Introduction

Primary dysautonomia is a rare degenerative neurologic disease that has been described in multiple veterinary species including dogs, cats, horses, llamas, and hares.^1–8 Various similar syndromes have also been described in humans.⁹ Sporadic cases in dogs have been reported in Europe and the US. In the US, most cases are focused within the Midwest, including Missouri, Kansas, and surrounding areas, but have been reported in other states.^2,10–12

Clinical signs of this disease are multisystemic and attributed to neuronal degeneration resulting in primarily parasympathetic dysfunction with lesser degrees of sympathetic and somatic dysfunction. Severity of clinical disease is dependent on the degree of autonomic ganglion degeneration and which bodily systems are affected. Although no definitive agreement for antemortem diagnostic criteria exists, antemortem diagnosis is typically made via documentation of physical signs of autonomic nervous system dysfunction as well as pharmacologic testing.^10,11,13 Commonly reported clinical signs and general physical examination findings associated with canine dysautonomia (CD) include lethargy, anorexia, weight loss, vomiting or regurgitation, diarrhea, tenesmus, constipation, dysuria, nasal discharge, coughing, dyspnea, xerostomia, ileus, decreased anal tone, distended and expressible urinary bladder, relative bradycardia, and weak peripheral pulses.^2,10,11,14 Antemortem pharmacologic testing options include administration of dilute topical ophthalmic pilocarpine, systemic atropine, and intradermal histamine to diagnose CD.^2,10,11,14 Radiographic or ultrasonographic evidence of megaesophagus and secondary aspiration pneumonia, ileus, and decreased cardiac contractility are also considered supportive of a clinical diagnosis of CD.^13,15 Antemortem full-thickness intestinal biopsy demonstrating neuronal degeneration has also been used to confirm the diagnosis of CD.¹⁴ Necropsy findings of generalized degeneration of ganglion neuronal cells and decreased neuronal cell density are considered confirmatory.^10,11 The cause of CD is unknown, but ingestion of a botulinum-like toxin or exposure to other environmental toxins or contagions have been suggested, and proposed risk factors include rural environment with an outdoor lifestyle.^11,14,16

Dogs with CD may exhibit several ocular abnormalities. Loss of parasympathetic innervation to the iris sphincter muscle results in resting mydriasis and loss of appropriate pupillary light reflexes (PLRs); though, in some dogs, midrange pupils and abnormal PLRs are observed, indicating loss of sympathetic control of the iris dilator muscle.¹⁰ Decreased lacrimation has also been reported commonly in dogs with CD, attributed to the loss of parasympathetic innervation of the lacrimal glands.¹⁰ The objective of this study was to retrospectively describe and determine the frequency of ocular abnormalities in dogs with CD.

Methods

An electronic medical records database search was performed using the keyword “dysautonomia.” Records of dogs with a clinical or histopathologic diagnosis of dysautonomia at the Kansas State University Veterinary Health Center (KSU-VHC) between the years 2004 and 2021 were included in the study.

Data collected from the medical records included signalment, current zip code, presenting complaint(s) and physical examination findings, ophthalmologic examination findings, pharmacologic testing results, and case outcome. Schirmer tear test (STT) readings per eye were grouped into 4 categories: ≤ 5 mm/min, 6 to 10 mm/min, 11 to 14 mm/min, and ≥ 15 mm/min.

Antemortem diagnosis of CD was based on 1 of 4 criteria: (1) an examination by a board-certified small animal internist and the presence of clinical signs or physical exam findings consistent with CD; (2) positive response to pharmacologic testing with atropine administered IV, intradermal histamine, or topical ophthalmic pilocarpine; (3) intestinal biopsy; or (4) necropsy. Clinical signs consistent with CD included any of the following: lethargy, anorexia, weight loss, vomiting or regurgitation, diarrhea, tenesmus, constipation, dysuria, nasal discharge, coughing, dyspnea, photophobia, ocular discharge, or dilated pupils. Supportive physical examination findings included nasal discharge, xerostomia, increased respiratory sounds, dyspnea, ocular discharge, resting mydriasis, diminished PLR, elevated third eyelid(s), ileus, decreased anal tone, distended and expressible urinary bladder, relative bradycardia, and weak peripheral pulses.

At the discretion of the attending clinician, pharmacologic testing using topical dilute pilocarpine, atropine administered IV, or intradermal histamine response tests was performed to support the presumptive diagnosis. Pupil constriction within 60 minutes after application of a single drop of 0.01%, 0.05%, or 0.1% pilocarpine was considered supportive of CD. A heart rate increase of at least 40 beats/min or a heart rate above 140 beats/min within 1 hour following administration of 0.02 mg/kg atropine IV was considered normal and inconsistent with a clinical diagnosis of CD. Alternatively, dogs were lightly exercised and observed for a change in heart rate. Lack of wheal and flare formation following intradermal histamine administration was considered consistent with CD. Radiographic findings of aspiration pneumonia, megaesophagus, functional ileus of the gastrointestinal tract, and urinary bladder distension, or decreased cardiac contractility on echocardiogram were all considered supportive of a clinical CD diagnosis. When a necropsy was performed, autonomic ganglion degeneration was considered confirmatory for CD.

Results

A medical record search for dogs with a diagnosis of “dysautonomia” returned a total of 89 records. Of those records, 7 were deemed insufficiently complete and those dogs were excluded. Three other dogs failed to meet the inclusion criteria and were excluded. A total of 79 dogs with a clinical (n = 60) or histopathologic (19) diagnosis of dysautonomia were included. Of the dogs with a clinical diagnosis of CD, 48 were supported with pharmacologic testing with atropine (n = 6), pilocarpine (30), or both (12). Intradermal histamine testing was performed in 1 dog, which was consistent with CD. Twelve dogs had a clinical diagnosis of CD based on an examination by a board-certified small animal internist and clinical signs and physical exam findings consistent with CD. Additional imaging was performed including thoracic radiographs (n = 43), abdominal radiographs (34), abdominal ultrasound (12), and echocardiogram (18). Two dogs had intestinal biopsies and 19 dogs had a necropsy performed, which confirmed the diagnosis of CD. Mixed-breed dogs were the most common (n = 17), followed by Labrador Retriever (9), German Shorthaired Pointer (6), German Shepherd Dog (5), Border Collie (5), Golden Retriever (5), Australian Shepherd (3), Bernese Mountain Dog (3), Rottweiler (3), Australian Cattle Dog (2), Brittany Spaniel (2), Boxer (2), Doberman Pinscher (2), Great Pyrenees (2), and Miniature Australian Shepherd (2). There was 1 dog represented from each of the following breeds: American Bulldog, Belgian Malinois, Dachshund, English Pointer, French Bulldog, Great Dane, Mastiff, Miniature Poodle, Newfoundland, and Weimaraner. There were 16 intact females, 27 intact males, 27 spayed females, and 9 castrated males. Mean age at time of presentation was 3.3 years (median, 1 year; range, 3 months to 11 years). Mean body weight was 21.6 kg (range, 5 to 69 kg). Zip codes of 79 dogs were available for review. Dogs originated from the states of Kansas (n = 74), Missouri (3), and Nebraska (2). There were 33 dogs from urban areas and 46 dogs residing in counties classified as rural. Peak months of diagnosis were May and March with 13 and 10 cases, respectively (Table 1).

None of the dogs had a prior history of ophthalmic disease as reported by the owner, documented in the medical record, or provided in documents from referring veterinarians. All dogs had at least 1 nonocular clinical sign and/or physical exam abnormality, including vomiting and/or regurgitation in 69 of 79 (87.3%) dogs, diarrhea in 34 of 79 (43.0%) dogs, anorexia or inappetence in 31 of 79 (39.2%) dogs, dysuria and/or a distended expressible bladder in 21 of 79 (26.6%) dogs, lethargy in 20 of 79 (25.3%) dogs, weight loss in 9 of 79 (11.4%) dogs, nasal discharge in 8 of 79 (10.1%) dogs, constipation in 6 of 79 (7.6%) dogs, coughing or increased respiratory noise in 3 of 79 (3.8%) dogs, dyspnea in 3 of 79 (3.8%) dogs, dysphagia in 1 of 79 (1.3%) dogs, and sneezing in 1 of 79 (1.3%) dogs. Mean duration of clinical signs reported by the owner prior to presentation was 10.5 days (range, 1 to 56 days).

A diminished PLR was the most common ocular abnormality (Table 2) and was reported in a total of 55 of 79 (69.6%) dogs. PLRs were diminished in 30 of 79 (38.0%) dogs and absent in 24 of 79 (30.4%) dogs. One (1.3%) dog had asymmetric PLRs with a diminished direct PLR in the right eye and an absent direct PLR in the left eye. Six (7.6%) dogs had normal PLRs, and the remaining 18 (22.8%) dogs did not have PLR results recorded. Two of the dogs with normal PLRs were pharmacologically tested with atropine, and 2 dogs were diagnosed on the basis of examination by a board-certified small animal internist. Two of the dogs with normal PLRs had CD confirmed on necropsy. PLRs were not recorded in the medical record of 18 dogs, but CD was diagnosed in these cases on the basis of necropsy and pilocarpine testing (n = 1), pilocarpine testing (3), atropine and pilocarpine testing (3), necropsy (4), or examination by a board-certified small animal internist (7).

Third eyelid elevation was the second most common ocular abnormality and was reported in 51 of 79 (64.6%) dogs. Other reported ocular abnormalities included resting mydriasis in 21 of 79 (26.6%) dogs, bilateral serous to mucoid ocular discharge in 14 of 79 (17.7%) dogs, photophobia in 10 of 79 (12.7%) dogs, bilateral blepharospasm in 5 of 79 (6.3%) dogs, corneal ulceration in 4 of 79 (5.1%) dogs, bilateral pallor of the conjunctival vessels in 1 of 79 (1.3%) dogs, and bilateral episcleral injection in 1 of 79 (1.3%) dogs. Aggressive behavior in 1 dog prevented a detailed ophthalmic examination, but no gross ocular abnormalities such as mydriasis or elevated third eyelids were appreciated. There was a specific comment reporting no apparent ocular abnormalities at the time of CD diagnosis in the medical record of 5 dogs.

Tear production was measured using an STT I in 112 eyes from 56 dogs. Median STT values of right and left eyes were 11.75 mm/min (range, 0 to 25 mm/min) and 10.5 mm/min (range, 0 to 24 mm/min), respectively. STT readings per eye were grouped into 4 categories: ≤ 5 mm/min, 6 to 10 mm/min, 11 to 14 mm/min, and ≥ 15 mm/min. Of the 112 eyes in which tear production was measured, 29 (25.9%) eyes from 16 (28.6%) dogs had STT values of ≤ 5 mm/min and 26 (23.2%) eyes from 18 (32.1%) dogs had STT values of 6 to 10 mm/min. Seventeen (15.2%) eyes from 12 (21.4%) dogs had STT readings from 11 to 14 mm/min, and the remaining 40 (35.7%) eyes from 24 (42.9%) dogs had normal STT values of ≥ 15 mm/min. Overall, 32 of 56 (57.1%) dogs had bilaterally low STT values of < 15 mm/min and 16 of 56 (28.6%) dogs had bilaterally normal STT values of ≥ 15 mm/min. Eight of 56 (14.3%) dogs had 1 eye with low STT results and 1 eye with normal STT results. All 4 dogs with corneal ulceration had low STT values. Three of the 4 (75%) dogs with corneal ulceration had an STT value of 0 mm/min in both eyes. One dog with bilateral corneal ulceration had STT values of 0 mm/min in the right eye and 9 mm/min in the left eye.

Testing using 0.01%, 0.05%, or 0.1% dilute topical pilocarpine was performed in 51 dogs in either 1 or both eyes. A total of 9 (17.6%) dogs demonstrated no constriction of the pupil, consistent with a negative test result (Table 3). The remaining 42 (82.4%) dogs had miosis in at least 1 eye following administration of dilute pilocarpine. One of the dogs with a positive test had constriction of the pupil in only the left eye, which was tested with 0.1%, but no response in the right eye, which was tested with 0.01%.

Of the 79 dogs diagnosed with CD, 32 (40.5%) survived to time of discharge from the hospital. Forty-four (55.7%) dogs were humanely euthanized, and 3 (3.8%) dogs died while hospitalized. Necropsy reports were available for 19 dogs. Necropsy findings included multifocal neuronal degeneration and/or necrosis of the peripheral autonomic ganglia and plexuses and brainstem nuclei.

Follow-up was available for 11 dogs that survived to discharge and returned to the KSU-VHC for repeated examination. The median length of follow-up available was 9 months (range, 1 to 60 months). One dog did not have sufficient documentation in the medical record at follow-up visits to determine whether ocular abnormalities had resolved. One dog had no ocular abnormalities at the time of diagnosis or during the subsequent 15 months for which follow-up was available. Four dogs had complete resolution of ocular abnormalities, and 3 dogs had partial resolution. Two dogs had no resolution of ocular abnormalities by the last time of follow-up.

Discussion

Ocular abnormalities were found in 92.4% of dogs diagnosed with CD. Age, sex, and breed representation were consistent with previous studies.^2,11,16 While individual ocular abnormalities such as diminished PLR, third eyelid elevation, and decreased tear production have previously been reported in the literature,^{1,2,10–12,14} to our knowledge no studies have reported the frequency of ocular clinical signs in dogs with CD. Diminished PLRs and elevation of the third eyelid were found to be the most common ocular abnormalities in our study, with 69.6% and 64.6% of dogs affected, respectively. Previously reported rates of diminished PLRs range from 49% to 100%.^2,11,14 Two of the dogs in our study had normal PLRs and were diagnosed with CD on necropsy. We found that third eyelid elevation was present in 51 of 79 (64.6%) dogs, a higher percentage than previously reported ranges of 45% to 60%.^2,11,14 It is possible that the third eyelid elevation occurs due to loss sympathetic tone to the smooth muscles of the periorbital tissues, causing enophthalmos and passive third eyelid elevation. Another proposed mechanism for third eyelid elevation is photophobia leading to globe retraction and enophthalmos with passive elevation. Ocular discomfort due to low tear production could also contribute to active globe retraction and passive elevation of the third eyelid. This study also described conjunctival vessel pallor in 1 dog, which has not been previously reported in CD cases. Surface ocular irritation or ulceration due to decreased tear production is suspected to result in conjunctival hyperemia in some dogs with CD. However, conjunctival vessel pallor may be observed as a result of other disease factors associated with poor vessel perfusion, including decreased cardiac output, relative bradycardia, and dehydration secondary to GI disturbance.^11,15,13

In this study, 42 of 51 (82.4%) dogs had a positive response to dilute topical pilocarpine testing. This is lower than previously reported response rates of 87% and 100% in the literature^2,11 describing dogs in the US tested with 0.1% pilocarpine and observed for up to 60 minutes, but higher than the reported rate of 73% for dogs in the UK, where the concentration of pilocarpine and duration of monitoring for response were not reported.¹⁴ The dogs in this study were monitored approximately every 15 to 20 minutes for development of miosis for up to 60 minutes after administration, as is typical for the institution and consistent with previous literature.^11,16 Depending on clinician preference, pilocarpine concentrations ranging from 0.01% to 0.1% were used to perform pharmacologic testing in this study. The difference in results found in our study could be due to variation in the concentration of pilocarpine used for testing, variation in degeneration of individual dog parasympathetic postganglionic neurons, which regulate pupil size, or due to a difference in sample size or population between studies. In this study, 0.1% pilocarpine was found to yield the highest percentage of positive test responses. Pilocarpine is not commercially available in the US at the concentration used for dysautonomia testing, therefore manual drug dilution and mixing are required. Due to the small volume of the drug used, this is often performed in a small volume syringe and vigorous mixing is required to ensure even drug distribution in the syringe prior to administration. It is possible that some dogs received a higher or lower dose of pilocarpine than intended if the drug and diluent were not thoroughly mixed prior to use; this could explain the variability of the response to testing observed in our study or in other clinical settings.

Diminished tear production is a common ocular manifestation of CD^2,11,14 that threatens the health of the ocular surface. Supportive care, including supplemental lubrication of the ocular surface and treatment with lacrimostimulants, may be beneficial. Abnormal tear production (< 15 mm/min) was reported less frequently (57.1%) in our study than in previous studies, which have reported decreased tear production in 80% to 93% of dogs.^2,11,14 However, decreased tear production affected at least 3 dogs that survived long term in this study. Of the surviving dogs, 2 of 3 with decreased tear production recovered normal tear production and did not require lifelong lacrimostimulant or lacrimomimetic therapy. A prospective study evaluating response to treatment with topical or systemic pilocarpine in CD could provide more information and help guide treatment recommendations for surviving dogs.

The median age of dogs in our study was 1 year. Sex was evenly distributed with large-breed dogs being most common as supported by the average weight of 21.6 kg for dogs in this study. Previous studies of CD reported a median age of 14 to 18 months, even sex distributions, and a majority of large-breed dogs.^2,11,16 Mixed-breed dogs and Labrador Retrievers were the most commonly represented breeds in this study, consistent with previous literature.^11,14,16 In our study, CD was most commonly diagnosed in the months of March and May; previously reported months with the highest numbers of canine dysautonomia diagnoses included February, March, and May.^11,16 Most dogs with CD were from rural areas, which is consistent with previously identified risk factors, but this may be due to other confounding factors such as the population served by the KSU-VHC and no control group available for comparison.¹⁶

In many cases, the diagnosis of CD was made on the basis of the presence of classic clinical signs and physical exam findings, which are highly suggestive of CD. When presented with diminished PLRs, elevation of the third eyelids, and clinical signs of gastrointestinal illness, dysautonomia should be considered as a differential. Additional diagnostics such as STT and pharmacologic testing with topical pilocarpine and atropine administered IV may be considered before invasive diagnostics such as exploratory laparotomy. While no definitive antemortem test exists for CD, a combination of consistent clinical signs and pharmacologic testing results are generally accepted as strongly supportive for the clinical diagnosis of CD.

Follow-up was limited in this study due in part to the mortality rate with CD, so the persistence of ocular abnormalities such as decreased tear production is unclear. In this study, only 32 of 79 (40.5%) dogs survived to discharge from the hospital. Previous studies reported mortality rates of 53% to 100%, indicating a grave prognosis for survival and limiting the number of cases for which follow-up information has been available.^2,11,14 However, a retrospective study by Clarke et al¹⁴ documented a survival to discharge rate of 47% for CD cases in the UK from 2007 to 2016, compared to a study from Harkin et al,¹¹ which documented a survival rate of 15% for cases in the US from 1993 to 2000. While differences in the canine populations may account for some variation in the survival rate, the population in this study was collected from the same institution as Harkin et al¹¹; the increase in survival rate may indicate an improvement in survival over time due to earlier recognition of disease leading to earlier intervention or advances in supportive care and treatment.

The ultimate progression of systemic signs of CD is variable, with some dogs recovering spontaneously while others develop fatal complications despite aggressive supportive therapy. It is possible that ocular abnormalities may resolve spontaneously with or without intervention if the dog survives long enough. Of the 11 surviving dogs that returned for serial examination, 6 had complete resolution of all clinical ocular abnormalities within the follow-up period.

The current study had several limitations owing to its retrospective nature. The medical records were not always complete, and multiple clinicians performed the examinations. This may have resulted in variation in reporting of abnormalities due to the subjective nature of certain findings, such as resting pupil size. A prospective study in which dogs suspected to have CD are examined by a veterinary ophthalmologist could describe ocular abnormalities in greater detail than the current study and could possibly correlate ophthalmic abnormalities with prognosis. The majority of our cases did not have necropsies performed to confirm the dysautonomia diagnosis, and lack of long-term follow-up limited the ability of the current study to predict recovery and resolution of ocular abnormalities in surviving dogs.

In conclusion, the most common ocular clinical signs of CD are diminished PLRs, elevation of the third eyelid, and decreased tear production. Dogs with CD may present with normal PLRs. Ocular abnormalities may resolve in CD survivors.