Distal Sensorimotor Polyneuropathy in Mature Rottweiler Dogs

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Vet Pathol 31:316-326 (1994)

                            Distal Sensorimotor Polyneuropathy in
                                   Mature Rottweiler Dogs
                               K. G. BRAUND,M. TOIVIO-KINNUCAN, J. M. VALLAT,
                                       J. R. MEHTA,AND D. C. LEVESQUE
     Neuromuscular Laboratory, Scott-Ritchey Research Center (KGB, JRM), and Department of Pathobiology (MTK),
                          Auburn University College of Veterinary Medicine, Auburn, AL;
                              Veterinary Neurological Center, Phoenix, AZ (DCL); and
                  Service dc Neurologic, H6pital Univcrsitaire Dupuytren, Limoges, France (JMV)

         Abstract. A polyneuropathy recognized in mature Rottweiler dogs is characterized by paraparesis that
      progresses to tetraparesis, spinal hyporeflexia and hypotonia, and appendicular muscle atrophy. Although signs
      may appear acutely, the course tends to be gradually progressive (up to 12 months or longer in some dogs) and
      may be relapsing. Nerve and muscle biopsies were examined from eight affected Rottweilers (six male and two
      female) between ages 1.5 and 4 years. Pronounced neurogenic atrophy was present in skeletal muscle samples.
      Changes in sensory and motor peripheral nerves included loss of myelinated nerve fibers, axonal necrosis, and
      variable numbers of fibers with inappropriately thin myelin sheaths. Ultrastructural findings included myelinated
      fibers showing myelinoaxonal necrosis, demyelinated fibers often associated with macrophage infiltration, many
      axons with myelinlike membranous profiles. increased endoneurial collagen, occasional axonal atrophy, and
      numerous Bungner bands. Lesions in unmyelinated fibers included increased numbers of Schwann cell profiles
      and loss of axons in Schwann cell subunits. Morphologic and morphometric studies indicated preferential loss
      of medium (5.5-8 pm) and large (8.5-12.5 pm) fibers. which was more severe in distal parts of nerves than in
      more proximal regions and nerve roots. The cause was not determined; however, histopathologic studies suggest
      this condition is a dying-back distal sensorimotor polyneuropathy that has morphologic and morphometric
      similarities to hereditary motor and sensory neuropathy (HMSN) type I1 in humans.

         Key words: Animal model; distal axonopathy; dogs; dying-back polyneuropathy; HMSN type 11; morphom-
      etry; muscle; nerve; teased fibers; ultrastructure.

   Several neurologic abnormalities have been reported                     detected in any dog. Although signs appeared acutely in two
in Rottweiler dogs, including leukoencephalopathy in                       dogs. the clinical course typically was slowly progressive (up
mature dogs,34.49.55
                   neuroaxonal dystrophy in immature                       to 12 months or longer in some dogs). In three dogs, the
and mature dogs,20.21.32an isolated case of polyneuritis                   clinical course was relapsing, and all three dogs responded
in a mature dog,' and spinal muscular atrophy, an                          variably to corticosteroid therapy. Numerous positive sharp
                                                                           waves and fibrillation potentials were detected in appendic-
abiotrophy that occurs in young Rottweiler puppies                         ular muscles by electromyographic testing, primarily in mus-
around 4-6 weeks of age.47.48  In this article, we report                  cles distal to the elbow and stifle. Few abnormal potentials
another neurologic disorder in this breed, a progressive                   were noted in proximal limb and paraspinal muscles. Motor
degenerative polyneuropathy with a distal axonal dis-                      nerve conduction velocities were reduced- I2 m/second, 39
tribution, that has been found to date only in mature                      m/second, and 40 m/second, respectively, as compared with
Rottweilers.                                                               normal values of 50-60 m/second4-in three of eight dogs
                                                                           tested. Sensory nerve conduction velocity was reduced in one
                                                                           dog tested-5 m/second as compared with normal values of
                 Materials and Methods                                     > 60 m / s e c ~ n d Hematology,
                                                                                                .~          blood chemistries, and spinal
   Eight mature Rottweilers (six male and two female) be-                  radiography/myelography were normal in all dogs tested. Ce-
tween ages 1.5 and 4 years were studied for progressive neu-               rebrospinal fluid protein was marginally elevated in one of
rologic disease. There was no historic evidence of any dog                 four dogs tested. Pleiocytosis was not observed. With the
being exposed to a toxic substance. Clinical signs were char-              exception of one dog that was serologically positive for valley
acterized by paraparesis that progressed to tetraparesis, spi-             fever and Ehrlichia canis ( 1 : 80), tests for immunologic (an-
nal hyporeflexia and hypotonia, and appendicular muscle                    tinuclear antibodies, rheumatoid factor, lupus erythematosus
atrophy in distal limb muscles. Dogs typically developed a                 cells, antiglobulin [Coombs']), endocrine (diabetes, hypothy-
plantigrade stance associated with a crouched, waddling gait.              roidism, hyperadrenocorticism), toxicity (lead, cholinester-
Cranial nerve function was normal. Sensory deficits were not               ase levels). and infectious (Rocky Mountain spotted fever,
                                                                      3 16

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Vet Pathol 31:3, 1994                    Distal Sensorimotor Polyneuropathy in Rottweilers                                              317

borreliosis, ehrlichiosis, canine distemper) disease were neg-
ative.8
   Muscle samples from biceps femoris, lateral head of the
gastrocnemius, superficial digital flexor, or cranial tibial mus-
cle, approximately 2 x 2 x 2 cm, were obtained without the
use of clamps from eight Rottweiler dogs under general an-
esthesia, placed in glass or plastic bottles, and cooled using
gel freeze packs. At the same time, fascicular segments of
nerves (either common peroneal, ulnar, tibial, superficial ra-
dial, saphenous, or proximal sciatic) were removed, gently
stretched on wooden tongue depressors with pins, and fixed
in a mixture of 4% formalin/l% glutaraldehyde, 2.5% glu-
taraldehyde in phosphate buffer, or 10% neutral buffered
formalin. Muscle and nerve biopsy samples were mailed via
overnight delivery to the Neuromuscular Laboratory, Scott-
Ritchey Research Center, Auburn University, for routine                        Fig. 1. Skeletal muscle; dog No. 1. Marked fiber size
processing. Upon receipt at the Neuromuscular Laboratory,                    variation associated with atrophic and hypertrophic fibers.
muscle samples were oriented in transverse and longitudinal                  HE. Bar = 50 fim.
planes and frozen in isopentane, precooled in liquid nitrogen.
Samples were stored in airtight plastic bottles at - 80 C. Serial
sections were cut at 8 l m and stained for routine morphologic               Dorsal and ventral nerve roots were sampled from lumbar
and histochemical                                                            cord segments and processed for single fiber teasing, semithin
   Nerves were divided into halves and washed in phosphate                   sections, and ultrathin sections.
buffer (pH 7.3) at 4 C overnight. One half was postfixed in                     For quantitative studies, transverse sections of ulnar, ra-
 1Yo osmium tetroxide for 6-8 hours, placed in 66% glycerin                  dial, proximal sciatic, and distal tibial nerves from the nec-
for 24 hours, and stored in 100% glycerin for single teased-                 ropsied dog, together with samples from age-matched control
fiber preparations as previously described. l o The second half              dogs, were projected onto a monitor using a computerized
of each nerve was further fixed in 1% osmium tetroxide for                   video-display image analysis system (Optomax semiauto-
 1 hour, washed in phosphate buffer, transferred through grad-               matic image analysis system, Optomax, Hollis, NH). The
ed ethanol solutions, and then processed for embedding in                    mean external diameters of the axons that were myelinated
Epon plastic medium. Semithin sections (1-2 pm) were cut                     were determined from a random field fiber count of approx-
transversely and stained with paraphenylene diamine31 or                     imately 1,500 for each nerve sample. Random counts were
toluidine blue.5 Silver to gray ultrathin sections of nerves                 made from four quadrants of each section to avoid the pos-
were cut, stained with uranyl acetate and lead citrate, and                  sibility of inadvertently over- or undersampling large or small
examined with a Philips 301 electron microscope. Nerve                       fibers. All measurements were made under oil objective at a
samples previously obtained from normal dogs of compa-                       final magnification of 2,940 x . Sections were acceptable for
rable ageIoJ2were similarly processed.                                       measurement only when the majority of fibers were circular
   Approximately 100 single fibers from each nerve sample                    in shape. The diameter of the lesser axis was used on oval
were teased at random from all fascicles, without preselection               fibers. Triangular fibers were measured across their base.
for size or abnormality, and were histologically classified                  Crenaled fibers were not measured.
according to the system of Dyck:28A = teased fiber of normal
appearance; B = normal fiber with excessive rnyelin irregu-                                               Results
larity, wrinkling, or folding; C = teased fiber with single or                Morphology
multiple regions of nodal lengthening or lack of internodal
myelin (as evaluated by use of high-dry light objective); D                      Skeletal muscle changes were characterized by
= single or multiple C and F abnormalities combined; E =                      marked fiber size variation associated with atrophic
teased fiber with linear rows of myelin ovoids and balls; F                   and hypertrophic fibers (Fig. 1). Atrophic fibers were
= teased fiber without site(s) of segmental demyelination but                 angular and sometimes formed small and large groups
with excessive variability of myelin thickness between in-                    in a disseminated random distribution. Most of the
ternodes (thickness of myelin of the internodes with the thin-                atrophic fibers were type 11, whereas hypertrophic fi-
nest myelin is < 50% of that of the internode with the thickest               bers were type I or type 11. Fiber type grouping was
myelin); and G = teased fiber without site(s) of segmental                    not seen in any sample. In some areas, there was a
demyelination but with excessive variability of myelin thick-
                                                                              relative increase in perimysial and sometimes endo-
ness within internodes to form globules or “sausages.” Fibers
with segmental demyelination and remyelination were rep-                      mysial connective tissue. Depletion of myelinated fi-
resented by the graded lesions, C , D, F, and G. Fibers un-                   bers was noted in some intramuscular nerves. Muscle
dergoing axonal degeneration were represented by E.                           changes were more prominent in distal muscles (such
   Only one dog was available for necropsy. Samples from                      as lateral head of gastrocnemius and cranial tibial mus-
lumbar spinal cord and brain were fixed in 10% neutral buf-                   cle) than in more proximal muscles (such as biceps
fered formol solution and processed for paraffin embedding,                   femoris). There was no evidence of necrosis, phago-

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318                                 Braund, Toivio-Kinnucan. Vallat. Mehta, and Levesque                               Vet Pathol 31:3, 1994

  Fig. 2. Sciatic nerve; control dog. Normal distribution of                 Fig. 3. Sciatic nerve; dog No. 5. Loss of myelinated nerve
small- and large-caliber fibers. Paraphenylene diamine. Bar               fibers and several fibers with inappropriately thin myelin
= 25 bm.                                                                  sheaths (arrows). Paraphenylene diamine. Bar = 25 pm.

cytosis, or inflammation in any muscle sample ex-                        with macrophages containing myelin debris within the
amined.                                                                  Schwann cell cytoplasm or in the endoneurium in close
   In cross-sectional preparations of nerves from af-                    proximity to the Schwann cell (Fig. 7). Additionally,
fected animals, changes were more severe in distal parts                 there was increased endoneurial collagen, occasional
of nerves than in more proximal regions and nerve                        fibers with excessively thick myelin sheaths and small
roots (Figs. 2-4). Abnormal findings included axonal                     axonal compartments (Fig. S), many axons with my-
necrosis, loss of myelinated nerve fibers (especially those              elinlike profiles (Fig. 9), and numerous Biingner bands
of larger caliber), occasional macrophage infiltration,                  (Fig. 10). Many axons had a watery appearance with
and variable numbers of fibers with inappropriately                      loss of neurofilaments and microtubules. There was no
thin myelin sheaths. Inflammation was not observed                       evidence of neurofilamentous accumulation. Regen-
in any nerve. The incidence of abnormalities in teased                   erating clusters were uncommon, and onion bulb for-
fibers from different nerves of affected dogs is given in                mation, indicative of repeated demyelination and re-
Table 1. The most dominant abnormality in all dogs                                             , ~ ~ rare (Fig. 11). In several nerves,
                                                                         m y e l i n a t i ~ n was
was axonal necrosis, characterized by linear rows of                     degenerating endoneurial fibroblasts were seen with
myelin ovoids and balls (graded lesion E) (Fig. 5). In                   dark pyknotic nuclei, disrupted plasma membranes,
several dogs, demyelination (graded lesion C) and re-                    and organelles lying free in the endoneurium. In one
myelination (graded lesion FJ or both involving the                      dog, the perineurium was thickened and contained nu-
same fiber (graded lesion D) were also observed. These                   merous cells filled with lipidlike vacuoles. Endoneurial
changes were more apparent in dogs with a chronic                        capillaries appeared normal. Lesions were commonly
clinical course. In one such dog, demyelination and                      noticed in unmyelinated fibers from affected dogs, but
remyelination were common in dorsal and ventral nerve                    not in those of controls. These lesions were character-
roots (Table 1).                                                         ized by increased numbers of Schwann cell profiles and
   Ultrastructural examination of motor nerves re-                       loss of axons in Schwann cell subunits (Fig. 12).
vealed occasional fibers with myelinoaxonal necrosis                     Schwann cell bands devoid of axons, enclosed by a
(Fig. 6) and variable numbers of demyelinated fibers                     continuous basement membrane with redundant loops,

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Vet Pathol 3 I :3, I994              Distal Sensorimotor Polyneuropathy in Rottweilers                                          319

                                                                           Fig. 5. Teased nerve fiber panel; dog No. 4. Osmium
                                                                        tetroxide. Bars = 25 pm. Fig. 5a. Normal myelinated fiber
                                                                        with node of Ranvier (arrow).Fig. 5b. Paranodal demyelin-
                                                                        ation. Fig. 5c. Linear rows of myelin ovoids and balls. Fig.
                                                                        5d. Intercalated internode (arrows = nodes of Ranvier).

                                                                        medium (5.5-8 pm) and large (8.5-12.5 pm) fibers.
                                                                        Similar findings were noted in radial nerve. Loss of
                                                                        medium- and large-caliber fibers was noted also in
                                                                        distal tibial nerve as compared with more proximal
                                                                        sciatic nerve segments in an affected dog, and the peak
                                                                        of the histogram in the distal nerve was situated be-
                                                                        tween 2 and 3 pm (Fig. 14). Mean fiber diameters for
                                                                        proximal and distal segments were 4.95 f 2.75 pm
                                                                        and 2.41 t 0.71 pm, respectively.
  Fig. 4. Distal tibial nerve; dog No. 5. Focal axonal de-
generation (arrow)and pronounced loss of medium- and large-                                    Discussion
caliber fibers. Paraphenylene diamine. Bar = 25 pm.                        This Rottweiler polyneuropathy appears to be a dis-
                                                                        tinct breed-related clinical entity. Clinical signs of mus-
                                                                        cle atrophy, hyporeflexia, and hypotonia are indicative
were common. Many axons of unmyelinated fibers also                     of a neuropathic syndrome6and therefore are clinically
had a watery appearance and contained sparse num-                       distinct from neuroaxonal dystrophy and leukoenceph-
bers of neurofilaments and microtubules. Collagen                       alomyelopathy described in this breed.20,21,32,34,49.55 Spi-
pockets were often seen.                                                nal muscular atrophy is an abiotrophic disorder af-
  Similar but less severe changes were observed in                      fecting ventral horn cells in the spinal cord of young
sensory nerves (such as superficial radial and saphe-                   Rottweiler puppies about 5-6 weeks of age.47.48          Af-
nous). In one dog with a chronic clinical course, fine                  fected puppies show signs of megaesophagus, progres-
granular deposits were observed in several nerves.                      sive ataxia, and pelvic limb weakness. In contrast with
These deposits were sometimes membrane bound and                        the Rottweilers in the present study, lesions include
were noted within Schwann cell cytoplasm of myelin-                     central chromatolysis and swelling of the perikarya in
ated and unmyelinated fibers, free in the endoneurium,                  many large motor neurons in the ventral gray matter
and within capillary walls (Fig. 7). These deposits may                 of the spinal cord and various brain stem nuclei. Chro-
represent a fixation artifact.                                          matolytic neurons have excess numbers of neurofila-
  No abnormalities were observed in brain or lumbar                     ments and an increase in and enlargement of Golgi
spinal cord segments from the one affected Rottweiler                   complexes. This Rottweiler polyneuropathy also dif-
available for necropsy.                                                 fers from the chronic polyneuritis reported in a 2-year-
                                                                        old Rottweiler.' Although the electromyogram initially
Morphometry                                                             revealed fibrillation potentials bilaterally in muscles
  The mean fiber diameters of myelinated fibers in                      below the elbows and stifles in this dog with polyneu-
ulnar nerves from control and affected dogs were 5.62                   ritis, weakness and atrophy developed in proximal limb
f 2.58 pm and 3.94 k 1.78 pm, respectively. The                         muscles, lumbar epaxial muscles, and muscles of the
histographic distribution of the control nerve was bi-                  head. Furthermore, initial clinical signs and muscle
modal. In contrast, that of the affected ulnar nerve was                atrophy were more pronounced in thoracic limbs. Fi-
unimodal (Fig. 13), with conspicuous reduction/loss of                  nally, pathologic changes were quite different in this

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320                                    Braund, Toivio-Kinnucan. Vallat, Mehta, and Levesque                                Vet Pathol 31:3. 1994

                                                         dog with polyneuritis, being characterized by inflam-
                                                         matory cell infiltrates of peripheral nerves (including
                                                         dorsal and ventral roots) and cranial nerves, demy-
                                                         elination, and focal meningitis and gliosis in the brain
                                                         at the entrance/exit points of cranial nerves.
                                                            The pathologic changes in the Rottweilers were char-
                                                         acterized by neurogenic muscle atrophy secondary to
                                                         a peripheral neuropathy that was dominated by axonal
                                                         necrosis. The changes were most severe in the motor
                                                         nerves, with less severe involvement of sensory nerves.
                                                         Presence of numerous bands of Biingner or denervated
                                                         Schwann cells, indicative of axonal loss in myelinated
                                                         fibers, together with many myelinated fibers showing
                                                         depletion of axonal contents, increased amounts of
                                                         electron-dense clumping, and watery appearance, are
                                                         hallmarks of axonal n e c r o s i ~ Membranous
                                                                                                   . ~ ~ ~ ~ ~ ~ma-
                                                                                                                 ~~
                                                         terial with myelinlike appearance seen in affected ax-
                                                         ons may suggest early axonal degeneration. Similar
                                                         axonal pathology has been seen in a variety of neu-
                                                         ropathies in animals and humans (personal observa-
                                                         tions) and has been reported recently in experimental
                                                         acrylamide intoxication in rats.35Ovoids contained a
                                                         mixture of disintegrating myelin segments and degen-
                                                         erated axonal component^.^^ There was conspicuous
                                                         involvement of unmyelinated fibers, as suggested by
  Fig. 6 . Electron micrograph. Nerve; dog No. 1. Myeli- the presence of collagen pockets, increased numbers of
noaxonal necrosis with vesiculomembranous accumulations. profiles in Schwann cell subunits, and increased num-
Bar = 1 urn.                                             ber of subunits devoid of ax on^,^^.^^.^^ as compared with
                                                         control nerves.

           Table 1. Percentage of abnormal teased nerve fibers from Rottweiler dogs with distal polyneuropathy.
                                                                               Histologic Classificationt           Total Percentage
                                                                                                                    Abnormal Fibers
 Dog       Sex        Age              Nerve*
  No.                (years)                                                                                       Affected       Control
                                                                C               D               E         F
                                                                                                                    Dogs           Dogs
   1       M          2           CPN                           0               0              45          0   0     45              0
                                  Ulnar                         3               0              24          0   0     27              0
   2       F                      CPN,                          3               0              16          0   0     19             0-3
   3       M                      Tibial                        I               0               7          0   1       9            0-3
   4       F                      Tibial                       13               2              33          3   0     51             0-3
   5       M                      Tibialt                       0               0              50          2   0     52             0-3
                                  Sup Radials                   2               0              14          0   0     16             0-3
                                  Tibia14                      14              10              46          0   0     70             0-3
                                  Dorsal root§                  0               0               0         24   0     24             0-3
                                  Ventral roots                 2               0               0         10   1     13             0-3
   6       M           1.5        Tibial                        0               0              50          0   0     50              0
   7       M          4           CPN II                        0               0               6          0   0      6             0-3
                                  Sciatic#                      8              20               4         32   2     66             0-3
   8       M          3           Sciatic                       5               0               7         2    5     19             0-3
 * CPN = common peroneal nerve; Sup Radial = superficial radial nerve.
 t C = single or multiple    regions of nodal lengthening or internodal myelin absence; D = single or multiple C and F abnormalities
combined E = linear rows of myelin ovoids and balls; F = 50% or more difference in myelin thickness between internodes; G = thickening
or reduplication of myelin to form globules within internodes.”
  #First biopsy (1 1/30/89).
  8 Necropsy (5/24/90).
  I( First biopsy (4/13/90).
  # Second biopsy (8/14/90)

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322                                Braund, Toivio-Kinnucan, Vallat, Mehta, and Levesque                          Vet Pathol 31:3. 1994

  Fig. 8. Electron micrograph. Nerve; dog No. 4. Fiber with               Fig. 9. Electron micrograph. Nerve; dog No. 3. Axon
excessively thick myelin sheath and small axonal cornpart-              with myelinlike profiles (arrows). Bar = 1 pm.
ment. Bar = 1 pm.

  Fig. 10. Electron micrograph. Nerve; dog No. 4.Bungner                   Fig. 11. Electron micrograph. Nerve; dog No. 6. Onion
band. Bar = 0.5 pm.                                                      bulb formation. Bar = 1 prn.

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Vet Pathol 31:3, 1994                    Distal Sensorimotor Polyneuropathy in Rottweilers                                 323

                                                                with vesiculomembranous accumulations were seen in
                                                                nerves from the Rottweilers, there was no evidence of
                                                                neurofilamentous accumulations as seen in CAN or in
                                                                acrylamide and hexacarbon toxicity,24,36,46,52      no intra-
                                                                axonal accumulations of proliferating endoplasmic re-
                                                                ticulum as seen in organophosphate n e ~ r o p a t h yand ,~~
                                                                no tubulovesicular accumulation^^^ or accumulations
                                                                of mitochondria and dense lamellar bodies associated
                                                                with axonal o ~ t p o u c h i n g sas
                                                                                                    ~ ~described in nerves of
                                                                horses with idiopathic laryngeal hemiplegia. Further-
                                                                more, there was no sign of the vesiculotubular profiles
                                                                in unmyelinated fibers reported in nerves from long-
                                                                haired Dachshunds with the distal sensory neuropa-
                                                                thy.26From these studies, a number of pathogenetic
                                                                mechanisms have been suggested to explain the dying-
                                                                back abnormalities: primary toxicity of the nerve cell
                                                                body,46Schwann cell a b n o r m a l i t i e ~primary
                                                                                                              ,~~     axonal
                                                                changes,soand disrupted axonal f l o ~ . ’ ~ , ~ ~
                                                                   The apparent depletion of large-caliber myelinated
                                                                fibers in the Rottweilers, as seen by light microscopic
                                                                and morphometric studies, is consistent with the dy-
                                                                ing-back concept.I9 A similar loss of larger myelinated
                                                                fibers has been reported from morphometric studies
                                                                in dogs with distal symmetrical polyne~ropathy~          and
                                                                distal sensory neuropathy26and in horses with idio-
  Fig. 12. Electron micrograph. Nerve; dog No. 6. Un- pathic laryngeal hemiplegia.13,25                 Nerve fiber diameter
myelinated fibers are flattened and there is loss of axons. Bar is reportedly  more    important       than  axonal length in
= 0.5 um.                                                       determining    differential    vulnerability    of peripheral
                                                                nerve fiber degeneration in experimental dying-back
                                                                diseases.53
                                                                   The Rottweiler polyneuropathy has clinical, electro-

                                     n = 1500 flbers (Contrd), 648 Qottweiler)
                                     Mean fiber diameter = 5.62 pm (Contrd), 3.94 pm (Rottweiler)

                                   0.5   1 1.5 1 l.5   3 3.5 4 4.5   5 5.5 6 6.5 7 13 1 1.5 9 9.5 LO 10311 11.511 113 13

                                                                         DLmctv
  Fig. 13. Ulnar nerve; dog No. 5. Bimodal histographic distribution of control nerve. Unimodal distribution of affected
ulnar nerve.

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324                                   Braund, Toivio-Kinnucan. Vallat. Mehta, a n d Levesque                                        Vet Pathol 31:3, 1994

                               300
                                                                         n = 828 fibers (Sciatic), 972 (Distal tibial)
                                                                         Mean fiber diameter = 4.95 pm (Sdatic),
                                                                         2 4 1 p n (Distal tibtl)

                               200

                         x
                         L

                         5
                         z
                                                                                                               Sdatk
                                                                                                               Dfstnltibid

                               100

                                 0
                                     0.1 1 1 3 1   U   3 3.1 4 4 3 1 S.S 6 6 3 'I 7 3 8 8 3 9 9.S I0 10.S11 l l . S I 2 1 1 3 1 3

                                                                         Diameter
  Fig. 14. Sciatic and tibial nerves; dog No. 5. Histogram of loss of medium- and large-caliber fibers in distal tibial nerve
as compared with more proximal sciatic nerve segments from an affected dog.

diagnostic, and pathologic (quantitative and qualita- where there is degeneration of the distal intramuscular
tive) similarities to distal symmetrical polyneuropathy axons and from which the majority of dogs recover.37
that has been described in large-breed dogs, including The chronic, relapsing course noted in three dogs and
Great D a n e ~ , ~Irish
                     . ~ * Setter crosses,22St. Bernards, the variable response to corticosteroids suggests a pos-
Newfoundlands, and Chesapeake Bay Retrievers (K. sible immunologic pathogenesis, although demyelin-
G. Braund, unpublished data). In the Rottweilers, dif- ation rather than axonal degeneration is more typically
ferences included the relapsing clinical course in some the dominant lesion in such disorders.54The nature of
dogs and more pronounced involvement of unmyelin- the granular deposits noted in several nerves of one
ated fibers.                                              dog is uncertain; however, they appear to be structur-
   The cause of the disease was not determined. A toxic ally different from immunoglobulin deposits and am-
cause was considered; however, based on absence of y10id.~~
both historic and laboratory evidence of exposure to        To determine if this Rottweiler polyneuropathy rep-
a toxin and lack of characteristic axonal pathology nor- resents a central-peripheral distal a x ~ n o p a t h y ' ~ . ~ ~ , ~ ~ . ~
mally seen with organophosphates, acrylamide, or tox- characterized by additional presence of axonal degen-
ic hexacarbons, toxicity was considered unlikely. There eration in selected pathways of the central nervous
was n o evidence of nutritional disorders, uremia, or system (e.g., spinocerebellar tracts and dorsal columns
diabetes, which have been associated with distal sym- in upper cervical cord segments, rubrospinal and cor-
metrical polyneuropathy in human^,^ and laboratory ticospinal tracts in lumbosacral cord segments), further
tests for immunologic, infectious, and endocrine dis- studies of spinal cord from affected animals are needed.
ease were negative. Apart from GAN in German She- Spinal cord (lumbar segments) was available from only
phard Dogs, sensory neuropathy in long-haired Dachs- one dog; however, no changes were observed. To date,
hunds, idiopathic laryngeal hemiplegia in horses, and central-peripheral distal axonopathy has been reported
distal symmetrical polyneuropathy in large-breed dogs, in several distal axonopathies of animals: in horses
a distal dying-back form of neuropathy also has been with idiopathic laryngeal hemiplegia,16J7in Birman
reported in a litter of Birman             in horses with        in German Shepherd Dogs with GAN,24.36        and
stringhalt,'* and in dogs with diabetic neuropathy,12.4i in long-haired Dachshunds with sensory neuropathy.26
and it is believed to be the mechanism underlying la-       This Rottweiler neuropathy has morphologic and
ryngeal paralysis with associated polyneuropathy in morphometric similarities to hereditary motor and
dogs, especially young Dalmatians. I I The Rottweiler sensory neuropathy (HMSN) type I1 in humans, a neu-
condition is clinically, electrodiagnostically, and path- ronal type of peroneal muscular a t r ~ p h y .Affected
                                                                                                          ~~,~~
ologically different from distal denervating disease      patients have  normal  or slightly reduced  nerve   con-

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Vet Pathol 3l:3, 1994                    Distal Sensorimotor Polyneuropathy in Rottweilers                                               325

duction velocities. Morphologically, HMSN type I1 is                              Neurology, ed. Oliver JE, Hoerlein BF, and Mayhew IG,
characterized by decreased numbers of myelinated fi-                              pp. 145-166. WB Saunders, Philadelphia, PA, 1987
bers, primarily large-diameter fibers (> 8 pm) as a re-     5                     Bradley WG: Disorders of Peripheral Nerves, pp. 129-
sult of axonal degeneration, with a shift to smaller                              309. Blackwell Scientific, Oxford, England, 1974
                                                            6                     Braund KG: Clinical Syndromes in Veterinary Neurol-
diameters in histograms, which typically have an uni-
                                                                                  ogy, pp. 40-43. Williams & Wilkins, Baltimore, MD,
modal peak in the 2-3 pm range. There is variable                                 1986
demyelination, especially paranodal, but with minimal       7                     Braund KG, Hoff EJ, Richardson KEY: Histochemical
onion bulb f ~ r m a t i o n . ~Changes
                                 ~ , ~ ~ .are
                                           ~ ~more severe                         identification of fiber types in canine skeletal muscle. Am
in distal portions of motor and sensory nerves.29.33.44                           J Vet Res 39:561-565, 1978
Autosomal dominant and autosomal recessive modes            8                     Braund KG, Levesque DC, Shores A, Northington JW,
of inheritance have been d e ~ c r i b e d .As
                                             ~ ~was
                                                . ~ ~noted                        Palmer D: Distal polyneuropathy in mature Rottweiler
in the Rottweilers, axonal regeneration is rare in re-                            dogs. J Vet Intern Med 5:147, 1991 [Abstract]
cessive HMSN type I1 cases, in contrast to the frequent     9                     Braund KG, Luttgen PJ, Redding RW, Rumph PF: Dis-
presence of clusters in the dominant form.33The rare                              tal symmetrical polyneuropathy in a dog. Vet Pathol 17:
observation of active axonal degeneration in patients                             422-435, 1980
                                                                                  Braund KG, McGuire JA, Lincoln CE: Age-related
with HMSN type I1 probably reflects the more chronic 10
                                                                                  changes in peripheral nerves ofthe dog. I. A morphologic
clinical course in humans, in whom the disease may                                and morphometric study of single-teased fibers. Vet Pathol
progress slowly for several decade^.^^.^^                                         19:365-378, 1982
   The possible role of genetic factors in the Rottweiler 11                      Braund KG, Steinberg HS, Shores A, Steiss JE, Mehta
polyneuropathy is presently unknown because pedi-                                 JR, Toivio-Kinnucan M, Amling KA: Laryngeal paral-
grees for the affected dogs were unavailable. Giant ax-                           ysis in immature and mature dogs: one manifestation of
onal neuropathy in German Shepherd Dogs, sensory                                  an underlying more diffuse distal polyneuropathy. J Am
neuropathy in long-haired Dachshunds, and the distal                              Vet Med Assoc 194: 1735-1740, 1989
axonopathy in Birman cats are believed to be inherited I 2                        Braund KG, Steiss JE: Distal neuropathy in spontaneous
as autosomal recessive trait^.^^,^^,^^,^^ A congenital or                         diabetes mellitus in the dog. Acta Neuropathol 57:263-
genetic cause has been suggested for idiopathic laryn-                            269, 1982
geal hemiplegia in                                         13                     Cahill JI, Goulden BE: Equine laryngeal hemiplegia. I.
                                                                                  A light microscopic study of peripheral nerves. NZ Vet
   This Rottweiler condition, if proven to be inherited,                          J 34~161-169, 1986
might be another useful animal model for the study of 14                          Cahill JI, Goulden BE: Equine laryngeal hemiplegia. 11.
distal polyneuropathies in humans and of HMSN type                                An electron microscopic study of peripheral nerve. NZ
I1 in particular.                                                                 Vet J 34:170-175, 1986
                        Acknowledgements                                     15   Cahill JI, Goulden BE: Equine laryngeal hemiplegia. 111.
                                                                                  A teased fiber study of peripheral nerves. NZ Vet J 34:
  We thank the following clinicians for providing tissue sam-                      18 1-1 85, 1986
ples: Dr. A. Shores, Michigan State University, East Lansing,                16   Cahill JI, Goulden BE: Equine laryngeal hemiplegia. V.
Michigan; Dr. J. Northington, Metropolitan Veterinary As-                         Central nervous system pathology. NZ Vet J 34: 19 1-1 93,
sociates, Valley Forge, Pennsylvania; Dr. D. Palmer, Texas                        1986
A&M University, College Station, Texas. We also thank Dr.                   17    Cahill JI, Goulden BE: Further evidence for a central
S. Wheeler, North Carolina State University, for providing                        nervous system component in equine laryngeal hemi-
brain and lumbar spinal cord from one affected dog. This                          plegia. NZ Vet J 37:89-90, 1989
study was supported by funds from the Neuromuscular Di-                      18   Cahill JI, Goulden BE, Jolly RD: Stringhalt in horses:
agnostic Laboratory, Scott-Ritchey Research Center, College                       a distal axonopathy. Neuropathol Appl Neurobiol 12:
of Veterinary Medicine, Auburn University, Auburn, Ala-                           459-475, 1986
bama.                                                                       19    Cavanagh JB: The significance of the “dying back” pro-
                                                                                  cess in experimental and human neurological disease. Int
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Request reprints from Dr. K. G. Braund, Neuromuscular Laboratory, Scott-Ritchey Research Center, Auburn University,
College of Veterinary Medicine, Auburn, AL 36849-5525 (USA).

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