Ömer aslankan Encephalopathy

1. Metabolic Encephalopathies
Encephalopathy;
is a term that means brain disease, damage, or malfunction.
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symptoms; dementia, seizures, coma, or death.
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Metabolic encephalopathies;
result from systemic illness, such as diabetes, liver disease and renal failure.
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symptoms; of consist of a generalized depression
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They usually develop acutely or subacutely
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There are two major types of metabolic encephalopathy:
1) those due to lack of glucose, oxygen or metabolic cofactors (vitamins, for example)
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2) those due to peripheral organ dysfunction.
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Hypoglycemia
is not in itself a disease but maybe a manifestation of some underlying disease.
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The body responds to the hypoglycaemic state by stimulating the sympathetic nervous system
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(↑ secretion of epinephrine, cortisol and glucagon which have the collective effect of suppressing insulin
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secretion).
hypoglycemic encephalopathy; it is caused from by neurotransmission failure (isoelectric EEG
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stages)
Prolonged hypoglycemia can lead to irreversible brain damage.
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Pyruvate derived from glucose is the major precursor of the acetyl group of ACh
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Inhibition of pyruvate oxidation results in reduced ACh synthesis
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as blood glucose falls lower than 2.5 mM (45 mg/dL), the brain attempts to use internal substrates such as
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glutamate and TCA cycle intermediates as fuels.
If blood glucose levels continue to fall lower than 1 mM (18 mg/dL), ATP levels become depleted.
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Utilization of amino acids such as glutamate and glutamine as alternative energy substrates in moderate to
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severe hypoglycemia results in accumulation of aspartate and ammonia in the brain.
substantial increase in extracellular concentrations of glutamate, GABA and dopamine
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Certain brain structures, in particular hippocampal and cortical structures, are selectively vulnerable to
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hypoglycemic insult.
As hypoglycemia progresses lower than 1 mM (18 mg/dL) and high-energy phosphate levels are depleted, the
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EEG becomes isoelectric, and neuronal cell death ensues
Alterations of neurotransmission mediated by ACh, glutamate, GABA and/or dopamine could contribute to the
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neurological signs and symptoms that characterize moderate hypoglycemia
Pathophysiologic mechanisms responsible for neuronal cell death in hypoglycemia include the involvement of
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glutamate excitotoxicity.
Hypoxia
Deficient oxygen supply at the tissue level
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occurs increase of lactate production and a fall of pH.
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result in diminished neurotransmitter synthesis
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Glutamate and GABA synthesis, are decreased as a result of elevated NADH levels
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Inhibition of pyruvate dehydrogenase diminishes acetylcholine synthesis
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HYPONATREMIC ENCEPHALOPATHY
is commonly defined as a serum sodium concentration below 135 meq/L.
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2. If uncontrolled, hyponatremia may cause increased intracranial pressure, brain herniation and death.
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The major cause; is an osmotic imbalance between extracellular fluid (consequently, brain edema.)
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Symptoms; Headache, lethargy, obtundation and eventually seizures, coma
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vasopressin; Both hyperosmolarity and increased intracranial pressure stimulate vasopressin release and
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intraperitoneal administration of vasopressin antagonists decrease brain volum
HYPERCAPNIC ENCEPHALOPATHY
Respiratory acidosis leads to decreased brain pH.
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Respiratory acidosis is a condition that occurs when the lungs cannot remove all of the carbon dioxide the body
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produces.
Patients with chronic pulmonary disorders may exhibit lethargy, confusion, memory loss and stupor.
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The respiratory acidosis associated with CO2 retention in blood leads to a proportional increase in brain tissue
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[H+].
Acute hypercapnic acidosis leads to an increase in concentrations of glycolytic intermediates above the
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phosphofructokinase step; a decrease below this step is probably due to inhibition of phosphofructokinase by
[H+].
As in hypoglycemia and hypoxia, neurotransmitter-related mechanisms that could contribute to hypercapnic
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encephalopathy include decreased neurotransmitter glutamate and GABA pools and decreased synthesis of
acetylcholine.
Hepatic encephalopathy
is a neuropsychiatric disorder resulting from liver failure.
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in chronic liver failure, on the other hand, is characterized neuropathologically by astrocytic changes
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Neurologically, hepatic encephalopathy evolves slowly.
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symptoms; Anxiety or irritability, Coordination or balance problems, Muscle twitches
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Seizures are occasionally encountered and mortality rates are high.
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Death most frequently results from brainstem herniation caused by increased intracranial pressure
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Liver failure leads to the accumulation of toxic substances in brain. (ammonia and manganese)
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Ammonia; has deleterious effects on brain function by direct and indirect mechanisms.
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concentrations of ammonia to brain preparations results in inhibition of α-ketoglutarate dehydrogenase
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(αKGDH).
αKGDH is a rate limiting enzyme of the TCA cycle and, consistent with decreased oxidation of pyruvate (and α-
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ketoglutarate), both acute and chronic liver failure result in increased brain lactate concentrations.
they are associated with alterations of multiple neurotransmitter systems in the brain.
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Glutamate uptake into cultured astrocytes is reduced by exposure to submillimolar concentrations of ammonia.
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PTBR (peripheral-type benzodiazepine receptor); is expressed in increased amounts in hepatic encephalopathy.
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Activation of the PTBR leads to the production of neurosteroids allopregnanolone
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Bilirubin encephalopathy.
Bilirubin, a product of hemoglobin metabolism, causes brain dysfunction and apoptotic cell death.
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In many premature neonatal infants, high levels of unconjugated bilirubin (UCB) occur in the blood, causing
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jaundice.
Uremic and dialysis encephalopathies.
Uremia; is characterized by retention in the blood of urea, phosphates, proteins, amines and a number of poorly
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defined low-molecular-weight compounds.
symptoms; disturbed sleep patterns, tremor and asterixis
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3. Whereas brain water, K+ and Mg2+ content are normal, Al3+ and Ca2+ concentrations are significantly
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increased
Uremia leads to alterations of the blood–brain barrier.
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Uremia results in increased permeability of the blood– brain barrier to sucrose and insulin; K+ transport is
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enhanced whereas Na+ transport is impaired.
There is an increase in brain osmolarity in acute renal failure due to the increase in urea concentrations.
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Acute renal failure, ATP, phosphocreatine and glucose are increased whereas AMP, ADP and lactate are
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decreased,
In uremic patients both EEG changes and neuropsychiatric symptoms are improved by either parathyroidectomy
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or medical suppression of PTH.
THIAMINE DEFICIENCY (WERNICKE’S)
ENCEPHALOPATHY
Wernicke’s encephalopathy (Wernicke–Korsakoff syndrome); is a neuropsychiatric disorder characterized by
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ophthalmoplegia, ataxia and memory loss.
The condition results from thiamine deficiency.
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the enzyme defect responsible for the ‘biochemical lesion’ was α-KGDH rather than pyruvate dehydrogenase
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(PHDC
α-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose
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oxidation
Thiamine is transported into brain and phosphorylated by the action of thiamine pyrophosphokinase
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Decreased activities of α-KGDH, decreased synthesis of glucose-derived excitatory and inhibitory amino acids
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including glutamate, aspartate and GABA with a concomitant increase in lactate and alanine
Oxidative stress contributes to selective neuronal cell death in thiamine-deficiency
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thiamine deficiency consistently show early damage to glial cells rather than neurons
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increases of expression of eNOS (endothelial nitric oxide synthase)
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PYRIDOXINE (VITAMIN B6) DEFICIENCY
Pyridoxine, in its phosphorylated form, pyridoxal phosphate, is an important coenzyme in several enzymic
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reactions, some of which are involved in neurotransmitter synthesis (e.g. decarboxylation of glutamate to
GABA)
Developing brain is particularly sensitive to pyridoxine deficiency, resulting in impaired synaptogenesis and
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hypomyelination.
Adult animals fed pyridoxinedeficient diets develop learning disabilities, irritability, gait ataxia and seizures; the
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latter develop in parallel with the fall in activity of glutamic acid decarboxylase and GABA synthesis.
COBALAMIN (VITAMIN B12) DEFICIENCY
Cobalamins have two biochemical functions.
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Adenosylcobalamin is the cofactor for the mutase enzyme that converts methylmalonyl CoA to succinyl CoA.
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Methylcobalamin, on the other hand, is a cofactor for the enzyme that converts homocysteine to methionine.
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Cobalamin deficiency occurs relatively commonly in the clinic and involves both hematological and
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neurological changes.
Neurologically, cobalamin deficiency results in paresthesias, loss of sensation and spastic
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