Neurologic Complications of Cancer

• INTRODUCTION RATIONALE for NEURO-ONCOLOGY Neurologic complications are common Neurologic complications are increasing Neurologic complications are serious Diagnosis is difficult Treatment helps Research is essential Biologic relationship of nervous system to cancer CLASSIFICATION OF NEURO- ONCOLOGIC DISORDERS Metastases Nonmetastatic complications Vascular disorders Infections Metabolic and Nutritional disorders Side Effects of Cancer Treatment "Remote Effects"-Paraneoplastic Syndromes APPROACH TO THE PATIENT Patient with known cancer Patient without known cancer EVALUATING THE PATIENT Relevant scales 2: Pathophysiology Of Nervous System Metastases INTRODUCTION PATHOPHYSIOLOGY OF THE METASTATIC PROCESS Transformation and Growth Vascularization (Angiogenesis) Invasion Intravasation (blood vessels, lymph channels) Circulation Arrest 1st capillary bed e.g. lung, liver, bone Passage to arterial circulation Arrest final capillary bed Tumor Emboli Extravasation Dormancy Growth in CNS CLINICAL CONSIDERATIONS RELEVANT TO NERVOUS SYSTEM METASTASIS Tumor Size and lymph node involvement Properties of Metastases Differences between a Primary Tumor and Its Metastasis Site of Metastases Hemodynamic hypothesis-relevance to nervous system metastases Seed and soil hypothesis- relevance to nervous system metastases Subtypes Timing of Metastases The Cascade Process PATHOPHYSIOLOGIC FACTORS RELEVANT TO SPREAD AND GROWTH OF CANCER TO SPECIFIC NEURAL STRUCTURES Brain Spinal Cord Vertebral metastases Foraminal invasion Epidural metastases Consequences of spinal cord compression Leptomeninges Cranial and Peripheral Nerves 3: Blood-Nervous System Barrier Dysfunction: Pathophysiology And Treatment INTRODUCTION ANATOMY AND PHYSIOLOGY Blood-Brain Barrier Blood-Peripheral Nerve Barrier Blood-Cerebrospinal Fluid Barrier DISRUPTION OF BLOOD-CENTRAL NERVOUS SYSTEM BARRIERS Brain Edema Other Sources of Disruption Other Substances Causing Blood-Brain Barrier Breakdown CONSEQUENCES OF BLOOD-BRAIN BARRIER DISRUPTION: INCREASED INTRACRANIAL PRESSURE, PLATEAU WAVES, AND CEREBRAL HERNIATION Treatment of Cerebral Herniation TRANSPORT OF CHEMOTHERAPEUTIC DRUGS ACROSS THE BLOOD-BRAIN BARRIER RESTORATION OF BLOOD-CENTRAL NERVOUS SYSTEM BARRIERS Lowering Intracranial Pressure Corticosteroids Brain metastases Spinal cord compression Corticosteroids for other neurologic complications of cancer Corticosteroid taper Mechanisms of corticosteroid action on blood-brain barrier 4: Supportive Care and Its Complications INTRODUCTION EDEMA/GLUCOCORTICOIDS Salutary effects of corticosteroids Unwanted side effects of corticosteroids MYOPATHY BEHAVIORAL/COGNITIVE SIDE-EFFECTS INSOMNIA HYPERGLYCEMIA BONE DISORDERS LIPOMATOSIS VISUAL PROBLEMS GASTROINTESTINAL DISORDERS Ulceration Bowel Perforation Pneumatosis Cystoides Intestinalis Colonic Ileus Constipation/Diarrhea OTHER SIDE-EFFECTS DRUG INTERACTIONS CORTICOSTEROID WITHDRAWL SEIZURES/ANTICONVULSANTS Incidence and Epidemiology Therapy STATUS EPILEPTICUS PROPHYLATIC ANTICONVULSANTS UNTOWARD EFFECTS of ANTICONVULSANTS Drug interactions Side-effects VENOUS THROMBOSIS/ANTICOAGULANTS PAIN/ANALGESIA Other Sources of Disruption Other Substances Causing Blood-Brain Barrier Breakdown CONSEQUENCES OF BLOOD-BRAIN BARRIER DISRUPTION: INCREASED INTRACRANIAL PRESSURE, PLATEAU WAVES, AND CEREBRAL HERNIATION Treatment of Cerebral Herniation TRANSPORT OF CHEMOTHERAPEUTIC DRUGS ACROSS THE BLOOD-BRAIN BARRIER RESTORATION OF BLOOD-CENTRAL NERVOUS SYSTEM BARRIERS Lowering Intracranial Pressure Corticosteroids Brain metastases Spinal cord compression Corticosteroids for other neurologic complications of cancer Corticosteroid taper Mechanisms of corticosteroid action on blood-brain barrier 4: Supportive Care and Its Complications INTRODUCTION EDEMA/GLUCOCORTICOIDS Salutary effects of corticosteroids Unwanted side effects of corticosteroids MYOPATHY BEHAVIORAL/COGNITIVE SIDE-EFFECTS INSOMNIA HYPERGLYCEMIA BONE DISORDERS LIPOMATOSIS VISUAL PROBLEMS GASTROINTESTINAL DISORDERS Ulceration Bowel Perforation Pneumatosis Cystoides Intestinalis Colonic Ileus Constipation/Diarrhea OTHER SIDE-EFFECTS DRUG INTERACTIONS CORTICOSTEROID WITHDRAWL SEIZURES/ANTICONVULSANTS Incidence and Epidemiology Therapy STATUS EPILEPTICUS PROPHYLATIC ANTICONVULSANTS UNTOWARD EFFECTS of ANTICONVULSANTS Drug interactions Side-effects VENOUS THROMBOSIS/ANTICOAGULANTS PAIN/ANALGESIA PSYCHOLOGICAL DISTRESS/PSYCHTROPIC AGENTS FATIGUE NAUSEA, VOMITING/ ANTI-EMETIC AGENTS INFECTION/ANTIBIOTICS INTENSIVE CARE/ COMMON AGENTS 5: INTRACRANIAL METASTASES GENERAL PRINCIPLES INTRODUCTIONCLASSIFICATION INCIDENCE BRAIN METASTASES (PARENCHYMAL) Source Pathophysiology of Neurologic Symptoms and Signs Pathology Clinical Findings Symptoms and Signs Headache Focal weakness Cognitive/behavioral impairment Seizures Other symptoms Presenting signs Onset of symptoms Laboratory findings MRI Biopsy Other tests Differential diagnosis Approach to patient without known cancer Treatment Symptomatic treatment Corticosteroids Radiation Therapy WBRT Radiosurgery Interstitial radiation Prophylactic radiation Re-irradiation Surgery Chemotherapy Prognosis SPECIFIC TUMORS Small-cell lung cancer Non-small-cell lung cancer Breast Melanoma Renal Colon Testes Gynocologic Sarcomas Hematologic Unknown primary LESS COMMON SITES of INTRACRANIAL METASTASES Calvarium Dura Pineal Choroid Pituitary 6: SPINAL METASTASES INTRODUCTION EPIDURAL METASTASES Frequency Biology of epidural metastases Pathophysiology of symptoms and signs Pathology Clinical findings Pain Local pain Mechanical instability Radicular pain Referred and funicular pain Weakness Upper motor neuron weakness Lower motor neuron weakness Sensory loss Lhermitte sign Autonomic dysfunction Ataxia Unusual symptoms and signs Laboratory examination Plain x-rays Radionuclide bone scans CT Positron emission tomography MRI Myelography Differential diagnosis Epidural hemorrhage Epidural abscess Herniated disk Other epidural masses Treatment Corticosteroids Hyperosmolar agents Hormonal and chemotherapeutic agents Radiation therapy Principles Prognosis Radiosurgery Re-irradiation Back braces and bed rest Surgery Indications for surgery Decision-making and epidural spinal cord compression Specific tumors Prostate cancer Breast cancer Lymphoma/myeloma Lung cancer Other cancers INTRADURAL and INTRAMEDULLARY METASTASES Diagnosis Treatment 7: Leptomeningeal Metastases INTRODUCTION FREQUENCY BIOLOGY OF LEPTOMENINGEAL METASTASES PATHOPHYSIOLOGY OF SIGNS AND SYMPTOMS Hydrocephalus Parenchymal Invasion Ischemia Metabolic Competition Immune Responses Inflammation Blood-Cerebrospinal Fluid Barrier Disruption CLINICAL FINDINGS Cerebral (Brain) Symptoms and Signs Headache Gait difficulty Cognitive dysfunction Episodic loss of consciousness Other cerebral complaints Neurologic signs Cranial Nerve Symptoms and Signs Spinal Symptoms and Signs LABORATORY TESTS Magnetic Resonance Scanning Lumbar Puncture CSF pressure Cell count Protein concentration Glucose concentration Cytologic examination Immunocytochemistry Flow Cytometry Biochemical/molecular Markers Other Diagnostic Tests Myelography Cerebral arteriography Electroencephalography Electromyography Meningeal biopsy Positron emission tomography CSF flow DIFFERENTIAL DIAGNOSIS DIAGNOSTIC APPROACH TREATMENT Radiation Therapy Chemotherapy Route of administration Chemotherapeutic agents Intrathecal agents Systematically administered agents Complications Surgery Complications PROGNOSIS 8: Cancer Involving Cranial, Peripheral Nerves And Muscles INTRODUCTION FREQUENCY CRANIAL NERVES Clinical Findings Olfactory nerve Optic nerve Ocular motor nerves Ocular motor syndromes Trigeminal nerve Gasserian ganglion syndrome Numb chin syndrome Other sites Facial nerve Glosspharyngeal/Vagus nerves Jugular foramen syndrome Syncope Facial pain Spinal accessory nerve Hypoglossal nerve Occipital condyle syndrome Diagnosis and Treatment SPINAL ROOTS NERVE PLEXUSES Cervical Plexus Brachial Plexus Clinical findings Laboratory tests Course Differential diagnosis Treatment Lumbosacral plexus Lumbar plexus Clinical findings Laboratory tests Differential diagnosis Treatment Sacral Plexus Clinical findings Laboratory tests Differential diagnosis Treatment PERIPHERAL NERVES Mononeuropathies Clinical findings Differential diagnosis Polyneuropathy MUSCLES 9: Vascular Disorders INTRODUCTION FREQUENCY PATHOPHYSIOLOGY OF CEREBROVASCULAR DISEASE Hypocoagulation Hypercoagulation CENTRAL NERVOUS SYSTEM HEMORRHAGE Hemorrhage into Brain Metastases Clinical findings Diagnosis Differential diagnosis Treatment Subdural Hemorrhage Clinical findings Diagnosis Treatment Coagulopathic Hemorrhage Intracerebral Hemorrhage Clinical Findings Treatment Spinal Hemorrhage Leukostasis Hyperviscosity Hypertension CENTRAL NERVOUS SYSTEM INFARCTION Atherosclerosis Disseminated Intravascular Coagulation Pathology Incidence Clinical Findings Laboratory Tests Differential Diagnosis Treatment Arterial Occlusion by Extrinsic Tumor Clinical Findings Cerebral Emboli Nonbacterial Thrombotic Endocarditis Clinical Findings Laboratory Tests Pathology Treatment Septic Arterial Occlusions Clinical Findings Pathology Treatment Tumor Emboli Thrombotic Microangiopathy Cerebral Vasculitis Intravascular Lymphoma) Thrombocytosis VENOUS OCCLUSION Compressive Venous Sinus Occlusion Clinical Findings Differential Diagnosis Treatment Venous Sinus Thrombosis Clinical Findings Treatment Prognosis and Sequelae Tumor Emboli OTHER DISORDERS Systemic Thrombophlebitis Episodic Neurologic Dysfunction in Patients with Hodgkin's Disease Systemic Hypotension Air embolism APPROACH TO THE PATIENT 10: Central Nervous System Infections INTRODUCTION PATHOPHYSIOLOGY OF CENTRAL NERVOUS SYSTEM INFECTION Host Defenses Physical barriers Immunologic defenses Multiple defects Infection Sites within the Central Nervous System Meningitis Cerebritis and brain abscess Meningoencephalitis CLINICAL FINDINGS Signs and Symptoms Meningitis General physical examination Neurologic examination Diagnosis Lumbar puncture CSF evaluation Imaging Meningoencephalitis Brain Abscess Vascular Lesions APPROACH TO THE PATIENT SPECIFIC ORGANISMS CAUSING CENTRAL NERVOUS SYSTEM INFECTION IN PATIENTS WITH CANCER T-Lymphocyte and Mononuclear Phagocyte Defects Bacteria Listeria Nocardia Fungi Viruses Varicella-Zoster Varicella Reye's syndrome Zoster Complications Post-herpetic neuralgia Paralysis Myelitis Urinary retention Encephalitis Cerebral vasculitis Multifocal encephalopathy Diagnosis Herpes Simplex Progressive multifocal leukoencephalopathy Cytomegalovirus Other viruses Parasites Toxoplasma Strongyloides Eosinophilic meningitis Neutrophil Defects Enteric bacteria Fungi Aspergillus Zygomycetes Candida Splenectomy or B-Cell Abnormalities Bacteria Streptococcus Pneumonia Cerebrospinal Fluid-Surface Communication Bacteria Parasites Other Infections Infectious endocarditis "Malignant" external otitis 11: Delirium And Metabolic And Nutritional Complications of Cancer INTRODUCTION DELIRIUM ASSOCIATED WITH CANCER Definitions Incidence Pathophysiology Clinical findings Diagnosis Causes of delirium METABOLIC BRAIN DISEASE IN PATIENTS WITH CANCER Incidence Clinical Signs Laboratory Tests Differential Diagnosis Treatment SPECIFIC METABOLIC CAUSES of DELIRIUM Postoperative delirium Drugs Substrate deprivation Hypoxia Ischemia Hypoglycemia Hyperglycemia Sepsis Critical illness weakness Electrolyte imbalance Hypercalcemia Hypocalcemia Hyponatremia Hypernatremia Hypomagnesemia Hypophosphatemia Endocrine and other organ dysfunction Adrenal dysfunction Adrenal failure Adrenal excess Hyper/hypo-thyroidism Organ failure Tumor lysis Lactic acidosis NUTRITIONAL DISORDERS ASSOCIATED WITH CANCER Malnutrition and Cachexia Disorders of Nutrient Deprivation Associated with Cancer Wernicke-Korsakoff syndrome Vitamin B12/Folate deficiency Carcinoid syndrome 12: Side Effects Of Chemotherapy INTRODUCTION CLINICAL FINDINGS AND DIAGNOSIS Peripheral Nervous System Diffuse neuropathy Focal neuropathy Central Nervous System Acute encephalopathy Chronic encephalopathy Other neurologic disorders Non-neurologic toxicity SPECIFIC AGENTS Cytotoxic Agents Alkylating Agents Platinum-based agents Cisplatin Peripheral neuropathy Cranial nerve neuropathy Lhermitte's sign Muscles Hearing/vestibular Visual/ocular toxicity Encephalopathy Nitrosoureas Mustards Ifosfamide Cyclophosphamide Melphalan Chlorambucil Other alkylating agents Busulfan Dacarbazine (DTIC)/ Temozolomide Nitrogen mustard (Mechlorethamine) Procarbazine Mitotane Altretamine (Hexamethylmelamine) Thiotepa Antineoplastic Antibiotics Anthracyclines Doxorubicin Idarubicin, epirubicin,daunorubicin Mitoxantrone Other antibiotics Bleomycin Mitomycin C Dactinomycin (Actinomycin D) Antimetabolites Antifolates Methotrexate (MTX) Aseptic meningitis Encephalomyelopathy Transverse myelopathy Acute/subacute encephalopathy Chronic encephalopathy Pathophysiology Pemetrexed Cytidine analogs Cytarabine (cytosine arabinoside, ara-C) 5-azacytidine/decitabine Gemcitabine Fluorinated pyridmidines 5-fluorouracil Capecitabine Pentostatin Purines and other antimetabolites Adenosine analogs Fludarabine Cladribine Pentostatin Guanine analogs Hydroxyurea Plant Alkaloids Vinca alkaloids Vincristine Vindesine, vinblastine, vinorelbine Podophyllins Etoposide Teniposide Taxanes Paclitaxel, docetaxel Other tubulin binding agents Estramustine Epothilones Miscellaneous Cytotoxic Agents L-Asparaginase Amsacrine Suramin Camptothecins Thalidomide Combination Chemotherapy Anti-neoplastic Hormones Anti-estogens Anti-androgens Biologic Agents Antibodies Cellular therapies Vaccines Cytokines Interleukins Interferons Immune enhancers Immunosuppressive agents Growth factors Erythropoietin Granulocyte stimulating factors Interleukin-11 Keratinocyte growth factor Small molecules Imatinib Gefitinib Sunitnib Sorafenib Lapatinib Tipifarnib Bortezomib Differentiation agents All-trans-retinoic acid/arsenic trioxide Hematopoietic stem cell transplantation Adjuvant agents Amifostine Allopurinol Zoledronic acid 13: SIDE Effects Of Radiation Therapy INTRODUCTION BIOLOGY OF RADIATION DAMAGE Ionization Fractionation Mechanisms of nervous system damage The Linear-Quadratic Concept DIAGNOSIS OF RADIATION-INDUCED NEUROTOXICITY Direct radiation damage to the nervous system Brain Acute encephalopathy Early-delayed encephalopathy Neurologic deterioration Radiation somnolence syndrome Focal encephalopathy Pathogenesis Late-delayed encephalopathy Radiation necrosis Cerebral atrophy Post-irradiation "migraine" Treatment Spinal Cord Acute myelopathy Early-delayed myelopathy Late-delayed myelopathy Progressive myelopathy Lower motor neuron syndrome Spinal hemorrhage Peripheral nervous system Cranial nerves Olfactory nerve Optic nerve Ocular motor nerves Trigeminal nerve Facial nerve Acoustic/Vestibular nerve Lower cranial nerves Peripheral Nerves Brachial plexus Acute brachial plexopathy Early-delayed plexopathy Late-delayed plexopathy Acute ischemic plexopathy Lumbosacral plexopathy Sacral plexopathy Muscle Trismus Dropped head syndrome Indirect radiation damage to the nervous system Radiogenic Tumors Radiation-Induced Vasculopathy Endocrine Dysfunction Combination Radiation and Drugs TREATMENT 14: Neurotoxicity Of Surgical And Diagnostic Procedures INTRODUCTION DISORDERS RESULTING from ANESTHESIA General Anesthesia CNS Complications Postoperative delirium/ Cognitive Dysfunction Peripheral Nerve Complications Regional anesthesia Intubation SURGERY Craniotomy Vascular lesions Infections Seizures Aseptic Meningitis Pneumocephalus Decompression Optic Neuropathy Headache Cerebellar Mutism Craniectomy Defect/CSF leak Electrolyte/other disorders Skull base surgery Spinal Surgery Head and Neck Surgery Breast Surgery Thoracotomy Abdominal/Pelvic surgery Extremity Surgery DIAGNOSTIC PROCEDURES Computed Tomography Lumbar Puncture Cerebral Herniation Intracranial Hypotension Spinal Herniation Spinal Hemorrhage Meningitis Arterial/venous catheters Epidural/intrathecal catheters 15: Paraneoplastic Syndromes INTRODUCTION GENERAL CONSIDERATIONS Classification Frequency Importance Pathogenesis Diagnosis Clinical approach Prognosis Treatment SPECIFIC SYNDROMES Paraneoplastic Cerebellar Degeneration Diagnosis Pathogenesis Pathology Treatment Subacute Sensory Neuronopathy/Encephalomyelitis Hippocampus (Limbic Encephalitis) Hypothalamus Brainstem Cerebellum Spinal cord Dorsal root ganglia Autonomic system Antibodies Treatment Opsoclonus/Myoclonus Spinal Cord Syndromes Myelitis Necrotizing myelopathy Motor neurons syndromes Stiff- person syndrome Cranial Nerves Retinopathy Carcinoma Associated Retinopathy (CAR) Melanoma associated retinopathy Optic neuropathy Peripheral Nerve Syndromes Sensory neuropathy Sensorimotor neuropathy Motor neuropathy Autonomic neuropathy Plasma cell dyscrasias Vasculitic neuropathy Neuromuscular Junction Syndromes Lambert-Eaton myasthenic syndrome Myasthenia gravis Neuromyotonia Muscle Syndromes Inflammatory myopathies Necrotizing myopathy

I would judge that this work may justly be described as a tour de force, a marvellous synthesis.