Section XV. The Nervous System

Cerebrovascular accidents (strokes, Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases) are a common cause of death and disability in the United States. They commonly complicate atherosclerotic and hypertensive arterial disease (see Chapter 20: The Blood Vessels). Cranial trauma (Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases) is a major problem in road traffic accidents and is responsible for a significant proportion of deaths in the 10- to 30-year age group.

Bacterial meningitis, cerebral abscess, and viral meningoencephalitis (Chapter 63: The Central Nervous System: II. Infections) are the common infections of the central nervous system. Infections related to AIDS are increasing in prevalence. Alzheimer's disease and Parkinson's disease (Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases) are common causes of severe disability in elderly patients. Neoplasms of the nervous system constitute a significant proportion of cancers in children (see Chapter 17: Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms). In adults, metastatic neoplasms, glial neoplasms (Chapter 65: The Central Nervous System: IV. Neoplasms), and peripheral nerve neoplasms (Chapter 66: The Peripheral Nerves & Skeletal Muscle) occur.

The Central Nervous System

The central nervous system is composed of the cerebral hemispheres, brain stem, cerebellum, and spinal cord. Microscopically, the principal cell types are neurons and neuroglial cells (Table 62-1). Neurons represent the basic functional unit of the nervous system. Each neuron is composed of a cell body plus cytoplasmic processes, including dendrites, which synapse with processes from other neurons, and axons, which carry impulses away from the cell body. The neuron has a large nucleus with a prominent nucleolus and an abundant pale eosinophilic cytoplasm in which the ribosomes form clumped masses (Nissl substance). Neurons are postmitotic (permanent) cells that have no mitotic capability. Neurons are found in the cerebral cortex, the cerebellar cortex, the basal ganglia, and in the nuclei and gray matter of the brain stem and spinal cord.

Neuroglial cells form the supporting connective tissue of the brain that represents the white matter. Neuroglial cells include astrocytes, oligodendroglial cells, and microglial cells. Neuroglial cells are capable of mitotic division and proliferate in a variety of conditions. Ependymal cells are specialized glial cells that line the ventricles and the central canal of the spinal cord.

The Peripheral Nervous System

The peripheral nervous system is composed of cranial and spinal nerves that originate in the brain stem or spinal cord and end in the periphery. The autonomic nervous system, with sympathetic and parasympathetic components, may be regarded as a specialized part of the peripheral nervous system with regulatory functions. Peripheral nerves are usually mixed motor and sensory nerves and are composed of bundles of nerve fibers that have their cell bodies in the motor nuclei (the anterior horn of the spinal cord or cranial nerve nuclei), the sensory nerve root ganglia, or the autonomic ganglia.

Clinical Examination

A detailed neurologic examination is the first step in assessing a patient with neurologic disease. Determination of the type and distribution of neurologic deficit, coupled with intimate knowledge of neuroanatomic pathways, often permits precise localization of the lesion.

Examination of Cerebrospinal Fluid

Lumbar puncture is generally a safe technique that permits collection of cerebrospinal fluid for chemical, microscopic, and microbiologic examination (Table 62-2). Lumbar puncture also permits measurement of the cerebrospinal fluid pressure, but it is contraindicated when increased pressure is suspected (eg, if papilledema is present).

Radiologic Examination

Computerized tomography (CT) and magnetic resonance imaging (MRI) permit evaluation of ventricular size, shifts of neural structures, and mass lesions. Positron emission tomography (PET) permits study of brain metabolism.

Carotid arteriography (injecting a contrast dye into the carotid artery) and ventriculography (injecting a dye into the ventricular system) are less frequently used. Myelography (injecting a dye into the lumbar subarachnoid space) remains a useful technique to evaluate spinal lesions.

Brain Biopsy

In the last decade, stereotactic brain biopsy has become increasingly popular as a means of diagnosis of mass lesions in the brain. This technique utilizes radiographic computer guidance to introduce a small biopsy needle into the mass. The procedure is performed under local anesthesia and is accurate in providing a precise histologic diagnosis of brain neoplasms.

Electroencephalography

The electroencephalogram (EEG) is generated from electrodes placed on the outer surface of the skull. Changes in the brain waves provide evidence of local masses or focal electrical excitability (epilepsy). Demonstration of a flat EEG over 24–48 hours is often used as a criterion for diagnosis of brain death.

The cerebrospinal fluid (CSF) fills the ventricular system of the brain, the central canal of the spinal cord, and the subarachnoid space.

CSF is secreted by the choroid plexuses, which are situated in the lateral ventricles. From the lateral ventricles, CSF passes through the foramen of Monro into the third ventricle and then through the cerebral aqueduct (aqueduct of Sylvius) in the midbrain into the fourth ventricle (Figure 62-1). The fourth ventricle houses the foramina of Luschka and Magendie, which permit the passage of CSF into the subarachnoid space. CSF then passes over the convexity of the brain to the region of the superior sagittal sinus, where it is absorbed into the venous system by the arachnoid villi.

Hydrocephalus

Hydrocephalus is defined as abnormal dilation of the ventricles (Figure 62-2). It is readily diagnosed by computerized tomography. Hydrocephalus may result from (1) increased secretion of CSF, as occurs very rarely with neoplasms of the choroid plexus; (2) obstruction to the flow of CSF, either in the ventricular system or in the subarachnoid space; or (3) failure of absorption of CSF (Table 62-3).

Classification

Anatomic Classification

1. Noncommunicating (obstructive) hydrocephalus occurs when there is an obstruction in the ventricular system that prevents CSF from passing into the subarachnoid space.

2. Communicating hydrocephalus occurs when CSF passes normally out of the ventricular system but either flow is obstructed in the subarachnoid space or reabsorption is reduced.

Functional Classification

1. High-pressure hydrocephalus is due to obstruction to CSF flow. If obstruction occurs after fusion of skull sutures, it causes an increase in intracranial pressure (see below). When it occurs in the fetus or infant before fusion of the sutures, it causes the skull to expand.

2. Low-pressure (or normal pressure) hydrocephalus is uncommon. There is slow dilation of the ventricles associated with free flow of CSF, cerebral atrophy, and dementia. The cause is unknown in most cases.

Increased Intracranial Pressure

Increased intracranial pressure is defined as elevation of the mean CSF pressure above 200 mm water (15 mm Hg) when measured with the patient in the lateral decubitus position. Raised intracranial pressure is a common and important pathologic state; it is a frequent cause of neurologic symptoms and, when severe, can cause death.

Etiology

(Table 62-4)

Due to Obstructive Hydrocephalus: See above.

Due to a Space-Occupying Mass Lesion in the Cranial Cavity

In general, the degree of elevation of intracranial pressure is proportionate to the size of the mass and the rate of expansion. For example, a slowly expanding subdural hematoma is associated with a lesser increase in intracranial pressure than a rapidly expanding extradural hematoma.

Cerebral Edema

Cerebral edema is accumulation of water in the brain.

1. Intracellular cytotoxic cerebral edema is an early manifestation of cell injury resulting from failure of normal energy production. It is most commonly seen in ischemic states.

2. Extracellular vasogenic edema is responsible for most cases of cerebral edema, occurring in infections, trauma, neoplasms, and metabolic disorders. Edema is caused by capillary damage, disruption of the normal blood–brain barrier, and leakage of fluid into the interstitium. New blood vessel formation in neoplasms or in the walls of abscesses causes edema because the new vessels are poorly developed and show increased permeability with lesser degrees of injury than do normal vessels.

Pathology

Raised pressure occurring within the fixed volume of the bony cranial cavity causes displacement of the brain (Figure 62-3).

Supratentorial Lesions

1. Caudal displacement of the entire brain stem may stretch the sixth cranial nerve (causing paralysis of the lateral rectus muscle) and may rupture vessels passing from the basilar artery to the brain stem. The resulting brain stem hemorrhages (Duret's hemorrhages; see Figure 62-4) interfere with vital centers and are a common cause of death.

2. Herniation of the uncinate gyrus of the temporal lobe through the tentorial opening (tentorial herniation) stretches the third nerve, causing eye muscle paralysis, ptosis, and pupillary changes. Compression of the pyramidal tract in the crus cerebri may also occur, causing motor paralysis in the contralateral side of the body.

Posterior Fossa Lesions

Posterior fossa lesions cause herniation of the cerebellar tonsils through the foramen magnum; late supratentorial lesions have a similar effect. Resulting compression of the medulla affects the cardiorespiratory centers, leading to death. Tonsillar herniation is particularly likely to occur if lumbar puncture is performed in patients with markedly raised intracranial pressure.

Clinical Features

Increased intracranial pressure presents with headache, vomiting, and papilledema. The headache is typically described as bursting, is present on waking in the morning, and is increased by coughing and straining, maneuvers that further increase the intracranial pressure. Vomiting is typically effortless, unaccompanied by nausea, and often projectile. Papilledema is edema of the optic disk as shown by ophthalmoscopic (funduscopic) examination of the retina. (The optic nerve is surrounded by a sheath of subarachnoid space into which the raised intracranial pressure is transmitted, thereby interfering with venous drainage of the optic disk and axoplasmic flow in the nerves, leading to edema followed by hemorrhage.) Prolonged papilledema leads to atrophy of the optic disk (secondary optic atrophy) and blindness.

Raised intracranial pressure also produces false localizing signs, caused by displacement of the brain. As noted above, sixth and third nerve palsies, pyramidal tract compression, and brain stem dysfunction are the commonest of these. Hemorrhage into the brain stem may cause unconsciousness and death.

The diagnosis of increased intracranial pressure is made by clinical examination. If increased intracranial pressure is suspected, lumbar puncture should not be performed because of the danger of precipitating tonsillar herniation.

Treatment

Increased intracranial pressure due to a mass lesion should be treated by removal of the mass. In cases of hydrocephalus caused by a lesion that cannot be removed, decompression of the dilated ventricles may be achieved by a ventricular shunt, which directs the CSF through a valved tube to an extracranial location such as the peritoneal cavity.

Increased intracranial pressure caused by cerebral edema may be treated with diuretics such as mannitol and with high doses of corticosteroids administered intravenously. Steroids stabilize the blood–brain barrier and decrease cerebral edema.

Defective Closure of the Neural Tube

Embryology

The central nervous system develops from a specialized part of the dorsal ectoderm known as the neural plate, which in early fetal life folds along its length to form the neural tube. The surrounding mesoderm is destined to form the skull and vertebral column and is covered over by skin.

Defective closure of the neural tube may occur throughout its extent but is most common at either end.

Defective Closure of the Caudal End (Spina Bifida)

Spina bifida is a general term for a group of disorders in which the vertebral arches of the lowest lumbar vertebrae are not fused posteriorly. All forms may be associated with Arnold-Chiari malformation and congenital hydrocephalus (see below). There are several degrees of severity (Figure 62-5).

1. Spina bifida occulta is the mildest form; it is characterized by failure of vertebral fusion only (the vertebral spine is bifid). The overlying skin often shows a dimple, a tuft of hair, or a fatty mass. In a few cases, a congenital dermal sinus passes from the epidermis through the vertebral defect into the spinal canal.

2. Meningocele–More severe degrees of spina bifida are associated with protrusion of a meningeal sac filled with CSF through the vertebral defect (Figure 62-6).

3. Meningomyelocele is a still more serious defect characterized by the presence of parts of the spinal cord in the sac and often associated with severe neurologic defects in the lower extremities, bladder, and rectum.

4. Spina bifida aperta, the most severe—and very rare—form of spina bifida, results from complete failure of fusion of the caudal end of the neural plate. The neural plate lies open on the skin surface. Severe neurologic defects in the legs, bladder, and rectum are invariably present.

Defective Closure of the Cranial End

Neural tube abnormalities at the cranial end are less common. Complete failure of development of the cranial end of the neural tube results in anencephaly, which is incompatible with life.

Occipital meningocele is protrusion of a CSF-filled sac of meninges through the skull in the occipital region. An encephalocele is similar but contains brain matter in the meningeal sac.

Clinical Features

Spina bifida occulta is a common abnormality that is usually asymptomatic and discovered when a radiograph of the lumbosacral spine is obtained. Rarely, these patients have an associated fistulous communication between the skin and the spinal canal that predisposes to recurrent meningitis in childhood. Also rarely, there may be a keratin-filled epidermal cyst in the spinal canal that may leak and cause chemical meningitis.

Meningocele, meningomyelocele, and spina bifida aperta present at birth with a detectable lesion in the lumbosacral region. Meningocele is cystic and translucent; it is not associated with a severe neurologic deficit. Meningomyelocele shows neural structures on transillumination of the cyst and is associated with lower limb weakness and with bladder and rectal dysfunction. Spina bifida aperta appears as a flat lesion in which the open spinal cord is visible; there is a profound neurologic deficit. All of these patients have an increased risk of meningitis and hydrocephalus from the frequently associated Arnold-Chiari malformation.

Anencephaly is incompatible with life after birth. Occipital meningocele and encephalocele are similar to their spinal counterparts. The most common location of the cystic mass is the nape of the neck. When very large, an occipital meningocele may obstruct normal vaginal delivery of the baby.

Antenatal Diagnosis

Raised levels of alpha-fetoprotein (AFP) in the amniotic fluid are of value in the antenatal diagnosis of neural tube defects. Over 95% of fetuses with open defects will show elevation due to leakage of AFP through the skin defect into the amniotic fluid. AFP levels are routinely measured in the amniotic fluid whenever amniocentesis is performed.

Ultrasound examination of the fetus is also an effective method of demonstrating the anatomic abnormality before birth. All of the clinically significant defects can be reliably detected.

Treatment

Meningocele, the most common serious lesion, should be closed soon after birth before infection and ulceration occur. In many patients, surgical drainage of the associated hydrocephalus is required. Neurologic deficit in the legs in meningomyelocele presents a serious additional problem. The neural elements in the cyst are irreversibly damaged, with corresponding neurologic defects. Many of these children require numerous operations to correct deformities resulting from abnormal muscle action. Bladder and rectal incontinence may also be a major problem. Spina bifida aperta has a high mortality rate.

Cerebral Palsy

Cerebral palsy is a common disorder characterized by a disturbance of motor function, usually nonprogressive, that is manifest at birth or presents in early infancy. The term cerebral palsy does not denote a specific disease but rather a variety of nonheritable motor disorders acquired in utero, during the birth process, or soon after delivery. Many patients with cerebral palsy reach adulthood, but life expectancy is often shortened. The following fairly characteristic syndromes are recognized.

Spastic Diplegia (Little's Disease)

Spastic diplegia is characterized by spastic weakness of all four extremities. Two groups are recognized. Spastic diplegia associated with prematurity is characterized by predominant involvement of the legs and is associated with minimal mental retardation. Premature infants have an increased risk of infarction and hemorrhage in the periventricular region. In patients who survive, the necrotic brain undergoes calcification and cystic change. This type of cerebral palsy often can be prevented by expert management of premature infants in neonatal intensive care units. Spastic diplegia associated with full-term delivery and difficult labor is believed to result from intrapartum asphyxia. The infant develops quadriplegia associated with severe mental retardation. The brain shows bilateral ischemic changes in the cortex and white matter.

Infantile Hemiplegia

Infantile hemiplegia usually results from unilateral infection or thrombosis of cerebral vessels that has occurred in utero or soon after birth. Mild mental retardation and convulsions are commonly associated. Pathologic changes consist of ischemic necrosis involving one cerebral hemisphere.

Trisomy 13 (Patau's Syndrome)

Trisomy 13 is characterized by failure of normal development of the forebrain, leading to formation of a brain with a single frontal lobe and a single ventricle (holoprosencephaly), absence of the olfactory bulbs (arhinencephaly), a single median eye (cyclopia, from the Cyclops of Greek mythology), and failure of formation of nasal structures.

Patau's syndrome is usually fatal soon after birth.

Congenital Hydrocephalus

Hydrocephalus is a common abnormality, affecting about 0.1–0.5% of births. It is caused by several different congenital anomalies (Table 62-3).

Aqueductal Stenosis & Atresia

Narrowing of the cerebral aqueduct is the most common cause of congenital noncommunicating hydrocephalus. There is controversy about whether the narrowing represents a primary developmental abnormality or whether it is the result of a perinatal inflammatory process causing gliotic occlusion.

Arnold-Chiari Malformation

Arnold-Chiari malformation is the most common cause of congenital communicating hydrocephalus. It is characterized by elongation of the medulla oblongata so that the fourth ventricular foramina open below the level of the foramen magnum. Cerebrospinal fluid passing from these foramina cannot pass upward to the arachnoid granulation for reabsorption because the subarachnoid space is blocked at the level of the foramen magnum by an associated protrusion of the cerebellum into the foramen.

Arnold-Chiari malformation is commonly associated with flattening of the base of the skull (platybasia), abnormalities in the cervical vertebrae, spina bifida, meningomyelocele, and syringomyelia.

Dandy-Walker Syndrome

Dandy-Walker syndrome is a rare cause of congenital noncommunicating hydrocephalus characterized by failure of development of the cerebellar vermis and obstruction of the fourth ventricular foramina of Luschka and Magendie (Figure 62-1).

Syringomyelia

Syringomyelia is an uncommon disease of adults believed to result from abnormal development of the cervical spine and upper spinal cord. It is characterized by development of fluid-filled spaces in the spinal cord, mainly the cervical cord. Its exact pathogenesis is unknown, but many cases are associated with Arnold-Chiari malformation.

Pathologically, the cystic spaces occupy the central part of the cervical cord and may or may not communicate with the central canal. The spaces are lined by fibrillary astrocytes (gliosis). Clinical effects are quite characteristic, depending on the nerve fibers or tracts destroyed (Figure 62-7).

Hereditary Neurocutaneous Syndromes

Hereditary neurocutaneous syndromes are a group of diseases inherited as autosomal dominant traits that are characterized by multiple hamartomatous lesions in the nervous system and skin (Table 62-5). They are also called phacomatoses.

Generalized Neurofibromatosis (Von Recklinghausen's Disease)

Neurofibromatosis is the most common hereditary neurocutaneous syndrome, with an estimated prevalence of 1:3000 in the United States. Two heritable forms of neurofibromatosis, both autosomal dominant, are recognized: (1) Neurofibromatosis 1 is the classic form of the disease, characterized by numerous neurofibromas in the skin (Figure 62-8) and peripheral nerves, associated with pigmented patches in the skin known as café au lait spots. It results from an abnormal gene carried on chromosome 17. Diffuse proliferation of nerve elements may cause massive enlargement of tissues (elephantiasis neurofibromatosa or Elephant Man disease). Malignant transformation of neurofibromas occurs in 5–10% of cases; and (2) Neurofibromatosis 2, the gene of which is carried on chromosome 22, is characterized by bilateral acoustic neuromas. In both types of neurofibromatosis, other neoplasms of the nervous system such as optic nerve glioma, meningioma, and astrocytoma may occur.

Tuberous Sclerosis (Bourneville's Disease)

Tuberous sclerosis is a rare autosomal dominant disease usually presenting in young adults. The mutant gene has been localized to chromosome 9 in some families. It is characterized by multiple hamartomas in the brain, each composed of abnormal neurons and astrocytes. They form hard cortical nodules that resemble raw potato tubers (hence the name). Intraventricular tumor masses composed of giant astrocytes (subependymal giant cell astrocytoma) may act as space-occupying lesions causing CSF obstruction, hydrocephalus, and increased intracranial pressure. These are benign hamartomas and must be distinguished from malignant astrocytic neoplasms. Mental retardation and epilepsy are common in these patients.

Small skin nodules composed of fibroblastic and vascular proliferation (adenoma sebaceum) involve mainly the face. Larger confluent papular skin lesions called shagreen patches occur over the buttocks. Visceral lesions include rhabdomyoma of the heart, pancreatic cysts, and, most commonly, angiomyolipomas of the kidney (Chapter 49: The Kidney: III. Tubulointerstitial Diseases; Vascular Diseases; Neoplasms).

Von Hippel-Lindau Disease

Von Hippel-Lindau disease, transmitted as an autosomal dominant trait, is characterized by multiple hemangiomas in the retina and brain, a benign neoplasm of the cerebellum called a hemangioblastoma, and cysts in the kidneys and pancreas. The mutant gene is located on chromosome 3. There is an increased incidence of renal adenocarcinoma and pheochromocytoma. Cerebellar hemangioblastoma is associated with erythropoietin secretion, and many such patients develop polycythemia.

Sturge-Weber Syndrome

Sturge-Weber syndrome is very rare. It is characterized by a large unilateral cutaneous angioma (port wine stain) of the face associated with a venous malformation involving the ipsilateral cerebral hemisphere and meninges. Adrenal pheochromocytoma may also be associated. The cerebral angioma leads to cortical atrophy and epilepsy. The angioma is visible radiologically due to its characteristic linear (rail-track) calcification.

The epilepsies are a group of disorders characterized by abnormal electrical discharges in the brain. Epilepsy is common: An estimated 1 million people in the United States are being maintained on lifetime anticonvulsant therapy.

Epilepsies may be classified according to manifestation into partial and generalized epilepsy (Table 62-6). In simple partial epilepsy, the abnormal electrical discharge originates in the cerebral cortex, resulting in stimulation of that area without impairment of consciousness—ie, jacksonian epilepsy is characterized by focal motor seizure activity, and temporal lobe epilepsy is characterized by an abnormal smell or memory phenomenon. In complex partial epilepsy, the seizure begins as a simple partial seizure with evidence of cortical stimulation but is rapidly followed by impairment of consciousness as the abnormal electrical discharge spreads to involve the reticular formation. In generalized epilepsy, the abnormal electrical discharge begins in the reticular formation, leading to sudden loss of consciousness without evidence of local cortical onset.

Two major forms of generalized epilepsy are recognized: grand mal, characterized by loss of consciousness followed by generalized clonic seizure, and petit mal, characterized by brief lapses of consciousness without clonic motor activity. In complex partial epilepsy, the cortical discharge spreads rapidly to the reticular formation and elsewhere, leading to seizures that closely resemble grand mal. In these cases, the initial cortical stimulation represents the aura of the epileptic attack.

Epilepsy may also be classified according to etiology (Table 62-6). Most cases of generalized epilepsy begin in childhood and have no detectable cause (idiopathic epilepsy). There is a familial tendency for the occurrence of idiopathic epilepsy without any well-defined inheritance pattern. Partial epilepsy is frequently caused by a cortical lesion (symptomatic epilepsy). In many cases, the cortical lesion is subtle, ie, many cases of temporal lobe epilepsy are believed to result from cortical scarring as a result of birth injury (mesial temporal sclerosis). However, approximately 30% of patients with partial epilepsy—particularly those occurring for the first time after age 30 years—have a treatable cause, eg, infection, vascular malformation, contusion, brain neoplasm, or granuloma. Approximately 45% of patients with partial seizures who have no surgically treatable lesion are refractory to medical treatment, approximately 360,000 patients in the United States. When an epileptogenic focus can be located in one temporal lobe, surgical removal of that temporal lobe produces improvement in 80% of patients. Mesial temporal sclerosis and cortical ectopia are the commonly found abnormalities in the removed temporal lobes.

Infections of the nervous system are classified according to the infected tissue into (1) meningeal infections (meningitis), which may involve the dura primarily (pachymeningitis) or the pia-arachnoid (leptomeningitis); and (2) infections of the cerebral and spinal parenchyma (encephalitis or myelitis). In many cases, both the meninges and the brain parenchyma are affected to varying degrees (meningoencephalitis).

Acute Leptomeningitis

Acute leptomeningitis is an acute inflammation of the pia mater and arachnoid. Most cases are caused by infectious agents; rarely, release of keratinaceous contents from an intradural epidermoid cyst or teratoma causes a chemical meningitis. When the term meningitis is used without qualification, it means leptomeningitis.

Classification

Acute meningitis may be classified according to etiology.

Acute Bacterial Meningitis

The incidence of bacterial meningitis in the United States is five to ten cases per 100,000 persons per year. Approximately 2000 deaths are reported per year. The bacterium involved varies with the age of the patient and other factors (Table 63-1). About 70% of all cases occur in children under 5 years of age.

Neonatal meningitis is acquired during passage of the fetus through the birth canal. Organisms found in the maternal vagina, commonly Escherichia coli and Streptococcus agalactiae (a group B streptococcus), are responsible.

In children up to 5 years of age, the most common pathogen causing meningitis is Haemophilus influenzae. In adolescents, Neisseria meningitidis (meningococcus) is the most common cause. Streptococcus pneumoniae (pneumococcus) causes meningitis in all age groups. Listeria monocytogenes and gram-negative bacilli are important causes in older, debilitated, and immunosuppressed patients.

Acute Viral Meningitis

Viral meningitis has an incidence of 10,000 cases per year in the United States, and 90% of these occur in patients under 30 years of age. This is a mild, benign illness, which rarely causes death. It is caused most commonly by enteroviruses, mumps virus, and lymphocytic choriomeningitis (LCM) virus. An acute meningitis occurs in 10% of patients with human immunodeficiency virus (HIV) infection, most commonly at the time of seroconversion.

Tuberculous Meningitis

Tuberculous meningitis is typically chronic; however, in the early stages there may be an exudative phase that resembles acute meningitis.

Other Causes

The fungi Cryptococcus neoformans, Histoplasma, Blastomyces, and Candida albicans may cause meningitis in immunocompromised patients. Free-living amebas belonging to the genera Naegleria and Acanthamoeba are rare causes of pyogenic meningitis.

Routes of Infection of the Meninges

Bloodstream spread accounts for the majority of cases; the primary entry site of the organism may be the respiratory tract (N meningitidis, H influenzae, S pneumoniae, C neoformans, many viruses), skin (bacteria causing neonatal meningitis), or intestine (enteroviruses).

Meningitis may also result from direct spread of organisms from an infected middle ear or paranasal sinus, especially in childhood. Meningitis may be associated with skull fractures, especially those at the base of the skull causing free communication between the subarachnoid space and the upper respiratory tract; brain surgery; or lumbar puncture. Organisms may also gain entry through the intact nasal cribriform plate (eg, free-living soil amebas in stagnant swimming pools).

Tuberculous meningitis may occur during severe tuberculous bacteremia (miliary tuberculosis) or as a result of reactivation of a meningeal focus, in which case the patient may have no evidence of tuberculosis elsewhere.

Pathology

Grossly, the leptomeninges are congested and opaque and contain an exudate. Microscopically, acute meningitis is characterized by hyperemia, fibrin formation, and inflammatory cells. In bacterial meningitis, neutrophils dominate (Figures 63-1A and 63-2); in acute viral meningitis, neutrophils are rare and lymphocytes dominate (Figure 63-1B). In acute tuberculous meningitis, there is an inflammatory exudate that contains increased numbers of both neutrophils and lymphocytes.

Clinical Features

Acute meningitis presents with fever and symptoms of meningeal irritation, which include headache, neck pain, and vomiting. Physical examination reveals neck stiffness and a positive Kernig sign (inability to straighten the raised leg because of pain), both of which are due to reflex spasm of spinal muscles, a consequence of irritation of nerves passing across the inflamed meninges.

In general, bacterial meningitis is a serious disease with considerable risk of death while viral meningitis is usually a mild, self-limited infection. Tuberculous meningitis has an insidious onset and a slow rate of progression but is frequently a severe illness with a fatal outcome if not treated.

Diagnosis

The diagnosis is made by examination of the cerebrospinal fluid (CSF), a sample of which is obtained by lumbar puncture. The leptomeningeal exudate becomes admixed with the CSF, which reflects the type of inflammatory response and contains the infectious agent (see Table 63-2 and Chapter 14: Infectious Diseases: II. Diagnosis of Infectious Diseases).

Treatment

Antibiotic treatment is urgent in bacterial and tuberculous meningitis. The initial choice of antibiotic should be based on a presumptive etiologic diagnosis as suggested by the clinical features and CSF findings: chemical examination, type of inflammatory cells present, and Gram or acid-fast stain (Table 63-2). Drug treatment must be started immediately after lumbar puncture with a combination of antibiotics that are effective against all possible causative agents and the choice of drugs reconsidered if necessary when results of culture and sensitivity assays become available.

Viral meningitis usually requires only supportive treatment.

Chronic Meningitis

Chronic meningitis is caused by facultative intracellular organisms such as Mycobacterium tuberculosis, fungi, and Treponema pallidum. It is now relatively uncommon in the United States but more prevalent in parts of Africa, India, South America, and Southeast Asia.

Pathology & Clinical Features

Chronic tuberculous and fungal meningitis are characterized by caseous granulomatous inflammation with fibrosis (Figure 63-1C). Marked fibrous thickening of the meninges is the dominant pathologic feature. The entire brain surface is involved, with the basal meninges more severely affected in cases of tuberculosis. The causative agent may be identified in tissue sections specially stained for acid-fast bacilli and fungi.

The meningovascular phase of syphilis also causes a basal chronic inflammation with marked fibrosis and obliterative vasculitis, with large numbers of plasma cells infiltrating the meninges; granulomas are not present.

Complications of chronic meningitis include (1) obliterative vasculitis (endarteritis obliterans), which may produce focal ischemia with microinfarcts in the brain and brain stem; (2) entrapment of cranial nerves in the fibrosis as they traverse the meninges, resulting in cranial nerve palsies; and (3) fibrosis around the fourth ventricular foramina, causing obstructive hydrocephalus.

Clinically, chronic meningitis is characterized by an insidious onset with symptoms of diffuse neurologic involvement, including apathy, somnolence, personality change, and poor concentration. These symptoms are thought to stem from a concomitant diffuse encephalopathy (Figure 63-1C). Headache and vomiting are less severe than in acute meningitis, and fever is often low-grade. Focal neurologic signs and epileptic seizures result from ischemia, cranial nerve palsies, or hydrocephalus.

Diagnosis & Treatment

The diagnosis is established by lumbar puncture (Table 63-2). Serologic tests for syphilis performed on both serum and CSF are positive in meningeal syphilis. Culture is commonly positive in cases caused by tuberculosis and fungal infection unless the patient has received antibiotics prior to lumbar puncture. Skin tests for tuberculosis and fungal infection are positive unless the patient is anergic.

Antibiotic therapy is indicated once the organism is identified. Treatment begun after extensive fibrosis has occurred does not produce complete recovery.

Cerebral Abscess

Cerebral abscess is a localized area of suppurative inflammation in the brain substance. The cavity contains thick pus formed from necrotic, liquefied brain tissue and large numbers of neutrophils and is surrounded by a fibrogliotic wall.

Etiology

Cerebral abscesses are caused by a large variety of bacteria; several organisms may occur in a single abscess, and anaerobic bacteria such as Bacteroides and anaerobic streptococci are common. Nocardia, Staphylococcus aureus, and gram-negative enteric bacteria may also be isolated.

Cerebral abscesses occur as complications of other diseases (Figure 63-3).

1. Chronic suppurative infections of the middle ear and mastoid air spaces and of the paranasal sinuses. The middle ear is separated from the middle and posterior cranial fossas by thin bony plates that may be eroded by infection. The temporal lobe and the cerebellum are usually involved. Infections of the paranasal sinuses are occasionally associated with frontal lobe abscesses.

2. Infective endocarditis with embolization to brain. These patients commonly develop parietal lobe abscesses, which are often small and multiple.

3. Right-to-left shunts (eg, in patients with congenital cyanotic heart disease) may divert infected systemic emboli to the brain.

4. Suppurative lung diseases such as chronic lung abscess and bronchiectasis are rarely complicated by embolization of infected material to the brain, leading to parietal lobe abscesses.

Pathology

Grossly, a cerebral abscess appears as a mass lesion in the brain. It has a liquefied center filled with pus and a fibrogliotic wall whose thickness depends on the duration of the abscess (Figure 63-4). The surrounding brain tissue frequently shows vasogenic edema.

Clinical Features & Diagnosis

Cerebral abscess presents with (1) features of a space-occupying lesion, including evidence of increased intracranial pressure (headache, vomiting, papilledema) and focal neurologic signs, depending on the location of the abscess; (2) features relating to the source of infection, such as chronic otitis media, suppurative lung disease, and endocarditis; and (3) general evidence of infection, such as fever, rapid (elevated) erythrocyte sedimentation rate, and weight loss in chronic cases.

In untreated cases, the abscess progressively enlarges and may cause death from increased intracranial pressure or rupture into the ventricular system.

The diagnosis of cerebral abscess is made clinically and confirmed by computed tomography (CT) scan or magnetic resonance imaging (MRI). Lumbar puncture is dangerous because of the risk of precipitating tonsillar herniation. The CSF may be normal or may show mild increases in protein, neutrophils, and lymphocytes (Table 63-2). CSF cultures may or may not be positive.

Treatment

Surgical evacuation of the abscess followed by antibiotic therapy is effective treatment and has reduced the previously high mortality rate of cerebral abscess to about 5–10%.

Viral Encephalitis

The frequency of viral encephalitis is difficult to estimate. In the United States, about 1500 cases are reported every year. Most of these are presumptive diagnoses—the etiologic virus is identified in only about 30% of cases. Worldwide, many cases of acute cerebral dysfunction in which no attempt is made to identify a virus probably go unreported.

Epidemics of encephalitis are most commonly the result of arthropod-borne viruses (arboviruses), mainly togaviruses and bunyaviruses (Table 63-3). Arboviruses have animal hosts, are transmitted to humans by arthropod bites, and have a distinctive geographic distribution. Sporadic cases of encephalitis may be caused by a large number of other viruses, most commonly herpes simplex virus.

Pathology

The virus usually reaches the brain via the bloodstream. It infects brain cells, causing neuronal necrosis and marked cerebral edema, which in turn leads to acute cerebral dysfunction and increased intracranial pressure. Perivascular lymphocytic infiltration (perivascular cuffing) is characteristic (Figure 63-5). In severe cases, hemorrhages occur.

Clinical Features

Viral encephalitis has an acute onset with fever, headache, and signs of brain dysfunction, the nature of which depend on the areas of brain involved. Convulsions may occur. There may be papilledema if cerebral edema is severe. In many cases of viral encephalitis, there is concomitant meningeal inflammation causing neck stiffness and CSF abnormalities typical of viral meningitis. The diagnosis is based on the clinical picture. Lumbar puncture with examination and culture of CSF may provide an etiologic diagnosis.

Treatment

Therapy is supportive. Control of cerebral edema with high doses of corticosteroids is important in preventing death in the acute phase from increased intracranial pressure. The mortality rate from severe viral encephalitis is high, and patients who recover are frequently left with permanent neurologic deficits due to irreversible neuronal necrosis.

Herpes Simplex Encephalitis

Incidence & Etiology

Herpes simplex encephalitis occurs in 3 classes of patients:

Neonates are infected during delivery to a woman with active genital herpes. The presence of herpes genitalis in the mother is an absolute indication for cesarian section. Herpes simplex type 2 is responsible for most cases.

Adults are infected through the bloodstream from a minor focus of viral replication, usually in the mouth. Herpes simplex type 1 is commonly involved.

Immunocompromised persons, particularly patients undergoing chemotherapy for the treatment of cancer, have an increased susceptibility not only to become infected by herpes simplex virus but also to develop viremia and encephalitis.

Pathology

Herpes simplex encephalitis affects the temporal and inferior frontal lobes selectively, producing a necrotizing, hemorrhagic acute encephalitis that may rapidly cause death. Patients who survive frequently suffer permanent neurologic defects, the nature of which depends on the neuronal loss.

Diagnosis

The diagnosis may be made by brain biopsy, which shows cerebral edema, necrosis, lymphocytic infiltration, and the presence of intranuclear Cowdry A inclusions in infected cells. Electron microscopy or, preferably, immunohistochemical or in situ hybridization tests demonstrate the virus in the majority of cases (Figure 63-6).

Treatment

Treatment of herpes simplex encephalitis with antiviral agents such as vidarabine improves prognosis if undertaken early.

HIV Encephalitis

HIV is a neurotrophic virus that causes subacute encephalitis characterized pathologically by small nodules composed of demyelination, reactive astroglial proliferation, and infiltration by lymphocytes and microglial cells. These microglial nodules occur in about 30% of patients with acquired immunodeficiency disease (AIDS). Their relationship to the occurrence of dementia in AIDS patients is uncertain.

Poliomyelitis

Poliomyelitis is caused by the poliovirus, an enterovirus transmitted by the fecal–oral route. The virus enters the body through the intestine (Figure 63-7) and infects the brain and spinal cord via the bloodstream. Poliomyelitis was once common but has become rare worldwide because of routine immunization during childhood. Poliomyelitis is expected to be eradicated in the early part of the next century.

The poliovirus selectively infects (1) the meninges, producing acute lymphocytic meningitis; and (2) the lower motor neurons in the anterior horn of the spinal cord and medulla oblongata. Loss of motor neurons causes acute paralysis of affected muscles. The paralysis is typically asymmetric and flaccid, with muscle atrophy and loss of deep tendon reflexes. With time, the atrophic muscles may undergo fibrous contracture.

Poliomyelitis is a very serious disease associated with a significant mortality rate in the acute phase, when paralysis of respiratory muscle results in failure of ventilation. Patients who survive are commonly left with permanent muscle paralysis.

Rabies

Rabies is rare in humans but occurs in a variety of wild animals and domestic pets, including dogs and cats, in whom it causes a fatal illness called hydrophobia characterized by abnormal behavior, difficulty in swallowing, and convulsions. Humans are infected when bitten by an infected animal. The rabies virus enters the cutaneous nerve radicles at the site of inoculation and passes proximally to the central nervous system. The incubation period is 1–3 months and is shortest in facial bites.

Rabies virus causes a severe necrotizing encephalitis that maximally affects the basal ganglia, hippocampus, and brain stem. Infected neurons show diagnostic eosinophilic intracytoplasmic inclusion bodies (Negri bodies). The virus can also be identified in the infected cells by electron microscopy and immunoperoxidase techniques.

Clinically, rabies presents with fever and generalized convulsions that are precipitated by the slightest of sensory stimulations such as a gust of wind, a faint noise, or the sight of water. Death is inevitable.

Because there is no treatment, prevention is essential and consists of controlling the disease in wild animals, rabies immunization of domestic pets, and administration of antirabies vaccine to humans immediately after viral exposure.

Cytomegalovirus Encephalitis

Cytomegalovirus infection of the brain occurs in the fetus during the last trimester of pregnancy as a result of transplacental infection. Periventricular necrosis and calcification lead to microcephaly and mental retardation; chorioretinitis is common. Cytomegalovirus encephalitis also occurs in immunocompromised persons, particularly patients with AIDS.

Progressive Multifocal Leukoencephalopathy (PML)

PML is caused by Jamestown Canyon (JC) virus, a specific serologic type of human papovavirus, and occurs particularly in patients with AIDS and those undergoing chemotherapy for cancer.

PML is characterized pathologically by widespread focal demyelination of cerebral white matter. Giant atypical astrocytes and intranuclear inclusions in oligodendroglial cells are typically present, along with a lymphocytic infiltrate. The JC virus can be identified by immunohistochemical techniques.

Clinically, PML presents as an acute, rapidly progressive illness associated with multifocal cerebral dysfunction. The diagnosis can be established by brain biopsy. The mortality rate is high.

Subacute Sclerosing Panencephalitis (SSPE)

SSPE is an uncommon disease that affects children several years after a known attack of measles. Boys are five times more commonly affected than girls. The measles virus, which has been demonstrated in the cerebral lesions of SSPE, is the causal agent, and SSPE is therefore regarded as a chronic measles virus infection. The exact mechanism by which the virus causes encephalitis is unknown. Immunologic factors may play a role, or there may be some alteration of the measles virus itself. The incidence has declined following measles vaccination.

Pathologically, SSPE is characterized by degeneration of neurons in the cerebral gray matter and basal ganglia. Intranuclear inclusions are present in infected cells, and measles virus particles are present on electron microscopy. The white matter shows demyelination, reactive astrocytic proliferation, and perivascular lymphocytic infiltration.

Clinically, patients present with personality changes and involuntary myoclonic-type movements. The disease is relentlessly progressive, causing extensive brain damage and leading to death, usually within 1–2 years after onset.

Prion (Slow Virus) Infections

Creutzfeldt-Jakob disease and kuru are infections of the human brain that are characterized by a long latent period after infection followed by a slowly progressive disease ending in death. Scrapie, an encephalopathy in sheep and goats, and bovine spongiform encephalopathy (BSE), or mad cow disease) in cattle are apparently animal counterparts. All of these diseases were once thought to be caused by slow-acting viruses because material remained infectious after passage through a filter sufficiently fine to exclude all bacteria. In the early 1980s, evidence began to accumulate that these diseases might be caused by an agent consisting solely of protein, a prion (for proteinaceous infectious particle). The mode of transmission and whether or not activation of host genes is involved in pathogenesis remain unclear. About 10% of cases of Creutzfeldt-Jakob disease may be inherited as a dominant trait; a gene responsible for production of prion proteins has been located in chromosome 20.

Creutzfeldt-Jakob disease has occurred in patients who had received transplants of infected tissue (eg, corneal and dural transplants). It is also important medically because the infectious agent is resistant to inactivation by formalin; this imposes a great risk of infection on pathologists and other medical personnel who handle infected tissues. Historically, Creutzfeldt-Jakob disease mainly affects persons 50–75 years old and occurs worldwide. The recent correlation of cases in younger persons in Great Britain with an outbreak of BSE in cattle that has been given feed containing protein derived from sheep carcasses has caused investigators to focus on possible transmission between species. Kuru has occurred mainly among cannibalistic tribes in Papua New Guinea, where the disease is believed to be transmitted by the ritualistic practice of eating brain tissue from deceased persons. The incidence of kuru is rapidly decreasing.

Clinically, patients present with confusion and dementia followed by ataxia. Symptoms progress slowly but relentlessly to a fatal outcome. There is no treatment.

Pathologically, both Creutzfeldt-Jakob disease and kuru are characterized by slowly progressive degeneration of the brain, with neuronal loss, demyelination, and spongiform change in the cerebral white matter. There is no inflammatory cell infiltration. Kuru tends to affect the cerebellum and is characterized microscopically by the presence of kuru plaques, which are amyloid bodies with radially arranged spicules. The plaques appear to consist of filaments of prion protein.

Neurosyphilis

Congenital syphilis and adult syphilis in its late tertiary phase may involve the nervous system in many ways (Table 63-4); it has, however, become relatively rare following the use of penicillin in the treatment of early syphilis.

The parenchymatous and meningovascular lesions of late syphilis may occur together in a given patient or separately. Parenchymatous disease may affect the cerebral cortex (general paresis) and the spinal cord (tabes dorsalis). Spirochetes are present in the brain in general paresis but not in the spinal cord in tabes dorsalis. Penicillin may prevent progression of neurosyphilis but will not reverse deficits already present (Table 63-4; see also Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases).

Granulomas of the Brain

Typical infectious granulomas due to Mycobacterium tuberculosis or fungi occur rarely in the brain. Tuberculomas represent a common mass lesion of the brain in countries such as India that have a high prevalence of tuberculosis. Granulomas present as mass lesions with increased intracranial pressure and focal neurologic signs depending on the location of the mass. Clinically and on radiologic examination, they resemble neoplasms. The diagnosis is made by biopsy, which shows typical histologic changes. The organisms can be identified with special stains and by culture.

Toxoplasmosis

Toxoplasma gondii is a protozoal parasite that has its definitive cycle in the intestine of cats. Humans become infected through contact with cat feces containing infective forms of the parasite. Cerebral toxoplasmosis occurs in two distinct forms, congenital and acquired.

Congenital Toxoplasmosis

Fetal infection with T gondii occurs transplacentally in the third trimester of pregnancy. The organism infects the fetal brain and the retina, leading to extensive necrosis, calcification, and gliosis. Many infants die soon after birth, and those who survive have a variety of defects such as microcephaly, hydrocephalus, mental retardation, and visual disturbances. Toxoplasma pseudocysts can be identified in the brain and retinal lesions.

Acquired Toxoplasmosis

Acquired toxoplasmosis rarely causes cerebral lesions in normal individuals. It may, however, occur as an opportunistic infection in patients with AIDS and in other patients with deficient cell-mediated immunity.

Cerebral toxoplasmosis in AIDS is characterized by the presence of multiple necrotic lesions ranging in size from 0.5 to 3 cm. Toxoplasma pseudocysts and tachyzoites may be seen in biopsies of lesions. Diagnosis in tissues is aided by staining for Toxoplasma antigens by immunoperoxidase techniques.

Clinically, patients present with fever and symptoms of acute cerebral dysfunction. Computerized tomography shows ring-enhancing mass lesions that are often multiple. Treatment with anti-Toxoplasma agents is effective.

Other Parasitic Diseases

Other parasitic diseases rarely involve the brain in the United States. In other countries, the following parasitic diseases occur commonly:

1. Cerebral malaria, due to Plasmodium falciparum.

2. African trypanosomiasis (sleeping sickness). This is caused by Trypanosoma rhodesiense in East Africa and Trypanosoma gambiense in West Africa.

3. Cysticercosis, due to the larval form of Taenia solium, the pork tapeworm.

4. Hydatid cyst, due to the larval form of Echinococcus granulosus.

5. Trichinosis, due to Trichinella spiralis.

6. Schistosomiasis, due to Schistosoma haematobium and Schistosoma mansoni (in the Middle East).

7. Amebiasis, due to Entamoeba histolytica, which causes brain abscesses. Free-living amebae of the genera Acanthamoeba and Naegleria are rare causes of meningoencephalitis.

Cerebral Injuries

Penetrating (Open) Injuries

Penetrating injuries are caused by gunshots and severe blunt trauma. They are associated with severe brain damage and a high incidence of infection. The symptoms and sequelae depend on the extent and area of damage.

Nonpenetrating (Closed) Injuries

Nonpenetrating injuries, usually caused by blunt trauma, may produce several degrees of damage.

Cerebral Concussion (Commotio Cerebri)

Cerebral concussion is transient loss of cerebral function—in most definitions including loss of consciousness—that immediately follows head injury. It is probably the result of relative motion between the brain stem and the cerebral hemispheres, causing temporary neuronal dysfunction in the reticular formation. The brain shows no gross or histologic abnormality.

Concussion is frequently associated with loss of memory for events occurring shortly before the traumatic episode (retrograde amnesia) or immediately afterward (posttraumatic amnesia). Recovery from concussion may be followed by recurrent headache, impaired ability to concentrate, and other minor neurologic symptoms (postconcussion syndrome). These symptoms are usually transient but in some cases may persist for years.

Cerebral Contusion

Rupture of small blood vessels in the brain near its surface and extravasation of blood into the brain substance is most commonly caused by movement of the brain relative to the skull (acceleration–deceleration injuries), causing it to strike bony prominences within the skull, such as those in the floor of the anterior cranial fossa or the internal occipital protuberance (Figure 64-1). Contusions also occur in the brain subjacent to the point of impact, particularly if there is a depressed skull fracture. Contusions may also occur on the side opposite the point of impact (contrecoup injuries).

Cerebral contusions appear initially as an area of subpial hemorrhage. Like an ordinary contusion (bruise) anywhere on the body, the lesion undergoes color change from red to brown as iron is deposited in the tissues. Cerebral contusions may serve as the focus for subsequent epileptic activity.

In rare patients who died of prolonged coma after a head injury, the only autopsy abnormality is surface contusion. In these patients, it is likely that widespread axonal disruption caused by shearing forces at the time of injury is responsible for the severe neurologic deficit. Such axonal shearing produces minimal microscopic changes and is difficult to demonstrate.

Cerebral Laceration

The most severe type of brain injury is tearing of cerebral tissue, resulting in acute hemorrhage in the subarachnoid or subdural space. Cerebral laceration is often associated with profound neurologic dysfunction and with a high mortality rate.

Spinal Cord Injuries

Spinal cord injuries result from forced movements (such as the whiplash injury of the cervical cord) or vertebral fractures and subluxations. Road traffic accidents, diving into shallow water, and sports injuries are common causes.

The basic injuries in the spinal cord are similar to those in the brain: concussion, contusion, and laceration. Their clinical effects, however, are often more severe because of the concentration of neural pathways in the spinal cord. With high cervical cord injury, quadriplegia occurs; death may result from respiratory muscle paralysis. Thoracic cord injuries may lead to paraplegia and dysfunction of the bladder and rectum.

Meningeal Tears

Meningeal tears occur with fractures of the base of the skull and are manifested clinically as a leak of cerebrospinal fluid through the nose (CSF rhinorrhea) or ears (CSF otorrhea). The diagnosis of fluid draining from the nose or ear as cerebrospinal fluid may be made by chemical examination (low protein content and presence of glucose—unlike mucus, which is high in protein and contains no glucose). The main risk is that the tear will serve as a pathway for infection.

Traumatic Intracranial Hemorrhage

Acute Extradural Hematoma

Extradural (epidural) hematoma is one of the most common and most important complications of nonpenetrating head injuries. It is an accumulation of blood between the skull and the dura (Figure 64-2). In 90% of cases, bleeding is from a branch of the middle meningeal artery. In the remainder, the bleeding is of venous origin. Laceration of the middle meningeal artery is often associated with fracture of the temporal region of the skull.

With arterial bleeding, the hematoma expands rapidly, and symptoms appear within hours after injury; with venous bleeding, progression is less rapid.

The clinical history is characteristic. After a head injury—often associated with a variable period of concussion—the patient appears normal for several hours. After this lucid interval, the patient develops evidence of increased intracranial pressure with headache, vomiting, altered consciousness, and papilledema. Tentorial herniation rapidly follows, with oculomotor nerve palsy (pupillary inequality appears first, followed by failure of reaction to light) and pyramidal tract compression. Compression of the brain stem follows, resulting in changes in heart rate, blood pressure, and respiration. Coma and death rapidly ensue in untreated cases.

This condition requires urgent diagnosis because treatment by surgical evacuation of the blood clot and hemostasis is successful if undertaken early.

Chronic Subdural Hematoma

Chronic subdural hematoma is a common lesion characterized by accumulation of blood in the subdural space, separated from the brain by the arachnoid and subarachnoid space (Figure 64-2). It occurs mainly in elderly patients with some degree of cerebral atrophy. The amount of trauma required is minimal, and many patients give no history of head injury.

Bleeding is the result of rupture of veins passing from the cerebral cortex to the superior sagittal sinus. Rupture occurs when there is movement of the brain relative to the fixed superior sagittal sinus and is most likely when cerebral atrophy is present. Chronic subdural hematomas are frequently bilateral.

Bleeding is slow and often can be quickly controlled by normal hemostatic mechanisms. The blood clot in the subdural space then breaks down and exerts an osmotic effect, drawing fluid from the adjacent subarachnoid space. This imbibed fluid causes the lesion to expand slowly, compressing the brain.

Grossly, chronic subdural hematoma contains fluid of a brownish color and is lined by dura on one side and a new fibrous “membrane” on the leptomeningeal side. The thickness of this “false membrane” is proportionate to the duration of the hematoma.

Clinically, patients present with slowly increasing intracranial pressure, causing headache, vomiting, papilledema, and fluctuating levels of consciousness. Compression of the underlying brain may cause focal epileptic convulsions and neurologic symptoms, most commonly contralateral spastic paralysis. With prolonged but less severe compression, atrophy of the brain occurs and causes dementia.

Treatment by surgical evacuation of the fluid collection is curative. Return of brain function is variable, depending upon the duration and degree of cerebral atrophy that has occurred.

The term stroke denotes a wide variety of nontraumatic cerebrovascular accidents of abrupt onset. So defined, stroke has many causes (Table 64-1; Figure 64-3); cerebral thrombosis with infarction is responsible for about 90% of cases. Stroke is one of the leading causes of death and morbidity in developed countries, accounting for approximately 200,000 deaths per year in the United States and 80,000 in Great Britain. Five percent of persons over 65 years in the United States suffer a stroke, and over 400,000 persons per year are released from hospitals after surviving a stroke.

Ischemic Strokes (Cerebral Infarction)

Etiology

Atherosclerosis and Thrombosis

Cerebral thrombosis resulting from atherosclerotic arterial disease is responsible for most cases of cerebral infarction. Atherosclerosis tends to involve the large arteries (Figure 64-4). Sites of arterial branching (such as the carotid bifurcation) and curvature (the carotid siphon in the petrous temporal bone) tend to show severe atherosclerosis. Small arteries on the surface of the brain are rarely affected.

The circle of Willis at the base of the brain is a highly effective anastomotic system between the carotid and vertebrobasilar arteries. Occlusions proximal to the circle of Willis are usually compensated for by the collaterals in the circle. Arteries distal to the circle are functionally end arteries, and their occlusion usually results in cerebral infarction.

Atherosclerosis may have several consequences: (1) narrowing in excess of 75% causes a significant decrease in blood flow; (2) thrombosis may occlude the artery—the most common site for thrombosis is at the carotid sinus and bifurcation; and (3) ulceration of an atherosclerotic plaque releases emboli into the distal circulation. These emboli are commonly composed of cholesterol or small platelet aggregates and may give rise to transient ischemic attacks (see below). Infarction follows any of the above if the blood supply falls below critical levels for a sufficiently long time.

Embolism

Small cerebral emboli are difficult to identify during life or at autopsy; they may be responsible for many cases of “nonocclusive” infarction. Recognizable emboli occur (1) after myocardial infarction due to detachment of mural thrombi; (2) with infective endocarditis due to detachment of valvular vegetations; (3) with prosthetic cardiac valves; (4) with mitral stenosis and atrial fibrillation; and (5) with atherosclerotic disease in the aortic arch, carotids, or circle of Willis.

Hypoxic Encephalopathy

Prolonged hypoxia, usually secondary to hypotensive shock, results in cerebral necrosis. This may be widespread in severe hypoxia, producing extensive autolysis of brain in patients whose lives are maintained artificially (respirator brain). With lesser degrees of hypoxia, selective necrosis of the most susceptible cells—neurons in the deep cortical gray matter—results. This necrosis of a layer of neurons in the cortex is called laminar necrosis. A similar lesion complicates severe hypoglycemia.

Other Causes

Rarely, cerebral ischemia is the result of vasculitides such as polyarteritis nodosa and giant cell arteritis affecting cerebral arteries (Table 64-1). Cerebral venous occlusion is a rare cause of stroke but an important one because it occurs in hypercoagulable states or in severe dehydration and is treatable if diagnosed early.

Pathology

The earliest gross change after infarction occurs at about 6 hours and is a softening of the brain with loss of the normal demarcation between gray and white matter (Figure 64-5). Microscopically, the neurons show nuclear pyknosis, cytoplasmic eosinophilia, and liquefaction. Glial cells disappear, and the myelin sheaths and axis cylinders in the white matter disintegrate.

At 48–72 hours the cerebral infarct is fully formed, appearing as a pale, soft area composed of liquefied necrotic cells. The surrounding brain shows edema. Ten to 20 percent of cerebral infarcts are hemorrhagic, due possibly to restoration of blood supply to the infarcted area, either by fibrinolysis or by fragmentation of the thrombus.

After a transient phase of neutrophil infiltration, macrophages appear in large numbers (Chapter 1: Cell Degeneration & Necrosis). They phagocytose the dead tissue, becoming converted to large cells with abundant pale foamy cytoplasm called gitter cells or compound granular corpuscles.

After about 3 weeks, the debris has been cleared, producing a cystic fluid-filled cavity (Figure 64-6) surrounded by a zone of reactive gliosis.

Clinical Features

Cerebral infarction is characterized by a sudden loss of neurologic function corresponding to the area involved (Table 64-2). The onset may be acute but is usually not as explosive as in cerebral hemorrhage. In many cases the neurologic deficit progresses over several hours to days. Infarction secondary to thrombosis has a slower onset than that caused by embolism.

Most patients with infarction also show evidence of increased intracranial pressure due to the presence of edema around the infarct. The edema may cause additional neurologic deficits that are reversible—unlike the deficit produced by the infarct itself.

Treatment & Prognosis

Treatment is supportive. In the acute phase, corticosteroids and diuretics such as furosemide and mannitol are used to decrease cerebral edema and intracranial pressure.

The overall prognosis for recovery of neurologic function after cerebral infarction is reasonably good. Even in patients in whom the initial deficit is severe, considerable improvement may occur, with reversal of cerebral edema and recovery of function by ischemic but not necrotic neurons.

Transient Ischemic Attacks

Transient ischemic attacks are caused by (1) low flow states in patients with widespread atherosclerotic narrowing of cerebral arteries, and (2) platelet or cholesterol emboli originating from ulcerative atherosclerotic plaques in the carotid arteries or even the aorta. The neurologic dysfunction depends on the area of brain affected. Attacks last a few seconds to a few minutes; by definition, recovery occurs within 24 hours. The frequency of attacks varies from several times a day (common in low flow states) to once in several months (typical of embolic episodes). In patients with embolic episodes, the diagnosis may be established by observing the embolic fragments in the vessels of the optic fundus. Cholesterol emboli have a bronze appearance, whereas platelet emboli are white. The brain shows no pathologic changes.

The occurrence of transient ischemic attacks indicates the presence of severe atherosclerosis in the cerebral arteries. Thirty percent of such patients will suffer cerebral infarction within 5 years; conversely, 30% of patients with cerebral infarction give a history of transient ischemic attacks. Patients with transient ischemic attacks should therefore be evaluated for surgically correctable vascular disease or for anticoagulant therapy. Aspirin has been used with some success in the treatment of transient ischemic attacks.

Hypertensive Encephalopathy

Hypertensive encephalopathy results from cerebral ischemia due to arterial spasm precipitated by extremely high blood pressure, usually in patients with malignant hypertension. Spasm is temporary and results in cerebral edema, usually with minimal or no necrosis.

Patients develop acute transient neurologic dysfunction, convulsions, and increased intracranial pressure. The condition requires immediate treatment to reduce blood pressure and decrease cerebral edema; recovery is then the rule.

Hemorrhagic Strokes

Several factors may contribute to cerebral hemorrhage (Table 64-1). The site of the bleeding distinguishes intracerebral hemorrhages (small arteries deep in the brain substance, eg, lenticulostriate arteries) from subarachnoid hemorrhage (larger arteries traversing the subarachnoid space). In practice, the bleeding site may not be identifiable in large hemorrhages that involve both subarachnoid space and brain substance, and the distinction is then somewhat arbitrary.

Spontaneous Intracerebral Hemorrhage

Cerebral hemorrhage is responsible for about 10% of strokes. Over 80% of intracerebral hemorrhages are secondary to hypertension. Most occur after age 40 years, and the most common site is around the basal ganglia and internal capsule from rupture of the lenticulostriate arteries (Figure 64-4).

Less commonly, intracerebral hemorrhage may result from rupture of arteriovenous malformations, particularly important as a cause in patients under 40 years of age. Rupture of a mycotic aneurysm complicating infective endocarditis, acute bleeding into a cerebral neoplasm, and bleeding diatheses such as thrombocytopenia and coagulation disorders are rare causes of intracerebral hemorrhage (Table 64-1).

Pathology

The site of rupture is frequently a microaneurysm (Charcot-Bouchard aneurysm) in the lenticulostriate arteries. Multiple microaneurysms occur at this location in a significant number (70%) of hypertensive patients (Figure 64-4). Rupture is commonly precipitated by a sudden increase in blood pressure. The rapidly expanding blood clot dissects and destroys brain tissue and may rupture into the ventricular system or subarachnoid space. Blood in the cerebrospinal fluid causes meningeal irritation.

The expanding hematoma (Figure 64-7) acts like a space-occupying lesion, causing rapid and marked increase in intracranial pressure and displacing brain substance. Tentorial herniation is common and may cause death by compressing the brain stem.

Recovery from intracerebral hemorrhage is followed by breakdown of the blood and necrotic brain tissue, leading to an area of gliosis and cystic change that appears brown because of the numerous hemosiderin-laden macrophages.

Clinical Features

Intracerebral hemorrhage results in abrupt onset of headache, dense neurologic deficit, papilledema, and loss of consciousness (cerebral apoplexy). Because bleeding is commonly in the region of the basal ganglia, hemiplegia from pyramidal tract involvement in the internal capsule is the most common neurologic deficit. Cerebral hemorrhage is associated with a high mortality rate.

Spontaneous Subarachnoid Hemorrhage

Spontaneous subarachnoid hemorrhage is less common than spontaneous intracerebral hemorrhage and usually (95% of cases) results from rupture of a berry aneurysm (saccular aneurysm) of the cerebral arteries.

Berry aneurysms are also called congenital aneurysms, although they are not present at birth. There is, however, a congenital defect of the media of the artery, which becomes the site of the aneurysm in later life. Berry aneurysms are commonly located in the circle of Willis. The common sites are the anterior communicating artery (30%), the junction of the posterior communicating and internal carotid arteries (30%), the middle cerebral artery (10%), and the basilar artery (10%). In 10–20% of cases, multiple berry aneurysms are present (Figure 64-4).

Pathology

Rupture of a berry aneurysm may occur at any time but is rare in childhood. The frequency of rupture increases with age. Hypertension and atherosclerosis result in further weakening of the aneurysm and predispose to rupture. Actual rupture of an aneurysm may be precipitated by exercise (one of the recognized complications of jogging) and sexual intercourse. Many aneurysms never rupture and are found incidentally at autopsy.

When aneurysms rupture, they usually cause rapid bleeding into the subarachnoid space (Figure 64-8). Many aneurysms leak a little blood before they burst, leading to adhesions between the wall of the aneurysm and adjacent structures. If such adhesions tether the aneurysm to the brain surface, final rupture of the aneurysm may occur into the substance of the brain, presenting as an intracerebral hemorrhage rather than a subarachnoid hemorrhage.

Intact berry aneurysms may become large enough to cause focal symptoms, eg, third nerve paralysis due to compression by a large posterior communicating artery aneurysm.

Clinical Features

Subarachnoid hemorrhage presents with sudden onset of severe “bursting” headache associated with vomiting, pain in the neck, and rapid loss of consciousness. Marked neck stiffness is present as a result of the meningeal irritation caused by the blood. Increased intracranial pressure with papilledema is common. Blood courses along the subarachnoid sheath around the optic nerve and may be visible ophthalmoscopically as an area of hemorrhage in the retina below the optic disk.

The diagnosis is made clinically. Computerized tomography and magnetic resonance imaging are useful in demonstrating the blood as well as the aneurysm in many cases. Lumbar puncture, which may be performed after the presence of a mass lesion in the brain has been excluded, shows the presence of blood in cerebrospinal fluid.

Death may occur rapidly. In patients who recover, there is a high risk of recurrence, and surgical correction is urgent.

Venous Occlusion

Occlusion of cerebral veins and venous sinuses is an uncommon cause of cerebrovascular accident. In general, venous drainage of the brain has many collaterals, and occlusion of a large vein is necessary before clinical effects are produced.

Superior sagittal sinus thrombosis may occur in severely malnourished or chronically sick individuals. It is characterized by edema, hemorrhage, and infarction involving both cerebral hemispheres.

Thrombophlebitis of the cortical cerebral veins occurs rarely in women after childbirth or abortion. When extensive, it causes fever, convulsions, and infarction of the cerebral hemisphere.

Thrombosis of the vein of Galen (internal cerebral vein) leads to hemorrhagic infarction of the thalamic region and deep white matter.

Cavernous sinus thrombophlebitis may result from spread of infection from the face and orbit and is associated with high fever, leukocytosis, orbital edema, congestion, and hemorrhage. This disorder presents with marked proptosis with pain and can result in blindness.

Lateral sinus thrombophlebitis may occur as a complication of suppurative otitis media. It is accompanied by severe bacteremia and associated with high fever and pain in the back of the head.

Demyelination is a common degenerative change in the nervous system. It is most often secondary to neuronal or axonal injury, but in the group of diseases known as the demyelinating diseases, demyelination is the primary pathologic process (Table 64-3).

Multiple Sclerosis

Multiple sclerosis is the most common demyelinating disease. Its incidence varies greatly in different parts of the world, being most common in the Scandinavian countries, with a prevalence of 80:100,000 in Norway. The incidence progressively declines as one moves south (10:100,000 in southern Europe). A similar distribution is seen in the United States, with Massachusetts having a higher incidence than Florida. Multiple sclerosis is rare in the tropics (1:100,000) and in Asia, even in the northern latitudes of Japan.

Individuals who migrate in early childhood from a low-risk to a high-risk area have the same risk of developing multiple sclerosis as those in the country to which they move. If the same move is made after adolescence, the risk remains low. This suggests that environmental factors operating during childhood are responsible for causing multiple sclerosis; it has been postulated that infection by an as yet unidentified virus in childhood may be followed by a 10- to 20-year latent period prior to disease manifestation.

The onset of multiple sclerosis is usually in the years from 20 to 40. Sixty percent of patients are female. There are racial differences in incidence within the same geographic area (Caucasians more commonly affected than African-Americans or Native Americans). There is an increased familial incidence, a 25% concordance in identical twins compared with 2–3% in fraternal twins, and an association with human leukocyte antigen (HLA)-B7 and -DR2, all suggesting an undefined role for genetic factors.

Etiology

Multiple sclerosis is currently thought to be the result of an immunologically mediated demyelination, possibly acting via damage to oligodendroglial cells, which are consistently absent in lesions. There is activation of macrophages and T lymphocytes and increased immunoglobulin synthesis in both blood and cerebrospinal fluid during the active phase of the disease. Activated T lymphocytes are present in the lesions of multiple sclerosis.

Attempts to isolate a virus from brain tissue of multiple sclerosis patients have failed. Electron microscopy has not shown virus particles. Despite this, a viral infection or a virus inciting an abnormal immune reaction have not been excluded as a possible cause of multiple sclerosis. An outbreak of multiple sclerosis in the Faroe Islands off Northern Scotland provided strong epidemiologic evidence for an infectious origin.

Pathology

Multiple sclerosis is characterized by the presence in the white matter of plaques of demyelination. These plaques are perivenular and appear as irregular, well-demarcated, gray or translucent lesions with a diameter varying from 0.1 cm to several centimeters. Multiple plaques, widely disseminated throughout the central nervous system, are common (Figure 64-9).

Any area of the brain can be affected. Sites of predilection are the optic nerves, paraventricular regions, brain stem, cerebellum, spinal cord, and deep cerebral white matter.

Microscopically, the plaques show demyelination (best seen in sections stained for myelin) and tangled masses of preserved axons (best seen in silver-stained sections). Lymphocytic infiltration is present in areas of active and recent demyelination. Macrophages are present and contain phagocytosed myelin. There is reactive astrocytic proliferation at the edges of the plaque. Oligodendroglial cells are typically absent in the plaque.

Clinical Features

Multiple sclerosis is a chronic disease with an extremely variable clinical course, characterized by episodic relapses and remissions over several years. Mean survival is over 30 years after the onset of disease. A minority of patients have a rapid course to death within months, and some appear to have only one or a few episodes from which they recover and have no further relapses.

The clinical manifestations depend on the area of brain affected and are therefore extremely varied. Common manifestations are abnormalities in vision, cerebellar dysfunction, paresthesias, weakness, and spinal cord dysfunction. The randomly disseminated nature of the lesions gives a characteristic clinical picture when multiple plaques are present.

The cerebrospinal fluid shows a mild increase in the number of lymphocytes, slightly elevated protein, and the presence of oligoclonal immunoglobulin bands on immunoelectrophoresis. Oligoclonal bands of IgG are not specific for multiple sclerosis, as they are seen also in neurosyphilis, subacute sclerosing panencephalitis, and Guillain-Barré syndrome (see Chapter 66: The Peripheral Nerves & Skeletal Muscle).

Treatment is limited to the management of complications. The course of the disease is not altered by treatment.

Demyelination in Immunologic Injuries

Experimental Allergic Encephalomyelitis

In the experimental setting, acute demyelination of nerve fibers in the central nervous system can be produced in many animals by injection of a brain emulsion in Freund's adjuvant. The active antigen is myelin protein, and the disease is thought to be caused by the action of sensitized T lymphocytes.

Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis is a rare group of diseases believed to have a pathogenesis similar to that of experimental allergic encephalomyelitis. Acute disseminated encephalomyelitis occurs after viral infections (most commonly measles and less often after chickenpox and rubella) and after immunization against smallpox, rabies (with the old Semple vaccine, which contained brain tissue; not with presently used vaccines), or pertussis (postvaccination). Lymphocytes from these patients exhibit cell-mediated immunologic reactivity against myelin protein in vitro.

Pathologically, there are innumerable small foci of acute demyelination of the white matter of the brain and spinal cord associated with lymphocyte infiltration. The manifestations and severity depend on the areas involved and the degree of involvement, but typically the mortality rate is high. Patients who survive improve slowly over several months, although many are left with neurologic deficits.

Cerebrocortical Degenerations

Alzheimer's Disease

Alzheimer's disease is extremely common—responsible for more than 50% of all cases of dementia (Table 64-4). It is characterized by progressive loss of neurons in the entire cerebral cortex. The frontal lobe is involved preferentially. Neuronal loss leads to dementia, which is the characteristic clinical presentation.

The term Alzheimer's disease was initially applied to patients who developed dementia under 65 years of age (presenile dementia), whereas dementia occurring after age 65 was called senile dementia. It has now become clear that the changes seen in most patients with senile dementia are identical to those of Alzheimer's disease. Alzheimer's disease occurs in 20% of persons over 80 years old.

Etiology

The cause remains unknown. However, abnormalities of chromosomes 14, 19, or 21 have been identified in affected families, providing some clues to possible pathologic mechanisms. Patients with Down syndrome (trisomy 21) frequently develop lesions of Alzheimer's disease in the third or fourth decade of life. The gene encoding the β-amyloid protein of Alzheimer's disease (see below) has been localized to chromosome 21, leading to the suggestion that the presence of an additional or defective copy of the gene may be instrumental in causing the deposition of β-amyloid in plaques. In addition, the formation of neurofibrillary tangles has been attributed to the presence in Alzheimer's patients of apoprotein E4 (ApoE4), which is less effective in stabilizing microtubules than ApoE2, the form present in most individuals. The gene for ApoE is on chromosome 19. Levels of the enzyme choline acetyltransferase, an essential catalyst of acetylcholine synthesis, also are consistently reduced in the cerebral cortex of patients with Alzheimer's disease.

Pathology

Grossly, there is atrophy of the cerebral cortex, with thinning of the gyri and widening of the sulci affecting the frontal parietal and medial temporal lobes. The cortical gray matter is greatly thinned and poorly demarcated. The lateral ventricles show compensatory dilatation.

Microscopically, there is neuronal loss and disorganization of the cerebrocortical layers. Alzheimer's disease is characterized by the presence of neurofibrillary tangles in the cytoplasm of affected neurons (best seen in silver stains). These are complexly interwoven masses of paired helical filaments 10 nm in diameter consisting of various proteins, including an abnormally phosphorylated form of the microtubule protein tau, and ubiquitin. Also characteristic of Alzheimer's disease—and best seen on silver stains—are neuritic plaques, which are large (150 μm) extracellular collections of degenerated cellular processes disposed around a central mass of β-amyloid protein material (Figure 64-10). The degenerated neuritic material contains paired helical filaments identical to those found in neurofibrillary tangles in affected neurons.

Amyloid protein similar to that seen in neuritic plaques is also present in the walls of small meningeal and cortical arteries (cerebral amyloid angiopathy) in patients with Alzheimer's disease.

Clinical Features

Alzheimer's disease usually occurs in patients over 50 years of age. The clinical symptoms are subtle at first, manifested as a loss of higher cortical functions. The loss of ability to solve problems, decreased agility of thought processes, and mild emotional lability are common early features. The dementia progresses inexorably over the next 5–10 years to an extent that the patient becomes unable to carry out daily activities. There is no effective treatment.

Pick's Disease

Pick's disease is an extremely uncommon cause of presenile dementia, occurring in the age group from 40 to 65 years. The cause is unknown. The clinical course is indistinguishable from that of Alzheimer's disease. However, there is selective atrophy of anterior frontal and temporal lobes, and neurofibrillary tangles and neuritic plaques are not present; instead, affected neurons contain Pick bodies—round, lightly eosinophilic cytoplasmic inclusions that stain strongly positive with silver stains.

Huntington's Disease

Huntington's disease (Huntington's chorea) is a rare disease that is inherited as an autosomal dominant trait with complete penetrance but delayed appearance. The abnormal gene is located on the terminal segment of the short arm of chromosome 4. Deoxyribonucleic acid (DNA) probes are now available to detect the abnormal gene in affected families before symptoms develop. This provides crucial information for genetic counseling.

Huntington's disease is characterized by atrophy and loss of neurons of the caudate nucleus and putamen, associated with variable cerebrocortical atrophy, particularly in the frontal lobe. There is a marked decrease in synthesis of the neurotransmitter γ-aminobutyric acid in the basal ganglia. Though inherited, the disease has its onset in adult life, usually between 20 and 50 years of age. It is characterized by dementia, due to cerebral involvement, and choreiform involuntary movements, due to involvement of the basal ganglia. The disease is slowly but inexorably progressive, leading to death in 10–20 years.

Basal Ganglia Degenerations

Idiopathic Parkinson's Disease

Idiopathic Parkinson's disease is a common disease, affecting 5% of persons over 70 years of age. The exact cause is unknown. There is degeneration of the pigmented nuclei of the brain stem, particularly the substantia nigra, producing dysfunction of the extrapyramidal system. Patients with Parkinson's disease have depletion of dopamine in the affected areas. Because dopamine is an important neurotransmitter in the extrapyramidal system, it has been postulated that failure of normal dopamine synthesis is responsible for the disease.

Pathology

Grossly, patients with Parkinson's disease have depigmentation of the substantia nigra and locus ceruleus. Microscopically, loss of pigmented neurons is accompanied by gliosis in the substantia nigra and other basal ganglia. Lewy bodies—rounded eosinophilic cytoplasmic inclusions—may be present in the remaining neurons; they are characteristic of Parkinson's disease.

Clinical Features

Onset is usually after the age of 50 years, and the disease is slowly progressive. It is characterized by extrapyramidal dysfunction, which causes increased rigidity of muscles, resting tremors, and slowness of movements (bradykinesia). Patients have a typical gait, walking stooped forward with short, quick shuffling steps (festinating gait). Up to 20% of patients with parkinsonism develop dementia. Slow, difficult speech is due to motor retardation.

Treatment with levodopa produces a good clinical response in most cases. However, the disease is progressive, and over time, control becomes difficult. Transplantation of autologous adrenal medulla or fetal tissue containing substantia nigra neurons into the basal ganglia by stereotactic surgery are under trial. The overall prognosis is poor.

Other Causes of Parkinson's Syndrome

Identical clinical features may be caused by several diseases that affect the extrapyramidal system.

1. Postencephalitic parkinsonism, which occurred in association with the influenza epidemic of 1914–1918, tended to occur in younger individuals and is uncommon today.

2. Ischemic damage to the basal ganglia is associated with atherosclerosis.

3. Wilson's disease is due to deposition of copper in the basal ganglia (see Chapter 43: The Liver: II. Toxic & Metabolic Diseases; Neoplasms).

4. Damage to the basal ganglia may result from exposure to toxic agents such as carbon monoxide and manganese.

5. Several drugs in therapeutic doses, notably the phenothiazines and reserpine, produce reversible Parkinson's syndrome.

6. Shy-Drager syndrome is intractable hypotension with various autonomic defects and Parkinson's syndrome.

Spinocerebellar Degenerations

These rare diseases are usually inherited as autosomal recessive traits. The most common is Friedreich's ataxia, in which there is degeneration of spinocerebellar tracts, posterior columns, the pyramidal tract, and the peripheral nerves. Clinical presentation is in late childhood, with incoordination and muscle weakness.

Olivopontocerebellar degeneration is characterized by degeneration of neurons in the cerebellar cortex, cerebellar nuclei, olivary nuclei, and pons.

Motor Neuron Disease

Motor neuron disease is characterized by degeneration of both upper and lower motor neurons. The cause is unknown. Most cases occur in a sporadic manner. A high incidence of familial occurrence has been reported in Guam, the Marianas, and the Caroline Islands.

Typically, motor neuron disease affects individuals over the age of 50 years. The neurologic deficit is purely motor and is characterized by loss of motor neurons in the cerebral cortex, in motor nuclei of the brain stem, and in the anterior horns of the spinal cord. Corticospinal tract degeneration follows cortical motor neuron loss. Depending on the distribution of lesions, four clinical variants of the disease have been recognized.

1. Amyotrophic lateral sclerosis (Lou Gehrig's disease) is the most common disease in this group. It is characterized by degeneration of the corticospinal tracts (lateral sclerosis) in the spinal cord, resulting in upper motor neuron paralysis in the extremities. The muscular paralysis is associated with absence of atrophy (amyotrophic), hypertonia, and exaggerated deep tendon reflexes.

2. Progressive muscular atrophy shows preferential degeneration of anterior horn motor nuclei, causing lower motor neuron paralysis in the extremities. Neuronal degeneration is associated with irregular neuronal discharge, leading to muscle fasciculations, which is a feature of the disease. Fasciculation is followed by muscle atrophy. A similar disorder in infants is termed Werdnig-Hoffmann disease.

3. Progressive bulbar palsy affects medullary motor nuclei, causing lower motor paralysis of the jaw, tongue, and pharyngeal muscles.

4. Pseudobulbar palsy is a disorder in which bilateral upper motor neuron paralysis of the jaw, tongue, and pharyngeal muscles occurs.

Note that overlapping clinical features appear as the disease progresses toward the end stage, with severe deficits of both upper and lower motor neurons. Death usually occurs in 1–6 years from bronchopneumonia associated with respiratory muscle paralysis. The rate of progression is variable, and there is no specific treatment.

Subacute Combined Degeneration of the Cord

Deficiency of vitamin B12 (see Chapter 24: Blood: I. Structure & Function; Anemias Due to Decreased Erythropoiesis) results in degeneration of several components of the nervous system. The most common lesion is subacute combined degeneration of the cord (Figure 64-11), in which there is demyelination of (1) the posterior columns, leading to loss of position and vibration sense and interference with the reflex arc for the deep tendon reflexes; (2) the lateral columns, resulting in upper motor neuron paralysis; and (3) the peripheral nerves. Peripheral neuropathy or optic neuropathy may also occur as isolated lesions in patients with vitamin B12 deficiency. The diagnosis is important, because vitamin B12 therapy will prevent progression—although it does not repair the demyelinated fibers.

Wernicke's Encephalopathy

Thiamin deficiency (see Chapter 10: Nutritional Diseases) is commonly seen in malnourished individuals and chronic alcoholics. It causes involvement of the floor of the third ventricle and the periaqueductal region of the midbrain. The mamillary bodies are maximally involved.

The early lesion is characterized by petechial hemorrhages and capillary proliferation. This is followed by atrophy and degeneration of neurons. The atrophic areas in Wernicke's encephalopathy typically show a brownish discoloration because of hemosiderin pigment deposition.

Clinically, Wernicke's encephalopathy is manifested by confusion, ocular muscle paralysis, and nystagmus—an abnormal involuntary motion of the eyes. Wernicke's encephalopathy is frequently associated with a psychotic state (Korsakoff's psychosis), which is also related to thiamin deficiency.

Pellagra Encephalopathy

Nicotinamide deficiency causes neuronal degeneration, affecting the cerebral cortex, pontine nuclei, cranial nerve nuclei, and anterior horn cells in the spinal cord. Dementia is the most common clinical manifestation.

Intracranial and spinal neoplasms may be primary or metastatic; in most autopsy series, metastatic tumors are more common. Primary intracranial neoplasms number about 13,000 new cases per year in the United States and represent about 2% of deaths from malignant neoplasms. They are the second most common group of neoplasms in children, after leukemia and lymphoma if considered as one group. Taken overall, 65% of primary intracranial neoplasms are of glial origin (gliomas), 10% meningiomas, 10% acoustic schwannomas, 5% medulloblastomas, and 10% others. Primary malignant lymphomas of the central nervous system have recently increased in frequency because they are common in patients with acquired immunodeficiency disease (AIDS). Tumors of neurons per se are extremely uncommon except in childhood (eg, medulloblastoma).

Classification

Histogenetic Classification

Classification on a histogenetic basis has great theoretical value and provides a means of logically remembering all the different kinds of intracranial neoplasms (Table 65-1).

Topographic Classification

When a patient presents with an intracranial neoplasm, its location can usually be ascertained by clinical examination and radiologic studies. According to their location, intracranial neoplasms may be classified as supratentorial or infratentorial. Further subdivisions in these main compartments are recognized (Table 65-2), leading to a topographic classification. When the location of the neoplasm is combined with the patient's age, a clinically useful differential diagnosis of the histologic type of the neoplasm can be derived. For example, if a child presents with a neoplasm in a cerebellar hemisphere, it is most likely a juvenile pilocytic astrocytoma (Table 65-2).

Classification According to Biologic Potential

The criteria used to determine malignancy in neoplasms are somewhat different from those used elsewhere in the body:

1. Even highly malignant intracranial neoplasms generally do not metastasize outside the craniospinal axis (Fig 65-1). Metastasis within the craniospinal axis via the cerebrospinal fluid does occur, most commonly with medulloblastoma, pineoblastoma, malignant ependymoma, pineal germinoma, and glioblastoma multiforme.

2. Destructive infiltration of the brain is the major criterion of malignancy for intracranial neoplasms, and infiltration of brain substance usually prevents complete removal at surgery. All glial neoplasms invade brain, and all must be considered malignant. Neurologic deficits resulting from destructive invasion by malignant neoplasms are irreversible. Benign neoplasms, on the other hand, cause neurologic deficits due to compression; these often reverse when the neoplasm is removed.

3. The rate of growth of neoplasms also correlates well with malignant behavior. Rapidly growing neoplasms such as glioblastoma multiforme and medulloblastoma are highly malignant. Low-grade malignant neoplasms such as well-differentiated astrocytoma and oligodendroglioma grow slowly. Benign neoplasms usually grow very slowly, enlarging over several years.

4. Recurrence after treatment is almost invariable with malignant intracranial neoplasms. Recurrence also occurs with many benign neoplasms such as meningioma and craniopharyngioma, and therefore recurrence of itself is not a criterion of malignancy.

5. The term benign for any intracranial neoplasm is probably inappropriate. Benign intracranial neoplasms frequently produce extremely serious clinical disease and may cause severe neurologic deficits and death unless treated. The term thus does not mean that these neoplasms are harmless but implies rather that they are slow growing and do not infiltrate the brain substance.

Pathology & Clinical Features

(Figure 65-1)

The specific clinicopathologic features of intracranial neoplasms will be considered with the individual neoplasms. In general, intracranial neoplasms cause the following clinical and pathologic changes:

Compression

Compression of adjacent neural tissues occurs with all expanding neoplasms. When the rate of growth is slow, compression leads to atrophy, which may cause symptoms of dysfunction—eg, atrophy of the motor cortex adjacent to a meningioma causes upper motor neuron paralysis; compression of a cranial nerve may cause cranial nerve palsy. In general, relief of compression is followed by significant recovery of function. With long-standing compression, there may be a permanent deficit.

Destruction

Destruction of neural tissues by direct infiltration with a malignant neoplasm produces an irreversible deficit.

Cerebral Edema

Cerebral edema is commonly present around infiltrative neoplasms and may be severe. It is believed to result from the neovascularization that accompanies malignant neoplasms. The new vessels have a poorly developed blood–brain barrier that permits exit of proteins and fluids more easily than from normal vessels. Cerebral edema tends to be most marked in highly malignant neoplasms. Cerebral edema causes elevation of intracranial pressure that is additive to the mass effect of the tumor.

Irritative Effects

Irritation of neural tissues may occur with both compressing and infiltrating neoplasms. Abnormal stimulation is usually manifested as either simple or complex partial focal epilepsy. A neoplasm near the motor cortex may generate an abnormal electrical potential that causes motor stimulation of the entire contralateral half of the body (jacksonian epilepsy). Up to 5% of individuals with intracranial neoplasms experience one or more seizures. Note that although only a minority of cases of epilepsy are due to tumors, seizures should be fully investigated for cause due to tumor or other treatable disease, particularly when the onset is in adult life or when the seizure is focal rather than generalized (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Hydrocephalus

Neoplasms in the region of the third ventricle or in the posterior fossa may cause obstructive hydrocephalus. This causes marked elevation of intracranial pressure.

Increased Intracranial Pressure

Intracranial neoplasms cause increased intracranial pressure due to (1) the mass effect of the neoplasm itself, (2) cerebral edema, or (3) hydrocephalus. Many patients with intracranial neoplasms present with the effects of increased intracranial pressure—headache, vomiting, papilledema, and false localizing signs due to displacement of the brain and to herniations (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases). Shift of structures can often be detected radiographically and provides a clue to the site of intracranial neoplasms.

Diagnosis

Clinical examination and radiologic imaging provide excellent localization of mass lesions of the nervous system. Specific diagnosis, however, is based on microscopic examination of a sample from the tumor. Stereotactic biopsy and open resection are the methods available for obtaining tissue samples. Examination of cerebrospinal fluid is rarely useful because (1) lumbar puncture is not usually performed in the presence of mass lesions, and (2) the yield of neoplastic cells in cerebrospinal fluid is low even with highly malignant neoplasms.

Cerebral Hemisphereastrocytoma

Astrocytoma in the cerebral hemisphere is the most common primary neoplasm of the brain and occurs chiefly in adults (Table 65-2).

Well-Differentiated (Grade I) Astrocytomas

Well-differentiated (grade I) astrocytomas are infiltrative, slowly growing neoplasms that form firm, white, ill-defined masses (Figure 65-2). Microscopically, they show slightly increased cellularity and astrocytes with cytologic features that deviate very slightly from normal. Neurofibrillary processes are present and, often, abundant (fibrillary astrocytoma). Well-differentiated astrocytomas, although low-grade malignant neoplasms, are practically impossible to excise surgically because of irregular extension beyond the apparent margin. They progress slowly to cause death approximately 5–10 years after presentation.

Anaplastic (Grade II & Grade III) Astrocytomas

Anaplastic astrocytoma is a more rapidly growing neoplasm that forms a white infiltrative mass in the cerebral hemisphere. Microscopically, it is composed of astrocytes that show greater cellularity, more pleomorphism, neovascularization with proliferation of endothelial cells, and an increased mitotic rate. Anaplastic astrocytomas show a higher rate of cell proliferation than well-differentiated astrocytoma. The proliferative rate may be measured by (1) the percentage of cells in the S phase of the cell cycle and (2) the percentage of cells expressing proliferation-associated antigens such as Ki67. They commonly cause death after 1–5 years.

Glioblastoma Multiforme (Grade IV Astrocytoma)

Glioblastoma multiforme is the most common type of astrocytoma. It is also one of the most malignant and rapidly growing neoplasms of the brain. Grossly, glioblastomas appear as large infiltrative masses that typically extend across the midline as the so-called “butterfly” tumor. The cut surface commonly shows hemorrhage and necrosis (Figure 65-3). Microscopically, they are composed of highly pleomorphic astrocytic cells with frequent mitotic figures. Necrosis is an important indicator of aggressive behavior (Figure 65-4). Prominent neovascularization is common. Glioblastoma multiforme is highly malignant, with a median survival of 1 year after diagnosis.

Juvenile Pilocytic Astrocytoma

Juvenile pilocytic astrocytoma is a neoplasm of children and adolescents found most commonly in the cerebellar hemispheres. It accounts for 25% of intracranial neoplasms in children under age 10 years. Grossly, it is well circumscribed and often cystic. Microscopically, it shows hypercellularity and is composed of cytologically uniform fibrillary astrocytes. Microcystic change and the presence of enlarged astrocytic fibers (Rosenthal fibers) are characteristic features.

Juvenile cerebellar pilocytic astrocytoma is a very slowly growing tumor that is extremely well circumscribed. It is almost benign in its biologic behavior. Surgical removal results in permanent cure in most cases.

Juvenile pilocytic astrocytoma may also occur in the region of the hypothalamus. Though slowly growing and circumscribed, it is rarely possible to completely remove a hypothalamic pilocytic astrocytoma, and it frequently causes death.

Brain Stem & Spinal Cord Astrocytoma

Astrocytomas also occur in the brain stem and spinal cord and are analagous to the different types occurring in the cerebral hemispheres.

Oligodendroglioma occurs in the cerebral hemisphere in adults 30–50 years of age. It is uncommon in pure form but more often is part of a mixed glial neoplasm with astrocytic and oligodendroglial components.

Grossly, oligodendrogliomas are well-circumscribed solid neoplasms. Seventy-five percent of oligodendrogliomas have speckled calcification that is visible on x-ray. Microscopically, the neoplasm is composed of numerous small uniform oligodendroglial cells. Mitotic activity is scarce.

Clinically, oligodendroglioma is a slowly growing neoplasm. The prognosis after surgical removal is good, although recurrence is common.

Ependymoma

Ependymoma is an uncommon neoplasm that occurs at all ages but is relatively more common in children. It accounts for 60% of intramedullary spinal cord neoplasms; in the brain, 60% occur in the fourth ventricle.

Grossly, ependymomas form well-circumscribed, reddish-brown nodular masses that occur in relation to the ventricular system. They grow slowly but have the ability to spread via the cerebrospinal fluid and should be considered as low-grade malignant neoplasms. Microscopically, ependymomas are highly cellular, with small polygonal cells that form ependymal tubules and perivascular pseudorosettes. Well-differentiated ependymomas tend to grow slowly and may be cured by complete surgical removal. Less differentiated ependymomas infiltrate, grow rapidly, and have a poor prognosis.

A specific type of ependymoma called myxopapillary ependymoma occurs in the filum terminale and presents as a cauda equina tumor in young adults.

Choroid Plexus Papilloma

Choroid plexus papilloma is a rare neoplasm that tends to occur in the ventricles of young children. Grossly, it is characterized by a highly vascular papillary mass growing into the ventricle. Microscopically, the papillary processes have vascular cores and are lined by uniform columnar cells. Calcification may be present. Rarely, infiltration of brain, cytologic atypia, and increased mitotic activity justify a diagnosis of choroid plexus carcinoma.

Choroid plexus papillomas may sometimes secrete increased amounts of cerebrospinal fluid and give rise to communicating hydrocephalus.

Colloid Cyst of the Third Ventricle

Colloid cysts are believed to have an ependymal origin. They occur in the anterior third ventricle and are unilocular cysts lined by cuboidal epithelium and containing thick gelatinous fluid. As they enlarge, colloid cysts may block the foramen of Monro, producing acute obstructive hydrocephalus.

Medulloblastoma is derived from primitive neuroectodermal cells. It occurs mainly in children, accounting for 25% of all intracranial neoplasms in children under age 10 years. Its most common location is the midline cerebellar vermis in the posterior fossa.

Grossly, medulloblastoma appears as a grayish-white fleshy mass with infiltrative margins. Microscopically, the tumor is highly cellular and composed of sheets of small primitive cells with hyperchromatic nuclei and scant cytoplasm. Mitotic figures are frequently present.

Medulloblastoma is highly malignant and frequently seeds the cerebrospinal fluid to produce metastases around the spinal cord. The prognosis is poor, but recent aggressive chemotherapeutic regimens have improved the outlook somewhat.

The pineal gland is situated in the midline, dorsal to the midbrain and the posterior part of the third ventricle. It is composed of pinealocytes, which are modified neuroectodermal cells.

Pinealocyte Neoplasms

Pineocytoma is a benign or low-grade malignant neoplasm composed of well-differentiated pinealocytes. It occurs mainly in adults.

Pineoblastoma resembles medulloblastoma. It occurs in childhood and is highly malignant.

Germ Cell Neoplasms

Neoplasms arising from primitive germ cells in the nervous system occur most commonly in the pineal region. Germinoma, which resembles the testicular seminoma microscopically, is most common and typically forms a well-circumscribed mass that compresses the midbrain, causing abnormalities in ocular movement and hydrocephalus. Germinomas are malignant and tend to spread along cerebrospinal fluid (CSF) pathways. Germinomas are extremely radiosensitive neoplasms, and cures have been recorded following radiation therapy.

Other germ cell neoplasms occurring in the region of the pineal gland include teratoma, embryonal carcinoma, yolk sac carcinoma, and choriocarcinoma. All are very uncommon.

Meningioma can occur at any age but is rare in childhood. Meningiomas occur most frequently in middle-aged women—the predominance in women is probably related to the presence of progesterone receptors on the tumor cells.

Pathology

Meningiomas usually arise outside of the brain substance and have an attachment to the dura. They present grossly as a firm encapsulated mass that compresses adjacent neural structures (Figure 65-5). Infiltration of the dura is usual and does not indicate malignancy. Meningiomas are frequently associated with hypertrophy of the overlying bone (hyperostosis); this may be so pronounced as to cause a palpable mass in the skull. Meningiomas may also infiltrate bone and extend into the scalp, a locally aggressive behavior pattern that still does not necessarily indicate malignancy. The term malignant meningioma is used only when the neoplasm infiltrates the underlying brain.

Microscopically, meningioma is composed of sheets or whorls of meningothelial cells, which are plump spindle cells with oval nuclei and scant cytoplasm (syncytial or meningothelial meningioma). In some cases, the meningothelial cells are more elongated, resembling fibroblasts (fibroblastic meningioma). Psammoma bodies (round, laminated calcifications) occur in many meningiomas. Mitoses are rare. When there is necrosis, cellular pleomorphism, or a high mitotic rate, the term atypical meningioma may be used.

Biologic Behavior

Meningioma is a benign neoplasm. However, because of infiltration of dura and bone, complete surgical removal may be difficult in some cases, and there is a 10% recurrence rate. The recurrence rate increases in (1) atypical meningiomas (20–30% recurrence rate) and (2) malignant meningiomas (90% without radiotherapy).

Clinical Features

Meningiomas occur throughout the craniospinal axis, producing specific clinical features that depend on their location (Figure 65-6). Sites of predilection are (1) the parasagittal region and falx cerebri, giving rise to motor deficits; (2) the surface of the cerebral hemispheres, causing focal epilepsy and cortical dysfunction depending on exact location; (3) the olfactory bulb, compressing the optic nerve and causing blindness; (4) the sphenoidal ridge, compressing the cranial nerves passing into the orbit; (5) the posterior fossa, with features of a cerebellopontine angle tumor; and (6) the spinal cord, causing spinal compression.

Neoplasms arising in the nerve sheaths—schwannoma and neurofibroma—will be considered in the section on soft tissue neoplasms (Chapter 66: The Peripheral Nerves & Skeletal Muscle). Nerve sheath neoplasms occur in relation to cranial and spinal nerve roots, particularly the sensory nerve roots.

The most common intracranial example is the acoustic schwannoma (neuroma), which arises in the eighth cranial nerve and presents as a cerebellopontine angle mass. In this location, it compresses adjacent cranial nerves and cerebellum. Schwannoma less frequently arises from the fifth cranial nerve.

Neurofibromas are the most common neoplasms occurring in the intradural but extramedullary compartment of the spinal column. They cause progressive spinal cord compression.

Cerebellar hemangioblastoma is a benign neoplasm that occurs either sporadically or as part of von Hippel-Lindau disease (Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases). It appears grossly as a well-circumscribed mass with cystic and solid components (Figure 65-7). Microscopically, numerous endothelium-lined vascular spaces are separated by trabeculae of cells with lipid-laden cytoplasm.

Clinically, presentation is with cerebellar dysfunction, hydrocephalus, or polycythemia (the tumor produces erythropoietin). Surgical removal is usually curative.

Primary malignant lymphoma of the brain is very uncommon in otherwise healthy individuals. Its incidence is greatly increased in immunocompromised patients, such as those with AIDS and persons who have received organ transplants.

Intracranial lymphoma most commonly occurs in the deep cerebral hemispheres and is frequently multifocal. The commonest types are high-grade B cell lymphomas, most commonly B-immunoblastic lymphoma. Treatment with chemotherapy is of limited efficacy, and the prognosis is poor.

Craniopharyngioma

Craniopharyngioma is believed to be derived from Rathke's pouch, the epithelial remnant of the foregut that contributes to the origin of the pituitary gland. It occurs mainly in childhood in the suprasellar region adjacent to the pituitary stalk.

Typically, craniopharyngioma is encapsulated and has cystic and solid components. In some cases, local infiltration makes complete surgical removal difficult. Microscopically, the cystic spaces are lined by stratified squamous epithelium and contain an oily fluid in which cholesterol crystals can be identified. The solid areas are composed of stroma and squamous epithelium that resembles tooth-forming ameloblastic epithelium. Calcification is usually present.

Craniopharyngiomas present with compression and destruction of (1) the pituitary, causing hypopituitarism—in children, growth retardation is a common finding; (2) the optic chiasm, causing visual field defects; and (3) the third ventricle, causing hydrocephalus. Treatment is surgical, often followed by radiation therapy in cases where complete surgical removal is not possible. The recurrence rate is high.

Epidermoid Cyst

Epidermoid cysts are derived from rare embryonic epidermal remnants. The most common locations are the cerebellopontine angle, the suprasellar region, and the lumbar region of the spinal cord in relation to spina bifida.

Epidermoid cysts are benign cystic structures lined by stratified squamous epithelium and filled with keratin. Surgical removal is curative.

Chordoma

Chordoma is a neoplasm derived from notochordal remnants found in the base of the skull and the dorsal aspect of the vertebral bodies. Chordoma occurs most commonly at either end of the notochord in the following locations: (1) in the sacrococcygeal region, where it causes compression of the cauda equina; (2) at the clivus, from which it extends into the posterior fossa, compressing the brain stem; and (3) in the suprasellar region, where it compresses the pituitary stalk and third ventricle.

Grossly, chordoma appears as a lobulated nodular mass that arises in bone and protrudes inward into the cranial cavity and spinal canal. It has a gelatinous appearance on cut section and histologically resembles the notochord, being composed of large cells with abundant bubbly cytoplasm (physaliphorous cells).

Chordomas are malignant neoplasms that grow slowly but inexorably. Complete surgical removal is rarely possible. Most patients die of their tumor, usually after several years.

Neoplasms metastatic to the brain are common and may be derived from melanomas or from primary tumors in almost any organ, most commonly the lung, breast, kidney, stomach, and colon. The brain metastasis may be the first manifestation of a previously occult malignant neoplasm, in which case differentiation from a primary intracranial neoplasm is difficult without biopsy. More frequently, metastasis to the brain occurs during the terminal phase in a patient with disseminated cancer (Fig 65-8).

Meningeal involvement by metastatic neoplasms occurs frequently in patients with acute leukemia. This presents a problem because the blood–brain barrier prevents chemotherapeutic agents from reaching the meningeal leukemic cells. The diagnosis of meningeal involvement can be made by identifying leukemic cells in cerebrospinal fluid. These patients can then be treated either with intrathecal chemotherapy or craniospinal irradiation.

The peripheral nerves, neuromuscular junction, and skeletal muscle represent the final component of the lower motor neuron unit and are discussed together for that reason. Diseases involving these structures result in muscle weakness. The peripheral nerves also have sensory and autonomic fibers, and—unlike diseases of muscle, which result in motor dysfunction alone—peripheral nerve diseases are manifested by a combination of motor and sensory loss.

Peripheral nerves are composed of axons leading to and from sensory, motor, and autonomic neurons. Each individual axon is surrounded by a myelin sheath of varying thickness. The nerves contain Schwann cells, which form the myelin, and supporting connective tissue (endo-, epi-, and perineurium). The blood supply to peripheral nerves is by small arterioles called the vasa nervorum.

Peripheral Neuropathy

Peripheral neuropathy is a clinical term that denotes nontraumatic disease of the nerves. Most peripheral neuropathies tend to affect the longest fibers first, producing a typical symmetric “glove and stocking” distribution of sensory loss and involvement of the muscles of the hands and feet. Sensory and mixed neuropathies are more common than pure motor neuropathy. Neuropathy affecting autonomic nerves results in autonomic dysfunction.

Two basic pathologic lesions occur in peripheral neuropathy: segmental demyelination and axonal degeneration. Both changes result in failure of nerve conduction. In the case of sensory nerves, the nerve damage results in degenerative changes in the neuron within the sensory nerve root ganglion. When neuronal loss occurs, the lesion is irreversible. There are many causes of peripheral neuropathy (Table 66-1). These are classified by etiology rather than by pathogenesis because pathologic examinations of nerve biopsy material are not routinely performed. Nerve biopsy (sural nerve) is indicated in (1) cases where vasculitis, amyloidosis, granuloma, or inflammation is suspected; and in (2) specialized centers for research into nerve diseases. Identification of fine structural changes in the myelin sheath and axons requires teased nerve preparations and electron microscopy. These techniques are not within the scope of the average pathology laboratory.

Ischemic neuropathy tends to result in asymmetric involvement of a single nerve (mononeuritis) or scattered individual nerves (mononeuritis multiplex).

Guillain-Barré Syndrome (Acute Demyelinating Polyneuritis)

Guillain-Barré syndrome is an uncommon disease believed to be the peripheral nervous system equivalent of experimental allergic encephalomyelitis (Chapter 64: The Central Nervous System: III. Traumatic, Vascular, Degenerative, & Metabolic Diseases). It follows viral infection in a majority of cases, most often with herpesvirus, Epstein-Barr virus, or cytomegalovirus infections; less frequently, it is precipitated by injection of foreign proteins, immunization, or trauma. Well-documented cases were reported following the swine-flu vaccination program of 1976–1977. Subsequent influenza vaccination programs have not been associated with this complication. Experimentally, a similar disease—experimental allergic neuritis—can be induced in animals by injection of peripheral myelin protein P2 with Freund's adjuvant; cytotoxic T lymphocytes develop that have the ability to produce demyelination in tissue culture.

Pathologically, Guillain-Barré syndrome is characterized by acute demyelination of multiple cranial and spinal nerve roots (polyradiculopathy), associated with lymphocytic infiltration of the involved nerves. The cerebrospinal fluid shows a typical change called cell–protein dissociation; the cell count is normal (< 5/μL), but the protein is markedly elevated.

Clinically, Guillain-Barré syndrome has a subacute onset with lower-motor-neuron-type weakness, mainly in the lower extremities (flaccid paraparesis with urinary incontinence). Involvement of the upper extremities and respiratory muscles occurs in severe cases. Sensory impairment is much less than motor impairment, and many patients have no sensory loss. The paralysis progresses for 1–4 weeks and then slowly improves over several months because of the slow regeneration of axons within the restored myelin sheaths. Ninety percent of patients recover completely.

Treatment is supportive. There is evidence that plasma exchange (plasmapheresis) produces a beneficial effect, presumably by removing immunologically active elements from the patient's plasma. Plasmapheresis should be undertaken in severe cases or in the presence of respiratory compromise.

Traumatic Nerve Injuries

Peripheral nerve injuries resulting in transection of the nerve are common. Transection injury is characterized by loss of motor and sensory function in the distribution of the nerve, the severity of which depends on how many nerve fibers within the nerve are interrupted.

Recovery from a nerve injury depends on several factors, most importantly whether the continuity of the nerve sheath of the damaged axon is maintained. Where the nerve sheath is not disrupted, complete recovery is the rule. This takes a period of several weeks because the axon and myelin sheath distal to the point of injury undergo wallerian degeneration and then regenerate slowly (1–2 cm per week) from the proximal end. In such nerve injuries, return of effective function depends on the degree of secondary degeneration that occurs in the end organ (motor end plate, muscle, sensory receptor, etc), which in turn depends on the time taken for reinnervation to occur.

More serious nerve injuries, which are much more common, are associated with transection of the nerve sheath as well as the axon. In most cases, the entire nerve trunk is severed. Wallerian degeneration occurs distally, with degeneration of axons and demyelination. The Schwann cells at the proximal end of the severed nerve fibers proliferate rapidly, and in some cases this process reestablishes continuity with the distal nerve sheath. Recovery of function is dependent on the number of nerve sheaths that reestablish continuity and permit axonal recovery. This depends mainly on the accuracy of apposition of the severed nerve ends. Effective functional recovery requires that the axon reestablish its original innervation. With complete transection of a mixed sensory and motor nerve, the chances of this occurring are slight.

The complications of nerve transection include (1) failure of return of function; (2) return of abnormal function, due to establishment of incorrect innervation, eg, proximal sensory fiber growing down a distal motor axon; and (3) development of a mass at the severed nerve end composed of proliferating Schwann cells—these resemble neurofibromas histologically and are called traumatic neuromas.

Neoplasms of Peripheral Nerves

Neoplasms of peripheral nerves are common. They may occur in any nerve and may be classified anatomically as (1) neoplasms within the skull or spinal canal; (2) neoplasms that involve both the spinal canal and the paraspinal soft tissue (termed dumbbell tumors because of their shape—2 large masses connected by a narrow mass within the intervertebral foramen); (3) neoplasms arising in large nerve trunks in extraspinal or extracranial soft tissues; and (4) neoplasms in small peripheral nerve filaments that appear as soft tissue masses without obvious connections to nerves.

In all of these anatomic sites, neural tumors fall into 3 groups: (1) schwannoma, (2) neurofibroma, and (3) malignant peripheral nerve sheath tumor—a type of sarcoma also called malignant schwannoma or neurofibrosarcoma. Most neural neoplasms occur as sporadic lesions. In a small number of cases, multiple neural neoplasms occur as part of the familial generalized neurofibromatosis syndrome of von Recklinghausen (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Schwannoma (Neurilemmoma)

(Figure 66-1)

Schwannoma is a slowly growing benign neoplasm that commonly occurs in relation to large nerve trunks. Sensory cranial nerves (eighth and fifth nerve schwannoma) and the sensory root of spinal nerves are common locations. In the extra-axial soft tissues, they most commonly occur in the posterior mediastinum, the retroperitoneum, the head and neck, and the extremities. Schwannomas are usually solitary; multiple schwannomas may be associated with von Recklinghausen's neurofibromatosis.

Clinically, schwannomas present as a mass lesion, usually causing compression of surrounding structures. Compression of the nerve of origin causes irritative and paralytic symptoms—eg, acoustic schwannoma results in tinnitus followed by nerve deafness. Pain in the distribution of affected sensory nerves is a common finding.

On gross examination, schwannomas appear as encapsulated masses that compress the nerve of origin, which is frequently splayed out on one side of the mass. There is usually a plane of cleavage separating the nerve from the mass that may permit the tumor to be removed surgically without sacrificing the nerve. Areas of hemorrhage and cystic change are seen commonly in schwannomas; rarely, the neoplasm is composed predominantly of a cyst.

Histologic examination shows the tumor to be composed of Schwann cells arranged in one or both of two distinct patterns (Figure 66-2). The Antoni A pattern is characterized by highly cellular, compact, spindle-shaped cells arranged in short bundles or fascicles. Palisade arrangement of nuclei (nuclei of a fascicle of cells arranged one below the other) and Verocay bodies (structures formed by two rows of palisaded nuclei separated by an oval mass of pink cytoplasm) are characteristic histologic features. The Antoni B pattern is a loose, haphazard arrangement of Schwann cells in a richly myxomatous stroma. Large vascular spaces with hyalinized walls are a common feature. Nuclear pleomorphism and atypia, sometimes marked, may be present. Mitotic figures may also be present. Neither cytologic atypia nor mitotic activity indicates malignancy. Immunohistochemical studies show the presence of S100 protein in the Schwann cells.

The malignant potential of schwannomas is very low.

Neurofibroma

(Figure 66-1)

Neurofibroma is a slowly growing benign neoplasm that occurs (1) in relation to large nerve trunks and (2) in peripheral tissues such as skin, where it arises from very small nerves. Neurofibroma most commonly occurs as a solitary neoplasm. In patients with von Recklinghausen's disease, there are multiple neurofibromas in the skin and viscera (Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Clinically, neurofibroma presents as a soft tissue mass. It is commonly associated with pain.

On gross examination, neurofibromas of large nerves appear as an expansion of the affected nerve (Figure 66-3). The mass is firm and rubbery, not demarcated from the nerve, and cannot be removed surgically without sacrificing the nerve. Cystic degeneration is common.

Histologic examination shows a varied spindle cell population composed of Schwann cells and fibroblasts. Cellularity is variable, and myxomatous change is commonly present in the stroma. Nuclear atypia and pleomorphism may be observed without indicating that the neoplasm is malignant. The presence of mitotic activity in a neurofibroma indicates a strong likelihood of malignant biologic potential. Immunohistochemical studies show the presence of S100 protein; this is a reliable method of confirming the histologic diagnosis of both schwannoma and neurofibroma. Neurofibroma carries a low but significant risk of malignant transformation. Risk of malignancy is greatest in patients with von Recklinghausen's disease.

Malignant Peripheral-Nerve-Sheath Tumor

The term malignant peripheral-nerve-sheath tumor is applied to all malignant neural neoplasms and is synonymous with malignant schwannoma and neurofibrosarcoma. Most such tumors occur de novo; a few complicate preexisting neurofibromas, particularly in patients with von Recklinghausen's disease.

Malignant peripheral-nerve-sheath tumors appear clinically as soft tissue neoplasms. Any location may be affected; most common are the extremities and retroperitoneum. The rate of growth varies, being slow in low-grade neoplasms and rapid in high-grade ones. The tumors are diffusely infiltrative, frequently invading surrounding structures. Many patients have evidence of metastatic disease at the time of presentation. The most common site of metastasis is the lung.

Grossly, malignant peripheral-nerve-sheath tumors are fleshy masses, frequently large and showing extensive infiltration. Areas of necrosis and hemorrhage are common. Microscopically, they are highly cellular spindle cell sarcomas with marked cytologic atypia and pleomorphism and a high mitotic rate. The diagnosis of malignant peripheral-nerve-sheath tumor may be made when (1) a sarcoma has its origin from a large peripheral nerve, (2) a sarcoma of appropriate histologic type occurs in a patient with von Recklinghausen's disease, (3) S100 protein is demonstrated in the tumor cells, or (4) electron microscopy demonstrate features typical of Schwann cells. Less than 50% of malignant peripheral-nerve-sheath tumors stain positively for S100 protein.

Normal Skeletal Muscle

Normal skeletal muscle is composed of fascicles of muscle fibers (myofibrils) that represent the cellular unit. A myofibril is a long, cylindric, multinucleate cell that is the contractile unit of the muscle. Myofibrils are invested by a delicate connective tissue (endomysium) that is continuous with the connective tissue present between the myofibrils (perimysium) and around the whole muscle (epimysium). The connective tissue binds the myofibrils and is continuous at the ends of the muscle with the tendons with which muscles gain attachment to bone.

Each myofibril has a cell membrane (the sarcolemma) and shows cross-striations because it is made up of regularly alternating bands of different refractility. Difference in refractility is related to the disposition of actin and myosin filaments in the myofibril.

Human muscle fibers are subdivided into two types on the basis of their staining with the myosin-ATPase reaction at pH 9.4. Type I fibers, which stain lightly, are slow-contracting, fatigue-resistant fibers rich in oxidative enzymes. They function in aerobic conditions using blood glucose as the main energy source (these are the fibers developed in marathon runners). Type II fibers, which stain darkly, are fast-contracting, fatigue-prone fibers rich in glycolytic enzymes. They function in anaerobic conditions using stored glycogen as the main energy source (these are the fibers developed in sprinters). Normal muscle has a random mixture of both fiber types.

Clinical Features of Muscle Disease

Muscle Weakness

Causes of muscle weakness include the following:

1. Neurologic diseases involving either the upper or lower motor neurons. Lower-motor-neuron paralysis is characterized by muscle atrophy and loss of deep tendon reflexes; it may clinically resemble primary muscle diseases. Upper-motor-neuron paralysis causes spasticity and brisk reflexes without significant muscle atrophy, at least initially.

2. Failure of neuromuscular transmission.

3. Disease involving skeletal muscle per se, including myositis, dystrophies, and myopathies.

Muscle Pain

Inflammatory lesions of muscle (myositis) are commonly associated with pain and tenderness in the involved muscles. Muscle pain and cramping induced by exercise occur in metabolic diseases associated with defective energy production in muscle. These include glycogen storage disease (most commonly muscle phosphorylase deficiency) and defects in the glycolytic pathway, both of which interfere with glucose utilization.

Myoglobinuria

Myoglobinuria results from acute muscle destruction (rhabdomyolysis) that may occur with acute toxic, metabolic, infectious, or traumatic muscle disease. Myoglobin is rapidly filtered into the urine, which becomes red. Myoglobinuria must be distinguished from (1) hematuria (the urine contains no erythrocytes in myoglobinuria) and (2) hemoglobinuria (by immunoassay or spectroscopy).

Diagnosis of Muscle Disease

Clinical Examination

The diagnosis of many muscle diseases is based on the distribution of involvement, family studies, and other clinical features.

Electromyography

Electromyography, which measures action potentials generated in muscles by means of an electrode inserted into the muscle belly, provides useful information regarding muscle function. The action potentials may be generated by voluntary contraction of the muscle or by stimulation of the nerve supply. The latter also permits evaluation of nerve conduction and neuromuscular transmission.

Serum Enzyme Levels

Serum levels of creatine kinase, aldolase, transaminases, and lactate dehydrogenase become elevated in many muscle diseases, especially the dystrophies and myositis (Table 66-2). Elevations of these enzymes, however, are not specific for muscle diseases, and clinical correlation is essential. Note that muscle atrophy secondary to neuronal lesions does not usually produce elevated enzyme levels. Mild elevation of serum enzyme levels may be present in normal individuals immediately after strenuous exercise.

Muscle Biopsy

Skeletal-muscle biopsy is a highly specialized procedure. The preferred site for biopsy is the gastrocnemius. After removal, the muscle sample should be placed in a special clamp before fixation to prevent contraction. In addition to routine light microscopy, muscle biopsies are examined by special histochemical methods—to assess their enzyme content—as well as by electron microscopy. Such techniques require special processing, and they are done in laboratories equipped for such procedures. Routine light microscopy shows features that permit differentiation of denervation atrophy, muscular dystrophy, and myositis (Figure 66-4).

Primary Muscle Diseases

Muscular Dystrophies

The muscular dystrophies are a group of rare inherited primary muscle diseases characterized by (1) onset in childhood, (2) distinctive distribution of involved muscles, and (3) nonspecific histologic changes (Figure 66-4) in muscle.

Types of Muscular Dystrophy

(Table 66-3)

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (pseudohypertrophic muscular dystrophy) is the most common entity within this group. It is inherited as an X-linked recessive trait. Females carry the abnormal gene and transmit it on average to 50% of their male offspring, who manifest the disease. The disease is due to the absence of a gene located on the short arm of the X chromosome at the Xp21 site. This results in the absence of the gene product dystrophin in skeletal muscle, a consistent finding in Duchenne's disease. Dystrophin is a membrane-associated structural protein that serves as a strut to maintain muscle fiber integrity during contraction. Identification of the female carriers is now possible.

Affected males are normal at birth and manifest the disease in early childhood. The disease progresses rapidly, with most children functionally disabled within a few years. Death commonly occurs by the end of the second decade.

Muscle weakness is symmetric and first affects the muscles of the pelvic girdle. This causes difficulty in getting up from a seated position: the child pushes up with the hands to compensate for pelvic girdle weakness. Walking becomes progressively more difficult, with a typical waddling gait leading to a disability so severe as to confine the child to a wheelchair within a few years. A few patients with Duchenne muscular dystrophy also have reduced intelligence and myocardial involvement. Death commonly results from involvement of respiratory muscles.

A typical feature of Duchenne muscular dystrophy is that the affected muscles appear larger than normal in the early stages. This is most easily seen in the calf muscles. Enlargement of muscle is caused by increased fat content (pseudohypertrophy); the myofibrils themselves show the randomly alternating muscle fiber atrophy and hypertrophy that characterizes all muscular dystrophies (Figure 66-4).

Other Muscular Dystrophies

Many other types of muscular dystrophy are recognized and characterized according to the distribution of initial muscle weakness and observed inheritance patterns (Table 66-3). Different entities have onset at different ages and different rates of progression of disease. Most are less severe than Duchenne muscular dystrophy. All are characterized by muscle weakness and atrophy, and histologic changes on muscle biopsy are identical. Becker's muscular dystrophy results from a deficiency of the same dystrophin gene whose absence causes Duchenne's disease. The dystrophin deficiency in Becker's disease results in milder disease manifesting in adult life.

One exception to these rules is myotonic dystrophy, which is characterized not by muscle weakness but by failure of relaxation of muscle after voluntary contraction. Onset is usually in adult life, and progression is very slow. Patients with myotonic dystrophy also may have cataracts, gonadal atrophy, mental retardation, abnormal insulin metabolism, and cardiac arrhythmias.

Congenital Myopathies

Congenital myopathies are a group of very rare primary muscle diseases characterized by (1) onset at birth or in early infancy, with muscle weakness and decreased muscle tone (floppy infant syndrome); (2) a very slowly progressive or nonprogressive course, with long survival being the rule; and (3) specific histologic changes on muscle biopsy that characterize individual entities within the group (Table 66-4). Most are inherited.

Acquired Myopathies

Many acquired diseases are associated with muscle weakness without causing histologic changes in the involved muscle. Common diseases causing acquired myopathies are thyrotoxicosis, hypercortisolism (Cushing's syndrome), acromegaly, and malignant neoplasia, in the last of which myopathy occurs as a paraneoplastic syndrome. Hypocalcemia associated with osteomalacia and abnormal potassium metabolism associated with familial periodic paralysis also cause myopathy.

Inflammation of Muscle (Myositis)

A large number of infectious agents affect muscle, leading to myositis (Table 66-5). In trichinosis, muscle involvement characterized by severe muscle pain and swelling is the dominant clinical manifestation in the acute phase. Bornholm disease is a coxsackievirus infection of chest-wall muscles characterized by severe chest pain aggravated by breathing. Skeletal muscle involvement also occurs in exotoxic bacterial infections. In diphtheria, there is necrosis of muscle with inflammation. Muscle pain (myalgia) is a common clinical accompaniment of many viral infections, typhoid fever, and leptospirosis.

Inflammation of muscle is common in several autoimmune diseases. In polymyositis (often associated with skin involvement—dermatomyositis), inflammation of muscles is the dominant clinical manifestation (see Chapter 68: Diseases of Joints & Connective Tissue). In other autoimmune diseases and in sarcoidosis, muscle involvement occurs as part of a general systemic illness. In myasthenia gravis, focal collections of lymphocytes (lymphorrhages) may be seen in muscle; they have little connection with the pathogenesis of the disease.

Myositis may also occur after high-dosage radiation (most commonly in treatment of cancer), ischemia, and when muscle is infiltrated by malignant neoplasms. A specific form of myositis called myositis ossificans is characterized by bone formation in the involved muscle. This usually appears as a hard mass in the muscle that may be mistaken for a neoplasm.

Disorders of Neuromuscular Transmission

Myasthenia Gravis

Myasthenia gravis is one of the more common muscle diseases, affecting 1:40,000 persons in the United States. The most common age at onset is 20–40 years. There is a female preponderance when the disease occurs under the age of 40 years.

Etiology

Myasthenia gravis is a clinical syndrome resulting from failure of neuromuscular transmission due to blockage and destruction of acetylcholine receptors by autoantibody (Figure 66-5). Myasthenia gravis is therefore an organ-specific autoimmune disease.

Antiacetylcholine-receptor antibody is present in the serum of almost all patients. It is an IgG antibody and may cross the placenta in pregnancy, causing neonatal myasthenia in the newborn.

The reason for the production of antiacetylcholinereceptor autoantibody is unknown. Thymectomy often improves the condition. It is believed that the thymus plays a role in the etiology of myasthenia gravis, either acting as a source of cross-reactive antigen (the thymic myoid cells bear acetylcholine receptors on their surface) or being involved in the production of helper T cells that influence production of the autoantibody. The thymus is not the source of the antibody, which is produced by the peripheral lymphoid tissue.

Patients with myasthenia frequently have other autoantibodies in their blood. The commonest of these is antistriated-muscle antibody, which reacts with skeletal muscle fibers away from the motor end plate. This autoantibody also cross-reacts with myoid cells in the thymus.

Pathology

Specific morphologic abnormalities are not seen on gross examination or light microscopy. Focal collections of lymphocytes (lymphorrhages) may be seen in affected muscle. Immunohistochemistry demonstrates the presence of IgG and complement components on the motor end plate. Electron microscopy shows damage to the motor end plate with loss of the normally complex folds.

Thymic abnormalities are seen in many patients with myasthenia gravis. These include thymic hyperplasia (presence of reactive lymphoid follicles in an adult thymus) in 65% and thymomas in 10%.

Clinical Features & Diagnosis

Myasthenia gravis is characterized by muscle weakness that is typically aggravated by repeated contraction. Muscles with the smallest motor units are affected first, the most typical clinical presentation being weakness of ocular muscles (causing bilateral ptosis, or drooping of the eyelid, and diplopia, or double vision). Twenty percent of patients with myasthenia have only ocular involvement (ocular myasthenia). In others, the disease progresses to include facial muscles, limb girdle muscles, and respiratory muscles (generalized myasthenia). Progression is variable but usually slow, with respiratory muscle involvement occurring 5–20 years after onset. Untreated, 40% of patients with myasthenia gravis will die of their disease within 10 years.

The clinical diagnosis of myasthenia gravis may be confirmed by therapeutic testing, electromyography, and serologic testing: (1) Edrophonium (Tensilon) is a short-acting anticholinesterase drug that produces immediate improvement in muscle weakness when administered intravenously; (2) Electromyography shows a progressive decline in amplitude of muscle action potentials in patients with myasthenia gravis when the muscle is subjected to repeated voluntary contraction; (3) Serum assay for antiacetylcholine-receptor antibody is an excellent test, being positive in 80% of patients with myasthenia gravis. It is highly specific, with a positive test being diagnostic of the disease. The titer of antibody does not correlate with disease severity.

Treatment

Anticholinesterases, which increase the acetylcholine levels at the motor end plate and compensate for the receptor blockage, represent the mainstay of treatment. In crisis situations, the use of high-dosage corticosteroids and plasma exchange, both of which reduce antibody activity, have proved effective.

Thymectomy produces variable remission of the symptoms of myasthenia in many patients. The improvement is most pronounced in young women with recent onset of myasthenia and thymic hyperplasia. The improvement is least in patients with thymoma. The reason for remission of myasthenia after thymectomy is unknown.

Other Causes of Neuromuscular Transmission Failure

Myasthenic Syndrome (Eaton-Lambert Syndrome)

Myasthenic syndrome is a paraneoplastic syndrome associated with cancer, particularly small-cell carcinoma of the lung. Very rarely, myasthenic syndrome occurs in patients without cancer.

Myasthenic syndrome is the result of an abnormality of acetylcholine release by nerve endings at the motor end plate caused by an autoantibody directed against calcium channels on the motor nerve terminals. It is characterized clinically by weakness of muscles in a distribution similar to that of myasthenia gravis, with early involvement of ocular muscles. The muscle weakness is not aggravated by effort and on electromyography shows progressive increase of amplitude of action potentials upon repeated contraction (an effect opposite to that seen in myasthenia gravis).

Botulism

The exotoxin of Clostridium botulinum in minute doses blocks release of acetylcholine at the motor end plate. Generalized muscle weakness rapidly leads to respiratory paralysis and death.

Tick Paralysis

Ticks of the genus Dermacentor—Dermacentor andersoni, the Rocky Mountain wood tick, and Dermacentor variabilis, the American dog tick—secrete a toxin that inhibits acetylcholine release. Removal of the tick is curative.

Aminoglycoside Drugs

Aminoglycosides in high dosage, especially in the presence of renal dysfunction, inhibit acetylcholine release and cause muscle weakness. These antimicrobial drugs should be avoided in patients with myasthenia gravis.

Neoplasms of Skeletal Muscle

Benign Neoplasms (Rhabdomyoma)

Benign neoplasms of skeletal muscle (rhabdomyoma) are extremely uncommon. Cardiac rhabdomyoma occurs rarely in patients with tuberous sclerosis (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Malignant Neoplasms (Rhabdomyosarcoma)

Rhabdomyosarcoma is an uncommon soft tissue sarcoma. Three histologic subtypes are recognized:

1. Embryonal rhabdomyosarcoma is the most common type, especially in children under 10 years of age. It presents as a rapidly growing neoplasm involving the soft tissues of the extremities, retroperitoneum, orbit, nasal cavity, and a variety of organs. It is extremely infiltrative and tends to metastasize via the bloodstream at an early stage. A special variant of embryonal rhabdomyosarcoma occurring in the vagina in very young girls is known as sarcoma botryoides. This tumor appears as an enlarging mass that protrudes from the vagina, having the appearance of a bunch of grapes. Histologically, embryonal rhabdomyosarcoma is highly cellular, being composed of small round and oval cells with primitive hyperchromatic nuclei, scanty cytoplasm, and a high mitotic rate. Skeletal muscle differentiation can be demonstrated by (1) the presence of scattered cells with abundant pink cytoplasm (strap cells) that show cross-striations; (2) the presence of irregular Z bands on electron microscopy; and (3) the presence of muscle proteins such as myoglobin, myosin, actin, and desmin as shown by immunohistochemical studies. Sarcoma botryoides is composed of similar cells but shows areas of low cellularity with myxomatous change in the stroma and a characteristic layer of small primitive cells beneath the vaginal epithelium (cambium layer). Aggressive chemotherapy has greatly improved survival of children with embryonal rhabdomyosarcoma.

2. Alveolar rhabdomyosarcoma is less common and occurs in the age group from 10 to 30 years. Patients often present with a mass around the shoulder or pelvis. The tumor is characterized by an alveolar arrangement of the small, primitive neoplastic skeletal muscle cells. Like embryonal rhabdomyosarcoma, it is rapidly growing and highly malignant. The response to chemotherapy is less satisfactory than in the embryonal type.

3. Pleomorphic rhabdomyosarcoma is an uncommon neoplasm of soft tissue that mainly affects the extremities and retroperitoneum in elderly patients. It is highly malignant and resistant to chemotherapy.