TOXIC and METABOLIC DISORDERS OF THE NERVOUS SYSTEM

HYPOXIC-ISCHEMIC (ISCHEMIC-ANOXIC) ENCEPHALOPATHY The basic disorder is a lack of oxygen and of blood flow to the brain The result of failure of the heart and circulation or of the lungs and respiration Hypoxic-ischemic encephalopathy Under a stable blood flow, the most important element in the delivery of O2 is O2 content of blood

Medical conditions that often lead to HIE 1. Reduction is cerebral blood flow 2. Hypoxia from suffocation 3. CO poisoning 4. Diseases that paralyze the respiratory muscles 5. General anesthesia accident In very simple terms, deficiency of O2 supply to the brain could be due to failure of cerebral perfusion (ischemia), hypoxemia, or insufficiency of Hb (hypoxia) Compensatory mechanism in cerebral hypoxia??? Brain damage in conditions of ischemia??? Brain damage in conditions of anoxia??? The nuclear structures of the brainstem and spinal cord are relatively resistant to anoxia and hypotension and stop functioning only after the cortex has been badly damaged Mechanism of injury is an arrest of the aerobic metabolic processes necessary to sustain the Krebs cycle and the electron transport system which accumulates lactic acid further leading to necrosis Following a cardiac arrest with loss of consciousness, theres complete recovery if oxygenation and circulation is restored within 3-5 minutes Permanent neurologic injury happens if restoration of oxygenation and circulation is >5 minutes Mild degrees of hypoxia without loss of consciousness has no lasting clinical effects and may induce only inattentiveness, poor judgment, and motor incoordination Cortical lesions vs Midbrain lesions oculocephalic reflex (Dolls-eye movements)??? Anoxic patients who demonstrate intact brainstem function have a more favorable outlook for recovery of consciousness and perhaps all of their faculties If the damage is almost total, there is persistence of coma, decerebrate posturing, and a bilateral Babinski sign

Brain Death Syndrome The most severe degree of oxygen lack Complete unawareness and unresponsiveness with abolition of all brainstem reflexes No electrical activity on EEG Blood pressure is maintained but respiration cannot be sustained Anesthesia, intoxication with certain drugs, and hypothermia must be ruled out why??? The presence of fixed, dilated pupils and paralysis of eye movement for 24 to 48 hours along with absence of motor responses to painful stimuli, signify irreversible cerebral damage

Posthypoxic Neurologic Syndromes The permanent neurologic sequelae observed most frequently are as follows:

1. Persistent coma or stupor 2. With lesser degrees of cerebral injury, dementia with or without extrapyramidal signs 3. EPS (Parkinsonian) with cognitive impairment 4. Choreoathetosis 5. Cerebellar ataxia 6. Intention or action myoclonus 7. Korsakoff amnesic state If ischemic hypoperfusion dominates, the patient may also display the manifestations of watershed infarctions, situated between the end territories of the major cerebral vessels

CARBON MONOXIDE POISONING

Carbon monoxide (CO) has a greater affinity for hemoglobin than does oxygen (240x greater) A CO partial pressure of 0.12 mmHg can displace as much as half O2 from hemoglobin The combination of CO to Hb shifts the HbO2 dissociation curve to the left significance??? CO is a toxin in which poisoning causes delayed neurologic deterioration

Patients in burn units, exposure to faulty furnace, and car exhaust Headache, nausea, dyspnea, confusion, dizziness, and clumsiness happens if carboxyhemoglobin (HbCO) is at 20-30% of total hemoglobin Cherry red lips (infrequent), cyanosis (common) Coma, decerebrate and decorticate posturing, seizures, slowing of EEG rhythms happen at 50-60% of carboxyhemoglobin Delayed neurologic deterioration 1-3 weeks after CO exposure occurs more frequently than with other forms of cerebral hypoxia Extrapyramidal signs and symptoms wherein of patients recover within a year Treatment

Initial treatment with inspired oxygen Hyperbaric O2 therapy at 2-3 atmospheres reduces the half life of CO (from 5 hours to 23 minutes) Hyperbaric O2 treatment is recommended at HbCO > 40% or in the presence of coma or seizures

HYPERCAPNIC PULMONARY DISEASE Hypercapnic respiratory failure (Ventilatory failure) can be caused by increased ventilatory dead space, increased CO2 production, or decreased alveolar ventilation Acute vs Chronic??? An elevated PaCO2 increases ventilatory drive in healthy subjects how??? Patient A 60 mmHg 25 mEq/L 7.25 60 mmHg 36 mEq/L 7.38 Patient B

PaCO2 HCO3 pH

DIRECT stimulus to central chemoreceptors increased hydrogen ion levels INDIRECT stimulus to central chemoreceptors increased CO2 levels (CO2 + H2O H2CO3 H + HCO3) DIRECT stimulus to peripheral chemoreceptors decreased PaO2 levels An elevated PaCO2 on top of hypoventilation could be due to the following problems:

1. Respiratory center is not responding normally to the elevated PaCO2 2. Respiratory center may be responding normally but the signal is not getting through the respiratory muscles 3. Despite normal neurological response mechanisms, lungs and chest bellows are incapable of providing adequate ventilation due to parenchymal lung disease or neuromuscular weakness Decreased Ventilatory Drive CNS insult or an overdose of sedative-hypnotic drugs Metabolic alkalosis, malnutrition, sleep deprivation, and hypothyroidism Metabolic encephalopathy or elevated ICP All these things reduce the drive to breath

Respiratory Muscle Fatigue and Weakness Respiratory muscles must be capable of bearing the load for effective ventilation An imbalance of work of breathing imposed on muscles and nutrient supply to the muscles Hypoxemia, decreased inspiratory muscle blood flow, poor nutrition, inability of muscles to extract energy from supplied substrates Neuromuscular diseases, COPD, kyphoscoliosis, obesity, etc

Signs and Symptoms of Hypercapnic Pulmonary Disease Headache, papilledema, mental dullness, drowsiness, confusion, stupor and coma, and asterixis

HYPOGLYCEMIC ENCEPHALOPATHY Preferred Fuels in the Well-Fed and Fasting States Organ/Tissue Well-fed state Fasting state Liver Glucose and amino acids Fatty acids Resting skeletal muscle Glucose Fatty acids, ketones Cardiac muscle Fatty acids Fatty acids, ketones Adipose tissue Glucose Fatty acids Brain Glucose Glucose (Ketones in prolonged fast) RBC Glucose Glucose

Normal brain has a glucose reserve of 1-2 grams mostly in the form of glycogen Glucose is utilized by the brain at a rate of 60-80 mg/min Glucose reserve will sustain cerebral activity for only about 30 minutes once blood glucose is no longer available Glucose entering the brain undergoes glycolysis or is stored as glycogen When blood glucose falls, the CNS can utilize keto acids and intermediates of glucose metabolism such as lactate, pyruvate, fructose, and other hexoses Hypoglycemia at 30 mg/dL results in confusion, nervousness, hunger, flushed facies, sweating, headache, palpitation, trembling, and anxiety which leads to bizarre combative behavior At 10 mg/dL, there will be seizures, profound coma resulting in irreparable brain injury if not corrected immediately

Common Causes of Hypoglycemic Encephalopathy 1. Insulin overdose or an overdose of oral diabetic agents 2. Islet cell insulin-secreting tumor 3. Depletion of liver glycogen due to an alcoholic binge, starvation, various acute liver diseases 4. Glycogen storage diseases 5. Idiopathic hypoglycemia in the neonatal period Treatment of Hypoglycemic Encephalopathy Correction of hypoglycemia at the earliest possible moment Seizures and twitching may not stop with anticonvulsants until the hypoglycemia is corrected

HYPERGLYCEMIA

Two syndromes have been identified mainly in diabetics:

1. Hyperglycemia with ketoacidosis (common in type 1 DM) 2. hyperosmolar nonketotic hyperglycemia (common in type 2 DM) 1. DIABETIC KETOACIDOSIS Plasma glucose > 250 mg/dL, pH < 7.30, HCO3 <15 mEq/L, and moderate ketonemia or ketonuria Results from severe insulin deficiency in association with stress and activation of counterregulatory hormones Ketone bodies are elevated in the blood and urine and there is a marked glycosuria Mild cerebral edema is observed during treatment with fluids and insulin due to accumulation of fructose and sorbitol in the brain Hyponatremia, hyperkalemia, azotemia, and hyperosmolality Dehydration, fatigue, weakness, headache, abdominal pain, dryness of the mouth, fruity-odor breath, respiratory distress, stupor or coma, and Kussmaul breathing

Treatment of DKA Restoration of circulating volume using isotonic saline Insulin therapy Correct electrolyte imbalances

2. NONKETOTIC HYPEROSMOLAR SYNDROME A serious life-threatening complication of type 2 DM Blood glucose > 600 mg/dL Ketoacidosis does not develop or is mild why??? Osmolality > 320 mOsm/L Hemoconcentration and azotemia Precipitating factors include dehydration, stress, infection, stroke, noncompliance with medications, dietary indiscretion, and alcohol and cocaine abuse In contrast to DKA, the onset of NKHS is usually insidious Several days of deteriorating glycemic control are followed by increasing lethargy Clinical evidence of severe dehydration is the rule

Some alterations in consciousness and focal neurologic deficits may be found at presentation or may develop during therapy Although the potassium level may be initially normal or even high, all patients with NKHS are potassium depleted Prerenal azotemia and lactic acidosis can develop

Treatment of NKHS Restoration of hemodynamic stability and intravascular volume by fluid replacement Correction of electrolyte abnormalities Gradual correction of hyperglycemia and hyperosmolarity with fluid replacement and insulin therapy Detection and treatment of underlying disease states and precipitating causes. However, such efforts should not delay fluid replacement and insulin therapy

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