Metabolic Encephalopathies

INTRACRANIAL DISEASE

0195-5616/96 $0.00 + .20

METABOLIC ENCEPHALOPATHIES Paul A. Cuddon, BVSc

The neuronal cell population of the brain has an extraordinarily high metabolic rate and depends on a stable extracellular environment to maintain metabolic functions. Variations in this environment, especially in the levels of oxygen, carbon dioxide, glucose, or electrolytes, may cause general derangement of brain function. These conditions are collectively termed metabolic encephalopathies. There is no spaceoccupying mass inside the cranium, and the neurologic deficit is potentially reversible with treatment of the underlying disease. CLINICAL SIGNS

Classically, metabolic diseases produce nonspecific diffuse or multifocal brain dysfunction. Asymmetric changes in postural reactions or tendon reflexes are much less likely with metabolic states than with structural brain lesions. 35 The earliest and most consistent signs are depression of consciousness (confusion, stupor, coma) and generalized seizures. Occasionally bizarre behavior and focal seizures can occur, though the latter is rare. Other neurologic signs will vary with the severity of the metabolic disturbance. These include pupillary abnormalities (miosis, anisocoria), apparent blindness (involvement of the occipital lobe or sensorimotor cortex), head pressing, aimless wandering, motor dysfunction, coarse body tremors (irregular 8 to 10 Hz movements), multifocal myoclonus (sudden, stimulus-induced, nonrhythmic, nonpatterned gross twitching involving parts of muscles or groups of muscles, From the Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 26 • NUMBER 4 • JULY 1996

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especially of the face and proximal limbs), decorticate or decerebrate rigidity, and abnormalities either in the rate and/or depth of respiration leading to hyper- or hypoventilation. 64, 66, 71,97 ENERGY METABOLISM WITHIN THE BRAIN

The brain has an absolute reliance on glucose and oxygen, requiring 200/0 of the total body's oxygen supply.60, 87 Oxygen consumption increases up the neuraxis as well as within the brain parenchyma where the gray matter consumes 94% of the supplied oxygen while the white matter consumes only 6%. The highest oxygen consumption occurs in the cerebrocortical pyramidal cells and in the cerebellar Purkinje cells. Capillary exchange of nutrients, oxygen, metabolic wastes, and carbon dioxide, however, is complicated by the blood-brain barrier (BBB). The brain depends on cytosolic glycolysis and the mitochondrial citric acid cycle/electron transport chain (oxidative phosphorylation) to synthesize its energy needs. 86 The latter, which requires oxygen, is much more efficient in generating ATP (1 mole of glucose produces 36 moles of ATP). Glycolysis alone cannot meet the brain's energy needs, because 1 mole of glucose can only produce 2 moles of ATP.16, 86 Though glucose is the primary energy substrate of the brain, supply of endogenous glucose and glycogen is limited. 16 The brain can utilize ketone bodies as an alternate energy source, especially via acetoacetic acid's entry into the citric acid cycle, though it cannot utilize free· fatty acids because of BBB exclusion. ATP, the energy source for the brain, is required for the function of ion pumps, especially the Na+-K+-ATPase pump, to maintain the resting membrane potential (residual metabolism) and for the synthesis, release, and reuptake o( neurotransmitters, intracellular transport, and the manufacture of axoplasm (activation metabolism).56, 66,86 Despite this high requirement for ATP, however, the brain has very low endogenous reserves and therefore ATP must be continually produced. The brain is very sensitive to any interference with energy metabolism, blood flow, or oxygen supply.26 OXYGEN DEPRIVATION

Oxygen deprivation of the brain can be due to either a decrease in the rate of blood flow and thus cerebral perfusion pressure (ischemia) or a decrease in the arterial oxygen content. The latter can be secondary to a lowered oxygen saturation (hypoxic hypoxia) or to a reduction in the oxygen-carrying capacity of hemoglobin (anemic hypoxia).86 An effective decrease in hemoglobin concentration occurs when it is bound to toxins such as carbon monoxide, producing carboxyhemoglobin; nitrates, producing methemoglobin; or acetaminophen. An acute decrease in arterial P02 below 40 to 50 mm Hg produces decreased cerebral function; at levels below 20 to 30 mm Hg, animals lose consciousness. 64

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Cerebral ischemia is usually accompanied by a decrease in brain glucose and an increase in carbon dioxide, whereas cerebral hypoxia is not. Therefore, greater risk of irreversible brain damage occurs with cerebral ischemia. Complete, sudden cerebral ischemia sets in motion a cascade of cellular events that lead to neuronal injury. Total oxygen consumption occurs in 10 seconds, and depletion of ATP stores occurs in 2 to 4 minutes. 6o The brain then switches to anaerobic glycolysis, which is inadequate in maintaining ATP production. Lactic acidosis ensues, leading to a failure of residual metabolism. As a consequence, cellular ion gradients are lost; intracellular communication is disrupted; enzymecatalyzed reactions are inhibited; and cellular membrane permeability is increased. 56,87 Cytotoxic and vasogenic edema occur and the BBB is disrupted.74 Complex biochemical changes also result from this cerebral ischemia (Fig. 1).9,44,60,74,87,89,104 Total cerebral ischemia results in a loss of consciousness within 10 seconds and cessation of spontaneous and evoked electric activity within 20 seconds, despite irreversible neuronal injury not occurring until 15 minutes after the onset of ischemia.74 Therapy-General Principles

If cerebral blood flow is reestablished within 5 minutes, neuronal function can be restored without compromise. Therefore, aggressive and immediate resuscitation is required. However, closed-chest cardiopulmonary resuscitation alone only delivers 3% to 10% of the normal cerebral blood flow to the brain. Hyperventilation, adequate oxygenation, and placing the neck in extension with the head elevated help alleviate further increases in intracranial pressure (ICP).60 Interestingly, clinical signs of cerebrocortical neuronal injury may not occur for several hours after successful resuscitation. This "postresuscitation hypoperfusion syndrome" is not completely understood. The initial cytotoxic edema produced during ischemia may be exacerbated by BBB breakdown because of increases in ICP secondary to chest compression. Also, the continued vasoactive effects of the accumulated arachidonic acid metabolites, free radicals, and excitatory neurotransmitters (glutamate and aspartate) potentiate the cerebral edema and vasoconstriction. 60 Paradoxically, the increase in oxygen to the brain potentiates lipid peroxidation via its involvement in the reaction, forming lipid hydroperoxides. Therapeutic intervention during the postresuscitation period in animals that have experienced global or local ischemia and/ or hypoxia should be aimed at producing diuresis to rapidly decrease ICP, preserving neuronal membrane integrity, stabilizing lysosomal membranes to decrease lipid peroxidation, scavenging free radicals, and preventing the further formation of prostaglandins. 60 Diuresis is achieved by the administration of 20% mannitol at a dosage of 1 g/kg given intravenously (IV) at a rate of 2 mL/kg/min,78 followed in 15 minutes by furosemide at a dose of 0.75 to 1 mg/kg IV. This combination results in

Cerebral Ischemia ATP store depletion Loss of Na+·K+ ATP'ase Loss of ion gradients

marked increase in extracellular potassium and intracellular sodium

activation of excitatory amino acid (N-methyl.D·aspartate) receptors intracellular movement of calcium and release of calcium from mitochondria and endoplasmic reticulum

1

production of nitric oxide

substantial increase in intracellular free calciwn

loss of compartmental (mitochondrial) control of free iron

activation of phospholipase A2

1

peroxidation of membrane phospholipids +- catalyst for hydroxyl radical production

calcium potentiated protein breakdown

1

superoxide anion production + nitric oxide

1 1 1

release of free fatty acids (arachidonic acid)

1 1

cellularDNAlRNA damage

formation of cyclooxygenases and lipoxygenases

formation of peroxynitrite

1

cellular toxicity

further disruption of cell phospholipid membrane integrity

Figure 1. The complex biochemical changes that occur with cerebral ischemia, which lead to functional and structural changes in the cerebrum.

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a larger and longer lasting decrease in ICP than occurs when mannitol is used alone (5 hours versus 2 hours).?2 The osmotic gradient established by mannitol is maintained by furosemide. Mannitol also acts as a scavenger of oxygen and hydroxyl free radicals. 60 The remainder of the aims of therapeutic intervention are achieved by the use of high potency corticosteroids. Methylprednisolone sodium succinate should be administered at an initial dose of 30 mg/kg IV, followed by a maintenance constant infusion rate of 5.4 mg/kg/hr for 24 to 48 hours.? Other drugs that have been suggested for therapy are either unproved or controversial. These include the calcium entry antagonists (verapamil, nifedipine, nimodipine, and flunarizine),60 free radical scavengers (dimethyl sulfoxide, superoxide dismutase, and polyethylene glycol superoxide dismutase),61 the iron chelator desferoxamine (25 to 50 mg/kg IV or intramuscularly [IM]),60, 105 and the opioid antagonists naloxone and thyrotropin-releasing hormone.28

Clinical Syndromes

In addition to cardiac arrest, which produces global cerebral ischemia, a number of other conditions produce varying degrees of global or regional cerebral ischemia or hypoxia. Hypertensive Encephalopathy

Hypertension in animals isusually secondary to underlying disease, though primary (essential) hypertension has also been recognized. 6 In dogs, normal mean arterial pressure has been reported as 100 ± 5 mm Hg, with dogs being considered hypertensive if the mean arterial pressure is greater than 120 mm Hg.6 In cats, normal systolic and diastolic blood pressure measurements have been reported as 118.4 ± 11 mm Hg and 83.8 ± 12 mm Hg, respectively, in one study using Doppler-shift ultrasonography 38; and 123 and 81.2 mm Hg, respectively, with a mean of 96.8 mm Hg, in another study using oscillometry.21 Cats are considered hypertensive if they have a sustained arterial systolic pressure greater than 160 to 170 mm Hg and diastolic pressure greater than 100 mm Hg.31,46 The major causes of hypertension in cats are chronic renal disease and hyperthyroidism. 31 In dogs, acute and chronic renal failure, glomerulonephritis, and hyperadrenocorticism are incriminated. 6 The main effect of protracted hypertension on the cerebrum is medial hypertrophy and increased tortuosity of the small cerebral arteries. Patchy fibrinoid necrosis of blood vessel walls can lead to localized cerebral edema, hemorrhage, and microthrombi within the brain. 66 Animals also can show acute blindness due to retinopathy. Treatment is directed towards the primary cause. Therapy for cats with hypertension secondary to cardiomyopathy or chronic renal disease and for dogs with congestive heart failure centers around the use of angiotensin-converting

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enzyme inhibitors (enalapril, captopril, and benazepril) or the calcium antagonist amlodipine besylate.31196 Hyperlipidemia

Two main neurologic manifestations can occur with hyperlipidemia. Firstly, acute episodes of loss of consciousness and seizures may occur, secondary to small fat emboli which may cause cerebrovascular insults. This has been reported in dogs, especially Miniature Schnauzers. Secondly, progressive paresis and ataxia may occur due to lipid and cholesterol deposits in medium-sized arteries and arterioles in the central nervous system (CNS). This has been reported in association with hypothyroidism. 69 Therapy with low fat diets, and levothyroxine in dogs with hypothyroidism, is indicated. Bacterial Endocarditis

Acute onset of seizures, paresis, blindness, or other focal neurologic dysfunction can be observed with bacterial endocarditis because of cerebral embolization with bacteria and parts of the vegetative valvular lesions. 94 Meningitis and encephalitis also can occur secondary to bacterial emboli. Other signs may include fever (though this can be intermittent), lethargy, decreased mentation, anorexia, myalgia/arthralgia, and cardiac arrhythmias. The aortic and mitral valves are most commonly affected. Diagnosis is based on the above clinical signs, the demonstration of arrhythmias and conduction disorders via electrocardiography, the demonstration of valvular vegetative lesions on echocardiography, and blood cultures that demonstrate the causative organism. Treatment consists of early, aggressive systemic antibiotic therapy based on antimicrobial sensitivity testing. Initial antibiotic therapy should be given intravenously for 7 to 10 days followed by appropriate bactericidal oral doses of antibiotics for at least 6 weeks. 94 Therapy for the secondary encephalopathy· may require anticonvulsant medication. Feline Ischemic Encephalopathy

A peracute onset of usually unilateral cerebral dysfunction occurs secondary to extensive ischemic necrosis of the cerebral cortex. Commonly, the major infarct is associated with the middle cerebral artery, though cerebral necrosis may be multifocal or may involve up to two thirds of one entire hemisphere. Signs are nonprogressive, as expected in a vascular disorder. 3 The cause of this syndrome, however, remains unknown. An insect-transmitted microfilarial aberrant migration is supported by the finding at necropsy of suspicious areas resembling parasite tract injury. These areas also have contained eosinophils. 93 Other theories include vasospasm secondary to hemorrhage, infarction secondary to cardiomyopathy (though cardiac lesions have rarely been found), and toxicity. Ischemic encephalopathy occurs primarily in adult cats of all

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ages and both sexes; incidence is much higher in the summer. The clinical signs are variable ranging from a mild decrease in mentation with a brief period of mild paresis and ataxia to severe alterations in mentation with marked behavior changes (aggression), seizures (often focal), cortical blindness, and constant pacing and circling. 108 Resolution of acute signs tends to occur within the first few days, though the cat is often left with permanent static signs of a lateralized cerebrocortical dysfunction (pacing, aggression, lateralized cortical blindness, and seizures).8 Long-term anticonvulsant medication may be required. HYPOGLYCEMIA

The brain depends on a concentration gradient to facilitate diffusion of glucose into the neuron (facilitated transport) and not on insulin. 1 Regulation of euglycemia involves carbohydrate intake/ absorption, hepatic production, and peripheral utilization. Hepatic glycogen provides only 14% of glucose needs in the first 24 hours of fasting, with the rest being supplied by hepatic gluconeogenesis. 20 The maintenance of euglycemia depends on a balance between insulin and the counterregulatory hormones (catecholamines, glucagon, cortisol, growth hormone, and adrenocorticotropic hormone).17,40 Marked cerebral utilization of ketone bodies occurs but is ineffective in preventing signs of acute hypoglycemia because 2 to 3 days are required to produce sufficient ketosis in the dog. The brain also cannot subsist entirely on ketones. With acute hypoglycemia, the brain's extraction of oxygen from perfused blood decreases, and therefore signs of neuroglycopenia resemble that of cerebral hypoxia. 97 As with hypoxia, the cerebral cortex and other areas of high metabolic rate (hippocampus, amygdala, cerebellar cortical Purkinje cells, and some thalamic and basal nuclei) are affected first. Laminar necrosis of layers II, III, and V of the cerebral cortex and especially the occipital cortex occurs. Death occurs as a result of respiratory center depression. 93 With less severe or transient hypoglycemia, brain metabolism decreases before decreases in ATP occur, leading to a -progressive decrease in mentation and possibly coma. Hypoglycemic coma can last up to 1 hour without structural damage. This coma is thought to be due to a decrease in acetylcholine secondary to a blockade of cholinergic pathways, a decrease in brain glutamine and glutamate, and an increase in ammonia. 1 Clinical Signs

Clinical signs are due both to the release of epinephrine and neuroglycopenic brain dysfunction. The early response to hypoglycemia is primarily through the action of epinephrine (and glucagon).lOl Clinical signs associated with epinephrine release include muscle tremors, tachycardia, and apprehension. Neuroglycopenia produces confusion, behav-

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ior change, weakness, ataxia, collapse, hypothermia, cortical blindness, seizures, and coma. 40 The onset of signs and the severity of CNS dysfunction is directly related to the rate of serum glucose decline and, to a lesser extent, the degree of hypoglycemia. 64

Insulinoma

Functional islet cell tumors are one of the most common causes of hypoglycemia in dogs. Dogs between 5 and 12 years of age are most commonly.affected, with the most common breeds being Standard Poodles, Boxers, Fox Terriers, German Shepherd Dogs, Irish Setters, and Collies. 102 Insulinomas, though rare, do occur in middle-aged to older cats. 109 Because the majority of insulinomas are functional carcinomas, clinical signs are caused by the resultant hyperinsulinism. Visceral metastasis is common, especially to regional lymph nodes, liver, and spleen. 102 Distant metastasis is rare. Seizures are the most common clinical sign. Initial suspicion of an insulinoma consists of finding a fasting hypoglycemia of less than 60 mg/ dL, though this may be intermittent and may not occur until after 24 to 48 hours of fasting. 97 Measurement of serum insulin levels at the time of hypoglycemia and calculation of the amended insulin-glucose ratio (AIGR): Insulin (f.LU/mL)

X 100

-7-

Glucose (mg/dL) - 30

will aid further in diagnosis. An AIGR of greater than 30 is considered suspicious of an insulinoma. 41 Dogs with higher preoperative serum insulin levels have significantly shorter survival times than do dogs with lower concentrations. 109 However, some islet cell tumors secrete predominantly proinsulin, which has only 10% to 15% of the biologic activity of insulin, and therefore serum insulin levels may be normal. 8 Abdominal radiography and ultrasound may also be helpful though normal studies do not exclude a diagnosis of insulinoma. Surgical removal (partial pancreatectomy) is the treatment of choice for insulinomas' after exploratory laparotomy is performed to confirm the diagnosis. Surgery alone, however, is seldom curative because most of these tumors have metastasized before diagnosis. 102 Even if extensive metastasis is found at surgery, the primary tumor should still be removed. Metastases are often nonfunctional, therefore many animals still do well postoperatively with or without the benefit of medical therapy.109 Medical management consists of frequent feedings of a high protein, high fat, and complex carbohydrate diet; prednisone at a dose of 0.25 to 0.5 mg/kg twice daily; and possibly diazoxide, an inhibitor of insulin secretion and a promoter of hepatic gluconeogenesis (at an initial dose of 3 mg/kg three times daily with food), if dietary therapy and prednisone are unsuccessful at controlling the clinical signs. Diazoxide may be increased up to a maximum dose of 20 mg/kg three times daily.40, 109 The long-term prognosis for dogs with insulinomas is poor, with a mean postoperative

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survival time of 12 to 14 months. 41 Hypoglycemia has also been reported with hepatocellular carcinoma, hepatoma, hepatic leiomyosarcoma, hemangiosarcoma, salivary gland adenocarcinoma, mammary carcinoma, melanoma, leukemia, and pulmonary adenocarcinoma. 43 Other Causes

A detailed list of the inherited and acquired diseases that can produce hypoglycemia in small animals is given below.

Clinical Syndromes Producing Hypoglycemia Glucose Overutilization Therapeutic insulin overdose Functional r3-cell tumor (insulinoma) Hypoglycemic drug ingestion r3-cell hyperplasia Extrapancreatic neoplasia (insulinlike substances) Cachexia with fat depletion Hunting dog hypoglycemia (extreme exercise) Glucose Underproduction Neonatal hypoglycemia (inadequate glycogen stores) Transient juvenile hypoglycemia Hypoadrenocorticism Substrate deficiencies (starvation, malabsorption) Liver disease (cirrhosis, portosystemic shunts, severe hepatitis) Enzyme deficiencies Glycogen storage disease Glucose-6-phosphatase deficiency (Von Gierke's disease) Acid a-glucosidase deficiency (Pompe's disease) Amylo-1-6 glucosidase (debrancher enzyme) deficiency (Cori's disease) Glucose Underproduction and Overutilization Sepsis

HYPOVITAMINOSIS B

Deficiencies of thiamine, riboflavin, niacin, pantothenic acid, and biotin all can result in seizures and weakness. Though thiamine (vitamin B1) deficiency is the most common cause of encephalopathy in small animals, it only occurs sporadically. In cats, it is associated with feeding an all-fish diet, which contains thiaminase. 93 Occasionally, chronic anorexia in cats also can lead to a deficiency in thiamine. Dietary thiamine can be destroyed by excess heating or cooking of meat or canned food, the primary cause of the syndrome in dogs.76 Thiamine deficiency has

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also been associated in cats and dogs with the feeding of meat preserved with sulfur dioxide. 92 Thiamine is an essential component of carbohydrate metabolism. A deficiency produces a decrease in the oxidative carboxylation of pyruvate, essential for the complete oxidation of glucose through the citric acid cycle in the mitochondria of neurons. This decrease in glucose oxidation leads to a dramatic decrease in ATP production and availability, through oxidative phosphorylation. 8 Thiamine deficiency also results in a decrease in active ion transport at nerve terminals, failure of membrane potential maintenance, and impairment of serotoninergic pathways in the thalamus and brain stem. Clinical· Signs

Initially, a mild vestibular ataxia occurs, followed by pronounced unresponsive pupillary dilation, seizures, marked active head and neck ventroflexion, lack of a menace response, head tremors, and decreased mentation. Recumbency, coma, and decerebrate posturing followed by death may be seen in severe cases. 8,93 Diagnostic Tests

No readily available diagnostic tests for thiamine deficiency exist, and clinicians usually have to rely on the dietary history and the presenting neurologic signs. Blood pyruvate and lactate are elevated and red blood cell transketolase is decreased, though these tests are not commonly performed. 93 Pathologic Changes

Bilaterally symmetric petechial hemorrhages with histologic degeneration and hemorrhagic necrosis of brain stem nuclei are seen. The caudal colliculi are most consistently involved, though lesions are also commonly seen in the vestibular, oculomotor, red, habenular, and lateral geniculate nuclei. The cerebral cortex, basal nuclei, and cerebellar vermis may also occasionally be involved. 93 This results from neuronal and vascular damage in the periaqueductal gray matter surrounding the third and fourth ventricles and the mesencephalic aqueduct, possibly secondary to impaired vascular perfusion. 8 Treatment

The prompt administration of thiamine hydrochloride in the early stages of the disease can result in complete remission of neurologic

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signs. Thiamine should be administered either by intravenous, intramuscular, or subcutaneous injection at a dose of 5 to 50 mg/ day/ dog and 1 to 20 mg/day/cat. 8 HEPATIC ENCEPHALOPATHY

The liver is essential for the maintenance of normal brain metabolism; it produces compounds (glucose) that the brain cannot manufacture and degrades other compounds that are toxic to the brain. The most common cause of hepatic encephalopathy is an anomalous connection between the portal vein and the systemic circulation in young animals. Shunts can be either intrahepatic or extrahepatic in origin. Intrahepatic shunts are usually congenital and single. 5 Extrahepatic shunts are either congenital or acquired, the former usually being singular with the latter tending to be multiple and tortuous. 93 The most common congenital shunt is patent ductus venosus, accounting for 50% of all reported canine cases. Next most common is the portocaval shunt, with the portoazygous shunt being less common. 19,33 The most commonly involved breeds include Yorkshire Terriers, Maltese Terriers, Australian Cattle Dogs, Miniature Schnauzers, and Irish Wolfhounds. 19, 51, 52 Smallbreed dogs have a much higher incidence of extrahepatic shunts, whereas medium to large breed dogs have a. much higher incidence of single, intrahepatic shunts. 51 The most common congenital shunt in the cat is the single, extrahepatic portocaval shunt. 5 Other described congenital causes of protosystemic shunting include hepatic arteriovenous fistulas (hamartomas, hemangiomas),34 hepatic venoocclusive disease with resultant idiopathic portal hypertension seen in American Cocker Spaniels,75 and hepatic microvascular dysplasia in Cairn Terriers. 84 Acquired shunts are associated with end-stage hepatic cirrhosis, most commonly secondary to chronic active hepatitis in dogs, and hepatic lipidosis in cats. This leads to portal hypertension with resultant formation of venous collaterals. 48,98 These collaterals are associated with portosystemic shunting of mesenteric blood resulting in reduced hepatic circulation "and further hepatic atrophy.19 Acquired portosystemic shunts tend to occur in middle-aged to older dogs and cats. 98 Arginosuccinate synthetase deficiency (a urea cycle enzyme), which has been described in the dog, produces hyperammonemia without portosystemic shunting or hepatocellular destruction. 91 Etiology of Cerebral Dysfunction-Current Theories

Current theories of the pathogenesis of hepatic encephalopathy are centered on four areas: (1) ammonia, with or without other synergistic toxins, is the putative neurotoxin; (2) abnormal aromatic amino acid metabolism secondarily leads to an alteration in cerebral monoamine neurotransmitters; (3) the amino acid neurotransmitters )I-amino butyric

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acid (GABA) and/ or glutamate are significantly altered in the brain; and (4) cerebral concentration of an endogenous benzodiazepine-like substance is increased. 52,53 Ammonia is produced in the gastrointestinal tract primarily by urease-producing bacterial metabolism of nitrogenous products and in particular urea. Due to the high pH, ammonia diffuses readily from the colon, with a normally functioning liver extracting 81% to 87% of this ammonia and converting it to urea. 19 With a significant decrease in or lack of hepatic contribution to the breakdown of ammonia, high circulating levels of ammonia readily cross the BBB and interfere with cerebral metabolism. 52 Interestingly, ammonia is normally continually produced in the brain, with concentrations being present in normal animals at much higher levels than in the blood. It is normally detoxified by astrocytes via the formation of glutamine from glutamate, which in itself may be neurotoxic. 93,99 Glutamate efflux from the brain and its concentration in the cerebrospinal fluid increases with hepatic encephalopathy.67, 99 Though increased blood ammonia concentrations are found in most patients with hepatic encephalopathy, whether and to what degree this correlates with the degree of encephalopathic signs seen is questionable. 58 Correlation in many animals is poor. Some animals have encephalopathic signs despite near-normal levels of blood ammonia. 52,99 One theory to explain this paradox is that hepatic failure may result in increased sensitivity to or increased blood-brain transfer of ammonia. Therefore, animals with hepatic encephalopathy may have high brain ammonia concentrations despite near-normal blood levels. If patients are also hypokalemic and/or alkalotic, the concentration of ammonium ions increases, which facilitates brain uptake of ammonia. lll Though mercaptans (methanethiol) and short-chained fatty acids are unlikely to be primary cerebral toxins, they do act synergistically with ammonia to produce neurotoxicity, which appears to be primarily related to an inhibition of sodium potassium ATPase with subsequent impaired neurotransmission. 58 Other potential synergistic toxins are phenols (from phenylalanine and tyrosine), bile salts, and middle molecules (molecular weight 500 to 5000 daltons).52 In chronic portosystemic encephalopathy, the plasma branchedchain amino acids (valine, leucine, and isoleucine) are decreased while the aromatic amino acids (tyrosine, phenylalanine, and free tryptophan) are increased. 99 Methionine may also be increased. 52 Branched-chain amino acids are mainly metabolized by muscle, whereas the aromatic amino acids are metabolized by the liver. Therefore, in hepatic failure, decreased clearance of aromatic amino acids occurs with increased utilization of the branched-chain amino acids for energy production.58 Because both amino acid groups compete for entry into the CNS by the same transport system (the neutral amino acid transporter), an increased influx of aromatic amino acids into the brain occurs. 32 A suspected increase in the transporter system activity also occurs because of the increased production and efflux of glutamine from the brain (transport exchange).27 One proposed mechanism of this altered amino acid

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profile's contribution to the encephalopathy centers around changes in the synthesis of brain amino acid-derived neurotransmitters (increases in tryptophan lead to increased production of serotonin and decreased synthesis of norepinephrine and dopamine). Other proposed mechanisms include the formation of false neurotransmitters (octopamine and phenylethylamine, though this theory has little experimental support) and tryptophan's toxic effect on the CNS.52, 58, 110 Because the above plasma amino acid alterations also occur in liver disease that is not associated with encephalopathy, the significance of these findings comes into question. However, in one study, CSF and not plasma amino acid alterations, appeared to correlate with the grade of encephalopathy.12 Definite indications exist for an imbalance of inhibitory (GABA) and excitatory (L-glutamate) neurotransmission in hepatic encephalopathy. Ammonia is believed to playa crucial role in regulating the interrelationship between the two compartments of brain glutamate and GABA metabolism. 52 An increase in brain (especially extracellular) L-glutamate concentration appears to occur, possibly because of impaired glutamate uptake, though brain GABA concentration and GABA receptor density and affinity appear not to be altered despite increases in peripheral plasma GABA concentration.10, 49, 50,57,68,81,95 The increased plasma GABA concentration may cross a compromised BBB in hepatic encephalopathy, allowing plasma gut-derived GABA to enter the CNS. However, the significance of this increased plasma GABA to the pathogenesis of hepatic encephalopathy still is not resolved. 52 The most recent theory of hepatic encephalopathy associated neurologic inhibition is the role of an endogenous benzodiazepine. 11 This is supported by the fact that the benzodiazepine antagonist flumazenil improves neurologic function in the early stages of hepatic encephalopathy.2,25 Benzodiazepine-like compounds are also increased in the CSF, plasma, and brain extracts with chronic hepatic encephalopathy.62 Benzodiazepine receptor density in the brain, however, does not appear to increase.50, 80 P.athologic Changes

Pathologic changes consist of varying degrees of cerebral edema in acute hepatic encephalopathy and hypertrophy and hyperplasia of protoplasmic astrocytes (Alzheimer type II astrocytosis) in chronic hepatic encephalopathy.93 Clinical Signs

Most dogs and cats with congenital portosystemic shunts usually show clinical signs at less than 1 year of age, often within the first few months of life. However, some dogs with congenital shunts have been diagnosed as late as 8 to 10 years of age. 98, 100 Affected animals are commonly small compared to their littermates and are in poor nutri-

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tional condition. 93 Animals usually show a history of chronic, intermittent, and relapsing cerebral dysfunction, consisting most commonly of changes in mentation (stupor, coma) or behavior (withdrawal, aggression, or hysteria).19, 99 Seizures can be present intermittently, though they are not a consistent finding. 51 Other signs include compulsive walking, circling, head pressing, amaurosis, and ataxia/ disorientation. 40, 98 Ptyalism is a common presenting sign of cats. 5 All of the above neurologic signs can be exacerbated by eating. Affected animals also may have systemic signs of their congenital or acquired hepatic dysfunction, including vomiting (often a predominant initial clinical sign), weight loss, anorexia, polyuria/polydipsia, and diarrhea. 4o,51 Ascites may also be present with advanced hepatic failure. Diagnosis

Diagnosis is based on initial history and clinical signs and abnormal serum biochemistry findings. These include decreases in total protein, albumin (and often globulin), blood urea nitrogen, glucose, and cholesterol. Serum alkaline phosphatase and alanine transferase levels are normal to mildly elevated. However, animals in acute, fulminant hepatic failure usually show marked elevations in both of these enzymes and in bilirubin. 98 Abnormal liver function tests further aid in the diagnosis of hepatic encephalopathy. Pre- and postprandial serum bile acid assays or ammonia tolerance testing are the two most commonly used function tests. After a 12-hour fast, resting serum bile acids can be nearly normal in animals with portosystemic shunts or decreased hepatic functional mass; therefore, an endogenous challenge test (2-hour postprandial bile acid assay) should be performed. Because animals with shunts cannot remove recycling bile acids from the blood, they show significant elevations in this second value. Animals with cholestatic disease have elevations in both pre- and postprandial bile acids. 98 One-hundred percent of animals with portosystemic shunts will have an abnormal ammonia tolerance test (given either orally or rectally), though resting blood ammonia levels may be equivocal in some. 51 Abdominal radiography commonly reveals a small liver. Renomegaly is often a concurrent finding. 51 Shunt confirmation can be achieved via contrast portal venography, radioisotope studies, and/ or ultrasound, though determining whether the shunt is intra- or extrahepatic is not always possible. One study concluded that if a shunt on portography is cranial to the T13 vertebra, it is most likely intrahepatic, and if it is caudal to T13, it is probably extrahepatic. 4 Final confirmation of the shunt type is made via exploratory surgery. Treatment

Surgical ligation of single, uncomplicated extrahepatic shunts is the most direct treatment. However, surgery carries risks both in the

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intraoperative and postoperative period. These include anesthetic complications, hypothermia, excessive portal hypertension after shunt ligation with resultant intestinal necrosis, intra-abdominal hemorrhage, and postoperative seizures/ status epilepticus. 29,ss The cause of postoperative seizures is not known. Many theories have been proposed, however, and include (1) the persistence of a biochemical factor continuing to produce hepatic encephalopathy despite shunt ligation, (2) a lowered seizure threshold secondary to the cerebral intramyelinic edema and Alzheimer type II astrocytosis produced by the original hepatic encephalopathy, (3) blood pressure, electrolyte, or osmolality changes, (4) an abrupt decrease in accumulated endogenous benzodiazepine agonists leading to a decrease in seizure threshold, or (5) the inability of a brain that has slowly adapted to the marked biochemical changes associated with portosystemic shunting to rapidly revert to a normal biochemical milieu and metabolism after shunt ligation. 29, ss Dogs and cats with multiple extrahepatic shunts and those with acquired shunts secondary to acute fulminant hepatic failure or cirrhosis are not candidates for surgical ligation of the portal vein. However, banding (suture attenuation) of the caudal vena cava has been recommended in dogs with multiple acquired shunts to control signs of encephalopathy and ascites. Banding increases caudal vena cava pressure slightly above portal pressure to encourage redirection of the portal flow back through the liver. 34 Medical therapy consists of dietary management and drugs. to decrease or prevent the formation and absorption of toxic substances from the gut. The diet should be readily digestible and consist of a protein source of low quantity but high quality.19 Lactulose, a synthetic disaccharide sugar that is not digested or absorbed from the small intestine, is degraded by bacteria in the colon. This acidifies the colon, which results in the conversion of ammonia to the ammonium ion (NH4), which is not absorbed through the colonic mucosa. The cathartic action of lactulose produces an osmotic diarrhea, which decreases colonic transit time and decreases the colonic bacterial flora. 19,98 The dose is 0.5 mL/kg orally, three times daily. Oral antibiotics are also commonly used to reduce colonic bacteria further. Neomycin (20 mg/kg orally three to four times daily in dogs and 10 to 20 mg/kg four times daily in cats) or metronidazole (10 mg/kg orally three times daily) are the most widely used antibiotics for this purpose. s, 30, 34, 98 In acute encephalopathy, lactulose enemas (diluted 1:2 with warm water) at a dosage of 20 to 30 mL/kg or providone-iodine solution diluted 1:10 with warm water can be administered with or without the addition of neomycin sulfate (22 mg/kg).s,30 Treatment of chronic or nonresponsive hepatoencephalopathy may include flumazenil, a benzodiazepine antagonist, though its use is still experimental. 48 Beware of the use of benzodiazepines and barbiturates in patients with hepatic encephalopathy, because they can worsen the observed neurologic signs. 48 Treatment of postsurgical status epilepticus requires seizure control with intravenous phenobarbital, maintenance of blood glucose levels in the high normal range, correction of abnormal serum electrolytes, possible use of a respirator to normalize P02 and

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PC02 levels; and mannitol (1 g/kg IV) with furosemide (0.75 to 1 mg/kg IV) if cerebral edema is suspected. 29

OSMOTIC AND ELECTROLYTE ABNORMALITIES

The CNS is delicately susceptible to imbalances in electrolytes and water. A critical factor in neuronal homeostasis is the maintenance of resting neuronal membrane potentials by the correct distribution of sodium (the major extracellular ion) and potassium (the major intracellular ion). Sodium

Sodium salts represent the major osmotically active solutes in the body. Clinically, hyponatremia is synonymous with hypoosmolality and, in most cases, hypernatremia with hyperosmolality. Rapid changes in serum osmolality produce more prominent neurologic signs than do slow changes because the protective mechanisms against osmolar shifts that are present in the brain take time to develop.71 The actual serum level of sodium at any particular time is far less important than the rate at which that level was reached. 1 HypernatremialHyperosmolality

Hypernatremia is defined as a serum sodium level greater than 156 mEq/L in the dog and greater than 161 mEq/L in the cat. T'he causes of hypernatremia are related either to excess water loss (hot weather, burns, respiratory infections, diabetes insipidus, osmotic diuresis, osmotic diarrhea, emesis), insufficient water intake (lack of access, inability to drink, primary central nervous system adipsia), or sodium gain (hyperaldosteronism, excess intake).63,73 Initial signs of lethargy and irritability are seen at osmolalities greater tpan 350 mOsm/kg (sodium greater than 170 mEq/L). Ataxia and tremors are seen at levels of 375 to 400 mOsm/ kg. Myoclonus, tonic spasms, seizures, blindness, coma, and death occur at osmolalities greater than 400 mOsm/kg. 63 Initial osmotic equilibrium in animals with acute hypernatremia is achieved by immediate water exit from cells in the CNS and across the BBB, resulting in neuronal cellular dehydration. The decrease in brain volume caused by cellular dehydration can cause tearing of cerebral veins, small bridging vessels between the dura and the inner aspect of the cranium, and meningeal vessels, resulting in intraparenchymal, subarachnoid, or subdural hemorrhage. Subarachnoid !lemorrhage can then lead to vasospasm from the release of vasoactive substances from the lysed red blood cells. 59, 66,82 With slower increases in extracellular osmolality, the brain compensates by increasing intracellular osmolality. Initially sodium, potassium, chloride, and glucose move into the cells

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from the extracellular fluid (making up approximately one half of the gained solute).63 The rest comes from the intracellular production of osmotically active particles (idiogenic osmoles or osmolytes), which are principally amino acids (glutamine, glutamate, aspartate, and taurine). Though they keep water from leaving the intracellular compartment, their increased concentrations may contribute to the neurologic dysfunction, perhaps by affecting membrane excitability.42, 59 Treatment. Acute hypernatremia can be quickly corrected by administration of 5% dextrose intravenously or orally. However, with chronic hypernatremia, after cerebral adaptation with new solute gain, sudden rehydration can lead to marked cerebral edema (water intoxication). This occurs because the newly gained neuronal solutes move much more slowly across the BBB than does water. Therefore, the rapid decrease in plasma osmolality causes water to move into the brain parenchyma. 40 The water deficit should be replaced using the formula: Water deficit (L) == 0.6

lean body weight (kg) normal Na - 1)

X

X

(patient's Na/

Five-percent dextrose should be used and replacement should take 48 to 72 hours. Serum sodium should be monitored and correction adjusted to limit the sodium decrease to 0.5 to 1 mEq/l/hr. 66 Treatment should also be aimed at the underlying cause of the hypernatremia, if appropriate. HyponatremialHypoosmolality

Hyponatremia is defined as serum sodium greater than 137 mEq/L in dogs and less than 150 mEq/L in cats. Neurologic signs usually begin at values less than 120 mEq/L (acute), or less than 110 mEq/L (chronic).63,82 Hypoosmolality may be caused either by hyponatremia with body sodium depletion/hypovolemia (decreased sodium intake, diarrhea, hypoadrenocorticism, diuretics) or hyponatremia with normal sodium stores (water intoxication) as a result of inappropriate secretion of antidiuretic hormone, psychogenic polydipsia, oliguric/anuric renal :failure with excessive fluid administration, or iatrogenic hypotonic fluids. 73,79,82 Hyperlipemia, hyperproteinemia, or hyperglycemia may spuriously lower the serum sodium measurement. This has no neurologic consequences. 71 ,82 Neurologic dysfunction in acute hyponatremia, and therefore, hypoosmolality, is primarily due to serum/brain osmotic differences leading to an increase in brain cell water content, cerebral edema, and increases in ICP. However, interference with transport mechanisms, energy metabolism, and membrane excitability may also be important. 63,71 The brain has no time to compensate for the rapid drop in serum osmolality. Neurologic signs include lethargy, nausea, and vomiting with progression to seizures, coma, and death. 66 As with hypernatremia, the brain compensates when faced with chronic hyponatremia; intracellular osmolality is lowered through active depletion of intracellular osmoles

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consisting principally of potassium but with contributions from amino acids. 59 Though inorganic ions can equilibrate relatively rapidly, amino acids are much slower. Too rapid a correction of chronic hyponatremia can lead to a syndrome in humans termed "central pontine myelinolysis"-a delayed myelinolysis in the central pons and in areas where gray and white matter are closely admixed (3 to 4 days after correction).90 This syndrome has been reported in two dogs, though the myelinolysis was located in the central thalamus and subcortical white matter. 65 This syndrome is possibly due to axonal shrinkage, separation of the axons from the myelin sheaths, and secondary delayed demyelination. Neurologic signs include depression, weakness, and ataxia progressing to spastic tetraparesis, hypermetria, trismus, and episodic flexor spasms. Rapid correction of acute hyponatremia of less than 2 to 3 days duration does not have any neurologic consequences. 14 Treatment. Therapy for chronic hyponatremia is based on calculation of the sodium deficit by using the formula: Sodium deficit (mEq/L) = 0.6 X lean body weight (kg) sodium - patient's sodium)

X

(normal

This deficit must be corrected with extreme care. An increase in brain water content of more than 10% may result in tentorial herniation. Therefore, correction of the sodium deficit should be aimed at a 5% increase (6 mEq/L/d using normal saline, or hypertonic saline in extreme cases). Do not exceed 10 to 12 mEq/L/d or 0.5 mEq/L/h.66/79 Treatment should also be aimed at the underlying cause of the hyponatremia. Potassium

Brain and cerebrospinal fluid potassium are maintained within narrow limits and are not significantly altered by hypo- or hyperkalemia. The primary signs with hypokalemia are muscle weakness and cardiac arrhythmias, though metabolic encephalopathy (disorientation) can occur. I Hypokalemia in small animals is seldom of clinical significance until the serum level decreases below 3 mEq/L. Hyperkalemia is not of clinical importance until the serum level is greater than 7 mEq/L, at which time severe life-threatening cardiac conduction disturbances occur. 82 In chronic cases of hyperkalemia, the CNS signs may precede cardiac failure. ACID-BASE ABNORMALITIES

Cerebrospinal fluid (CSF) pH changes occur more readily with shifts in Pco2 (respiratory acidosis and alkalosis) than with shifts in bicarbonate (metabolic acidosis and alkalosis) due to the low BBB permeability

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to bicarbonate. Physiologic mechanisms protect brain acid-base balance against even large changes in serum pH via respiratory compensation initiated by the medullary respiratory centers, cerebral blood flow changes, establishment of ionic gradients, and CNS cellular buffering. This works best with metabolic acidosis but is largely ineffective for respiratory acidosis.59, 71 Respiratory Acidosis

Respiratory acidosis is produced by hypoventilation or venous admixture of blood secondary to significant pulmonary disease. Decreased mentation, delirium, or coma is due to carbon dioxide narcosis and incre(1~ed CSF pressure. The latter is produced by an increase in cerebral blood flow secondary to a decrease in CSF pH.59 The metabolic dysfunction may be related to decreases in glutamate and aspartate, because acidosis inhibits enzymatic steps in glycolysis. The concomitant hypoxia also contributes to the observed encephalopathy.40 Neurologic manifestations are most prominent when pulmonary deterioration is rapid, because the synthesis of brain bicarbonate and other intracellular buffers lags behind carbonic acid accumulation.59 No permanent neurologic dysfunction remains after cerebral pH returns to normal. Respiratory Alkalosis

Respiratory alkalosis is commonly caused by hyperventilation secondary to hypoxia, with a resultant decrease in carbon dioxide. 40 The resultant confusion and disorientation is due partly to decreased cerebral blood flow secondary to an increase in CSF pH. This is caused by constriction of cerebral arterioles with a secondary increase in lactic acid production. However, because the decrease in cerebral blood flow is transient, prolonged respiratory alkalosis is unlikely to significantly interfere with cerebral function. 71 Metabolic Acidosis

Metabolic acidosis is caused by a loss of bicarbonate from the body or excess formation or excretion failure of metabolic acids. The presence or severity of neurologic signs depends on the cause of the systemic metabolic defect, the magnitude of the effect of the systemic drop in pH on CNS pH, the rate of development of acidosis, and the specific anion causing the metabolic disorder. 71 A decrease in mentation occurs, though it is not as severe or as common as that with respiratory acidosis. Measurements of CSF pH better correlate with the observed clinical signs than does serum pH. Too rapid a treatment of metabolic acidosis with bicarbonate can lead to a transient further reduction in CSF pH in

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the face of higher arterial pH. This is termed paradoxical cerebrospinal acidosis. Bicarbonate combines with the excess hydrogen ions (largely excluded from the brain) producing carbonic acid, which in turn breaks down into water and carbon dioxide. The carbon dioxide readily crosses the BBB and enters the CSF where it again combines with water, producing an increase in the brain concentration of carbonic acid. This will lower CSF pH. This is only a transient phenomenon, and though it may clinically be accompanied by a decrease in responsiveness, it is neither profound nor life threatening.40, 71 ENDOCRINE ABNORMALITIES Diabetes Mellitus

Neurologic dysfunction can be seen with two syndromes associated with advanced diabetes mellitus, namely diabetic ketoacidosis and hyperosmolar nonketotic diabetes mellitus. 97 Diabetic Ketoacidosis

The relative deficiency of insulin and relative excess of counterregulatory hormones in diabetes mellitus promotes hepatic glycogenolysis and gluconeogenesis and stimulates hormone-sensitive lipase, causing a release of free fatty acids from adipose stores.18, 103 These free fatty acids are then converted to acetyl CoA by the liver. Metabolic acidosis develops secondary to the accelerated production of acetoacetate and its metabolites, acetone and beta-hydroxybutyric acid (ketones).59,97 Ketone bodies are acids and release hydrogen ions, which leads to metabolic acidosis because of the overwhelming of the compensatory buffering systems. Hypovolemia (from osmotic diuresis) and a total-body sodium and potassium depletion also occur. 103 The resultant CNS depression has a multifactorial etiology, though hyperosmolality, produced by the hyperglycemia and accentuated by the water loss from the osmotic diuresis, is probably the most important factor. With impaired glucose utilization, a decrease also occurs in cerebral oxygen consumption. Though metabolic acidosis is present, no correlation exists between the state of consciousness and the serum pH. The clinical signs are essentially those seen with hyperosmolar (hypernatremic) encephalopathy.59 Diagnosis. Diagnosis is based on the identification of metabolic acidosis, hyperglycemia, hyperosmolality, and ketoacidosis. Clinical signs of polyuria/polydipsia and weight loss are followed by anorexia, decreased mentation, vomiting, and diarrhea. The breath has a fruity odor. 18,103 A biochemistry panel, urinalysis, and anion gap, osmolality, and blood gas determinations confirm the diagnosis. Treatment. Therapy revolves around correction of hypovolemia, reversal of the hyperglycemia (+ / - acidemia), and correction of electrolyte disturbances. Intravenous fluid therapy is used for correction

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of dehydration and hypovolemia. Initially this is accomplished with crystalloid isotonic fluids (0.9% saline or lactated Ringer's solution) until the hypovolemia is corrected, followed by 0.45% saline for maintenance. Fluid therapy alone also helps to lower blood glucose levels via osmotic diuresis and glycosuria, though judicious use of regular crystalline insulin is also required. The route of administration of regular insulin can be either intravenous or intramuscular. Detailed dosage regimens for both routes have been described elsewhere. 18,83 Once the blood glucose level decreases to 250 mg/ dL, 5% dextrose should be added to the fluids to prevent hypoglycemia. Potassium should be monitored extremely closely while treating the diabetic ketoacidotic patient. If the animal is normo- to hypokalemic prior to therapy, potassium supplementation should be started immediately. The starting rate is 0.1 to 0.2 mEq/kg/ h. If hyperkalemia is present initially, potassium supplementation is withheld for the first 2 hours. 18 Correction of the accompanying metabolic acidosis is rarely warranted. Autocorrection usually occurs with the above treatment plan. l03 Hyperosmolar Nonketotic Diabetes

This syndrome occurs if serum glucose is greater than 600 mg/ dL, with a resultant hyperosmolality of greater than 330 to 350 mOsm/kg.l03 Ketones are absent or minimal in serum or urine. Free fatty acids and the counterregulatory hormone levels are lower and insulin secretion is higher compared to the respective findings with diabetic ketoacidosis. This, along with the marked hyperosmolality, prevents lipolysis. 97 Hypokalemia and hyponatremia are often secondary complications. 83 Renal function is compromised either because of primary renal disease or the severe hypovolemia. This leads to a decreased glomerular filtration rate, a decreased excretion of glucose, and thus profound hyperglycemia (and hyperosmolality).103 Serum hyperosmolality and extreme dehydration is again the most likely cause of the neurologic dysfunction (depression and coma).S9, 103 However, recent evidence indicates that activation of excitatory amino acid (glutamate) receptors (both N-methyl-o-aspartate . [NMDA] and non-NMDA) also plays a role in the pathophysiology of seizures in this syndrome. 4s,47 Diagnosis. Marked hyperglycemia and hyperosmolality, often with hypokalemia and acidemia, are seen. 83 Treatment. The aims of therapy are the treatment of circulatory collapse, replacement of sodium and potassium deficits, and slow correction of the hyperglycemia over 24 to 48 hours. Fluid therapy should be initiated with 20 to 30 mL/kg 0.9% saline given rapidly IV, followed by maintenance 0.45% saline (60 mL/kg/ d). Estimated body fluid deficits should be replaced over 48 hours. The addition of 20 to 40 mEq KCI/L of fluids is important to correct whole-body potassium deficits. Insulin therapy must be avoided until after the initial bolus of 0.9% saline and 6 hours of hypotonic fluids have been administered to avoid possible

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cerebral edema and life-threatening hypokalemia. Insulin therapy is administered in the same fashion as with diabetic ketoacidosis. 103 Hypothyroidism

Myxedema, irritability, confusion, stupor, and coma are caused by diminished metabolic processes, decreased cerebral blood flow, and a decrease in cerebral oxygen consumption in profound hypothyroidism. Hypothyroidism also causes a decrease in nucleoprotein synthesis in synapses and neurons of the immature brain. 71 ,97 Hypothermia without shivering is commonly present, which is either due to impaired hypothalamic temperature regulation or impaired calorigenesis. 97 Most recognized cases of myxedema coma have occurred in Doberman Pinschers, with associated high mortality rates. 36 Cerebral artery atherosclerosis is a rare complication in dogs, producing disorientation, blindness, seizures, head tilt, and ataxia secondary to cerebral hypoxia and cerebral infarction. 54, 69 Other effects of atherosclerosis (hypertension, retinopathy, and renal failure) may also be present. 13 Triglycerides are usually elevated and serum cholesterol is usually above 400 mg/dL. Diagnosis

Initial suspicion is based on clinical signs, a fasting hypercholesterolemia, and a low resting serum T4 level. Confirmation is obtained via the performance of a thyroid stimulating hormone (TSH) stimulation test and/or free T4 levels. Electroencephalographs from animals with hypothyroid encephalopathy show diffuse flattening of electric activity in all leads, with periodic spike and slow-wave discharges. 97 Treatment

Treatment with levothyroxine (10 to 20 ~g/kg orally twice daily) usually reverses the· neurologic signs in mildly to moderately affected patients within a few weeks. 1 Animals with myxedema stupor or coma should be regarded as an emergency and treatment with intravenous Lthyroxine should begin prior to serum T4 levels being obtained. Therapy should also consist of parenteral glucocorticoids, broad-spectrum antibiotics, and possible respiratory support. The animal should also be rewarmed if it has a subnormal temperature. 13 Hypoparathyroidism

Hypoparathyroidism is characterized by hypocalcemia, hypophosphatemia, and either transient or permanent parathyroid hormone insufficiency.7o The most common cause of hypoparathyroidism in dogs is immune-mediated lymphocytic parathyroiditis, whereas in cats it is the

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915

accidental damage to or removal of the parathyroid glands at the time of thyroidectomy for hyperthyroidism. 23, 39, 70, 8S Animals with hypoparathyroidism can show an acute onset of eNS disturbances including muscle tremors, seizures, behavior change, hypersensitivity, disorientation, irritability, and gait abnormalities. ls, 8S Neurologic signs can be intermittent and subtle in the early stages of hypoparathyroidism and signs can be initiated by sudden excitement, activity, or petting. 97 Severe hypocalcemia (serum calcium less than 5 mg/ dL) produces life-threatening tetany or seizures. 82 The pathophysiology of these signs is related to a lack of ionized calcium, which normally stabilizes cell membranes. With a decrease in calcium, neuronal membrane permeability and excitability progressively increase. The ataxia and extensor muscle rigidity may be related to cerebellar or extrapyramidal motor system dysfunction.8s, 97 Diagnosis

Diagnosis is based on the history, the clinical/neurologic signs, the demonstration of true hypocalcemia and hypophosphatemia on the biochemistry panel, and the ruling out of other causes of hypocalcemia (hypoalbuminemia, pancreatitis, renal failure, malabsorption, nutritional secondary hyperparathyroidism, and eclampsia).ls,70 Treatment

Treatment is based on the severity of calcium-specific signs as well as the magnitude of the functional hypocalcemia. Acute, subacute, and chronic rescue treatments exist for calcium supplementation. ls Hypocalcemic tetany or convulsions require immediate intravenous administration of 0.5 to 1 mL/kg of 10% calcium gluconate (diluted in 5% dextrose) over 10 to 20 minutes. Electrocardiographic monitoring is essential. This infusion should be stopped if bradycardia or a shortened QT interval occurs. 1S Once seizures are controlled, intravenous 10% calcium gluconate should be continued as a slow infusion (5 to 15 mg/kg/h) to maintain normal calcium. ls Though continuous calcium infusions main.tain normocalcemia, the effect is short-lived, with hypocalcemia returning within hours of therapy cessation. Therefore, oral vitamin D and calcium should be initiated as soon as possible. Dihydrotachysterol should be administered orally initially at a dose of 0.02 to 0.03 mg/kg/ d for 2 to 3 days followed by a maintenance dose of 0.01 to 0.02 mg/kg every 24 to 48 hours. Stable serum calcium concentrations can usually be achieved within 1 week. ls, 70 In addition, oral elemental calcium supplementation should be given at a dose of 25 to 50 mg/kg/d. ls Hyperparathyroidism

Primary and pseudohyperparathyroidism (hypercalcemia of malignancy [lymphosarcoma, anal sac adenocarcinoma]) can produce de-

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pressed mentation and seizures secondary to an increase in calcium concentration. 97 Primary hyperparathyroidism is most commonly caused by a functional adenoma of the chief cells. 15, 77 Other causes of hypercalcemia include local osteolysis by neoplasia or infection, acute and chronic renal failure, and hypoadrenocorticism. 15 Increased calcium depresses the excitability of cerebrocortical neurons and subsequently results in depressed mentation. The etiology of seizures is only speculative, though a possible scenario is that the increase in calcium selectively depresses the zone of inhibitory neurons surrounding a seizure focus, thus allowing a seizure focus to spread. 97 The most common signs associated with hypercalcemia are polyuria/polydipsia and anorexia. Diagnosis

Initial diagnosis centers around the finding of persistent hypercalcemia with a history of polyuria/polydipsia and anorexia. Other causes of hypercalcemia should be ruled out before making a diagnosis of primary hyperparathyroidism. Therefore a rectal examination, thoracic and abdominal radiographs, abdominal ultrasonography, lymph node aspirates, bone marrow aspirates biopsy, and a bone scan should be considered. Measurement of serum parathormone levels also may be helpful to suggest primary hyperparathyroidism. 77 Treatment

Treatment or removal of the underlying cause is the definitive treatment. Supportive treatments are used to reduce the magnitude of the hypercalcemia. These include intravenous 0.9% saline (100 to 125 mL/kg/d), diuretics (furosemide at 2 to 4 mg/kg twice to three times daily), glucocorticoids (prednisone at 1 to 2 mg/kg twice daily), diphosphonates (etidronate 5 to 15 mg/kg orally once to twice daily), and calcitonin (4 to 6 IV/kg subcutaneously twice to three times daily).15 Sodium bicarbonate promotes translocation of serum ionized calcium to protein binding sites and is used as an emergency treatment if the hypercalcemia is life threatening. 15 Hyperadrenocorticism

Excessive concentrations of adrenal corticosteroids as a result of primary or iatrogenic hyperadrenocorticism may produce anxiety, aggression, psychotic behavior, depressed mentation, or somnolence. 37, 97 Proposed mechanisms include a depletion of GABA and/or an increase in serotonin biosynthesis. The limbic system is rich in receptor sites for cortisol, which may relate to the behavior changes. Hyperadrenocorticism may also result in systemic hypertension and hypertensive encephalopathy.

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UREMIC ENCEPHALOPATHY

Cerebral dysfunction (seizures, mentation changes, confusion, delirium, and altered consciousness) is related to the intensity of the metabolic disorder caused by acute or chronic renal failure and its rate of development. These neurologic signs can be episodic. 1 Various abnormal respiratory patterns also occur. Kussmaul respiration occurs secondary to severe metabolic acidosis. 59,107 Ataxic respiration (slow, shallow, irregular respiration that is not altered by hypoxia or hypercapnia) is a reflection of hyposensitivity of the brain stem to chemoreceptor stimulation. Random roving eye movements are common, as are muscle tremors and spasms (most commonly related to the facial muscles).8,24 However, no correlation exists between the severity of signs and the degree of azotemia, acid-base abnormalities, electrolyte disturbances, or phosphorous levels. 24, 59, 71 Acute renal failure is more likely to produce seizures, whereas chronic renal failure is more likely to produce dementia. 24 Multiple suspected origins exist for the encephalopathy associated with uremia. These include arterial hypertension, increased brain calcium with resultant mineralization (most pronounced in the cerebral cortex, amygdala, and hippocampus), increased parathyroid hormone (which alters tissue membranes and facilitates calcium influx), abnormal serum magnesium levels, uremic toxins (methylguanidine, guanidinosuccinic acid, phenolic acid, middle molecules), sodium-potassium ATPase system depression (leading to a failure of the sodium pump and ion transport), reduced cerebral blood flow, and neurotransmitter imbalance (especially glutamine, glycine, and amino acids).l, 24, 59,64,71 In addition, the increased permeability of the BBB and cerebral neuronal membranes caused by uremic vasculitis and aseptic meningitis allows passage of uremic toxins through the BBB and their accumulation in brain tissue. 59,71 Diagnosis

Laboratory determinations usually indicate elevations in blood urea nitrogen, creatinine, and phosphorus. Metabolic acidosis commonly is seen. Urine specific gravity is isosthenuric. However, renal failure is accompanied by other complex biochemical, osmotic, and vascular abnormalities that are not readily appreciated on routine bloodwork but do contribute to the resultant encephalopathy. Therefore, the degree of uremia differs widely in patients with equally severe symptoms.71 Treatment

In the treatment of uremic encephalopathy, the nature of the renal disease assumes paramount importance. If the renal disease is irreversible and progressive, the prognosis is poor without dialysis or renal transplantation. 1 If the primary renal dysfunction can be reversed or

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at least managed so that compensation occurs, the encephalopathy is potentially reversible. PANCREATIC ENCEPHALOPATHY

An episodic encephalopathy consisting of varying degrees of stupor and coma may occur with chronic relapsing or acute pancreatitis in humans and has been observed in a small number of dogs by the author. 22 Possible pathogeneses include a direct effect of the exocrine pancreatic enzymes lipase and proteolase, which are increased in the CSF; disseminated intravascular coagulation (in acute pancreatitis); fat embolism; and biochemical complications of the pancreatitis (hypotension and cerebral circulatory insufficiency from shock, hyperosmolality, hypocalcemia, hypoglycemia, and diabetic ketoacidosis).1/71 Diagnosis

Other signs of pancreatitis accompany the encephalopathy including emesis, diarrhea (often with melena), dehydration, fever, shock, and cranial abdominal pain. Serum amylase, lipase, phospholipase A 2, and trypsin-like immunoreactivity are usually elevated. 106 Nonspecific laboratory abnormalities include leukocytosis, prerenal azotemia, increased hepatic enzymes, hyperglycemia, hypocalcemia, hypercholesterolemia, hypertriglyceridemia, and hypoproteinemia. 88/ 106 Radiographs may reveal increased density, granularity, and diminished contrast in the right cranial abdomen and the "sentinel loop sign" related to gas accumulation in the proximal descending duodenum. Ultrasound and computed tomography are also helpfu1. 88 Treatment

Treatment includes the withholding of all oral food and water, intensive fluid therapy, correction of electrolyte imbalances, parenteral antiemetics, antibiotics (cephalosporins or ampicillin), fresh or freshfrozen plasma (10 to 20 mL/kg), and possible analgesics and corticosteroids (short-term therapy for animals in shock).88, 106 With successful therapy, the associated encephalopathy usually resolves. SUMMARY

Numerous metabolic derangements originate from outside the CNS that potentially can have a profound effect on cerebral function. The pathogenesis of the resultant dysfunction to the cerebrum and other regions of the brain is extremely varied. However, the CNS can only

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react in limited ways to these insults. Therefore, the veterinarian should recognize the clinical patterns of neurologic signs associated with the metabolic encephalopathies, sift through the multiple potential causes with the aid of other accompanying extracranial clinical signs and clues from biochemical data, understand the underlying pathogenesis of the cerebral dysfunction, and, finally, formulate a rational plan of treatment. Though immediate attention is often directed at restoring homeostasis to the eNS, success is only ultimately achieved via correct and timely treatment of the underlying metabolic disease. Only then does strong potential exist for a permanent reversal of the neurologic deficit. References 1. Adams RD, Victor M: The acquired metabolic disorders of the nervous system. In Principles of Neurology, ed 5. New York, McGraw-Hill, 1993, pp 877-902 2. Bansky G, Meier P, Riederer, et al: Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology 97:744-750, 1989 3.. Bernstein NM, Fiske RA: Feline ischemic encephalopathy in a cat. J Am Anim Hosp Assoc 22:205-206, 1986 4. Birchard SJ, Biller DS, Johnson SE: Differentiation of intrahepatic versus extrahepatic portosystemic shunts in dogs using positive-contrast portography. J Am Anim Hosp Assoc 25:13-17, 1989 5. Birchard SJ, Sherding RG: Feline portosystemic shunts. Compend Continu Educ Pract Vet 14:1295-1301, 1992 6. Bovee KC, Burkett D: Factors that affect blood pressure in dogs. Proceedings of the 13th American College of Veterinary Internal Medicine Forum, Lake Buena Vista, Florida, 1995, pp 608-610 7. Bracken MB, Shepard MJ, Collins WF, et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: Results of the second national acute spinal cord injury study.N Engl J Med 322:1405-1411, 1990 8. Braund KG: Neurological diseases. In Clinical Syndromes in Veterinary Neurology, ed 2. St. Louis, Mosby, 1994 9. Brown S, Hall ED: Role of oxygen-derived free radicals in the pathogenesis of shock and trauma, with focus on central nervous system injuries. J Am Vet Med Assoc 200:1849-1859, 1992 10. Butterworth RF, Lavoie J, Giguere J-F, et al: Cerebral GABA-ergic and glutaminergic function in hepatic encephalopathy. Neurochemistry and Pathology 6:131-144, 1987 11. Butterworth RF, Pomier Layrargues G: Benzodiazepine receptors and hepatic encephalopathy. Hepatology 11:499-501, 1990 12. Cascino A, Cangiano C, Fiaccadori F, et al: Plasma and cerebrospinal fluid patterns in hepatic encephalopathy. Dig Dis Sci 27:828-832, 1982 13. Chastain CB: Unusual manifestations of hypothyroidism in dogs. In Kirk RW, Bonagura JD (eds): Current Veterinary Therapy XI: Small Animal Practice. Philadelphia, WB Saunders, 1992, pp 330-334 14. Cheng J-C, Zikos D, Skopicki HA, et al: Long-term neurologic outcome in psychogenic water drinkers with severe symptomatic hyponatremia: The effect of rapid correction. Am J Med 88:561-566, 1990 15. Chew DJ, Carothers MA: Disorders of calcium: Hypocalcemia and hypercalcemia. In Proceedings of the 13th American College of Internal Veterinary Medicine ACVIM Forum, Lake Buena Vista, Florida, 1995, pp 632-636 16. Clarke DD, Sokoloff L: Circulation and energy metabolism of the brain. In Siegal GJ, Agranoff BW, Albers RW, et al (eds): Basic Neurochemistry, ed 5. New York, Raven Press, 1994, pp 645-680 17. Cryer PE: Physiology of glucose counterregulation in humans. In Proceedings of the

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