As normal nervous system function depends on a closely regulated environment, systemic metabolic disorders often affect the nervous system. Early neurological signs can be vague and intermittent, and varies from mild weakness or ataxia to profound weakness, blindness or seizures. Common metabolic diseases can be readily diagnosed on blood work. However, others can be challenging to diagnose, and involve appropriate specific laboratory tests, repeated or serial tests.
This lecture is to give the audience an overview of this group of disease, and only selected diseases will be discussed. Interested audience should consult other texts for in-depth description of the diagnosis and treatment of each disease.
Hepatic Encephalopathy (HE)
Parenchymal liver disease severely alters the normal metabolic functions such as metabolism of ammonia to urea. Portosystemic venous shunts divert a significant portion of the portal blood past the liver into the systemic circulation; bypassing the detoxification process normally performed by the liver. Neurological signs are related to excessive neurotoxins (ammonia and other synergistic toxins), and lack of factors normally synthesized by the liver necessary for normal brain function. Forebrain signs include behavior change, head pressing, pacing aimlessly, dull, and seizure; usually wax and wane and frequently worse after feeding high protein meal. Other signs include prolonged recovery from general anesthesia, retarded growth, small liver on palpation, urolithiasis (ammonium biurate crystals), and ptyalism (common in cats).
Factors that exacerbate HE:
Increased dietary protein and fatty acid
Constipation leading to bacteria production in large bowel
Hypokalemia, hypovolemia, alkalosis - increase blood and tissue ammonia levels, aggravated by diuretics
Transfusion of stored blood - stored products contain excessive ammonia
Decreased renal function - reduce elimination of ammonia and other metabolites
Fever and infection - cause increased tissue catabolism and nitrogen release
Use of depressant drugs (sedatives, narcotics, anaesthetics) or other drugs metabolized in liver
Inability of the kidneys to perform 3 basic functions: regulation of water and electrolytes, excretion of organic solutes, and production of hormones. Neurological signs are related to uremic acidosis, alterations of parathyroid hormones and electrolytes (especially calcium and potassium). Terminal stages of renal failure may present in seizures and tetany. Metabolic acidosis develops because of impaired renal tubular ammonia production, decreased urinary excretion of hydrogen ion and reduced renal tubular reabsorption of bicarbonate. Renal secondary hyperparathyroidism results from phosphorus retention and decreased production of calcitriol. Parathyroid hormone (a uremic toxin) can have a primary neurotoxic effect and secondarily cause hypercalcemia. Weakness related to hypokalemia due to inappetence thus inadequate dietary intake or low potassium content of the diet.
Neurological signs include episodic altered mental status, disorientation, weakness, ataxia, and somnolence. Differential diagnoses for metabolic acidosis include toxins, uremic acidosis, ketoacidosis, or organic acidosis (e.g., D-lactic acidosis). In cats small bowel disease inhibits cobalamin uptake, and cobalamin deficiency can result in metabolic acidosis.
Disorders that affect electrolytes and glucose homeostasis can result in neuromuscular dysfunction, resulting in weakness.
Hypoglycemia (blood glucose < 40 mg/dl) causes altered CNS function similar to that associated with hypoxia. Blood glucose concentration is vital for normal neuronal metabolism because glucose oxidation is the primary energy source. No glycogen stores are present in the CNS. Glucose enters nervous tissue by non-insulin dependent transport mechanisms. Seizures (either partial facial twitching or generalized seizure) are common. CNS signs are related more to the rate of decrease than to the actual glucose concentration. Sudden drop in glucose levels are more likely to cause seizure; whereas slowly progressive hypoglycemia causes weakness, paresis, behavioral changes or stupor.
Hyperglycemia (Diabetic Neuropathy)
Insulin deficiency results in failure of glucose transport into muscle and adipose tissue. Clinical signs including exercise intolerance and weakness, poorly controlled diabetic cats may develop peripheral neuropathy (plantigrade stance) with lower motor neuron (LMN) sign (reduced muscle tone, decreased spinal reflexes, sensation and muscle mass), due to demyelination and axonal degeneration of the peripheral nerves. Ketotic cats develop metabolic acidosis resulting in depressed cerebral function, and hyperkalemia causes flaccid muscles by depressing neuromuscular and cardiovascular functions. Remember that with correction of the acidosis and insulin therapy, potassium re-enters cells and can result in hypokalemia, again leading to muscle weakness and depression. Coma may result from severe metabolic acidosis (DKA) or hyperosmolar effect of glucose on cerebral cortex (hyperosmolar non-ketotic coma).
Hypercalcemia (> 14 mg/dl) increased membrane active potential threshold, thus more difficult to depolarize, resulting in hypoexcitablity of the muscle membrane. Clinically manifested by muscle weakness and sluggish reflexes. Hypercalcemia develops primarily when there is an increase in bone mobilization of calcium, increased intestinal calcium absorption, or a decrease in urinary loss of calcium. Ionized calcium (iCa) is the only biologically active form and should be measured to confirm hypercalcemia. Sequelae to hypercalcaemia include chronic renal failure, tubular cell toxicity and reduced excitability of smooth muscle, which may result in altered gastrointestinal function; depressed skeletal and cardiac muscle contractility, leading to generalized weakness and cardiac arrhythmias.
Causes of hypercalcemia:
Idiopathic hypercalcemia (IHC) - Unexplained disturbances in calcium homeostasis resulting in ionized hypercalcemia are attributed to parathyroid-independent hypercalcemia in over 50% of cats. Interestingly, most IHC cats have few or no clinical signs. Signs reported include vomiting, weight loss, dysuria, anorexia, constipation, calcium oxalate urolithiasis, and inappropriate urination. Diagnosis of IHC requires eliminating other known causes of hypercalcemia including neoplasia, CKD, primary hyperparathyroidism, hypoadrenocorticism, toxin ingestion (e.g., cholecalciferol, calcipotriene), granulomatous disease, and osteolytic disease.
Primary hyperparathyroidism - Functioning parathyroid adenomas secrete PTH in the presence of increasing calcium concentrations.
Paraneoplastic syndromes - Also called "hypercalcemia of malignancy", due to secretion of PTH-like substances by non-endocrine tumors such as lymphoma, squamous cell carcinoma, thymoma, anal sac adenocarcinoma.
Rodenticides intoxication - Containing analogues of vitamin D promote absorption of calcium from gastrointestinal tract.
Iatrogenic calcium therapy.
Related to primary hypoparathyroidism, or by inadvertent surgical resection of the parathyroid glands during thyroidectomy. Chronic renal disease can lead to hypocalcemia. Hypocalcemia increases membrane hyperexcitability by decreasing the membrane threshold to more easily elicit an action potential. Signs of hypocalcemia such as tetany occurs when total serum calcium concentration falls below 6–7 mg/dl (1.5 mmol/l), or iCa < 0.6–0.7 mmol/l.
Decreases skeletal muscle activity because the membranes are hyperpolarized, i.e., the resting muscle membrane potential is increased (more difficult to reach the action potential level). Hypokalemic myopathy is commonly seen in cats with renal failure, chronic anorexia and eating low-potassium diets.
Neurological signs are related to the metabolic effects of hypercortisolemia (i.e., catabolic effect of glucocorticoids) resulting in generalized weakness. Pituitary macroadenoma invading into the hypothalamus may cause forebrain signs such as blindness (involvement of the optic chiasm), depression, circling, ataxia and seizures.
A significant percentage of hyperthyroid cats present with decreased ability to jump, reluctance to walk and cervical ventroflexion. However, whether this represents actual peripheral nerve injury, muscle disease or simply metabolic weakness is unclear (human hyperthyroid patients may develop sensorimotor axonal neuropathy).
Thiamine Deficiency (TD)
Vitamin B1 is an essential vitamin. Its phosphate derivatives are involved in many cellular processes (e.g., as a co-enzyme in carbohydrates and amino acids catabolism) and required in the biosynthesis of the neurotransmitter acetylcholine and gamma-aminobutyric acid (GABA). Thiamine derivatives and thiamine-dependent enzymes are present in all cells. The nervous system is particularly sensitive to TD, because of its dependence on oxidative metabolism. TD cause pathologic changes in both CNS and PNS. Cats often display profound weakness characterized by ventroflexion of the head and neck (when picked up cat curls up, and the mandible touches the sternum), central vestibular ataxia, tetraparesis, seizures, mydriasis, blindness, coma and death. Malacia and hemorrhage were found in multiple sites in the CNS. MRI study in TD cats showed characteristic lesions.
Inborn Errors of Metabolism (Storage Disease)
This is a group of genetic disease with lack of or dysfunction of a key enzyme in the neurons, glia and other cells. Dysfunction is associated with direct metabolic disturbance or building up of metabolic wastes inside these cells. Affected kittens are usually born normal then developed progressive multifocal CNS signs. Storage disease can affect many organs but some only affect the myelin thus signs only confined to the nervous system. Due to the delayed development of the cerebellum and its sensitivity to myelin disorders, the cerebellum is often affected by storage disease. Cerebellar ataxia is often noted first. Other clinical signs include weakness, tremors, facial deformity, corneal opacity and spinal fusion. Reported storage diseases in cats: mannosidosis, mucopolysaccharidosis, glycogenosis, sphingolipidosis and lipofuscinosis. Kittens suffered from panleukopenia virus-induced cerebellar hypoplasia usually improve with time or remain stable, in contrast to the storage cats which will inevitably deteriorate.
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