Autonomic dysfunction in a Jack Russell terrier

Abstract

A 4-year-old Jack Russell terrier was presented with an array of clinical signs suggestive of autonomic dysfunction. Many of the clinical signs were consistent with a diagnosis of dysautonomia; however, both chronicity and resolution of signs contradicted a diagnosis of this disease.

A 4-year-old castrated male Jack Russell terrier was presented to the Ontario Veterinary College with a 7-week history of lethargy, vomiting, diarrhea, anorexia, weight loss, and episodes of collapse. Bilateral keratoconjunctivitis sicca (KCS) was diagnosed approximately 1 wk after the onset of gastrointestinal signs. Transient dysuria was also reported, but had resolved by the time of presentation. Diagnostic tests performed by the referring veterinarian included abdominal radiographs, fecal analysis, complete blood (cell) count (CBC), serum biochemistry profile, and an adrenocorticotropic hormone (ACTH) stimulation test. The results of these tests were within reference ranges. The dog was treated for its gastrointestinal signs with famotidine, sucralfate, metoclopramide, ampicillin, metronidazole, and intravenous fluids. The dog was referred to the Ontario Veterinary College Teaching Hospital (OVCTH) for further diagnostic and treatment options when no improvement in clinical signs was observed with the prescribed therapy.

Case description

On presentation to the OVCTH, the dog’s demeanor was quiet but alert. Physical examination revealed a body condition score of 1.5/5 and normal vital parameters. Marked xerostomia was observed, although other indicators of dehydration (prolonged skin tent) were not noted. Ocular discomfort was evident and characterized by persistent bilateral blepharospasm. Samples for a CBC, biochemistry panel, blood gas analysis, urinalysis, and fecal analysis were submitted to the Animal Health Laboratory in Guelph, Ontario. Values for all the tests were in the normal range. No abnormalities were detected on abdominal ultrasound. Electrocardiography showed a normal sinus rhythm.

Ophthalmologic consultation revealed mild anisocoria with mild bilateral mydriasis (left eye more severe than right eye) and bilateral absence of direct and consensual pupillary light reflexes. The remaining neuro-ophthalmic examination showed no abnormalities. Schirmer tear test revealed a bilateral decrease in tear production (right eye: 2 mm/min; left eye: 4 mm/min) (Alcon Laboratories, Forth Worth, Texas, USA). There was no fluorescein stain uptake in either eye. Intraocular pressures were within normal range (11 mmHg right eye; 16 mmHg left eye; Tonovet; Helsinki, Finland). Moderate to severe blepharospasm was present in both eyes and there was a mild protrusion of both third eyelids. The ocular structures were normal except for a mild bilateral hyperemia of bulbar, palpebral, and third eyelid conjunctivas. A prescription of 0.2% cyclosporine (Optimmune; Shering-Plough Canada, Pointe Claire, Quebec) and artificial tear lubricant (Teargel; Novartis Pharmaceuticals Canada, Dorval, Quebec) was given for the treatment of KCS.

A neurology consultation confirmed the absence of pupillary light reflexes and mild anisocoria. The remaining cranial nerves, postural reactions, and spinal reflexes were normal. Anal tone was normal. The findings of the remaining neurologic examination were unremarkable.

The ophthalmologic and neurologic findings, combined with the gastrointestinal signs, were indicative of autonomic dysfunction. Dysautonomia, a rare idiopathic neurodegenerative disorder of the autonomic nervous system, was high on our differential list. To further rule in this condition, 0.1% topical ophthalmic pilocarpine (Isoptocarpine; Alcon Canada, Mississauga, Ontario) was administered in both eyes and the pupils were monitored for constriction. Miosis was observed within 12 to 26 min of application.

The patient was hospitalized and supportive care was administered. Despite lack of other clinical indicators of dehydration, fluid resuscitation was initiated to address the xerostomia; however, this condition persisted despite appropriate fluid therapy.

The dog was discharged the following day and returned 1 wk later for further diagnostic tests. Blood was collected for antinuclear antibody test, erlichia/lyme/heartworm/anaplasma enzyme-linked immunosorbent assay (ELISA) test, and lead concentration. The results of all tests were within normal ranges. Thoracic radiographs were normal, without evidence of megaesophagus. A repeat Schirmer tear test revealed improvement in tear production with values of 5 mm/min in the right eye and 15 mm/min in the left, attributed to the topical 0.2% cyclosporine treatment. The topical ophthalmic pilocarpine test was repeated at a dilution of 0.05% and miosis was again noted in less than 25 min. Intradermal histamine injection produced both a wheal and a flare. Echocardiogram revealed reduced systolic function characterized by reduced fractional shortening percentage (12%) with no evidence of diastolic dysfunction (no left atrial enlargement, normal transmitral flow profiles). Pimobendan therapy was initiated in an effort to improve systolic function. At that time, the gastrointestinal signs had improved, and did not warrant further treatment.

The dog returned 1 mo later for re-evaluation. At that time his clinical appearance had improved greatly. The dog was bright and energetic, with rare episodes of gastrointestinal upset. Episodes of collapse had greatly decreased in frequency; however, an echocardiogram showed no improvement in contractility. The anisocoria was still present and the direct and consensual pupillary light reflexes were still absent. Tear production had again increased and was 10 mm/min in the right eye and 13 mm/min in the left eye. Blepharospasm, although still present, had decreased significantly in severity. The conjunctiva was normal in appearance in both eyes. Incipient posterior capsular cataracts were noted in the right eye after pupillary dilation with tropicamide 1% (Mydriacyl, Alcon Canada). All previously prescribed medications were continued.

A re-evaluation 5 mo after initial presentation revealed the ocular condition was stable. Blepharospasm was persistent, and a repeat pilocarpine test again showed constriction of both pupils in less than 30 min. An echocardiogram 1 y after presentation revealed no further deterioration in either systolic or diastolic function. Fractional shortening percentage remained at 12%. Pimobendan therapy was discontinued at the owner’s discretion. Most recent correspondence with the owner revealed that the dog had a normal energy level and normal appetite. Ocular therapy consisting of cyclosporine and lubricant continues to date.

Discussion

The etiology of this patient’s autonomic dysfunction is unclear, and whether this can be classified as a case of canine dysautonomia remains speculative. Canine dysautonomia is a non-inflammatory, neurodegenerative condition that results in the neuronal degeneration of the autonomic ganglia (1). Clinical signs manifest as various failures of the sympathetic and parasympathetic nervous systems.

The autonomic nervous system maintains homeostasis through its effects on the endocrine, cardiac, respiratory, digestive, and integumentary systems. Two distinct divisions are recognized, the sympathetic and parasympathetic nervous systems, whose effects counterbalance each other. The sympathetic nervous system (SNS) is responsible for the fight or flight response, while the parasympathetic nervous system predominates when the body is at rest. Outflow of the sympathetic nervous system arises from the thoracolumbar divisions of the spinal cord, and ganglia tend to be located relatively close to the spinal cord. The parasympathetic nervous system arises from both the brain stem and the sacral spinal cord, and its ganglia lie close to, or directly on, the effector organ. Cranial nerves III, VII, IX, and X carry parasympathetic fibers from the brain stem, while parasympathetic axons arising from the sacral spinal cord unite to form the pelvic nerve.

Both systems use acetylcholine as the neurotransmitter of the preganglionic fibers, binding to nicotinic receptors on the postganglionic neuron. Acetylcholine is also the neurotransmitter for postganglionic fibers of the parasympathetic nervous system, binding to muscarinic receptors of the effector organ. Norepinephrine is the neurotransmitter of the postganglionic neuron of the SNS, binding to alpha and beta receptors of the effector organs.

Various diseases of the autonomic nervous system are well-described in human medicine and include such afflictions as Parkinson’s disease, familial dysautonomia, multiple system atrophy, and fibromyalgia. However, there are relatively few documented diseases of autonomic dysfunction in veterinary medicine.

Dysautonomia is a disease characterized by failure of both the parasympathetic and sympathetic nervous systems. The disease was first recognized in horses in the early 1900’s (2). Since that time it has been reported in cats, dogs, llamas, and hares (1,3–14). Both the geographic and temporal distributions of canine and feline dysautonomia are intriguing. The disease has been well-documented in cats in the United Kingdom and Scandinavia, with a peak incidence between 1982 and 1986 (15). The first canine case was reported in England in 1983 (3). A subsequent case series of 5 dogs in England was reported in 2007 (16). There is a marked regional distribution of canine cases, with the vast majority of cases documented in the US Midwest (17). The cause of this disease remains unknown; however, an infectious or toxic etiology has been proposed (12,17). An entire family (dam and puppies) of dogs was diagnosed with the disease, and passage of a toxin or contagion was proposed as a possible route of exposure for these puppies (18). Many risk factors have been identified (19). Dogs affected with dysautonomia tend to be young (median 18 mo), live in rural areas, spend greater than 50% of their time outdoors, have close proximity to pasture and cattle, and have consumed wildlife. Our patient had no genetic or heritability factor as no other relatives of the dog were known to be affected. Furthermore, our patient had no history of travel to the US Midwest as he had never left the region of southwestern Ontario, Canada.

The most frequently documented clinical signs of dysautonomia include: lethargy, anorexia, weight loss, dysuria, megaesophagus, vomiting or regurgitation, diarrhea, constipation, decreased anal tone, decreased tear production, prolapsed third eyelid, absent pupillary light reflexes, photophobia, and xerostomia (17). Abdominal radiographs often reveal ileus and gastric distension. Findings from CBC and biochemistry panel are generally unremarkable (20). A recent study revealed that many dogs with dysautonomia have reduced fractional shortening on echocardiogram (21). Most of these clinical signs were present in our patient.

Definitive diagnosis is via histology of the affected ganglia, characterized by chromatolytic degeneration of the neurons of autonomic ganglia, without evidence of inflammation (22). In the absence of a histologic diagnosis, antemortem diagnosis is based on clinical presentation coupled with an array of pharmacologic tests. The essence of these tests relies on the super-sensitivity of receptors due to degeneration of post-ganglionic neurons, resulting in rapid response to low doses of parasympathomimetic drugs. Pilocarpine diluted to 0.1% to 0.05% results in rapid miosis (< 45 min) and this was consistently seen with our patient (23). Healthy dogs develop a wheal and flair reaction following intradermal histamine injection. A wheal is dependent on the direct actions of histamine on blood vessels and should be intact in dogs with dysautonomia, whereas the flare response depends on a sympathetic neuron reflex. Lack of a response provides further evidence of cardiovascular involvement. In our patient, intradermal histamine injection produced both a wheal and a flare. There is evidence suggesting that the flare response is not completely blunted in some dogs with dysautonomia, in that a flare response developed in 1 dog and did not develop in 29 dogs in a case series of 30 dogs (17). Similarly, bethanechol can be administered at 0.5 mg/kg subcutaneously to evaluate effect on bladder volume. Other antemortem tests include documentation of orthostatic hypotension, and administration of atropine to evaluate effect on heart rate. We elected not to perform further tests due to potential side effects.

Treatment for dysautonomia is limited to supportive and symptomatic therapy. Prognosis is reported to be grave, and most dogs die within weeks to months after the onset of clinical signs (12). In this case, some clinical signs improved/resolved and the patient has survived 16 mo from first admission.

The dog in this report had many clinical features suggestive of dysautonomia; however, the chronicity of the disease, combined with the fact that many of this dog’s clinical signs resolved, refute a diagnosis of classical dysautonomia. Reports of dogs that survive the disease are rare (17,23). Still, no alternative explanation for the cause of the autonomic signs has been found, and to date the diagnosis remains open. There is report of a similar case of a dog in Greece that had chronic progressive signs of autonomic failure over a 4-year period (24). Postmortem examination of the submucosal and myenteric plexuses revealed lymphocytic and plasmocytic infiltration of the ganglia, comparable to autonomic inflammatory neuropathies reported in humans. Without histologic examination of the ganglia of the dog in this report, no further definitive diagnosis can be made.

Autonomic dysfunction, regardless of the etiology, causes an array of clinical signs that can pose a diagnostic challenge to practitioners. Though not uncommon in parts of the US Midwest, dysautonomia is rarely, if ever, documented in Canada. Clinicians presented with patients with any combination of gastrointestinal dysfunction, ocular signs, dysuria, and aspiration pneumonia secondary to megaesophagus should include autonomic dysfunction on their list of differentials. CVJ