Metabolic Encephalopathy (eBook)

Title Page 3
Copyright Page 4
Preface 6
Contents 8
Contributors 11
Chapter 1 15
Functional Anatomy of the Brain 15
Introduction 15
Protective Structures 15
Organization of the Central Nervous System 17
Vascular Supply 22
Functions of Brain Regions 25
Physically Induced Alterations in Consciousness 26
Conclusion 27
References Cited 28
General References 28
Chapter 2 29
Brain Metabolic Adaptations to Hypoxia 29
Introduction 29
Oxygen, Brain, and Energy Metabolism 29
Hypoxia 30
Acute and Chronic Exposure 30
Metabolic Adaptations to Hypoxia 31
Glucose Metabolism 31
Activation of Glycolysis: Ph Paradox 32
Enzyme Related Changes in Oxidative Metabolism 33
Intrinsic Brain Tissue Oxygen Sensors and Regulators 34
Hypoxic Inducible Factor: Energy Metabolism 34
Brain Metabolic Indicators of Hypoxia: Glucose and Ketone Body Transporters 34
Glutamate Transporters 35
Ketosis and Hypoxia 36
Hypoxic-Tolerance with Ketosis 37
Conclusions 39
References 41
Chapter 3 45
Hypoglycemic Brain Damage 45
Historical Aspects of Hypoglycemia 45
The EEG in Hypoglycemia 46
Neurochemistry 47
Neuropathology 50
References 52
Chapter 4 54
Experimental Ischemia: Summary of Metabolic Encephalopathy 54
Introduction 54
Energy Metabolism in the Brain 55
Biochemical and Physiological Consequences of Experimental Ischemia 56
Flow Thresholds 56
Ischemia Impact on Intermediary Metabolism 58
Triggered Events Secondary to Energy Failure 60
Ion Homeostasis 61
Acidosis 62
Second Messengers 63
Recirculation Postischemia 64
Free Radicals 65
Metabolic Consequence of Reperfusion: Reversal of Ischemic Process? 67
Recovery: Mitochondrial Dysfunction 69
Reperfusion: Molecular Events and Cell Death 71
Necrosis 71
Autophagy 72
Apoptosis 73
Ischemic Neuroprotection 74
Summary 74
References 75
Chapter 5 81
Metabolic Encephalopathy Stroke - Clinical Features 81
Introduction 81
Predictors of Good Outcome 81
Duration of Ischemia 81
Infarct Size and Stroke Severity 82
Collateral Flow 83
Patient’s Age 84
Hyperglycemia and History of Diabetes 84
Hypertension 85
Role of Preconditioning 85
Acute Stroke Treatment 86
Recanalization 87
Neuroprotection 88
Beyond Clot Removal 88
Maintenance of Perfusion Pressure 88
Management of Hyperthermia, Hypothermic Treatments 89
Management of Hyperglycemia 90
Future in Stroke Therapies 90
References 90
Chapter 6 96
The Role of Animal Models in the Study of Epileptogenesis 96
Introduction 96
Epileptogenesis in Human Epilepsies and Experimental Models 96
Hippocampal Sclerosis 98
Animal Models of Epilepsy 99
Post-status Epilepticus Models 100
Pilocarpine Model 101
Perforant Path Stimulation 101
Tetanus Toxin Model 102
The Kindling Model 102
Cellular Alterations During Epileptogenesis 103
Neuronal Loss 103
The Creation of New Circuits: Mossy Fibre Sprouting 104
Growth Factors 106
The Dormant Basket Cell Hypothesis 106
Gliogenesis 107
Neurogenesis 108
Altered Inhibition 108
Non-synaptic Mechanisms in Epileptogenesis 109
Receptor/Acquired Channel Changes 110
GABA A Receptors 110
GABA B Receptors 111
Metabotropic Glutamate Receptors (mGluRs) 111
NMDA Receptors 112
Kainate Receptors 112
Channelopathies 113
Interventions to Prevent Epileptogenesis 113
Initial Insult Modification 113
Neuroprotection to Prevent Epileptogenesis 114
Antiepileptogenesis 114
Conclusion 115
References 115
Chapter 7 124
Seizure-Induced Neuronal Plasticity and Metabolic Effects 124
Introduction 124
Historical Perspective 124
Insights from Experimental Models and Human Studies 125
Neuronal Loss 126
Mitochondrial Dysfunction 128
Role of Free Radicals 129
Activation of Proteolytic and Catabolic Enzymes 129
Neurogenesis 129
Axonal Sprouting and Dendritic Changes 130
Astrocyte Dysfunction 130
Altered Gene Expression 131
Altered Neurotransmitter Receptors Within Epileptic Foci 132
Altered Ion Channel Function 132
Altered Neurochemistry 132
Do Seizures Cause More Seizures? 133
Seizure-Associated Changes in the Developing Brain 133
Contributions of Neuroimaging 134
Volumetric MRI 134
Positron Emission Topography (PET) 135
Magnetic Resonance Spectroscopy (MRS) 135
Diffusion Tensor Imaging (DTI) 135
Functional MRI 136
Clinical Perspective and Future Considerations 137
Conclusion 138
References 139
Chapter 8 147
Metabolic Encephalopathies in Children 147
Metabolic Encephalopathies in Children 147
Inborn Errors of Metabolism 148
Valproate: Induced Hyperammonemic Encephalopathy 148
Hepatic Encephalopathy 149
Astrocytes and Ammonia 149
Therapy for Hyperammonemic and Hepatic Encephalopathy 149
Plasma Filtration or Removal 150
Charcoal Hemoperfusion 151
MARS 151
Hepatocyte Columns 151
Hepatectomy 152
Common Strategies in Hepatic Encephalopathy 152
Diabetic Ketoacidosis 153
Conclusion 156
References 156
Chapter 9 159
Pathophysiology of Hepatic Encephalopathy: Studies in Animal Models 159
Introduction 159
Neuropathology of HE 160
The Astrocyte 160
Neuronal Cell Death in HE 161
Pathogenesis of HE: Role of Blood-Borne Toxins 162
Ammonia 162
Manganese 166
Brain Glucose Metabolism in HE 167
Astrocyte Metabolism and Function in HE 168
Astrocyte Structural Proteins 168
Glutamine Synthesis, the Glutamate-Glutamine Cycle 169
Glutamate and Glycine Transporters 169
“ Peripheral-Type ” Benzodiazepine Receptors, Neurosteroids 171
Astrocyte - Astrocyte “ Crosstalk ” 172
Neurotransmitter Function in HE 173
Glutamate 173
GABA 173
Serotonin 175
Dopamine 176
Histamine 177
Opioid System 177
Oxidative/Nitrosative Stress and Inflammation 178
Nitric Oxide 178
Inflammation 178
Therapeutic Advances 179
Ammonia-Lowering Strategies 179
Neuropharmacologic Advances 180
Hypothermia 181
Liver Support Systems 181
Summary 182
References 183
Chapter 10 191
Hepatic Encephalopathy 191
Clinical Features of Hepatic Encephalopathy 191
Acute Liver Failure 191
Seizures and Intracranial Hypertension are Frequent in Acute Liver Failure 192
Brain Edema: the Most Severe Complication of Acute Liver Failure 193
Prognosis of Acute Liver Failure 196
Encephalopathy Associated with Cirrhosis and Portal Hypertension (Type C) 196
Minimal Hepatic Encephalopathy 198
Chronic Persistent Hepatic Encephalopathy 199
Hepatic Myelopathy 200
Diagnosis and Differential Diagnosis of Type C HE 200
Imaging 200
Laboratory Findings 201
EEG and Evoked Potentials 201
Wernicke’s Disease is the Most Important Differential Diagnosis of HE 201
Diagnosis of Minimal Hepatic Encephalopathy 202
Therapy for Hepatic Encephalopathy 203
References 205
Chapter 11 210
Uremic and Dialysis Encephalopathies 210
Introduction 210
Uremic Encephalopathy 211
Diagnosis of Uremic Encephalopathy 212
Acute Renal Failure 212
Chronic Renal Failure 213
Psychological Testing 214
Biochemical Changes in the Brain 215
Central Nervous System Pathology with Uremia 216
Pathophysiology of Uremic Encephalopathy 217
Uremic Neurotoxins 218
Central Nervous System 218
Guanidine Compounds 219
Advanced Glycation End Products 220
Neurologic Complications of End-Stage Renal Disease and Its Therapy 221
Dialysis Disequilibrium Syndrome 221
Chronic Dialysis Dependent Encephalopathy 222
Radiologic and Pathologic Examination of Uremic Brain 222
Dialysis Dementia 224
Alternative Etiologies 229
Other Central Nervous System Complications of Dialysis 230
Stroke in Patients Treated with Chronic Hemodialysis 231
Sexual Dysfunction in Uremia 234
References 235
Chapter 12 244
Thiamine Deficiency: A Model of Metabolic Encephalopathy and of Selective Neuronal Vulnerability 244
Introduction 244
Thiamine-Dependent Processes are Altered in Multiple Human Diseases 246
Thiamine-Dependent Processes are also Diminished in Animal Models of Neurological Disease 247
TD Models Both the Acute and Chronic Effects of Mild Impairment of Oxidative Metabolism 248
Behavioral Deficits due to TD Precede Neuronal Death (Acute Treatment) 249
TD-Induced Behavioral Deficits are Altered by Age and Genetics 250
Reversal of TD-Induced Behavioral Deficits Provides Insight into Underlying Mechanisms 250
TD-Induced Neurological Deficits that are Not Reversed by Thiamine Administration 251
Impairing Thiamine-Dependent Processes Alters Cholinergic Function and Behavioral Performance, and Induces Cell Death 252
The Temporal Sequence of Selective Neuronal Death in TD Can Be Used to Study Mechanism 252
Immunocytochemical, Histochemical and Message Studies to Evaluate Selective Vulnerability 253
Ex Vivo Studies to Evaluate Selective Vulnerability 255
TD-Induced Changes in Inflammation and Oxidative Stress Support their Role in the Selective Neuronal Death During TD 255
Selective Changes in the Blood-Brain Barrier Suggest that they are Involved in Selective Neurodegeneration 258
Changes in Amyloid Precursor Protein in Response to TD 259
Prevention of Cell Death as a Test of Mechanism 260
The Cellular Basis of Cell Death in Response to Mild Impairment of Oxidative Metabolism (Fig. 12.2 ) 261
Cell Culture 261
Protein Processing 263
Translocation of Proteins to the Nucleus 264
Other Roles of Thiamine May also Be Critical in TD-Induced Cell Death 264
Conclusion 265
References 265
Chapter 13 270
Alcohol, Neuron Apoptosis, and Oxidative Stress 270
Introduction 270
Ethanol Damage and Neuron Loss in the “ Developing ” Brain 270
Ethanol Effects on the Developing Brain 270
Ethanol Elicits Neuron Death 271
Oxidative Stress 271
Oxidative Stress in Biological Systems 271
Ethanol-Related Origins of Oxidative Stress 272
Ethanol and the Adult Brain 273
Ethanol and the Developing Brain 273
Apoptotic Death of Neurons 275
Mitochondria and Apoptosis 275
Caspases 276
Bcl-2 Family Proteins 276
Ethanol Induction of Apoptotic Death of Neurons in the Developing Brain 277
Bcl-2 Family Proteins in Ethanol-Mediated Apoptosis 277
Caspases in Ethanol-Mediated Apoptosis 278
Summary 279
Ethanol-Mediated Apoptosis and Antioxidant Interventions 279
Ethanol and Oxidative Stress-Mediated Apoptosis 279
Neuron Glutathione Homeostasis, a Key Role for Astrocytes 280
Summary and Conclusions 282
References 283
Chapter 14 289
Wernicke’s Encephalopathy 289
Introduction 289
Prevalence 290
Clinical Features 291
Diagnosis 294
Neuroimaging 295
Pathology 296
Role of Thiamine 297
Thiamine Absorption 299
Pathogenesis of Wernicke’s Encephalopathy 300
Treatment 303
Prevention 304
Conclusion 304
References 305
Chapter 15 310
The Genetics of Myelination in Metabolic Brain Disease: The Leukodystrophies 310
Introduction 310
Leukodystrophies 310
Globoid Cell Leukodystrophy (Krabbe Disease) 310
X-linked Adrenoleukodystrophy (X-ALD) 313
Canavan Disease 316
Impacts of Leukodystrophies 319
Economic Impacts of Genetic Metabolic Brain Diseases 319
Social Impacts 319
Conclusion 319
References 320
Chapter 16 327
Bilirubin Encephalopathy 327
Bilirubin Metabolism 327
Bilirubin Toxicity 328
In-Vivo Animal Studies 329
The Gunn Rat Model 330
Human Bilirubin Encephalopathy-Pathology 332
Bilirubin Encephalopathy-Treatment 334
References 335
Chapter 17 339
Infectious and Inflammatory Metabolic Encephalopathies 339
Normal Brain Homeostasis 339
CNS Viral Infections 341
Acute Lytic Infections of the Brain with Focal or Regional Necrosis, Edema and Brain Herniation 341
Acute Viral Encephalopathy Without Significant Necrosis or Inflammation 341
Oxidative Stress from Reactive Oxygen Species/Intermediates 342
Acute Excitotoxicity and Coma 342
Viral Infection and Neuronal Apoptosis 343
Chronic Virus Persistence in the Brain 344
Role of Astrocytes in Viral Encephalitis 344
Hiv Related Encephalopathy 345
West Nile Virus Encephalitis 346
CNS Bacterial Infections 347
Bacterial Meningitis 347
Metabolic Encephalopathy with Systemic Infections/Inflammation 347
Post Infectious Encephalomyelitis 348
Encephalopathy in the Transplant Recipient 349
Progressive Multifocal Leukoencephalopathy 350
Summary 351
References 351
Chapter 18 355
Major Depression and Metabolic Encephalopathy: Syndromes More Alike Than Not? 355
Introduction 355
Metabolic Encephalopathy: A Brief Overview 357
Is Depressive Illness a Metabolic Encephalopathy? 360
Glutamate and GABA in Disorders of Mood and Their Association with Encephalopathy 362
The Role of GABA 363
The Role of Glutamate 363
Depression as an Encephalopathy: Implications for Onset of Antidepressant Action 365
Conclusion 366
References 367
Chapter 19 376
Attention-Deficit/Hyperactivity Disorder as a Metabolic Encephalopathy 376
Attention-Deficit Hyperactivity Disorder 376
Developmental Aspects 376
Genetics 377
Environmental Risk Factors 378
Ubiquitous Nature of ADHD Symptoms 379
Structural Abnormalities 379
Functional Abnormalities 379
Neurophysiology 381
Treatment 382
Animal Models of ADHD 384
Energetics 386
Conclusion 387
References 387
Chapter 20 397
Brain Damage in Phenylalanine, Homocysteine and Galactose Metabolic Disorders 397
Introduction 397
Disorders of Phenylalanine Metabolism 398
Clinical Features 398
Biochemical Defects 398
Pathogenesis of Mental Retardation in Phenylketonuria 400
Laboratory Diagnosis 400
Variant Forms of Hyperphenylalaninemia 401
Treatment 402
Dihydropteridine Reductase Deficiency 403
Clinical Features 403
Biochemical Defects 403
Biopterin Deficiency: Hyperphenylalaninemia 403
Treated PKU 404
Neuropsychological Effects Despite Treatment 405
Factors Related to Neuropsychological Performance in Treated PKU 406
Neuropsychological Tests 407
Phenylketonuria vs Dopamine 408
Animal Studies 410
Phenylalanine vs. Blood – Brain Barrier 411
Brain Magnetic Resonance Spectrometry 415
Conclusion 416
Efficiency of Long-Term Tetrahydrobiopterin Monotherapy in Phenylketonuria 417
Brain Abnormalities in Maternal PKU 417
Disorders of Homocysteine Metabolism 418
Clinical Features 418
Biochemical Defects 420
Pathophysiology 422
Laboratory Diagnosis 423
Treatment 423
Defects in Homocystine Remethylation 423
Defective Activity of N 5 -Methyltetrahydrofolate: Homocysteine Methyl-Transferase and Cobalamin Activation 423
Decreased N 5,10 Methylenetetrahydrofolate Reductase Activity 424
Animal Studies 425
Neuropsychologic Disturbances 428
The Effect of Vitamin Supplementations on Plasma tHcy Concentrations 435
Galactosemia 437
Genetics and Epidemiology 437
Metabolic Derangement and Intoxication 438
Evidence From Animal Models 440
Autopsy Studies 440
Central Nervous System White Matter 441
Influence of Genotype on Cognitive Outcome 442
Acute Neonatal Presentation and Diagnosis Presentation 443
Diagnosis 443
Non-Neurologic Sequelae 443
Neurologic Sequelae 444
Acute Elevated Intracranial Pressure in Infants 444
Cognitive Impairment: Gender Effects and Possible Regression with Age 444
Speech Apraxia Commonly Occurs 445
Motor Function: A Subgroup Develops More Severe Ataxia and Tremor 445
Seizures are Uncommon 445
Pathophysiology of Neurology Dysfunction in Galactosemia 446
Treatment: Standard of Care, Controversies, and Clinical Trials 446
Treatment of Symptomatic Infants – Standard of Care 446
Long-term Nutrition Management: Standard of Care and Recent Issues 446
Effects of Dietary Treatment: Does Strict Dietary Treatment After Early Childhood Improve Adult Outcomes? 447
References 448
Chapter 21 462
Wilson Disease 462
The Wilson Disease Gene 462
He´patic Copper Metabolism and the Role of ATP7B 463
Pathogenesis 465
Clinical Presentations 467
Kayser-Fleischer Rings 467
Liver Disease 468
Acute Wilsonian Hepatitis and Fulminant Wilson Disease 468
Chronic Hepatitis due to Wilson Disease 469
Psychiatric Presentation 470
Other Clinical Manifestations 470
Diagnosis 471
Patients with Neurological Disease 471
Patients with Liver Disease and Hemolytic Anemia 472
Laboratory Parameters 472
Routine Laboratory Parameters of Liver Disease 472
Serum Ceruloplasmin 472
Serum Copper 473
Urinary Copper Excretion 473
Hepatic Copper Content 473
Liver Biopsy 475
Light Microscopy 475
Electron Microscopy 475
Mutation Analysis 475
Direct Mutation Analysis 475
Haplotype Analysis 476
Family Screening 477
Treatment 477
D-Penicillamine 477
Trientine 478
Ammonium Tetrathiomolybdate 479
Zinc 479
Monitoring Therapy 480
Liver Transplantation 480
Prognosis 481
Liver Disease 481
Neurological Disease 482
References 483
Chapter 22 486
Metabolic Abnormalities in Alzheimer Disease 486
Alzheimer’s Disease 486
History 486
Epidemiology 486
Diagnosis 487
Clinical 487
Pathological 487
Presentation and Metabolism 487
beta -Amyloid Precursor Protein 488
Tau 494
Function of Tau 495
Phosphorylation of Tau 496
Abnormal Tau 496
Mitogen-Activated Protein (MAP) Kinases 496
p38 497
c-Jun Kinase (JNK) also called Stress Activated Protein Kinases, SAPK 498
Glycogen Synthase Kinase 3 (GSK3) 498
Cyclin-dependent Kinases 499
cAMP-dependent Protein Kinase A (PKA) 500
Calcium/Calmodium-dependent Protein Kinase II (CaM Kinase II) 500
Casein Kinase 1 (Ck 1) 501
The Presenilins PS1 and PS2 501
Protein Phosphatases 502
Oxidative Stress 504
DNA Oxidation 505
Proteins 505
Hemeoxygenases 506
Glucose 507
Apoe 509
Insulin and Related Factors 510
Concluding Remarks 512
References 512
Chapter 23 534
Prions and the Transmissible Spongiform Encephalopathies 534
Introduction and Overview 534
Transmission of Prion Diseases Between Humans and Animals 535
Gaps and Enigmas in the Prion Concept 536
Prion Disease Prevention 537
The Mechanism of Protein Infectivity 538
Origin and Acceptance of the Prion Hypothesis 540
Function of Normal Prion Protein 541
Mechanism of the Prion Protein Misfolding and Disease 543
Progression from Exposure to Disease 546
Horizontal Spread of Prion Disease 547
Conclusions 547
References 548
Chapter 24 554
Lead Encephalopathy 554
Introduction 554
Clinical Lead Encephalopathy 555
Leaded Gasoline Encephalopathy 557
Delayed Effects in Adults 558
Occupational Exposures 558
Amyloidogenesis 558
Calcification 560
Vulnerability of the Injured Brain 560
Subclinical Effects in Children 561
Mechanisms of Action 563
Mechanisms Proposed for Brain Edema 564
Mechanisms Proposed Developmental Effects 565
Conclusions 566
References 567
Index 575