Disorders of the Nervous System PDF

Here is the conversion of the provided text into a structured markdown format: # 17 Disorders of the Nervous System ## OUTLINE * Congenital Malformations of the CNS, 280 * Cerebral Edema, Herniation, and Hydrocephalus, 280 * Cerebrovascular Diseases, 281 * Cerebral Artery Thrombosis,...

Here is the conversion of the provided text into a structured markdown format: # 17 Disorders of the Nervous System ## OUTLINE * Congenital Malformations of the CNS, 280 * Cerebral Edema, Herniation, and Hydrocephalus, 280 * Cerebrovascular Diseases, 281 * Cerebral Artery Thrombosis, Embolism, and Brain Infarction, 281 * Intracranial Hemorrhage, 282 * Other Vascular Diseases, 283 * CNS Trauma, 283 * Parenchymal Brain Injury, 283 * Chronic Traumatic Encephalopathy, 284 * Perinatal Brain Injury, 284 * CNS Infections, 284 * Prion Diseases, 286 * Demyelinating Diseases, 287 * Multiple Sclerosis, 287 * Other Acquired Demyelinating Disorders, 287 * Leukodystrophies, 287 * Neurodegenerative Diseases, 288 * Alzheimer Disease, 289 * Frontotemporal Lobar Degeneration (FTLD), 289 * Parkinson Disease, 290 * Huntington Disease, 291 * Spinocerebellar Ataxias, 291 * Amyotrophic Lateral Sclerosis, 291 * CNS Tumors, 292 * General Features and Pathogenesis of Astrocytoma, 292 * Classification of Astrocytomas, 292 * Other CNS Tumors, 293 * Inherited Syndromes Associated with CNS Tumors, 294 * Retinoblastoma, 294 * Disorders of Peripheral Nerves, 295 * Peripheral Neuropathy, 295 * Peripheral Nerve Tumors, 295 * Diseases of Neuromuscular Junctions, 295 Diseases of the central nervous system (CNS) have characteristics distinct from disorders of other organ systems. These stem from features unique to the CNS, including the tight physical constraints within the skull, the extreme sensitivity of neurons to hypoxia and other injurious stimuli, and the inability of neurons to regenerate. This chapter focuses on diseases of the brain. Spinal cord involvement is mentioned when relevant. We conclude with a brief discussion of the major diseases of peripheral nerves. ## CONGENTIAL MALFORMATIONS OF THE CNS Congenital malformations of the CNS may result from genetic abnormalities, neonatal or perinatal trauma, or other insults. CNS malformations giving rise to intellectual disability, cerebral palsy, or neural tube defects are seen in an estimated 1% to 2% of births. The underlying cause can be established in only a minority of cases. The malformations may affect different regions of the brain or spinal cord, and are usually associated with severe functional deficits (Table 17.1). Neural tube defects are associated with folate deficiency during the first month of pregnancy. Because this time period precedes the detection of most pregnancies, reduction of risk requires folate sup-plementation throughout a woman's reproductive years. ## CEREBRAL EDEMA, HERNIATION, AND HYDROCEPHALUS These disorders are usually complications of some underlying disease. Their severity reflects the anatomic constraints on the brain. Cerebral edema is the accumulation of fluid in the brain parenchyma. It may Table 17.1 Congenital Malformations of the Brain and Spinal Cord | Defect | Features | | :----------------------------- | :--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | | **Neural Tube Defects** | | | Spina bifida | Outpouching of disorganized segment of spinal cord covered by meninges due to failure of closure of posterior segment of neural tube | | Myelomeningocele | Extension of spinal cord through defect in vertebral column, usually lumbosacral | | Anencephaly | Absence of the forebrain caused by malformation of anterior end of neural tube | | Encephalocele | Outpouching of CNS tissue, usually the occipital region, through a cranial defect | | **Forebrain Malformations** | | | Microcephaly | Small brain in a small cranium; associated with chromosomal abnormalities, fetal alcohol syndrome, Zika virus infection acquired in utero | | Defects in neuronal migration or differentiation | Examples include disruption of normal midline patterns (holoprosencephaly), loss of gyri (liss-encephaly), increased numbers of improperly formed gyri (polymicrogyria) | | **Posterior Fossa Abnormalities** | | | Arnold-Chiari malformation | Small posterior fossa causing misshapen cerebellum and extension of vermis through foramen magnum | | Dandy-Walker malformation | Enlarged posterior fossa, absence of the cerebellar vermis, and a large midline cyst. | **result from** inflammation, ischemic or toxic injury to neurons and glia, or space-filling lesions (e.g., tumors), and typically stems from increased vascular permeability. In the setting of generalized edema, the gyri are swollen and flattened, the sulci are narrowed, and the ventricles are com-pressed. The clinical manifestations range from subtle neurologic defects to loss of consciousness and are usually dictated by the underlying condition. When severe, edema may lead to herniation. Herniation is the displacement of brain tissue from one compart-ment to another because of increased intracranial pressure. It may damage tissue directly or indirectly by compressing blood vessels. There are three types of herniation: * Subfalcine (cingulate) herniation occurs when expansion of one cerebral hemisphere pushes the cingulate gyrus under the falx. It may compress the middle cerebral artery. * Transtentorial (uncinate) herniation occurs when the temporal lobe is compressed against the free margin of the tentorium. Pressure on the third cranial nerve causes pupillary dilation (blown pupil) due to impaired ocular reflexes on the side of the lesion. The posterior cerebral artery may also be compressed, leading to ischemic injury to the primary visual cortex. With progressive herniation, pressure on the midbrain may compress the contralateral cerebral peduncle against the tentorium, resulting in hemiparesis ipsilateral to the side of the herniation. Brain stem compression causes loss of consciousness. Linear or flame-shaped hemorrhages in the midbrain and pons, termed Duret hemorrhages, may occur because of tearing of the vessels in this region. * Tonsillar herniation is displacement of the cerebellar tonsils through the foramen magnum. It causes brain stem compression, resulting in respiratory and cardiac failure. Hydrocephalus is an increase in volume of the cerebrospinal fluid (CSF) within the ventricles of the brain, usually due to obstruction of CSF outflow. When obstruction results in dilation of only the ventricles upstream of the block, it is called noncommunicating hydrocephalus. If the accumulation of CSF occurs secondary to defective absorption (or, rarely, excessive production), all the ventricles are affected (communicating hydrocephalus). If the ventri-cles enlarge because of atrophy of the brain parenchyma, it is called hydrocephalus ex vacuo. When hydrocephalus develops in infancy before closure of the cranial sutures it produces enlargement of the head. Obstruction of CSF outflow may be caused by congenital malfor-mations, tumors, and some infections. It is more common in children than in adults, and may present with headache, behavioral changes, lethargy, and delayed development. ## CEREBROVASCULAR DISEASES The major cerebrovascular disorders are caused by thromboembolic diseases, which lead to infarction, and hemorrhage. Clinically, these conditions are called stroke. They are a leading cause of death and the most preventable cause of neurologic morbidity and mortality. The brain is highly dependent on oxygen. Although the brain constitutes only about 2% of the body weight, it receives 15% of the resting cardiac output and is responsible for 20% of the body's oxygen consumption. Therefore, compromise of the blood supply to the brain has devastating consequences. In this section, we discuss the common causes of stroke and some of the downstream consequences, such as cerebral edema and herniation. ## Cerebral Artery Thrombosis, Embolism, and Brain Infarction Occlusion of the arterial supply to any region of the brain results in liquefactive necrosis, creating an infarct. Pathogenesis. **Arterial occlusion may be caused by** * Embolism, which may be from the heart (e.g., thrombi formed fol-lowing myocardial infarction, atrial fibrillation, and in valvular dis-eases), or from a deep vein thrombus (paradoxical embolism in a patient with a patent foramen ovale). The territory of the middle cerebral artery is the most common site of embolic occlusion. * Thrombosis superimposed on an atherosclerotic plaque in an artery, for example, at the carotid bifurcation, the origin of the middle cerebral artery, or either end of the basilar artery Occlusions may cause infarction of significant areas of the brain. Thrombotic occlusions of small penetrating arteries are usually asso-ciated with hypertension and lead to small, so-called lacunar infarcts. Ischemic injury to the brain may also be the result of global isch-emia without a focal vascular obstruction. Global ischemia results from severe hypotension (blood pressure < 50 mm Hg), as may occur with cardiac arrest and various types of shock. Morphology. Infarcts are typically nonhemorrhagic at the outset, but can evolve into hemorrhagic lesions, especially if the blood supply to the infarcted region is restored. Hemorrhagic infarcts are associated with petechial hemorrhages, whereas nonhemorrhagic infarcts evolve from initial edema to gelatinous, friable tissue followed by liquefaction, leaving a cystic cavity. Microscopically, the earliest changes result from ischemic injury in neurons (cytoplasmic eosinophilia, producing so-called red neurons, and edema), followed by infiltration of neutrophils and then monocytes. Surrounding astrocytes are activated (reactive gliosis). Global ischemia produces similar microscopic changes that are typically widespread. Hypotensive episodes may cause focal infarcts in the most distal areas of the arterial supply (so-called watershed infarcts). Clinical Features. The clinical manifestations depend on the anatomic location of the infarct, together with the effects of cerebral edema, described earlier. Treatment of thrombotic occlusions with fibrinolytic agents within 4.5 hours of the onset of symptoms can reduce or prevent permanent brain injury; thus, rapid clinical and radiological evaluation and diagnosis is critical in patients with suspected stroke. ## Intracranial Hemorrhage Hemorrhages in different compartments of the brain may result from traumatic injury of vessels, vascular injury due to hypertension, or structural abnormalities of vessels such as aneurysms and arteriovenous malformations. Pathogenesis. Hemorrhages may occur in the epidural, subdural, or subarachnoid spaces or within the brain parenchyma (Table 17.2). Each has different underlying causes and distinct clinical manifestations. Trauma is a major cause of vascular injury in the brain because physical displacement of the brain tends to tear vessels. * Epidural and subdural hematomas are almost always secondary to trauma. * Subarachnoid hemorrhage is most often due to rupture of a saccular (berry) aneurysm (described below). Less commonly, the bleed is from a ruptured arteriovenous malformation (AVM). AVMS may be present at birth, but aneurysms usually develop over time. * Parenchymal hemorrhages are usually associated with hypertension causing rupture of small arteries. Morphology. Epidural and subdural hematomas are collections of blood in the cranial space that do not extend into the brain. If the patient survives the acute episode, the hematoma resolves like other collections of blood (see Chapter 3). Hypertensive parenchymal bleeds typically involve the basal ganglia, thalamus, pons, and cerebellum. They compress the adjacent tissue and, over time, are converted into cavities with residual hemosiderin around the edges. Aneurysms are thin-walled outpouchings of arteries. The vast majority are in the anterior cerebral circulation near arterial branch points. They lack a muscular wall and are lined only by intima, so they are prone to rupture, especially during acute increases in intracranial pressure (e.g., when straining at stool or during sexual intercourse). AVMs are tangled networks of vascular tissue, often involving subarachnoid vessels. Clinical Features. The manifestations of different types of hemorrhage are summarized in Table 17.2. Some distinctive features are the lucid interval that may follow a traumatic epidural bleed before the abrupt appearance of neurologic signs; and the sudden, excruciating headache that follows an aneurysm rupture (thunderclap headache) followed by rapid loss of consciousness due to subarachnoid bleeding. Localizing symptoms may also be seen and are related to the area of brain that is affected. Table 17.2 Brain Hemorrhages | Location | Etiology | Additional Features | | :---------------- | :---------------------- | :--------------------------------------------------------------------------------------------------------------------------------------------------------------- | | Epidural space | Trauma | Usually associated with a skull fracture (in adults); rapidly evolving neurologic symptoms require prompt surgical intervention | | Subdural space | Trauma | Level of trauma may be mild; slowly evolving neurologic symptoms, often with a delay from the time of injury | | Subarachnoid space | Vascular abnormalities (AVM or aneurysm) | Sudden onset of severe headache, often with rapid neurologic deterioration; secondary injury may emerge due to vasospasm | | Intraparenchymal | Trauma(contusions) | Typically associated with underlying contusions | | | Hemorrhagic conversion of an ischemic infarction | Selective involvement of the crests of gyri where the brain contacts the skull (frontal and temporal tips, orbitofrontal surface) | | | Cerebral amyloid angiopathy| Petechial hemorrhages in an area of previously ischemic brain, usually following the cortical ribbon | | | Hypertension | "Lobar" hemorrhage, involving cerebral cortex, often with extension into the subarachnoid space | | | Tumors(primary or metastatic) | Centered in the deep white matter, thalamus, basal ganglia, or brain stem; may extend into the ventricular system | | | | Associated with high-grade gliomas and certain metastases(e.g., melanoma, choriocarcinoma, renal cell carcinoma)| ## Other Vascular Diseases Hypertension and amyloid deposition may lead to clinically significant vascular abnormalities in the CNS. With sustained hypertension, small arteries and arterioles show hyaline sclerosis and their walls are weakened. Rupture of affected vessels may result in small or large parenchymal hemorrhages or lacunar infarcts. Sudden severe increases in blood pressure may cause the syndrome of acute hypertensive encephalopathy, in which there is an increase in intracranial pressure and global dysfunction manifested by headaches, confusion, convulsions, and coma. The brain may show edema, necrosis of arterioles, and petechiae. In cerebral amyloid angiopathy, deposits of amyloid in small- and medium-sized arteries weaken their walls, resulting in small hemor-rhages that often occur in the lobes of the cerebral cortex (lobar hemor-rhages). The amyloid is derived from amyloid precursor protein (APP), the same protein that gives rise to amyloid deposits within the brain in Alzheimer disease (described later). Some, but not all, individuals with cerebral amyloid angiopathy also have dementia. ## CNS TRAUMA Trauma to the brain may injure the parenchyma or blood vessels. Vascular trauma was described earlier in the context of cerebral hemorrhage. In this section, we discuss parenchymal injury and two forms of traumatic injury that are unique to the brain. ### Parenchymal Brain Injury When an object impacts the head, brain injury may occur at the site of impact (a coup injury) or opposite the site of impact on the other side of the brain (a contrecoup injury). The latter occurs when the brain strikes the opposite inner surface of the skull after sudden deceleration. Both coup and contrecoup lesions are contusions, hemorrhagic foci of tissue injury and edema caused by rapid tissue displacement, most common in regions of the brain overlying rough and irregular inner skull surfaces (i.e., the orbitofrontal regions and the temporal lobe tips). Grossly, contusions are wedge shaped, with the widest aspect closest to the point of impact. Microscopically, the lesions show evi-dence of neuronal injury (cytoplasmic eosinophilia, nuclear pyknosis) and hemorrhage. Older lesions typically involve the crests of gyri and appear as depressed, yellowish-brown patches with gliosis and residual hemosiderin-filled macrophages. Trauma may also cause more subtle but widespread injury to axons within the brain (called diffuse axonal injury) that can result in coma. The movement of one region of brain relative to another is thought to disrupt axonal integrity and function. This form of injury may underlie some of the CNS dysfunction seen in individuals exposed to explosive blast waves, such as soldiers and victims of terror attacks. Concussion is a clinical term for a reversible change in brain function, with or without loss of consciousness, resulting from head trauma. The characteristic transient neurologic dysfunction includes loss of consciousness, temporary respiratory arrest, and loss of reflexes. ### Chronic Traumatic Encephalopathy Repeated head trauma may lead to cognitive defects, parkinson-ism, and neurodegeneration. Chronic traumatic encephalopathy is now recognized as a distinct disorder in individuals involved in contact sports, and has thus captured the attention of physicians and the lay public. Many of the features seen in neurodegenerative diseases (discussed later) are present in this condition as well, including cortical atrophy and accumulation of neurofibrillary tangles. Patients present with slowly developing dementia, typically years after the trauma. The pathogenesis is not understood. ### Perinatal Brain Injury Cerebral hemorrhages and infarcts in the perinatal period can lead to long-term neurologic deficits. Premature infants are especially susceptible to parenchymal hemorrhages and infarcts. These are mostly in the germinal matrix and may extend to the ventricles. Infarcts typically occur in supratentorial periventricular white matter and when extensive can cause massive destruction and formation of residual cystic lesions. Perinatal injury may lead to the clinical condition called cerebral palsy, which refers to nonprogressive neurologic deficits characterized by spasticity, dystonia, ataxia, and paresis. However, in most cases of cerebral palsy, no specific injuries are identified. ## CNS INFECTIONS A wide range of bacteria, viruses, and fungi can infect the brain parenchyma, causing encephalitis, or the leptomeninges covering the brain, causing meningitis. The host responses to these infectious agents are similar to the reactions in other tissues. Here we discuss the general principles of CNS infections, and then the group of prion diseases that are unique to the CNS. Pathogenesis. **Infectious pathogens enter the brain through one of four routes:** * Hematogenous spread from a distant site: Predisposing conditions include bacterial endocarditis, in which infected vegetations are prone to embolization; congenital heart disease associated with right-to-left shunts and pulmonary arteriovenous shunts, in both instances because of a lack of pulmonary "filter" function; and chronic lung infections, which provide a source of organisms. * Direct implantation of microbes as a result of trauma or (uncommonly) a surgical procedure or lumbar puncture. * Local extension from infected sinuses, osteomyelitis, or an infected malformation, such as a meningomyelocele. * Retrograde spread from peripheral nerves, the major route of infection with rabies and varicella zoster viruses. Both generalized neurologic manifestations (headaches, seizures, coma) and localizing signs may be seen. The analysis of CSF obtained by lumbar puncture is an important part of the diagnostic workup, especially in suspected cases of meningitis. In bacterial infections, the CSF shows increased pressure, increased protein, decreased glucose, and abundant neutrophils. By contrast, in viral infections, there is an early neutrophilic pleocytosis that rapidly converts to a lymphocytosis; the protein concentration is elevated, but the glucose is normal and the pressure is normal or only slightly elevated. Table 17.3 CNS Infections | | Common Organisms | Pathology and Clinical Features| :-----------|:-------------|:------------- Meningitis| | Bacterial| Neisseria, Streptococcus| Headache, neurologic signs; culture maybe positive| Aseptic| presumptive viral agent| Less fulminant, bacterial culture is negative| Chroinc| Fungi, Tuberculosis and Neurosyphilis| Diffuse Inflammation or opportunistic infection in suppressed patients| Encephalitis| | Brain abscess| various bacteria | Discrete and destructive lesions with central necrosis surrounded by granulation in gliosis | Viral|abroviruses Herpesviruses, Polioviruses| cause epidemic encephalitis espically in areas with tropical weather | Fungal and parasitic infection| Candida, Mucor, Aspergillus Toxoplasma |granulomatous inflammation or acquired congenital from birth causes chorioretinitis|