Congenital Portosystemic Shunts in Five Mature Dogs With Neurological Signs
Congenital portosystemic shunts are a common cause of hepatic encephalopathy and are typically first identified when dogs are <2 years of age. This case series describes five dogs with congenital portosystemic shunts; the dogs were presented for severe encephalopathic signs during middle or old age. Three dogs had portoazygos shunts, and four dogs had multifocal and lateralizing neurological abnormalities, including severe gait abnormalities and vestibular signs. All five dogs responded to medical or surgical treatment, demonstrating that older animals can respond to treatment even after exhibiting severe neurological signs.
Introduction
Congenital portosystemic shunts (PSS) are the most common cause of hepatic encephalopathy in dogs.1 Most extrahepatic shunts are portocaval, originating from the portal vein or one of its branches (i.e., left gastric, gastroduodenal, splenic, cranial mesenteric, and caudal mesenteric veins) and draining into the caudal vena cava. A much smaller percentage are portoazygos, branching from the portal vein to the azygos or left hemiazygos vein.2–6
Congenital extrahepatic shunts are found most frequently in Yorkshire terriers and are hereditary in this breed.3,4,7 Other breeds that have a high incidence of extrahepatic shunts include the Maltese, Dandie Dinmont terrier, pug, miniature schnauzer, shihtzu, and bichonfrise.3,4,7 Clinical signs are typically apparent by 1 year of age, but a small percentage of dogs are presented as young to middle-aged adults.4,8–10 Few reports have documented congenital PSS in dogs >8 years of age.7,9–11
Clinical signs in dogs with PSS typically relate to the neurological, gastrointestinal, or urological systems. Neurological manifestations occur in 95% of dogs with PSS and include behavioral changes, ataxia, aimless wandering, pacing, circling, head pressing, blindness, seizures, and coma.2,7,12–14 Neurological signs are usually mild and predominantly reflect bilateral cerebral cortical dysfunction; lateralizing signs are rarely observed.12 Signs of hepatic encephalopathy frequently occur episodically, with pronounced signs for 1 to 2 days followed by weeks of less severe or absent signs.5
This study describes the presenting signs, treatments, and outcomes of five dogs with congenital PSS that were presented with severe encephalopathic signs during middle or old age. The majority of the dogs had portoazygos shunts and neurological abnormalities reflecting involvement of the forebrain and brain stem, occasionally with lateralization of signs.
Case Descriptions
Case No. 1
A 6-year-old, 3-kg, spayed female dachshund/Chihuahua cross was referred for a 2-month history of progressive ataxia, behavioral changes (decreased aggression), paraparesis, and bumping into household objects. The owner reported two traumatic incidents shortly before the onset of clinical signs—one in which the dog was shaken by the neck and one episode of falling off the couch and subsequent disorientation.
After the falling episode, the dog was examined by the referring veterinarian and found to be disoriented and hypermetric, with decreased proprioception in the pelvic limbs. Prednisonea (unknown dose) was prescribed, and the owners were advised to cage-rest the dog. The dog was again presented to the referring veterinarian 2 weeks later after a generalized tonic-clonic seizure. Anticonvulsant therapy with phenobarbitalb (4 mg/kg per os [PO] q 12 hours) was instituted, but excessive ataxia prompted a dosage reduction (2 mg/kg q 12 hours) 2 days later. A tapering dose of prednisone (0.83 mg/kg q 24 hours for 14 days, then 0.83 mg/kg q 48 hours for 14 days) was also prescribed.
The neurological deficits continued to wax and wane despite medical therapy. The dog was seen again by the referring veterinarian 1 month later for right thoracic-limb and bilateral pelvic-limb paresis, as well as for proprioceptive deficits. At this point, the dog was referred for further evaluation.
Upon presentation to North Carolina State University Veterinary Teaching Hospital (NCSU-VTH), the dog was depressed, ataxic, and falling to the right, with a right-sided head tilt. When encouraged to walk (with support), the dog was hypermetric in both thoracic limbs [Table 1]. Conscious proprioception was decreased, and hopping reactions were absent in both pelvic limbs. Tactile placing was absent in the right thoracic limb and both pelvic limbs. The dog appeared to be blind without a menace response, but pupillary light reflexes were intact bilaterally. Anisocoria was seen, with the left pupil smaller than the right, and a right-sided facial hypoalgesia was present. These neurological signs appeared to be multifocal with involvement of 1) the forebrain (especially the left side), given the seizures, blindness with intact pupillary light reflexes, and right-sided facial hypoalgesia; 2) the right brain stem, based on the head tilt and paresis with postural reaction deficit; and 3) the cerebellum, based on the hypermetric gait.
Extracranial diagnostic evaluation included a complete blood count (CBC), biochemical panel, coagulation panel, bile-acid tolerance test, urinalysis, abdominal ultrasonography, and rectal scintigraphy. Intracranial diagnostic evaluation was performed because of the multifocal nature of the neurological signs. This evaluation included computed tomography (CT) of the brain and cisternal cerebrospinal fluid (CSF) analysis [Tables 2, 3]. The neurological signs were attributed to hepatic encephalopathy, based on supportive clinicopathological findings, the diagnosis of PSS using rectal scintigraphy, and the absence of abnormalities on the brain CT scan and CSF analysis [Table 3].
Medical treatment before surgery included intravenous fluids, intravenous dextrose for treatment of persistent hypoglycemia, and oral lactulosec q 6 hours. Surgical exploration revealed a single, large extrahepatic shunt vessel (presumably the left gastric vein). Histopathological evaluation of a liver biopsy revealed Ito-cell hyperplasia and hemosiderin deposits consistent with PSS. The shunt vessel was ligated. (An ameroid ring was not used.) Postoperative therapy included oral lactulose q 6 hours, phenobarbital (1 mg/kg intravenously [IV] q 12 hours), 60 mL fresh-frozen plasma, and intravenous opioids as needed for pain.
After surgery, the dog remained euglycemic without dextrose supplementation. Neurological status improved significantly, with the dog becoming more mentally alert and regaining vision. Discharge instructions included feeding a low-protein diet and administering phenobarbital (1 mg/kg PO q 12 hours). When contacted 2 weeks after surgery, the owner reported that the dog was doing well.
Although it is possible that some of the presenting neurological signs (i.e., paraparesis) were the results of a secondary disease process (e.g., intervertebral disk disease, trauma), the response to medical treatment indicated that these deficits could have been solely related to hepatic encephalopathy.
Case No. 2
An 11-year-old, 3.4-kg, spayed female Yorkshire terrier was presented to NCSU-VTH for a 3-day history of behavioral changes that rapidly progressed to dementia, vocalizing, apparent blindness, compulsive circling, and head pressing. The referring veterinarian suspected PSS, based on elevated pre- and postprandial bile-acid concentrations identified 1 year prior, and intermittent bouts of abnormal behavior. The dog had reportedly been stable for months before this severe encephalopathic episode. Medical history included severe pyelonephritis and ureteroliths 1 year earlier and treatment for a resistant urinary tract infection (Escheria [E.] coli) over the past several months.
An abdominal ultrasound performed at a veterinary imaging center 1 day before the dog was presented at NCSU-VTH revealed a possible extrahepatic shunt vessel. The dog had been treated at an emergency facility with intravenous fluids, lactulose, and neomycind enemas before presentation. Depression and lethargy had been noted 1 to 2 weeks previously, and a CBC performed by the referring veterinarian showed a moderate leukocytosis (24,000 cells/μL; reference range 6000 to 16,900 cells/μL), which had improved from a severe leukocytosis (60,000 cells/μL) after antibiotic therapy 2 months earlier.
Neurological abnormalities at presentation included dementia, alternation between hyperexcitability and depression, compulsive pacing, head pressing, inconsistent circling to the right, absent menace response bilaterally, apparent blindness, occasional ventrolateral strabismus of the right eye, and intermittent horizontal nystagmus with fast phase to the right [Table 1]. Neuroanatomical localization was the forebrain (right was worse than left) with possible evidence of involvement of the vestibular system (based on the nystagmus). Ophthalmological examination revealed a hypermature cataract in the right eye and an immature cataract in the left eye, a bilateral decrease in retinal vasculature, and hyperreflective tapetum bilaterally. Direct and consensual pupillary light responses were intact.
Diagnostic evaluation included a CBC, biochemical panel, urinalysis, urine culture, blood ammonia level, coagulation panel, bile-acid tolerance test, thoracic radiographs, abdominal ultrasonography, rectal scintigraphy, CT of the brain, and cisternal CSF analysis. Computed tomography and CSF analysis were performed because of the spontaneous nystagmus and signs of lateralization [Tables 2, 3]. Although no PSS were visualized on ultrasound, a 76% shunt fraction was identified on rectal scintigraphy. Ultrasound-guided liver biopsy revealed lobular disarray with moderate hepatocellular atrophy. An E. coli urinary tract infection was diagnosed from the urine culture.
The biochemical abnormalities and rectal scintigraphy results were consistent with hepatic encephalopathy, which was suspected based on the neurological signs. Intracranial causes of encephalopathy were considered unlikely based on 1) the absence of lesions on brain CT; 2) very mild mononuclear pleocytosis (total nucleated count=6 cells/μL [normal range <5 cells/μL]) consisting of 20% polymorphonuclear cells, 76% large mononuclear cells, and 4% lymphocytes; and 3) an elevated protein concentration (40.6 g/dL) in the CSF (which was not thought to be consistent with encephalitis).
Medical therapy during hospitalization included a lowprotein diet (Hill’se k/d), argininef supplementation (44 mg/kg PO q 8 hours), enrofloxacing (5 mg/kg IV q 12 hours), ampicillin-sulbactamh (20 mg/kg IV q 8 hours), neomycin-sulfate retention enemas (20 mg/kg of neomycin and 2 to 1 ratio of lactulose to water to give a final volume of 15 mL) q 6 hours, and vitamin Ki (5 mg/kg subcutaneously [SC] q 12 hours). Diazepamj (0.7 mg/kg IV) and oxymorphonek (0.025 mg/kg IV) were administered as needed to decrease agitation.
The dog showed significant clinical improvement with medical therapy and was discharged after 6 days of hospitalization. Prescribed medications for hepatic encephalopathy included arginine (44 mg/kg PO q 8 hours), neomycin (20 mg/kg PO q 8 hours for 14 days), lactulose (5 mL PO q8 hours), enrofloxacin (6.6 mg/kg PO q 12 hours for 7 days), and amoxicillin-clavulanic acidl (18.4 mg/kg PO q 12 hours for 7 days). Cefiximem (5.9 mg/kg PO q 12 hours for 14 days) was also prescribed to treat the E. coli urinary tract infection. The owners were instructed to feed Hill’s k/d and fat-free chicken broth. One month later, the dog was reportedly well but had experienced one mild episode of hepatic encephalopathy 2 weeks after discharge. The anemia had improved, and the microcytosis and hypochromasia resolved.
Case No. 3
A 12-year-old, 4.2-kg, spayed female dachshund was presented to the NCSU-VTH for a 3-month history of lethargy, progressive inappetence, weight loss, diarrhea, and intermittent melena. Encephalopathic signs included aimless wandering, circling, stumbling, dysphagia, and bumping into walls. A course of enrofloxacin prescribed by the referring veterinarian exacerbated the neurological symptoms. Pertinent medical history included intervertebral disk surgery 2 years earlier (with a complete recovery of neurological function after surgery), chronic elevation of liver enzymes, urolith (unknown type) removal 6 months earlier, polyuria/polydipsia, and bilaterally symmetric truncal alopecia.
Physical abnormalities on presentation included mental dullness, bilaterally symmetric alopecia, and scaling over the ears and dorsal trunk. Neurological examination revealed profound dementia consistent with diffuse forebrain disease. Diagnostic evaluation included a CBC, biochemical panel, urinalysis, serum bile-acid concentration, blood-ammonia concentration, coagulation panel, adrenocorticotropin hormone (ACTH) stimulation test (to check for hyperadrenocorticism), thoracic radiographs, and abdominal ultrasonography [Tables 2, 3]. Neurological dysfunction was attributed to hepatic encephalopathy, based on biochemical abnormalities and visualization of a portoazygos shunt on abdominal ultrasound.
An ameroid ring constrictor was placed around the shunt vessel during exploratory laparotomy. A liver biopsy revealed abnormal lobar architecture and vascular abnormalities consistent with a vascular anomaly.A percutaneous endoscopic gastrostomy (PEG) tube was placed 4 days after surgery, because the dog was stuporous and was not eating. When the dog was discharged, the clients were instructed to feed a Hill’s l/d slurry q 4 to 6 hours. They were also instructed to administer lactulose (2.5 mL q 8 hours for 14 days), amoxicillin-clavulanic acid (13.7 mg/kg q 12 hours for 14 days), famotidinen (0.6 mg/kg q 24 hours for 14 days), and potassium bromideo (54 mg/kg q 24 hours for 1 month). All medications were to be administered via the PEG tube.
The encephalopathic signs completely resolved after surgery. Chemistry panels during the next several months and years showed that blood urea nitrogen (BUN) and albumin levels returned to normal. The elevated alkaline phosphatase (ALP) and alanine aminotransferase (ALT) levels persisted, but this may have been caused by pituitary-dependent hyperadrenocorticism, which was diagnosed 3 years after surgical correction of the PSS.
Case No. 4
A 4-year-old, 3.4-kg, castrated male Chihuahua was presented to the NCSU-VTH for a 1-day history of seizures. The left radius and ulna had been fractured 6 days previously in a dog fight. The radial fracture was repaired with a bone plate, and the dog recovered from anesthesia without complication. One day before admission, the dog was taken to the referring veterinarian because of right-sided twitching that progressed to a focal, right-sided seizure. The dog had three more seizures, which were treated with diazepam before referral.
On neurological examination, the dog was encephalopathic, with absent menace response and normal pupillary light reflexes bilaterally [Table 1]. The dog was nonambulatory, tetraparetic, and dysmetric in the thoracic limbs when supported. Conscious proprioception was absent, but spinal reflexes were intact in all limbs. A crossed-extensor reflex was present in both pelvic limbs. The multifocal neurological abnormalities suggested dysfunction in the forebrain (seizures, blindness), in the brain stem or cervical spinal cord (tetraparesis), and in the cerebellum (dysmetria).
Diagnostic evaluation included a CBC, biochemical panel, urinalysis, urine culture, fasting serum bile-acid concentration, blood-ammonia level, abdominal ultrasonography, rectal scintigraphy, and brain ultrasonography [Tables 2, 3]. Radiographs of the cervical spine, taken to exclude atlanto-axial luxation secondary to trauma, were unremarkable. Ophthalmological examination (including electroretinography) revealed a normal fundus and optic nerve. Brain ultrasonography was unremarkable, but biochemistry, abdominal ultrasonography, and rectal scintigraphy were all consistent with PSS.
Medical treatment included intravenous fluids, lactulose enemas q 6 hours, ampicillinp (20 mg/kg IV q 8 hours), and mannitol q (0.5 g/kg IV once). Potassium bromide was administered at a loading dose of 100 mg/kg PO q 24 hours for five doses, followed by a maintenance dose of 30 mg/kg q 24 hours.
The dog initially improved with intravenous medications and enemas and was switched to oral medications on day 3 of hospitalization. However, blood-ammonia level increased (134 μmol/L; reference range 0 to 40 μmol/L), and the dog’s neurological status deteriorated into stupor and seizures. The absent menace response persisted, and anisocoria developed
Complete surgical ligation of the portoazygos shunt was performed 10 days after presentation. The dog recovered without complication and was discharged 3 days after surgery. At discharge, the dog was mentally alert without anisocoria and with a normal menace response. The bloodammonia level had decreased (37 μmol/L; reference range 0 to 40 μmol/L). Discharge instructions included feeding a low-protein diet and administering potassium bromide (30 mg/kg PO q 24 hours for 4 weeks), neomycin (17.6 mg/kg PO q 8 hours for 4 weeks), and lactulose (5 mL PO q 6 hours for 3 weeks). The dog was clinically normal, and the biochemical abnormalities resolved 1 month later.
Case No. 5
A 14-year-old, 8-kg, castrated male Lhasa apso was referred to the NCSU-VTH for acute onset of mental stupor after a 3-month history of progressive dementia, head pressing, pacing, stumbling, bumping into household furniture, and circling predominantly to the left. The dog was stuporous and tetraparetic on neurological examination, with minimal voluntary movement [Table 1]. The dog’s head turned to the left, and increased extensor rigidity was present in the right thoracic and pelvic limbs. Conscious proprioception and postural reactions were absent in all four limbs. The menace response and pupillary light reflex were intact in the right eye, but they could not be evaluated in the left eye because of severe corneal pathology. Although the dog’s history was suggestive of a left forebrain lesion, the tetraparesis suggested involvement of the brain stem and/or cervical spinal cord.
Diagnostic evaluation for extracranial causes of encephalopathy included a CBC, biochemical panel, urinalysis, serum postprandial bile-acid concentration, bloodammonia concentration, blood-lead concentration, thoracic radiographs, and abdominal ultrasonography [Tables 2, 3]. Diagnostic tests to exclude intracranial disease included brain CT, brain stem auditory evoked response (BAER), and cisternal CSF analysis [Table 3].
Hepatic encephalopathy was suspected based on the neurological signs and suggestive biochemical abnormalities; normal CT, BAER, and CSF analysis; and the visualization of an extrahepatic shunt on abdominal ultrasonography. A neurodegenerative brain disease was also suspected (given the dog’s advanced age), but this could not be excluded without histopathological evaluation of the brain.
The dog began to seize shortly after hospitalization and before diagnostic results could be evaluated. Diazepam (0.5 mg/kg IV) and phenobarbital (4 mg/kg IV) were administered. Within hours, the dog became comatose and exhibited slight twitching of the eyes and forelimbs. Medical management on day 2 of hospitalization included diazepam (0.5 mg/kg IV prn), lactulose/water retention enemas q 6 hours, and ampicillin (15 mg/kg IV q 8 hours). Medical management was continued for several days because of the dog’s age and the potential for a condition more serious than a shunt vessel. Alimentation was accomplished by feeding small amounts of Hill’s a/d slurry via a nasoesophageal tube.
The dog remained stuporous to comatose and continued to have intermittent generalized seizures despite medical therapy. The owner opted for surgery in spite of concerns about a separate, underlying neurodegenerative process. An exploratory surgery performed on day 7 of hospitalization revealed a single extrahepatic portoazygos shunt, which was ligated completely using silk suture. Liver biopsies taken during surgery revealed no significant histopathological lesions.
Postoperative therapy included sodium bromider (2.5 mg/kg per hour as a constantrate infusion [CRI]) for the first 12 hours after surgery, ampicillin (15 mg/kg IV q 8 hours), and diazepam (0.5 mg/kg IV prn). The dog’s mental status was quiet but alert on the day after surgery, and he was able to hold himself in a sternal position. No seizure activity was observed, although generalized twitching persisted. Postoperative serum bile-acid concentration improved dramatically and was only slightly above the normal reference range (33.8 μmol/L; reference range 0 to 20 μmol/L). Despite this significant clinical improvement, the dog died 2 days after surgery due to complications with the nasoesophageal feeding tube.
Necropsy revealed mild, multifocal, lymphoplasmacytic hepatitis along with a mild, fibrinous perihepatitis. Both conditions were suspected to be secondary to surgery. Two ligatures were identified around separate blood vessels near the pancreas, with two adjacent ligatures around one blood vessel near the left liver lobes and caudal vena cava just caudal to the diaphragm. Sections of the caudate nucleus, hippocampus, cerebellum, and pons revealed a severe and diffuse degenerative leukoencephalopathy with severe histiocytic perivascular infiltrates. The white matter was moderately to severely vacuolated with occasional spheroids or necrotic macrophages. Periodic acid-Schiff (PAS) staining of the brain revealed PAS-positive material within the perivascular macrophages, along with positive staining of the basement membrane regions of the blood vessels. Some mild accumulation of PAS within neurons was seen throughout the brain. These changes were thought to be secondary changes related to age, which were exacerbated by hepatic encephalopathy. The dramatic improvement associated with surgical ligation of the shunt suggests that many of the neurological signs were related to hepatic encephalopathy rather than to a degenerative neurological disease. However, a late-onset storage disorder such as ceroid lipofuscinosis was also possible.
Discussion
The dogs in this case series were unusual in that they developed hepatic encephalopathy later in life. Most had multifocal neurological signs, and three had a single portoazygos shunt. All dogs had biochemical profiles consistent with congenital PSS, rather than an acquired shunt secondary to primary hepatic disease (e.g., cirrhosis).
All breeds in this case series have been reported to be at increased risk of developing extrahepatic PSS, although PSS are found most frequently in Yorkshire terriers (case no. 2).3,5,7 Tobias and Rohrbach reported an odds ratio of 58.7 for Yorkshire terriers compared with 5.4 for Lhasa apsos, 4.9 for Chihuahuas, and 3.8 for dachsunds.7 All five dogs in this study were ≥ 4 years of age on presentation, and three of the five were >10 years of age. Case no. 2 (age 11), case no. 3 (age 12), and case no. 5 (age 14) represent three of the oldest dogs with congenital PSS ever reported.
In a retrospective study of 2400 dogs with congenital PSS, Tobias and Rohrbach reported that 72% were <2 years of age at presentation, 16% were 2 to 4 years, 8% were 4 to 7 years, 2% were 7 to 10 years, and <1% were ≥ 15 years.7 This agrees with the findings of other studies, in which most (75%) dogs with congenital PSS were presented by 2 years of age, and nearly all were presented by 5 years of age.4,8–10 By comparison, congenital PSS are rare in people, although most cases are in elderly patients.20–22
Possible theories as to why congenital PSS may not manifest until late in life include increased sensitivity of the aging brain to ammonia and other metabolic products; decreased liver function with age; and morphological or functional brain changes resulting from long-term, persistent, intermittent hyperammonemia.22,23 Previous blood work of several of the dogs reported here had shown no evidence of PSS, making it likely that decreases in residual liver function and/or age-related increases in shunt fraction caused the eventual onset of clinical signs.
Portoazygos shunts comprise about 10% to 25% of all extrahepatic shunts, making them relatively rare compared with portocaval shunts.3,4,6,8 Three dogs in the current study had portoazygos shunts, including the oldest dogs (case nos. 3, 5) in the series. In another case report of two older dogs (aged 7 and 10) with congenital PSS, both had portoazygos shunts.11 These findings are consistent with other studies suggesting that signs of portoazygos shunts tend to develop in older (1 to 5 years of age) dogs.8 The reason dogs with portoazygos shunts often develop clinical signs later in life is unclear. One possibility is a smaller shunt fraction, so that toxic metabolites do not accumulate as rapidly. As previously stated, the authors hypothesize that the shunt fraction increases with age and/or that liver function decreases with age, leading to development of neurological signs.
Intermittent neurological signs (often occurring over the life of the animal) are the most common primary reason for presentation of dogs with PSS.4,12,14 All dogs in the current series were presented for severe encephalopathic signs that progressed rather rapidly, leading to seizures in case nos. 1, 4, and 5 and to coma in case no. 5. It is notable that these late-onset cases seemed predisposed to neurological signs, although considerable selection bias exists in any case series presented to a neurology service.
In people, clinical signs of hepatic encephalopathy are similar to those in dogs; they include repeated abnormal behavior and disturbances of consciousness over a period of months to years.22 However, seizures and coma are uncommon in human patients with PSS, and they are associated with the highest grades of encephalopathy.12,14
Previous reports of dogs with PSS suggest that neurological signs reflect abnormalities in the forebrain (abnormal behavior, pacing, circling, head pressing).2,7,12–14 However, four of the five dogs in this case series presented with multifocal neurological signs that reflected involvement of the brain stem and cerebellum and/or spinal cord, in addition to the forebrain. In several cases, paresis was significant in three (case no. 1) or four (case nos. 4, 5) limbs, indicating involvement of either the brain stem or cervical spinal cord. Although it is possible that paresis in these dogs resulted from a secondary disease process (e.g., intervertebral disk disease or trauma), the presence of other forebrain signs typical of hepatic encephalopathy, as well as their progression and resolution after treatment of the PSS, all suggest an association with hepatic encephalopathy. This was demonstrated clearly in case no. 4, in which the neurological signs developed 6 days after the traumatic episode but resolved when lactulose enemas were given to reduce elevated ammonia levels. Signs then recurred when ammonia levels rose, resolving yet again with surgical ligation of the shunt vessel.
Several cases were presented with vestibular signs, including head tilt (case nos. 1, 5), nystagmus (case no. 2), and strabismus (case no. 2). It is interesting to note that the literature contains other reports of forebrain diseases causing vestibular signs. For example, infarcts of the thalamus and midbrain have been reported to cause head tilt, positional nystagmus, and positional ventral strabismus in dogs.24 This may be due to involvement of the vestibular thalamic area and/or connections to the vestibular nuclei of the brain stem (via the medial longitudinal fasciculus).25 In people and cats, the thalamus has also been identified as an important relay station for vestibular input to the cortex.26–28 In the current case series, the vestibular signs may have reflected thalamic involvement in the metabolic encephalopathy rather than involvement of the brain stem.
Most cases were presented with lateralizing signs, which indicate asymmetry of the affected brain regions. These signs included right head tilt, falling to the right, decreased facial sensation on the right, anisocoria, and proprioceptive deficits in the right thoracic limb (case no. 1); circling to the right and ventrolateral strabismus in the right eye (case no. 2); right-sided facial twitching and partial seizure (case no. 4); and left head turn and circling to the left (case no. 5). Primary intracranial lesions were excluded by performing an intracranial evaluation in all dogs with lateralizing signs, paresis, or vestibular signs. In two dogs, white blood cell counts in the CSF were mildly elevated, and in one dog CSF protein was elevated. However, such changes were thought to be secondary to metabolic encephalopathy rather than evidence of primary encephalitis. Hepatic encephalopathy typically reflects bilateral cerebral cortical dysfunction and is rarely lateralizing, but it should not be excluded as a differential diagnosis in cases that display lateralizing or brainstem signs.12
It is possible that some of the dogs in the current case series had a concurrent disease process not identified on CT or ultrasonography of the brain. Such disease processes may have contributed to neurological disease and may have improved without specific treatment (e.g., ischemic infarct). However, the progressive clinical course of signs and the fact that the neurological abnormalities improved with either medical (case no. 2) or surgical (case nos. 1, 4, 5) treatment for PSS suggest that these lateralizing signs were indeed caused by hepatic encephalopathy.
All dogs in the current study had recent predisposing incidents that may have precipitated the onset of severe neurological signs:
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Two dogs developed clinical signs after episodes of trauma (falling off the couch and being shaken [case no. 1] or fighting [case no. 4]). Trauma (such as traffic accidents) is a reported cause of hepatic encephalopathy in people22 and could have exacerbated pre-existing, subclinical encephalopathy in these current cases.
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Case no. 4 was anesthetized by the referring veterinarian for treatment of a radial-tibial fracture shortly before onset of neurological signs. The dog recovered rapidly from anesthesia, but sedatives, tranquilizers, and anesthetics have been reported to predispose to hepatic encephalopathy.12,29
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Case no. 2 developed signs after being treated for pyelonephritis and resistant urinary tract infections of several months’ duration. Infections have been suggested to predispose animals with PSS to hepatic encephalopathy, due to increased tissue catabolism and the subsequent increased ammonia load presented to a failing liver.12,30
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Case no. 3 developed worsening neurological signs after the owners began noticing melena. Gastrointestinal bleeding has been reported to predispose animals to hepatic encephalopathy because of an increased nitrogen load from the digested blood.12
In people, stressful life events have been shown to increase catecholamine-mediated release of proinflammatory cytokines in the brain. Such proinflammatory cytokines are thought to exacerbate neural degeneration and other psychological disorders, such as depression and anxiety.31 In the current case series, the stress associated with illness and trauma could have initiated similar responses, which may have contributed to the onset of hepatic encephalopathy.
The clinical pathological findings (i.e., hypoalbuminemia, hypoglycemia, hypocholesterolemia, microcytosis, hypochromasia, elevated ALP, elevated ALT, ammonium biurate crystals) in the current cases were similar to those seen in other studies.2,8,10,13,15 In two of the cases in this study, the partial thromboplastin time was mildly prolonged, which has been reported in dogs with congenital PSS.15
Bile-acid levels were very elevated in four dogs in the current series (case nos. 2 through 5); however, case no. 1 had only mild pre- and postprandial bile-acid elevations, despite a 63% shunt fraction. Other laboratory abnormalities (i.e., microcytosis, hypochromasia, ammonium biurate crystals) were consistent with PSS. These findings agree with the literature suggesting that bile-acid concentrations show poor specificity for PSS.32 Blood ammonia levels also do not appear to correlate well with degree of hepatic encephalopathy.23 Blood ammonia levels, measured in four of the five dogs in the current series, were mildly (case no. 3) or moderately (case nos. 2, 4) elevated; however, blood ammonia levels were normal in case no. 5, despite severe encephalopathy and coma. Increased metabolic rate and cerebral extraction of ammonia, along with increased permeability to ammonia in the brain, may explain why ammonia levels are not necessarily increased in all animals with hepatic encephalopathy.12
Nephroliths and/or cystoliths were more common among the current cases (i.e., three of five dogs) when compared with previous reports in which nephroliths were identified in 20% to 50% of dogs with PSS.14,16 The higher percentage of nephroliths in the current series may be due to either random choice or the chronicity of ammonium biurate accumulation in older dogs with PSS.
In this case series, ultrasonography revealed microhepatica in all five dogs and PSS in three dogs (case nos. 3–5). Shunt vessels may not have been visualized in the other two dogs because of inexperience of the ultrasonographer or difficulty visualizing smaller PSS or portoazygos shunts. The PSS in case no. 5 was identified as a portocaval shunt on ultrasonography, but it was determined to be a portoazygos shunt intraoperatively. According to Santilli and Gerboni, ultrasonography has a sensitivity of 74% to 80.5% and a specificity of 66.7% to 100% for detecting PSS, resulting in a large number of false negatives.16 The addition of Doppler increases the sensitivity to 95%, the specificity to 98%, and the diagnostic accuracy to 94%.16
Rectal scintigraphy was performed in three of the five dogs (case nos. 1, 2, 4), revealing shunt fractions of 63%, 76%, and 73%, respectively. Mean shunt fractions in dogs with PSS are reported to be 79%to 84%(range 60%to 94%), compared with a mean of 5% to 15% for normal dogs.16,18,19 Small-breed dogs tend to have higher shunt-fraction indexes than large-breed dogs.16 The relatively low shunt fraction in the dogs of this study (compared with other dogs) may have contributed to the delayed onset of clinical signs. Shunt fractions need to be interpreted carefully, however, because they can be quite variable within an individual animal and are not highly reproducible among radiologists.17
Computed tomography of the brain, performed in case nos. 1, 2, and 5, was considered normal in all three dogs. This is consistent with the human literature, in which brain CT may show no abnormalities or evidence of brain atrophy in patients with PSS.20,22 Reports of CT findings in dogs with PSS have been few. However, in a recent study using magnetic resonance imaging (MRI), all dogs with PSS had brain atrophy and widened sulci.33 Hepatic encephalopathy has been reported to cause cerebral atrophy, which can lead to compensatory hydrocephalus.8 Evidence of brain atrophy may have been found in the cases reported here if MRI had been performed instead of CT.
Gross pathological changes are rarely observed in dogs with hepatic encephalopathy.34 The two hallmark histopathological findings in dogs with hepatic encephalopathy include spongiform changes in the white matter and the presence of single (or small groups of) astrocytes containing clear, swollen nuclei (Alzheimer type II cells). Polymicrocavitation is often the most obvious change and may be the only abnormal finding described.34 Vacuolation may be found in the peripheral fibers of the corona radiata, internal capsule, thalamus, hypothalamus, cerebellar medulla and peduncles, pons, and medulla oblongata.34
Among the current cases, histopathology of the brain was available only for case no. 5, which had accumulation of ceroid lipofuscin throughout the brain. This has not been reported in other cases of hepatic encephalopathy in dogs. Ceroid accumulates with age, and, while some degree of accumulation would be expected in a 14-year-old dog, the ceroid content appeared excessive in case no. 5. Ceroidlipofuscinosis has been reported in young and middle-aged dogs of several breeds and in older Tibetan terriers.34–36 However, the clinicopathological abnormalities (i.e., high postprandial bile-acid level) and improvement in neurological status after surgery indicate that the neurological signs were probably attributable (at least in part) to hepatic encephalopathy. The authors hypothesize that this dog suffered from two disease processes but that hepatic encephalopathy contributed significantly to the neurological signs. The profound improvement after surgical correction of the shunt suggests that many of these neurological signs were caused by hepatic encephalopathy rather than by a degenerative process.
All five dogs in the current series responded to therapy, which included surgery in four cases (case nos. 1, 3–5) and medical therapy in one case (case no. 2). In most cases, medical management was tried initially to avoid surgery. The current study agrees with the findings reported by some authors that middle-aged and geriatric dogs can do well after surgery, despite claims by other authors that dogs >2 years of age have a poorer prognosis with surgery.4,10,37 The dramatic postsurgical improvement in the dogs of this study also casts doubt on the contention of some authors that dogs with encephalopathic signs have poorer postsurgical outcomes than do dogs without encephalopathic signs.38
Conclusion
These cases provide further evidence that congenital PSS may not be identified until very late in life in some dogs, and that PSS should still be considered as a differential diagnosis in older animals with encephalopathic signs. Most of the dogs in this case series had portoazygos shunts, supporting the finding that dogs with portoazygos shunts may develop clinical signs later in life than dogs with portocaval shunts. The neurological abnormalities in most dogs were multifocal and lateralizing, demonstrating that encephalopathy may be diffuse and associated with gait abnormalities and vestibular signs. The encephalopathic signs improved with surgical or medical treatment in all dogs, demonstrating that older animals can respond well to treatment, even after severe neurological signs.
Prednisone tablets USP; United Research Laboratories, Inc., Philadelphia, PA 19124
Sodium Phenobarbital for injection; Wyeth Pharmaceuticals, Philadelphia, PA 19101
Constulose; Alpharma USPD, Inc., Baltimore, MD 21244
Neomycin oral solution; Phoenix Scientific, Inc., St. Joseph, MO 64503
Hill’s Pet Nutrition, Inc., Topeka, KS 66601
L-arginine; Major Pharmaceuticals, Livonia, MI 48150
Baytril; Bayer Healthcare LLC, Shawnee Mission, KS 66201
Unasyn; Baxter Healthcare Corporation, Deerfield, IL 60015
Vitamin K1 injection; Neogen Corporation, Lexington, KY 40511
Valium; Roche Laboratories, Inc., Nutley, NJ 07110
Oxymorphone HCl for injection; Endo Pharmaceuticals, Chadds Ford, PA 19317
Clavamox; Pfizer Animal Health, Exton, PA 19341
Suprax; Luprin Pharmaceuticals, Inc., Baltimore, MD 21202
Pepcid; J & J Merck CPC, Fort Washington, PA 19034
Potassium bromide 3%. (Extemporaneously compounded by the pharmacy at North Carolina State University Veterinary Teaching Hospital, Raleigh, NC 27606.)
Sodium Ampicillin for injection; American Pharmaceutical Partners, Inc., Schaumberg, IL 60173
25% Mannitol for injection, USP; Hospira, Inc., Lake Forest, IL 60045
Sodium bromide 3% injection. (Extemporaneously compounded by the pharmacy at North Carolina State University Veterinary Teaching Hospital, Raleigh, NC 27606.)
Contributor Notes
