Deowall Chattar-Cora, MD

• Department of Orthopedic Surgery
• Division of Plastic and Reconstructive Surgery
• University of Texas Health Science Center at San Antonio
• San Antonio, Texas
• Plastic and Reconstructive Surgery of Puerto Rico
• San Juan, Puerto Rico

Degeneration of anterior hom cells with progressive muscular atrophy may be a feature heart attack zippy purchase 75 mg triamterene with amex, although this is more characteristic of the adult-onset variety (see further on) arrhythmia signs triamterene 75 mg with amex. Late Gaucher Disease With Polymyoclonus A type of Gaucher disease is occasionally encountered in which seizures heart attack 60 best 75mg triamterene, severe diffuse myoclonus heart attack jeff x ben buy triamterene 75 mg with visa, supranuclear gaze disorders (slow saccades blood pressure medication headache buy triamterene 75 mg on-line, saccadic and pursuit horizon tal gaze palsies) arrhythmia young adults generic triamterene 75 mg amex, and cerebellar ataxia begin in late child hood, adolescence, or adult life. The pathologic and biochemical abnormali ties are the same as those of Gaucher disease of earlier onset. Chemj-Red Spot-Myoclonus Syndrome (Sialidosis Type 1, a-Neuraminidase Deficiency) this is a geneti cally distinct class of disease characterized by the storage in nervous tissue of sialylated glycopeptides. In some of the patients, the onset was in late childhood or adolescence, and in others, even later. In addition to the patients initially reported by Rapin and coworkers, 24 similar cases have appeared in the medical literature. In one case, there was severe episodic pain in the hands, legs, and feet during hot weather, reminiscent of Fabry dis ease. Polymyoclonus followed within a few years and, together with cerebellar ataxia, disabled the patients. Liver and spleen were not enlarged, but storage material was found in the Kupffer cells, neurons of the myenteric plexus, and cerebral neurons, and presumably in cerebellar and retinal neurons. The cases of Thomas and colleagues were young adults, all members of one generation, who had devel oped dysarthria, intention myoclonus, cerebellar ataxia, and cherry-red macular lesions. The two patients described by Tsuji and associates (1982) are noteworthy in that they were of age 50 and 30 years. In addition to the macular lesions, polymyoclonia, and cerebellar ataxia, there were gargoyle-like facial features, corneal opacities, and vertebral dysplasia. Other clinical syndromes in this category include choreoathetosis, dystonia, and spasms of gaze. When the parkinsonian syndrome or some com ponent thereof has its onset in middle or late adult life, it usually indicates idiopathic Parkinson disease or related multisystem forms. The development of such an extrapyramidal motor disorder in late childhood and adolescence instead suggests Wilson disease, juvenile Huntington disease, Hallervorden-Spatz disease, and the Segawa type of L-dopa-responsive dystonia as well as other so-called parkin mutations (see Chap. The onset is in late childhood; both sexes are vulnerable, and it probably has more than one cause. The neurons of the dentate nuclei and their ascending and descending brainstem axons gradually disappear. Berkovic and associates studied 84 cases of polymyoc lonus, 13 of which conformed to the Hunt syndrome. However, there are other reports (Tassinari et al) in which muscle biopsies showed no mitochondrial abnor malities. In the series of 30 cases reported by Marsden and coworkers (1990) the onset was usually before the age of 21 years. Cortical electrographic discharges were found to precede each myoclonic twitch (cortical myoclo nus). A biochemically supported diagnosis could not be made in nearly half of their cases. Extremely chronic forms of rhythmic myoclonus involving only the facial and bulbar muscles also occur. Although this benign familial polymyoclonia has not been associated with any biochemical abnormality, its association with cellular mitochondrial abnormalities in some cases justifies its inclusion in this chapter rather than with the degenerative diseases. The mitochon drial diseases as a group are considered in the last part of this chapter. The seizures may occur at all ages but more frequently in the neonate, infant, or young child than in the older child or adolescent. Most often they are generalized grand mal or partial types; typical petit mal probably does not occur. Some diseases may cause focal seizures, simple or complex partial, before becom ing generalized. The combination of series of polymyo clonic jerks progressing to a generalized motor seizure is always highly suggestive of one of the hereditary metabolic diseases. A similar neurologic disorder had been described previously by Gowers (1906) under the title of "tetanoid chorea" and by Westphal (1883) and Striimpell (1898), as "pseudo sclerosis. Interestingly, none of these authors, includ ing Wilson, noticed the golden-brown (Kayser-Fleischer) corneal ring, the one pathognomonic sign of the disease. In 1952, Scheinberg and Gitlin discovered that ceruloplasmin, the serum protein that binds copper, is reduced in this disease (see reviews by Scheinberg and Sternlieb for a full historical account and references). One of the curious aspects of the genetics of the disease is the multitude of mutations within this gene that give rise to the disease and no one mutation accounts for more than 30 percent of cases. As noted further on, liver transplanta tion halts progression of the disease, indicating that the primary biochemical effect of the mutation is in the liver rather than the nervous system. The mutation gives rise to two fundamental distur bances of copper metabolism: (1) a reduced rate of incor poration of copper into ceruloplasmin and (2) a reduction in biliary excretion of copper. The deposition of copper in tissues is the cause of virtually all the manifestations of the disease-cirrhosis, hemolytic anemia, renal tubular changes, Kayser-Fleischer rings, and, in all likelihood, the cerebral damage-as discussed below. A notable feature is the tendency for the motor disorders to be concentrated in the bulbar muscula ture and to spread caudally. Usually elements of cerebellar ataxia and intention tremor of variable degree are added at some stage of the disease. The patient becomes mute, immobile, extremely rigid, dystonic, and slowed mentally, the latter usually being a late and variable effect. With progression of the neurologic disease, the Kayser-Fleischer rings become more evident. They take the form of a crescentic rusty-brown discol oration of the deepest layer of the cornea (Descemet membrane). In the purely hepatic stage of the disease, the rings may not be evident (in 25 percent of cases), but the onset of neurologic symptoms is usually in the second, and less often in the third, decade, but rarely beyond that time. Half of patients are symptomatic by age 15 years, but exceptional cases, including two under our care, had their first clinical manifestations as late as their midfifties. In all instances the initial event is a deposition of copper in the liver, leading to an acute or chronic hepatopathy and eventually to multilobular cirrhosis and splenomegaly (Scheinberg and Sternlieb). In childhood, the liver disorder often takes the form of attacks of jaundice, unexplained hepatosplenomegaly, or hypersplenism with thrombocytopenia and bleed ing. The hepatic abnormalities may be asymptomatic (except for elevated serum transaminases), in which case the initial clinical presentation is neurologic. In some instances, a hemolytic anemia or, less often, renal tubular acidosis may first draw attention to the disease. The first neurologic manifestations are most often extrapyramidal with a proclivity to affect the oropharyn geal musculature. The typical presentations are tremor of a limb or of the head and generalized slowness of move ment. Exceptionally; an abnormality of behavior (argumentativeness, impulsiveness, excessive emotional ity; depression, delusions) or a gradual impairment of intellectual faculties precedes other neurologic signs by a year or more (see Starosta-Rubinstein et al). As the disease progresses, the "classic syndrome" evolves: dysphagia and drooling, rigidity and slowness of movements of the limbs; flexed limb postures; fixity they are virtually always present (if properly sought) once the neurologic signs become manifest. A slit-lamp examination may be necessary for their early detection, particularly in brown-eyed patients, but in the majority of patients with neurologic signs the rings can be visualized with the naked eye or with the aid of an indirect ophthalmoscope focused on the limbus. The diagnosis is virtually certain when there is a similar syndrome in a sibling or when an extrapyramidal motor disorder of this type is conjoined with liver disease and the corneal rings. Laboraton Findings In both the typical and variant J forms of the disease, the finding of a low serum cerulo plasmin level (less than 20 mg/ dL in 80 to 90 percent of patients), low serum copper (3 to 10 mM/L; normal ll to 24 mM/L), and increased urinary copper excretion (more than 100 mg Cu/24 h) corroborate the diagnosis. Because 90 percent of copper is carried by ceruloplasmin and the latter is generally reduced in Wilson disease, serum copper values alone may be misleadingly normal. Early in the course of the illness, the most reliable diagnostic findings are a high copper content in a biopsy of liver tissue (more than 200 f/-g Cu/ g dry weight) and a failure to incorporate labeled 64Cu into ceruloplasmin. The latter test, however, fails to dependably differentiate asymp tomatic carriers from affected individuals. Measurement of increased cupruresis after the administration of peni cillamine has not been shown to be more sensitive than an unenhanced 24-h urine collection for copper. Persistent aminoaciduria, reflecting a renal tubular abnormality, is present in most but not all patients. Liver function tests are usually abnormal; some patients are jaundiced and other signs of liver failure may appear late in the illness. In these patients, the serum ammonia may be elevated and the symptomatology may worsen with increases in dietary protein. The cirrhosis is not always evident in a liver biopsy (some regenerative nodules are large, and the biopsy may be taken from one of them). On the other hand, the diagnosis in children may be revealed when a liver biopsy is taken for the evaluation of cirrhosis. As mentioned earlier, the large number of mutations that give rise to the disease makes it impractical to use genetic analysis for diagnosis, but once the gene abnormality has been established in a given family, linkage studies may be used to identify other affected sibs. It has been established that copper deposition in the liver is the initial disturbance; over time it leads to cir rhosis, so that, as already mentioned, the hepatic stage of the disease precedes neurologic involvement. The lateral ventricles and often the third ventricle are slightly enlarged, the cerebral and cerebellar sulci are widened, the brainstem appears shrunken, and the posterior parts of the lenticular nuclei, red nuclei, and dentate nuclei become hypodense (Ropper et al). With treatment, these radiologic changes become less marked (Williams and Walshe). Signal changes are almost universally found in the claustrum and also in the midbrain (pars compacta of the substantia nigra), dentate nucleus of the cerebellum, pons, and thalami. Exceptionally, in the rapidly advancing and fatal form, there is frank cavitation in the lenticular (putamina! In the more chronic form, there is only shrinkage and a light-brown discoloration of these structures. Nerve cell loss and some degree of degeneration of myelinated fibers in lenticular nuclei, substantia nigra, and dentate nuclei are usually appar ent. Treatment Ideally, treatment should be started before the appearance of neurologic signs; if this can be implemented, neurologic deterioration can be prevented to a large extent. Treatment consists of (1) reduction of dietary copper to less than 1 mg/d, which can usually be accomplished by avoidance of copper-rich foods (liver, mushrooms, cocoa, chocolate, nuts, and shellfish), and (2) administration of the copper chelating agent o-penicillamine (1 to 3 g/d) by mouth, in divided doses. Sensitivity reactions to the drug (rash, arthralgia, fever, leukopenia) develop in 20 percent of patients and require a temporary reduction of dosage or a course of prednisone to bring them under control. Reinstitution of drug therapy should then be undertaken, using low dosages (250 mg daily) and, later, small, widely spaced increases. If the patient is still sensitive to o-pen icillamine or if severe reactions (lupus-like or nephrotic syndromes or myasthenia gravis) occur, the drug should be discontinued and another chelating agent, triethylene tetramine (trientine) or ammonium tetrathiomolybdate may be substituted. Zinc, which blocks the intestinal absorption of copper, is also a suitable treatment, but ineffective alone. It is given as zinc acetate, 100 to 150 mg daily in 3 to 4 divided doses at least 1 h before meals (Hoogenraad et al). Some women report improvement in neurologic symptoms during pregnancy, although there is no apparent change in copper metabo lism during this time. The Kayser Fleischer rings disappear and liver function tests may return to normal, although the abnormalities of copper metabolism remain unchanged. It is also well known that the institution of treatment with penicillamine may induce an abrupt worsening of neurologic signs, and we have witnessed several such instances, including one that culminated fatally from a cardiac arrhythmia. Presumably this deterioration is a result of the rapid mobilization of copper from the liver and its redistribution to the brain. The additional use of zinc or one of the newer agents mentioned above should be instituted as soon as neurologic deterioration becomes evident. In the few patients who develop seizures, they may become appar ent soon after therapy is begun. Many wilsonian patients with advanced liver disease have been subjected to liver transplantation, which is curative for the underlying metabolic defect. The degree of neurologic improvement varies; in some it has been remarkable and sustained, confirming that the hepatic defect is primary and that the brain is involved second arily. According to Schilsky and coworkers, the main indication for transplantation is severe and progressive liver damage, but the operation has been used success fully in some patients with intractable neurologic deterio ration and only mild signs of liver disease. An important aspect of treatment is the screening of potentially affected relatives for abnormalities of serum copper and ceruloplasmin; if any relative is found to have the disease, penicillamine should be given indefi nitely to prevent the emergence of neurologic symptoms. A full explanation of the dangers of ceasing the medi cation must be given, and compliance may have to be monitored. Cirrhosis and Kayser-Fleischer rings are not features of the disease but diabetes is common and extrapyramidal signs may or may not arise. Rather than copper, iron is deposited in the brain and liver (see discussion by Logan). Those few cases that have been well studied, mainly Japanese, show mainly an ataxic disorder (Miyajima et al). It is associated with low serum copper levels, usually idiopathic but this disease, recently renamed because of ignoble associa tions of the eponymous Hallervorden and Spatz, is also known as pigmentary degeneration of the globus pallidus. The onset of symptoms is in late childhood or early adolescence with slow progression over a period of 10 or more years. The early signs are highly variable but are predominantly motor, both corticospinal (spasticity, hyperreflexia, Babinski signs) and extrapyramidal (rigid ity, dystonia, and choreoathetosis). In individual cases, ataxia and myoclonus have appeared at some phase of the illness. The spasticity and rigidity are most prominent in the legs, but in some instances they begin in the bulbar muscles, interfering with speech and swallowing, as happens in Wilson disease. We have observed patients who, over a period of years, exhibited only dystonia of the tongue, blepharospasm, or arching of the back. The relationship of this restricted form to the complete syndrome remains unsettled. Eventually; the patient becomes almost com pletely inarticulate and unable to walk or use his or her arms.

Diseases

• Aplasia
• Blastoma
• Self-defeating personality disorder
• Wiskott Aldrich syndrome
• Loose anagen hair syndrome
• Thin ribs tubular bones dysmorphism
• Purpura, thrombotic thrombocytopenic
• Richards Rundle syndrome

These views on the site and mechanism of concus sion are not fully accepted but have been supported by a number of additional physiologic observations pulse pressure 36 purchase triamterene. Foltz and Schmidt heart attack usher mp3 order 75 mg triamterene with visa, in 1956 heart attack hereditary best 75mg triamterene, suggested that the reticular formation of the upper brainstem was the anatomic site of concus sive injury heart attack meme purchase triamterene 75 mg mastercard. They showed that in the concussed monkey; lemniscal sensory transmission through the brainstem was unaltered arteria znaczenie slowa buy genuine triamterene on line, but its effect in activating the reticular formation was blocked and that the electrical activity of the medial reticular formation was depressed for a longer time and more severely than that of the cerebral cortex blood pressure medication good for pregnancy cheap 75 mg triamterene with visa. What was further noteworthy in most of these cases, and in those reported by ellinger and Seitelberger, was the presence of additional lesions in the region of the reticular activating system and small hemorrhagic soften ings in the corpus callosum, superior cerebellar pedun cles, and dorsolateral tegmentum of the midbrain. As discussed further on, Strich paralysis of nervous function History of Concepts of Concussion the mechanism of concussive "cerebral paralysis" has been interpreted in various ways throughout medical history in light of the state of knowledge at a particular period of time. Jefferson, in his essay on the nature of concussion (1944), convincingly refuted these vascular hypotheses. Later, Shatsky and cowork ers, by the use of high-speed cineangiography, showed displacement of vessels but no arrest of circulation imm e diately after impact. Beginning with the work of Denny-Brown and Russell in 1941, the physical factors involved in head and brain injuries were subjected to careful analysis. These investigators demonstrated that in monkey and cat the concussion resulted when the freely moving head was struck by a heavy mass. If the head was prevented from moving at the moment of impact, the same degree of force invariably failed to produce concussion. The impor tance of head motion was verified by Gennarelli and col leagues, who were able to induce concussion in primates by rapid acceleration of the freely moving head without impact, a condition that rarely occurs in humans. Holbourn, a Cambridge physicist, from a study of gelatin models under conditions simulating head trauma, deduced that when the head is struck, move ment of the partly tethered but suspended brain always lags (because of inertia), but inevitably the brain moves also, and when it does it must rotate in an arc because of attachment to the neck. Ommaya and Gennarelli (1974) proved the correctness of this assumption by photographing the brain through a transparent cal varium at the moment of impact. The brain was thus subjected to stresses set up by rotational forces mainly in the sagittal plane, centered at its point of tethering in the high midbrain. The torque at the level of the upper reticular formation would explain the immediate loss of consciousness, as described later. An extensive and scholarly review of the pathophysiology of concussion was done by Shaw (although we are uncertain of the validity of his view of a seizure-concussive mechanism). Symonds elaborated on this view and saw in the shearing stresses, which are maximal at the point where the cerebral hemispheres rotate on the relatively fixed upper brainstem, the explanation of concussion. The aftereffects of concussion in causing anxiety, sleep disturbance, mental fogginess and cognitive difficulty, and dizziness are common to both and are discussed further on. A recent summary from the American Academy of Neurology can be consulted (authored by Giza and colleagues). The later-life development of dementia and other neurode generative conditions in professional athletes is discussed further on. Second, most prospective studies show a decline in reaction time and in other neuropsychologic tests after concussion, which returns to baseline over several days or weeks. Third, there is an indication from sev eral series of concussions in National Collegiate Athletic Association and National Football League players that the number of recollected concussions is proportional to the degree of impairment on neuropsychologic tests (McCrea et al). Similar results have been found in other pursuits such as jockeying (Wall et al), but there are few adequate prospective studies. The appropriate duration of removal from play has been the subject of numerous and largely arbitrary sys tems. The basis of most rules has been an appropriate conservatism that requires the absence of cerebral symp toms both at rest and under physical stress testing such as running or repetitive squatting. The duration of loss of consciousness and of amnesia was formerly a major component of the decision about return to play. More cur rent guidelines focus instead on slowness in answering questions, uncertainty about plays or game assignments, and clumsiness, with or without loss of consciousness or amnesia. After medical evaluation, which may include imaging and neuropsychologic testing, a program of physical and cognitive "rest" is followed by graduated physical and mental activity under observation and a return to a lower level if symptoms occur (McCrory et al). Specifically, light aerobic exercise is followed by sport-specific training and noncontact, then contact, drills. In its fullest form, the characteristic clinical signs of concussive brain injury are the immediate abolition of consciousness, suppression of supportive reflexes (falling to the ground if standing), transient arrest of respiration, a brief period of bradycardia, and fall in blood pressure following a momentary rise at the time of impact. Rarely, if these abnormalities are sufficiently intense, death may occur at the moment of impact, presumably from respira tory arrest. In its mildest form, there is no apparent loss of consciousness or collapse, only a brief period of stunned disorientation, staggering, and subsequent amnesia dur ing which the individual appears outwardly normal. The vital signs usually return to normal and stabilize within a few seconds even if the patient remains unconscious. Brief tonic extension of the limbs, clonic convulsive movements lasting up to approximately 20 s, and other peculiar movements may occur immediately after the loss of consciousness (see McCrory et al). These "concus sive convulsions" are probably of little prognostic sig nificance and have not been shown to confer an increased risk of later seizures. McCrory and colleagues noted an association between motor and convulsive movements and facial impact, and we have seen this feature several times in teenagers who collided while pursuing a ball. In the period during which the patient is unconscious and for a few moments afterwards, the plantar reflexes are extensor. Corneal, pharyngeal, and cutaneous reflexes, originally depressed, return, and the limbs withdraw from painful stimuli. Gradually, con tact is made with the environment and the patient begins to obey simple commands and respond slowly to ques tions. Memories are not formed during this period; the patient may even carry on a conversation, which he can not later recall. Finally, there is ostensibly full neurologic recovery corresponding to the time when the patient can form consecutive memories of current experiences. The time required for the patient to pass through these stages of recovery may be only a few seconds or minutes, several hours, or possibly a limited number of days; but again, between these extremes there seem to be only quantitative differences. To the observer, such patients are comatose only from the moment of injury until they open their eyes and begin to speak; however, for the patient, the period of unconsciousness in one limited perspective extends from a point before the injury occurred (retrograde amnesia) until the time when he is able to form consecutive memories at the end of the period of anterograde amnesia. The duration of the amnesic period, particularly of anterograde amnesia, is but one index of the severity of the concussive injury. Although momentary "stunning " without loss of con sciousness represents the mildest degree of concussion, Pathologic Changes Associated With Severe Head Injury In contrast to concussion, in cases of traumatic brain injury that are fatal or very serious, the brain is usually bruised (contused), swollen, or lacerated, and there are hemorrhages, both meningeal and intracerebral, as well as hypoxic-ischemic lesions. Of these lesions, the most frequent are contusions of the surface of the brain beneath the point of impact (coup lesion) and the sometimes more extensive lac erations and contusions on the side opposite the site of impact (contrecoup lesion), as shown in. Blows to the front of the head may produce mainly coup lesions, whereas blows to the back of the head may cause mainly contrecoup lesions. Irrespective of the site of the impact, the common sites of cerebral contusions are in the frontal and temporal lobes, as illus trated in. The inertia of the malleable brain-which causes it to be flung against the side of the skull that is struck, to be pulled away from the contralat eral side, and to be impelled against bony promontories within the cranial cavity, explains these coup-contrecoup patterns. Relative sparing of the occipital lobes in coup contrecoup injury has been explained by the smooth inner surface of the occipital bones and subadjacent ten torium, as pointed out by Courville. The contused cortex is diffusely swollen and hemor rhagic, most of the blood being found around paren chymal vessels. The bleeding points may coalesce and give the appearance of a unitary clot in the cortex and immediately adjacent white matter. The predilection of these lesions for the crowns of con volutions attests to their traumatic origin (being thrown against the overlying skull) and distinguishes them from cerebrovascular and other types of cerebral lesions. There may be ball hemorrhages within the hemispheres that are independent of contusions as discussed below. Not surprisingly, such deep areas of bleeding are com mon in patients receiving anticoagulant or antiplatelet medications. Of equal importance are axonal lesions that occur at the time of impact or evolve soon afterwards. Strich (1961) described the neuropathologic findings in patients who died months after severe closed head injuries that had caused immediate and protracted coma. In cases of shorter survival (up to 6 weeks), she observed ballooning and interrup tion of axis cylinders. These findings were subsequently confirmed and expanded by Nevin, by Adams and col leagues (1982), and by Gennarelli and coworkers, the last of these groups also working with monkeys. A rrows incticate point of application and direction of force; dark red areas incti. Frontotemporal contusion as a result of injury to opposite tempo rooccipital region. Distribution of contusions empha sizing the frontal and frontotemporal ct istribu tion in 40 consecutive autopsy cases collected by Courville. There may also be scattered hemorrhages in the white matter along lines of force from the point of impact to the contralateral side. The degeneration of white matter from diffuse axonal injury can be remarkably diffuse, with no apparent relationship to focal destruc tive lesions, although differentiating it from secondary wallerian change that originates in a surface or callosal contusion can be difficult. There is a lso slight subarachnoid blood a long the tentorium and in the insular cisterns, both of which are typical of trauma tic bleeding. However, in most cases of severe cranial injury and protracted coma, there have been major sites of injury in the midbrain and subthalamus, i. This was true of the cases of persistent coma described by Jellinger and Seitelberger. Notable, again, was that these deep lesions coincided with the postulated locus of reversible concus sive paralysis. Primary brainstem hemorrhages due to torsion and tearing of tissue at the time of impact are distin guished from the secondary hemorrhages that are a result of the effects of downward displacement of the brainstem. Duret originally emphasized the medullary location of these secondary hemorrhages, but the term Duret hemorrhage has come to signify all brainstem hemorrhages when there is mass effect that distorts the brainstem. In addition to contusions and extradural, subdural, subarachnoid, and intracerebral hemorrhages, closed head injury induces variable degrees of vasogenic edema that increases during the first 24 to 48 h and sometimes, small zones of infarction that have been attributed to vascular spasm caused by subarachnoid blood surrounding basal vessels. The frequency and importance of this type of secondary cerebral infarction have been debated. A retro spective imaging study by Marino and colleagues found that 17 of 89 patients had regions of stroke after moderate or severe head injury. Most were in the distribution of a major branch or penetrating cerebral vessel or in a water shed territory. The presence of intracranial hypertension has also been associated with a higher incidence of infarction. Marmarou and colleagues demonstrated that brain swell ing after head injury is essentially the result of edema and not of an increase in cerebral blood volume, as has long been postulated. In children, and in some cases in adults, the cerebral edema may be massive and lead to second ary brainstem compression. Most patients with fat embolism recover sponta neously in 3 or 4 days, although a mortality rate of up to 10 percent is cited, usually related to underlying systemic and bony injuries. It is usually pos sible to categorize the patient by assessing the mental and neurologic status when first seen and at intervals after the accident. The Glasgow Coma Scale is used as a rapid refer ence to accomplish this purpose (Table 35-1) but does not substitute for a fuller neurologic examination. The scale registers three aspects of neurologic function: eye opening, verbal response, and motor response to various stimuli. This sequence is a result of systemic fat embolism, first of the lungs and then of the brain. In some cases the onset of pulmonary symptoms is associated with a petechial rash over the thorax, especially in the axillae and also in the conjunctivea and 1 in 3 cases is said to show fat globules in the urine. Respiratory distress is the most important and often the only feature of the fat embolism syndrome, evident in the chest film as fluffy infiltrates in both lungs. Roughly, two degrees of disturbed function can be rec ognized within this category. This is underscored by the results of a study of In one, the patient was not 215 children with minor head trauma unconscious at all but only stunned momentarily, "saw stars," or was briefly disoriented. This injury is insig nificant when judged in terms of life or death and brain damage, although, as we point out further on, there is still the small possibility of a skull fracture or the later devel opment of an epidural or subdural hematoma. Moreover, some patients are liable to a troublesome posttraumatic syndrome consisting of headache, giddiness, fatigability, insomnia, and nervousness that can appear soon after or within a few days of the injury. In the instance of consciousness that was temporarily abolished for a few seconds or minutes, recovery may already be complete, or the patient may be in one of the stages of partial recovery described earlier. Even though mentally clear, there is amnesia for events immediately preceding and following the injury. The latter produces a circumscribed confusional state that is usually confined to inattention and may be ongoing when the patient is first examined. It is characterized by a dazed appearance and repetitive questions from the patient about the circumstances that led to his being found. They include features that are sensitive but not spe cific for intracranial injury, such as age above 60 years, intoxication, more than 30 min of retrograde amnesia, suspected skull fracture, seizure, anticoagulation, and dangerous mechanism of injury, (see Smits et al and Stiell et al). Whether to obtain imaging of the head routinely in such patients is an unresolved problem. If there is no subarachnoid blood (a common finding) or intraparenchymal clot or contusion, and the patient is mentally clear there is little chance of developing an extradural hemorrhage. The presence of a fracture may increase these odds but most studies, such as the one by Lloyd and colleagues have found that the presence of a skull fracture in children proves to be a relatively poor indicator of intracranial injury. The exception is a fracture through the squamous bone and the groove of the middle meningeal artery, which represents a risk for arterial bleeding and epidural hemorrhage. Minor and seemingly trivial head injuries may sometimes be followed by a number of puzzling and worrisome clinical phenomena, some insignificant, oth ers serious and indicative of a pathologic process other than concussion.

If the condition of the host is compromised arteria3d pack unity buy triamterene 75mg mastercard, the outcome is often fatal blood pressure normal lying down best 75mg triamterene, but most of our patients without serious medical disease have made a full and prompt recovery with treatment hypertension diet plan buy triamterene 75 mg lowest price. It should be suspected in returning travelers from that region but the disease is blood pressure medication and memory loss best buy for triamterene, of course prehypertension remedies generic triamterene 75mg with amex, well known to physicians in areas endemic for the organism percentil 95 arteria uterina triamterene 75mg without prescription. There is usually an associated pulmo nary infection but this may be minor and the degree of temperature elevation varies. There is a commercial serologic test but there are high background rates of positivity in endemic regions. Treatment this is in two phases, an intesive eradica tion component with high intravenous doses of ceftazi dime (or several equivalent regimens) for 10 to 14 days, followed by an eradication phase that is necessary to pre vent relapse, using co-trimoxazole alone or accompanied by doxycycline. Legionella this potentially fatal respiratory disease caused by the gram-negative bacillus Legionella pneumophila, first came to medical notice in July 1976, when a large number of members of the American Legion fell ill at their annual convention in Philadelphia. Lees and Tyrrell described patients with severe and diffuse cerebral involvement, and Baker and associates and Shetty and colleagues described oth ers with cerebellar and brainstem syndromes. One constellation consisted of head ache, obtundation, acute confusion or delirium with high fever, and evidence of pulmonary distress; another took the form of tremor, nystagmus, cerebellar ataxia, extra ocular muscle and gaze palsies, and dysarthria. Serologic tests are available but require paired sera and have little impact on clinical decision making. To date, the Legionella bacillus has not been isolated from the brain or spinal fluid. Treatment Treatment in adults has consisted of one of levofloxacin, moxifloxacin, or azithromycin; rifampin is sometimes used. The caus ative organism is a gram-negative bacillus now called Bartonella henselae (formerly Rochalimaea henselae). The ill ness begins as unilateral axillary or cervical adenopathy occurring after a seemingly innocuous scratch (rarely a bite) from an infected cat. The cases with which we are familiar began with an encephalopathy and high fever (higher temperature than with most of the other organ isms that are capable of causing a bacterial encephalitis), followed by seizures or status epilepticus. Treatment First-line treatment is with azithromycin or doxycycline, sometimes with rifampin in recalcitrant cases. Most patients recover completely, but one of our patients and a few reported by others have died. In the Middle East, infection with Brucella is still frequent, attribut able to the ingestion of raw milk. In Saudi Arabia, for example, al Deeb and coworkers reported on a series of 400 cases of brucellosis, of which 13 presented with brain involvement (acute meningoencephalitis, papilledema and increased intracranial pressure, and meningovas cular manifestations). Treatment Prolonged treatment with doxycycline with streptomycin or gentamicin; an alternative is doxy cycline plus rifampin to suppress the infection. Whipple Disease this is a rare but often-discussed disorder, predomi nantly of middle-aged men. Weight loss, fever, anemia, steatorrhea, abdominal pain and distention, arthralgia, lymphadenopathy, and hyperpigmentation are the usual systemic manifestations. It is caused by a gram-positive bacillus, Tropheryma whipplei, which resides predominantly in the gut. The neurologic manifestations most often take the form of a slowly progressive memory loss or dementia of subacute or early chronic evolution. Supranuclear ophthalmoplegia, ataxia, seizures, myoclonus, nystag mus, and a highly characteristic oculomasticatory move ment described as myorhythmia (which looks to us like rhythmic myoclonus) have been noted less often than the dementing syndrome. The rhythmic myoclonus or spasm occurs in synchronous bursts involving several adjacent regions, mainly the eyes, jaw, and face. This movement disorder is fairly specific but insensitive for Whipple disease, occurring in only approximately 10 percent of patients. As pointed out by Matthews and colleagues, cerebellar ataxia, although obviously much less specific for Whipple disease of the brain, is more frequent, occur ring in about half the documented cases. Almost always, the myorhythmias are accompanied by a supranuclear vertical gaze paresis that sometimes affects horizontal eye movements as well. Presumably, the neurologic com plications are the result of infiltration of the brain by the organism, but this has not been satisfactorily established. A variety of brain imaging abnormalities have been recorded, none characteristic, but either enhancing focal lesions or a normal scan may be found. In cases of subacute progressive Anthrax this rare form of meningoencephalitis is included here because of the current interest in Bacillus anthracis as a bioweapon. Lanska was able to collect from the literature 70 patients with meningeal infection, most of whom were encephalopathic. He has estimated that fewer than 5 percent of infected individuals will acquire a meningo encephalitis; in a 2001 U. Reflecting the main site of natural infection, the majority of cases originated in cutaneous anthrax. In addition to a typically fulminating course after a prodrome of one or several days, the exceptional feature was a hemorrhagic and inflammatory spinal fluid formula. Subarachnoid hemorrhage was prominent in autopsy material, presum ably reflecting necrosis of the vessel walls as a toxic effect of B. Treatment Although natural isolates are sensitive to penicillin, bioengineered strains are resistant; therefore, combined treatment with ciprofloxacin with clindamy cin, rifampin, or meropenem has been recommended initially. The benefit of specific antitoxin is uncertain once meningoencephalitis has occurred. Recently, very similar overwhelming cases with men ingitis and subarachnoid hemorrhage caused by Bacillus cereus have appeared in immunosuppressed patients. Brucellosis this worldwide disease of domesticated livestock is frequently transmitted to humans in areas where the infection is enzootic. Rarely, the neurologic symptoms may occur in the absence of gastrointestinal disease (Adams et al, 1987). In the review of 84 cases of cerebral Whipple disease by Louis and colleagues, 71 percent had cognitive changes, half with psychiatric features; 31 percent had myoclonus; 18 percent had ataxia; and 20 percent had the oculomasti catory and skeletal myorhythmias (Schwartz et al). Treatment A course of induction by penicillin or ceftriaxone for 2 weeks followed by trimethoprim-sul famethoxazole or doxycycline continued for 1 year are the currently recommended regimens. An alternative approach is 2 weeks of ceftriaxone followed by treatment with trimethoprim-sulfamethoxazole or a tetracycline for a year. Antibiotic-resistant cases and instances of relapse after antibiotic treatment are known. During the height of a systemic bacterial or sometimes viral infection, the child sinks into coma, seizures are infrequent, the neck is supple, and the spinal fluid shows no changes or only a few cells. This is undoubtedly an ill ness of diverse causes, common among them being fluid overload and electrolyte imbalance, Reye syndrome (see Chap. Nonetheless, cases continue to be reported, such as those of Thi and colleagues, which can only be classified as a noninfectious bacterial encephalopathy or encephalitis. A relationship to the "septic encephalopathy" of adults, which has been emphasized by the group from London, Ontario, is possible but unproved. The term acute toxic encephalopathy still has some utility in cases of obscure cause, but a careful search for better-characterized causes of febrile coma must be undertaken. The acute necrotiz ing encephalopathy that has been reported, particularly in Asian children after influenza, belongs to this category and consists of a number of diseases as discussed by Mizuguchi and coworkers. The infection usually originates in the frontal or ethmoid or, less often, the sphenoid sinuses and in the middle ear and mastoid cells. As with bacterial menin gitis, in the last decade there have been an increasing number of cases that follow surgery of the sinuses and other cranial structures. In infants and children, and infrequently in adults, there may be a spread from a lep tomeningitis. Infection gains entry to the subdural space by direct extension through bone and dura or by spread from septic thrombosis of the venous sinuses, particu larly the superior longitudinal sinus. Rarely, the subdural infection is metastatic from infected lungs; hardly ever is it secondary to bacteremia or septicemia. It is of interest that cases of sinus origin have pre dominated in adolescent and young adult men (Kaufman et al), a distinction for which there is no explanation. In such cases, streptococci (nonhemolytic and viridans) are the most common organisms, followed by faculta tive anaerobic streptococci (often Streptococcus milleri) or Bacteroides. In about half the cases unre lated to surgery, no organisms can be cultured or seen on Gram stain. Pathology A collection of subdural pus ranging from a few milli liters to 100 to 200 mL lies over the cerebral hemisphere. Pus may spread into the interhemispheric fissure or be confined there; occasionally it is found in the pos terior fossa, covering the cerebellum. The arachnoid, when cleared of exudate, is cloudy, and thrombosis of meningeal veins may be seen. The underlying cerebral hemisphere is compressed, and in fatal cases there is often an ipsilateral temporal lobe herniation. Microscopic examination discloses various degrees of organization of the exudate on the inner surface of the dura and infiltra tion of the underlying arachnoid with small numbers of neutrophilic leukocytes, lymphocytes, and mononuclear cells. Thrombi in cerebral veins seem to begin on the sides of the veins nearest the subdural exudate. The superficial layers of the cerebral cortex undergo ischemic necrosis, which probably accounts for focal seizures and other signs of disordered cerebral function (Kubik and Adams). The term subdural abscess, among others, had been applied to this condition but the proper name is empyema, indicating suppuration in a preformed space. Thrombosis of the underlying cortical veins and dural sinuses is a common accompaniment. Contrary to prevailing opinion, subdural empyema is not a rarity Sym ptomatology and La boratory Findings Usually the history includes reference to chronic sinusitis or mastoiditis with a recent flare-up causing local pain and increase in purulent nasal or aural discharge. In sinus cases, the pain is over the brow or between the eyes; it is associated with tenderness on pressure over these parts and sometimes with orbital swelling. General malaise, fever, and headache-at first localized, then severe and generalized and associated with vomiting are the first indications of intracranial spread. At about the same time, focal neu rologic signs appear, the most important of which are unilateral motor seizures, hemiplegia, hemianesthesia, aphasia, and paralysis of lateral conjugate gaze. If the patient is stuporous or comatose, there is a risk associated with performing a lumbar puncture, and one should proceed first with imaging procedures. Empyema that follows meningitis in children tends to localize on the undersurface of the temporal lobe and may require coronal views to be well visualized. Several conditions must be distinguished clinically from subdural empyema: a treated subacute bacterial meningitis, cerebral thrombophlebitis, brain abscess (see further on), herpes simplex encephalitis (see Chap. Rarely, the infection is metastatic or spreads outward from a dural sinus thrombophlebitis. Pus and granulation tissue accumulate on the outer surface of the dura, separating it from the cranial bone. The symptoms are those of a local infl ammatory process: frontal or auricular pain, purulent discharge from sinuses or ear, and fever and local ten derness. Rarely, a focal seizure may occur, or the fifth and sixth cranial nerves may be involved with infections of the petrous part of the tempo ral bone. Treatment consists of antibiotics, usually vancomycin alone or with a cephalosporin, aimed at the appropriate pathogen(s) often S. Later, the diseased bone in the frontal sinus or the mastoid, from which the extradural infection had arisen, may have to be removed. Treatment Most subdural empyemas, by the time they are recog nized clinically, require drainage through multiple burr holes, or through a craniotomy in cases with an inter hemispheric, subtemporal, or posterior fossa location. The surgical procedure should be coupled with appropri ate antibiotic therapy, generally a third-generation cepha losporin and metronidazole. Bacteriologic findings or an unusual presumed source may dictate a change to differ ent drugs, particularly to later-generation cephalosporins. Without such massive antimicrobial therapy and surgery, some patients will die, usually within 7 to 14 days. On the other hand, patients who are treated promptly may make a surprisingly good recovery, including full or partial resolution of their focal neurologic deficits. The resolution (or lack thereof) of the empyema can be readily followed by repeated imaging of the brain (Leys et al). The largest and most important of these, and the ones usually involved by infection, are the lateral (transverse), cavernous, petrous, and, less frequently; the longitudinal (sagittal) sinuses. A complex system of lesser sinuses and cerebral veins connects these large sinuses to one another as well as to the diploic and meningeal veins and veins of the face and scalp. The basilar venous sinuses are contiguous to several of the paranasal sinuses and mastoid cells. Usually there is evidence that septic thrombophlebi this of the large dural sinuses has extended from an infec tion of the middle ear and mastoid cells, the paranasal sinuses, or skin around the upper lip, nose, and eyes. Other forms of intracranial infection frequently compli cate these cases, including meningitis, epidural abscess, subdural empyema, and brain abscess. Occasionally, infection may be introduced by direct trauma to large veins or dural sinuses. A variety of organisms, including all the ones that ordinarily inhabit the paranasal sinuses and skin of the nose and face, may give rise to intracra nial thrombophlebitis. With the exception of fever and poorer outcome, the syndromes associated with septic phlebitis discussed below are similar to those produced by bland thrombosis of the veins, as discussed in Chap. If the thrombophlebitis remains confined to the transverse sinus, there are no other neurologic signs. Spread to the jugular bulb may give rise to the syndrome of the jugular foramen (see Table (see Chap 34), leads to ptosis, varying degrees of ocular palsy, pain around the eye, and sensory loss over the forehead. Within a few days, spread through the circular sinus to the opposite cavernous sinus results in bilateral symptoms.

The clinical syndrome of siderosis of the meninges consists essentially of a progressive ataxia and nerve deafness; sometimes a spastic paraparesis is added and blood pressure medication kinds cheap triamterene 75 mg amex, rarely blood pressure gap cheap triamterene 75 mg on-line, mental impairment blood pressure on forearm generic triamterene 75 mg fast delivery, probably from hydrocepha lus heart attack 19 years old cheap triamterene on line. Koeppen and associates attributed the vulnerability of the acoustic nerves to their extended meningeal exposure before acquiring a fibroblastic peri neurium and epineurium prehypertension not overweight purchase generic triamterene on-line. There is no treatment other than finding the source of the meningeal blood and pre venting further hemorrhage and treating hydrocephalus if it is present heart attack the song order 75 mg triamterene free shipping. Curiously, the systemic disease hemochromatosis, does not affect the brain or meninges. The clinical syn drome includes dementia, seizures, stroke-like episodes, subarachnoid hemorrhage, ataxia, myelopathy, deafness, radiculopathy, and ocular amyloidosis, usually affecting the vitreous. There is no proven therapy, but liver transplantation could theoretically be effective. Ames A, Sakanoue M, Endo S: Na, K, Ca, Mg and Cl concentra tions in choroid plexus fluid and cistemal. Cinalli G, Sainte-Rose C, Simon I, et al: Syl vian aqueduct syndrome and global rostral midbrain dysfunction associated with shunt malfunction. A, MeteUus P, Levrier 0, et al: Endovascular treatment of idiopathic intracranial hypertension. Lessell S, Rosman P: Permanent visual impairment in childhood pseudotumor cerebri. Lundberg N: Continuous recording and control of ventricular fluid pressure in neurosurgical practice. Seckl J, Lightman S: Cerebrospinal fluid neurohypophysial peptides in benign intracranial hypertension. Savoiardo M, Minati L, Farina L, et al: Spontaneous intracranial hypotension with deep brain swelling. J Pediatr Parpaley Y, Urbach H, Kovacs A, et a]: Pseudohypoxic brain swell ing (postoperative intracranial hypotension-associated venous congestion) after spinal surgery: Report of 2 cases. J Neural Neurosurg Psychiatry Wall M, George D: Vi s ual loss in pseudotumor cerebri. Their importance derives from their great variety; the nwnerous neurologic symptoms caused by their size, location, and invasive qualities; the destruction and dis placement of tissues in which they are situated; the eleva tion of intracranial pressure they cause; and, most of all, their lethality. Slowly, this dismal state of affairs is chang ing as a result of advances in anesthesiology, stereotactic and microneurosurgical techniques, focused radiation therapy, and the use of new chemotherapeutic agents. For clinicians, the several generalizations should be a matter of general knowledge about brain tumors. First, many types of tumor, both primary and secondary, occur in the cranial cavity and spinal canal but certain ones are much more frequent than others and are prone to occur in particular age groups. Secondary metastatic deposits are more common than primary brain tumors in adults and the opposite is true in children. Furthermore, certain can cers (breast, lung, melanoma, renal cell cancer) display a tendency to metastasize to nervous tissue and many others do not do so. Second, some primary intracranial and spinal tumors, such as craniopharyngioma, meningioma, and schwannoma, have a disposition to grow in particular parts of the cranial cavity, thereby producing characteristic neu rologic syndromes. Fourth, the growth rates and invasiveness of tumors vary; some, like glioblastoma, are highly malignant, invasive, and rapidly progressive and others, like meningioma, are most often benign, slowly progressive, and compressive. These different qualities have substantial clinical implications, frequently providing the explanation of slowly or rapidly evolving clinical states as well as potential surgical cure and prognosis. Finally, a special class of disorders result from the production of autoantibodies that are elaborated by sys temic, nonneural, tumors and target cerebral and spinal neurons. These remote effects, referred to as paraneoplas tic, often constitute the initial or only clinical manifesta tion of the underlying neoplasm. Of these, the nwnber of patients who died of primary tumors of the brain seems comparatively small (approximately 20,000, half of them malignant gliomas), but in roughly another 130,000 patients the brain is affected at the time of death by metastases. Thus, in approximately 25 percent of all the patients with cancer, the brain or its coverings are involved by neoplasm at some time in the course of the illness. Among causes of death from intracranial disease in adults, tumor is exceeded in frequency only by stroke, whereas in children primary brain tumors constitute the most common solid tumor and represent 22 percent of all childhood neoplasms, second in frequency only to leu kemia. Viewed from another perspective, in the United States, the yearly incidence of all tumors that involve the brain is 46 per 100,000, and of primary brain tumors, 15 per 100,000. It is difficult to obtain accurate statistics as to the types of intracranial tumors, for most of them have been obtained from university hospitals with special ized cancer and neurosurgical centers. From the figures of Posner and Chernik, one can infer that secondary tumors of the brain greatly outnwnber primary ones; yet in the large series reported in the past (those of Cushing [1932], Olivecrona, Zillch, and Zimmerman), only 4 to 8 percent were of this type. In the autopsy statistics of municipal hospitals, where one would expect a more natural selection of cases, the figures for metastatic tumors vary widely, from 20 to 42 percent (Rubinstein, 1972). Even these estimates probably underestimate the incidence, particularly of metastatic disease. With these qualifications, the figures in Table 31-1 may be taken as representative. Seventy percent of gliomas in children are infra tentorial; in adults, 70 percent are supratentorial. Table 31-2 provides a detailed tabulation compiled by the Central Brain Tumor Registry. Notable in all series, and empha sized in this table, is the higher frequency of certain tumors during childhood. At that time, the incidence of this tumor, formerly called reticulum cell sarcoma, was negligible. In the last 25 years, the number in our hospitals has more than tripled; in specialized centers such as the Memorial Sloan-Kettering Cancer Center, the increase has been even more dramatic (DeAngelis). Most classifications have been based on the presumed cell of origin of the neoplasm, while grading systems are meant to be an estimate of the rate of growth and clinical behavior, but the two are often concordant. Table 31-3 shows the main items and a discussion of this system can be found in the article by Louis and colleagues (2007). In the past, the numerical grading system of Daumas-Duport and coworkers (also known as the St. Granular cell tumor of the neurohypophysis Pi tuicytoma Spindle cell oncocytoma of the adenohypophysis and are cited in the literature. The various classification systems notwithstanding, it is clear that there are practi cal and prognostic consequences to subclassifying tumors by additional molecular methods that are predictive of outcome and of treatment response (see further on). These grades represent a spectrum in terms of growth potential (degree of nuclear atypia, cellu larity, mitoses, and vascular proliferation) and prognosis. The glioblastomas are largely defined by the features of necrosis and anaplasia of nonneural elements such as vascular proliferation and are set apart from anaplastic astrocytomas on the basis not only of their histology but also by a later age of onset than astrocytoma and a more rapid course. The grade I classification for astrocytomas is reserved for the relatively benign group that includes pilocytic astrocytomas (well-differentiated tumors mostly of children and young adults); the pleomorphic xanthoas trocytoma (with lipid-filled cells), and the subependymal giant cell astrocytoma (associated with tuberous sclerosis). They have been set apart because of their different growth patterns, pathologic features, and better prognosis. The ependymomas are subdivided into cellular, myxo papillary, clear cell, and mixed types; the anaplastic epen dymoma and the subependymoma are given separate status. The pathologic criteria of malignant astrocytoma do not apply to oligodendroglioma, for reasons elaborated further on. Meningiomas are classified on the basis of their cytoar chitecture and genetic origin into 4 categories: (1) the com mon meningothelial or syncytial type, (2) the fibroblastic and (3) angioblastic variants, and (4) the malignant type. Tumors of the pineal gland, which were not included in earlier classifications, comprise germ cell tumors, the rare pineocytomas, and pineoblastomas. The medulloblastoma has been reclassified with other tumors of presumed neu roectodermal origin, namely neuroblastoma, retinoblas toma, neuroepithelioma, and ependymoblastoma. Tumors derived from the choroid plexus are divided into two classes, both rare: papillomas and carcinomas. Given separate status also are the intracranial mid line germ cell tumors, such as germinoma, teratoma, choriocarcinoma, and endodermal sinus carcinoma. Tumors of cranial and peripheral nerves differentiate into three main types: schwannomas, neurofibromas, and neurofibrosarcomas. Most are sporadic but the neurofi bromas assume special importance in neurofibromatosis. It is well known that a number of lesions may simulate brain tumors in their clinical manifestations and histologic appearance but are really hamartomas and not true tumors. The difficulty one encounters in dis tinguishing it from a true neoplasm, whose constituent cells multiply without restraint, is well illustrated by tuberous sclerosis and von Recklinghausen neurofibro matosis, where hamartomas and neoplasms are both found. Similarly, in a number of mass lesions-such as certain cerebellar astrocytomas, bipolar astrocytomas of the pons and optic nerves, von Hippel-Lindau cerebellar cysts, and pineal teratomas-a clear distinction between neoplasms and hamartomas is often not possible. Many studies of the pathogenesis of brain tumors have gradually shed light on their origin. Johannes Milller cerebral astrocytomas have also been reported occasion ally in more than one member of a family but the study of such families has not disclosed the operation of an identi fiable genetic factor. Although there is only indirect evidence for an asso ciation between viruses and certain primary tumors of the nervous system, epidemiologic and experimental data drawn from studies of the human papillomavirus and the hepatitis B, Epstein-Barr, and human T-lymphotropic viruses-indicate that they may be involved or act as risk factors in certain human cancers. Each of these viruses possesses a small number of genes that are incorporated in a cellular component of the nervous system (usually a dividing cell such as an astrocyte, oligodendrocyte, ependymocyte, endothelial cell, or lymphocyte). The virus is believed to act to force the cell from its normal activity into an unrestrained replicative cycle. Because of this capacity to transform the cellular genome, the virus product is called an oncogene; such oncogenes are capable of immortalizing, so to speak, the stimulated cell to form a tumor. Oncogenes are also found in normal cells and may contain mutations or are capable of being activated by cel lular and environmental (epigenetic) events as noted later. In transgenic mice, (1838), in his atlas Structure and Function of Neoplasms, first enunciated the appealing idea that tumors might originate in embryonic cells left in the brain during devel opment. This idea was elaborated upon by Cohnheim (1878), who postulated that the source of tumors was an anomaly of the embryonic anlage. Ribbert, in 1904, extended this hypothesis by postulating that the potential for differentiation of these stem cells would favor blasto matous growth. Although it is not a popular notion today, Bailey and Cushing attached the suffix blastoma to indicate all tumors com posed of primitive-looking cells, such as glioblastoma and medulloblastoma. One prominent theory was that most tumors arise from neoplastic transformation of mature adult cells (dedifferentiation). A normal astro cyte, oligodendrocyte, microgliocyte, or ependymocyte is transformed into a neoplastic cell and, as it multiplies, the daughter cells become variably anaplastic, more so as the degree of malignancy increases. What has emerged from these studies is the view that the biogenesis and progression of brain tumors are a consequence of defects in the control of the cell cycle. Some molecular defects predispose to tumor genesis; others underlie subsequent progression and accelerated malignant transformation and yet others may confer sensitivity or resistance to chemotherapeutic agents. This model presupposes the acquisition of mul tiple genetic defects over time since, with the exception of special inherited conditions such as neurofibromatosis, ataxia telangectasia, and a few others, these are not germ line mutations but are acquired as somatic events in the course of tumor evolution. In cases that have an inherited and transmissible germ line defect there may be additional events that also cause somatic genetic mutations. Typically, inher ited mutations affect only one of two copies of a tumor suppressor gene that, by itself, does not cause cancer. These ideas are consistent with the observation that many of the gene defects that predispose to cancer are dominantly inher ited. More recently, single nucleotide polymorphisms have been identified that in combination predispose to certain childhood tumors such as neuroblastoma, or to the more aggressive forms of various tumors. If this is indeed the case, it may be that the apparent dedifferentiation of tumor cells is an artifact of their histo logic appearance and not a fundamental property. Medulloblastomas, polar spongioblasto mas, optic nerve gliomas, and pinealomas occur mainly before the age of 20 years, and meningiomas and glio blastomas are most frequent in the sixth decade of life. A number of mutations, only some inherited, also figure greatly in the genesis of certain tumors, particularly retinoblastomas, neurofibromas, and hemangioblasto mas. The gliomas associated with neurofibromatosis and tuberous sclerosis and the cerebellar hemangioblastomas of von Hippel-Lindau are the best examples of a genetic determinant. The rare familial disorders of multiple endo crine neoplasia and multiple hamartomas are associated with an increased incidence of anterior pituitary tumors and meningiomas, respectively. Other early changes include overexpres sion of genes that control growth factors or their receptors as noted below. After the tumor develops, progression to a more malignant grade of astrocytoma or to a glioblastoma may be triggered by defects in the p16-retinoblastoma gene signaling pathway, loss of chromosome 10 (seen in approximately 90 percent of high-grade gliomas), or over expression of the epidermal growth factor gene. In fact, it is striking that analysis of the patterns of these defects in some tumors correlates with the staging and aggressive characteristics of these tumors. Knowledge of the molecular signatures of certain tumors may have considerable clinical value. For example, oligodendrogliomas that have combined deletions in chromosomes 1p and 19q respond well to chemother apy and this property increases survival (Reifenberger and Louis; Louis et al, 2002). Much of the modern genetic understanding of brain tumors is derived from the technical gene microarrays. The patterns of these multiple gene analyses are able to distinguish some types of medulloblastomas from the similar-appearing, primitive neuroectodermal tumors; the medulloblastomas express classes of genes that are characteristic of cerebellar granule cells, suggesting they arise from these cells. Also, gene expression signatures confer useful prognostic information in a more general way than noted above for oligodendroglioma. For exam ple, medulloblastomas that express genes indicative of cerebellar differentiation are associated with longer sur vival than those expressing genes related to cell division (Pomeroy et al). These findings, taken together, sug gest an autocrine stimulation of growth by these factors and an interaction with some of the aforementioned gene defects. However, having emphasized molecular and chromosomal changes, it is not yet clear that any of them is truly causative or if they simply reflect an aberrant genetic process that accompanies the evolution of tumor growth and progression. Finally, epigenetic events related to the attachment of histones to various tumor genes alter transcription in ways that may be relevant to growth and treatment effects. Some of the specifics of these new data are pre sented in the following discussions of particular tumor types. A more extensive review can be found in the article by Osborne and colleagues, and the text by Kaye and Laws. Pathophysiology of Brain Tu mors the production of symptoms by tumor growth is gov erned by certain principles of mechanics and physiol ogy, some of which were discussed in Chaps. According to the Monro Kellie doctrine, the total bulk of the three elements is at all times constant, and any increase in the volume of one of them must be at the expense of the others, as discussed in Chap.

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