Dysautonomia in a Family of German Shorthaired Pointers
Four, 5-week-old German shorthaired pointers from a litter of five puppies were presented for evaluation of vomiting and diarrhea. The dam was euthanized for suspected dysautonomia, and the fifth puppy died 1 day prior to presentation. On presentation, two puppies had vomiting and diarrhea, and the other two appeared healthy. The results of testing supported the diagnosis of dysautonomia in the two affected puppies but not in the healthy puppies. On day 5 of hospitalization, one apparently healthy puppy developed vomiting and diarrhea and had supportive testing for dysautonomia. Dysautonomia was confirmed at necropsy in affected dogs.
Case Reports
Four, 5-week-old German shorthaired pointers from a litter of five puppies were referred to the Kansas State University Veterinary Medical Teaching Hospital (KSU-VMTH) for evaluation of lethargy, vomiting, and diarrhea. Dysautonomia was suspected in the puppies, as the 2-year-old dam was recently euthanized for clinical signs consistent with dysautonomia. The dogs were from a rural area in northeastern Kansas and lived on a farm that raised cattle and pheasants. The puppies had been kept in the house since whelping and had no exposure to other dogs or livestock. There were four female puppies and one male puppy in the litter. The dam had access to a two-acre area surrounding the house and had contact with the pheasants, but not with the cattle. The dam was current on vaccinations, and no vaccinations were administered during the pregnancy or whelping period. There were two other dogs on the farm: a male sibling of the dam and an older, male chow chow. Both of these dogs were healthy. The dam was fed a commercial puppy food during whelping, and the puppies were still nursing when the dam became ill.
The dam presented to the referring veterinarian with an acute onset of vomiting and diarrhea 9 days prior to the puppies’ admission to KSU-VMTH. Other than moderate dehydration, there were no other abnormalities noted on the physical examination at that time. The results of a complete blood count (CBC) and serum biochemical profile were within reference ranges, and the dog was treated with intravenous fluids. The dog continued to vomit, and radiographs taken on the second and third day of hospitalization showed moderate ileus, possibly consistent with intestinal obstruction. No intestinal foreign bodies or obstructions were noted on an abdominal exploratory and enterotomy performed on day 3. On day 4, the dog developed dry and crusted nostrils, elevated nictitans bilaterally, and poor anal tone. Dysautonomia was suspected, and euthanasia was performed. The dog was sent to KSU-VMTH for necropsy.
One day prior to presentation at KSU-VMTH and 4 days after the dam was euthanized, three female puppies developed an acute onset of vomiting and diarrhea. One of these puppies died that night and was sent to KSU-VMTH for necropsy. The two puppies that continued to have vomiting and diarrhea and the remaining two puppies that appeared to be healthy were referred for evaluation.
Case No. 1
The first puppy with vomiting and diarrhea was a 2.17-kg female. On presentation, she had crusting around the nose and mouth, the rectal temperature was 102.5°F (39.2°C), and the heart rate was 100 beats per minute. The puppy was emaciated, 5% to 8% dehydrated, and lethargic. On abdominal palpation, the intestinal loops were subjectively thickened. The puppy attempted to drink water when it was offered but regurgitated immediately. The diarrhea was pasty and tan, and an enzyme-linked immunosorbent assay (ELISA) performed on the feces for parvovirus was positive. A CBC showed a total white blood cell (WBC) count of 6.0 × 103 cells/μL (reference range, 6.0 to 17.0 × 103 cells/μL), with 2.0 × 103 segmented neutrophils/μL (reference range, 3.0 to 11.5 × 103 cells/μL), 1.4 × 103 band cells/μL (reference range, 0 to 300 cells/μL), 1.8 × 103 lymphocytes/μL (reference range, 1.5 to 5.0 × 103 cells/μL), 780 monocytes/μL (reference range, 100 to 800 cells/μL), and 60 eosinophils/μL (reference range, 0 to 750 cells/μL). Abdominal radiographs showed evidence of severe ileus.
Case No. 2
The second puppy with vomiting and diarrhea was a 2.0-kg female. She was emaciated, dehydrated, and lethargic on presentation, and she had crusting around the nostrils. The rectal temperature was 102°F (38.9°C), heart rate was 90 beats per minute, and intestinal loops were also subjectively thickened. The diarrhea was similar to the first puppy, and an ELISA for parvovirus was positive. A CBC showed a total WBC count of 2.53 × 103 cells/μL, with 780 segmented neutrophils/μL, 530 band cells/μL, 1.1 × 103 lymphocytes/μL, and 100 monocytes/μL. Abdominal radiographs showed marked ileus, and thoracic radiographs showed a mild bronchointerstitial pattern.
Case No. 3
The third puppy was an apparently healthy, 2.15-kg female. She was bright and alert, with a rectal temperature of 101°F (38.3°C) and a heart rate of 100 beats per minute. The puppy readily ate food and drank water during the examination. An ELISA for parvovirus was also performed on this puppy and was positive. A CBC was not performed on the first day.
Case No. 4
The fourth puppy was an apparently healthy, 3.65-kg male. He was bright and alert, with a rectal temperature of 101.4°F (39°C) and a heart rate of 160 beats per minute. This puppy also readily ate food and drank water during the examination. An ELISA for parvovirus was positive; however, a CBC was not performed at this time.
Case Outcomes
The first two puppies were treated with lactated Ringer’s solution and cefoxitin (22 mg/kg body weight, subcutaneously [SC] q 8 hours), and all puppies were kept in isolation. The healthy puppies were housed together and physically separated from the two sick puppies that were housed together.
On the second day, case nos. 1 and 2 were more depressed, respirations were slightly more rapid and labored, and they began to cough intermittently. Pupillary light response (PLR), intradermal histamine response, Schirmer’s tear test (STT), and response to ocular administration of 0.1% pilocarpine were evaluated on all four puppies; the results are summarized in the Table. Based on these results, case nos. 1 and 2 were suspected of having dysautonomia. Therapy as previously described was continued on these two puppies; however, they died that night. A necropsy was performed on both puppies.
On day 4 of hospitalization, case no. 3 became mildly depressed and lethargic and would only eat a small amount of canned food. A CBC performed on this day showed a WBC count of 18.3 × 103 cells/μL, with 14.3 × 103 segmented neutrophils/μL, 2.9 × 103 lymphocytes/μL, and 1.1 × 103 monocytes/μL. The ELISA for parvovirus was still positive at this time. This puppy was treated similarly to the other two puppies. Case no. 4 remained clinically healthy, and a CBC showed a WBC count of 18.4 × 103 cells/μL, with 9.0 × 103 segmented neutrophils/μL, 8.1 × 103 lymphocytes/μL, and 1.3 × 103 monocytes/μL.
On day 5, case no. 3 was more depressed, very weak, and began vomiting. The PLR was absent in both eyes (OU); the STT was now depressed at 0 mm per minute in the left eye (OS) and 5 mm per minute in the right eye (OD); an intradermal injection of histamine produced a wheal but no flare; and administration of 0.1% pilocarpine produced marked miosis within 30 minutes. The puppy was euthanized because of the rapidly declining condition, and a necropsy was performed.
Case no. 4, the only male in the litter, was clinically healthy through day 11 of hospitalization. This puppy was released to the owner at this time and has shown no evidence of dysautonomia 10 months later.
Gross Pathology
The dam was in good body condition and externally was normal. There was a food bolus in her pharynx, and green, watery fluid that contained ingesta was present in her esophagus, frontal sinuses, and trachea. At the enterotomy site in the colon, a small amount of purulent material exuded from around the sutures, and there were fibrinous adhesions between the colon and the pancreas, duodenum, jejunum, and omentum. The right middle lung lobe and the adjacent parenchyma in the surrounding lobes were dark red, firm, and heavy.
The four puppies were externally normal. In three of four puppies, the oral cavity, pharynx, and trachea contained green fluid and mucus that contained a small amount of feed material. The esophagus in each of the same three puppies was dilated and filled with ingesta. In all puppies, almost the entire small and large intestines were dilated to 1.25 to 1.5 cm in diameter and filled with mucus and ingesta that progressed from liquid in the cranial half of the small intestine to firm in the distal small intestine and colon.
Histopathology
Neurons in the cranial mesenteric, celiac, periadrenal, and cervicothoracic ganglia of the mother and puppies all contained degenerative lesions compatible with those described for dysautonomia of dogs and other species [Figure 1].1 In many neurons, the cytoplasm was hypereosinophilic and either lacked Nissl granules or contained only a thin, peripheral rim of Nissl granules (i.e., central chromatolysis). Most nuclei in affected neurons were peripherally located and pyknotic, while nuclei in normal neurons were large and vesicular with prominent nucleoli. Scattered neurons, especially in the puppies, were shrunken and hypereosinophilic with pyknotic or karyorrhectic nuclei. The cytoplasm of many neurons contained peripherally located vacuoles. Most vacuoles were empty, but a few were partially filled with flocculent, eosinophilic material. When compared to ganglia from normal dogs, neuron numbers in ganglia from the dam were decreased, and there was mild infiltration by lymphocytes, plasma cells, glial cells, and macrophages.
In two of the puppies and the dam, there was fibri-nosuppurative bronchopneumonia caused by aspiration. The esophageal mucosa of one puppy was almost entirely ulcerated. The puppy that died prior to presentation had chronic pyelonephritis and purulent cystitis with gram-negative bacilli attached to the bladder mucosa. In samples from the mother, there were microabscesses surrounding the colonic sutures, and neutrophils extended to the serosa where there was fibrinopurulent peritonitis. There were no intestinal lesions in any of the dogs to indicate an active parvovirus infection.
Discussion
Primary dysautonomia is a noninflammatory, neurodegenerative disorder of sympathetic and parasympathetic neurons.1 The disease has been described in horses, cats, dogs, and rabbits; however, the etiology of the neuronal degeneration remains a mystery. From many countries there have been isolated case reports of canine dysautonomia; however, the largest number of cases reported was from the midwestern United States.2–8 Dysautonomia was described in 25 cats in a closed colony that developed the disease over a 3-week period and in two cats from the same household that developed the disease simultaneously.910 This study describes the first cluster of cases of canine dysautonomia, the first report of dysautonomia in related dogs, and the youngest reported cases in the dog.
The clinical signs and physical examination findings in these dogs were consistent with those previously reported.2–811 Vomiting, diarrhea, dry mucous membranes, decreased STT, absent PLR, and decreased anal tone were seen in the dogs of this report and are reportedly common in dogs with dysautonomia. Dysuria was not reported in the bitch and was not evident in the puppies. The dam of this report had a sudden onset of vomiting and diarrhea with progression of clinical signs over 4 days. A progression of signs toward complete autonomic nervous system dysfunction has been previously reported.23 The first three puppies had a peracute onset of clinical signs, whereas the last puppy had slower progression of autonomic dysfunction.
Relative bradycardia and failure to respond to administration of anticholinergic drugs, such as atropine, are reported as common findings in dogs with dysautonomia.811 As a result of the loss of sympathetic nervous system innervation of the heart, no change in rate is seen after the administration of anticholinergics. It is interesting to note that the two puppies that presented with clinical dysautonomia and the puppy that developed dysautonomia 4 days later had heart rates in the range of 90 to 100 beats per minute, whereas case no. 4 had a heart rate of 160 beats per minute on presentation. An atropine response test was not performed on these puppies.
Loss of postganglionic parasympathetic innervation to the iris is responsible for the mydriasis and loss of the PLR in dogs with dysautonomia.8 The dramatic and rapid miosis that occurred with the administration of 0.1% pilocarpine in case nos. 1 and 2 is consistent with denervation hypersensitivity of the smooth muscle of the iris. Case no. 3 did not have a response to 0.1% pilocarpine when initially tested on day 2, but she had miosis when tested on day 5. The OD was tested on both days in case no. 3, since this eye demonstrated a normal PLR on day 2. The OS had a sluggish PLR on day 2, but it was not tested. It is possible that degeneration of the parasympathetic neurons innervating the OS were at a more advanced stage of degeneration than the OD in this puppy on day 2.
The absence of a wheal and flare response has been attributed to the loss of sympathetic innervation to the blood vessels.7811 In response to intradermal histamine, a wheal response is seen in humans with familial dysautonomia, but the flare response is absent.12 The wheal is a direct response to the actions of histamine on blood vessels, but the flare is dependent on antidromic transmission along sensory fibers.12 This has been attributed to loss of sensory function and not autonomic function in patients with familial dysautonomia.12 Case nos. 1 and 2 lacked a flare in response to intradermal histamine administration, but case no. 2 retained a slight wheal response. Case no. 3 had a strong wheal and flare response on day 2, but lacked a flare response when tested on day 5. The lack of a wheal response seen in case no. 1 of this report and reported in other dogs with dysautonomia is difficult to explain. It is possible that a transient and mild wheal does occur but is not observed, and intensification of the wheal is dependent on mechanisms similar to the flare response.
The presence of dry mucous membranes is a common finding in dogs with dysautonomia and can be quantified with the STT.811 A decreased STT was seen in case nos. 1 and 2 when initially tested. Case no. 3 had a normal STT on day 2 but had an abnormal result on day 5. This further underscores the rapid degeneration of parasympathetic neurons that occurred in this dog.
Variable leukocyte responses have been reported in dogs with dysautonomia, including neutropenia, a left shift, neutrophilia, and lymphopenia.8 Case nos. 1 and 2 had neutropenia on day 1, which could also be consistent with parvovirus infection. Despite the positive parvovirus ELISA tests on all puppies, however, there were no lesions found at necropsy consistent with parvovirus enteritis. Case no. 4 did not develop clinical disease consistent with parvovirus. A CBC was not repeated on these puppies during their hospitalization to monitor possible changes in the WBC count. These puppies may have been exposed to parvovirus but possibly were protected from disease by maternal immunity.
The etiology of dysautonomia remains unknown. Current theories revolve around the possibility of an infectious agent, environmental toxin, or biological toxin.1811 These puppies had no exposure to the outside environment and were housed in a clean environment. Other than the dam and the owner, no other animal had access to these puppies. This raises the possibility that an environmental or biological toxin was passed through the milk or that the dam was shedding a contagion (either nasal-oral or fecal-oral) that infected the puppies. Assuming the puppies were infected at or near the time that the dam first demonstrated clinical signs, an incubation period of 10 to 15 days would be predicted. However, it is possible that the dam and puppies were infected much earlier. Given the age of the puppies, the longest incubation period could only be 5 weeks, assuming that exposure was not in utero. If the puppies ingested a toxin from the milk, this toxin demonstrates a delayed neurotoxicity. It is possible that a toxic agent resulted in disordered axonal transport with subsequent delayed neuronal death.
Although no gender predilection has been reported with canine dysautonomia, it is interesting that the only surviving dog from this group was the sole male puppy. All other dogs in this group were female, and the two other male dogs at home were also unaffected. Although the survival of the male puppy likely represents a chance occurrence, it is interesting to speculate on possible mechanisms of his survival. None of the puppies had been weaned at the time that the dam became ill, so all puppies had similar exposure conditions.
Conclusion
Dysautonomia—a rare, idiopathic, neurodegenerative disease—was diagnosed in a family of dogs with vomiting and diarrhea. Results of pharmacological testing supported the diagnosis in the affected dogs, and the diagnosis was confirmed at necropsy. The disease was uniformly fatal in every dog that developed clinical signs.
Acknowledgment
The authors thank Dr. Shera Chaloupka from the Oskaloosa Animal Clinic, Oskaloosa, Kansas, for the referral of the dogs in this report.
Citation: Journal of the American Animal Hospital Association 38, 1; 10.5326/0380055
Autonomic ganglion from one of the puppies. Several neurons are brightly eosinophilic, lack Nissl bodies, and have pyknotic nuclei (large, solid arrowhead). Compare to normal neurons which have Nissl bodies throughout their cytoplasm and which have large vesicular nuclei that contain distinct nucleoli (open arrowhead). Also note the neuron in which there is a cytoplasmic vacuole that contains lightly eosinophilic, amorphous material (small, solid arrowhead) (Hematoxylin and eosin stain, bar=40 μm).
