J. F. Cummings

Canine X-linked muscular dystrophy : morphologic lesions

Gross pathologic lesions and light microscopic and ultrastructural features of skeletal muscle lesions in canine X-linked muscular dystrophy (CXMD) were studied in dogs from 3 months to 6 years of age. Necrosis and regeneration were present at all ages, but were most prominent in the youngest dogs studied. Increased intracytoplasmic calcium, as evidenced by positive alizarin red S staining, was associated with fiber necrosis, but was also seen in small numbers of otherwise normal fibers. Progressive changes included development of severe fiber size variation, endomysial and perimysial fibrosis, prominent cytoplasmic disorganization, internalization of myonuclei, mitochondrial proliferation, mild fat infiltration, and alterations in the fiber-type pattern. The most consistent early ultrastructural changes were dilatation of the sarcoplasmic reticulum and focal subsarcolemmal areas of degeneration. Convincing sarcolemmal defects were not found. Z-band streaming was present at all ages, and Z-band duplication and nemaline rods were seen in older dogs. Evidence for abnormal regeneration was found in the oldest dog, and was associated with extensive fibrosis. These findings document the progression of lesions in CXMD, and illustrate the profound alterations in fiber organization and fiber type that may occur in late stages of dystrophin-deficient muscular dystrophy.

Progressive muscular dystrophy in a golden retriever dog: light microscope and ultrastructural features at 4 and 8 months.

SummaryThe clinical and morphological features of a congenital myopathy in a young male golden retriever dog were studied. Muscle biopsies at 4 and 8 months of age were examined with light and electron microscopy. Clinical features included early onset of generalized muscle weakness with selective muscle atrophy and hypertrophy, splaying of the limbs, stiff gait, and marked elevation of serum creatine kinase (CK). An electromyograph revealed spontaneous electrical activity characterized by sustained high-frequency activity, which was not abolished by neuromuscular blockade.Morphologically there was marked hypercontraction and segmental necrosis of muscle fibers with phagocytosis and regeneration. Ultrastructurally, dilatation of sarcoplasmic reticulum was the most consistent feature associated with early fiber degeneration. No abnormalities were noted in the central or peripheral nervous system. Progression of the disease was evident at 8 months. It was concluded that the findings are consistent with a dystrophic process of primary muscle origin. The probable genetics and comparison to other animal models of muscular dystrophy and to Duchenne dystrophy are discussed.

Feline sphingolipidosis resembling Niemann-Pick disease type C

SummaryA 9-week old domestic short-hair kitten with progressive neurological dysfunction had histopathological lesions consistent with a lysosomal storage disease. Light microscopy of the brain, spinal cord, and ganglia revealed distention and vacuolation of many neuronal populations, and extensive neuroaxonal dystrophy. Large numbers of foamy macrophages were observed in the liver, spleen, lymph nodes, and lung. Hepatocytes appeared pale and swollen. Ultrastructural examination of all affected tissues and organs revealed heterogeneous membranous inclusions. Lipid analysis of liver revealed an excess of cholesterol, glucosylceramide, lactosylceramide and phospholipids including sphingomyelin. There was some increase in the levels of brain GM2 and GM3 gangliosides. Sphingomyelinase activity in liver was partially deficient or low normal. Skin fibroblasts were cultured from two affected cats from the colony established with littermates of the subject of this report. The cultured skin fibroblasts had partially decreased sphingomyelinase activity and a greatly decreased ability to esterify exogenous cholesterol. Clinical, morphological, and biochemical findings suggest that this cat had sphingolipidosis similar to human Niemann-Pick disease type C, a disease not previously described in the cat. The feline form of this storage disease may provide a useful model for studies on the human disease.

Coonhound paralysis. An acute idiopathic polyradiculoneuritis in dogs resembling the Landry-Guillain-Barré syndrome.

Abstract We have studied clinically nine dogs, and pathologically five dogs, with coonhound paralysis. We have shown that the disease is an acute polyradiculoneuritis. The typical clinical picture is an acute ascending flaccid paralysis often with facial diplegia. Pathologically, the disease is characterized by inflammation and segmental demyelination of ventral roots and spinal nerves. We have shown that the bite of a raccoon has invariably preceded the illness by an interval of between 7 and 14 days. Coonhound paralysis has been compared in detail to the Landry-Guillain-Barre syndrome in man, and has been found to be nearly identical clinically and pathologically. This great similarity strongly suggests a pathogenesis common to both entities. The raccoon bite has been compared to the viral infections that so often precede the Landry-Guillain-Barre syndrome. The raccoon bite may be looked upon as an antigenic stimulus triggering immunological disturbances that damage Schwann cells. This hypothesis is in line with the prevalent theory of the role of viral disease in the Landry-Guillain-Barre syndrome.

GM2 gangliosidosis in a Japanese Spaniel

SummaryA storage disease in a 2-year-old Japanese Spaniel resembled a GM2 gangliosidosis previously identified in a now extinct line of German Shorthaired Pointers. Despite a later appearance of signs in the Japanese Spaniel, the distribution, staining, and ultrastructure of the stored material were similar in the two breeds. Golgi studies of cerebral cortical neurons revealed the formation of spiny and aspiny enlargements at the axon hillock region (meganeurites) and the growth of secondary neurites from this region. As in the German Shorthaired Pointer model, there was massive storage of GM2 ganglioside as well as a seemingly paradoxical increase in total β-hexosaminidase activity measured in vitro.

Motor and sensory centers for the innervation of mandibular and sublingual salivary glands: A horseradish peroxidase study in the dog

Horeradish peroxidase was injected at multiple sites in the mandibular and sublingual salivary glands in order to label the preganglionic salivatory neurons in the brain stem. The same injections resulted in retrograde labeling of the sympathetic and sensory neurons that project to these glands. Labeled fusiform and multipolar salivatory neurons were found ipsilaterally in the lateral reticular formation of the medulla where they extended over the rostral four-fifths of the facial nucleus and the caudal one-third of the dorsal nucleus of the trapezoid body. The vast majority of the small and medium-sized, labeled neurons appeared in thally at the ventral and lateral aspects of the facial nucleus. Enzyme injections into these glands labeled sympathetic neurons that were concentrated in the caudal one-third of the ipsilateral cranial cervical ganglion. Labeled sensory neurons were distributed randomly in the ipsilateral proximal vagal and geniculate ganglia. Large numbers of sensory neurons were concentrated ventromedially within the mandibular zone of the trigeminal ganglion.

The origins of innervation of the esophagus of the dog

This study defined the origins of extrinsic efferent and afferent innervation of the normal canine esophagus. When all the layers of the wall of the 3 esophageal regions (cervical, thoracic and abdominal) were injected with horseradish peroxidase (HRP), labeled nerve cells were found in the nucleus ambiguus (NA) and parasympathetic nucleus of X (PX) of the brainstem. Most labeled cells in the NA were located in the compact column (retrofacial nucleus) while labeled cells in the PX were located in separate rostral and caudal areas. There was no somatotopic organization in either the NA or PX. Labeled sympathetic postganglionic neurons were found in the cranial cervical, middle cervical, cervicothoracic, thoracic sympathetic trunk and celiacomesenteric ganglia. The HRP injection of the esophageal wall labeled sensory cell bodies in the glossopharyngeal, proximal and distal vagal, and C2-T6 spinal ganglia. There was no discernible pattern of distribution of labeled cells in the autonomic or sensory ganglia. When the HRP injections were confined to the mucosa-submucosa layers of the thoracic esophagus, a small number of labeled cells were identified in the NA; however, no labeled cells were found in the NA when injections were confined to the mucosa-submucosa of either the cervical or abdominal esophageal regions. With these confined injections, the labeled nerve cells appeared in the rostral part of the PX. Thus, it appeared that the internal tunics of the esophagus (i.e., the mucosa and submucosa) were innervated by neurons in the rostral PX while the muscular tunic was innervated by neurons in the caudal PX and the rostral NA. After mucosa-submucosa injections, labeled sympathetic neurons appeared in the same ganglia that were identified after whole wall injections and these had a similar random distribution. These injections also labeled neurons in the glossopharyngeal, proximal vagal, and distal vagal ganglia, but unlike the whole wall injections there was no labeling in the spinal ganglia. This suggested that the labeled cells of the spinal ganglia seen after whole wall injections conveyed impulses from the tunica muscularis and serosa.

Article Commentary: Acquired Equine Motor Neuron Disease:

Equine motor neuron disease (EMND) is an acquired neuromuscular disease of horses that was first recognized in 1985 and reported in a preliminary report often horses in 1 990.3 The disease is characterized pathologically by degeneration of motor neurons in the ventral horns of the spinal cord and in selected brain stem nuclei. Death of motor neurons results in secondary axonal degeneration and denervation atrophy of skeletal muscle. Clinical signs of diffuse neuromuscular disease are seen in EMND and include marked weight loss due to muscle atrophy despite a normal appetite, generalized weakness with a short-strided gait, a characteristic stance with low head carriage and feet positioned well under the body, frequent shifting of weight from limb to limb, excessive recumbency, excessive sweating, especially following exercise, and muscle fasciculations. Involvement of neurons in the spinal ganglia is thought to be the basis of the hyperesthesia noted in some cases. Clinicopathologic features include mild to moderately increased serum levels of creatine kinase and/or aspartate aminotransferase and frequent increase in cerebrospinal fluid protein concentrations. Denervation potentials, primarily positive sharp waves, can be detected with concentric needle e l ec t r~myography .~ .~ .~ .~~ The clinical and pathologic features of the equine disorder closely resemble those of the motor neuron diseases of human beings, of which the most important is amyotrophic lateral sclerosis (ALS; “Lou Gehrig’s disease”). 1,23,14.18.22 This name is applied to a group of fatal, degenerative motor neuron disorders that are characterized by progressive degeneration of spinal and selected brain stem motor neurons ,~~2~8~14~18~22 with only mild involvement of sensory n e ~ r o n s . ~ J ~ The pathology of the human disorder differs from that of EMND, however, in that extensive degeneration of pyramidal tracts is seen in human beings with classical ALS. 1,2,8~14~Ig,22 Only mild degeneration of pyramidal tracts is present in horses with EMND. However, the pyramidal tracts are poorly developed, and less extensive, in ungulates as compared to human beings.I0 Alternatively, EMND may be more analogous to progressive muscular atrophy, a variant of ALS in which pyramidal tracts are spared. I Histopathologic and ultrastructural lesions in neurons of horses with EMND3 closely resemble those seen in ALS. 1,2,8,14,18320322 Immunocytochemical studies have shown that the swollen neurons in EMND contain dense aggregates of neur~filaments,~ a finding similar to those in ALS.17 This equine disorder is distinctly different, clinically and pathologically, from previously described diseases of the equine neuraxis. Equine degenerative myeloencephalopathy and cervical stenotic myelopathy are diseases of spinal cord white matter and result in clinical evidence of spastic paresis and ataxia. Protozoal encephalomyelitis may result in focal or multifocal degeneration of motor neurons and degeneration of the white matter of the brain and spinal cord, but the resulting lower motor neuron weakness is localized and frequently asymmetric. Rabies virus polioencephalomyelitis may initially produce signs suggestive of lower motor neuron disease. However, the rapid, diffuse spread of this lesion will be accompanied by other neurologic ~ i g n s . ~ J ~ The motor neuron degeneration seen in EMND is pathologically similar to that seen in a presumed inherited motor neuron disease of zebras (Equus burchelli),12 but EMND is clearly a sporadic acquired disorder affecting horses of all ages and breed^.^,^,^ Quarter Horses are overrepresented in the various breeds affected, and Thoroughbreds are also at increased risk. The risk of EMND increases with age, with a peak at 16 years of age.I6 At the time of this writing, 67 cases of EMND have been confirmed by pathologic and/or clinical and clinicopathologic findings, and many more are suspected. Most of the 67 recognized cases of EMND have occurred in the northeastern USA, the area from which most cases seen at the New York State College of Veterinary Medicine are drawn. However, cases have been confirmed in Ohio (four), Indiana (two), West Virginia (one), Maryland (one), Kentucky (one), Alaska (two), California (one), Oregon (one), Nebraska (one), Tennessee (one), Florida (one), and Ontario, Canada (one). Confirmation has relied on recognition of typical clinical and clinicopathologic findings and on frozen section histochemistry applied to muscle samples mailed by overnight carrier to appropriate laboratories. Additional cases are suspected in Great Britain.” At Cor-

Equine Motor Neuron Disease

This article reviews the subject of equine motor neuron disease, a neurodegenerative disease of horses. The authors discuss various topics, including epidemiology, pathophysiology, clinical signs, laboratory findings, diagnosis, and treatment.

Acral mutilation and nociceptive loss in English Pointer dogs

SummaryAcral mutilation and analgesia occurred in three of a litter of nine pups produced by a mating of clinically normal English Pointer dogs. Post-mortem studies on one of the affected pups revealed changes at the level of the primary sensory neuron which included: a reduction in spinal ganglia size, a 22–50% deficiency of ganglionic neurons, and a disproportionately large population of small sensory cell bodies. The only change noted in the spinal cord occurred in the dorsolateral fasciculus where reduced fiber density appeared to correlate well with the observed nociceptive defect. Light- and electron-microscopic examination of spinal roots, ganglia, and peripheral nerves provided evidence of myelinated and unmyelinated fiber degeneration. The neuronal degeneration, however, appeared quantitatively inadequate to account for the deficiency of sensory cell bodies. It was concluded that this mutilating acropathy was a manifestation of a sensory neuropathy in which the neuronal deficiency resulted from insufficient development and slowly progressive, postnatal degeneration.The clinical and pathologic findings in this canine disorder were compared with those reported in hereditary sensory neuropathies of man and other animals.