + + + + + + + + 6 ventrolateral + + - 4: - - 4-5 _ U + T ventromedial - + _ I BRAIN 0 N pyramidal tract + - + + - + + - + + O medial lemniscus - - + + - +.i. + - F spinal tract of trigeminal nerve + + + + + + + + L caudal cerebellar peduncle + + + + + + + + + E - _ S medulla cerebelli + + + + + + - + i + + I crus cerebri - - - - + 0 + - + - N optic nerve + + + + + + + + + S corona radiata - - - - + + - - - + - - + = present, - = absent, x = unilaterally, NE = not examined, NA = no autopsy,

All had a history of progressive gait abnormality. The onset of signs was insidious. The age at onset varied from 1.5 and 3.5 years with a mean of 2.2 years (Table 1). In 12 dogs signs were first noted in the fore limbs, and usually were clumsiness, knuckling and dragging. In 4 dogs the hind limbs were affected first. Signs progressively worsened during a period of several months up to 1 year. In dog 12, which was observed closely for a period of 6 months, the initially progressive course was followed by a period of gradual improvement and stabilisation of the signs. The owner of dog 7 had noticed a personality change of his dog. This dog showed a periodic hyperactivity, whined a lot, and had become disobedient. In some dogs it was mentioned that weight loss had occured concurrently with the gait abnormalities. Clinical findings On general physical examination no signs other than locomotor disturbances were seen. All dogs were bright and alert, and showed no evidence of pain. Varying degrees of ataxia of all 4 limbs were evident on examination of the gait. The ataxia was often most obvious in the fore limbs. During protraction of the fore limbs the joints were hardly flexed, and the toes were often dragged on the ground causing the nails to be worn dorsally. Some dogs showed goose-stepping with the fore limbs. Abnormal positioning, such as wide or narrow placing and crossing of the limbs, frequently occurred, as well as occasional knuckling and stumbling. When lowering the head, for sniffing the ground, the dogs often leaned on a flexed carpus. The hind limb movements were also rather stiff and incoordinated. Swaying, adduction or abduction into abnormal postures, sideways sliding of both leggs on a slippery floor, and loss of postural control during micturition and defaecation were especially noticable. One dog showed incoordination of the head. Some dogs showed obvious paresis at the time of presentation. These dogs had difficulty in rising and standing and were reluctant to move. They had no muscle atrophy and extensor tone was often increased. Cerebral reflexes were normal in all dogs. Proprioceptive positioning was delayed or absent in all limbs. Postural reactions such as hopping and placing were tested in only a few animals and were found to be decreased. Spinal reflexes were normal or exaggerated, especially the patellar reflexes. Crossed extensor reflexes could be elicited in fore and hind limbs in dogs 1, 15, and 16. Pain sensation was difficult to evaluate, but appeared to be decreased in some dogs. The main neurologic examination findings are summarised in Table I. Routine haematologic and blood chemical examination findings were normal in all dogs. Cerebrospinal fluid examination in 4 dogs revealed no abnormalities. Plain and contrast radiographs of the spine did not reveal any space occupying lesion or stenosis of the vertebral canal in any ofthe dogs examined. Electromyographic examination of 3 dogs revealed no abnormal potentials at any of the sample sites. Electroneurographic examination in these dogs revealed no abnormal values for any of the measured variables: motor nerve conduction velocity, amplitude of the compound muscle action potential, velocity, amplitude, number of positive peaks, and duration of sensory evoked potentials. Pathologic findings No gross lesions were found outside the central nervous system. In all dogs lesions, were grossly visible in the cervical spinal cord after transverse sectioning. These lesions were more or less symmetrically distributed in the white matter of the cord, and were characterised by a white appearance and a loss of transparency (Fig. 1). The lateral funiculi, especially their dorsal parts, were almost constantly affected throughout the length of the cervical cord with occasional extension into the upper thoracic segments. Lesions were also frequently seen in the dorsal funiculi, but rarely in the ventral funiculi. The lesions usually reached their most transverse extent at the midcervical level. Four patterns of lesion distribution were observed in the spinal cord of 11 dogs examined (Fig. 2). Histologically these lesions were characterised by myelin breakdown and phagocytic THE VETERINARY QUARTERLY, VOL. 8, No. 2, APRIL 1986 91

I,:e, n.' -..... ii -....... lb- g.o..r. `?. 4 i...-v.,,, r -?,,. --' 3/4... p 6.."`eqi. J. :k7.;'. el J. ' I v.,. ' Fig. 1. Transverse section of spinal cord at C8 (dog 4). Bilaterally symmetric lesion areas with opaque white appearance in dorsolateral funiculi. n.4 n.2 n.2 n.1 C2 fr,\111 C4 ti (0 T2 Cr), Fig. 2. Schematic representation of the various observed patterns of lesion distribution in the spinal cords of 11 Rottweiler dogs. 92 THE VETERINARY QUARTERLY, VOL. 8, No. 2, APRIL 1986

removal. Demyelination was especially evident with the applied myelin stain, for which a marked loss of staining affinity was seen (Fig. 3). The demyelination was associated with a marked proliferation and hypertrophy of astrocytes (Fig. 4). Gemistocytic astrocytes occasionally showed vacuolation of their peripheral cytoplasm. In chronic lesions there was intense fibrillary gliosis. Axons appeared to be generally preserved even in areas of severe myelin loss (Fig. 5). In chronic lesions many axons could be observed, which had very thin myelin sheaths (Fig. 6). occasionally axonal spheroids were noticed in the lesions. A very slight Wallerian type degeneration was seen proximally and distally from the lesions in the spinal cord. Similar demyelinating lesions were present in the brain. There was some variation in the extent and distribution of the brain lesions between individual dogs, but in most dogs a stereotyped pattern with bilateral symmetry could be recognized. Lesions were constantly present in the caudal brain stem, especially in the spinal tracts of the trigeminal nerve, the caudal cerebellar peduncles, the pyramidal tracts, and the medial lemniscus. The optic nerves and tracts were affected in all dogs. Diffuse slight demyelination was often seen in the medulla cerebelli and in the crus cerebri. Occasional diffuse or patchy lesions were found in the corona radiata. In Table 1 the distribution of lesions in the CNS is summarised for all dogs. evr Fig. 3. Transverse section of spinal cord at C5 (dog I). Symmetric demyelination of dorsal and lateral funiculi. Superficial rim of white matter relatively spared. Luxol fast blue-cresyl echt violet stain; x 8. Fig. 4. Cervical spinal cord. Longitudinal section of white matter (dog 6). Severe loss of myelin sheaths, phagocytic activity, and hypertrophy of astrocytes (arrows). Luxol fast blue-cresyl echt violet stain; x 400. THE VETERINARY QUARTERLY, Vol.. 8, No. 2, APRII. 1986 93

Fig. 5. Cervical spinal cord. Longitudinal section of white matter (dog 6). Preservation of axons in area of almost complete myelin loss. Holmes-luxol fast blue stain; x 400. Fig. 6. Cervical spinal cord. Transverse section of white matter (dog 15). Chronic lesion showing axonal profiles surrounded by very thin myelin sheaths. Holmes-luxol fast blue stain; x 400. Pedigree analysis Pedigrees of 14 affected dogs were available. An analysis of these pedigrees revealed that all these dogs were related and had a common male ancestor (Fig. 7, no. I). It was also evident that considerable inbreeding had been practised. One pair of parent dogs (II and III) had produced 6 affected progeny in 3 subsequent litters. Two of these dogs were not examined by the authors, but they had a similar history of progressive gait abnormalities and were euthanatised at the age of 2 years. On two other occasions 2 littermates were affected (dogs 7, 8, and 13, 14 respectively). The other affected dogs were single cases as far as could be traced. No pedigree information was available on dogs 5 and 11. Dog 11 originated from a brother-sister mating. 94 Dog 5 was a crossbred Rottweiler, allegedly sired by a German Pointer. DISCUSSION The similarity of the historical, clinical and pathological data of the 16 Rottweiler dogs described here, suggests that the observed disease constitutes a nosological entity. The obvious predisposition for the Rottweiler breed and the results of the pedigree analysis indicate that there is an important genetic component. As to the mode of transmission, nothing can be stated until the results of test matings are known. The fact that affected dogs were of both sexes, and had clinically normal parents, would be compatible with an autosomal recessive mode of inheritance. However, the occur- THE VETERINARY QUARTERLY, VOL. 8, No. 2, APRIL 1986

litee4n 2 ill161341.obbb 00 normal male, female affected, verified by post mortem examination MO affected, not verified by post mortem examination MI6 parent of affected dog Fig, 7. E-Fal OS suspected carrier 00 no data available 4 ku),t--en id ;1111110 lid) (t, CL.I Pedigree chart of affected Rottweiler dogs. Figures refer to dog numbers in the text. " I,b 1 4.1 13 14 -ED rence of disease in a crossbred Rottweiler would not be likely with this mode of inheritance. Insufficient data are available to allow a statistical analysis. The disease affects young mature dogs from an age of 1.5 years. The onset of signs is insidious and early signs may be easily missed by inexperienced owners. The disease is characterised by progressive ataxia of all 4 limbs, often commencing in the fore limbs. A more or less apparent paresis may accompany the incoordination and may ultimately dominate the clinical picture. A remission of signs may occur. The neurologic examination findings suggest a focal cervical or multifocal spinal cord lesion. Pathological examination reveals the presence of circumscribed and diffuse demyelinating lesions in the CNS, with a characteristic more or less symmetric distribution. These lesions are most pronounced in the cervical spinal cord, but also occur in the brain, especially in the brain stem, optic tracts, and cerebellar medulla. A demyelinating leukoencephalomyelopathy observed in 2 Rottweiler dogs in the USA (2), appears to be similar to the disease described by us. The American dogs, a 3-year-old female and a 4-year-old male were also related. They showed ataxia of all 4 limbs, hypermetria, loss of conscious proprioception and weakness, and a progressive clinical course over 7 and 9 months THE VETERINARY QUARTERLY, VOL. 8, No. 2, APRIL 1986 respectively. As in our dogs, demyelinating lesions affecting the lateral and dorsal funiculi of the cervical spinal cord were found. In 1 dog minor lesions extended caudally as far as L3. Lesions were also observed in the pyramidal tracts and the deep cerebellar white matter. The observed myelin breakdown in our dogs is considered to be primary demyelination, since there was considerable preservation of axons in the lesions. As demyelination causes slowing or block of conduction along affected fibres (3), it is reasonable to relate the neurological deficits with these lesions. Multiple functional systems were involved simultaneously, including ascending as well as descending fibre tracts. The observed incoordination may have been partly due to deficient conscious and/or unconscious proprioception. Lesions in the dorsal spinal tracts and medial lemniscus may have interfered with conscious proprioception. Lesions in the spinocerebellar pathways in the cervical cord and caudal cerebellar peduncles may have caused deficient unconscious proprioceptive input into the cerebellum, which was probably responsible for the hypermetria seen in some dogs (4). The observation that the -ataxia was often less severe in the hind limbs as compared with the fore limbs, is compatible with the relative preservation of superficially located spinal tracts like the gracile, and dorsal and ventral spinocere- 95

bellar tracts, which contain fibres from the hind limbs, in contrast with the more centrally located fibres from the fore limbs which constitute the cuneate, cuneocerebellar and rostral spinocerebellar tracts (5). In all dogs the demyelinating lesions involved the deep dorsolateral spinal tracts adjacent to the dorsal horns. These tracts correspond with the lateral corticospinal and rubrospinal tracts (5). In addition, corticospinal tracts in the brain stem were affected in many dogs. These tracts mediate impulses of the so called voluntary motor control system, which facilitate flexor and distal limb mucles and reciprocally inhibit antigravity muscles (4). Inadequate function of this system probably was responsible for the observed hyperactivity ofmyotatic reflexes and increased extensor tone, and may also have contributed to the peculiar stiff limb protraction and dragging of the toes. The latter might thus not only be the effect of deficient conscious proprioception, which is supported by the finding of intact dorsal spinal tracts in dogs 7, 10, 11, and 13. In all dogs the demyelinating lesions involadditional involvement of the ventrolateral or ventral tracts, which contain the reticulospinal and vestibulospinal pathways (5). This supports the concept that postural control is mediated by these pathways through facilitation of antigravity muscles and inhibition of flexors, in direct contrast to the voluntary motor control system (4). The gradual improvement observed in dog 12 may have been attributable to remyelination. In chronic lesions axons with thin myelin sheaths suggesting remyelination (6) were seen. This was also reported in the American dogs (2). The optic tracts were affected in all dogs, but none of the dogs was apparently blind, and pupillary and menace reflexes were normal. However, minor visual defects, not detectable on routine examination, may have existed. Neither were sensory defects of the trigeminal nerve found in any of the dogs, as might have been expected from the frequent findings of lesions in the descending sensory tracts of this cranial nerve. With the possible exception of dog 7, mental functions were unaffected in all dogs, which is compatible with the infrequent presence and small size of lesions in the cerebral white matter. The disease must be differentiated clinically from cervical cord compression, especially cervical vertebral malformationmalarticulation (wobbler syndrome) (7), which we have observed in young Rottweiler dogs. The onset of signs in vertebral malformation-malarticulation is usually earlier, often before 1 year of age, but the signs may closely mimic those seen in the dogs presented here. Myelography is indispensable to exclude this possibility as well as other compressive lesions. Canine distemper myelitis would be another possible cause of the clinical signs observed. Cerebrospinal fluid analysis may be helpful for differentation, because a high protein content and pleocytosis are usually seen in canine distemper encephalomyelitis (8). Neuraxonal dystrophy, which has been recently described in Rottweiler dogs in the USA (9, 10) is another hereditary disease causing progressive ataxia in all 4 limbs. Careful evaluation of the history and neurologic signs may reveal certain differences between neuraxonal dystrophy and the disease described here. In neuraxonal dystrophy, gait abnormalities may be noted before 1 year of age and the course of disease is slowly progressive over several years. Hypermetria (especially in the fore limbs) and incoordination and tremors of the head are obvious features in longstanding cases. Positional nystagmus may also be evident. Conscious proprioception is spared and there is no paresis. Pathomorphologically neuraxonal dystrophy is characterised by the presence of large numbers of axonal spheroids throughout the gray matter s,tructures of the central nervous system with the exception of the cerebral cortex. Furthermore there is mild cerebellar atrophy due to loss of Purkinje cells (7). It is impossible, at the present state of knowledge, to classify the disease of the Rottweiler dogs described here. Since breakdown of central myelin is the most conspicuous pathological feature of the disease, it is logical to place the disease in the existing categories of demyelinating disease and leukodystrophy. The symmetry of the lesions, the absence of immunocytes in the lesions, and the apparant hereditary basis 96 THE VETERINARY QUARTERLY, VOL. 8, No. 2, APRIL 1986

of the disease exclude it from being classified with the acquired demyelinating diseases (11). These features would rather suggest a leukodystrophy, but the limited topography of the lesions and the late onset of signs, are not in favour of a leukodystrophy (12). The disease bears some resemblance of hereditary myelopathy of Afghan hounds (13). This myelopathy is also characterised by symmetric demyelinating lesions, but without the intense astroglial response as seen in the Rottweiler dogs. The Afghan myelopathy is considered to be a myelinolytic rather than a dysmyelogenic (leukodystrophic) disease, and has been compared with myelinopathies of toxic/ metabolic origin (13). Such a pathogenesis with a possibly extracerebral inborn metabolic error causing demeyelination, seems also to be an attractive hypothesis for the disease in the Rottweiler dogs. 8. Vandevelde, M. and Spano, S. Cerebrospinal fluid cytology in canine neurologic disease. Am. J. Vet. Res. 1977; 38: 1827-32, 9. Cork, L. C., Troconso, J. C., Price, D. L., Stanley, E. F., and Griffin, J. W. Canine new-axonal dystrophy. J. Neuropathol. Exp. Neurol. 1983; 42: 268-96. 10. Chrisman, C. L., Cork, L. C., and Gamble, D. A. Neuraxonal dystrophy of Rottweiler dogs. J. Am. Vet. Assoc. 1984; 464-7. 11. Oppenheimer, D. R. Dernyelinating diseases, in Blackwood W., Corsellis J. A. N. (ed). Greenfield's Neuropathology, ed. 3. London, Edward Arnold, 1976; 470-99. 12. Crome, L. and Stern, J. Inborn lysosomal enzyme deficiences, in Blackwood, W., Corsellis J. A. N. (ed). Greenfield's Neuropathology, ed. 3. London, Edward Arnold 1976; 541-57. 13. Cummings, J. F. and Lahunta, A. de. Hereditary myelopathy of Afghan hounds, a myelinolytic disease. Acta Neuropathol. (Berl.) 1978; 42: 173-81. ADDENDUM After completion of the manuscript the information became available that a female littermate of dog 12 was also affected with the disease. In dog 16 the diagnosis was confirmed by post-mortem examination. REFERENCES I. Wouda, W. and Nes, J. J. van. A demeyelinating disease in Rottweiler dogs with suspected autosomal recessive inheritance, in Proceedings Woorjaarsdagen', Royal Netherlands Vet. Assoc. 1984; 100-2. 2. Gamble, D. A. and Chrisman, C. L. A leukoencephalomyelopathy of Rottweiler dogs. Vet. Pathol. 1984; 21: 274-80. 3. Rasminsky, M. Physiological consequences of demyelination, in Spencer, P. S. and Schaumburg, H. H. (ed). Experimental and Clinical Neurotoxicology. Baltimore, Williams and Wilkins, 1980; 257-71. 4. Latshaw, W. K. A model for the neural control of locomotion. J. Am. Anim. Hosp. Assoc. 1974; 10: 598-607. 5. Jenkins, T. W. Functional mammalian neuroanatomy, ed. 2. Philadelphia, Lea and Febiger, 1978. 6. Ludwin, S. K. Central nervous system demyelinating and remyelination in the mouse. An ultrastructural study of Cuprizone toxicity. Lab. Invest. 1978; 39: 597-612. 7. Lahunta, A. de. Veterinary Neuroanatomy and Clinical Neurology, ed. 2. Philadelphia W. B. Saunders Co; 1983; 200-4. THE VETERINARY QUARTERLY, VOL 8, No. 2, APRIL 1986 97