Cerebral Energy Metabolism and Metabolic Encephalopathy

In recent years, there has been rapid growth in knowledge pertaining to the nervous system. This has, in some measure, been due to the development and application of a number of techniques such as the 2-deoxyglucose method and microchemical methods for measuring metabolites and regional cerebral blood flow. Data from the application of these techniques are just beginning to be collected, and the next few years promise to bring many new and exciting findings. The study of energy metabolism in brain is particularly interesting due to the fact that although the brain has scant energy reserves (as compared with the liver), it has one of the highest metabolic rates in the body. Recent studies from several laboratories have shown a surprising divergence of re­ sponses to metabolic insult in different areas of brain. In this regard, the cer­ ebellum, for example, may have metabolic features which are uniqve from those of any other region. The high-energy phosphate compounds ATP and phos­ phocreatine, supplied by the oxidative metabolism of glucose, are necessary for normal cerebral functions such as the maintenance of membrane potentials, transmission of impulses, and synthetic processes. Interruption of substrate or "poisoning" of the system by a variety of means lead to a rapid change in cellular energetics, and ultimately cell death. From the clinical standpoint, an interesting feature of metabolic encephalopathy is that in many cases, early diagnosis and treatment may result in a rapid reversal of symptoms.

I. Introduction.- 1 Cerebral Energy Metabolism.- 1. Introduction.- 2. Cerebral Energy Requirements.- 3. Blood-Brain Barrier.- 4. Fuels of Cerebral Energy Metabolism.- 4.1. Glucose.- 4.2. Ketone Bodies.- 4.3. Lactate.- 4.4. Amino Acids.- 4.5. Free Fatty Acids.- 5. Study of Cerebral Energy Metabolism at the Tissue Level.- 5.1. Analytic Techniques.- 5.2. Complimentary Autoradiographic Techniques.- References.- II. Metabolic Encephalopathy Associated with Severe Interruption of Substrate.- 2 Hypoglycemia and Cerebral Energy Metabolism.- 1. Introduction.- 2. Normal Glucose Metabolism.- 2.1. Glucose Transport.- 2.2. Glucose Pathways.- 3. Models of Experimental Hypoglycemia.- 3.1. Methods of Induction.- 3.2. Selection of Animals.- 3.3. Histologic, EEG, and Behavioral Changes.- 3.4. Blood Flow and Oxygen Consumption.- 3.5. Hypothermia.- 4. Neurochemical Aspects of Hypoglycemia.- 4.1. Glycolysis.- 4.2. Citric Acid Cycle.- 4.3. Energy Metabolites.- 4.4. Acetylcholine.- 4.5. Cyclic Nucleotides.- 4.6. Amino Acids.- 5. Summary.- References.- 3 Hypoxia.- 1. Introduction.- 2. Delivery of Oxygen to Tissue in Vivo and in Vitro.- 3. Effects of Hypoxia in Man.- 3.1. Changes in Mental Function.- 3.2. Sensory Function in Man.- 3.3. Human EEG and Evoked Potentials.- 3.4. Changes in Cerebral Blood Flow and Cerebral Metabolic Rate for Glucose and Oxygen.- 3.5. Chronic Hypoxia.- 4. Animal Models of Hypoxia.- 4.1. Hypoxic Hypoxia.- 4.2. Hypobaric Hypoxia.- 4.3. Anemic Hypoxia.- 4.4. Histotoxic Hypoxia.- 4.5. Acute versus Chronic Hypoxia.- 4.6. Complications Due to Carbon Dioxide.- 4.7. In Vitro Hypoxia.- 4.8. Ex Vivo Hypoxia.- 5. Physiological Changes in Animal Models of Hypoxia.- 5.1. Animal EEG.- 5.2. Evoked Potentials.- 5.3. Hypoxia and Peripheral Responses.- 5.4. Cerebral Blood Flow and Oxygen Consumption.- 5.5. Behavior and Memory.- 5.6. Histological Changes.- 6. Biochemical Changes during Hypoxia.- 6.1. Glucose Utilization and Cerebral Metabolic Rate for Oxygen.- 6.2. Levels of Energy Metabolites.- 6.3. Redox States.- 6.4. Ionic Changes.- 6.5. Neurotransmitter Metabolism.- 6.6. Cyclic Nucleotide Alterations.- 6.7. Fatty Acids.- 7 Conclusion.- References.- 4 Ischemic Encephalopathy.- 1. Introduction.- 2. Models of Ischemia.- 3. Physiological Response to Ischemia.- 4. Metabolic Changes with Ischemia.- 4.1. Energy Metabolism.- 4.2. Glycolysis.- 4.3. Lactate.- 4.4. Tricarboxylic Acid Cycle and Respiration.- 4.5. Neurotransmitters and Cyclic Nucleotides.- 4.6. Status of the Brain at the Onset of Recirculation.- 5. Recovery after an Ischemic Episode.- 5.1. Cerebral Circulation.- 5.2. Physiological Recovery after Ischemia.- 5.3. Metabolic Recovery.- 6. Regional Response to Ischemia.- 6.1. Biochemical Models of Selective Vulnerability.- 6.2. Physiological Response and Blood Flow.- 6.3. Regional Metabolic Changes during Ischemia.- 6.4. Glucose Utilization.- 6.5. Regional Metabolites.- 7. Miscellaneous.- 7.1. Edema.- 7.2. Treatment Affecting the Outcome of Ischemia.- 7.3. Brain Injury Induced by Ischemia: Is There a Culprit?.- 8. Summary.- References.- III. Metabolic Encephalopathy Resulting Primarily from Intrinsic Factors.- 5 Pyruvate Dehydrogenase Deficiency Disorders.- 1. Introduction.- 2. Inherited Disorders of PDHC.- 2.1. Inherited Disorders of Pyruvate Decarboxylase (E1; EC: 4.1.1.1.).- 2.2. Inherited Disorders of Dihydrolipoyl Transacetylase (E2; EC: 2.3.1.12).- 2.3. Inherited Disorders of Dihydrolipoyl Dehydrogenase (E3; EC: 1.6.4.3).- 2.4. PDHC Abnormalities in Spinocerebellar Disorders.- 2.5. PDHC Deficiency in Leigh’s Subacute Necrotizing Encephalomyelopathy.- 2.6. Other Neurological Disease Associated with PDHC Deficiency.- 3. Acquired Disorders of PDHC.- 4. Pathophysiology of PDHC Deficiency Disorders.- 4.1. PDHC: The Rate-Limiting Step in Cerebral Glucose Oxidation.- 4.2. PDHC in Mammalian Brain during Postnatal Development.- 4.3. PDHC and Cerebral Energy Metabolism.- 4.4. PDHC Deficiency and Neurotransmitter Function.- 4.5. PDHC and Neuronal Plasticity.- 5. Treatment of PDHC Deficiency Disorders.- 5.1. Thiamine.- 5.2. Ketogenic Diets.- 5.3. Dichloroacetate.- 5.4. Other Therapeutic Approaches.- 6. Summary.- References.- 6 Carbon Dioxide Narcosis.- 1. Introduction.- 2. Normal Physiology of CO2.- 2.1. Production of Elimination of CO2.- 2.2. Acid—Base Chemistry.- 2.3. CO2 Metabolism in the Brain.- 3. Clinical, Psychological, and Neurophysiological Aspects.- 3.1. Clinical Manifestations.- 3.2. Medical and Nonmedical Causes of Hypercapnic Acidosis.- 3.3. Amnestic Properties of CO2.- 3.4. Neurophysiological Effects of Hypercapnic Acidosis.- 4. Metabolic Aspects.- 4.1. Rates of Oxygen Consumption and Glucose Utilization.- 4.2. Brain Metabolite Concentrations.- 5. Overview.- References.- 7 Encephalopathy Due to Short- and Medium-Chain Fatty Acids.- 1. Introduction.- 1.1. Definition, Properties, Sources, and Disposition.- 1.2. Clinical Evidence of an Encephalopathic Role for Fatty Acids.- 2. Biochemical Effects.- 3. Pharmacologic Effects.- 3.1. Coma Induction—Energy Metabolism.- 3.2. Ammonia Disposition.- 3.3. Electrical Activity.- 3.4. Endocrine Effects.- 3.5. Synergism with Other Encephalopathic Agents.- 4. Pathophysiologic Role of Fatty Acids in Disease.- 5. Summary.- References.- 8 Encephalopathy Due to Mercaptans and Phenols.- Mercaptans.- 1. Introduction.- 2. Metabolism—Biochemical Effects.- 3. Pharmacological Effects.- 3.1. Toxicity Studies.- 3.2. Coma Induction Studies.- 3.3. Synergism with Other Encephalopathic Agents.- 3.4. Visual-Evoked Potential (VEP) Studies.- 3.5. Urea Formation.- 4. Pathophysiologic Role of Mercaptans in Disease.- 5. Summary.- Phenols.- 6. Introduction.- 7. Metabolism.- 7.1. Origin.- 7.2. Disposition.- 8. Pharmacologic Effects.- 8.1. Toxicity.- 8.2. Cerebral Effects.- 8.3. Abnormality in Liver Disease.- 8.4. Coma Induction and Synergism with Other Toxins.- 9. Pathophysiologic Role of Phenols in Disease.- 10. Summary.- References.- 9 Ammonia-Induced Encephalopathy.- 1. Introduction.- 2. Conditions Associated with Hyperammonemia.- 2.1. Primary Disturbances of Ammonia Metabolism.- 2.2. Secondary Disturbances of Ammonia Metabolism.- 3. Ammonia Metabolism by Noncerebral Tissues.- 4. Neuropathology of Hyperammonemia and Related Disorders.- 5. Physicochemical Considerations.- 6. Neurophysiological Aspects of Hyperammonemia -.- 7. Pathophysiological Aspects of Ammonia Intoxication.- 7.1. Cerebral Blood Flow, Oxygen, and Glucose Metabolism.- 7.2. Metabolic Fate of Ammonia in Brain.- 7.3. Effects of Ammonia on Brain Energy Metabolism.- 7.4. Amino Acids and Biogenic Amines.- 7.5. Toxin Synergism.- 8. Summary.- References.- 10 Bilirubin Encephalopathy.- 1. Introduction-Human Bilirubin Encephalopathy.- 2. Animal Models of Bilirubin Encephalopathy.- 3. The Transport of Bilirubin in the Circulation and Its Mode of Entry into the Central Nervous System.- 4. The Aqueous Solubility and Behavior of Bilirubin.- 5. The Susceptibility of Neonatal Central Nervous System Tissue to Bilirubin Toxicity.- 6. The Cytotoxicity of Bilirubin.- References.- 11 Uremic and Dialysis Encephalopathies.- 1. Introduction.- 2. Uremic Encephalopathy.- 2.1. Definition.- 2.2. Differential Diagnosis.- 2.3. Objective Measurements of Encephalopathic Impairments.- 3. Dialysis-Related Encephalopathic Syndromes.- 3.1. Dialysis Disequilibrium Syndrome (DDS).- 3.2. Dialysis Dementia.- 4. Commentary and Prospect.- References.- 12 Epilepsy: Pathophysiology of Cerebral Dysfunction.- 1. Introduction.- 2. Focal Seizures-Functional Anatomy.- 2.1. Seizures from Neocortex.- 2.2. Seizures from Limbic Cortex.- 2.3. Recurrent Limbic Seizures-Complex Partial Status Epilepticus.- 3. Metabolic Effects of Focal Seizures.- 3.1. Cerebral Energy Metabolism and Blood Flow.- 3.2. Synaptic Function and Structure.- 4. Generalized Seizures.- 4.1. Clinical Picture.- 4.2. Status Epilepticus.- 5. Summary.- References.- IV. Metabolic Encephalopathy that May Result from Extrinsic Factors.- 13 Niacin-Nicotinamide Defici