DISORDERS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS AND THE NEUROMUSCULAR JUNCTION

Focal Brain Injury: Focal brain injury is specific and involves grossly observable brain lesions. The force of impact (translational acceleration) typically produces brain contusions (bruises from blood seeping from microhemorrhages into brain tissue) and intracranial bleeding that displaces brain tissue (i.e., extradural, subdural, and intracerebral hematomas). Contusion and bleeding occur because of small tears in blood vessels resulting from these forces. The focal injury may be coup (directly below the point of impact) or contrecoup (on the pole opposite the site of impact) (Figure 17-1). Objects (e.g., baseball bat, weapon) striking the front of the head usually produce only coup injuries (contusions and fractures) because the inner skull in the occipital area is smooth. Objects striking the back of the head usually result in both coup and contrecoup injuries because of the irregularity of the inner surface of the frontal bones (see Figure 17-1). Objects striking the side of the head may produce coup or contrecoup injuries. The same is true when the head strikes an immovable object with little velocity (e.g., a short fall). Brain edema forms around and in damaged neural tissues, contributing to the increasing ICP. Within the contused areas are infarction and necrosis, multiple hemorrhages, and edema. The tissue has a pulpy quality. The maximum effects of injury related to contusion, bleeding, and edema peak 18 to 36 hours after severe head injury.

Contusions (Figure 17-2) are found most commonly in the frontal lobes, particularly at the poles and along the inferior orbital surfaces; in the temporal lobes, especially in the anterior poles and along the inferior surface; and at the frontotemporal junction. The severity of contusion is associated with the amount of energy transmitted by the skull to underlying brain tissue. In addition, the smaller the area of impact, the greater the severity of injury because the force is concentrated into a smaller area. Contusions result in changes in attention, memory, executive attentional function (motivation, goal selection or formation, planning, self-monitoring, and use of feedback), affect, emotion, and behavior. Less commonly, contusions occur in the parietal and occipital lobes. Focal cerebral contusions are superficial, involving just the gyri. Hemorrhagic contusions may coalesce into a large, confluent intracranial hematoma.

The clinical manifestations of a contusion may include immediate loss of consciousness (generally accepted to last no longer than 5 minutes); loss of reflexes, which results in the individual falling to the ground; transient cessation of respiration; brief period of bradycardia; and decrease in blood pressure (lasting 30 seconds to a few minutes). A momentary increase in cerebrospinal fluid (CSF) pressure and changes on electrocardiogram (ECG) and electroencephalogram (EEG) have been demonstrated to occur on impact. Vital signs may stabilize to normal values in a few seconds. Reflexes return next and the person begins to regain consciousness. Returning to being fully awake and alert can vary from minutes to days. Regaining a full level of consciousness may be extremely slow and residual deficits may persist. In some persons, full level of consciousness never returns. Evaluation should include a complete history and physical examination. Skull and spinal radiographs are taken frequently and a computed tomography (CT) scan or magnetic resonance imaging (MRI) may be done. Large contusions and lacerations with hemorrhage may be excised surgically. Otherwise, treatment is directed at controlling ICP and managing symptoms.

Extradural hematomas (epidural hematomas or epidural hemorrhages) represent 1% to 2% of major head injuries and occur in all age groups, but usually in people 20 to 40 years of age. Extradural hematomas are caused most commonly by motor vehicle accidents (MVAs), occasionally by minor falls and sporting accidents. A temporal fracture causes 90% of temporal lobe extradural hematomas. Direct frontal lobe trauma is associated with frontal extradural hematomas. Posterior extradural hematomas are associated with a fracture across the transverse sinus from an occipital blow.

An artery is the source of bleeding in 85% of extradural hematomas (Figure 17-3); 15% result from injury to the meningeal vein or dural sinus. Ninety percent of individuals also have a skull fracture. The temporal fossa is the most common site of extradural hematoma caused by injury to the middle meningeal artery or vein. The resulting shift of the temporal lobe medially precipitates uncal and hippocampal gyrus herniation through the tentorial notch. Extradural hemorrhages are found occasionally in the subfrontal area (especially in the young and older adult populations), caused by injury to the anterior meningeal artery or a venous sinus, and in the occipital-suboccipital area, which results in herniation of the posterior fossa contents through the foramen magnum. CT and MRI show a lens-shaped mass over the surface of the cortex.

Individuals with classic temporal extradural hematomas (i.e., over the temporal lobe) experience loss of consciousness at the time of injury, followed by a lucid period that lasts from a few hours to a few days in one third of individuals (if bleeding from a vein). As the hematoma accumulates, a headache of increasing severity, vomiting, drowsiness, confusion, seizure, and hemiparesis may develop. Level of consciousness may dwindle rapidly as temporal lobe herniation begins. Clinical manifestations of temporal lobe herniation also include ipsilateral pupillary dilation and contralateral hemiparesis.

The diagnosis of an extradural hematoma is usually made by CT or MRI. In some instances, diagnosis is made by history and clinical findings, because time for a CT or MRI is not available. The prognosis is usually good if intervention is initiated before bilateral dilation of the pupils. Surgical therapy is evacuation of the hematoma through burr holes, followed by ligation of the bleeding vessel or vessels. Extradural hematomas are almost always medical emergencies.

Subdural hematomas arise in 10% to 20% of TBIs. MVAs are the most common cause of subdural hematomas; 50% of subdural hematomas are associated with skull fractures. Falls, especially in older adults or in those with long-term alcohol abuse, are associated with chronic subdural hematomas.

Acute subdural hematomas rapidly develop (within 48 hours) and usually are located at the top of the skull (the cerebral convexities). On CT they appear as a high-density mass. Bilateral hematomas occur in 15% to 20% of persons. Subacute subdural hematomas develop more slowly, often over 48 hours to 2 weeks. On CT they appear as a mixed-density mass. Chronic subdural hematomas (commonly found in older adults and those who abuse alcohol who have some degree of brain atrophy with a subsequent increase in the extradural space) develop over weeks to months. Tearing of the bridging veins is the major cause of rapidly developing and subacutely developing subdural hematomas, although torn cortical veins or venous sinuses and contused tissue may be the source. These subdural hematomas act as expanding masses, giving rise to increased ICP that eventually compresses the bleeding vessels (Figures 17-4 and 17-5). The displacement of brain tissue can result in a herniation syndrome.

In acute, rapidly developing subdural hematomas the expanding clots directly compress the brain, giving rise to the clinical manifestations. As the ICP rises the bleeding veins are compressed and thus bleeding is self-limiting, although cerebral compression and displacement of brain tissue can cause temporal lobe herniation.

An acute subdural hematoma classically begins with headache, drowsiness, restlessness or agitation, slowed cognition, and confusion. These symptoms worsen over time and progress to loss of consciousness, respiratory pattern changes, and pupillary dilation (the symptoms of temporal lobe herniation). These manifestations are more pronounced than focal manifestations such as dysphasia, dyspraxia, or hemiparesis. Other clinical manifestations may include homonymous hemianopia (defective vision in either the right or the left field), disconjugate gaze, and gaze palsies.

The pathogenesis of a chronic subdural hematoma is different. The existing subdural space gradually fills with blood. A vascular membrane forms around the hematoma in approximately 2 weeks. Further enlargement takes place in some persons, but the mechanism of this enlargement is unclear.

Presenting manifestations of chronic subdural hematomas vary. Of those affected, 80% have chronic headaches and tenderness over the hematoma on percussion. Most appear to have a progressive dementia accompanied by generalized rigidity (paratonia).

Whereas most acute and subacute subdural hematomas are treated with clot evacuation through a burr hole, chronic subdural hematomas (and some that are subacute) require a craniotomy to evacuate the gelatinous blood. The membrane around a chronic subdural hematoma is then dissected away from the dura mater and arachnoid membranes. A technique for percutaneous drainage for chronic subdural hematomas has proved successful.

Intracerebral hematomas (intraparenchymal hemorrhages)⁴ occur in 2% to 3% of head injuries usually associated with MVAs and falls from some distance. Intracerebral hematomas may be single or multiple, and they are associated with contusions. Although most commonly located in the frontal and temporal lobes, intracerebral hematomas may occur in the hemispheric deep white matter. Small blood vessels are traumatized by penetrating injury or shearing forces. The intracerebral hematoma then acts as an expanding mass, resulting in increased ICP and compression of brain tissues with resultant edema (Figure 17-6). Delayed intracerebral hematomas may appear 3 to 10 days after the head injury.

A decreasing level of consciousness is associated with an intracerebral hematoma. Coma or a confusional state from other injuries, however, can make the cause of this increasing unresponsiveness difficult to detect. Contralateral hemiplegia also may occur. As the ICP rises, clinical manifestations of temporal lobe herniation may appear. In delayed intracerebral hematoma, the presentation is similar to that of hypertensive brain hemorrhage: sudden, rapidly progressive decreased level of consciousness with pupillary dilation; breathing pattern changes; hemiplegia; and bilateral positive Babinski reflexes.

Evacuation of a singular intracerebral hematoma has only occasionally been helpful, mostly for subcortical white matter hematomas. Otherwise, treatment is directed at reducing the ICP and allowing the hematoma to reabsorb slowly.

Open trauma produces discrete (focal) injuries and includes compound fractures and missile injuries. A compound fracture opens a communication between the cranial contents and the environment and should be investigated whenever there are lacerations of the scalp, tympanic membrane, a sinus, an eye, or mucous membranes. Such fractures may involve the cranial vault or the base of the skull (basilar skull fracture). The injury incurred from bone fragments is mainly a tangential injury (injury caused by direct contact) and occasionally a penetrating injury. Bone fragments may lacerate or contuse brain tissues or blood vessels. In addition, cranial nerves may be damaged with a basilar skull fracture.

Missiles include bullets, rocks, shell fragments, knives, and blunt instruments. The mechanisms of injury are crush injury and stretch injury. Crush injury is the laceration and crushing of whatever tissue the missile touches, with the amount of crush related to the degree of fragmentation, deformity, size, and shape. A tangential injury is injury to the coverings of the brain (scalp lacerations), skull fractures, laceration of the meninges, and cerebral lacerations. Projectiles and debris from scalp and skull injury, when driven into the brain substance, produce a penetrating brain injury. Occasionally projectiles are so forceful that they exit the cranial vault in addition to entering it, producing a through-and-through injury. Primary damage is localized along the path of the penetrating object, and direct tissue disruption along the projectile tract results. A high-velocity bullet produces contusions at the site of entry, caused by bone striking the brain tissue on impact. Bone fragments are driven inward.

Stretch injury involves blood vessels and nerves that are damaged without direct contact due to the amount of tissue stretched secondary to shape, deformation, and striking velocity. Air compressed in front of a bullet exerts an explosive effect on entry, producing extreme distant tissue damage and an immediate primary increase in ICP; a cavity many times greater than the size of the bullet is produced because the brain tissue is propelled away from the tract. The cavity and pressure produce contrecoup injuries. The intracranial volume is increased directly by the projectile and the debris. The temporary cavity collapses back onto itself, leaving a smaller, permanent cavity. Intracranial bleeding occurs into the permanent cavity and may cause the cavity to expand. Edema in and around the injured brain tissue rapidly develops; edema and bleeding contribute markedly to ICP. This second rise in ICP to 60 to 100 mmHg may last 2 to 5 minutes. Because of acute ischemic damage to the tract, necrosis of tissue begins. Within hours after bullet-induced injury, tissue within 1 cm adjacent to the tract disintegrates. Demyelination of white matter affected by hemorrhage and edema occurs by the second day. Unconsciousness, flaccidity, or decerebrate posture (see Chapter 16) are associated with a 94% mortality.

With open-head injury, most victims lose consciousness. The depth of the coma and the length of the unresponsive state are related to the location of injury, extent of damage, and amount of bleeding. Open-head injury often requires surgery to débride the traumatized tissues to prevent infection and to remove blood clots to help reduce the ICP. ICP also is managed with steroids, dehydrating agents, osmotic diuretics, or a combination of these drugs. Broad-spectrum antibiotics are administered.

The diagnosis of a compound fracture is made through physical examination, skull radiographs, or both. The diagnosis of a basilar skull fracture is made on the basis of clinical findings. Skull radiographs often do not demonstrate the fracture, although intracranial air or air in the sinuses on radiograph, CT, or MRI is indirect evidence of a basilar skull fracture.

A compound linear fracture is débrided nonsurgically in cooperative adults and surgically in children and uncooperative adults. Cranioplasty with insertion of bone or an artificial graft may be necessary but often is delayed until antibiotics have been given. Antibiotics are administered after surgery.

Bed rest and close observation for meningitis and other complications are prescribed for a basilar skull fracture. Use of prophylactic antibiotics is controversial because studies have failed to demonstrate that they reduce the rate of infection.

Diffuse Brain Injury: Diffuse brain injury (diffuse axonal injury [DAI]) results from a shaking effect (inertial effects of mechanical input to the head associated with high levels of acceleration and deceleration, effects of head motion). Rotational acceleration (twisting movement) is the primary mechanism of injury, producing strains and distortions within the brain (see Figure 17-1). The brain tissues experience shearing stresses set up by the rotational forces that operate when a freely moving head is struck because of the skull’s motion from its attachment to the neck. Shearing, tearing, or stretching of nerve fibers with subsequent axonal damage results. Forces applied axially as a result of centrifugal acceleration of the head establish a gradient of injury severity from the hemispheres to the brain stem. The most severe axonal injuries are located more peripheral to the brainstem, thus accounting for the tremendous cognitive and affective impairments seen in survivors of traumatic brain injury from MVAs. The frontal and temporal axonal tracts are particularly vulnerable. Damage reduces the speed of informational processing and responding and disrupts attention.

The common pathologic substrate in diffuse brain injury is axonal damage (disruption). Pathophysiologically, at the time of injury, the damage can be seen only with an electron microscope and involves either numerous axons alone or axonal injury in conjunction with actual tissue tears (Figure 17-7). Areas where axons and small blood vessels are torn appear as small hemorrhages, located particularly in the corpus callosum and dorsolateral quadrant of the rostral brain stem at the superior cerebellar peduncle.

Oxygen-free radicals contribute to secondary injury. Free radicals damage proteins and the phospholipid components of cells and organelle membranes. Membrane depolarization caused by the trauma permits nonselective opening of voltage-sensitive calcium channels, resulting in abnormal calcium accumulation in neurons and glial cells. These calcium shifts are associated with activation of lipolytic and proteolytic enzymes, protein kinases, protein phosphatases, dissolution of microtubules, and altered gene expression. Abnormal calcium influx occurs through activation of excitatory amino acid receptors. Widespread exotoxicity occurs after trauma, resulting in cell swelling, vacuolization, and death.⁴

Progressively increasing numbers of damaged axons are visible 12 hours to several days after the injury. Chromatolysis of the neurons involving eccentric relocation of the nucleus, swelling of the axon hillock, and redistribution of the rough endoplasmic reticulum in the cell body is evident. During this time the torn axons, which resemble dilated sausage links, also regress into round balls called retraction balls. These retraction balls are visible with light microscopy.

The number of retraction balls increases during the first week or two but begins to diminish in 2 to 3 weeks. Clusters of microglia appear in their place. Lastly, astrocytosis (gliosis, equivalent to scarring) occurs at the sites of axonal damage. Demyelination is seen particularly in the long axon tracts of the upper brainstem.

Severity of the diffuse injury correlates with the direction and velocity of rotation, that is, how much shearing force was applied to the brainstem. Figure 17-8 illustrates the spectrum of the diffuse injury as the magnitude increases. DAI is not associated with intracranial hypertension soon after injury, but acute brain swelling (increased intravascular blood within the brain, vasodilation, and increased cerebral blood volume) is seen often.

Several categories of diffuse brain injury exist: mild concussion, classic concussion, mild DAI, moderate DAI, and severe DAI. An organic component is present within each category, in contrast to the previous conceptualization that concussion had no structural injury component.

Mild concussion involves temporary axonal disturbances. Cerebrocortical dysfunction related to attentional and memory systems results, but consciousness is not lost. Three forms have been described:

Recommended guidelines for return to play after sports-related concussive injuries are contained in What’s New? Sports-Related Concussion.

Mild concussion is characterized by an immediate onset of clinical manifestations at the time of injury and the transitory nature of clinical manifestations. A momentary rise in CSF pressure and changes in ECG and EEG have been demonstrated to occur on impact in the laboratory. No loss of consciousness is experienced. The initial confusional state exists for a moment to several minutes. Amnesia for events preceding the trauma (retrograde amnesia) may be experienced. Anterograde amnesia may exist transiently. Persons may experience head pain and complain of nervousness and “not being oneself” for up to a few days.

Classic cerebral concussion (grade IV) involves diffuse cerebral disconnection from the brainstem reticular activating system and is a phenomenon of physiologic, neurologic dysfunction without substantial anatomic disruption. Evidence of this disconnection is the immediate loss of consciousness, which lasts less than 6 hours. Retrograde and anterograde (posttraumatic) amnesia is present. This type of diffuse injury frequently is associated with focal pathologic findings, especially cerebral contusions that yield focal signs, not loss

of consciousness. There are two forms of classic cerebral contusion: uncomplicated classic cerebral concussion (without focal injury) and complicated classic cerebral concussion (accompanied by focal injury).

In classic cerebral concussion loss of consciousness lasts as long as 6 hours and reflexes are lost, causing falls. Reflexes are regained as responsiveness returns. Transient cessation of respiration, brief periods of bradycardia, and a decrease in blood pressure lasting 30 seconds or less occur. Vital signs stabilize within a few seconds to within normal limits. Retrograde and anterograde amnesia exist. A confusional state persists for hours to days. The individual experiences head pain, nausea, and fatigue. Attentional and memory system impairments may persist for weeks to months and may include inability to concentrate and forgetfulness. Mood and affect changes may persist for weeks to months and may include nervousness, anxiety reactions, depression, irritability, fatigability, and insomnia.

Some of the effects of a concussion may persist for weeks or months, depending on the severity of the injury. Fifty percent of persons have a postconcussive syndrome that includes headache, cognitive impairments, psychologic and somatic complaints, and cranial nerve signs and symptoms.⁴ Treatment entails reassurance and symptomatic relief. Close observation for 24 hours by a reliable individual is indicated so that immediate intervention can be obtained if delayed effects become severe.

DAI produces prolonged traumatic coma lasting more than 6 hours because of axonal disruption. Three forms of DAI exist: mild, moderate, and severe. In mild diffuse axonal injury, posttraumatic coma lasts 6 to 24 hours. Death is uncommon but residual cognitive, psychologic, and sensorimotor deficits may persist. Mild DAI is a relatively uncommon lesion, occurring in 8% of all severe head injuries and 19% of all cases of DAI. In mild DAI 30% of persons display decerebrate or decorticate posturing; they may experience prolonged periods of stupor or restlessness (see Figure 16-5).

In moderate diffuse axonal injury, widespread physiologic impairment exists throughout the cerebral cortex and diencephalon. Actual tearing of some axons in both hemispheres occurs. Basal skull fracture, a focal injury, is commonly associated with moderate DAI. Prolonged coma lasting more than 24 hours is present but prominent brainstem signs do not exist with moderate DAI. Recovery often is incomplete in 93% of those individuals who survive. Moderate DAI is the most common type of DAI and is found in 20% of severe head injuries and 45% of all cases of DAI.

In moderate DAI, the GCS score is 4 to 8 initially and 6 to 8 by 24 hours. Thirty-five percent of victims have transitory decerebration or decortication. The person often remains unconscious for days or weeks and on awakening is confused. He or she experiences a long period of posttraumatic anterograde and retrograde amnesia and often has permanent deficits in memory, selective attention, vigilance, detection, working memory, data processing, vision or perception, and language, as well as mood and affect changes ranging from mild to severe.

Severe diffuse axonal injury, formerly called primary brainstem injury or brainstem contusion, involves severe mechanical disruption of many axons in both cerebral hemispheres and those extending to the diencephalon and brainstem. Severe DAI represents 16% of all severe head injuries and 36% of all cases of DAI. With an initial GCS score of 3, the mortality rate is 78%²; with an initial score between 3 and 8, the mortality rate is 36%; and 16% of persons have either a moderate or severe disability and 5% survive in a coma (unresponsive) state.²

Severe DAI is associated with brainstem signs that disappear in a few weeks. The person experiences immediate autonomic dysfunction that resolves in a few weeks. Increased ICP appears 4 to 6 days after injury. Pulmonary complications occur frequently, with profound sensorimotor and cognitive system deficits. Severely compromised coordinated movements and verbal and written communication, inability to learn and reason, and inability to modulate behavior also are found.

CT scan and MRI are the diagnostic tests of choice for TBI.^2,5 There is no strong research evidence that any treatment reduces the complications of moderate to severe TBI, although various treatment protocols are instituted. Specifically, the evidence is inconclusive about the effectiveness of hyperventilation, mild hypothermia, and use of mannitol.² Barbiturates have not been shown to be effective in reducing intracranial pressure or preventing adverse outcomes after TBI.² The Corticosteroid Randomisation After Significant Head Injury (CRASH) trial showed corticosteroids increase mortality with acute TBI, so these drugs are no longer used. Carbamazepine and phenytoin may reduce the occurrence of early seizures but have not been shown to reduce the onset of late seizures, neurologic disability, or death.² Prophylactic antibiotics also have not been shown to reduce the risk of meningitis or death with a skull fracture.² Extensive research is under way to discover effective therapeutic interventions. The role of fluid and nutrition management has emerged as critically important in the care of individuals with severe brain injuries.⁶

Thrombotic Stroke: Thrombotic strokes (cerebral thrombosis) arise from arterial occlusions caused by thrombi formed in the arteries supplying the brain or in the intracranial vessels. The development of a cerebral thrombosis most frequently is attributed to atherosclerosis and inflammatory disease processes (arteritis) that damage arterial walls. Increased coagulation can lead to thrombus formation. Conditions causing inadequate cerebral perfusion (e.g., dehydration, hypotension, prolonged vasoconstriction from malignant hypertension) increase the risk of thrombosis. Over 20 to 30 years atheromatous plaques (stenotic lesions) tend to form at branchings and curves in the cerebral circulation. The smooth stenotic area can degenerate, forming an ulcerated area of vessel wall. Platelets and fibrin adhere to the damaged wall, and clots form, gradually occluding the artery. The thrombus may enlarge both distally and proximally in the vessel. Portions of the clot break off and travel up the vessel to distant sites where occlusion occurs, producing a stroke syndrome.

The distinction between transient ischemic attacks and thrombotic stroke is losing importance. With increasing use of brain imaging, many persons with symptoms lasting less than 24 hours are found to have had a brain infarction. The new definition for transient ischemic attack (TIA) is a brief episode of neurologic dysfunction caused by a focal disturbance of brain or retinal ischemia with clinical symptoms typically lasting less than 1 hour and without evidence of infarction.¹⁷ TIAs probably represent thrombotic particles causing an intermittent blockage of circulation or spasm. Recurrence of symptoms is 10.7% at 90 days, 60% at 6 months, and 80% at 1 year without definitive treatment.¹⁷

Embolic Stroke: Cardioembolism accounts for 30% of all CVAs, 25% to 30% of strokes in persons less than 45 years of age.¹⁹ An embolic stroke involves fragments that break from a thrombus formed outside the brain or in the heart, aorta, common carotid, or thorax. Emboli infrequently arise from the ascending aorta or common carotid artery. The embolus usually involves small vessels and obstructs at a bifurcation or other point of narrowing, thus causing ischemia. An embolus may plug the lumen entirely and remain in place or break into fragments and move up the vessel. High-risk sources for the onset of embolic stroke are atrial fibrillation (15% to 25% of strokes), left ventricular aneurysm or thrombus, left atrial thrombus, recent myocardial infarction, rheumatic valvular disease, mechanical prosthetic valve, nonbacterial thrombotic endocarditis, bacterial endocarditis, patent foramen ovale, and primary intracardiac tumors.^19,20 In persons who experience an embolic stroke, a second stroke usually follows at some point because the source of emboli continues to exist. The 7-day recurrence risk is 6.5%, in-hospital mortality is 27.3%, and 5-year prognosis is as high as 80%.¹⁹ Embolization is usually in the distribution of the middle cerebral artery.

Hemorrhagic Stroke: Hemorrhagic stroke (intracranial hemorrhage [ICH]) is the third most common cause of CVA (10% of strokes) and accounts for 10% to 15% of CVAs in whites but 30% in blacks and Asians.¹⁸ There are 40,000 ICHs in the United States per year.²¹ The most common causes of spontaneous primary hemorrhagic strokes are hypertension (56% to 81%), ruptured aneurysms, arteriovenous malformation and fistula, amyloid angiopathy, and cavernous angioma.²¹ ICH can occur secondary to TBI, bleeding into the ischemic brain infarction or tumor, or a bleeding disorder or anticoagulation. Risk factors for hemorrhagic stroke include hypertension, previous cerebral infarct, coronary artery disease, and diabetes mellitus.

A hypertensive hemorrhage is associated with a significant increase in systolic and diastolic pressure over several years and usually occurs within the brain tissue. A mass of blood is formed, and its volume increases. Adjacent brain tissue is displaced and compressed and rupture or seepage into the ventricular system occurs in many cases. Hemorrhages are described as massive, small, slit, or petechial. A massive hemorrhage is several centimeters in diameter; a small hemorrhage is 1 to 2 cm in diameter; a slit hemorrhage lies in the subcortical area; and a petechial hemorrhage is the size of a pinhead bleed. The most common sites for hypertensive hemorrhages are in the putamen of the basal ganglia (a portion of the lentiform nucleus) (40%), the thalamus (15%), the cortex and subcortex (22%), the pons (8%) (Figure 17-16), caudate (7%), and cerebellar hemispheres (8%).

Lacunar Stroke: A lacunar stroke (lacunar infarct) is a microinfarct smaller than 1 cm in diameter and involves the small perforating arteries, predominantly in the basal ganglia, internal capsules, and pons. Lacunar infarcts are caused by lipohyalinosis, subintimal lipid-loading foam cells, and fibrinoid materials that thicken the arterial walls and are associated with smoking,¹⁸ hypertension, and diabetes mellitus. Because of the subcortical location and small area of infarction, these strokes may have pure motor and sensory deficits.

PATHOPHYSIOLOGY

Cerebral Infarction: Cerebral infarction results when an area of the brain loses blood supply because of vascular occlusion. The pathologic manifestation is either (1) a global process that affects neurons most susceptible to ischemia (pyramidal and striatal neurons), Purkinje cells of the cerebral hemispheres, and the border zones at the very end of the arteries’ circulation; or (2) a focal process with a central zone of cell loss surrounded by a zone of injured cells, the ischemic penumbra, that if perfused in 1 hour will survive. Proposed pathogenesis may include (1) abrupt vascular occlusion (e.g., embolus), (2) gradual vessel occlusion (e.g., atheroma), and (3) vessels that are stenosed but not completely occluded. Cerebral thrombi and cerebral emboli are the most common causes of occlusion, but atherosclerosis and hypotension are the dominant underlying processes.

Cerebral infarctions are ischemic or hemorrhagic. In ischemic infarcts (pale infarcts, “white stroke”), cytotoxic ischemic events and interaction between blood elements and blood vessels combine to produce brain injury. The affected area becomes slightly discolored and softens about 6 to 12 hours after the occlusion. Necrosis, swelling around the insult, and mushy disintegration have appeared by 48 to 72 hours after infarction. At a microscopic level, neuronal cell bodies change, myelin sheaths and axis cylinders are interrupted and disintegrate, and there is loss of oligodendrites and astrocytes.

Cellular and biochemical events involve the loss of glucose and oxygen delivery resulting in depletion of high-energy phosphate compounds (failure of mitochondrial energy production) allowing cell membrane depolarization. With membrane depolarization, neurotransmitters, including glutamate, are released and cannot be reuptaken. Glutamate promotes excess entry of extracellular calcium. Unregulated, elevated calcium concentrations activate degrading enzymes.²² Production and accumulation of lactic acid also result in an associated focal vasodilation. Infarcted areas may lose autoregulation of blood flow.

A syndrome of luxury perfusion in areas adjacent to the infarct develops first from the loss of autoregulation. The vascular bed in this area dilates. Later, capillary sprouting (neovascularization) supports this luxury perfusion syndrome.

In hemorrhagic infarcts (“red strokes”), bleeding occurs into the infarcted area as a result of restoration of blood flow. Reperfusion occurs when the embolus fragments, or lysis or compressive forces lessen, allowing blood flow to be reestablished into the infarcted area. Most hemorrhagic infarcts are located in the cerebral cortex. Unfortunately, reperfusion has been shown to compromise recovery by accelerating the sequence of metabolically damaging events including oxidative stress (reperfusion injury).

Cerebral Hemorrhage: The primary cause of cerebral hemorrhage is hypertension. (Aneurysms and arteriovenous malformations are discussed on pp. 606-608.) The pathogenesis of hypertensive cerebral hemorrhage is not fully understood. Hypertension involves primarily smaller arteries and arterioles, resulting in thickening of the vessel walls, and increased cellularity of the vessels and hyalinization. Necrosis may be present. Microaneurysms in these smaller vessels or arteriolar necrosis precipitates the bleeding.

A mass of blood is formed as bleeding continues into the brain tissue. In massive ICH (volume greater than 150 ml), cerebral perfusion falls to zero and cerebral blood flow stops, resulting in death.²¹ Adjacent brain tissue is deformed, compressed, and displaced. Necrosis around the hematoma is present within 6 hours. Edema forms and the blood-brain barrier is disrupted. An inflammatory reaction in surrounding brain tissue appears rapidly and peaks in several days.²¹ Figure 17-17 illustrates additional detail. Rupture or seepage of blood into the ventricular system occurs in many cases.

The cerebral hemorrhage resolves through reabsorption. Macrophages and astrocytes appear to clear away the blood. A cavity forms, surrounded by a dense gliosis after removal of the blood.

CLINICAL MANIFESTATIONS Because neurons surrounding the ischemic or infarcted areas undergo changes that disrupt plasma membranes, cellular edema results, causing further compression of capillaries. Most persons survive an initial hemispheric ischemic stroke unless massive cerebral edema develops. However, massive brain stem infarcts, caused by basilar thrombosis or embolism, are almost always fatal.

Clinical manifestations of thrombotic stroke vary, depending on the artery obstructed. Different sites of obstruction create different occlusion syndromes (Table 17-6).

With hemorrhagic stroke, clinical manifestations vary according to the location and size of the bleed. Focal neurologic deficits are found in 80% of individuals experiencing hemorrhagic strokes; altered consciousness occurs in 50%. Once a deep unresponsive state occurs the immediate prognosis is grave, and the individual rarely survives. If the person survives, however, recovery of function frequently is possible.

Individuals experiencing intracranial hemorrhage from a ruptured or leaking aneurysm have one of three sets of symptoms: (1) onset of an excruciating generalized headache with an almost immediate lapse into an unresponsive state; (2) headache, but with consciousness maintained; and (3) sudden lapse into unconsciousness. If the hemorrhage is confined to the subarachnoid space, there may be no local signs. If bleeding spreads into the brain tissue, hemiparesis/paralysis, dysphasia, or homonymous hemianopia may be present. Warning signs of an impending aneurysm rupture may include headache, transient unilateral weakness, transient numbness and tingling, and transient speech disturbance. Warning signs, however, often are not present.

EVALUATION AND TREATMENT No identifiable cause can be established by conventional diagnostic tests in up to 40% of CVAs and are classified as having “undetermined” or “cryptogenic” mechanisms.²⁰ The principle of acute stroke treatment is “time is brain.” Time to treatment is often too great considering the time limits for reversibility of brain ischemia. Treatment needs to be initiated within 6 hours of symptom onset. Research evidence related to acute stroke management is as follows:

Research evidence preventing a recurrence is as follows:

Rehabilitation is indicated in thrombotic and embolic stroke. Treatment of an intracranial bleed, regardless of cause, is focused on stopping or reducing the bleeding, controlling the increased ICP, preventing a rebleed, and preventing vasospasm. Occasionally an attempt is made to evacuate or aspirate the blood.

Astrocytoma: Astrocytomas are the most common primary CNS tumors (50% of all brain and spinal cord tumors). Astrocytomas develop from astrocytes and grow by expansion and infiltration into the normal surrounding brain tissues. These tumor cells are believed to have lost normal growth restraint, and thus they proliferate uncontrollably.

One third of astrocytomas are classified at diagnosis as grade I or grade II. These slow-growing but infiltrative gliomas tend to form cavities (pseudocysts); however, some are firm, noncavitating, avascular, gray-white masses that are difficult to distinguish from normal white matter of the brain. Although these tumors may occur anywhere in the brain or spinal cord, they are located most commonly in the cerebrum, hypothalamus, or pons. Low-grade astrocytomas in adults tend to have a lateral or supratentorial location, and they tend to be midline or near midline in position in children, often in the posterior fossa.

Headache and subtle neurobehavioral changes may be an early symptom. Approximately half of persons with low-grade astrocytomas experience a focal or generalized seizure. Onset of a focal seizure disorder between the second and sixth decades of life is suggestive of an astrocytoma. Other general or focal neurologic manifestations develop gradually. Increased ICP is usually a late clinical manifestation.

Grade I astrocytomas are treated with surgery and follow-up CT scans. Grade II astrocytomas are treated surgically if they are accessible or by conventional external radiation, local radiation, or stereotactic radiosurgery. Following surgery alone, the 5-year survival rate is 25%; with surgery followed by radiotherapy, the 5-year survival rate is 50%.

Grades III and IV astrocytomas are found predominantly in the frontal lobes and cerebral hemispheres (Figures 17-25 and 17-26). These tumors also may be located in the brainstem (Figure 17-27), cerebellum, and spinal cord. They are found twice as frequently in men as in women. Grades III and IV astrocytomas are the third most common cancer in the 15- to 34-year-old age group and the fourth most common in the 35- to 54-year-old age group.⁴⁶ Grades III and IV astrocytomas are often large and well circumscribed with a variegated pattern. The peripheral rim is pinkish gray and solid with a soft, yellow necrotic center and points of hemorrhage. Microscopically, there is increased cellularity, vascular proliferation, cellular pleomorphism, and necrosis. Necrosis is the main histologic difference between an anaplastic grade III tumor and a grade IV glioblastoma multiforme.

Grade IV glioblastoma multiformes are highly vascular and extensively infiltrative. They may become large enough to extend from the meningeal surface through the ventricular wall. Fifty percent of glioblastomas are bilateral or at least occupy more than one lobe at the time of death. There are reports of grade IV astrocytomas found outside the central nervous system.⁵¹

The typical clinical presentation for a glioblastoma multiforme is that of diffuse, nonspecific clinical manifestations, such as headache, irritability, and personality changes, that progress to more clear-cut manifestations of increased ICP, such as headache on position change; papilledema; or vomiting. Of those affected, 30% to 40% experience seizure activity. Symptoms may progress to definite focal signs, such as hemiparesis, dysphasia, dyspraxia, cranial nerve palsies, and visual field deficits, in addition to the generalized signs from increased ICP.

Diagnosis of high-grade astrocytomas most commonly takes 3 to 6 months from onset of the first clinical manifestations because the person does not recognize the need to consult a healthcare provider.

Grade III astrocytomas are treated with surgery if they are accessible; radiotherapy; and chemotherapy possibly before, during, and after other therapies. Chemotherapy is given in cycles. With treatment, 1-year survival for grade III astrocytomas is 55% to 60%, 30% to 35% survive 2 years, and 10% survive longer than 5 years. Grade IV gliomas are also treated with surgery if accessible, radiotherapy and chemotherapy, or placement of wafers. The median survival rate is 3 years.⁴⁶

Oligodendroglioma: A far less commonly occurring glioma is oligodendroglioma, comprising 2% of all brain tumors and 10% to 15% of all gliomas. Oligodendrogliomas are typically slow-growing well-differentiated tumors, often with cysts and calcification present. Most are macroscopically indistinguishable from other gliomas. They occur most often from 30 to 50 years of age and are more common in males than females. Their etiology is unknown. Most oligodendrogliomas are in the frontal and temporal lobes, often in deep white matter; 20% are in both hemispheres. They may be found also in other parts of the cerebrum, third ventricle, brainstem, cerebellum, and spinal cord. A high incidence of this tumor occurs in young adults with a history of temporal lobe epilepsy. Approximately half of these tumors generally classified as oligodendrogliomas (a grade II tumor) are actually oligoastrocytomas (a grade III tumor).⁵² Malignant degeneration occurs in approximately one third of persons with oligodendrogliomas. If there is extension to the pia mater or ependymal wall (see Figure 14-15), oligodendrogliomas may metastasize to distant CNS sites through the ventriculoarachnoid spaces.

More than 50% of individuals experience a focal or generalized seizure as the first clinical manifestation; approximately half have experienced increased ICP at the time of diagnosis and surgery, and only one third develop any focal manifestations. The time from first clinical manifestation to surgical intervention often ranges from 2 to 6 years. Treatment options are surgery; radiotherapy (conventional external beam or stereotactic gamma knife and converged beam); and chemotherapy before, during, and after radiation. Median survival, when surgery and radiotherapy are both used, is 5 to 10 years.⁴⁶

Ependymoma: Ependymomas are gliomas that arise from ependymal cells that form the walls of the ventricles and grow either into the ventricle or into adjacent brain tissue; they are not encapsulated (Figure 17-28 and see Table 17-9). They comprise 6% of all primary brain tumors in adults and 10% in children and adolescents. Among children and adolescents, 50% of those affected are younger than 5 years of age. Seventy percent of ependymomas occur in the fourth ventricle (i.e., in the posterior fossa) and manifest as difficulty with balance, unsteady gait, uncoordinated muscle movement, and difficulty with fine motor skills. Other common sites for ependymomas are the third ventricle, lateral ventricles, and caudal portion of the spinal cord. The clinical presentation of a lateral and third ventricle ependymoma that involves the cerebral hemispheres is seizures, visual changes, and contralateral weakness of a body part on one side of the body. Approximately 40% of infratentorial ependymomas occur in children younger than 10 years. Occurrence of cerebral (supratentorial) ependymomas is distributed among all ages but more common in adults. Etiology for these tumors is unknown.

Blockage of the CSF pathway by the tumor clinically results in the presence of headache, nausea, and vomiting related to the hydrocephalus produced. Brainstem or upper spinal cord ependymomas may cause neck pain as well.

Clinical manifestations and progression of dysfunction associated with ependymomas may follow a short or long course. The interval between first manifestations and surgery may be as short as 4 weeks with some ependymoblastomas to as long as 7 to 8 years with others.

Ependymomas are treated surgically and with radiotherapy of the tumor region and operative site (possibly of the entire brain and spine); stereotactic radiosurgery focused on eradication; and chemotherapy. The 5-year survival rate is between 20% and 50%. Some persons benefit from a shunting procedure when the ependymoma has caused a noncommunicating hydrocephalus (see Chapter 16).

Meningioma: Meningioma constitutes about 20% of all intracranial tumors. The annual incidence is 6 cases per 100,000, with a peak incidence in the sixth and seventh decades, and is more common in women.⁵³ Predisposing factors to developing a meningioma are having neurofibromatosis (NF) type 2 (NF2, see p. 616) and ionizing radiation after a several-decade latency period.⁵⁴ Genetically, formation of benign meningiomas has been linked to NF2 gene mutation and chromosome 22q loss along with DAL-1 loss on chromosome 18. Atypical and anaplastic meningiomas have been linked to additional gene alterations involving multiple other chromosomes.⁵⁵

A meningioma is a sharply circumscribed mass that derives its shape from the space it occupies; the cause is unknown. These slow-growing, often encapsulated tumors arise from arachnoidal (meningeal) cap cells in the dural coverings of the brain.⁵⁶ Rarely do meningiomas arise from arachnoid cells of the choroid plexus of the ventricles. Most are attached to the dura mater and arise within the intracranial cavity, the spinal cavity, or, rarely, the orbit (Figure 17-29).⁵⁶ A meningioma may extend to the dural surface and erode the cranial bones or produce an osteoblastic reaction. Small meningiomas (less than 2 cm in diameter) are often found on postmortem examination in middle-aged and older adults who had experienced no clinical manifestations and died of totally unrelated causes. A few meningiomas exhibit malignant, invasive qualities.

Only when meningiomas reach a certain size—at which time they begin to indent the brain parenchyma—do they begin to produce clinical manifestations. Focal seizures are frequently the first manifestation. Other clinical manifestations depend on the tumor’s location. Clinical features based on site of origin are as follows:

Because of the extremely slow-growing nature of most meningiomas, increased ICP is less common than with gliomas.

The most common symptom is seizures (40%). Diagnosis is made using contrast-enhanced CT, MRI, or both. The primary treatment is surgical resection. Sterotactic radiotherapy is used with incomplete resection or recurrence (20% rate). Conventional radiotherapy also is used. Hydroxyurea has been used in recurrence.⁵⁷

Nerve Sheath Tumors: Nerve sheath tumors are either neurofibroma or schwannoma (neuroma, neurolemma). NF is an inherited autosomal dominant disorder accounting for 5% of all neuromas and are divided into two types: NF1 and NF2, which are clinically and genetically distinct disorders. The gene products are neurofibromin and merlin (schwannomin), both of which are thought to be tumor suppressors.⁵⁸ Alterations in chromosomes 17 (17q11.2 for NF1) and 22 (NF2) are associated with both neurofibromas and schwannomas.⁵⁹ NF1 is associated with cutaneous manifestations, iris hamartomas, and tumors primarily involving the peripheral nervous system and, occasionally, the CNS.⁶⁰ NF2 is associated with cataracts, hearing loss and tumors primarily in the CNS, most commonly vestibular schwannoma.⁶⁰ Criteria for the diagnosis of neurofibromatosis types 1 and 2 are presented in Box 17-2. The remainder of neuromas is benign tumors that arise from the sheath of Schwann cells surrounding the axons of the cranial nerves. The tumors most commonly affect people older than 50 years, women more often than men. The vestibular division of cranial nerve VIII is most commonly affected, although neuroma of the acoustic division of cranial nerves VIII, V, VII, and IX are found (Figure 17-30).

The tumor originates most commonly just distal to the junction between the nerve root and the brainstem. As the tumor grows, it extends into the posterior fossa to occupy the cerebropontine angle and compress adjacent nerves. Eventually the brainstem is displaced, and the CSF flow is obstructed.

Initial clinical manifestations may include headache, tinnitus, hearing loss, impaired balance, unsteady gait, facial pain, and loss of facial sensations. Later, vertigo with nausea and vomiting, a sense of pressure in the ear, and moderate to severe unsteadiness with rapid position changes may appear. CT or MRI can establish the diagnosis. Posterior fossa dye studies may be required. Treatment is by surgical excision and radiotherapy of the neuroma. Pituitary tumors are discussed in Chapter 21, and cerebral tumors in children are discussed in Chapter 19.

Brain Metastases: Brain metastases are approximately 10 times more common than primary brain tumors. The incidence may be as high as 200,000 cases per year. At autopsy, 20% to 40% of persons with metastases have brain metastases. Lung and breast are the most common tumors to have brain metastases within 1 to 3 years, but renal cell carcinoma, and malignant melanomas have an even higher brain metastasis incidence.⁶¹ Carcinoma of the gallbladder, liver, thyroid, testes, uterus, ovary, and pancreas also may metastasize to the brain. Other tumors, besides carcinomas, that metastasize only occasionally are rhabdomyosarcomas, Ewing tumors, chorioepithelioma, and lymphoma.

Metastasis of a cancer to the brain parenchyma or the meninges is a late occurrence in the disease process. Metastasis to the brain parenchymna is believed to be hematogenous in origin.⁶² Two thirds of metastatic tumors are located within the brain and one third are located in extradural spaces. The cerebral hemispheres are the site of 75% of metastases, most predominantly in the frontal lobes followed by the parietal, occipital, and temporal lobes in order of frequency of location. Tumors of the pelvis or retroperitoneal space have a predilection to metastasize to the cerebellum, pons, or their coverings.⁶³ In more than three fourths of persons with metastasis, the metastases are multiple and found in both the cerebrum and cerebellum in a scattered distribution. The metastatic tumors often are located in the meninges and near the brain surface in the gray matter and subcortical white matter. These tumors produce little glial cell reaction in the brain tissue but do cause vasogenic, peritumoral edema in the surrounding brain tissue due to blood-brain barrier incompetence.⁶²

The brain metastatic process requires a series of sequential events, called the “metastatic cascade,” as follows:

Hematogenesis metastasis to the CNS is an inherently inefficient process depending on an interaction between tumor cells with host defenses and the microenvironment. To produce brain metastasis, tumor cells must reach the brain vasculature by attaching themselves to the endothelial cells of the brain microvessels in the blood-brain barrier, extravasate into the brain parenchyma, induce blood vessel development (angiogenesis), and proliferate in response to growth factors. Local brain invasion, in itself, is a process requiring mechanisms for cell motility, cell adhesion, and enzymatic remodeling of the extracellular components. Cytokines, chemokines, and growth factors have been demonstrated to participate in the process.⁶⁴

The clinical manifestations of parenchymal brain metastasis are headache or alteration in cognition, mental status, and behavior,⁶² although several unusual syndromes do exist. Carcinomatous encephalopathy causes headache, nervousness, depressed mood, trembling, confusion, and forgetfulness. In carcinomatosis of the cerebellum, headache, dizziness, and ataxia are found. Carcinomatosis of the craniospinal meninges (carcinomatous meningitis) manifests with headache, confusion, and manifestations of cranial or spinal nerve root dysfunction.

Contrasted enhancing imaging is the most sensitive imaging procedure for metastatic brain tumors. Prognosis is poor. If one to three tumors are found, surgical excision is indicated. Radiotherapy is commonly used to treat solitary as well as multiple tumors. Whole brain radiation prior to stereotactic radiosurgery improves regional control.⁶⁵ Chemotherapy is increasingly becoming part of the treatment plan.⁶⁵